HEMATOLOGIC CANCER TREATMENTS

Abstract

Disclosed herein are improved compositions and methods involved in treating hematologic cancers, i.e., cancers that begin in blood-forming tissue, such as the bone marrow, or in the cells of the immune system. The compositions comprise complexes containing albumin-containing nanoparticles (e.g., ABRAXANE® nanoparticles) and antibodies. The compositions are used to effect hematologic cancer cell death.

Claims

1. A unit dose of a composition comprising albumin-containing nanoparticles complexed with an antibody wherein said nanoparticles contain albumin and paclitaxel at a ratio of about 9:1 albumin to paclitaxel as well as a plurality of humanized antibodies complexed thereto wherein said nanoparticles are solids which have a size less than 1 micron provided that at least a portion of the said antibodies are arranged in a manner that said nanoparticle complexes retain antibody mediated target binding specificity and wherein the antibody is an anti-CD52 polypeptide humanized antibody-or an anti-CD38 polypeptide humanized antibody, wherein said unit dose comprises from about 17.5 mg/m.sup.2 to about 125 mg/m.sup.2 of said antibody and about 75 mg/m.sup.2 to about 250 mg/m.sup.2 paclitaxel.

2. The nanoparticles of claim 1 wherein the antibody is rituximab, Alemtuzumab, or SAR650984.

3. The nanoparticle of claim 2 wherein the antibody is rituximab.

4. The nanoparticles of claim 1 wherein the antibodies are non-covalently complexed with the nanoparticles.

5. A method to effect hematological cancer cell death said method comprising contacting the cancer cell with a composition comprising albumin-containing nanoparticles complexed with an antibody wherein said nanoparticles contain albumin and paclitaxel at a ratio of about 9:1 albumin to paclitaxel as well as a plurality of humanized antibodies complexed thereto wherein said nanoparticles are solids which have a size less than 1 micron provided that at least a portion of the said antibodies are arranged in a manner that said nanoparticle-complexes retain antibody mediated target binding specificity and wherein the antibody is an anti-CD52 polypeptide humanized antibody or an anti-CD38 polypeptide humanized antibody, wherein said unit dose comprises from about 17.5 mg/m.sup.2 to about 125 mg/m.sup.2 of said antibody and about 75 mg/m.sup.2 to about 250 mg/m.sup.2 paclitaxel.

6. The method of claim 5, wherein the hematologic cancer cell is a leukemia cell, a lymphoma cell, or myeloma cell.

7. The method of claim 6, wherein the leukemia cell is an acute myelogenous (granulocytic) leukemia (AML) cell, chronic myelogenous (granulocytic) leukemia (CML) cell, acute lymphocytic (lymphoblastic) leukemia (ALL) cell, chronic lymphocytic leukemia (CLL) cell, or hairy cell leukemia).

8. The method of claim 6, wherein the lymphomas cell is a cell of a mature B-cell neoplasm, a mature T cell neoplasm, a mature natural killer cell neoplasm, an immunodeficiency-associated lymphoproliferative disorders, Hodgkin lymphoma cell, and non-Hodgkin lymphoma cell.

9. The method of claim 6, wherein the myeloma is a multiple myeloma cell.

10. The method of claim 5, wherein the unit dose comprises about 100 mg/m.sup.2 to about 200 mg/m.sup.2 paclitaxel.

11. The method of claim 5, wherein the unit dose comprises about 150 mg/m.sup.2 paclitaxel.

12. The method of claim 5, wherein the unit dose comprises about 35 mg/m.sup.2 to about 100 mg/m.sup.2 of the antibody.

13. The method of claim 5, wherein the unit dose comprises about 50 to about 100 mg/m.sup.2 of the antibody.

14. A method for lysing a hematological cancer cell in a patient, the method comprises administering to the patient an effective amount of a composition comprising albumin-containing nanoparticles complexed with an antibody wherein said nanoparticles contain albumin and paclitaxel at a ratio of about 9:1 albumin to paclitaxel as well as a plurality of humanized antibodies complexed thereto wherein said nanoparticles are solids which have a size less than 1 micron provided that at least a portion of the said antibodies are arranged in a manner that said nanoparticle-complexes retain antibody mediated target binding specificity and wherein the antibody is an anti-CD52 polypeptide humanized antibody or an-anti-CD38 polypeptide humanized antibody, wherein said unit dose comprises from about 17.5 mg/m.sup.2 to about 125 mg/m.sup.2 of said antibody and about 75 mg/m.sup.2 to about 250 mg/m.sup.2 paclitaxel.

