Treatment of lymphoma

Abstract

The present disclosure provides methods and materials related to treating lymphoma. For example, methods and materials are provided that involve treating lymphoma using albumin-containing nanoparticle / antibody complexes (e.g., / anti-CD20 polypeptide antibody complexes).

Description

[0001] This application is a divisional application of a Chinese patent application with application number 201580031452.9, filing date June 12, 2015, and invention title "Treatment of Lymphoma". The original application is a national phase application of an international application with international application number PCT / US2015 / 035505, which claims the priority of a US application with application date June 13, 2014 and application number 62 / 012,190. The disclosure of this US application is considered to be part of the disclosure of this application (and is incorporated herein by reference). Background Art 1. Technical Field

[0003] This document relates to methods and materials involved in the treatment of lymphoma (e.g., mature B-cell malignancies, mature T-cell malignancies, mature natural killer cell malignancies, immunodeficiency-related lymphoproliferative diseases, Hodgkin lymphoma, and non-Hodgkin lymphoma). For example, this document relates to methods and materials involved in the treatment of lymphoma using a complex containing albumin nanoparticles (e.g., nanoparticles) and an antibody (e.g., an anti-CD20 polypeptide antibody such as rituximab).

[0004] 2. Background Information

[0005] Lymphoma is a blood cancer that occurs when B or T lymphocytes become cancerous. They can develop in lymph nodes, the spleen, bone marrow, blood, or other organs and eventually form tumors. Summary of the Invention

[0006] This document provides methods and materials involved in the treatment of lymphoma (e.g., mature B-cell malignancies, mature T-cell malignancies, mature natural killer cell malignancies, immunodeficiency-related lymphoproliferative diseases, Hodgkin lymphoma, and non-Hodgkin lymphoma). For example, this document provides methods and materials for treating lymphoma using a complex containing albumin nanoparticles (e.g., nanoparticles) and an antibody (e.g., an anti-CD20 polypeptide antibody such as rituximab).

[0007] is available from Celgene Corp. and is a nanoparticle formulation combining paclitaxel with human albumin. Anti-CD20 polypeptide antibodies such as rituximab are available under trade names such as Rituxan TM , MabThera TM and Zytux TMObtained below from Genentech Inc., Roche, and Aryogen Biopharma. Rituximab is a chimeric monoclonal antibody directed against the CD20 polypeptide present on the surface of lymphocytes (see, e.g., U.S. Patent No. 5,736,137).

[0008] As herein, in vitro mixing of albumin-containing nanoparticles (e.g., nanoparticles) and an antibody (e.g., rituximab) can result in the formation of macromolecular complexes, the properties of which (e.g., size, antibody content, or chemotherapeutic drug content) can be customized as needed. In some cases, such macromolecular complexes can retain antibody-mediated target-binding specificity, can retain or exhibit enhanced chemotherapeutic tumor cell cytotoxicity, and can not exhibit additional toxicity beyond that of the nanoparticles alone. Also as herein, contacting with an anti-CD20 polypeptide antibody (e.g., rituximab) prior to administration to a human (e.g., a human lymphoma cancer patient) can produce a complex that, when administered as a complex, has an increased ability to treat lymphoma compared to treatment regimens that include administering the and anti-CD20 polypeptide antibody separately in a manner that does not form / anti-CD20 polypeptide antibody complexes.

[0009] The methods and materials provided herein can be used to increase progression-free survival in lymphoma patients. Increasing progression-free survival can enable lymphoma cancer patients to survive longer.

[0010] Generally, one aspect of the present invention features a method for treating a mammal afflicted with lymphoma. The method comprises or consists essentially of: administering to the mammal, under conditions in which the length of progression-free survival is increased, a composition comprising nanoparticles containing albumin complexed with an anti-CD20 polypeptide antibody and paclitaxel. The mammal can be a human. The lymphoma can be Hodgkin's lymphoma. The composition can comprise rituximab complexed with the nanoparticles. The composition can comprise an alkylating agent complexed with the nanoparticles. The alkylating agent can be a platinum compound. The platinum compound can be carboplatin. The anti-CD20 polypeptide antibody can be a humanized antibody. The anti-CD20 polypeptide antibody can be a chimeric antibody. The composition can be administered by injection. The progression-free survival can be increased by 15%. The progression-free survival can be increased by 25%. The progression-free survival can be increased by 50%. The progression-free survival can be increased by 75%. The progression-free survival can be increased by 100%. The composition can be administered under conditions in which the time to progression is increased.

[0011] In another aspect, the present disclosure features a method for treating a mammal afflicted with lymphoma. The method comprises or consists essentially of: administering to the mammal a composition comprising an albumin-containing nanoparticle / antibody complex, wherein the complex has an average diameter between 0.1 and 0.9 μm, and wherein the antibody is an anti-CD20 antibody. The mammal can be a human. The lymphoma can be a mature B-cell malignancy. The lymphoma can be a mature T-cell malignancy. The lymphoma can be Hodgkin lymphoma. The albumin-containing nanoparticle / antibody complex can be / rituximab complex. The composition or the albumin-containing nanoparticle / antibody complex can comprise an alkylating agent. The alkylating agent can be a platinum compound. The platinum compound can be carboplatin. The composition can comprise an anti-inflammatory agent. The anti-CD20 polypeptide antibody can be a humanized antibody. The anti-CD20 polypeptide antibody can be a chimeric antibody. The composition can be administered by injection. Administration of the composition can effectively increase the progression-free survival by 25%. Administration of the composition can effectively increase the progression-free survival by 50%. Administration of the composition can effectively increase the progression-free survival by 75%. Administration of the composition can effectively increase the progression-free survival by 100%. Administration of the composition can be carried out under the condition that the median progression time of the population of mammals afflicted with lymphoma is at least 150 days. Administration of the composition can be carried out under the condition that the median progression time of the population of mammals afflicted with lymphoma is at least 165 days. Administration of the composition can be carried out under the condition that the median progression time of the population of mammals afflicted with lymphoma is at least 170 days. The average diameter of the complex can be from 0.1 to 0.3 μm. The average diameter of the complex can be from 0.15 to 0.3 μm. The average diameter of the complex can be from 0.2 to 0.5 μm. The average diameter of the complex can be from 0.3 to 0.5 μm. The average diameter of the complex can be from 0.2 to 0.8 μm. The average diameter of the complex can be from 0.2 to 0.7 μm.

