The present invention relates to antibodies that bind human N3pGlu Amyloid Beta peptide and their use in treating diseases related to Amyloid Beta (herein referred to as AP or Abeta) peptide.
The cleavage of the amyloid precursor protein results in Ap peptides ranging in size from 38 to 43 amino acids. Conversion of Ap from soluble to insoluble forms having high p-sheet content and the deposition of these insoluble forms as neuritic and cerebrovascular plaques in the brain has been associated with a number of conditions and diseases, including Alzheimer's disease (AD), Down's syndrome, and cerebral amyloid angiopathy (CAA).
The deposits found in plaques are comprised of a heterogeneous mixture of Ap peptides. N3pGlu AP, also referred to as N3pE, pE3-X, or ApP3~x, is an N-terminal truncated form of Ap peptide and is primarily found in plaque. N3pGlu Ap lacks the first two amino acid residues at the N-terminus of human Ap and has a pyroglutamate which was derived from the glutamic acid at the third amino acid position. Although N3pGlu Ap peptide is a minor component of the deposited Ap in the brain, studies have demonstrated that N3pGlu Ap peptide has aggressive aggregation properties and accumulates early in the deposition cascade.
Antibodies to N3pGlu Ap are known in the art. For example, U.S. Patent Number 8,679,498 discloses human N3pGlu Ap antibodies (e.g. B12L; also known as LY3002813) and methods of treating diseases, such as Alzheimer's disease, with said antibodies. A clinical trial has demonstrated concerns with anti-drug antibodies against an anti- N3pGlu Ap antibody (LY3002813). Anti-drug antibodies were present in the plasma of almost everyone treated in this trial, and an associated problem with the immune reaction was a shortened half-life of LY3002813. Therefore, there still remains a need for alternative anti-N3pGlu Ap antibodies.
The antibodies of the present invention seek to provide anti-N3pGlu Ap antibodies that bind N3pGlu Ap, lower plaque (AP1-42) in vivo, but which also demonstrate reduced immunogenicity. Such anti-N3pGlu Ap antibodies may also demonstrate reduced non-specific binding to plasma proteins. In addition, such anti-

N3pGlu Ap antibodies may also provide a reduced predicted T-Dependent Ab Response, Such anti-N3pGlu Ap antibodies may also provide increased antibody half-life and an improved safety profile for a potential human therapeutic with pharmacokinetics for a better dosing schedule. The antibodies within the scope of the present invention seek to possess at least one of these desirable characteristics.
The present invention provides an antibody that binds human N3pGlu Ap, comprising an LCVR and an HCVR, wherein said LCVR comprises LCDRl, LCDR2, and LCDR3, and wherein said HCVR comprises HCDR1, HCDR2, and HCDR3, and wherein the amino acid sequences are SEQ ID NO:4 or 5 for LCDRl, SEQ ID NO:6 or 7 for LCDR2, SEQ ID NO:8 for LCDR3, SEQ ID NO: 1 for HCDR1, SEQ ID NO:2 for HCDR2, and SEQ ID NO:3 for HCDR3. In a particular embodiment, the anti-N3pGlu Ap antibody comprises the amino sequences of SEQ ID NO:4 for LCDRL SEQ ID NO:6 for LCDR2, SEQ ID NO:8 for LCDR3, SEQ ID NO: 1 for HCDR1, SEQ ID NO: 2 for HCDR2, and SEQ ID NO:3 for HCDR3. In another particular embodiment, the anti-N3pGlu Ap antibody comprises the amino sequences of SEQ ID NO:5 for LCDRl, SEQ ID NO:7 for LCDR2, SEQ ID NO:8 for LCDR3, SEQ ID NO: 1 for HCDR1, SEQ ID NO:2 for HCDR2, and SEQ ID NO:3 for HCDR3.
The present invention also provides an antibody that binds human N3pGlu Ap, wherein said antibody comprises a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 11, and a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 9. In a particular embodiment, the present invention provides an antibody that binds human N3pGlu Ap, wherein said antibody comprises a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 10, and a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 9. In another particular embodiment, the present invention provides an antibody that binds human N3pGlu Ap, wherein said antibody comprises a light chain variable region (LCVR) having the amino acid sequence of SEQ ID NO: 11, and a heavy chain variable region (HCVR) having the amino acid sequence of SEQ ID NO: 9.
In an embodiment, the present invention provides an antibody that binds human N3pG3u Ap, comprising a light chain (LC) and a heavy chain (HC), wherein the amino

acid sequence of the LC is SEQ ID NO: 13 or 14, and the amino acid sequence of the HC is SEQ ID NO: 12. In a more particular embodiment, the present invention provides an antibody that binds human N3pG3u Ap, comprising a light chain (LC) and a heavy chain (HC), wherein the amino acid sequence of the LC is SEQ ID NO: 13, and the amino acid sequence of the HC is SEQ ID NO: 12. In another particular embodiment, the present invention provides an antibody that binds human N3pGlu AP, comprising a light chain (LC) and a heavy chain (HC), wherein the amino acid sequence of the LC is SEQ ID NO: 14, and the amino acid sequence of the HC is SEQ ID NO: 12. In a further embodiment, the present invention provides an antibody comprising two LC and two HC, wherein the amino acid sequence of each LC is SEQ ID NO: 13 or 14, and the amino acid sequence of each HC is SEQ ID NO: 12. In a more particular embodiment, the present invention provides an antibody comprising two LC and two HC, wherein the amino acid sequence of each LC is SEQ ID NO: 13, and the amino acid sequence of each HC is SEQ ID NO: 12. In a more particular embodiment, the present invention provides an antibody comprising two LC and two HC, wherein the amino acid sequence of each LC is SEQ ID NO: 14, and the amino acid sequence of each HC is SEQ ID NO: 12.
The present invention further provides pharmaceutical compositions comprising an antibody of the present invention and one or more pharmaceutical] y acceptable earners, diluents or excipients. Further, the present invention provides a method of treating a disease characterized by deposition of Ap, comprising administering to a patient in need thereof a pharmaceutical composition comprising an antibody of the present invention. In another embodiment, the present invention provides a method of treating a disease characterized by deposition of Ap, comprising administering an effective amount of an antibody of the present invention. Particularly, the present invention provides a method of treating or preventing a condition selected from clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA comprising administering to said patient an effective amount of an antibody of the present invention. In another embodiment, the present invention provides a method of treating or preventing clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical CAA comprising administering to a patient in need thereof an effective amount of a pharmaceutical composition comprising an antibody of the present invention.

