Modified immunoglobulins for targeting amyloid deposits

Abstract

To provide modified immunoglobulins for targeting amyloid deposits.SOLUTION: Provided herein are modified immunoglobulins comprising an amyloid reactive peptide joined to an antibody, as well as humanized antibodies that bind to human amyloid fibrils and antibody-peptide fusion proteins. Also provided herein are methods of treating amyloid-based diseases by administering a modified immunoglobulin, humanized antibody, or antibody-peptide fusion protein.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 936,002, filed November 15, 2019, and U.S. Provisional Application No. 63 / 074,912, filed September 4, 2020, the contents of which are incorporated herein by reference in their entireties.

[0002] Submitting a sequence listing as an ASCII text file The contents of the following submission in an ASCII text file are incorporated herein by reference in their entirety: Sequence Listing in Computer Readable Form (CRF) (Filename: 165992000140SEQLIST.TXT, Recorded: November 12, 2020, Size: 52KB).

[0003] This application relates to modified immunoglobulins for targeting amyloid deposits, humanized antibodies that bind to human amyloid fibrils, and antibody-peptide fusion proteins, and methods of using them. [Background technology]

[0004] Amyloidosis is a fatal protein folding disorder characterized by the aggregation and deposition of proteinaceous fibrils and heparan sulfate proteoglycans in vital organs and tissues (Non-Patent Documents 1, 2, 3, 4). The unrelenting accumulation of amyloid inevitably leads to organ dysfunction and severe morbidity or mortality. Deposits can be cerebral, as in patients with Alzheimer's disease, Huntington's disease, or prion disease, or peripheral, as in patients with light-chain (AL) amyloidosis and type 2 diabetes. Further subgrouping into localized and systemic amyloidosis indicates whether precursor proteins are produced locally (at the deposition site) or circulate in the bloodstream and are deposited at distant anatomical sites, respectively (Non-Patent Document 5). While amyloid can affect any organ or tissue, the kidneys, pancreas, liver, spleen, nervous tissue, and heart constitute the primary deposition sites in patients with familial or sporadic peripheral amyloid diseases. Alzheimer's disease currently affects more than 4 million Americans, a figure estimated to increase to more than 16 million by 2050. It is the most common form of amyloidosis and has the greatest socioeconomic impact. In contrast, peripheral (or systemic) amyloidosis is an orphan disorder, yet accounts for more than 5,000 new cases annually in the United States alone.

[0005] Of these, the major peripheral amyloidosis is light chain-associated (AL) amyloidosis, a sporadic monoclonal plasma cell dyscrasia resulting in the deposition of fibrils composed of immunoglobulin light chain proteins. AL accounts for approximately two-thirds of all peripheral amyloid cases, with a calculated incidence of approximately 1.4 cases per 100,000 people per year in the United States, comparable to acute lymphocytic leukemia and chronic myeloid leukemia (Non-Patent Document 6). AL is one-fifth as common as the related plasma cell dyscrasia multiple myeloma, but is more devastating, with a median survival of only 13.2 months, due in part to the rapidly progressive nature of organ destruction, the lack of effective anti-amyloid therapeutics, and the inability to effectively diagnose the disease before organ failure occurs. Fewer than 5% of all AL patients survive for more than 10 years from the time of diagnosis (Non-Patent Document 7). Furthermore, the median survival time for patients with cardiac AL amyloidosis is less than five months.

[0006] ATTR is a form of systemic amyloidosis. Twenty-five percent of patients with ATTR amyloidosis die within 24 months of diagnosis (Non-Patent Document 8). Current therapies cannot prevent organ damage. ATTR amyloidosis is caused by transthyretin (TTR) fibrils. Transthyretin is a protein produced by the liver that helps transport thyroid hormones and vitamin A in the blood. Normally, TTR is a tetramer consisting of four single-chain monomers. In hereditary ATTR amyloidosis, TTR gene mutations are thought to destabilize the protein, causing the tetramer to dissociate into monomers, which then aggregate into amyloid fibrils. In wild-type ATTR amyloidosis, normal TTR protein becomes unstable, misfolds, and forms amyloid fibrils.

[0007] These amyloid fibrils then accumulate in multiple organs throughout the body. For example, in the wrist, they accumulate in a narrow passageway called the carpal tunnel. This can cause carpal tunnel syndrome, which can cause numbness and tingling in the hand and arm. In the spinal canal, they can cause narrowing of the spinal column (spinal stenosis). In the heart, they can cause heart failure and / or an irregular heartbeat called atrial fibrillation.

[0008] Another common form of peripheral amyloidosis in the United States is inflammation-associated (AA) amyloidosis, which is associated with chronic inflammatory disorders such as arthritis, tuberculosis, and familial Mediterranean fever. The incidence of AA is highest in certain parts of Europe, and its frequency varies among ethnic groups (Non-Patent Document 9). In areas where familial Mediterranean fever is endemic and untreated, the incidence of AA can be as high as 100%. In Europe, the incidence of AA is estimated to be 0.86% based on an autopsy study conducted in Denmark (Non-Patent Document 10). However, in patients with rheumatoid or psoriatic arthritis, the incidence of AA can be as high as 26%. Such a high prevalence may necessitate screening programs to detect the disease earlier. Amyloid deposition is associated with persistent increases in plasma concentrations of serum amyloid protein A (sAA), the precursor of amyloid fibrils (Non-Patent Document 11). Although AA differs from AL in the type of precursor protein that is deposited, both share common mechanistic features related to fibril formation and deposition (Non-patent Document 12, Non-patent Document 13).

[0009] In addition to disorders in which amyloid pathogenesis is well established, fibrillar deposits with structural and coloring characteristics of amyloid have been identified in other syndromes, although their association with disease states has not yet been established. For example, in type 2 diabetes, islet amyloid precursor protein (IAPP) is deposited as amyloid in the islets of Langerhans (Non-Patent Document 14). Aggregation of IAPP results in oligomeric structures that are toxic to pancreatic cells (Non-Patent Document 15). Thus, it has been suggested that IAPP amyloid formation in type 1 diabetes patients contributes to the destruction of β cells and initiates the transition to insulin dependence (Non-Patent Document 16). In another example, plaques containing amyloid fibrils composed of apolipoprotein A-I have been identified in more than half of patients with atherosclerotic carotid arteries (Non-Patent Document 17, Non-Patent Document 18). Although these fibrillar deposits were more common in older patients, apoA-I is undoubtedly present early in plaque development (Non-Patent Document 19). As a final example, Apo-AI amyloid was recently identified in knee menisci obtained from patients undergoing knee replacement surgery and may contribute to the physical deterioration of the joint (Non-Patent Document 20).

[0010] In total, over 29 proteins have been identified chemically or serologically as components of fibrils in amyloid deposits. It is the properties of these proteins that differentiate disease, determine treatment, and establish prognosis. Although amyloid fibrils are associated with a clinically heterogeneous group of diseases and can form from structurally distinct and functionally diverse precursor proteins, the deposits themselves share several strikingly similar features, including fibrillar structure, fibrillar epitopes, and the occurrence of similar accessory molecules, including heparan sulfate proteoglycans (HSPGs). Amyloids are heterogeneous complexes that contain glycosaminoglycans (GAGs), particularly perlecan HSPGs, in addition to fibrils (Non-Patent Document 21, Non-Patent Document 22, Non-Patent Document 23, Non-Patent Document 24, Non-Patent Document 25, Non-Patent Document 26). Figure 1 shows a partial list of amyloids and amyloid-related disorders.

[0011] To date, the most effective therapeutic intervention for removing amyloid deposits, which can promote the recovery of organ function and improve prognosis, involves the use of amyloid-reactive antibodies as a means of immunotherapy. Several immunotherapies (antibodies) have been developed for amyloid-related diseases, including the monoclonal antibody 11-1F4 for the treatment of AL amyloidosis, NEOD001 for patients with AL amyloidosis, GSK2398852 (an anti-SAP monoclonal antibody) for amyloidosis, solanezumab for Alzheimer's disease, intravenous IgG (IVIG) for Alzheimer's disease, and bapineuzumab for Alzheimer's disease. Each of these approaches has had limitations or failed to meet primary outcomes in late-stage clinical trials (Phase 2 / 3). [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Merlini, G. et al. (2003) N. Engl. J. Med. 349, 583-596 [Non-patent document 2] Merlini, G. et al. (2004) J. Intern. Med. 255, 159-178 [Non-patent document 3] De Lorenzi, E. et al. (2004) Curr. Med. Chem. 11, 1065-1084 [Non-patent document 4] Merlini, G. (2004) Neth. J. Med. 62, 104-105 [Non-patent document 5] Westermark, P. et al. (2007) Amyloid.14, 179-183 [Non-patent document 6] Group, USCSW (2007) United States Cancer Statistics: 1999-2003 Incidence and Mortality Web-Based Report, USDepartment of Health and Human Services Centers for Disease Control and Prevention National Cancer Institute, Atlanta

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Non-licensed literature 9

Non-licensed literature 10

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Non-Patent Document 16

Non-Patent Document 17

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Non-Patent Document 21

[0014] Also provided herein are methods of detecting and treating amyloidosis, or methods using the modified immunoglobulins provided herein.

[0015] Further provided herein are nucleic acids encoding modified immunoglobulins. In some embodiments, provided herein are host cells comprising nucleic acids encoding modified immunoglobulins. In some embodiments, the host cells are CHO cells.

[0016] In one aspect, the present invention provides a modified immunoglobulin comprising an amyloid-reactive peptide and an Ig antibody or functional fragment thereof that binds to human amyloid fibrils, The functional fragment comprises a heavy chain and a light chain, and the peptide and Ig antibody or functional fragment thereof are linked together at the N-terminus of the Ig light chain and / or the N-terminus and / or C-terminus of the Ig heavy chain.

[0017] In some embodiments, the amyloid-reactive peptide comprises an amino acid sequence having at least 85% sequence identity with any one of the amino acid sequences set forth in SEQ ID NOs: 1-14.

[0018] In some embodiments, the amyloid reactive peptide and the Ig antibody or functional fragment thereof are linked together at the N-terminus of the Ig light chain.

[0019] In some embodiments, the modified immunoglobulin comprises a spacer sequence between the amyloid-reactive peptide and the Ig antibody or functional fragment thereof.

[0020] In some embodiments, the modified immunoglobulin comprises at least two amyloid-reactive peptides, wherein the amyloid-reactive peptides are the same peptide or different peptides.

[0021] In some embodiments, the Ig antibody or functional fragment thereof comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises a CDRL1 set forth in SEQ ID NO: 20, a CDRL2 set forth in SEQ ID NO: 21, and a CDRL3 set forth in SEQ ID NO: 22, and the VH comprises a CDRH1 set forth in SEQ ID NO: 17, a CDRH2 set forth in SEQ ID NO: 18, and a CDRH3 set forth in SEQ ID NO: 19.

[0022] In some embodiments, the Ig antibody or functional fragment thereof is a chimeric antibody or functional fragment thereof.

[0023] In some embodiments, the Ig antibody or functional fragment thereof comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein a) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 64 to 70, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19, or b) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 71 to 81, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19.

[0024] In some embodiments, the Ig antibody or functional fragment thereof comprises human framework sequences.

[0025] In some embodiments, the Ig antibody comprises a human Fc region.

[0026] In some embodiments, the modified immunoglobulin comprises at least two amyloid-reactive peptides, wherein the peptides are the same peptide or different peptides.

[0027] In some embodiments, the modified immunoglobulin binds to rVλ6Wil, Aβ, Aβ(1-40), IAAP, ALκ4, A1λ1, or ATTR fibrils.

[0028] In another embodiment, a human amyloid fibril-binding peptide is fused to an amyloid-reactive peptide. Provided herein are antibody-peptide fusion proteins comprising an antibody comprising a light chain variable region (VL) and a heavy chain variable region (VH).

[0029] In some embodiments, the VL comprises CDR-L1 having the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 having the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 having the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 having the amino acid sequence set forth in SEQ ID NO: 19.

[0030] In some embodiments, the antibody is a chimeric antibody.

[0031] In some embodiments, a) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 64 to 70, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19; or b) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22. a) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 64 to 70, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 71 to 81, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19; or b) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 64 to 70, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22.

[0032] In some embodiments, the VL comprises a CDR-L1 having the amino acid sequence set forth in SEQ ID NO: 64, a CDR-L2 having the amino acid sequence set forth in SEQ ID NO: 21, and a CDR-L3 having the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises a CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 17, a CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 73, and a CDR-H3 having the amino acid sequence set forth in SEQ ID NO: 19.

[0033] In some embodiments, the VL comprises a Leu at position 46 and a Phe at position 87, and the VH comprises a Leu at position 48, a Ser at position 96, a Val at position 78, a Leu at position 79, a Phe at position 80, and a Thr at position 94.

[0034] In some embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:36 and the VH comprises the amino acid sequence set forth in SEQ ID NO:55.

[0035] In some embodiments, the VL comprises one or more amino acid residues selected from the group consisting of: Tyr at position 36, Leu at position 37, Leu at position 46, Leu at position 85, and Phe at position 87. In some embodiments, the VH comprises one or more amino acid residues selected from the group consisting of: Val at position 37, Leu at position 48, Leu at position 67, Ser at position 68, Lys at position 71, Ser at position 76, Val at position 78, Leu at position 79, Phe at position 80, Thr at position 89, Val at position 93, and Thr at position 94 (amino acid positions are numbered according to the Kabat numbering system).

[0036] In some embodiments, the VL comprises a Tyr at position 36, a Leu at position 37, a Leu at position 46, a Leu at position 85, and a Phe at position 87; and the VH comprises a Val at position 37, a Leu at position 48, a Leu at position 67, a Ser at position 68, a Lys at position 71, and a T at position 89. hr, Val at position 93, and Thr at position 94.

[0037] In some embodiments, the VL comprises a Leu at position 46 and a Phe at position 87, and the VH comprises a Leu at position 48, a Ser at position 96, a Val at position 78, a Leu at position 79, a Phe at position 80, and a Thr at position 94.

[0038] In some embodiments, the VL comprises an amino acid sequence set forth in the group consisting of SEQ ID NOs: 32-42.

[0039] In some embodiments, the VH comprises an amino acid sequence set forth in the group consisting of SEQ ID NOs: 43-63.

[0040] In some embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:34 and the VH comprises the amino acid sequence set forth in SEQ ID NO:48.

[0041] In some embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:35 and the VH comprises the amino acid sequence set forth in SEQ ID NO:51.

[0042] In some embodiments, the amyloid-reactive peptide comprises the amino acid sequence set forth in SEQ ID NOs: 1-14.

[0043] In some embodiments, the amyloid-reactive peptide is fused to the N-terminus of VL or VH.

[0044] In some embodiments, the amyloid-reactive peptide is fused to the N-terminus of VL or VH via a spacer. In some embodiments, the spacer is a peptide spacer. In some embodiments, the spacer comprises the amino acid sequence GGGYS.

[0045] In some embodiments, the antibody-peptide fusion protein binds to rVλ6Wil, Aβ, Aβ(1-40), IAAP, ALκ4, A1λ1, or ATTR fibrils.

[0046] In another aspect, provided herein are pharmaceutical compositions comprising the modified immunoglobulin or antibody-peptide fusion proteins.

[0047] In another aspect, provided herein are nucleic acid(s) encoding the modified immunoglobulins and antibody-peptide fusion proteins. In another aspect, provided herein are vectors comprising the nucleic acid(s). In another aspect, provided herein are host cells comprising the vectors.

[0048] In another aspect, the invention provides a method for producing a modified immunoglobulin or antibody-peptide fusion protein, comprising culturing a host cell described in paragraph

[0045] under conditions suitable for expression of a vector encoding the modified immunoglobulin or antibody-peptide fusion protein, and recovering the modified immunoglobulin or antibody-peptide fusion protein.

[0049] In another aspect, the invention provides a method of treating a subject having an amyloid-related disorder, comprising administering to the subject an effective amount of a modified immunoglobulin or antibody-peptide fusion protein.

[0050] In some embodiments, the amyloid-related disorder is amyloidosis.

[0051] In some embodiments, the amyloid-related disorder is selected from the group consisting of AL, AH, Aβ2M, ATTR, transthyretin, AA, AApoAI, AApoAII, AGel, ALys, ALEct2, AFib, ACys, ACal, AMed, AIAPP, APro, AIns, APrP, or Aβ amyloidosis.

[0052] In some embodiments, the subject is a human.

[0053] In another aspect, the present invention provides a method of targeting amyloid deposits for clearance, comprising contacting the amyloid deposits with a modified immunoglobulin or antibody-peptide fusion protein provided herein. In some embodiments, the amyloid deposits are removed. In some embodiments, the amyloid deposits are opsonized by the modified immunoglobulin or antibody-peptide fusion protein.

[0054] In another aspect, provided herein is a method of targeting amyloid deposits for clearance comprising contacting the amyloid deposits with a modified immunoglobulin or antibody-peptide fusion protein.

[0055] In some embodiments, targeting amyloid deposits for clearance results in clearance of the amyloid deposits.

[0056] In some embodiments, clearance results from opsonization of amyloid deposits.

[0057] In some embodiments, the half-life of the amyloid-reactive peptide in the modified immunoglobulin or antibody-peptide fusion protein is increased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or more compared to the amyloid-reactive peptide alone.

[0058] In another aspect, provided herein is a method of producing a modified immunoglobulin, the method comprising: providing a first expression vector and a second expression vector, wherein the first expression vector comprises a first nucleic acid sequence encoding an Ig antibody light chain or a functional fragment thereof, and the second expression vector comprises a second nucleic acid sequence encoding an Ig antibody heavy chain or a functional fragment thereof, and the first expression vector and / or the second expression vector comprises a third nucleic acid sequence encoding a first peptide, wherein the third nucleic acid sequence is located adjacent to the first nucleic acid sequence and / or the second nucleic acid sequence; and inserting the first expression vector and the second expression vector into a cell, wherein expression of the first expression vector and the second expression vector in the cell results in an immunoglobulin linked to the first peptide.

[0059] In some embodiments, the first expression vector and / or the second expression vector comprises a fourth nucleic acid sequence encoding a second peptide, wherein the fourth nucleic acid sequence is located adjacent to the first nucleic acid sequence and / or the second nucleic acid sequence.

[0060] In some embodiments, expression of the first expression vector and the second expression vector in the cell results in an immunoglobulin linked to the first peptide and the second peptide.

[0061] In some embodiments, a spacer nucleic acid sequence is located between the third nucleic acid sequence and the first nucleic acid sequence and / or the second first nucleic acid sequence.

[0062] In another aspect, the present invention provides a method for treating a subject suffering from an amyloid-based disease or a subject suffering from an amyloid-based disease. A method of treating a subject suspected of suffering from a disease is provided, comprising: i) administering to the subject a modified immunoglobulin or antibody-peptide fusion protein, wherein the modified immunoglobulin or antibody-peptide fusion comprises a detectable label; ii) determining whether a signal associated with the detectable label can be detected from the subject; and b) administering an amyloidosis treatment to the subject if a signal is detected.

[0063] In some embodiments, if no signal is detected, the method further comprises monitoring the subject for subsequent development of amyloid deposits.

[0064] In some embodiments, the method further comprises determining the intensity of the signal and comparing the signal to a threshold value, whereby if the threshold value is exceeded, the subject is determined to have amyloid deposits.

[0065] In some embodiments, the amyloidosis treatment comprises administering to the subject a modified immunoglobulin or antibody-peptide fusion protein.

[0066] In some embodiments, administration of the modified immunoglobulin or antibody-peptide fusion protein results in clearance of amyloid deposits in the subject.

[0067] In another aspect, the invention provides a method for identifying amyloid deposits in a subject, comprising administering to the subject a modified immunoglobulin or antibody-peptide fusion protein, where the modified immunoglobulin or antibody-peptide fusion comprises a detectable label, and detecting a signal from the modified immunoglobulin or antibody-peptide fusion protein.

[0068] In some embodiments, the subject is determined to have amyloid-free or monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), or one or more related plasma cell dyscrasias.

[0069] In another aspect, the invention provides a method of detecting a ligand, comprising detectably labeling a modified immunoglobulin or antibody-peptide fusion according to any one of the paragraphs, wherein the peptide of the modified immunoglobulin or antibody-peptide fusion protein has binding affinity for the ligand, contacting the ligand with the modified immunoglobulin or antibody-peptide fusion protein, and determining a signal from the detectable label, thereby detecting the ligand.

[0070] In some embodiments, the modified immunoglobulin or antibody peptide fusion protein is conjugated to a detectable label.

[0071] In some embodiments, the modified immunoglobulin or antibody-peptide fusion protein comprises a spacer N-terminal to the amyloid-reactive peptide.

[0072] In some embodiments, the amyloid-reactive peptide is linked to the N-terminus of the VH of the antibody.

[0073] In one aspect, provided herein is a humanized antibody that binds to human amyloid fibrils, the humanized antibody comprising a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19, wherein VL comprises one or more amino acid residues selected from the group consisting of: Tyr at position 36, Leu at position 37, Leu at position 46, Leu at position 85, and Phe at position 87; and VH comprises one or more amino acid residues selected from the group consisting of: Val at position 37, Leu at position 48, Leu at position 67, Ser at position 68, Lys at position 71, Ser at position 76, Val at position 78, Leu at position 79, Phe at position 80, Thr at position 89, Val at position 93, and Thr at position 94 (wherein the amino acid positions are numbered according to the Kabat numbering system).

[0074] In some embodiments, the VL comprises a Tyr at position 36, a Leu at position 37, a Leu at position 46, a Leu at position 85, and a Phe at position 87, and the VH comprises a Val at position 37, a Leu at position 48, a Leu at position 67, a Ser at position 68, a Lys at position 71, a Thr at position 89, a Val at position 93, and a Thr at position 94.

[0075] In some embodiments, the VL comprises a Leu at position 46 and a Phe at position 87, and the VH comprises a Leu at position 48, a Ser at position 96, a Val at position 78, a Leu at position 79, a Phe at position 80, and a Thr at position 94.

[0076] In some embodiments, the VL comprises an amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42.

[0077] In some embodiments, the VH comprises an amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63.

[0078] In some embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:34 and the VH comprises the amino acid sequence set forth in SEQ ID NO:48.

[0079] In some embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:35 and the VH comprises the amino acid sequence set forth in SEQ ID NO:51.

[0080] In another aspect, provided herein is a humanized antibody that binds to human amyloid fibrils, the humanized antibody comprising a light chain variable region (VL) and a heavy chain variable region (VH), wherein a) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NOs: 64 to 70, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19, or b) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 22. c) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 64 to 70, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 71 to 81, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19, or

[0081] In some embodiments, the VL comprises one or more amino acid residues selected from the group consisting of: Tyr at position 36, Leu at position 37, Leu at position 46, Leu at position 85, and Phe at position 87; the VH comprises one or more amino acid residues selected from the group consisting of: including: Val at position 37, Leu at position 48, Leu at position 67, Ser at position 68, Lys at position 71, Ser at position 76, Val at position 78, Leu at position 79, Phe at position 80, Thr at position 89, Val at position 93, and Thr at position 94 (wherein the amino acid positions are numbered according to the Kabat numbering system).

