Treatment of al amyloidosis by combination of monoclonal antibody against immunoglobulin light chain and monoclonal antibody against CD38 cell membrane molecule on antibody-producing and other immune cells

Abstract

To provide a treatment of AL amyloidosis by combination of a monoclonal antibody to an immunoglobulin light chain and a monoclonal antibody to a CD38 cell membrane molecule on antibody-producing cells or other immune cells.SOLUTION: Disclosed is a treatment of AL amyloidosis by combination of a monoclonal antibody against an immunoglobulin a light chain and aggregates thereof and a monoclonal antibody against a CD38 cell membrane molecule on antibody-producing or other immune cells. Typically, the effective dosage of these antibodies is effective to achieve an improvement in both hematologic and cardiac or other organ function. The dosage may be effective to achieve an improvement in both hematologic and organ function, for example, cardiac function.SELECTED DRAWING: None

Description

[Technical field]

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

[0002] background Amyloid light chain (AL) amyloidosis involves a hematological disorder caused by clonal plasma cells that produce immunoglobulin light chains that can become misfolded and contribute to the disease. Excessive production of misfolded light chains by plasma cells leads to the deposition of abnormal AL protein (amyloid) in tissues and organs of individuals with AL amyloidosis. Clinical features of AL amyloidosis include a constellation of symptoms and organ dysfunction that can include 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 deposits and prefibrillar aggregates may contribute to the cytotoxic effects on organs observed in patients with AL amyloidosis. AL amyloidosis is an entity in its own right, but can occur concomitantly in a proportion of patients with multiple myeloma (up to 15%) or monoclonal gammopathy of undetermined significance (MGUS; up to 9%). Patients with cardiac complications have a high-risk disease, as demonstrated by the fact that approximately 25% of patients with cardiac complications die within 6 months of diagnosis, despite today's clinical advances.

[0003] AL amyloidosis is a rare disorder with an estimated prevalence of 8 per 1,000,000. Only 1200-3200 new cases of AL amyloidosis are reported annually in the United States. Two-thirds of patients with AL amyloidosis are men, and less than 5% are under the age of 40. Both the cause and origin of AL amyloidosis remain poorly understood.

[0004] Current treatment of patients with AL amyloidosis aims to reduce or eliminate bone marrow damage (i.e., plasma cells responsible for light chain production), thereby suppressing or stopping the production of amyloid. The most aggressive treatment options include stem cell transplantation and high-dose chemotherapy for patients who can tolerate them. Other treatment regimens include combinations of drugs frequently used to treat hematological malignancies, such as melphalan, prednisone, dexamethasone, and proteasome inhibitors (e.g., bortezomib), in an attempt to reduce light chain production. CD38 antibodies, such as daratumumab (DARZALEX®) and isatuximab, have been developed for the treatment of multiple myeloma. Daratumumab binds to CD38 present on the surface of myeloma cells. Daratumumab's action is believed to be both by directly killing tumor cells and by stimulating an immune response against cancer cells.

[0005] Currently, there are no approved treatments for AL amyloidosis, and none that directly target potentially toxic forms of the amyloidogenic protein. Although several treatment options may ameliorate some of the morbidity associated with AL amyloidosis, few, if any, have been demonstrated to achieve high rates of hematologic and cardiac responses in patients.

[0006] Thus, there is a need for therapies that improve outcomes for patients with AL amyloidosis. Summary of the Invention [Means for solving the problem]

[0007] Abstract The present disclosure relates to a method of treating a patient with AL amyloidosis with multiple antibodies targeting different proteins associated with AL amyloidosis or plasma cell dyscrasia, and the present disclosure provides a method of treating a patient with AL amyloidosis, comprising administering effective dosages of an antibody that specifically binds to an amyloid light chain and an antibody that specifically binds to CD38 (e.g., a chimeric or humanized monoclonal antibody against CD38). Typically, the dosages are effective to achieve an improvement in hematological function or cardiac or other organ function. The dosages may be effective to achieve an improvement in both hematological function and organ function (e.g., cardiac function). In some methods, the amyloid light chain antibody or CD38 antibody is administered as a Fab, Fab', F(ab') antibody. 2 , F(ab)c, Dab, Nanobody, or Fv.

[0008] In some methods disclosed herein, the amyloid light chain antibody competes with antibody 2A4 (ATCC deposit number 9662) or 7D8 (ATCC deposit number PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or binds to or competes with the same epitope as 11-1F4 for binding to human kappa or lambda light chain immunoglobulin. In some methods, the amyloid light chain antibody is a humanized version of 2A4 or 7D8. In some methods, the antibody is a humanized bispecific or multispecific version containing a combination of 11-1F4, 2A4, and / or 7D8.

[0009] In some methods disclosed herein, the amyloid light chain antibody comprises a light chain variable region comprising the three complementarity determining regions defined as SEQ ID NOs: 3, 4, and 5, and a heavy chain variable region comprising the three complementarity determining regions defined as SEQ ID NOs: 6, 7, and 8.

[0010] In some methods disclosed herein, the light chain variable region of an amyloid light chain antibody comprises the amino acid sequence set forth as SEQ ID NO: 1. In some methods, the heavy chain variable region of an amyloid light chain antibody comprises the amino acid sequence set forth as SEQ ID NO: 2. For example, the light chain variable region of the amyloid light chain antibody may comprise the amino acid sequence set forth as SEQ ID NO: 1 and the heavy chain variable region of the amyloid light chain antibody may comprise the amino acid sequence set forth as SEQ ID NO: 2.

[0011] In some methods disclosed herein, the amyloid light chain 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 methods, the amyloid light chain 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 methods, the amyloid light chain antibody is birtamimab (also known as NEOD001).

[0012] In some methods disclosed herein, the amyloid light chain antibody is present in the formulation at a concentration of about 50 mg / mL, the histidine buffer is present in the formulation at a concentration of about 25 mM, the trehalose is present in the formulation at a concentration of about 230 mM, the polysorbate 20 is present in the formulation at a concentration of about 0.2 g / L, and the pH is about 6.5.

[0013] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14 or 15. In some methods, the CD38 antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 or 18. In some methods, the CD38 antibody comprises heavy and light chain variable region amino acid sequences set forth in (a) SEQ ID NO: 14 and 17, respectively; (b) SEQ ID NO: 15 and 18, respectively; or (c) SEQ ID NO: 16 and 19, respectively; (d) SEQ ID NO: 43 and 44, respectively; (e) SEQ ID NO: 53 and 54, respectively; (f) SEQ ID NO: 57 and 58, respectively; (g) SEQ ID NO: 59 and 60, respectively; (h) SEQ ID NO: 61 and 62, respectively; or (i) SEQ ID NO: 63 and 64, respectively.

[0014] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 47, 48, and 49, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 50, 51, and 52, respectively.

[0015] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 26, 27, and 28, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 29, 30, and 31, respectively.

[0016] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:32, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:33.

[0017] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:34, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:35.

[0018] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:36, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:37.

[0019] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:38, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:39.

[0020] In some methods disclosed herein, the CD38 antibody is daratumumab. In some methods, the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 43 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 44.

[0021] In some methods disclosed herein, the CD38 antibody is isatuximab or other CD38 antibodies disclosed in WO2016 / 187546 and US2017 / 0008966, which are incorporated by reference in their entireties. In some methods, the CD38 antibody is isatuximab.

[0022] In some methods disclosed herein, the CD38 antibody binds at least the region SKRNIQFSCKNIYR (SEQ ID NO: 45), and the region EKVQTLEAWVIHGG (SEQ ID NO: 56). In some methods, the CD38 antibody comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 47, 48, and 49, respectively, and a light chain variable region comprising the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 50, 51, and 52, respectively.

[0023] In some methods, the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 53 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 54. In some methods, the CD38 antibody comprises a heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 55 and a light chain comprising the amino acid sequence set forth as SEQ ID NO: 56.

[0024] In some methods disclosed herein, the CD38 antibody comprises heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and CDR3 of: (a) the variable heavy chain region of SEQ ID NO:57 and the variable light chain region of SEQ ID NO:58; (b) the variable heavy chain region of SEQ ID NO:59 and the variable light chain region of SEQ ID NO:60; (c) the variable heavy chain region of SEQ ID NO:61 and the variable light chain region of SEQ ID NO:62; or (d) the variable heavy chain region of SEQ ID NO:63 and the variable light chain region of SEQ ID NO:64. In some methods, the CD38 antibody comprises the variable heavy chain region of SEQ ID NO:57 and the variable light chain region of SEQ ID NO:58. In some methods, the CD38 antibody comprises the variable heavy chain region of SEQ ID NO:59 and the variable light chain region of SEQ ID NO:60. In some methods, the CD38 antibody comprises the variable heavy chain region of SEQ ID NO:61 and the variable light chain region of SEQ ID NO:62. In some methods, the CD38 antibody comprises the variable heavy chain region of SEQ ID NO:63 and the variable light chain region of SEQ ID NO:64.

[0025] In some methods, the antibody is a humanized bispecific or multispecific version that includes a combination of daratumumab, isatuximab, or other CD38 antibodies. In some methods, the antibody is a humanized bispecific or multispecific version that includes a combination of daratumumab, isatuximab, or other CD38 antibodies with 11-1F4, 2A4, and / or 7D8 or other human light chain amyloid antibodies.

[0026] In some methods disclosed herein, the patient has previously been treated with ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin, doxycycline, daratumumab, autograft, or combinations thereof. In some methods, the patient has not responded to treatment with bortezomib.

[0027] In some methods disclosed herein, the amyloid light chain antibody and the CD38 antibody are administered to the patient by intravenous infusion two days apart. In some methods, the amyloid light chain antibody is administered first. Alternatively, the CD38 antibody may be administered first.

[0028] In some methods disclosed herein, the patient achieves a higher VGPR (very good partial response) after treatment compared to patients receiving the CD38 antibody alone. In some methods, the patient shows an improvement in VGPR of greater than 85% after treatment. In some methods, the improvement is at least 88%. In some methods, the patient achieves a hematological response in a shorter time after treatment compared to patients receiving the CD38 antibody alone. In some methods, the patient shows an improvement in hematological response in less than 60 days after treatment. In some methods, the patient shows an improvement in less than 45 days. In some methods, the patient shows an improvement within 33 days.

[0029] In some methods disclosed herein, the patient achieves a cardiac response in a shorter time after treatment compared to patients receiving the CD38 antibody alone. In some methods, the patient achieves a greater reduction in N-terminal proBNP after treatment compared to patients receiving the CD38 antibody alone. In some methods, the N-terminal proBNP level is reduced by at least 55% after treatment. In some methods, the N-terminal proBNP level is reduced by at least 65%. In some methods, the reduction in N-terminal proBNP level is 74% or more.

