Anti-amyloid beta antibodies and uses thereof

Abstract

The present application provides anti-Aβ constructs (e.g., anti-Aβ antibodies) that bind to Aβ (e.g., Aβ40 and Aβ42), nucleic acid molecules encoding an amino acid sequence of the anti-Aβ constructs, vectors comprising the nucleic acid molecules, host cells containing the vectors, methods of preparing the anti-Aβ constructs, pharmaceutical compositions containing the anti-Aβ constructs, and methods of using the anti-Aβ constructs or compositions.

Description

Attorney Docket No.: 193852001340ANTI-AMYLOID BETA ANTIBODIES AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U. S. Provisional Application 63 / 761,781, filed on February 21, 2025, the content of which is incorporated by reference in its entirety for all purposes.REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (193852001340SEQLIST.xml; Size: 62,092 bytes; and Date of Creation: February 19, 2026) is herein incorporated by reference in its entirety.TECHNICAL FIELD

[0003] The present disclosure relates to anti-amyloid beta (Aβ) constructs (such as anti-Aβ antibodies) and the uses thereof.BACKGROUND OF THE APPLICATION

[0004] Amyloid beta (AP) (also referred to as ABeta or beta-amyloid) are small peptides, typically 40 or 42 amino acids long, derived from the parent protein called Aβ-precursor protein (APP). These peptides are the main component of amyloid plaques, which are the accumulation of aggregated Aβ peptide in the brain. Aβ (1-40) (Aβ40) and Aβ (1-42) (Aβ42) are the predominant forms found in amyloid plaques, and are implicated in the pathology of Alzheimer’s disease.

[0005] The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entirety.BRIEF SUMMARY OF THE APPLICATION

[0006] The present application in one aspect provides an anti-amyloid beta (anti-Aβ) construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: a) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs; and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an1ny-2904277Attorney Docket No.: 193852001340LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs; b) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs; and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs; c) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs; and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 32, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs; d) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs; and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs; or e) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs; and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs.

[0007] The present application in another aspect provides an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising: a) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a 2ny-2904277Attorney Docket No.: 193852001340heavy chain variable region (VH) having the sequence set forth in any one of SEQ ID NOs: 1-3 and 7; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within light chain variable region (VL) having the sequence set forth in any one of SEQ ID NOs: 11-13 and 17; b) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in any one of SEQ ID NOs: 4-6 and 8; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in any one of SEQ ID NOs: 14-16 and 18; c) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in SEQ ID NO: 9; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in SEQ ID NO: 19; d) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in SEQ ID NO: 10; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in SEQ ID NO: 20; or e) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in SEQ ID NO: 7; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in SEQ ID NO: 18.

[0008] The present application in another aspect provides an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: a) the VHcomprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, optionally wherein the VH comprises the amino acid sequence of any one of SEQ ID NOs: 1-3 and 7, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 1-3 and 7, and wherein the VL comprises the amino acid sequence of any one of SEQ ID NOs: 11-13 and 17, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 11-13 and 17; b) the VH comprises 3ny-2904277Attorney Docket No.: 193852001340an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38, optionally wherein the VH comprises the amino acid sequence of any one of SEQ ID NOs: 4-6 and 8, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 4-6 and 8, and wherein the VL comprises the amino acid sequence of any one of SEQ ID NOs: 14-16 and 18, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 14-16 and 18; c) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 32, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, optionally wherein the VH comprises the amino acid sequence of SEQ ID NO: 9, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 9, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 19, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 19; d) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40, optionally wherein the VH comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 10, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 20; or e) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38, optionally wherein the VH comprises the amino acid sequence of SEQ ID NO: 7, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 7, and wherein the VL comprises the amino acid4ny-2904277Attorney Docket No.: 193852001340sequence of SEQ ID NO: 18, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 18.

[0009] In some embodiments according to any of the embodiments described above, the VH comprises the amino acid sequence of any one of SEQ ID NOs: 1-10, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 1-10; and wherein the VL comprises the amino acid sequence of any one of SEQ ID NOs: 11-20, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 11-20.

[0010] In some embodiments according to any of the embodiments described above, a) the VH comprises the amino acid sequence of SEQ ID NO: 1, and the VL comprises the amino acid sequence of SEQ ID NO: 11; b) the VH comprises the amino acid sequence of SEQ ID NO: 2, and the VL comprises the amino acid sequence of SEQ ID NO: 11; c) the VH comprises the amino acid sequence of SEQ ID NO: 3, and the VL comprises the amino acid sequence of SEQ ID NO: 11; d) the VH comprises the amino acid sequence of SEQ ID NO: 1, and the VL comprises the amino acid sequence of SEQ ID NO: 12; e) the VH comprises the amino acid sequence of SEQ ID NO: 2, and the VL comprises the amino acid sequence of SEQ ID NO: 12; f) the VH comprises the amino acid sequence of SEQ ID NO: 3, and the VL comprises the amino acid sequence of SEQ ID NO: 12; g) the VH comprises the amino acid sequence of SEQ ID NO: 1, and the VL comprises the amino acid sequence of SEQ ID NO: 13; h) the VH comprises the amino acid sequence of SEQ ID NO: 2, and the VL comprises the amino acid sequence of SEQ ID NO: 13; i) the VH comprises the amino acid sequence of SEQ ID NO: 3, and the VL comprises the amino acid sequence of SEQ ID NO: 13; j) the VH comprises the amino acid sequence of SEQ ID NO: 4, and the VL comprises the amino acid sequence of SEQ ID NO: 14; k) the VH comprises the amino acid sequence of SEQ ID NO: 5, and the VL comprises the amino acid sequence of SEQ ID NO: 14; 1) the VH comprises the amino acid sequence of SEQ ID NO: 6, and the VL comprises the amino acid sequence of SEQ ID NO: 14; m) the VH comprises the amino acid sequence of SEQ ID NO: 4, and the VL comprises the amino acid sequence of SEQ ID NO: 15; n) the VH comprises the amino acid sequence of SEQ ID NO: 5, and the VL comprises the amino acid sequence of SEQ ID NO: 15; o) the VH comprises the amino acid sequence of SEQ ID NO: 6, and the VL comprises the amino acid sequence of SEQ ID NO: 15; p) the VH comprises the amino acid sequence of SEQ ID NO: 4, and the VL comprises the amino acid sequence of SEQ ID NO: 16; q) the VH comprises the amino acid sequence of SEQ ID NO: 5, and the VL comprises the amino acid sequence of SEQ ID NO: 16; r) the VH comprises the amino acid sequence of SEQ ID NO: 6, and the VL comprises the amino acid sequence of SEQ ID NO: 16; s) the VH comprises the 5ny-2904277Attorney Docket No.: 193852001340amino acid sequence of SEQ ID NO: 7, and the VL comprises the amino acid sequence of SEQ ID NO: 17; t) the VH comprises the amino acid sequence of SEQ ID NO: 8, and the VL comprises the amino acid sequence of SEQ ID NO: 18; u) the VH comprises the amino acid sequence of SEQ ID NO: 9, and the VL comprises the amino acid sequence of SEQ ID NO: 19; v) the VH comprises the amino acid sequence of SEQ ID NO: 10, and the VL comprises the amino acid sequence of SEQ ID NO: 20; or w) the VH comprises the amino acid sequence of SEQ ID NO: 7, and the VL comprises the amino acid sequence of SEQ ID NO: 18.

[0011] In some embodiments according to any of the embodiments described above, the antibody moiety is an antibody or antigen-binding fragment thereof selected from the group consisting of a full-length antibody, a bispecific antibody, a single-chain Fv (scFv) fragment, a Fab fragment, a Fab’ fragment, a F(ab’)2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a Fv-Fc fusion, a scFv-Fc fusion, a scFv-Fv fusion, a diabody, a tribody, and a tetrabody.

[0012] In some embodiments according to any of the embodiments described above, the antibody moiety is a full-length antibody.

[0013] In some embodiments according to any of the embodiments described above, the antibody moiety comprises light chain constant region, wherein the light chain constant region is a kappa or lambda constant region.

[0014] In some embodiments according to any of the embodiments described above, the antibody moiety comprises an Fc fragment from IgG, IgA, IgD, IgE, or IgM. In some embodiments according to any of the embodiments described above, the Fc fragment is from IgGl, IgG2, IgG3, or IgG4. In some embodiments according to any of the embodiments described above, the Fc fragment comprises one or more substitutions and has a reduced effector function as compared to a corresponding wildtype Fc fragment. In some embodiments according to any of the embodiments described above, the Fc fragment comprises one or more substitutions and has an extended half-life as compared to a corresponding wildtype Fc fragment.

[0015] In some embodiments according to any of the embodiments described above, the construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 41, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 51. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 42, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 51. In some embodiments, the two heavy chains each comprises an amino acid sequence 6ny-2904277Attorney Docket No.: 193852001340of SEQ ID NO: 43, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 51. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 41, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 52. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 42, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 52. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 43, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 52. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 41, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 53. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 42, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 53. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 43, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 53. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 44, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 54. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 45, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 54. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 46, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 54. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 44, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 55. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 45, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 55. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 46, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 55. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 44, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 56. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 45, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 56. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 46, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 56. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 47, and the two light 7ny-2904277Attorney Docket No.: 193852001340chains each comprises an amino acid sequence of SEQ ID NO: 57. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 48, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 58. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 49, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 59. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 50, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 60. In some embodiments, the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 47, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 58.

[0016] In some embodiments according to any of the embodiments described above, the antibody moiety of the anti-Aβ construct has reduced non-specific binding to human plasma as compared to a benchmark antibody (such as lecanemab and / or donanemab). In some embodiments, the benchmark antibody is lecanemab and / or donanemab. In some embodiments according to any of the embodiments described above, the non-specific binding of the antibody moiety or the construct to human plasma is reduced by at least about any of 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to the benchmark antibody. In some embodiments according to any of the embodiments described above, the binding to human plasma is reduced by at least about 50% as compared to a benchmark antibody.

[0017] In some embodiments according to any of the embodiments described above, the antibody moiety of the anti-Aβ construct mediates clearance of Aβ.

[0018] In some embodiments according to any of the embodiments described above, the antibody moiety of the anti-Aβ construct binds Aβ isoforms amyloid-beta 40 (Aβ40) and / or amyloid-beta 42 (Aβ42).

[0019] In some embodiments according to any of the embodiments described above, the antibody moiety of the anti-Aβ construct binds Aβ protein aggregates.

[0020] In some embodiments according to any of the embodiments described above, the anti-Aβ antibody moiety binds to Aβ with a dissociation constant (KD) of <5xl0'7M, <10'7M, 5x<10'8M, <10’8M, <5xl0'9M, <10’9M, <5xl()-10M, <10’10M, <5xl0-nM, <10-nM, <5xl0'12M, or <10’12M, optionally wherein the KD is within 5xl0'7M to 10'7M, 10'7M to 5xl0'8M, 5xl0'8M to IO’8M, IO’8M to 5xl0’9M, 5xl0’9M to IO’9M, IO’9M to SxlO’10M, 5xl0'10M to IO’10M, IO’10M to SxlO’11M, SxlO’11M to 10’11M, 10’11M to 5xl0’12M, or 5xlO'12Mto 10’12M.8ny-2904277Attorney Docket No.: 193852001340

[0021] In some embodiments according to any of the embodiments described above, the Aβ is a human Aβ.

[0022] In some embodiments according to any of the embodiments described above, the anti-Aβ antibody moiety does not bind to a mouse Aβ, a rat Aβ and / or a monkey Aβ.

[0023] In some embodiments according to any of the embodiments described above, the construct comprises a humanized anti-Aβ antibody.

[0024] The present application in another aspect provides an anti-Aβ construct comprising an anti-Aβ antibody moiety, wherein the anti-Aβ antibody moiety binds to Aβ competitively with any of the anti-Aβ constructs described above.

[0025] The present application in another aspect provides a pharmaceutical composition comprising any of the anti-Aβ constructs described above, and a pharmaceutical acceptable carrier.

[0026] The present application in another aspect provides an isolated nucleic acid encoding any of the anti-Aβ constructs described above.

[0027] The present application in another aspect provides a vector comprising any of the isolated nucleic acids described above.

[0028] The present application in another aspect provides an isolated host cell comprising any of the isolated nucleic acids described above, or any of the vectors described above.

[0029] The present application in another aspect provides a method of producing an anti-Aβ construct comprising: a) culturing any of the isolated host cells described above under conditions effective to express the anti-Aβ construct or a portion or a fragment thereof; and b) obtaining the expressed anti-Aβ construct or a portion or a fragment thereof from the host cell.

[0030] In some embodiments according to any of the embodiments described above, method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of any of the anti-Aβ constructs described above, or any of the pharmaceutical compositions described above. In some embodiments according to any of the embodiments described above, the disease or condition is a neurological disorder or a neurodegenerative disease. In some embodiments according to any of the embodiments described above, the disease or condition is Alzheimer’s disease. In some embodiments according to any of the embodiments described above, the anti-Aβ construct is administered intravenously or subcutaneously into the individual. In some embodiments according to any of the embodiments described above, the anti-Aβ construct promotes clearance of Aβ protein plaques. In some embodiments according to any of the embodiments described above, the 9ny-2904277Attorney Docket No.: 193852001340anti-Aβ construct is administered at a dose of about 0.001 mg / kg to about 100 mg / kg. In some embodiments according to any of the embodiments described above, the anti-Aβ construct is administered with a second agent. In some embodiments according to any of the embodiments described above, the individual is a human.

[0031] The present application in another aspect provides a kit comprising any of the anti-Aβ constructs described above.BRIEF DESCRIPTION OF THE DRAWINGS

[0032] FIG. 1 shows binding affinity of DC3301 antibodies to Aβ40 and Aβ42 aggregates by direct ELISA.

[0033] FIG. 2 shows binding affinity data of DC3301 antibodies to Aβ aggregates by SPR.

[0034] FIGs. 3A-3B show binding specificity of DC3301 antibodies to human plasma.

[0035] FIG. 4 shows DC3301 antibody-mediated intracellular clearance of Aβ aggregates by phagocytosis assay.

[0036] FIG. 5 shows DC3301 antibody pharmacokinetics compared to benchmark antibodies.DETAILED DESCRIPTION OF THE APPLICATION

[0037] The present application provides novel anti-Aβ constructs that specifically bind to Aβ (such as Aβ40 and / or Aβ42), methods of preparing the anti-Ap constructs, and methods of using the constructs (e.g., methods of treating a disease or condition, such as Alzheimer’s disease).

[0038] Recent anti-amyloid therapies such as lecanemab and donanemab show promise for Alzheimer’s treatment but are limited by reduced half-life due to e.g., non-specific plasma protein binding, particularly with fibrinogen. Inventors of the present application developed optimized anti-amyloid antibodies that reduce plasma binding dramatically, e.g., by at least 60% while maintaining activity. Using AI-driven maturation, antibodies were engineered with substantially reduced plasma interactions compared to lecanemab and donanemab. The present invention seeks to enhance anti-amyloid treatment profiles with extended half-life and bioavailability.

[0039] AI-driven antibody maturation yielded candidates with comparable Aβ affinity to lecanemab or donanemab and significantly reduced plasma binding, indicating potential for improved pharmacokinetics in Alzheimer’s therapy.10ny-2904277Attorney Docket No.: 193852001340I. Definitions

[0040] The term “antibody” is used in its broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies and antigen-binding fragments thereof, so long as they exhibit the desired antigen-binding activity. The term “antibody moiety” refers to a full-length antibody or an antigen-binding fragment thereof.

[0041] A full-length antibody comprises two heavy chains and two light chains. The variable regions of the light and heavy chains are responsible for antigen binding. The variable domains of the heavy chain and light chain may be referred to as “VH” and “VL”, respectively. The variable regions in both chains generally contain three highly variable loops called the complementarity determining regions (CDRs) (light chain (LC) CDRs including LC-CDR1, LC-CDR2, and LC-CDR3, heavy chain (HC) CDRs including HC-CDR1, HC-CDR2, and HC-CDR3). CDR boundaries for the antibodies and antigen-binding fragments disclosed herein may be defined or identified by the conventions of Kabat, Chothia, or Al-Lazikani (Al-Lazikani 1997; Chothia 1985; Chothia 1987; Chothia 1989; Kabat 1987; Kabat 1991). The three CDRs of the heavy or light chains are interposed between flanking stretches known as framework regions (FRs), which are more highly conserved than the CDRs and form a scaffold to support the hypervariable loops. The constant regions of the heavy and light chains are not involved in antigen binding, but exhibit various effector functions. Antibodies are assigned to classes based on the amino acid sequence of the constant region of their heavy chain. The five major classes or isotypes of antibodies are IgA, IgD, IgE, IgG, and IgM, which are characterized by the presence of α, δ, ε, γ, and μ heavy chains, respectively. Several of the major antibody classes are divided into subclasses such as IgGl (yl heavy chain), lgG2 (y2 heavy chain), lgG3 (y3 heavy chain), lgG4 (y4 heavy chain), IgAl (al heavy chain), or lgA2 (a2 heavy chain). Chimeric Fc regions (such as IgG2 / 4 mixture) are also contemplated herein.

[0042] The term “antigen-binding fragment” as used herein refers to an antibody fragment including, for example, a diabody, a Fab, a Fab’, a F(ab’)2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv (dsFv-dsFv’), a disulfide stabilized diabody (ds diabody), a single-chain Fv (scFv), an scFv dimer (bivalent diabody), a multispecific antibody formed from a portion of an antibody comprising one or more CDRs, a camelid single domain antibody, a nanobody, a domain antibody, a bivalent domain antibody, or any other antibody fragment that binds to an antigen but does not comprise a complete antibody structure. An antigen-binding fragment is capable of binding to the same antigen to which the parent antibody or a parent antibody fragment (e.g., a parent scFv) binds. In some 11ny-2904277Attorney Docket No.: 193852001340embodiments, an antigen-binding fragment may comprise one or more CDRs from a particular human antibody grafted to a framework region from one or more different human antibodies.

[0043] “Fv” is the minimum antibody fragment, which contains a complete antigenrecognition and -binding site. This fragment consists of a dimer of one heavy- and one lightchain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the heavy and light chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although often at a lower affinity than the entire binding site.

[0044] “Single-chain Fv,” also abbreviated as “sFv” or “scFv,” are antibody fragments that comprise the VH and VL antibody domains connected into a single polypeptide chain. In some embodiments, the scFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen binding. For a review of scFv, see Plückthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer- Verlag, New York, pp. 269-315 (1994).

