US20160250351A1 - Treating Lymphomas - Google Patents

Treating Lymphomas Download PDF

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Publication number
US20160250351A1
US20160250351A1 US15/030,567 US201515030567A US2016250351A1 US 20160250351 A1 US20160250351 A1 US 20160250351A1 US 201515030567 A US201515030567 A US 201515030567A US 2016250351 A1 US2016250351 A1 US 2016250351A1
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abraxane
complexes
dose
albumin
treatment
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Svetomir N. Markovic
Wendy K. Nevala
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Mayo Foundation for Medical Education and Research
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Mayo Foundation for Medical Education and Research
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Definitions

  • lymphomas e.g., mature B-cell neoplasms, mature T cell neoplasms, mature natural killer neoplasms, immunodeficiency-associated lymphoproliferative disorders, Hodgkin lymphomas, and non-Hodgkin lymphomas.
  • lymphomas e.g., mature B-cell neoplasms, mature T cell neoplasms, mature natural killer neoplasms, immunodeficiency-associated lymphoproliferative disorders, Hodgkin lymphomas, and non-Hodgkin lymphomas.
  • this document relates to methods and materials involved in using complexes containing albumin-containing nanoparticies e.g., ABRAXANE® nanoparticles) and antibodies (e.g., anti-CD20 polypeptide antibodies such as Rituximab) to treat lymphomas.
  • albumin-containing nanoparticies e.g., ABRAXANE® nanoparticles
  • antibodies e
  • Lymphomas are blood cancers that occur when B or T lymphocytes become cancerous. They can develop in the lymph nodes, spleen, bone marrow, blood, or other organs and eventually form a tumor.
  • lymphomas e.g., mature B-cell neoplasms, mature T cell neoplasms, mature natural killer cell neoplasms, immunodeficiency-associated lymphoproliferative disorders, Hodgkin lymphomas, and non-Hodgkin lymphomas.
  • this document provides methods and materials for using complexes containing albumin-containing nanoparticles (e.g., ABRAXANE® nanoparticles) and antibodies (e.g., anti-CD20 polypeptide antibodies such as Rituximab) to treat lymphomas.
  • albumin-containing nanoparticles e.g., ABRAXANE® nanoparticles
  • antibodies e.g., anti-CD20 polypeptide antibodies such as Rituximab
  • ABRAXANE® is available from Celgene Corp. and is a nanopartick formulation that combines paclitaxel with human albumin.
  • Anti-CD20 polypeptide antibodies such as Rituximab are available from Genentech Inc., Roche, and Aryogen Biopharma under trade names such as RituxanTM, MabTheraTM, and ZytuxTM.
  • Rituximab is a chimeric monoclonal antibody against CD20 polypeptides presents on surface of lymphocyte cells (see, e.g., U.S. Pat. No. 5,736,137).
  • macromolecular complexes the characteristics of which (e.g., size, antibody content, or chemotherapeutic drug content) can be customized depending on need.
  • macromolecular complexes can retain antibody mediated target binding specificity, can retain or exhibit enhanced chemotherapeutic tumor cell cytotoxicity, and can exhibit no additional toxicity beyond that of ABRAXANE® nanoparticles alone.
  • contacting ABRAXANE® with an anti-CD20 polypeptide antibody e.g., Rituximab
  • a human e.g., a human lymphoma cancer patient
  • a complex that, when administered as a complex, has an increased ability to treat lymphoma as compared to a treatment regimen that includes administering ABRAXANE® and the anti-CD20 polypeptide antibody separately in a manner that does not form ABRAXANE®/anti-CD20 polypeptide antibody complexes.
  • the methods and materials provided herein can be used to increase the progression-free survival rate in lymphoma patients. Increasing progression-free survival can allow lymphoma cancer patients to live longer.
  • one aspect of this document features a method for treating a mammal having lymphoma.
  • the method comprises, or consisting essentially of administering to the mammal a composition comprising nanoparticles containing albumin and placitaxel complexed with an anti-CD20 polypeptide antibody under conditions wherein the length of progression-free survival is increased.
  • the mammal can be a human.
  • the lymphoma can be a Hodgkin lymphomas.
  • 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 percent.
  • the progression-free survival can be increased by 25 percent.
  • the progression-free survival can be increased by 50 percent.
  • the progression-free survival can be increased by 75 percent.
  • the progression-free survival can be increased by 100 percent.
  • the composition can be administered under conditions wherein the time to progression is increased.
  • this document features a method for treating a mammal having lymphoma.
  • the method comprises, or consists essentially of, administering, to the mammal, a composition comprising albumin-containing nanoparticle/antibody complexes, wherein the average diameter of the complexes is between 0.1 and 0.9 ⁇ m, and wherein the antibody is an anti-CD20 antibody.
  • the mammal can be a human
  • the lymphoma can be a mature B-cell neoplasm.
  • the lymphoma can be a mature T neoplasm.
  • the lymphoma can be a Hodgkin lymphoma.
  • the albumin-containing nanopartictelantibody complexes can be ABRAXANE®/Rituximab complexes.
  • the composition or the albumin-containing nanopartictelantibody complexes can comprise an atkylating agent.
  • the aikyiating agent can be a platinum compound.
  • the platinum compound can be carboplatin.
  • the composition can comprise an anti-inflammatory agent.
  • the anti-CD20 polypeptide antibodies can be humanized antibodies.