[0030] In some methods disclosed herein, the dosage of the amyloid light chain antibody is about 0.5 mg / kg to about 30 mg / kg, and the amyloid light chain antibody is administered intravenously or subcutaneously at a frequency of about once a week to about once a quarter. In some methods, the duration of treatment is at least 9 months. In some methods, the duration of treatment is at least 12 months.

[0031] In some methods disclosed herein, a dosage of amyloid light chain antibody is administered intravenously after transferring the amount of formulation required for that dosage from a vial to an intravenous infusion bag containing the liquid.

[0032] In some methods disclosed herein, the dosage of the amyloid light chain antibody is about 24 mg / kg and the antibody is administered intravenously once every 28 days. In some methods, the dosage of the CD38 antibody is 16 mg / kg.

[0033] In some methods disclosed herein, the patient was treatment naive prior to receiving treatment with either the amyloid light chain antibody or the CD38 antibody.

[0034] The present disclosure also provides a combination of an amyloid light chain antibody and a CD38 antibody for use in treating AL amyloidosis.

[0035] In some combinations for use in treating AL amyloidosis, the amyloid light chain antibody competes with antibody 2A4 (ATCC deposit number 9662) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or competes with 11-1F4 for binding to human kappa or lambda light chain immunoglobulin. In some combinations, the amyloid light chain antibody is a humanized version of 2A4.

[0036] In some combinations for use in treating AL amyloidosis, the amyloid light chain antibody comprises a light chain variable region comprising the three complementarity determining regions defined as SEQ ID NOs:3, 4, and 5, and a heavy chain variable region comprising the three complementarity determining regions defined as SEQ ID NOs:6, 7, and 8.

[0037] In some combinations for use in treating AL amyloidosis, the light chain variable region of an amyloid light chain antibody comprises the amino acid sequence set forth as SEQ ID NO: 1. In some combinations, the heavy chain variable region of an amyloid light chain antibody comprises the amino acid sequence set forth as SEQ ID NO: 2. In some combinations, the light chain variable region of an amyloid light chain antibody comprises the amino acid sequence set forth as SEQ ID NO: 1 and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence set forth as SEQ ID NO: 2.

[0038] In some combinations for use in treating AL amyloidosis, the amyloid light chain antibody comprises a light chain comprising an amino acid sequence set forth as SEQ ID NO: 10 and a heavy chain comprising an amino acid sequence set forth as SEQ ID NO: 11, 12, or 13. In some combinations, the amyloid light chain antibody comprises a light chain comprising an amino acid sequence set forth as SEQ ID NO: 10 and a heavy chain comprising an amino acid sequence set forth as SEQ ID NO: 12. In some combinations, the amyloid light chain antibody is vilutamimab.

[0039] In some combinations for use in treating AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14, 15, 16, 43, 53, 57, 59, 61 or 63, and the CD38 antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17, 18, 19, 44, 54, 58, 60, 62 or 64. In some combinations, the CD38 antibody comprises heavy and light chain variable region amino acid sequences as set forth in (a) SEQ ID NOs: 14 and 17, respectively; (b) SEQ ID NOs: 15 and 18, respectively; or (c) SEQ ID NOs: 16 and 19, respectively; (d) SEQ ID NOs: 43 and 44, respectively; (e) SEQ ID NOs: 53 and 54, respectively; (f) SEQ ID NOs: 57 and 58, respectively; (g) SEQ ID NOs: 59 and 60, respectively; (h) SEQ ID NOs: 61 and 62, respectively; or (i) SEQ ID NOs: 63 and 64, respectively.

[0040] In some combinations for use in the treatment of AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 47, 48, and 49, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 50, 51, and 52, respectively.

[0041] In some combinations for use in the treatment of AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 20, 21, and 22, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 23, 24, and 25, respectively.

[0042] In some combinations for use in the treatment of AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 26, 27, and 28, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 29, 30, and 31, respectively.

[0043] In some combinations for use in the treatment of AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:32, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:33.

[0044] In some combinations for use in the treatment of AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:34, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:35.

[0045] In some combinations for use in the treatment of AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:36, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:37.

[0046] In some combinations for use in the treatment of AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:38, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:39.

[0047] In some combinations for use in treating AL amyloidosis, the CD38 antibody is daratumumab. In some combinations, the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 43 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 44.

[0048] In some combinations for use in treating AL amyloidosis, the CD38 antibody is isatuximab. In some combinations, the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO:53 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO:54.

[0049] In some combinations for use in the treatment of AL amyloidosis, patients were treatment naive prior to receiving treatment with either NEOD001 or daratumumab.

[0050] The present disclosure also relates to a method of treating a plasma cell dyscrasia in a patient, wherein the patient is first treated with a combination therapy of an amyloid light chain antibody and a CD38 antibody prior to receiving plasma cell therapy. In some methods, the plasma cell dyscrasia is selected from the group consisting of monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma, multiple myeloma, PC leukemia, and plasmacytoma. In some methods, the plasma cell dyscrasia can cause the development of AL amyloidosis. In some methods, the co-treatment with CD38 antibody and amyloid light chain antibody is performed prophylactically prior to the development of AL amyloidosis. In some methods, the plasma cell therapy is selected from ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin, doxycycline, and CD38 antibody. In some methods, the plasma cell therapy is bortezomib.

[0051] In some methods, the combination therapy stabilizes or improves the patient's health and reduces the risk of plasma cell therapy intolerance and the risk of treatment-related complications, where the stabilization or improvement in the patient's health is measured by very good partial response (VGPR) and / or N-terminal pro-BNP level. In some methods, the stabilization or improvement in the patient's health includes stabilization or improvement in the patient's cardiac function before receiving plasma cell therapy. In some methods, the stabilization or improvement in the patient's health includes stabilization or improvement in the patient's functional status, as measured by Karnofsky performance status or ECOG performance status, or an equivalent functional assessment tool. In some methods, the stabilization or improvement in the patient's health includes the patient's unintentional weight loss, reduced endurance, frailty, low walking speed, and low physical activity. In some methods, the stabilization or improvement in the patient's health includes stabilization or improvement in the patient's instrumental activities of daily living. In some methods, the patient receives plasma cell therapy after achieving a reduction in N-terminal pro-BNP level compared to the patient's N-terminal pro-BNP level before receiving the combination therapy of amyloid light chain antibody and CD38 antibody. In some methods, N-terminal proBNP levels are reduced by at least 55%. In some methods, N-terminal proBNP levels are reduced by at least 65%. In some methods, the reduction in N-terminal proBNP levels is 74% or greater.

[0052] In some methods, the combination therapy is administered at least 9 months prior to the plasma cell therapy. In some methods, the combination therapy is administered at least 12 months prior to the plasma cell therapy. In some methods, the patient shows an improvement in VGPR of more than 85% following the combination therapy. In some methods, the improvement in VGPR is at least 88%. In some methods, the patient shows an improvement in hematological response less than 60 days after treatment with the combination therapy prior to treatment with the plasma cell therapy. In some methods, the patient shows an improvement in hematological response less than 45 days after treatment with the combination therapy prior to treatment with the plasma cell therapy. In some methods, the patient shows an improvement in hematological response 1 to 28 days 33 (e.g., 7 days, 14 days, 21 days, or 28 days after treatment with the combination therapy) prior to treatment with the plasma cell therapy.

[0053] In some methods disclosed herein, the methods include a method of improving cardiac function in AL patients non-responsive to treatment with NEOD001, comprising adding an effective dosing regimen of a CD38 antibody to the patient's treatment.

[0054] In some methods, the non-responsiveness of a patient to NEOD001 treatment is determined by an N-terminal proBNP level in the patient during a period following NEOD001 treatment being greater than or equal to the N-terminal proBNP level in the patient prior to NEOD001 treatment.

[0055] In some methods, the N-terminal proBNP level is higher than said N-terminal proBNP level prior to NEOD001 treatment.

[0056] In some methods, the period of time following NEOD001 treatment is at least two months.

[0057] In some methods, the patient has received at least two doses of NEOD001 prior to receiving said CD38 antibody.

[0058] In some methods, the patient has received at least three doses of NEOD001 prior to receiving said CD38 antibody.

[0059] In some methods, the CD38 antibody is administered after an increase in N-terminal proBNP in said patient exceeds about 6,000 pg / mL.

[0060] In some methods, the CD38 antibody is administered after an increase in N-terminal proBNP in said patient exceeds about 12,000 pg / mL.

[0061] In some methods, the CD38 antibody is administered after the level of N-terminal proBNP has increased by at least about 100%. In some methods, the CD38 antibody is administered after the level of N-terminal proBNP has increased by at least about 200%. In some methods, the CD38 antibody is administered after the level of N-terminal proBNP has increased by at least about 300%.

[0062] In some methods, the AL patient has previously received NEOD001 and CyBorD.

[0063] In some methods, the CD38 antibody is daratumumab or isatuximab. In some methods, the CD38 antibody is daratumumab.

[0064] In some methods, daratumumab is administered to the patient at 16 mg / kg once every 28 days.

[0065] In some methods, NEOD001 is administered to the patient at 24 mg / kg once every 28 days.

[0066] In some methods, the duration of treatment with a CD38 antibody is effective to reduce the patient's N-terminal proBNP levels to at least the level prior to receiving NEOD001 treatment. In some methods, the duration is effective to reduce the patient's N-terminal proBNP levels to below the level prior to receiving NEOD001 treatment.