[0012] In another aspect, the present document features a method for treating a mammal afflicted with lymphoma. The method comprises or consists essentially of: administering to the mammal a composition comprising an albumin-containing nanoparticle / antibody complex, wherein at least 5% of the complexes in the composition have an average diameter between 0.1 and 0.9 μm, and wherein the antibody is an anti-CD20 antibody. The mammal can be a human. The lymphoma can be a mature B-cell malignancy. The lymphoma can be a mature T-cell malignancy. The lymphoma can be Hodgkin lymphoma. The albumin-containing nanoparticle / antibody complex can be / Rituximab complex. The composition or albumin nanoparticle / antibody complex may comprise an alkylating agent. The alkylating agent may be a platinum compound. The platinum compound may be carboplatin. The composition may comprise an anti-inflammatory agent. The anti-CD20 polypeptide antibody may be a humanized antibody. The anti-CD20 polypeptide antibody may be a chimeric antibody. The composition may be administered by injection. Administration of the composition may effectively increase the progression-free survival by 25%. Administration of the composition may effectively increase the progression-free survival by 50%. Administration of the composition may effectively increase the progression-free survival by 75%. Administration of the composition may effectively increase the progression-free survival by 100%. Administration of the composition may be carried out under the condition that the median progression time in a mammalian population with lymphoma is at least 150 days. Administration of the composition may be carried out under the condition that the median progression time in a mammalian population with lymphoma is at least 165 days. Administration of the composition may be carried out under the condition that the median progression time in a mammalian population with lymphoma is at least 170 days. The average diameter of at least 5% of the complexes of the composition may be 0.2 to 0.9 μm. The average diameter of at least 5% of the complexes of the composition may be 0.2 to 0.8 μm. The average diameter of at least 5% of the complexes of the composition may be 0.2 to 0.7 μm. The average diameter of at least 5% of the complexes of the composition may be 0.2 to 0.6 μm. The average diameter of at least 5% of the complexes of the composition may be 0.2 to 0.5 μm. The average diameter of at least 5% of the complexes of the composition may be 0.2 to 0.4 μm. The average diameter of at least 10% of the complexes of the composition may be between 0.1 and 0.9 μm. The average diameter of at least 50% of the complexes of the composition may be between 0.1 and 0.9 μm. The average diameter of at least 75% of the complexes of the composition may be between 0.1 and 0.9 μm. The average diameter of at least 90% of the complexes of the composition may be between 0.1 and 0.9 μm.

[0013] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used to practice the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0014] Details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. Brief Description of the Drawings

[0015] Figure 1 is a graph depicting the particle size distribution of ABX dissolved in Rituxan (RIT) as measured using a Mastersizer 2000E (Malvern Instruments Ltd., Worcestershire, England). ABX (10 mg / mL) was reduced to 1 mL of the indicated amount of RIT, and the mixture was incubated at room temperature for 30 minutes. (ABX) in 1 mL of the indicated amount of RIT, and the mixture was incubated at room temperature for 30 minutes.

[0016] Figure 2 is a graph depicting the percent change in tumor size from baseline in nude mice bearing lymphoma (Daudi cell line) tumors treated with PBS, Rituxan only (RIT; 12 mg / kg), only (30 mg / kg), Rituxan (RIT; 12 mg / kg) followed by (30 mg / kg) one day later, or an AR160 complex (0.159 μm; where (10 mg / mL) was premixed with 2 mg / mL Rituxan and incubated for 60 minutes prior to injection) over 7 days.

[0017] Figure 3 is a graph depicting the survival rate of nude mice bearing lymphoma (Daudi cell line) tumors treated with PBS, Rituxan only (RIT; 12 mg / kg), only (30 mg / kg), Rituxan (RIT; 12 mg / kg) followed by (30 mg / kg) one day later, or an AR160 complex (0.159 μm; where (10 mg / mL) was premixed with 2 mg / mL Rituxan and incubated for 60 minutes prior to injection) over 7 days. DETAILED DESCRIPTION

[0018] Methods and materials are provided herein for treating lymphoma (e.g., mature B-cell malignancies, mature T-cell malignancies, mature natural killer cell malignancies, immunodeficiency-associated lymphoproliferative diseases, Hodgkin lymphoma, and non-Hodgkin lymphoma). For example, methods and materials are provided herein for treating lymphoma using a complex comprising albumin-containing nanoparticles (e.g., nanoparticles) and an antibody (e.g., an anti-CD20 polypeptide antibody such as rituximab).

[0019] The methods and materials provided herein can be used to treat any type of lymphoma. For example, the methods and materials provided herein can be used to treat mature B-cell malignancies, mature T-cell malignancies, mature natural killer cell malignancies, immunodeficiency-associated lymphoproliferative disorders, Hodgkin lymphoma, or non-Hodgkin lymphoma. In some cases, the methods and materials provided herein can be used to treat any type of mammal, including but not limited to, mice, rats, dogs, cats, horses, cows, pigs, monkeys, and humans with lymphoma.

[0020] In some cases, a complex containing albumin nanoparticles (e.g., nanoparticles) and an antibody (e.g., an anti-CD20 polypeptide antibody such as rituximab) can be designed to have an average diameter greater than 1 μm. For example, an appropriate concentration of albumin nanoparticles and an antibody can be used such that a complex with an average diameter greater than 1 μm is formed. In some cases, procedures such as centrifugation can be used to form a formulation of albumin nanoparticle / antibody complexes, wherein the average diameter of those complexes is greater than 1 μm. In some cases, the formulations of albumin nanoparticle / antibody complexes provided herein can have an average diameter between 1 μm and 5 μm (e.g., between 1.1 μm and 5 μm, between 1.5 μm and 5 μm, between 2 μm and 5 μm, between 2.5 μm and 5 μm, between 3 μm and 5 μm, between 3.5 μm and 5 μm, between 4 μm and 5 μm, between 4.5 μm and 5 μm, between 1.1 μm and 4.5 μm, between 1.1 μm and 4 μm, between 1.1 μm and 3.5 μm, between 1.1 μm and 3 μm, between 1.1 μm and 2.5 μm, between 1.1 μm and 2 μm, or between 1.1 μm and 1.5 μm). The formulations of albumin nanoparticle / antibody complexes provided herein having an average diameter between 1 μm and 5 μm can be administered systemically (e.g., intravenously) to treat lymphoma located within a mammal. In some cases, the formulations of albumin nanoparticle / antibody complexes provided herein can have an average diameter between 5 μm and 50 μm (e.g., between 6 μm and 50 μm, between 7 μm and 50 μm, between 10 μm and 50 μm, between 15 μm and 50 μm, between 20 μm and 50 μm, between 25 μm and 50 μm, between 30 μm and 50 μm, between 35 μm and 50 μm, between 5 μm and 45 μm, between 5 μm and 40 μm, between 5 μm and 35 μm, between 5 μm and 30 μm, between 5 μm and 25 μm, between 5 μm and 20 μm, between 5 μm and 15 μm, or between 10 μm and 30). The formulations of albumin nanoparticle / antibody complexes provided herein having an average diameter between 5 μm and 50 μm can be administered into a tumor (e.g., intratumorally) or into the area of a tumor located within a mammal.

