Methods of treating al amyloidosis

Abstract

To provide antibody formulations useful for treatment of patients with AL amyloidosis.SOLUTION: Provided herein are methods of treating a Mayo Stage IV patient with AL amyloidosis, comprising administering an effective dosage of birtamimab. In some embodiments, the method reduces the risk of mortality in the patient. In some embodiments, the method reduces the risk of all-cause mortality in the patient. In some embodiments, the method of treatment reduces the risk of cardiac mortality in the patient.SELECTED DRAWING: None

Description

[Technical field]

[0001] Field The present disclosure relates to the technical fields of immunology and medicine.

[0002] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 814,252, filed March 5, 2019, and U.S. Provisional Patent Application No. 62 / 942,722, filed December 2, 2019, each of which is incorporated by reference herein in its entirety.

[0003] Sequence Listing Reference This application contains a Sequence Listing that has been submitted as an electronic text file entitled "19-467-WO_Sequence-Listing_ST25.txt", having a size of 22 kb, created on March 5, 2020. The information contained in this electronic file is incorporated herein by reference in its entirety in accordance with 37 CFR § 1.52(e)(5). [Background technology]

[0004] background AL amyloidosis involves a hematological disorder caused by clonal plasma cells that produce immunoglobulin light chains that may be misfolded and contribute to the disease. Overproduction of misfolded light chains by plasma cells results in the deposition of abnormal AL protein (amyloid) in tissues and organs of individuals with AL amyloidosis. Clinical features of AL amyloidosis include a variety of symptoms and organ dysfunction, including cardiac, renal and hepatic dysfunction, gastrointestinal complications, neuropathy and macroglossia. The mechanism by which amyloidogenic immunoglobulin light chains cause organ dysfunction has not been fully characterized, but it has been hypothesized that both amyloid deposition and prefibrillar aggregation may contribute to the cytotoxic effects on organs observed in patients with AL amyloidosis. Although AL amyloidosis may occur concomitantly in a subset of patients with multiple myeloma (up to 15%) or monoclonal gammopathy of undetermined significance (MGUS; up to 9%), AL amyloidosis is a disease entity in its own right.

[0005] AL amyloidosis is a rare disorder with an estimated incidence of 8 cases per 1,000,000. Approximately 1200 to 3200 new cases of AL amyloidosis are reported annually in the United States. Two-thirds of patients with AL amyloidosis are male, and less than 5% of patients are under 40 years of age. Both the cause and origin of AL amyloidosis remain poorly understood. Disease outcomes for patients with AL amyloidosis can be predicted based on the Mayo 4-stage prognostic staging system discussed in Kumar et al., 2012 (Kumar et al., Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements, J Clin Oncol 30:989-995 2012), where outcomes for stage IV patients are very severe.

[0006] Current treatments for patients with AL amyloidosis aim to reduce or eliminate bone marrow damage, i.e., plasma cells responsible for producing light chains, thereby limiting or stopping the production of amyloid. The most aggressive treatment options include stem cell transplantation and high-dose chemotherapy for patients who can tolerate it. Other therapeutic regimens include drug combinations such as melphalan, prednisone, and dexamethasone, often used to treat hematological malignancies, and proteosome inhibitors such as bortezomib to reduce light chain production. There are currently no approved treatments for AL amyloidosis, and none that directly target the potentially toxic form of the amyloidogenic protein. Some treatment options can provide some relief from morbidity associated with AL amyloidosis, but few, if any, have been demonstrated to improve patient outcomes. Furthermore, Mayo stage IV patients with AL amyloidosis represent a patient subset with no currently approved treatment and a very high burden of morbidity and mortality, a population estimated to amount to approximately 2,760 patients in the United States and 6,900 to 10,350 patients in the United States and European Union combined.

[0007] Thus, there is an unmet need for treatments that improve health, including reducing the risk of death or enhancing quality of life, in patients with AL amyloidosis. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Kumar et al., Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements, J Clin Oncol 30:989-995 2012 Summary of the Invention [Means for solving the problem]

[0009] overview The present disclosure relates to methods of treating certain patients with AL amyloidosis.

[0010] As used herein, the method includes determining the patient's Mayo stage of AL amyloidosis, and / or the patient's 6-minute walking distance (6MWD) or ejection fraction (EF), or determining the patient's Mayo stage and EF, and determining whether the patient is in Mayo stage IV or later. Methods for treating patients with AL amyloidosis are provided, comprising: selecting a patient for treatment with an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to human kappa (κ) or lambda light chain immunoglobulin, if the patient has AL amyloidosis, has 6MWD≧150 meters and EF>50% at baseline, has Mayo stage IV and EF>50% at baseline, or has Mayo stage IV, 6MWD≧150 meters and EF>50% at baseline, and administering an effective dose of the antibody. In some embodiments, the patient has Mayo stage IV AL amyloidosis. A portion of such Mayo stage IV patients have an EF>50%, and a portion of such patients also have a 6MWD>=150 meters.

[0011] Also provided herein is a method of treating a patient with AL amyloidosis comprising administering an effective dose of an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa or lambda light chain immunoglobulin, wherein the patient has (a) Mayo stage IV AL amyloidosis, (b) 6-minute walk distance (MWD) > 150 meters and ejection fraction (EF) > 50%, (c) Mayo stage IVC and EF > 50%, or (d) Mayo stage IV and 6MWD > 150 meters and EF > 50%. In some embodiments, the patient has Mayo stage IV AL amyloidosis. In some embodiments, patients have a 6MWD > 150 meters and an EF > 50%, and some such patients have Mayo stage IV AL amyloidosis. In some embodiments, Mayo stage IV patients have an EF > 50%.

[0012] Provided herein are methods of treating a Mayo stage IV patient with AL amyloidosis, comprising administering an effective dosage of an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to human kappa (κ) or lambda light chain immunoglobulin. In some embodiments, the method reduces the risk of death in the patient. In some embodiments, the method reduces the risk of total mortality in the patient. In some embodiments, the method of treatment reduces the risk of cardiac death in the patient.

[0013] Provided herein is a method of treating a Mayo stage IV patient with AL amyloidosis, comprising administering an effective dose of birtamimab. In some embodiments, the method reduces the risk of death in the patient. In some embodiments, the method reduces the risk of all-cause mortality in the patient. In some embodiments, the method of treatment reduces the risk of cardiac death in the patient. In some embodiments, the dosage is about 0.5 mg / kg to about 30 mg / kg, and the birtamimab is administered intravenously or subcutaneously at a frequency of about once a week to about four times a year. In some embodiments, the dosage is about 24 mg / kg, and the birtamimab is administered intravenously every 28 days.

[0014] In some embodiments provided herein, the antibody comprises a light chain variable region that comprises the three complementarity determining regions of 2A4, 7D8 or 11-1F4, and a heavy chain variable region that comprises the three complementarity determining regions of 2A4, 7D8 or 11-1F4, respectively. In some embodiments, the antibody is a humanized version of 2A4. In some embodiments, the antibody is a humanized or chimeric version of 11-1F4.

[0015] In some embodiments, the antibody binds to the same epitope as 2A4, 7D8 or 11-1F4. In some embodiments, the patient is administered an antibody that competes with 2A4 (ATCC Accession No. 9662) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa or lambda light chain immunoglobulin. In some embodiments, the antibody binds to the same epitope as 2A4 or 11-1F4. In some embodiments, the antibody is a humanized version of 2A4. In some embodiments, the antibody is a humanized or chimeric version of 11-1F4. In some embodiments, the antibody is a humanized bispecific or multispecific version that includes a combination of 11-1F4, 2A4 and / or 7D8.

[0016] In some embodiments provided herein, the antibody comprises a light chain variable region comprising the three complementarity determining regions set forth as SEQ ID NO:3, 4, and 5 or SEQ ID NO:16, 17, and 18, and a heavy chain variable region comprising the three complementarity determining regions set forth as SEQ ID NO:6, 7, and 8 or SEQ ID NO:19, 20, and 21. In some embodiments, the light chain variable region of the antibody comprises the amino acid sequence set forth as SEQ ID NO:1 or 14. In some embodiments, the heavy chain variable region of the antibody comprises the amino acid sequence set forth as SEQ ID NO:2 or 15. In some embodiments, the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO:1 or 14, and the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO:2 or 15. In some embodiments provided herein, the antibody comprises a light chain comprising the amino acid sequence set forth as SEQ ID NO:10 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:11, 12, or 13. In some embodiments, the antibody comprises a light chain comprising the amino acid sequence set forth as SEQ ID NO:10 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:12. In some embodiments, the antibody is vilutamimab.

[0017] In some embodiments provided herein, the patient is newly diagnosed and naïve to AL amyloidosis treatment. In some embodiments, the patient has previously or concomitantly undergone treatment with melphalan, prednisone, dexamethasone, bortezomib, cyclophosphamide, lenalidomide, doxorubicin, doxycycline, daratumumab, autologous transplantation, or combinations thereof. In certain methods, the patient has undergone treatment with humanized 2A4, 7D8, or 11-1F4 prior to undergoing plasma cell therapy. Previously or concurrently received.

[0018] Provided herein is a method comprising administering to a Mayo stage IV patient an effective dose of an antibody that competes with antibody 2A4 (ATCC Accession No. 9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin, thereby reducing the relative risk of death in the patient by at least about 35%.

[0019] Also provided herein are methods of treating a patient with AL amyloidosis, comprising determining that the patient has a 6-minute walk distance (6MWD) of ≧150 meters and an ejection fraction (EF)>50%, selecting the patient for treatment with an antibody that competes with antibody 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin; and administering an effective dosage of the antibody.

[0020] Also provided herein is a method of treating a patient with AL amyloidosis, who has a documented 6-minute walk distance (6MWD) greater than or equal to 150 meters and an ejection fraction (EF) greater than 50%, comprising administering to the patient an effective dosage of an antibody that competes with antibody 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or that competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to κ light chain immunoglobulin.

[0021] Also provided herein is a method of improving 6-minute walking distance (6MWD) in a patient with AL amyloidosis, comprising administering to the patient an effective dosage of an antibody that competes with antibody 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin. In some embodiments, the patient has Mayo stage IV AL amyloidosis. In some embodiments, the patient has an EF>50%. In some embodiments, the Mayo stage IV patient has an EF>50%.

[0022] Also provided herein is a method of reducing the risk of death in a patient having AL amyloidosis by at least 45% compared to a control condition (relative risk), comprising administering to the patient an effective dosage of an antibody that competes with antibody 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or that competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin, wherein the patient has Mayo stage IV AL amyloidosis and / or has a documented 6-minute walk distance (6MWD) greater than or equal to 150 meters and an ejection fraction (EF) greater than 50%, or has Mayo stage IV AL amyloidosis and an EF>50%. In some embodiments, the method reduces the risk of all-cause mortality in the patient. In some embodiments, the risk of total mortality is reduced by at least about 48.9% compared to a control condition. In some embodiments, the risk of total mortality is reduced by at least about 50% compared to a control condition. In some embodiments, the risk of total mortality is reduced by at least about 50.2% compared to a control condition. In some embodiments, the risk of total mortality is reduced by at least about 60% compared to a control condition. In some embodiments, the risk of total mortality is reduced by at least about 70% compared to a control condition. In some embodiments, the risk of total mortality is reduced by at least about 75% compared to a control condition. In some embodiments, the risk of total mortality is reduced by at least about 79.9% compared to a control condition. In some embodiments, the risk of total mortality is reduced by at least 81.5% compared to a control condition. In some embodiments, the method reduces the risk of cardiac death in the patient. In some embodiments, the risk of cardiac death is reduced by at least about 62.2% compared to a control condition. In some embodiments, the risk of cardiac death is reduced by at least about 75% compared to a control condition.

[0023] In some embodiments provided herein, after treatment with the antibody, the patient shows improvement in the 36-Item Short Form Survey Physical Component Score (SF-36PCS) or SF-36v2. found that after 9 months of treatment, the change in a patient's score on the SF-36PCS or SF-36v2 is at least 5 points higher than a different patient who did not receive the antibody at the same time point.

[0024] In some embodiments provided herein, an effective dosage of the antibody is administered from a pharmaceutical formulation comprising the antibody at a concentration within the range of about 1 mg / mL to about 100 mg / mL. In some embodiments provided herein, an effective dosage of the antibody is administered from a pharmaceutical formulation comprising a histidine buffer at a concentration within the range of about 20 mM to about 30 mM, a trehalose at a concentration within the range of about 210 mM to about 250 mM, and a polysorbate 20 at a concentration within the range of about 0.005% by weight to about 0.05% by weight, the formulation having a pH within the range of about 6 to about 7. In some embodiments, the dosage is about 0.5 mg / kg to about 30 mg / kg, and the antibody is administered intravenously or subcutaneously at a frequency of about once a week to about four times a year. In some embodiments, the antibody is present at a concentration of about 50 mg / mL. In some embodiments provided herein, the pharmaceutical formulation comprises histidine buffer at a concentration of about 25 mM, trehalose at a concentration of about 230 mM, polysorbate 20 at a concentration of about 0.2 g / L, and has a pH of about 6.5.

[0025] In some embodiments provided herein, the dose is administered subcutaneously without dilution from a vial containing the formulation. In some embodiments, the dose is administered intravenously after transferring the amount of the formulation required for the dose from the vial to an intravenous bag containing liquid.

[0026] In some embodiments provided herein, the dosage is about 24 mg / kg and the antibody is administered intravenously every 28 days. In some embodiments provided herein, the dosage is administered intravenously (IV) at 24 mg / kg (not to exceed 2500 mg) once every 28 days (± 5 days). In some embodiments, the duration of treatment is at least 9 months. In some embodiments, the duration of treatment is at least 12 months. In some embodiments, the duration is effective to achieve or maintain at least about a 3-point increase from baseline in SF-36 PCS.

[0027] In some embodiments provided herein, the antibody is a Fab, Fab', F(ab')2, F(ab)c, Dab, Nanobody or Fv.

[0028] Also provided herein is an antibody that competes with antibody 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin, for use in a method of treating patients with Mayo stage IV AL amyloidosis, patients with a documented 6-minute walk distance (6MWD) greater than or equal to 150 meters at baseline and an ejection fraction (EF) greater than 50%, Mayo stage IV patients with an EF greater than 50% at baseline, or Mayo stage IV patients with a 6MWD greater than or equal to 150 meters and an EF greater than 50% at baseline. In some embodiments, the antibody is a humanized version of 2A4. Some such antibodies comprise a light chain variable region comprising the three complementarity determining regions set forth as SEQ ID NOs: 3, 4 and 5 or SEQ ID NOs: 16, 17 and 18, and a heavy chain variable region comprising the three complementarity determining regions set forth as SEQ ID NOs: 6, 7 and 8 or SEQ ID NOs: 19, 20 and 21. In some antibodies, the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1 or 14. In some antibodies, the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2 or 15. In some antibodies, the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1 or 14 and the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2 or 15.