[0082] In some embodiments, the antibody is a full-length antibody, a Fab fragment, or an scFv.

[0083] In some embodiments, the antibody comprises an Fc region.

[0084] In some embodiments, the Fc region is an Fc region of an IgG1, IgG2, IgG3, or IgG4 isotype.

[0085] In some embodiments, the humanized antibody or antibody-peptide fusion protein is conjugated to a detectable label.

[0086] In some embodiments, the humanized antibody binds to rVλ6Wil fibrils, Per125 wtATTR extract, KEN hATTR extract, SHI ALλ liver extract, and / or TAL ALκ liver extract.

[0087] In some embodiments, the humanized antibody binds to rVλ6Wil, Aβ, Aβ(1-40), IAAP, ALκ4, A1λ1, or ATTR fibrils.

[0088] In another aspect, the present invention provides a pharmaceutical composition comprising the humanized antibody. In another aspect, the present invention provides a nucleic acid(s) encoding the humanized antibody. In another aspect, provided herein is a vector comprising the nucleic acid(s). In another aspect, provided herein is a host cell comprising the vector.

[0089] In another aspect, the invention provides a method for producing a humanized antibody, comprising culturing a host cell described in paragraph 88 under conditions suitable for expression of a vector encoding the humanized antibody, and recovering the humanized antibody.

[0090] In another aspect, the present invention provides a method for treating a subject having an amyloid-related disorder, comprising administering to the subject an effective amount of a humanized antibody. In some embodiments, the amyloid-related disorder is amyloidosis. In some embodiments, the amyloid-related disorder is selected from the group consisting of AL, AH, Aβ2M, ATTR, transthyretin, AA, AApoAI, AApoAII, AGel, ALys, ALEct2, AFib, ACys, ACal, AMed, AIAPP, APro, AIns, APrP, or Aβ amyloidosis. In some embodiments, the subject is a human.

[0091] In another aspect, the invention provides a method of treating a subject suffering from or suspected of suffering from an amyloid-based disease, the method comprising: determining whether the subject has amyloid deposits by detectably labeling a humanized antibody; administering the humanized antibody to the subject; determining whether a signal associated with the detectable label can be detected in the subject; and administering an amyloidosis treatment to the subject if a signal is detected.

[0092] In some embodiments, if no signal is detected, the method further comprises monitoring the subject for subsequent development of amyloid deposits.

[0093] In some embodiments, the method further comprises determining an intensity of the signal and comparing the signal with a threshold. and comparing the threshold value to determine if the subject has amyloid deposits. In some embodiments, the amyloidosis treatment comprises administering to the subject a humanized antibody.

[0094] In another aspect, the invention provides a method for identifying amyloid deposits in a subject, comprising detectably labeling a humanized antibody, administering the humanized antibody to the subject, and detecting a signal from the humanized antibody.

[0095] In some embodiments, the subject is determined to have amyloid-free or monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), or one or more related plasma cell dyscrasias. [Brief explanation of the drawings]

[0096] [Figure 1] A partial list of amyloid and amyloid-related disorders is provided. [Figure 2] Schematic diagram of Ig-peptide fusions. Panel A shows a schematic of peptide p5 (SEQ ID NO: 1) fused to the N-terminus of an Ig light chain. Panel B shows an Ig-peptide fusion, showing an Ig structure with two Ig light chains fused to peptide p5 (SEQ ID NO: 1). [Figure 3] A schematic of the proposed mode of action of Ig-peptide fusions (not to scale) for clearing amyloid deposits is shown: Ig-peptides bind to amyloid through peptide interactions with amyloid fibrils (or heparan sulfate glycosaminoglycans), which recruit macrophages, which then engulf (phagocytose) the amyloid for destruction. [Figure 4] An autoradiograph of 125I-Igp5 after SDS-PAGE gel electrophoresis is shown. Under non-reducing conditions, the protein migrated as a single Ig, and upon reduction, it was shown to contain heavy and light chains-p5, consistent with an intact Ig molecule. [Figure 5] 12 shows the biodistribution of 125I-Igp5 in AA amyloid mice (AA) and healthy amyloid-free mice (WT) 20 hours after injection. [Figure 6] SPECT / CT images of 125I-Igp5 in AA mice and healthy wild-type controls 20 hours after injection of Igp5 show uptake in the amyloid-containing liver and spleen of AA mice and the long blood pool half-life of the reagent in WT animals. H, heart; L, liver; S, spleen. Red / yellow indicates the presence of 125I-Igp5. [Figure 7]Figure 1 shows in vitro phagocytosis of pHrodo Red-labeled rVλ6Wil fibrils in the presence of human THP1 monocytes / macrophages. Increased fluorescence intensity indicates the presence of labeled amyloid substrate in the low pH environment of macrophage phagolysosomes. MOPC 31c is a mouse monoclonal antibody control with no reactivity with fibrils. [Figure 8] An autoradiograph of I-Igp5 after SDS-PAGE gel electrophoresis is shown. Igp5 was purified from tissue culture supernatant and radiolabeled with I, and the product was characterized by SDS-PAGE using mouse 11-1F4 (IgG1κ) as a control. Proteins were analyzed under both reducing (Red.) and non-reducing (NR) conditions. [Figure 9] Figure 1 shows the binding of 125I-Igp5 to various amyloid-related substrates. Panel A shows the binding of 125I-m11-1F4 and 125I-Igp5 to κ4-peptide-coated beads or rVλ6Wil fibrils. 125I-m11-1F4 binds to κ4-peptide-coated beads but not to rVλ6Wil fibrils, whereas 125I-Igp5 binds to both substrates. Panel B shows quantification of the binding of 125I-Igp5 and m11-1F4 to various synthetic amyloid fibrils and amyloid extracts. Panel C shows the correlation between the binding of 125I-Igp5 and 125I-p5 to substrates. Binding of 125I-Igp5 to various synthetic amyloid fibrils and amyloid extracts was significantly enhanced compared to m11-1F4, and reactivity correlated with that of the p5 peptide alone, indicating that binding was driven by the peptide. [Figure 10]Microautoradiography (ARG) analysis and Congo red staining of various tissues are shown. Panel A shows the retention of 125I-Igp5 in hepatosplenic AA amyloid as well as amyloid-bound in other tissues in mice. ARG and Congo red staining demonstrate the specific retention of 125I-Igp5 in hepatosplenic AA amyloid as well as amyloid-bound in other tissues in mice. Panel B shows the results of ARG analysis of amyloid-free tissues. In healthy (WT) mice, no specific reactivity with amyloid-free tissues was observed, and the only identified source of 125I-Igp5 was the blood pool. [Figure 11A] 1 shows a schematic diagram of mIgG-p5. From left to right, the C-terminal to N-terminal region of mIgG-p5 is depicted, including the Ig light chain sequence ("IgLC", 220 amino acids), a spacer sequence, peptide p5 (31 amino acids), a spacer sequence, and an N-terminal secretory leader sequence. [Figure 11B] The amino acid sequence of a region of mIgG-p5 is shown, including, from left to right, the N-terminus of the Ig light chain (starting with amino acid residues DVVMTQTP (SEQ ID NO: 82)), the spacer sequence at the C-terminus of the p5 peptide (amino acid residues VTPTV (SEQ ID NO: 24)), peptide p5 (amino acid residues KAQKAQAKQAKQAQKAQKAQAKQAKQ (SEQ ID NO: 1)), and the N-terminal spacer sequence (amino acid residues AQAGQAGQAQGGGYS (SEQ ID NO: 23)). The amino acid sequence is shown from the C-terminus to the N-terminus. [Figure 11C] 1 shows a proposed structural model of peptide p5 fused to the N-terminus of an Ig light chain. [Figure 11D] Autoradiographs of I-labeled mIgG-p5, I-m11-1F4, and I-p5 after SDS-PAGE gel electrophoresis are shown, with the relative positions of the full-length antibody ("Ig"), heavy chain ("HC"), light chain ("LC"), and peptide p5 indicated for each protein under non-reducing ("NR") or reducing ("R") conditions. [Figure 11E]1 shows the biodistribution of 125I-labeled mIgG-p5 in wild-type amyloid-free mice 24, 48, or 72 hours after injection of 125I-mIgG-p5. The y-axis shows the level of biodistribution as a percentage of the injected dose per gram of tissue, and tissue types are indicated on the x-axis. [Figure 11F] Figure 1 shows the biodistribution of I-labeled mIgG-p5 in mice with AA amyloidosis (primarily liver and spleen) 24, 48, or 72 hours after injection of I-mIgG-p5. The y-axis shows the level of biodistribution as a percentage of the injected dose per gram of tissue, and tissue types are indicated on the x-axis. [Figure 11G] Microautography images showing 125I-labeled mIg-p5 in mice with AA amyloidosis 24 hours after injection are shown. 24 hours are shown in black, 48 hours are shown in dark gray, and 72 hours are shown in light gray. [Figure 12] The annotated VH (top, SEQ ID NO: 15) and VL (bottom, SEQ ID NO: 16) amino acid sequences of the parental murine antibody m11-1F4 are shown. CDRs are indicated by boxes, residues in the canonical framework regions are underlined, and residues at the VH-VL interface are shown in bold and italic. [Figure 13A] Data are shown from a europium-linked immunosorbent assay (EuLISA) measuring binding of chimeric (c)11-1F4 and humanized variants VH10 / VL4, VH9 / VL4, VH8 / VL4, VH7 / VL4, or VH6 / VL3 to synthetic rVλ6Wil light chain amyloid-like fibrils. [Figure 13B] Shown are data from EuLISA measuring binding of 70% pure VH6 / VL3-p5 (6-3-p5), 65% pure VH6 / VL3-p5R (6-3-p5R), c11-1F4, or VH6 / VL3 to rVλ6Wil fibrils. [Figure 13C] Shown are data from EuLISA measuring binding of VH9 / VL / 4-p5R to rVλ6Wil fibrils, Per125 wtATTR extracts, Ken ATTR extracts, SHI ALλ liver extracts, or TAL ALκ liver extracts. [Figure 13D] Shown are data from EuLISA measuring binding of VH9 / VL / 4-p5 to rVλ6Wil fibrils, Per125 wtATTR extracts, Ken ATTR extracts, SHI ALλ liver extracts, or TAL ALκ liver extracts. [Figure 13E] Data from EuLISA measuring binding of c11-1F4, m11-1F4, or VH9 / VL4 to rVλ6Wil fibrils are shown. [Figure 13F] Shown is data from EuLISA measuring binding of VH6 / VL3-p5 to Sno ATTR extracts (dark grey circles) or Ken ATTR extracts (light grey circles), and c11-1F4 to Sno ATTR extracts (black squares). [Figure 13G] Data are shown from EuLISA measuring binding of VH6 / VL3-p5R to Per125 wtATTR (gray circles, see labels), Sno ATTR extract (dark gray circles), or Ken ATTR extract (light gray circles), and binding of c11-1F4 to Sno ATTR extract (black squares). The x-axis shows the log-transformed molar concentration (-log(M)) of the monoclonal antibody, and the y-axis shows the level of binding (femtomole europium). [Figure 14] Figure 1 shows the results of 125I-mIgG-p5 binding to rVλ6Wil amyloid-like fibrils and human amyloid extracts obtained from tissues in pull-down assays. The y-axis indicates the percentage of 125I-mIgG-p5 bound; the percentage of binding for each sample is indicated above the histogram bars. The x-axis indicates the type of amyloid extract tested, which, from left to right, include rVλ6Wil fibrils (71% binding), SNO hereditary (h)ATTR (12% binding), KEN hATTR (15% binding), Per125 wtATTR (31% binding), Per253 wild-type (wt)ATTR (17% binding), ALκ HIG extract (10% binding), ALκ TAL extract (37% binding), ALλ SHI extract (34% binding), and ALλ TYL extract (21% binding). Error bars represent standard deviation. [Figure 15A]The uptake of pHrodo Red-labeled rVλ6Wil fibrils by human THP-1 macrophages alone or in the presence of human (h)IgG control, ch11-1F4, muIgp5 (produced in expiHEK293 cell line), VH6 / VL3-p5, or VH6 / VL3-p5R, as indicated from left to right on the x-axis. The y-axis shows the level of uptake of rVλ6Wil fibrils (measured in fluorescence units), and error bars represent standard deviation. [Figure 15B] Phagocytosis of pHrodo Red-labeled rVλ6Wil fibrils by THP-1 macrophages in the presence of hIgG control, c11-1F4, mIgp5, VH9 / VL4-p5, or VH9 / VL4-p5R, as indicated from left to right on the x-axis. The y-axis indicates the level of phagocytosis (fluorescence units), and error bars represent standard deviation. [Figure 15C] Phagocytosis of pHrodo Red-labeled rVλ6Wil fibrils by macrophages in the presence of hIgG control, 5 μg of Rituxan (chimeric mAb as a negative control), 5 μg of c11-1F4, 5 μg of VH6 / VL3, 5 μg of VH9 / VL4, VH6 / VL3-p5R, or VH6 / VL3-p5, as indicated from left to right on the x-axis. The y-axis indicates the level of phagocytosis (pHrodo fluorescence), and error bars represent standard deviation. [Figure 16] Figure 1 shows a pharmacokinetic (PK) analysis of 125I-labeled VH9 / VL4 antibody administered intravenously to wild-type ("WT") mice. The x-axis shows time after administration in hours, and the y-axis shows blood radioactivity levels in counts per minute ("cpm"). Curve fitting uses a double exponential decay equation. [Figure 17A] 1 shows the biodistribution of 125I-VH9 / VL4-p5 in WT amyloid-free mice. The x-axis indicates the organs sampled, including (from left to right) muscle, liver, pancreas, spleen, left kidney, right kidney, stomach, upper intestine, lower intestine, heart, lung, and blood, and the y-axis indicates the biodistribution level as a percentage of injected dose per gram of tissue. [Figure 17B]1 shows the biodistribution of 125I-VH9 / VL4-p5R in WT amyloid-free mice. The x-axis indicates the organs sampled, including (from left to right) muscle, liver, pancreas, spleen, left kidney, right kidney, stomach, upper intestine, lower intestine, heart, lung, and blood, and the y-axis indicates the biodistribution level as a percentage of injected dose per gram of tissue. [Figure 18] Data from a peptide capture ELISA measuring the stability of VH6 / VL3-p5 in mouse plasma are shown. 100 nM VH6 / VL3-p5 was added to either 4°C PBS (darkest gray), 37°C PBS (medium-light gray circle), 37°C EDTA-anticoagulated plasma (medium-light gray circle), or 37°C heparin-anticoagulated plasma (lightest gray circle). The x-axis indicates time in days after administration, and the y-axis indicates antibody binding to the ligand in absorbance units ("au"). DETAILED DESCRIPTION OF THE INVENTION

[0097] Provided herein are modified immunoglobulins that bind to amyloid. In some embodiments, the modified immunoglobulin is a peptide-Ig fusion.

[0098] I. Definition Unless otherwise specified, technical terms are used according to conventional usage. Definitions of common terms in molecular biology can be found in Benjamin Lewin, Genes IX, Jones and Bartlet, 2008 (ISBN 0763752223), Kendrew et al. (eds.), The Encyclopedia of Molecular Biology, Blackwell Science Ltd., 1994 (ISBN 0632021829), and Robert A. Meyers (ed.), Molecular Biology and Biotechnology: a Comprehensive Desk Reference, VCH Publishers, Inc., 1995 (ISBN 9780471185710), and other similar references. As used herein, the singular forms "a," "an," and "the" refer to both the singular and the plural, unless the context clearly indicates otherwise. The abbreviation "eg" comes from the Latin exempli gratia and is used herein to indicate a non-limiting example. Thus, the abbreviation "eg" is synonymous with the term "for example." As used herein, the term "comprises" means "includes."

[0099] As used herein, ranges can be expressed as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another aspect includes from one particular value in the range and / or to the other particular value in the range. It will be further understood that each endpoint of a range is significant both in relation to the other endpoint and independently of the other endpoint. Similarly, when values ​​are expressed as approximations, the use of the antecedent "about" will be understood to indicate that the particular value forms another aspect. In certain exemplary embodiments, the term "about" is understood to refer within the normal acceptance in the art, e.g., within two standard deviations of the mean. About may be understood to refer to within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from the context, all numerical values ​​provided herein can be modified by the term about. Furthermore, terms used herein such as "example," "exemplary," or "exemplary" are not meant to indicate a preference, but rather to explain that the subsequently discussed embodiment is merely one example of the embodiments presented.

[0100] It should be further understood that all base sizes or amino acid sizes, and all molecular weight or molecular mass values ​​given for nucleic acids or polypeptides are approximate and are provided for illustration purposes. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. In case of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0101] In order to facilitate review of the various embodiments of the disclosure, the following explanations of specific terms are provided:

[0102] Administration: The introduction of a composition into a subject by a selected route. For example, if the selected route is intravenous, the composition is administered by introducing the composition into the subject's vein. In some examples, the subject is administered a peptide.

[0103] The terms amyloid, amyloid deposit, amyloid fibril, and amyloid fiber refer to insoluble fibrous protein aggregates that share certain structural features. Protein aggregates, for example, are formed by the aggregation of any of several different proteins and have a tertiary structure consisting of an ordered arrangement of beta sheets stacked perpendicular to the fiber axis. See Sunde et al., J. Mol. Biol. (1997) 273:729-39. Abnormal accumulation of amyloid in organs can lead to amyloidosis. Although their occurrence is diverse, all amyloids share common morphological characteristics in that they stain with certain dyes, such as Congo Red, and have a characteristic reddish-green birefringent appearance in polarized light after staining. Amyloids also share common ultrastructural features and common X-ray diffraction and infrared spectra.

[0104] Amyloidosis refers to a pathological condition or disease characterized by the presence of amyloid (e.g., the presence of amyloid deposits). An "amyloid disease" or "amyloidosis" is a disease associated with the formation, deposition, accumulation, or persistence of amyloid fibrils. Such diseases include, but are not limited to, Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, and cerebral beta-amyloid angiopathy. Other amyloid diseases, such as systemic AA amyloidosis, AL amyloidosis, ATTR amyloidosis, ALect2 amyloidosis, and IAPP amyloidosis in type II diabetes, are also amyloid diseases.

[0105] Amyloidogenicity refers to the production or tendency to produce amyloid deposits. For example, certain soluble monomeric proteins can undergo large-scale conformational changes, leading to their aggregation into highly ordered, unbranched, 8-10 nm-wide fibrils, ultimately resulting in the formation of amyloid aggregates. For example, in humans, over 30 proteins have been found to form amyloid deposits (or amyloids). Not all proteins within a diverse protein class, such as immunoglobulin light chains, are capable of forming amyloid; some proteins are non-amyloidogenic, i.e., they do not tend to form amyloid. However, other proteins in this class are capable of forming amyloid deposits and are therefore amyloidogenic. Furthermore, some proteins within the light chain protein class may be considered more "amyloidogenic" than others based on their ease of forming amyloid fibrils. Certain light chain proteins are considered non-amyloidogenic or low-amyloidogenic because they do not readily form amyloid fibrils in patients or in vitro.

[0106] Animal: Living multi-cellular vertebrate organisms, a category that includes, for example, mammals and birds. The term mammal includes both human and non-human mammals. Similarly, the term "subject" includes both human and veterinary subjects. In some examples, the subject is a subject, such as a subject suffering from an amyloid disease.

[0107] Clearance: The term "clear" or "clearance" means to a measurable degree "Amyloid" refers to a reduction or removal of amyloid deposits to a measurable or discernible extent. For example, clearance of amyloid deposits as described herein relates to a reduction or removal of deposits to a measurable or discernible extent. Clearance can result in 100% removal, but need not be 100% removal. Rather, clearance can result in less than 100% removal (e.g., about 10%, 20%, 30%, 40%, 50%, 60%, or more removal).

[0108] Conjugate: As used herein, the term "conjugate" refers to the product of the binding or linkage of two or more materials, where the resulting product has at least two distinct elements, such as at least two domains. The bound materials may be the same or different. Such binding may be via one or more linking groups. A "protein conjugate" results, for example, from the coupling of two or more amino acid sequences. A conjugate of two proteins results, for example, in a single protein having domains corresponding to each of the individually linked proteins.

[0109] Antibodies refer to single-, double-, and multi-chain proteins and glycoproteins belonging to the classes of polyclonal, monoclonal, chimeric, and heteroimmunoglobulins (monoclonal antibodies are preferred), including synthetic and genetically engineered variants of these immunoglobulins. "Antibody fragments" include Fab, Fab', F(ab')2, and Fv fragments, as well as any portion of an antibody that has specificity for a desired target epitope(s). A "monoclonal antibody" is an antibody produced by a single clone of B lymphocytes. Monoclonal antibodies are produced by methods known to those skilled in the art (e.g., by generating hybrid antibody-forming cells from the fusion of myeloma cells and immune spleen cells).

[0110] An epitope refers to the site on an antigen that is recognized by an antibody and is determined by the specificity of the antibody's amino acid sequence. An epitope is also called an antigenic determinant. For example, an epitope may be a part of a recombinant protein that is recognized by a specific antibody. Furthermore, an epitope may be a conformational epitope or a linear epitope.

[0111] A chimeric antibody refers to an antibody that contains sequences derived from two different antibodies, typically from different species. Most typically, a chimeric antibody contains a human antibody fragment and a murine antibody fragment (generally a human constant region and a murine variable region).

[0112] A humanized antibody refers to an antibody derived from a non-human antibody (typically a mouse), and which retains or substantially retains the antigen-binding properties of the parent antibody, but is less immunogenic in humans.

[0113] Complementarity-determining regions, or CDRs, refer to amino acid sequences that together define the binding affinity and specificity of the native Fv region of a native immunoglobulin binding site. The light and heavy chains of an immunoglobulin each have three CDRs, designated L-CDR1, L-CDR2, and L-CDR3, and H-CDR1, H-CDR2, and H-CDR3, respectively. By definition, the light chain CDRs are bounded by residues at positions 24 and 34 (L-CDR1), residues at positions 50 and 56 (L-CDR2), and residues at positions 89 and 97 (L-CDR3), while the heavy chain CDRs are bounded by residues at positions 31 and 35b (H-CDR1), residues at positions 50 and 65 (H-CDR2), and residues at positions 95 and 102 (H-CDR3) (Kabat et al., 2001). et al.,(1991)Sequences of Proteins of Immunological Interest,5th Edition,Department of Health and Human Services,Public Health Service,National Institutes of Health,Bethesda(NIH Publication No.91-324 2) using the numbering convention depicted by

[0114] Framework regions refer to the amino acid sequences interposed between the CDRs. These portions of an antibody serve to hold the CDRs in the proper orientation for antigen binding.

[0115] Specificity Determining Residues or SDRs refer to the amino acid residues of an immunoglobulin that are directly involved in antigen contact.