[0045] As used herein, the term “CDR” or “complementarity determining region” is intended to mean the non-contiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. These particular regions have been described by Kabat et al., J. Biol. Chem. 252:6609-6616 (1977); Kabat et al., U. S. Dept, of Health and Human Services, “Sequences of proteins of immunological interest” (1991); Chothia et al., J. Mol. Biol. 196:901-917 (1987); Al-Lazikani B. et al., J. Mol. Biol., 273: 927-948 (1997); MacCallum et al., J. Mol. Biol. 262:732-745 (1996); Abhinandan and Martin, Mol. Immunol., 45: 3832-3839 (2008); Lefranc M. P et al., Dev. Comp. Immunol., 27: 55-77 (2003); and Honegger and Pluckthun, J. Mol. BioL, 309:657-670 (2001), where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or grafted antibodies or variants thereof is intended to be within the scope of the term as defined and used herein. The amino acid residues which encompass the CDRs as defined by each of the above-cited references are set forth below in Table 1 as a comparison. CDR prediction algorithms and interfaces are known in the art, including, for example, Abhinandan and Martin, Mol. Immunol., 45: 3832-3839 (2008); Ehrenmann F. et al, Nucleic Acids Res., 38: D301-D307 (2010); and Adolf-Bryfogle J. et al., Nucleic Acids Res., 43: D432-D438 (2015). The contents of the references cited in this paragraph are incorporated herein by reference in their entireties for use in the 12ny-2904277Attorney Docket No.: 193852001340present application and for possible inclusion in one or more claims herein. In some embodiments, the CDR sequences provided herein are based on IMGT definition. For example, the CDR sequences may be determined by the VBASE2 tool (http: / / www.vbase2.org / vbase2.php, see also Retter I, Althaus HH, Munch R, Muller W: VBASE2, an integrative V gene database. Nucleic Acids Res. 2005 Jan 1; 33 (Database issue): D671-4, which is incorporated herein by reference in its entirety).TABLE 1: CDR DEFINITIONSKabat1Chothia2MacCallum3IMGT4AHo5VHCDR1 31-35 26-32 30-35 27-38 25-40 VHCDR2 50-65 53-55 47-58 56-65 58-77 VHCDR3 95-102 96-101 93-101 105-117 109-137 VLCDR1 24-34 26-32 30-36 27-38 25-40 VLCDR2 50-56 50-52 46-55 56-65 58-77 VLCDR3 89-97 91-96 89-96 105-117 109-137'Residue numbering follows the nomenclature of Kabat et al., supra2Residue numbering follows the nomenclature of Chothia et al., supra3Residue numbering follows the nomenclature of MacCallum et al., supra4Residue numbering follows the nomenclature of Lefranc et al., supra5Residue numbering follows the nomenclature of Honegger and Plückthun, supra

[0046] The expression “variable-domain residue-numbering as in Kabat” or “amino-acid-position numbering as in Kabat,” and variations thereof, refers to the numbering system used for heavy-chain variable domains or light-chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or hypervariable region (HVR) of the variable domain. For example, a heavy-chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g. residues 82a, 82b, and 82c, etc. according to Kabat) after heavy-chain FR residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.

[0047] Unless indicated otherwise herein, the numbering of the residues in an immunoglobulin heavy chain is that of the EU index as in Kabat et al., supra. The “EU index as in Kabat” refers to the residue numbering of the human IgGl EU antibody.13ny-2904277Attorney Docket No.: 193852001340

[0048] “Framework” or “FR” residues are those variable-domain residues other than the CDR residues as herein defined.

[0049] “Humanized” forms of non-human (e.g., rodent) antibodies are chimeric antibodies that contain minimal sequence derived from the non-human antibody. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (HVR) of the recipient are replaced by residues from a hypervariable region of a non-human species (donor antibody) such as mouse, rat, rabbit or non-human primate having the desired antibody specificity, affinity, and capability. In some instances, framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, See Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992).

[0050] A “human antibody” is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and / or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter, J. Mol. BioL, 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner etal., J. Immunol., 147(l):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5: 368-74 (2001). Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U. S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also, for example, Li etal., Proc. Natl.14ny-2904277Attorney Docket No.: 193852001340Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology.

[0051] “Percent (%) amino acid sequence identity” or “homology” with respect to the polypeptide and antibody sequences identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the polypeptide being compared, after aligning the sequences considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, Megalign (DNASTAR), or MUSCLE software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared. For purposes herein, however, % amino acid sequence identity values are generated using the sequence comparison computer program MUSCLE (Edgar, R. C., Nucleic Acids Research 32(5): 1792-1797, 2004; Edgar, R. C., BMC Bioinformatics 5(1): 113, 2004).

[0052] “Homologous” refers to the sequence similarity or sequence identity between two polypeptides or between two nucleic acid molecules. When a position in both of the two compared sequences is occupied by the same base or amino acid monomer subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percent of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared times 100. For example, if 6 of 10 of the positions in two sequences are matched or homologous then the two sequences are 60% homologous. By way of example, the amino acid sequences TKLEIK and TALGIE share 50% homology. Generally, a comparison is made when two sequences are aligned to give maximum homology.

[0053] The term “constant domain” refers to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable domain, which contains the antigen-binding site. The constant domain contains the CH1, CH2 and CH3 domains (collectively, CH) of the heavy chain and the CHL (or CL) domain of the light chain.

[0054] The “light chains” of antibodies (immunoglobulins) from any mammalian species can be assigned to one of two clearly distinct types, called kappa (“K”) and lambda (“ ”), based on the amino acid sequences of their constant domains.15ny-2904277Attorney Docket No.: 193852001340

[0055] The “CHI domain” (also referred to as “Cl” of “Hl” domain) usually extends from about amino acid 118 to about amino acid 215 (EU numbering system).

[0056] “Hinge region” is generally defined as a region in IgG corresponding to Glu216 to Pro230 of human IgGl (Burton, Molec. Immunol.22 161-206 (1985)). Hinge regions of other IgG isotypes may be aligned with the IgGl sequence by placing the first and last cysteine residues forming inter-heavy chain S-S bonds in the same positions.

[0057] The “CH2 domain” of a human IgG Fc region (also referred to as “C2” domain) usually extends from about amino acid 231 to about amino acid 340. The CH2 domain is unique in that it is not closely paired with another domain. Rather, two N-linked branched carbohydrate chains are interposed between the two CH2 domains of an intact native IgG molecule. It has been speculated that the carbohydrate may provide a substitute for the domain-domain pairing and help stabilize the CH2 domain. Burton, Molec Immunol. 22: 161-206 (1985).

[0058] The “CH3 domain” (also referred to as “C2” domain) comprises the stretch of residues C-terminal to a CH2 domain in an Fc region (i.e. from about amino acid residue 341 to the C-terminal end of an antibody sequence, typically at amino acid residue 446 or 447 of an IgG).

[0059] The term “Fc region” or “fragment crystallizable region” herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. In some cases, the subsequent C-terminal glycine (residue 446 according to the EU numbering system) of the Fc region may also be removed. Accordingly, a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue. Suitable native-sequence Fc regions for use in the antibodies described herein include human IgGl, IgG2 (IgG2A, IgG2B), IgG3 and IgG4.

[0060] “Fc receptor” or “FcR” describes a receptor that binds the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors,16ny-2904277Attorney Docket No.: 193852001340FcyRII receptors include FcyRIIA (an “activating receptor”) and FcyRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain. See M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991); Capel et al., Immunomethods 4: 25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995). Neonatal Fc receptors (FcRN) are encompassed herein. Other FcRs, including those to be identified in the future, are also encompassed by the term “FcR” herein.

[0061] The term “epitope” as used herein refers to the specific group of atoms or amino acids on an antigen to which an antibody or antibody moiety binds. Two antibodies or antibody moieties may bind the same epitope within an antigen if they exhibit competitive binding for the antigen.

[0062] As used herein, a first antibody or fragment thereof “competes” for binding to a target antigen with a second antibody or fragment thereof when the first antibody or fragment thereof inhibits the target antigen binding of the second antibody of fragment thereof by at least about 50% (such as at least about any one of 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98% or 99%) in the presence of an equimolar concentration of the first antibody or fragment thereof, or vice versa. A high throughput process for “binning” antibodies based upon their cross-competition is described in PCT Publication No. WO 03 / 48731.

[0063] As use herein, the terms “specifically binds,” “specifically recognizing,” and “is specific for” refer to measurable and reproducible interactions, such as binding between a target and an antibody or antibody moiety, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules, including biological molecules. For example, an antibody or antibody moiety that specifically recognizes a target (which can be an epitope) is an antibody or antibody moiety that binds this target with greater affinity, avidity, more readily, and / or with greater duration than its bindings to other targets. In some embodiments, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, e.g., by a radioimmunoassay (RIA). In some embodiments, an antibody that specifically binds a target has a dissociation constant (KD) of <10’5M, <10’6M, <10’7M, <10’8M, <10’9M, <10’10M, <10-nM, or <10’12M. In some embodiments, an antibody specifically binds an epitope on a protein that is conserved among the protein from different species. In some embodiments, specific binding can include, but does 17ny-2904277Attorney Docket No.: 193852001340not require exclusive binding. Binding specificity of the antibody or antigen-binding domain can be determined experimentally by methods known in the art. Such methods comprise, but are not limited to Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIACORE™ -tests and peptide scans.

[0064] An “isolated” antibody (or construct) is one that has been identified, separated and / or recovered from a component of its production environment (e.g., natural or recombinant). Preferably, the isolated polypeptide is free of association with all other components from its production environment.

[0065] An “isolated” nucleic acid molecule encoding a construct, antibody, or antigenbinding fragment thereof described herein is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule with which it is ordinarily associated in the environment in which it was produced. Preferably, the isolated nucleic acid is free of association with all components associated with the production environment. The isolated nucleic acid molecules encoding the polypeptides and antibodies described herein is in a form other than in the form or setting in which it is found in nature. Isolated nucleic acid molecules therefore are distinguished from nucleic acid encoding the polypeptides and antibodies described herein existing naturally in cells. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0066] The term “control sequences” refers to DNA sequences necessary for the expression of an operably linked coding sequence in a particular host organism. The control sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

[0067] Nucleic acid is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence. For example, DNA for a presequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, “operably linked” means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist,18ny-2904277Attorney Docket No.: 193852001340the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.

[0068] The term “vector,” as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a selfreplicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”

[0069] The term “transfected” or “transformed” or “transduced” as used herein refers to a process by which exogenous nucleic acid is transferred or introduced into the host cell. A “transfected” or “transformed” or “transduced” cell is one which has been transfected, transformed or transduced with exogenous nucleic acid. The cell includes the primary subject cell and its progeny.

[0070] The terms “host cell,” “host cell line,” and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include “transformants” and “transformed cells,” which include the primary transformed cell and progeny derived therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, and may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0071] The term “immunoconjugate” includes reference to a covalent linkage of a therapeutic agent or a detectable label to an antibody such as an antibody moiety described herein. The linkage can be direct or indirect through a linker (such as a peptide linker).

[0072] As used herein, “treatment” or “treating” is an approach for obtaining beneficial or desired results, including clinical results. For purposes of this application, beneficial or desired clinical results include, but are not limited to, one or more of the following: alleviating one or more symptoms resulting from the disease, diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the recurrence of the disease, delaying or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, decreasing the dose of one or more other medications required to treat the disease, delaying the progression of the disease, increasing or improving19ny-2904277Attorney Docket No.: 193852001340the quality of life, increasing weight gain, and / or prolonging survival. The methods of the application contemplate any one or more of these aspects of treatment.

[0073] The terms “inhibition” or “inhibit” refer to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic. To “reduce” or “inhibit” is to decrease, reduce or arrest an activity, function, and / or amount as compared to that of a reference. In certain embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 20% or greater. In another embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 50% or greater. In yet another embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater.

[0074] A “reference” as used herein, refers to any sample, standard, or level that is used for comparison purposes. A reference may be obtained from a healthy and / or non-diseased sample. In some examples, a reference may be obtained from an untreated sample. In some examples, a reference is obtained from a non-diseased or non-treated sample of an individual. In some examples, a reference is obtained from one or more healthy individuals who are not the individual or patient.

[0075] As used herein, “delaying development of a disease" means to defer, hinder, slow, retard, stabilize, suppress and / or postpone development of the disease. This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.

[0076] “Preventing” as used herein, includes providing prophylaxis with respect to the occurrence or recurrence of a disease in an individual that may be predisposed to the disease but has not yet been diagnosed with the disease.

[0077] The terms “subject,” “individual,” and “patient” are used interchangeably herein to refer to a mammal, including, but not limited to, human, bovine, horse, feline, canine, rodent, or primate. In some embodiments, the individual is a human.

[0078] An “effective amount” of an agent refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. The specific dose may vary depending on one or more of: the particular agent chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to be imaged, and the physical delivery system in which it is carried.

[0079] The terms “pharmaceutical formulation” and “pharmaceutical composition” refer to a preparation which is in such form as to permit the biological activity of the active 20ny-2904277Attorney Docket No.: 193852001340ingredient(s) to be effective, and which contains no additional components which are unacceptably toxic to an individual to which the formulation would be administered. Such formulations may be sterile.

[0080] A “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent that together comprise a “pharmaceutical composition” for administration to an individual. A pharmaceutically acceptable carrier is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The pharmaceutically acceptable carrier is appropriate for the formulation employed.

[0081] A “sterile” formulation is aseptic or essentially free from living microorganisms and their spores.

[0082] Administration “in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive or sequential administration in any order.

[0083] The term “concurrently” is used herein to refer to administration of two or more therapeutic agents, where at least part of the administration overlaps in time or where the administration of one therapeutic agent falls within a short period of time relative to administration of the other therapeutic agent. For example, the two or more therapeutic agents are administered with a time separation of no more than about 60 minutes, such as no more than about any of 30, 15, 10, 5, or 1 minutes.

[0084] The term “sequentially” is used herein to refer to administration of two or more therapeutic agents where the administration of one or more agent(s) continues after discontinuing the administration of one or more other agent(s). For example, administration of the two or more therapeutic agents are administered with a time separation of more than about 15 minutes, such as about any of 20, 30, 40, 50, or 60 minutes, 1 day, 2 days, 3 days, 1 week, 2 weeks, or 1 month, or longer.

[0085] As used herein, “in conjunction with” refers to administration of one treatment modality in addition to another treatment modality. As such, “in conjunction with” refers to administration of one treatment modality before, during or after administration of the other treatment modality to the individual.

[0086] The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and / or warnings concerning the use of such therapeutic products.21ny-2904277Attorney Docket No.: 193852001340

[0087] An “article of manufacture” is any manufacture (e.g., a package or container) or kit comprising at least one reagent, e.g., a medicament for treatment of a disease or disorder, or a probe for specifically detecting a biomarker described herein. In certain embodiments, the manufacture or kit is promoted, distributed, or sold as a unit for performing the methods described herein.

[0088] It is understood that embodiments of the application described herein include “consisting” and / or “consisting essentially of’ embodiments.

[0089] Reference to “about” a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.

[0090] As used herein, reference to “not” a value or parameter generally means and describes “other than” a value or parameter. For example, the method is not used to treat a disease of type X means the method is used to treat the disease of types other than X.

[0091] The term “about X-Y” used herein has the same meaning as “about X to about Y”

[0092] As used herein and in the appended claims, the singular forms “a,” “or,” and “the” include plural referents unless the context clearly dictates otherwise.II. Anti-Aβ constructs

[0093] The present application provides anti-Aβ constructs comprising an anti-Aβ antibody moiety that specifically binds to Aβ (such as Aβ40 and Aβ42) as described herein.

[0094] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs.

[0095] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions 22ny-2904277Attorney Docket No.: 193852001340in the HC-CDRs, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs.

[0096] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 32, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs.

[0097] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs.

[0098] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs.

[0099] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of 23ny-2904277Attorney Docket No.: 193852001340SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NO: 11, 12, 13, and 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NO: 11, 12, 13, and 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NO: 11, 12, 13, and 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NO: 11, 12, 13, and 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 41, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 51-53 and 57, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one 24ny-2904277Attorney Docket No.: 193852001340of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 42, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 51-53 and 57, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 43, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 51-53 and 57, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 47, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 51-53 and 57, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0100] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 4, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NO: 14, 15, 16, and 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 5, or a variant comprising an amino acid sequence having at least 25ny-2904277Attorney Docket No.: 193852001340about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NO: 14, 15, 16, and 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 6, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NO: 14, 15, 16, and 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 8, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NO: 14, 15, 16, and 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 44, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 54-56 and 58, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 45, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 54-56 and 58, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 46, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 54-56 and 58, or a variant comprising an amino acid 26ny-2904277Attorney Docket No.: 193852001340sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 48, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 54-56 and 58, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0101] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 32, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 9, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 19, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 49, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 59, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0102] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an 27ny-2904277Attorney Docket No.: 193852001340LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 10, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 20, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 50, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 60, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0103] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38.

[0104] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 21 or 22, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 23-25, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 26-29, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs, and the VL comprises an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 30-33, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 34-36, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 37-40, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs.

[0105] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a heavy chain variable region (VH) and a light chain variable 28ny-2904277Attorney Docket No.: 193852001340region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 21 or 22, an HC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 23-25, and an HC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 26-29, and the VL comprises an LC-CDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 30-33, an LC-CDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 34-36, and an LC-CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 37-40.