[0029] Some antibodies provided herein are formulated as pharmaceutical formulations comprising an antibody at a concentration in the range of about 1 mg / mL to about 100 mg / mL, a histidine buffer at a concentration in the range of about 20 mM to about 30 mM, trehalose at a concentration in the range of about 210 mM to about 250 mM, polysorbate 20 at a concentration in the range of about 0.005% to about 0.05% by weight, and the pharmaceutical formulation is characterized by a pH in the range of about 6 to about 7.

[0030] Some uses of the antibody include a dosage of about 0.5 mg / kg to about 30 mg / kg, where the antibody is administered intravenously or subcutaneously about once a week to about four times a year. For some uses, the antibody is present at a concentration of about 50 mg / mL, the histidine buffer is present at a concentration of about 25 mM, the trehalose is present at a concentration of about 230 mM, the polysorbate 20 is present at a concentration of about 0.2 g / L, and the pH is about 6.5.

[0031] Also provided herein are steps for determining (a) whether a patient has Mayo stage I, stage II, stage III, or stage IV AL amyloidosis, (b) the patient's six minute walk distance (6MWD), and / or (c) the patient's ejection fraction (EF), and determining whether the patient has (i) stage IV AL amyloidosis, (ii) 6MWD≧150 meters and EF>50%, (iii) stage IV AL amyloidosis and 6MWD≧150 meters and EF>50%, or (iv) stage IV The present invention provides a method for identifying patients who are likely to receive health benefits from treatment with an antibody that competes with antibody 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin, comprising the steps of selecting a patient with AL amyloidosis and EF>50% for treatment. In some embodiments, the selected patient has Mayo stage IV AL amyloidosis. In some embodiments, the selected patient has 6MWD>150 meters and ejection fraction>50%. In some embodiments, the selected patient has Mayo stage IV AL amyloidosis and 6MWD>150 meters and ejection fraction>50%. Some methods further include administering intravenously to the patient a dose ranging from about 0.5 mg / m2 to about 500 mg / m2 of a chimeric or humanized version of 11-1F4; or a dose ranging from about 0.5 mg / kg to about 30 mg / kg of a humanized version of 2A4. In certain embodiments, for example, the following are provided: (Item 1) a) (i) the patient's Mayo stage of AL amyloidosis, or (ii) the patient's 6-minute walk distance (6MWD) and ejection fraction (EF); or (iii) the patient's Mayo stage and EF determining b) said patient having: (i) have Mayo stage IV AL amyloidosis; or (ii) have a 6MWD ≥ 150 meters and EF > 50% at baseline; (iii) have Mayo stage IV and EF>50% at baseline; or (iv) if they had Mayo stage IV, 6MWD ≥ 150 meters, and EF > 50% at baseline; selecting said patient for treatment with an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin; and c) administering an effective dose of said antibody. 23. A method of treating a patient with AL amyloidosis comprising: (Item 2) 2. The method of claim 1, wherein the patient has Mayo stage IV amyloidosis. (Item 3) The method of item 1, wherein the patient has a 6MWD≧150 meters and an EF>50%. (Item 4) The method of item 2, wherein the patient has an EF>50%. (Item 5) 5. The method of claim 4, wherein the patient has a 6MWD≧150 meters. (Item 6) 1. A method of treating a patient with AL amyloidosis comprising administering an effective dose of an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or that competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin, wherein the patient has (a) Mayo stage IV AL amyloidosis, (b) a 6 minute walking distance (6MWD) of ≧150 meters and an EF>50%, (c) Mayo stage IV and an EF>50%, or (d) Mayo stage IV and a 6MWD of ≧150 meters and an EF>50%. (Item 7) The method of claim 6, wherein the patient has Mayo stage IV AL amyloidosis. (Item 8) 7. The method of item 6, wherein the patient has a 6MWD≧150 meters and an EF>50%. (Item 9) 8. The method of claim 7, wherein the patient has a 6MWD≧150 meters and an EF>50%. (Item 10) The method of claim 7, wherein the patient has an EF>50%. (Item 11) 2. The method of any of the preceding items, wherein the antibody comprises a light chain variable region comprising the three complementarity determining regions of 2A4, 7D8 or 11-1F4, and a heavy chain variable region comprising the three complementarity determining regions of 2A4, 7D8 or 11-1F4, respectively. (Item 12) The method of any of the preceding items, wherein the antibody is a humanized version of 2A4. (Item 13) 12. The method according to any of items 1 to 11, wherein the antibody is a humanized or chimeric version of 11-1F4. (Item 14) 11. The method according to any of items 1 to 10, wherein the antibody comprises a light chain variable region comprising the three complementarity determining regions set forth as SEQ ID NOs: 3, 4 and 5 or SEQ ID NOs: 16, 17 and 18, and a heavy chain variable region comprising the three complementarity determining regions set forth as SEQ ID NOs: 6, 7 and 8 or SEQ ID NOs: 19, 20 and 21. (Item 15) 11. The method according to any of items 1 to 10, wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1 or 14. (Item 16) 11. The method according to any one of items 1 to 10, wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2 or 15. (Item 17) 11. The method according to any of items 1 to 10, wherein the light chain variable region comprises the amino acid sequence shown as SEQ ID NO: 1 or 14, and the heavy chain variable region comprises the amino acid sequence shown as SEQ ID NO: 2 or 15. (Item 18) 11. The method according to any of items 1 to 10, wherein the antibody comprises a light chain comprising the amino acid sequence set forth as SEQ ID NO: 10, and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 11, 12 or 13. (Item 19) 11. The method according to any of items 1 to 10, wherein the antibody comprises a light chain comprising the amino acid sequence described as SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence described as SEQ ID NO: 12. (Item 20) 11. The method according to any of items 1 to 10, wherein the antibody is vilutamimab. (Item 21) The method of any of the preceding items, wherein the patient is newly diagnosed and is treatment naive for AL amyloidosis. (Item 22) 12. The method according to any of items 1 to 11, wherein the patient has previously undergone or is concurrently undergoing treatment with melphalan, prednisone, dexamethasone, bortezomib, cyclophosphamide, lenalidomide, doxorubicin, doxycycline, daratumumab, autologous transplantation or a combination thereof. (Item 23) 10. The method of any of items 2, 4, 7 or 9, comprising administering to a Mayo stage IV patient an effective dosage of an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or that competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin, thereby reducing the risk of death of said patient by at least about 35%. (Item 24) a) determining that the patient has a 6-minute walk distance (6MWD) > 150 meters and an ejection fraction (EF) > 50%; b) selecting said patient for treatment with an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin; and c) administering an effective dose of said antibody. 23. A method of treating a patient with AL amyloidosis comprising: (Item 25) A method of treating a patient with AL amyloidosis, having a documented 6 minute walk distance (6MWD) greater than or equal to 150 meters and an ejection fraction (EF) greater than 50%, comprising administering to the patient an effective dose of an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or that competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin. (Item 26) 1. A method of reducing the risk of death in a patient with AL amyloidosis by at least 45%, comprising administering to the patient an effective dose of an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or that competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin, wherein the patient has Mayo stage IV AL amyloidosis and / or has a documented 6-minute walk distance (6MWD) greater than or equal to 150 meters and an ejection fraction (EF) of greater than 50%, or wherein the patient has Mayo stage IV AL amyloidosis and an EF of >50%, the method comprising administering to the patient an effective dose of an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human kappa or lambda light chain immunoglobulin, (Item 27) 27. The method of item 26, wherein the risk of mortality is total mortality. (Item 28) Item 29. The method according to item 27, wherein the risk of all-cause mortality is reduced by at least about 48.9%. 28. The method of item 27, wherein the risk of all-cause mortality is reduced by at least about 50%. (Item 30) The method according to item 27, wherein the risk of all-cause mortality is reduced by at least about 50.2%. 28. The method of item 27, wherein the risk of all-cause mortality is reduced by at least about 60%. (Item 32) 28. The method of item 27, wherein the risk of all-cause mortality is reduced by at least about 70%. (Item 33) The method according to item 27, wherein the risk of all-cause mortality is reduced by at least about 79.9%. The method according to item 27, wherein the risk of all-cause mortality is reduced by at least about 81.5%. 27. The method of item 26, wherein the risk of death is cardiac death. (Item 36) 36. The method of claim 35, wherein the risk of cardiac death is reduced by at least about 75%. (Item 37) 36. The method of claim 35, wherein the risk of cardiac death is reduced by at least about 62.2%. (Item 38) 38. The method according to any of items 23 to 37, wherein the antibody is viltamimab. (Item 39) The method according to any of the preceding items, wherein the patient shows improvement in the Short Form 36 Physical Component Score (SF-36PCS) or SF-36v2 after treatment with the antibody. 40. The method of claim 39, wherein after 9 months of treatment, the change in the patient's score on the SF-36PCS or SF-36v2 is at least 5 points higher than a different patient who has not been administered the antibody at the same time point. (Item 41) The method of any of the preceding items, wherein the effective dose of the antibody is administered from a pharmaceutical formulation comprising the antibody at a concentration in the range of about 1 mg / mL to about 100 mg / mL. (Item 42) The method of any of the preceding items, wherein the dosage is from about 0.5 mg / kg to about 30 mg / kg and the antibody is administered intravenously or subcutaneously at a frequency of from about once per week to about four times per year. (Item 43) 42. The method of claim 41, wherein the antibody is present at a concentration of about 50 mg / mL. (Item 44) 44. The method according to any of items 41 to 43, wherein the dose is administered intravenously after transferring an amount of the formulation required for the dose from a vial to an intravenous bag containing liquid. (Item 45) 44. The method of any of items 41 to 43, wherein the dosage is about 24 mg / kg and the antibody is administered intravenously every 28 days. (Item 46) The method according to any of the preceding items, wherein the duration of the treatment is at least 9 months. 25. The method of claim 24, wherein the duration of the treatment is at least 12 months. (Item 48) The method of any of the preceding items, wherein the duration is effective to achieve or maintain at least about a 3 point increase from baseline in SF-36PCS or SF-36v2. (Item 49) The method of any of the preceding items, wherein the antibody is a Fab, Fab', F(ab')2, F(ab)c, Dab, Nanobody or Fv. (Item 50) An antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin, for use in a method of treating patients with Mayo stage IV AL amyloidosis, patients with a documented 6 minute walk distance (6MWD) greater than or equal to 150 meters at baseline and an ejection fraction (EF) greater than 50%, Mayo stage IV patients with an EF greater than 50% at baseline, or Mayo stage IV patients with a documented 6MWD greater than or equal to 150 meters and an EF greater than 50% at baseline. (Item 51) 51. The antibody for use according to item 50, which is a humanized version of 2A4. (Item 52) 51. The antibody for use according to item 50, comprising a light chain variable region comprising the three complementarity determining regions set forth as SEQ ID NOs: 3, 4 and 5 or SEQ ID NOs: 16, 17 and 18, and a heavy chain variable region comprising the three complementarity determining regions set forth as SEQ ID NOs: 6, 7 and 8 or SEQ ID NOs: 19, 20 and 21. (Item 53) 51. The antibody for use according to item 50, wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1 or 14. (Item 54) 51. The antibody for use according to item 50, wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2 or 15. (Item 55) 51. The antibody for use according to item 50, wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1 or 14 and the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2 or 15. (Item 56) 51. The antibody for use according to item 50, which is virutamimab. (Item 57) 57. The antibody for use according to any of items 50 to 56, formulated as a pharmaceutical formulation comprising the antibody at a concentration in the range of about 1 mg / mL to about 100 mg / mL. (Item 58) 58. The antibody for use according to item 57, comprising a dosage of about 0.5 mg / kg to about 30 mg / kg, administered intravenously or subcutaneously at a frequency of about once a week to about four times a year. (Item 59) 59. The antibody for use according to item 58, which is present in a concentration of about 50 mg / mL. (Item 60) (a) determining whether a patient has Mayo stage I, stage II, stage III, or stage IV AL amyloidosis, (b) the patient's six-minute walking distance (6MWD), and / or (c) the patient's ejection fraction (EF), and determining whether the patient has stage IV AL amyloidosis, (i) a patient with stage IV AL amyloidosis, (ii) a 6MWD≧150 meters and an EF>50%, (iii) stage IV AL amyloidosis and a 6MWD≧150 meters and an EF>50%, or (iv) stage IV A method for identifying patients who are likely to receive health benefit from treatment with an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin, comprising the step of selecting patients with AL amyloidosis and EF>50% for treatment. (Item 61) 61. The method of claim 60, wherein the selected patient has Mayo stage IV AL amyloidosis. (Item 62) 61. The method of item 60, wherein the selected patient has a 6MWD≧150 meters and an ejection fraction>50%. (Item 63) 61. The method of item 60, wherein the selected patient has Mayo stage IV AL amyloidosis, 6MWD≧150 meters and ejection fraction>50%. (Item 64) 61. The method of item 60, wherein the selected patient has Mayo stage IV AL amyloidosis and an ejection fraction >50%. (Item 65) To said patient: a) a dose ranging from about 0.5 mg / m2 to about 500 mg / m2 of a chimeric or humanized version of 11-1F4; or b) The method according to any one of items 60 to 64, further comprising the step of intravenously administering a dose ranging from about 0.5 mg / kg to about 30 mg / kg of the humanized version of 2A4. (Item 66) A method of improving six-minute walking distance (6MWD) in a patient with AL amyloidosis, comprising administering to the patient an effective dosage of an antibody that competes with 2A4 (ATCC Accession No. PTA-9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or that competes with 11-1F4 (ATCC Accession No. PTA-105) for binding to kappa light chain immunoglobulin. (Item 67) 67. The method of item 66, wherein the AL amyloidosis is Mayo stage IV AL amyloidosis. (Item 68) The method according to item 66 or 67, wherein the patient has an ejection fraction (EF) of >50%. 69. The method according to any of items 60 to 68, wherein the antibody is viltamimab. [Brief description of the drawings]

[0032] [Figure 1A-1B] Figures 1A-1B show the primary endpoint (all-cause mortality or cardiac hospitalization >= 91 days) through 12 months in AL amyloidosis patients treated with NEOD001 versus placebo in Mayo stage I-III patients (Figure 1A) and Mayo stage IV patients (Figure 1B), respectively.

[0033] [Figure 2A-2B] 2A-2B show total mortality in AL amyloidosis patients treated with NEOD001 versus placebo in Mayo stage I-III patients (FIG. 2A) and Mayo stage IV patients (FIG. 2B), respectively.