  • the anti-CD20 polypeptide antibodies can be chimeric antibodies.
  • the composition can be administered by injection.
  • the administration of the composition can be effective to increase progression-free survival by 25 percent.
  • the administration of the composition can be effective to increase progression-free survival by 50 percent.
  • the administration of the composition can be effective to increase progression-free survival by 75 percent.
  • the administration of the composition can be effective to increase progression-free survival by 100 percent.
  • the administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the lymphoma is at least 150 days.
  • the administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the lymphoma is at least 165 days.
  • the administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the lymphoma is at least 170 days.
  • the average diameter of the complexes can be from 0,1 ⁇ m to 0.3 ⁇ m.
  • the average diameter of the complexes can be from 0.15 ⁇ m to 0.3 ⁇ m.
  • the average diameter of the complexes can be from 0.2 ⁇ m to 0.5 ⁇ m.
  • the average diameter of the complexes can be from 0.3 ⁇ m to 0.5 ⁇ m.
  • the average diameter of the complexes can be from 0.2 ⁇ m to 0.8 ⁇ m.
  • the average diameter of the complexes can be from 0.2 ⁇ m to 0.7 ⁇ m.
  • this document features a method for treating a mammal having lymphoma.
  • the method comprises, or consists essentially of, administering, to the mammal, a composition comprising albumin-containing nanoparticle/antibody complexes, wherein the average diameter of at least 5 percent of the complexes of the composition is between 0.1 and 0.9 ⁇ m, and wherein the antibodies are anti-CD20 antibodies.
  • the mammal can be a human.
  • the lymphoma can be a mature B-cell neoplasm.
  • the lymphoma can be a mature T neoplasm.
  • the lymphoma can be a Hodgkin lymphoma.
  • albumin-containing nanoparticte/antibody complexes can be ABRAXANE®/Rituximab complexes.
  • the composition or the albumin-containing nanoparticte/antibody complexes 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 antibodies can be humanized antibodies.
  • the anti-CD20 polypeptide antibodies can be chimeric antibodies.
  • the composition can be administered by injection.
  • the administration of the composition can be effective to increase progression-free survival by 25 percent.
  • the administration of the composition can be effective to increase progression-free survival by 50 percent.
  • the administration of the composition can be effective to increase progression-free survival by 75 percent.
  • the administration of the composition can be effective to increase progression-free survival by 100 percent.
  • the administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the lymphoma is at least 150 days.
  • the administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the lymphoma is at least 165 days.
  • the administration of the composition can be under conditions wherein the median time to progression for a population of mammals with the lymphoma is at least 170 days.
  • the average diameter of at least 5 percent of the complexes of the composition can be from 0.2 ⁇ m to 0.9 run.
  • the average diameter of at least 5 percent of the complexes of the composition can be from 0.2 ⁇ m to 0.8 ⁇ m.
  • the average diameter of at least 5 percent of the complexes of the composition can be from 0.2 ⁇ m to 0.7 ⁇ m.
  • the average diameter of at least 5 percent of the complexes of the composition can be from 0.2 ⁇ m to 0.6 ⁇ m.
  • the average diameter of at least 5 percent of the complexes of the composition can be from 0.2 ⁇ m to 0.5 ⁇ m.
  • the average diameter of at least 5 percent of the complexes of the composition can be from 0.2 ⁇ m to 0.4 ⁇ m.
  • the average diameter of at least 10 percent of the complexes of the composition can be between 0.1 and 0.9 ⁇ m.
  • the average diameter of at least 50 percent of the complexes of the composition can be between 0.1 and 0.9 ⁇ m.
  • the average diameter of at least 75 percent of the complexes of the composition can be between 0.1 and 0.9 ⁇ m.
  • the average diameter of at least 90 percent of the complexes of the composition can be between and 0.9 ⁇ m.
  • FIG. 1 is a graph plotting the particle size distribution for ABRAXANE® (ABX) dissolved in Rituxan (RIT) as determined using a Mastersizer 2000E (Malvern Instruments Ltd., Worcestershire, England). ABX (10 mg/mL) was reconstituted in 1 mL of the indicated amount of RIT, and the mixtures were incubated at room temperature for 30 minutes,
  • FIG. 2 is a graph plotting percent change at seven days in tumor size from baseline of lymphoma (Daudi cell line) tumor bearing nude mice treated with PBS, Rituxan (RIT; 12 mg/kg) only, ABRAXANE® (30 mg/kg) only, Rituxan (RIT; 12 mg/kg) followed by ABRAXANE® (30 mg/kg) one day later, or AR160 complexes (0.159 ⁇ m; complexes where ABRAXANE® (10 mg/mL) was premixed with 2 mg/mL Rituxan and incubated for 60 minutes before injection).
  • FIG. 3 is a Kaplan Meier graph plotting survival of lymphoma (Daudi cell line) tumor bearing nude mice treated with PBS, Rituxan (RIT; 12 mg/kg) only, ABRAXANE® (30 mg/kg) only, Rituxan (RIT; 12 mg/kg) followed by ABRAXANE® (30 mg/kg) one day later, or AR160 complexes (0.159 ⁇ m; complexes where ABRAXANE® (10 mg/mL) was premixed with 2 mg/mL Rituxan and incubated for 60 minutes before injection).
  • lymphomas e.g., mature B-cell neoplasms, mature T cell neoplasms, mature natural killer cell neoplasms, immunodeficiency-associated lymphoproliferative disorders, Hodgkin lymphomas, and non-Hodgkin lymphomas.