[0106] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 16, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid 29ny-2904277Attorney Docket No.: 193852001340sequence of SEQ ID NO: 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 16, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%,30ny-2904277Attorney Docket No.: 19385200134095%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 16, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 16, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light 31ny-2904277Attorney Docket No.: 193852001340chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 41, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 54-56 and 58, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 42, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 54-56 and 58, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 43, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 54-56 and 58, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 47, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 54-56 and 58, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0107] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 32, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the VH comprises an amino 32ny-2904277Attorney Docket No.: 193852001340acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 19, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 19, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 19, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 19, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of any one of SEQ ID NOs: 41-43 and 47, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 59, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0108] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, and the VL comprises 33ny-2904277Attorney Docket No.: 193852001340an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 20, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 20, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 20, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 20, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of any one of SEQ ID NOs: 41-43 and 47, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 60, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0109] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a heavy chain variable region (VH) and a light chain variable 34ny-2904277Attorney Docket No.: 193852001340region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:4, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NOs: 11, 12, 13, and 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:5, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NOs: 11, 12, 13, and 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:6, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NOs: 11, 12, 13, and 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO:8, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NOs: 11, 12, 13, and 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of any one of SEQ ID NOs: 44-46 and 48, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 51, or a variant comprising an amino 35ny-2904277Attorney Docket No.: 193852001340acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of any one of SEQ ID NOs: 44-46 and 48, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 52, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of any one of SEQ ID NOs: 44-46 and 48, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 53, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of any one of SEQ ID NOs: 44-46 and 48, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 57, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0110] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 32, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the VH comprises an amino acid sequence of any one of SEQ ID NOs:4, 5, 6, and 8, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 19, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence 36ny-2904277Attorney Docket No.: 193852001340identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of any one of SEQ ID NOs: 44-46 and 48, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 59, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0111] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40. In some embodiments, the VH comprises an amino acid sequence of any one of SEQ ID NOs:4, 5, 6, and 8, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 20, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of any one of SEQ ID NOs: 44-46 and 48, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 60, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0112] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, and the VL comprises 37ny-2904277Attorney Docket No.: 193852001340an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 9, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NOs: 11, 12, 13, and 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 49, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 51-53 and 57, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0113] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 9, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NOs: 14, 15, 16, and 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 49, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains 38ny-2904277Attorney Docket No.: 193852001340comprise an amino acid sequence of any one of SEQ ID NOs: 54-56 and 58, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0114] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 9, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 20, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 49, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 60, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0115] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 10, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 39ny-2904277Attorney Docket No.: 19385200134099%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NOs: 11, 12, 13, and 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 50, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 51-53 and 57, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0116] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 10, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of any one of SEQ ID NOs: 14, 15, 16 and 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 50, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of any one of SEQ ID NOs: 54-56 and 58, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0117] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable 40ny-2904277Attorney Docket No.: 193852001340region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 32, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the VH comprises an amino acid sequence of SEQ ID NO: 10, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and the VL comprises an amino acid sequence of SEQ ID NO: 19, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the construct comprises an antibody having two heavy chains and two light chains. In some embodiments, the one or both of the heavy chains comprise an amino acid sequence of SEQ ID NO: 50, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein the one or both of the light chains comprise an amino acid sequence of SEQ ID NO: 59, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0118] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising: an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a heavy chain variable region (VH) having the sequence set forth in any one of SEQ ID NOs: 1-3 and 7; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a light chain variable region (VL) having the sequence set forth in any one of SEQ ID NOs: 11-13 and 17.

[0119] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising: an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in any one of SEQ ID NOs: 4-6 and 8; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in any one of SEQ ID NOs: 14-16 and 18.

[0120] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising: an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively 41ny-2904277Attorney Docket No.: 193852001340comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in SEQ ID NO: 9; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in SEQ ID NO: 19.

[0121] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising: an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in SEQ ID NO: 10; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in SEQ ID NO: 20.

[0122] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising: an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in SEQ ID NO: 7; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in SEQ ID NO: 18.

[0123] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, optionally wherein the VH comprises the amino acid sequence of any one of SEQ ID NOs: 1-3 and 7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of any one of SEQ ID NOs: 11-13 and 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0124] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of 42ny-2904277Attorney Docket No.: 193852001340SEQ ID NO: 27, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38, optionally wherein the VH comprises the amino acid sequence of any one of SEQ ID NOs: 4-6 and 8, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of any one of SEQ ID NOs: 14-16 and 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0125] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 32, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, optionally wherein the VH comprises the amino acid sequence of SEQ ID NO: 9, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 19, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0126] In some embodiments, there is provided an anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40, optionally wherein the VH comprises the amino acid sequence of SEQ ID NO: 10, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 20, or a variant comprising an amino acid sequence having at least43ny-2904277Attorney Docket No.: 193852001340about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0127] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein: the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38, optionally wherein the VH comprises the amino acid sequence of SEQ ID NO: 7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0128] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 11, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 1, and the VL comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 41, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 51, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0129] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence 44ny-2904277Attorney Docket No.: 193852001340of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 11, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 2, and the VL comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 42, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 51, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0130] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 11, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 3, and the VL comprises the amino acid sequence of SEQ ID NO: 11. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 43, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 51, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0131] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence 45ny-2904277Attorney Docket No.: 193852001340identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 12, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 1, and the VL comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 41, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 52, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0132] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 12, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 2, and the VL comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 42, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 52, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0133] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 12, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one 46ny-2904277Attorney Docket No.: 193852001340of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 3, and the VL comprises the amino acid sequence of SEQ ID NO: 12. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 43, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 52, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0134] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 13, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 1, and the VL comprises the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 41, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 53, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0135] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 13, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 2, and the VL comprises the amino 47ny-2904277Attorney Docket No.: 193852001340acid sequence of SEQ ID NO: 13. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 42, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 53, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0136] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 13, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 3, and the VL comprises the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 43, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 53, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0137] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 4, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 4, and the VL comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of 48ny-2904277Attorney Docket No.: 193852001340the two heavy chains comprise an amino acid sequence of SEQ ID NO: 44, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 54, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0138] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 5, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 5, and the VL comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 45, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 54, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0139] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 6, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 6, and the VL comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 46, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one 49ny-2904277Attorney Docket No.: 193852001340of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 54, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0140] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 4, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 4, and the VL comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 44, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 55, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0141] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 5, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 5, and the VL comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 45, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 55, or a variant 50ny-2904277Attorney Docket No.: 193852001340comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0142] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 6, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 6, and the VL comprises the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 46, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 55, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0143] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 4, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 16, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 4, and the VL comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 44, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 56, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.51ny-2904277Attorney Docket No.: 193852001340

[0144] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 5, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 16, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 5, and the VL comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 45, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 56, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0145] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 6, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 16, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 6, and the VL comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 46, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 56, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0146] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence 52ny-2904277Attorney Docket No.: 193852001340of SEQ ID NO: 7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 7, and the VL comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 47, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 57, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0147] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 8, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 8, and the VL comprises the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 48, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 58, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0148] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 9, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence 53ny-2904277Attorney Docket No.: 193852001340identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 19, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 9, and the VL comprises the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 49, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 59, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0149] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 10, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 20, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 10, and the VL comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 50, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 60, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0150] In some embodiments, there is provided an anti-Ap construct comprising an anti-Ap antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one 54ny-2904277Attorney Docket No.: 193852001340of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the VH comprises the amino acid sequence of SEQ ID NO: 7, and the VL comprises the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-Ap construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein one or both of the two heavy chains comprise an amino acid sequence of SEQ ID NO: 47, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, wherein one or both of the two light chains comprise an amino acid sequence of SEQ ID NO: 58, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity.

[0151] In some embodiments, the anti-Ap construct has reduced non-specific binding to human plasma. The non-specific binding refers to a binding that is not specific for Ap, e.g., AP42 and / or Ap 40. In some embodiments, the non-specific binding of the anti-Ap construct to human plasma is reduced by about 20% (for example, by at least about 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more) as compared to a benchmark antibody (e.g., lecanemab or donanemab). In some embodiments, the anti-Ap construct has reduced non-specific binding to human plasma by at least about 60%.

[0152] In some embodiments, the anti-Ap construct mediates clearance of Ap.

[0153] In some embodiments, the anti-Ap construct binds amyloid-beta 40 (Ap40). In some embodiments, the anti-Ap construct binds amyloid-beta 42 (Ap42). In some embodiments, the anti-Ap construct binds Ap40 and Ap42.

[0154] In some embodiments, the anti-Ap construct binds Ap protein aggregates. In some embodiments, the Ap protein aggregates are oligomeric Ap protein, fibrillar Ap protein, and / or Ap protein plaques. In some embodiments, the anti-Ap construct binds Ap protein monomers.

[0155] In some embodiments, the anti-Ap construct comprises or is an antibody or antigenbinding fragment thereof selected from the group consisting of a full-length antibody, a bispecific antibody, a single-chain Fv (scFv) fragment, a Fab fragment, a Fab’ fragment, a F(ab’)2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a VHH, a Fv-Fc fusion, a scFv-Fc fusion, a scFv-Fv fusion, a diabody, a tribody, and a tetrabody.

[0156] In some embodiments, the anti-Ap antibody moiety is a full-length antibody.

[0157] In some embodiments, the anti-Ap antibody moiety described above comprises an Fc fragment of an immunoglobulin selected from the group consisting of IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof. In some embodiments, the anti-Ap antibody moiety or the full-length antibody described above comprises an Fc fragment of an immunoglobulin 55ny-2904277Attorney Docket No.: 193852001340selected from the group consisting of IgGl, IgG2, IgG3, IgG4, and combinations and hybrids thereof. In some embodiments, the anti-Ap antibody moiety or the full-length antibody described above comprises an Fc fragment of IgGl. In some embodiments, the Fc fragment has a reduced effector function as compared to the corresponding wildtype Fc fragment. In some embodiments, the Fc fragment has an enhanced effector function as compared to the corresponding wildtype Fc fragment. In some embodiments, the Fc fragment has an extended half-life as compared to the corresponding wildtype Fc fragment. In some embodiments, the anti-Ap antibody moiety or the full-length antibody described above comprises light chain constant region, wherein the light chain constant region is a kappa or lambda constant region. In some embodiments, the anti-Ap antibody moiety or the full-length antibody described above comprises an Fc fragment of IgGl and a kappa light chain region.

[0158] In some embodiments, the anti-Ap antibody moiety binds to both human Ap and mouse Ap. In some embodiments, the anti-Ap antibody moiety binds to human Ap. In some embodiments, the anti-Ap antibody moiety binds to mouse Ap. In some embodiments, the anti-Ap antibody moiety does not bind to mouse Ap.

[0159] In some embodiments, the anti-Ap construct comprises oris an anti-Ap fusion protein. In some embodiments, the anti-Ap construct comprises an anti-Ap antibody moiety (e.g., an anti-Ap scFv) and a second moiety. In some embodiments, the second moiety comprises a halflife extending moiety. In some embodiments, the half-life extending moiety is an albumin binding moiety (e.g., an albumin binding antibody moiety). In some embodiments, the anti-Ap antibody moiety and the half-life extending moiety is linked via a linker (such as a peptide linker, such as a GS linker).

[0160] In some embodiments, the anti-Ap construct comprises or is an anti-Ap immunoconjugate comprising an anti-Ap antibody moiety (such as any of the anti-Ap antibody moieties described herein) and a second agent. In some embodiments, the second agent is a therapeutic agent. In some embodiments, the second agent is a label.Amyloid beta

[0161] Amyloid beta (AP) is a peptide derived from precursor protein amyloid beta precursor protein (APP). APP is an integral transmembrane protein with an extracellular domain expressed in many tissues, but concentrated in the synapses of neurons. P-secretases and y-secretases cleave APP, producing insoluble Ap fibrils which oligomerize and aggregate to form plaques (Tiwari S, et al. (2019) Int J Nanomedicine. 14:5541-5554). The production of Ap peptide and the extracellular deposit of Ap plaques are associated with a variety of diseases and conditions such as Alzheimer’s disease (Murphy MP, LeVine H 3rd. (2010) J Alzheimer s Dis.56ny-2904277Attorney Docket No.: 19385200134019(1):311-23). Alzheimer’s disease is a progressive neurodegenerative disease that is one of the leading causes of dementia. Over 5 million people are estimated to have Alzheimer’s disease in the United States alone (Alzheimer’s Association. (2015) Alzheimer s Dement.11 (3):332-84). Therefore, targeting Ap may be an important molecule in the reduction of Ap plaques in the treatment of Alzheimer’s disease.

[0162] Ap gene is located on 21q21.2, and is highly conserved across vertebrate species. Human APP sequence can be found with NCBI Reference number NM 000484.4. Depending on the isoform, human APP may be up to 770 amino acids (NCBI Reference number: NP_00475)a) Antibody affinity

[0163] Binding specificity of the antibody moieties can be determined experimentally by methods known in the art. Such methods comprise, but are not limited to Western blots, ELISA-, RIA-, ECL-, IRMA-, EIA-, BIACORE™ -tests and peptide scans.

[0164] In some embodiments, the KD of the binding between the antibody moiety and Ap is about 10'7M to about 10'12M, about 10'7M to about 10'8M, about 10'8M to about 10'9M, about 10'9M to about IO'10M, about IO'10M to about 10'11M, about 10'11M to about 10'12M, about 10'7M to about 10'12M, about 10'8M to about 10'12M, about 10'9M to about 10'12M, about IO'10M to about 10'12M, about 10'7M to about 10'11M, about 10'8M to about 10'11M, about 10'9M to about 10'11M, about 10'7M to about IO'10M, about 10'8M to about IO'10M, or about 10'7M to about 10'9M. In some embodiments, the KD of the binding between the antibody moiety and Ap is stronger than about any one of 10'7M, 10'8M, 10'9M, IO'10M, 10’11M, or IO’12M. In some embodiments, the Aβ is a human Aβ. In some embodiments, the Ap is aAp40. In some embodiments, the Ap is a Ap42.

[0165] In some embodiments, the Konof the binding between the antibody moiety and Ap is about 103M^s'1to about 108M’1, about 103M^s'1to about 104M^s’1, about 104M^s'1to about 105M’1, about 105M^s'1to about 106M^s’1, about 106M^s'1to about 107M’1, or about 107M^s'1to about 108M^s'1. In some embodiments, the Konof the binding between the antibody moiety and Ap is about 103M^s'1to about 105M^s’1, about 104M^s'1to about 106M’1, about 105M^s'1to about 107M^s’1, about 106M^s'1to about 108M’1, about 104M’ to about 107M’1, or about 105M^s'1to about 108M^s'1. In some embodiments, the Konof the binding between the antibody moiety and Ap is no more than about any one of 103M-1s'1, 104M'1S'1, 105M'1S'1, 106M'1S'1, 107M'1S'1or 108M'1S'1. In some embodiments, Ap is human Ap. In some embodiments, the Ap is a Ap40. In some embodiments, the Ap is a Ap42.57ny-2904277Attorney Docket No.: 193852001340

[0166] In some embodiments, the Koffof the binding between the antibody moiety and Ap is about 1 s'1to about 10’6s’1, about 1 s’1to about 10’2s’1, about 10’2s’1to about 10’3s’1, about 10’3s’1to about 10’4s’1, about 10’4s’1to about 10’5s’1, about 10’5s’1to about 10’6s’1, about 1 s’1to about 10’5s’1, about 10’2s’1to about 10’6s’1, about 10’3s’1to about 10’6s’1, about 10’4s’1to about 10’6s’1, about 10’2s’1to about 10’5s’1, or about 10’3s’1to about 10’5s’1. In some embodiments, the K0fr of the binding between the antibody moiety and Ap is at least about any one of 1 s’1, 10’2s’1, 10’3s’1, 10’4s’1, 10’5s’1or 10’6s’1. In some embodiments, Ap is human Ap. In some embodiments, the Ap is a AP40. In some embodiments, the Ap is a Ap42.

[0167] In some embodiments, the binding affinity of the anti-Ap antibody moiety or anti-Ap construct are higher (for example, has a smaller KD value) than an existing anti-Ap antibody e.g., lecanamab or donanemab).b) Chimeric or humanized antibodies

[0168] In some embodiments, the anti-Ap antibody moiety is a chimeric antibody. In some embodiments, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from mouse) and a human constant region. In some embodiments, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

[0169] In some embodiments, the anti-Ap antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs, e.g, CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.

[0170] Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat’l Acad. Set. USA 86:10029-10033 (1989); US Patent Nos. 5, 821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing SDR (a-CDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing “resurfacing”); Dall’Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka 58ny-2904277Attorney Docket No.: 193852001340et al., Br J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling).

[0171] Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); Framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Set. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem.272:10678-10684 (1997) and Rosok etal., J. Biol. Chem. 271:22611-22618 (1996)).

[0172] It is understood that the humanization of mouse derived antibodies is a common and routinely used art. It is therefore understood that a humanized format of any and all of the anti-Ap antibodies disclosed in Sequence Table can be used in a preclinical or clinical setting. In cases where a humanized format of any of the referenced anti-Ap antibodies or their antigenbinding regions thereof is used in such a preclinical or clinical setting, the then humanized format is expected to bear the same or similar biological activities and profiles as the original non-humanized format.c) Human antibodies

[0173] In some embodiments, the anti-Ap antibody moiety is a human antibody (known as human domain antibody, or human DAb). Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001), Lonberg, Curr. Opin. Immunol. 20:450-459 (2008), and Chen, Mol. Immunol. 47(4):912-21 (2010). Transgenic mice or rats capable of producing fully human single-domain antibodies (or DAb) are known in the art. See, e.g., US20090307787A1, U. S. Pat. No. 8,754,287, US20150289489A1, US20100122358A1, and W02004049794.

[0174] Human antibodies (e.g., human DAbs) may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge. Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes. In such transgenic mice, the endogenous immunoglobulin loci have generally been inactivated. For review of methods for obtaining 59ny-2904277Attorney Docket No.: 193852001340human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, e.g., U. S. Patent Nos. 6,075,181 and 6,150,584 describing XENOMOUSE™ technology; U. S. Patent No. 5,770,429 describing HUMAB® technology; U. S. Patent No.7,041,870 describing K-M MOUSE® technology, and U. S. Patent Application Publication No. US 2007 / 0061900, describing VELOCIMOUSE® technology). Human variable regions from intact antibodies generated by such animals may be further modified, e.g., by combining with a different human constant region.

[0175] Human antibodies (e.g., human DAbs) can also be made by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described (See, e.g., Kozbor J. Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner etal., J. Immunol., 147: 86 (1991)). Human antibodies generated via human B-cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods include those described, for example, in U. S. Patent No. 7,189,826 (describing production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3): 185-91 (2005).

[0176] Human antibodies (e.g., human DAbs) may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.d) Library-derived antibodies

[0177] The anti-Ap antibody moieties described herein may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics. Such methods are reviewed, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, 2001) and further described, e.g., in the McCafferty et al., Nature 348:552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol.222: 581-597 (1992); Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee 60ny-2904277Attorney Docket No.: 193852001340et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2): 119-132(2004). Methods for constructing single-domain antibody libraries have been described, for example, See U. S. Pat. NO. 7371849.

[0178] In certain phage display methods, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994). Phage typically displays antibody fragments, either as scFv fragments or as Fab fragments. Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas. Alternatively, the naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self-antigens without any immunization as described by Griffiths et al., EMBO J, 12: 725-734 (1993). Finally, naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. BioL, 227: 381-388 (1992). Patent publications describing human antibody phage libraries include, for example: US Patent No. 5,750,373, and US Patent Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360.