[0034] [Figure 3A-3B] 3A-3B show cardiac death over a 12-month period in AL amyloidosis patients treated with NEOD001 versus placebo in Mayo stage I-III patients (FIG. 3A) and Mayo stage IV patients (FIG. 3B), respectively.

[0035] [Figure 4A-4B] Figures 4A-4B show total mortality in AL amyloidosis patients with baseline 6MWD ≥ 150 meters and EF > 50% treated with NEOD001 vs. placebo for all Mayo stages (Figure 4A) and Mayo stage IV patients (Figure 4B), respectively.

[0036] [Diagram 5] FIG. 5 shows Kaplan-Meier estimates of the primary composite endpoint of time to ACM or CH.

[0037] [Figure 6] FIG. 6 shows Kaplan-Meier estimates of ACM in stage IV (mITT).

[0038] [Figure 7] Figure 7 shows the change from baseline in SF-36PCS scores for Mayo stage IV subjects (mITT). *P<0.05 and **P<0.005 using Student's t-test comparing change from baseline between treatment groups. Error bars = standard error of the mean (SEM). mITT, modified intent-to-treat; SE, standard error; SF-36PCS, Short Form 36 Physical Component Summary; SOC, standard of care. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0039] explanation The present disclosure provides methods of treating certain AL amyloidosis patients, i.e., patients with Mayo stage IV AL amyloidosis, patients with a baseline 6-minute walk distance (6MWD; sometimes referred to as 6-minute walk test (6MWT) distance) greater than or equal to 150 meters and an ejection fraction (EF) greater than 50%, Mayo stage IV patients with a baseline 6MWD greater than or equal to 150 meters and an ejection fraction (EF) greater than 50%, and Mayo stage IV patients with a baseline 6MWD greater than or equal to 150 meters and an ejection fraction (EF) greater than 50%. The method includes administering to such a patient an antibody that competes with antibody 2A4 (ATCC Accession No. PTA-9662) or antibody 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or that competes with antibody 11-1F4 (ATCC Accession No. PTA-150) for binding to a kappa immunoglobulin light chain. In some embodiments, the antibody is virutamimab.

[0040] I. Definition The term "antibody" includes intact antibodies and antigen-binding fragments thereof. Typically, fragments compete with the intact antibody from which they are derived for specific binding to a target and include separated heavy and light chains Fab, Fab', F(ab')2, F(ab)c, Dab, nanobody and Fv. Fragments may be produced by recombinant DNA techniques or by enzymatic or chemical separation of intact immunoglobulins. The term "antibody" also includes bispecific or multispecific antibodies and / or humanized antibodies. Bispecific or bifunctional or multifunctional antibodies are artificial hybrid antibodies having two or more different heavy / light chain pairs and two or more different binding sites (see, for example, Songsivilai and Lachmann, Clin. Exp. Immunol., 79:315-321 (1990); Kostelny et al., J. Immunol., 148:1547-53 (1992)).

[0041] The term "censored" refers to a situation in which the value of a measurement or observation is only partially known. For example, if a study is conducted to measure the effect of a drug on mortality, patients who discontinue the study are considered to have survived throughout the duration of the study, regardless of their unknown fate (i.e., alive or dead), and survival is estimated for the period of the study where data indicating mortality are missing.

[0042] The term "ejection fraction" or "EF" refers to a measurement of how much blood the left ventricle pumps out with each contraction. An ejection fraction of 50 percent means that 50 percent of the total volume of blood in the left ventricle is pushed out with each heartbeat. Ejection fraction is used as a measurement of heart failure. The EF of a normal heart is typically between 50 and 70 percent. 41 to 49 percent is considered borderline, and an EF below 40 percent may be evidence of heart failure or cardiomyopathy.

[0043] The term "hazard ratio" or "HR" reflects the instantaneous probability of an event (death or progression) in the experimental arm as a ratio to the likelihood in the comparison arm (i.e., hazard rate). When the HR is 1.0, there is no clear advantage to either arm. The lower the HR value, the greater the reduction in risk of death or progression for the experimental treatment arm of the study, calculated as 1-HR. For example, an HR of 0.84 is equivalent to a 16% relative reduction in event risk compared to the control arm of the study.

[0044] The term "humanized immunoglobulin" or "humanized antibody" refers to an immunoglobulin or antibody that comprises at least one humanized immunoglobulin or antibody chain (i.e., at least one humanized light or heavy chain). The term "humanized immunoglobulin chain" or "humanized antibody chain" (i.e., "humanized immunoglobulin light chain" or "humanized immunoglobulin heavy chain") refers to an immunoglobulin or antibody chain (i.e., light or heavy chain, respectively) that has a variable region that comprises a variable framework region substantially derived from a human immunoglobulin or antibody and a complementarity determining region (CDR) substantially derived from a non-human immunoglobulin or antibody (e.g., at least one CDR, preferably two CDRs, more preferably three CDRs), and further comprises a constant region (e.g., at least one constant region or portion thereof in the case of a light chain, and preferably three constant regions in the case of a heavy chain). The term "humanized variable region" (e.g., "humanized light chain variable region" or "humanized heavy chain variable region") refers to a variable region comprising a variable framework region substantially derived from a human immunoglobulin or antibody and complementarity determining regions (CDRs) substantially derived from a non-human immunoglobulin or antibody.

[0045] The term "Mayo stage IV patient" or "stage IV" refers to patients with stage IV disease who meet the prognostic staging system established by the Mayo Clinic, which incorporates both cardiac biomarkers and levels of amyloidogenic light chain synthesis (Kumar et al., Revised Prognostic Staging System for Light Chain Amyloidosis Incorporating Cardiac Biomarkers and Serum Free Light Chain Measurements, J Clin Oncol 30:989-995 2012). Patients with stage III disease are referred to herein as "Mayo stage I-III patients" or "stage I-III patients." In some embodiments, patients are identified as having stage IV AL amyloidosis if they meet the criteria for the following three prognostic variables: troponin-T (cTnT) ≧0.025 ng / mL, N-terminal pro-B-type natriuretic peptide (NT-ProBNP) ≧1,800 pg / mL, and difference between involved and uninvolved light chains (FLC-diff or dFLC) ≧18 mg / dL. In certain embodiments, patients may be identified as Mayo stage IV as defined by: (1) NT-proBNP ≧1800 pg / mL, (2) troponin-T>0.03 ng / mL, and (3) dFLC ≧18 mg / dL.

[0046] The term "p-value" or "p" refers to a number between 0 and 1 that relates to the significance of the results obtained. A small p-value indicates strong evidence against the null hypothesis (i.e., that there is no effect), e.g., ≦0.1 indicates statistical significance, and p≦0.001 is even more statistically significant (less than 1 error in 1000 opportunities).

[0047] The phrase "substantially derived from a human immunoglobulin or antibody" means that the region shares at least 80-90%, preferably 90-95%, more preferably 95-99% identity (i.e., local sequence identity) with a human framework or constant region sequence, taking into account, for example, conservative substitutions, common sequence substitutions, germline substitutions, back mutations, etc., when sequenced with a human immunoglobulin or antibody amino sequence for comparison purposes. The introduction of conservative substitutions, common sequence substitutions, germline substitutions, back mutations, etc. is often referred to as "optimization" of the humanized antibody or chain. The phrase "substantially derived from a non-human immunoglobulin or antibody" or "substantially non-human" means having an immunoglobulin or antibody sequence that is at least 80-95%, preferably 90-95%, more preferably 96%, 97%, 98% or 99% identical to that of a non-human organism, e.g., a non-human mammal.

[0048] Thus, all regions or residues of a humanized immunoglobulin or antibody, or of a humanized immunoglobulin or antibody chain, except possibly for the CDRs, are substantially identical to the corresponding regions or residues of one or more native human immunoglobulin sequences. The term "corresponding region" or "corresponding residue" refers to a region or residue on a second amino acid or nucleotide sequence that occupies the same (i.e., equivalent) position as a region or residue on a first amino acid or nucleotide sequence when the first and second sequences are optimally aligned for comparison purposes.

[0049] The phrases "risk reduction" and "risk of" refer to relative risk, unless the average absolute risk is specified.

[0050] II. Treatment Methods and Suitable Subjects Patients suitable for treatment can be identified by determining the Mayo stage of the patient's AL amyloidosis. Alternatively or additionally, patients who are likely to benefit from the treatment can be identified by determining the patient's 6MWD and determining the patient's ejection fraction. Patients who are likely to respond positively to treatment include those with stage IV AL amyloidosis, patients with a 6MWD of ≧150 meters and an EF of >50% at baseline, patients with Mayo stage IV AL amyloidosis with an EF of >50% at baseline, and Mayo stage IV patients with a 6MWD of ≧150 meters and an EF of >50% at baseline.

[0051] Provided herein are methods of treating a human patient who is symptomatic of or diagnosed as having Mayo stage IV AL amyloidosis and / or has a baseline 6MWD of ≧150 meters and a baseline EF of >50%, comprising administering to the patient a regimen of any of the antibodies or antibody formulations described herein that is effective to improve the health status of the patient. Some patients have Mayo stage IV AL amyloidosis, and the human patient has a baseline 6MWD of ≧150 meters and a baseline EF of >50%. Some patients have Mayo stage IV AL amyloidosis, and the human patient has a baseline 6MWD of ≧150 meters and a baseline EF of >50%. Have AL amyloidosis and a baseline EF of >50%. Some patients have systemic organ dysfunction due to AL amyloidosis, including cardiac, renal, hepatic, peripheral nervous system, gastrointestinal system, autonomic nervous system, pulmonary, and / or soft tissue or lymphatic system dysfunction.

[0052] Some methods include determining the baseline levels of troponin-T, NT-proBNP and the relative levels of involved and uninvolved light chains in a patient, selecting the patient for treatment if the patient has cTnT≧0.025ng / mL or >0.03ng / mL, NT-ProBNP≧1,800pg / mL (and <8500pg / mL) and FLC-diff≧18mg / dL at baseline levels, and administering an effective dose of any of the antibodies disclosed herein.Some methods include determining the 6MWD and EF of a patient at baseline, and selecting the patient for treatment if the patient has a 6MWD of ≧150 meters and an EF of >50%.In some cases, Mayo stage IV patients with a baseline 6MWD of ≧150 meters and a baseline EF of >50% are selected for treatment.Some methods include determining the Mayo stage and EF of a patient, and in some cases, Mayo stage IV patients with a baseline EF of >50% are selected for treatment.

[0053] In some embodiments, the patient is treatment naive, meaning that the patient has not previously received any treatment for AL amyloidosis. Patients suitable for treatment also include patients who have received, are currently receiving, or will receive alternative treatments for the treatment of AL amyloidosis or related conditions, such as inflammatory diseases, chronic microbial infections, malignant neoplasms, inherited inflammatory diseases, and lymphoproliferative disorders. For example, the patient may also receive or have received one or more therapeutic agents disclosed herein in relation to combination therapy. By way of example, patients suffering from AL amyloidosis may also receive, have received, or will receive bortezomib, melphalan, lenalidomide, prednisone, dexamethasone, cyclophosphamide, pomalidomide, carfilzomib, doxorubicin, doxycycline, daratumumab, autologous transplantation, or combinations thereof. For these patients who have previously received alternative treatments for the treatment of amyloid diseases, such treatments may or may not have been successful according to relevant clinical measurements, and likely did not improve their health status. Additional examples of such treatments include: (1) CyBorD, a combination therapy including cyclophosphamide, bortezomib, and dexamethasone, (2) BMDex, a combination of bortezomib, melphalan, and dexamethasone, (3) MDex, a combination of melphalan and dexamethasone, (4) LDex, a combination of lenalidomide and dexamethasone, (5) CLD, a combination of cyclophosphamide, lenalidomide, and dexamethasone, (6) PomDex, a combination of pomalidomide and dexamethasone, and (7) CRd, a combination of lenalidomide, cyclophosphamide, and dexamethasone. Such patients may or may not experience cardiac and / or renal improvement as a result of such treatment.

[0054] Improvement in health status can be established when a patient shows improvement in the six minute walk distance (meters) outcome measure (6MWD).

[0055] Improvements in the Short Form 36 Physical Component Score (SF-36PCS) or Short Form 36 Questionnaire (SF-36v2) may also indicate an improvement in the patient's health status. For example, a patient treated with an antibody for at least 9 months who scored at least 5 points higher on the SF-36PCS or SF-36v2 questionnaire than a different patient who did not receive the antibody at the same time point achieved an improvement in health status.In some embodiments, treatment with an antibody disclosed herein reduces or eliminates at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least 44, at least 45, at least 46, at least 47 , resulting in an increase of at least 48, at least 49, at least 50, at least 51, at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, at least 60, at least 61, at least 62, at least 63, at least 64, at least 65, at least 66, at least 67, at least 68, at least 69, at least 70, at least 71, at least 72, at least 73, at least 74, at least 75, at least 76, at least 77, at least 78, at least 79, at least 80, at least 81, at least 82, at least 83, at least 84, at least 85, at least 86, at least 87, at least 88, at least 89, at least 90, at least 91, at least 92, at least 93, at least 94, at least 95, at least 96, at least 97, at least 98 or at least 99.In some embodiments, treatment with an antibody disclosed herein reduces or eliminates about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 100, about 101 , about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99 or about 100.

[0056] A reduction in the length of hospitalization or a reduction in the frequency of hospitalization for more than 90 days in patients treated with an antibody as disclosed herein compared to patients not receiving the antibody may also indicate an improvement in the health status of the patient. An improvement in health status may also be indicated by a longer survival of antibody-treated patients compared to untreated patients over the same period.In some embodiments, treatment with an antibody disclosed herein reduces the risk of all-cause mortality for treated patients by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 22%, at least 24%, at least 26%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 72%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 82%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least The concentration can be reduced by at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

[0057] In some embodiments, treatment with an antibody disclosed herein reduces the risk of all-cause mortality for treated patients by about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109 ...9%, 109%, 109%, 109%, 109%, 109%, 109%, 110%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 1 3%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% reduction. In some embodiments, treatment with an antibody disclosed herein can reduce the risk of all-cause mortality for treated patients by about 45%, 48.9%, 50%, 50.2%, 60%, 62.2%, 65%, 70%, 75%, 79.9%, 80%, or 81.5% compared to control treated patients, as can be determined by calculating the hazard ratio between treated and untreated patients.

[0058] For example, the risk of total mortality for some Mayo stage IV patients can be reduced by approximately 50.2%, and for some Mayo stage IV patients by approximately 79.9%, if such patients have a certain level of functional reserve pre-treatment, defined by a baseline 6MWD of ≧150 meters and an ejection fraction of >50%.