In another embodiment, the present invention provides a method of treating or preventing a condition selected from prodromal AD (sometimes also referred to as AP-related mild cognitive impairment, or MCI), mild AD, moderate AD, and severe AD, comprising administering to a patient in need thereof an effective amount of an antibody of the present invention. In another embodiment, the present invention provides a method of treating or preventing a condition selected from prodromal AD, mild AD, moderate AD, and severe AD, comprising administering to a patient in need thereof a pharmaceutical composition comprising an antibody of the present invention.
In another embodiment the present invention provides a method of slowing cognitive decline in a patient diagnosed with pre-elinical Alzheimer's disease, clinical Alzheimer's disease, Down's syndrome, or clinical or pre-clinical cerebral amyloid angiopathy, comprising administering a pharmaceutical composition comprising an antibody of the present invention. More particularly, the present invention further provides a method of slowing cognitive decline in a patient diagnosed with a condition selected from prodromal AD, mild AD, moderate AD and severe AD, comprising administering a pharmaceutical composition comprising an antibody of the present invention. Tn another such embodiment the present invention provides a method of slowing cognitive decline in a patient diagnosed with pre-clinical Alzheimer's disease, clinical Alzheimer's disease, Down's syndrome, or clinical or pre-clinical cerebral amyloid angiopathy, comprising administering an effective amount of an antibody of the present invention. More particularly, the present invention further provides a method of slowing cognitive decline in a patient diagnosed with a condition selected from prodromal AD, mild AD, moderate AD and severe AD, comprising administering an effective amount of an antibody of the present invention.
In another embodiment the present invention provides a method of slowing functional decline in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering a pharmaceutical composition comprising an antibody of the present invention. More particularly, the present invention provides a method of slowing functional decline in a patient diagnosed with a condition selected from prodromal AD, mild AD, moderate AD and severe AD, comprising administering a pharmaceutical composition comprising an antibody of the present invention. In another such embodiment the present invention provides a method of slowing functional decline

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in a patient diagnosed with pre-clinical Alzheimer's disease or clinical Alzheimer's disease, comprising administering an effective amount of an antibody of the present invention. More particularly, the present invention provides a method of slowing functional decline in a patient diagnosed with a condition selected from prodromal AD, 5 mild AD, moderate AD and severe AD, comprising administering an effective amount of an antibody of the present invention.
In another embodiment the present invention provides a method of reducing brain Ap amyloid plaque load in a patient diagnosed with pre-clinical or clinical Alzheimer's disease, comprising administering a pharmaceutical composition comprising an antibody
10 of the present invention. More particularly, the present invention provides a method of reducing brain A|3 amyloid plaque load in a patient diagnosed with a condition selected from prodromal AD, mild AD, moderate AD or severe AD, comprising administering a pharmaceutical composition comprising an antibody of the present invention.
In another embodiment the present invention provides a method of preventing
15 memory loss or cognitive decline in an asymptomatic patient comprising administering to the patient a pharmaceutical composition comprising an antibody of the present invention. In a preferred embodiment, the patient has low levels of A[31 -42 in the cerebrospinal fluid (CSF) or Aj3 plaques in the brain.
In another embodiment the present invention provides a method of treating
20 asymptomatic patients known to have an Alzheimer's disease-causing genetic mutation, comprising administering to the said patient a pharmaceutical composition comprising an antibody of the present invention. In a particular embodiment, the present invention provides a method of treating asymptomatic patients known to have a PSEN1 E280A Alzheimer's disease-causing genetic mutation (Paisa mutation), comprising administering
25 to the said patient a pharmaceutical composition comprising an antibody of the present invention. In another particular embodiment, the present invention provides a method of treating asymptomatic patients with a genetic mutation, such as a mutation in the APP, PSEN1, or PSEN2 gene, that causes autosomal-dominant Alzheimer's disease, comprising administering to the said patient a pharmaceutical composition comprising an antibody of
30 the present invention.
In another embodiment the present invention provides a method of preventing memory loss or cognitive decline in asymptomatic patients known, to have an Alzheimer's

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disease-causing genetic mutation, comprising administering to the said patient a pharmaceutical composition comprising an antibody of the present invention. In a particular embodiment, the present invention provides a method of preventing memory loss or cognitive decline in asymptomatic patients known, to have a PSEN1 E280A 5 Alzheimer's disease-causing genetic mutation (Paisa mutation), comprising administering to the said patient a pharmaceutical composition comprising an antibody of the present invention. In another particular embodiment, the present invention provides a method of preventing memory loss or cognitive decline in asymptomatic patients with a genetic mutation that causes autosomal-dominant Alzheimer's disease, comprising administering
10 to the said patient a pharmaceutical composition comprising an antibody of the present invention.
In another embodiment the present invention provides a method of slowing cognitive decline in an asymptomatic patient known to have an Alzheimer's disease-causing genetic mutation, comprising administering to the said patient a pharmaceutical
15 composition comprising an antibody of the present invention. In a particular embodiment, the present invention provides a method of slowing cognitive decline in asymptomatic patients known to have a PSEN1 E280A Alzheimer's disease-causing genetic mutation (Paisa mutation), comprising administering to the said patient a pharmaceutical composition comprising an antibody of the present invention. In another particular
20 embodiment, the present invention provides a method of slowing cognitive decline in asymptomatic patients with a genetic mutation that causes autosomal-dominant Alzheimer's disease, comprising administering to the said patient a pharmaceutical composition comprising an antibody of the present invention.
The present invention also provides an antibody of the present invention for use
25 in therapy. In an embodiment, the present invention provides an antibody of the present invention for use in the treatment of a disease characterized by deposition of Ap. In another embodiment, the present invention provides an antibody of the present invention for use in treatment of clinical or pre-clinical Alzheimer's disease, Down's syndrome, or clinical or pre-clinical cerebral amyloid angiopathy. In another embodiment, the present
30 invention provides an antibody of the present invention for use in treatment of a condition selected from prodromal AD, mild AD, moderate AD and severe AD. In another embodiment, the present invention provides an antibody of the present invention for use