  • this document provides methods and materials for using complexes containing albumin-containing nanoparticles (e.g., ABRAXANE® nanoparticles) and antibodies (e.g., anti-CD2( )polypeptide antibodies such as Rituximab) to treat lymphomas.
  • albumin-containing nanoparticles e.g., ABRAXANE® nanoparticles
  • antibodies e.g., anti-CD2( )polypeptide antibodies such as Rituximab
  • the methods and materials provided herein can be used to treat any type of lymphoma.
  • the methods and materials provided herein can be used to treat mature B-cell neoplasms, mature T cell neoplasms, mature natural killer cell neoplasms, immunodeficiency-associated lymphoproliferative disorders, Hodgkin lymphomas, or non-Hodgkin lymphomas.
  • the methods and materials provided herein can be used to treat lymphomas in any type of mammal including, without limitation, mice, rats, dogs, cats, horses, cows, pigs, monkeys, and humans.
  • complexes containing albumin-containing nanoparticles e.g., ABRAXANE® nanoparticles
  • antibodies e.g., anti-CD20 polypeptide antibodies such as Rituximab
  • albumin-containing nanoparticles and antibodies can be designed to have an average diameter that is greater than 1 ⁇ m.
  • appropriate concentrations of albumin-containing nanoparticles and antibodies can be used such that complexes having an average diameter that is greater than 1 ⁇ m are formed.
  • manipulations such as centrifugation can be used to form preparations of albumin-containing nanoparticle/antibody complexes where the average diameter of those complexes is greater than 1 ⁇ m.
  • the preparations of albumin-containing nanoparticle/antibody complexes provided herein can have an average diameter that is between 1 ⁇ m and 5 ⁇ m e.g., between 1.1 ⁇ m and 5 ⁇ m, between 1.5 ⁇ m and 5 ⁇ m, between 2 ⁇ m and 5 ⁇ m, between 2.5 ⁇ m and 5 ⁇ m, between 3 ⁇ m and 5 ⁇ m, between 3.5 ⁇ m and 5 ⁇ m, between 4 ⁇ m and 5 ⁇ m, between 4.5 ⁇ m and 5 ⁇ m, between 1.1 ⁇ m and 4.5 ⁇ m, between 1.1 ⁇ m and 4 ⁇ m, between 1.1 ⁇ m and 3.5 ⁇ m, between 1.1 ⁇ m and 3 ⁇ m, between 1.1 ⁇ m and 2.5 ⁇ m, between 1.1 ⁇ m and 2 ⁇ m, or between 1.1 ⁇ m and 1.5 ⁇ m).
  • Preparations of albumin-containing nanoparticle/antibody complexes provided herein having an average diameter that is between 1 ⁇ m and 5 ⁇ m can be administered systemically (e.g., intravenously) to treat lymphomas located within a mammal's body.
  • the preparations of albumin-containing nanoparticie/antibody complexes provided herein can have an average diameter that is between 5 ⁇ m and 50 ⁇ m (e.g., between 6 ⁇ m and 50 ⁇ m, between 7 ⁇ m and 50 ⁇ m, ween 10 ⁇ m and 50 ⁇ m, between 15 ⁇ m and 50 ⁇ m, between 20 ⁇ m and 50 ⁇ m, between 25 ⁇ m and 50 ⁇ m, between 30 ⁇ m and 50 ⁇ m, between 35 ⁇ m and 50 ⁇ m, between 5 ⁇ m and 45 ⁇ m, between 5 ⁇ m and 40 ⁇ m, between 5 ⁇ m and 35 ⁇ m, between 5 ⁇ m and 30 ⁇ m, between 5 ⁇ m and 25 ⁇ m, between 5 ⁇ m and 20 ⁇ m, between 5 ⁇ m and 15 ⁇ m, or between 10 ⁇ m and 30 ⁇ m).
  • 5 ⁇ m and 50 ⁇ m e.g., between 6 ⁇ m and 50 ⁇ m, between 7 ⁇
  • Preparations of albumin-containing nanoparticie/antibody complexes provided herein having an average diameter that is between 5 ⁇ m and 50 ⁇ m can be administered into a tumor (e.g., intratumorally) or in a region of a tumor located within a mammal's body.
  • a preparation of albumin-containing nanoparticle/antibody complexes provided herein can have greater than 60 percent (e.g., greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the complexes having a diameter that is between 1 ⁇ m and 5 ⁇ m (e.g., between 1.1 ⁇ m and 5 ⁇ m, between 1.5 ⁇ m and 5 ⁇ m, between 2 ⁇ m and 5 ⁇ m, between 2.5 ⁇ m and 5 ⁇ m, between 3 ⁇ m and 5 ⁇ m, between 3.5 ⁇ m and 5 ⁇ m, between 4 ⁇ m and 5 ⁇ m, between 4.5 ⁇ m and 5 ⁇ m, between 1.1 ⁇ m and 4.5 ⁇ m, between 1.1 ⁇ m and 4 ⁇ m, between 1.1 ⁇ m and 3.5 ⁇ m, between 1.1 ⁇ m and 3 ⁇ m, between 1.1 ⁇ m and 2.5 ⁇ m, between 1.1 ⁇ m and 2 ⁇ m, or between 1.1 ⁇ m and 1.5
  • Preparation of albumin-containing nanoparticle/antibody complexes provided herein having greater than 60 percent (e,g., greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the complexes with a diameter that is between 1 ⁇ m and 5 ⁇ m can be administered systemically (e.g., intravenously) to treat lymphomas located within a mammal's body.
