Combination of monoclonal antibodies against immunoglobulin light chains with CD38 cell membrane molecules on antibody producing cells and other immune cells for treatment of AL amyloidosis

Abstract

AL amyloidosis is treated using a combination of monoclonal antibodies against immunoglobulin light chains and immunoglobulin light chain aggregates with CD38 cell membrane molecules on antibody producing cells and other immune cells.

Description

[0001] This application is a divisional application of a Chinese invention patent application with an application date of December 16, 2019, a priority date of February 12, 2019, an application number of 201980094744.5, and an invention name of “Combination of monoclonal antibodies against immunoglobulin light chains and CD38 cell membrane molecules on antibody-producing cells and other immune cells for the treatment of AL amyloidosis”. Technical Field

[0002] The present disclosure relates to the fields of immunology and medical technology. Background Art

[0003] Amyloid light chain (AL) amyloidosis involves a hematological disorder caused by clonal plasma cells that produce immunoglobulin light chains that can misfold and cause disease. Excessive production of misfolded light chains by plasma cells results in deposition of abnormal AL protein (amyloid) in tissues and organs of individuals with AL amyloidosis. The clinical features of AL amyloidosis include a spectrum of symptoms and organ dysfunction that may include cardiac, renal, and hepatic dysfunction, gastrointestinal involvement, neuropathy, and macroglossia. However, the mechanism by which amyloidogenic immunoglobulin light chains cause organ dysfunction is not well characterized, and it is 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 a disease entity in itself, but AL amyloidosis may coexist in a small subset of patients with multiple myeloma (up to 15%) or in patients with monoclonal gammopathy of undetermined significance (MGUS; up to 9%). Patients with cardiac involvement are at high risk for disease, as it has been shown that, despite advances in current treatments, approximately 25% of patients with cardiac involvement die within 6 months of diagnosis.

[0004] AL amyloidosis is a rare disease with an estimated incidence of 8 per 1,000,000 people. Only 1,200 to 3,200 new cases of AL amyloidosis are reported in the United States each year. Two-thirds of patients with AL amyloidosis are male, and less than 5% of patients are under the age of 40. The cause and origin of AL amyloidosis remain poorly understood.

[0005] Current treatments for patients with AL amyloidosis are aimed at reducing or eliminating the bone marrow cells responsible for producing light chains, thereby limiting or stopping the production of amyloid. The most aggressive treatment options include stem cell transplantation and high-dose chemotherapy for patients who can tolerate it. Other treatment options include combinations of drugs commonly used to treat hematological malignancies (e.g., melphalan, prednisone, dexamethasone) and proteasome inhibitors (e.g., bortezomib) to try to reduce light chain production. CD38 antibodies (e.g., daratumumab) have been developed and isatuximab) are used to treat multiple myeloma. Daratumumab sticks to CD38 on the surface of myeloma cells. It is thought to both kill tumor cells directly and stimulate an immune response against cancer cells.

[0006] There are currently no approved treatments for AL amyloidosis, nor are there any approaches that directly target the potentially toxic form of amyloid. While some treatment options may improve some of the morbidity associated with AL amyloidosis, few, if any, have been shown to achieve high hematologic and cardiac responses in patients.

[0007] Therefore, there is a need for therapies that can improve treatment outcomes for patients with AL amyloidosis. Summary of the invention

[0008] The present disclosure relates to methods for treating patients with AL amyloidosis with antibodies targeting different proteins associated with amyloidosis or plasma cell dyscrasia, and provides a method for treating patients with AL amyloidosis, the method comprising administering an effective dose of an antibody that specifically binds to an amyloid light chain and an antibody that specifically binds to CD38, for example, a chimeric or humanized monoclonal antibody against CD38. Typically, the dose is effective to improve blood system or heart or other organ function. The dose is effective to improve blood system and organ function, such as heart function. In some methods, the amyloid light chain antibody or CD38 antibody is Fab, Fab', F(ab')2, F(ab)c, Dab, nanobody or Fv.

[0009] In some methods disclosed herein, the amyloid light chain antibody competes with antibody 2A4 (ATCC Accession No. 9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or human lambda light chain immunoglobulin, or the amyloid light chain antibody binds to the same epitope as 11-1F4, or competes with 11-1F4 for binding to human kappa or human lambda light chain immunoglobulin. In some methods, the amyloid light chain antibody is a humanized form of 2A4 or 7D8. In some methods, the antibody is a humanized bispecific or multispecific form comprising a combination of 11-1F4, 2A4 and / or 7D8.

[0010] In some methods disclosed herein, the amyloid light chain antibody comprises a light chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 3, 4 and 5 and a heavy chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 6, 7 and 8.

[0011] In some methods disclosed herein, the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO: 1. In some methods, the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO: 2. For example, the light chain variable region of the amyloid light chain antibody may comprise the amino acid sequence shown in SEQ ID NO: 1, and the heavy chain variable region of the amyloid light chain antibody may comprise the amino acid sequence shown in SEQ ID NO: 2.

[0012] In some methods disclosed herein, the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 11, 12 or 13. In some methods, the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 12. In some methods, the amyloid light chain antibody is politimab (also known as NEOD001).

[0013] 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, trehalose is present in the formulation at a concentration of about 230 mM, polysorbate 20 is present in the formulation at a concentration of about 0.2 g / L, and the pH is about 6.5.

[0014] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 14 or 15. In some methods, the CD38 antibody comprises a light chain variable region comprising an amino acid sequence as 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 as set forth in (a) SEQ ID NOs: 14 and 17, (b) SEQ ID NOs: 15 and 18, (c) SEQ ID NOs: 16 and 19, (d) SEQ ID NOs: 43 and 44, (e) SEQ ID NOs: 53 and 54, (f) SEQ ID NOs: 57 and 58, (g) SEQ ID NOs: 59 and 60, (h) SEQ ID NOs: 61 and 62, or (i) SEQ ID NOs: 63 and 64, respectively.

[0015] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region including CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 47, 48 and 49, respectively, and a light chain variable region including CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 50, 51 and 52, respectively.

[0016] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region including CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 26, 27 and 28, respectively, and a light chain variable region including CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 29, 30 and 31, respectively.

[0017] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:32, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:33.

[0018] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:34, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:35.

[0019] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:36, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:37.

[0020] In some methods disclosed herein, the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:38, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:39.

[0021] 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 shown in SEQ ID NO:43 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:44.

[0022] In some methods disclosed herein, the CD38 antibody is isatuximab or other CD38 antibodies disclosed in WO 2016 / 187546 and US2017 / 0008966 (the entire contents of which are incorporated herein by reference). In some methods, the CD38 antibody is isatuximab.

[0023] In some methods disclosed herein, the CD38 antibody binds to at least the SKRNIQFSCKNIYR region (SEQ ID NO: 45) and the EKVQTLEAWVIHGG region (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 shown in SEQ ID NOs: 47, 48 and 49, respectively, and a light chain variable region comprising the CDR1, CDR2 and CDR3 amino acid sequences shown in SEQ ID NOs: 50, 51 and 52, respectively.

[0024] In some methods, the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 53 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 54. In some methods, the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 55 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 56.

[0025] In some methods disclosed herein, the CD38 antibody comprises the heavy chain CDR1, CDR2 and CDR3 and the light chain CDR1, CDR2 and CDR3 of (a) the heavy chain variable region of SEQ ID NO: 57 and the light chain variable region of SEQ ID NO: 58, (b) the heavy chain variable region of SEQ ID NO: 59 and the light chain variable region of SEQ ID NO: 60, (c) the heavy chain variable region of SEQ ID NO: 61 and the light chain variable region of SEQ ID NO: 62, or (d) the heavy chain variable region of SEQ ID NO: 63 and the light chain variable region of SEQ ID NO: 64. In some methods, the CD38 antibody comprises the heavy chain variable region of SEQ ID NO: 57 and the light chain variable region of SEQ ID NO: 58. In some methods, the CD38 antibody comprises the heavy chain variable region of SEQ ID NO: 59 and the light chain variable region of SEQ ID NO: 60. In some methods, the CD38 antibody comprises the heavy chain variable region of SEQ ID NO: 61 and the light chain variable region of SEQ ID NO: 62. In some methods, the CD38 antibody comprises a heavy chain variable region of SEQ ID NO:63 and a light chain variable region of SEQ ID NO:64.

[0026] In some methods, the antibody is a humanized bispecific or multispecific format comprising a combination of daratumumab, isatuximab or other CD38 antibodies. In some methods, the antibody is a humanized bispecific or multispecific format comprising a combination of daratumumab, isatuximab or other CD38 antibodies and 11-1F4, 2A4 and / or 7D8 or other human light chain amyloid antibodies.

[0027] 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, autologous transplantation, or a combination thereof. In some methods, the patient did not respond to bortezomib therapy.

[0028] In some methods disclosed herein, the amyloid light chain antibody and the CD38 antibody are administered to the patient by intravenous infusion every two days. In some methods, the amyloid light chain antibody is administered first. Alternatively, the CD38 antibody is administered first.

[0029] In some methods disclosed herein, the patient achieves a higher VGPR (very good partial response) after treatment compared to patients receiving a single CD38 antibody. 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 a single CD38 antibody. In some methods, the patient shows an improvement in hematological response within 60 days after treatment. In some methods, the patient shows an improvement within 45 days. In some methods, the patient shows an improvement in 33 days or less.

[0030] 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 NT-proBNP levels after treatment compared to patients receiving the CD38 antibody alone. In some methods, the NT-proBNP levels are reduced by at least 55% after treatment. In some methods, the NT-proBNP levels are reduced by at least 65%. In some methods, the NT-proBNP levels are reduced by 74% or more.

[0031] 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 weekly to about quarterly. In some methods, the treatment duration is at least 9 months. In some methods, the treatment duration is at least 12 months.

[0032] In some methods disclosed herein, a dose of the amyloid light chain antibody is administered intravenously after transferring an amount of formulation required for the dose from a vial to an intravenous infusion bag containing a fluid.

[0033] In some methods disclosed herein, the dose 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 dose of the CD38 antibody is 16 mg / kg.

[0034] In some methods disclosed herein, the patient has not received treatment prior to receiving the amyloid light chain antibody or CD38 antibody.

[0035] The present disclosure also provides a combination of an amyloid light chain antibody and a CD38 antibody for use in treating AL amyloidosis.

[0036] In some combinations for treating AL amyloidosis, the amyloid light chain antibody competes with antibody 2A4 (ATCC Accession No. 9662) for binding to human amyloid A peptide or human kappa or human 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 form of 2A4.

[0037] In some combinations for treating AL amyloidosis, the amyloid light chain antibody comprises a light chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 3, 4 and 5 and a heavy chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 6, 7 and 8.

[0038] In some combinations for treating AL amyloidosis, the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO: 1. In some combinations, the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO: 2. In some combinations, the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO: 1, and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO: 2.

[0039] In some combinations for treating AL amyloidosis, the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 11, 12 or 13. In some combinations, the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 12. In some combinations, the amyloid light chain antibody is politimab.

[0040] In some combinations for treating AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown as 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 shown as SEQ ID NO:17, 18, 19, 44, 54, 58, 60, 62 or 64. In some combinations, the CD38 antibody comprises the heavy and light chain variable region amino acid sequences shown as (a) SEQ ID NOs: 14 and 17, (b) SEQ ID NOs: 15 and 18, (c) SEQ ID NOs: 16 and 19, (d) SEQ ID NOs: 43 and 44, (e) SEQ ID NOs: 53 and 54, (f) SEQ ID NOs: 57 and 58, (g) SEQ ID NOs: 59 and 60, (h) SEQ ID NOs: 61 and 62, or (i) SEQ ID NOs: 63 and 64, respectively.

[0041] In some combinations for treating AL amyloidosis, the CD38 antibody comprises a heavy chain variable region including CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 47, 48 and 49, respectively, and a light chain variable region including CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 50, 51 and 52, respectively.

[0042] In some combinations for treating AL amyloidosis, the CD38 antibody comprises a heavy chain variable region including CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 20, 21 and 22, respectively, and a light chain variable region including CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 23, 24 and 25, respectively.

[0043] In some combinations for treating AL amyloidosis, the CD38 antibody comprises a heavy chain variable region including CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 26, 27 and 28, respectively, and a light chain variable region including CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 29, 30 and 31, respectively.

[0044] In some combinations for treating AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:32, and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:33.

[0045] In some combinations for treating AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:34, and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:35.

[0046] In some combinations for treating AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:36, and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:37.

[0047] In some combinations for treating AL amyloidosis, the CD38 antibody comprises a heavy chain variable region comprising the CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:38, and a light chain variable region comprising the CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:39.

[0048] In some combinations for 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 shown in SEQ ID NO:43 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:44.

[0049] In some combinations for 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 shown in SEQ ID NO:53 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:54.