15. The method of claim 14, wherein the unit dose comprise about of 100 mg/m.sup.2 to about 200 mg/m.sup.2 paclitaxel.

16. The method of claim 14, wherein the unit dose comprise about 150 mg/m.sup.2 paclitaxel.

17. The method of claim 14, wherein the unit dose comprise about 35 mg/m.sup.2 to about 100 mg/m.sup.2 antibody.

18. The method of claim 14, wherein the unit dose comprise about 50 to about 100 mg/m.sup.2.

19. The method of claim 14, wherein the hematologic cancer cell is a leukemia cell, a lymphoma cell, or myeloma cell.

20. The method of claim 19, wherein the leukemia cell is an acute myelogenous (granulocytic) leukemia (AML) cell, chronic myelogenous (granulocytic) leukemia (CML) cell, acute lymphocytic (lymphoblastic) leukemia (ALL) cell, chronic lymphocytic leukemia (CLL) cell, or hairy cell leukemia).

21. The method of claim 19, wherein the lymphomas cell is a cell of a mature B-cell neoplasm, a mature T cell neoplasm, a mature natural killer cell neoplasm, an immunodeficiency-associated lymphoproliferative disorders, Hodgkin lymphoma, and non-Hodgkin lymphoma.

22. The method of claim 18, wherein the myeloma is a multiple myeloma cell.

23. The method of claim 14, wherein the patient is a mammal.

24. The method of claim 23, wherein the mammal is a human.

25. The method of claim 14, wherein said pharmaceutical composition comprises a humanized anti-CD52 polypeptide antibody.

26. The method of claim 14, wherein said pharmaceutical composition comprises a humanized anti-CD38 polypeptide antibody.

27. A unit dose of a composition comprising albumin-containing nanoparticles complexed with an antibody wherein said nanoparticles contain albumin and paclitaxel at a ratio of about 9:1 albumin to paclitaxel as well as a plurality of humanized antibodies complexed thereto wherein said nanoparticles are solids which have a size less than 1 micron provided that at least a portion of the said antibodies are arranged in a manner that said nanoparticle complexes retain antibody mediated target binding specificity and wherein the antibody is an anti-CD20 polypeptide humanized antibody, wherein said unit dose comprises from about 17.5 mg/m.sup.2 to about 125 mg/m.sup.2 of said antibody and about 75 mg/m.sup.2 to about 250 mg/m.sup.2 paclitaxel.

Description

DESCRIPTION OF THE FIGURES

[0024] FIG. 1 presents a graph plotting percent change at ten days in tumor size from baseline of lymphoma (Daudi cell line) tumor bearing nude mice treated with PBS, Rituxan (RIT12; 12 mg/kg) only, Rituxan (RIT18; 18 mg/kg) ABRAXANE® (ABX30, 30 mg/kg) only, ABRAXANE® (ABX45, 45 mg/kg) only, AR160 30 and AR160 45 complexes.

[0025] FIG. 2 is a Kaplan Meier graph plotting survival of lymphoma (Daudi cell line) tumor bearing nude mice treated with PBS, Rituxan (RIT12; 12 mg/kg) only, Rituxan (RIT18; 18 mg/kg) only ABX30 (ABRAXANE®, 30 mg/kg) only, ABX 45 (ABRAXANE®, 45 mg/kg) only, or AR160 complexes, AR160 30 (ABX 30mg/kg, RIT 12 mg/kg), AR160 45 (ABX 45mg/kg, RIT 18 mg/kg). At 80 days 9/9 AR160 45 mice responded to therapy and 2 progressed, 7/9 complete responses. The graph illustrated the criticality of the effective dose of AR160 wherein the survival rate more than triples as compared to the effect of Rituxan or ABRAXANE® alone.

DETAILED DESCRIPTION

[0026] This invention provides methods and materials involved in treating 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). For example, this invention 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 hematologic cancers, e.g., leukemias, lymphomas, and myelomas.

[0027] The methods and materials provided herein can be used to treat any type of hematologic cancer. For example, the methods and materials provided herein can be used to treat leukemias (e.g., AML, CML, ALL, CLL, and hairy cell leukemia), 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), and myelomas (e.g., multiple myeloma, light chain myeloma, and non-secretory myeloma). In some cases, the methods and materials provided herein can be used to treat hematologic cancer in any type of mammal including, without limitation, mice, rats, dogs, cats, horses, cows, pigs, monkeys, and humans.