[0021] In some cases, the formulations of albumin nanoparticle / antibody complexes provided herein can have greater than 60% (e.g., greater than 65%, 70%, 75%, 80%, 90%, 95%, or 99%) of the complexes having a diameter between 1 μm and 5 μm (e.g., between 1.1 μm and 5 μm, between 1.5 μm and 5 μm, between 2 μm and 5 μm, between 2.5 μm and 5 μm, between 3 μm and 5 μm, between 3.5 μm and 5 μm, between 4 μm and 5 μm, between 4.5 μm and 5 μm, between 1.1 μm and 4.5 μm, between 1.1 μm and 4 μm, between 1.1 μm and 3.5 μm, between 1.1 μm and 3 μm, between 1.1 μm and 2.5 μm, between 1.1 μm and 2 μm, or between 1.1 μm and 1.5 μm). The formulations of albumin nanoparticle / antibody complexes provided herein having greater than 60% (e.g., greater than 65%, 70%, 75%, 80%, 90%, 95%, or 99%) of the complexes having a diameter between 1 μm and 5 μm can be administered systemically (e.g., intravenously) to treat lymphoma located within a mammalian body. In some cases, the formulations of albumin nanoparticle / antibody complexes provided herein can have greater than 60% (e.g., greater than 65%, 70%, 75%, 80%, 90%, 95%, or 99%) of the complexes having a diameter between 5 μm and 50 μm (e.g., between 6 μm and 50 μm, between 7 μm and 50 μm, between 10 μm and 50 μm, between 15 μm and 50 μm, between 20 μm and 50 μm, between 25 μm and 50 μm, between 30 μm and 50 μm, between 35 μm and 50 μm, between 5 μm and 45 μm, between 5 μm and 40 μm, between 5 μm and 35 μm, between 5 μm and 30 μm, between 5 μm and 25 μm, between 5 μm and 20 μm, between 5 μm and 15 μm, or between 10 μm and 30 μm). The formulations of albumin nanoparticle / antibody complexes provided herein having greater than 60% (e.g., greater than 65%, 70%, 75%, 80%, 90%, 95%, or 99%) of the complexes having a diameter between 5 μm and 50 μm can be administered into a tumor (e.g., intratumorally) or into the tumor region located within a mammalian body.

[0022] In some cases, containing albumin nanoparticles (e.g., Complexes of nanoparticles) and antibodies (e.g., anti-CD20 polypeptide antibodies such as rituximab) can be designed to have an average diameter of less than 1 μm. For example, appropriate concentrations of albumin-containing nanoparticles and antibodies (e.g., rituximab) can be used such that complexes with an average diameter of less than 1 μm are formed. In some cases, formulations of the albumin-containing nanoparticle / antibody complexes provided herein can have an average diameter between 0.1 μm and 1 μm (e.g., between 0.1 μm and 0.95 μm, between 0.1 μm and 0.9 μm, between 0.1 μm and 0.8 μm, between 0.1 μm and 0.7 μm, between 0.1 μm and 0.6 μm, between 0.1 μm and 0.5 μm, between 0.1 μm and 0.4 μm, between 0.1 μm and 0.3 μm, between 0.1 μm and 0.2 μm, between 0.2 μm and 1 μm, between 0.3 μm and 1 μm, between 0.4 μm and 1 μm, between 0.5 μm and 1 μm, between 0.2 μm and 0.6 μm, between 0.3 μm and 0.6 μm, between 0.2 μm and 0.5 μm, or between 0.3 μm and 0.5 μm). Formulations of the albumin-containing nanoparticle / antibody complexes provided herein having an average diameter between 0.1 μm and 0.9 μm can be administered systemically (e.g., intravenously) to treat lymphoma located within a mammalian body.

[0023] In some cases, formulations of the albumin-containing nanoparticle / antibody complexes provided herein can have greater than 60% (e.g., more than 65%, 70%, 75%, 80%, 90%, 95%, or 99%) of the complexes having a diameter between 0.1 μm and 0.9 μm (e.g., between 0.1 μm and 0.95 μm, between 0.1 μm and 0.9 μm, between 0.1 μm and 0.8 μm, between 0.1 μm and 0.7 μm, between 0.1 μm and 0.6 μm, between 0.1 μm and 0.5 μm, between 0.1 μm and 0.4 μm, between 0.1 μm and 0.3 μm, between 0.1 μm and 0.2 μm, between 0.2 μm and 1 μm, between 0.3 μm and 1 μm, between 0.4 μm and 1 μm, between 0.5 μm and 1 μm, between 0.2 μm and 0.6 μm, between 0.3 μm and 0.6 μm, between 0.2 μm and 0.5 μm, or between 0.3 μm and 0.5 μm). Formulations of the albumin-containing nanoparticle / antibody complexes provided herein having more than 60% (e.g., more than 65%, 70%, 75%, 80%, 90%, 95%, or 99%) of the complexes having a diameter between 0.1 μm and 0.9 μm can be administered systemically (e.g., intravenously) to treat cancer located within a mammalian body.

[0024] Generally, albumin-containing nanoparticles such as Contact with an antibody such as an anti-CD20 polypeptide antibody (e.g., rituximab) to form an albumin nanoparticle / antibody complex (e.g., nanoparticle / anti-CD20 polypeptide antibody complex). As described herein, any suitable albumin nanoparticle formulation and any suitable antibody can be used. For example, as described herein, nanoparticles can be used. Examples of antibodies that can be used to form albumin nanoparticle / antibody complexes as described herein include but are not limited to rituximab (e.g., Rituxan TM , MabThera TM , or Zytux TM ). For example, an appropriate dose of and a suitable dose of rituximab can be mixed together in the same container. The mixture can be incubated at a suitable temperature (e.g., room temperature, between 15 and 30 °C, between 15 and 25 °C, between 20 and 30 °C, or between 20 and 25 °C) for a period of time (e.g., about 30 minutes, or between about 5 and 60 minutes, between about 5 and 45 minutes, between about 15 and 60 minutes, between about 15 and 45 minutes, between about 20 and 400 minutes, or between about 25 and 35 minutes) before being administered to a cancer patient (e.g., a lymphoma patient). In some cases, can be contacted with an anti-CD20 polypeptide antibody by injecting both and the anti-CD20 polypeptide antibody either separately or as a pre-mixed combination into an IV bag containing an IV bag solution. The contents of the IV bag comprising / anti-CD20 polypeptide antibody complex can be introduced into the patient to be treated.

[0025] In some cases, albumin nanoparticles such as can be contacted with an antibody such as an anti-CD20 polypeptide antibody (e.g., rituximab) to form an albumin nanoparticle / antibody complex (e.g., / anti-CD20 polypeptide antibody complex) that is stored before being administered to a cancer patient (e.g., a lymphoma patient). For example, a composition comprising an albumin nanoparticle / antibody complex can be formed as described herein and stored for a period of time (e.g., several days or weeks) before being administered to a cancer patient.

[0026] Any suitable method can be used to obtain albumin nanoparticles such as and an antibody such as an anti-CD20 polypeptide antibody. For example, It can be obtained from Celgene Corp. or as described elsewhere (U.S. Patent No. 6,537,579). Rituximab can be obtained from Genentech Corp. or Roche Corp. or as described elsewhere (U.S. Patent No. 5,736,137).