[0059] In some embodiments, the risk of all-cause mortality for some Mayo stage IV patients is at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24% if they have an ejection fraction >50%. , at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least It may be reduced by 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.In some embodiments, the risk of all-cause mortality for some Mayo stage IV patients is about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75% , about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100%. In some embodiments, the risk of all-cause mortality in some Mayo stage IV patients may be reduced by about 81.5% if they have an ejection fraction of >50%.

[0060] In some embodiments, the risk of all-cause mortality in some patients with a baseline 6MWD of ≥ 150 meters and an ejection fraction >50% is at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 82%, at least 83%, at least 84%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47% , at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least The amount of oxidative stress can be reduced by at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.In some embodiments, the risk of all-cause mortality in some patients with a baseline 6MWD of ≥ 150 meters and an ejection fraction > 50% is about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44% if they have an ejection fraction > 50%, regardless of Mayo stage. ,About 45%,About 46%,About 47%,About 48%,About 49%,About 50%,About 51%,About 52%,About 53%,About 54%,About 55%,About 56%,About 57%,About 58%,About 59%,About 60%,About 61%,About 62%,About 63%,About 64%,About 65%,About 66%,About 67%,About 68%,About 69%,About 70%,About 71%,About 72%,About 73% , about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100%. In some embodiments, the risk of total death in some patients with a baseline 6MWD of ≧150 meters and an ejection fraction of >50% may be reduced by about 48.9% regardless of Mayo stage. The risk of cardiac death for some Mayo stage IV patients may be reduced by about 62.2%.

[0061] In some embodiments, treatment with an antibody disclosed herein provides a therapeutically effective amount of at least 1 meter, at least 2 meters, at least 3 meters, at least 4 meters, at least 5 meters, at least 6 meters, at least 7 meters, at least 8 meters, at least 9 meters, at least 10 meters, at least 11 meters, at least 12 meters, at least 13 meters, at least 14 meters, at least 15 meters, at least 16 meters, at least 17 meters, at least 18 meters, at least 19 meters, at least 20 meters, at least 21 meters, at least 22 meters, at least 23 meters, at least 24 meters, at least 25 meters, at least 26 meters, at least 27 meters, at least 28 meters, at least 29 meters, at least 30 meters, at least 31 meters, at least 32 meters, at least 33 meters, at least 34 meters, at least 35 meters, at least 36 meters, at least 37 meters, at least 38 meters, at least 39 meters, at least 40 meters, at least 41 meters, at least 42 meters, at least 43 meters, at least 44 meters, at least 45 meters, at least 46 meters, at least 47 meters, at least 48 meters, at least 49 meters, at least 50 meters, at least 51 meters, at least 52 meters, at least 53 meters, at least 54 meters, at least 55 meters, at least 56 meters, at least 57 meters, at least 58 meters, at least 59 meters, at least 60 meters, at least 61 meters, at least 62 meters, at least 63 meters, at least 64 meters, at least 65 meters, at least 66 meters, at least 67 meters, at least 68 meters, at least 69 meters, at least 70 meters, at least 71 meters, at least 72 0 meters, at least 41 meters, at least 42 meters, at least 43 meters, at least 44 meters, at least 45 meters, at least 46 meters, at least 47 meters, at least 48 meters, at least 49 meters, at least 50 meters, at least 51 meters, at least 52 meters, at least 53 meters, at least 54 meters, at least 55 meters, at least 56 meters, at least 57 meters, at least 58 meters, at least 59 meters, at least 60 meters, at least 61 meters, at least 62 meters, at least 63 meters, at least 64 meters, at least 65 meters, at least 66 meters, at least 67 meters, at least 68 meters, at least 69 meters, at least 70 meters, at least 71 meters, at least 72 meters, at least 73 meters, at least 74 meters, at least 75 meters, at least 76 meters, at least 77 meters, at least 78 meters, at least 79 meters, at least 80 meters, at least 81 meters,resulting in an increase in the patient's 6MWD of at least 82 meters, at least 83 meters, at least 84 meters, at least 85 meters, at least 86 meters, at least 87 meters, at least 88 meters, at least 89 meters, at least 90 meters, at least 91 meters, at least 92 meters, at least 93 meters, at least 94 meters, at least 95 meters, at least 96 meters, at least 97 meters, at least 98 meters, at least 99 meters or at least 100 meters. In some embodiments, treatment with an antibody disclosed herein can be administered to a subject in need of treatment with an antibody of about 1 meter, about 2 meters, about 3 meters, about 4 meters, about 5 meters, about 6 meters, about 7 meters, about 8 meters, about 9 meters, about 10 meters, about 11 meters, about 12 meters, about 13 meters, about 14 meters, about 15 meters, about 16 meters, about 17 meters, about 18 meters, about 19 meters, about 20 meters, about 21 meters, about 22 meters, about 23 meters, about 24 meters, about 25 meters, about 26 meters, about 27 meters, about 28 meters, about 29 meters, about 30 meters, about 31 meters, about 32 meters, about 33 meters, about 34 meters, about 35 meters, about 36 meters, about 37 meters, about 38 meters, about 39 meters, about 40 meters, about 41 meters, about 42 meters, about 43 meters, about 44 meters, Approximately 45 meters, approximately 46 meters, approximately 47 meters, approximately 48 meters, approximately 49 meters, approximately 50 meters, approximately 51 meters, approximately 52 meters, approximately 53 meters, approximately 54 meters, approximately 55 meters, approximately 56 meters, approximately 57 meters, approximately 58 meters, approximately 59 meters, approximately 60 meters, approximately 61 meters, approximately 62 meters, approximately 63 meters, approximately 64 meters, approximately 65 meters, approximately 66 meters, approximately 67 meters, approximately 68 meters, approximately 69 meters, approximately 70 meters, approximately 71 meters, approximately 72 meters, approximately 73 meters, approximately 74 meters, approximately 75 meters, approximately 76 meters, approximately 77 meters, approximately 78 meters, approximately 79 meters, approximately 80 meters, approximately 81 meters, approximately 82 meters, approximately 83 meters, approximately 84 meters, approximately 85 meters, approximately 86 meters, approximately 87 meters, approximately 88 meters, approximately 89 meters, approximately 90 meters, approximately 91 meters,resulting in an increase in the patient's 6MWD of about 92 meters, about 93 meters, about 94 meters, about 95 meters, about 96 meters, about 97 meters, about 98 meters, about 99 meters, or about 100 meters.

[0062] In some embodiments, treatment with an antibody disclosed herein improves or reduces the IL-18 expression level by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 82%, at least 83%, at least 84 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least resulting in an increase in 6MWD of 6%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or at least 100%.In some embodiments, treatment with an antibody disclosed herein reduces the incidence of HIV infection by about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, resulting in an increase in 6MWD of 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99% or about 100%.

[0063] In some embodiments, treatment with the antibodies disclosed herein comprises administering to at least one patient a In some embodiments, treatment with an antibody disclosed herein results in an increase in patient survival of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, or at least 24 months. In some embodiments, treatment with an antibody disclosed herein results in an increase in patient survival of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months, or at least 24 months. month, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months , about 15 months, about 16 months, about 17 months, about 18 months, about 19 months, about 20 months, about 21 months, about 22 months, about 23 months, about 24 months.

[0064] In some embodiments, treatment is stopped for patients with one or more of the following: - NT-proBNP >8,500 pg / mL or NT-proBNP <1800 pg / mL or >8,500 pg / mL Troponin-T ≤ 0.03ng / mL or < 0.025ng / mL - dFLC < 18 mg / dL - Absolute neutrophil count (ANC) < 1.0 x 10 9 / L - Platelet count <75 x 10 9 / L - Hemoglobin < 9 g / dL - Total bilirubin >2x upper limit of normal (ULN) - Aspartate aminotransferase (AST) / serum glutamic oxaloacetic transaminase (SGOT) >3×ULN - Alanine aminotransferase (ALT) / serum glutamic pyruvic transaminase (SGPT) >3×ULN - Alkaline phosphatase (ALP) >5×ULN - Estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m as estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula 2 - Sitting systolic blood pressure <90 or >180mmHg - Distance walked during the 6MWT is <30 meters or >550 meters - Underwent ASCT or organ transplant - Electrocardiogram (ECG) evidence of myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmia or acute ischemia - Severe valvular stenosis (e.g., valve area <1.0 cm 2 aortic or mitral stenosis) or severe congenital heart disease - ECG evidence of acute ischemia or active conduction system abnormalities with any of the following exceptions: 1st degree AV-block, 2nd degree AV-block type 1 (Mobitz type 1 / Wenckebach type), right or left bundle branch block and atria with controlled ventricular rate Fibrillation (uncontrolled [>110 bpm] heart rate is not permitted [determined by average of 3 beats in Lead II or 3 representative beats if Lead II does not represent the entire EKG]) - Peripheral neuropathy rated as National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 2, Grade 3, or Grade 4 with pain - Active malignancies with the exception of any of the following: adequately treated basal cell carcinoma, squamous cell carcinoma or in situ cervical cancer, adequately treated stage I cancer in which the subject is currently in remission and has been in remission (e.g., for 2 years), low-risk prostate cancer with a Gleason score < 7 and prostate specific antigen < 10 mg / mL, and any other cancer in which the subject is disease-free (e.g., for ≥ 2 years), - Epilepsy or seizure disorders other than febrile convulsions of childhood.

[0065] Suitable antibodies, formulations and treatment regimens for the methods and uses disclosed herein are discussed in further detail below.

[0066] III. Antibodies The method of the present disclosure includes administering to a patient an antibody that specifically binds to an immunoglobulin light chain. Examples include an antibody that competes with 11-1F4 for binding to an immunoglobulin light chain, and an antibody that competes with 2A4 or 7D8 for binding to human amyloid A peptide, or specifically binds to the same epitope as 11-1F4 (US Pat. No. 8,105,594), 2A4, or 7D8 (US Pat. No. 7,928,203). In some embodiments, the antibody is a humanized version of 2A4. In some embodiments, the antibody is a chimeric or humanized version of 11-1F4, such as Ch mAb 11-1F4, CAEL-101, for example. In some embodiments, the antibody is one disclosed in US20190038745A1, US20200002410A1, and US10,046,050. In some embodiments, the antibody comprises a light chain variable region comprising the three complementarity determining regions set forth as SEQ ID NOs: 3, 4, and 5, and a heavy chain variable region comprising the three complementarity determining regions set forth as SEQ ID NOs: 6, 7, and 8. In some embodiments, the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1. In some embodiments, the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2.

[0067] In other methods, the antibody comprises the light and heavy chain variable regions of mouse, chimeric or humanized 2A4 antibody or mouse, chimeric or humanized 7D8 antibody, as described in U.S. Patent No. 7,928,203 and PCT International Publication No. WO2009 / 086539, each of which is incorporated herein by reference in its entirety, and the light and heavy chain variable region sequences described in the referenced patents and patent publications are expressly incorporated herein by reference.Some formulations for the methods disclosed herein are described in U.S. Patent No. 9,089,529 and PCT International Publication No. WO2013 / 063284.

[0068] In some embodiments, the antibody comprises a light chain comprising the amino acid sequence set forth as SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth as any one of SEQ ID NOs: 11-13. For example, the antibody may comprise a light chain comprising the amino acid sequence set forth as SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 12. The antibody may or may not include leader sequences for the light and heavy chain amino acid sequences set forth above. In some embodiments, the antibody is vilutamimab (CAS Registry No. 1608108-91-3).

[0069] In other methods, the antibody is a fragment of the 2A4 or 7D8 antibody, including chimeric and humanized versions thereof, such as a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a F(ab)c, a Dab, a nanobody or an Fv. As discussed in more detail below, the antibody may be administered as a pharmaceutical formulation.

[0070] IV. Pharmaceutical Formulations and Products In some embodiments disclosed herein, the antibody may be administered to the patient in a pharmaceutical formulation that includes, for example, in addition to the antibody, a histidine buffer, trehalose, and polysorbate 20. In some such formulations used in the methods described above, the antibody is present at a concentration in the range of about 1 mg / mL to about 100 mg / mL, the histidine buffer is present at a concentration in the range of about 20 mM to about 30 mM, the trehalose is present at a concentration in the range of about 210 mM to about 250 mM, the polysorbate 20 is present at a concentration in the range of about 0.005% to about 0.05% by weight, and the pH is in the range of about 6 to about 7. Some suitable formulations for the methods disclosed herein are described in more detail below.

[0071] In some formulations, the antibody is present at a concentration in the range of about 5 mg / mL to about 100 mg / mL. In some formulations, the antibody is present at a concentration in the range of about 5 mg / mL to about 15 mg / mL. In some formulations, the antibody is present at a concentration in the range of about 25 mg / mL to about 75 mg / mL. For example, the antibody may be present at a concentration of about 10 mg / mL, or at a concentration of about 50 mg / mL. The antibody may be present in a sterile liquid dosage form of about 50 mg / vial to about 500 mg / vial, or more. For example, the antibody may be present in a sterile liquid dosage form of about 100 mg / vial. In another non-limiting example, the antibody may be present as a sterile lyophilized dosage form that can be reconstituted with about 500 mg / vial of sterile liquid dosage form. In another non-limiting example, the antibody may be present as a sterile lyophilized dosage form that can be reconstituted with about 10 mL of sterile liquid to a dosage form of about 50 mg / mL or about 500 mg / vial.

[0072] The antibodies used in the formulations of the present disclosure may be coupled to a therapeutic moiety such as a cytotoxic agent, a radiotherapeutic agent, an immunomodulatory agent, a secondary antibody (e.g., to form an antibody heteroconjugate), or any other biologically active agent that promotes or enhances the activity of the chimeric or humanized 2A4 or chimeric or humanized 7D8 antibody. Exemplary therapeutic moieties include agents known to be useful for the treatment, management, or amelioration of amyloid diseases or symptoms of amyloid diseases.

[0073] Therapeutic moieties and / or detectable substances may be coupled or conjugated directly to the murine, chimeric or humanized 2A4 antibody or the murine, chimeric or humanized 7D8 antibody or indirectly through an intermediate (e.g., a linker) using techniques known in the art. See, for example, Arnon et al., "Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy, pp. 243-56 (Alan R. Liss, Inc. 1985); Controlled Drug Delivery (2nd ed.), Robinson et al. (eds.), Hellstrom et al., Antibodies For Drug Delivery, pp. 623-53 (Marcel Dekker, Inc. 1987); Monoclonal Antibodies Vol. 84: Biological And Clinical Applications, Thorpe, Pinchera et al. (eds.), Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review, pp. 475-506 (1985); Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy, pp. 303-16 (Academic Press 1985) and Thorpe et al., Immunol. Rev., 1982, 62:119-58.