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in slowing cognitive decline in a patient diagnosed with clinical or pre-clinica3 Alzheimer's disease, Down's syndrome, or clinical or pre-clinical cerebral amyloid angiopathy. In another embodiment, the present invention provides an antibody of the present invention for use in slowing cognitive decline in a patient diagnosed with 5 prodromal AD, mild AD, moderate AD, or severe AD,
The present invention also provides an antibody of the present invention for use in reducing brain Aj3 amyloid plaque load. In another embodiment, the present invention provides an antibody of the present invention for use in treating a condition characterized by deposition of Ap in a patient having the PSEN1 E280A genetic mutation. In another
10 embodiment, the present invention provides an antibody of the present invention for use in treating memory loss or cognitive decline in a patient having the PSEN1 E280A genetic mutation. In another embodiment, the present invention provides an antibody of the present invention for use in preventing memory loss or cognitive decline in a patient having the PSEN1 E280A genetic mutation.
15 The present invention also provides an antibody of the present invention for use in
the prevention of a condition selected from clinical or pre-clinical AD, Down's syndrome, and clinical or pre-clinical CAA. In another embodiment, the present invention provides an antibody of the present invention for use in the prevention of a condition selected from prodromal AD, mild AD, moderate AD, and severe AD.
20 Further, the present invention provides a pharmaceutical composition comprising
an antibody of the present invention for use in therapy. In an embodiment, the present invention provides a pharmaceutical composition comprising an antibody for use in the treatment of a disease characterized by deposition of Ap.
The present invention also provides the use of an antibody of the present invention
25 in the manufacture of a medicament for the treatment of a disease characterized by deposition of Ap. In an embodiment, the present invention provides the use of an antibody of the present invention in the manufacture of a medicament for the treatment of clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy. In an embodiment, the present invention provides the use of
30 an antibody of the present invention in the manufacture of a medicament for the treatment of prodromal AD, mild AD, moderate AD or severe AD. In another embodiment, the present invention provides the use of an antibody of the present invention in the

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manufacture of a medicament for slowing cognitive decline in a patient diagnosed with a condition selected from clinical or pre-clinical Alzheimer's disease, Down's syndrome, and clinical or pre-clinical cerebral amyloid angiopathy. In another embodiment, the present invention provides the use of an antibody of the present invention in the 5 manufacture of a medicament for slowing cognitive decline in a patient diagnosed with a condition selected from prodromal AD, mild AD, moderate AD and severe AD.
The present invention also provides the use of an antibody of the present invention in the manufacture of a medicament for reducing brain A|3 amyloid plaque load. In another embodiment, the present invention provides the use of an antibody of the present
10 invention in the manufacture of a medicament for treating a condition characterized by-deposition of Ap in a patient having the PSEN1 E280A genetic mutation. In another embodiment, the present invention provides the use of an antibody of the present invention in the manufacture of a medicament for treating memory loss or cognitive decline in a patient having the PSEN1 E280A genetic mutation. In another embodiment,
15 the present invention provides the use of an antibody of the present invention in the manufacture of a medicament for preventing memory loss or cognitive decline in a patient. In a preferred embodiment, the patient has the PSEN1 E280A genetic mutation. In another embodiment, the present invention provides the use of an antibody of the present invention in the manufacture of a medicament for preventing a condition selected
20 from clinical or pre-clinical AD, Down's syndrome, and clinical or pre-clinical CAA. In another embodiment, the present invention provides the use of an antibody of the present invention in the manufacture of a medicament for preventing a condition selected from prodromal AD, mild AD, moderate AD, and severe AD.
In an embodiment, the present invention provides a DNA molecule comprising a
25 polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12, In an embodiment, the present invention provides a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 13. In an embodiment, the present invention provides a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino
30 acid sequence of SEQ ID NO: 14. In a further embodiment, the present invention
provides a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12, and comprising a polynucleotide

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sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 13. In another embodiment, the present invention provides a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12, and comprising a polynucleotide sequence encoding a polypeptide having the 5 amino acid sequence of SEQ ID NO: 14. In another embodiment, the present invention provides a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12, and a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 13. In another embodiment, the present invention provides a DNA molecule
10 comprising a polynucleotide sequence encoding a polypeptide having the amino acid
sequence of SEQ ID NO: 12, and a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 14. In a particular embodiment the polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12 is SEQ ID NO: 15 and the polynucleotide
15 sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 13 is SEQ ID NO: 16. In a particular embodiment the polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12 is SEQ ID NO: 15, the polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 14 is SEQ ID NO: 17, and the polynucleotide sequence encoding a polypeptide
20 having the amino acid sequence of SEQ ID NO: 13 is SEQ ID NO: 16.
Further, the present invention provides a mammalian cell comprising a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12 and a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 13 or
25 14. Preferably the mammalian cell comprises a DNA molecule comprising a
polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12 and a polypeptide having the amino acid sequence SEQ ID NO: 13. In another embodiment, the mammalian cell comprises a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ
30 ID NO: 12 and a polypeptide having the amino acid sequence of SEQ ID NO: 14. In an embodiment the mammalian cell line is a Chinese Hamster Ovary (CHO) or Hamster embryonic kidney (HEK) cell line.

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The present invention also provides a mammalian cell comprising a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12 and/or a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 13, 5 wherein the cell is capable of expressing an antibody comprising a HC having the amino acid sequence of SEQ ID NO: 12 and a LC having the amino acid sequence of SEQ ID NO: 13. Preferably the mammalian cell comprises a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12 and a polypeptide having the amino acid sequence SEQ ID NO: 13. The
10 present invention also provides a mammalian cell comprising a DNA molecule
comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12 and/or a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 13, wherein the cell is capable of expressing an antibody comprising a HC having the amino
15 acid sequence of SEQ ID NO: 12 and a LC having the amino acid sequence of SEQ ID NO: 13. Preferably the mammalian cell comprises a DNA molecule comprising a polynucleotide sequence encoding a polypeptide having the amino acid sequence of SEQ ID NO: 12 and a polypeptide having the amino acid sequence SEQ ID NO: 13. In an embodiment the mammalian ceil line is a CHO or HEK cell line.
20 In another embodiment, the present invention provides a process for producing an
antibody comprising a LCVR. having an amino acid sequence of SEQ ID NO: 10 and a HCVR having an amino acid sequence of SEQ ID NO:9, wherein the process comprises cultivating a mammalian cell comprising a DNA encoding an LCVR having an amino acid sequence of SEQ ID NO: 10 and/or a DNA encoding an HCVR having an amino
25 acid sequence of SEQ ID NO:9 under conditions such that the antibody is expressed, and recovering the expressed antibody. The invention includes an antibody obtainable by the process of the invention as described immediately above. The present invention also provides a process for producing an antibody comprising a LCVR having an amino acid sequence of SEQ ID NO: 11 and a HCVR having an amino acid sequence of SEQ ID
30 NO:9, wherein the process comprises cultivating a mammalian cell comprising a DNA encoding an LCVR having an amino acid sequence of SEQ ID NO: 11 and/or a HCVR having an amino acid sequence of SEQ ID NO:9 under conditions such that the antibody