[0027] In some cases, the combination of albumin-containing nanoparticles such as and an antibody such as an anti-CD20 polypeptide antibody can include one or more other agents such as alkylating agents (e.g., platinum compounds). Examples of platinum compounds that can be used as alkylating agents include, but are not limited to, carboplatin cisplatin oxaliplatin and BBR3464. Examples of other agents that can be included in the albumin-containing nanoparticle / antibody complexes provided herein include, but are not limited to, adriamycin, cyclophosphamide, vincristine, prednisone, dexamethasone, cytarabine, methotrexate, thiotepa, ifosfamide, chlorambucil, dacarbazine, bleomycin, campath-B, gemcitabine, revlimid, sirolimus, temsirolimus, bexxar, brentuximab, bendamustine, and etoposide. For example, the albumin-containing nanoparticle / antibody complexes provided herein (e.g., / anti-CD20 polypeptide antibody complex) can include brentuximab, cyclophosphamide, adriamycin, or vincristine as part of the complex.

[0028] Any suitable method can be used to administer the albumin-containing nanoparticle / antibody complexes provided herein (e.g., / anti-CD20 polypeptide antibody complex) to a mammal. For example, a composition containing an albumin-containing nanoparticle / antibody complex such as / anti-CD20 polypeptide antibody complex can be administered by injection (e.g., subcutaneous injection, intramuscular injection, intravenous injection, or intrathecal injection).

[0029] Prior to administering to a mammal a composition comprising an albumin nanoparticle / antibody complex provided herein (e.g., / anti-CD20 polypeptide antibody complex), the mammal can be evaluated to determine whether the mammal has lymphoma. Any suitable method can be used to determine whether the mammal has lymphoma. For example, a mammal (e.g., a human) can be identified as having lymphoma using standard diagnostic techniques. In some cases, a tissue biopsy (e.g., a lymph node tissue sample) can be collected and analyzed to determine whether the mammal has lymphoma.

[0030] After the mammal is determined to have lymphoma, the mammal is administered a composition comprising an albumin nanoparticle / antibody complex provided herein (e.g., / anti-CD20 polypeptide antibody complex). For example, a composition containing / anti-CD20 polypeptide antibody complex can be administered before surgical resection of the tumor or in place of surgical resection of the tumor. In some cases, a composition comprising an albumin nanoparticle / antibody complex provided herein (e.g., / anti-CD20 polypeptide antibody complex) can be administered after resection of the tumor.

[0031] A composition comprising an albumin nanoparticle / antibody complex provided herein (e.g., / anti-CD20 polypeptide antibody complex) can be administered to a mammal in any suitable amount, at any suitable frequency, and for any suitable duration effective to achieve a desired result (e.g., increasing progression-free survival). In some cases, a composition comprising an albumin nanoparticle / antibody complex provided herein (e.g. / anti-CD20 polypeptide antibody complex) can be administered to a mammal having lymphoma to reduce the progression rate of lymphoma by 5%, 10%, 25%, 50%, 75%, 100% or more. For example, the progression rate can be reduced such that no additional cancer progression is detected. Any suitable method can be used to determine whether the progression rate of lymphoma is reduced. For example, the progression rate of lymphoma can be evaluated by imaging the tissue at different time points and determining the amount of cancer cells present. The amount of cancer cells measured in the tissue at different times can be compared to determine the progression rate. After treatment as described herein, the progression rate can be measured again at another time interval. In some cases, the stage of cancer (e.g., lymphoma) after treatment can be determined and compared to the stage before treatment to determine whether the progression rate is reduced.

[0032] In some cases, it can be compared with the median progression-free survival of a corresponding mammal with untreated lymphoma or with a / antibody complex that is not formed (e.g., not formed / anti-CD20 polypeptide antibody complex) compared to the median progression-free survival of a corresponding mammal with lymphoma treated with an antibody (e.g., an anti-CD20 polypeptide antibody), the progression-free survival is increased (e.g., 5%, 10%, 25%, 50%, 75%, 100%, or higher), a composition comprising an albumin nanoparticle / antibody complex provided herein (e.g., / anti-CD20 polypeptide antibody complex) is administered to a mammal having lymphoma. In some cases, a composition comprising an albumin nanoparticle / antibody complex provided herein (e.g., / anti-CD20 polypeptide antibody complex) can be administered to a mammal having lymphoma to increase the progression-free survival by 5%, 10%, 25%, 50%, 75%, 100%, or higher compared to the median progression-free survival of a corresponding mammal with lymphoma that has been treated alone with or an antibody (e.g., an anti-CD20 polypeptide antibody). The progression-free survival can be measured over any length of time (e.g., one month, two months, three months, four months, five months, six months or longer).

[0033] In some cases, a composition comprising an albumin nanoparticle / antibody complex provided herein (e.g. / anti-CD20 polypeptide antibody complex) can be administered to a mammal having lymphoma under conditions where the 8-week progression-free survival rate of the mammalian population is 65% or greater (e.g., 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 79%, 80% or greater) higher than that observed in a comparable mammalian population not receiving a composition comprising an albumin nanoparticle / antibody complex provided herein (e.g., / anti-CD20 polypeptide antibody complex). In some cases, a composition comprising an albumin nanoparticle / antibody complex provided herein (e.g., / anti-CD20 polypeptide antibody complex) can be administered to a mammal having lymphoma under conditions where the median time to progression of the mammalian population is at least 150 days (e.g., at least 155, 160, 163, 165 or 170 days).

[0034] An effective amount of a composition comprising an albumin nanoparticle / antibody complex provided herein (e.g., / anti-CD20 polypeptide antibody complex) can be any amount that reduces the rate of lymphoma progression, increases the progression-free survival, or increases the median time to progression without causing significant toxicity to the mammal. Generally, an effective amount of can be about 50 mg / m2 to about 150 mg / m 2 (e.g., about 80 mg / m 2 ), and an effective amount of an anti-CD20 polypeptide antibody such as rituximab can be from about 5 mg / kg to about 20 mg / kg (e.g., about 10 mg / kg or 375 mg / m 2 ). If a particular mammal fails to respond to a particular amount, then the dosage of the anti-CD20 polypeptide antibody can be increased, e.g., doubled. After receiving the higher concentration, the responsiveness of the mammal to both the treatment and toxic symptoms can be monitored and adjusted accordingly. The effective amount can remain constant or can be increased or decreased proportionally or adjusted in variable dosages depending on the mammal's response to the treatment. Various factors can affect the actual effective amount for a specific application. For example, the frequency of administration, duration of treatment, use of multiple therapeutic agents, route of administration, and severity of the lymphoma may require an increase or decrease in the effective amount actually administered.