[0074] The antibody used in the formulation of the present disclosure also includes modified forms of mouse, chimeric or humanized 2A4 antibody or mouse, chimeric or humanized 7D8 antibody that have extended in vivo half-life compared to the corresponding unmodified antibody. Such modified forms may be prepared, for example, by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, linking to cellular ligands or other proteins, etc. As an example, a representative method for antibody half-life extension is described in PCT International Publication No. WO02 / 060919.

[0075] In some formulations, the histidine buffer may be present at a concentration of about 25 mM.In some formulations, the histidine buffer comprises L-histidine and L-histidine HCl monohydrate.For example, in some formulations, L-histidine is present at a concentration within the range of about 16 mM to about 22 mM, and L-histidine HCl monohydrate is present at a concentration within the range of about 4 mM to about 8 mM.

[0076] In some formulations trehalose is present at a concentration of about 210 mM to about 250 mM, for example about 230 mM. In some formulations a different non-reducing sugar is used, such as sucrose, mannitol or sorbitol.

[0077] In some formulations, polysorbate 20 is present at a concentration in the range of about 0.005% to about 0.05% by weight, such as 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, or 0.05% by weight. Alternatively, in some formulations, polysorbate 20 is present at a concentration in the range of about 0.05 g / L, 0.1 g / L, 0.15 g / L, 0.2 g / L, 0.25 g / L, 0.3 g / L, 0.35 g / L, 0.4 g / L, 0.45 g / L, or 0.5 g / L. Some formulations include polysorbate 20 at a concentration of 0.2 g / L.

[0078] Some formulations are characterized by a pH in the range of about 6-7, e.g., a pH of 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.0. Some formulations have a pH of about 6.5. Some formulations are characterized by an osmolality of about 300 mOsm / kg. Bulking agents may also be included in some formulations.

[0079] Typically the formulations are sterile, as accomplished by, for example, sterile filtration using a 0.2 μm or 0.22 μm filter. The formulations disclosed herein are also generally stable to freezing and thawing.

[0080] Optionally, the formulations disclosed herein may further include other excipients such as sugars, polyols, and amino acids (eg, arginine, lysine, and methionine).

[0081] The present disclosure also provides formulations that are substantially free of surfactants, inorganic salts, added sugars and / or other excipients, i.e., formulations that contain less than about 0.0005%, less than 0.0003% or less than 0.0001% of such compounds.

[0082] An exemplary formulation comprises an antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth as any one of SEQ ID NOs: 11, 12 or 13 present at a concentration of about 50 mg / mL, histidine buffer present at a concentration of about 25 mM, trehalose present at a concentration of about 230 mM, polysorbate 20 present at a concentration of about 0.2 g / L, and has a pH of about 6.5. Some formulations comprise an antibody comprising a light chain comprising the amino acid sequence set forth as SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 12 present at a concentration of about 50 mg / mL, histidine buffer present at a concentration of about 25 mM, trehalose present at a concentration of about 230 mM, polysorbate 20 present at a concentration of about 0.2 g / L, and has a pH of about 6.5. Some formulations comprise viltamimab present in a concentration of about 50 mg / mL, histidine buffer present in a concentration of about 25 mM, trehalose present in a concentration of about 230 mM, polysorbate 20 present in a concentration of about 0.2 g / L, and have a pH of about 6.5.

[0083] The methods disclosed herein relate to a pharmaceutical product comprising a lyophilized antibody drug substance and instructions for reconstitution and use. For example, a representative pharmaceutical product may comprise: (a) a vial containing about 100 mg of antibody in powder form; (b) instructions for reconstitution of the antibody; and (c) instructions for preparing the reconstituted antibody for injection, where (i) the antibody comprises a light chain comprising the amino acid sequence set forth as SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence set forth as any one of SEQ ID NOs: 12-15, and (ii) the reconstitution instructions call for reconstitution with water for injection to an extractable volume of 10 mL.

[0084] IV. Treatment Regimens As used herein, the terms "treat" and "treatment" refer to alleviating or ameliorating one or more symptoms or effects associated with a disease, preventing, inhibiting or delaying the onset of one or more symptoms or effects of a disease, lessening the severity or frequency of one or more symptoms or effects of a disease, and / or increasing or directing toward a desired outcome as described herein.

[0085] The desired outcome of the treatment disclosed herein varies depending on the amyloid disease and the patient profile, and can be easily determined by those skilled in the art. The desired outcome includes an improvement in the health status of the patient. In general, the desired outcome includes measurable indicators such as reduction or clearance of pathological amyloid fibrils, reduction or inhibition of amyloid aggregation and / or deposition of amyloid fibrils, and increase in immune response to pathological and / or aggregated amyloid fibrils. The desired outcome also includes the alleviation of specific symptoms of amyloid diseases. For example, the desired outcome for the treatment of AL amyloidosis includes a reduction in the incidence or severity of known symptoms, including organ dysfunction, peripheral and autonomic neuropathy, carpal tunnel syndrome, macroglossia, restrictive cardiomyopathy, arthropathy of large joints, immune cachexia, myeloma, and latent cachexia.

[0086] For example, the 6-minute walk test (6MWT) may be a surrogate endpoint used to assess cardiac function response (Pulido et al., The six-minute walk test in patients with AL amyloidosis: a single centre case series, British Journal of Haematology, 2017, 177, 388-394). The SF-36 Health Survey measures the distance a patient can walk in 6 minutes along a 6-minute walking distance scale. For example, it has been shown that the mean 6-minute walking distance (6MWD) of AL amyloidosis patients with cardiac complications is significantly shorter than the distance walked by AL amyloidosis patients without cardiac complications. Furthermore, increased walking distance correlates with reduced mortality. Positive changes in health-related quality of life have also been reported, for example, in the SF-36 Health Survey (White et al., Psychometric validation of the SF-36 Health Survey in light chain amyloidosis: results from community-based and clinic-based samples, Patient Related Outcome Measures 2017:8). 157-167). The F-36 includes scores that represent eight aspects of functioning and well-being: physical functioning, role limitations due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitations due to emotional problems and mental health, and summary scores, such as physical summary (PCS) and mental summary (MCS). Higher SF-36 scores represent better health. The desired outcomes of the treatments of the present disclosure are generally quantifiable measurements compared to a control or baseline measurement. As used herein, relative terms such as "improvement," "increase," or "reduction" refer to values ​​compared to a control, such as measurements in the same individual before the start of the treatment described herein, or measurements in a control individual or group. A control individual is an individual who suffers from the same amyloid disease as the individual to be treated, is approximately the same age as the individual to be treated (to ensure that the stage of the disease is comparable in treated and control individuals), but has not been treated using the antibody formulation of the present disclosure. In this case, the effectiveness of the antibody formulation of the present disclosure is evaluated by a shift or trend from a measurable indicator in untreated controls. Alternatively, the control individual is a healthy individual of approximately the same age as the individual to be treated.In this case, the efficacy of the antibody formulation of the present disclosure is evaluated by shift or trend from the measurable indicator in healthy control.The change or improvement in response to treatment is generally statistically significant, and is considered significant when described by a p-value of less than or equal to 0.1, less than 0.05, less than 0.01, less than 0.005 or less than 0.001.

[0087] Typically, treatment involves multiple dosing over an extended period of time. Treatment may be monitored by assaying for antibodies or using radiolabeled SAP scintigraphy over time. A decrease in response may indicate the need for additional dosing. Changes in the patient's health status may be monitored based on outcome measures such as 6MWD, SF-36PCS (SF-36v2), hospitalization, and survival, as discussed in detail above. Additionally, the response of patients with AL amyloidosis to treatment may be monitored by assessing cardiac markers such as NT-proBNP and / or troponin, serum creatine and / or alkaline phosphatase; by performing serum free light chain (SFLC) assays, quantitative immunoglobulin assays, biopsies, serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), serum, urine immunofixation electrophoresis (IFE), and / or organ imaging techniques. Exemplary complete response (CR) can be determined from response criteria including negative serum and urine IFE, normal kappa / lambda ratio and / or <5% plasma cells in bone marrow. Exemplary very good partial response (VGPR) can be determined from dFLC of <40mg / L. Exemplary partial response (PR) can be determined from a ≥50% decrease in dFLC. In the kidney, response to treatment can be determined from, for example, a ≥50% decrease in 24-hour urinary protein excretion (e.g., >0.5g / 24 hours) in the absence of either a ≥25% decrease in eGFR or an increase in serum creatine of ≥0.5mg / dL. In the liver, response to treatment can be determined from, for example, a ≥50% decrease in initially elevated alkaline phosphatase or a ≥2cm decrease in liver size on CT scan or MRI. In the heart, response to treatment can be determined, for example, from a reduction in NT-proBNP of >30% and >300 ng / L in patients with a baseline of NT-proBNP >650 ng / L. In the kidney, response to treatment can be determined, for example, from a reduction in proteinuria of >30% or a reduction in proteinuria to <0.5 g / 24 hours in the absence of renal progression. Neuropathic responders are generally characterized by an increase in NIS-LL of <2 points from baseline.Improvement in neuropathy (e.g., improvement in neurological function) is determined by a reduction in NIS-LL from baseline. Improvement in health status can also be determined by a reduction in hospitalization frequency, a reduction in hospitalization for more than 90 days, or a longer survival compared to untreated different patients with similar prognosis at diagnosis, such as AL amyloidosis patients with cardiac complications.

[0088] The antibody formulation may be administered intravenously or subcutaneously at a dosage range of about 0.5 mg / kg to about 30 mg / kg of host body weight. For example, the dosage may be about 0.5 mg / kg body weight, about 1.0 mg / kg, about 1.5 mg / kg, about 2.0 mg / kg, about 4.0 mg / kg, about 5.0 mg / kg, about 8.0 mg / kg, about 10 mg / kg, about 15 mg / kg, about 16 mg / kg, about 20 mg / kg, about 24 mg / kg, about 25 mg / kg, or about 30 mg / kg body weight. The dosage may also be administered according to body surface area from about 0.5 mg / m2 to about 500 mg / m2, for example, 0.5, 5, 10, 50, 100, 250, or 500 mg / m2. For intravenous dosing, a quantity of antibody formulation sufficient to achieve the desired dosage for an individual patient is transferred from one or more vials into one or more intravenous bags containing fluid (e.g., saline) and administered to the patient.

[0089] Antibodies are usually administered multiple times. Exemplary treatment regimens require administration once every two weeks, once a month, or once every three to six months. For example, a patient may receive the antibody formulation on a cycle of once every four weeks, for example, every 28 days. The dosing frequency may be adjusted depending on the pharmacokinetic profile of the antibody formulation in the patient. For example, the half-life of the antibody may warrant a two-week frequency of dosing. In some embodiments, the pharmaceutical formulation is administered intravenously at an antibody dosage of about 24 mg / kg every 28 days. For example, some patients may receive an intravenous dose of about 24 mg / kg virutamimab every 28 days. For example, some patients may receive an intravenous dose of about 24 mg / kg virutamimab every 28 days (± 5 days). In certain embodiments, a minimum of 21 days between doses is required. For some such patients, the virutamimab formulation transferred to the intravenous bag was initially reconstituted from a lyophilized formulation to a formulation having a pH of about 6.5 and including about 50 mg / ml virutamimab, about 25 mM histidine buffer, about 230 mM trehalose, and about 0.2 g / L polysorbate 20. The desired dose for some patients may be administered subcutaneously undiluted from a vial containing any of the formulations disclosed herein.

[0090] In some embodiments disclosed herein, the antibody is administered to the patient for at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months or even longer.For example, the pharmaceutical formulation is administered to the patient for a duration effective to achieve or maintain the improvement in health status indicated by the increase in 6MWD or SF-36PCS score, or for a duration long enough to achieve or maintain a lower risk of death compared to untreated patients.For some patients, the lower risk can be established after at least 8 months of treatment.For some patients, the lower risk can be established after at least 9 months of treatment.For some patients, the lower risk can be established after at least 12 months of treatment or after at least 18 months of treatment or after 24 months of treatment.For these patients, the lower risk of death correlates with a longer survival time compared to untreated patients.

[0091] Also disclosed herein is a combination therapy for treating or preventing AL amyloidosis. Such combination therapy is carried out by administering the antibody formulation disclosed herein in combination with one or more second therapeutic agents, such as another treatment for treating or preventing AL amyloidosis. The combination therapy disclosed herein may be carried out in combination with a second treatment, and is used to treat or prevent diseases or conditions associated with amyloid disease, such as inflammatory disease, chronic microbial infection, neoplasm (including malignant neoplasm), inherited inflammatory disease, and / or lymphoproliferative disorder. Numerous treatments are available commercially and in clinical evaluation and preclinical development, any of which may be selected for use in combination with the antibody formulation of the present disclosure. Such treatments fall into several major categories, including, but not limited to: (i) nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., detoprofen, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenameate, mefenamic acid, meloxicam, nabumeone, naproxen sodium, oxaprozin, piroxicam, sulindac, tolme); (ii) steroids (e.g., cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone); (iii) DMARDs, i.e., disease-modifying antirheumatic drugs (e.g., cyclosporine, azathioprine, methotrexate, leflunomide, cyclophosphamide, hydroxychloroquine, sulfasalazine, D-penicillamine, minocycline, and gold); (iv) recombinant proteins (e.g., ENBREL® (etanercept, a soluble TNF receptor) and REMICADE® (infliximab) chimeric monoclonal anti-TNF antibody); (v) stem cell transplantation; and / or (vi) chemotherapy. Patients with AL amyloidosis may receive treatment regimens including drugs or drug combinations often used to treat hematological malignancies, such as melphalan, prednisone, dexamethasone, lenalidomide (REVLIMID®), proteosome inhibitors such as bortezomib (VELCADE®) and carfilzomib (KYPROLIS®), and CD38 agents such as daratumumab (DARZALEX®), at dosages in the standard of care range.

[0092] When combination therapy is practiced, two or more drug substances are administered simultaneously or sequentially in any order, i.e., the formulations disclosed herein are administered prior to administration of the second drug substance, simultaneously with the second drug substance, or subsequent to administration of the second drug substance. For example, combination therapy may be performed by administering a first treatment prior to (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously with, or subsequently to (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a second agent / treatment.

[0093] The dosage, frequency and mode of administration of each component of the combination may be independently controlled. For example, one therapeutic agent / treatment may be administered orally three times a day, while the second therapeutic agent / treatment may be administered intramuscularly once a day. The combination therapy may be given in an on-off cycle with a drug holiday. The compounds may be mixed or otherwise formulated together such that one administration delivers both compounds. In this case, each therapeutic agent is generally present in an amount of 1-95% by weight of the total weight of the composition. Alternatively, the antibody formulations disclosed herein and the second therapeutic agent may be formulated separately in individual dosages. The drug combination for treatment may be provided as a component of a pharmaceutical package.