[0050] In some combinations for the treatment of AL amyloidosis, patients were treatment-naive prior to receiving either NEOD001 or daratumumab.

[0051] The present disclosure also relates to a method for treating plasma cell dyscrasia in a patient, wherein the patient is treated with a combination therapy of an amyloid light chain antibody and a CD38 antibody before receiving plasma cell therapy. In some methods, the plasma cell dyscrasia is selected from the group consisting of monoclonal gammopathy of unknown significance (MGUS), asymptomatic myeloma, multiple myeloma, PC leukemia, plasma cell tumor. In some methods, plasma cell dyscrasia can lead to progression of AL amyloidosis. In some methods, a combination therapy of CD38 antibody and an amyloid light chain antibody is used prophylactically before progression of AL amyloidosis. In some methods, the plasma cell therapy is selected from the group consisting of 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.

[0052] In some methods, the combination therapy can stabilize or improve the patient's health to reduce the risk level of intolerance to plasma cell therapy and the risk level of treatment-related complications, wherein the stabilization or improvement of the patient's health is measured by very good partial response (VGPR) and / or NT-proBNP level. In some methods, the stabilization or improvement of the patient's health includes stabilization or improvement of the patient's cardiac function before receiving plasma cell therapy. In some methods, the stabilization or improvement of the patient's health includes stabilization or improvement of the patient's functional status as measured by Karnofsky performance status score or ECOG performance status score or equivalent functional assessment tool. In some methods, the stabilization or improvement of the patient's health includes stabilization or improvement of the patient's unintentional weight loss, poor endurance, weakness, slow gait, and low physical activity. In some methods, the stabilization or improvement of the patient's health includes stabilization or improvement of the patient's instrumental daily living activities. In some methods, the patient receives plasma cell therapy after achieving a decrease in NT-proBNP level relative to the patient's NT-proBNP level before receiving the combination therapy with amyloid light chain antibody and CD38 antibody. In some methods, the NT-proBNP level is reduced by at least 55%. In some methods, NT-proBNP levels are reduced by at least 65%. In some methods, NT-proBNP levels are reduced by 74% or more.

[0053] In some methods, the combination therapy is applied at least 9 months before plasma cell therapy. In some methods, the combination therapy is applied at least 12 months before plasma cell therapy. In some methods, after the combination therapy, the patient shows a VGPR improvement of more than 85%. In some methods, VGPR improves by at least 88%. In some methods, the patient shows an improvement in hematological response within 60 days after treatment with the combination therapy before treatment with plasma cell therapy. In some methods, the patient shows an improvement in hematological response within 45 days after treatment with the combination therapy before treatment with plasma cell therapy. In some methods, before treatment with plasma cell therapy, between 1 and 28 days after treatment with the combination therapy, the patient shows an improvement in hematological response, for example, 7 days, 14 days, 21 days or 28 days after treatment with the combination therapy.

[0054] In some methods disclosed herein, the method includes a method of improving cardiac function in a patient with AL who is unresponsive to treatment with NEOD001, the method comprising adding an effective dosing regimen of a CD38 antibody to the patient's treatment.

[0055] In some methods, non-response of the patient to NEOD001 treatment is determined based on the patient's NT-proBNP level after NEOD001 treatment being greater than or equal to the patient's NT-proBNP level before NEOD001 treatment.

[0056] In some methods, the NT-pro-BNP level is greater than the NT-proBNP level before NEOD001 treatment.

[0057] In some methods, the time period following NEOD001 treatment is at least 2 months.

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

[0059] In some methods, the patient received at least three doses of NEOD001 prior to receiving the CD38 antibody.

[0060] In some methods, the CD38 antibody is administered after NT-proBNP levels in the patient increase above about 6,000 pg / mL.

[0061] In some methods, the CD38 antibody is administered after NT-proBNP levels in the patient increase above about 12,000 pg / mL.

[0062] In some methods, the CD38 antibody is administered after NT-proBNP levels have increased by at least about 100%. In some methods, the CD38 antibody is administered after NT-proBNP levels have increased by at least about 200%. In some methods, the CD38 antibody is administered after NT-proBNP levels have increased by at least about 300%.

[0063] In some methods, the AL patient previously received NEOD001 and CyBorD.

[0064] In some methods, the CD38 antibody is daratumumab or isatuximab. In one method, the CD38 antibody is daratumumab.

[0065] In some methods, daratumumab is administered to the patient at 16 mg / kg every 28 days.

[0066] In some methods, NEOD001 is administered to the patient at 24 mg / kg every 28 days.

[0067] In some methods, the duration of treatment with the CD38 antibody is effective to reduce the patient's NT-proBNP level to at least the level before receiving NEOD001 treatment. In some methods, the duration is effective to reduce the patient's NT-proBNP level to below the level before receiving NEOD001 treatment.

[0068] In some methods, the treatment includes at least one dose of CD38 antibody. In some methods, the treatment includes at least two doses of CD38 antibody. In some methods, the treatment includes at least three doses of CD38 antibody. In some methods, the duration is at least 9 months. In some methods, the treatment time is at least 12 months. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 Cardiac responses to an example of a dual antibody therapy according to the present disclosure comprising NEOD001 and daratumumab are shown.

[0070] Figure 2A and 2B After showing an example of a dual antibody therapy according to the present disclosure including NEOD001 and daratumumab, based on NT-proBNP response ( Figure 2A ) and asymptotic lambda light chains ( Figure 2B ) is the overlap of the two curves. DETAILED DESCRIPTION

[0071] The present disclosure provides methods of treating a patient suffering from AL amyloidosis, the methods comprising administering to such patient a combination of an antibody that specifically binds to an amyloid light chain and an antibody that specifically binds to CD38.

[0072] I. Definitions

[0073] The term "antibody" includes complete antibodies and antigen-binding fragments thereof. Typically, the fragment competes with the complete antibody from which it is derived for specific binding to targets such as isolated heavy chains, light chain Fabs, Fab', F(ab')2, F(ab)c, Dabs, nanobodies and Fv. Fragments can be produced by recombinant DNA technology, or by enzymatic or chemical separation of complete immunoglobulins. The term "antibody" also includes bispecific antibodies and / or humanized antibodies. The term "amyloid light chain antibody" includes antibodies that specifically bind to new epitopes exposed in misfolded light chains and are described 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 and are described in more detail below.

[0074] 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 chain 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 a variable region comprising a variable framework region substantially from a human immunoglobulin or antibody and a complementary determining region (CDR) substantially from a non-human immunoglobulin or antibody (e.g., at least one CDR, preferably two CDRs, more preferably three CDRs), and also includes a constant region (e.g., in the case of a light chain, at least one constant region or a portion thereof, and in the case of a heavy chain, preferably three constant regions) immunoglobulin or antibody chain (i.e., a light chain or heavy chain, respectively). The term "humanized variable region" (e.g., "humanized light chain variable region" or "humanized heavy chain variable region") refers to a variable region that includes 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.

[0075] The phrase "essentially from a human immunoglobulin or antibody" means that when aligned with a human immunoglobulin or antibody amino acid sequence for comparison purposes, the region shares at least 80-90%, preferably 90-95%, and more preferably 95-99% identity (i.e., local sequence identity) with a human framework region or constant region sequence, allowing for, for example, conservative substitutions, consensus sequence substitutions, germline substitutions, back mutations, etc. The introduction of conservative substitutions, consensus sequence substitutions, germline substitutions, back mutations, etc. is generally referred to as "optimization" of a humanized antibody or chain. The phrase "essentially from a non-human immunoglobulin or antibody" or "essentially non-human" refers to an immunoglobulin or antibody sequence that contains at least 80-95%, preferably 90-95%, and more preferably 96%, 97%, 98% or 99% the same as an immunoglobulin or antibody sequence of a non-human organism (e.g., a non-human mammal).

[0076] Thus, all regions or residues of a humanized immunoglobulin or antibody or humanized immunoglobulin or antibody chain (except possibly CDRs) are substantially identical to corresponding regions or residues of one or more native human immunoglobulin sequences. The term "corresponding region" or "corresponding residue" refers to a region or residue on a second amino acid or nucleotide sequence that occupies the same (i.e., equivalent) position as a region or residue on a first amino acid or nucleotide sequence when the first and second sequences are optimally aligned for comparison purposes.

[0077] II. Treatment Methods and Amenable Subjects

[0078] Provided herein are methods for treating a human patient who exhibits symptoms of AL amyloidosis including cardiac dysfunction or is diagnosed with amyloidosis including cardiac dysfunction, the method comprising administering to the patient any amyloid light chain antibody described herein in combination with any CD38 antibody described herein, effective to achieve a positive hematological response and / or cardiac response in the patient. Some such patients may suffer from other systemic organ dysfunction caused by AL amyloidosis, including dysfunction of the kidney, liver, peripheral nervous system, gastrointestinal system, autonomic nervous system, lung and / or soft tissue or lymphatic system.

[0079] Patients amenable to treatment also include AL amyloidosis patients who have received, are receiving, or will later receive alternative therapies for AL amyloidosis or related conditions (e.g., inflammatory diseases, chronic microbial infections, malignancies, inherited inflammatory diseases, and lymphoproliferative diseases). For example, the patient may also receive or have received one or more therapeutic agents identified herein for combination therapy. As an example, a patient with AL amyloidosis may also receive or have received or may later receive bortezomib, ixazomib, venetoclax, melphalan, thalidomide, lenalidomide, prednisone, dexamethasone, cyclophosphamide, pomalidomide, carfilzomib, doxorubicin, doxycycline, autologous transplantation, or a combination thereof. For those patients who have previously received alternative therapies for amyloid disease, such therapies may have been successful or failed by relevant clinical measures, and may not have improved health. Other examples of such prior therapies include (1) daratumumab alone, (2) CyBorD, which is a combination therapy comprising cyclophosphamide, bortezomib and dexamethasone, (3) BMDex, which is a combination therapy of bortezomib, melphalan and dexamethasone, (4) MDex, which is a combination therapy of melphalan and dexamethasone, (5) LDex, which is a combination therapy of lenalidomide and dexamethasone, (6) CLD, which is a combination of cyclophosphamide, lenalidomide and dexamethasone, (7) PomDex, which is a combination therapy of lenalidomide and dexamethasone, (8) CRd, which is a combination therapy of lenalidomide, cyclophosphamide and dexamethasone, and (9) isatuximab. Such patients may or may not achieve cardiac and / or renal improvement as a result of such treatment.

[0080] An improvement in hematologic response can be determined by observing a greater than VGPR (very good partial response). To conclude a VGPR, one or more of the following conditions must be met: (i) serum and / or urine M protein that can be detected by immunofixation rather than electrophoresis; and (ii) a 90% reduction in serum M protein and / or urine M protein <100 mg / 24 h. If these are not measurable, the difference between the levels of relevant and irrelevant free light chains is reduced by 90%, provided that the serum free light chain analysis shows a relevant level>10 mg / dL and the serum free light chain ratio is abnormal). Patients treated with the combination therapy disclosed herein may show an improvement in VGPR of more than 80%, for example, at least 85%, 88%, or more than 88%. Patients may achieve maximum improvement in hematologic response within 75 days, for example, within 60 days, within 45 days, within 33 days, or within less than 33 days.

[0081] Improved cardiac response can be determined by a decrease in NT-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 decrease in NYHA (New York Heart Association) functional class (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 exhibit a decrease in NT-proBNP levels relative to baseline of greater than 50%, e.g., greater than 55%, greater than 65%, 74%, or greater than 74%.

[0082] Suitable antibodies, formulations and treatment regimens for the methods and uses disclosed herein are discussed in more detail below.

[0083] III. Antibodies

[0084] The methods of the present disclosure comprise administering an amyloid light chain antibody and a CD38 antibody to a patient with AL amyloidosis.

[0085] 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 Accession No. 9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or human lambda light chain immunoglobulins, or antibodies that specifically bind to the same epitope as 11-1F4 (U.S. Patent No. 8,105,594), 2A4 or 7D8 (U.S. Patent No. 7,928,203), or antibodies that compete with 11-1F4, 2A4 or 7D8 for binding to human kappa or human lambda light chain immunoglobulins. In some methods, the antibody is a humanized form of 2A4. In some methods, the antibody comprises a light chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 3, 4, and 5 and a heavy chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 6, 7, and 8. In some methods, the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO: 1. In some methods, the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO: 2. In some methods, the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO: 1, and the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO: 2. In some methods, the antibody comprises a light chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 9, 4, and 5 and a heavy chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 6, 7, and 8.

[0086] In other methods, the antibody comprises the light chain and heavy chain variable regions of a murine, chimeric or humanized 2A4 antibody, or the light chain and heavy chain variable regions of a murine, chimeric or humanized 7D8 antibody, as described in U.S. Pat. No. 7,928,203 and PCT International Publication No. WO 2009 / 086539 (the entire contents of which are incorporated herein by reference); and the light chain and heavy chain variable region sequences described in the referenced patents and publications are specifically incorporated herein by reference. Some formulations for use in the methods disclosed herein are described in U.S. Pat. No. 9,089,529 and PCT International Publication No. WO 2013 / 063284.