[0116] The constant region refers to the portion of an antibody molecule that confers effector function. In the present invention, the variant antibody comprises a constant region derived from human immunoglobulin. The heavy chain constant region can be selected from any of five isotypes: alpha, delta, epsilon, gamma, or mu. Various subclasses of heavy chains (e.g., IgG heavy chain subclasses) carry different effector functions. Therefore, by selecting the desired heavy chain constant region, a humanized antibody with the desired effector function can be produced. The light chain constant region can be kappa or lambda (preferably kappa).

[0117] Effective amount or therapeutically effective amount: An amount of an agent sufficient to prevent, treat (including prophylactic), reduce, and / or alleviate any of the symptoms and / or underlying causes of a disorder or disease (e.g., to prevent, inhibit amyloidosis). In some embodiments, an "effective amount" is sufficient to reduce or eliminate the symptoms of the disease. An effective amount can be administered one or more times. For example, an effective amount of a peptide is an amount sufficient to bind to amyloid. The peptide can be effective, for example, when administered parenterally in an amount greater than about 1 μg / kg to about 30 mg / kg of body weight.

[0118] Expression control sequence: A nucleic acid sequence that regulates the expression of an operably linked heterologous nucleic acid sequence. An expression control sequence is operably linked to a nucleic acid sequence if the expression control sequence controls and regulates the transcription and proper translation of the nucleic acid sequence. Thus, an expression control sequence may include an appropriate promoter, enhancer, transcription terminator, a start codon (ATG) in front of a protein-coding gene, splicing signals for introns, maintaining the correct reading frame of the gene to allow proper translation of mRNA, and a stop codon. The term "control sequence" is intended to include at least components whose presence can affect expression, and may also include additional components whose presence is advantageous (e.g., leader sequences and fusion partner sequences). An expression control sequence may include a promoter.

[0119] A promoter is a minimal sequence sufficient to induce transcription. Also included are promoter elements that are sufficient to render promoter-dependent gene expression cell-type specific, tissue-specific, or inducible by external signals or agents, and such elements may be located in the 5' or 3' region of the gene. Both constitutive and inducible promoters are included (see, e.g., Bitter et al., Methods in Enzymology 153:516-544, 1987). For example, when cloning in a bacterial system, inducible promoters such as pL, plac, ptrp, and ptac (ptrp-lac hybrid promoter) of bacteriophage λ can be used. In one embodiment, when cloning in a mammalian cell system, promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or promoters derived from mammalian viruses (e.g., retroviral long terminal repeat, adenovirus late promoter, vaccinia virus 7.5K promoter) can be used. Promoters produced by recombinant DNA or synthetic techniques can also be used to provide transcription of nucleic acid sequences. Polynucleotides can be inserted into expression vectors containing promoter sequences that promote efficient transcription of the inserted gene sequence in the host. Expression vectors typically contain an origin of replication, It contains a promoter as well as specific nucleic acid sequences that allow for phenotypic selection of transformed cells.

[0120] Inhibit: To measurably reduce. Inhibition does not require, for example, a complete loss or complete cessation of the function of the aspect being measured. For example, inhibiting plaque formation can mean stopping further growth of plaque, slowing further growth of plaque, or reducing the size of plaque.

[0121] Disease suppression or treatment: Preventing the full development of a disease or condition (e.g., preventing amyloidosis). "Treatment" refers to a therapeutic intervention that improves signs or symptoms after a disease or pathological condition has begun to develop. The term "alleviating" refers to any observable beneficial effect of treatment with respect to a disease or pathological condition. A beneficial effect can be evidenced, for example, by a delay in the onset of clinical symptoms of the disease in a susceptible subject, a reduction in the severity of some or all clinical symptoms of the disease, a delay in the progression of the disease, an improvement in the subject's overall health or well-being, or other parameters well known in the art that are specific to a particular disease. "Prophylactic" treatment is treatment administered to a subject who does not show signs of the disease or who shows only early signs, with the aim of reducing the risk of developing the condition.

[0122] With respect to the formation of amyloid deposits, "inhibition" refers to preventing a decrease in the formation of amyloid deposits, such as compared to a control. For example, inhibition can result in about a 10%, 20%, 30%, 40%, 50%, 60%, or more decrease in amyloid deposits, as compared to a control.

[0123] A label refers to any detectable compound or composition that is directly or indirectly conjugated to another molecule to facilitate detection of that molecule. Specific, non-limiting examples of labels include fluorescent tags, chemiluminescent tags, haptens, enzyme conjugates, and radioisotopes. A "detectably labeled" protein means, for example, that the presence of the protein can be determined by the label associated with the protein.

[0124] Isolated: An "isolated" biological component, e.g., a peptide (e.g., one or more of the peptides disclosed herein), cell, nucleic acid, or serum sample, has been substantially separated, separately produced, or purified from other biological components (e.g., other chromosomal and extrachromosomal DNA and RNA, and proteins) of the cells of the organism in which it naturally occurs. Thus, "isolated" nucleic acids, peptides, and proteins include nucleic acids and proteins purified by standard purification methods. The term also encompasses nucleic acids, peptides, and proteins prepared by recombinant expression in a cell, as well as chemically synthesized peptides and nucleic acids. The terms "isolated" or "purified" do not require absolute purity; rather, they are intended as relative terms. Thus, for example, an isolated peptide preparation is one in which the peptide or protein is more enriched than it is in its natural environment within a cell. Preferably, the preparation is purified such that the protein or peptide represents at least 50% of the total peptide or protein content of the preparation (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or even at least 99% of the peptide or protein concentration).

[0125] Linked: As used herein, the terms "join," "joined," "link," or "linked" refer to any method known in the art for operatively connecting proteins and / or protein domains. For example, one protein domain may be linked by a covalent bond, with or without intervening sequences or domains, e.g., in a recombinant fusion protein. Linked may be linked to another protein domain via a bond, and may also include incorporating two sequences together, e.g., placing two nucleic acid sequences together on the same nucleic acid strand so that the sequences are expressed together.

[0126] Nucleic acid: A polymer composed of nucleotide units (ribonucleotides, deoxyribonucleotides, related naturally occurring structural variants, and non-naturally occurring synthetic analogs thereof) linked via phosphodiester bonds. Thus, the term includes nucleotide polymers in which the nucleotides and the linkages therebetween contain non-naturally occurring synthetic analogs, such as, but not limited to, phosphorothioates, phosphoramidates, methyl phosphonates, chiral methyl phosphonates, 2-O-methyl ribonucleotides, peptide nucleic acids (PNAs), and the like. Such polynucleotides can be synthesized, for example, using an automated DNA synthesizer. The term "oligonucleotide" typically refers to short polynucleotides, generally no longer than about 50 nucleotides. Where a nucleotide sequence is represented by a DNA sequence (i.e., A, T, G, C), it is understood that this also includes RNA sequences in which "T" is replaced by "U" (i.e., A, U, G, C).

[0127] Nucleotides include, but are not limited to, monomers containing a base linked to a sugar (e.g., pyrimidine, purine, or synthetic analogs thereof) or a base linked to an amino acid (e.g., peptide nucleic acid (PNA)). A nucleotide is one monomer in a polynucleotide. Nucleotide sequence refers to the sequence of bases in a polynucleotide.

[0128] Conventional notation is used herein to describe nucleotide sequences: the left-hand end of a single-stranded nucleotide sequence is the 5'-end, and the leftward direction of a double-stranded nucleotide sequence is referred to as the 5'-direction. The direction of 5' to 3' addition of nucleotides to a nascent RNA transcript is referred to as the transcription direction. The DNA strand having the same sequence as the mRNA is referred to as the "coding strand," and the sequence on the DNA strand having the same sequence as the mRNA transcribed from that DNA and located 5' to the 5' end of the RNA transcript is referred to as the "upstream sequence." The sequence on the DNA strand having the same sequence as the RNA and located 3' to the 3' end of the coding RNA transcript is referred to as the "downstream sequence."

[0129] cDNA refers to DNA that is complementary or identical to mRNA, in either single- or double-stranded form.

[0130] Encoding refers to the inherent property of a particular sequence of nucleotides in a polynucleotide (e.g., a gene, cDNA, or mRNA) to serve as a template for the synthesis in biological processes of other polymers and macromolecules having either a defined sequence of nucleotides (e.g., rRNA, tRNA, and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of the mRNA produced by that gene produces the protein in a cell or other biological system. Both the coding strand of a gene or cDNA (the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in a sequence listing) and the non-coding strand (used as a template for transcription) can be said to encode the protein or other product of that gene or cDNA. Unless otherwise specified, "nucleotide sequences encoding amino acid sequences" are degenerate versions of each other and include all nucleotide sequences that encode the same amino acid sequence. Protein- and RNA-encoding nucleotide sequences can contain introns.

[0131] Recombinant nucleic acid refers to a nucleic acid having nucleotide sequences that are not naturally linked together This includes nucleic acid vectors (e.g., adenoviral vectors), including amplified or constructed nucleic acids that can be used to transform suitable host cells. A host cell containing a recombinant nucleic acid is referred to as a "recombinant host cell." Genes are then expressed in the recombinant host cell to produce "recombinant polypeptides," etc. Recombinant nucleic acids can also serve non-coding functions (such as promoters, origins of replication, ribosome binding sites, etc.). A first sequence is "antisense" with respect to a second sequence if a polynucleotide whose sequence is the first sequence specifically hybridizes to a polynucleotide whose sequence is the second sequence.

[0132] Pharmaceutically acceptable carriers: The pharmaceutically acceptable carriers used are conventional. Remington's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995), describes compositions and formulations suitable for pharmaceutical delivery of the fusion proteins disclosed herein.

[0133] Generally, the nature of the carrier will depend on the particular mode of administration being used. For example, parenteral formulations usually comprise an injectable fluid containing pharmaceutically and physiologically acceptable fluids (e.g., water, physiological saline, balanced salt solution, aqueous dextrose, glycerol, or the like as a vehicle). For solid compositions (e.g., in powder, pill, tablet, or capsule form), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate. In addition to biologically neutral carriers, the administered pharmaceutical composition can contain minor amounts of non-toxic auxiliary substances (e.g., wetting or emulsifying agents, preservatives, and pH buffering agents), such as, for example, sodium acetate or sorbitan monolaurate.

[0134] Polypeptide: A polymer in which the monomers are amino acid residues and are linked together through amide bonds. When the amino acids are alpha amino acids, either the L-optical isomer or the D-optical isomer can be used (L-isomers are preferred). As used herein, the term "polypeptide" or "protein" is intended to encompass any amino acid sequence, including modified sequences such as glycoproteins. The term "polypeptide" is specifically intended to encompass naturally occurring proteins as well as those produced recombinantly or synthetically. In some examples, the peptide is one or more of the peptides disclosed herein.

[0135] Purified: The term "purified" does not require absolute purity, but rather is intended as a relative term. Thus, for example, a purified protein preparation is one in which the referenced protein is more pure than the protein in its natural environment within a cell or production reaction chamber (as appropriate).

[0136] Recombinant: A recombinant nucleic acid is one having a sequence that is not found in nature or that is made by the artificial combination of two otherwise separated segments of sequence, often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acid (e.g., by genetic engineering techniques).

[0137] Sequence identity: The similarity between two nucleic acid sequences or two amino acid sequences is expressed in terms of the similarity between the sequences and is called sequence identity. Sequence identity is frequently measured in terms of the percentage of identity (or similarity or homology), and the higher the percentage, the more similar the two sequences are.

[0138] Methods for aligning sequences for comparison are well known in the art. For column algorithms, see Smith&Waterman Adv.Appl.Math.2:482,1981, Needleman&Wunsch J.Mol.Biol.48:443,1970, Pearson&Lipman Proc.Natl.Acad.Sci.USA 85:2444,1988, Higgins&Sharp Gene 73:237-244,1988, Higgins&Sharp CABIOS 5:151-153,1989, Corpet et al.Nuc.Acids Res.16,10881-90,1988, Huang et al.Computer Appls.In the Biosciences 8,155-65,1992, and Pearson et al. al.Meth.Mol.Bio.24,307-31,1994.Altschul et al. al. (J. Mol. Biol. 215:403-410, 1990), which presents a detailed discussion of sequence alignment methods and homology calculations.

[0139] The NCBI Basic Local Alignment Search Tool (BLAST) (Altschul et al. J. Mol. Biol. 215:403-410, 1990) is available from several sources, including the National Center for Biotechnology Information (NCBI, Bethesda, MD), and is available on the Internet for use in conjunction with the sequence analysis programs blastp, blastn, blastx, tblastn, and tblastx.

[0140] Operably linked: A first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed into a functional relationship with the second nucleic acid sequence. For example, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Generally, operably linked DNA sequences are contiguous, in the same reading frame, and, where necessary, to join two protein-coding regions.

[0141] Drug: A compound or composition that is capable of eliciting a desired therapeutic or prophylactic effect when properly administered to a subject or cell.

[0142] Vector: A nucleic acid molecule that is introduced into a host cell, thereby producing a transformed host cell. A recombinant DNA vector is a vector that contains recombinant DNA. A vector can contain nucleic acid sequences that allow it to replicate in a host cell, such as an origin of replication. A vector can also contain one or more selectable marker genes and other genetic elements known in the art. A viral vector is a recombinant DNA vector that contains at least some nucleic acid sequences derived from one or more viruses. The term vector includes plasmids, linear nucleic acid molecules, and adenoviral vectors and adenoviruses, as described throughout.

[0143] Subject refers to a vertebrate. The vertebrate may be a mammal (e.g., a human). The subject may be a human patient. The subject may be suffering from or suspected of suffering from a disease or condition, and may be in need of treatment or diagnosis, or may need monitoring for the progression of the disease or condition. The patient may also be undergoing a therapy that needs to be monitored for effectiveness. In some exemplary embodiments, the subject includes a subject suffering from amyloidosis (e.g., Alzheimer's disease, Huntington's disease, or prion disease), or peripheral amyloidosis (as seen in patients with light chain (AL) amyloidosis and type 2 diabetes).

[0144] The term treating or treatment refers to the treatment of symptoms after a disease or pathological condition has begun to develop. "Prophylactic" refers to a therapeutic intervention that alleviates signs or symptoms. The term "alleviating" refers to any observable beneficial effect of treatment with respect to a disease or pathological condition. A beneficial effect can be demonstrated, for example, by delaying the onset of clinical symptoms of a disease in a susceptible subject, reducing the severity of some or all clinical symptoms of a disease, delaying the progression of a disease, improving the subject's overall health or well-being, or other parameters well known in the art that are specific to a particular disease. "Prophylactic" treatment is a treatment administered to a subject who does not show signs of a disease or who only shows early signs, with the aim of reducing the risk of developing a pathological condition.

[0145] Preferably, non-identical residue positions differ by conservative amino acid substitutions. The term "conservative amino acid substitution" refers to the interchangeability of residues with similar side chains. For example, the group of amino acids with aliphatic side chains is glycine, alanine, valine, leucine, and isoleucine; the group of amino acids with aliphatic-hydroxyl side chains is serine and threonine; the group of amino acids with amide-containing side chains is asparagine and glutamine; the group of amino acids with aromatic side chains is phenylalanine, tyrosine, and tryptophan; the group of amino acids with basic side chains is lysine, arginine, and histidine; and the group of amino acids with sulfur-containing side chains is cysteine ​​and methionine. Preferred conservative amino acid substitutions are valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamic acid-aspartic acid, and asparagine-glutamine.

[0146] As discussed herein, minor variations in the amino acid sequence of an antibody or immunoglobulin molecule are contemplated as being encompassed by the present disclosure, provided that the variation in amino acid sequence maintains at least 75%, more preferably at least 80%, 90%, 95%, and most preferably 99% integrity. Specifically, conservative amino acid substitutions are contemplated. Conservative substitutions are those that occur within a family of amino acids that are related in their side chains. Genetically encoded amino acids are generally classified into the following families: (1) acidic amino acids are aspartic acid and glutamic acid; (2) basic amino acids are lysine, arginine, and histidine; (3) nonpolar amino acids are alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, and tryptophan; and (4) uncharged polar amino acids are glycine, asparagine, glutamine, cysteine, serine, threonine, and tyrosine. Hydrophilic amino acids include arginine, asparagine, aspartic acid, glutamine, glutamic acid, histidine, lysine, serine, and threonine. Hydrophobic amino acids include alanine, cysteine, isoleucine, leucine, methionine, phenylalanine, proline, tryptophan, tyrosine, and valine. Other amino acid families include: (i) the aliphatic hydroxy family, serine and threonine; (ii) the amide-containing family, asparagine and glutamine; (iii) the aliphatic family, alanine, valine, leucine, and isoleucine; and (iv) the aromatic family, phenylalanine, tryptophan, and tyrosine. For example, it is reasonable to expect that the single substitution of leucine with isoleucine or valine, aspartic acid with glutamic acid, and threonine with serine, or similar substitutions of amino acids with structurally related amino acids, especially when the substitution does not involve an amino acid in a framework region, will not have a significant effect on the binding or properties of the resulting molecule. Whether an amino acid change results in a functional peptide can be readily determined by assaying the specific activity of the polypeptide derivative, assays which are described in detail herein.Fragments or analogs of antibody or immunoglobulin molecules can be readily prepared by one skilled in the art. The amino and carboxy termini of preferred fragments or analogs occur near boundaries of functional domains. Structural and functional domains can be identified by comparison of the nucleotide and / or amino acid sequence data to public or proprietary sequence databases. Preferably, fragments or analogs conform to sequence motifs or sequences that occur in other proteins of known structure and / or function. Computerized comparison methods are used to identify known or predicted protein conformational domains. Methods for identifying protein sequences that fold into known three-dimensional structures are known (Bowie et al. Science 253:164 (1991)). Thus, the foregoing examples demonstrate that one skilled in the art can recognize sequence motifs and structural conformations that can be used to define structural and functional domains in accordance with the present invention.

[0147] Preferred amino acid substitutions are those that (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) change binding affinity for forming protein complexes, (4) change binding affinity, or (5) confer or modify other physicochemical or functional properties of such analogs. Analogs can include various mutant proteins of a sequence other than the naturally occurring peptide sequence. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) can be made in the naturally occurring sequence (preferably in the portion of the polypeptide outside the domain(s) that form intermolecular contacts). Conservative amino acid substitutions do not substantially alter the structural characteristics of the parent sequence (e.g., the substituted amino acids do not tend to disrupt helices occurring in the parent sequence or other types of secondary structure that characterize the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are found in Proteins, Structures and Molecular Principles (Creighton, Ed., W.H. Freeman and Company, New York (1984)), Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, NY (1991)), and Thornton et al. Nature 354:105 (1991).

[0148] With the exception of CDR1 in VH, CDRs generally comprise amino acid residues that form hypervariable loops. CDRs also comprise "specificity-determining residues" or "SDRs," which are residues that contact the antigen. SDRs are contained within regions of CDRs called abbreviated CDRs or a-CDRs. Exemplary CDRs (a-CDR-L1, a-CDR-L2, a-CDR-L3, a-CDR-H1, a-CDR-H2, and a-CDR-H3) occur at amino acid residues 31-34 (L1), 50-55 (L2), 89-96 (L3), 31-35B (H1), 50-58 (H2), and 95-102 (H3) (see Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)).

[0149] "Framework" or "FR" refers to residues of the variable domain other than the CDR residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the CDR and FR sequences generally appear in the following sequence for VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4, or FR1-CDR-H1(L1)-FR2-CDR-H2(L2)-FR3-CDR3-H3(L3)-FR4.

[0150] II. Modified Immunoglobulins and Antibody-Peptide Fusion Proteins A. Modified Immunoglobulins In certain exemplary embodiments, modified immunoglobulins that target amyloid are provided. Such modified immunoglobulins include, for example, amyloid-reactive peptides that are linked to immunoglobulins (Ig), for example, via fragments, N-terminal extensions of Ig light chain proteins in the antigen-binding (Fab) region, or via the C-terminus of the heavy chain, thereby forming peptide-Ig fusions. The modified immunoglobulins can be used to treat amyloidosis in subjects, for example, by administering the modified immunoglobulin to the subject. In some embodiments, the modified immunoglobulin is a fusion protein comprising an antibody linked to an amyloid-reactive peptide.

[0151] In some embodiments, the modified immunoglobulin comprises an antibody linked to a peptide. In some embodiments, the modified immunoglobulin comprises an antibody comprising one, two, three, four, five, or six CDRs of antibody 11-1F4. In some embodiments, the antibody comprises the VH and / or VL of antibody 11-1F4. In some embodiments, the antibody comprises the heavy chain and / or light chain of antibody 11-1F4, and the antibody is linked to a peptide.

[0152] In certain embodiments, the modified immunoglobulin comprises an antibody, the antibody comprising a VH comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19, wherein the antibody is linked to a peptide.

[0153] In certain embodiments, the modified immunoglobulin comprises an antibody, wherein the antibody comprises a VL comprising (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the antibody is linked to a peptide.

[0154] In one embodiment, the modified immunoglobulin comprises an antibody comprising a VL comprising the amino acid sequence of SEQ ID NO: 16 and a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the antibody is linked to a peptide.

[0155] In another aspect, the modified immunoglobulin comprises an antibody, wherein the antibody comprises a VH comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19, and a VL comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the antibody is linked to a peptide. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences listed in Table 1. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0156] In another aspect, the modified immunoglobulin comprises an antibody, wherein the antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 of the VH having the sequence set forth in SEQ ID NO: 15, and a VL CDR1, a VL CDR2, and a VL of the VL having the sequence set forth in SEQ ID NO: 16, wherein the antibody is linked to a peptide. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences listed in Table 1. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0157] In some embodiments, the modified immunoglobulin comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide. In some embodiments, the modified immunoglobulin comprises a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 without a C-terminal lysine residue and a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the antibody is linked to a peptide.

[0158] In another aspect, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences listed in Table 1. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the peptide is linked to the N-terminus of the light chain or the C-terminus of the heavy chain of the antibody. In some embodiments, the antibody also comprises a spacer amino acid sequence between the peptide and the N-terminus of the light chain or the C-terminus of the heavy chain. In some embodiments, the peptide is linked to the N-terminus of the light chain. In some embodiments, the peptide is linked to the N-terminus of the heavy chain.

[0159] In some embodiments, the modified immunoglobulin comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the heavy chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the modified immunoglobulin comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the modified immunoglobulin comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0160] In some embodiments, the modified immunoglobulin comprises an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the modified immunoglobulin comprises an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the modified immunoglobulin comprises an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0161] In some embodiments, the modified immunoglobulin comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1.

[0162] In some embodiments, the modified immunoglobulin comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide is linked to the light chain at the N-terminus.

[0163] In some embodiments, the modified immunoglobulin comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the peptide is linked to the light chain at the N-terminus.

