WO2010105160A2

WO2010105160A2 - Method of treating hematological malignancies and hematological neoplasms

Info

Publication number: WO2010105160A2
Application number: PCT/US2010/027144
Authority: WO
Inventors: Debra K. Bowes; Allan L. Goldstein
Original assignee: Regenerx Biopharmaceuticals, Inc.
Priority date: 2009-03-13
Filing date: 2010-03-12
Publication date: 2010-09-16
Also published as: WO2010105160A3

Abstract

The invention relates to a method of treating hematological malignancies or hematological neoplasms in a subject, which comprises administering to a subject an effective amount of a peptide agent having actin-sequestering, actin-binding or actin-modulating peptide having a peptide motif as described herein, including the preferred motifs LKKTET (SEQ ID NO:10), KLKKTET (SEQ ID NO:25), LKKTETQ (SEQ ID NO:26) and LKKTNT (SEQ ID NO:11). Preferred peptides include TB4, a TB4 isoform, a TB4 N-terminal fragment, a TB4 C-terminal fragment, TB4^ala, TB9, TB10, TB11, TB12, TB13, TB14, TB15, gelsolin, vitamin D binding protein (DBP), profilin, cofilin, adsevertin, propomyosin, fincilin, depactin, DNaseI, vilin, fragmin, severin, capping protein, β-actinin, acumentin, TB4 sulfoxide, lymphoid TB4 or a functional variant thereof, and others, and any combination thereof. The method optionally further comprises administering a second agent, which can be a stimulating agent that stimulates production of the peptide agent and/or at least one antineoplastic agent.

Description

METHOD OF TREATING HEMATOLOGICAL MALIGNANCIES AND HEMATOLOGICAL NEOPLASMS

BACKGROUND OF THE INVENTION

[0001] This application claims the benefit of co-pending provisional application serial no. 61/160,029, filed March 13, 2009, the entire contents of which are hereby incorporated by reference.

Field of the Invention

[0002] The present invention relates to the field of treating hematological malignancies or hematological neoplasms.

Description of the Background Art

[0003] Multiple myeloma (also known as MM, myeloma, plasma cell myeloma, or Kahler's disease (after Otto Kahler)) is part of a broad group of diseases sometimes called hematological malignancies or hematological neoplasms. It is a cancer of plasma cells which are formed in bone marrow. Myeloma presently is regarded as incurable, but remissions may be induced with steroids, chemotherapy, thalidomide and stem cell transplants. Myeloma frequently becomes resistant to chemotherapies and to radiation, resulting in negative outcomes for the patient.

[0004] Leukemias (sometimes referred to as "liquid cancers" or "blood cancers") also belong to the hematological malignancies and encompass cancers of the bone marrow (the site of blood cell production). Leukemias, like other cancers, are characterized by an abnormal proliferation of blood cells. The disease often is associated with the overproduction of immature white blood cells (leukocytes). These immature white blood cells do not perform as well as normal mature cells, resulting in a tendency to suffer from infection. Leukemia also affects red blood cells and can cause poor blood clotting and fatigue due to anemia. Examples of leukemia include myelogenous or granulocytic leukemias (malignancy of the myeloid and granulocytic white blood cell series) , lymphatic, lymphocytic, or lymphoblastic leukemias (malignancy of the lymphoid and lymphocytic blood cell series) , and polycythemia vera or erythremia (malignancy of various blood cell products, but with red cells predominating). [0005] Because of the poor long-term prognosis with these cancers, there remains a distinct need in the art for methods and compositions for treating hematological malignancies and hematological neoplasms.

SUMMARY OF THE INVENTION

[0006] Therefore, in accordance with one aspect of the invention, a method of treating hematological malignancies or hematological neoplasms, comprises administering to a subject an effective amount of a pharmaceutical combination comprising a first component comprising a peptide agent comprising a polypeptide comprising at least one of TB4, an isoform of TB4, an N-terminal fragment of TB4, a C-terminal fragment of TB4, an N-terminal variant of TB4, a C-terminal variant of TB4, TB4ala, TB9, TB10, TB11 , TB12, TB13, TB14, TB15, gelsolin, vitamin D binding protein (DBP) profilin, cofilin, adsevertin, propomyosin, fincilin, depactin, DNasel, vilin, fragmin, severin, capping protein, β-actinin or acumentin, TB4 sulfoxide, lymphoid TB4 or a functional variant thereof, an LKKTET (SEQ ID NO:10) peptide or a conservative variant thereof, an LKKTNT (SEQ ID NO:11 ) peptide or a conservative variant thereof, a KLKKTET (SEQ ID NO:25) peptide or a conservative variant thereof, an LKKTETQ (SEQ ID NO:26) peptide or a conservative variant thereof, an oxidized or superoxidized modified normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof, isolated R-enantiomer thereof or isolated S-enantiomer thereof, a modified beta thymosin peptide, isoform, fragment or variant thereof having a non-methionine amino acid substituent substituted for at least one methionine of an amino acid sequence of a normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof, TB4 sulfone, TB4^ala sulfone, TB4^xen sulfone, TB4^met sulfone, TB10 sulfone, TB13 sulfone, TB4^leu, an actin-sequestering peptide, an actin binding peptide, an actin- mobilizing peptide or an actin polymerization-modulating peptide, or a stimulating agent that stimulates production of said polypeptide, or a conservative variant thereof, in said subject; said pharmaceutical combination further comprising at least one additional component comprising at least one additional antineoplastic agent for treating hematological malignancies or hematological neoplasms. Each component of the pharmaceutical combination of the invention may be administered separately or together.