[0087] In some methods, the antibody comprises a light chain comprising an amino acid sequence as shown in SEQ ID NO: 10 and a heavy chain comprising an amino acid sequence as shown in any one of SEQ ID NO: 11-13. For example, the antibody may include a light chain comprising an amino acid sequence as shown in SEQ ID NO: 10 and a heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 12. The antibody may or may not include the leader sequence of the above light chain and heavy chain amino acid sequences. In some methods, the antibody is Botox (CAS Registry No. 1608108-91-3), also known as NEOD001.

[0088] In other methods, the antibody is a fragment of the 2A4 or 7D8 antibody, including chimeric and humanized forms thereof, such as a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a F(ab)c, a Dab, a Nanobody, or a Fv.

[0089] CD38 antibodies are antibodies that specifically bind to the epitope of CD38 on antibody-producing plasma cells, B cells and other lymphoid immune cells (SEQ ID NO: 40). Some such antibodies bind within amino acids 44 to 206 of CD38 (SEQ ID NO: 40), for example, within amino acids 44-66, 82-94, 142-154, 148-164, 158-170 or 192-206. Some CD38 antibodies bind to the SKRNIQFSCKNIYR region (SEQ ID NO: 41) and the EKVQTLEAWVIHGG region (SEQ ID NO: 42). Some such CD38 antibodies mediate complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytic activity and trogocytosis of CD38+ target cells. In some methods, the CD38 antibody is daratumumab (CAS registration number 945721-28-8). Certain exemplary CD38 antibodies are disclosed in US Pat. No. 7,829,673 (the '673 patent), US Pat. No. 8,263,746 (the '746 patent), and US Pat. No. 9,249,226, the entire contents of which are incorporated herein by reference.

[0090] 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, in 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, in 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, in 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, in the '673 patent).

[0091] Some CD38 antibodies comprise a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence set forth in SEQ ID NO:32 (SEQ ID NO:5 in the '746 patent), and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence set forth in SEQ ID NO:33 (SEQ ID NO:13 in the '746 patent). Some CD38 antibodies comprise a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence set forth in SEQ ID NO:34 (SEQ ID NO:6 in the '746 patent), and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence set forth in SEQ ID NO:35 (SEQ ID NO:14 in the '746 patent). Some CD38 antibodies comprise a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence set forth in SEQ ID NO:36 (SEQ ID NO:7 in the '746 patent), and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence set forth in SEQ ID NO:37 (SEQ ID NO:15 in the '746 patent). Some CD38 antibodies comprise a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence set forth in SEQ ID NO:38 (SEQ ID NO:8 in the '746 patent), and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence set forth in SEQ ID NO:39 (SEQ ID NO:16 in the '746 patent).

[0092] For example, a CD38 antibody may include a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 14, 15, or 16 (SEQ ID NO: 7, 17, 27, respectively, in the '673 patent). A CD38 antibody may include a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NO: 17, 18, or 19 (SEQ ID NO: 2, 12, 22, respectively, in the '673 patent). Suitable CD38 antibodies may comprise a combination of heavy chain variable regions and light chain variable regions disclosed herein. For example, some such CD38 antibodies comprise heavy and light chain variable region amino acid sequences as set forth in (a) SEQ ID NO: 14 and 17, (b) SEQ ID NO: 15 and 18, or SEQ ID NO: 16 and 19, respectively.

[0093] Alternatively, the CD38 antibody can be isatuximab, or a CD38 antibody disclosed in WO 2016 / 187546 or US 2017 / 0008966 (disclosure of U.S. patent application Ser. No. 15 / 160,476 ('476 application)). Some CD38 antibodies bind to at least the SKRNIQFSCKNIYR region (SEQ ID NO:45) and the EKVQTLEAWVIHGG region (SEQ ID NO:56). For example, the CD38 antibody can include a heavy chain variable region comprising the CDR1, CDR2, and CDR3 amino acid sequences shown in SEQ ID NOs:47, 48, and 49, respectively, and a light chain variable region comprising the CDR1, CDR2, and CDR3 amino acid sequences shown in SEQ ID NOs:50, 51, and 52, respectively. Some suitable CD38 antibodies include a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 53 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 54. In some methods, the CD38 antibody includes a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 55 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 56.

[0094] Some CD38 antibodies comprise heavy chain CDR1, CDR2 and CDR3 and light chain CDR1, CDR2 and CDR3 of (a) heavy chain variable region SEQ ID NO: 57 and light chain variable region SEQ ID NO: 58, (b) heavy chain variable region SEQ ID NO: 59 and light chain variable region SEQ ID NO: 60, (c) heavy chain variable region SEQ ID NO: 61 and light chain variable region SEQ ID NO: 62, or (d) heavy chain variable region SEQ ID NO: 63 and light chain variable region SEQ ID NO: 64. For example, the CD38 antibody may comprise a heavy chain variable region SEQ ID NO: 57 and a light chain variable region SEQ ID NO: 58. In some methods, the CD38 antibody may comprise a heavy chain variable region SEQ ID NO: 59 and a light chain variable region SEQ ID NO: 60. As another example, the CD38 antibody may comprise a heavy chain variable region SEQ ID NO: 61 and a light chain variable region 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.

[0095] In some methods, the patient is administered polituximab and daratumumab. In another method, the patient is administered polituximab and isatuximab. As discussed in more detail below, the antibodies can be administered as a pharmaceutical formulation.

[0096] IV. Pharmaceutical Formulations and Products

[0097] In some methods disclosed herein, the antibody can be administered to a patient with AL amyloidosis as a pharmaceutical formulation, for example, comprising, in addition to the antibody, a histidine buffer, trehalose, and polysorbate 20, such as the formulation disclosed in U.S. Pat. No. 9,884,020 (the entire contents of which are incorporated herein by reference).

[0098] 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 as different pharmaceutical formulations. In some such methods, the amyloid light chain antibody is prepared as any of the above formulations, and the CD38 antibody is prepared as a different formulation, for example, any formulation disclosed in U.S. Patent Publication No. US2017 / 0121414 or U.S. Patent No. 9,364,542, the entire contents of which are incorporated herein by reference.

[0099] V. Treatment options

[0100] As used herein, the term "treat" refers to alleviating or ameliorating one or more symptoms or effects associated with a disease, preventing, inhibiting or delaying the onset of one or more symptoms or effects of a disease, reducing the severity or frequency of one or more symptoms or effects of a disease, and / or enhancing or tending to achieve a desired effect as described herein.

[0101] The expected therapeutic effects disclosed herein vary according to amyloid disease and patient profiles, and are easily determined by those skilled in the art. The expected effects include improvements in patient health. Typically, the expected effects include measurable indicators, such as reducing or removing pathological amyloid fibers, reducing or inhibiting the aggregation and / or deposition of amyloid fibers, and increasing the immune response to pathological and / or aggregated amyloid fibers. The expected effects also include improving amyloid disease-specific symptoms. For example, the expected therapeutic effects of AL amyloidosis include known symptoms (including organ dysfunction, peripheral and autonomic neuropathy, carpal tunnel syndrome, macroglossia, restrictive cardiomyopathy, arthropathy of large joints, immune disorders, myeloma, and occult dyscrasias) The incidence or severity of the reduction. The expected effects of the disclosed therapy are usually quantitative indicators compared to control or baseline measurements. As used herein, relative terms such as "improvement", "increase" or "reduction" represent values ​​relative to a control group (e.g., the measurement results in the same individual before starting treatment described herein, or the measurement results of a control individual or control group). A control individual refers to an individual with the same amyloid disease as the treated individual, whose age is approximately the same as the treated individual (to ensure that the disease stages of the treated individual and the control individual include comparability), but who has not received treatment with the disclosed antibody formulation. In this case, the efficacy of the disclosed antibody formulation is evaluated by deviation or departure from a measurable indicator of an untreated control. Alternatively, the control individual is a healthy individual of approximately the same age as the treated individual. In this case, the efficacy of the disclosed antibody formulation is evaluated by changing or trending toward a measurable indicator of a healthy control. Changes or improvements in response to therapy generally include statistical significance and are described by a p-value of less than or equal to 0.1, and p-values ​​less than 0.05, less than 0.01, less than 0.005, or less than 0.001 are considered significant.

[0102] Treatment usually requires multiple doses over a period of time. Treatment can be monitored in real time by detecting antibodies or using radiolabeled SAP scintigraphy. If the response decreases, the dose may need to be increased. In addition, the response of patients with AL amyloidosis to treatment can be monitored by evaluating cardiac markers such as NT-proBNP and / or troponin, serum creatine and / or alkaline phosphatase; using serum free light chain (SFLC) analysis, quantitative immunoglobulin determination, biopsy, 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 according to response criteria, including negative serum and urine IFE, normal kappa / lamda (κ / λ) ratio and / or plasma cells <5% in the 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 a dFLC reduction of ≥50%. For example, in the kidney, response to treatment can be determined by a ≥50% reduction in 24-hour urine protein excretion (e.g., >0.5 g / 24 hours) in the absence of a ≥25% decrease in eGFR or an increase in serum creatine of ≥0.5 mg / dL. In the liver, response to treatment can be determined, for example, by a ≥50% decrease in initially elevated alkaline phosphatase or a 2 cm reduction in the liver on a CT scan or MRI. In the heart, response to treatment can be determined, for example, by a >30% and >300 ng / L decrease in NT-proBNP in patients with a baseline NT-proBNP level of >650 ng / L. In the kidney, response to treatment can be determined, for example, by a >30% decrease in proteinuria or a decrease in proteinuria to <0.5 g / 24 hours in the absence of renal progression. Neuropathy responders are typically characterized by an increase in NIS-LL of <2 points from baseline. Improvement in neuropathy (e.g., improvement in neurological function) is dependent on a decrease in NIS-LL from baseline.

[0103] Antibody formulations can be administered intravenously or subcutaneously at a dosage within the range of about 0.5mg / kg body weight to about 30mg / kg body weight. For example, dosage can be about 0.5mg / kg body weight, about 1.0mg / kg body weight, about 1.5mg / kg body weight, about 2.0mg / kg body weight, about 4.0mg / kg body weight, about 5.0mg / kg body weight, about 8.0mg / kg body weight, about 10mg / kg body weight, about 15mg / kg body weight, about 16mg / kg body weight, about 20mg / kg body weight, about 24mg / kg body weight, about 25mg / kg body weight or about 30mg / kg body weight. For intravenous administration, the amount of the antibody formulation sufficient to reach the required dosage of individual patients is transferred from one or more vials to one or more intravenous bags comprising liquid (e.g., normal saline), and administered to the patient. In some methods, the patient is administered any amyloid light chain antibody disclosed herein, such as Boteimab, of about 24mg / kg dosage. In some methods, the patient is administered a dose of about 16 mg / kg of any of the CD38 antibodies disclosed herein, such as daratumumab.

[0104] Antibodies are typically administered in a variety of situations. Exemplary treatment regimens include administration every two weeks, monthly, or every 3 to 6 months. For example, a patient may receive an antibody formulation once every four weeks as a cycle (e.g., every 28 days). The frequency of administration may be adjusted according to the pharmacokinetic profile of the antibody formulation in the patient. For example, the half-life of an antibody may require administration once every two weeks.

[0105] In some methods, a pharmaceutical formulation of about 24 mg / kg of amyloid light chain antibody is administered intravenously once every 28 days. For example, some patients may receive an intravenous infusion dose of about 24 mg / kg of any amyloid light chain antibody disclosed herein, such as botoximab, once every 28 days. Some such patients receive intravenous injection doses (e.g., a dose of 16 mg / kg) of any CD38 antibody disclosed herein, such as daratumumab, at a frequency of once every 28 days. Some patients receive CD38 antibodies once a week. Some patients receive CD38 antibodies once every two weeks. Some patients initially receive CD38 antibodies more frequently, and over time, the frequency of receiving CD38 antibodies decreases. For example, a patient may receive CD38 antibodies once a week for a period of time, then once every two weeks for a period of time, and then once a month or every 28 days during treatment. One of the dosing regimens is to administer a CD38 antibody (such as daratumumab) once a week for eight weeks, then once every two weeks for four months, and then once a month during treatment.

[0106] For some such patients, the amyloid light chain antibody formulation transferred to the intravenous bag is first reconstituted from a lyophilized formulation into a formulation having a pH of about 6.5 and comprising about 50 mg / ml amyloid light chain antibody (e.g., podecathiazine), about 25 mM histidine buffer, about 230 mM trehalose, and about 0.2 g / L polysorbate 20.