[0028] In some cases, complexes containing albumin-containing nanoparticles (e.g., ABRAXANE® nanoparticles) and antibodies (e.g., anti-CD52 polypeptide antibodies such as Alemtuzumab, anti-CD20 polypeptide antibodies such as Rituximab and anti-CD38 polypeptide antibodies such as SAR650984). can be designed to have an average diameter that is greater than 1 μm. For example, appropriate concentrations of albumin-containing nanoparticles and antibodies can be used such that complexes having an average diameter that is greater than 1 μm are formed. Preparations of albumin-containing nanoparticle/antibody complexes provided herein having an average diameter that is greater than 1 μm should be administered into a tumor (e.g., intratumorally) or in a region of a tumor located within a mammal's body.

[0029] In some cases, complexes containing albumin-containing nanoparticles (e.g., ABRAXANE® nanoparticles) and antibodies (e.g., anti-CD52 polypeptide antibodies such as Alemtuzumab, anti-CD20 polypeptide antibodies such as Rituximab and anti-CD38 polypeptide antibodies such as SAR650984) can be designed to have an average diameter that is less than 1 μm. For example, appropriate concentrations of albumin-containing nanoparticles and antibodies (e.g., Alemtuzumab, Rituximab and SAR650984) can be used such that complexes having an average diameter that is less than 1 μm are formed. In some cases, the preparations of albumin-containing nanoparticle/antibody complexes provided herein can have an average diameter that is 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 1μm, between 0.3 μm and 1 μm, 30 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).

[0030] Preparations of albumin-containing nanoparticle/antibody complexes provided herein having an average diameter that is between 0.1 μm and 0.9 μm can be administered systemically (e.g., intravenously) to treat a hematologic cancer located within a mammal's body.

[0031] In general, albumin-containing nanoparticles such as ABRAXANE® can be contacted with an antibody such as an anti-CD20 polypeptide antibody (e.g., Alemtuzumab, Rituximab and SAR650984) prior to administration to a human to form an albumin-containing nanoparticle/antibody complex (e.g., an ABRAXANE®/anti-CD52 polypeptide antibody complex, an ABRAXANE®/anti-CD20 polypeptide antibody complex, or an ABRAXANE®/anti-CD38 polypeptide antibody complex). Any appropriate albumin-containing nanoparticle preparation and any appropriate antibody can be used as described herein. For example, ABRAXANE® nanoparticles can be used as described herein. Examples of antibodies that can be used to form albumin-containing nanoparticle/antibody complexes as described herein include, without limitation, Alemtuzumab, SAR650984, Rituximab (e.g., Rituxan™, MabThera™, or Zytux™). For example, an appropriate dose of ABRAXANE® and an appropriate dose of Alemtuzumab, SAR650984, or 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. and 25° C.) for a period of time (e.g., about 30 minutes, or between about 5 minutes and about 60 minutes, between about 5 minutes and about 45 minutes, between about 15 minutes and about 60 minutes, between about 15 minutes and about 45 minutes, between about 20 minutes and about 400 minutes, or between about 25 minutes and about 35 minutes) before being administered to a hematologic cancer patient (e.g., a lymphoma patient).

[0032] In some cases, albumin-containing nanoparticles such as ABRAXANE® can be contacted with an antibody such as an anti-CD52 polypeptide antibody (e.g., Alemtuzumab), anti-CD20 polypeptide antibody (e.g., Rituximab), or anti-CD38 polypeptide antibody (e.g., SAR650984) to form albumin-containing nanoparticle/antibody complexes (e.g., ABRAXANE®/antibody complexes) that are stored prior to being administered to a hematologic cancer patient (e.g., a lymphoma patient). For example, 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. Storage can take the form of a lyophilized composition or an aqueous composition.

[0033] Any appropriate method can be used to obtain albumin-containing nanoparticles such as ABRAXANE® and an antibody such as an anti-CD52 polypeptide antibody, an anti-CD20 polypeptide antibody or an anti-CD38 polypeptide antibody. For example, 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). Alemtuzumab can be obtained from Genzyme Corporation. SAR650984 can be obtained from Sanofi-Aventis.

[0034] In some cases, the combination of an albumin-containing nanoparticle such as ABRAXANE® and an antibody such as an anti-CD52 polypeptide antibody, an anti-CD20 polypeptide antibody or an anti-CD38 polypeptide antibody can include one or more other agents such as an alkylating agent (e.g., a platinum compound). Examples of platinum compounds that can be used as an alkylating agent include, without limitation, carboplatin (PARAPLATIN®), cisplatin (PLATINOL ®), oxaliplatin (ELOXATIN®), and BBR3464. Examples of other agents that can be included within an albumin-containing nanoparticle/antibody complex provided herein 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. For example, an albumin-containing nanoparticle/antibody complex provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complex, e.g., ABRAXANE®/anti-CD20 polypeptide antibody complex, and e.g., ABRAXANE®/anti-CD38 polypeptide antibody complex) can include brentuximab, cyclophosphamide, adriamycin, or vincristine as part of the complex.