[0179] Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.e) Substitution, insertion, deletion and variants

[0180] In some embodiments, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the HVRs (or CDRs) and FRs. Conservative substitutions are shown in Table 2 under the heading of “Preferred substitutions.” More substantial changes are provided in Table 2 under the heading of “exemplary substitutions,” and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained / improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.61ny-2904277Attorney Docket No.: 193852001340Table 2. Amino acid substitutionsOriginal Residue Exemplary Substitutions Preferred Substitutions Ala (A) Val; Leu; Ile ValArg (R) Lys; Gin; Asn LysAsn (N) Gin; His; Asp, Lys; Arg GinAsp (D) Glu; Asn GluCys (C) Ser; Ala SerGin (Q) Asn; Glu AsnGlu (E) Asp; Gin AspGly (G) Ala AlaHis (H) Asn; Gin; Lys; Arg ArgIle (I) Leu; Val; Met; Ala; Phe; Norleucine LeuLeu (L) Norleucine; Ile; Val; Met; Ala; Phe IleLys (K) Arg; Gin; Asn ArgMet (M) Leu; Phe; Ile LeuPhe (F) Trp; Leu; Val; Ile; Ala; Tyr TyrPro (P) Ala AlaSer (S) Thr ThrThr (T) Val; Ser SerTrp (W) Tyr; Phe TyrTyr (Y) Trp; Phe; Thr; Ser PheVal (V) Ile; Leu; Met; Phe; Ala; Norleucine Leu

[0181] Amino acids may be grouped according to common side-chain properties: (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gin; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; and (6) aromatic: Trp, Tyr, Phe.

[0182] Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

[0183] One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Generally, the resulting variant(s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity, reduced immunogenicity) relative to the parent antibody and / or will have substantially retained certain biological properties of the parent antibody. An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, e.g., using phage display -based affinity maturation techniques such as those described herein. Briefly, one or more HVR residues are mutated and the variant62ny-2904277Attorney Docket No.: 193852001340antibodies displayed on phage and screened for a particular biological activity (e.g. binding affinity).

[0184] Alterations (e.g., substitutions) may be made in HVRs, e.g., to improve antibody affinity. Such alterations may be made in HVR “hotspots,” i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or SDRs (a-CDRs), with the resulting variant VH or VL being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O’Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain 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. Another method to introduce diversity involves HVR-directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.

[0185] In some embodiments, substitutions, insertions, or deletions may occur within one or more HVRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such alterations may be outside of HVR “hotspots” or CDRs.

[0186] A useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells (1989) Science, 244: 1081-1085. In this method, a residue or group of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with antigen is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigen-antibody complex to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties.63ny-2904277Attorney Docket No.: 193852001340

[0187] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antibody. f) Glycosylation variants

[0188] In some embodiments, the anti-Ap antibody moiety is altered to increase or decrease the extent to which the construct is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.

[0189] Where the antibody moiety comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in the antibody moiety may be made in order to create antibody variants with certain improved properties.

[0190] In some embodiments, the anti-Ap antibody moiety has a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008 / 077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003 / 0157108 (Presta, L.); US 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003 / 0157108; WO 2000 / 61739; WO 2001 / 29246; US 2003 / 0115614;64ny-2904277Attorney Docket No.: 193852001340US 2002 / 0164328; US 2004 / 0093621; US 2004 / 0132140; US 2004 / 0110704; US 2004 / 0110282; US 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; W02005 / 053742; W02002 / 031140; Okazaki etal. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lecl3 CHO cells deficient in protein fucosylation (Ripka etal. Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application No. US 2003 / 0157108 Al, Presta, L; and WO 2004 / 056312 Al, Adams et al., especially at Example 11), and knockout cell lines, such as alpha- 1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki etal. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. etal., Biotechnol. Bioeng., 94(4):680-688 (2006); and W02003 / 085107).

[0191] In some embodiments, the anti-Ap antibody moiety has bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003 / 011878 (Jean-Mairet et al., US Patent No. 6,602,684 (Umana et al.); and US 2005 / 0123546 (Umana etal.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997 / 30087 (Patel et al.); WO 1998 / 58964 (Raju, S.); and WO 1999 / 22764 (Raju, S.).g) Fc region variants

[0192] In some embodiments, the anti-Ap antibody moiety comprises an Fc fragment.

[0193] The term “Fc region,” “Fc domain,” “Fc fragment” or “Fc” refers to a C-terminal non-antigen binding region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native Fc regions and variant Fc regions. In some embodiments, a human IgG heavy chain Fc region extends from Cys226 to the carboxyl -terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present, without affecting the structure or stability of the Fc region. Unless otherwise specified herein, numbering of amino acid residues in the IgG or Fc region is according to the EU numbering system for antibodies, also called the EU index, as described in Kabat etal., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0194] In some embodiments, the Fc fragment is from an immunoglobulin selected from the group consisting of IgG, IgA, IgD, IgE, IgM, and combinations and hybrids thereof. In some65ny-2904277Attorney Docket No.: 193852001340embodiments, the Fc fragment is from an immunoglobulin selected from the group consisting of IgGl, IgG2, IgG3, IgG4, and combinations and hybrids thereof.

[0195] In some embodiments, the Fc fragment has a reduced effector function as compared to corresponding wildtype Fc fragment (such as at least about 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, or 95% reduced effector function as measured by the level of antibodydependent cellular cytotoxicity (ADCC)).

[0196] In some embodiments, the Fc fragment is an IgGl Fc fragment. In some embodiments, the IgGl Fc fragment comprises a L234A mutation and / or a L235A mutation. In some embodiments the IgGl Fc fragment comprises an L235A mutation and / or a G237A mutation. In some embodiments, the Fc fragment is an IgG2 or IgG4 Fc fragment. In some embodiments, the Fc fragment is an IgG4 Fc fragment comprising a S228P, F234A, and / or a L235 A mutation. In some embodiments, the Fc fragment comprises a N297 A mutation. In some embodiments, the Fc fragment comprises a N297G mutation.

[0197] In some embodiments, one or more amino acid modifications may be introduced into the Fc region of the antibody moiety, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human IgGl, IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification (e.g. a substitution) at one or more amino acid positions.

[0198] In some embodiments, the Fc fragment possesses some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody moiety in vivo is important yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious. In vitro and / or in vivo cytotoxicity assays can be conducted to confirm the reduction / depletion of CDC and / or ADCC activities. For example, Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability. The primary cells for mediating ADCC, NK cells, express FcyRIII only, whereas monocytes express FcyRI, FcyRII and FcyRIII. FcR expression on hematopoietic cells is summarized in Table 2 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest is described in U. S. Patent No.5,500,362 (see, e.g. Hellstrom, I. et al. Proc. Nat’lAcad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat’l Acad. Sci. USA 82:1499-1502 (1985); 5,821,337 (See Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ non-radioactive cytotoxicity66ny-2904277Attorney Docket No.: 193852001340assay for flow cytometry (CellTechnology, Inc. Mountain View, CA; and CytoTox 96® nonradioactive cytotoxicity assay (Promega, Madison, WI)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes etal. Proc. Nat ’I Acad. Sci. USA 95:652-656 (1998). Clq binding assays may also be carried out to confirm that the antibody is unable to bind Clq and hence lacks CDC activity. See, e.g., Clq and C3c binding ELISA in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay may be performed (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202: 163 (1996); Cragg, M. S. et al., Blood 101:1045-1052 (2003); and Cragg, M. S. and M. J. Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life determinations can also be performed using methods known in the art (see, e.g., Petkova, S. B. et al., Int’l. Immunol.18(12): 1759-1769 (2006)).

[0199] Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U. S. Patent No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581). In some embodiments, the Fc fragment comprises a N297A mutation. In some embodiments, the Fc fragment comprises a N297G mutation.

[0200] Certain antibody variants with improved or diminished binding to FcRs are described. (See, e.g., U. S. Patent No. 6,737,056; WO 2004 / 056312, and Shields etal., J. Biol. Chem. 9(2): 6591-6604 (2001).)

[0201] In some embodiments, the Fc fragment is an IgGl Fc fragment. In some embodiments, the IgGl Fc fragment comprises a L234A mutation and / or a L235A mutation. In some embodiments, the IgGl Fc fragment comprise an L235A mutation and / or a G237A mutation. In some embodiments, the Fc fragment is an IgG2 or IgG4 Fc fragment. In some embodiments, the Fc fragment is an IgG4 Fc fragment comprising a S228P, F234A, and / or a L235 A mutation.

[0202] In some embodiments, the antibody moiety comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and / or 334 of the Fc region (EU numbering of residues).

[0203] In some embodiments, alterations are made in the Fc region that result in altered (i.e., either improved or diminished) Clq binding and / or Complement Dependent Cytotoxicity 67ny-2904277Attorney Docket No.: 193852001340(CDC), e.g., as described in US Patent No. 6,194,551, WO 99 / 51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).

[0204] In some embodiments, the Fc fragment has one or more mutations at Thr250, Met252, Ser254, The256, Thr307. Glu 380, Met428, His433, and / or Asn 434.

[0205] In some embodiments, the antibody moiety variant comprising a variant Fc region comprising one or more amino acid substitutions which alters half-life and / or changes binding to the neonatal Fc receptor (FcRn). Antibodies with increased half-lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer etal., J. Immunol. 117:587 (1976) and Kim etal., J. Immunol. 24:249 (1994)), are described in US2005 / 0014934A1 (Hinton et al.). Those antibodies comprise an Fc region with one or more substitutions therein which alters binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues, e.g., substitution of Fc region residue 434 (US Patent No. 7,371,826).

[0206] See also Duncan & Winter, Nature 322:738-40 (1988); U. S. Patent No. 5,648,260; U. S. Patent No. 5,624,821; and WO 94 / 29351 concerning other examples of Fc region variants. h) Cysteine engineered antibody variants

[0207] In some embodiments, it may be desirable to create cysteine engineered antibody moieties, e.g., “thioMAbs,” in which one or more residues of an antibody are substituted with cysteine residues. In particular embodiments, the substituted residues occur at accessible sites of the antibody. By substituting those residues with cysteine, reactive thiol groups are thereby positioned at accessible sites of the antibody and may be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein. In some embodiments, any one or more of the following residues may be substituted with cysteine: Al 18 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine engineered antibody moieties may be generated as described, e.g., in U. S. Patent No. 7,521,541.i) Antibody derivatives

[0208] In some embodiments, the antibody moiety described herein may be further modified to comprise additional nonproteinaceous moieties that are known in the art and readily available. The moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers. Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1, 3, 6-trioxane, ethylene / maleic anhydride copolymer, polyaminoacids (either 68ny-2904277Attorney Docket No.: 193852001340homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide / ethylene oxide copolymers, poly oxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The polymer may be of any molecular weight, and may be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and / or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in diagnosis under defined conditions, etc.

[0209] In some embodiments, the antibody moiety may be further modified to comprise one or more biologically active protein, polypeptides or fragments thereof. “Bioactive” or “biologically active”, as used herein interchangeably, means showing biological activity in the body to carry out a specific function. For example, it may mean the combination with a particular biomolecule such as protein, DNA, etc.., and then promotion or inhibition of the activity of such biomolecule. In some embodiments, the bioactive protein or fragments thereof include proteins and polypeptides that are administered to patients as the active drug substance for prevention of or treatment of a disease or condition, as well as proteins and polypeptides that are used for diagnostic purposes, such as enzymes used in diagnostic tests or in vitro assays, as well as proteins and polypeptides that are administered to a patient to prevent a disease such as a vaccine.III. Methods of preparation

[0210] In some embodiments, there is provided a method of preparing an anti-Ap construct or antibody moiety that specifically binds to Ap (such as Ap40 and / or Ap42) and a composition such as polynucleotide, nucleic acid construct, vector, host cell, or culture medium that is produced during the preparation of the anti-Ap construct or antibody moiety. The anti-Ap construct or antibody moiety or composition described herein may be prepared by a number of processes as generally described below and more specifically in the Examples.Antibody Expression and Production

[0211] The antibodies described herein can be prepared using any known methods in the art, including those described below and in the Examples.69ny-2904277Attorney Docket No.: 193852001340Monoclonal antibodies

[0212] Monoclonal antibodies are obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and / or post-translational modifications (e.g., isomerizations, amidations) that may be present in minor amounts. Thus, the modifier “monoclonal” indicates the character of the antibody as not being a mixture of discrete antibodies. For example, the monoclonal antibodies may be made using the hybridoma method first described by Kohler etal., Nature, 256:495 (1975), or may be made by recombinant DNA methods (U. S. Pat. No. 4,816,567). In the hybridoma method, a mouse or other appropriate host animal, such as a hamster or a llama, is immunized as hereinabove described to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind the protein used for immunization. Alternatively, lymphocytes may be immunized in vitro. Lymphocytes then are fused with myeloma cells using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986). Also See Example 1 for immunization in Camels.

[0213] The immunizing agent will typically include the antigenic protein or a fusion variant thereof. Generally, either peripheral blood lymphocytes (“PBLs”) are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell. Goding, Monoclonal Antibodies: Principles and Practice, Academic Press (1986), pp. 59-103.

[0214] Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells thus prepared are seeded and grown in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, parental myeloma cells. For example, if the parental myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (HAT medium), which are substances that prevent the growth of HGPRT-deficient cells.

[0215] Preferred immortalized myeloma cells are those that fuse efficiently, support stable high-level production of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. Among these, preferred are murine myeloma lines, such as those derived from MOPC-21 and MPC-11 mouse tumors available from the Salk Institute Cell Distribution Center, San Diego, Calif. USA, and SP-2 cells (and derivatives thereof, e.g., X63- 70ny-2904277Attorney Docket No.: 193852001340Ag8-653) available from the American Type Culture Collection, Manassas, Va. USA. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987)).

[0216] Culture medium in which hybridoma cells are growing is assayed for production of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA).

[0217] The culture medium in which the hybridoma cells are cultured can be assayed for the presence of monoclonal antibodies directed against the desired antigen. Preferably, the binding affinity and specificity of the monoclonal antibody can be determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked assay (ELISA). Such techniques and assays are known in the in art. For example, binding affinity may be determined by the Scatchard analysis of Munson etal., Anal. Biochem., 107:220 (1980).

[0218] After hybridoma cells are identified that produce antibodies of the desired specificity, affinity, and / or activity, the clones may be subcloned by limiting dilution procedures and grown by standard methods (Goding, supra). Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 medium. A cell sorter may also be used. In addition, the hybridoma cells may be grown in vivo as tumors in a mammal.

[0219] The monoclonal antibodies secreted by the subclones are suitably separated from the culture medium, ascites fluid, or serum by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0220] Monoclonal antibodies may also be made by recombinant DNA methods, such as those described in U. S. Pat. No. 4,816,567, and as described above. DNA encoding the monoclonal antibodies is readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells serve as a preferred source of such DNA. Once isolated, the DNA may be placed into expression vectors, which are then transfected into host cells such as E. coli cells, simian COS cells, HEK cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, in order to synthesize monoclonal antibodies in such recombinant host cells. Review articles 71ny-2904277Attorney Docket No.: 193852001340on recombinant expression in bacteria of DNA encoding the antibody include Skerra et al., Curr Opinion in Immunol., 5:256-262 (1993) and Plückthun, Immunol. Revs. 130:151-188 (1992).

[0221] In a further embodiment, antibodies can be isolated from antibody phage libraries generated using the techniques described in McCafferty et al., Nature, 348:552-554 (1990). Clackson etal., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991) describe the isolation of murine and human antibodies, respectively, using phage libraries. Subsequent publications describe the production of high affinity (nM range) human antibodies by chain shuffling (Marks etal., Bio / Technology, 10:779-783 (1992)), as well as combinatorial infection and in vivo recombination as a strategy for constructing very large phage libraries (Waterhouse et al., Nucl. Acids Res., 21:2265-2266 (1993)). Thus, these techniques are viable alternatives to traditional monoclonal antibody hybridoma techniques for isolation of monoclonal antibodies.

[0222] The DNA also may be modified, for example, by substituting the coding sequence for human heavy- and light-chain constant domains in place of the homologous murine sequences (U. S. Pat. No. 4,816,567; Morrison, et al., Proc. Natl Acad. Sci. USA, 81:6851 (1984)), or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Typically, such non-immunoglobulin polypeptides are substituted for the constant domains of an antibody, or they are substituted for the variable domains of one antigen-combining site of an antibody to create a chimeric bivalent antibody comprising one antigen-combining site having specificity for an antigen and another antigencombining site having specificity for a different antigen.

[0223] The monoclonal antibodies described herein may by monovalent, the preparation of which is well known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and a modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain crosslinking. Alternatively, the relevant cysteine residues may be substituted with another amino acid residue or are deleted so as to prevent crosslinking. In vitro methods are also suitable for preparing monovalent antibodies. Digestion of antibodies to produce fragments thereof, particularly Fab fragments, can be accomplished using routine techniques known in the art.

[0224] Chimeric or hybrid antibodies also may be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins may be constructed using a disulfide-exchange reaction or by forming a72ny-2904277Attorney Docket No.: 193852001340thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate.Nucleic Acid Molecules Encoding antibody moieties

[0225] In some embodiments, there is provided a polynucleotide encoding any one of the anti-Ap constructs or antibody moieties described herein. In some embodiments, there is provided a polynucleotide prepared using any one of the methods as described herein. In some embodiments, a nucleic acid molecule comprises a polynucleotide that encodes a heavy chain or a light chain of an antibody moiety (e.g., anti-Ap antibody moiety). In some embodiments, a nucleic acid molecule comprises both a polynucleotide that encodes a heavy chain and a polynucleotide that encodes a light chain, of an antibody moiety (e.g., anti-Ap antibody moiety). In some embodiments, a first nucleic acid molecule comprises a first polynucleotide that encodes a heavy chain and a second nucleic acid molecule comprises a second polynucleotide that encodes a light chain.

[0226] In some such embodiments, the heavy chain and the light chain are expressed from one nucleic acid molecule, or from two separate nucleic acid molecules, as two separate polypeptides. In some embodiments, such as when an antibody is an scFv, a single polynucleotide encodes a single polypeptide comprising both a heavy chain and a light chain linked together.

[0227] In some embodiments, a polynucleotide encoding a heavy chain or light chain of an antibody moiety (e.g., anti-Ap antibody moiety) comprises a nucleotide sequence that encodes a leader sequence, which, when translated, is located at the N terminus of the heavy chain or light chain. As discussed above, the leader sequence may be the native heavy or light chain leader sequence, or may be another heterologous leader sequence.