[0094] Preferably, the combination therapy of the present disclosure produces a synergistic therapeutic effect, i.e., an effect that is greater than the sum of their individual effects or therapeutic outcomes. Measurable therapeutic outcomes are described herein. For example, a synergistic therapeutic effect may be at least about 2-fold greater, or at least about 5-fold greater, or at least about 10-fold greater, or at least about 20-fold greater, or at least about 50-fold greater, or at least about 100-fold greater than the sum of the therapeutic effects produced by the single agents of a given combination. A synergistic therapeutic effect may also be observed as an increase in therapeutic effect of at least 10%, or at least 20%, or at least 30%, or at least 40%, or at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 100% or more compared to the sum of the therapeutic effects produced by the single agents of a given combination. A synergistic effect is also an effect that allows the dosage of therapeutic agents to be reduced when used in combination.

[0095] Some methods of the present disclosure include treating a subject with AL amyloidosis by determining one or more of the following prognostic indicators: (1) the patient's Mayo stage of AL amyloidosis; (2) the patient's 6-minute walking distance (6MWD) and ejection fraction (EF) and / or the patient's Mayo stage and EF. Once the prognostic indicator(s) are determined, the patient is selected for treatment if it meets one of the following treatment criteria: (1) has Mayo stage IV AL amyloidosis; (2) has 6MWD≧150 meters and EF>50% at baseline; (3) has Mayo stage IV and EF>50% at baseline; or (4) has Mayo stage IV, 6MWD≧150 meters and EF>50% at baseline. Treatment includes administering an effective dose of an antibody disclosed herein.

[0096] In one method of the disclosure, patients who meet one or more prognostic indicators are treated with virutamimab (24 mg / kg) supplied as a sterile, lyophilized dosage form in 20 / 25 mL vials containing 500 mg virutamimab. Each vial is reconstituted with 9.6 mL of sterile water for injection (WFI) to a concentration of 50 mg / mL, resulting in a buffered, isotonic, preservative-free solution. Vilutamimab is administered once every 28 days as an initial 120 (± 10) minute IV infusion. If the subject tolerates the initial infusion, subsequent infusions may be administered over 60 (± 10) minutes. Doses are administered at intervals of at least 21 days.

[0097] Patients may be treated with concurrent standard of care chemotherapy, which may include, for example, bortezomib administered subcutaneously every week. EXAMPLES

[0098] The following examples are included to illustrate the modes disclosed herein. Certain aspects of the following examples are described in terms of the techniques and procedures discovered or contemplated by the present co-inventors to fully implement the practices disclosed herein. In light of this disclosure and the general level of skill of those skilled in the art, it will be understood that the following examples are intended to be illustrative only, and that numerous changes, modifications and alterations may be used without departing from the scope of the present disclosure.

[0099] Example 1 Phase 2b Clinical Evaluation of NEOD001, Also Known as Virutamimab (Humanized 2A4) A phase 2b global, multicenter, randomized, double-blind, placebo-controlled clinical study of NEOD001 versus placebo was conducted in previously treated patients with AL amyloidosis and persistent cardiac dysfunction (PRONTO study). The study enrolled 129 patients. Patients were randomized on a 1:1 basis to receive NEOD001 (n=66) or placebo (n=63) at 24 mg / kg via intravenous infusion every 28 days. The primary endpoint was best cardiac response as measured by NT-proBNP throughout 12 months of treatment. Secondary endpoints included change in the Short-Form 36 (SF-36 questionnaire, change in the 6-minute walk test (6MWT), best renal response as measured by proteinuria, change in Neuropathy Score-Leg (NIS-LL) score, and NT-proBNP slope. Additional information about the clinical study design is available at https: / / clinicaltrials.gov. The PRONTO study did not meet its primary and secondary endpoints.

[0100] Example 2 Phase 3 Clinical Evaluation of NEOD001 A phase 3 global, multicenter, randomized, double-blind, placebo-controlled clinical study of NEOD001 versus placebo was conducted in newly diagnosed, treatment-naive patients with AL amyloidosis and cardiac dysfunction with both arms of the study receiving standard of care (VITAL study; VITAL Amyloidosis Study, A Global Phase 3, Efficacy and Safety Study of NEOD001 in Patients with AL Amyloidosis (VITAL), ClinicalTrials.gov Identifier: NCT02312206). The study enrolled 260 patients (see Table 1).

[0101] [Table 1-1] [Table 1-2]

[0102] Patients were randomized on a 1:1 basis to receive NEOD001 at 24 mg / kg or placebo via intravenous infusion every 28 days. All patients received bortezomib-based chemotherapy concurrently with NEOD001 or placebo. Placebo was administered as a 250 mL bag of saline once every 28 days. The primary outcome was a composite of time to all-cause death or cardiac hospitalization. Secondary outcome measures were NT-proBNP best response, time to cardiac death or cardiac hospitalization, change in 6-minute walk test, change in the Short-Form-36 questionnaire, change in the Kansas City Cardiomyopathy Questionnaire, Palladini et al, The clinical study design included best renal response assessed using the 2014 criteria and best hepatic response assessed using the Comenzo et al, 2012 criteria. Additional information regarding the clinical study design is available at https: / / clinicaltrials.gov. Based on the results from the PRONTO study, a futility analysis was performed for the ongoing VITAL study. The futility analysis, based on 103 adjudicated events of 156 identified as completing the study, was not statistically significant. The hazard ratio (HR) was 0.84 in favor of NEOD001 versus the control arm (HR, 0.84; 95% confidence interval [CI], 0.57-1.204; P=0.386). Based on the results from the futility analyses of the PRONTO and VITAL studies, clinical development of NEOD001 was discontinued.

[0103] Example 3 Statistical analysis of the VITAL study - surprising results in certain patients Following discontinuation of NEOD001 development, statistical analysis was performed on the VITAL study data, which necessarily included censored data due to study completion. Data were censored at 12 months. Final study results were consistent with futility analysis. NEOD001 did not significantly differ from controls for the primary endpoints of all-cause mortality or cardiac hospitalization (≥91 days) (HR, 0.835; 95% CI 0.5799-1.2011; P=0.330; see Table 2 and Figure 5). NEOD001 did not significantly differ from controls for any of the key secondary endpoints (SF-36PCS, 6MWD, NT-proBNP best response, or best renal response). Subsequent post-hoc analysis of subjects classified as Mayo stage IV provided even stronger results in favor of virutamimab (HR=0.538), revealing a potential survival benefit for this subset of patients.

[0104] [Table 2]

[0105] Surprisingly, analysis of the data suggested improvements in health status in certain subsets of patients, namely Mayo stage IV patients (n=77 of 260; approximately 30% of patients enrolled in the VITAL study were Mayo stage IV) as well as patients with baseline 6MWD longer than 150 meters and ejection fraction greater than 50% regardless of Mayo stage (n=135). The hazard ratios for such patient subpopulations were 0.498 and 0.511 in favor of treatment, respectively, with median overall survival in stage IV (mITT) being 8.3 months in the placebo+SOC group and not reached (>12 months) in the NEOD001+SOC group (see FIG. 6). Moreover, the observed benefit appears to be further enhanced for Mayo stage IV patients (n=36) with baseline 6MWD ≧150 meters and ejection fraction (EF) >50%. The hazard ratio for such patients was 0.201 in favor of treatment. In addition, benefit was also observed in Mayo stage IV patients (n=37) with ejection fraction (EF) >50%, regardless of 6MWD. It is surprising that greater improvements were observed in Mayo stage IV patients than in stage I-III patients, since it is generally accepted that treatment intervention at earlier stages of disease related to amyloid burden is necessary to achieve improvement.

[0106] Example 4 Mayo Stage IV Patient Response As shown in Figures 1A and 1B, Mayo stage IV patients treated with NEOD001 showed greater improvement in health status compared to the difference seen in stage I-III patients as measured by a composite of all-cause mortality or cardiac hospitalization longer than 91 days over 12 months compared to patients treated with placebo, with stage IV patients resulting in an HR of 0.635 (relative risk reduction 36.5%), p=0.1409 (Figure 1B) compared to an HR of 0.879 (relative risk reduction 12.15%) for stage I-III patients, p=0.6125 (Figure 1A).

[0107] As shown in Figures 2A and 2B, compared to patients treated with placebo, stage IV patients treated with NEOD001 showed even greater improvement in health status compared to the difference seen in stage I-III patients, with stage IV patients resulting in an HR of 0.498 (relative risk reduction 50.2%), p=0.0556 (Figure 2B), compared to a HR of 1.244 (relative risk reduction -24.4%) for stage I-III patients, p=0.5159 (Figure 2A).

[0108] As shown in Figures 3A and 3B, stage IV patients treated with NEOD001 showed even greater improvement in health status compared to the difference seen in stage I-III patients as measured by cardiac death over 12 months compared to patients treated with placebo, with stage IV patients resulting in an HR of 0.378 (relative risk reduction 62.2%), p=0.0142 (Figure 3B) compared to a HR of 1.051 (relative risk reduction -5.1%) for stage I-III patients, p=0.8971 (Figure 3A).

[0109] As shown in Table 3, stage IV patients treated with NEOD001 showed greater improvement in health status compared to the difference seen in stage I-III patients, as measured by SF-36PCS score change from baseline to month 9 compared to patients treated with placebo, with stage IV patients showing a change of +5.54 points, p=0.0258, compared to a change of -0.65 points, p=0.7150, for stage I-III patients. Abbreviations: LSM (least squares mean); SE (standard error); CI (confidence interval). In mITT analysis, SF-36PCS scores showed significantly less deterioration from baseline at month 6 (P<0.05) and month 9 (P<0.005) in the NEOD001+SOC group compared to the placebo+SOC group (see FIG. 7), and the change from baseline in 6MWD was significantly greater at all time points up to month 12 in the NEOD001+SOC group versus the placebo+SOC group.

[0110] [Table 3]

[0111] As shown in Table 4, stage IV patients treated with NEOD001 showed greater improvement in health status compared to the difference seen in stage I-III patients as measured by 6MWD change in rank from baseline to month 9 compared to patients treated with placebo, with stage IV patients showing a change in rank of +36.74, p=0.0462 compared to -4.26, p=0.6911 for stage I-III patients.

[0112] [Table 4]

[0113] Changes from baseline in 6MWD were significantly greater in the NEOD001+SOC group versus the placebo+SOC group at all time points through month 12. The mean (SD) duration of exposure was 389.4 (245.65) years in the NEOD001+SOC group and 352.7 (248.30) years in the placebo+SOC group. The mean (SD) number of infusions received was 14.5 (8.60) and 13.3 (8.71) in the NEOD001+SOC and placebo+SOC groups, respectively. Table 5 provides a summary of the VITAL study results in Mayo stage IV patients.

[0114] [Table 5]

[0115] Example 5 Responses in patients with a 6MWD of ≥150 meters and an EF of >50% As shown in Figures 4A and 4B, patients with a baseline 6-minute walk distance (6MWD) greater than or equal to 150 meters and an ejection fraction (EF) greater than 50% and treated with NEOD001 showed greater improvements in health status as measured by all-cause mortality through 12 months compared to patients treated with placebo. Results for all Mayo stage patients with baseline 6MWD ≥ 150 meters and EF > 50% were HR 0.511 (relative risk reduction 48.9%), p = .0741 and 95% CI (0.241, 1.083) (Figure 4A). Results for Mayo stage IV patients with baseline 6MWD ≥ 150 meters and EF > 50% were HR 0.201 (relative risk reduction 79.9%), p = .0090 and 95% CI (0.053, 0.762), Figure 4B. Additionally, Mayo stage IV patients with a baseline EF >50% had a HR of 0.185 (relative risk reduction 81.5%), p=0.0049 and 95% CI (0.050, 0.689).

[0116] Overall, 257 patients in the safety population experienced one or more treatment-emergent AEs (TEAEs; see Table 6). The most common TEAEs (fatigue, nausea, peripheral edema, constipation, and diarrhea) were similar in both treatment arms, and both treatment arms had a similar frequency of serious TEAEs (NEOD001+SOC, 67.7%; placebo+SOC, 70.0%). 288 serious AEs were reported by 88 NEOD001-treated patients, the majority (95.5%) of which were considered unrelated to the study drug, and TEAEs resulting in death occurred more frequently in the placebo+SOC group (28 subjects, 21.5%) than in the NEOD001+SOC group (20 subjects, 15.4%). No deaths were considered related to the study drug; causes of death in both groups were consistent with underlying disease and known risk of cardiac complications. Overall safety results were similar within and across Mayo stages.

[0117] [Table 6]

[0118] Example 6 A Phase 3, Multicenter, Open-Label, Single-Arm, Efficacy and Safety Study of Virutamimab (NEOD001) Plus Standard of Care in Mayo Stage IV Subjects with Light-Chain (AL) Amyloidosis The primary objective of the study (NEOD001-301) is to evaluate the efficacy of virutamimab plus standard of care when administered intravenously to Mayo stage IV subjects with AL amyloidosis by assessing time to all-cause mortality. Secondary objectives are to evaluate virutamimab plus standard of care on: (1) change from baseline to 9 months in health-related quality of life using the Short Form 36 questionnaire (SF-36v2) and (2) change from baseline to 9 months in 6-minute walk test (6MWT) distance (meters).

[0119] Newly diagnosed, Mayo stage IV subjects with AL amyloidosis will receive local standard of care chemotherapy plus virutamimab. The initial first-line chemotherapy regimen should include bortezomib. Subjects will remain in the study until study completion, when approximately 16 primary endpoint events (all-cause deaths) have been achieved or 62 subjects have completed 9 months of treatment. If a subject discontinues study drug before study completion but is willing to continue participating in study visits, the subject should have an Early Treatment Discontinuation (ETD) visit within 28-35 days after the last study drug administration and then be evaluated every 3 months (see Table 8). All visits after the ETD visit should occur as scheduled, i.e., when the visits would have occurred if the subject had remained on study drug.

[0120] Subject screening will occur 28 days prior to the first dose of study drug on Month Day 1. The screening period may be extended with approval by the Medical Monitor. Screening assessments are listed herein in Table 7.

[0121] Two screening 6MWTs are required prior to the first dose of study drug. The first screening 6MWT should be performed between days -28 and 5, within 2 days prior to month 1, and at least 4 days prior to the second screening 6MWT. The post-baseline 6MWT may be performed on the same day as study drug administration and must be completed prior to study drug infusion. If all eligibility requirements are met, the month 1 day 1 assessment is completed and treatment begins. Each visit will note the first study drug infusion date as month 1 day; subsequent months will be noted by their "month" and "day" using sequential numbers (e.g., the second dose will be administered on month 2 day 1). "Cycles" will be reserved to note chemotherapy administration. Assessment and visit windows will be described in the Event Schedule (Table 7). Each month, subjects will receive their study drug infusion on day 1 at the study site. For months 1 through 3, subjects will be evaluated weekly, although not all visits need to be at the study site. For month 3 and all subsequent months until study termination, subjects are only required to return to the study site every 28 days for Day 1 dosing of study medication.