[0067] In some methods, the treatment comprises at least one dose of said CD38 antibody. In some methods, the treatment comprises at least two doses of said CD38 antibody. In some methods, the treatment comprises at least three doses of said CD38 antibody. In some methods, the duration is at least 9 months. In some methods, the duration of treatment is at least 12 months. In certain embodiments, for example, the following are provided: (Item 1) A method of treating a patient with AL amyloidosis comprising administering to the patient an effective dosage of amyloid. A method comprising administering to a patient a light chain antibody in combination with a CD38 antibody. (Item 2) The method of claim 2, wherein the amyloid light chain antibody competes with antibody 2A4 (ATCC deposit no. 9662) or 7D8 (ATCC deposit no. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or binds to or competes with the same epitope as 11-1F4 for binding to human kappa or lambda light chain immunoglobulin. (Item 3) The method of claim 2, wherein the amyloid light chain antibody is a humanized version of 2A4. (Item 4) The method of claim 1, wherein the amyloid light chain antibody comprises a light chain variable region comprising the three complementarity determining regions defined as SEQ ID NOs: 3, 4, and 5, and a heavy chain variable region comprising the three complementarity determining regions defined as SEQ ID NOs: 6, 7, and 8. (Item 5) 2. The method of claim 1, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence set forth as SEQ ID NO:1. (Item 6) 2. The method of claim 1, wherein the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence set forth as SEQ ID NO:2. (Item 7) 2. The method of claim 1, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence set forth in SEQ ID NO:1, and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence set forth in SEQ ID NO:2. (Item 8) 2. The method of claim 1, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence defined as SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence defined as SEQ ID NO: 11, 12, or 13. (Item 9) 9. The method of claim 8, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence defined as SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence defined as SEQ ID NO: 12. (Item 10) 9. The method of claim 8, wherein the amyloid light chain antibody is vilutamimab. (Item 11) 13. The method of any of the preceding items, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14 or 15. (Item 12) 16. The method of any of the preceding items, wherein the CD38 antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 or 18. (Item 13) 11. The method of any of items 1 to 10, wherein the CD38 antibody comprises heavy and light chain variable region amino acid sequences as set forth in: (a) SEQ ID NOs: 14 and 17, respectively; (b) SEQ ID NOs: 15 and 18, respectively; (c) SEQ ID NOs: 16 and 19, respectively; (d) SEQ ID NOs: 43 and 44, respectively; (e) SEQ ID NOs: 53 and 54, respectively; (f) SEQ ID NOs: 57 and 58, respectively; (g) SEQ ID NOs: 59 and 60, respectively; (h) SEQ ID NOs: 61 and 62, respectively; or (i) SEQ ID NOs: 63 and 64, respectively. (Item 14) the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 47, 48, and 49, respectively; and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in Nos. 50, 51, and 52, respectively. (Item 15) 11. The method according to any of items 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 20, 21, and 22, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 23, 24, and 25, respectively. (Item 16) 11. The method according to any of items 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 26, 27, and 28, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 29, 30, and 31, respectively. (Item 17) 11. The method according to any of Items 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 32, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 33. (Item 18) 11. The method according to any of items 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 35. (Item 19) 11. The method according to any of items 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 36, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 37. (Item 20) 11. The method according to any of items 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 38, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 39. (Item 21) 11. The method according to any of items 1 to 10, wherein the CD38 antibody is daratumumab. (Item 22) 11. The method according to any of items 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence defined as SEQ ID NO: 43 and a light chain variable region comprising the amino acid sequence defined as SEQ ID NO: 44. (Item 23) 11. The method according to any of items 1 to 10, wherein the CD38 antibody is isatuximab. (Item 24) 11. The method according to any of items 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence defined as SEQ ID NO: 53 and a light chain variable region comprising the amino acid sequence defined as SEQ ID NO: 54. (Item 25) The patient has previously received ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, The method of any of the preceding items, wherein the patient has been treated with rituximab, pomalidomide, lenalidomide, doxorubicin, doxycycline, daratumumab, an autograft, or a combination thereof. (Item 26) The method of any of the preceding items, wherein the patient has not responded to treatment with bortezomib. (Item 27) The method of any of the preceding items, wherein the amyloid light chain antibody and the CD38 antibody are administered to the patient by intravenous infusion two days apart. (Item 28) 28. The method of claim 27, wherein the amyloid light chain antibody is administered first. (Item 29) 28. The method of item 27, wherein the CD38 antibody is administered first. (Item 30) The method of any of the preceding items, wherein the patient achieves a higher VGPR after treatment compared to patients receiving the CD38 antibody alone. (Item 31) The method of any of the preceding items, wherein the patient achieves a hematological response in a shorter time following treatment compared to patients receiving the CD38 antibody alone. (Item 32) The method of any of the preceding items, wherein the patient achieves a cardiac response in a shorter time following treatment compared to a patient receiving the CD38 antibody alone. (Item 33) The method of any of the preceding items, wherein the patient achieves a greater reduction in N-terminal proBNP following treatment compared to patients receiving the CD38 antibody alone. (Item 34) The method of any of the preceding items, wherein the dosage of the amyloid light chain antibody is from about 0.5 mg / kg to about 30 mg / kg, and the amyloid light chain antibody is administered intravenously or subcutaneously at a frequency of from about once a week to about once a quarter. (Item 35) The effective dosage of an amyloid light chain antibody is a) the amyloid light chain antibody at a concentration of about 50 mg / mL; b) said histidine buffer at a concentration of about 25 mM; c) the trehalose at a concentration of about 230 mM; d) the polysorbate 20 is at a concentration of about 0.2 g / L; pH is about 6.5 The method of any of the preceding items, wherein the compound is administered as a formulation comprising: (Item 36) The amyloid light chain antibody or the CD38 antibody is a Fab, Fab', F(ab') 2 , F(ab)c, Dab, Nanobody, or Fv. (Item 37) 36. The method of claim 35, wherein the dosage of the amyloid light chain antibody is administered intravenously after transferring the amount of the formulation required for the dosage from a vial to a liquid-containing intravenous infusion bag. (Item 38) The method of any of the preceding items, wherein the dosage of the amyloid light chain is about 24 mg / kg and the antibody is administered intravenously, once every 28 days. (Item 39) The method of any of the preceding items, wherein the duration of said treatment is at least 9 months. Law. (Item 40) 37. The method of claim 36, wherein the duration of the treatment is at least 12 months. (Item 41) The method of any of the preceding items, wherein said patient shows an improvement in VGPR of greater than 85% following treatment. (Item 42) 42. The method of claim 41, wherein the improvement is at least 88%. (Item 43) The method of any of the preceding items, wherein the patient shows improved hematological response less than 60 days after treatment. (Item 44) 44. The method of claim 43, wherein the patient shows improvement in less than 45 days. (Item 45) 44. The method of claim 43, wherein the patient shows improvement in 33 days or less. (Item 46) The method of any of the preceding items, wherein the patient's N-terminal proBNP level is reduced by at least 55% after treatment. (Item 47) 47. The method of item 46, wherein the N-terminal proBNP level is reduced by at least 65%. (Item 48) 47. The method of claim 46, wherein the decrease in N-terminal proBNP level is 74% or more. (Item 49) The method of any of the preceding items, wherein the patient was treatment naive prior to treatment with either the amyloid light chain antibody or the CD38 antibody. (Item 50) 1. A method for treating a plasma cell dyscrasia in a patient, wherein the patient is first treated with a combination therapy of an amyloid light chain antibody and an antibody to CD38 prior to receiving plasma cell therapy. (Item 51) 51. The method of item 50, wherein the plasma cell dyscrasia is selected from the group consisting of monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma, multiple myeloma, PC leukemia, and plasmacytoma. (Item 52) 52. The method of claim 51, wherein the plasma cell dyscrasia causes AL amyloidosis in the patient. (Item 53) 53. The method of any of items 50 to 52, wherein the plasma cell therapy is selected from the group consisting of ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin, and doxycycline. (Item 54) 54. The method of any of items 50 to 53, wherein the combination therapy stabilizes or improves the patient's health, and the stabilization or improvement in the patient's health is measured by very good partial response (VGPR) and / or N-terminal proBNP levels. (Item 55) 55. The method of item 54, wherein the stabilization or improvement in the patient's health comprises stabilization or improvement in the patient's cardiac function prior to receiving the plasma cell therapy. (Item 56) 56. The method of any of items 50 to 55, wherein the patient receives the plasma cell therapy after achieving a decrease in N-terminal proBNP levels compared to the patient's N-terminal proBNP levels before receiving the combination therapy of an amyloid light chain antibody and a CD38 antibody. (Item 57) 57. The method of item 56, wherein the N-terminal proBNP level is reduced by at least 55%. (Item 58) 57. The method of item 56, wherein the N-terminal proBNP level is reduced by at least 65%. (Item 59) 57. The method of item 56, wherein the decrease in N-terminal proBNP level is 74% or more. (Item 60) 60. The method of any of items 50 to 59, wherein the amyloid light chain antibody competes with antibody 2A4 (ATCC Deposit No. 9662) or 7D8 (ATCC Deposit No. PTA-9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or binds to or competes with the same epitope as 11-1F4 for binding to human kappa (κ) or human lambda (λ) light chain immunoglobulin. (Item 61) 61. The method of claim 60, wherein the amyloid light chain antibody is a humanized version of 2A4. (Item 62) 62. The method according to any of Items 50 to 61, wherein the amyloid light chain antibody comprises a light chain variable region comprising the three complementarity determining regions defined as SEQ ID NOs: 3, 4, and 5, and a heavy chain variable region comprising the three complementarity determining regions defined as SEQ ID NOs: 6, 7, and 8. (Item 63) 63. The method of claim 62, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence set forth as SEQ ID NO:1. (Item 64) 64. The method according to any of Items 62 to 63, wherein the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence defined as SEQ ID NO:2. (Item 65) 65. The method according to any one of Items 62 to 64, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence defined as SEQ ID NO: 1, and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence defined as SEQ ID NO: 2. (Item 66) 66. The method according to any of items 62 to 65, wherein the amyloid light chain antibody comprises a light chain comprising an amino acid sequence defined as SEQ ID NO: 10 and a heavy chain comprising an amino acid sequence defined as SEQ ID NO: 11, 12, or 13. (Item 67) 67. The method of claim 66, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence defined as SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence defined as SEQ ID NO: 12. (Item 68) 68. The method according to any of items 50 to 67, wherein the amyloid light chain antibody is vilutamimab. (Item 69) 69. The method according to any of Items 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14 or 15. (Item 70) 69. The method according to any of items 50 to 68, wherein the CD38 antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 or 18. (Item 71) 69. The method of any of items 50 to 68, wherein the CD38 antibody comprises heavy and light chain variable region amino acid sequences as set forth in (a) SEQ ID NOs: 14 and 17, respectively; (b) SEQ ID NOs: 15 and 18, respectively; (c) SEQ ID NOs: 16 and 19, respectively; (d) SEQ ID NOs: 43 and 44, respectively; (e) SEQ ID NOs: 53 and 54, respectively; (f) SEQ ID NOs: 57 and 58, respectively; (g) SEQ ID NOs: 59 and 60, respectively; (h) SEQ ID NOs: 61 and 62, respectively; or (i) SEQ ID NOs: 63 and 64, respectively. (Item 72) 69. The method according to any of Items 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 47, 48, and 49, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 50, 51, and 52, respectively. (Item 73) 69. The method