[0228] In some embodiments, the polynucleotide is a DNA. In some embodiments, the polynucleotide is an RNA. In some embodiments, the RNA is an mRNA.

[0229] Nucleic acid molecules may be constructed using recombinant DNA techniques conventional in the art. In some embodiments, a nucleic acid molecule is an expression vector that is suitable for expression in a selected host cell.Nucleic acid construct

[0230] In some embodiments, there is provided a nucleic acid construct comprising any one of the polynucleotides described herein. In some embodiments, there is provided a nucleic acid construct prepared using any method described herein.73ny-2904277Attorney Docket No.: 193852001340

[0231] In some embodiments, the nucleic acid construct further comprises a promoter operably linked to the polynucleotide. In some embodiments, the polynucleotide corresponds to a gene, wherein the promoter is a wild-type promoter for the gene.Vectors

[0232] In some embodiments, there is provided a vector comprising any polynucleotides that encode the heavy chains and / or light chains of any one of the antibody moieties described herein (e.g., anti-Ap antibody moieties) or nucleic acid construct described herein. In some embodiments, there is provided a vector prepared using any method described herein. Vectors comprising polynucleotides that encode any of anti-Ap constructs such as antibodies, scFvs, fusion proteins or other forms of constructs described herein (e.g., anti-Ap scFv) are also provided. Such vectors include, but are not limited to, DNA vectors, phage vectors, viral vectors, retroviral vectors, etc. In some embodiments, a vector comprises a first polynucleotide sequence encoding a heavy chain and a second polynucleotide sequence encoding a light chain. In some embodiments, the heavy chain and light chain are expressed from the vector as two separate polypeptides. In some embodiments, the heavy chain and light chain are expressed as part of a single polypeptide, such as, for example, when the antibody is an scFv.

[0233] In some embodiments, a first vector comprises a polynucleotide that encodes a heavy chain and a second vector comprises a polynucleotide that encodes a light chain. In some embodiments, the first vector and second vector are transfected into host cells in similar amounts (such as similar molar amounts or similar mass amounts). In some embodiments, a mole- or mass-ratio of between 5:1 and 1:5 of the first vector and the second vector is transfected into host cells. In some embodiments, a mass ratio of between 1:1 and 1:5 for the vector encoding the heavy chain and the vector encoding the light chain is used. In some embodiments, a mass ratio of 1:2 for the vector encoding the heavy chain and the vector encoding the light chain is used.

[0234] In some embodiments, a vector is selected that is optimized for expression of polypeptides in CHO or CHO-derived cells, or in NSO cells. Exemplary such vectors are described, e.g., in Running Deer et al., BiotechnoL Prog. 20:880-889 (2004).Host Cells

[0235] In some embodiments, there is provided a host cell comprising any polypeptide, nucleic acid construct and / or vector described herein. In some embodiments, there is provided a host cell prepared using any method described herein. In some embodiments, the host cell is capable of producing any of antibody moieties described herein under a fermentation condition.74ny-2904277Attorney Docket No.: 193852001340

[0236] In some embodiments, the antibody moieties described herein (e.g., anti-Aβ antibody moieties) may be expressed in prokaryotic cells, such as bacterial cells; or in eukaryotic cells, such as fungal cells (such as yeast), plant cells, insect cells, and mammalian cells. Such expression may be carried out, for example, according to procedures known in the art. Exemplary eukaryotic cells that may be used to express polypeptides include, but are not limited to, COS cells, including COS 7 cells; 293 cells, including 293 -6E cells; CHO cells, including CHO-S, CHO-GS, DG44. Lecl3 CHO cells, and FUT8 CHO cells; PER. C6® cells (Crucell); HEK cells, and NSO cells. In some embodiments, the antibody moieties described herein (e.g., anti-Ap antibody moieties) may be expressed in yeast. See, e.g., U. S. Publication No. US 2006 / 0270045 Al. In some embodiments, a particular eukaryotic host cell is selected based on its ability to make desired post-translational modifications to the heavy chains and / or light chains of the antibody moiety. For example, in some embodiments, CHO cells produce polypeptides that have a higher level of sialylation than the same polypeptide produced in 293 cells.

[0237] Introduction of one or more nucleic acids into a desired host cell may be accomplished by any method, including but not limited to, calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, etc. Non-limiting exemplary methods are described, e.g., in Sambrook et al., Molecular Cloning, A Laboratory Manual, 3rded. Cold Spring Harbor Laboratory Press (2001). Nucleic acids may be transiently or stably transfected in the desired host cells, according to any suitable method.

[0238] The present application also provides host cells comprising any of the polynucleotides or vectors described herein. In some embodiments, the invention provides a host cell comprising an anti-Ap antibody. Any host cells capable of over-expressing heterologous DNAs can be used for the purpose of isolating the genes encoding the antibody, polypeptide or protein of interest. Non-limiting examples of mammalian host cells include but not limited to COS, HeLa, and CHO cells. See also PCT Publication No. WO 87 / 04462. Suitable non-mammalian host cells include prokaryotes (such as E. coli or B. subtilis) and yeast (such as S. cerevisae, S. pombc, or K. lactis).

[0239] In some embodiments, the antibody moiety is produced in a cell-free system. Nonlimiting exemplary cell-free systems are described, e.g., in Sitaraman et al., Methods Mol. Biol.498: 229-44 (2009); Spirin, Trends Biotechnol. 22: 538-45 (2004); Endo et al., Biotechnol. Adv.21: 695-713 (2003).75ny-2904277Attorney Docket No.: 193852001340Culture medium

[0240] In some embodiments, there is provided a culture medium comprising any antibody moiety, polynucleotide, nucleic acid construct, vector, and / or host cell described herein. In some embodiments, there is provided a culture medium prepared using any method described herein.

[0241] In some embodiments, the medium comprises hypoxanthine, aminopterin, and / or thymidine (e.g., HAT medium). In some embodiments, the medium does not comprise serum. In some embodiments, the medium comprises serum. In some embodiments, the medium is a D-MEM or RPMI-1640 medium.

[0242] In some embodiments the culture medium is chemically defined. In some embodiments the culture medium is specifically derived for a specific cell line (e.g., CHO GS cells).Purification of antibody moieties

[0243] The anti-Ap constructs may be purified by any suitable method. Such methods include, but are not limited to, the use of affinity matrices or hydrophobic interaction chromatography. Suitable affinity ligands include the ROR1 ECD and ligands that bind antibody constant regions. For example, a Protein A, Protein G, Protein A / G, or an antibody affinity column may be used to bind the constant region and to purify an anti-Ap construct comprising an Fc fragment. Hydrophobic interactive chromatography, for example, a butyl or phenyl column, may also be suitable for purifying some polypeptides such as antibodies. Ion exchange chromatography (e.g. anion exchange chromatography and / or cation exchange chromatography) may also be suitable for purifying some polypeptides such as antibodies. Mixed-mode chromatography (e.g. reversed phase / anion exchange, reversed phase / cation exchange, hydrophilic interaction / anion exchange, hydrophilic interaction / cation exchange, etcl) may also be suitable for purifying some polypeptides such as antibodies. Many methods of purifying polypeptides are known in the art.IV. Methods of Treatments

[0244] Also provided here are methods of treating a disease or condition in an individual. The methods comprise administering the anti-Ap construct described herein into individuals (e.g., mammals such as humans). Also provided here is a use of the anti-Ap constructs as disclosed herein for the manufacture of a medicament for treating a disease or condition in an individual. The use comprises administering the medicament comprising the anti-Ap construct described herein into individuals (e.g., mammals such as humans).76ny-2904277Attorney Docket No.: 193852001340

[0245] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of an anti-Ap construct described herein. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the disease or condition is associated with amyloid plaque formation in the brain. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0246] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises the amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 11, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0247] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 11, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0248] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of 77ny-2904277Attorney Docket No.: 193852001340SEQ ID NO: 11, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0249] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 12, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0250] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 12, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0251] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 12, or a variant comprising an amino acid sequence having at least about 80%78ny-2904277Attorney Docket No.: 193852001340(such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0252] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 1, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 13, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0253] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 2, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 13, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0254] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 3, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 13, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence 79ny-2904277Attorney Docket No.: 193852001340identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0255] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 4, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0256] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 5, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0257] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 6, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 14, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or 80ny-2904277Attorney Docket No.: 193852001340neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0258] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 4, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0259] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 5, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0260] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 6, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 15, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or81ny-2904277Attorney Docket No.: 193852001340neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0261] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 4, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 16, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0262] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 5, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 16, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0263] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 6, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 16, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or82ny-2904277Attorney Docket No.: 193852001340neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0264] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 17, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0265] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 8, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0266] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 9, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 19, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or83ny-2904277Attorney Docket No.: 193852001340neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0267] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 10, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 20, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0268] In some embodiments, there is provided a method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct comprising an antibody moiety comprising a VH and a VL, wherein the VH comprises the amino acid sequence of SEQ ID NO: 7, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 18, or a variant comprising an amino acid sequence having at least about 80% (such as at least about any one of 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%) sequence identity. In some embodiments, the disease or condition is a neurological disorder or neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer’s disease.

[0269] In some embodiments, the anti-Ap construct used in treating a disease or condition (e.g., Alzheimer’s disease) mediates clearance of Ap (e.g., Ap40 and / or Ap42) by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to a corresponding construct that does not bind Ap (e.g., an isotype control).

[0270] In some embodiments, the anti-Ap construct used in treating a disease or condition (e.g., Alzheimer’s disease) reduces Ap plaque size (e.g., Ap40 and / or Ap42) by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to a corresponding construct that does not bind Ap (e.g., an isotype control).

[0271] In some embodiments, the individual or subject is a mammal (such as a human).84ny-2904277Attorney Docket No.: 193852001340

[0272] In some embodiments, the individual has a lower AP42 / AP40 ratio ( / .<., the concentration of Ap42 divided by the concentration of Ap40) as compared to an individual who does not have the disease or condition (e.g., an AP42 / AP40 ratio at least about 5%, 10%, 20%, 40%, 60%, 80%, 100%, 150%, 200%, 300%, 400%, or 500% lower than the AP42 / AP40 ratio of a healthy individual). In some embodiments, the concentration of Ap42 and / or Ap40 is measured in the cerebrospinal fluid or blood plasma. In some embodiments, the individual has an elevated level of Ap (such as Ap40 and / or Ap42) (e.g., at least about 20%, 40%, 60%, 80%, 100%, 150%, 200%, 300%, 400%, or 500% higher level Ap than that of a healthy individual). In some embodiments, the individual has an elevated expression level or protein level of Ap (such as AP40 and / or Ap42) (e.g., at least about 20%, 40%, 60%, 80%, 100%, 150%, 200%, 300%, 400%, or 500% higher level Ap than that of a healthy individual). In some embodiments, the individual has increased deposition of Ap or Ap plaques as compared to an individual who does not have the disease or condition (e.g, increased by at least about 20%, 40%, 60%, 80%, 100%, 150%, 200%, 300%, 400%, or 500% than that of a healthy individual). In some embodiments, the individual has increased presence of Ap and / or aggregated Ap as compared to an individual who does not have the disease or condition (e.g, increased by at least about 20%, 40%, 60%, 80%, 100%, 150%, 200%, 300%, 400%, or 500% than that of a healthy individual).Dosing and Method of Administering the anti-Af Construct

[0273] The dosing regimen of the anti-Ap construct (such as the specific dosages and frequencies) used for treating a disease or disorder as described herein administered into the individual may vary with the particular anti-Ap construct (such as anti-Ap monoclonal antibodies or anti-Ap fusion proteins), the mode of administration, and the type of disease or condition being treated. In some embodiments, the type of disease or condition is Alzheimer’s disease. In some embodiments, the effective amount of the anti-Ap construct is an amount that is effective to result in an objective response (such as a partial response or a complete response). In some embodiments, the effective amount of the anti-Ap construct is an amount that is sufficient to result in a complete response in the individual. In some embodiments, the effective amount of the anti-Ap construct is an amount that is sufficient to result in a partial response in the individual. In some embodiments, the effective amount of anti-Ap construct is an amount that is sufficient to produce an overall response rate of more than about any of 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 64%, 65%, 70%, 75%, 80%, 85%, or 90% among a population of individuals treated with the anti-Ap construct. Responses of an individual to the85ny-2904277Attorney Docket No.: 193852001340treatment of the methods described herein can be determined, for example, based on levels of Ap or presence and / or size of Ap plaques.

[0274] In some embodiments, the effective amount of the anti-Ap construct is an amount that is sufficient to prolong progress-free survival of the individual. In some embodiments, the effective amount of the anti-Ap construct is an amount that is sufficient to prolong overall survival of the individual. In some embodiments, the effective amount of the anti-Ap construct is an amount that is sufficient to produce clinical benefit of more than about any of 50%, 60%, 70%, 80%, or 90% among a population of individuals treated with the anti-Ap construct.

[0275] In some embodiments, the effective amount of the anti-Ap construct alone or in combination with a second, third, and / or fourth agent, is an amount sufficient to decrease the size of an Ap plaque, decrease the number of Ap plaques, or decrease the growth rate of Ap plaques by at least about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared to the corresponding Ap plaque size, number of Ap plaques, or Ap plaque growth rate in the same subject prior to treatment or compared to the corresponding activity in other subjects not receiving the treatment (e.g., receiving a placebo treatment). In some embodiments, the Ap plaques are in the brain of the individual. Standard methods can be used to identify and measure Ap plaques, such as with imaging techniques, tissue biopsy, or blood work.

[0276] In some embodiments, the effective amount of the anti-Ap construct is an amount that is below the level that induces a toxicological effect ( / .<., an effect above a clinically acceptable level of toxicity) or is at a level where a potential side effect can be controlled or tolerated when the composition is administered to the individual.

[0277] In some embodiments, the effective amount of the anti-Ap construct is an amount that is close to a maximum tolerated dose (MTD) of the composition following the same dosing regimen. In some embodiments, the effective amount of the anti-Ap construct is more than about any of 80%, 90%, 95%, or 98% of the MTD.

[0278] In some embodiments, the effective amount of the anti-Ap construct is an amount that slows or inhibits the progression of the disease or condition (for example, by at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%) as compared to that of the individual not receiving the treatment. In some embodiments, the disease or condition is Alzheimer’s.

[0279] In some embodiments, the effective amount of the anti-Ap construct is an amount that reduces the side effects (auto-immune response) of a condition (e.g., transplantation) (for example, by at least about 5%, 10%, 15%, 20%, 30%, 40%, or 50%) as compared to that of the individual not receiving the treatment.86ny-2904277Attorney Docket No.: 193852001340

[0280] The anti-Ap construct can be administered to an individual (such as human) via various routes. In some embodiments, the anti-Ap construct is included in a pharmaceutical composition while administered into the individual. In some embodiments, the composition is administered intravenously. In some embodiments, the composition is administered intraperitoneally. In some embodiments, the composition is administered subcutaneously. In some embodiments, the composition is administered orally.Combination therapy

[0281] This application also provides for the use of an anti-Ap construct for the manufacture of a medicament to be administered to an individual for treating a disease or condition, wherein the method further comprises administering a second agent or therapy. In some embodiments, the second agent or therapy is a standard or commonly used agent or therapy for treating the disease or condition. In some embodiments, the disease or condition is Alzheimer’s disease.

[0282] In some embodiments, the medicament comprising the anti-Ap construct is administered simultaneously with the second agent or therapy. In some embodiments, the medicament comprising the anti-Ap construct is administered concurrently with the second agent or therapy. In some embodiments, the medicament comprising the anti-Ap construct is administered sequentially with the second agent or therapy. In some embodiments, the medicament comprising the anti-Ap construct is administered prior to the second agent or therapy. In some embodiments, the medicament comprising the anti-Ap construct is administered after the second agent or therapy. In some embodiments, the medicament comprising the anti-Ap construct is administered in the same unit dosage form as the second agent or therapy. In some embodiment, the medicament comprising the anti-Ap construct is administered in a different unit dosage form from the second agent or therapy. In some embodiments, the medicament comprising the anti-Ap construct is administered in the same unit dosage form as the second agent or therapy. In some embodiment, the medicament comprising the anti-Ap construct is administered in a different unit dosage form from the second agent or therapy. In some embodiments, the second agent or therapy is a small molecule (e.g., a small molecule inhibitor).V. Compositions, Kits and Articles of manufacture

[0283] Also provided herein are compositions (such as formulations) comprising any one of the anti-Ap constructs or anti-Ap antibody moieties described herein, nucleic acid encoding the antibody moieties, vector comprising the nucleic acid encoding the antibody moieties, or host cells comprising the nucleic acid or vector.87ny-2904277Attorney Docket No.: 193852001340

[0284] Suitable formulations of the anti-Ap construct described herein can be obtained by mixing the anti-Ap construct or anti-Ap antibody moiety having the desired degree of purity with optional pharmaceutically acceptable carriers, excipients or stabilizers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Lyophilized formulations adapted for subcutaneous administration are described in WO97 / 04801. Such lyophilized formulations may be reconstituted with a suitable diluent to a high protein concentration and the reconstituted formulation may be administered subcutaneously to the individual to be imaged, diagnosed, or treated herein.

[0285] The formulations to be used for in vivo administration must be sterile. This is readily accomplished by, e.g, filtration through sterile filtration membranes.

[0286] Also provided are kits comprising any one of the anti-Ap construct or anti-Ap antibody moiety described herein. The kits may be useful for any of the methods of modulating cell composition or treatment described herein.

[0287] In some embodiments, there is provided a kit comprising an anti-Ap construct specifically binding to Ap (e.g., Ap40 and / or Ap42).

[0288] In some embodiments, the kit further comprises a device capable of delivering the anti-Ap construct into an individual. One type of device, for applications such as parenteral delivery, is a syringe that is used to inject the composition into the body of a subject. Inhalation devices may also be used for certain applications.88ny-2904277Attorney Docket No.: 193852001340

[0289] In some embodiments, the kit further comprises a therapeutic agent for treating a disease or condition, e.g., infectious disease, autoimmune disease, or transplantation.

[0290] The kits of the present application are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Kits may optionally provide additional components such as buffers and interpretative information.