[0164] In some embodiments, the modified immunoglobulins described herein bind to amyloid deposits or amyloid fibrils. In some embodiments, the modified immunoglobulins bind to one or more amyloidogenic peptides of amyloid. In some embodiments, the amyloid bound by the modified immunoglobulins comprises an amyloidogenic λ6 variable domain protein (Vλ6Wil) or an amyloidogenic immunoglobulin light chain (AL), Aβ(1-40) amyloid-like fibrils or amyloidogenic Aβ precursor protein, or serum amyloid protein A (AA). In other embodiments, the amyloid bound by the modified immunoglobulins comprises an amyloidogenic form of immunoglobulin heavy chain (AH), β2-microglobulin (Aβ2M), transthyretin variant (ATTR), apolipoprotein A (AA), or amyloidogenic forms of immunoglobulin heavy chain (AH). The amyloidogenic peptides include amyloidogenic peptides such as apolipoprotein AI (AApoAI), apolipoprotein AII (AApoAII), gelsolin (AGel), lysozyme (ALys), leukocyte chemoattractant (ALect2), fibrinogen A variant (AFib), cystatin variant (ACys), calcitonin (ACal), lactadherin (AMed), islet amyloid polypeptide (AIAPP), prolactin (APro), insulin (AIns), prion protein (APrP), alpha-synuclein (AαSyn), tau (ATau), atrial natriuretic factor (AANF), or IAAP, ALκ4, A1λ1, and other amyloidogenic peptides. The amyloidogenic peptides bound by the modified immunoglobulin may be proteins, protein fragments, or protein domains. In some embodiments, the amyloid deposits or amyloid fibrils comprise recombinant amyloidogenic proteins. In some embodiments, amyloid is part of the pathology of a disease.

[0165] As those skilled in the art will appreciate, an antigen-binding fragment (or Fab region) is the head of an antibody that naturally interacts with a target antigen. The Fab region components, for example, enable the antibody to bind to a specific ligand and, through this interaction, further activate the immune system. For antibody isotypes IgG, IgA, IgD, IgE, and IgM, Ig consists of two proteins, a heavy chain and a light chain, which interact in pairs to form an intact Ig containing two heavy chains and two light chains. Both the heavy and light chains are further divided into variable and constant domains (light and heavy variable domains, which contain the Fab functional region, and the heavy chains, which form the fragment crystallizable (Fc) domain, which interacts with cellular receptors and complement). The Fc region of Ig contains highly conserved N-glycosylation sites.

[0166] In certain exemplary embodiments, one or more of the peptides shown in Table 1 below can be linked to an Ig antibody or functional fragment thereof via the N-terminus of the light chain protein or the C-terminus of the heavy chain, thereby forming a modified immunoglobulin. That is, any of the sequences identified below in Table 1 can be linked independently or simultaneously to the heavy or light chain of an Ig antibody or functional fragment thereof to form a peptide-Ig conjugate. For example, two of the amyloid-reactive peptides can be linked to a single Ig antibody by linking the amino acid sequence of the amyloid-reactive peptide to the N-terminus of the Ig light chain protein. [Table 1]

[0167] Without wishing to be bound by any particular theory, it is believed that the peptide domain of the peptide-Ig conjugate targets the modified immunoglobulin to amyloid deposits when administered to a subject. The Fc domain then triggers an immune response at the location of the amyloid, thereby resulting in its removal by opsonization or the like. In addition, the modified immunoglobulin is believed to have a longer half-life than the amyloid-reactive peptide alone. For example, the circulating half-life of IgG in humans is approximately 21 days, while the half-life of the amyloid-reactive peptide alone in humans is approximately 11 hours. Thus, Ig enhances the half-life of the modified immunoglobulin in circulation. In certain exemplary embodiments, contacting amyloid deposits with the modified immunoglobulin reduces amyloid deposits by about 10%, 20%, or 30% compared to contacting amyloid deposits with the amyloid-reactive peptide alone. , resulting in a 40%, 50%, 60%, 70%, 80% or more increased half-life. Thus, when administered to a subject, the modified immunoglobulin is able to exert an immunostimulatory effect at the location of amyloid deposits for a longer period of time, thereby increasing the immune response at the location of amyloid deposits.

[0168] In some embodiments, the amyloid-reactive peptide of the modified immunoglobulin peptides described herein comprises an amino acid sequence that is at least 80%, 85%, 90%, or more identical to the amino acid sequence set forth as any one of SEQ ID NOs: 1-14 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence set forth as any one of SEQ ID NOs: 1-14). In some embodiments, the amyloid-reactive peptide conjugated to an Ig antibody or functional fragment thereof can comprise or consist of from about 10 to about 55 amino acids. The amyloid-reactive peptides of the present invention can comprise or consist of, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 amino acids. Such peptides are described, for example, in International Patent Application No. WO2016032949 (incorporated herein in its entirety).

[0169] The amino acids forming all or part of the amyloid-reactive peptide bound to an Ig antibody or fragment thereof can be stereoisomers and modifications, such as naturally occurring amino acids, non-naturally occurring amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, and constructs or structures designed to mimic amino acids. The amino acids forming the peptides of the invention can be one or more of the 20 common amino acids found in naturally occurring proteins, or one or more modified and unconventional amino acids. Modified immunoglobulins can be produced by any technique known to those of skill in the art, including chemical synthesis or recombinant means using standard molecular biology techniques.

[0170] In certain exemplary embodiments, recombinant DNA technology can be used to clone nucleotide sequences encoding the peptides of the present invention, fuse them to an Ig light chain, insert them into an expression vector, transform or transfect them into a suitable host cell, and culture them under conditions suitable for expression (see Examples). The peptide-Ig light chain fusion is then isolated. Advantageously, as those skilled in the art will understand in light of the present disclosure, any peptide sequence can be linked to an Ig antibody using the methods described herein. That is, although an amyloid-reactive peptide is used as an example of a peptide linked to an Ig antibody, the method of linking a peptide to an Ig antibody (e.g., to the N-terminus of an Ig light chain protein and / or the N-terminus and / or C-terminus of an Ig heavy chain protein) can be used for a variety of different peptides to link the peptide to an Ig antibody.

[0171] In certain exemplary embodiments, multiple identical or different peptides may be linked to a single Ig antibody or functional fragment thereof. For example, a first expression vector may contain a light chain nucleic acid sequence integrated with a nucleic acid sequence encoding peptide A, with the nucleic acid sequence for peptide A being placed in the vector so that peptide A is linked to the N-terminus of the light chain protein and expressed. Furthermore, a second expression vector may contain a heavy chain nucleic acid sequence integrated with a nucleic acid sequence encoding peptide B, with the nucleic acid sequence for peptide B being placed in the vector so that peptide B is linked to the N-terminus of the light chain protein and expressed.

[0172] In such an exemplary embodiment, when both expression vectors are expressed in the same cell, the resulting Ig protein will contain one peptide A sequence at the N-terminus of each light chain (for a total of two peptide A sequences). A vector can have peptide A at the N-terminus of the heavy chain and peptide B at the N-terminus of the heavy chain. In certain exemplary embodiments, the vector can include peptide C at the C-terminus, resulting in an antibody with two peptide A sequences (one for each light chain), a peptide B sequence at the N-terminus of the heavy chain, and a peptide C sequence linked to the C-terminus of the heavy chain. Thus, as one of skill in the art will understand based on this disclosure, expression vectors can be tailored to modify immunoglobulins with the same or different protein combinations. As a specific example using an amyloid-reactive peptide, the modified immunoglobulin can contain two p5 protein sequences (SEQ ID NO: 1), i.e., one at the N-terminus of each light chain. In other exemplary embodiments, the peptide linked to the immunoglobulin can have affinity for a ligand and can therefore be used to detect the ligand.

[0173] In certain exemplary embodiments, the modified immunoglobulins can be obtained by isolation or purification. Protein purification techniques involve, at one level, homogenization and crude fractionation of cells, tissues, or organs into peptide and non-peptide fractions. Other protein purification techniques include, for example, precipitation with ammonium sulfate, polyethylene glycol (PEG), antibodies, etc., or by heat denaturation, followed by centrifugation, chromatographic steps (e.g., ion exchange, gel filtration, reverse phase, hydroxylapatite, and affinity chromatography), isoelectric focusing, gel electrophoresis, e.g., polyacrylamide gel electrophoresis, and combinations of these and other techniques.

[0174] Various chromatographic techniques include, but are not limited to, ion exchange chromatography, gel exclusion chromatography, affinity chromatography, immunoaffinity chromatography, and reverse-phase chromatography. A particularly efficient method for purifying peptides is fast performance liquid chromatography (FPLC) or high performance liquid chromatography (HPLC). In certain exemplary embodiments, the Fc domain can be linked to the amyloid-reactive peptide via a GGGYS linker sequence (SEQ ID NO: 27).

[0175] In certain embodiments, the modified immunoglobulin may include an amino acid spacer sequence between the N-terminus of the light chain or the C-terminus of the heavy chain and the amyloid-reactive peptide. In certain embodiments, the peptide-Ig conjugate may include an amino acid spacer sequence between the N-terminus of the peptide and a leader sequence required for secretion of the Ig peptide from cells expressing the reagent. In some embodiments, the spacer peptide may comprise or consist of from about 3 to about 55 amino acids. The spacer peptide of the present invention can comprise or consist of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 amino acids. As used herein, a nucleic acid sequence or amino acid sequence is "adjacent" to another nucleic acid sequence or amino acid sequence if the nucleic acid sequence or amino acid sequence is adjacent to each other in sequence. For example, two nucleic acid sequences can be adjacent to each other as described herein, but still contain an intervening spacer sequence.

[0176] B. Antibody-Peptide Fusion Protein Also provided herein are antibody-peptide fusion proteins that target amyloid.Such antibody-peptide fusion proteins include, for example, amyloid-reactive peptides, which are linked to immunoglobulin (Ig) through, for example, fragments, N-terminal extensions of Ig light chain proteins in antigen binding (Fab) regions, or through the C-terminal ends of heavy chains, thereby forming peptide-Ig fusions.Antibody-peptide fusion proteins can be used to treat subjects suffering from amyloidosis, for example, by administering antibody-peptide fusion proteins to subjects.

[0177] In some embodiments, the antibody-peptide fusion protein comprises an antibody linked to a peptide, hi some embodiments, the antibody-peptide fusion protein comprises an antibody comprising one, two, three, four, five, or six CDRs of an antibody as shown in Table 3.

[0178] In certain embodiments, the antibody-peptide fusion protein comprises an antibody, wherein the antibody comprises a VH comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19, wherein the antibody is linked to a peptide.

[0179] In certain embodiments, the antibody-peptide fusion protein comprises an antibody, wherein the antibody comprises a VL comprising (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the antibody is linked to a peptide.

[0180] In one embodiment, the antibody-peptide fusion protein comprises an antibody comprising a VL comprising the amino acid sequence of SEQ ID NO: 16 and a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the antibody is linked to a peptide.

[0181] In another aspect, an antibody-peptide fusion protein comprises an antibody, wherein the antibody comprises a VH comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19, and a VL comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the antibody is linked to a peptide. In some embodiments, the antibody-peptide fusion protein comprises the antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences listed in Table 1. In some embodiments, the antibody-peptide fusion protein comprises the antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the antibody-peptide fusion protein comprises the antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0182] In another aspect, an antibody-peptide fusion protein comprises an antibody, wherein the antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 of a VH having the sequence set forth in SEQ ID NO: 15, and a VL CDR1, a VL CDR2, and a VL of a VL having the sequence set forth in SEQ ID NO: 16, wherein the antibody is linked to a peptide. In some embodiments, the antibody-peptide fusion protein comprises an antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences listed in Table 1. In some embodiments, the antibody-peptide fusion protein comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the antibody-peptide fusion protein comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0183] In some embodiments, the antibody-peptide fusion protein comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide. In some embodiments, the antibody-peptide fusion protein comprises a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 without the C-terminal lysine residue and a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the antibody is linked to a peptide.

[0184] In another aspect, the antibody-peptide fusion protein comprises an antibody linked to an amyloid-reactive peptide. In some embodiments, the antibody-peptide fusion protein is an antibody linked to an amyloid-reactive peptide listed in Table 1. In some embodiments, the antibody-peptide fusion protein comprises an antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences set forth in SEQ ID NO: 1. In some embodiments, the antibody-peptide fusion protein comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the peptide is linked to the N-terminus of the light chain or the C-terminus of the heavy chain of the antibody. In some embodiments, the antibody also comprises a spacer amino acid sequence between the peptide and the N-terminus of the light chain or the C-terminus of the heavy chain. In some embodiments, the peptide is linked to the N-terminus of the light chain.

[0185] In some embodiments, an antibody-peptide fusion protein comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the heavy chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, an antibody-peptide fusion protein comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, an antibody-peptide fusion protein comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0186] In some embodiments, the antibody-peptide fusion protein comprises an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the antibody-peptide fusion protein comprises an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the antibody-peptide fusion protein comprises an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0187] In some embodiments, the antibody-peptide fusion protein comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1.

[0188] In some embodiments, the antibody-peptide fusion protein comprises an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide is linked to the light chain at the N-terminus.

[0189] In some embodiments, the antibody-peptide fusion protein comprises an antibody, comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15, and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the peptide is linked to the light chain at the N-terminus.

[0190] In some embodiments, the antibody-peptide fusion proteins described herein bind to amyloid deposits or amyloid fibrils. In some embodiments, the antibody-peptide fusion proteins bind to one or more amyloidogenic peptides of amyloid. In some embodiments, the amyloid bound by the antibody-peptide fusion protein comprises an amyloidogenic λ6 variable domain protein (Vλ6Wil) or an amyloidogenic immunoglobulin light chain (AL), Aβ(1-40) amyloid-like fibrils or amyloidogenic Aβ precursor protein, or serum amyloid protein A (AA). In other embodiments, the amyloid bound by the antibody-peptide fusion protein comprises an amyloidogenic form of immunoglobulin heavy chain (AH), β2-microglobulin (Aβ2M), transthyretin variant (ATTR), apolipoprotein AI (AApoAI), apolipoprotein B (AApoA1), or amyloidogenic forms of immunoglobulin heavy chain (AH). Examples of amyloidogenic peptides include protein AII (AApoAII), gelsolin (AGel), lysozyme (ALys), leukocyte chemoattractant (ALect2), fibrinogen A variant (AFib), cystatin variant (ACys), calcitonin (ACal), lactadherin (AMed), islet amyloid polypeptide (AIAPP), prolactin (APro), insulin (AIns), prion protein (APrP), alpha-synuclein (AαSyn), tau (ATau), atrial natriuretic factor (AANF), or IAAP, ALκ4, A1λ1, and other amyloidogenic peptides. The amyloidogenic peptide bound by the antibody-peptide fusion protein may be a protein, protein fragment, or protein domain. In some embodiments, the amyloid deposits or amyloid fibrils comprise recombinant amyloidogenic proteins. In some embodiments, amyloid is part of the pathology of a disease.

[0191] In some embodiments, the antibodies provided herein specifically bind to amyloid light chain fibrils. In some embodiments, the amyloid-reactive peptide binds to various amyloid fibrils, such as amyloidogenic λ6 variable domain protein (Vλ6Wil) or amyloidogenic immunoglobulin light chain (AL), Aβ(1-40) amyloid-like fibrils or amyloidogenic Aβ precursor protein, or serum amyloid protein A (AA). In other embodiments, the amyloid bound by the antibody-peptide fusion protein comprises amyloidogenic forms of immunoglobulin heavy chain (AH), beta2-microglobulin (Aβ2M), transthyretin variant (ATTR), apolipoprotein AI (AApoAI), apolipoprotein AII (AApoAII), gelsolin (AGel), lysozyme (ALys), leukocyte chemoattractant (ALect2), fibrinogen A variant (AFib), cystatin variant (ACys), calcitonin (ACal), lactadherin (AMed), islet amyloid polypeptide (AIAPP), prolactin (APro), insulin (AIns), prion protein (APrP), alpha-synuclein (AαSyn), tau (ATau), atrial natriuretic factor (AANF), or IAAP, ALκ4, A1λ1, or other amyloidogenic peptides. In some embodiments, the amyloid reactive peptide binds to heparan sulfate glycosaminoglycans.

[0192] As those skilled in the art will appreciate, an antigen-binding fragment (or Fab region) is the head of an antibody that naturally interacts with a target antigen. The Fab region components, for example, enable the antibody to bind to a specific ligand and, through this interaction, further activate the immune system. For antibody isotypes IgG, IgA, IgD, IgE, and IgM, Ig consists of two proteins, a heavy chain and a light chain, which interact in pairs to form an intact Ig containing two heavy chains and two light chains. Both the heavy and light chains are further divided into variable and constant domains (light and heavy variable domains, which contain the Fab functional region, and the heavy chains, which form the fragment crystallizable (Fc) domain, which interacts with cellular receptors and complement). The Fc region of Ig contains highly conserved N-glycosylation sites.

[0193] In certain exemplary embodiments, one or more of the peptides shown in Table 1 below can be linked to an Ig antibody or functional fragment thereof via the N-terminus of the light chain protein or the C-terminus of the heavy chain, thereby forming an antibody-peptide fusion protein. That is, any of the sequences identified below in Table 1 can be linked independently or simultaneously to the heavy or light chain of an Ig antibody or functional fragment thereof to form a peptide-Ig conjugate. For example, two of the amyloid-reactive peptides can be linked to a single Ig antibody by linking the amino acid sequence of the amyloid-reactive peptide to the N-terminus of the Ig light chain protein.

[0194] Without wishing to be bound by any particular theory, it is believed that the peptide domain of the peptide-Ig conjugate acts to activate the antibody-peptide fusion protein when administered to a subject. The antibody-peptide fusion protein is believed to target amyloid deposits. The Fc domain then triggers an immune response at the site of the amyloid, resulting in removal of the amyloid, such as by opsonization. In addition, the antibody-peptide fusion protein is believed to have a longer half-life than the amyloid-reactive peptide alone. For example, the circulating half-life of IgG in humans is approximately 21 days, while the half-life of the amyloid-reactive peptide alone in humans is approximately 11 hours. Thus, the Ig enhances the half-life of the antibody-peptide fusion protein in circulation. In certain exemplary embodiments, contacting amyloid deposits with the antibody-peptide fusion protein results in an increased half-life of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or more compared to contacting amyloid deposits with the amyloid-reactive peptide alone. Thus, when administered to a subject, the antibody-peptide fusion protein is able to exert a longer immunostimulatory effect at the site of amyloid deposition, thereby increasing the immune response at the site of amyloid deposition.

[0195] In some embodiments, the amyloid-reactive peptide of the antibody-peptide fusion proteins described herein comprises an amino acid sequence that is at least 80%, 85%, 90%, or more identical to the amino acid sequence set forth as any one of SEQ ID NOs: 1-14 (e.g., at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence set forth as any one of SEQ ID NOs: 1-14). In some embodiments, the amyloid-reactive peptide attached to the Ig antibody or functional fragment thereof may comprise or consist of from about 10 to about 55 amino acids. The amyloid-reactive peptides of the present invention can comprise or consist of, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 amino acids. Such peptides are described, for example, in International Patent Application No. WO2016032949 (incorporated herein in its entirety).

[0196] The amino acids forming all or part of the amyloid-reactive peptide bound to an Ig antibody or fragment thereof can be stereoisomers and modifications, such as naturally occurring amino acids, non-naturally occurring amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, and constructs or structures designed to mimic amino acids. The amino acids forming the peptides of the invention can be one or more of the 20 common amino acids found in naturally occurring proteins, or one or more modified and unconventional amino acids. Antibody-peptide fusion proteins can be produced by any technique known to those of skill in the art, including chemical synthesis or recombinant means using standard molecular biology techniques.

[0197] In certain exemplary embodiments, recombinant DNA technology can be used to clone nucleotide sequences encoding the peptides of the present invention, fuse them to an Ig light chain, insert them into an expression vector, transform or transfect them into a suitable host cell, and culture them under conditions suitable for expression (see Examples). The peptide-Ig light chain fusion is then isolated. Advantageously, as those skilled in the art will understand in light of the present disclosure, any peptide sequence can be linked to an Ig antibody using the methods described herein. That is, although an amyloid-reactive peptide is used as an example of a peptide linked to an Ig antibody, the method of linking a peptide to an Ig antibody (e.g., to the N-terminus of an Ig light chain protein and / or the N-terminus and / or C-terminus of an Ig heavy chain protein) can be used for a variety of different peptides to link the peptide to an Ig antibody.

[0198] In certain exemplary embodiments, multiple peptides, the same or different, may be linked to a single Ig antibody or functional fragment thereof. For example, a first expression vector encodes peptide A. The second expression vector may comprise a light chain nucleic acid sequence integrated with a nucleic acid sequence encoding peptide B, with the nucleic acid sequence for peptide A being placed in the vector so that peptide A is linked to the N-terminus of the light chain protein and expressed. Additionally, the second expression vector may comprise a heavy chain nucleic acid sequence integrated with a nucleic acid sequence encoding peptide B, with the nucleic acid sequence for peptide B being placed in the vector so that peptide B is linked to the N-terminus of the light chain protein and expressed.

[0199] In such exemplary embodiments, when both expression vectors are expressed in the same cell, the resulting Ig protein can have one peptide A sequence at the N-terminus of each light chain (for a total of two peptide As) and a peptide B sequence at the N-terminus of the heavy chain. In certain exemplary embodiments, the vector can include a peptide C at the C-terminus, resulting in an antibody with two peptide A sequences (one for each light chain), a peptide B sequence at the N-terminus of the heavy chain, and a peptide C sequence linked to the C-terminus of the heavy chain. Thus, as one of skill in the art would understand based on this disclosure, expression vectors can be tailored to modify immunoglobulins with the same or different protein combinations. As a specific example using an amyloid-reactive peptide, an antibody-peptide fusion protein can contain two p5 protein sequences (SEQ ID NO: 1), i.e., one at the N-terminus of each light chain. In other exemplary embodiments, the peptide linked to the immunoglobulin can have affinity for a ligand and can therefore be used to detect the ligand.

[0200] In certain exemplary embodiments, the antibody-peptide fusion protein can be obtained by isolation or purification. Protein purification techniques involve, at one level, homogenization and crude fractionation of cells, tissues, or organs into peptide and non-peptide fractions. Other protein purification techniques include, for example, precipitation with ammonium sulfate, polyethylene glycol (PEG), antibodies, etc., or precipitation by heat denaturation, followed by centrifugation, chromatographic steps (e.g., ion exchange, gel filtration, reverse phase, hydroxylapatite, and affinity chromatography), isoelectric focusing, gel electrophoresis, e.g., polyacrylamide gel electrophoresis, and combinations of these and other techniques.

[0201] Various chromatographic techniques include, but are not limited to, ion exchange chromatography, gel exclusion chromatography, affinity chromatography, immunoaffinity chromatography, and reverse-phase chromatography. A particularly efficient method for purifying peptides is fast performance liquid chromatography (FPLC) or high performance liquid chromatography (HPLC). In certain exemplary embodiments, the Fc domain can be linked to the amyloid-reactive peptide via a GGGYS linker sequence (SEQ ID NO: 27).