  • a preparation of albumin-containing nanoparticle/antibody complexes provided herein can have greater than 60 percent (e.g., greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the complexes having a diameter that is between 5 ⁇ m and 50 ⁇ m (e.g., between 6 ⁇ m and 50 ⁇ m, between 7 ⁇ m and 50 ⁇ m, between 10 ⁇ m and 50 ⁇ m, between 15 ⁇ m and 50 ⁇ m, between 20 ⁇ m and 50 ⁇ m, between 25 ⁇ m and 50 ⁇ m, between 30 ⁇ m and 50 ⁇ m, between 35 ⁇ m and 50 ⁇ m, between 5 ⁇ m and 45 ⁇ m, between 5 ⁇ m and 40 ⁇ m, between 5 ⁇ m and 35 ⁇ m, between 5 ⁇ m and 30 ⁇ m, between 5 ⁇ m and 25 ⁇ m, between 5 ⁇ m and 20 ⁇ m, between 5 ⁇ m and 15 ⁇ m, or between 10 ⁇ m and 30 ⁇ m,
  • Preparation of albumin-containing nanoparticle/antibody complexes provided herein having greater than 60 percent (e.g., greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the complexes with a diameter that is between 5 ⁇ m and 50 ⁇ m can be administered into a tumor (e.g., intratumorally) or in a region of a tumor located within a mammal's body.
  • complexes containing albumin-containing nanoparticles e.g., ABRAXANE® nanoparticles
  • antibodies e.g., anti-CD20 polypeptide antibodies such as Rituximab
  • albumin-containing nanoparticles and antibodies can be designed to have an average diameter that is less than 1 ⁇ m.
  • appropriate concentrations of albumin-containing nanoparticles and antibodies e.g., Rituximab
  • complexes having an average diameter that is less than 1 ⁇ m are formed.
  • the preparations of albumin-containing nanoparticle/antibody complexes provided herein can have an average diameter that is between 0.1 ⁇ m and 1 ⁇ m (e.g., between 0.1 ⁇ m and 0.95 ⁇ m, between 0.1 ⁇ m and 0.9 ⁇ m, between 0.1 ⁇ m and 0.8 ⁇ m, between 0.1 ⁇ m and 0.7 ⁇ m, between 0.1 ⁇ m and 0.6 ⁇ m, between 0.1 ⁇ m and 0.5 ⁇ m, between 0.1 ⁇ m and 0.4 ⁇ m, between 0.1 ⁇ m and 0.3 ⁇ m, between 0.1 ⁇ m and 0.2 ⁇ m, between 0.2 ⁇ m and 1 p,m, between 0.3 ⁇ m and 1 ⁇ m, between 0.4 ⁇ m and 1 ⁇ m, between 0.5 ⁇ m and 1 ⁇ m, between 0.2 ⁇ m and 0.6 ⁇ m, between 0.3 ⁇ m and 0.6 ⁇ m, between 0.2 ⁇ m and 0.5 ⁇ m, or between
  • Preparations of albumin-containing nanoparticle/antibody complexes provided herein having an average diameter that is between 0.1 ⁇ m and 0.9 ⁇ m can be administered systemically (e.g., intravenously) to treat lymphomas located within a mammal's body.
  • a preparation of albumin-containing nanoparticle/antibody complexes provided herein can have greater than 60 percent (e.g., greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the complexes having a diameter that is between 0.1 ⁇ m and 0.9 ⁇ m (e.g., between 0.1 ⁇ m and 0.95 ⁇ m, between 0.1 ⁇ m and 0.9 ⁇ m, between 0.1 ⁇ m and 0.8 ⁇ m, between 0.1 ⁇ m and 0.7 ⁇ m, between 0.1 ⁇ m and 0.6 ⁇ m, between 0.1 ⁇ m and 0.5 ⁇ m, between 0.1 ⁇ m and 0.4 ⁇ m, between 0.1 ⁇ m and 0.3 ⁇ m, between 0.1 ⁇ m and 0.2 ⁇ m, between 0.2 ⁇ m and 1 ⁇ m, between 0.3 ⁇ m and 1 ⁇ m, between 0.4 ⁇ m and 1 ⁇ m, between 0.5 ⁇ m and 1 ⁇ m, between 0.2 ⁇ m and
  • Preparation of albumin-containing nanoparticte/antibody complexes provided herein having greater than 60 percent (e.g., greater than 65, 70, 75, 80, 90, 95, or 99 percent) of the complexes with a diameter that is between 0.1 ⁇ m and 0.9 ⁇ m can be administered systemically (e.g., intravenously) to treat cancers located within a mammal's body.
  • albumin-containing nanoparticles such as ABRAXANE® can be contacted with an antibody such as an anti-CD20 polypeptide antibody (e.g., Rituximab) prior to administration to a human form an albumin-containing nanoparticle/antibody complex (e.g., an ABRAXANE®/anti-CD20 polypeptide antibody complex).
  • an antibody such as an anti-CD20 polypeptide antibody (e.g., Rituximab)
  • an albumin-containing nanoparticle/antibody complex e.g., an ABRAXANE®/anti-CD20 polypeptide antibody complex
  • Any appropriate albumin-containing nanoparticie preparation and any appropriate antibody can be used as described herein.