[0035] Any appropriate method can be used to administer an albumin-containing nanoparticle/antibody complex provided herein (e.g., an ABRAXANE®/anti-CD52 polypeptide antibody complex, an ABRAXANE®/anti-CD20 polypeptide antibody complex, and an ABRAXANE®/anti-CD38 polypeptide antibody complex) to a mammal. For example, 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).

[0036] Before administering a composition containing an albumin-containing nanoparticle/antibody complex provided herein (e.g., ABRAXANE®/antibody complexes) to a mammal, the mammal can be assessed to determine whether or not the mammal has a hematologic cancer and, if so, what type of cancer it is, e.g., a leukemia, a lymphoma or myeloma. Any appropriate method can be used to determine whether or not a mammal has a hematologic cancer and the type of hematologic cancer. For example, a mammal (e.g., human) can be identified as having hematologic cancer, e.g., leukemia, lymphoma or myeloma, 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 a hematologic cancer.

[0037] After identifying a mammal as having hematologic cancer and the type of hematologic cancer, the mammal can be administered a composition containing albumin-containing nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complexes for a leukemia, ABRAXANE®/anti-CD20 polypeptide antibody complexes for a leukemia or lymphoma, or ABRAXANE®/anti-CD38 polypeptide antibody complexes for a myeloma).

[0038] A composition containing albumin-containing nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complexes, ABRAXANE®/anti-CD20 polypeptide antibody complexes or ABRAXANE®/anti-CD38 polypeptide antibody complexes) 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). In some cases, a composition containing albumin-containing nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complexes, ABRAXANE®/anti-CD20 polypeptide antibody complexes, or ABRAXANE®/anti-CD38 polypeptide antibody complexes) can be administered to a mammal having hematologic cancer to reduce the progression rate of the lymphoma by 5, 10, 25, 50, 75, 100, or more percent. For example, 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 hematologic cancer is reduced. For example, the progression rate of the hematologic cancer can be readily assessed. In one example, assaying blood samples or imaging tissue at different time points can be conducted to determine the amount of cancer cells present. The amounts of cancer cells determined within a blood sample or 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.

[0039] In some cases, the stage of cancer (e.g., leukemia, lymphoma, or myeloma) after treatment can be determined and compared to the stage before treatment to determine whether or not the progression rate was reduced.

[0040] In some cases, a composition containing albumin-containing nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complexes, ABRAXANE®/anti-CD20 polypeptide antibody complexes or ABRAXANE®/anti-CD38 polypeptide antibody complexes) can be administered to a mammal having a hematologic cancer 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 an untreated hematologic cancer of the same type or the median progression-free survival of corresponding mammals having a hematologic cancer treated with ABRAXANE® and an antibody (e.g., an anti-CD52 polypeptide antibody, an anti-CD20 polypeptide antibody, or an anti-CD38 polypeptide antibody) without forming ABRAXANE®/antibody complexes (e.g., without forming ABRAXANE®/anti-CD20 polypeptide antibody complexes). In some cases, a composition containing albumin- containing nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complexes, ABRAXANE®/anti-CD20 polypeptide antibody complexes, or ABRAXANE®/anti-CD38 polypeptide antibody complexes) can be administered to a mammal having a hematologic cancer 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 the hematologic cancer and having received ABRAXANE® or an antibody (e.g., an anti-CD52 polypeptide antibody, anti-CD20 polypeptide antibody, or anti-CD38 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).

[0041] In some cases, a composition containing albumin-containing nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complexes, ABRAXANE®/anti-CD20 polypeptide antibody complexes, or ABRAXANE®/anti-CD38 polypeptide antibody complexes) can be administered to a mammal having a hematologic cancer 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 nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complexes, ABRAXANE®/anti-CD20 polypeptide antibody complexes, or ABRAXANE®/anti-CD38 polypeptide antibody complexes). In some cases, a composition containing albumin-containing nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complexes, ABRAXANE®/anti-CD20 polypeptide antibody complexes, or ABRAXANE®/anti-CD38 polypeptide antibody complexes) can be administered to a mammal having a hematologic cancer 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).