[0202] In certain embodiments, antibody-peptide fusion proteins may contain an amino acid spacer sequence between the N-terminus of the light chain or the C-terminus of the heavy chain and the amyloid-reactive peptide. In certain embodiments, peptide-Ig conjugates may contain an amino acid spacer sequence between the N-terminus of the peptide and a leader sequence required for secretion of the Ig peptide from cells expressing the reagent. In some embodiments, the spacer peptide may comprise or consist of from about 3 to about 55 amino acids. The spacer peptide of the present invention can comprise or consist of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 amino acids. As used herein, a nucleic acid sequence or amino acid sequence is "adjacent" to another nucleic acid sequence or amino acid sequence if the nucleic acid sequence or amino acid sequence is adjacent to each other in sequence. For example, two nucleic acid sequences can be adjacent to each other as described herein, but still contain an intervening spacer sequence.

[0203] III. Humanized Antibodies that Bind to Human Amyloid Fibrils Provided herein are humanized antibodies that bind to human amyloid fibrils. In some embodiments, the humanized antibodies comprise a light chain variable region (VL) and a heavy chain variable region (VH) that comprise one or more CDRs of a murine antibody. In some embodiments, the VH and / or VL are derived from human VH and / or VL sequences (e.g., "human acceptor sequences"). In some embodiments, the VH and / or VL comprise amino acid substitutions, e.g., in the framework regions of the VH and / or VL.

[0204] A. Humanized Antibodies In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises one, two, three, four, five, or six CDRs of an antibody as set forth in Table 3. In some embodiments, the humanized antibody comprises CDR-H1, CDR-H2, and CDR-H3 of the VH, which have the amino acid sequences set forth in SEQ ID NO: 15, respectively, and CDR-L1, CDR-L2, and CDR-L3 of the VL, which have the amino acid sequences set forth in SEQ ID NO: 16, respectively. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20 with one or more conservative amino acid substitutions, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21 with one or more conservative amino acid substitutions, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22 with one or more conservative amino acid substitutions, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17 with one or more conservative amino acid substitutions, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18 with one or more conservative amino acid substitutions, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19 with one or more conservative amino acid substitutions. In some embodiments, the humanized antibody comprises one, two, three, four, five, or six CDRs of an antibody shown in Table 3, with one or more conservative amino acid substitutions.In some embodiments, the humanized antibody comprises CDR-H1, CDR-H2, and CDR-H3 of the VH comprising the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3, respectively, having the sequence set forth in SEQ ID NO: 15 with one or more conservative amino acid substitutions, and CDR-L1, CDR-L2, and CDR-L3 of the VL comprising the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3, respectively, having the sequence set forth in SEQ ID NO: 16 with one or more conservative amino acid substitutions.

[0205] In some embodiments, a humanized antibody that binds to human amyloid fibrils comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises framework regions (FR), and the VH comprises framework regions (FR). In some embodiments, the framework regions are FR1, FR2, FR3, or FR4. In some embodiments, the VL comprises FR1, FR2, FR3, and FR4. In some embodiments, the VL comprises, from N-terminus to C-terminus, FR1, CDR-L1, FR2, CDR-L2, FR3, CDR-L3, and FR4. In some embodiments, the VH comprises FR1, FR2, FR3, or FR4. In some embodiments, the VH comprises, from N-terminus to C-terminus, FR1, CDR-H1, FR2, CDR-H2, FR3, CDR-H3, and FR4. In some embodiments, a humanized antibody comprises a VL and / or VH that contain amino acid substitutions at one or more positions in the framework regions (e.g., FR1, FR2, FR3, or FR4) compared to the human acceptor sequence with the grafted CDRs (e.g., SEQ ID NO: 32 or SEQ ID NO: 43).

[0206] In some embodiments, the humanized antibody comprises a VL comprising an amino acid substitution in FR2 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the amino acid substitution in FR2 is selected from the group consisting of an amino acid substitution at position 36, an amino acid substitution at position 37, and an amino acid substitution at position 46, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in FR2 is selected from the group consisting of a Tyr at position 36, a Leu at position 37, and a Leu at position 46, wherein the amino acid positions are numbered according to the Kabat numbering system.

[0207] In some embodiments, the humanized antibody comprises a VL comprising an amino acid substitution in FR3 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the amino acid substitution in FR3 is selected from the group consisting of an amino acid substitution at position 85 and an amino acid substitution at position 87, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in FR3 is selected from the group consisting of a Leu at position 85 and a Phe at position 87, wherein the amino acid positions are numbered according to the Kabat numbering system.

[0208] In some embodiments, the humanized antibody comprises a VH comprising an amino acid substitution in FR2 compared to a VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the amino acid substitution in FR2 is selected from the group consisting of an amino acid substitution at position 37 and an amino acid substitution at position 48, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in FR2 is selected from the group consisting of a Val at position 37 and a Leu at position 48, wherein the amino acid positions are numbered according to the Kabat numbering system.

[0209] In some embodiments, the humanized antibody comprises a VH comprising an amino acid substitution in FR3 compared to a VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the amino acid substitution in FR3 is selected from the group consisting of an amino acid substitution at position 67, an amino acid substitution at position 48, an amino acid substitution at position 71, an amino acid substitution at position 76, an amino acid substitution at position 78, an amino acid substitution at position 79, an amino acid substitution at position 80, an amino acid substitution at position 89, an amino acid substitution at position 93, and an amino acid substitution at position 94, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in FR3 is selected from the group consisting of a Leu at position 67, a Ser at position 48, a Lys at position 71, a Ser at position 76, a Val at position 78, a Leu at position 79, a Phe at position 80, a Thr at position 89, a Val at position 93, and a Thr at position 94, wherein the amino acid positions are numbered according to the Kabat numbering system.

[0210] In some embodiments, the humanized antibody comprises a VL comprising one or more amino acid substitutions at one or more positions in the VL compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32, wherein the amino acid positions are numbered sequentially starting from the N-terminus of SEQ ID NO: 32. In some embodiments, the humanized antibody comprises a VL comprising an amino acid substitution at position 33 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the humanized antibody comprises a VL comprising an amino acid substitution at position 34 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the humanized antibody comprises a VL comprising an amino acid substitution at position 41 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the humanized antibody comprises a VL comprising an amino acid substitution at position 42 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the humanized antibody comprises a VL comprising an amino acid substitution at position 51 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the humanized antibody comprises a VL comprising an amino acid substitution at position 90 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the humanized antibody comprises a VL comprising an amino acid substitution at position 92 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In embodiments, the humanized antibody comprises a VL that comprises 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions compared to a VL that comprises the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the humanized antibody comprises a VL that comprises 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions compared to a VL1 as shown in Table 6A.

[0211] In some embodiments, a humanized antibody comprises a VL comprising one or more amino acid residues at one or more positions of the VL, where the amino acid positions are numbered starting from the N-terminus of the VL according to the numbering of SEQ ID NO: 32. In some embodiments, a humanized antibody comprises a VL comprising Ser, Gln, Glu, His, or Ala at position 33. In some embodiments, a humanized antibody comprises a VL comprising Ala or Val at position 34. In some embodiments, a humanized antibody comprises a VL comprising Tyr at position 41. In some embodiments, a humanized antibody comprises a VL comprising Leu at position 42. In some embodiments, a humanized antibody comprises a VL comprising Leu at position 51. In some embodiments, a humanized antibody comprises a VL comprising Leu at position 90. In some embodiments, a humanized antibody comprises a VL comprising Phe at position 92.

[0212] In some embodiments, a humanized antibody comprises a VH comprising one or more amino acid residues at one or more positions of the VH, where the amino acid positions are numbered starting from the N-terminus of the VH. In some embodiments, a humanized antibody comprises a VH comprising Val at position 37. In some embodiments, a humanized antibody comprises a VH comprising Leu at position 48. In some embodiments, a humanized antibody comprises a VH comprising Leu at position 67. In some embodiments, a humanized antibody comprises a VH comprising Ser at position 68. In some embodiments, a humanized antibody comprises a VH comprising Lys at position 71. In some embodiments, a humanized antibody comprises a VH comprising Ser at position 76. In some embodiments, a humanized antibody comprises a VH comprising Val at position 78. In some embodiments, a humanized antibody comprises a VH comprising Leu at position 79. In some embodiments, a humanized antibody comprises a VH comprising Phe at position 80. In some embodiments, a humanized antibody comprises a VH comprising Thr at position 92. In some embodiments, the humanized antibody comprises a VH that comprises a Val at position 96. In some embodiments, the humanized antibody comprises a VH that comprises a Thr at position 97.

[0213] In some embodiments, a humanized antibody comprises a VL comprising one or more amino acid residues at one or more positions in the VL, where the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, a humanized antibody comprises a VL comprising a Tyr at position 36. In some embodiments, a humanized antibody comprises a VL comprising a Leu at position 37. In some embodiments, a humanized antibody comprises a VL comprising a Leu at position 46. In some embodiments, a humanized antibody comprises a VL comprising a Leu at position 85. In some embodiments, a humanized antibody comprises a VL comprising a Phe at position 87.

[0214] In some embodiments, a humanized antibody comprises a VL comprising one or more amino acid residues at one or more positions in the VL, where the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, a humanized antibody comprises a VL comprising a Tyr at position 36 and a Leu at position 37. In some embodiments, a humanized antibody comprises a VL comprising a Tyr at position 36, a Leu at position 37, a Leu at position 46, a Leu at position 85, and a Phe at position 87. In some embodiments, a humanized antibody comprises a VL comprising a Leu at position 46 and a Phe at position 87.

[0215] In some embodiments, the humanized antibody comprises a VH comprising one or more amino acid residues at one or more positions in the VH, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the humanized antibody comprises a VH comprising Val at position 37. In some embodiments, the humanized antibody comprises a VH comprising Leu at position 48. In some embodiments, the humanized antibody comprises a VH comprising Leu at position 67. In some embodiments, the humanized antibody comprises In some embodiments, the humanized antibody comprises a VH comprising Ser at position 68. In some embodiments, the humanized antibody comprises a VH comprising Lys at position 71. In some embodiments, the humanized antibody comprises a VH comprising Ser at position 76. In some embodiments, the humanized antibody comprises a VH comprising Val at position 78. In some embodiments, the humanized antibody comprises a VH comprising Leu at position 79. In some embodiments, the humanized antibody comprises a VH comprising Phe at position 80. In some embodiments, the humanized antibody comprises a VH comprising Thr at position 89. In some embodiments, the humanized antibody comprises a VH comprising Val at position 93. In some embodiments, the humanized antibody comprises a VH comprising Thr at position 94.

[0216] In some embodiments, a humanized antibody comprises a VH comprising one or more amino acid residues at one or more positions in the VH, where the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, a humanized antibody comprises a VH comprising Val at position 37 and Leu at position 48. In some embodiments, a humanized antibody comprises a VH comprising Leu at position 67, Ser at position 68, Thr at position 89, Val at position 93, and Thr at position 94. In some embodiments, a humanized antibody comprises a VH comprising Val at position 37, Leu at position 48, Leu at position 67, and Ser at position 68. In some embodiments, a humanized antibody comprises a VH comprising Val at position 37, Leu at position 48, Val at position 93, and Thr at position 94. In some embodiments, the humanized antibody comprises a VH comprising Val at position 37, Leu at position 48, Leu at position 67, Ser at position 68, Lys at position 71, Thr at position 89, Val at position 93, and Thr at position 94. In some embodiments, the humanized antibody comprises a VH comprising Lys at position 71, Val at position 78, Leu at position 79, Val at position 93, and Thr at position 94. In some embodiments, the humanized antibody comprises a VH comprising Lys at position 71, Ser at position 76, Val at position 93, and Thr at position 94. In some embodiments, the humanized antibody comprises a VH comprising Leu at position 48, Ser at position 96, Val at position 78, Leu at position 79, Phe at position 80, and Thr at position 94. In some embodiments, the humanized antibody comprises a VH comprising Leu at position 48, Leu at position 67, Ser at position 68, Lys at position 71, Ser at position 76, Val at position 78, Leu at position 79, Val at position 93, and Thr at position 94.

[0217] In some embodiments, the humanized antibody comprises a VL comprising a Tyr at position 36, a Leu at position 37, a Leu at position 46, a Leu at position 85, and a Phe at position 87, and a VH comprising a Val at position 37, a Leu at position 48, a Leu at position 67, a Ser at position 68, a Lys at position 71, a Thr at position 89, a Val at position 93, and a Thr at position 94. In some embodiments, the humanized antibody comprises a VL comprising a Leu at position 46 and a Phe at position 87, and a VH comprising a Leu at position 48, a Ser at position 96, a Val at position 78, a Leu at position 79, a Phe at position 80, and a Thr at position 94. In some embodiments, the humanized antibody comprises a VL comprising a Leu at position 46 and a Phe at position 87, and a VH comprising a Leu at position 48, a Leu at position 67, a Ser at position 68, a Lys at position 71, a Val at position 93, and a Thr at position 94. In some embodiments, the humanized antibody comprises a VL comprising a Leu at position 46 and a Phe at position 87, and a VH comprising a Lys at position 71, a Ser at position 76, a Val at position 93, and a Thr at position 94. In some embodiments, the humanized antibody comprises a VL comprising a Leu at position 46 and a Phe at position 87, and a VH comprising a Lys at position 71, a Val at position 78, a Leu at position 79, a Val at position 93, and a Thr at position 94.

[0218] In some embodiments, the humanized antibody comprises the amino acid sequence of a VL set forth in Table 6 A. In some embodiments, the humanized antibody comprises a VL selected from the group consisting of VL2, VL3, VL4, VL4-N33S, VL4-N33Q, VL4-N33E, VL4-N33A, VL4-N33H, VL4-G34A, or VL4-G34V set forth in Table 6 A. In some embodiments, the VL comprises the amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42.

[0219] In some embodiments, the humanized antibody comprises the amino acid sequence of a VH set forth in Table 6B. In some embodiments, the humanized antibody comprises a VH selected from the group consisting of VH2, VH3, VH4, VH5, VH6, VH7, VH8, VH9, VH10, VH9-D54S, VH9-D54Q, VH9-D54E, VH9-D54A, VH9-D54H, VH9-G55A, VH9-G55V, VH9-M64V, VH9-M64I, VH9-M64L, or VH9-M64A set forth in Table 6B. In some embodiments, the VH comprises the amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63.

[0220] In some embodiments, the humanized antibody comprises a VL of VL4 shown in Table 6A and a VH of VH9 shown in Table 6B. In some embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:35, and the VH comprises the amino acid sequence set forth in SEQ ID NO:51.

[0221] In some embodiments, the humanized antibody comprises a VL of VL3 shown in Table 6A and a VH of VH6 shown in Table 6B. In some embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:34, and the VH comprises the amino acid sequence set forth in SEQ ID NO:48.

[0222] In some embodiments, the humanized antibody comprises a VL of VL4 shown in Table 6A and a VH of VH10 shown in Table 6B. In some embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:35, and the VH comprises the amino acid sequence set forth in SEQ ID NO:52. In some embodiments, the humanized antibody comprises a VL of VL4 shown in Table 6A and a VH of VH8 shown in Table 6B. In some embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:35, and the VH comprises the amino acid sequence set forth in SEQ ID NO:50. In some embodiments, the humanized antibody comprises a VL of VL4 shown in Table 6A and a VH of VH7 shown in Table 6B. In some embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:35, and the VH comprises the amino acid sequence set forth in SEQ ID NO:69.

[0223] In some embodiments, the humanized antibody is a full-length antibody, a Fab fragment, or an scFv.

[0224] Humanized antibodies with CDR replacements In some embodiments, the humanized antibody comprises one or more CDR substitutions. In some embodiments, the CDR substitutions are in CDR-L1. In some embodiments, the CDR substitutions are in CDR-H2.

[0225] In some embodiments, the humanized antibody comprises a VL comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 64 to 70, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and a VH comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a VL comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and a VH comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 71 to 81, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a VL comprising one or more amino acid residues selected from the group consisting of Tyr at position 36, Leu at position 37, Leu at position 46, Leu at position 85, and Phe at position 87, where the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the humanized antibody comprises a VH comprising one or more amino acid residues selected from the group consisting of Val at position 37, Leu at position 48, Leu at position 67, Ser at position 68, Lys at position 71, Ser at position 76, Val at position 78, Lys at position 79, Lys at position 80, Lys at position 81, Lys at position 82, Lys at position 83, Lys at position 84, Lys at position 85, Lys at position 86, Lys at position 87, Lys at position 88, Lys at position 89, Lys at position 90, Lys at position 91, Lys at position 92, Lys at position 93, Lys at position 94, Lys at position 95, Lys at position 96, Lys at position 97, Lys at position 98, Lys at position 99, Lys at position 100, Lys at position 101, Lys at position 102, Lys at position 103, Lys at position 104, Lys at position 105, Lys at position 106, Lys at position 107, Lys at position 108, Lys at position 109, Lys at position 110, Lys at position 111, Lys at position 112, Lys at position 113, Lys at position 114, Lys at position 115, Lys at position 116, Lys at position 117, Lys at position 118, Lys at position 119, Ly eu, Phe at position 80, Thr at position 89, Val at position 93, Thr at position 94 (amino acid positions are numbered according to the Kabat numbering system).

[0226] In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 64, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 65, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 66, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 67, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19.In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 68, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 69, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 70, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19.

[0227] In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 71, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20. and CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 21, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 72, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 73, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 74, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 75, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19.In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 76, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 77, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 78, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 79, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19.In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 80, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 21. and CDR-L3 having the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 81, and CDR-H3 having the amino acid sequence set forth in SEQ ID NO: 19.

[0228] In some embodiments, the humanized antibody comprises one, two, three, four, five, or six CDRs of an antibody shown in Table 6C and / or Table 6D.

[0229] In some embodiments, the humanized antibody comprises CDR-H1, CDR-H2, and CDR-H3 of the VH having the amino acid sequences set forth in SEQ ID NOs: 53 to 63, respectively. In some embodiments, the humanized antibody comprises CDR-L1, CDR-L2, and CDR-L3 of the VL having the amino acid sequences set forth in SEQ ID NOs: 36 to 42, respectively.

[0230] In some embodiments, the humanized antibody comprises a VL comprising an amino acid substitution in CDR-L1 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 35. In some embodiments, the amino acid substitution in CDR-L1 is selected from the group consisting of an amino acid substitution at position 28 and an amino acid substitution at position 29, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in CDR-L1 is selected from the group consisting of Ser, Gln, Glu, His, or Ala at position 28, wherein the amino acid position is numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in CDR-L1 is selected from the group consisting of Ala or Val at position 29, wherein the amino acid position is numbered according to the Kabat numbering system.

[0231] In some embodiments, the humanized antibody comprises a VH comprising an amino acid substitution in CDR-H2 compared to a VH comprising the amino acid sequence set forth in SEQ ID NO: 51. In some embodiments, the amino acid substitution in CDR-H2 is selected from the group consisting of an amino acid substitution at position 54, position 55, or position 64, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in CDR-H2 is selected from the group consisting of Ser, Gln, Glu, Ala, or His at position 54, wherein the amino acid position is numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in CDR-H2 is selected from the group consisting of Ala or Val at position 55, wherein the amino acid position is numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in CDR-H2 is selected from the group consisting of Val, Ile, Leu, or Ala at position 64, wherein the amino acid position is numbered according to the Kabat numbering system.

[0232] B. Antibody-peptide fusion proteins, including humanized antibodies Also provided herein are antibody-peptide fusion proteins comprising a humanized antibody that binds to human amyloid fibrils fused to an amyloid-reactive peptide. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody described herein. In some embodiments, the humanized antibody is any one of the humanized antibodies described above.

[0233] In certain embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO:20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO:18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO:19. In some embodiments, the humanized antibody comprises one, two, three, four, five, or six CDRs of an antibody as shown in Table 3. In some embodiments, the humanized antibody comprises CDR-H1, CDR-H2, and CDR-H3 of the VH comprising the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3, respectively, having the sequence set forth in SEQ ID NO: 15, and CDR-L1, CDR-L2, and CDR-L3 of the VL comprising the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3, respectively, having the sequence set forth in SEQ ID NO: 16. In some embodiments, the humanized antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20 with one or more conservative amino acid substitutions, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21 with one or more conservative amino acid substitutions, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22 with one or more conservative amino acid substitutions, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17 with one or more conservative amino acid substitutions, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18 with one or more conservative amino acid substitutions, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19 with one or more conservative amino acid substitutions. In some embodiments, the humanized antibody comprises one, two, three, four, five, or six CDRs of an antibody shown in Table 3, with one or more conservative amino acid substitutions. In some embodiments, the humanized antibody comprises CDR-H1, CDR-H2, and CDR-H3 of the VH comprising the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3, respectively, having the sequence set forth in SEQ ID NO: 15 with one or more conservative amino acid substitutions, and CDR-L1, CDR-L2, and CDR-L3 of the VL comprising the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3, respectively, having the sequence set forth in SEQ ID NO: 16 with one or more conservative amino acid substitutions.

[0234] In some embodiments, the humanized antibody comprises a VL comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 64-70, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and a VH comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and a VH comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 71-81, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19.

[0235] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising an amino acid substitution in FR2 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the amino acid substitution in FR2 is selected from the group consisting of an amino acid substitution at position 36, an amino acid substitution at position 37, and an amino acid substitution at position 46, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in FR2 is selected from the group consisting of a Tyr at position 36, a Leu at position 37, and a Leu at position 46, wherein the amino acid positions are numbered according to the Kabat numbering system.

[0236] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising an amino acid substitution in FR3 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the amino acid substitution in FR3 is selected from the group consisting of an amino acid substitution at position 85 and an amino acid substitution at position 87, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in FR3 is selected from the group consisting of a Leu at position 85 and a Phe at position 87, wherein the amino acid positions are numbered according to the Kabat numbering system.

[0237] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution in FR2 compared to a VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the amino acid substitution in FR2 is selected from the group consisting of an amino acid substitution at position 37 and an amino acid substitution at position 48, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in FR2 is selected from the group consisting of a Val at position 37 and a Leu at position 48, wherein the amino acid positions are numbered according to the Kabat numbering system.

[0238] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution in FR3 compared to a VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the amino acid substitution in FR3 is selected from the group consisting of an amino acid substitution at position 67, an amino acid substitution at position 48, an amino acid substitution at position 71, an amino acid substitution at position 71, an amino acid substitution at position 76, an amino acid substitution at position 78, an amino acid substitution at position 79, an amino acid substitution at position 80, an amino acid substitution at position 89, an amino acid substitution at position 93, and an amino acid substitution at position 94, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in FR3 is selected from the group consisting of Leu at position 67, Ser at position 48, Lys at position 71, Ser at position 76, Val at position 78, Leu at position 79, Phe at position 80, Thr at position 89, Val at position 93, and Thr at position 94, wherein the amino acid positions are numbered according to the Kabat numbering system.