[0035] The frequency of administration can be any frequency that reduces the rate of lymphoma progression, increases the rate of progression-free survival, or increases the median time to progression without causing significant toxicity to the mammal. For example, the frequency of administration can be from about once a month to about three times a month, or from about twice a month to about six times a month, or from about once every two months to about three times every two months. The frequency of administration can remain constant or can be variable during the duration of treatment. The course of treatment with a composition containing / anti-CD20 polypeptide antibody complex can include rest periods. For example, a composition containing / anti-CD20 polypeptide antibody complex can be administered over a two-week period, followed by a two-week rest period, and this regimen can be repeated multiple times. As with the effective amount, various factors can affect the actual frequency of administration for a specific application. For example, the effective amount, duration of treatment, use of multiple therapeutic agents, route of administration, and severity of the lymphoma may require an increase or decrease in the frequency of administration.

[0036] The effective duration for administering the compositions provided herein can be any duration that reduces the rate of lymphoma progression, increases the progression-free survival rate, or increases the median time to progression without causing significant toxicity to the mammal. Thus, the effective duration can vary from a few days to weeks, months, or years. Generally, the effective duration for treating lymphoma can be in the range of a few weeks to a few months. In some cases, the effective duration can be as long as the survival of the individual mammal. Multiple factors can affect the actual effective duration for a specific treatment. For example, the effective duration can vary with the frequency of administration, effective amount, use of multiple therapeutic agents, route of administration, and severity of the lymphoma.

[0037] Compositions comprising the albumin-containing nanoparticle / antibody complexes provided herein (e.g., / anti-CD20 polypeptide antibody complexes) can be in any suitable form. For example, the compositions provided herein can be in the form of a solution or powder, with or without a diluent, to prepare an injectable suspension. The composition can also contain other ingredients, including but not limited to pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers can be, for example, saline, water, lactic acid, mannitol, or combinations thereof.

[0038] After administering the compositions provided herein to a mammal, the mammal can be monitored to determine if the lymphoma has been treated. For example, the mammal can be evaluated after treatment to determine if the rate of progression of the lymphoma has decreased (e.g., stopped). As described herein, any method can be used to evaluate progression and survival.

[0039] In some cases, as in the method set forth in Example 3, the formulation of the / Rituxan complex described in Example 1 can be administered to human lymphoma patients.

[0040] In some cases, albumin-containing nanoparticles (e.g., nanoparticles with an albumin shell) and a reagent other than paclitaxel can be used to replace or in combination with as described herein. For example, albumin-containing nanoparticles designed to carry a cancer chemotherapeutic agent can be used to form nanoparticle / anti-CD20 polypeptide antibody complexes that can be used as described herein. Examples of such cancer chemotherapeutic agents include but are not limited to vinblastine.

[0041] In some cases, the composition can be formulated to include albumin-containing nanoparticles (e.g., nanoparticles with an albumin shell) that bind to an antibody, a reagent, or a combination of an antibody and a reagent to form a complex for treating lymphoma. For example, albumin nanoparticles can be formulated to include doxorubicin, cyclophosphamide, vincristine, prednisone, dexamethasone, cytarabine, methotrexate, thiotepa, ifosfamide, chlorambucil, dacarbazine, bleomycin, alemtuzumab-B, gemcitabine, lenalidomide, sirolimus, temsirolimus, bexarotene, ceritinib, bendamustine, etoposide, or combinations thereof, with or without rituximab.

[0042] In certain cases, albumin-containing nanoparticles (e.g., nanoparticles with an albumin shell) or the complexes described herein (e.g., / rituximab complex) with one or more anti - chronic inflammation therapeutic agents designed to reduce the global state of immune dysfunction and / or chronic inflammation present in cancer patients. For example, steroidal anti - inflammatory agents (e.g., prednisone), non - steroidal anti - inflammatory agents (e.g., naproxen), lymphodepleting cytotoxic agents (e.g., cyclophosphamide), immune cell - and / or cytokine - targeting antibodies (e.g., infliximab) or combinations thereof can be incorporated into the albumin - containing nanoparticles or / rituximab complex. In some cases, anti - IL - 4 agents (e.g., anti - IL - 4 antibodies), anti - IL - 13 agents (e.g., soluble IL - 13 receptor) and combinations thereof can be incorporated into the albumin - containing nanoparticles or / rituximab complex.

[0043] Any suitable method can be used to evaluate whether the global state of immune dysfunction and / or chronic inflammation is reduced after anti - chronic inflammation treatment. For example, the cytokine profile present in the blood (e.g., IL - 4, IL - 13, IL - 4, IL - 13, IL - 5, IL - 10, IL - 2 and interferon - γ) can be evaluated before or after anti - chronic inflammation treatment to determine whether the global state of immune dysfunction and / or chronic inflammation is reduced.

[0044] Embodiments of various aspects provided by the present invention are also described by any one of the following paragraphs.

[0045] Embodiment 1. A method for treating a mammal having lymphoma, the method comprising administering to the mammal a composition comprising nanoparticles containing albumin and paclitaxel complexed with an anti - CD20 polypeptide antibody under conditions where the length of the progression - free survival is increased.

[0046] Embodiment 2. The method according to Embodiment 1, wherein the mammal is a human.

[0047] Embodiment 3. The method according to Embodiment 1, wherein the lymphoma is Hodgkin lymphoma.

[0048] Embodiment 4. The method according to Embodiment 1, wherein the composition comprises rituximab complexed with the nanoparticles.

[0049] Embodiment 5. The method according to Embodiment 1, wherein the composition comprises an alkylating agent complexed with the nanoparticles.

[0050] Embodiment 6. The method according to Embodiment 5, wherein the alkylating agent is a platinum compound.

[0051] Embodiment 7. The method according to embodiment 6, wherein the platinum compound is carboplatin.

[0052] Embodiment 8. The method according to embodiment 1, wherein the anti-CD20 polypeptide antibody is a humanized antibody.

[0053] Embodiment 9. The method according to embodiment 1, wherein the anti-CD20 polypeptide antibody is a chimeric antibody.

[0054] Embodiment 10. The method according to embodiment 1, wherein the composition is administered by injection.

[0055] Embodiment 11. The method according to embodiment 1, wherein the progression-free survival is increased by 15%.

[0056] Embodiment 12. The method according to embodiment 1, wherein the progression-free survival is increased by 25%.

[0057] Embodiment 13. The method according to embodiment 1, wherein the progression-free survival is increased by 50%.

[0058] Embodiment 14. The method according to embodiment 1, wherein the progression-free survival is increased by 75%.

[0059] Embodiment 15. The method according to embodiment 1, wherein the progression-free survival is increased by 100%.

[0060] Embodiment 16. The method according to embodiment 1, wherein the composition is administered under conditions in which the time to progression is increased.

[0061] Embodiment 17. A method for treating a mammal having lymphoma, wherein the method comprises administering to the mammal a composition comprising an albumin nanoparticle / antibody complex, wherein the average diameter of the complex is from 0.1 to 0.9 μm, and wherein the antibody is an anti-CD20 antibody.