  • ABRAXANE® nanoparticles can be used as described herein.
  • antibodies that can be used to form albumin-containing nanoparticle/antibody complexes as described herein include, without limitation, Rituximab (e.g., RituxanTM, MabTheraTM, or ZytuxTM).
  • Rituximab e.g., RituxanTM, MabTheraTM, or ZytuxTM
  • an appropriate dose of ABRAXANE® and an appropriate dose of Rituximab can be mixed together in the same container. This mixture can be incubated at an appropriate temperature (e.g., room temperature, between 15° C. and 30° C., between 15° C and 25° C., between 20° C. and 30° C., or between 20° C.
  • ABRAXANE® can be contacted with an anti-CD20 polypeptide antibody by injecting both ABRAXANE® and the anti-CD20 polypeptide antibody either individually or as a pre-mixed combination into an IV bag containing an IV bag solution.
  • the contents of the IV bag including ABRAXANE®/anti-CD20 polypeptide antibody complexes can be introduced into the patient to be treated.
  • albumin-containing nanoparticles such as ABRAXANE® can be contacted with an antibody such as an anti-CD20 polypeptide antibody (e.g., Rituximab) to form albumin-containing nanoparticle/antibody complexes (e.g., ABRAXANE®/anti-CD20 polypeptide antibody complexes) that are stored prior to being administered to a cancer patient (e.g., a lymphoma patient).
  • a composition containing albumin-containing nanoparticle/antibody complexes can be formed as described herein and stored for a period of time (e.g., days or weeks) prior to being administered to a cancer patient.
  • albumin-containing nanoparticles such as ABRAXANE® and an antibody such as an anti-CD20 polypeptide antibody.
  • ABRAXANE® can be obtained from Celgene Corp. or as described elsewhere (U.S. Pat. No. 6,537,579).
  • Rituximab can be obtained from Genentech Corp. or Roche Corp. or as described elsewhere (U.S. Pat. No. 5,736,137).
  • an albumin-containing nanoparticle such as ABRAXANE® and an antibody such as anti-CD20 polypeptide antibody can include one or more other agents such as an alkylating agent (e.g., a platinum compound).
  • an alkylating agent e.g., a platinum compound
  • platinum compounds that can be used as an alkylating agent include, without carboplatin (PARAPLATIN®), cisplatin (PLATINOL®), oxaliplatin (ELOXATIN®), and BBR3464.
  • agents that can be included within an albumin-containing nanoparticle/antibody complex include, without limitation, adriamycin, cyclophosphamide, vincristine, prednisone, dexamethasone, cytarabine, methotrexate, thiotepa, ifosfamide, chlorambucil, dacarbazine, bleomycin, ibrutinib, campath-B, gemcitabine, revlimid, sirolimus, temsirolimus, bexxar, brentuximab, bendamustine, and etoposide.
  • an albumin-containing nanoparticle/antibody complex provided herein can include brentuximab, cyclophosphamide, adriamycin, or vincristine as part of the complex.
  • albumin-containing nanoparticle/antibody complex provided herein (e.g., ABRAXANE®/anti-CD20 polypeptide antibody complexes)
  • a composition containing albumin-containing nanoparticle/antibody complexes such as ABRAXANE®/anti-CD20 polypeptide antibody complexes can be administered via injection(e.g., subcutaneous injection, intramuscular injection, intravenous injection, or intrathecal injection).
  • the mammal Before administering a composition containing an albumin-containing nanoparticie/antibody complex provided herein (e.g.4BRAXANE®/anti-CD20 polypeptide antibody complexes) to a mammal, the mammal can be assessed to determine whether or not the mammal has lymphoma. Any appropriate method can be used to determine whether or not a mammal has lymphoma. For example, a mammal (e.g., human) can be identified as having lymphoma using standard diagnostic techniques. In some cases, a tissue biopsy (e.g., lymph node tissue sample) can be collected and analyzed to determine whether or not a mammal has lymphoma.
  • a tissue biopsy e.g., lymph node tissue sample
  • the mammal can be administered a composition containing albumin-containing nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD20 polypeptide antibody complexes).
  • a composition containing ABRAXANE®/anti-CD20 polypeptide antibody complexes can be administered prior to or in lieu of surgical resection of a tumor.
  • a composition containing albumin-containing nanoparticle/antibody complexes provided herein e.g., ABRAXANE®/anti-CD20 polypeptide antibody complexes can be administered following resection of a tumor.
  • a composition containing albumin-containing nanoparticle/antibody complexes provided herein can be administered to a mammal in any appropriate amount, at any appropriate frequency, and for any appropriate duration effective to achieve a desired outcome (e.g., to increase progression-free survival).
  • a composition containing albumin-containing nanoparticle/antibody complexes provided herein e.g., ABRAXANE®/anti-CD20 polypeptide antibody complexes can be administered to a mammal having lymphoma to reduce the progression rate of the lymphoma by 5, 10, 25, 50, 75, 100, or more percent.
  • the progression rate can be reduced such that no additional cancer progression is detected.
  • Any appropriate method can be used to determine whether or not the progression rate of lymphoma is reduced.
  • the progression rate of lymphoma can be assessed by imaging tissue at different time points and determining the amount of cancer cells present. The amounts of cancer cells determined within tissue at different times can be compared to determine the progression rate. After treatment as described herein, the progression rate can be determined again over another time interval.