[0291] The present application thus also provides articles of manufacture. The article of manufacture can comprise a container and a label or package insert on or associated with the container. Suitable containers include vials (such as sealed vials), bottles, jars, flexible packaging, and the like. Generally, the container holds a composition, and may have a sterile access port (for example the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The label or package insert indicates that the composition is used for imaging, diagnosing, or treating a particular condition in an individual. The label or package insert will further comprise instructions for administering the composition to the individual and for imaging the individual. The label may indicate directions for reconstitution and / or use. The container holding the composition may be a multi-use vial, which allows for repeat administrations (e.g. from 2-6 administrations) of the reconstituted formulation. Package insert refers to instructions customarily included in commercial packages of diagnostic products that contain information about the indications, usage, dosage, administration, contraindications and / or warnings concerning the use of such diagnostic products. Additionally, the article of manufacture may further comprise a second container comprising a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0292] The kits or article of manufacture may include multiple unit doses of the compositions and instructions for use, packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.

[0293] Those skilled in the art will recognize that several embodiments are possible within the scope and spirit of this invention. The invention will now be described in greater detail by reference to the following non-limiting examples. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.89ny-2904277Attorney Docket No.: 193852001340EXAMPLES

[0294] The examples below are intended to be purely exemplary of the application and should therefore not be considered to limit the application in any way. The following examples and detailed description are offered by way of illustration and not by way of limitation.Example 1. Summary of DC3301 anti-Ap antibodies

[0295] Thirty anti-Ap antibodies were generated and then tested in the following Examples. Sequences of the exemplary antibodies were shown in Tables E1-E3.

[0296] Experimental methods included enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR) for on-target binding (Ap40, Ap42, PyroE3), as well as SPR assessment for off-target binding in human plasma and serum samples, using lecanemab and donanemab biosimilar as a benchmark control in all experiments. Additional tests included antibody-dependent phagocytosis of amyloid aggregates, plasma stability assays, and a comprehensive pharmacokinetics and pharmacodynamics (PK / PD) profile using a single 15 mg / kg dose in non-human primates.

[0297] Among the thirty antibodies tested, we identified three clones with affinity to monomeric and oligomeric Ap comparable to lecanemab and donanemab. Of these, two clones demonstrated over 60% reduction in plasma protein binding in head-to-head comparisons with lecanemab and donanemab. Non-human primate data are currently under analysis.

[0298] A summary of DC3301 antibody clones are listed in Table El.Table El: DC3301 anti-Ap antibody VH / VL sequence summaryAntibody VH / CDR / Heavy Chain (HC) (SEQ ID VL / CDR / Light Chain (LC) (SEQ ID clone NO) NO)DC3301-1 > DC3301_hl-VHl (SEQ ID NO: 1) > DC3301_hl-VLl (SEQ ID NO: 11)CDR SEQ ID NOs: 21, 23, 26 CDR SEQ ID NOs: 30, 34, 37 Heavy chain (HC) SEQ ID NO: 41 Light chain (LC) SEQ ID NO: 51 DC3301-2 > DC3301_hl-VH2 (SEQ ID NO: 2) > DC3301_hl-VLl (SEQ ID NO: 11)CDR SEQ ID NOs: 21, 23, 26 CDR SEQ ID NOs: 30, 34, 37 HC SEQ ID NO: 42 LC SEQ ID NO: 51 DC3301-3 > DC3301_hl-VH3 (SEQ ID NO: 3) > DC3301_hl-VLl (SEQ ID NO: 11)CDR SEQ ID NOs: 21, 23, 26 CDR SEQ ID NOs: 30, 34, 37 HC SEQ ID NO: 43 LC SEQ ID NO: 51 DC3301-4 > DC3301_hl-VHl (SEQ ID NO: 1) > DC3301_hl-VL2 (SEQ ID NO: 12)90ny-2904277Attorney Docket No.: 193852001340Antibody VH / CDR / Heavy Chain (HC) (SEQ ID VL / CDR / Light Chain (LC) (SEQ ID clone NO) NO)CDR SEQ ID NOs: 21, 23, 26 CDR SEQ ID NOs: 30, 34, 37 HC SEQ ID NO: 41 LC SEQ ID NO: 52 DC3301-5 > DC3301_hl-VH2 (SEQ ID NO: 2) > DC3301_hl-VL2 (SEQ ID NO: 12)CDR SEQ ID NOs: 21, 23, 26 CDR SEQ ID NOs: 30, 34, 37 HC SEQ ID NO: 42 LC SEQ ID NO: 52 DC3301-6 > DC3301_hl-VH3 (SEQ ID NO: 3) > DC3301_hl-VL2 (SEQ ID NO: 12)CDR SEQ ID NOs: 21, 23, 26 CDR SEQ ID NOs: 30, 34, 37 HC SEQ ID NO: 43 LC SEQ ID NO: 52 DC3301-7 > DC3301_hl-VHl (SEQ ID NO: 1) > DC3301_hl-VL3 (SEQ ID NO: 13)CDR SEQ ID NOs: 21, 23, 26 CDR SEQ ID NOs: 30, 34, 37 HC SEQ ID NO: 41 LC SEQ ID NO: 53 DC3301-8 > DC3301_hl-VH2 (SEQ ID NO: 2) > DC3301_hl-VL3 (SEQ ID NO: 13)CDR SEQ ID NOs: 21, 23, 26 CDR SEQ ID NOs: 30, 34, 37 HC SEQ ID NO: 42 LC SEQ ID NO: 53 DC3301-9 > DC3301_hl-VH3 (SEQ ID NO: 3) > DC3301_hl-VL3 (SEQ ID NO: 13)CDR SEQ ID NOs: 21, 23, 26 CDR SEQ ID NOs: 30, 34, 37 HC SEQ ID NO: 43 LC SEQ ID NO: 53 DC3301-10 > DC3301_h4-VHl (SEQ ID NO: 4) > DC3301_h4-VLl (SEQ ID NO: 14)CDR SEQ ID NOs: 22, 24, 27 CDR SEQ ID NOs: 31, 35, 38 HC SEQ ID NO: 44 LC SEQ ID NO: 54 DC3301-11 > DC3301_h4-VH2 (SEQ ID NO: 5) > DC3301_h4-VLl (SEQ ID NO: 14)CDR SEQ ID NOs: 22, 24, 27 CDR SEQ ID NOs: 31, 35, 38 HC SEQ ID NO: 45 LC SEQ ID NO: 54 DC3301-12 > DC3301_h4-VH3 (SEQ ID NO: 6) > DC3301_h4-VLl (SEQ ID NO: 14)CDR SEQ ID NOs: 22, 24, 27 CDR SEQ ID NOs: 31, 35, 38 HC SEQ ID NO: 46 LC SEQ ID NO: 54 DC3301-20 > DC3301_h4-VHl (SEQ ID NO: 4) > DC3301_h4-VL2 (SEQ ID NO: 15)CDR SEQ ID NOs: 22, 24, 27 CDR SEQ ID NOs: 31, 35, 38 HC SEQ ID NO: 44 LC SEQ ID NO: 55 DC3301-21 > DC3301_h4-VH2 (SEQ ID NO: 5) > DC3301_h4-VL2 (SEQ ID NO: 15)CDR SEQ ID NOs: 22, 24, 27\ CDR SEQ ID NOs: 31, 35, 38 HC SEQ ID NO: 45 LC SEQ ID NO: 55 DC3301-22 > DC3301_h4-VH3 (SEQ ID NO: 6) > DC3301_h4-VL2 (SEQ ID NO: 15)CDR SEQ ID NOs: 22, 24, 27 CDR SEQ ID NOs: 31, 35, 38 HC SEQ ID NO: 46 LC SEQ ID NO: 5591ny-2904277Attorney Docket No.: 193852001340Antibody VH / CDR / Heavy Chain (HC) (SEQ ID VL / CDR / Light Chain (LC) (SEQ ID clone NO) NO)DC3301-23 > DC3301_h4-VHl (SEQ ID NO: 4) > DC3301_h4-VL3 (SEQ ID NO: 16)CDR SEQ ID NOs: 22, 24, 27 CDR SEQ ID NOs: 31, 35, 38 HC SEQ ID NO: 44 LC SEQ ID NO: 56 DC3301-24 > DC3301_h4-VH2 (SEQ ID NO: 5) > DC3301_h4-VL3 (SEQ ID NO: 16)CDR SEQ ID NOs: 22, 24, 27 CDR SEQ ID NOs: 31, 35, 38 HC SEQ ID NO: 45 LC SEQ ID NO: 56 DC3301-25 > DC3301_h4-VH3 (SEQ ID NO: 6) > DC3301_h4-VL3 (SEQ ID NO: 16)CDR SEQ ID NOs: 22, 24, 27 CDR SEQ ID NOs: 31, 35, 38 HC SEQ ID NO: 46 LC SEQ ID NO: 56 DC3301-26 > DC3301_h8_VHl (SEQ ID NO: 7) > DC3301_h8_VLl (SEQ ID NO: 17)CDR SEQ ID NOs: 21, 23, 26 CDR SEQ ID NOs: 30, 34, 37 HC SEQ ID NO: 47 LC SEQ ID NO: 57 DC3301-27 > DC3301_h8_VH2 (SEQ ID NO: 8) > DC3301_h8_VL2 (SEQ ID NO: 18)CDR SEQ ID NOs: 22, 24, 27 CDR SEQ ID NOs: 31, 35, 38 HC SEQ ID NO: 48 LC SEQ ID NO: 58 DC3301-28 > DC3301_h8_VH3 (SEQ ID NO: 9) > DC3301_h8_VL3 (SEQ ID NO: 19)CDR SEQ ID NOs: 21, 25, 28 CDR SEQ ID NOs: 32, 34, 39 HC SEQ ID NO: 49 LC SEQ ID NO: 59 DC3301-29 > DC3301_h8_VH4 (SEQ ID NO: 10) > DC3301_h8_VL4 (SEQ ID NO: 20)CDR SEQ ID NOs: 22, 24, 29 CDR SEQ ID NOs: 33, 36, 40 HC SEQ ID NO: 50 LC SEQ ID NO: 60 DC3301-30 > DC3301_h8_VHl (SEQ ID NO: 7) > DC3301_h8_VL2 (SEQ ID NO: 18)CDR SEQ ID NOs: 21, 23, 26 CDR SEQ ID NOs: 31, 35, 38 HC SEQ ID NO: 47 LC SEQ ID NO: 58Table E2: DC3301 anti-Ap antibody HCDR sequence summaryVH (SEQ ID NO) CDR-H1 CDR-H2 CDR-H3(SEQ ID NO) (SEQ ID NO) (SEQ ID NO) Al > DC3301_hl-VHl TSGMGVG HIWWDDDKYYNPSLKS RGLRPTDAMDY (SEQ ID NO: 1) (SEQ ID NO: (SEQ ID NO: 23) (SEQ ID NO: 26) > DC3301_hl-VH2 21)(SEQ ID NO: 2)> DC3301_hl-VH3(SEQ ID NO: 3)A2 > DC3301_h4-VHl TSGMGVS HIYWDDDKRYNPSLKS RIIYYGRVDAMDY (SEQ ID NO: 4) (SEQ ID NO: (SEQ ID NO: 24) (SEQ ID NO: 27) > DC3301_h4-VH2 22)(SEQ ID NO: 5)92ny-2904277Attorney Docket No.: 193852001340VH (SEQ ID NO) CDR-H1 CDR-H2 CDR-H3(SEQ ID NO) (SEQ ID NO) (SEQ ID NO) > DC3301_h4-VH3(SEQ ID NO: 6)A3 > DC3301_h8_VHl TSGMGVG HIWWDDDKYYNPSLKS RGLRPTDAMDY (SEQ ID NO: 7) (SEQ ID NO: (SEQ ID NO: 23) (SEQ ID NO: 26)21)A4 > DC3301_h8_VH2 TSGMGVS HIYWDDDKRYNPSLKS RIIYYGRVDAMDY (SEQ ID NO: 8) (SEQ ID NO: (SEQ ID NO: 24) (SEQ ID NO: 27)22)A5 > DC3301_h8_VH3 TSGMGVG HIWWDGDESYNPSLKS NRYDPPWFVD (SEQ ID NO: 9) (SEQ ID NO: (SEQ ID NO: 25) (SEQ ID NO: 28)21)A6 > DC3301_h8_VH4 TSGMGVS HIYWDDDKRYNPSLKS LYGFTYGFAY (SEQ ID NO: 10) (SEQ ID NO: (SEQ ID NO: 24) (SEQ ID NO: 29)22)Consensus TSGMGVX HIX1WDX2DX3X4YNPSLKSsequence X=G or S Xi = WorY, X2= D or G, X3= E or K, X4= R, S orY,Table E3: DC3301 anti-Ap antibody LCDR sequence summaryVL (SEQ ID NO) CDR-L1 CDR-L2 CDR-L3(SEQ ID NO) (SEQ ID NO) (SEQ ID NO) Bl > DC3301_hl-VLl RSSQSIVHSNGNTYLE KVSNRFS FQGSRVPPT (SEQ ID NO: 11) (SEQ ID NO: 30) (SEQ ID NO: 34) (SEQ ID NO: 37) > DC3301_hl-VL2(SEQ ID NO: 12)> DC3301_hl-VL3(SEQ ID NO: 13)B2 > DC3301_h4-VLl KASENVVTYVS GASNRYT GQGYSYPYT (SEQ ID NO: 14) (SEQ ID NO: 31) (SEQ ID NO: 35) (SEQ ID NO: 38) > DC3301_h4-VL2(SEQ ID NO: 15)> DC3301_h4-VL3(SEQ ID NO: 16)B3 > DC3301_h8_VLl RSSQSIVHSNGNTYLE KVSNRFS FQGSRVPPT (SEQ ID NO: 17) (SEQ ID NO: 30) (SEQ ID NO: 34) (SEQ ID NO: 37) B4 > DC3301_h8_VL2 KASENVVTYVS GASNRYT GQGYSYPYT (SEQ ID NO: 18) (SEQ ID NO: 31) (SEQ ID NO: 35) (SEQ ID NO: 38) B5 > DC3301_h8_VL3 RSSQIIVHNNGNTYLE KVSNRFS FQGSHVPFT (SEQ ID NO: 19) (SEQ ID NO: 32) (SEQ ID NO: 34) (SEQ ID NO: 39) B6 > DC3301_h8_VL4 RSSQSVVYSDGDTYLE KVSRRFS FQGSHVPYT (SEQ ID NO: 20) (SEQ ID NO: 33) (SEQ ID NO: 36) (SEQ ID NO: 40) Consensus sequence X1X2SX3RX4X5 X1QGX2X3X4P X5T Xi = G or K, X2= XI = F or G, X2= S A orV, X3= N or orY, X3= H, Ror R, X4=F orY, X5S, X4= V orY, X5= S orT = P, F orY93ny-2904277Attorney Docket No.: 193852001340Example 2. ELISA binding assay and SPR affinity evaluation of DC3301 antibody binding to A 4O and A 42

[0299] The candidate therapeutic antibodies were evaluated by an ELISA assay to assess binding against recombinant human Ap42 and Ap40. All the selected DC3301 series antibodies shown in Table El have demonstrated comparatively strong affinity to Ap aggregates (Ap42 and Ap40) as compared to benchmark antibody lecanemab. Some of the results are shown in FIG. 1 and Table E4.Table E4: EC50 values of DC3301 antibodies against Ap aggregatesECso forAp 1-42 ECso forAp 1-40 Category Antibody(Aggregated) nM (Aggregated) nM Benchmark Lecanemab 0.027 0.044 Benchmark Donanemab HIGH HIGH Candidate Clone DC3301-1 0.104 0.067 Candidate Clone DC3301-2 0.152 0.085 Candidate Clone DC3301-3 0.094 0.097 Candidate Clone DC3301-4 0.088 0.086 Candidate Clone DC3301-5 0.079 0.093 Candidate Clone DC3301-6 0.018 0.032 Candidate Clone DC3301-7 0.023 0.041 Candidate Clone DC3301-8 0.018 0.041 Candidate Clone DC3301-9 0.019 0.044 Candidate Clone DC3301-26 0.033 0.029

[0300] Binding of DC3301 antibodies to Ap40 and Ap42 were also analyzed by SPR. An initial screen was performed using a Protein A chip by Fc capturing antibodies and flow serially diluted analyte AP40 and AP42. Antibodies that have positive binding on Protein A chip were immobilized on a CM5 chip with high density via amine coupling. Ap40 and Ap42 was flowed over chip from 6 nM to 2 pM. In summary, DC3301 series antibodies demonstrate comparatively strong affinity to Ap aggregates.

[0301] Results are shown in FIG. 2 and Table E5.Table E5: KD values of DC3301 antibodies against A aggregatesAggregated Ap 42 binding Aggregated Ap 40 binding (M)(M)Koff KoffCategory Antibody Kon KD Kon KD KD4O / KD4294ny-2904277Attorney Docket No.: 193852001340Benchmark Lecanemab 2.11E+ 6.47E-04 3.06E-07 5.44E+ 1.60E- 2.95E-08 10.403 03 04Benchmark Donanemab No No No 1.74E+ 1.32E- 7.57E-08 n / a binding binding binding 03 04Candidate DC3301-1 4.02E+ 8.85E-04 2.20E-07 3.53E+ 9.62E- 2.72E-08 8.1 Clone 03 03 05Candidate DC3301-2 4.52E+ 3.05E-04 6.74E-08 7.27E+ 1.69E- 2.33E-08 2.9 Clone 03 03 04Candidate DC3301-3 8.29E+ 5.82E-04 7.02E-08 4.58E+ 1.02E- 2.24E-08 3.1 Clone 03 03 04Candidate DC3301-4 1.32E+ 9.83E-03 7.44E-07 3.86E+ 1.22E- 3.16E-07 2.4 Clone 04 03 03Candidate DC3301-5 1.40E+ 6.17E-03 4.42E-07 3.86E+ 1.04E- 2.69E-07 1.6 Clone 04 03 03Candidate DC3301-6 7.56E+ 4.73E-03 6.25E-07 3.62E+ 1.05E- 2.91E-07 2.1 Clone 03 03 03Candidate DC3301-7 1.58E+ 6.94E-03 4.39E-07 4.46E+ 1.28E- 2.86E-07 1.5 Clone 04 03 03Candidate DC3301-8 1.28E+ 6.61E-03 5.15E-07 2.94E+ 1.17E- 3.99E-07 1.3 Clone 04 03 03Candidate DC3301-9 1.72E+ 7.09E-03 4.12E-07 3.63E+ 1.11E- 3.04E-07 1.4 Clone 04 03 03Candidate DC3301-26 1.27E+ 5.12E-03 4.02E-07 3.88E+ 1.03E- 2.65E-07 1.5 Clone 04 03 03

[0302] In summary, SPR and ELISA results confirm nanomolar-range binding to Ap aggregates, with candidate clones DC3301-6, DC3301-7, DC3301-8, and DC3301-26 exhibiting the strongest affinities.Example 3. Binding study of DC3301 antibodies with normal human plasma

[0303] DC3301-1, DC3301-2, DC3301-3, DC3301-4, DC3301-5, DC3301-6, DC3301-7, DC3301-8, DC3301-9, DC3301-26 were selected and tested for human plasma binding.Benchmark antibodies lecanemab and donanemab, anti-Ap42 (positive control), and VRC01-hlgGl (negative control) were included for controls. Four lots of normal human plasma were tested, two male and two female.