[0042] The results presented herein see, e.g., FIG. 1, demonstrate that the dose of the albumin-containing nanoparticle/antibody complexes is critical in achieving inhibition and regression of tumor growth. An effective amount of a composition containing albumin-containing nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complexes, ABRAXANE®/anti-CD20 polypeptide antibody complexes, or ABRAXANE®/anti-CD38 polypeptide antibody complexes) can be any amount that reduces the progression rate of the hematologic cancer, increases the progression-free survival rate, or increases the median time to progression without producing significant toxicity to the mammal. An effective dosage amount of ABRAXANE® is from about 75 mg/m.sup.2 to about 250 mg/m.sup.2, 100 mg/m.sup.2 to about 200 mg/m.sup.2, or about 150 mg/m.sup.2. An effective dosage amount of an anti-CD52 polypeptide antibody, e.g., Alemtuzumab, anti-CD20 polypeptide antibody such as Rituximab, and anti CD38 polypeptide antibody, e.g., SAR650984 can be from about 17.5 mg/m.sup.2 to about 125 mg/m.sup.2, about 35 mg/m.sup.2 to about 100 mg/m.sup.2, and about 50 to about 100 mg/m.sup.2.

[0043] If a particular mammal fails to respond to a particular amount, then the amount of ABRAXANE® or anti-CD52, anti-CD20, or anti-CD38 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 hematologic cancer may require an increase or decrease in the actual effective amount administered.

[0044] The frequency of administration can be any frequency that reduces the progression rate of the hematologic cancer, increases the progression-free survival rate, or increases the median time to progression without producing significant toxicity to the mammal. For example, the frequency of administration can be from about once every three months, 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®/antibody complexes can include rest periods. For example, a composition containing ABRAXANE®/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. As with 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 hematologic cancer may require an increase or decrease in administration frequency.

[0045] An effective duration for administering a composition provided herein can be any duration that reduces the progression rate of the hematologic cancer, increases the progression-free survival rate, or increases the median time to progression without producing significant toxicity to the mammal. Thus, the effective duration can vary from several days to several weeks, months, or years. In general, the effective duration for the treatment of the hematologic cancer 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 hematologic cancer.

[0046] A composition containing albumin-containing nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complexes, ABRAXANE®/anti-CD20 polypeptide antibody complexes, or ABRAXANE®/anti-CD38 polypeptide antibody complexes) can be in any appropriate form. For example, 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.

[0047] After administering a composition provided herein to a mammal, the mammal can be monitored to determine whether or not the hematologic cancer was treated. For example, a mammal can be assessed after treatment to determine whether or not the progression rate of the cancer was reduced (e.g., stopped). As described herein, any method can be used to assess progression and survival rates.

[0048] In some cases, a formulation of ABRAXANE®/Rituxan complexes described in Example 1 can be administered to a human patient having a leukemia or a lymphoma to effect cancer cell death as described in the methods set forth in Example 2.

[0049] In some cases, nanoparticles containing albumin (e.g., nanoparticles with an albumin shell) and an agent other than paclitaxel can be used as described herein in place of or in combination with ABRAXANE®. For example, albumin-containing nanoparticles designed to carry a cancer chemotherapeutic agent can be used to form nanoparticle/anti-CD20 polypeptide antibody (or anti-CD52 polypeptide antibody or anti-CD38 polypeptide antibody) complexes that can be used as described herein. An example of such a cancer chemotherapeutic agent includes, without limitation, vinblastine and cyclophosphamide.

[0050] In some cases, a composition can be formulated to include nanoparticles 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 a hematologic cancer. For example, 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.

[0051] In some cases, nanoparticles containing albumin (e.g., nanoparticles with an albumin shell) or a complex described herein (e.g., ABRAXANE®/Alemtuzumab complexes, ABRAXANE®/SAR650984 complexes, or 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. For example, 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), or a combination thereof can be incorporated into nanoparticles containing albumin or ABRAXANE®/Alemtuzumab complexes, ABRAXANE®/SAR650984 complexes, or ABRAXANE®/Rituximab complexes. 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 nanoparticles containing albumin or ABRAXANE® I rituximab complexes.

[0052] Any appropriate method can be used to assess whether or not the global state of immune dysfunction and/or chronic inflammation was reduced following an anti-chronic inflammation treatment. For example, cytokine profiles (e.g., IL-4, IL-13, IL-4, IL-13, IL-5, IL-10, IL-2, and interferon gamma) present in blood can be assessed before and after an anti-chronic inflammation treatment to determine whether or not the global state of immune dysfunction and/or chronic inflammation was reduced.