  • the stage of cancer (e,g., lymphoma) after treatment can be determined and compared to the stage before treatment to determine whether or not the progression rate was reduced.
  • a composition containing albumin-containing nanoparticle/antibody complexes provided herein e.g., ABRAXANE®/anti-CD20 polypeptide antibody complexes can be administered to a mammal having lymphoma under conditions where progression-free survival is increased (e.g., by 5, 10, 25, 50, 75, 100, or more percent) as compared to the median progression-free survival of corresponding mammals having untreated lymphoma or the median progression-free survival of corresponding mammals having lymphoma treated with ABRAXANE® and an antibody (e.g., an anti-CD20 polypeptide antibody) without forming ABRAXANE®/antibody complexes (e.g., without forming ABRAXNE/anti-CD20 polypeptide antibody complexes).
  • progression-free survival is increased (e.g., by 5, 10, 25, 50, 75, 100, or more percent) as compared to the median progression-free survival of corresponding mammals having untreated lymphoma or the median progression-free survival of corresponding mammals having
  • a composition containing albumin-containing nanoparticle/antibody complexes provided herein e.g., ABRAXANE®/anti-CD20 polypeptide antibody complexes can be administered to a mammal having lymphoma to increase progression-free survival by 5, 10, 25, 50, 75, 100, or more percent as compared to the median progression-free survival of corresponding mammals having lymphoma and having received ABRAXANE® or an antibody (e.g., an anti-CD20 polypeptide antibody) alone, 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),
  • a composition containing albumin-containing nanoparticle/antibody complexes provided herein can be administered to a mammal having lymphoma under conditions where the 8-week progression-free survival rate for a population of mammals is 65% or greater (e.g., 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80% or greater) than that observed in a population of comparable mammals not receiving a composition containing albumin-containing nanoparticie/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD20 polypeptide antibody complexes).
  • composition containing albumin-containing nanoparticle/antibody complexes provided herein(e.g., ABRAXANE®/anti-CD20 polypeptide antibody complexes can be administered to a mammal having lymphoma under conditions where the median time to progression for a population of mammals is at least 150 days (e.g., at least 155, 160, 163, 165, or 170 days).
  • An effective amount of a composition containing albumin-containing nanoparticle/antibody complexes provided herein e.g., ABRAXANE®/anti-CD20 polypeptide antibody complexes can be any amount that reduces the progression rate of lymphoma, increases the progression-free survival rate, or increases the median time to progression without producing significant toxicity to the mammal.
  • an effective amount of ABRAXANE® can be from about 50 mg/m 2 to about 150 mg/m 2 (e.g., about 80 mg/m 2 )
  • 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 ).
  • the amount of ABRAXANE® or anti-CD20 polypeptide antibody can be increased by, for example, two fold. After receiving this higher concentration, the mammal can be monitored for both responsiveness to the treatment and toxicity symptoms, and adjustments made accordingly.
  • the effective amount can remain constant or can be adjusted as a sliding scale or variable dose depending on the mammal's response to treatment. Various factors can influence the actual effective amount used for a particular application. For example, the frequency of administration, duration of treatment, use of multiple treatment agents, route of administration, and severity of the lymphoma may require an increase or decrease in the actual effective amount administered.
  • the frequency of administration can be any frequency that reduces the progression rate of lymphoma, increases the progression-free survival rate, or increases the median time to progression without producing significant toxicity to the mammal.
  • 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.
  • a course of treatment with a composition containing ABRAXANE®/anti-CD20 polypeptide antibody complexes can include rest periods.
  • composition containing ABRAXANE®/anti-CD20 polypeptide antibody complexes can be administered over a two week period followed by a two week rest period, and such a regimen can be repeated multiple times.
  • the effective amount various factors can influence the actual frequency of administration used for a particular application. For example, the effective amount, duration of treatment, use of multiple treatment agents, route of administration, and severity of the lymphoma may require an increase or decrease in administration frequency.
  • An effective duration for administering a composition provided herein can be any duration that reduces the progression rate of lymphoma, increases the progression-free survival rate, or increases the median time to progression without producing significant toxicity to the mammal.
  • the effective duration can vary from several days to several weeks, months, or years.
  • the effective duration for the treatment of lymphoma can range in duration from several weeks to several months. :In some cases, an effective duration can be for as long as an individual mammal is alive. Multiple factors can influence the actual effective duration used for a particular treatment. For example, an effective duration can vary with the frequency of administration, effective amount, use of multiple treatment agents, route of administration, and severity of the lymphoma.
  • a composition containing albumin-containing nanoparticle/antibody complexes provided herein can be in any appropriate form.
  • a composition provided herein can be in the form of a solution or powder with or without a diluent to make an injectable suspension.
  • a composition also can contain additional ingredients including, without limitation, pharmaceutically acceptable vehicles.
  • a pharmaceutically acceptable vehicle can be, for example, saline, water, lactic acid, mannitol, or combinations thereof.
  • the mammal After administering a composition provided herein to a mammal, the mammal can be monitored to determine whether or not the lymphoma was treated. For example, a mammal can be assessed after treatment to determine whether or not the progression rate of lymphoma was reduced (e.g., stopped). As described herein, any method can be used to assess progression and survival rates.
  • a formulation of ABRAXANE®/Rituxan complexes described in Example 1 can be administered to a human lymphoma patient as described in the methods set forth in Example 3.