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-Il¬ls expressed, and recovering the expressed antibody. The invention includes an antibody obtainable by the process of the invention as described immediately above.
In another embodiment, the present invention provides a process for producing an antibody comprising a LC having an amino acid sequence of SEQ ID NO: 13 and a HC 5 having an amino acid sequence of SEQ ID NO: 12, wherein the process comprises cultivating a mammalian cell comprising a DNA encoding a LC having an amino acid sequence of SEQ ID NO: 13 and/or a HC having an amino acid sequence of SEQ ID NO: 12 under conditions such that the antibody is expressed, and recovering the expressed antibody. The invention includes an antibody obtainable by the process of the invention
10 as described immediately above. The present invention also provides a process for
producing an antibody comprising a LC having an amino acid sequence of SEQ ID NO: 14 and a HC having an amino acid sequence of SEQ ID NO: 12, wherein the process comprises cultivating a mammalian cell comprising a DNA encoding a LC having an amino acid sequence of SEQ ID NO: 14 and/or a HC having an amino acid sequence of
15 SEQ ID NO: 12 under conditions such that the antibody is expressed, and recovering the expressed antibody. The invention includes an antibody obtainable by the process of the invention as described immediately above.
The present invention includes a process for producing an antibody, which antibody comprises two HCs and two LCs, in which the amino sequence of each of the
20 two HCs is SEQ ID NO: 12, and the amino acid sequence of each of the two LCs is SEQ ID NO: 13, and which process comprises: a) cultivating a mammalian cell of the invention, as described above, under conditions such that the antibody is expressed, and b) recovering the expressed antibody. The invention includes an antibody obtainable by the process of the invention as described immediately above. The present invention also
25 includes a process for producing an antibody, which antibody comprises two HCs and
two LCs, in which the amino sequence of each of the two HCs is SEQ ID NO: 12 and the amino acid sequence of each of the two LCs is SEQ ID NO: 14, and which process comprises: a) cultivating a mammalian cell of the invention, as described above, under conditions such that the antibody is expressed, and b) recovering the expressed antibody.
30 The invention includes an antibody obtainable by the process of the invention as described immediately above.

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The antibodies of the present invention bind to N3pGlu Ap. The sequence of N3pGlu Ap is the amino acid sequence of SEQ ID NO: 22, and carboxyl terminal variants thereof. Examples of a carboxyl terminal variants of N3pGlu Ap include ApP3-40
andApP3-43.
5 As used herein, an "antibody" is an immunoglobulin molecule comprising two
heavy chains (HC) and two light chains (LC) interconnected by disulfide bonds. The amino terminal portion of each LC and HC includes a variable region responsible for antigen recognition via the complementarity determining regions (CDRs) contained therein. The CDRs are interspersed with regions that are more conserved, termed
10 framework regions. Assignment of amino acids to CDR domains within the LCVR and HCVR regions of the antibodies of the present invention is based on the well-known Kabat numbering convention (Kabat, et al., Ann. NY Acad. Sci. 190:382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991)), and
15 North numbering convention (North et al., A New Clustering of Antibody CDR Loop Conformations, Journal of Molecular Biology, 406:228-256 (2011)).
The antibodies of the present invention include kappa LC and IgG HC. In a particular embodiment, the antibodies of the present invention are IgGl.
The antibodies of the present invention are monoclonal antibodies ("mAbs").
20 Monoclonal antibodies can be produced, for example, by hybridoma technologies,
recombinant technologies, phage display technologies, synthetic technologies, e.g., CDR-grafting, or combinations of such or other technologies known in the art. In another embodiment of the present invention, the antibody, or the nucleic acid encoding the same, is provided in isolated form. As used herein, the term "isolated" refers to a protein,
25 peptide or nucleic acid that is not found in natui'e and is free or substantially free from other macromolecular species found in a cellular environment. "Substantially free", as used herein, means the protein, peptide or nucleic acid of interest comprises more than 80% (on a molar basis) of the macromolecular species present, preferably more than 90% and more preferably more than 95%.
30 Following expression and secretion of the antibody, the medium is clarified to
remove cells and the clarified media is purified using any of many commonly-used

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techniques. The purified antibody may be formulated into pharmaceutical compositions according to well-known methods for formulating proteins and antibodies for parenteral administration, particularly for subcutaneous, intrathecal, or intravenous administration. The antibody may be lyophilized, together with appropriate pharmaceutically-acceptable 5 excipients, and then later reconstituted with a water-based diluent prior to use.
Alternatively, the antibody may be formulated in an aqueous solution and stored for up to 1-3 years prior to use. In either case, the stored form and the injected form of the pharmaceutical compositions of the antibody will contain a pharmaceutically-acceptable excipient or excipients, which are ingredients other than the antibody. Whether an
10 ingredient is pharmaceutically-acceptable depends on its effect on the safety and
effectiveness or on the purity, and potency of the pharmaceutical composition. If an ingredient is judged to have a sufficiently unfavorable effect on safety or effectiveness (or on purity or potency) to warrant it not being used in a composition for administration to humans, then it is not pharmaceutically-acceptable to be used in a pharmaceutical
15 composition of the antibody.
A pharmaceutical composition comprising an antibody of the present invention can be administered to a patient at risk for, or exhibiting, diseases or disorders as described herein by parental routes (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular). Subcutaneous and intravenous routes are preferred. A pharmaceutical
20 composition of the present invention contains an "effective" amount of an antibody of the present invention. An effective amount refers to an amount necessary (at dosages and for periods of time and for the means of administration) to achieve the desired therapeutic result. An effective amount of the antibody may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody to
25 elicit a desired response in the individual. An effective amount can be readily determined by the attending diagnostician or health care professional, as one skilled in the art, by using known techniques and by observing results. Frequency of dosing is dependent on actual pharmacokinetics and pharmacodynamics in humans. Duration of treatment will vary depending on many factors and it will be determined by the patient's diagnostician
30 or treating health care provider, based on experience and skill in the art. Frequency and duration of treatment may vary by indication. The terms "treatment," "treating" or "to teat" and the like include restraining, slowing or stopping the progression or severity of

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an existing symptom, condition, disease, or disorder in a patient. The term "patient" refers to a human. The terms "prevent" and "preventing" means prophylactic administration of an antibody of the present invention to an asymptomatic patient in order to keep the patient from having symptoms or clinical features of neurodegenerative 5 diseases such as AD.
The term "condition characterized by deposition of Ap\" is a disease that is pathologically characterized by A(3 deposits in the brain or in brain vasculature. This includes diseases such as Alzheimer's disease, Down's syndrome, and cerebral amyloid angiopathy. A clinical diagnosis, staging or progression of Alzheimer's disease can be
10 readily determined by the attending diagnostician or health care professional, as one skilled in the art, by using known techniques and by observing results. This generally includes some form of brain plaque imagining, mental or cognitive assessment (e.g. Clinical Dementia Rating - summary of boxes (CDR-SB), Mini-Mental State Exam (MMSE) or Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog)) or functional
15 assessment (e.g. Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL). "Clinical Alzheimer's disease" as used herein is a diagnosed stage of Alzheimer's disease. It includes conditions diagnosed as prodromal Alzheimer's disease, mild Alzheimer's disease, moderate Alzheimer's disease and severe Alzheimer's disease. The term "pre-clinical Alzheimer's disease" is a stage that precedes clinical Alzheimer's
20 disease, where measurable changes in biomarkers (such as CSF AJ342 levels or deposited brain plaque load by amyloid PET) indicate the earliest signs of a patient with Alzheimer's pathology, progressing to clinical Alzheimer's disease. This is usually before symptoms such as memory loss and confusion are noticeable.
The following Examples and assays demonstrate that the antibodies of the present
25 invention are useful for treating a disease characterized by deposition of AB, such as of Alzheimer's disease, Down's syndrome, and CAA. It should be understood however, that the following Examples are set forth by way of illustration and not limitation, and that various modifications may be made by one of ordinary skill in the art.
Examples
30 Expression and Piirifieatien of Engineered N3pGln AB Antibodies
N3pGlu Ap antibodies of the present invention can be expressed and purified essentially as follows. A glutamine synthetase (GS) expression vector containing the