according to any of Items 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 20, 21, and 22, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 23, 24, and 25, respectively. (Item 74) 69. The method according to any of Items 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 26, 27, and 28, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 29, 30, and 31, respectively. (Item 75) 69. The method according to any of Items 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 32, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 33. (Item 76) The method according to any of Items 50 to 6568, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 35. (Item 77) 69. The method according to any of Items 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 36, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 37. (Item 78) 69. The method according to any of Items 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 38, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 39. (Item 79) 79. The method according to any of items 50 to 78, wherein the CD38 antibody is daratumumab. (Item 80) 80. The method of any of items 50 to 79, wherein the plasma cell therapy is bortezomib. (Item 81) 81. The method according to any of items 50 to 80, wherein the dosage of the amyloid light chain antibody is about 0.5 mg / kg to about 30 mg / kg, and the amyloid light chain antibody is administered intravenously or subcutaneously at a frequency of about once a week to about once a quarter. (Item 82) 82. The method of any of items 81, wherein the dosage of the amyloid light chain is about 24 mg / kg and the antibody is administered intravenously once every 28 days. (Item 83) The dosage of the amyloid light chain antibody is a) the amyloid light chain antibody at a concentration of about 50 mg / mL; b) histidine buffer at a concentration of about 25 mM; c) trehalose at a concentration of about 230 mM; d) polysorbate 20 at a concentration of about 0.2 g / L; pH is about 6.5 83. The method according to any of items 81 to 82, wherein the compound is administered as a formulation comprising (Item 84) 84. The method of claim 83, wherein the dosage of the amyloid light chain antibody is administered intravenously after transferring the amount of the formulation required for the dosage from a vial to a liquid-containing intravenous infusion bag. (Item 85) 85. The method of any of items 50 to 84, wherein the combination therapy is administered at least 9 months prior to the plasma cell therapy. (Item 86) 85. The method of any of items 50 to 84, wherein the combination therapy is administered at least 12 months prior to the plasma cell therapy. (Item 87) 87. The method according to any of items 50 to 86, wherein the patient shows an improvement in VGPR of greater than 85% after combination therapy. (Item 88) 88. The method of claim 87, wherein said improvement in VGPR is at least 88%. (Item 89) 89. The method according to any of items 50 to 88, wherein the patient shows improved hematological response less than 60 days after treatment with the combination therapy. (Item 90) 90. The method of item 89, wherein the patient shows improved hematological response less than 45 days after treatment with the combination therapy. (Item 91) 90. The method of item 89, wherein the patient shows improved hematological response between 1 and 28 days after treatment with the combination therapy. (Item 92) 92. The method of item 91, wherein the treatment for the plasma cell therapy is initiated at least 28 days after treatment with the combination therapy. (Item 93) A combination of an amyloid light chain antibody and a CD38 antibody for use in the treatment of AL amyloidosis. (Item 94) The amyloid light chain antibody is selected from the group consisting of antibody 2A4 (ATCC Accession No. 966) and antibody 2A5 (ATCC Accession No. 966) for binding to human amyloid A peptide or human kappa or human lambda light chain immunoglobulins. 2) or competes with 11-1F4 for binding to human kappa or human lambda light chain immunoglobulins. (Item 95) 95. The combination for use according to item 94, wherein the amyloid light chain antibody is a humanized version of 2A4. (Item 96) 94. The combination for use according to item 93, wherein the amyloid light chain antibody comprises a light chain variable region comprising the three complementarity determining regions defined as SEQ ID NOs: 3, 4, and 5, and a heavy chain variable region comprising the three complementarity determining regions defined as SEQ ID NOs: 6, 7, and 8. (Item 97) 97. The combination for use according to item 96, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence set forth as SEQ ID NO:1. (Item 98) 97. The combination for use according to item 96, wherein the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence set forth as SEQ ID NO:2. (Item 99) 97. The combination for use according to item 96, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence set forth in SEQ ID NO:1 and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence set forth in SEQ ID NO:2. (Item 100) 94. The combination for use according to item 93, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence defined as SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence defined as SEQ ID NO: 11, 12, or 13. (Item 101) 101. The combination for use according to item 100, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence defined as SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence defined as SEQ ID NO: 12. (Item 102) 102. The combination for use according to any of items 93 to 101, wherein the amyloid light chain antibody is vilutamimab. (Item 103) 103. The combination for use according to any of items 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NOs: 14 and 15. (Item 104) 103. The combination for use according to any of items 93 to 102, wherein the CD38 antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NOs: 17 and 18. (Item 105) 103. The combination for use according to any of items 93 to 102, wherein the CD38 antibody comprises heavy and light chain variable region amino acid sequences as defined in (a) SEQ ID NO: 14 and 17, respectively; (b) SEQ ID NO: 15 and 18, respectively; or (c) SEQ ID NO: 16 and 19, respectively; (d) SEQ ID NO: 43 and 44, respectively; (e) SEQ ID NO: 53 and 54, respectively; (f) SEQ ID NO: 57 and 58, respectively; (g) SEQ ID NO: 59 and 60, respectively; (h) SEQ ID NO: 61 and 62, respectively; or (i) SEQ ID NO: 63 and 64, respectively. (Item 106) The CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 47, 48, and 49, respectively, and a CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 50, 51, and 52, respectively. R2, and a light chain variable region comprising a CDR3 sequence. (Item 107) 103. The combination for use according to any of Items 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 20, 21, and 22, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 23, 24, and 25, respectively. (Item 108) A combination for use according to any of claims 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 26, 27, and 28, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences defined in SEQ ID NOs: 29, 30, and 31, respectively. (Item 109) 103. The combination for use according to any of Items 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 32, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 33. (Item 110) 103. The combination for use according to any of Items 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 35. (Item 111) 103. The combination for use according to any of Items 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 36, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 37. (Item 112) 103. The combination for use according to any of Items 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 38, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO: 39. (Item 113) 103. The combination for use according to any of items 93 to 102, wherein the CD38 antibody is daratumumab. (Item 114) 103. The combination for use according to any of Items 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence defined as SEQ ID NO: 43 and a light chain variable region comprising the amino acid sequence defined as SEQ ID NO: 44. (Item 115) 103. The combination for use according to any of items 93 to 102, wherein the CD38 antibody is isatuximab. (Item 116) 103. The combination for use according to any of Items 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence defined as SEQ ID NO: 53 and a light chain variable region comprising the amino acid sequence defined as SEQ ID NO: 54. (Item 117) Prior to treatment with either the amyloid light chain antibody or the CD38 antibody, 117. The combination for use according to any of items 93 to 116, wherein the patient was treatment naive. (Item 118) A method for improving cardiac function in AL patients non-responsive to treatment with NEOD001, comprising adding an effective dosing regimen of a CD38 antibody in combination with NEOD0001 to the patient's treatment. (Item 119) Item 118. The method of item 118, wherein the non-responsiveness of the patient to NEOD001 treatment is determined by an N-terminal proBNP level in the patient during the period following NEOD001 treatment being higher than or equal to the N-terminal proBNP level in the patient prior to NEOD001 treatment. (Item 120) 120. The method of claim 119, wherein the N-terminal proBNP level is higher than the N-terminal proBNP level before NEOD001 treatment. (Item 121) 121. The method of any of items 118 to 120, wherein the period after NEOD001 treatment is at least 2 months. (Item 122) 122. The method of any of items 118-121, wherein the patient has received at least two doses of NEOD001 prior to receiving the CD38 antibody. (Item 123) 122. The method of any of items 118-121, wherein the patient has received at least three doses of NEOD001 prior to receiving the CD38 antibody. (Item 124) 124. The method of any of items 118 to 123, wherein the CD38 antibody is administered after an increase in N-terminal proBNP in the patient exceeds about 6,000 pg / mL. (Item 125) 124. The method of any of items 118 to 123, wherein the CD38 antibody is administered after an increase in N-terminal proBNP in the patient exceeds about 12,000 pg / mL. (Item 126) 126. The method according to any of items 118 to 125, wherein the CD38 antibody is administered after the level of N-terminal proBNP level has increased by at least about 100%. (Item 127) 126. The method according to any of items 118 to 125, wherein the CD38 antibody is administered after the level of N-terminal proBNP level has increased by at least about 200%. (Item 128) 126. The method according to any of items 118 to 125, wherein the CD38 antibody is administered after the level of N-terminal proBNP level has increased by at least about 300%. (Item 129) The method of any of items 118 to 128, wherein the AL patient has previously received NEOD001 and CyBorD. (Item 130) 129. The method of any of items 118 to 128, wherein the CD38 antibody is daratumumab or isatuximab. (Item 131) 131. The method of item 130, wherein the CD38 antibody is daratumumab. (Item 132) 132. The method of claim 131, wherein daratumumab is administered to the patient at 16 mg / kg once every 28 days. (Item 133) 133. The method of any of items 118 to 132, wherein NEOD001, when administered in combination with a CCD38 antibody, is administered to the patient at 24 mg / kg once every 28 days. (Item 134) 134. The method of any of items 118 to 133, wherein the duration of treatment with the CD38 antibody is effective to reduce the patient's N-terminal proBNP levels to at least the level before receiving NEOD001 treatment. (Item 135) 135. The method of claim 134, wherein the duration is effective to reduce the patient's N-terminal proBNP level below the level prior to receiving NEOD001 treatment. (Item 136) 135. The method of claim 134, wherein the treatment comprises at least one dose of the CD38 antibody. (Item 137) 135. The method of claim 134, wherein the treatment comprises at least two doses of the CD38 antibody. (Item 138) 135. The method of claim 134, wherein the treatment comprises at least three doses of the CD38 antibody. (Item 139) Item 135. The method of item 134, wherein the duration is at least 9 months. (Item 140) Item 135. The method of item 134, wherein the duration is at least 12 months. (Item 141) 49. The method of any one of items 1 to 48, wherein the patient is treated with a combination of an amyloid light chain antibody and a CD38 antibody to stabilize or improve the patient's health prior to receiving plasma cell therapy. (Item 142) 141. The method of claim 140, wherein the plasma cell therapy comprises one or more of the following therapies: ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin, and / or doxycycline, thereby enhancing the patient's ability to tolerate side effects of the plasma cell therapy. (Item 143) 142. The method of claim 141, wherein the stabilization or improvement in the patient's health is measured by VGPR and / or N-terminal proBNP levels. (Item 144) 142. The method of claim 141, wherein the stabilizing or improving the patient's health comprises stabilizing or improving the patient's cardiac function. (Item 145) 145. The method of claim 144, wherein the patient receives the plasma cell therapy after achieving a reduction in N-terminal proBNP compared to the patient's N-terminal proBNP level before treatment with the combination of the amyloid light chain antibody and the CD38 antibody. (Item 146) 146. The method of item 145, wherein said decrease in N-terminal proBNP is at least 55%. (Item 147) 142. The method of any of items 141, wherein the amyloid light chain antibody is vilutamimab. (Item 148) 142. The method of any of items 141, wherein the CD38 antibody is daratumumab. (Item 149) 142. The method of any of items 141, wherein the plasma cell therapy is bortezomib. [Brief description of the drawings]