[0007] In particular, embodiments of the invention include use of a peptide agent comprising at least one of Thymosin beta (TB)4, a TB4 isoform, an N-terminal fragment of TB4; a C-terminal fragment of TB4; an N-terminal variant of TB4; a C-terminal variant of TB4; TB3; TB4^ala; TB9; TB10; TB11 ; TB12; TB13; TB14; TB15; gelsolin; vitamin D binding protein (DBP); profilin; cofilin; adsevertin; propomyosin; fincilin; depactin; DNasel; vilin; fragmin; severin; capping protein; β-actinin; acumentin; TB4 sulfoxide; lymphoid TB4 or a functional variant thereof; an LKKTET (SEQ ID NO:10) peptide or a conservative variant thereof; an LKKTNT (SEQ ID NO:11 ) peptide or a conservative variant thereof; a KLKKTET (SEQ ID NO:25) peptide or a conservative variant thereof; an LKKTETQ (SEQ ID NO:26) peptide or a conservative variant thereof; an oxidized or superoxidized modified normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof isolated R-enantiomer thereof or isolated S-enantiomer thereof; a modified beta thymosin peptide, isoform, fragment or variant thereof having a non-methionine amino acid substituent substituted for at least one methionine of an amino acid sequence of a normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof; thymosin beta 4 sulfone; TB4^ala sulfone; TB4^xen sulfone; TB4^met sulfone; TB10 sulfone; TB13 sulfone; TB4^leu; an actin-sequestehng peptide; an actin binding peptide; an actin-mobilizing peptide; an actin polymerization- modulating peptide; or a stimulating agent that stimulates production of said polypeptide, or conservative variant thereof, for the treatment of a hematological malignancy or neoplasm in a subject. Preferred agents are TB4 or a TB4 isoform. [0008] Additional embodiments encompass uses wherein the peptide agent comprises a peptide selected from the group consisting of KLKKTET (SEQ ID NO:25), LKKTETQ (SEQ ID NO:26), an N-terminal variant of TB4, a C-terminal variant of TB4, and a TB4 isoform. Further embodiments include uses wherein said peptide agent is formulated for administration by direct administration to said subject, or by injection, or by intravenous, intraperitoneal, intramuscular, subcutaneous, transdermal or oral administration, to said subject, including uses wherein the peptide agent is formulated for administration systemically. The peptide agent may be formulated as a solution, tablet, capsule, gel, cream, paste, lotion, spray, suspension, dispersion, nebulization, aerosol, salve, hydrogel, ointment, foam or oil, and may be formulated in a dosage form for administration of a dosage within a range of 1 to 30 micrograms. [0009] Further embodiments include uses wherein the peptide agent is a recombinant or synthetic peptide and wherein the hematological malignancy or neoplasm is selected from the group consisting of myeloma, acute erythroid leukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, Burkitt's lymphoma, chronic lymphatic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, diffuse large B- cell lymphoma, erythremia, granulocytic leukemia, hairy cell leukemia, hepatosplenic T- cell lymphoma, Hodgkin's lymphoma, juvenile myelomonocytic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, myelogenous leukemia, NK-cell lymphoma, non- Hodgkin's lymphoma, polycythemia vera, post-transplant lymphoproliferative disorder, Sezary's syndrome, small lymphocytic leukemia, T-cell lymphoma, Waldenstrom's macroglobulinemia, and any subtype thereof. Preferably, the hematological malignancy or neoplasm is myeloma or a leukemia and the use further comprises the use of a second agent, wherein said agent is an antineoplastic agent, which can be selected from the group consisting of surgery, radiation, nitrogen mustards, aziridine, alkyl sulfonate, nitrosoureas, platinum complexes, nonclassic alkylators, folate analogs, purine analogs, adenosine analogs, pyrimidine analogs, substituted ureas, antitumor antibiotics, epipodophyllotoxins, taxanes, epothilones, vinca alkaloids, camptothecin analogs, anti-cancer enzymes, imidazotetrazinone analogs, oligonucleotides, integhn inhibitors, glutarimide analogs, 17AAG analogs, retinoids, PDGFR inhibitors, RAF-1 inhibitors, EGFR Inhibitors, mTOR inhibitors, 26S proteasome inhibitors, quinolinones, anti-CD20 antibody agents, HER2 mediators, anti-CD52 antibody agents, VEGF inhibitors, EGFR inhibitors, TRAIL receptor agonists, and any combination thereof. The peptide agent and said antineoplastic agent can be formulated in separate dosage forms or in a combined dosage form, for example the antineoplastic agent can be formulated for administration subsequent to administration of the peptide agent. [0010] Additional embodiments involve a method of treating a hematological malignancy or neoplasm which comprises administering to a subject in need thereof a peptide agent comprising at least one of Thymosin beta (TB)4, a TB4 isoform, an N- terminal fragment of TB4; a C-terminal fragment of TB4; an N-terminal variant of TB4; a C-terminal variant of TB4; TB3; TB4^ala; TB9; TB10; TB11 ; TB12; TB13; TB14; TB15; gelsolin; vitamin D binding protein (DBP); profilin; cofilin; adsevertin; propomyosin; fincilin; depactin; DNasel; vilin; fragmin; severin; capping protein; β-actinin; acumentin; TB4 sulfoxide; lymphoid TB4 or a functional variant thereof; an LKKTET (SEQ ID NO:10) peptide or a conservative variant thereof; an LKKTNT (SEQ ID NO:11 ) peptide or a conservative variant thereof; a KLKKTET (SEQ ID NO:25) peptide or a conservative variant thereof; an LKKTETQ (SEQ ID NO:26) peptide or a conservative variant thereof; an oxidized or superoxidized modified normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof isolated R-enantiomer thereof or isolated S-enantiomer thereof; a modified beta thymosin peptide, isoform, fragment or variant thereof having a non-methionine amino acid substituent substituted for at least one methionine of an amino acid sequence of a normally methionine- containing beta thymosin peptide, isoform, fragment or variant thereof; thymosin beta 4 sulfone; TB4^ala sulfone; TB4^xen sulfone; TB4^met sulfone; TB10 sulfone; TB13 sulfone; TB4^leu; an actin-sequestehng peptide; an actin binding peptide; an actin-mobilizing peptide; an actin polymerization-modulating peptide; or a stimulating agent that stimulates production of said polypeptide, or conservative variant thereof. Preferred peptide agents are TB4 or a TB4 isoform.