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DNA sequence encoding the LC amino acid sequence of SEQ ID NO: 13 or 14, and the DNA sequence encoding the HC amino acid sequence of SEQ ID NO: 12 is used to transfect a Chinese hamster ovary cell line (CHO) by electroporation. The expression vector encodes an SV Early (Simian Virus 40E) promoter and the gene for GS. Post-transfection, cells undergo bulk selection with 0-50 uM L-methionine sulfoximine (MSX). Selected bulk cells or master wells are then scaled up in serum-free, suspension cultures to be used for production.
Clarified medium, into which the antibody has been secreted, is applied to a Protein A affinity column that has been equilibrated with a compatible buffer, such as phosphate buffered saline (pH 7.4). The column is washed with 1 M NaCl to remove nonspecific binding components. The bound N3pGlu Aj3 antibody is eluted, for example, with sodium citrate at pH (approx.) 3.5 and fractions are neutralized with 1 M Tris buffer. N3pG3u Ap antibody fractions are detected, such as by SDS-PAGE or analytical size-exclusion, and then are pooled. N3pGlu Ap antibody of the present invention is concentrated in either PBS buffer at pH 7.4 or 10 mM NaCitrate buffer, 150 mM NaCl at pH around 6. The final material can be sterile filtered using common techniques. The purity of N3pGlu Ap antibody is greater than 95%. An N3pGlu Ap antibody of the present invention may be immediately frozen at -70°C or stored at 4°C for several months. Amino acid SEQ ID NOs for exemplified antibodies of the present invention are shown below. Table 1. Amino acid sequences of exemplified N3pGlu A3 antibodies.

Antibody SEQ ID NOs
Antibody Light Chain Heavy Chain LCVR HCVR
201c 13 12 10 9
201eYB 14 12 11 9

Antibody SEQ ID NOs
Antibody LCDR1 I-jC^UiNLZ LCDR3
201c 4 6 8
201cYD 5 7 8

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Antibody SEQ ID NOs
Antibody HtJDKl HC.OM2 HCDR3
201c and201cYD 1 2 3
Binding Kinetics and Avidity
The binding kinetics and avidity of N3pGlu Ap antibody to pE3-42 Ap peptide is measured by surface plasmon resonance using Biacore® 3000 (GE Healthcare). The binding avidity is measured by immobilizing about 120 RU pE3-42 Ap peptide via amine coupling on a Biacore® CMS chip, and flowing N3pGlu Ap antibody, starting from 500 nM in 2-fold serial dilution down to 15.6 nM. The experiments are carried out at 25 °C in HBS-EP buffer (GE Healthcare Bill00669; 10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% surfactant P20, pH 7.4). For each cycle, 250 (iL antibody sample is flowed through flow cell 1 and 2 at 50 fil/min, and then dissociated for 10 minutes. The chip surface is regenerated with 5 uL injection of glycine buffer at pH 1.5 at 10 fiL/mL flow rate. The data is fit to a 1:1 Langmiur binding model to derive k^, koff, and to calculate KD. Following procedures essentially as described above, the following parameters (shown in Table 2) were observed.
Table 2. Binding kinetics and avidity.

Antibody fen (1/MS) koff (1/s) KD (IVI)
20ic Mean 1.64E+03 6.98E-05 4.57E-08
S.D. 3.88E+Q2 1.36E-05 2.06E-08
281eYD Mean 2.41E+03 6.39E-05 2.67E-08
S.D. 2.01E+Q2 2.15E-06 2.61E-09
These data demonstrate that the antibodies of the present invention bind pE3-42 Ap. Ex Vivo Target Engagement
To determine ex vivo target engagement on brain sections from a fixed PDAPP brain, irnrnunohistochemical analysis is performed with exogenously added N3pGlu Ap antibodies of the present invention or the 201 c H3B antibody. The 201 c H3B antibody differs by one amino acid from the 201c antibody, and this difference is located in the

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heavy chain HCDR3 (Tyr at position 10 in 201c HCDR3 is Phe in 201c H3B). The 201c
H3B antibody comprises a heavy chain amino acid sequence given by SEQ ID NO: 20
and a light chain amino acid sequence given by SEQ ID NO: 13.
Cryostat serial coronal sections from aged PDAPP mice (26 or 20-month old) are 5 incubated with 5 ug/mL or 20 ug/mL of an exemplified N3pGlu Ap antibody of the
present invention (201c or 201cYD). Secondary HRP reagents specific for human IgG
are employed and the deposited plaques are visualized with DAB-Pius (DAKO).
Biotinylated murine 3D6 antibody followed by Step-HRP secondary is used as a positive
control,
10 The exemplified N3pGlu Ap antibodies of the present invention labeled deposited
Ap in these brain sections. However, a higher background staining for the 201c H3B
antibody at the exogenous 20\ig/ml concentration was observed. These histological
studies demonstrated that the exemplified N3pG3u Ap antibodies of the present invention
engaged deposited Ap target ex vivo. 15
Ex vivo Phagocytosis
An ex vivo phagocytosis assay is performed to investigate whether N3pGlu Ap
antibodies of the present invention can facilitate microglial phagocytosis of plaque.
Frozen sections from human Alzheimer's brain (20 um) are pre-incubated with 10 ug/mL 20 of an exemplified N3pGlu Ap antibody of the present invention (201c or 201cYD),
controls, or the 201c H3B antibody for one hour at 37°C in 24-well plates. There are four
wells per treatment. Primary murine microglia cells (8x105; C57/BL6) are then added
and incubated for 24 hours. Tissue in each well is homogenized in 5.2 M guanidine
buffer and the Api„42 content is evaluated by ELISA. Since the Ap content can vary over 25 the span of multiple sections, a sister section control is implemented for every test well
and the content of the test well is normalized to that of the sister section.
Compared to the positive control samples, exemplified N3pGlu Ap antibodies of
the present invention (201c and 201cYD) and 201c H3B had significantly reduced APi.42.
The negative control samples had negligible clearance of deposited AP1-42. Therefore, ex 30 vivo phagocytosis analyses show that exemplified N3pGlu Ap antibodies of the present
invention can clear plaque ex vivo by phagocytosis.