[0068] [Figure 1] FIG. 1 shows cardiac responses to an example of a two-drug antibody therapy according to the present disclosure, including NEOD001 and daratumumab.

[0069] [Diagram 2] Figures 2A and 2B show the curves of N-terminal pro-BNP response (Figure 2A) and the modest overlap of the curves of lambda light chain (Figure 2B) following an example of a two-agent antibody therapy of the present disclosure, including NEOD001 and daratumumab. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0070] explanation The present disclosure provides a method of treating a patient with AL amyloidosis comprising administering to the patient an antibody that specifically binds to an amyloid light chain in combination with an antibody that specifically binds to CD38.

[0071] I. Definition The term "antibody" includes intact antibodies, and antigen-binding fragments thereof. Typically, fragments compete with the intact antibody from which they were derived for specific binding to a target and comprise a heavy chain, a light chain, Fab, Fab', F(ab') 2, F(ab)c, Dab, Nanobody, and Fv. Fragments can be generated by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins. The term "antibody" also includes bispecific and / or humanized antibodies. The term "amyloid light chain antibody" includes antibodies that specifically bind to neoepitopes exposed in misfolded light chains, as discussed in more detail below. The term "CD38 antibody" includes antibodies that bind to the CD38 antigen expressed on plasma cells and other lymphoid immune cells, as discussed in more detail below.

[0072] The term "humanized immunoglobulin" or "humanized antibody" refers to an immunoglobulin or antibody comprising 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 chain or heavy chain, respectively) having a variable region comprising 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 comprising a constant region (e.g., in the case of a light chain, at least one constant region or portion thereof, and in the case of a heavy chain, preferably three constant regions). 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 a complementarity determining region (CDR) substantially derived from a non-human immunoglobulin or antibody.

[0073] The phrase "substantially derived from a human immunoglobulin or antibody" refers to a region that, when aligned with a human immunoglobulin or antibody amino acid sequence for comparison purposes, 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, allowing for, e.g., conservative substitutions, consensus sequence substitutions, germline substitutions, back mutations, and the like. The introduction of conservative substitutions, consensus sequence substitutions, germline substitutions, back mutations, and the like 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" refers to having an immunoglobulin or antibody sequence that is at least 80-95%, preferably 90-95%, more preferably 96%, 97%, 98%, or 99% identical to the immunoglobulin or antibody sequence of a non-human organism (e.g., a non-human mammal).

[0074] Thus, all regions or residues of a humanized immunoglobulin or antibody, or all regions or residues 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 naturally occurring 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 the region or residue on a first amino acid or nucleotide sequence when the first and second sequences are optimally aligned for comparison purposes.

[0075] II. Treatment Methods and Suitable Subjects Provided herein is a method of treating a human patient exhibiting symptoms of AL amyloidosis with cardiac dysfunction or diagnosed with AL amyloidosis with cardiac dysfunction, comprising administering to the patient any of the amyloid light chain antibody regimes described herein in combination with any of the CD38 antibodies described herein effective to achieve a positive hematologic and / or cardiac response in said patient. Some of these patients may have other systemic organ dysfunctions due to AL amyloidosis, including renal, liver, peripheral nervous system, gastrointestinal system, autonomic nervous system, lung, and / or soft tissue or lymphatic system dysfunction.

[0076] Patients suitable for treatment also include AL amyloidosis patients who have undergone, are currently undergoing, or will undergo alternative therapy for the treatment of AL amyloidosis or related conditions (e.g., inflammatory diseases, chronic microbial infections, malignant neoplasms, inherited inflammatory diseases, and lymphoproliferative disorders, etc.). For example, the patient may also be receiving or may have received one or more of the therapeutic agents identified herein for combination therapy. By way of example, a patient suffering from AL amyloidosis may also be receiving, may have received, or may have received, bortezomib, ixazomib, venetoclax, melphalan, thalidomide, lenalidomide, prednisone, dexamethasone, cyclophosphamide, pomalidomide, carfilzomib, doxorubicin, doxycycline, autograft, or a combination thereof. For patients who have previously undergone alternative therapies for the treatment of amyloid disease, such therapies may or may not have been successful and may not have improved health status by appropriate clinical measures. Additional examples of such prior therapies include: (1) daratumumab alone; (2) CyBorD, which is a combination therapy including cyclophosphamide, bortezomib, and dexamethasone; (3) BMDex, which is a combination of bortezomib, melphalan, and dexamethasone; (4) MDex, which is a combination of melphalan and dexamethasone; (5) LDex, which is a combination of lenalidomide and dexamethasone; (6) CLD, which is a combination of cyclophosphamide, lenalidomide, and dexamethasone; (7) PomDex, which is a combination of pomalidomide and dexamethasone; (8) CRd, which is a combination of lenalidomide, cyclophosphamide, and dexamethasone; and (9) isatuximab. Such patients may or may not experience cardiac and / or renal improvement as a result of such treatment.

[0077] An improvement in hematological response can be established by observing greater than VGPR (very good partial response). To conclude a VGPR, one or more of the following must be present: (i) serum and / or urinary M protein detectable by immunofixation but not by electrophoresis; and (ii) a reduction in serum M protein and / or urinary M protein levels of ≧90% and <100 mg / 24 hours. If these are not measurable, a reduction in the difference between associated and unassociated free light chain levels of ≧90%, provided that associated free light chain levels are >10 mg / dL as indicated by serum-free light chain assay and serum-free light chain ratios are abnormal. Patients treated with the combination therapy disclosed herein may show greater than 80% improvement in VGPR, for example, at least 85%, 88%, or greater than 88% improvement. A patient may achieve maximum improvement in hematologic response in less than 75 days, e.g., in less than 60 days, in less than 45 days, in 33 days, or in less than 33 days.

[0078] Improved cardiac response may be established by a reduction in N-terminal proBNP (N-terminal pro b-type natriuretic peptide) levels (Bay et al., 2003, NT-proBNP: a new diagnostic screening tool to differentiate between patients with normal and reduced left ventricular systolic function, Heart, v. 89(2): p150-154), and / or a reduction in NYHA (New York Heart Association) functional classification of heart failure (Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994: 253-256). Patients treated with the combination therapy disclosed herein may show a reduction in N-terminal proBNP of more than 50% relative to baseline, e.g., a reduction of more than 55%, more than 65%, of 74%, or more than 74%.

[0079] Suitable antibodies, formulations, and treatment regimens for the methods and uses disclosed herein are discussed in further detail below.

[0080] III. Antibodies The methods of the disclosure include administering an amyloid light chain antibody and a CD38 antibody to a patient with AL amyloidosis.

[0081] Amyloid light chain antibodies are antibodies that specifically bind to immunoglobulin light chains. Examples include antibodies that compete with 11-1F4 (also known as CAEL-101) for binding to immunoglobulin light chains, and antibodies that compete with 2A4 (ATCC deposit number 9662) or 7D8 (ATCC deposit number PTA-9468) for binding to human amyloid A peptide or human kappa or human lambda light chain immunoglobulins, or that specifically bind to or compete with the same epitope as 11-1F4 (US Pat. No. 8,105,594), 2A4, or 7D8 (US Pat. No. 7,928,203) binding to human kappa or human lambda light chain immunoglobulins. In some methods, the antibody is a humanized version of 2A4. In some methods, the antibody comprises a light chain variable region comprising three complementarity determining regions defined as SEQ ID NOs: 3, 4, and 5, and a heavy chain variable region comprising three complementarity determining regions defined as SEQ ID NOs: 6, 7, and 8. In some methods, the light chain variable region comprises the amino acid sequence defined as SEQ ID NO: 1. In some methods, the heavy chain variable region comprises the amino acid sequence defined as SEQ ID NO: 2. In some methods, the light chain variable region comprises the amino acid sequence defined as SEQ ID NO: 1 and the heavy chain variable region comprises the amino acid sequence defined as SEQ ID NO: 2. In some methods, the antibody comprises a light chain variable region comprising three complementarity determining regions defined as SEQ ID NOs: 9, 4, and 5, and a heavy chain variable region comprising three complementarity determining regions defined as SEQ ID NOs: 6, 7, and 8.

[0082] In other methods, the antibody comprises the light and heavy chain variable regions of the murine, chimeric, or humanized 2A4 antibody, or the light and heavy chain variable regions of the murine, chimeric, or humanized 7D8 antibody, as described in U.S. Patent No. 7,928,203 and International Publication No. WO2009 / 086539, each of which is incorporated herein by reference in its entirety (the light and heavy chain variable region sequences described in these referenced patents and publications are specifically incorporated herein by reference).Some formulations for the methods disclosed herein are described in U.S. Patent No. 9,089,529 and International Publication No. WO2013 / 063284.

[0083] In some methods, 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 comprise leader sequences for the light and heavy chain amino acid sequences set forth above. In some methods, the antibody is vilutamimab (CAS Registry No. 1608108-91-3) (also known as NEOD001).

[0084] In other methods, the antibody may be 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') fragment, or a Fab' fragment. 2 fragment, F(ab)c, Dab, Nanobody, or Fv.

[0085] CD38 antibodies are antibodies that specifically bind to an epitope of CD38 (SEQ ID NO: 40) on antibody-producing plasma cells and B cells, as well as on other lymphoid immune cells. Some such antibodies bind within amino acids 44-206 of CD38 (SEQ ID NO: 40), such as within amino acids 44-66, 82-94, 142-154, 148-164, 158-170, or 192-206. Some CD38 antibodies bind to the region SKRNIQFSCKNIYR (SEQ ID NO: 41) and the region EKVQTLEAWVIHGG (SEQ ID NO: 42). Some such CD38 antibodies mediate complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent phagocytosis, and trogocytosis of CD38+ target cells. In some methods, the CD38 antibody is daratumumab (CAS Registry No. 945721-28-8). Some exemplary CD38 antibodies are disclosed in U.S. Pat. No. 7,829,673 (the '673 patent), U.S. Pat. No. 8,263,746 (the '746 patent), and U.S. Pat. No. 9,249,226, which are incorporated by reference in their entireties.

[0086] Some CD38 antibodies comprise a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs:20, 21, and 22, respectively (SEQ ID NOs:8, 9, and 10, respectively, of the '673 patent), and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs:23, 24, and 25, respectively (SEQ ID NOs:3, 4, and 5, respectively, of the '673 patent). Some CD38 antibodies comprise a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs:26, 27, and 28, respectively (SEQ ID NOs:18, 19, and 20, respectively, of the '673 patent), and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs:29, 30, and 31, respectively (SEQ ID NOs:13, 14, and 15, respectively, of the '673 patent).

[0087] Some CD38 antibodies comprise a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:32 (SEQ ID NO:5 of the '746 patent) and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:33 (SEQ ID NO:13 of the '746 patent). Some CD38 antibodies comprise a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:34 (SEQ ID NO:6 of the '746 patent) and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:35 (SEQ ID NO:14 of the '746 patent). Some CD38 antibodies comprise a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:36 (SEQ ID NO:7 of the '746 patent) and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:37 (SEQ ID NO:15 of the '746 patent). Some CD38 antibodies comprise a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:38 (SEQ ID NO:8 of the '746 patent) and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences derived from an antibody comprising the amino acid sequence set forth in SEQ ID NO:39 (SEQ ID NO:16 of the '746 patent).