[0053] Also contemplated herein are unit doses of the pharmaceutical compositions comprising albumin-containing nanoparticle/antibody complexes provided herein (e.g., ABRAXANE®/anti-CD52 polypeptide antibody complexes, ABRAXANE®/anti-CD20 polypeptide antibody complexes, or ABRAXANE®/anti-CD38 polypeptide antibody complexes). A suitable unit dose of the pharmaceutical composition may comprise about 75 mg/m.sup.2 to about 250 mg/m.sup.2, about 100 mg/m.sup.2 to about 200 mg/m.sup.2 , and about 150 mg/m.sup.2 paclitaxel, and from about 17.5 mg/m.sup.2 to about 125 mg/m.sup.2, about 35 mg/m.sup.2 to about 100 mg/m.sup.2, and about 50 to about 100 mg/m.sup.2 of an antibody described herein.

[0054] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

EXAMPLES

Example 1

[0055] Preparation of AR160 for mouse injections:

[0056] ABRAXANE® was reconstituted with Rituxan in 0.5 ml of 0.9% saline to provide a final concentration of 10 mg/ml paclitaxel and 4 mg/ml Rituxan. The solution was then incubated at room temperature for 30 minutes to allow the formation complexes of albumin-paclitaxel and Rituxan, AR160. The AR160 solution was then diluted in 0.9% saline as follows for administration to mice: For AR160 30, 60u1 of the AR160 solution was added to 40 ul 0.9% saline; For AR160 45, 90ul of AR160 solution was added to 10 ul 0.9% saline. 100 ul of AR160 30 or AR 160 45 were injected intravenously into lymphoma (Daudi cell line) tumor bearing athymic nude mice by the tail vein injection. The final concentration of each drug given to the mice were 30mg/kg paclitaxel and 12 mg/kg Rituxan for AR160 30 and 45mg/kg paclitaxel and 18 mg/kg Rituxan for AR160 45.

[0057] Controls for this experiment were 100 ul of 0.9% saline (PBS), 100 ul of ABRAXANE® resuspended in 0.9% saline to provide a dose of 30 mg/kg paclitaxel (ABX30), 100 ul of ABRAXANE® resuspended in 0.9% saline to provide a dose of 45 mg/kg paclitaxel (ABX45), 100 ul of Rituxan resuspended in 0.9% saline to provide a dose of 12 mg/kg (RIT12), and 100 ul of Rituxan resuspended in 0.9% saline to provide a dose of 18 mg/kg (RIT18), injected intravenously into lymphoma (Daudi cell line) tumor bearing athymic nude mice by tail vein injection.

[0058] The percent change in the tumor size from baseline and survival of were then monitored. The results are presented in FIG. 1 and FIG. 2.

[0059] FIG. 1 presents a graph plotting percent change at ten days in tumor size from baseline of the lymphoma bearing nude mice treated with PBS, RIT12, RIT18, ABX30, ABX45, AR160 30 and AR160 45.

[0060] FIG. 2 is a Kaplan Meier graph plotting survival of the mice treated with PBS, Rituxan (RIT12; 12 mg/kg) only, Rituxan (RIT18; 18 mg/kg) only ABX30 (30 mg/kg paclitaxel) only, ABX 45 (45 mg/kg paclitaxel) only, or AR160 complexes, AR160 30 (paclitaxel 30 mg/kg, RIT 12 mg/kg), AR160 45 (paclitaxel 45 mg/kg, RIT 18 mg/kg). At 80 days from administration 9/9 AR160 45 mice responded to therapy: 2 progressed and 7/9 had complete responses in that the tumor was undetectable by visual inspection. The graph illustrates the criticality of the effective dose of AR160 wherein the survival rate more than triples as compared to the effect of Rituxan or ABRAXANE® alone.

Example 2

[0061] ABRAXANE®/Rituxan complexes as Targeted Therapy for Lymphomas

[0062] A 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).

TABLE-US-00001 TABLE 1 Agent Dose Route Days ReRx ABRAXANE ®/ assigned at IV over 60 minutes 1, 8 and Every Rituxan time of (only 1.sup.st dose; 15 28 days* complexes registration subsequent doses infused over 30 minutes) *One treatment cycle = 28 days +/− 3 days

TABLE-US-00002 TABLE 2 Dose Escalation Scheme. Dose Level Dose (ABX) Dose (RIT) −2   75 mg/m.sup.2 30 mg/m.sup.2 −1  100 mg/m.sup.2 40 mg/m.sup.2   1* 125 mg/m.sup.2 50 mg/m.sup.2 2 150 mg/m.sup.2 60 mg/m.sup.2 3 175 mg/m.sup.2 70 mg/m.sup.2 *Starting dose.