[0239] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising one or more amino acid substitutions at one or more positions in the VL compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32, wherein the amino acid positions are numbered starting from the N-terminus of SEQ ID NO: 32. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising an amino acid substitution at position 33 compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising an amino acid substitution at position 34 compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising an amino acid substitution at position 41 compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising an amino acid substitution at position 42 compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising an amino acid substitution at position 51 compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising an amino acid substitution at position 90 compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising an amino acid substitution at position 92 compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions compared to the VL1 as shown in Table 6A.

[0240] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising one or more amino acid substitutions at one or more positions in the VH compared to a VH comprising the amino acid sequence set forth in SEQ ID NO:43, wherein the amino acid positions are from the N-terminus to the N-terminus of SEQ ID NO:43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 37 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 48 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 67 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 68 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 71 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 76 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 78 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 79 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 80 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 92 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 96 compared to a VH comprising the amino acid sequence set forth in SEQ ID NO:43.In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising an amino acid substitution at position 97 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions compared to VH1 as shown in Table 6B.

[0241] In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising one or more amino acid residues at one or more positions of the VL, where the amino acid positions are numbered starting from the N-terminus of the VL. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising Ser, Gln, Glu, His, or Ala at position 33. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising Ala or Val at position 34. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising Tyr at position 41. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising Leu at position 42. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising Leu at position 51. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising Leu at position 90. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising a Phe at position 92.

[0242] In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising one or more amino acid residues at one or more positions in the VH, wherein the amino acid positions are Numbering begins at the N-terminus. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Val at position 37. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Leu at position 48. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Leu at position 67. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Ser at position 68. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Lys at position 71. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Ser at position 76. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Val at position 78. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Leu at position 79. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Phe at position 80. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Thr at position 92. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Val at position 96. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Thr at position 97.

[0243] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising one or more amino acid substitutions at one or more positions in the VL, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising a Tyr at position 36. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising a Leu at position 37. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising a Leu at position 46. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising a Leu at position 85. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising a Phe at position 87.

[0244] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising one or more amino acid residues at one or more positions in the VL, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising a Tyr at position 36 and a Leu at position 37. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising a Tyr at position 36, a Leu at position 37, a Leu at position 46, a Leu at position 85, and a Phe at position 87. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising a Leu at position 46 and a Phe at position 87.

[0245] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising one or more amino acid residues at one or more positions in the VH, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Val at position 37. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Leu at position 48. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Leu at position 67. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Ser at position 68. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Lys at position 71. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Ser at position 76. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Val at position 78. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Leu at position 79. In some embodiments, the antibody-peptide fusion comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Phe at position 80. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Thr at position 89. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Val at position 93. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Thr at position 94.

[0246] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising one or more amino acid residues at one or more positions in the VH, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Val at position 37 and a Leu at position 48. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Leu at position 67, a Ser at position 68, a Thr at position 89, a Val at position 93, and a Thr at position 94. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Val at position 37, a Leu at position 48, a Leu at position 67, and a Ser at position 68. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Val at position 37, Leu at position 48, Val at position 93, and Thr at position 94. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Val at position 37, Leu at position 48, Leu at position 67, Ser at position 68, Lys at position 71, Thr at position 89, Val at position 93, and Thr at position 94. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Lys at position 71, Val at position 78, Leu at position 79, Val at position 93, and Thr at position 94. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising Lys at position 71, Val at position 78, Leu at position 79, Val at position 93, and Thr at position 94. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Leu at position 48, a Ser at position 96, a Val at position 78, a Leu at position 79, a Phe at position 80, and a Thr at position 94. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH comprising a Leu at position 48, a Leu at position 67, a Ser at position 68, a Lys at position 71, a Ser at position 76, a Val at position 78, a Leu at position 79, a Val at position 93, and a Thr at position 94.

[0247] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, the humanized antibody comprising a VL comprising a Tyr at position 36, a Leu at position 37, a Leu at position 46, a Leu at position 85, and a Phe at position 87, and a VH comprising a Val at position 37, a Leu at position 48, a Leu at position 67, a Ser at position 68, a Lys at position 71, a Thr at position 89, a Val at position 93, and a Thr at position 94. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, the humanized antibody comprising a VL comprising a Leu at position 46 and a Phe at position 87, and a VH comprising a Leu at position 48, a Ser at position 96, a Val at position 78, a Leu at position 79, a Phe at position 80, and a Thr at position 94. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, the humanized antibody comprising a VL comprising a Leu at position 46 and a Phe at position 87, and a VH comprising a Leu at position 48, a Leu at position 67, a Ser at position 68, a Lys at position 71, a Ser at position 76, a Val at position 78, a Leu at position 79, a Val at position 93, and a Thr at position 94. ... and a VH comprising a Lys at position 71, a Ser at position 76, a Val at position 93, and a Thr at position 94. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL comprising a Leu at position 46 and a Phe at position 87, and a VH comprising a Lys at position 71, a Val at position 78, a Leu at position 79, a Val at position 93, and a Thr at position 94.

[0248] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising the amino acid sequence of a VL set forth in Table 6 A. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VL selected from the group consisting of VL2, VL3, VL4, VL4-N33S, VL4-N33Q, VL4-N33E, VL4-N33A, VL4-N33H, VL4-G34A, or VL4-G34V set forth in Table 6 A. In some embodiments, the VL comprises the amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42.

[0249] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising the amino acid sequence of a VH set forth in Table 6B. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a VH selected from the group consisting of VH2, VH3, VH4, VH5, VH6, VH7, VH8, VH9, VH10, VH9-D54S, VH9-D54Q, VH9-D54E, VH9-D54A, VH9-D54H, VH9-G55A, VH9-G55V, VH9-M64V, VH9-M64I, VH9-M64L, or VH9-M64A set forth in Table 6B. In some embodiments, the VH comprises the amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63.

[0250] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a VL of VL4 set forth in Table 6A and a VH of VH9 set forth in Table 6B. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:35 and a VH comprising the amino acid sequence set forth in SEQ ID NO:51.

[0251] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a VL of VL3 set forth in Table 6A and a VH of VH6 set forth in Table 6B. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:34 and a VH comprising the amino acid sequence set forth in SEQ ID NO:48.

[0252] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a VL of VL4 set forth in Table 6A and a VH of VH10 set forth in Table 6B. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:35 and a VH comprising the amino acid sequence set forth in SEQ ID NO:52. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a VL of VL4 set forth in Table 6A and a VH of VH8 set forth in Table 6B. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:35 and a VH comprising the amino acid sequence set forth in SEQ ID NO:50. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a VL of VL4 set forth in Table 6A and a VH of VH7 set forth in Table 6B. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:35 and a VH comprising the amino acid sequence set forth in SEQ ID NO:69.

[0253] In some embodiments, the antibody-peptide fusion protein comprises an amyloid-reactive peptide. In some embodiments, the amyloid-reactive peptide comprises one or more of the peptides shown in Table 1. In certain embodiments, the amyloid-reactive peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-14. In some embodiments, the amyloid-reactive peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-14. The amyloid-reactive peptide comprises the amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the amyloid-reactive peptide comprises the amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the amyloid-reactive peptide is positively charged.

[0254] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a light chain. In some embodiments, the amyloid-reactive peptide is fused to the N-terminus of the light chain. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody, wherein the humanized antibody comprises a light chain, and the amyloid-reactive peptide is fused to the N-terminus of the light chain via a linker. In some embodiments, the linker is a peptide linker. In some embodiments, the linker comprises the amino acid sequence GGGYS. In some embodiments, the linker comprises the amino acid sequence set forth in SEQ ID NO: 27. In some embodiments, the linker is uncharged.

[0255] In some embodiments, one or more of the peptides shown in Table 1 below can be attached to a humanized antibody or functional fragment thereof via the N-terminus of the light chain protein or the C-terminus of the heavy chain, thereby forming an antibody-peptide fusion protein comprising the humanized antibody. That is, any of the following sequences identified in Table 1 can be linked, independently or simultaneously, to the heavy or light chain of a humanized antibody or functional fragment thereof to form an antibody-peptide fusion protein. For example, two of the amyloid-reactive peptides can be linked to a single Ig antibody by linking the amino acid sequence of an amyloid-reactive peptide to the N-terminus of the light chain of the humanized antibody.

[0256] In some embodiments, the antibody-peptide fusion protein comprises a light chain and comprises, from N-terminus to C-terminus, an amyloid-reactive peptide and a light chain. In some embodiments, the light chain comprises, from N-terminus to C-terminus, a VL and a CL1. In some embodiments, the VL is any one of the VLs described herein. In some embodiments, the antibody-peptide fusion protein comprises a heavy chain and comprises, from N-terminus to C-terminus, a VH, a CH1, a CH2, and a CH3. In some embodiments, the VH is any one of the VHs described herein.

[0257] In some embodiments, the antibody-peptide fusion protein comprises a light chain and comprises, from N-terminus to C-terminus, an amyloid-reactive peptide, a spacer peptide, and the light chain. In some embodiments, the spacer peptide comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments, the spacer peptide comprises the amino acid sequence of SEQ ID NO: 27. In some embodiments, the light chain comprises, from N-terminus to C-terminus, a VL and a CL1. In some embodiments, the VL is any one of the VLs described herein. In some embodiments, the antibody-peptide fusion protein comprises a heavy chain and comprises, from N-terminus to C-terminus, a VH, a CH1, a CH2, and a CH3.

[0258] In some embodiments, the antibody-peptide fusion protein comprises, from N-terminus to C-terminus, a secretory leader peptide, a first spacer peptide, an amyloid-reactive peptide, a second spacer peptide, and a light chain. In some embodiments, the first spacer peptide comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments, the first spacer peptide comprises the amino acid sequence of SEQ ID NO: 27. In some embodiments, the second spacer peptide comprises the amino acid sequence of SEQ ID NO: 24. In some embodiments, the light chain comprises, from N-terminus to C-terminus, a VL and a CL1. In some embodiments, the VL is any one of the VLs described herein. In some embodiments, the antibody-peptide fusion protein comprises a heavy chain comprising, from N-terminus to C-terminus, a VH, a CH1, a CH2, and a CH3. In some embodiments, the VH is any one of the VHs described herein. In some embodiments, the VH is any one of the VHs described herein. In some embodiments, the antibody-peptide fusion protein comprises the structure depicted in Figure 11A or 11B.

[0259] In some embodiments, the antibody-peptide fusion protein comprises an amino acid spacer sequence between the N-terminus of the light chain and the amyloid-reactive peptide. In some embodiments, the antibody-peptide fusion protein comprises an amino acid spacer sequence between the N-terminus of the peptide and a leader sequence necessary for secretion of the antibody-peptide fusion protein from cells expressing the antibody-peptide fusion protein. In some embodiments, the spacer peptide is a flexible spacer peptide. In some embodiments, the spacer peptide is uncharged. In some embodiments, the spacer peptide is a glycine-serine linker. In some embodiments, the spacer peptide comprises a glycine-serine linker. In some embodiments, the spacer peptide comprises or consists of about 3 to about 55 amino acids. Spacer peptides of the invention can comprise or consist of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 amino acids. In some embodiments, the spacer peptide is about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 50, 100, or 155 amino acids in length (including any value or range between these values). In some embodiments, the spacer peptide comprises 15 amino acids. In some embodiments, the spacer peptide comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments, the spacer peptide comprises the amino acid sequence of SEQ ID NO: 24. In some embodiments, the spacer peptide comprises the amino acid sequence of SEQ ID NO: 27. In some embodiments, the antibody-peptide fusion protein does not comprise a spacer between the amyloid-reactive peptide and the antibody.

[0260] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63 and a light chain comprising a VL comprising the amino acids set forth in the group consisting of SEQ ID NOs: 33-42, wherein the light chain is linked to a peptide. In some embodiments, the antibody-peptide fusion protein comprises a heavy chain comprising a VH comprising the amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63 without a C-terminal lysine residue and a VL comprising the amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42, wherein the antibody is linked to a peptide. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 51 and a light chain comprising a VL comprising the amino acids of SEQ ID NO: 35, wherein the light chain is linked to a peptide. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 51 without a C-terminal lysine residue and a VL comprising the amino acids of SEQ ID NO: 35, wherein the antibody is linked to a peptide. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 48 and a light chain comprising a VL comprising amino acids of SEQ ID NO: 34, wherein the light chain is linked to a peptide. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 48 without the C-terminal lysine residue and a VL comprising amino acids of SEQ ID NO: 34, wherein the antibody is linked to a peptide.

[0261] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63, wherein the heavy chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2 ... In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:51, wherein the heavy chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:51, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:51, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:48, wherein the heavy chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:48, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:48, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:2.

[0262] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a light chain comprising a VL comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a light chain comprising a VL comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a light chain comprising a VL comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 35, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 35, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 35, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 34, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 34, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 34, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0263] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 51 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 35, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1.

[0264] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 51 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 35, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide is linked to the light chain at the N-terminus.

[0265] In some embodiments, the antibody-peptide fusion protein comprises a human antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:51 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO:35. In some embodiments, the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the peptide is linked to the light chain at the N-terminus.

[0266] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 48 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 34, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1.

[0267] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 48 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 34, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the peptide is linked to the light chain at the N-terminus.

[0268] In some embodiments, the antibody-peptide fusion protein comprises a humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 48 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 34, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the peptide is linked to the light chain at the N-terminus.

[0269] C. Humanized Antibodies and Antibody-Peptide Fusion Proteins Comprising Humanized Antibodies In some embodiments, a humanized antibody or an antibody-peptide fusion protein comprising a humanized antibody of the present disclosure comprises an Fc region. In some embodiments, the Fc is an IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments, a humanized antibody or an antibody-peptide fusion protein comprising a humanized antibody promotes Fc-mediated antibody effector function. In some embodiments, a humanized antibody or an antibody-peptide fusion protein comprising a humanized antibody promotes antibody-dependent cellular phagocytosis.

[0270] In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils with a dissociation constant (Kd) that is less than about 100, 10, 1, 0.1, or 0.01 μM. In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils with a dissociation constant (Kd) that is less than about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, or 100 μM (including any value or range therebetween). In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils with a dissociation constant (Kd) that is less than 500, 100, 10, or 1 nM. In some embodiments, a humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils with a dissociation constant (Kd) that is less than about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2000, or 2200 nM. In some embodiments, a humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils with a dissociation constant (Kd) that is less than about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 250, 500, 750, 1000, 2000, or 2200 nM (including any value or range therebetween). In some embodiments, a humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils with a dissociation constant (Kd) that is about 40-50 nM. In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils with a dissociation constant (Kd) of 40-50 nM. In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils with a dissociation constant (Kd) of less than 50 nM. In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils with a dissociation constant (Kd) that is less than the Kd at which c11-1F4 binds to human amyloid fibrils.

[0271] In some embodiments, the humanized antibody or antibody-peptide fusion protein has a half-maximal binding concentration (EC) of the antibody that is less than about 0.01, 0.1, or 1 μM. 50 In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils at a half-maximal binding concentration (EC) of the antibody that is about 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 μM (including any value or range therebetween). 50 In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils at a half-maximal binding concentration (EC) of the antibody that is less than about 1, 10, 100, or 1000 nM. 50 In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils at a half-maximal binding concentration (EC) of the antibody that is about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 100, 250, 500, 750, or 1000 nM (including any value or range therebetween). 50 In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils with a half-maximal binding concentration (EC) of the antibody that is about 17 nM, 7 nM, 16 nM, 75 nM, or 95 nM. 50 In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to human amyloid fibrils at a half-maximal binding concentration (EC) of the antibody that is less than about 10 nM, 20 nM, 80 nM, or 100 nM. 50 ) binds to human amyloid fibrils. In some embodiments, the humanized antibody or antibody-peptide fusion protein has an EC of c11-1F4 that binds to human amyloid fibrils. 50 The half-maximal binding concentration (EC 50 ) and binds to human amyloid fibrils.

[0272] Dissociation constant and EC 50Methods for calculating the EC are known in the art and include, for example, surface plasmon resonance and EuLISA (see, e.g., the Examples, Table 7, and Figures 13A-13G). In some embodiments, the dissociation constant is determined by measuring binding to the Len(1-22) monomer peptide, for example, using surface plasmon resonance. In some embodiments, the EC 50 is determined using EuLISA. 50 is determined using EuLISA to measure the level of binding to rVλ6Wil fibrils, Per125 wtATTR extract, Ken ATTR extract, SHI ALλ liver extract, or TAL ALκ liver extract.

[0273] In some embodiments, the humanized antibody or antibody-peptide fusion protein is conjugated to a detectable label. In some embodiments, the detectable label is a radionuclide (e.g., I- 125 , I- 123 , I- 131 , Zr- 89 , Tc- 99m , Cu- 64 , Br- 76 , F- 18 ), enzymes (horseradish peroxidase), biotin, fluorophores, and the like. Any means known in the art for detectably labeling proteins can be used and / or adapted for use with the methods described herein. For example, the humanized antibody or antibody-peptide fusion protein can be radiolabeled with a radioisotope, or labeled with a fluorescent or chemiluminescent tag. Exemplary radioisotopes include, for example, 18 F, 111 In, 99m Tc, and 123 I and 125I. These and other radioisotopes can be attached to humanized antibodies or antibody-peptide fusion proteins using well-known chemistries, which may or may not involve the use of chelators such as DTPA or DOTA covalently attached to the light chain protein of the humanized antibody or antibody-peptide fusion protein. Exemplary fluorescent or chemiluminescent tags include fluorescein, Texas Red, rhodamine, Alexa dyes, and luciferase, which can be conjugated to humanized antibodies or antibody-peptide fusion proteins by reaction with lysine, cysteine, glutamic acid, and aspartic acid side chains. In one embodiment, the labels are labeled using fluorescence microplate reader technology, using excitation and emission wavelengths appropriate for the tag used. The radiolabel can be detected using a gamma counter or a scintillation counter depending on the type of radioactive emission, using an energy window suitable for accurate detection of the specific radionuclide. However, any other suitable technology for detecting radioisotopes can also be used to detect the label. In some embodiments, the detectable label is 125 I.

[0274] In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to rVλ6Wil fibrils, Per125 wtATTR extract, KEN hATTR extract, SHI ALλ liver extract, and / or TAL ALκ liver extract. In some embodiments, the humanized antibody or antibody-peptide fusion protein described herein binds to amyloid deposits or amyloid fibrils. In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to one or more amyloidogenic peptides of amyloid. In some embodiments, the amyloid bound by the humanized antibody or antibody-peptide fusion protein comprises an amyloidogenic λ6 variable domain protein (Vλ6Wil) or an amyloidogenic immunoglobulin light chain (AL), Aβ(1-40) amyloid-like fibrils or amyloidogenic Aβ precursor protein, or serum amyloid protein A (AA). In other embodiments, the amyloid bound by the humanized antibody or antibody-peptide fusion protein comprises amyloidogenic forms of immunoglobulin heavy chain (AH), β2-microglobulin (Aβ2M), transthyretin variant (ATTR), apolipoprotein AI (AApoAI), apolipoprotein AII (AApoAII), gelsolin (AGel), lysozyme (ALys), leukocyte chemoattractant (ALect2), fibrinogen A variant (AFib), cystatin variant (ACys), calcitonin (ACal), lactadherin (AMed), islet amyloid polypeptide (AIAPP), prolactin (APro), insulin (AIns), prion protein (APrP), alpha-synuclein (AαSyn), tau (ATau), atrial natriuretic factor (AANF), or IAAP, ALκ4, A1λ1, or other amyloidogenic peptides. The amyloidogenic peptide bound by the humanized antibody or antibody-peptide fusion protein may be a protein, protein fragment, or protein domain. In some embodiments, the amyloid deposits or amyloid fibrils comprise recombinant amyloidogenic proteins. In some embodiments, amyloid is part of the pathology of a disease.

[0275] In some embodiments, binding of the humanized antibody or antibody-peptide fusion protein to human amyloid promotes phagocytosis of human amyloid fibrils. In some embodiments, the humanized antibody or antibody-peptide fusion protein opsonizes human amyloid fibrils. In some embodiments, the humanized antibody or antibody-peptide fusion protein opsonizes rVλ6Wil fibrils. In some embodiments, contacting human amyloid fibrils with a humanized antibody or antibody-peptide fusion protein of the present disclosure in the presence of macrophages promotes uptake of human amyloid fibrils by macrophages. In some embodiments, contacting human amyloid fibrils with a humanized antibody or antibody-peptide fusion protein of the present disclosure in the presence of macrophages promotes opsonization of human amyloid fibrils. In some embodiments, binding of the humanized antibody or antibody-peptide fusion protein to human amyloid promotes phagocytosis of human amyloid fibrils to an extent comparable to or greater than that of a control antibody (e.g., mIgp5 and / or c11-1F4). In some embodiments, the humanized antibody or antibody-peptide fusion protein comprising the humanized antibody promotes antibody-dependent cellular phagocytosis.

[0276] Also provided herein are pharmaceutical compositions comprising any of the modified immunoglobulins, humanized antibodies, or antibody-peptide fusion proteins described herein. The pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0277] IV. Diagnostic and Detection Methods In certain exemplary embodiments, the modified immunoglobulins, humanized antibodies, and antibody-peptide fusion proteins may be labeled with various agents to allow for their detection in in vivo and in vitro assays, for example, after purification of the fusion peptide. This includes, but is not limited to, radionuclides (e.g., I- 125 , I- 123 , I- 131 , Zr- 89 , Tc- 99m , Cu- 64 , Br-76 , F- 18 ), enzymes (horseradish peroxidase), biotin, and fluorophores. Any means known in the art for detectably labeling proteins can be used and / or adapted for use with the methods described herein. For example, Ig antibodies or fragments thereof, and / or amyloid-reactive peptides can be radiolabeled with radioisotopes or labeled with fluorescent or chemiluminescent tags. Exemplary radioisotopes include, for example, 18 F, 111 In, 99m Tc, and 123 I and 125 Examples of radioisotopes include I. These and other radioisotopes can be attached to isolated immunoglobulin light chains using well-known chemistries, with or without the use of chelators such as DTPA or DOTA covalently attached to the light chain protein of an Ig antibody. Exemplary fluorescent or chemiluminescent tags include fluorescein, Texas Red, rhodamine, Alexa dyes, and luciferase, which can be conjugated to proteins by reaction with lysine, cysteine, glutamic acid, and aspartic acid side chains. In one embodiment, the label is detected using a fluorescence microplate reader or fluorometer, using excitation and emission wavelengths appropriate for the tag used. Radiolabels can be detected, for example, using a gamma counter or scintillation counter, depending on the type of radioactive emission, by using an energy window suitable for accurate detection of the particular radionuclide. However, any other suitable technique for detecting radioisotopes can also be used to detect the label.