[0088] For example, a CD38 antibody may comprise a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14, 15, or 16 (SEQ ID NO: 7, 17, 27 of the '673 patent, respectively). A CD38 antibody may comprise a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17, 18, or 19 (SEQ ID NO: 2, 12, or 22 of the '673 patent, respectively). A suitable CD38 antibody may comprise a combination of heavy and light chain variable regions disclosed herein. For example, some such CD38 antibodies have heavy and light chain variable region amino acid sequences (a) set forth in SEQ ID NO: 14 and 17, respectively; (b) set forth in SEQ ID NO: 15 and 18, respectively; or set forth in SEQ ID NO: 16 and 19, respectively.

[0089] Alternatively, the CD38 antibody may be isatuximab or a CD38 antibody disclosed in WO2016 / 187546 or US2017 / 0008966 (publication of U.S. Patent Application No. 15 / 160,476 ('476 Application)). Some CD38 antibodies bind at least the region SKRNIQFSCKNIYR (SEQ ID NO: 45) and the region EKVQTLEAWVIHGG (SEQ ID NO: 56). For example, the CD38 antibody may comprise a heavy chain variable region comprising the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 47, 48, and 49, respectively, and a light chain variable region comprising the CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NOs: 50, 51, and 52, respectively. Some suitable CD38 antibodies comprise a heavy chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 53 and a light chain variable region comprising the amino acid sequence set forth as SEQ ID NO: 54. In some methods, the CD38 antibody comprises a heavy chain comprising the amino acid sequence set forth as SEQ ID NO:55 and a light chain comprising the amino acid sequence set forth as SEQ ID NO:56.

[0090] Some CD38 antibodies comprise heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and CDR3 of (a) a heavy chain variable region of SEQ ID NO: 57 and a light chain variable region of SEQ ID NO: 58; (b) a heavy chain variable region of SEQ ID NO: 59 and a light chain variable region of SEQ ID NO: 60; (c) a heavy chain variable region of SEQ ID NO: 61 and a light chain variable region of SEQ ID NO: 62; or (d) a heavy chain variable region of SEQ ID NO: 63 and a light chain variable region of SEQ ID NO: 64. For example, the CD38 antibody may comprise a heavy chain variable region of SEQ ID NO: 57 and a light chain variable region of SEQ ID NO: 58. In some methods, the CD38 antibody comprises a variable heavy chain region of SEQ ID NO: 59 and a variable light chain region of SEQ ID NO: 60. As another example, the CD38 antibody may comprise a heavy chain variable region of SEQ ID NO: 61 and a light chain variable region of SEQ ID NO: 62. As yet another example, the CD38 antibody may comprise a heavy chain variable region of SEQ ID NO:63 and a light chain variable region of SEQ ID NO:64.

[0091] In some methods, the patient is administered virutamimab and daratumumab. In other methods, the patient is administered virutamimab and isatuximab. As discussed in more detail below, the antibody can be administered as a pharmaceutical formulation.

[0092] IV. Pharmaceutical Formulations and Products In some methods disclosed herein, the antibody can be administered to a patient with AL amyloidosis in a pharmaceutical formulation that includes, for example, in addition to the antibody, a histidine buffer, trehalose, and polysorbate 20 (e.g., a formulation disclosed in U.S. Pat. No. 9,884,020, incorporated herein by reference).

[0093] In some methods, the amyloid light chain antibody and the CD38 antibody are formulated together. In other methods, the amyloid light chain antibody and the CD38 antibody are prepared in separate pharmaceutical formulations. In some of such methods, the amyloid light chain antibody is prepared in one of the above formulations, and the CD38 antibody is prepared in a separate formulation, such as, for example, one of the formulations disclosed in U.S. Patent Application Publication No. US2017 / 0121414 or U.S. Patent No. 9,364,542 (which are incorporated herein by reference in their entirety).

[0094] V. Treatment regime As used herein, the terms "treat" and "treatment" refer to the alleviation or amelioration of one or more symptoms or effects associated with a disease, the prevention, inhibition, or delay of the onset of one or more symptoms or effects of a disease, the reduction in the severity or frequency of one or more symptoms or effects of a disease, and / or the improvement or tendency toward a desired outcome, as described herein.

[0095] 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 enhancement of immune response against pathological and / or aggregated amyloid fibrils. The desired outcome also includes alleviation of symptoms specific to amyloid diseases. For example, the desired outcome for the treatment of AL amyloidosis includes 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 disease (dyscrasia), myeloma, and latent disease (dyscrasia). The desired outcome of the therapy disclosed herein is generally a quantifiable measurement compared to a control or baseline measurement. As used herein, relative terms such as "improve", "increase" or "reduce" refer to values ​​compared to a control, such as measurements in the same individual before starting the treatment described herein, or measurements in a control individual or control group. A control individual is an individual suffering from the same amyloid disease as the individual receiving treatment, who is approximately the same age as the individual receiving treatment (to ensure that the stage of the disease in the treated and control individuals is comparable), but who has not been treated with the antibody formulation of the present disclosure. In this case, the efficacy of the antibody formulation of the present disclosure is evaluated by a shift or trend away from the measurable indicator in the untreated control. Alternatively, the control individual is a healthy individual, who is approximately the same age as the individual receiving treatment. In this case, the efficacy of the antibody formulation of the present disclosure is evaluated by a shift or trend toward the measurable indicator in the healthy control. Changes or improvements in response to therapy are generally statistically significant and described by a p-value, where a p-value of 0.1 or less, less than 0.05, less than 0.01, less than 0.005, or less than 0.001 can be considered significant.

[0096] Treatment typically requires multiple doses over a period of time. Treatment can be monitored over time by assaying for antibodies or by using radiolabeled SAP scintigraphy. If response decreases, booster dosing may be indicated. In addition, the response of patients with AL amyloidosis to treatment can be monitored by assaying cardiac markers such as N-terminal pro-BNP 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. An exemplary complete response (CR) can be determined by response criteria including negative serum and urine IFE, normal kappa / lambda (κ / λ) ratio, and / or <5% plasma cells in bone marrow. An exemplary very good partial response (VGPR) can be determined by dFLC < 40mg / L. An exemplary partial response (PR) can be determined by dFLC reduction of ≧50%. In the kidney, response to treatment can be determined by, for example, a reduction in eGFR of ≧25% or an increase in serum creatine of ≧0.5mg / dL, and a reduction in urinary protein excretion within 24 hours of ≧50% (e.g., >0.5g / 24 hours). In the liver, response to treatment can be determined by, for example, a reduction in initially elevated alkaline phosphatase of ≧50% or a reduction in liver size of ≧2cm by CT scan or MRI. In the heart, response to treatment can be determined by, for example, a reduction in N-terminal proBNP of >30% and >300ng / L in patients with a baseline N-terminal proBNP of >650ng / L. In the kidney, response to treatment can be determined, for example, by the absence of renal progression and a reduction in proteinuria of >30%, or a reduction in proteinuria of <0.5 g / 24 hours.Neuropathic responders are generally characterized by an increase in NIS-LL from baseline of <2 points. Neuropathic improvement (e.g., improvement in neurological function) is determined by a decrease in NIS-LL from baseline.

[0097] The antibody formulation can be administered intravenously or subcutaneously in a dosage range of about 0.5 mg / kg body weight to about 30 mg / kg body weight. For example, the dosage can be about 0.5 mg / kg body weight, about 1.0 mg / kg body weight, about 1.5 mg / kg body weight, about 2.0 mg / kg body weight, about 4.0 mg / kg body weight, about 5.0 mg / kg body weight, about 8.0 mg / kg body weight, about 10 mg / kg body weight, about 15 mg / kg body weight, about 16 mg / kg body weight, about 20 mg / kg body weight, about 24 mg / kg body weight, about 25 mg / kg body weight, or about 30 mg / kg body weight. For intravenous administration, a sufficient amount of the antibody formulation to achieve the desired dosage for an individual patient is transferred from one or more vials to one or more intravenous infusion bags containing liquid (e.g., saline) and administered to the patient. In some methods, any of the amyloid light chain antibodies disclosed herein (such as, for example, virutamimab) is administered to the patient at a dose of about 24 mg / kg. In some methods, any of the CD38 antibodies disclosed herein (such as, for example, daratumumab) is administered to the patient at a dose of about 16 mg / kg.

[0098] Antibodies are typically administered on multiple occasions. Exemplary treatment regimes require administration once every two weeks, once a month, or once every three to six months. For example, a patient may receive an antibody formulation once every four weeks (e.g., once every 28 days). The dosing frequency can be adjusted depending on the pharmacokinetic profile of the antibody formulation in the patient. For example, the dosing frequency may be once every two weeks based on the half-life of the antibody.

[0099] In some methods, the pharmaceutical formulation is administered intravenously at an amyloid light chain antibody dosage of about 24 mg / kg, once every 28 days. For example, some patients may receive an intravenous dose of any of the amyloid light chain antibodies disclosed herein (such as vilutamimab) at a dose of about 24 mg / kg, once every 28 days. Some such patients may receive an intravenous dose of any of the CD38 antibodies disclosed herein (such as daratumumab) at a dose of, for example, 16 mg / kg, once every 28 days. Some patients receive the CD38 antibody once a week. Some patients receive the CD38 antibody once every two weeks. Some patients receive the CD38 antibody more frequently at first, and less frequently over time. For example, a patient may receive a CD38 antibody once a week for a period of time, then once every two weeks for a period of time, then once a month or once every 28 days for the duration of treatment. One such dosing regimen is a weekly dosing of a CD38 antibody such as daratumumab for 8 weeks, then once every two weeks for 4 months, then once a month for the duration of treatment.

[0100] For some of these patients, the amyloid light chain antibody formulation transferred to the intravenous infusion bag was first reconstituted from a lyophilized formulation to a formulation comprising about 50 mg / mL of an amyloid light chain antibody, such as virutamimab, about 25 mM histidine buffer, about 230 mM trehalose, and about 0.2 g / L polysorbate 20, with a pH of about 6.5.

[0101] For some patients, a desired dosage of one or more amyloid light chain antibodies and / or CD38 antibodies can be administered subcutaneously, undiluted, from a vial containing any of the formulations disclosed herein.

[0102] In some methods disclosed herein, the antibody is administered to the patient for at least 9 months, at least 12 months, or longer.

[0103] When a combination therapy with an amyloid light chain antibody and an antibody to CD38 is performed, the two antibodies may be administered simultaneously or sequentially in any order, i.e., one antibody may be administered before, simultaneously with, or after the other antibody. For example, the combination therapy may involve administration of a first antibody 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 prior to), concurrently with, or after (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 the second antibody. In some methods, the amyloid light chain antibody and the CD38 antibody are administered to the patient on the same day, e.g., simultaneously, or sequentially within a day. In some methods, the two antibodies are administered at least 24 hours apart, 2 days apart, 3 days apart, 4 days apart, 5 days apart, 6 days apart, or 1 week apart. If the two antibodies are not administered simultaneously, in some methods, the CD38 antibody is administered first, followed by the amyloid light chain antibody. In other methods, the amyloid light chain antibody is administered first, followed by the CD38 antibody.