TABLE-US-00003 TABLE 3 Dose Limiting Toxicities (DLT). Toxicity DLT Definition Hematologic Grade 4 ANC, Grade 4 Hgb, or PLT <25,000 Renal Serum creatinine ≧2 times baseline Other nonhematologic ≧grade 3 as per NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

[0063] ABRAXANE®/Rituxan Complexes

[0064] ABRAXANE®/Rittman 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.

[0065] Reconstituted ABRAXANE® is used immediately. Rituxan is classified as an anti-CD20 monoclonal antibody.

[0066] 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.

[0067] As with other cytotoxic anticancer drugs, caution is exercised in handling ABRAXANE®. The use of gloves is recommended.

[0068] Using a sterile 3 mL syringe, 1.6 mL (40 mg) of Rituxan 25 mg/mL is withdraw and slowly injected, over a minimum of 1 minute, onto the inside wall of each of the vials containing 100 mg of ABRAXANE®. Unused Rituxan left in the 25 mg/mL vial is discarded, as the product contains no preservatives. Injecting the Rituxan solution directly onto the lyophilized cake is avoided as this will result in foaming. Using a sterile 12 mL sterile syringe, 8.4 mL of 0.9% Sodium Chloride Injection, USP, is withdrawn and slowly injected, over a minimum of 1 minute, onto the inside wall of each vial containing ABRAXANE® 100 mg and Rituxan 40 mg. Once the addition of Rituxan 1.6 mL and 0.9% Sodium Chloride Injection, USP 8.4 mL is complete in each vial, each vial is gently swirled and/or inverted slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. The generation of foam is avoided. The concentration of each vial is 100 mg/10 mL ABRAXANE® and 40 mg/10 mL Rituxan. 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. After 60 minutes is elapsed, 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 Rittman 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.

[0069] Determination of Maximum Tolerated Dose (MTD)

[0070] 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.

[0071] Enrollment and Determination of MTD

[0072] A minimum of two or a maximum of six patients are accrued to a given dose level. For 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. For 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 tested, this is considered the MTD.

[0073] For this protocol, 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.

[0074] Dosage Modification Based on Adverse Events

[0075] The modifications in Table 4 are followed until individual treatment tolerance is ascertained. If multiple adverse events (Table 5) are seen, dose is administered based on greatest reduction required for any single adverse event observed. Dose modifications apply to the treatment given in the preceding cycle and are based on adverse events observed since the prior dose.

TABLE-US-00004 TABLE 5 Use Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0* unless otherwise specified CTCAE Category Adverse Event Dose Reduction Investigations ANC <1000 Day 1: Holduntil counts above these levels. or Day 8: Omit dose that day and retreat at same dose PLT <75,000 level on day 15 if counts have recovered. Day 15: Omit dose that day. NOTE: if two consecutive cycles of therapy require omission of a dose, subsequent treatment cycles should begin (day 1) at next lower dose. AST or Alkaline Day 1: Hold until resolved to <Grade 2 then reduce Phosphatase dose by ONE dose level. ≧Grade 2 If treatment needs to be held >4 weeks, discontinue study treatment and go to event monitoring. Neurology Neuropathy Day 1: Hold until resolved to <Grade 2 then reduce disorders ≧Grade 2 dose by ONE dose level. Day 8 OR 15- Omit dose that day. If resolved to <Grade 2 by next scheduled dose, then dose reduce by one level If treatment needs to be held >4 weeks, discontinue study treatment and go to Event Monitoring All other non- ≧Grade 3 Day 1: Hold until resolved to < Grade 2 then hematologic reduce dose by ONE dose level. adverse events Day 8: Omit dose that day. If resolved to ≦Grade 2 by day 15, then dose reduce by one level and retreat. Day 15: Omit dose that day. NOTE: if two consecutive cycles of therapy require omission of a dose, subsequent treatment cycles should begin (day 1) at next lower dose. If treatment needs to be held >4 weeks, discontinue study treatment and go to Event Monitoring Gastrointestinal Bowel Discontinue all study treatment and proceed to Disorders perforation Event Monitoring Bowel Obstruction Grade 1 Continue patient on study for partial bowel obstruction NOT requiring medical intervention. Grade 2 Hold for partial obstruction requiring medical intervention. If resolved to Grade 0 within 4 weeks, treatment may be restarted. If treatment needs to be held >4 weeks, discontinue all study treatment and go to Event Monitoring. Grade 3 or 4 For complete bowel obstruction, discontinue study treatment and proceed to Event Monitoring Cardiac Disorders Hypertension Hypertension should be treated as per general ≧Grade 3 practice. If hypertension (≧150/100) persists despite treatment, hold treatment until blood pressure is below this level If treatment needs to be held >4 weeks due to uncontrolled hypertension, discontinue study treatment and go to Event Monitoring. Left ventricular systolic function- Hold until resolution to Grade ≦1. If treatment Grade 3 needs to be held >4 weeks, discontinue all study treatment and go to Event Monitoring. Grade 4 Discontinue treatment and proceed to Event Monitoring Respiratory, Bronchopulmonary thoracic and Hemorrhage mediastinal ≧Grade 2 Discontinue all study treatment and proceed to disorders Event Monitoring Coagulation Hemorrhage Grade 3 Hold until ALL of the following criteria are met: 1. Bleeding has resolved and Hb is stable . 2. There is no bleeding diathesis that would increase the risk of therapy. 3. There is no anatomic or pathologic condition that could increase the risk of hemorrhage recurrence. Grade 4 If treatment needs to be held >4 weeks, discontinue study treatment and go to Event Monitoring Patients who experience a recurrence of Grade 3 hemorrhage are to discontinue all study treatment and proceed to Event Monitoring. Discontinue study treatment and proceed to Event Monitoring Bleeding Discontinue study treatment and proceed to Event diathesis Monitoring Grade 3 or 4 Vascular disorders Venous thrombosis Grade 3 Hold treatment. If the planned duration of full- or dose anticoagulation is <2 weeks, treatment asymptomatic should be held until the full-dose Grade 4 anticoagulation period is over. If 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 Symptomatic (usually 2-3) on a stable dose of warfarin, or on Grade 4 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. Discontinue treatment and proceed to Event Monitoring Arterial Discontinue treatment and proceed to Event thrombosis Monitoring (Angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, or any other arterial thromboembolic events) ANY Grade