  • nanoparticles containing albumin e.g., nanoparticles with an albumin shell
  • an agent other than placitaxel can be used as described herein in place of or in combination with ABRAXANE®.
  • 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.
  • An example of such a cancer chemotherapeutic agent includes, without vinblastine.
  • a composition can be formulated to include nanoparticies containing albumin (e,g., nanoparticles with an albumin shell) that are conjugated to an antibody, agent, or combination of antibodies and agents to form complexes for treating lymphoma.
  • albumin e.g., nanoparticles with an albumin shell
  • albumin nanoparticles can be formulated to include adriamycin, cyclophosphamide, vincristine, prednisone, dexamethasone, cytarabine, methotrexate, thiotepa, ifosfamide, chlorambucil, dacarbazine, bleomycin, ibrutinib, campath-B, gemcitabine, revlimid, sirolimus, temsirolimus, bexxar, brentuximab, bendamustine, etoposide, or combinations thereof with or without including rituximab.
  • nanoparticles containing albumin e.g., nanoparticles with an albumin shell
  • a complex described herein e.g., ABRAXANE®/rituximab complexes
  • ABRAXANE®/rituximab complexes can be formulated to include one or more anti-chronic inflammation treatment agents designed to reduce the global state of immune dysfunction and/or chronic inflammation present within a cancer patient.
  • steroidal anti-inflammatory agents e.g., prednisone
  • non-steroidal anti-inflammatory agents e.g., naproxen
  • lympho-depleting cytotoxic agents e.g., cyclophosphamide
  • immune cell and/or cytokine targeting antibodies e.g., infliximab
  • a combination thereof can be incorporated into nanoparticles containing albumin or ABRAXANE®/rituximab complexes.
  • anti-IL-4 agents e.g., anti-IL-4 antibodies
  • anti-IL-13 agents e.g., soluble IL-13 receptor
  • combinations thereof can be incorporated into nanoparticles containing albumin or ABRAXANE®/rituximab complexes.
  • cytokine profiles e.g., IL-4, IL-13, IL-4, IL-13, IL-5, IL-10, IL-2, and interferon gamma
  • cytokine profiles e.g., IL-4, IL-13, IL-4, IL-13, IL-5, IL-10, IL-2, and interferon gamma
  • ABRAXANE® was incubated with various increasing concentrations of Rituxan® (rituximab) to form ABRAXANE®/Rituxan® complexes of increasing diameter.
  • Ten milligrams of ABRAXANE® was reconstituted in 1 mL of Rituxan® at 0, 2, 4, 6, 8, and 10 mg/mL, and the mixture was incubated at room temperature for 30 minutes. After incubation, the distributions of particle sizes were determined with the Mastersizer 2000. The median particle size ranged from 0.147 ⁇ m to 8.286 ⁇ m for 0 and 10 mg/mL Rituxan®, respectively ( FIG. 1 ).
  • mice Female athymic nude mice were injected with 1 ⁇ 10 6 lymphoma cells (Daudi cell line). Tumors were allowed to grow, and treatments were administered when tumors were between 800 and 1000 mm 3 . Mice were treated with (a) a single dose of 100 ⁇ L PBS on day 0, (b) a single dose of Rituxan (12 mg/kg) on day 0, (c) a single dose of ABRAXANE® (30 mg/kg) on day 0, (d) a single dose of Rituxan (12 mg/kg) on day 0 followed by a single dose of ABRAXANE® (30 mg/kg) on day 1, or (e) a single dose of AR160 (equivalent to 30 mg/kg of ABRAXANE®) on day 0. Tumor volumes (mm 3 ) were monitored, and the percent change in tumor volume seven days after treatment was determined.
  • the AR160 complexes were produced as follows. 10 mg ABRAXANE® was reconstituted in 2 mg of Rituxan in 500 ⁇ L 0.9% saline and incubated for 1 hour at room temperature. After incubation, AR160 was brought to 1 mL with 0.9% saline. AR160 was further diluted, and 100 ⁇ L was administered to mice at a dose equivalent to 12 mg/kg Rituxan and 30 mg/kg ABRAXANE®. Average particle size for AR160 was 0.159 ⁇ m.
  • the treatment schedule for ABRAXANE®/Rituxan complexes is repeated each month (every 28 days +/ ⁇ 3 days) or until disease progression, patient refusal, or unacceptable toxicity (Table 1) with the indicated dose escalation scheme (Table 2) and dose limiting toxicities (Table 3).
  • Dose Escalation Scheme Dose Level Dose (ABX) Dose (RIT) ⁇ 2 75 mg/m 2 30 mg/m 2 ⁇ 1 100 mg/m 2 40 mg/m 2 1* 125 mg/m 2 50 mg/m 2 2 150 mg/m 2 60 mg/m 2 3 175 mg/m 2 70 mg/m 2 *Starting dose.
  • ABX Dose Level Dose
  • RIT Dose (RIT) ⁇ 2 75 mg/m 2 30 mg/m 2 ⁇ 1 100 mg/m 2 40 mg/m 2 1* 125 mg/m 2 50 mg/m 2 2 150 mg/m 2 60 mg/m 2 3 175 mg/m 2 70 mg/m 2 *Starting dose.
  • DLT Dose Limiting Toxicities
  • the maximum tolerated dose is defined as the highest dose level among those tested where at most one out of six patients develops a DLT prior to the start of their second cycle of treatment and the next highest dose level is such that two out of a maximum of six patients treated at this dose level developed a DLT prior to the start of their second cycle of treatment.