[0062] Embodiment 18. The method according to embodiment 17, wherein the mammal is a human.

[0063] Embodiment 19. The method according to embodiment 17, wherein the lymphoma is a mature B-cell malignancy.

[0064] Embodiment 20. The method according to embodiment 17, wherein the lymphoma is a mature T-cell malignancy.

[0065] Embodiment 21. The method according to embodiment 17, wherein the lymphoma is Hodgkin lymphoma.

[0066] Embodiment 22. The method according to embodiment 17, wherein the albumin nanoparticle / antibody complex is / rituximab complex.

[0067] Embodiment 23. The method according to embodiment 17, wherein the composition or the albumin nanoparticle / antibody complex comprises an alkylating agent.

[0068] Embodiment 24. The method according to embodiment 23, wherein the alkylating agent is a platinum compound.

[0069] Embodiment 25. The method according to embodiment 24, wherein the platinum compound is carboplatin.

[0070] Embodiment 26. The method according to embodiment 17, wherein the composition comprises an anti-inflammatory agent.

[0071] Embodiment 27. The method according to embodiment 17, wherein the anti-CD20 polypeptide antibody is a humanized antibody.

[0072] Embodiment 28. The method according to embodiment 17, wherein the anti-CD20 polypeptide antibody is a chimeric antibody.

[0073] Embodiment 29. The method according to embodiment 17, wherein the composition is administered by injection.

[0074] Embodiment 30. The method according to embodiment 17, wherein the administration of the composition effectively increases the progression-free survival by 25%.

[0075] Embodiment 31. The method according to embodiment 17, wherein the administration of the composition effectively increases the progression-free survival by 50%.

[0076] Embodiment 32. The method according to embodiment 17, wherein the administration of the composition effectively increases the progression-free survival by 75%.

[0077] Embodiment 33. The method according to embodiment 17, wherein the administration of the composition effectively increases the progression-free survival by 100%.

[0078] Embodiment 34. The method according to embodiment 17, wherein the administration of the composition is under the condition that the median progression time of a population of mammals having the lymphoma is at least 150 days.

[0079] Embodiment 35. The method according to embodiment 17, wherein the administration of the composition is under the condition that the median progression time of a population of mammals having the lymphoma is at least 165 days.

[0080] Embodiment 36. The method according to embodiment 17, wherein the administration of the composition is under the condition that the median progression time of a population of mammals having the lymphoma is at least 170 days.

[0081] Embodiment 37. The method according to embodiment 17, wherein the average diameter of the complex is from 0.1 μm to 0.3 μm.

[0082] Embodiment 38. The method according to embodiment 17, wherein the average diameter of the complex is from 0.15 μm to 0.3 μm.

[0083] Embodiment 39. The method according to embodiment 17, wherein the average diameter of the complex is from 0.2 μm to 0.5 μm.

[0084] Embodiment 40. The method according to embodiment 17, wherein the average diameter of the complex is from 0.3 μm to 0.5 μm.

[0085] Embodiment 41. The method according to embodiment 17, wherein the average diameter of the complex is from 0.2 μm to 0.8 μm.

[0086] Embodiment 42. The method according to embodiment 17, wherein the average diameter of the complex is from 0.2 μm to 0.7 μm.

[0087] Embodiment 43. A method for treating a mammal having lymphoma, the method comprising administering to the mammal a composition comprising an albumin nanoparticle / antibody complex, wherein the average diameter of at least 5% of the complexes in the composition is from 0.1 to 0.9 μm, and wherein the antibody is an anti-CD20 antibody.

[0088] Embodiment 44. The method according to embodiment 43, wherein the mammal is a human.

[0089] Embodiment 45. The method according to embodiment 43, wherein the lymphoma is a mature B-cell malignancy.

[0090] Embodiment 46. The method according to embodiment 43, wherein the lymphoma is a mature T-cell malignancy.

[0091] Embodiment 47. The method according to embodiment 43, wherein the lymphoma is Hodgkin lymphoma.

[0092] Embodiment 48. The method according to embodiment 43, wherein the albumin nanoparticle / antibody complex is / rituximab complex.

[0093] Embodiment 49. The method according to embodiment 43, wherein the composition or the albumin nanoparticle / antibody complex comprises an alkylating agent.

[0094] Embodiment 50. The method according to embodiment 49, wherein the alkylating agent is a platinum compound.

[0095] Embodiment 51. The method according to embodiment 50, wherein the platinum compound is carboplatin.

[0096] Embodiment 52. The method according to embodiment 43, wherein the composition comprises an anti-inflammatory agent.

[0097] Embodiment 53. The method according to embodiment 43, wherein the anti-CD20 polypeptide antibody is a humanized antibody.

[0098] Embodiment 54. The method according to embodiment 43, wherein the anti-CD20 polypeptide antibody is a chimeric antibody.

[0099] Embodiment 55. The method according to embodiment 43, wherein the composition is administered by injection.

[0100] Embodiment 56. The method according to embodiment 43, wherein the administration of the composition effectively increases the progression-free survival by 25%.

[0101] Embodiment 57. The method according to embodiment 43, wherein the administration of the composition effectively increases the progression-free survival by 50%.

[0102] Embodiment 58. The method according to embodiment 43, wherein the administration of the composition effectively increases the progression-free survival by 75%.

[0103] Embodiment 59. The method according to embodiment 43, wherein the administration of the composition effectively increases the progression-free survival by 100%.

[0104] Embodiment 60. The method according to embodiment 43, wherein the administration of the composition is under the condition that the median progression time of a population of mammals having the lymphoma is at least 150 days.

[0105] Embodiment 61. The method according to embodiment 43, wherein the administration of the composition is carried out under the condition that the median progression time of a population of mammals having the lymphoma is at least 165 days.

[0106] Embodiment 62. The method according to embodiment 43, wherein the administration of the composition is carried out under the condition that the median progression time of a population of mammals having the lymphoma is at least 170 days.

[0107] Embodiment 63. The method according to embodiment 43, wherein the average diameter of at least 5% of the complexes of the composition is from 0.2 μm to 0.9 μm.

[0108] Embodiment 64. The method according to embodiment 43, wherein the average diameter of at least 5% of the complexes of the composition is from 0.2 μm to 0.8 μm.

[0109] Embodiment 65. The method according to embodiment 43, wherein the average diameter of at least 5% of the complexes of the composition is from 0.2 μm to 0.7 μm.

[0110] Embodiment 66. The method according to embodiment 43, wherein the average diameter of at least 5% of the complexes of the composition is from 0.2 μm to 0.6 μm.

[0111] Embodiment 67. The method according to embodiment 43, wherein the average diameter of at least 5% of the complexes of the composition is from 0.2 μm to 0.5 μm.

[0112] Embodiment 68. The method according to embodiment 43, wherein the average diameter of at least 5% of the complexes of the composition is from 0.2 μm to 0.4 μm.