[0011] Additional embodiments include methods wherein the peptide agent comprises a peptide selected from the group consisting of KLKKTET (SEQ ID NO:25), LKKTETQ (SEQ ID NO:26), an N-terminal variant of TB4, a C-terminal variant of TB4, and a TB4 isoform. The methods of the invention are contemplated as involving administering the peptide agent by direct administration to said subject, or by injection, or by intravenous, intraperitoneal, intramuscular, subcutaneous, transdermal or oral administration, to said subject. Preferably the method involves administering the peptide agent system ical Iy. [0012] The peptide agents can be formulated as a solution, tablet, capsule, transdermal patch, gel, cream, paste, lotion, spray, suspension, dispersion, nebulization, aerosol, salve, hydrogel, ointment, foam or oil, and preferably are formulated to administer a dosage of about 1 to about 30 micrograms. The peptide agent can be a recombinant or synthetic peptide.

[0013] Further embodiments of the invention include methods wherein the hematological malignancy or neoplasm is selected from the group consisting of myeloma, acute erythroid leukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, Burkitt's lymphoma, chronic lymphatic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, erythremia, granulocytic leukemia, hairy cell leukemia, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, juvenile myelomonocytic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, myelogenous leukemia, NK-cell lymphoma, non-Hodgkin's lymphoma, polycythemia vera, post-transplant lymphoproliferative disorder, Sezary's syndrome, small lymphocytic leukemia, T-cell lymphoma, Waldenstrom's macroglobulinemia, and any subtype thereof, and preferably the hematological malignancy or neoplasm is myeloma or a leukemia.

[0014] The preferred methods of the invention are methods which further comprise administering a second agent, wherein said agent is an antineoplastic agent. This antineoplastic agent preferably is selected from the group consisting of surgery, radiation, nitrogen mustards, azihdine, alkyl sulfonate, nitrosoureas, platinum complexes, nonclassic alkylators, folate analogs, purine analogs, adenosine analogs, pyhmidine analogs, substituted ureas, antitumor antibiotics, epipodophyllotoxins, taxanes, epothilones, vinca alkaloids, camptothecin analogs, anti-cancer enzymes, imidazotetrazinone analogs, oligonucleotides, integrin inhibitors, glutarimide analogs, 17AAG analogs, retinoids, PDGFR inhibitors, RAF-1 inhibitors, EGFR Inhibitors, mTOR inhibitors, 26S proteasome inhibitors, quinolinones, anti-CD20 antibody agents, HER2 mediators, anti-CD52 antibody agents, VEGF inhibitors, EGFR inhibitors, TRAIL receptor agonists, and any combination thereof, and may be administered separately, or together with the peptide agent, for example the antineoplastic agent can be administered subsequent to administering the peptide agent.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The invention described and claimed herein relates to a method of treating hematological malignancies and hematological neoplasms, particularly those that are or have become resistant to standard anti-cancer therapies such as chemo- or radiotherapies, stem cell transplant therapy or gene therapies. This treatment involves administering to a patient Thymosin beta (TB)4 or a member of the family of peptides to which TB4 belongs, as described herein. These peptide compounds are able to increase the sensitivity of hematological neoplastic and/or malignant cells to standard anti-cancer therapies, such as chemo- and radiation therapies, that have proved ineffective, or only temporarily effective, in treating these diseases. [0016] Terminal deoxynucleotidyl transferase (TdT) is a non-template-directed DNA polymerase that catalyzes the polymerization of monophosphates and is located in the nucleus of immature lymphocytes, including thymocytes before they leave the thymus. TdT thus serves as a specific marker for immature lymphocytes. Lymphoid malignancies of immature cells usually are TdT-positive, whereas malignancies of mature lymphoid cells, such as chronic lymphatic leukemia, multiple myeloma, Sezary's syndrome, Burkitt's lymphoma, acute lymphoblastic leukemia and hairy cell leukemia, for example, are TdT-negative.

[0017] TB4 and the peptides described herein can convert a sub-population of TdT- negative bone marrow cells into TdT-positive cells. See Table I, below. This activity indicates that the peptides mimic the event or process that occurs naturally in the thymus medulla that is responsible for the maturation of bone marrow stem cells to immature thymocytes. TdT-positive status indicates immaturity and potential for pluhpotential differentiation, i.e. de-differentiation, as discussed above. It now has been discovered that TB4 can de-differentiate cells present in mature lymphoid malignancies that are or have become resistant to standard therapies, including chemotherapies and radiation therapies, and that, contrary to expectation, de-differentiation of the cancerous cells, rather than increasing the malignancy, increased the cells' sensitivity to other cancer therapeutic methods used to treat such mature blood and bone marrow cancers.

Table I Peptide Name Peptide Sequence SEQ ID NO:

Thymosin beta 4 Ac-SDKPDMAEI EKFDKSKLKKTET QEKNPLPSKETIEQEKQAGES

Thymosin beta 4_aι_a AC-ADKPDMAEI EKFDKSKLKKTET QEKNPLPSKETIEQEKQAGES

Thymosin beta 9 Ac-ADKPDLGEINSFDKAKLKKTET QEKNTLPTKETIEQEKQAK

Thymosin beta 10 Ac-ADKPDMGEIASFDKAKLKKTET QEKNTLPTKETIEQEKRSEIS

Thymosin beta 1 1 Ac-SDKPNLEEVASFDKTKLKKTET QEKNPLPTKETIEQEKQAS

Thymosin beta 12 Ac-SDKPDLAEVSNFDKTKLKKTET QEKNPLPTKETIEQEKQATA

Thymosin beta 13 Ac-ADKPDMGEIASFDKAKLKKTET QEKNTLPTKETIEQEKQAK

Thymosin beta 14 Ac-SDKPDISEVSSFDKTKLKKTET AEKNTLPTKETI EQEKTA

Thymosin beta 15 Ac-SDKPDLSEVETFDKSKLKKTNT EEKNTLPSKETIQQEKEYNQRS

[0018] An embodiment of the invention therefore encompasses a method of treating hematological malignancies or hematological neoplasms in a subject, comprising administering to the subject an effective amount of one or more of any of the peptides, modified peptides, variants, mutants, derivatives, or fragments discussed herein, including any combination thereof. The invention therefore contemplates pharmaceutical compositions comprising any of the peptides discussed herein, including the preferred peptides TB4, the TB4 isoforms TB4^ala, TB9, TB10, TB11 , TB12, TB13, TB14 and TB15, and further comprising a pharmaceutically acceptable carrier. The peptides useful in the invention may be isolated from a natural source or may be synthetic or recombinant.