  • a minimum of two or a maximum of six patients are accrued to a given dose level.
  • dose level 1 (and if accrued to, dose levels ⁇ 1 & ⁇ 2)
  • enrollment is temporarily halted after each patient has been enrolled in order to gather acute adverse event data over the first cycle of their treatment.
  • dose levels 2 & 3 patients are accrued to these dose levels so that at any given time no more than two patients are receiving their first cycle of treatment and acute adverse event data over the first treatment cycle for all other patients treated at the current dose level is known. If, at any time in the enrollment process, two patients treated at the current dose level develop a DLT during the first cycle of treatment, enrollment is closed to that dose level.
  • Enrollment is re-opened to the next lower dose level if fewer than six patients have been treated at that dose level. If none of the first three patients treated at a given dose level develops a DLT during the first cycle of treatment, enrollment to the dose level is closed and enrollment is reopen at next higher dose level. If there are no other higher dose levels to be tested, three additional patients are enrolled at the current dose level to confirm MTD. If one of the first three patients treated at a given dose level develops a DLT during the first cycle of treatment, three additional patients are enrolled (sequentially) onto the current dose level. If at any time in the enrollment of these three additional patients, a patient develops a DLT, enrollment is closed to this dose level.
  • Enrollment is re-opened to the next lower dose level if fewer than six patients are treated at that dose level. If none of these three additional patients develops a DLT during the first cycle of treatment, enrollment to this dose level is closed and enrollment is reopened at next higher dose level. If there are no other higher dose levels to be tooted, this is considered the MTD.
  • the patient returns for evaluation and retreatment (at least every 28+/ ⁇ 3 days) according to the schedule. If a patient fails to complete the first cycle of treatment for reasons other than toxicity, an additional patient is enrolled to replace this patient.
  • the planned duration of full-dose anticoagulation is >2 weeks, treatment may be resumed during the period of full-dose anticoagulation IF all of the criteria below are met:
  • the subject must have an in-range INR (usually 2-3) on a stable dose of warfarin, or on stable dose of heparin prior to restarting treatment.
  • the subject must not have pathological conditions that carry high risk of bleeding (e.g. tumor involving major vessels or other conditions)
  • the subject must not have had hemorrhagic events while on study If thromboemboli worsen/recur upon resumption of study therapy, discontinue treatment.
  • G-CSF colony-stimulating factor
  • GM-CSF GM-CSF Routine use of colony-stimulating factors (G-CSF or GM-CSF) is not recommended. Prophylactic use of colony-stimulating factors during the study is not allowed. Therapeutic use in patients with serious neutropenic complications such as tissue infection, sepsis syndrome, fungal infection, etc., may be considered at physician discretion. Recombinant erythropoietin to maintain adequate hemoglobin levels and avoid packed red blood cell transfusions is allowed.
  • Patients do not require premedication prior to administration of ABRAXANE®/Rituxan complexes.
  • treatment with antihistamines, H2 blockers, and corticosteroids is recommended. Patients should be pre-medicated with the typical regimen for paclitaxel regimens for subsequent cycles.
  • premedication may be administered using the premedication regimen the institution typically uses for solvent-based paclitaxel.
  • ABRAXANE®/Rituxan complexes are prepared as a hazardous low risk product.
  • ABRAXANE® is supplied as a white to off-white lyophilized powder containing 100 mg of paclitaxel and approximately 900 mg Albumin Human USP (HA) as a stabilizer in a 50 mL, single-use vial. Each vial of the lyophilized product is reconstituted as set forth below. Unreconstituted ABRAXANE® is stored at controlled room temperature in its carton. Reconstituted ABRAXANE® is used immediately.
  • Rituxan is classified as an anti-CD20 monoclonal antibody.
  • the dose appropriate number of vials of Rituxan are obtained, and each vial is further diluted per the following directions to 4 mg/mL.
  • the dose appropriate number of ABRAXANE® (paclitaxel) 100 mg vials is obtained and each vial is reconstituted per the following directions to a final concentration containing 10 mg/mL nanoparticle albumin-bound (nab) paclitaxel. It is not a requirement to use filter needles in the preparation of, or in-line filters during administration. In addition, filters of pore-size less than 15 micrometers are to be avoided.
  • the vials containing the ABRAXANE® and Rituxan are allowed to sit for 60 minutes.
  • the vial(s) are gently swirled and/or inverted every 10 minutes to continue to mix the complexes.
  • a sterile 60- to 100-mL syringe (appropriate size for the volume being administered) is used to withdraw the calculated dosing volume of ABRAXANE® and Rituxan from each vial.
  • a sufficient quantity of 0.9% Sodium Chloride Injection, USP is added to make the final concentration of ABRAXANE® 5 mg/mL and Rituxan 2 mg/mL.
  • the syringe is gently swirled and/or inverted slowly for 1 minute to mix.
  • the storage and stability is for up to 4 hours at room temperature following final dilution.
  • the IV initial complex dose is infused over 60 minutes via syringe pump.
  • the infusion may be shortened to 30 minutes if the initial infusion is well tolerated.
  • Infusion is monitored closely during the infusion process for signs/symptoms of an infusion reaction.
  • the patient's line is flushed after administration with 20 mL 0.9% Sodium Chloride.
  • Each patient's response to treatment with a ABRAXANE®/Rituxan complex formulation is monitored.

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