[0113] Embodiment 69. The method according to embodiment 43, wherein the average diameter of at least 10% of the complexes of the composition is from 0.1 to 0.9 μm.

[0114] Embodiment 70. The method according to embodiment 43, wherein the average diameter of at least 50% of the complexes of the composition is from 0.1 to 0.9 μm.

[0115] Embodiment 71. The method according to embodiment 43, wherein the average diameter of at least 75% of the complexes of the composition is from 0.1 to 0.9 μm.

[0116] Embodiment 72. The method according to embodiment 43, wherein the average diameter of at least 90% of the complexes in the composition is from 0.1 to 0.9 μm.

[0117] The present invention will be further described in the following examples, which do not limit the scope of the present invention described in the claims.

[0118] Examples

[0119] Example 1 - Preparation Complex

[0120] will be incubated with different increasing concentrations of (rituximab) to form complexes with increasing diameters. Ten milligrams of will be reduced in 1 mL of at 0, 2, 4, 6, 8, and 10 mg / mL, and the mixture will be incubated at room temperature for 30 minutes. After incubation, the particle size distribution will be determined using a Mastersizer 2000. For 0 and 10 mg / mL of , the median particle sizes are in the ranges of 0.147 μm to 8.286 μm ( ). These results demonstrate that the antibody concentration at which Figure 1 is incubated affects the size of the nanoparticles. Manipulating the size of the particles can alter the pharmacokinetics and biodistribution of the drug complex, which in turn can improve the clinical efficacy of the drug complex. will

[0121] Example 2 - / Rituxan complex is more effective than alone Rituxan and Rituxan in combination with sequential use in inhibiting tumor growth

[0122] Female athymic nude mice will be injected with 1 × 10 6 lymphoma cells (Daudi cell line). The tumors will be allowed to grow, and treatment will be administered when the tumors are between 800 and 1000 mm 3 . Treatment will be with (a) a single dose of 100 μL of PBS on day 0, (b) a single dose of Rituxan (12 mg / kg) on day 0, (c) a single dose of (30 mg / kg) on day 0, (d) a single dose of Rituxan (12 mg / kg) on day 0 followed by a single dose of (30 mg / kg) on day 1, or (e) a single dose of AR160 (equivalent to 30 mg / kg of )Treat mice. Monitor tumor volume (mm 3 ), and determine the percentage change in tumor volume seven days after treatment.

[0123] The AR160 complex was prepared as follows. 10 mg was reduced to 2 mg of Rituxan in 500 μL of 0.9% saline and incubated at room temperature for 1 hour. After incubation, AR160 was adjusted to 1 mL with 0.9% saline. AR160 was further diluted and 100 μL was administered to mice at a dose equivalent to 12 mg / kg Rituxan and 30 mg / kg . The average particle size of AR160 was 0.159 μm.

[0124] On day 7 after treatment, mice treated with AR160 showed tumors with significantly smaller tumor sizes compared to other treatment groups ( Figure 2 ). Survival data also revealed an improvement in mice treated with / Rituxan complex ( Figure 3 ). These results demonstrate that the albumin nanoparticle / antibody complexes provided herein (e.g., / anti-CD20 polypeptide antibody complex) can be effectively used for the treatment of lymphoma.

[0125] Example 3 - / Rituxan complex as a targeted therapy for lymphoma

[0126] Repeat the / Rituxan complex treatment plan monthly (every 28 days + / - 3 days) or until disease progression, patient refusal, or unacceptable toxicity (Table 1) and dose-limiting toxicity (Table 3) with the specified dose escalation protocol (Table 2).

[0127] Table 1.

[0128]

[0129] *One treatment cycle = 28 days + / - 3 days

[0130] Table 2. Dose escalation protocol.

[0131] Dose level Dose (ABX) Dose (RIT) -2 <![CDATA[75mg / m 2 > <![CDATA[30mg / m 2 > -1 <![CDATA[100mg / m 2 > <![CDATA[40mg / m 2 > <![CDATA[1 * > <![CDATA[125mg / m 2 > <![CDATA[50mg / m 2 > 2 <![CDATA[150mg / m 2 > <![CDATA[60mg / m 2 > 3 <![CDATA[175mg / m 2 > <![CDATA[70mg / m 2 >

[0132] *Starting dose.

[0133] Table 3. Dose-limiting toxicity (DLT).

[0134]

[0135] Determination of the maximum tolerated dose (MTD)

[0136] The maximum tolerated dose is defined as the highest dose level among those tested where at most one out of six patients shows a DLT before the start of their second cycle of treatment, and the next highest dose level is such that at most two out of six patients treated at this dose level show a DLT before the start of their second treatment cycle.

[0137] Enrollment and determination of the MTD

[0138] Accumulate a given dose level in at least two or at most six patients. For dose level 1 (and if cumulative, dose levels -1 and -2), temporarily stop enrollment after each patient is enrolled in order to collect acute adverse event data during their first cycle of treatment. For dose levels 2 and 3, accumulate patients to these dose levels such that at no given time are more than two patients receiving their first cycle of treatment and acute adverse event data is known for all other patients being treated at the current dose level during the first treatment cycle. If at any time during the enrollment process, two patients being treated at the current dose level show a DLT during the first cycle of treatment, close enrollment for that dose level. If fewer than six patients are being treated at that dose level, reopen enrollment at the next lower dose level. If none of the first three patients being treated at a given dose level show a DLT during the first cycle of treatment, close enrollment for that dose level and reopen enrollment at the next higher dose level. If there are no other higher dose levels to test, enroll three additional patients at the current dose level to confirm the MTD. If one of the first three patients being treated at a given dose level shows a DLT during the first cycle of treatment, enroll three additional patients (sequentially) at the current dose level. If at any time during the enrollment of these three additional patients, a patient shows a DLT, close enrollment for that dose level. If fewer than six patients are being treated at that dose level, reopen enrollment at the next lower dose level. If none of these three additional patients show a DLT during the first cycle of treatment, close enrollment for that dose level and reopen enrollment at the next higher dose level. If there are no other higher dose levels to test, consider it the MTD.

[0139] For the protocol, patients return according to schedule for evaluation and retreatment (at least every 28 + / - 3 days). If a patient cannot complete the first cycle of treatment for reasons other than toxicity, enroll another patient to replace that patient.

[0140] Dose modification based on adverse events

[0141] Follow the modifications in Table 4 until the treatment tolerance of the monomer is determined. If multiple adverse events are observed (Table 5), the dose is given based on the maximum reduction required for any single adverse event observed. Dose modifications apply to the treatment given in the previous cycle and are based on the adverse events observed since the previous dose.

[0142] Table 4. Dose levels based on adverse events.

[0143]

[0144] *Dose level 1 refers to the starting dose.

[0145] Table 5.