[0304] 100 pg / mL antibodies were immobilized on a CM5 chip using amine coupling.Plasma was flowed on chip with serial dilutions 1:10, 1:40, 1:160, 1:640, and 1:2560.Association level analysis was calculated by: (amount of all species bound on antibody(RU)) / (Antibody immobilized level(RU)). Dissociation KD was calculated from the software.95ny-2904277Attorney Docket No.: 193852001340

[0305] In summary, results show DC3301 series antibodies demonstrate less non-specific binding to human plasma proteins than benchmark antibodies lecanemab and donanemab. See e g, FIGs.3A-3BExample 4. DC3301 antibody-mediated A 42 intracellular clearance

[0306] This Example uses a phagocytosis assay to characterize the DC3301 antibodies in Ap clearance. The phagocytosis assay used TUP-1 derived macrophages.

[0307] TUP-1 cells (l.lxlO5cells / well in a 96-well plate) were differentiated for 5 days in complete RPMI-1640 medium (supplemented with 10% fetal bovine serum (FBS) and Penicillin-Streptomycin (Pen / Strep)) containing 100 nM phorbol 12-myristate 13-acetate (PMA). A media change containing PMA was performed on Day 3. On Day 5, media was changed to complete RPMI-1640 without PMA. On Day 6, media was aspirated off, cells were washed once with phosphate buffered saline (PBS), then changed to 50 pL FluoroBrite™ DMEM medium containing 2% FBS and cells were incubated at 37 °C. Ap42 was purchased from Anaspec and labeled in house with Alexa Fluor® 647. 4x concentration of labeled Ap42 (170 pL) and 4x concentration of antibody (170 pL) were mixed, incubated at room temperature for 30 min, then 50 pL of mixture was added to corresponding wells. Image acquisition with IncuCyte® occurred every 10 min for 1 hour.

[0308] In summary, these results show the DC3301 series antibodies mediate comparatively strong phagocytosis of Ap aggregates. See e.g., in FIG. 4.Example 5. Pilot study of the pharmacokinetics and pharmacokinetics / pharmacodynamics (PKPD) of selected DC3301 antibodies in cynomolgus monkeys

[0309] Objective: To administer a certain dose of test substance 1 (Antibody clone DC3301-1) and test substance 2 (Antibody clone DC3301-7), commercial control 1 (DC3301 BM1 / donanemab) and commercial control 2 (DC3301 BM2 / lecanemab) to cynomolgus monkeys by intravenous infusion, detect the drug concentration and anti-drug antibody in the serum and cerebrospinal fluid of the animals at different time points before and after administration, and investigate the pharmacokinetic and immunogenic characteristics of the drugs in cynomolgus monkeys at the set doses. This will provide a reference for the design of subsequent non-clinical and clinical trials.

[0310] Methods: This study used 8 cynomolgus monkeys, half male and half female, divided into 4 groups, with 1 monkey / sex / group: Test group 1 male and female (1M01 and96ny-2904277Attorney Docket No.: 1938520013401F02, respectively), test group 2 male and female (2M01 and 2F02, respectively), test group 3 male and female (3M01 and 3F02, respectively), and test group 4 male and female (4M01 and 4F02, respectively). Test group 1 (receiving DC3301-1), test group 2 (receiving DC3301-7), commercial control group 1 (receiving donanemab) and commercial control group 2 (receiving lecanemab) each received a dose of 15 mg / kg. The day of administration was day 1 (DI), and blood biochemistry and hematology tests were performed before administration (D-l). Animals with no abnormal test indicators were included in the group. Serum samples were collected from the enrolled animals before administration, 0.25 h (immediately after administration), 2 h, 6 h, 24 h (D2), 48 h (D3), 72 h (D4), 120 h (D6), 168 h (D8), 240 h (Dll), 336 h (D15), 408 h (D18) and 504 h (D22) after administration for pharmacokinetic detection. Serum samples were collected from the animals before administration for antidrug antibody detection at 0 h (DI), 336 h (D15), 408 h (D18) and 504 h (D22).Cerebrospinal fluid samples were collected from the animals before administration (collected 1 day in advance), 240 h (Dll) and 504 h (D22) after administration for pharmacokinetic and anti-drug antibody detection. ELISA was used to detect drug concentration and anti-drug antibody in the collected serum and cerebrospinal fluid samples. Phoenix WinNonlin noncompartmental model (NCA) was used to calculate the main pharmacokinetic parameters of the drug: half-life (Tl / 2), maximum blood concentration (Cmax), time to peak (Tmax), area under the concentration-time curve (AUC0~t and AUC0~°°), volume of distribution (Vz), clearance (Cl), mean residence time (MRT0~t and MRT0~°°), etc.

[0311] Results: After a single intravenous infusion of 15 mg / kg of test substance 1 (DC3301-1), test substance 2 (DC3301-7), commercial control 1 (donanemab), and commercial control 2 (lecanemab) was given to cynomolgus monkeys, the pharmacokinetic parameters of the drug concentrations in the serum of all animals were analyzed. DC3301 series antibodies demonstrate better pharmacokinetics than benchmark antibodies. Results are shown in Table E6.Table E6: Pharmacokinetics of anti-Ap antibodiesDC3301 BM1 DC3301 BM2 DC3301-1PK (Unit) (donanemab) (lecanemab)1F01 1M01 3F01 3M01 4F01 4M01TI / 2 (h) 100.24 199.18 128.43 134.16 133.80 147.73Tmax(h) 0.25 0.25 2 2 2 0.25Cmax (jlg / mL) 393.26 454.41 187.51 293.97 327.46 339.8597ny-2904277Attorney Docket No.: 193852001340AUCo-5O4h 43491 48229 17085 19801 41306 32949 (h*pg / mU)AUCo-oo (h*pg / mU) 46445 57122 17950 21223 46621 35791AUC %Extrap (%) 6.36 15.57 4.82 6.70 11.40 7.94Vz (mL / kg) 46.70 75.46 154.84 136.80 62.11 89.32Cl (mL / h / kg) 0.323 0.263 0.836 0.707 0.322 0.419 MRTo-so4h (h) 169.59 166.24 119.41 132.99 176.90 142.54 MRTo-oo (h) 200.05 263.53 146.86 170.81 236.19 188.15T 1 / 2 = half-life; Tmax = time to peak; Cmax = maximum blood concentration; AUC0~t and AUC0~oo = area under the concentration-time curve; Vz = volume of distribution; Cl = clearance; MRT0~t and MRTO-oo = mean residence time

[0312] In the PKPD analysis, DC3301-1 shows a 34.8% longer half-life and 46.4% improved bioavailability compared to lecanemab, with a 59.6% improvement over donanemab in total drug exposure (AUC).

[0313] Results are shown in FIG. 5 and Table E7.

[0314] DCC3301-7 is also tested in the PKPD analysis.

[0315] In Vivo Testing: Initial primate pharmacokinetics studies indicate enhanced circulation time and reduced clearance for DC3301 clones.Table E7: PKPD of anti-Ap antibodiesPKPD parametersUecanemab Donanemab DC3301-1 (Unit)TI / 2 (h) 147.7337156 134.1613311 199.1771314 Tmax(h) 0.25 2 0.25(jlg / mL) 339.845 293.967 454.411 AUCfl-504h 32949.18313 19801.48013 48229.47538 (h*pg / mU)AUCo-oo (h*pg / mU) 35791.33433 21223.32698 57122.15338 AUC %Extrap (%) 7.940892011 6.699453179 15.56782698 Vz (mE / kg) 89.32386964 136.7979822 75.45720254 Cl (mU / h / kg) 0.419095859 0.706769491 0.262595142 MRTo-so4h (h) 142.5355751 132.9937976 166.2369139 MRTo-oo (h) 188.1539449 170.8078621 263.5342673Tl / 2 = half-life; Tmax = time to peak; Cmax = maximum blood concentration; AUC0~t and AUC0~oo = area under the concentration-time curve; Vz = volume of distribution; Cl = clearance; MRT0~t and MRT0~oo = mean residence time98ny-2904277Attorney Docket No.: 193852001340SEQUENCE TABLE SEQ ID Description SequenceNO:1 > DC3301_ QVTLKESGPTLVKPTQTLTLTCTFSGFSLSTSGMGVGWIRQPPG hl-VHl KALEWLAHIWWDDDKYYNPSLKSRLTITKDTSKNQWLTMTN MDP VDT AT YYCTRRGLRPTD AMD YWGQGTL VT VS S2 > DC3301_ QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTSGMGVGWIRQPPG hl-VH2 KALEWLAHIWWDDDKYYNPSLKSQLTITKDTSKNQVVLTMTN MDP VDT AT YYCTRRGLRPTD AMD YWGQGTL VT VS S3 > DC3301_ QVTLKESGPTLVKPTQTLTLTCSFSGFSLSTSGMGVGWIRQPPG hl-VH3 KALEWLAHIWWDDDKYYNPSLKSQLTISKDTSKNQVFLTMTN MDP VDT AT YYCTRRGLRPTD AMD YWGQGTL VT VS S4 > DC3301_ QVTLKESGPALVKPTQTLTLTCTFSGFSLRTSGMGVSWIRQPPG h4-VHl KALEWLAHIYWDDDKRYNPSLKSRLTITKDTSKNQVVLTMTN MDP VDT AT YYC ARRIIYYGRVD AMD YWGQGTL VT VS S5 > DC3301_ QVTLKESGPALVKPTQTLTLTCSFSGFSLRTSGMGVSWIRQPPG h4-VH2 KALEWLAHIYWDDDKRYNPSLKSRLTITKDTSKNQVFLTMTN MDP VDT AT YYC ARRIIYYGRVD AMD YWGQGTL VT VS S6 > DC3301_ QVTLKESGPALVKPTQTLTLTCSFSGFSLRTSGMGVSWIRQPPG h4-VH3 KALEWLAHIYWDDDKRYNPSLKSRLTISKDTSKNQVFLTMTN MDP VDT AT YYC ARRIIYYGRVD AMD YWGQGTL VT VS S7 > DC3301_ QVTLKESGPGILKPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSGK h8_VHl GLEWLAHIWWDDDKYYNPSLKSQLTISKDTSRNQVFLKITSVD TADTATYYCTRRGLRPTDAMDYWGQGTSVTVSS8 > DC3301_ QVTLKESGPGILQPSQTLSLTCSFSGFSLRTSGMGVSWIRQPSGK h8_VH2 GLEWLAHIYWDDDKRYNPSLKSRLTISKDTSRNQVFLKITSVDT ADT ATYYC ARRIIYYGRVD AMD YWGQGTSVT VS S9 > DC3301_ QVQLQESGPGLVKPSQTLSLTCSFSGFSLSTSGMGVGWIRQPSG h8_VH3 KGLEWLAHIWWDGDESYNPSLKSRLTISKDTSKNQVSLKITSVT AADT AVYFCARNRYDPPWF VDWGQGTL VT VS S10 > DC3301_ QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSGMGVSWIRQPSGK h8_VH4 GLEWLAHIYWDDDKRYNPSLKSRLTISKDTSRNQVFLKITSVDT ADT ATYYC ARLYGFTYGFAYWGQGTLVT VS S11 > DC3301_ DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLEWFQQR hl-VLl PGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVG VYYCFQGSRVPPTFGGGTKLEIK12 > DC3301_ DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLEWYQQR hl-VL2 PGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVG VYYCFQGSRVPPTFGGGTKLEIK13 > DC3301_ DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLEWYLQR hl-VL3 PGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVG VYYCFQGSRVPPTFGGGTKLEIK14 > DC3301_ DIQMTQSPSSLSASVGDRVTITCKASENVVTYVSWYQQKPGKA h4-VLl PKLLIYGASNRYTGVPDRF SGSGSGTDFTLTIS SLQPEDF ATYHC GQGYSYPYTFGGGTKLEIK15 > DC3301_ DIQMTQSPSSLSASVGDRVTITCKASENVVTYVSWYQQKPGKA h4-VL2 PKLLIYGASNRYTGVPDRFTGSGSGTDFTLTIS SLQPEDF ATYHCGQGYSYPYTFGGGTKLEIK99ny-2904277Attorney Docket No.: 193852001340 16 > DC3301_ NIQMTQSPSSLSASVGDRVTITCKASENVVTYVSWYQQKPGKA h4-VL3 PKLLIYGASNRYTGVPDRFTGSGSGTDFTLTISSLQPEDFADYHC GQGYSYPYTFGGGTKLEIK17 > DC3301_ DVLMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLEWYLQK h8_VLl PGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLG VYYCFQGSRVPPTFGGGTKLEIK18 > DC3301_ NIVMTQSPKSMSMSVGERVTLTCKASENVVTYVSWYQQKPEQ h8_VL2 SPKLLIYGASNRYTGVPDRFTGSGSATDFTLTISSVQAEDLADY HCGQGYSYPYTFGGGTKLEIK19 > DC3301_ DVLMTQIPVSLPVSLGDQASISCRSSQIIVHNNGNTYLEWYLQK h8_VL3 PGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLG VYYCFQGSHVPFTFGSGTKLEIK20 > DC3301_ DVLMTQTPLSLPVSLGGQASISCRSSQSVVYSDGDTYLEWYLQ h8_VL4 KPGQSPKLLIYKVSRRFSGVPDRFSGSGSGTDFTLKISRVETEDL GVYYCFQGSHVPYTFGGGTKLEIK21 > DC3301_ TSGMGVGhl-VHl> DC3301_hl-VH2> DC3301_hl-VH3> DC3301_h8_VHl> DC3301_h8_VH3CDR-H122 > DC3301_ TSGMGVSh4-VHl> DC3301_h4-VH2> DC3301_h4-VH3> DC3301_h8_VH2> DC3301_h8_VH4CDR-H123 > DC3301_ HIWWDDDKYYNPSLKShl-VHl> DC3301_hl-VH2> DC3301_hl-VH3> DC3301_h8_VHlCDR-H2100ny-2904277Attorney Docket No.: 19385200134024 > DC3301_ HIYWDDDKRYNPSLKS h4-VHl> DC3301_h4-VH2> DC3301_h4-VH3> DC3301_h8_VH2> DC3301_h8_VH4CDR-H225 > DC3301_ HIWWDGDESYNPSLKS h8_VH3CDR-H226 > DC3301_ RGLRPTDAMDYhl-VHl> DC3301_hl-VH2> DC3301_hl-VH3> DC3301_h8_VHlCDR-H327 > DC3301_ RIIYYGRVDAMDYh4-VHl> DC3301_h4-VH2> DC3301_h4-VH3> DC3301_h8_VH2CDR-H328 > DC3301_ NRYDPPWFVD h8_VH3CDR-H329 > DC3301_ LYGFTYGFAY h8_VH4CDR-H330 > DC3301_ RSSQSIVHSNGNTYLE hl-VLl> DC3301_hl-VL2> DC3301_hl-VL3101 ny-2904277Attorney Docket No.: 193852001340> DC3301_h8_VLlCDR-L131 > DC3301_ KASENVVTYVSh4-VLl> DC3301_h4-VL2> DC3301_h4-VL3> DC3301_h8_VL2CDR-L132 > DC3301_ RSSQIIVHNNGNTYLE h8_VL3CDR-L133 > DC3301_ RSSQSVVYSDGDTYLE h8_VL4CDR-L134 > DC3301_ KVSNRFShl-VLl> DC3301_hl-VL2> DC3301_hl-VL3> DC3301_h8_VLl> DC3301_h8_VL3CDR-L235 > DC3301_ GASNRYTh4-VLl> DC3301_h4-VL2> DC3301_h4-VL3> DC3301_h8_VL2CDR-L236 > DC3301_ KVSRRFSh8_VL4CDR-L237 > DC3301_ FQGSRVPPThl-VLl102 ny-2904277Attorney Docket No.: 193852001340> DC3301_hl-VL2> DC3301_hl-VL3> DC3301_h8_VLlCDR-L338 > DC3301_ GQGYSYPYTh4-VLl> DC3301_h4-VL2> DC3301_h4-VL3> DC3301_h8_VL2CDR-L339 > DC3301_ FQGSHVPFTh8_VL3CDR-L340 > DC3301_ FQGSHVPYTh8_VL4CDR-L341 > DC3301_ MGWSCIILFLVATATGVHSQVTLKESGPTLVKPTQTLTLTCTFS hl-VHl GFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNPSLKS HC RLTITKDTSKNQVVLTMTNMDPVDTATYYCTRRGLRPTDAMD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEP VT VSWNSGALTSGVHTFPAVLQS SGL YSLS S VVTVPS S S LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAI< TI< PREEQYNSTYRVVSVLTVLHQDWLNGI< EYI< CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK42 > DC3301_ MGWSCIILFLVATATGVHSQVTLKESGPTLVKPTQTLTLTCSFS hl-VH2 GFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNPSLKS HC QLTITKDTSKNQVVLTMTNMDPVDTATYYCTRRGLRPTDAMD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEP VT VSWNSGALTSGVHTFPAVLQS SGL YSLS S VVTVPS S S LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAI< TI< PREEQYNSTYRVVSVLTVLHQDWLNGI< EYI< CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK103ny-2904277Attorney Docket No.: 19385200134043 > DC3301_ MGWSCIILFLVATATGVHSQVTLKESGPTLVKPTQTLTLTCSFS hl-VH3 GFSLSTSGMGVGWIRQPPGKALEWLAHIWWDDDKYYNPSLKS HC QLTISKDTSKNQVFLTMTNMDPVDTATYYCTRRGLRPTDAMD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEP VT VSWNSGALTSGVHTFPAVLQS SGL YSLS S VVTVPS S S LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAI< TI< PREEQYNSTYRVVSVLTVLHQDWLNGI< EYI< CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK44 > DC3301_ MGWSCIILFLVATATGVHSQVTLKESGPALVKPTQTLTLTCTFS h4-VHl GFSLRTSGMGVSWIRQPPGKALEWLAHIYWDDDKRYNPSLKSR HC LTITKDTSKNQVVLTMTNMDPVDTATYYCARRIIYYGRVDAM DYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVK DYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWY VDGVEVHNAI< TI< PREEQYNSTYRVVSVLTVLHQDWLNGI< EY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK45 > DC3301_ MGWSCIILFLVATATGVHSQVTLKESGPALVKPTQTLTLTCSFS h4-VH2 GFSLRTSGMGVSWIRQPPGKALEWLAHIYWDDDKRYNPSLKSR HC LTITKDTSKNQVFLTMTNMDPVDTATYYCARRIIYYGRVDAMD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEP VT VSWNSGALTSGVHTFPAVLQS SGL YSLS S VVTVPS S S LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAI< TI< PREEQYNSTYRVVSVLTVLHQDWLNGI< EYI< CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK46 > DC3301_ MGWSCIILFLVATATGVHSQVTLKESGPALVKPTQTLTLTCSFS h4-VH3 GFSLRTSGMGVSWIRQPPGKALEWLAHIYWDDDKRYNPSLKSR HC LTISKDTSKNQVFLTMTNMDPVDTATYYCARRIIYYGRVDAMD YWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKD YFPEP VT VSWNSGALTSGVHTFPAVLQS SGL YSLS S VVTVPS S S LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAI< TI< PREEQYNSTYRVVSVLTVLHQDWLNGI< EYI< CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK47 > DC3301_ MGWSCIILFLVATATGVHSQVTLKESGPGILKPSQTLSLTCSFSG h8_VHl FSLSTSGMGVGWIRQPSGKGLEWLAHIWWDDDKYYNPSLKSQ HC LTISKDTSRNQVFLKITSVDTADTATYYCTRRGLRPTDAMDYW GQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS 104ny-2904277Attorney Docket No.: 193852001340VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK48 > DC3301_ MGWSCIILFLVATATGVHSQVTLKESGPGILQPSQTLSLTCSFSG h8_VH2 FSLRTSGMGVSWIRQPSGKGLEWLAHIYWDDDKRYNPSLKSRL HC TISKDTSRNQVFLKITSVDTADTATYYCARRIIYYGRVDAMDY WGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY FPEP VT VSWNSGALTSGVHTFP AVLQS SGL YSLS S VVTVPS S SL GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYV DGVEVHNAI< TI< PREEQYNSTYRVVSVLTVLHQDWLNGI< EYI< CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVS LTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK49 > DC3301_ MGWSCIILFLVATATGVHSQVQLQESGPGLVKPSQTLSLTCSFS h8_VH3 GFSLSTSGMGVGWIRQPSGKGLEWLAHIWWDGDESYNPSLKS HC RLTISKDTSKNQVSLKITSVTAADTAVYFCARNRYDPPWFVDW GQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFP EPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK50 > DC3301_ MGWSCIILFLVATATGVHSQVTLKESGPGILQPSQTLSLTCSFSG h8_VH4 FSLSTSGMGVSWIRQPSGKGLEWLAHIYWDDDKRYNPSLKSRL HC TISKDTSRNQVFLKITSVDTADTATYYCARLYGFTYGFAYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEP VTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVF LFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEV HNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK ALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKS RWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK51 > DC3301_ MGWSCIILFLVATATGVHSDVVMTQSPLSLPVTLGQPASISCRS hl-VLl LC SQSIVHSNGNTYLEWFQQRPGQSPRLLIYKVSNRFSGVPDRFSG SGSGTDFTLKISRVEAEDVGVYYCFQGSRVPPTFGGGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC52 > DC3301_ MGWSCIILFLVATATGVHSDVVMTQSPLSLPVTLGQPASISCRS hl-VL2 LC SQSIVHSNGNTYLEWYQQRPGQSPRLLIYKVSNRFSGVPDRFSG SGSGTDFTLKISRVEAEDVGVYYCFQGSRVPPTFGGGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC105ny-2904277Attorney Docket No.: 19385200134053 > DC3301_ MGWSCIILFLVATATGVHSDVVMTQSPLSLPVTLGQPASISCRS hl-VL3 LC SQSIVHSNGNTYLEWYLQRPGQSPKLLIYKVSNRFSGVPDRFSG SGSGTDFTLKISRVEAEDVGVYYCFQGSRVPPTFGGGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC54 > DC3301_ MGWSCIILFLVATATGVHSDIQMTQSPSSLSASVGDRVTITCKA h4-VLl LC SENVVTYVSWYQQKPGKAPKLLIYGASNRYTGVPDRFSGSGSG TDFTLTISSLQPEDFATYHCGQGYSYPYTFGGGTKLEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC55 > DC3301_ MGWSCIILFLVATATGVHSDIQMTQSPSSLSASVGDRVTITCKA h4-VL2 LC SENVVTYVSWYQQKPGKAPKLLIYGASNRYTGVPDRFTGSGSG TDFTLTISSLQPEDFATYHCGQGYSYPYTFGGGTKLEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC56 > DC3301_ MGWSCIILFLVATATGVHSNIQMTQSPSSLSASVGDRVTITCKA h4-VL3 LC SENVVTYVSWYQQKPGKAPKLLIYGASNRYTGVPDRFTGSGSG TDFTLTISSLQPEDFADYHCGQGYSYPYTFGGGTKLEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQ SGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH QGLSSPVTKSFNRGEC57 > DC3301_ MGWSCIILFLVATATGVHSDVLMTQTPLSLPVSLGDQASISCRS h8_VLl SQSIVHSNGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSG LC SGSGTDFTLKISRVEAEDLGVYYCFQGSRVPPTFGGGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVD NALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYAC EVTHQGLSSPVTKSFNRGEC58 > DC3301_ MGWSCIILFLVATATGVHSNIVMTQSPKSMSMSVGERVTLTCK h8_VL2 ASENVVTYVSWYQQKPEQSPKLLIYGASNRYTGVPDRFTGSGS LC ATDFTLTISSVQAEDLADYHCGQGYSYPYTFGGGTKLEIKRTVA APSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNAL QSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC59 > DC3301_ MGWSCIILFLVATATGVHSDVLMTQIPVSLPVSLGDQASISCRSS h8_VL3 QIIVHNNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGS LC GSGTDFTLKISRVEAEDLGVYYCFQGSHVPFTFGSGTKLEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDN ALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLS SP VTKSFNRGEC60 > DC3301_ MGWSCIILFLVATATGVHSDVLMTQTPLSLPVSLGGQASISCRS h8_VL4 SQSVVYSDGDTYLEWYLQKPGQSPKLLIYKVSRRFSGVPDRFS LC GSGSGTDFTLKISRVETEDLGVYYCFQGSHVPYTFGGGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV DNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLS SP VTKSFNRGEC106ny-2904277