[0107] For some patients, the desired dose of one or more amyloid light chain antibodies and / or CD38 antibodies can be administered subcutaneously from a vial containing any of the formulations disclosed herein without dilution.

[0108] In some methods disclosed herein, the patient is administered the antibody for at least 9 months, at least 12 months, or longer.

[0109] When using an amyloid light chain antibody and a CD38 antibody for combination therapy, the two antibodies can be administered simultaneously in any order, i.e., one antibody can be administered before, simultaneously with, or after the administration of the other antibody. For example, the first antibody can be administered before (e.g., 1 minute, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), simultaneously, 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) the 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, for example, simultaneously or sequentially in one 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 one week apart. If the two antibodies are not administered at the same time, in some methods, the CD38 antibody is administered first, and then the amyloid light chain antibody is administered. In other methods, the amyloid light chain antibody is administered first, and then the CD38 antibody is administered.

[0110] The dosage, frequency and mode of administration of each component of the combination can be controlled independently. For example, one therapeutic agent / therapy can be taken orally three times a day, while a second therapeutic agent / therapy can be injected intramuscularly once a day. The combination therapy can be divided into an on-off cycle including a rest period. The compounds can also be mixed or otherwise formulated together so that both compounds can be delivered in a single administration. In this case, the content of each therapeutic agent is generally 1-95% of the total weight of the composition. Alternatively, the antibody formulation disclosed herein and the second therapeutic agent can be formulated separately and in individual doses. The drug combination for treatment can be provided as a component of a drug package.

[0111] In some combinations for the treatment of AL amyloidosis, patients were treatment-naive prior to receiving NEOD001 or daratumumab. For example, patients had previously received any treatment for AL amyloidosis, even standard of care treatment.

[0112] In some methods disclosed herein, the patient first receives an amyloid light chain antibody or a CD38 antibody before treating plasma cell dyscrasia. Plasma cell dyscrasia (PCD; also known as plasma cell disease or plasma cell proliferative disease) is a series of increasingly severe monoclonal gammopathy in which one or more clones of plasma cells overproduce immunoglobulins or fragments thereof and secrete them into the bloodstream. PCD may include, but is not limited to, monoclonal gammopathy of unknown significance (MGUS), asymptomatic myeloma, multiple myeloma, PC leukemia, plasma cell tumors. 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), and then treated with plasma cell therapy, such as one or more of ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin, doxycycline, or CD38 antibodies. Treatment with plasma cell therapy may include CD38 antibodies, provided that treatment with plasma cell therapy occurs after combined treatment with amyloid light chain antibodies and CD38 antibodies. In one such method of the present disclosure, treatment with a combination of amyloid light chain antibodies and CD38 antibodies is followed by treatment of plasma cell dyscrasias, wherein the treatment of plasma cell dyscrasias is CD38 antibodies, or wherein the treatment of plasma cell dyscrasias is bortezomib.

[0113] Pretreatment with an anti-amyloid light chain antibody and an anti-CD38 antibody can enhance the patient's ability to tolerate the side effects of subsequent plasma cell therapy. Pretreatment can also reduce the risk level of intolerance to plasma cell therapy and the risk of treatment-related complications. In some methods, a combination of an anti-CD38 antibody and an anti-amyloid light chain antibody is administered prophylactically before AL amyloidosis develops.

[0114] In such methods, the order and dosing regimen of the amyloid light chain antibody and the CD38 antibody can be as described herein. For example, as described herein, a combination of an amyloid light chain antibody and a CD38 antibody can be used to treat a patient to improve the patient's health. For example, the improvement can be a reduction in NT-proBNP prior to the administration of plasma cell therapy (e.g., bortezomib). For example, prior to treatment with plasma cell therapy, a patient treated with the combination therapy disclosed herein may exhibit a decrease in NT-proBNP relative to baseline of greater than 50%, e.g., greater than 55%, greater than 65%, 74%, or greater than 74%. Other measures to improve patient health are described herein, e.g., by measuring other cardiac markers (troponin, serum creatine, and / or alkaline phosphatase), and by using serum free light chain (SFLC) analysis, quantitative immunoglobulin assay, biopsy, serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), serum, urine immunofixation electrophoresis (IFE), and / or organ imaging techniques. Other measures of improvement include stabilization or improvement of patients' functional status as measured by the Karnofsky performance status score or the Eastern Cooperative Oncology Group performance status score or equivalent functional assessment tools, improvement of patients' unintentional weight loss, poor endurance, weakness, slow gait, and low physical activity, and / or improvement of patients' instrumental activities of daily living.

[0115] Therefore, some methods disclosed herein relate to methods for treating plasma cell dyscrasias in patients, wherein the patient first receives a combination therapy of an amyloid light chain antibody and a CD38 antibody, and then receives plasma cell therapy. Various manifestations of PCD may require different treatment regimens. PCD therapy may include the use of hematopoietic stem cell transplantation (HSCT) and / or chemotherapeutic agents. In some methods, plasma cell therapy is one or more of ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin, and doxycycline. In some methods, plasma cell therapy is bortezomib.

[0116] In some such methods, the patient first receives a combination therapy of an amyloid light chain antibody and a CD38 antibody to stabilize or improve the patient's health (e.g., the patient's cardiac function) and then receives plasma cell therapy. The improvement in the patient's health can be determined, for example, by determining that the patient's NT-proBNP level is reduced by more than 50% compared to baseline. In particular, a reduction in NT-proBNP level of more than 55%, more than 65%, 74%, or more than 74% compared to baseline can indicate an improvement in the patient's health. The improvement in the patient's health can increase the patient's ability to tolerate the side effects of subsequent plasma cell therapy. In such methods, the order and dosing regimen of the combination therapy of an amyloid light chain antibody and a CD38 antibody can be as described herein. For example, a patient can receive a combination therapy of an amyloid light chain antibody and a CD38 antibody to achieve a reduction in NT-proBNP levels of at least 55% and then receive plasma cell therapy (e.g., bortezomib).

[0117] As described herein, the combined antibody therapy can overlap with the plasma cell therapy to maintain the improvement in health obtained by the patient before the plasma cell therapy. Alternatively, the combined antibody therapy can be stopped immediately a few days, weeks or months before the plasma cell therapy, as long as the patient's health has improved to the extent that the patient can more easily tolerate the side effects of the plasma cell therapy. For example, before the plasma cell therapy, the combined therapy can be administered using the dosing regimen described herein for at least 9 months or at least 12 months, and terminated before or during the antibody combined therapy.

[0118] In some methods, after the combination therapy, the patient shows an improvement in VGPR of more than 85%. In some methods, the VGPR improves by at least 88%. In some methods, the patient shows an improvement in hematological response within 60 days after treatment with the combination therapy before treatment with plasma cell therapy. In some methods, the patient shows an improvement in hematological response within 45 days after treatment with the combination therapy before treatment with plasma cell therapy. In some methods, the patient shows an improvement in hematological response between 1 and 28 days after treatment with the combination therapy before treatment with plasma cell therapy, such as 7 days, 14 days, 21 days or 28 days after treatment with the combination therapy.

[0119] Amyloid light chain antibodies can be as described herein, and can be provided in the amyloid light chain antibody sequence. Similarly, CD38 antibodies are as described herein, and can be, for example, daratumumab. Similarly, as described herein, the dosage of the amyloid light chain antibody can be about 0.5 mg / kg to about 30 mg / kg, which can be administered intravenously or subcutaneously at a frequency of about weekly to about quarterly. In a method herein, the dosage of the amyloid light chain is about 24 mg / kg, and the antibody is injected intravenously once every 28 days, and can include the formulation described herein.

[0120] In some methods disclosed herein, the method includes a method of improving cardiac function in AL patients who are unresponsive to NEOD001 treatment, the method comprising adding an effective dosing regimen of a CD38 antibody to the patient's treatment. Patients who are unresponsive to NEOD001 include patients treated with CyBorD (cyclophosphamide, bortezomib, dexamethasone). Patient response can be measured as a cardiac response, such as NT-proBNP levels. Unresponsive patients include patients who do not improve with NEOD001 (with or without CyBorD) or patients whose condition continues to worsen, such as Figure 1 For example, a patient's lack of response to NEOD001 treatment may be determined by the patient's NT-proBNP level after NEOD001 treatment being greater than or equal to the patient's NT-proBNP level before NEOD001 treatment. For example, the NT-proBNP level is higher than the NT-proBNP level before NEOD001 treatment.

[0121] Dosing schedules may vary and may include a period of time after NEOD001 treatment, i.e., at least two months prior to administration of the CD38 antibody. In some cases, 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 an increase of about 2,000 pg / mL to about 15,000 pg / mL NT-pro-BNP. For example, the increase in NT-proBNP in the patient 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 NT-proBNP. In some methods, the CD38 antibody is administered after an increase of about 12,000 pg / mL NT-proBNP in the patient.

[0122] In some methods of the present disclosure, the CD38 antibody is administered after NT-proBNP levels have increased by at least about 100%. In some methods, the CD38 antibody is administered after NT-proBNP levels have increased by at least about 200%. In some methods, the CD38 antibody is administered after NT-proBNP levels have increased by at least about 300%. As further described herein, the CD38 antibody can be daratumumab or isatuximab.

[0123] In some methods of the present disclosure, daratumumab is administered to the patient at 16 mg / kg every 28 days. In some methods, NEOD001 is administered to the patient at 24 mg / kg every 28 days.

[0124] In some methods of the present disclosure, the duration of treatment with a CD38 antibody in combination with an amyloid light chain antibody is effective to reduce the patient's NT-proBNP level to at least the level before receiving the amyloid light chain antibody treatment. In some methods, the duration is effective to reduce the patient's NT-proBNP level to below the level before receiving the amyloid light chain antibody treatment.

[0125] In some methods of the present disclosure, the patient has received at least one dose, at least two doses, at least three doses, at least four doses, at least 5 to 12 doses, or more than 12 doses of CD38 antibody. In addition, the duration of treatment can be at least 3 months, at least 6 months, at least 9 months, at least 12 months, and can include multiple doses of CD38 antibody.

[0126] Example

[0127] The following examples are included herein to illustrate the methods disclosed herein. Certain aspects of the following examples are described with respect to techniques and procedures discovered or contemplated by the present co-inventors to work well in the practice disclosed herein. In light of the present disclosure and the general level of skill in the art, it will be appreciated by those skilled in the art that the following examples are exemplary only and that numerous changes, modifications, and variations may be made without departing from the scope of the present disclosure.

[0128] Example 1. Phase 3 Clinical Evaluation of NEOD001

[0129] The Phase 3 global, multicenter, randomized, double-blind, placebo-controlled clinical study of NEOD001 versus placebo was conducted in newly diagnosed, untreated patients with AL amyloidosis and cardiac dysfunction, with both arms of the study receiving standard care (the "VITAL study"). Patients were randomized on a 1:1 basis to receive 24 mg / kg NEOD001 or placebo via intravenous infusion every 28 days. All patients received bortezomib-based chemotherapy in parallel with NEOD001 or placebo. Placebo was administered once every 28 days in a 250 mL bag of normal saline. More information about the clinical study design is available at https: / / clinicaltrials.gov.

[0130] Example 2. Evaluation of patients treated with NEOD001 and daratumumab

[0131] Nine patients with AL amyloidosis from the VITAL study who were treated with the investigational monoclonal antibody NEOD001 also received daratumumab at a dose of 16 mg / kg, with the first dose administered over two days. Patients were treated with daratumumab weekly for eight weeks, then every two weeks for four months, and then every 28 days. Of these nine patients, there were four men and five women, with a median age of 68 years (range, 52 to 75 years), and 261 days from diagnosis (range, 51 to 2037 days). The median NT-proBNP was 3807 pg / ml (1326 to 13193 pg / ml). Infusions of NEOD001 and daratumumab were separated by 2 days and were well tolerated without any unexpected toxic effects. These nine patients with cardiac involvement did not respond to initial treatment with a bortezomib-based regimen. See Figure 1 .

[0132] 88% of patients using daratumumab + NEOD001 achieved >VGPR within a median of 33 days and cardiac response within <90 days. In contrast, patients who did not participate in the VITAL study and received daratumumab alone (n=10) achieved hematologic and cardiac responses at a later time (Table 1). In this study, monoclonal antibodies targeting different amyloid light chains and CD38 were safely combined for patients with systemic AL amyloidosis with cardiac involvement. As shown in Table 1, the combination of daratumumab and NEOD001 achieved higher hematologic and cardiac response rates compared to patients receiving daratumumab alone.

[0133] Table 1 Patient characteristics and outcomes

[0134]

[0135] Figure 1 Shown is a representative response measured by NT-proBNP levels of a patient with advanced worsening AL cardiac involvement despite treatment with NEOD001 and CyBorD (cyclophosphamide, bortezomib, dexamethasone) and then the addition of daratumumab to therapy. The dual antibody combination therapy was able to reverse the worsening of cardiac response.