[0019] The hematological malignancies and neoplasms that can be treated according to the methods of the invention include any cancer of the blood or bone marrow that affects mature lymphoid cells. The hematological malignancies and neoplasms that are contemplated for this invention include, but are not limited to myelomas and any of the leukemias and lymphomas of mature, TdT-negative lymphoid cells, for example: acute erythroid leukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, Burkitt's lymphoma, chronic lymphatic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T- cell lymphoma, diffuse large B-cell lymphoma, erythremia, granulocytic leukemia, hairy cell leukemia, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, juvenile myelomonocytic leukemia, Kahler's disease, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, multiple myeloma, myelogenous leukemia, NK-cell lymphoma, non- Hodgkin's lymphoma, plasma cell myeloma, polycythemia vera, post-transplant lymphoproliferative disorder, Sezary's syndrome, small lymphocytic leukemia, T-cell lymphoma, Waldenstrom's macroglobulinemia, and any subtype thereof. Once the malignancy or neoplasm has been sensitized to anti-neoplastic therapy, it is contemplated that the cancer preferably is treated subsequently with an anti-cancer treatment such as any known cancer chemotherapy, radiation therapy, surgery, or another cancer treatment. Persons of skill in the art, such as oncologists, are aware of anti-cancer treatments, which usually are tumor-specific, and any of these are contemplated for use with the invention. [0020] In another embodiment, the invention encompasses a method of treating these hematological malignancies or hematological neoplasms in a subject, comprising administering an effective amount of a combination which includes a peptide agent, including one or more of any of the peptides, modified peptides, variants, mutants, derivatives, or fragments discussed herein. Combinations contemplated as part of the invention include a combination of one or more peptide agent as discussed herein, and further include a second agent. The agent can be an antineoplastic agent, as discussed herein, for example in the context of pharmaceutical compositions, for use in the invention, an agent that stimulates production of one or more of the peptide agents discussed herein, a radiation therapy, surgery, or any other known cancer treatment. [0021] Although any known anti-cancer agent may be used, the preferred cancer therapies contemplated for use in embodiments of the invention include, for example, treatment with one or more of the exemplary classes of oncology treatments listed in Table II, below, and combinations thereof, and include antibody agents, targeted toxin treatments, cell therapies, gene therapies, surgery or radiation. See Table Il for non- limiting examples of classes of cancer chemotherapeutic agents which may be used with the invention. Further examples of anti-cancer agents also include antimetabolites, topomerase Il inhibitors, free radical generators, anthracyclines, immunosuppressants, antibody-targeted toxins, and the like. Combinations of these agents, the agents of Table II, or any suitable anti-cancer agents also are contemplated, as is a use of an anti-cancer agent with radiation treatment, surgery or any non-chemotherapeutic anticancer agent.

Table II. Exemplary Classes of Oncology Treatments

In other embodiments, the invention encompasses the use of a peptide agent as discussed herein in the manufacture of a medicament for treatment of a hematological malignancy or neoplasm and compositions for use in the treatment of hematological malignancies or neoplasm.

[0022] The subject preferably is a human or other animal, and most preferably is a non-human mammal or a human. The administering may be directly, orally, by inhalation or systemically. Examples of direct administration include, for example, direct application, injection or infusion, with a solution, lotion, salve, gel, cream, paste, spray, suspension, dispersion, nebulization, aerosol, hydrogel, ointment, transdermal or other patch, foam or oil comprising a peptide agent as described herein. Systemic administration includes, for example, intravenous, intraperitoneal, intramuscular or other injections, or by inhalation, topically or transdermally, of a composition containing a peptide agent as described herein, in a pharmaceutically acceptable carrier such as water for injection. Suitable compositions, dosage amounts and routes of administration are discussed below in the context of the compositions which are contemplated for use with the invention.

[0023] The components of a combination in accordance with the present invention can be administered separately or together in a regimen daily, every other day, every other week, every other month, etc., with a single application or multiple applications per day of administration, such as applications 2, 3, 4 or more times per day of administration. [0024] Thymosin beta 4 (TB4) is a thymic peptide hormone which has been identified in a variety of tissues and was initially isolated from thymosin fraction 5, a known thymus preparation. TB4 is a 43 amino acid, 4.9 kDa ubiquitous polypeptide (SEQ ID NO:1 ) that is up-regulated during endothelial cell migration and differentiation in vitro. TB4 is a member of a family of actin-sequestering or actin-binding peptides that each contain the amino acid motif, LKKTET (SEQ ID NO:10) or an active or conservative variant thereof. This family of peptides and the motifs they share have been recognized in the art and includes, for example, oxidized and superoxidized forms of TB4, a number of isoforms and active fragments of TB4, enantiomers, and modified or mutant TB4 peptides that have non-methionine amino acid substituents in place of methionine residues in normally methionine-containing beta thymosin peptides, and variations of such peptides. All of these peptides are contemplated for use with the embodiments of this invention. International Application Serial No. PCT/US2006/001141 , incorporated herein by reference in its entirety, discloses TB4 peptides, including oxidized or superoxidized modified normally methionine-containing beta thymosin peptides, isoforms thereof, fragments thereof, isolated R-enantiomers thereof or isolated S- enantiomers thereof, modified beta thymosin peptides, isoforms and fragments thereof having non-methionine amino acid substituents substituted for methionines of the amino acid sequences of a normally methionine-containing beta thymosin peptides, isoforms and fragments thereof. All of these peptides also are contemplated for use in the embodiments of this invention.