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In Vivo Target Engagement
The ability of N3pGlu Ap antibodies of the present invention to cross the blood-brain-barrier and bind to deposited plaque in vivo is measured. Aged PDAPP transgenic 5 mice (18.5 to 32 months of age) are given intraperitoneal injections with N3pGlu Ap antibody (201c) or negative control IgG. Six mice per group receive one 40 mg/kg injection of antibody on day 1 and on day 3. In vivo target engagement is determined on day 6, when mice are sacrificed and brains are collected for histochemical analyses.
The extent of in vivo target engagement is quantified as the percent area positive
10 for the in vivo N3pGlu Ap antibody engagement normalized to the total plaque area as defined by exogenous 3D6 antibody immunostaining on sister sections (TE Ratio). The TE Ratio is generated by measuring the percent of area bound by the antibody and normalizing the value against the total percent of area of possible target (total deposited Ap visualized by exogenous immunohistochemistry with a positive control antibody
15 (3D6) on a sister section).
Following procedures essentially as described above, the 201c antibody had a TE Ratio of 2.8%. The 201c antibody demonstrated in vivo target engagement within the hippocampus and to a limited extent in the cortex, whereas the animals injected with control IgG show no plaque-specific staining.
20
In Vivo Plaque Clearance
Studies are performed with chimera surrogate antibodies with LCVR and HCVR of 201c or 201c H3B fused to murine constant kappa region and IgG2a Fc to evaluate in vivo plaque clearance in aged PDAPP mice. Aged PDAPP mice (21-months of age, n ===
25 23 to 25 per group) are injected subcutaneously once a week for 7 weeks with 12.5 mg/kg of chimera 201c antibody, chimera 201c H3B antibody, or control IgG. Control aged PDAPP mice (sacrificed at the onset of the study) are used to evaluate the levels of pre¬existing deposition prior to therapeutic treatment.
At the conclusion of the study, final drug levels are measured in plasma, and
30 brains are evaluated by ELISA for levels of Ap 1-42. The aged PDAPP mice are at the
plaque ceiling as evidenced by a non-significant further accrual of AP1-42 over the 7-week

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treatment period with the control IgG. The 201c chimera antibody group and the 201c H3B chimera antibody group show significant reduction in Api.42 (26%, p < 0.0182 and 26%, p = 0.0121, respectively) compared to control. Antibody exposure level was measured at the end of 7-week dosing period, and 201c chimera had a level of 91 jig/mL, 5 and 201c H3B had a level of 56 ug/mL, This study demonstrated that the exemplified chimera N3pGlu A|3 antibody 201c was able to lower plaque (Apj.42) in vivo.
Lack of Low Affinity PJasroa Binding
In vitro studies are performed to investigate potential low-affinity interactions of
10 anti-N3PG antibodies of the present invention (201c and 201cYD) with plasma proteins. Antibody 201c, 201cYD, or 201c H3B is covalently coupled to Sepharose beads and incubated with 10 mis of normal human plasma for 2 hours at 37°C before performing column chromatography. The bead/plasma mixture was packed into columns and washed. Selectively bound proteins are eluted with glycine (pH 2.5) in different fractions.
15 Each fraction is then analyzed on high-resolution sodium dodecyl sulfate (SDS)--
polyacrylamide gel electrophoresis (PAGE) gradient gels (4% to 16%). Silver stain is used to visualize the proteins and bands of interest were excised and analyzed by mass spectrometry. In parallel, multiple control human IgGl antibodies are analyzed.
Following procedures essentially as described above, visualization of the silver
20 stained gels demonstrated the presence of histidine rich glycoprotein (~64kDa band), fibrinogen alpha-chain (~60kDa band), and fibrinogen beta-chain (~50kDa band) in fraction-5 from the 201c H3B antibody elution as compared to the control IgGl antibodies. Conversely, the 201c and 201 cYD antibodies lacked appreciable low affinity binding to human plasma proteins as compared to the control IgG and the 201c H3B
25 antibody.
Ex Vivo T-cell Proliferation EpiSereen Assay
An Epi Screen ex vivo human T-cell assay is used to measure activation (proliferation, cytokine secretion) of human CD4+ T cells in response to an exemplified 30 N3pGlu Ap antibody of the present invention (201c) or the 201c H3B antibody.
EpiScreen utilizes samples from 50 healthy donors that best represent the number and

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frequency of HLA-DR and DQ allotypes expressed in the European/North American and world populations. Two positive controls are included in the assay: humanized A33, a clinical benchmark antibody that shows high levels of immunogenicity in the clinic (73%)
and routinely induces 20-30% T-cell response in the EpiScreen ^ assay, and KLH
(keyhole limpet hemocyanin), a mitogen-like protein containing neoantigens. A matched buffer negative control is also included in the assay.
The percent of T-cell proliferation is calculated from the average of all positive donor responses observed during the time course (days 5-8). The percent T-cell proliferation was 20% and 94% for the positive controls A3 3 and KLH, respectively, and was 24% for 201c H3B. However, the percent T-cell proliferation was 10% for 201c. These data demonstrate that the 201c antibody has a low T-cell response rate compared to positive controls and the 201c H3B antibody.
In Silico Immnnogenkity Analysis
An EpiMatrix ^ assay scans protein sequences for potential T-cell epitopes and
uses an algorithm to predict immunogenicity. It also considers Tregitope content and the effect on negatively regulating immunogenic response. The amino acid sequences of antibodies 201c, 201cYD, and B12L (antibody B12L comprises a heavy chain given by SEQ ID NO: 23 and a light chain given by SEQ ID NO: 24) were analyzed by
EpiMatrix . The EpiMatrix predicted scores are shown below in Table 3. Table 3. EpiMatrix scores.

Antibody EpiMatrix
Protein
Score Tregitope-Adj usted EpiMatrix Protein Score Predicted T-Dependent Ab Response
201c 39.14 -35.49 0.28%
201cYD 24.76 -49.87 0.00%
B12L 0.44 -17.92 4.03%
These data demonstrate that the predicted T cell-dependent antibody response is lower for the N3pGlu Ap antibodies of the present invention (201c and 201cYD) as compared to the B12L antibody.