[0136] Figure 2A -B shows the overlay of two curves showing rapid cardiac improvement based on NT-proBNP response ( Figure 2A ) and improvement of progressive lambda light chains after dual antibody therapy ( Figure 2B ). This pattern is not typical for AL patients who experience an organ response. Typically, the organ response is several months behind the light chain response.

[0137] The disclosure of each patent, patent application, and publication cited herein is incorporated herein by reference in its entirety. Although the present disclosure has been disclosed with reference to specific embodiments, other embodiments and variations of the present disclosure may be designed by other 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.

[0138] sequence

[0139] SEQ ID NO:01 Humanized antibody sequence containing mouse and human residues (Humanized 2A4 light chain variable region version 3)

[0140]

[0141] SEQ ID NO:02 Humanized antibody sequence containing mouse and human residues (Humanized 2A4 heavy chain variable region version 3)

[0142]

[0143] SEQ ID NO:03 2A4 VL CDR1

[0144]

[0145] SEQ ID NO:04 2A4 VL CDR2

[0146]

[0147] SEQ ID NO:05 2A4 VL CDR3

[0148]

[0149] SEQ ID NO:06 2A4 VH CDR1

[0150]

[0151] SEQ ID NO:07 2A4 VH CDR2

[0152]

[0153] SEQ ID NO:08 2A4 VH CDR3

[0154]

[0155] SEQ ID NO:09 7D8 VL CDR1

[0156]

[0157] SEQ ID NO: 10 Humanized antibody sequence containing mouse and human residues (humanized 2A4 kappa light chain)

[0158]

[0159]

[0160] SEQ ID NO: 11 Humanized antibody sequence containing mouse and human residues (humanized 2A4 IgG1 heavy chain variant 1 (G1m1 allotype))

[0161]

[0162] SEQ ID NO: 12 Humanized antibody sequence containing mouse and human residues (humanized 2A4 IgG1 heavy chain variant 2 (G1m3 allotype))

[0163]

[0164] SEQ ID NO: 13 Humanized antibody sequence containing mouse and human residues (humanized 2A4 IgG2 heavy chain)

[0165]

[0166] SEQ ID NO: 14 is from SEQ ID NO: 7 of U.S. Patent No. 7,829,673

[0167]

[0168] SEQ ID NO: 15 is from SEQ ID NO: 17 of U.S. Patent No. 7,829,673

[0169]

[0170] SEQ ID NO: 16 is from SEQ ID NO: 27 of U.S. Patent No. 7,829,673

[0171]

[0172] SEQ ID NO: 17 is from SEQ ID NO: 2 of U.S. Patent No. 7,829,673

[0173]

[0174] SEQ ID NO: 18 is from SEQ ID NO: 12 of U.S. Patent No. 7,829,673

[0175] EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIK

[0176] SEQ ID NO: 19 is from SEQ ID NO: 22 of U.S. Patent No. 7,829,673

[0177]

[0178] SEQ ID NO: 20 is from SEQ ID NO: 8 of U.S. Patent No. 7,829,673

[0179]

[0180] SEQ ID NO:21 is from SEQ ID NO:9 of U.S. Patent No. 7,829,673

[0181]

[0182] SEQ ID NO:22 is from SEQ ID NO:10 of U.S. Patent No. 7,829,673

[0183]

[0184] SEQ ID NO:23 is from SEQ ID NO:3 of U.S. Patent No. 7,829,673

[0185]

[0186] SEQ ID NO:24 is from SEQ ID NO:4 of U.S. Patent No. 7,829,673

[0187]

[0188] SEQ ID NO: 25 is from SEQ ID NO: 5 of U.S. Patent No. 7,829,673

[0189]

[0190] SEQ ID NO:26 is derived from SEQ ID NO:18 of U.S. Patent No. 7,829,673

[0191]

[0192] SEQ ID NO:27 is derived from SEQ ID NO:19 of U.S. Patent No. 7,829,673

[0193]

[0194] SEQ ID NO:28 is from SEQ ID NO:20 of U.S. Patent No. 7,829,673

[0195]

[0196] SEQ ID NO:29 is from SEQ ID NO:13 of U.S. Patent No. 7,829,673

[0197]

[0198] SEQ ID NO:30 is from SEQ ID NO:14 of U.S. Patent No. 7,829,673

[0199]

[0200] SEQ ID NO:31 is from SEQ ID NO:15 of U.S. Patent No. 7,829,673

[0201]

[0202] SEQ ID NO:32 is from SEQ ID NO:5 of U.S. Patent No. 8,263,746

[0203]

[0204] SEQ ID NO:33 is from SEQ ID NO:13 of U.S. Patent No. 8,263,746

[0205]

[0206] SEQ ID NO:34 is from SEQ ID NO:6 of U.S. Patent No. 8,263,746

[0207]

[0208] SEQ ID NO:35 is derived from SEQ ID NO:14 of U.S. Patent No. 8,263,746

[0209]

[0210] SEQ ID NO:36 is from SEQ ID NO:7 of U.S. Patent No. 8,263,746

[0211]

[0212] SEQ ID NO:37 is derived from SEQ ID NO:15 of U.S. Patent No. 8,263,746

[0213]

[0214] SEQ ID NO:38 is from SEQ ID NO:8 of U.S. Patent No. 8,263,746

[0215]

[0216] SEQ ID NO:39 is derived from SEQ ID NO:16 of U.S. Patent No. 8,263,746

[0217]

[0218] SEQ ID NO:40 is derived from SEQ ID NO:22 of U.S. Patent No. 8,263,746

[0219]

[0220] SEQ ID NO:41

[0221] SEQ ID NO:42

[0222] SEQ ID NO:43 The heavy chain sequence is shown in https: / / www.genome.jp / dbget-bin / www_bget?dr:D10777

[0223]

[0224] SEQ ID NO:44 The light chain sequence is shown in https: / / www.genome.jp / dbget-bin / www_bget?dr:D10777

[0225]

[0226] SEQ ID NO:2 of SEQ ID NO:45US2017 / 0008966

[0227]

[0228] SEQ ID NO: 46, SEQ ID NO: 3 of US2017 / 0008966

[0229]

[0230] SEQ ID NO: 47, SEQ ID NO: 6 of US2017 / 0008966

[0231]

[0232] SEQ ID NO: 48, SEQ ID NO: 7 of US2017 / 0008966

[0233]

[0234] SEQ ID NO: 49, SEQ ID NO: 8 of US2017 / 0008966

[0235]

[0236] SEQ ID NO: 50, SEQ ID NO: 9 of US2017 / 0008966

[0237]

[0238] SEQ ID NO: 51, SEQ ID NO: 10 of US2017 / 0008966

[0239]

[0240] SEQ ID NO: 52, SEQ ID NO: 11 of US2017 / 0008966

[0241]

[0242] SEQ ID NO: 53, SEQ ID NO: 4 of US2017 / 0008966

[0243]

[0244] SEQ ID NO: 54, SEQ ID NO: 5 of US2017 / 0008966

[0245]

[0246] SEQ ID NO: 55, SEQ ID NO: 12 of US2017 / 0008966

[0247]

[0248] SEQ ID NO:13 of SEQ ID NO:56US2017 / 0008966

[0249]

[0250] SEQ ID NO:14 of SEQ ID NO:57US2017 / 0008966

[0251]

[0252] SEQ ID NO:15 of SEQ ID NO:58US2017 / 0008966

[0253]

[0254] SEQ ID NO:16 of SEQ ID NO:59US2017 / 0008966

[0255]

[0256] SEQ ID NO:17 of SEQ ID NO:60US2017 / 0008966

[0257]

[0258] SEQ ID NO:18 of SEQ ID NO:61US2017 / 0008966

[0259]

[0260] SEQ ID NO:19 of SEQ ID NO:62US2017 / 0008966

[0261]

[0262] SEQ ID NO:20 of SEQ ID NO:63US2017 / 0008966

[0263]

[0264] SEQ ID NO:21 of SEQ ID NO:64US2017 / 0008966

[0265]

[0266] The present application further relates to embodiments:

[0267] 1. A method of treating a patient suffering from AL amyloidosis, the method comprising administering to the subject an effective dose of an amyloid light chain antibody in combination with a CD38 antibody.

[0268] 2. A method as described in embodiment 2, wherein the amyloid light chain antibody competes with antibody 2A4 (ATCC Accession No. 9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or human lambda light chain immunoglobulin, or binds to the same epitope as 11-1F4 and competes with 11-1F4 for binding to human kappa or human lambda light chain immunoglobulin.

[0269] 3. A method as described in embodiment 2, wherein the amyloid light chain antibody is a humanized form of 2A4.

[0270] 4. A method as described in embodiment 1, wherein the amyloid light chain antibody comprises a light chain variable region comprising three complementarity determining regions as shown in SEQ ID 3, 4 and 5 and a heavy chain variable region comprising three complementarity determining regions as shown in SEQ ID NO: 6, 7 and 8.

[0271] 5. A method as described in embodiment 1, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:1.

[0272] 6. A method as described in embodiment 1, wherein the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:2.

[0273] 7. A method as described in embodiment 1, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:1, and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:2.

[0274] 8. A method as described in embodiment 1, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:11, 12 or 13.

[0275] 9. A method as described in embodiment 8, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:12.

[0276] 10. The method of embodiment 8, wherein the amyloid light chain antibody is birtamimab.

[0277] 11. The method of any one of the preceding embodiments, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 14 or 15.

[0278] 12. The method of any one of the preceding embodiments, wherein the CD38 antibody comprises a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 17 or 18.

[0279] 13. A method as described in any one of embodiments 1 to 10, wherein the CD38 antibody comprises heavy chain and light chain variable region amino acid sequences as shown in (a) SEQ ID NOs: 14 and 17; (b) SEQ ID NOs: 15 and 18; (c) SEQ ID NOs: 16 and 19; (d) SEQ ID NOs: 43 and 44; (e) SEQ ID NOs: 53 and 54; (f) SEQ ID NOs: 57 and 58; (g) SEQ ID NOs: 59 and 60; (h) SEQ ID NOs: 61 and 62; or (i) SEQ ID NOs: 63 and 64, respectively.

[0280] 14. A method as described in any one of embodiments 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 47, 48 and 49, respectively, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 50, 51 and 52, respectively.

[0281] 15. A method as described in any one of embodiments 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 20, 21 and 22, respectively, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 23, 24 and 25, respectively.

[0282] 16. A method as described in any one of embodiments 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 26, 27 and 28, respectively, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 29, 30 and 31, respectively.

[0283] 17. A method as described in any one of embodiments 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:32, and the light chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:33.

[0284] 18. A method as described in any one of embodiments 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:34, and the light chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:35.

[0285] 19. A method as described in any one of embodiments 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:36, and the light chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:37.

[0286] 20. A method as described in any one of embodiments 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:38, and the light chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:39.

[0287] 21. The method of any one of embodiments 1 to 10, wherein the CD38 antibody is daratumumab.

[0288] 22. A method as described in any one of embodiments 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:43 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:44.

[0289] 23. The method of any one of embodiments 1 to 10, wherein the CD38 antibody is isatuximab.

[0290] 24. A method as described in any one of embodiments 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown as SEQ ID NO:53 and a light chain variable region comprising the amino acid sequence shown as SEQ ID NO:54.

[0291] 25. The method of any of the preceding embodiments, wherein the patient has previously been treated with ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin, doxycycline, daratumumab, autologous transplantation, or a combination thereof.

[0292] 26. The method of any one of the preceding embodiments, wherein the patient has not responded to bortezomib therapy.

[0293] 27. The method of any one of the preceding embodiments, wherein the amyloid light chain antibody and the CD38 antibody are administered to the patient by intravenous infusion two days apart.

[0294] 28. A method as described in embodiment 27, wherein the amyloid light chain antibody is administered first.

[0295] 29. The method of embodiment 27, wherein the CD38 antibody is administered first.

[0296] 30. The method of any of the preceding embodiments, wherein the patient achieves a higher VGPR after treatment relative to patients receiving the CD38 antibody alone.

[0297] 31. The method of any of the preceding embodiments, wherein the patient achieves a hematological response in a shorter time after treatment relative to a patient receiving the CD38 antibody alone.

[0298] 32. The method of any of the preceding embodiments, wherein the patient achieves a cardiac response in a shorter time after treatment relative to a patient receiving the CD38 antibody alone.

[0299] 33. The method of any one of the preceding embodiments, wherein the patient achieves a greater reduction in NT-proBNP following treatment relative to a patient receiving the CD38 antibody alone.

[0300] 34. A method as described in any of the preceding embodiments, wherein the dose 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 weekly to about quarterly.