[0025] The actin-sequestehng/actin-binding or actin modulating activity of this family of peptides (e.g., depolymehzing F-actin by sequestering free G-actin) is necessary for and allows these compounds to exhibit the activities on TdT and cancer cell responsiveness to therapy. The peptide sequence motifs that impart actin-sequestehng or actin-binding activity include LKKTET (SEQ ID NO:10), LKKTNT (SEQ ID NO:11 ), FKHWP (SEQ ID NO:12), LKERLQ (SEQ ID NO:13), LKSKMI (SEQ ID NO:14), LKMKYS (SEQ ID NO:15), LKKEKG (SEQ ID NO:16), LKHIES (SEQ ID NO:17), LKHAET (SEQ ID NO:18), LKEAET (SEQ ID NO:19), RKHAET (SEQ ID NO:20), LKRAES (SEQ ID NO:21 ), LRRAEC (SEQ ID NO:22), LKHIES (SEQ ID NO:23), and LKSAET (SEQ ID NO:24), and conservative variants thereof. Therefore, actin- modulating peptides containing any of these motifs or a conservative variant thereof are considered members of the TB4 family of peptides which are useful in the invention here. Preferred peptides have at least one of the above peptide motif sequences and are 70% or more homologous to TB4 or a TB4 isomer, and may or may not be N- acetylated. Preferred peptides also optionally are oxidized and/or contain a substitution of the initial methionine amino acid residue. Preferred peptides also are fragments of these peptides that contain the motif.

[0026] As used herein, the term "conservative variant," or grammatical variations thereof, denotes the replacement of an amino acid residue by another, biochemically similar residue, such as are known in the art. Examples of conservative variations include the replacement of a hydrophobic residue such as isoleucine, valine, leucine or methionine with another, the replacement of a polar residue for another, such as the substitution of arginine with lysine, glutamic acid with aspartic acid, or glutamine with asparagine, and the like. Therefore, peptides having a motif with these conservative substitutions are useful in the invention, including functional variants, mutants or fragments of these peptides which may contain other substitutions of amino acids in the sequence elsewhere than the motif sequence. Preferred amino acid substitutions include leucine, valine, isoleucine, alanine, phenylalanine and/or proline. A specific example is a TB4 peptide which comprises a modified TB4 amino acid sequence having leucine substituted for methionine at position 6 thereof. Derivatives of these peptides also are contemplated for use in the invention, including oxidized forms of the peptides, such as superoxidized sulfones (including TB4 sulfone, TB4^ala sulfone, TB4^xen sulfone, TB4^met sulfone, TB10 sulfone and TB13 sulfone, for example. A functional variant, mutant, derivative or fragment as described herein are intended to encompass any variant, mutant or fragment of the specifically disclosed compounds discussed herein which have at least 25% of the activity of TB4 and/or the peptide to which the variant, mutant or fragment corresponds, and more preferably has at least 50%, 60%, 70%, 80%, 90%, 95%, 99% or more of said activity.

[0027] Non-limiting examples of peptides which are included in the family of peptides having the activity useful in the method of this invention and a motif as described above include TB3, TB4, lymphoid TB4, TB4^ala, TB4^leu, TB4^xen, TB9^met, TB10, TB11 , TB12, TB13, TB14, TB15, any TB4 isoform, gelsolin, vitamin D binding protein (DBP) profilin, cofilin, adsevertin, propomyosin, fincilin, depactin, DNasel, vilin, fragmin, severin, capping protein, β-actinin or acumentin, and specifically include the peptides KLKKTET (SEQ ID NO:25) and LKKTETQ (SEQ ID NO:26) and peptides comprising or consisting essentially of SEQ ID NOs: 25 and 26. Thus, the term "family of peptides" refers to any of the peptides disclosed herein. Sequences of certain TB4 isoforms are known in the art and have been published in Huff et al., Intl. J. Biochem. Cell Biol. 33:205-220, 2001 , which is incorporated herein by reference in its entirety.

[0028] Compositions which may be used in accordance with the present invention include any peptide described herein, or preferred peptide agents such as TB4 and/or TB4 isoforms, analogs or derivatives, including oxidized TB4, lymphoid TB4 or a functional variant thereof, N-terminal variants of TB4, C-terminal variants of TB4, polypeptides or peptide fragments comprising or consisting essentially of the amino acid sequence LKKTET (SEQ ID NO:10) or LKKTNT (SEQ ID NO:11 ), or conservative variants thereof, for treating hematological malignancies or hematological neoplasms as described herein. International Application Serial No. PCT/US99/17282, incorporated herein by reference, discloses isoforms of TB4 which may be useful in accordance with the present invention as well as amino acid sequence LKKTET (SEQ ID NO:10) and conservative variants thereof, which may be used with the present invention. International Application Serial No. PCT/GB99/00833 (WO 99/49883), incorporated herein by reference, discloses oxidized TB4, which may be used in accordance with the present invention.

[0029] Although the present invention may be described primarily in terms of TB4 or TB4 isoforms in the description here, the description is intended to be equally applicable to a polypeptide comprising at least one of any of the beta thymosin or other peptides having a peptide motif as discussed above, including, for example, TB4, polymers of TB4 or TB4 sequences, a TB4 isoform, an N-terminal fragment of TB4, a C-terminal fragment of TB4, an N-terminal variant of TB4, a C-terminal variant of TB4, TB4^ala, TB9, TB10, TB11 , TB12, TB13, TB14, TB15, gelsolin, vitamin D binding protein (DBP) profilin, cofilin, adsevertin, propomyosin, fincilin, depactin, DNasel, vilin, fragmin, severin, capping protein, β-actinin or acumentin, TB4 sulfoxide, lymphoid TB4 or a functional variant thereof, an LKKTET (SEQ ID NO:10) peptide or a conservative variant thereof, an LKKTNT (SEQ ID NO:11 ) peptide or a conservative variant thereof, a KLKKTET (SEQ ID NO:25) peptide or a conservative variant thereof, an LKKTETQ (SEQ ID NO:26) peptide or a conservative variant thereof, an oxidized or superoxidized modified normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof, isolated R-enantiomer thereof or isolated S-enantiomer thereof, a modified beta thymosin peptide, isoform, fragment or variant thereof having a non- methionine amino acid substituent substituted for at least one methionine of an amino acid sequence of a normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof, TB4 sulfone, TB4^ala sulfone, TB4^xen sulfone, TB4^met sulfone, TB10 sulfone, TB13 sulfone, TB4^leu, an actin-sequestering peptide, an actin binding peptide, an actin-mobilizing peptide, an actin polymerization-modulating peptide or a functional fragment or variant of any of the above, or consisting essentially of said polypeptide, isoform, fragment or variant.