[0076] Ancillary Treatment/Supportive Care

[0077] 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.

[0078] Patients should receive full supportive care while on this 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 antidiarrheals, analgesics, and anti-emetics received from the first administration of study drugs until 30 days after the final dose are to be recorded in the medical record. Patients participating in phase I program clinical trials are not to be considered for enrollment in any other study involving a pharmacologic agent-(drugs, biologics, immunotherapy approaches, gene therapy) whether for symptom control or therapeutic intent.

[0079] Hypersensitivity Reactions

[0080] Patients do not require premedication prior to administration of ABRAXANE®/Rituxan complexes. In the unlikely event of a hypersensitivity reaction, treatment with antihistamines, H2 blockers, and corticosteroids is recommended. Patients should be pre-medicated with the typical regimen for paclitaxel regimens for subsequent cycles. In the unlikely event of a mild hypersensitivity reaction, premedication may be administered using the premedication regimen the institution typically uses for solvent-based paclitaxel.

[0081] Administration

[0082] 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. An example calculation and preparation is as follows:

[0083] Dose level 1: ABRAXANE® 125 mg/m.sup.2/Rituxan 50 mg/m.sup.2 BSA=2 m.sup.2

[0084] Doses required: ABRAXANE® 250 mg/Rituxan 100 mg

[0085] Obtain three 100 mg vials of ABRAXANE®.

[0086] Obtain one 100 mg vial of Rituxan 25 mg/mL.

[0087] Withdraw 1.6 mL (40 mg) of Rituxan 25 mg/mL and slowly inject over 1 minute onto the inside wall of one of the 100 mg ABRAXANE® vials. Repeat this procedure for each of the remaining two ABRAXANE® 100 mg vials.

[0088] Add 8.4 mL 0.9% Sodium Chloride Injection, USP onto the inside wall of one of the vials containing ABRAXANE® and Rituxan. Repeat this procedure for each of the remaining two ABRAXANE® and Rituxan vials.

[0089] Let mixture sit for 60 minutes (swirling every 10 minutes). The final concentration of each vial should be 100 mg ABRAXANE®/10 mL and 40 mg Rituxan /10 mL.

[0090] Withdraw 25 mL from the ABRAXANE® and Rituxan containing vial and place in a 100 mL sterile syringe. Add 25 mL 0.9% Sodium Chloride Injection, USP for a final ABRAXANE® concentration of 5 mg/mL and Rituxan concentration of 2 mg/mL. Infuse via syringe pump over 60 minutes (first dose, 30 minutes subsequent doses).

[0091] Response to ABRAXANE®/Rituxan Complex Treatment

[0092] Each patient's response to treatment with a ABRAXANE®/Rituxan complex formulation is monitored.