[0301] 35. The method of any one of the preceding embodiments, wherein the effective dose of the amyloid light chain antibody is administered as a formulation comprising:

[0302] a) the amyloid light chain antibody at a concentration of about 50 mg / mL;

[0303] b) a histidine buffer having a concentration of about 25 mM;

[0304] c) trehalose at a concentration of about 230 mM;

[0305] d) polysorbate 20 at a concentration of about 0.2 g / L; and

[0306] The pH is about 6.5.

[0307] 36. A method as described in any of the preceding embodiments, wherein the amyloid light chain antibody or the CD38 antibody is Fab, Fab', F(ab')2, F(ab)c, Dab, nanobody or Fv.

[0308] 37. A method as described in embodiment 35, wherein the dose of the amyloid light chain antibody is administered intravenously after transferring a certain amount of formulation required for the dose from a vial to an intravenous bag containing a fluid.

[0309] 38. A method as described in any of the preceding embodiments, wherein the dose of the amyloid light chain is about 24 mg / kg and the antibody is administered intravenously once every 28 days.

[0310] 39. The method of any one of the preceding embodiments, wherein the duration of treatment is at least 9 months.

[0311] 40. The method of embodiment 36, wherein the duration of treatment is at least 12 months.

[0312] 41. The method of any one of the preceding embodiments, wherein the patient exhibits an improvement in VGPR of greater than 85% after treatment.

[0313] 42. The method of embodiment 41, wherein the improvement is at least 88%.

[0314] 43. The method of any one of the preceding embodiments, wherein the patient exhibits an improved hematological response within less than 60 days after treatment.

[0315] 44. The method of embodiment 43, wherein the patient shows improvement in less than 45 days.

[0316] 45. The method of embodiment 43, wherein the patient shows improvement in 33 days or less.

[0317] 46. ​​The method of any one of the preceding embodiments, wherein the patient's NT-proBNP level is reduced by at least 55% after treatment.

[0318] 47. The method of embodiment 46, wherein the NT-proBNP level is reduced by at least 65%.

[0319] 48. The method of embodiment 46, wherein the NT-proBNP level is reduced by 74% or more.

[0320] 49. The method of any one of the preceding embodiments, wherein the patient has not received treatment prior to receiving the amyloid light chain antibody or CD38 antibody.

[0321] 50. A method for treating plasma cell dyscrasia in a patient, wherein the patient is treated with a combination therapy of an amyloid light chain antibody and an antibody to CD38 prior to receiving plasma cell therapy.

[0322] 51. The method of embodiment 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, plasmacytoma.

[0323] 52. The method of embodiment 51, wherein the plasma cell dyscrasia has led to AL amyloidosis in the patient.

[0324] 53. The method of any one of embodiments 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.

[0325] 54. The method of any one of embodiments 50 to 53, wherein the combination therapy stabilizes or improves the patient's health, wherein the stabilization or improvement of the patient's health is measured by very good partial response (VGPR) and / or NT-proBNP levels.

[0326] 55. A method as described in embodiment 54, wherein the stabilization or improvement of the patient's health includes stabilization or improvement of the patient's cardiac function prior to receiving the plasma cell therapy.

[0327] 56. The method of any one of embodiments 50 to 55, wherein the patient receives the plasma cell therapy after achieving a decrease in NT-proBNP level relative to the NT-proBNP level before the patient received the combination therapy with the amyloid light chain antibody and the CD38 antibody.

[0328] 57. The method of embodiment 56, wherein the NT-proBNP level is reduced by at least 55%.

[0329] 58. The method of embodiment 56, wherein the NT-proBNP level is reduced by at least 65%.

[0330] 59. The method of embodiment 56, wherein the NT-proBNP level is reduced by 74% or more.

[0331] 60. A method as described in any one of embodiments 50 to 59, wherein the amyloid light chain antibody competes with antibody 2A4 (ATCC Accession No. 9662) or 7D8 (ATCC Accession No. 9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulin, or binds to the same epitope as 11-1F4, and competes with 11-1F4 for binding to kappa (κ) or human lambda (λ) light chain immunoglobulin.

[0332] 61. The method of embodiment 60, wherein the amyloid light chain antibody is a humanized form of 2A4.

[0333] 62. A method as described in any one of embodiments 50 to 61, wherein the amyloid light chain antibody comprises a light chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 3, 4 and 5 and a heavy chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 6, 7 and 8.

[0334] 63. A method as described in embodiment 62, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:1.

[0335] 64. A method as described in any one of embodiments 62 to 63, wherein the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:2.

[0336] 65. A method as described in any one of embodiments 62 to 64, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:1, and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:2.

[0337] 66. A method as described in any one of embodiments 62 to 65, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:11, 12 or 13.

[0338] 67. A method as described in embodiment 66, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:12.

[0339] 68. The method of any one of embodiments 50 to 67, wherein the amyloid light chain antibody is podectes.

[0340] 69. A method as described in any one of embodiments 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown as SEQ ID NO: 14 or 15.

[0341] 70. A method as described in any one of embodiments 50 to 68, wherein the CD38 antibody comprises a light chain variable region comprising the amino acid sequence shown as SEQ ID NO: 17 or 18.

[0342] 71. A method as described in any one of embodiments 50 to 68, wherein the CD38 antibody comprises heavy chain and light chain variable region amino acid sequences as shown in (a) SEQ ID NOs: 14 and 17; (b) SEQ ID NOs: 15 and 18; (c) SEQ ID NOs: 16 and 19; (d) SEQ ID NOs: 43 and 44; (e) SEQ ID NOs: 53 and 54; (f) SEQ ID NOs: 57 and 58; (g) SEQ ID NOs: 59 and 60; (h) SEQ ID NOs: 61 and 62; or (i) SEQ ID NOs: 63 and 64, respectively.

[0343] 72. A method as described in any one of embodiments 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 47, 48 and 49, respectively, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 50, 51 and 52, respectively.

[0344] 73. A method as described in any one of embodiments 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 20, 21 and 22, respectively, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 23, 24 and 25, respectively.

[0345] 74. A method as described in any one of embodiments 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 26, 27 and 28, respectively, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 29, 30 and 31, respectively.

[0346] 75. A method as described in any one of embodiments 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:32, and the light chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:33.

[0347] 76. A method as described in any one of embodiments 50 to 6568, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:34, and the light chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:35.

[0348] 77. A method as described in any one of embodiments 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:36, and the light chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:37.

[0349] 78. A method as described in any one of embodiments 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:38, and the light chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:39.

[0350] 79. The method of any one of embodiments 50 to 78, wherein the CD38 antibody is daratumumab.

[0351] 80. The method of any one of embodiments 50 to 79, wherein the plasma cell therapy is bortezomib.

[0352] 81. A method as described in any one of embodiments 50 to 80, wherein the dose 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 weekly to about quarterly.

[0353] 82. The method of embodiment 81, wherein the dose of the amyloid light chain is about 24 mg / kg and the antibody is administered intravenously once every 28 days.

[0354] 83. The method of any one of embodiments 81 to 82, wherein the dose of the amyloid light chain antibody is administered as a formulation comprising:

[0355] a) the amyloid light chain antibody at a concentration of about 50 mg / mL;

[0356] b) a histidine buffer having a concentration of about 25 mM;

[0357] c) trehalose at a concentration of about 230 mM;

[0358] d) polysorbate 20 at a concentration of about 0.2 g / L; and

[0359] The pH is about 6.5.

[0360] 84. A method as described in embodiment 83, wherein the dose of the amyloid light chain antibody is administered intravenously after transferring a certain amount of formulation required for the dose from a vial to an intravenous bag containing a liquid.

[0361] 85. The method of any one of embodiments 50 to 84, wherein the combination therapy is administered for at least 9 months prior to the plasma cell therapy.

[0362] 86. The method of any one of embodiments 50 to 84, wherein the combination therapy is administered for at least 12 months prior to the plasma cell therapy.

[0363] 87. The method of any one of embodiments 50 to 86, wherein the patient exhibits an improvement in VGPR of greater than 85% following the combination therapy.

[0364] 88. The method of embodiment 87, wherein the improvement in VGPR is at least 88%.

[0365] 89. The method of any one of embodiments 50 to 88, wherein the patient exhibits an improved hematologic response in less than 60 days after treatment with the combination therapy.

[0366] 90. The method of embodiment 89, wherein the patient exhibits an improved hematologic response in less than 45 days after treatment with the combination therapy.

[0367] 91. The method of embodiment 89, wherein the patient exhibits an improved hematologic response between 1 day and 28 days after treatment with the combination therapy.

[0368] 92. The method of embodiment 91, wherein treatment with the plasma cell therapy is initiated at least 28 days after treatment with the combination therapy.

[0369] 93. A combination of an amyloid light chain antibody and a CD38 antibody for use in treating AL amyloidosis.

[0370] 94. A combination for use as described in embodiment 93, wherein the amyloid light chain antibody competes with antibody 2A4 (ATCC Accession No. 9662) for binding to human amyloid A peptide or human kappa or human lambda light chain immunoglobulin, or competes with 11-1F4 for binding to human kappa or human lambda light chain immunoglobulin.

[0371] 95. The combination for use as described in embodiment 94, wherein the amyloid light chain antibody is a humanized form of 2A4.

[0372] 96. A combination for use as described in embodiment 93, wherein the amyloid light chain antibody comprises a light chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 3, 4 and 5 and a heavy chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 6, 7 and 8.

[0373] 97. A combination for use as described in embodiment 96, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:1.

[0374] 98. A combination for use as described in embodiment 96, wherein the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:2.

[0375] 99. A combination for use as described in embodiment 96, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:1, and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:2.

[0376] 100. A combination for use as described in embodiment 93, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:11, 12 or 13.

[0377] 101. The combination for use as described in embodiment 100, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:12.

[0378] 102. The combination for use as described in any one of embodiments 93 to 101, wherein the amyloid light chain antibody is politumab.

[0379] 103. The combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NOs: 14 and 15.

[0380] 104. The combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises a light chain variable region comprising the amino acid sequence shown in SEQ ID NOs: 17 and 18.

[0381] 105. A combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises heavy and light chain variable region amino acid sequences as shown in (a) SEQ ID NOs: 14 and 17; (b) SEQ ID NOs: 15 and 18; (c) SEQ ID NOs: 16 and 19; (d) SEQ ID NOs: 43 and 44; (e) SEQ ID NOs: 53 and 54; (f) SEQ ID NOs: 57 and 58; (g) SEQ ID NOs: 59 and 60; (h) SEQ ID NOs: 61 and 62; or (i) SEQ ID NOs: 63 and 64, respectively.

[0382] 106. A combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 47, 48 and 49, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 50, 51 and 52, respectively.

[0383] 107. A combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 20, 21 and 22, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 23, 24 and 25, respectively.

[0384] 108. A combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 26, 27 and 28, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 29, 30 and 31, respectively.

[0385] 109. A combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:32, and a light chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:33.

[0386] 110. A combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:34, and the light chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:35.

[0387] 111. A combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:36, and the light chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:37.

[0388] 112. A combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:38, and the light chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:39.

[0389] 113. The combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody is daratumumab.

[0390] 114. A combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:43 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:44.

[0391] 115. The combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody is isatuximab.

[0392] 116. A combination for use as described in any one of embodiments 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:53 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:54.

[0393] 117. The combination for use as described in any one of embodiments 93 to 116, wherein the patient has not received treatment prior to receiving treatment with the amyloid light chain antibody or the CD38 antibody.

[0394] 118. A method of improving cardiac function in an AL patient who is unresponsive to treatment with NEOD001, the method comprising adding to the treatment of said patient an effective dosing regimen of a CD38 antibody in combination with NEOD001.

[0395] 119. The method of embodiment 118, wherein the patient's non-response to NEOD001 treatment is determined by the patient's NT-proBNP level during a period of time after NEOD001 treatment being greater than or equal to the patient's NT-proBNP level before NEOD001 treatment.

[0396] 120. The method of embodiment 119, wherein the NT-pro-BNP level is greater than the NT-proBNP level before NEOD001 treatment.

[0397] 121. The method of any one of embodiments 118 to 120, wherein the time period following NEOD001 treatment is at least two months.

[0398] 122. The method of any one of embodiments 118 to 121, wherein the patient received at least two doses of NEOD001 prior to receiving the CD38 antibody.

[0399] 123. The method of any one of embodiments 118 to 121, wherein the patient received at least three doses of NEOD001 prior to receiving the CD38 antibody.

[0400] 124. The method of any one of embodiments 118 to 123, wherein the CD38 antibody is administered after NT-proBNP increases above about 6,000 pg / mL in the patient.

[0401] 125. The method of any one of embodiments 118 to 123, wherein the CD38 antibody is administered after NT-proBNP increases above about 12,000 pg / mL in the patient.

[0402] 126. The method of any one of embodiments 118 to 125, wherein the CD38 antibody is administered after the NT-proBNP level is increased by at least about 100%.