[0030] Many TB4 isoforms have been identified and have about 70%, or about 75%, or about 80% or more homology to the known amino acid sequence of TB4. Such isoforms include, for example, TB4^ala, TB9, TB10, TB11 , TB12, TB13, TB14 and TB15. Similar to TB4, the TB10 and TB15 isoforms, for example, have been shown to sequester actin. In addition, the peptide agents described here, such as TB4 and TB4 isoforms, including oxidized TB4, decrease inflammatory chemokine, cytokine and caspase activity. As such, TB4 isoforms and the peptides and modified peptides described here are useful in the methods of the invention, including the methods practiced in a subject. Thus, it is specifically contemplated that known TB4 isoforms, such as TB4^ala, TB9, TB10, TB11 , TB12, TB13, TB14 and TB15, as well as TB4 isoforms not yet identified, will be useful in the methods of the invention. [0031] In general, the pharmaceutical compositions can be prepared in various forms, such as tablets, capsules, powders, lozenges, granules, solutions, suspensions, oils and the like for oral delivery; solutions, suspensions, and the like for intravenous administration, intramuscular administration, subcutaneous administration, intrathecal administration or delivery to a body cavity, aerosols, powders, mists and the like for intranasal or inhalation administration; ointments, creams, oils, butters, salves, lotions, transdermal patches and the like for topical or transdermal delivery; or any suitable pharmaceutical excipient known in the art for convenient delivery of the active agent(s) to the subject suffering from a hematological malignancy or neoplasm. The agent preferably is administered systemically (for example intravenously), but may be administered by any convenient route (for example, but not limited to, direct administration, local injection, inhalation). In general, any pharmaceutical grade organic or inorganic carher(s) and/or diluent(s) use can be used to make up compositions comprising the therapeutically active compounds. Diluents known to the art include aqueous media, vegetable and animal oils, fats, or other liquids, gases or solids. The pharmacological compositions may include non-active ingredients as needed for convenience, bioavailability, stability, and the like. For example, pH modifiers and/or buffers and buffer systems, stabilizers, antioxidants, preservatives (such as bacteriostats, antimicrobials, antivirals, antifungals or other anti-pathogenic agents), wetting and emulsifying agents, chelating agents, salts for varying the osmotic pressure, or compounds to modify oncotic pressure or buffers for securing an adequate pH value can be used as auxiliary agents in the pharmaceutical compositions. [0032] The preferred dosage of the active agent(s) administered in the methods of the invention will depend on many factors, including the size and health of a subject, and the severity and type of disease. However, persons of ordinary skill in the art can use teachings describing the methods and techniques for determining dosages as disclosed in PCT/US99/17282, supra, and the references cited therein, to determine the appropriate dosage to use. Suitable formulations for administration of a peptide should be formulated preferably to administer the peptide agent as described herein at a concentration within the range of about 0.001 % to about 50% by weight, more preferably within the range of about 0.01 % to about 0.1 % by weight, and most preferably about 0.05% by weight. Suitable formulations also may be produced in accordance with one embodiment, to be administered in a composition at a concentration within a range of about 0.01 nanograms/mL to about 1.0 micrograms/mL, more preferably within a range of about 0.1 nanograms/mL to about 100 micrograms/mL, and most preferably within a range of about 1 nanogram/mL to about 10 micrograms/mL or about 10 nanograms/mL to about 5 micrograms/mL. [0033] The peptide agent(s) for use in the invention, as described herein, may be administered in any effective amount and any effective dosage schedule. For example, TB4, a TB4 isoform or any a peptide agent or combination of peptide agents as described herein may be administered in dosages within the range of about 0.0001 micrograms to about 1 gram, more preferably in amounts within the range of about 0.1 micrograms to about 5 milligrams, and most preferably within the range of about 1 microgram to about 30 micrograms.

[0034] In another embodiment of the invention, the peptides of the invention may be used in combination with one or more other agents in a treatment of hematologic malignancy or neoplasm. Preferred combinations of this type comprise a first component comprising a peptide agent (which may be a polypeptide comprising at least one of TB4, an isoform of TB4, an N-terminal fragment of TB4, a C-terminal fragment of TB4, an N-terminal variant of TB4, a C-terminal variant of TB4, TB4^ala, TB9, TB10, TB11 , TB12, TB13, TB14, TB15, gelsolin, vitamin D binding protein (DBP) profilin, cofilin, adsevertin, propomyosin, fincilin, depactin, DNasel, vilin, fragmin, severin, capping protein, β-actinin or acumentin, TB4 sulfoxide, lymphoid TB4 or a functional variant thereof, an LKKTET (SEQ ID NO:10) peptide or a conservative variant thereof, an LKKTNT (SEQ ID NO:11 ) peptide or a conservative variant thereof, a KLKKTET (SEQ ID NO:25) peptide or a conservative variant thereof, an LKKTETQ (SEQ ID NO:26) peptide or a conservative variant thereof, any peptide that contains the LKKTET (SEQ ID NO:10) motif or a related motif as described herein, or a member of this family of peptides, an oxidized or superoxidized modified normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof, isolated R-enantiomer thereof or isolated S-enantiomer thereof, a modified beta thymosin peptide, isoform, fragment or variant thereof having a non-methionine amino acid substituent substituted for at least one methionine of an amino acid sequence of a normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof, TB4 sulfone, TB4^ala sulfone, TB4^xen sulfone, TB4^met sulfone, TB10 sulfone, TB13 sulfone, TB4^leu, an actin- sequestehng peptide, an actin binding peptide, an actin-mobilizing peptide, or an actin polymerization-modulating peptide) and at least a second component comprising one or more antineoplastic agents for treating hematological malignancies or hematological neoplasms. Each component of the pharmaceutical combination of the invention is contemplated for administration separately or together, simultaneously or sequentially. [0035] The antineoplastic agent(s) in the combination can be any antineoplastic or anti-cancer agent contemplated for beneficial use in the treatment of a hematological malignancy or neoplasm, including, for example, any of the agents listed in Table II, cell therapy, gene therapy, radiation, surgery, or any combination of these. See Table II, above for an exemplary list of classes of chemotherapy agent types which can be useful in the invention. The additional antineoplastic agent(s) may be administered at any appropriate dosage for treating hematological malignancies or neoplasms as determined by a treating physician or other person of skill in the art. Such dosages are well known in the art.