[0122] First-line chemotherapy must be a bortezomib-containing regimen, with bortezomib administered subcutaneously (SC) weekly. The first dose of bortezomib-containing chemotherapy will be administered after Month 1 Day 1 study drug administration (after the post-study drug infusion observation period) such that Month 1 Day 1 of the study is the same as Cycle 1 Day 1 of chemotherapy. In addition to the visits outlined above, during the first cycle of chemotherapy, subjects must return to the study site for each weekly dose of bortezomib and for pre-dose evaluations. During the second and third cycles of chemotherapy, bortezomib must be administered at the study site during the Month 2 Day 1, Month 2 Day 15, and Month 3 Day 1 visits (i.e., Cycle 2 Day 1, Cycle 2 Day 15, and Cycle 3 Day 1, respectively). If for any reason in the investigator's opinion the subject should continue to come to the study site weekly (e.g., toxicity beyond the expected side effects of chemotherapy), the other cycle 2 and cycle 3 weekly bortezomib administrations may be performed at the study site as well. At the investigator's discretion, if the subject does not experience any unexpected or significant toxicity, the subject may be administered bortezomib by their local physician on cycle 2 days 8 and 22 and cycle 3 days 8, 15 and 22 by the investigator. Within one day prior to or on the day of each administration of bortezomib by the local physician, a medical professional must obtain pre-administration vital signs and central laboratory samples. However, if bortezomib is administered on a Monday (or there is a holiday in between), it is acceptable to perform a homecare visit on the preceding Friday.

[0123] If a bortezomib dose is missed, chemotherapy cycles may not be aligned with monthly study drug dosing. In this case, weekly visits during months 1 through 3 should continue as described above to closely monitor the subject's health during the first month of concurrent chemotherapy. Throughout the study, monthly doses of study drug should not be delayed or skipped due to adjustments made for chemotherapy dosing.

[0124] Safety and efficacy assessments will be performed at each visit.

[0125] Inclusion Criteria (subjects must meet all of the following criteria): 1. Age ≥ 18 years 2. Newly diagnosed, treatment-naive AL amyloidosis 3. Bone marrow demonstrates clonal plasma cells 4. Confirmed diagnosis of AL amyloidosis by: Histochemical diagnosis of amyloidosis as determined by polarized light microscopy of green birefringent material in Congo red-stained tissue specimens or characteristic electron microscopic findings And Confirmatory immunohistochemistry or mass spectrometry for AL amyloidosis 5. A confirmed diagnosis of AL amyloidosis by mass spectrometry or immunoelectron microscopy of amyloid material in tissue biopsy if the subject meets any of the following: · Are black or African-American Age over 75 years and concurrent monoclonal hypergammaglobulinemia History of familial amyloidosis with concomitant monoclonal hypergammaglobulinemia or If a subject meets any of the above three criteria and has echocardiographic evidence of amyloidosis, biopsy-diagnosed amyloidosis with monoclonal gammopathy, and no tissue is available for mass spectrometry or immunoelectron microscopy, the subject must have gene sequencing consistent with transthyretin (TTR) wild type (e.g., no TTR mutations are present) and be immunoreactive with technetium-99m-3,3-diphosphono-1,2propanodicarboxylic acid (99mTc DPD; Rapezzi 2011), hydroxymethylenediphosphone (HA) or HT. 99mTc HMDP; Galat 2015) or pyrophosphate (99mTc P YP; Bokhari 2013) Scintigraphy must score 0 6. Cardiac complications as defined by all of the following: A definitive diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure requires previously described or currently documented clinical signs and symptoms that support the diagnosis of heart failure. Either an endomyocardial biopsy demonstrating AL amyloidosis or an echocardiogram demonstrating a mean left ventricular wall thickness in diastolic >12 mm in the absence of other causes (e.g., severe hypertension, aortic stenosis) that adequately explain the degree of wall thickening. 7. Confirmed Mayo stage IV as defined by: NT-proBNP ≥ 1800 pg / mL, and Troponin-T>0.03ng / mL, and dFLC ≥ 18 mg / dL 8. Planned first-line chemotherapy includes bortezomib administered subcutaneously (SC) weekly 9. Adequate bone marrow reserve, liver function and renal function as demonstrated by: Absolute neutrophil count (ANC) ≥ 1.0 × 109 / L · Platelet count ≧75×109 / L Hemoglobin ≥ 9g / dL Total bilirubin ≦2x upper limit of normal (×ULN) Aspartate aminotransferase (AST) / serum glutamic oxaloacetic transaminase (SGOT) ≤ 3 × ULN Alanine aminotransferase (ALT) / serum glutamic pyruvic transaminase (SGPT) ≤ 3 × ULN Alkaline phosphatase (ALP) ≤ 5 x ULN (excluding subjects with hepatomegaly and isoenzymes specific to liver rather than bone) Estimated glomerular filtration rate (eGFR) ≥ 30 mL / min / 1.73 m2 as estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula 10. Sitting systolic blood pressure: 90-180mmHg 11. 6MWT walking distance ≥ 30 meters and ≤ 550 meters at each screening 12. Women of childbearing potential (WOCBP) must have two negative pregnancy tests at screening, the second within 24 hours prior to the first dose of study drug, and agree to use highly effective physician-approved contraception from screening through 90 days after the last dose of study drug. 13. Male subjects must be surgically sterile or agree to use highly effective physician-approved contraception from screening through 90 days after the last study drug dose 14. Ability to understand and willingness to sign an informed consent form prior to the start of all study procedures.

[0126] Exclusion Criteria (subjects must not meet any of the following criteria): 1. Non-AL amyloidosis 2. NT-proBNP>8,500pg / mL 3. Meets the International Myeloma Working Group (IMWG) definition of multiple myeloma * Note: Subjects meeting the IMWG definition of symptomatic multiple myeloma with signs and / or symptoms attributable solely to concomitant amyloidosis may be eligible with sponsor approval. 4. Subject is eligible to undergo and plans to undergo ASCT or organ transplant during the study 5. Symptomatic orthostatic hypotension that, in the investigator's medical judgment, interferes with the subject's ability to safely undergo procedures or complete study assessments. 6. Electrocardiogram (ECG) evidence of myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmia, or acute ischemia within 6 months prior to the 1st month visit 7. Severe valvular stenosis (e.g., aortic or mitral stenosis with valve area <1.0 cm2) or severe congenital heart disease 8. ECG evidence of acute ischemia or active conduction system abnormality with any of the following exceptions: 1st degree AV block 2nd degree AV-block type 1 (Mobitz type 1 / Wenckebach type) Right or left bundle branch block Atrial fibrillation with controlled heart rate (uncontrolled [>110 bpm] heart rate is not permitted [determined by average of 3 beats in Lead II or 3 representative beats if Lead II does not represent the entire EKG]) 9. Peripheral neuropathy rated as National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 2, Grade 3, or Grade 4 with pain 10.Subject has received oral or IV antibiotics, antifungals, or antivirals, excluding prophylactic oral agents, within 1 week of the first day of the month 11. Prior treatment with hematopoietic growth factors, blood, or blood product transfusions within 1 week of Month 1 12. Prior radiation therapy within 4 weeks of day 1 of month 1 13. Major surgery within 4 weeks of Month 1 or planned major surgery during the study 14. Active malignancies with the exception of any of the following: Appropriately treated basal cell carcinoma, squamous cell carcinoma or in situ cervical carcinoma Adequately treated stage I cancer in which the subject is currently in remission and has been in remission for 2 years Low-risk prostate cancer with Gleason score <7 and prostate-specific antigen <10mg / mL Any other cancer in which the subject has been disease-free for ≥2 years 15. History of severe allergy to any of the components of virutamimab, such as histidine / L-histidine hydrochloride monohydrate, trehalose dehydrate, or polysorbate 20, or history of grade ≥ 3 infusion-related AE or hypersensitivity to another monoclonal antibody or known hypersensitivity to diphenhydramine (or H1 antihistamine equivalent) or acetaminophen (or its equivalent, paracetamol). 16. Known or history of uncontrolled, active HIV, Hepatitis B or Hepatitis C infection 17. Pretreatment with plasma cell-directed chemotherapy, virutamimab, daratumumab, 11-1F4, anti-serum amyloid P antibodies, doxycycline against amyloid or other investigational treatments directed against amyloid 18. Treatment with another investigational drug within 30 days of Month 1 19. Pregnant or breastfeeding women 20. Any condition that may interfere with the conduct of the study, or the procedure therefor may interfere with the conduct of the study, or which in the investigator's opinion unacceptably increases the risk to the subject from participation in the study. 21. The subject is under legal control 22. History of epilepsy or seizure disorder except for febrile convulsions in childhood 23. Waldenström hypergammaglobulinemia and / or Immunoglobulin M (IgM) monoclonal hypergammaglobulinemia

[0127] Study Drug: Study drug consists of virutamimab (24 mg / kg) supplied as a sterile lyophilized dosage form in 20 / 25 mL vials containing 500 mg virutamimab. Each vial is reconstituted with 9.6 mL sterile water for injection (WFI) to a concentration of 50 mg / mL, resulting in a buffered, isotonic, preservative-free solution. Study drug is administered once every 28 days as an initial 120 (± 10) minute IV infusion. If the subject tolerates the initial infusion, subsequent infusions may be administered over 60 (± 10) minutes. The length of the infusion may be extended to a longer period if clinically indicated. A minimum of 21 days is required between doses.

[0128] Premedication: All subjects will be premedicated for each dose of study drug with 25 mg diphenhydramine (or equivalent dose of H1 antihistamine) and 650 mg acetaminophen (or equivalent dose of paracetamol) within 30-90 minutes prior to study drug administration.

[0129] Standard of care chemotherapy: All subjects will receive concurrent standard of care chemotherapy, which must include bortezomib administered subcutaneously weekly for the initial first-line chemotherapy regimen. Subsequent chemotherapy regimens may be prescribed as standard of care at the investigator's discretion. Antiviral prophylaxis is required.

[0130] Statistical considerations Analysis Populations. The intention to treat (ITT) population includes all subjects with Mayo stage IV AL amyloidosis and receiving any amount of study drug. The ITT population is the primary population used for efficacy and safety analyses.

[0131] Efficacy Analyses. Primary Analysis - The primary endpoint is time to all-cause mortality. All-cause mortality includes all deaths occurring after the first infusion of study drug (Study Day 1) through the last visit of the last subject in the study (LSLV). An exponential survival model is used to estimate the estimated survival percentage at 9 months. An exact binomial test is used to compare the estimated survival percentage to the historical control value of 49%.

[0132] Key Secondary Efficacy Analyses - If the primary analysis concludes in favor of virutamimab, then data for placebo plus SOC Mayo stage IV subjects from Study NEOD001 CL0002 [VITAL] will be used to compare: (1) change from baseline to 9 months in SF-36v2 PCS score, and / or (2) change from baseline to 9 months in 6MWT distance (meters). For both of these variables, the change from baseline to 9 months and 95% confidence intervals will be calculated. If the lower limit of the confidence interval is greater than that observed from the placebo group in VITAL, then the study will conclude that virutamimab is superior to control.