[0104] The dosage, frequency, and mode of administration of each component of the combination can be controlled independently. For example, one therapeutic agent / therapy may be administered orally three times a day, while a second therapeutic agent / therapy may be administered intramuscularly once a day. The combination therapy may be administered in an on-off cycle with rest periods. The compounds may also be mixed or otherwise formulated together such that one administration delivers both compounds. In this case, the amount of each therapeutic agent present is generally 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 and administered in individual dosages. The drug combination for treatment may be provided as components of one pharmaceutical pack.

[0105] In some combinations for use in treating AL amyloidosis, the patient is treatment naive prior to treatment with either NEOD001 or daratumumab, e.g., the patient has previously received any treatment (even standard of care treatment) for AL amyloidosis.

[0106] In some methods disclosed herein, the patient is treated with either an amyloid light chain antibody or a CD38 antibody prior to treatment for the plasma cell dyscrasia. Plasma cell dyscrasia (PCD; also called plasma cell disorder or plasma cell dysplasia) is a spectrum that progresses to more severe monoclonal gammopathy, in which a clone or multiple clones of plasma cells overproduce and secrete immunoglobulins or fragments thereof into the bloodstream. PCD can include, but is not limited to, monoclonal gammopathy of undetermined significance (MGUS), asymptomatic myeloma, multiple myeloma, PC leukemia, plasmacytoma. In some such methods, the patient is first treated with an amyloid light chain antibody and a CD38 antibody to stabilize or improve the patient's health (e.g., the patient's cardiac function) prior to treatment with plasma cell therapy (e.g., one or more of ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin, doxycycline, or a CD38 antibody). The treatment for the plasma cell therapy may include a CD38 antibody, provided that the treatment for the plasma cell therapy is administered after the treatment with the amyloid light chain antibody and the CD38 antibody. In one such method of the present disclosure, the treatment with the combination of amyloid light chain antibody and CD38 antibody is followed by a treatment for the plasma cell disorder, where the treatment for the disorder is a CD38 antibody or the treatment for the disorder is bortezomib.

[0107] Pretreatment with amyloid light chain antibodies and CD38 antibodies may enhance a patient's ability to tolerate the side effects of subsequent plasma cell therapy. This pretreatment may also reduce the level of risk of plasma cell therapy intolerance and the risk of treatment-related complications. In some methods, combined treatment with CD38 antibodies and amyloid light chain antibodies is administered prophylactically, prior to the onset of AL amyloidosis.

[0108] In such methods, the order of administration and dosing regimen of the amyloid light chain antibody and the CD38 antibody may be as described herein. For example, a patient may be treated with a combination of amyloid light chain antibody and CD38 antibody as described herein, toward improving the health of the patient. For example, the improvement may be a reduction in N-terminal pro-BNP prior to administration of plasma cell therapy (e.g., bortezomib). For example, a patient treated with the combination therapy disclosed herein may show a reduction in N-terminal pro-BNP of more than 50% relative to baseline, e.g., a reduction of more than 55%, more than 65%, 74%, or more than 74%, prior to treatment with plasma cell therapy. Other indicators of improved patient health are described herein, for example, by measuring other cardiac markers (troponin, serum creatine, and / or alkaline phosphatase, and 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. Other indicators of improvement also include stabilization or improvement in the patient's functional status as measured by Karnofsky Performance Status or ECOG Performance Status, or equivalent functional assessment tools, improvement in the patient's unintentional weight loss, reduced endurance, frailty, low walking speed, and low physical activity, and / or improvement in the patient's instrumental activities of daily living.

[0109] Thus, some of the methods disclosed herein relate to a method of treating plasma cell disorders in a patient, where the patient is first treated with a combination therapy of amyloid light chain antibody and CD38 antibody before undergoing plasma cell therapy. Various indications of PCD may require different treatment regimens. PCD therapy may include hematopoietic stem cell transplantation (HSCT), and / or the use of chemotherapeutic agents. In some methods, the plasma cell therapy is one or more of the following therapies: ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin, and doxycycline. In some methods, the plasma cell therapy is bortezomib.

[0110] In some such methods, the patient is first treated with a combination therapy of amyloid light chain antibody and CD38 antibody to stabilize or improve the patient's health (e.g., the patient's cardiac function) prior to treatment with plasma cell therapy. The improvement in the patient's health can be determined, for example, by determining that the patient has a greater than 50% reduction in N-terminal proBNP relative to baseline. In particular, the improvement in the patient's health can be indicated by a reduction in N-terminal proBNP of greater than 55%, greater than 65%, greater than 74%, or greater than 74% relative to baseline. The improvement in the patient's health can enhance the patient's ability to tolerate the side effects of subsequent plasma cell therapy. In such methods, the order and dosing regimen of administration of the combination therapy of amyloid light chain antibody and CD38 antibody can be as described herein. For example, the patient can be treated with a combination of amyloid light chain antibody and CD38 antibody to achieve a reduction in N-terminal proBNP of at least 55% prior to administration of plasma cell therapy (e.g., bortezomib, etc.).

[0111] The combined antibody therapy described herein may overlap with plasma cell therapy to maintain the improvement in the patient's health obtained before plasma cell therapy. Alternatively, the combined antibody therapy may be stopped just before, days before, weeks or months before plasma cell therapy, as long as the patient's health has improved to the extent that the side effects of plasma cell therapy can be more easily tolerated. For example, the combined therapy may be administered with the dosing regimen described herein for at least 9 months or at least 12 months before plasma cell therapy, and terminated before or during the antibody combination therapy.

[0112] In some methods, the patient exhibits an improvement in VGPR of greater than 85% after the combination therapy. In some methods, the improvement in VGPR is at least 88%. In some methods, the patient exhibits an improvement in hematological response less than 60 days after treatment with the combination therapy prior to treatment with plasma cell therapy. In some methods, the patient exhibits an improvement in hematological response less than 45 days after treatment with the combination therapy prior to treatment with plasma cell therapy. In some methods, the patient exhibits a hematological improvement between 1 and 28 days after treatment with the combination therapy (e.g., 7 days, 14 days, 21 days, or 28 days after treatment with the combination therapy) prior to treatment with plasma cell therapy.

[0113] The amyloid light chain antibody may be as described herein or as provided in the sequence for the amyloid light chain antibody. Similarly, the CD38 antibody may be as described herein, e.g., daratumumab. Similarly, as described herein, the dosage of the amyloid light chain antibody may be about 0.5 mg / kg to about 30 mg / kg, which may be administered intravenously or subcutaneously at a frequency of about once a week to about once a quarter. In one method herein, the dosage of the amyloid light chain is about 24 mg / kg, and the antibody is administered intravenously once every 28 days, and may include a formulation as described herein.

[0114] In some methods disclosed herein, the method includes a method of improving cardiac function in AL patients unresponsive to treatment with NEOD001, comprising adding an effective dosing regimen of CD38 antibody to the treatment of the patient. Patients unresponsive to NEOD001 include patients treated with CyBorD (cyclophosphamide, bortezomib, dexamethasone). Patient response may be measured as a cardiac response, such as N-terminal proBNP. Unresponsive patients include patients who do not improve to NEOD001 (with or without CyBorD) or whose condition continues to deteriorate as shown in FIG. 1. For example, the unresponsiveness of a patient to NEOD001 treatment may be determined by the N-terminal proBNP level in the patient in the period after NEOD001 treatment being higher than or equal to the N-terminal proBNP level in the patient before NEOD001 treatment. For example, the N-terminal proBNP level is higher than the N-terminal proBNP level before NEOD001 treatment.

[0115] The dosing regimen may vary and may include a period following NEOD001 treatment of at least two months prior to administration of the CD38 antibody. In some instances, the patient may have received at least two or three doses of NEOD001 prior to receiving the CD38 antibody. The CD38 antibody is administered after the increase in N-terminal proBNP exceeds about 2,000 pg / mL (about 15,000 pg / mL). For example, the increase in N-terminal proBNP may be 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 11,000, 12,000, 13,000, 14,000, or 15,000 pg / mL of N-terminal proBNP in the patient. In some of the methods, the CD38 antibody is administered after an increase in N-terminal proBNP in the patient exceeds about 12,000 pg / mL.

[0116] In some of the methods of the disclosure, the CD38 antibody is administered after the level of the N-terminal proBNP level has increased by at least about 100%. In some methods, the CD38 antibody is administered after the level of the N-terminal proBNP level has increased by at least about 200%. In some methods, the CD38 antibody is administered after the level of the N-terminal proBNP level has increased by at least about 300%. As further described herein, the CD38 antibody may be daratumumab or isatuximab.

[0117] In some of the methods of the disclosure, daratumumab is administered to the patient at 16 mg / kg once every 28 days. In some methods, NEOD001 is administered to the patient at 24 mg / kg once every 28 days.

[0118] In some of the disclosed methods, the duration of treatment with a CD38 antibody in combination with an amyloid light chain antibody is effective to reduce the patient's N-terminal proBNP levels to at least the level prior to receiving the amyloid light chain antibody treatment. In some of the methods, the duration is effective to reduce the patient's N-terminal proBNP levels to below the level prior to receiving the amyloid light chain antibody treatment.

[0119] In some of the methods of the disclosure, the patient receives at least one dose, at least two doses, at least three doses, at least four doses, at least 5-12 doses, or more than 12 doses of a CD38 antibody, and the duration of treatment may be at least 3 months, at least 6 months, at least 9 months, at least 12 months, and may include multiple doses of a CD38 antibody. EXAMPLES

[0120] The following examples are included to demonstrate the modes disclosed herein. Certain aspects of the following examples are described by techniques and procedures that the co-inventors have found or anticipated to work well in the practice disclosed herein. Given this disclosure and the general state of the art, it will be understood by those skilled in the art that the following examples are intended to be illustrative only, and that numerous changes, modifications, and variations are possible without departing from the scope of the present disclosure.

[0121] Example 1. Phase 3 clinical evaluation of NEOD001 A Phase 3, global, multicenter, randomized, double-blind, placebo-controlled clinical trial of NEOD001 was conducted in newly diagnosed, treatment-naive patients with AL amyloidosis and cardiac dysfunction, both arms of the study receiving standard of care (VITAL trial). Patients were randomized 1:1 to receive NEOD001 at 24 mg / kg intravenously once every 28 days or placebo. All patients received bortezomib-based chemotherapy concurrently with NEOD001 or placebo. Placebo was administered as a 250 mL bag of normal saline once every 28 days. Further information regarding the clinical trial design can be obtained at https: / / clinicaltrials.gov.