[0403] 127. The method of any one of embodiments 118 to 125, wherein the CD38 antibody is administered after the NT-proBNP level is increased by at least about 200%.

[0404] 128. The method of any one of embodiments 118 to 125, wherein the CD38 antibody is administered after the NT-proBNP level is increased by at least about 300%.

[0405] 129. The method of any one of embodiments 118 to 128, wherein the AL patient has previously received NEOD001 and CyBorD.

[0406] 130. The method of any one of embodiments 118 to 128, wherein the CD38 antibody is daratumumab or isatuximab.

[0407] 131. The method of embodiment 130, wherein the CD38 antibody is daratumumab.

[0408] 132. The method of embodiment 131, wherein daratumumab is administered to the patient at 16 mg / kg every 28 days.

[0409] 133. The method of any one of embodiments 118 to 132, wherein NEOD001 is administered to the patient at 24 mg / kg every 28 days when administered in combination with the CD38 antibody.

[0410] 134. The method of any one of embodiments 118 to 133, wherein the duration of treatment with the CD38 antibody is effective to reduce the patient's NT-proBNP level at least to the level before receiving NEOD001 treatment.

[0411] 135. The method of embodiment 134, wherein the duration is effective to reduce the patient's NT-proBNP level to below the level before receiving NEOD001 treatment.

[0412] 136. The method of embodiment 134, wherein the treatment comprises at least one dose of the CD38 antibody.

[0413] 137. The method of embodiment 134, wherein the treatment comprises at least two doses of the CD38 antibody.

[0414] 138. The method of embodiment 134, wherein the treatment comprises at least three doses of the CD38 antibody.

[0415] 139. The method of embodiment 134, wherein the duration is at least 9 months.

[0416] 140. The method of embodiment 134, wherein the duration is at least 12 months.

[0417] 141. A method as described in any one of embodiments 1 to 48, wherein the patient is treated with a combination of an amyloid light chain antibody and a CD38 antibody prior to receiving plasma cell therapy to stabilize or improve the patient's health.

[0418] 142. The method of embodiment 140, wherein the plasma cell therapy comprises one or more of the following: ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin and / or doxycycline, thereby improving the patient's ability to tolerate the side effects of the plasma cell therapy.

[0419] 143. A method as described in embodiment 141, wherein the stabilization or improvement of the patient's health is measured by VGPR and / or NT-proBNP levels.

[0420] 144. The method of embodiment 141, wherein stabilization or improvement of the patient's health comprises stabilization or improvement of the patient's cardiac function.

[0421] 145. A method as described in embodiment 144, wherein the patient receives the plasma cell therapy after achieving a reduction in NT-proBNP level relative to the NT-proBNP level before the patient received the combination treatment with the amyloid light chain antibody and the CD38 antibody.

[0422] 146. The method of embodiment 145, wherein the reduction in NT-proBNP is at least 55%.

[0423] 147. The method of any one of embodiments 141, wherein the amyloid light chain antibody is podectomomab.

[0424] 148. The method of any one of embodiments 141, wherein the CD38 antibody is daratumumab.

[0425] 149. The method of any one of embodiments 141, wherein the plasma cell therapy is bortezomib.

Claims

1. A method of treating a patient suffering from AL amyloidosis, the method comprising administering to the subject an effective dose of an amyloid light chain antibody in combination with a CD38 antibody.

2. The method of claim 2, wherein the amyloid light chain antibody competes with antibody 2A4 (ATCC Accession No. 9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or human lambda light chain immunoglobulin, or binds to the same epitope as 11-1F4 and competes with 11-1F4 for binding to human kappa or human lambda light chain immunoglobulin.

3. The method of claim 2, wherein the amyloid light chain antibody is a humanized form of 2A4.

4. The method of claim 1, wherein the amyloid light chain antibody comprises a light chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 3, 4 and 5 and a heavy chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 6, 7 and 8. 5 . The method of claim 1 , wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

1.

6. The method of claim 1, wherein the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

2.

7. The method of claim 1, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO: 1, and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

2.

8. The method of claim 1, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO: 11, 12 or 13.

9. The method of claim 8, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO: 10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:

12.

10. The method of claim 8, wherein the amyloid light chain antibody is birtamimab.

11. The method of any of the preceding claims, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 14 or 15.

12. The method of any one of the preceding claims, wherein the CD38 antibody comprises a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 17 or 18.

13. The method of any one of claims 1 to 10, wherein the CD38 antibody comprises heavy and light chain variable region amino acid sequences as shown in (a) SEQ ID NOs: 14 and 17; (b) SEQ ID NOs: 15 and 18; (c) SEQ ID NOs: 16 and 19; (d) SEQ ID NOs: 43 and 44; (e) SEQ ID NOs: 53 and 54; (f) SEQ ID NOs: 57 and 58; (g) SEQ ID NOs: 59 and 60; (h) SEQ ID NOs: 61 and 62; or (i) SEQ ID NOs: 63 and 64, respectively.

14. The method of any one of claims 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown 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 shown in SEQ ID NOs: 50, 51 and 52, respectively.

15. The method of any one of claims 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown 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 shown in SEQ ID NOs: 23, 24 and 25, respectively.

16. The method of any one of claims 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown 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 shown in SEQ ID NOs: 29, 30 and 31, respectively.

17. The method of any one of claims 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO: 32, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

33.

18. The method of any one of claims 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO: 34, and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

35.

19. The method of any one of claims 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO: 36, and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

37.

20. The method of any one of claims 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO: 38, and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

39.

21. The method of any one of claims 1 to 10, wherein the CD38 antibody is daratumumab.

22. The method of any one of claims 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 43 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:

44.

23. The method of any one of claims 1 to 10, wherein the CD38 antibody is isatuximab.

24. The method of any one of claims 1 to 10, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 53 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:

54.

25. The method of any of the preceding claims, wherein the patient has previously been treated with ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin, doxycycline, daratumumab, autologous transplantation, or a combination thereof.

26. The method of any one of the preceding claims, wherein the patient has not responded to bortezomib therapy.

27. The method of any of the preceding claims, wherein the amyloid light chain antibody and the CD38 antibody are administered to the patient by intravenous infusion two days apart.

28. The method of claim 27, wherein the amyloid light chain antibody is administered first.

29. The method of claim 27, wherein the CD38 antibody is administered first.

30. The method of any of the preceding claims, wherein the patient achieves a higher VGPR following treatment relative to patients receiving the CD38 antibody alone.

31. The method of any of the preceding claims, wherein the patient achieves a hematological response in a shorter time after treatment relative to a patient receiving the CD38 antibody alone.

32. The method of any of the preceding claims, wherein the patient achieves a cardiac response in a shorter time after treatment relative to a patient receiving the CD38 antibody alone.

33. The method of any one of the preceding claims, wherein the patient achieves a greater reduction in NT-proBNP following treatment relative to a patient receiving the CD38 antibody alone.

34. The method of any of the preceding claims, wherein the dose 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 weekly to about quarterly.

35. The method of any one of the preceding claims, wherein the effective dose of the amyloid light chain antibody is administered as a formulation comprising: a) the amyloid light chain antibody at a concentration of about 50 mg / mL; b) a histidine buffer having 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; and The pH is about 6.

5.

36. The method of any of the preceding claims, wherein the amyloid light chain antibody or the CD38 antibody is a Fab, Fab', F(ab')2, F(ab)c, Dab, nanobody or Fv.

37. The method of claim 35, wherein the dose of the amyloid light chain antibody is administered intravenously after transferring an amount of the formulation required for the dose from a vial to an intravenous bag containing a fluid.

38. The method of any of the preceding claims, wherein the dose of the amyloid light chain is about 24 mg / kg and the antibody is administered intravenously once every 28 days.

39. The method of any of the preceding claims, wherein the duration of treatment is at least 9 months.

40. The method of claim 36, wherein the duration of treatment is at least 12 months.

41. The method of any of the preceding claims, wherein the patient exhibits an improvement in VGPR of greater than 85% following treatment.

42. The method of claim 41, wherein the improvement is at least 88%.

43. The method of any of the preceding claims, wherein the patient exhibits an improved hematologic response in less than 60 days following treatment.

44. The method of claim 43, wherein the patient shows improvement in less than 45 days.

45. The method of claim 43, wherein the patient shows improvement in 33 days or less.

46. ​​The method of any one of the preceding claims, wherein the patient's NT-proBNP levels are reduced by at least 55% following treatment.

47. The method of claim 46, wherein the NT-proBNP level is reduced by at least 65%.

48. The method of claim 46, wherein the NT-proBNP level is reduced by 74% or more.

49. The method of any of the preceding claims, wherein the patient has not received treatment prior to receiving the amyloid light chain antibody and CD38 antibody.

50. A method for treating plasma cell dyscrasia in a patient, wherein the patient is treated with a combination therapy of an amyloid light chain antibody and an antibody to CD38 prior to receiving plasma cell therapy.

51. The method of claim 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, plasmacytoma.

52. The method of claim 51, wherein the plasma cell dyscrasia has resulted in AL amyloidosis in the patient.

53. The method of any one of claims 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.

54. The method of any one of claims 50 to 53, wherein the combination therapy stabilizes or improves the patient's health, wherein the stabilization or improvement of the patient's health is measured by very good partial response (VGPR) and / or NT-proBNP levels.

55. The method of claim 54, wherein the stabilization or improvement of the patient's health comprises stabilization or improvement of the patient's cardiac function prior to receiving the plasma cell therapy.

56. The method of any one of claims 50 to 55, wherein the patient receives the plasma cell therapy after achieving a decrease in NT-proBNP level relative to the NT-proBNP level before the patient received the combination therapy with an amyloid light chain antibody and a CD38 antibody.

57. The method of claim 56, wherein the NT-proBNP level is reduced by at least 55%.

58. The method of claim 56, wherein the NT-proBNP level is reduced by at least 65%.

59. The method of claim 56, wherein the NT-proBNP level is reduced by 74% or more.

60. A method as described in any one of claims 50 to 59, wherein the amyloid light chain antibody competes with antibody 2A4 (ATCC Accession No. 9662) or 7D8 (ATCC Accession No. 9468) for binding to human amyloid A peptide or human kappa or lambda light chain immunoglobulins, or binds to the same epitope as 11-1F4, and competes with 11-1F4 for binding to human kappa (κ) or human lambda (λ) light chain immunoglobulins.

61. The method of claim 60, wherein the amyloid light chain antibody is a humanized form of 2A4.

62. The method of any one of claims 50 to 61, wherein the amyloid light chain antibody comprises a light chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 3, 4 and 5 and a heavy chain variable region comprising three complementarity determining regions as shown in SEQ ID NOs: 6, 7 and 8.

63. The method of claim 62, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

1.

64. The method of any one of claims 62 to 63, wherein the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

2.

65. The method of any one of claims 62 to 64, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO: 1, and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

2.

66. A method as described in any one of claims 62 to 65, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:11, 12 or 13.

67. The method of claim 66, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:

12.

68. The method of any one of claims 50 to 67, wherein the amyloid light chain antibody is podectomomab.

69. The method of any one of claims 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 14 or 15.

70. The method of any one of claims 50 to 68, wherein the CD38 antibody comprises a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 17 or 18.

71. The method of any one of claims 50 to 68, wherein the CD38 antibody comprises heavy and light chain variable region amino acid sequences as shown in (a) SEQ ID NOs: 14 and 17; (b) SEQ ID NOs: 15 and 18; (c) SEQ ID NOs: 16 and 19; (d) SEQ ID NOs: 43 and 44; (e) SEQ ID NOs: 53 and 54; (f) SEQ ID NOs: 57 and 58; (g) SEQ ID NOs: 59 and 60; (h) SEQ ID NOs: 61 and 62; or (i) SEQ ID NOs: 63 and 64, respectively.

72. The method of any one of claims 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown 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 shown in SEQ ID NOs: 50, 51 and 52, respectively.

73. The method of any one of claims 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown 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 shown in SEQ ID NOs: 23, 24 and 25, respectively.

74. The method of any one of claims 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown 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 shown in SEQ ID NOs: 29, 30 and 31, respectively.

75. The method of any one of claims 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO: 32, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

33.

76. The method of any one of claims 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO: 34, and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

35.

77. The method of any one of claims 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO: 36, and a light chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

37.

78. The method of any one of claims 50 to 68, wherein the CD38 antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO: 38, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

39.

79. The method of any one of claims 50 to 78, wherein the CD38 antibody is daratumumab.

80. The method of any one of claims 50 to 79, wherein the plasma cell therapy is bortezomib.

81. The method of any one of claims 50 to 80, wherein the dose 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 weekly to about quarterly.

82. The method of claim 81, wherein the dose of the amyloid light chain is about 24 mg / kg and the antibody is administered intravenously once every 28 days.