[0036] In addition, other agents or proteins having anti-inflammatory activity and/or actin sequestering or binding capability, or that can mobilize actin or modulate actin polymerization, as demonstrated in an appropriate sequestering, binding, mobilization or polymerization assay, or identified by the presence of an amino acid sequence that mediates actin binding, such as LKKTET (SEQ ID NO:10), LKKTNT (SEQ ID NO:11 ) or any of the peptide motifs listed above, or a conservative variant thereof, for example, can similarly be employed in the methods of the invention. For example, any combination of the peptides discussed above may be used. An example of a peptide combination include a TB4 peptide or TB4 isoform combined with gelsolin, vitamin D binding protein (DBP), profilin, cofilin, depactin, DNasel, vilin, fragmin, severin, capping protein, β-actinin or acumentin, to be administered sequentially or simultaneously, in separate pharmaceutical dosage forms or in a combination pharmaceutical dosage form. As such methods include those practiced in a subject, the invention further provides pharmaceutical compositions comprising any combination of 2 or more of the peptides discussed above, such as TB4, a TB4 isoform, gelsolin, vitamin D binding protein (DBP), profilin, cofilin, depactin, DNasel, vilin, fragmin, severin, capping protein, β-actinin, acumentin, and the like, as set forth herein.

[0037] TB4 is produced in a number of tissues and cell types. Thus, agents which stimulate the production of TB4, a TB4 isoform or any other natural peptide such as at least one of TB4, a TB4 isoform, TB4ala, TB3, TB9, TB10, TB11 , TB12, TB13, TB14, TB15, gelsolin, vitamin D binding protein (DBP), profilin, cofilin, adsevertin, propomyosin, fincilin, depactin, DNasel, vilin, fragmin, severin, capping protein, β-actinin or acumentin, lymphoid TB4, or an oxidized or superoxidized, modified normally methionine-containing, or any modified, variant or mutant thereof produced in the body of the subject thereof, or any known functional actin-sequestering/binding/mobilizing peptide, in said subject optionally can be further included in pharmaceutical combinations and for use in the method of the invention for a combination treatment. Such stimulating agents generally include members of the family of growth factors, such as insulin-like growth factor (IGF-1 ), platelet derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor beta (TGF-β), basic fibroblast growth factor (bFGF), thymosin alpha 1 (TA1 ) and vascular endothelial growth factor (VEGF). More preferably, the stimulating agent is transforming growth factor beta (TGF-β) or other members of the TGF-β superfamily, which are known in the art. In accordance with embodiments involving agents which stimulate the production of an active peptide agent as described above or administration of such stimulating agents to a subject for treatment of a hematological malignancy or neoplasm, the second component is administered to the subject in combination with a peptide agent as described as useful for the invention herein, simultaneously or sequentially, in separate or one combined pharmaceutical dosage form. Suitable doses for administration of these stimulating agents are known in the art and can be optimized by the person of skill. For example, stimulating agents may be administered in any suitable dosage form in a concentration of, for example within in a range of about 10 picograms/mL to about 1 microgram/mL, more preferably within a range of about 100 picograms/mL to about 100 nanograms/mL, and most preferably within a range of about 1 nanogram/mL to about 50 nanograms/mL.

Claims

1. Use of a peptide agent comprising at least one of Thymosin beta (TB)4, a TB4 isoform, an N-terminal fragment of TB4; a C-terminal fragment of TB4; an N-terminal variant of TB4; a C-terminal variant of TB4; TB3; TB4^ala; TB9; TB10; TB11 ; TB12; TB13; TB14; TB15; gelsolin; vitamin D binding protein (DBP); profilin; cofilin; adsevertin; propomyosin; fincilin; depactin; DNasel; vilin; fragmin; severin; capping protein; β- actinin; acumentin; TB4 sulfoxide; lymphoid TB4 or a functional variant thereof; an LKKTET (SEQ ID NO:10) peptide or a conservative variant thereof; an LKKTNT (SEQ ID NO:11 ) peptide or a conservative variant thereof; a KLKKTET (SEQ ID NO:25) peptide or a conservative variant thereof; an LKKTETQ (SEQ ID NO:26) peptide or a conservative variant thereof; an oxidized or superoxidized modified normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof isolated R-enantiomer thereof or isolated S-enantiomer thereof; a modified beta thymosin peptide, isoform, fragment or variant thereof having a non-methionine amino acid substituent substituted for at least one methionine of an amino acid sequence of a normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof; thymosin beta 4 sulfone; TB4^ala sulfone; TB4^xen sulfone; TB4^met sulfone; TB10 sulfone; TB13 sulfone; TB4^leu; an actin-sequestering peptide; an actin binding peptide; an actin-mobilizing peptide; an actin polymerization-modulating peptide; or a stimulating agent that stimulates production of said polypeptide, or conservative variant thereof, for the treatment of a hematological malignancy or neoplasm in a subject.

2. The use of claim 1 , wherein said peptide agent is TB4 or a TB4 isoform.

3. The use of claim 1 , wherein said peptide agent is TB4.

4. The use of claim 1 wherein said peptide agent comprises a peptide selected from the group consisting of KLKKTET (SEQ ID NO:25), LKKTETQ (SEQ ID NO:26), an N- terminal variant of TB4, a C-terminal variant of TB4, and a TB4 isoform.

5. The use of claim 1 , wherein said peptide agent is formulated for administration by direct administration to said subject, or by injection, or by intravenous, intraperitoneal, intramuscular, subcutaneous, transdermal or oral administration, to said subject.