[0278] With respect to amyloidosis, for example, such labels can be used to diagnose the presence of amyloid, determine amyloid protein load, monitor the ability of a modified immunoglobulin, humanized antibody, or antibody-peptide fusion protein to bind to amyloid in a particular subject, monitor the progression of amyloidosis, and / or monitor the subject's response to amyloid therapy (including therapy involving administration of a modified immunoglobulin, humanized antibody, or antibody-peptide fusion protein to a subject). For example, a modified immunoglobulin containing an amyloid-reactive peptide, humanized antibody, or antibody-peptide fusion protein can be labeled with a detectable label as described herein and then administered to a subject suffering from or suspected of suffering from an amyloid-based disease (e.g., amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), or related plasma cell dyscrasia). The subject can then be imaged, for example, to detect the presence of the detectably labeled immunoglobulin, humanized antibody, or antibody-peptide fusion protein.

[0279] In certain exemplary embodiments, the signal from the detectably labeled modified immunoglobulin, humanized antibody, or antibody-peptide fusion protein can be quantified, thereby providing an indication of the level of amyloid deposits in the subject. For example, the signal intensity can be compared to a standard signal threshold, above which amyloidosis is present, and below which amyloidosis is absent or low. The subject may be diagnosed with amyloid, in which case treatment such as chemotherapy, corticosteroid drugs (lenalidomide or thalidomide), and / or bortezomib (Velcade) may be administered. Additionally or alternatively, the modified immunoglobulins, humanized antibodies, or antibody-peptide fusion proteins described herein can be used in combination with other immunoglobulins, humanized antibodies, or antibody-peptide fusion proteins as described herein. , can be administered to a subject to treat the subject. In certain exemplary embodiments, subjects can be stratified into one or more groups, such as low amyloid burden, intermediate amyloid burden, or high amyloid burden, and then treated accordingly. To monitor the progress of treatment, subjects can be readministered the detectably labeled modified immunoglobulin, humanized antibody, or antibody-peptide fusion protein, and their amyloid burden can be reassessed accordingly.

[0280] V. Treatment Methods A. Methods of Using Modified Immunoglobulins In certain exemplary embodiments, a method for treating a subject with amyloidosis is provided herein. For example, an effective amount of a modified immunoglobulin described herein is administered to the subject, thereby treating the subject or enabling diagnostic imaging of amyloid deposits. In certain exemplary aspects, a method for clearing amyloid deposits in a subject is provided. The method includes, for example, selecting a subject with amyloidosis and administering to the subject an effective amount of a modified immunoglobulin described herein. The modified immunoglobulin includes, for example, an amyloid-reactive peptide that binds to amyloid deposits and is linked to an Ig antibody or a fragment thereof via the N-terminus of the light chain protein or the C-terminus of the heavy chain of the Ig antibody or fragment thereof. Administration of the amyloid-reactive Ig fusion peptide results in amyloid clearance, thereby treating the subject.

[0281] In some embodiments, the modified immunoglobulin binds to amyloid in an individual. In some embodiments, the amyloid deposits may contribute to disease pathology. In other embodiments, the amyloid deposits may be indicative of amyloidosis or an amyloid-related disease in an individual. In some embodiments, the modified immunoglobulin binds to amyloid in an individual with amyloidosis. In some embodiments, the amyloidosis is localized to a specific tissue or organ system, such as the liver, heart, or central nervous system. In other embodiments, the amyloidosis is systemic amyloidosis. In some embodiments, the amyloidosis is familial amyloidosis. In other embodiments, the amyloidosis is sporadic amyloidosis. In some embodiments, the amyloidosis or amyloid-related disease is AA amyloidosis, AL amyloidosis, AH amyloidosis, Aβ amyloidosis, ATTR amyloidosis, ALect2 amyloidosis, IAPP amyloidosis in type II diabetes, Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with Dutch amyloidosis, cerebral β amyloid angiopathy, spongiform encephalopathy, thyroid tumor, Parkinson's disease, dementia with Lewy bodies, tauopathy, Huntington's disease, senile systemic amyloidosis, familial hemodialysis, senile systemic aging, age-related pituitary disorders, iatrogenic syndrome, spongiform encephalopathy, reactive chronic inflammation, thyroid tumor, myeloma, or other forms of cancer. In some embodiments, the modified immunoglobulin binds to amyloid associated with normal aging. In other embodiments, the modified immunoglobulin is used in the diagnosis, treatment, or prognosis of amyloidosis or amyloid-related disease in a subject.

[0282] In certain exemplary embodiments, a method for both diagnosing and treating a subject suffering from amyloidosis is provided. Such a method includes administering to the subject a detectably labeled modified immunoglobulin comprising an amyloid-reactive peptide, and determining that the subject suffers from amyloidosis based on the administration of the labeled modified immunoglobulin. An effective amount of an amyloid therapeutic agent can then be administered to the subject. For example, an effective amount of one or more modified immunoglobulins comprising an amyloid-reactive peptide can be administered.

[0283] In some embodiments, the subject is a mammal, such as a primate, cow, rodent, or pig, hi some embodiments, the subject is a human.

[0284] B. Methods Using Humanized Antibodies or Antibody-Peptide Fusion Proteins Also provided herein is a method of treating a subject having an amyloid-related disorder, comprising administering to the subject an effective amount of a humanized antibody or antibody-peptide fusion protein of the present disclosure.

[0285] In some embodiments, the amyloid-related disorder is selected from the group consisting of AL, AH, Aβ2M, ATTR, transthyretin, AA, AApoAI, AApoAII, AGel, ALys, ALEct2, AFib, ACys, ACal, AMed, AIAPP, APro, AIns, APrP, α-synuclein, au, or Aβ amyloidosis. In some embodiments, the amyloidosis or amyloid-related disease is AA amyloidosis, AL amyloidosis, AH amyloidosis, Aβ amyloidosis, ATTR amyloidosis, ALect2 amyloidosis, and IAPP amyloidosis in type II diabetes, Alzheimer's disease, Down's syndrome, hereditary cerebral hemorrhage with Dutch amyloidosis, cerebral β amyloid angiopathy, spongiform encephalopathy, thyroid tumor, Parkinson's disease, dementia with Lewy bodies, tauopathy, Huntington's disease, senile systemic amyloidosis, familial hemodialysis, senile systemic aging, age-related pituitary disorders, iatrogenic syndrome, spongiform encephalopathy, reactive chronic inflammation, thyroid tumor, myeloma, or other forms of cancer. In some embodiments, the amyloid-related disorder is systemic amyloidosis. In some embodiments, the humanized antibody or antibody-peptide fusion protein binds to amyloid associated with normal aging. In other embodiments, the humanized antibody or antibody-peptide fusion protein is used in the diagnosis, treatment, or prognosis of amyloidosis or an amyloid-related disease in a subject.

[0286] Also provided herein are methods of targeting amyloid deposits for clearance. In some embodiments, the methods comprise contacting amyloid deposits with a humanized antibody or antibody-peptide fusion protein of the present disclosure. In some embodiments, the amyloid deposits are removed. In some embodiments, the amyloid deposits are cleared. In some embodiments, the amyloid deposits are opsonized by the humanized antibody or antibody-peptide fusion protein. In some embodiments, binding of the humanized antibody or antibody-peptide fusion protein to human amyloid fibrils promotes phagocytosis of the human amyloid fibrils and removal of the amyloid deposits. In some embodiments, the humanized antibody or antibody-peptide fusion protein opsonizes human amyloid fibrils, thereby removing the amyloid deposits. In some embodiments, the humanized antibody or antibody-peptide fusion protein opsonizes rVλ6Wil fibrils. In some embodiments, binding of the humanized antibody or antibody-peptide fusion protein to human amyloid fibrils promotes phagocytosis and / or opsonization of human amyloid fibrils to an extent comparable to or greater than that of a control antibody (e.g., mIgp5 and / or c11-1F4).

[0287] In some embodiments, provided herein are methods of treating an amyloid-related disorder, comprising administering a modified immunoglobulin or antibody-peptide fusion protein conjugated to a detectable label, detecting the label, and administering amyloidosis treatment to the subject if a signal is detected. In some embodiments, the detectable label is a radiolabel. In some embodiments, the detectable label is an I 125 , Tc 99In some embodiments, the detectable label is a label. In some embodiments, the detectable label is a fluorescent label. In some embodiments, the detectable label is an enzymatic label. In some embodiments, the label is horseradish peroxidase or alkaline phosphatase. The label further comprises a chemical moiety (e.g., biotin), which can be detected via binding to a specific cognate detectable moiety (e.g., labeled avidin). In some embodiments, amyloid deposits are identified in the liver, spleen, or blood of the subject. In some embodiments, the amyloidosis treatment comprises a modified immunoglobulin or antibody-peptide fusion protein provided herein.

[0288] Also provided herein are methods of identifying amyloid deposits in a subject, comprising administering a modified immunoglobulin or antibody-peptide fusion protein, wherein the modified immunoglobulin or antibody-peptide fusion protein is conjugated to a detectable label. In some embodiments, the method comprises detecting a signal from the modified immunoglobulin or antibody-peptide fusion protein. In some embodiments, the detectable label is a radiolabel. In some embodiments, the detectable label is an I 125 , Tc 99 In some embodiments, the detectable label is a label. In some embodiments, the detectable label is a fluorescent label. In some embodiments, the detectable label is an enzyme label. In some embodiments, the label is horseradish peroxidase or alkaline phosphatase. The label further comprises a chemical moiety (e.g., biotin), which can be detected via binding to a specific cognate detectable moiety (e.g., labeled avidin). In some embodiments, amyloid deposits are identified in the liver, spleen, or blood of the subject.

[0289] In some embodiments, provided herein are methods of detecting a ligand, comprising contacting the ligand with a modified immunoglobulin or antibody-peptide fusion conjugated to a detectable label and determining a signal from the detectable label. In some embodiments, the detectable label is a radiolabel. In some embodiments, the detectable label is an I125 , Tc 99 In some embodiments, the detectable label is a label. In some embodiments, the detectable label is a fluorescent label. In some embodiments, the detectable label is an enzyme label. In some embodiments, the label is horseradish peroxidase or alkaline phosphatase. The label further comprises a chemical moiety (e.g., biotin), which can be detected via binding to a specific cognate detectable moiety (e.g., labeled avidin). In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo.

[0290] VI. Nucleic Acids, Vectors, Host Cells, and Methods of Producing Antibodies A. Nucleic Acids Encoding Modified Immunoglobulins or Antibody-Peptide Fusion Proteins Also provided herein are nucleic acids encoding modified immunoglobulins. In some embodiments, the nucleic acid encodes any of the modified immunoglobulins described herein.

[0291] In some embodiments, the nucleic acid encodes a modified immunoglobulin comprising an antibody comprising the VH and / or VL of antibody 11-1F4, wherein the antibody is linked to a peptide. In some embodiments, the nucleic acid encodes an antibody comprising the heavy chain and / or light chain of antibody 11-1F4, wherein the antibody is linked to a peptide.

[0292] In certain embodiments, the nucleic acid encodes a modified immunoglobulin comprising an antibody comprising a VH comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19, wherein the antibody is linked to a peptide.

[0293] In certain embodiments, the nucleic acid encodes a modified immunoglobulin comprising an antibody comprising a VL comprising (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the antibody is linked to a peptide.

[0294] In one embodiment, the nucleic acid encodes a modified immunoglobulin comprising an antibody comprising a VL comprising the amino acid sequence of SEQ ID NO: 16 and a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the antibody is linked to a peptide.

[0295] In another embodiment, the nucleic acid comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19. and a VL comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO:20, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:21, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:22, wherein the antibody is linked to a peptide. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences listed in Table 1. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO:1. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO:2.

[0296] In another aspect, the nucleic acid encodes a modified immunoglobulin comprising an antibody comprising a VH CDR1, VH CDR2, and VH CDR3 of a VH having the sequence set forth in SEQ ID NO: 15, and a VL CDR1, VL CDR2, and VL CDR3 of a VL having the sequence set forth in SEQ ID NO: 16, wherein the antibody is linked to a peptide. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences listed in Table 1. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the modified immunoglobulin comprises an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0297] In some embodiments, the nucleic acid encodes a modified immunoglobulin comprising an antibody comprising an antibody heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide. In some embodiments, the modified immunoglobulin comprises an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 15 without a C-terminal lysine residue and a light chain comprising the amino acid sequence of SEQ ID NO: 16, wherein the antibody is linked to a peptide.

[0298] In another aspect, a nucleic acid encodes a modified immunoglobulin comprising an antibody comprising a VH of any of the above provided embodiments and a VL of any of the above provided embodiments, wherein the antibody is linked to a peptide.

[0299] In some embodiments, the nucleic acid encodes an antibody linked to an amyloid-reactive peptide. In some embodiments, the nucleic acid encodes an antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences listed in Table 1. In some embodiments, the nucleic acid encodes an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the nucleic acid encodes an antibody comprising a light chain linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the peptide is linked to the N-terminus of the antibody light chain or the C-terminus of the antibody heavy chain. In some embodiments, the nucleic acid encodes an antibody that also comprises a spacer amino acid sequence between the peptide and the N-terminus of the antibody light chain or the C-terminus of the heavy chain. In some embodiments, the peptide is linked to the N-terminus of the antibody light chain.

[0300] In some embodiments, the nucleic acid encodes a modified immunoglobulin, including an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 linked to a peptide comprising any of the amino acid sequences of Table 1. In some embodiments, the nucleic acid encodes an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 linked to a peptide comprising the amino acid sequence of SEQ ID NO: ...2.

[0301] In some embodiments, the nucleic acid encodes a modified immunoglobulin, including an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16 linked to a peptide comprising any of the amino acid sequences in Table 1. ... In some embodiments, the nucleic acid encodes an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16 linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the nucleic acid encodes an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16 linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0302] In some embodiments, the nucleic acid encodes a modified immunoglobulin, including an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1.

[0303] In some embodiments, the nucleic acid encodes a modified immunoglobulin comprising an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1.

[0304] In some embodiments, the nucleic acid encodes a modified immunoglobulin comprising an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0305] Also provided herein are nucleic acid(s) encoding the antibody-peptide fusion proteins. In some embodiments, the nucleic acid encodes any of the antibody-peptide fusion proteins described herein.

[0306] In certain embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody, wherein the antibody comprises a VH comprising (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17, (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19, wherein the antibody is linked to a peptide.

[0307] In certain embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody, wherein the antibody comprises a VL comprising (a) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, (b) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and (c) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, and wherein the antibody is linked to a peptide.

[0308] In one embodiment, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody comprising a VL comprising the amino acid sequence of SEQ ID NO: 16 and a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the antibody is linked to a peptide.

[0309] In another aspect, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody, wherein the antibody comprises a VH comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 19, and a VL comprising a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 20, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 21, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 22, wherein the antibody is linked to a peptide. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising the antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences listed in Table 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising the antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising the antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0310] In another embodiment, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody, wherein the antibody comprises a VH CDR1, a VH CDR2, and a VH CDR3 having the sequence set forth in SEQ ID NO: 15. and a VL CDR1, a VL CDR2, and a VL having the sequence set forth in SEQ ID NO: 16, wherein the antibody is linked to a peptide. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising the antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences listed in Table 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising the antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising the antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0311] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 without the C-terminal lysine residue and a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the antibody is linked to a peptide.

[0312] In another aspect, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody linked to an amyloid-reactive peptide. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody linked to an amyloid-reactive peptide comprising any of the amino acid sequences listed in Table 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody linked to an amyloid-reactive peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the peptide is linked to the N-terminus of the light chain or the C-terminus of the heavy chain of the antibody. In some embodiments, the antibody also comprises a spacer amino acid sequence between the peptide and the N-terminus of the light chain or the C-terminus of the heavy chain.

[0313] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the heavy chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15, wherein the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0314] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody comprising a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0315] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1.

[0316] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1.

[0317] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising an antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 15 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 16, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0318] B. Nucleic Acids Encoding Humanized Antibodies or Antibody-Peptide Fusion Proteins Comprising Humanized Antibodies Also provided herein are nucleic acid(s) encoding the humanized antibodies or antibody-peptide fusion proteins of the present disclosure. The humanized antibodies or antibody-peptide fusion proteins can be any of the humanized antibodies or antibody-peptide fusion proteins described herein.

[0319] In some embodiments, the nucleic acid encodes a humanized antibody comprising a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the nucleic acid encodes a humanized antibody comprising one, two, three, four, five, or six CDRs of an antibody as set forth in Table 3. In some embodiments, the nucleic acid encodes a humanized antibody comprising CDR-H1, CDR-H2, and CDR-H3 of the VH, which have the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3, respectively, having the sequence set forth in SEQ ID NO: 15, and CDR-L1, CDR-L2, and CDR-L3 of the VL, which have the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3, respectively, having the sequence set forth in SEQ ID NO: 16.

[0320] In some embodiments, the nucleic acid encodes a humanized antibody, wherein the humanized antibody comprises one or more CDR substitutions. In some embodiments, the humanized antibody comprises a VL comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO:64-70, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and a VH comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO:18, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO:19. In some embodiments, the nucleic acid encodes a humanized antibody, wherein the humanized antibody comprises a VL comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO:20, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:21, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and a VH comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO:71-81, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO:19.

[0321] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising one or more amino acid substitutions at one or more positions in the VL compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32, wherein the amino acid positions are numbered sequentially starting from the N-terminus of SEQ ID NO: 32. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising an amino acid substitution at position 33 compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising an amino acid substitution at position 34 compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising an amino acid substitution at position 35 compared to the VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising an amino acid substitution at position 41 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising an amino acid substitution at position 42 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising an amino acid substitution at position 51 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising an amino acid substitution at position 90 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising an amino acid substitution at position 92 compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions compared to a VL comprising the amino acid sequence set forth in SEQ ID NO: 32. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL that contains 1, 2, 3, 4, 5, 6, 7, or 8 amino acid substitutions compared to VL1, as shown in Table 6A.

[0322] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising one or more amino acid substitutions at one or more positions in the VH compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43, where the amino acid positions are numbered starting from the N-terminus of SEQ ID NO:43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 37 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 48 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 67 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 68 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 71 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 76 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO:43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 78 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 79 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 80 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 92 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 96 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising an amino acid substitution at position 97 compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43.In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH that comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions compared to the VH comprising the amino acid sequence set forth in SEQ ID NO: 43. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH that comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions compared to VH1 as shown in Table 6B.

[0323] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising one or more amino acid residues at one or more positions of the VL, where the amino acid positions are numbered starting from the N-terminus of the VL. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising Ser, Gln, Glu, His, or Ala at position 33. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising Ala or Val at position 34. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising Tyr at position 41. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Leu at position 42. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Leu at position 51. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Leu at position 90. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Phe at position 92.

[0324] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising one or more amino acid residues at one or more positions of the VH, where the amino acid positions are numbered starting from the N-terminus of the VH. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Val at position 37. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Leu at position 48. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Leu at position 67. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Ser at position 68. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Lys at position 71. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Ser at position 76. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Val at position 78. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Leu at position 79. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Phe at position 80. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising a Thr at position 92. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising a Val at position 96. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising a Thr at position 97.

[0325] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising one or more amino acid residues at one or more positions in the VL, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Tyr at position 36. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Leu at position 37. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Leu at position 46. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Leu at position 85. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Phe at position 87.

[0326] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising one or more amino acid residues at one or more positions in the VL, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Tyr at position 36 and a Leu at position 37. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Tyr at position 36, a Leu at position 37, a Leu at position 46, a Leu at position 85, and a Phe at position 87. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Leu at position 46 and a Phe at position 87.

[0327] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising one or more amino acid residues at one or more positions in the VH, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Val at position 37. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Leu at position 48. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Leu at position 67. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Ser at position 68. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Lys at position 71. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Ser at position 76. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Val at position 78. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Leu at position 79. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Leu at position 79. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising a Phe at position 80. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising a Thr at position 89. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising a Val at position 93. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising a Thr at position 94.

[0328] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising one or more amino acid residues at one or more positions in the VH, where the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Val at position 37 and Leu at position 48. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Leu at position 67, Ser at position 68, Thr at position 89, Val at position 93, and Thr at position 94. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Val at position 37, Leu at position 48, Leu at position 67, and Ser at position 68. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Val at position 37, Leu at position 48, Val at position 93, and Thr at position 94. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Val at position 37, Leu at position 48, Leu at position 67, Ser at position 68, Lys at position 71, Thr at position 89, Val at position 93, and Thr at position 94. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Lys at position 71, Val at position 78, Leu at position 79, Val at position 93, and Thr at position 94. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Lys at position 71, Ser at position 76, Val at position 93, and Thr at position 94. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising Leu at position 48, Ser at position 96, Val at position 78, Leu at position 79, Phe at position 80, and Thr at position 94. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising a Leu at position 48, a Leu at position 67, a Ser at position 68, a Lys at position 71, a Ser at position 76, a Val at position 78, a Leu at position 79, a Val at position 93, and a Thr at position 94.

[0329] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Tyr at position 36, a Leu at position 37, a Leu at position 46, a Leu at position 85, and a Phe at position 87, and a VH comprising a Val at position 37, a Leu at position 48, a Leu at position 67, a Ser at position 68, a Lys at position 71, a Thr at position 89, a Val at position 93, and a Thr at position 94. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Leu at position 46 and a Phe at position 87, and a VH comprising a Leu at position 48, a Ser at position 96, a Val at position 78, a Leu at position 79, a Phe at position 80, and a Thr at position 94. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Leu at position 46 and a Phe at position 87, and a VH comprising a Leu at position 48, a Leu at position 67, a Ser at position 68, a Lys at position 71, a Ser at position 76, a Val at position 78, a Leu at position 79, a Val at position 93, and a Thr at position 94. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Leu at position 46 and a Phe at position 87, and a VH comprising a Lys at position 71, a Ser at position 76, a Val at position 93, and a Thr at position 94. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising a Leu at position 46 and a Phe at position 87, and a VH comprising a Lys at position 71, a Val at position 78, a Leu at position 79, a Val at position 93, and a Thr at position 94.

[0330] In some embodiments, the nucleic acid encodes a humanized antibody comprising the amino acid sequence of a VL set forth in Table 6 A. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL selected from the group consisting of VL2, VL3, VL4, VL4-N33S, VL4-N33Q, VL4-N33E, VL4-N33A, VL4-N33H, VL4-G34A, or VL4-G34V set forth in Table 6 A. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising the amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42.

[0331] In some embodiments, the nucleic acid encodes a humanized antibody comprising the amino acid sequence of a VH set forth in Table 6B. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH selected from the group consisting of VH2, VH3, VH4, VH5, VH6, VH7, VH8, VH9, VH10, VH9-D54S, VH9-D54Q, VH9-D54E, VH9-D54A, VH9-D54H, VH9-G55A, VH9-G55V, VH9-M64V, VH9-M64I, VH9-M64L, or VH9-M64A set forth in Table 6B. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VH comprising the amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63.

[0332] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL of VL4 set forth in Table 6A and a VH of VH9 set forth in Table 6B. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:35 and a VH comprising the amino acid sequence set forth in SEQ ID NO:51.