[0146]

[0147]

[0148]

[0149]

[0150] Adjuvant therapy / Supportive care

[0151] The routine use of colony-stimulating factors (G-CSF or GM-CSF) is not recommended. The prophylactic use of colony-stimulating factors is not allowed during the study. The treatment use in patients with severe neutropenia syndromes such as tissue infection, septicemia syndrome, fungal infection, etc. can be considered at the discretion of the doctor. Recombinant erythropoietin is allowed to maintain adequate hemoglobin levels and avoid concentrated red blood cell transfusions.

[0152] Patients should receive full supportive care during the study. This includes blood product support, antibiotic treatment, and treatment of other newly diagnosed or concurrent medical conditions. All blood products and concomitant medications such as antidiarrheal agents, analgesics, and antiemetics received from the first administration of the study drug until 30 days after the final dose should be recorded in the medical record. Patients participating in a Phase I clinical trial should not be considered for participation in any other study involving pharmacological agents - (drugs, biologics, immunotherapeutic methods, gene therapy), whether for symptom control or treatment intent.

[0153] Hypersensitivity reaction

[0154] Patients, when given Premedication is not required before the / Rituxan complex. In the unlikely event of a hypersensitivity reaction, treatment with antihistamines, H2 blockers, and corticosteroids is recommended. Patients should be premedicated with the typical regimen used for the paclitaxel regimen for the next cycle. In the unlikely event of a mild hypersensitivity reaction, the premedication regimen typically used by the institution for solvent-based paclitaxel can be used to administer premedication.

[0155] / Rituxan complex

[0156] The / Rituxan complex is prepared as a low-risk product for hazards. The is supplied as a white to off-white lyophilized powder containing 100 mg of paclitaxel and approximately 900 mg of human albumin USP (HA) as a stabilizer in a 50 mL single-use vial. The lyophilized product in each vial is reconstituted as described below. The unreconstituted is stored in its carton at controlled room temperature. Use the reconstituted Rituximab is classified as an anti-CD20 monoclonal antibody.

[0157] Obtain the appropriate number of vials of Rituxan and further dilute each vial to 4 mg / mL according to the following instructions. Obtain the appropriate number of (paclitaxel) 100 mg vials and reconstitute each vial to a final concentration of 10 mg / mL of nab-paclitaxel according to the following instructions. There is no need to use a filter needle during preparation or an in-line filter during administration. In addition, filters with a pore size less than 15 microns should be avoided.

[0158] As with other cytotoxic anticancer drugs, handle with care. The use of gloves is recommended.

[0159] Using a sterile 3 mL syringe, withdraw 1.6 mL of (40 mg) 25 mg / mL Rituxan and slowly inject it over at least 1 minute onto the inner wall of each vial containing 100 mg of . Discard the unused Rituxan remaining in the 25 mg / mL vial as the product contains no preservatives. Avoid injecting the Rituxan solution directly onto the lyophilized cake as this will cause foaming. Using a sterile 12 mL syringe, withdraw 8.4 mL of 0.9% sodium chloride injection (USP) and slowly inject it over at least 1 minute into the vial containing 100 mg On the inner wall of each vial of Rituxan 40 mg. Once 1.6 mL of Rituxan and 8.4 mL of 0.9% Sodium Chloride Injection, USP have been added to each vial, gently rotate and / or slowly invert each vial for at least 2 minutes until complete dissolution of any cake / powder occurs. Avoid foaming. The concentration of each vial is 100 mg / 10 mL and 40 mg / 10 mL Rituxan. Vials containing and Rituxan are allowed to stand for 60 minutes. Gently rotate and / or invert the vials every 10 minutes to continue mixing the complex. After 60 minutes have elapsed, withdraw the calculated dose volume of and Rituxan from each vial using a sterile 60 to 100 mL syringe (of a suitable size for the volume to be administered). Add sufficient 0.9% Sodium Chloride Injection (USP) to make the final concentration 5 mg / mL and Rituxan 2 mg / mL. Gently rotate and / or slowly invert the syringe for 1 minute to mix. Storage and stability are up to 4 hours at room temperature after final dilution.

[0160] Administer

[0161] Infuse the IV initial complex dose over 60 minutes using an infusion pump. If the initial infusion is well tolerated, the infusion may be shortened to 30 minutes. Monitor the patient closely for signs / symptoms of infusion reactions during the infusion. After administration with 20 mL of 0.9% Sodium Chloride, flush the patient's line. Example calculations and formulations are as follows:

[0162] Dose level 1: 125 mg / m 2 / Rituxan 50 mg / m 2

[0163] BSA = 2 m 2

[0164] Required dose: 250 mg / Rituxan 100 mg

[0165] Obtain three vials of 100 mg

[0166] Obtain one vial of Rituxan 25 mg / mL of 100 mg.

[0167] Withdraw 1.6 mL (40 mg) of Rituxan 25 mg / mL and slowly inject it over 1 minute onto the inner wall of one of the 100 mg vials. For the remaining two Repeat this process for each 100 mg vial.

[0168] Add 8.4 mL of 0.9% Sodium Chloride Injection, USP to the inner wall of one of the vials containing and Rituxan. Repeat this process for each of the remaining two and Rituxan vials.

[0169] Let the mixture stand for 60 minutes (rotate every 10 minutes). The final concentration in each vial should be 100 mg / 10 mL and 40 mg Rituxan / 10 mL.

[0170] Withdraw 25 mL from the vial containing and Rituxan and place it in a 100 mL sterile syringe. Add 25 mL of 0.9% Sodium Chloride Injection USP for a final concentration of 5 mg / mL and 2 mg / mL Rituxan concentration. Infuse over 60 minutes via an infusion pump (first dose, subsequent doses at 30 minutes).

[0171] For / Rituxan complex treatment response

[0172] Monitor each patient's response to treatment with / Rituxan complex formulation.

[0173] Other embodiments

[0174] It should be understood that although the invention has been described in conjunction with its detailed description, the foregoing description is intended to illustrate and not limit the scope of the invention as defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. Use of a composition comprising nanoparticles / antibody complexes containing albumin and paclitaxel conjugated with rituximab in the preparation of a medicament for treating a mammal having lymphoma, wherein the average diameter of the complexes is from 0.1 to 0.3 μm.

2. The use according to claim 1, wherein, the average diameter of the complexes is from 0.15 to 0.3 μm.

3. The use according to claim 2, wherein, the average diameter of the complexes is 0.159 μm.

4. The use according to any one of claims 1 - 3, wherein, the lymphoma is a mature B - cell malignancy, a mature T - cell malignancy, or Hodgkin lymphoma.

5. The use according to any one of claims 1 - 3, wherein, the composition further comprises an alkylating agent or an anti - inflammatory agent.

6. The use according to claim 5, wherein, the alkylating agent or the anti - inflammatory agent is conjugated with the nanoparticles / antibody complexes.

7. The use according to any one of claims 1 - 3, wherein, the rituximab is a humanized antibody or a chimeric antibody.

8. The use according to any one of claims 1 - 3, wherein, the composition is administered by injection.

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