83. The method of any one of claims 81 to 82, wherein the dose of the amyloid light chain antibody is administered as a formulation comprising: a) the amyloid light chain antibody at a concentration of about 50 mg / mL; b) a histidine buffer having 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; and The pH is about 6.

5.

84. The method of claim 83, wherein the dose of the amyloid light chain antibody is administered intravenously after transferring an amount of formulation required for the dose from a vial to an intravenous bag containing a fluid.

85. The method of any one of claims 50 to 84, wherein the combination therapy is administered for at least 9 months prior to the plasma cell therapy.

86. The method of any one of claims 50 to 84, wherein the combination therapy is administered for at least 12 months prior to the plasma cell therapy.

87. The method of any one of claims 50 to 86, wherein the patient exhibits greater than 85% improvement in VGPR following the combination therapy.

88. The method of claim 87, wherein the improvement in VGPR is at least 88%.

89. The method of any one of claims 50 to 88, wherein the patient exhibits an improved hematological response in less than 60 days following treatment with the combination therapy.

90. The method of claim 89, wherein the patient exhibits an improved hematologic response in less than 45 days following treatment with the combination therapy.

91. The method of claim 89, wherein the patient exhibits an improved hematologic response between 1 day and 28 days after treatment with the combination therapy.

92. The method of claim 91, wherein treatment with the plasma cell therapy is initiated at least 28 days after treatment with the combination therapy.

93. A combination of an amyloid light chain antibody and a CD38 antibody for use in treating AL amyloidosis.

94. A combination for use as described in claim 93, wherein the amyloid light chain antibody competes with antibody 2A4 (ATCC Accession No. 9662) for binding to human amyloid A peptide or human kappa or human lambda light chain immunoglobulin, or competes with 11-1F4 for binding to human kappa or human lambda light chain immunoglobulin.

95. A combination for use as described in claim 94, wherein the amyloid light chain antibody is a humanized form of 2A4.

96. A combination for use as described in claim 93, wherein the amyloid light chain antibody comprises a light chain variable region comprising three complementarity determining regions as shown in SEQ ID NO: 3, 4 and 5 and a heavy chain variable region comprising three complementarity determining regions as shown in SEQ ID NO: 6, 7 and 8.

97. A combination for use as described in claim 96, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

1.

98. The combination for use as described in claim 96, wherein the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

2.

99. A combination for use as described in claim 96, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:1, and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

2.

100. The combination for use as described in claim 93, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:11, 12 or 13.

101. The combination for use as described in claim 100, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:

12.

102. The combination for use as claimed in any one of claims 93 to 101, wherein the amyloid light chain antibody is politumab.

103. The combination for use as claimed in any one of claims 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NOs: 14 and 15.

104. The combination for use as claimed in any one of claims 93 to 102, wherein the CD38 antibody comprises a light chain variable region comprising the amino acid sequence shown in SEQ ID NOs: 17 and 18.

105. A combination for use as described in any one of claims 93 to 102, wherein the CD38 antibody comprises the heavy chain and light chain variable region amino acid sequences shown as (a) SEQ ID NOs: 14 and 17; (b) SEQ ID NOs: 15 and 18; (c) SEQ ID NOs: 16 and 19; (d) SEQ ID NOs: 43 and 44; (e) SEQ ID NOs: 53 and 54; (f) SEQ ID NOs: 57 and 58; (g) SEQ ID NOs: 59 and 60; (h) SEQ ID NOs: 61 and 62; or (i) SEQ ID NOs: 63 and 64, respectively.

106. A combination for use as described in any one of claims 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 47, 48 and 49, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 50, 51 and 52, respectively.

107. A combination for use as described in any one of claims 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 20, 21 and 22, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 23, 24 and 25, respectively.

108. A combination for use as described in any one of claims 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 26, 27 and 28, respectively, and the light chain variable region includes CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 29, 30 and 31, respectively.

109. A combination for use as described in any one of claims 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO: 32, and a light chain variable region comprising the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:

33.

110. A combination for use as described in any one of claims 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO: 34, and the light chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:

35.

111. A combination for use as described in any one of claims 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO: 36, and the light chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:

37.

112. A combination for use as described in any one of claims 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO: 38, and the light chain variable region comprises the CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown as SEQ ID NO:

39.

113. The combination for use as claimed in any one of claims 93 to 102, wherein the CD38 antibody is daratumumab.

114. The combination for use as claimed in any one of claims 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:43 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:

44.

115. A combination for use as claimed in any one of claims 93 to 102, wherein the CD38 antibody is isatuximab.

116. The combination for use as claimed in any one of claims 93 to 102, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 53 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:

54.

117. A combination for use as described in any one of claims 93 to 116, wherein the patient has not received treatment prior to receiving treatment with the amyloid light chain antibody or the CD38 antibody.

118. A method of improving cardiac function in an AL patient who is unresponsive to treatment with NEOD001, the method comprising adding to the treatment of said patient an effective dosing regimen of a CD38 antibody in combination with NEOD001.

119. The method of claim 118, wherein the patient's non-response to NEOD001 treatment is determined by the patient's NT-proBNP level during a period of time after NEOD001 treatment being greater than or equal to the patient's NT-proBNP level before NEOD001 treatment.

120. The method of claim 119, wherein the NT-pro-BNP level is greater than the NT-proBNP level before NEOD001 treatment.

121. The method of any one of claims 118 to 120, wherein the time period following NEOD001 treatment is at least two months.

122. The method of any one of claims 118 to 121, wherein the patient received at least two doses of NEOD001 prior to receiving the CD38 antibody.

123. The method of any one of claims 118 to 121, wherein the patient received at least three doses of NEOD001 prior to receiving the CD38 antibody.

124. The method of any one of claims 118 to 123, wherein the CD38 antibody is administered after NT-proBNP increases above about 6,000 pg / mL in the patient.

125. The method of any one of claims 118 to 123, wherein the CD38 antibody is administered after NT-proBNP increases above about 12,000 pg / mL in the patient.

126. The method of any one of claims 118 to 125, wherein the CD38 antibody is administered after the NT-proBNP level has increased by at least about 100%.

127. The method of any one of claims 118 to 125, wherein the CD38 antibody is administered after the NT-proBNP level has increased by at least about 200%.

128. The method of any one of claims 118 to 125, wherein the CD38 antibody is administered after the NT-proBNP level has increased by at least about 300%.

129. The method of any one of claims 118 to 128, wherein the AL patient has previously received NEOD001 and CyBorD.

130. The method of any one of claims 118 to 128, wherein the CD38 antibody is daratumumab or isatuximab.

131. The method of claim 130, wherein the CD38 antibody is daratumumab.

132. The method of claim 131, wherein daratumumab is administered to the patient at 16 mg / kg every 28 days.

133. The method of any one of claims 118 to 132, wherein NEOD001 is administered to the patient at 24 mg / kg every 28 days when administered in combination with the CD38 antibody.

134. The method of any one of claims 118 to 133, wherein the duration of treatment with the CD38 antibody is effective to reduce the patient's NT-proBNP level at least to the level before receiving NEOD001 treatment.

135. The method of claim 134, wherein the duration is effective to reduce the patient's NT-proBNP level to below the level before receiving NEOD001 treatment.

136. The method of claim 134, wherein the treatment comprises at least one dose of the CD38 antibody.

137. The method of claim 134, wherein the treatment comprises at least two doses of the CD38 antibody.

138. The method of claim 134, wherein the treatment comprises at least three doses of the CD38 antibody.

139. The method of claim 134, wherein the duration is at least 9 months.

140. The method of claim 134, wherein the duration is at least 12 months.

141. The method of any one of claims 1 to 48, wherein the patient is treated with a combination of an amyloid light chain antibody and a CD38 antibody prior to receiving plasma cell therapy to stabilize or improve the patient's health.

142. The method of claim 140, wherein the plasma cell therapy comprises one or more of: ixazomib, venetoclax, melphalan, prednisone, dexamethasone, bortezomib, carfilzomib, cyclophosphamide, thalidomide, pomalidomide, lenalidomide, doxorubicin and / or doxycycline, thereby increasing the patient's ability to tolerate the side effects of the plasma cell therapy.

143. The method of claim 141, wherein the stabilization or improvement of the patient's health is measured by VGPR and / or NT-proBNP levels.

144. The method of claim 141, wherein stabilization or improvement of the patient's health comprises stabilization or improvement of the patient's cardiac function.

145. The method of claim 144, wherein the patient receives the plasma cell therapy after achieving a reduction in NT-proBNP relative to the NT-proBNP level before the patient received the combination treatment with the amyloid light chain antibody and the CD38 antibody.

146. The method of claim 145, wherein the reduction in NT-proBNP is at least 55%.

147. The method of any one of claims 141, wherein the amyloid light chain antibody is poretimab.

148. The method of any one of claims 141, wherein the CD38 antibody is daratumumab.

149. The method of any one of claims 141, wherein the plasma cell therapy is bortezomib.

150. A pharmaceutical composition comprising an amyloid light chain antibody and a CD38 antibody.

151. A pharmaceutical composition as described in claim 150, wherein the amyloid light chain antibody competes with antibody 2A4 (ATCC Accession No. 9662) or 7D8 (ATCC Accession No. PTA-9468) for binding to human amyloid A peptide or human kappa or human lambda light chain immunoglobulin, or competes with 11-1F4 for binding to human kappa or human lambda light chain immunoglobulin.

152. The pharmaceutical composition of claim 150 or 151, wherein the amyloid light chain antibody is a humanized form of 2A4.

153. A pharmaceutical composition as described in any one of claims 150-152, wherein the amyloid light chain antibody comprises a light chain variable region comprising three complementarity determining regions as shown in SEQ ID 3, 4 and 5 and a heavy chain variable region comprising three complementarity determining regions as shown in SEQ ID NO:6, 7 and 8.

154. A pharmaceutical composition as described in any one of claims 150-153, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

1.

155. A pharmaceutical composition as described in any one of claims 150-154, wherein the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

2.

156. A pharmaceutical composition as described in any one of claims 150-155, wherein the light chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:1, and the heavy chain variable region of the amyloid light chain antibody comprises the amino acid sequence shown in SEQ ID NO:

2.

157. A pharmaceutical composition as described in any one of claims 150-155, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:11, 12 or 13.

158. A pharmaceutical composition as described in claim 157, wherein the amyloid light chain antibody comprises a light chain comprising the amino acid sequence shown in SEQ ID NO:10 and a heavy chain comprising the amino acid sequence shown in SEQ ID NO:

12.

159. The pharmaceutical composition of claim 150, wherein the amyloid light chain antibody is birtamimab.

160. The pharmaceutical composition of any one of claims 150-159, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 14 or 15.

161. A pharmaceutical composition as described in any one of claims 150-160, wherein the CD38 antibody comprises a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 17 or 18.

162. A pharmaceutical composition as described in any one of claims 150-159, wherein the CD38 antibody comprises heavy chain and light chain variable region amino acid sequences as shown in (a) SEQ ID NOs: 14 and 17; (b) SEQ ID NOs: 15 and 18; (c) SEQ ID NOs: 16 and 19; (d) SEQ ID NOs: 43 and 44; (e) SEQ ID NOs: 53 and 54; (f) SEQ ID NOs: 57 and 58; (g) SEQ ID NOs: 59 and 60; (h) SEQ ID NOs: 61 and 62; or (i) SEQ ID NOs: 63 and 64, respectively.

163. A pharmaceutical composition as described in any one of claims 150-159, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 47, 48 and 49, respectively, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 50, 51 and 52, respectively.

164. A pharmaceutical composition as described in any one of claims 150-159, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 20, 21 and 22, respectively, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 23, 24 and 25, respectively.

165. A pharmaceutical composition as described in any one of claims 150-159, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 26, 27 and 28, respectively, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences comprising the amino acid sequences shown in SEQ ID NOs: 29, 30 and 31, respectively.

166. A pharmaceutical composition as described in any one of claims 150-159, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:32, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

33.

167. A pharmaceutical composition as described in any one of claims 150-159, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:34, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

35.

168. A pharmaceutical composition as described in any one of claims 150-159, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:36, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

37.

169. A pharmaceutical composition as described in any one of claims 150-159, wherein the CD38 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:38, and the light chain variable region comprising CDR1, CDR2 and CDR3 sequences from an antibody comprising the amino acid sequence shown in SEQ ID NO:

39.

170. The pharmaceutical composition of any one of claims 150-159, wherein the CD38 antibody is daratumumab.

171. A pharmaceutical composition as described in any one of claims 150-159, wherein the CD38 antibody comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:43 and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:

44.

172. The pharmaceutical composition of any one of claims 150-159, wherein the CD38 antibody is isatuximab.

173. The pharmaceutical composition of any one of claims 150-172, wherein the pharmaceutical composition further comprises a buffer.

174. The pharmaceutical composition of claim 173, wherein the buffer is a histidine buffer.

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