[0333] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL of VL3 set forth in Table 6A and a VH of VH6 set forth in Table 6B. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:34 and a VH comprising the amino acid sequence set forth in SEQ ID NO:48.

[0334] In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL of VL4 shown in Table 6A and a VH of VH10 shown in Table 6B. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:35 and a VH comprising the amino acid sequence set forth in SEQ ID NO:52. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL of VL4 shown in Table 6A and a VH of VH8 shown in Table 6B. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:35 and a VH comprising the amino acid sequence set forth in SEQ ID NO:50. In some embodiments, the nucleic acid encodes a humanized antibody comprising a VL of VL4 shown in Table 6A and a VH of VH7 shown in Table 6B. In some embodiments, the VL comprises the amino acid sequence set forth in SEQ ID NO:35 and the VH comprises the amino acid sequence set forth in SEQ ID NO:69.

[0335] Also provided herein are nucleic acid(s) encoding an antibody-peptide fusion protein comprising a humanized antibody of the present disclosure. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising any one of the humanized antibodies of the present disclosure.

[0336] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, the humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63 and a light chain comprising a VL comprising the amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42, wherein the light chain is linked to a peptide. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein, the humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63 without a C-terminal lysine residue and a VL comprising the amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42, wherein the antibody is linked to a peptide. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein, the humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 51 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 35, wherein the light chain is linked to a peptide. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, the humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 51 without the C-terminal lysine residue, and a VL comprising the amino acid sequence of SEQ ID NO: 35, wherein the antibody is linked to a peptide. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, the humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 48, and a VL comprising the amino acid sequence of SEQ ID NO: 34. and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 48 without the C-terminal lysine residue, wherein the light chain is linked to a peptide. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 48 without the C-terminal lysine residue, and a VL comprising the amino acid sequence of SEQ ID NO: 34, wherein the antibody is linked to a peptide.

[0337] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a heavy chain comprising a VH comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63, and the heavy chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a heavy chain comprising a VH comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63, and the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a heavy chain comprising a VH comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 44-63, and the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 51, and the heavy chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:51, and the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:51, and the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:48, and the heavy chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:48, and the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:1.In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:48, and the heavy chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:2.

[0338] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a light chain comprising a VL comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42, and the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a light chain comprising a VL comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42, and the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a light chain comprising a VL comprising an amino acid sequence set forth in the group consisting of SEQ ID NOs: 33-42, and the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 35, and the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 35, and the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 35, and the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 34, and the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 34, and the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 34, and the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO: 2.

[0339] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, the humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 51 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 35, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1.

[0340] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, the humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:51 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO:35, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:1.

[0341] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, wherein the humanized antibody comprises a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:51 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO:35, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:2.

[0342] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, the humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO: 48 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO: 34, wherein the light chain is linked to a peptide comprising any of the amino acid sequences in Table 1.

[0343] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, the humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:48 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO:34, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:1.

[0344] In some embodiments, the nucleic acid encodes an antibody-peptide fusion protein comprising a humanized antibody, the humanized antibody comprising a heavy chain comprising a VH comprising the amino acid sequence of SEQ ID NO:48 and a light chain comprising a VL comprising the amino acid sequence of SEQ ID NO:34, wherein the light chain is linked to a peptide comprising the amino acid sequence of SEQ ID NO:2.

[0345] C. Vectors and Host Cells In some embodiments, the nucleic acids provided herein are in one or more vectors. For example, in some embodiments, vectors are provided herein that include a heavy chain and a light chain of a modified immunoglobulin, wherein the light chain is linked to a peptide. In some embodiments, the heavy chain and the light chain linked to the peptide are in different vectors.

[0346] In some embodiments, the vector comprises a nucleic acid(s) encoding a humanized antibody or antibody-peptide fusion protein of the disclosure.

[0347] For antibody production, the heavy and light chains ligated into the peptide expression vectors are selected from those known in the art. The antibody can be introduced into a known suitable production cell line. The introduction of the expression vector can be achieved by co-transfection via electroporation or any other suitable transformation technique available in the art. Then, antibody-producing cell lines can be selected, grown, and antibody can be purified. The purified antibody can then be analyzed by standard techniques such as SDS-PAGE.

[0348] Host cells are also provided, containing nucleic acids encoding any of the modified immunoglobulins described herein. Suitable host cells for cloning or expressing antibody-encoding vectors include the prokaryotic or eukaryotic cells described herein. For example, modified immunoglobulins can be produced in bacteria, particularly when glycosylation and Fc effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254 (for a description of the expression of antibody fragments in E. coli)). After expression, the peptide-linked antibody can be isolated from the bacterial cell paste in a soluble fraction and further purified.

[0349] In some embodiments, the host cell comprises a vector comprising a nucleic acid(s) encoding a humanized antibody or antibody-peptide fusion protein of the disclosure.

[0350] Suitable host cells for the expression of glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant cells and insect cells. Numerous strains of baculovirus have been identified and can be used in conjunction with insect cells, particularly for transfection of Spodoptera frugiperda cells.

[0351] Plant cell cultures can also be used as host cells. See, e.g., U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES™ technology for producing antibodies in transgenic plants).

[0352] Vertebrate cells may also be used as hosts, for example, mammalian cell lines adapted to grow in suspension may be useful. Other examples of useful mammalian host cell lines include SV40-transformed monkey kidney CV1 cells (COS-7), human embryonic kidney cell lines (293 or 293 cells, e.g., Graham et al., J. Gen Virol. 36:59 (1977)), baby hamster kidney cells (BHK), mouse Sertoli cells (e.g., TM4 cells described in Mather, Biol. Reprod. 23:243-251 (1980)), monkey kidney cells (CV1), African green monkey kidney cells (VERO-76), human cervical carcinoma cells (HELA), canine kidney cells (MDCK), buffalo rat liver cells (BRL3A), human lung cells (W138), human liver cells (HepG2), mouse mammary tumor (MMT060562), TRI cells (e.g., Mather et al., Annals NY. Acad. Sci. 383:44-68 (1982)), MRC5 cells, and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)), and myeloma cell lines (such as Y0, NS0, and Sp2 / 0). For a review of specific mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Tottori, Japan). a, NJ), pp. 255-268 (2003).

[0353] D. Methods for Producing Antibodies or Antibody-Peptide Fusion Proteins Also provided herein are methods of making the modified immunoglobulins, humanized antibodies, or antibody-peptide fusion proteins of the present disclosure. In some embodiments, the methods comprise culturing a host cell of the present disclosure under conditions suitable for expression of a vector encoding the modified immunoglobulin, humanized antibody, or antibody-peptide fusion protein, and recovering the modified immunoglobulin, humanized antibody, or antibody-peptide fusion protein.

[0354] VII. Methods for Humanizing Mouse Antibodies Methods for humanizing a murine antibody are provided herein. In some embodiments, the murine antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH), wherein the VL comprises CDR-L1, CDR-L2, and CDR-L3, and the VH comprises CDR-H1, CDR-H2, and CDR-H3, and wherein the VH and VL comprise one or more framework residues. In some embodiments, the CDR-L1 of the murine antibody comprises the amino acid sequence set forth in SEQ ID NO: 20, the CDR-L2 of the murine antibody comprises the amino acid sequence set forth in SEQ ID NO: 21, the CDR-L3 of the murine antibody comprises the amino acid sequence set forth in SEQ ID NO: 22, the CDR-H1 of the murine antibody comprises the amino acid sequence set forth in SEQ ID NO: 17, the CDR-H2 of the murine antibody comprises the amino acid sequence set forth in SEQ ID NO: 18, and the CDR-H3 of the murine antibody comprises the amino acid sequence set forth in SEQ ID NO: 19. In some embodiments, the murine antibody comprises one, two, three, four, five, or six CDRs of antibody 11-1F4, as shown in Table 3. In some embodiments, the murine antibody comprises CDR-H1, CDR-H2, and CDR-H3 of the VH comprising the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3, respectively, having the sequence set forth in SEQ ID NO: 15, and CDR-L1, CDR-L2, and CDR-L3 of the VL comprising the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3, respectively, having the sequence set forth in SEQ ID NO: 16.

[0355] In some embodiments, a method for humanizing a mouse antibody includes: i. performing homology modeling to obtain a modeled structure of the mouse antibody; ii. calculating the solvent-accessible surface area of ​​framework residues in the modeled structure of the mouse antibody; iii. determining whether the framework residues are buried residues, where buried residues are residues with a solvent-accessible surface area of ​​less than about 15%; iv. providing a human VH and VL; v. introducing CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 of the mouse antibody into the human VH and VL, respectively, thereby generating a grafted antibody; and vi. introducing back mutations at positions in the grafted antibody, where the back mutation positions are buried residues. In some embodiments, step vi is repeated. In some embodiments, step vi is performed 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times.

[0356] In some embodiments, the backmutation position is adjacent to a CDR. In some embodiments, the backmutation position is separated from the CDR by no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues. In some embodiments, the backmutation position is separated from the CDR by no more than 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 angstroms (including any range or value therebetween).

[0357] In some embodiments, a back mutation is introduced into a human VL, and the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, a back mutation is introduced into a human VL, and the back mutation comprises a Tyr at position 36. In some embodiments, a back mutation is introduced into a human VL, and the back mutation comprises a Leu at position 37. In some embodiments, a back mutation is introduced into a human VL. In some embodiments, a back mutation is introduced into the human VL, where the back mutation comprises Leu at position 46. In some embodiments, a back mutation is introduced into the human VL, where the back mutation comprises Leu at position 85. In some embodiments, a back mutation is introduced into the human VL, where the back mutation comprises Phe at position 87.

[0358] In some embodiments, back mutations are introduced into the human VH, and the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, back mutations are introduced into the human VH, and the back mutation comprises Val at position 37. In some embodiments, back mutations are introduced into the human VH, and the back mutation comprises Leu at position 48. In some embodiments, back mutations are introduced into the human VH, and the back mutation comprises Leu at position 67. In some embodiments, back mutations are introduced into the human VH, and the back mutation comprises Ser at position 68. In some embodiments, back mutations are introduced into the human VH, and the back mutation comprises Lys at position 71. In some embodiments, back mutations are introduced into the human VH, and the back mutation comprises Ser at position 76. In some embodiments, back mutations are introduced into the human VH, and the back mutation comprises Val at position 78. In some embodiments, back mutations are introduced into the human VH, and the back mutation comprises Leu at position 79. In some embodiments, a back mutation is introduced into the human VH, where the back mutation comprises a Phe at position 80. In some embodiments, a back mutation is introduced into the human VH, where the back mutation comprises a Thr at position 89. In some embodiments, a back mutation is introduced into the human VH, where the back mutation comprises a Val at position 93. In some embodiments, a back mutation is introduced into the human VH, where the back mutation comprises a Thr at position 94.

[0359] In some embodiments, the method further comprises introducing one or more amino acid substitutions into the CDRs of the grafted antibody. In some embodiments, the humanized antibody comprises a VL comprising an amino acid substitution in CDR-L1 compared to the VL of the grafted antibody. In some embodiments, the amino acid substitution in CDR-L1 is selected from the group consisting of an amino acid substitution at position 28 and an amino acid substitution at position 29, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in CDR-L1 is selected from the group consisting of Ser, Gln, Glu, His, or Ala at position 28, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in CDR-L1 is selected from the group consisting of Ala or Val at position 29, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the humanized antibody comprises a VH comprising an amino acid substitution in CDR-H2 compared to the VH of the grafted antibody. In some embodiments, the amino acid substitution in CDR-H2 is selected from the group consisting of an amino acid substitution at position 54, position 55, or position 64, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in CDR-H2 is selected from the group consisting of Ser, Gln, Glu, Ala, or His at position 54, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in CDR-H2 is selected from the group consisting of Ala or Val at position 55, wherein the amino acid positions are numbered according to the Kabat numbering system. In some embodiments, the amino acid substitution in CDR-H2 is selected from the group consisting of Val, Ile, Leu, or Ala at position 64, wherein the amino acid positions are numbered according to the Kabat numbering system.

[0360] Embodiment Embodiment 1. A modified immunoglobulin comprising: an amyloid-reactive peptide comprising an amino acid sequence having at least 85% sequence identity with any one of the amino acid sequences set forth in SEQ ID NOs: 1 to 14; and an Ig antibody or a functional fragment thereof.

[0361] Embodiment 2. The amyloid-reactive peptide and the Ig antibody or functional fragment thereof , linked together at the N-terminus of the Ig light chain protein or the C-terminus of the Ig heavy chain protein.

[0362] Embodiment 3. The modified immunoglobulin of embodiment 1 or 2, wherein the modified immunoglobulin comprises a spacer sequence between the amyloid-reactive peptide and the Ig antibody or functional fragment thereof.

[0363] Embodiment 4. The modified immunoglobulin of any of embodiments 1 to 3, wherein the modified immunoglobulin comprises at least two amyloid-reactive peptides, and the amyloid-reactive peptides are the same or different peptides.

[0364] Embodiment 5. A method of treating a subject suffering from amyloidosis, comprising administering to the subject an effective amount of a modified immunoglobulin of any one of Embodiments 1-4.

[0365] Embodiment 6. A method of targeting amyloid deposits for clearance, comprising contacting the amyloid deposits with a modified immunoglobulin of any one of embodiments 1-4.

[0366] Embodiment 7. The method of embodiment 6, wherein targeting said amyloid deposits for clearance results in clearance of said amyloid deposits.

[0367] Embodiment 8 The method of embodiment 6 or 7, wherein clearance results from opsonization of said amyloid deposits.

[0368] Embodiment 9. The method of any one of embodiments 1 to 8, wherein the amyloid-reactive peptide linked to the Ig antibody or functional fragment thereof binds to one or more amyloid deposit types, including AA, AL, AH, ATTR, Aβ2M, ALect2, wild-type, TTR, AApoAI, AApoAII, AGel, ALys, ALect2, Afib, ACys, ACal, AMedin, AIAPP, APro, AIns, APrP, or Aβ.

[0369] Embodiment 10. The method of any of embodiments 6-8, wherein contacting the amyloid deposit with the amyloid-reactive peptide linked to the Ig antibody or functional fragment thereof increases the half-life of the amyloid-reactive Igp5 conjugate by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or more compared to the amyloid-reactive peptide alone.

[0370] Embodiment 11. A modified immunoglobulin, comprising: A peptide, and an Ig antibody or functional fragment thereof, wherein the peptide and the Ig antibody or functional fragment thereof are linked together at the N-terminus of the Ig light chain protein and / or the N-terminus and / or C-terminus of the Ig heavy chain protein.

[0371] Embodiment 12. The modified immunoglobulin of embodiment 11, wherein the modified immunoglobulin comprises a spacer sequence between the peptide and the Ig antibody or functional fragment thereof.

[0372] Embodiment 13. The modified immunoglobulin of any of embodiments 1 to 3, wherein the modified immunoglobulin comprises at least two peptides, which peptides are the same or different peptides.

[0373] Embodiment 14. A method for producing a modified immunoglobulin, comprising: providing a first expression vector and a second expression vector, the first expression vector comprises a first nucleic acid sequence encoding an Ig antibody light chain or a functional fragment thereof; the second expression vector comprises a second nucleic acid sequence encoding an Ig antibody heavy chain or a functional fragment thereof; providing, wherein the first expression vector and / or the second expression vector comprises a third nucleic acid sequence encoding a first peptide, the third nucleic acid sequence being located adjacent to the first nucleic acid sequence and / or the second nucleic acid sequence; and inserting the first and second expression vectors into a cell, wherein expression of the first and second expression vectors in the cell results in an immunoglobulin linked to the first peptide.

[0374] Embodiment 15. The method of embodiment 14, wherein the first expression vector and / or the second expression vector comprises a fourth nucleic acid sequence encoding a second peptide, and the fourth nucleic acid sequence is located adjacent to the first nucleic acid sequence and / or the second nucleic acid sequence.

[0375] Embodiment 16. The method of embodiment 15, wherein expression of the first and second expression vectors in the cell results in an immunoglobulin linked to the first peptide and the second peptide.

[0376] Embodiment 17. The method of embodiment 14, wherein a spacer nucleic acid sequence is located between the third nucleic acid sequence and the first nucleic acid sequence and / or the second first nucleic acid sequence.

[0377] Embodiment 18. The method of embodiment 14, wherein the first peptide comprises an amino acid sequence having at least 85% sequence identity to any one of the amino acids set forth in SEQ ID NOs: 1-14.

[0378] Embodiment 19. A modified immunoglobulin produced by the method of any one of embodiments 14 to 19.

[0379] Embodiment 20. A method of treating a subject suffering from or suspected of suffering from an amyloid-based disease, comprising: determining whet...

Claims

1. 1. An antibody-peptide fusion protein that binds to human amyloid fibrils, comprising an antibody fused to an amyloid-reactive peptide, the amyloid-reactive peptide comprises the amino acid sequence set forth in SEQ ID NO: 1 or 2; the antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH); a) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 64, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 73, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19; b) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO:64 to 70, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO:18, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO:19; c) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 20, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequences set forth in SEQ ID NOs: 71 to 81, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19; or d) the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NOs: 64 to 70, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NOs: 71 to 81, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19; The antibody-peptide fusion protein.

2. The antibody-peptide fusion protein of claim 1, wherein the amyloid-reactive peptide comprises the amino acid sequence set forth in SEQ ID NO:

2.

3. 2. The antibody-peptide fusion protein of claim 1, wherein the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO:64, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:22, and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO:17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO:73, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO:

19.

4. 4. The antibody-peptide fusion protein of claim 3, wherein said VL comprises a Leu at position 46 and a Phe at position 87, and said VH comprises a Leu at position 48, a Ser at position 76, a Val at position 78, a Leu at position 79, a Phe at position 80, and a Thr at position 94, wherein the amino acid positions are numbered according to the Kabat numbering system.

5. 5. The antibody-peptide fusion protein of claim 4, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:36 and the VH comprises the amino acid sequence set forth in SEQ ID NO:

55.

6. 2. The antibody-peptide fusion protein of claim 1, wherein the antibody is fused to the amyloid-reactive peptide by a linker.

7. The antibody-peptide fusion protein of claim 1, wherein the antibody comprises an Fc region.

8. The antibody-peptide fusion protein of claim 7, wherein the human Fc region is of the IgG1, IgG2, IgG3, or IgG4 isotype.

9. The antibody-peptide fusion protein of any one of claims 1 to 8, wherein the antibody binds to rVλ6Wil, ALκ4, or Alλ1 fibrils.

10. The antibody-peptide fusion protein of any one of claims 1 to 8, wherein the antibody binds to rVλ6Wil fibrils, SHI ALλ liver extracts, and / or TAL ALκ liver extracts.

11. The antibody-peptide fusion protein of any one of claims 1 to 8, wherein the antibody is humanized.

12. A pharmaceutical composition comprising the antibody-peptide fusion protein of any one of claims 1 to 8.

13. A nucleic acid encoding the antibody-peptide fusion protein of any one of claims 1 to 8.

14. A vector comprising the nucleic acid of claim 13.

15. A host cell comprising the vector of claim 14.

16. 19. A method of producing the antibody-peptide fusion protein of any one of claims 1 to 8, comprising culturing a host cell of claim 15 under conditions suitable for expression of the vector encoding said antibody-peptide fusion protein, and recovering said antibody-peptide fusion protein.

17. 10. Use of the antibody-peptide fusion protein of any one of claims 1 to 8 in the manufacture of a medicament, wherein said medicament is for the treatment of an amyloid-related disorder in a subject.

18. A composition comprising the antibody-peptide fusion protein of any one of claims 1 to 8 for treating an amyloid-related disorder in a subject.

19. 18. The use according to claim 17, wherein the amyloid-related disorder is amyloidosis.

20. 18. The use of claim 17, wherein the amyloid-related disorder is selected from the group consisting of AL, AH, Aβ2M, ATTR, transthyretin, AA, AApoAI, AApoAII, Agel, Alys, ALEct2, Afib, Acys, Acal, Amed, AIAPP, APro, Ains, AprP, α-synuclein, tau, or Aβ amyloidosis.

21. 18. The use according to claim 17, wherein the amyloid-related disorder is systemic amyloidosis.

22. 18. The use according to claim 17, wherein the amyloid-related disorder is AL.

23. 18. The use of claim 17, wherein the amyloid-related disorder is ATTR.

24. 18. The use according to claim 17, wherein the subject is a human.

25. 19. The composition of claim 18, wherein the amyloid-related disorder is amyloidosis.

26. 19. The composition of claim 18, wherein the amyloid-related disorder is selected from the group consisting of AL, AH, Aβ2M, ATTR, transthyretin, AA, AApoAI, AApoAII, AGel, ALys, ALEct2, AFib, ACys, ACal, AMed, AIAPP, APro, AIns, APrP, α-synuclein, tau, or Aβ amyloidosis.

27. 19. The composition of claim 18, wherein the amyloid-related disorder is systemic amyloidosis.

28. 19. The composition of claim 18, wherein the amyloid-related disorder is AL.

29. 19. The composition of claim 18, wherein the amyloid-related disorder is ATTR.

30. 20. The composition of claim 18, wherein the subject is a human.

31. 13. Use of the pharmaceutical composition of claim 12 in the manufacture of a medicament for treating an amyloid-based disease in a subject.

32. 1. An antibody-peptide fusion protein that binds to human amyloid fibrils, comprising an antibody fused to an amyloid-reactive peptide, the antibody-peptide fusion protein is an antibody-peptide fusion protein for the treatment of AL amyloidosis in a subject; the amyloid-reactive peptide comprises the amino acid sequence set forth in SEQ ID NO: 1 or 2; the antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH); the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 64, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 73, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19; The antibody-peptide fusion protein.

33. 33. The antibody-peptide fusion protein of claim 32, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:36 and the VH comprises the amino acid sequence set forth in SEQ ID NO:

55.

34. 34. The antibody-peptide fusion protein of claim 32 or 33, wherein the amyloid-reactive peptide comprises the amino acid sequence set forth in SEQ ID NO:

2.

35. 1. An antibody-peptide fusion protein that binds to human amyloid fibrils, comprising an antibody fused to an amyloid-reactive peptide, the antibody-peptide fusion protein is an antibody-peptide fusion protein for treating ATTR amyloidosis in a subject; the amyloid-reactive peptide comprises the amino acid sequence set forth in SEQ ID NO: 1 or 2; the antibody comprises a light chain variable region (VL) and a heavy chain variable region (VH); the VL comprises CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 64, CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 21, and CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 22; and the VH comprises CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 17, CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 73, and CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 19; The antibody-peptide fusion protein.

36. 36. The antibody-peptide fusion protein of claim 35, wherein the VL comprises the amino acid sequence set forth in SEQ ID NO:36 and the VH comprises the amino acid sequence set forth in SEQ ID NO:

55.

37. 37. The antibody-peptide fusion protein of any one of claims 35 or 36, wherein the amyloid-reactive peptide comprises the amino acid sequence set forth in SEQ ID NO:2.

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