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An Affinity Capture Elution (ACE) Bridge assay using biotin and ruthenium labeled 201c or biotin and ruthenium labeled 201 cYD is performed in order to assess whether anti-drug antibodies directed against the LY3002813 antibody could bind to 201c or201cYD.
In this assay format, the ADA bridge between the two labeled antibodies (e.g. biotin and ruthenium labeled 201c). The complex then binds to a plate coated with streptavidin (via the biotin-labeled antibody) and the detection uses Ruthenium to generate signal in a Mesoscale platform. If the ADA does not recognize either the 201c or 201cYD antibody, no signal will be generated. Rabbit anti-human IgG most likely binds preferentially to the Fc, and is used as a positive control to show that labeled 201c or 201c YD could bind antibodies.
The antibodies directed against LY3002813 include antibodies affinity purified from two patient samples from a clinical trial (I5T-MC-AACC NCT01837641) after LY3002813 administration. These patients had developed ADA response for LY3002813 over time as shown by a positive binding signal in ACE bridge.
Following procedures essentially as described above, no signal was observed above background when detecting binding of either 201c or 201cYD to antibodies against LY3002813. These data demonstrate that ADA directed against LY3002813 in humans does not recognize 201c and 201cYD.

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Seqisences
Antibody 201c, Antibody 201cYD, and Antibody 2©le H3B HCDR1 (SEQ ID NO: 1)
AASGFTFSSYPMS 5 Antibody 201c, Antibody 201cYD, and Antibody 201c H3B HCDR2 (SEQ ID NO: 2)
AISGSGGSTYYADSVKG
Antibody 201c and Antibody 201cYD HCDR3 (SEQ ID NO: 3)
AREGGSGSYYNGFDY
Antibody 201c and Antibody 201e IBB LCDR1 (SEQ ID NO: 4) 10 RASQSLGNWLA
Antibody 201cYD LCDR1 (SEQ ID NO: 5)
RASQSLGNYLA
Antibody 201c and Antibody 201c H3B LCDR2 (SEQ ID NO: 6)
YQASTLES 15 Antibody 201cYD LCDM2 (SEQ ID NO: 7)
YDASTLES
Antibody 201c, Antibody 201cYD, and Antibody 201e H3B LCDR3 (SEQ ID NO: 8)
QHYKGSFWT
Antibody 201c and Antibody 201 cYD HCVR (SEQ ID NO: 9) 20 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAESGS
GGSTYYADSVKGRFTISRDNSKNTLYLXJMNSLRAEDTAVYYCAREGGSGSYYN
GFDYWGQGTLVTVSS
Antibody 201c and Antibody 201e IBB LCVR (SEQ ID NO: 10)
DIQMTQSPSTLSASVGDR\rnTCRASQSLGNWLAWYQQKPGKAPKLLIYQASTLE 25 SGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHYKGSFWTFGQGTKVEIK
Antibody 201cYD LCVR (SEQ ID NO: 11)
DIQMTQSPSTLSASVGDRVTITCRASQSLGNYLAWYQQKPGKAPKLLIYDASTLE
SGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHYKGSFWTFGQGTKVEIK
Antibody 201c and Antibody 201cYD Heavy Chain (SEQ ID NO: 12) 30 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAISGS
GGSTYYADSVKGRFT7SRDNSKNTXYIXJMNSLRAEDTAVYYCAREGGSGSYYN
GFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVS

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WNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSIXJTQTYICNVNHKPSNTKVD KKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSH EDPE\nOTSnATVVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTBCNQVSLTCLVKGFYPSD 5 IAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE ALHNHYTQKSLSLSPG
Antibody 201c and Antibody 201c H3B Light Chain (SEQ ID NO: 13) DIQMTQSPSTLSASVGDRVTITCRASQSLGNWLAWYQQKPGKAPKLLrYQASTLE SGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHYKGSFWTFGQGTKVEIKRTVA
10 APSVFIFPPSDEQLKSGTAS^^CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSl^STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Antibody 201cYD Light Chain (SEQ ID NO: 14)
DIQMTQSPSTLSASVGDRVTITCRASQSLGNYLAWYQQKPGKAPKLLIYDASTLE SGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQHYKGSFWTFGQGTKVEIKRTVA
15 APSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQ DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC Exemplified DNA for Expressing Antibody Heavy Chain of SEQ ID NO: 12 (SEQ ID NO: 15) gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtccctgagactctcctgtgcagcctctggattcacct
20 ttagcagctatcctatgagctgggtccgccaggctccagggaaggggctggagtgggtctcagctattagtggtagtggtggtag cacatactacgcagactccgtgaagggccggttcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacag cctgagagccgaggacacggccgtatattactgtgcgagagaggggggctcagggagttattataacggctttgattattgggg ccagggaaccctggtcaccgtctcctcagcctccaccaagggcccatcggtcttcccgctagcaccctcctccaagagcacctc tgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctg
25 accagcggcgtgeacacettcccggctgtcetacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagc
agcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatc ttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaaccc aaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagtt caactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgt 30 ggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccag cccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggacg

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agctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaat gggcagccggagaacaactacaagaccacgccccccgtgctggactccgacggctccttcttcctctatagcaagctcaccgtg gacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagag cctctccctgtctccgggt
5 Exemplified DNA for Expressing Antibody Light Chain of SEQ ID NO: 13 (SEQ ID NO: 16)
gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccgggccagtcagagtct tggtaactggttggcctggtatcagcagaaaccagggaaagcccctaaactcetgatctatcaggcgtctactttagaatetgggg tcccatcaagattcagcggcagtggatctgggacagagttcactctcaccatcagcagcctgcagcctgatgattttgcaacttatt 10 actgccaacattataaaggttctttttggacgttcggccaagggaccaaggtggaaatcaaacggaccgtggctgcaccatctgtc ttcatcttcccgccatctga.tgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataaettctatcccagagaggcca aagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagca cctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatca gggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgc
15 Exemplified DNA for Expressing Antibody Light Chain of" SEQ ID NO: 14 (SEQ ID NO: 17)
gacatccagatgacccagtctccttccaccctgtctgcatctgtaggagacagagtcaccatcacttgccgggccagtcagagtct tggtaactatttggcctggtatcagcagaaaccagggaaagcccctaaactcctgatctatgatgcgtctactttagaatctggggt cccatcaagattcagcggcagtggatctgggacagagttcactctcaccatcagcagcctgcagcctgatgattttgcaacttatta
20 ctgccaacattetaaaggttctttttggacgttcggccaagggaccaaggtggaaatcaaacggaccgtggctgcaccatctgtct tcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaa agtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcac ctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcag ggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgc
25 Antibody 201c H3B HCDR3 (SEQ ID NO: 18)
AREGGSGSYFNGFDY
Antibody 201c H3B HCVR (SEQ ID NO: 19)
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAESGS
GGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGGSGSYFNG 30 FDYWGQGTLVTVSS
Antibody 201c H3B Heavy Cham (SEQ ID NO: 20)

EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYPMSWVRQAPGKGLEWVSAISGS
GGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTA\rYYCAREGGSGSYFNG
FDY^-GQGTLVTVrSSASTKGPSVFPLAPSSKSTSGGTAALGC:LVKDYFPEPVTVSW
NSGALTSGVHTT^PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDK
KVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKl>KDTLMISRTPEVTC\rVrVDVSHE
DPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKC
KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI
AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHE
ALHNHYTQKSLSLSPG
Exemplified DNA for Expressing Antibody Heavy Chain of SEQ ID NO: 20 (SEQ
ID NO: 21)
gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtccctgagactctcctgtgcagcctctggattcacct
ttagcagctatcctatgagctgggtccgccaggctccagggaaggggctggagtgggtctcagctaitagtggtagtggtggtag
cacatactacgcagactccgtgaagggccggttcaccatctccagagacaattccaagaacacgctgtatctgcaaatgaacag
cctgagagccgaggacacggccgtatattactgtgcgagagaggggggctcagggagttattttaacggctttgattattggggc
cagggaaccctggtcaccgtctcctcagcctccaccaagggcccatcggtcttcccgctagcaccctcctccaagagcacctct
gggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctga
ccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagca
gcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatct
tgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaaccca
aggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttc
aactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtg
gtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagc
ccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggacga
gctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatg
ggcagccggagaacaactacaagaccacgccccccgtgctggactccgacggctccttcttcctctatagcaagctcaccgtgg
acaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagc
ctctccctgtctccgggt
N3pGlu Ap (SEQ ID NO: 22)
[pE]FRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGWIA
Antibody B12L Heavy Chain (SEQ ID NO: 23)

QVQLVQSGAEVKKPGSSVKVSCKASGYDFTRYYINWVRQAPGQGLEWMGWINP
GSGNTKYNEKFK(mVTITADESTSTAYMELSSLRSEDTA\TYCAREGITVYWGQ
GTTVTVSSASTXGPSWPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT
SGVHTFPAVLQSSGLYSLSSVV1"VPSSSLGTQTYICNVNHKPSNTK_VDKKVEPKS
CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKF
NWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWES
NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY
TQKSLSLSPG
Antibody B12L Light Chain (SEQ ID NO: 24)
DIVMTQTPLSLSVTPGQPASISCKSSQSLLYSRGKTYLNWLLQKPGQSPQLLIYAV
SKLDSGVPDRFSGSGSGTDFTLKlSRVEAEDVG\rYYCVQGTHYPFTFGQGTlCLEI
KRTVAAPSVFIFPPSDEQLKSGTASV\rCLLNNFYPREAKVQWKVDNALQSGNSQ
ESVTEQDSKDSTYSI^STLTLSKADYEKHKVYACE\nTHQGLSSPVTKSFNRGEC

WE CLAIM:

An antibody that binds human N3pGlu A|3, comprising a light chain
variable region (LCVR) and a heavy chain variable region (HCVR),
wherein the LCVR comprises LCDR1 having the amino acid sequence of
SEQ ID NO: 4 or 5, LCDR2 having the amino acid sequence of SEQ ID
NO: 6 or 7, and LCDR3 having the amino acid sequence of SEQ ID NO:
8, and wherein the HCVR comprises HCDR1 having the amino acid
sequence of SEQ ID NO: 1, HCDR2 having the amino acid sequence of
SEQ ID NO: 2, and HCDR3 having the amino acid sequence of SEQ ID
NO: 3.
The antibody of Claim 1, wherein LCDR1 has the amino acid sequence of
SEQ ID NO: 4 and LCDR2 has the amino acid sequence of SEQ ID NO:
6.
The antibody of Claim 1, wherein LCDR1 has the amino acid sequence of
SEQ ID NO: 5 and LCDR2 has the amino acid sequence of SEQ ID NO:
7.
The antibody of any one of Claims 1-3, wherein the LCVR has the amino
acid sequence of SEQ ID NO: 10 or 11, and the HCVR has the amino acid
sequence of SEQ ID NO:9.
The antibody of Claim 4, comprising a LCVR having the amino acid
sequence of SEQ ID NO: 10, and a HCVR having the amino acid sequence
of SEQIDNO:9.
The antibody of Claim 4, comprising a LCVR having the amino acid
sequence of SEQ ID NO: 11, and a HCVR having the amino acid sequence
of SEQIDNO:9.
The antibody of any one of Claims 1-6, comprising a light chain (LC)
having the amino acid sequence of SEQ ID NO: 13 or 14, and a heavy
chain (HC) having the amino acid sequence of SEQ ID NO: 12.
The antibody of Claim 7, comprising a LC having the amino acid sequence
of SEQ ID NO: 13 and a HC having the amino acid sequence of SEQ ID
NO: 12.

The antibody of Claim 7, comprising a LC having the amino acid sequence
of SEQ ID NO: 14 and a HC having the amino acid sequence of SEQ ID
NO: 12.
The antibody of any one of Claims 1-9, comprising two LCs and two HCs,
wherein the amino acid sequence of each LC is SEQ ID NO: 13 or 14, and
the amino acid sequence of each HC is SEQ ID NO: 12.
The antibody of Claim 10, wherein the amino acid sequence of each LC is
SEQ ID NO: 13, and the amino acid sequence of each HC is SEQ ID NO:
12.
The antibody of Claim 10, wherein the amino acid sequence of each LC is
SEQ ID NO: 14, and the amino acid sequence of each HC is SEQ ID NO:
12.
A pharmaceutical composition comprising the antibody of any one of
Claims 1 to 12 and one or more pharmaceutically acceptable carriers,
diluents or excipients.
A DNA molecule comprising a polynucleotide that encodes the antibody
heavy chain given by the amino acid sequence of SEQ ID NO: 12.
The DNA molecule of Claim 14, wherein the amino acid sequence of the
polynucleotide is SEQ ID NO: 15.
A DNA molecule comprising a polynucleotide that encodes the antibody
light chain given by the amino acid sequence of SEQ ID NO: 13.
The DNA molecule of Claim 16, wherein the amino acid sequence of the
polynucleotide is SEQ ID NO: 16.
A DNA molecule comprising a polynucleotide that encodes the antibody
light chain given by the amino acid sequence of SEQ ID NO: 14.
The DNA molecule of Claim 18, wherein the amino acid sequence of the
polynucleotide is SEQ ID NO: 17.
A DNA molecule comprising a polynucleotide sequence that encodes the
antibody heavy chain having the amino acid sequence of SEQ ID NO: 12
and a polynucleotide sequence that encodes the antibody light chain
having the amino acid sequence of SEQ ID NO: 13 or 14.
The DNA molecule of Claim 20, wherein the polynucleotide sequence that
encodes the antibody heavy chain is SEQ ID NO: 15, and the

polynucleotide sequence that encodes the antibody light chain is SEQ ID NO:16 or 17.