Claims

Attorney Docket No.: 193852001340CLAIMS1. An anti-amyloid beta (anti-Aβ) construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein:a) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs; and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs;b) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDRS comprising the amino acid sequence of SEQ ID NO: 27, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs; and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs;c) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an HC-CDRS comprising the amino acid sequence of SEQ ID NO: 28, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs; and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 32, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs;d) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDRS comprising the amino acid sequence of SEQ ID NO: 29, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs; and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, an LC-107ny-2904277Attorney Docket No.: 193852001340CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs; ore) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the HC-CDRs; and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38, or a variant thereof comprising up to 5, 4, 3, 2, or 1 amino acid substitutions in the LC-CDRs.

2. An anti-Aβ construct comprising an anti-Aβ antibody moiety comprising:a) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a heavy chain variable region (VH) having the sequence set forth in any one of SEQ ID NOs: 1-3 and 7; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within light chain variable region (VL) having the sequence set forth in any one of SEQ ID NOs: 11-13 and 17;b) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in any one of SEQ ID NOs: 4-6 and 8; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in any one of SEQ ID NOs: 14-16 and 18;c) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in SEQ ID NO: 9; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in SEQ ID NO: 19;d) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in SEQ ID NO: 10; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in SEQ ID NO: 20; or108ny-2904277Attorney Docket No.: 193852001340e) an HC-CDR1, an HC-CDR2, and an HC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VH having the sequence set forth in SEQ ID NO: 7; and an LC-CDR1, an LC-CDR2, and an LC-CDR3, respectively comprising the amino acid sequences of a CDR1, a CDR2, and a CDR3 within a VL having the sequence set forth in SEQ ID NO: 18.

3. An anti-Aβ construct comprising an anti-Aβ antibody moiety comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein:a) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 37,optionally wherein the VH comprises the amino acid sequence of any one of SEQ ID NOs: 1-3 and 7, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 1-3 and 7, and wherein the VL comprises the amino acid sequence of any one of SEQ ID NOs: 11-13 and 17, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 11-13 and 17;b) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38,optionally wherein the VH comprises the amino acid sequence of any one of SEQ ID NOs: 4-6 and 8, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 4-6 and 8, and wherein the VL comprises the amino acid sequence of any one of SEQ ID NOs: 14-16 and 18, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 14-16 and 18;c) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 28, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 32, an LC-CDR2 comprising the109ny-2904277Attorney Docket No.: 193852001340amino acid sequence of SEQ ID NO: 34, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 39,optionally wherein the VH comprises the amino acid sequence of SEQ ID NO: 9, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 9, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 19, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 19;d) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 22, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 29, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 33, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 40,optionally wherein the VH comprises the amino acid sequence of SEQ ID NO: 10, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 10, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 20, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 20; ore) the VH comprises an HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, an HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 26, and the VL comprises an LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LC-CDR3 comprising the amino acid sequence of SEQ ID NO: 38,optionally wherein the VH comprises the amino acid sequence of SEQ ID NO: 7, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 7, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 18, or a variant thereof having at least 80% sequence identity to SEQ ID NO: 18.

4. The anti-Aβ construct of any one of claims 1-3, wherein the VH comprises the amino acid sequence of any one of SEQ ID NOs: 1-10, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 1-10; and wherein the VL comprises the amino acid sequence of any one of SEQ ID NOs: 11-20, or a variant thereof having at least 80% sequence identity to any one of SEQ ID NOs: 11-20.

5. The anti-Aβ construct of claim 4, wherein:110ny-2904277Attorney Docket No.: 193852001340a) the VHcomprises the amino acid sequence of SEQ ID NO: 1, and wherein the VLcomprises the amino acid sequence of SEQ ID NO: 11;b) the VH comprises the amino acid sequence of SEQ ID NO: 2, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 11;c) the VH comprises the amino acid sequence of SEQ ID NO: 3, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 11;d) the VHcomprises the amino acid sequence of SEQ ID NO: 1, and wherein the VLcomprises the amino acid sequence of SEQ ID NO: 12;e) the VH comprises the amino acid sequence of SEQ ID NO: 2, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 12;f) the VH comprises the amino acid sequence of SEQ ID NO: 3, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 12;g) the VHcomprises the amino acid sequence of SEQ ID NO: 1, and wherein the VLcomprises the amino acid sequence of SEQ ID NO: 13;h) the VH comprises the amino acid sequence of SEQ ID NO: 2, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 13;i) the VH comprises the amino acid sequence of SEQ ID NO: 3, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 13;j) the VH comprises the amino acid sequence of SEQ ID NO: 4, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 14;k) the VH comprises the amino acid sequence of SEQ ID NO: 5, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 14;l) the VH comprises the amino acid sequence of SEQ ID NO: 6, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 14;m) the VH comprises the amino acid sequence of SEQ ID NO: 4, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 15;n) the VH comprises the amino acid sequence of SEQ ID NO: 5, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 15;o) the VH comprises the amino acid sequence of SEQ ID NO: 6, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 15;p) the VH comprises the amino acid sequence of SEQ ID NO: 4, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 16;q) the VH comprises the amino acid sequence of SEQ ID NO: 5, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 16;111ny-2904277Attorney Docket No.: 193852001340r) the VH comprises the amino acid sequence of SEQ ID NO: 6, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 16;s) the VH comprises the amino acid sequence of SEQ ID NO: 7, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 17;t) the VH comprises the amino acid sequence of SEQ ID NO: 8, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 18;u) the VH comprises the amino acid sequence of SEQ ID NO: 9, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 19;v) the VH comprises the amino acid sequence of SEQ ID NO: 10, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 20; orw) the VH comprises the amino acid sequence of SEQ ID NO: 7, and wherein the VL comprises the amino acid sequence of SEQ ID NO: 18.

6. The anti-Ap construct of any one of claims 1-5, wherein the antibody moiety is an antibody or antigen-binding fragment thereof selected from the group consisting of a full-length antibody, a bispecific antibody, a single-chain Fv (scFv) fragment, a Fab fragment, a Fab’ fragment, a F(ab’)2, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a Fv-Fc fusion, a scFv-Fc fusion, a scFv-Fv fusion, a diabody, a tribody, and a tetrabody.

7. The anti-Ap construct of any one of claims 1-6, wherein the antibody moiety is a full-length antibody.

8. The anti-Ap construct of any one of claims 1-7, wherein the antibody moiety comprises light chain constant region, wherein the light chain constant region is a kappa or lambda constant region.

9. The anti-Ap construct of any one of claims 1-8, wherein the antibody moiety comprises an Fc fragment from IgG, IgA, IgD, IgE, or IgM, optionally wherein the Fc fragment is from IgGl, IgG2, IgG3, or IgG4.

10. The anti-Ap construct of claim 9, wherein the Fc fragment comprises one or more substitutions and has a reduced effector function as compared to a corresponding wildtype Fc fragment.112ny-2904277Attorney Docket No.: 19385200134011. The anti-Ap construct of claim 9 or claim 10, wherein the Fc fragment comprises one or more substitutions and has an extended half-life as compared to a corresponding wildtype Fc fragment.

12. The anti-Ap construct of any one of claims 1-11, wherein the construct comprises an anti-Aβ antibody comprising two heavy chains and two light chains, wherein:a) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 41, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 51;b) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 42, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 51;c) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 43, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 51;d) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 41, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 52;e) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 42, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 52;f) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 43, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 52;g) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 41, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 53;h) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 42, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 53;i) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 43, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 53;j) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 44, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 54;k) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 45, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 54;l) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 46, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 54;m) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 44, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 55;n) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 45, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 55;113ny-2904277Attorney Docket No.: 193852001340o) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 46, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 55;p) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 44, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 56;q) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 45, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 56;r) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 46, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 56;s) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 47, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 57;t) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 48, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 58;u) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 49, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 59;v) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 50, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 60; or w) the two heavy chains each comprises an amino acid sequence of SEQ ID NO: 47, and the two light chains each comprises an amino acid sequence of SEQ ID NO: 58.

13. The anti-Ap construct of any one of claims 1-12, wherein the antibody moiety of the anti-Ap construct or the construct has reduced non-specific binding to human plasma as compared to a benchmark antibody, optionally wherein the benchmark antibody is lecanemab and / or donanemab, further optionally the non-specific binding of the antibody moiety or the construct to human plasma is reduced by at least about any of 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% as compared to the benchmark antibody.

14. The anti-Ap construct of claim 13, wherein the non-specific binding to human plasma is reduced by at least about 50% as compared to the benchmark antibody.

15. The anti-Ap construct of any one of claims 1-14, wherein the antibody moiety of the anti-Aβ construct mediates clearance of Aβ.

16. The anti-Ap construct of any one of claims 1-15, wherein the antibody moiety of the anti-Ap construct or the construct binds Ap isoforms amyloid-beta 40 (Ap40) and / or amyloid-beta 42 (Ap42).114ny-2904277Attorney Docket No.: 19385200134017. The anti-Ap construct of any one of claims 1-16, wherein the antibody moiety of the anti-Ap construct or the construct binds Ap protein aggregates.

18. The anti-Ap construct of any one of claims 1-17, wherein the anti-Ap antibody moiety or the construct binds to Ap with a dissociation constant (KD) of <5xl0'7M, <10'7M, 5x<10'8M, <10’8M, <5xl0'9M, <10’9M, <5x1 CT10M, <1O’10M, <5xl0-nM, <10-nM, <5xl0'12M, or <10’12M, optionally wherein the KD is within 5xl0'7M to 10'7M, 10'7M to 5xl0'8M, 5xl0'8M to IO’8M, IO’8M to 5xl0’9M, 5xl0’9M to IO’9M, IO’9M to SxlO’10M, 5xlO'10M to IO’10M, IO’10M to SxlO’11M, SxlO’11M to IO’11M, IO’11M to 5xl0’12M, or 5xlO'12Mto 10’12M.

19. The anti-Ap construct of any one of claims 1-18, wherein the Aβ is a human Aβ.

20. The anti-Ap construct of any one of claims 1-19, wherein the anti-Aβ antibody moiety does not bind to a mouse Aβ, a rat Aβ and / or a monkey Aβ.

21. The anti-Ap construct of any one of claims 1-20, wherein the construct comprises a humanized anti-Aβ antibody.

22. An anti-Ap construct comprising an anti-Ap antibody moiety, wherein the anti-Ap antibody moiety binds to Ap competitively with the anti-Ap construct of any one of claims 1-21.

23. A pharmaceutical composition comprising the anti-Ap construct of any one of claims 1-22, and a pharmaceutical acceptable carrier.

24. An isolated nucleic acid encoding the anti-Ap construct of any one of claims 1-22.

25. A vector comprising the isolated nucleic acid of claim 24.

26. An isolated host cell comprising the isolated nucleic acid of claim 24, or the vector of claim 25.

27. A method of producing an anti-Ap construct comprising:a) culturing the isolated host cell of claim 26 under conditions effective to express the anti-Ap construct or a portion or a fragment thereof; andb) obtaining the expressed anti-Ap construct or a portion or a fragment thereof from the host cell.115ny-2904277Attorney Docket No.: 19385200134028. A method of treating a disease or condition in an individual, comprising administering to the individual an effective amount of the anti-Ap construct of any one of claims 1-22, or the pharmaceutical composition of claim 23.

29. The method of claim 28, wherein the disease or condition is a neurological disorder or a neurodegenerative disease.

30. The method of claim 28 or claim 29, wherein the disease or condition is Alzheimer’s disease.

31. The method of any one of claims 28-30, wherein the anti-Aβ construct is administered intravenously or subcutaneously into the individual.

32. The method of any one of claims 28-31, wherein the anti-Aβ construct promotes clearance of Aβ protein plaques.

33. The method of any one of claims 28-32, wherein the anti-Ap construct is administered at a dose of about 0.001 mg / kg to about 100 mg / kg.

34. The method of any one of claims 28-33, wherein the anti-Ap construct is administered with a second agent.

35. The method of any one of claims 28-34, wherein the individual is a human.

36. A kit comprising the anti-Ap construct of any one of claims 1-22.116ny-2904277

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