[0122] Example 2. Evaluation of Patients Receiving NEOD001 and Daratumumab Nine patients with AL amyloidosis from the VITAL trial who received treatment with the investigational monoclonal antibody NEOD001 also received treatment with daratumumab at 16 mg / kg in a first dose divided over 2 days. Patients received daratumumab once a week for 8 weeks, then once every 2 weeks for 4 months, then once every 28 days. Of these nine patients, there were four men and five women, with a median age of 68 years (range 52-75 years) and 261 days since diagnosis (range 51-2037 days). Median N-terminal pro-BNP was 3807 pg / ml (1326-13193 pg / ml). NEOD001 and daratumumab were infused 2 days apart and were well tolerated without any unexpected toxicity. These nine patients with cardiac complications did not respond to initial therapy with a bortezomib-based regimen. See Figure 1.

[0123] 88% of patients achieved >VGPR with daratumumab + NEOD001 in 33 days (median), and cardiac responses were achieved in <90 days. In contrast, patients who received daratumumab alone (n=10), who were not part of the VITAL study, achieved hematologic and cardiac responses later (Table 1). In this study, monoclonal antibodies targeting separate amyloid light chains and CD38 could be safely combined in patients with systemic AL amyloidosis with cardiac complications. As shown in Table 1, a higher rate of hematologic and cardiac responses was achieved with the combination of daratumumab and NEOD001 compared with patients who received daratumumab alone.

[0124] [Table 1]

[0125] Figure 1 shows a typical response of a patient with progressive and worsening cardiac complications of AL despite treatment with NEOD001 and CyBorD (cyclophosphamide, bortezomib, dexamethasone) who subsequently added daratumumab to the therapy, as measured by N-terminal proBNP. This two-agent antibody combination therapy was able to reverse the worsening cardiac response.

[0126] Figures 2A-B show the overlap of curves showing rapid cardiac improvement based on N-terminal proBNP response (Figure 2A) with curves showing gradual improvement in lambda light chain (Figure 2B) following dual antibody therapy. This pattern is not typical for AL patients who experience an organ response; typically, the organ response is out of phase with the short chain response by several months.

[0127] All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety. Although the present disclosure has been disclosed with reference to certain 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.

[0128] 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 SEQ ID NO: 7 from U.S. Patent No. 7,829,673 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQAPGQGLEWMGRVIPFLGIANSAQKFQGRVTITADKSTSTAYMDLSSLRSEDTAVYYCARDDIAALGPFDYWGQGTLVTVSSAS SEQ ID NO:15 SEQ ID NO:17 from U.S. Patent No. 7,829,673 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSSAS SEQ ID NO: 16 SEQ ID NO: 27 from U.S. Patent No. 7,829,673 EVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIYPHDSDARYSPSFQGQVTFSADKSISTAYLQWSSLKASDTAMYYCARHVGWGSRYWYFDLWGRGTLVTVSS SEQ ID NO: 17 SEQ ID NO: 2 from U.S. Patent No. 7,829,673 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPRTFGQGTKVEIK SEQ ID NO:18 SEQ ID NO:12 from U.S. Patent No. 7,829,673 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK SEQ ID NO: 19 SEQ ID NO: 22 from U.S. Patent No. 7,829,673 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPGLLIYDASNRASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK SEQ ID NO:20 SEQ ID NO:8 from U.S. Patent No. 7,829,673 SYAFS SEQ ID NO:21 SEQ ID NO:9 from U.S. Patent No. 7,829,673 RVIPFLGIANSAQKFQ SEQ ID NO:22 SEQ ID NO:10 from U.S. Patent No. 7,829,673 DDIAALGPFDY SEQ ID NO:23 SEQ ID NO:3 from U.S. Patent No. 7,829,673 RASQGISSWLA SEQ ID NO:24 SEQ ID NO:4 from U.S. Patent No. 7,829,673 AASSLQS SEQ ID NO: 25 SEQ ID NO: 5 from U.S. Patent No. 7,829,673 QQYNSYPRT SEQ ID NO:26 SEQ ID NO:18 from U.S. Patent No. 7,829,673 SFAMS SEQ ID NO:27 SEQ ID NO:19 from U.S. Patent No. 7,829,673 AISGSGGGTYYADSVKG SEQ ID NO:28 SEQ ID NO:20 from U.S. Patent No. 7,829,673 DKILWFGEPVFDY SEQ ID NO:29 SEQ ID NO:13 from U.S. Patent No. 7,829,673 RASQSVSSYLA SEQ ID NO:30 SEQ ID NO:14 from U.S. Patent No. 7,829,673 DASNRAT SEQ ID NO:31 SEQ ID NO:15 from U.S. Patent No. 7,829,673 QQRSNWPPTF SEQ ID NO: 32 SEQ ID NO: 5 from U.S. Patent No. 8,263,746 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYSINWVRQAPGQGLEWMGYIDPNRGNTNYAQKFQGRVTMTRDTSISTAYMELSSLRSEDTAVYYCAREYIYFIHGMLDFWGQGTLVTVSS SEQ ID NO:33 SEQ ID NO:13 from U.S. Patent No. 8,263,746 DIVMTQSPLSLPVTPGEPASISCRSSQSLLFIDGNNYLNWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQYSSKSATFGQGTKVEIKRT SEQ ID NO:34 SEQ ID NO:6 from U.S. Patent No. 8,263,746 QVQLVESGGGLVQPGGSLRLSCAASGFTFSNYGMHWVRQAPGKGLEWVSNIRSDGSWTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRYWSKSHASVTDYWGQGTLVTVSS* SEQ ID NO: 35 SEQ ID NO: 14 from U.S. Patent No. 8,263,746 DIQMTQSPSSLSASVGDRVTITCRASQDISAFLNWYQQKPGKAPKLLIYKVSNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAYSGSITFGQGTKVEIKRT SEQ ID NO: 36 SEQ ID NO: 7 from U.S. Patent No. 8,263,746 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVSNIYSDGSNTFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARNMYRWPFHYFFDYWGQGTLVTVSS SEQ ID NO: 37 SEQ ID NO: 15 from U.S. Patent No. 8,263,746 DIELTQPPSVSVAPGQTARISCSGDNIGNKYVSWYQQKPGQAPVVVIYGDNNRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCSSYDSSYFVFGGGTKLTVLGQ SEQ ID NO:38 SEQ ID NO:8 from U.S. Patent No. 8,263,746 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSNGMSWVRQAPGKGLEWVSNISYLSSSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARFYGYFNYADVWGQGTLVTVSS SEQ ID NO:39 SEQ ID NO:16 from U.S. Patent No. 8,263,746 DIELTQPPSVSVAPGQTARISCSGDNIGHYYASWYQQKPGQAPVLVIYRDNDRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQSYDYLHDFVFGGGTKLTVLGQ SEQ ID NO: 40 SEQ ID NO: 22 from U.S. Patent No. 8,263,746 MANCEFSPVSGDKPCCRLSRRAQLCLGVSILVLILVVVLAVVVPRWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCNITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLL GYLADDLTWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSRSKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNIQFSCKNIYRPDKFLQCVKNPEDSSCTSEI SEQ ID NO:41 SKRNIQFSCKNIYR SEQ ID NO:42 EKVQTLEAWVIHGG SEQ ID NO: 43: DARZALEX® heavy chain sequence as shown in https: / / www.genome.jp / dbget-bin / www_bget?dr:D10777 [ka] SEQ ID NO: 44: DARZALEX® light chain sequence as shown in https: / / www.genome.jp / dbget-bin / www_bget?dr:D10777 [ka] SEQ ID NO: 45 SEQ ID NO: 2 of US 2017 / 0008966 SKRNIQFSCKNIYR SEQ ID NO: 46 SEQ ID NO: 3 of US 2017 / 0008966 EKVQTLEAWVIHGG SEQ ID NO: 47 SEQ ID NO: 6 of US 2017 / 0008966 SFAMS SEQ ID NO: 48 SEQ ID NO: 7 of US 2017 / 0008966 AISGSGGGTYYADSVK SEQ ID NO: 49 SEQ ID NO: 8 of US 2017 / 0008966 DKILWFGEPVFDY SEQ ID NO: 50 SEQ ID NO: 9 of US 2017 / 0008966 RASQSVSSYLA SEQ ID NO: 51 SEQ ID NO: 10 of US 2017 / 0008966 DASNRAT SEQ ID NO: 52 SEQ ID NO: 11 of US 2017 / 0008966 QQRSNWPPTF SEQ ID NO:53 SEQ ID NO:4 of US 2017 / 0008966 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS SEQ ID NO:54 SEQ ID NO:5 of US 2017 / 0008966 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK SEQ ID NO: 55 SEQ ID NO: 12 of US 2017 / 0008966 EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 56 SEQ ID NO: 13 of US 2017 / 0008966 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 57 SEQ ID NO: 14 of US 2017 / 0008966 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAFSWVRQAPGQGLEWMGRVIPFLGIANSAQKFQGRVTITADKSTSTAYMDLSSLRSEDTAVYYCARDDIAALGPFDYWGQGTLVTVSSAS SEQ ID NO: 58 SEQ ID NO: 15 of US 2017 / 0008966 DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPRTFGQGTKVEIK SEQ ID NO: 59 SEQ ID NO: 16 of US 2017 / 0008966 EVQLVQSGAEVKKPGESLKISCKGSGYSFSNYWIGWVRQMPGKGLEWMGIIYPHDSDARYSPSFQGQVTFSADKSISTAYLQWSSLKASDTAMYYCARHVGWGSRYWYFDLWGRGTLVTVSS SEQ ID NO: 60 SEQ ID NO: 17 of US 2017 / 0008966 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK SEQ ID NO: 61 SEQ ID NO: 18 of US 2017 / 0008966 QVQLVESGGGLVQPGGSLRLSCAASGFTFSSYYMNWVRQAPGKGLEWVSGISGDPSNTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLPLVYTGFAYWGQGTLVTVSS SEQ ID NO: 62 US 2017 / 0008966 SEQ ID NO: 19 DIELTQPPSVSVAPGQTARISCSGDNLRHYYVYWYQQKPGQAPVLVIYGDSKRPSGIPERFSGSNSGNTATLTISGTQAEDEADYYCQTYTGGASLVFGGGTKLTVLGQ SEQ ID NO: 63 SEQ ID NO: 20 of US 2017 / 0008966 QVQLVQSGAEVAKPGTSVKLSCKASGYTFTDYWMQWVKQRPGQGLEWIGTIYPGDGDTGYAQKFQGKATLTADKSSKTVYMHLSSLASEDSAVYYCARGDYYGSNSLDYWGQGTSVTVSS SEQ ID NO: 64 SEQ ID NO: 21 of US 2017 / 0008966 DIVMTQSHLSMSSTSLGDPVSITCKASQDVSTVVAWYQQKPGQSPRRLIYSASYRYIGVPDRFTGSGAGTDFTFTISSVQAEDLAVYYCQQHYSPPYTFGGGTKLEIK

Claims

[Claim 1] The invention described in the specification.

Images