[0133] [Table 7-1] [Table 7-2] Table 7 footnotes 1. The 28-day screening period may be extended with approval by the Medical Supervisor. Individual test results not meeting eligibility requirements may be repeated with the exception of the 6MWT; full rescreening is permitted once per subject. 2. Bortezomib-containing chemotherapy on cycle 2 days 8 and 22 and cycle 3 days 8, 15 and 22 should be administered at the study site by the investigator if the subject has significant toxicity, otherwise may be administered by a local physician at the investigator's discretion. 3. The EOT / ETD visit will occur 28-35 days after the last study drug administration. 4. Obtain a comprehensive cardiac, hematological and oncological medical history; in addition, obtain relevant medical history for the past 5 years for all other conditions (including any significant hospitalizations and surgeries), and the subject's current medical condition. 5. Results from mass spectrometry histotyping, immunoelectron microscopy, gene sequencing and / or 99mTc scintigraphy must be available prior to randomization to assess eligibility for subjects identified in inclusion criterion #5. 6. At visits where the SF-36v2 (Appendix 4) is to be administered, the SF-36v2 must be administered prior to the administration of any other study assessments that day. 7. If an echocardiogram is performed within 90 days prior to Screening Day-28, it does not need to be repeated at Screening and the previous result may be used for eligibility. After Screening, perform an echocardiogram within 10 days prior to Day 1 every 6 months; if not performed within 60 days prior to visit, repeat at EOT / ETD. To be eligible for additional cardiac imaging analysis, subjects must undergo a 4-chamber, 2-dimensional echocardiogram with Doppler. 8. ECGs will be performed 3 times as follows: Month 1 Day 1: within 30 minutes pre-dose and 1 hour (± 15 minutes) after EOI; All other visits (every 3 months starting at Months 1, 2, 3 and 6): within 30 minutes pre-dose or any time on non-infusion days. Medications given for prevention of chemotherapy-induced side effects should not be administered prior to completion of the post-infusion ECG. 9. A thorough PE should include height (screening only), weight, and examination of: general appearance; head, ears, eyes, nose, and throat; neck; skin; cardiovascular system; respiratory system; gastrointestinal system; and nervous system. Assess macroglossia, submandibular lymph nodes / distention, gland enlargement, ecchymosis, liver / spleen size (palpable + / -), ascites (+ / -), and edema (to be quantified on a scale of 0-4). 10. A symptom-based PE should be as clinically indicated and also include weight and assessment of macroglossia, submandibular lymph nodes / distention, gland enlargement, ecchymosis, liver / spleen size (palpable + / -), ascites (+ / -), and edema (to be quantified on a scale of 0-4). 11. Local laboratory results for hematology and chemistry should be used for subject management and reviewed for safety assessment prior to administration of chemotherapy, but will not be collected in electronic case report forms or clinical databases. 12. Performed only if the subject returns to the study site for this visit. 13. Month 1, Day 1 Use a local laboratory for a serum pregnancy test within 24 hours prior to study drug administration. 14. Obtain an on-site urine pregnancy test prior to study drug administration. 15. Obtain a local laboratory serum pregnancy test 90 (± 5) days after the last study drug dose. 16. Collect central laboratory samples prior to 6MWT if performed on the same day. 17. PT / INR and PTT were collected at each time point. 18. NT-proBNP should be collected prior to the 6MWT if performed on the same calendar day. 19. Subjects should be scheduled to return to the same clinic for each 6MWT from Screening 1 through Month 9. Post-baseline 6MWTs may be performed on the same calendar days that study drug is administered (i.e., Months 3, 6, 9, etc.) as long as the NT-proBNP sample is collected before the 6MWT is performed and the 6MWT is completed before the start of study drug infusion. BP and HR will be collected before and after the 6MWT. 20. The first screening 6MWT should be performed between days -28 and -5 and within 2 days prior to the Month 1 visit (i.e., on day -2 or day -1), at least 4 days prior to the second screening 6MWT. 21. Archived serum samples will only be collected from subjects who have consented to the collection and storage of samples for future correlation testing. 22. All subjects will receive 25 mg diphenhydramine (or equivalent dose of H1 antihistamine) and 650 mg acetaminophen (or equivalent dose of paracetamol) within 30 90 minutes prior to the start of the infusion. 23. Vital signs include BP, HR, RR and temperature; assessed in the same location for all time points after the subject has rested for ≥5 minutes. Pre-medication assessments should be performed after administration of premedication. Screening and non-infusion days: Any time; Month 1 Day: Within 30 minutes pre-dose, mid-infusion (i.e., approximately 60 minutes after the start of the infusion), immediately at EOI (+10 minutes), 0.5 hours (±10 minutes) and 1 hour (±10 minutes) after EOI. All other months Day 1: Within 30 minutes pre-dose, EOI (+10 minutes) and 1 hour (±10 minutes) after EOI. 24. Subjects should be closely monitored for 90 (± 10) minutes after completion of study drug infusion. The investigator may extend this standard monitoring time if deemed appropriate or in accordance with local standards. In the event of any clinical problems or suspicious signs or symptoms after infusion, subjects will remain under observation for as long as the investigator deems appropriate. 25. First-line chemotherapy must be a bortezomib-containing regimen with bortezomib administered SC weekly according to approved prescribing information and local institutional practice. Antiviral prophylaxis is required. If chemotherapy is administered on the same day as study drug, chemotherapy must be administered after the post-study drug infusion observation period. The number of first-line chemotherapy cycles and subsequent chemotherapy regimens will be administered per standard of care at the investigator's discretion. 26. Bortezomib must be administered at the study site following local laboratory review, study drug administration, and post-study drug infusion observation periods on Cycle 1 days 1, 8, 15, and 22; Cycle 2 days 1 and 15; and Day 1 of subsequent cycles. 27. On cycle 2 days 8 and 22 and cycle 3 days 8, 15 and 22 chemotherapy may be administered within one day prior to or on the day of each bortezomib dose by the local physician with a home care visit by a Prothena sponsored health care provider to obtain vital signs, blood samples and bioanalytical samples (if applicable) for central laboratory testing. If bortezomib is administered on a Monday, a home care visit may be conducted on the preceding Friday. If significant toxicity occurs during cycle 1, the subject must return to the study site for cycle 2 and cycle 3 visits until deemed appropriate by the investigator for local dosing. 28. Any new SAE occurring beyond the EOT / ETD visit or >28 days after the last dose of study drug, whichever occurs later, will be reported to the sponsor and his / her designee only if, in the investigator's judgment, the SAE is related to any protocol intervention (i.e., related to study procedures or prior study drug exposure). 29. For all subjects who received a dose of study drug: Vital status assessment will be performed approximately 3 months after the subject's last visit and approximately every 3 months thereafter.

[0134] [Table 8] Table 8 footnotes 1. If a subject discontinues study drug before the end of the study but is willing to continue participating in study visits, the subject should have an ETD visit within 28-35 days after the last study drug administration and then be evaluated every 3 months (i.e., at months 3, 6, 9, and 12 or whichever remains of these visits). All visits after the ETD visit should occur as scheduled, i.e., at the times that the visits would occur if the subject remained on study drug. 2. If the subject is willing to return to the research facility, otherwise the subject will undergo vital status. 3. SF-36v2 will be performed prior to the performance of any other study assessments on the day it is performed. 4. Echocardiogram will be performed within 10 days prior to Day 1 of Months 6 and 12. 5. ECG performed 3 times. 6. Symptom-based PE should be as clinically indicated and include assessment of body weight and macroglossia, submandibular lymph nodes / distention, gland enlargement, ecchymosis, liver / spleen size (palpable + / -), ascites (+ / -) and edema (which should be quantified on a scale of 0 to 4). 7. Obtain a local laboratory serum pregnancy test 90 (± 5) days after the last study drug dose. 8. Collect central laboratory samples prior to 6MWT if performed on the same day. 9. PT / INF and PTT were collected at each time point. 10. From Month 12 onwards, if the subject is willing to return to the study site, the following will be performed or collected every 3 months (e.g., Months 15, 18, 21): 6MWT (including pre- and post-6MWT BP and HR), adverse events, concomitant medications, general health status and details of any hospitalizations. 11. Withdraw if early samples establish the presence of anti-NEOD001 antibodies or if subject discontinues treatment due to suspected immunological reaction. 12. BP, HR, RR and temperature will be collected at any time during the visit. 13. Newly occurring SAEs beyond the EOT / ETD visit or >28 days after the last dose of study drug, whichever occurs later, will be reported to the sponsor and his / her designee only if, in the investigator's judgment, the SAE is related to any protocol intervention (i.e., related to study procedures or prior study drug exposure). 14. All hospitalizations and deaths occurring during this period must be reported to the Sponsor and his / her designee. 15. Vital status assessment will be performed approximately 3 months after the subject's last visit and approximately every 3 months thereafter.

[0135] The disclosures of all patents, patent applications and publications cited herein are incorporated herein by reference in their entirety. Although the present invention has been disclosed with reference to specific embodiments, other embodiments and variations of the present disclosure may be devised by others skilled in the art without departing from the true spirit and scope of the present disclosure. The appended claims include all such embodiments and equivalent variations.

[0136] array SEQ ID NO: 01 Humanized antibody sequence containing mouse and human residues (humanized 2A4 light chain variable region version 3) DVVMTQSPLSLPVTPGEPASISCRSSQSLVHSTGNTYLHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPFTFGGGTKVEIK SEQ ID NO: 02 Humanized antibody sequence containing mouse and human residues (humanized 2A4 heavy chain variable region version 3) EVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMYWIRQAPGKGLEWVARIRSKSNNYAIYYADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARPYSDSFAYWGQGTLVTVSS SEQ ID NO: 03 2A4 VL CDR1 RSSQSLVHSTGNTYLH SEQ ID NO: 04 2A4 VL CDR2 KVSNRFS SEQ ID NO: 05 2A4 VL CDR3 SQSTHVPFT SEQ ID NO: 06 2A4 VH CDR1 GFTFNTYAMY SEQ ID NO: 07 2A4 VH CDR2 RIRSKSNNYAIYYADSVKD SEQ ID NO: 08 2A4 VH CDR3 PYSDSFAY SEQ ID NO: 09 7D8 VL CDR1 RSSLSLVHSTGNTYLH SEQ ID NO:10 Humanized antibody sequence containing mouse and human residues (humanized 2A4 kappa light chain) DVVMTQSPLSLPVTPGEPASISCRSSQSLVHSTGNTYLHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPFTFGGGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 11 Humanized antibody sequence containing mouse and human residues (humanized 2A4 IgG1 heavy chain variant 1 (G1m1 allotype)) EVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMYWIRQAPGKGLEWVARIRSKSNNYAIYYADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARPYSDSFAYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 12 Humanized antibody sequence containing mouse and human residues (humanized 2A4 IgG1 heavy chain variant 2 (G1m3 allotype)) EVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMYWIRQAPGKGLEWVARIRSKSNNYAIYYADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARPYSDSFAYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:13 Humanized antibody sequence containing mouse and human residues (humanized 2A4 IgG2 heavy chain) EVQLVESGGGLVQPGGSLRLSCAASGFTFNTYAMYWIRQAPGKGLEWVARIRSKSNNYAIYYADSVKDRFTISRDDSKNSLYLQMNSLKTEDTAVYYCARPYSDSFAYWGQ GTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCC VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKT ISKTKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO:14 11-1F4 Monoclonal Antibody Variable Light [Kappa] DVVMTQTPLSLPVSLGDQASISCRSSQSLVHRNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKI SRVEAEDLGLYFCFQTTYVPNTFGGGTKLEIK SEQ ID NO:15 11-1F4 monoclonal antibody variable heavy QVQLKESGPGLVAPSQSLSITCTVSGFSLSSYGVSWVRQPPGKGLEWLGVIWGDGSTNYKPNLMSRLSISKDISKSQVLFKLNSLQTDDTATYYCVTLDYWGQGTSVTVSS SEQ ID NO: 16 11-1F4 monoclonal antibody CDR1 light chain RSSQSLVHRNGNYTLH SEQ ID NO: 17 11-1F4 monoclonal antibody CDR2 light chain LVSNRFS SEQ ID NO: 18 11-1F4 monoclonal antibody CDR3 light chain FNTTYVPNT SEQ ID NO: 19 11-1F4 monoclonal antibody CDR1 heavy chain SYGVSW SEQ ID NO: 20 11-1F4 monoclonal antibody CDR2 heavy chain VIWGDGSTNYHPNLMSRLSIS SEQ ID NO: 21 11-1F4 monoclonal antibody CDR3 heavy chain L.D.Y. SEQ ID NO:22 11-1F4 Monoclonal Antibody Variable Light [Kappa] [ka] SEQ ID NO:23 11-1F4 monoclonal antibody variable heavy [ka]

Claims

1. A composition comprising an antibody comprising a heavy chain variable region comprising the heavy chain CDRs of SEQ ID NOs:6, 7, and 8, and a light chain variable region comprising the light chain CDRs of SEQ ID NOs:3, 4, and 5, for use in a method for improving the Simplified 36-item Physical Component Score (SF-36PCS) or SF-36v2 in a patient with AL amyloidosis, wherein the patient is (a) Mayo stage IV AL amyloidosis; (b) 6MWD ≥150 meters at baseline and EF >50% at baseline; (c) Mayo stage IV AL amyloidosis and EF >50% at baseline; or (d) Mayo stage IV AL amyloidosis, 6MWD of ≥150 meters at baseline, and EF of >50% at baseline The composition of matter has previously been classified as having

2. The composition described in claim 1, wherein the patient has been classified as having Mayo stage IV AL amyloidosis.

3. The composition described in claim 1, wherein the patient has been classified as having a 6MWD of ≧150 meters at baseline and an EF of >50% at baseline.

4. The composition of claim 1, wherein the patient has been classified as having Mayo stage IV AL amyloidosis and an EF of >50% at baseline.

5. The composition of claim 1, wherein the patient has been classified as having Mayo stage IV AL amyloidosis, a 6MWD of ≧150 meters at baseline, and an EF of >50% at baseline.

6. The composition described in any one of claims 1 to 5, wherein the patient is newly diagnosed and treatment-naive for AL amyloidosis.

7. The composition of any one of claims 1 to 5, wherein the patient has previously undergone or is concurrently undergoing treatment with melphalan, prednisone, dexamethasone, bortezomib, cyclophosphamide, lenalidomide, doxorubicin, doxycycline, daratumumab, autologous transplantation or a combination thereof.

8. The composition of any one of claims 1 to 5, wherein the patient has previously undergone or is concurrently undergoing treatment with cyclophosphamide, bortezomib, and dexamethasone (CyBorD).

9. The composition described in any one of claims 1 to 8, wherein the antibody is viltamimab.

10. The composition of claim 9, wherein the effective amount of viltamimab is administered from a pharmaceutical formulation comprising viltamimab at a concentration ranging from about 1 mg / mL to about 100 mg / mL.

11. The composition described in claim 9 or 10, wherein the dosage is about 0.5 mg / kg to about 30 mg / kg and viltamimab is administered intravenously or subcutaneously at a frequency of about once a week to about four times a year.

12. The composition of claim 10 or 11, wherein viltamimab is present at a concentration of about 50 mg / mL.

13. The composition of claim 11 or 12, wherein the dosage is about 24 mg / kg and viltamimab is administered intravenously every 28 days.

14. A composition comprising an antibody comprising a heavy chain variable region comprising the heavy chain CDRs of SEQ ID NOs:6, 7, and 8, and a light chain variable region comprising the light chain CDRs of SEQ ID NOs:3, 4, and 5, for use in a method for improving 6-minute walk distance (6MWD) in a patient with AL amyloidosis, wherein the patient is (a) Mayo stage IV AL amyloidosis; (b) 6MWD ≥150 meters at baseline and EF >50% at baseline; (c) Mayo stage IV AL amyloidosis and EF >50% at baseline; or (d) Mayo stage IV AL amyloidosis, 6MWD of ≥150 meters at baseline, and EF of >50% at baseline The composition of matter has previously been classified as having 15. The composition of claim 14, wherein the patient has been classified as having Mayo stage IV AL amyloidosis.

16. The composition described in claim 14, wherein the patient has been classified as having a 6MWD of ≧150 meters at baseline and an EF of >50% at baseline.

17. The composition of claim 14, wherein the patient has been classified as having Mayo stage IV AL amyloidosis and an EF of >50% at baseline.

18. The composition described in claim 14, wherein the patient has been classified as having Mayo stage IV AL amyloidosis, a 6MWD of ≧150 meters at baseline, and an EF of >50% at baseline.

19. The composition described in any one of claims 14 to 18, wherein the patient is newly diagnosed and treatment-naive for AL amyloidosis.

20. The composition of any one of claims 14 to 18, wherein the patient has previously undergone or is concurrently undergoing treatment with melphalan, prednisone, dexamethasone, bortezomib, cyclophosphamide, lenalidomide, doxorubicin, doxycycline, daratumumab, autologous transplantation, or a combination thereof.

21. The composition of any one of claims 14 to 18, wherein the patient has previously undergone or is concurrently undergoing treatment with cyclophosphamide, bortezomib, and dexamethasone (CyBorD).

22. The composition described in any one of claims 14 to 21, wherein the antibody is viltamimab.

23. The composition of claim 22, wherein the effective amount of viltamimab is administered from a pharmaceutical formulation comprising viltamimab at a concentration ranging from about 1 mg / mL to about 100 mg / mL.

24. The composition described in claim 22 or 23, wherein the dosage is about 0.5 mg / kg to about 30 mg / kg and viltamimab is administered intravenously or subcutaneously at a frequency of about once per week to about four times per year.

25. The composition of claim 23 or 24, wherein viltamimab is present at a concentration of about 50 mg / mL.

26. The composition of claim 24 or 25, wherein the dosage is about 24 mg / kg and viltamimab is administered intravenously every 28 days.

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