6. The use of claim 1 , wherein said peptide agent is formulated for administration systemically.

7. The use of claim 1 , wherein said peptide agent is formulated as a solution, tablet, capsule, gel, cream, paste, lotion, spray, suspension, dispersion, nebulization, aerosol, salve, hydrogel, ointment, foam or oil.

8. The use of claim 1 , wherein said peptide agent is formulated in a dosage form for administration of a dosage within a range of 1 to 30 micrograms.

9. The use of claim 1 , wherein said peptide agent is a recombinant or synthetic peptide.

10. The use of claim 1 , wherein said hematological malignancy or neoplasm is selected from the group consisting of myeloma, acute erythroid leukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, Burkitt's lymphoma, chronic lymphatic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, diffuse large B- cell lymphoma, erythremia, granulocytic leukemia, hairy cell leukemia, hepatosplenic T- cell lymphoma, Hodgkin's lymphoma, juvenile myelomonocytic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, myelogenous leukemia, NK-cell lymphoma, non- Hodgkin's lymphoma, polycythemia vera, post-transplant lymphoproliferative disorder, Sezary's syndrome, small lymphocytic leukemia, T-cell lymphoma, Waldenstrom's macroglobulinemia, and any subtype thereof.

11. The use of claim 1 , wherein said hematological malignancy or neoplasm is myeloma or a leukemia.

12. The use of claim 1 , which further comprises the use of a second agent, wherein said agent is an antineoplastic agent.

13. The use of claim 12, wherein said antineoplastic agent is selected from the group consisting of surgery, radiation, nitrogen mustards, aziridine, alkyl sulfonate, nitrosoureas, platinum complexes, nonclassic alkylators, folate analogs, purine analogs, adenosine analogs, pyrimidine analogs, substituted ureas, antitumor antibiotics, epipodophyllotoxins, taxanes, epothilones, vinca alkaloids, camptothecin analogs, anticancer enzymes, imidazotetrazinone analogs, oligonucleotides, integrin inhibitors, glutarimide analogs, 17AAG analogs, retinoids, PDGFR inhibitors, RAF-1 inhibitors, EGFR Inhibitors, mTOR inhibitors, 26S proteasome inhibitors, quinolinones, anti-CD20 antibody agents, HER2 mediators, anti-CD52 antibody agents, VEGF inhibitors, EGFR inhibitors, TRAIL receptor agonists, and any combination thereof.

14. The use of claim 12, wherein said peptide agent and said antineoplastic agent are formulated in separate dosage forms.

15. The use of claim 13, wherein said peptide agent and said antineoplastic agent are formulated in a combined dosage form.

16. The use of claim 14, wherein said antineoplastic agent is formulated for administration subsequent to administration of said peptide agent.

17. A method of treating a hematological malignancy or neoplasm which comprises administering to a subject in need thereof a peptide agent comprising at least one of Thymosin beta (TB)4, a TB4 isoform, an N-terminal fragment of TB4; a C-terminal fragment of TB4; an N-terminal variant of TB4; a C-terminal variant of TB4; TB3; TB4^ala; TB9; TB10; TB11 ; TB12; TB13; TB14; TB15; gelsolin; vitamin D binding protein (DBP); profilin; cofilin; adsevertin; propomyosin; fincilin; depactin; DNasel; vilin; fragmin; severin; capping protein; β-actinin; acumentin; TB4 sulfoxide; lymphoid TB4 or a functional variant thereof; an LKKTET (SEQ ID NO:10) peptide or a conservative variant thereof; an LKKTNT (SEQ ID NO:11 ) peptide or a conservative variant thereof; a KLKKTET (SEQ ID NO:25) peptide or a conservative variant thereof; an LKKTETQ (SEQ ID NO:26) peptide or a conservative variant thereof; an oxidized or superoxidized modified normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof isolated R-enantiomer thereof or isolated S-enantiomer thereof; a modified beta thymosin peptide, isoform, fragment or variant thereof having a non- methionine amino acid substituent substituted for at least one methionine of an amino acid sequence of a normally methionine-containing beta thymosin peptide, isoform, fragment or variant thereof; thymosin beta 4 sulfone; TB4^ala sulfone; TB4^xen sulfone; TB4^met sulfone; TB10 sulfone; TB13 sulfone; TB4^leu; an actin-sequestering peptide; an actin binding peptide; an actin-mobilizing peptide; an actin polymerization-modulating peptide; or a stimulating agent that stimulates production of said polypeptide, or conservative variant thereof.

18. The method of claim 17, wherein said peptide agent is TB4 or a TB4 isoform.

19. The method of claim 17, wherein said peptide agent is TB4.

20. The method of claim 17, wherein said peptide agent comprises a peptide selected from the group consisting of KLKKTET (SEQ ID NO:25), LKKTETQ (SEQ ID NO:26), an N-terminal variant of TB4, a C-terminal variant of TB4, and a TB4 isoform.

21. The method of claim 17, which comprises administering said peptide agent by direct administration to said subject, or by injection, or by intravenous, intraperitoneal, intramuscular, subcutaneous, transdermal or oral administration, to said subject.

22. The method of claim 17, which comprises administering said peptide agent systemically.

23. The method of claim 17, wherein said peptide agent is formulated as a solution, tablet, capsule, transdermal patch, gel, cream, paste, lotion, spray, suspension, dispersion, nebulization, aerosol, salve, hydrogel, ointment, foam or oil.

24. The method of claim 17, wherein said peptide agent is administered at a dosage of about 1 to about 30 micrograms.

25. The method of claim 17, wherein said peptide agent is a recombinant or synthetic peptide.

26. The method of claim 17, wherein said hematological malignancy or neoplasm is selected from the group consisting of myeloma, acute erythroid leukemia, acute lymphoblastic leukemia, acute monocytic leukemia, acute myeloid leukemia, acute myelogenous leukemia, Burkitt's lymphoma, chronic lymphatic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, erythremia, granulocytic leukemia, hairy cell leukemia, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, juvenile myelomonocytic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, myelogenous leukemia, NK- cell lymphoma, non-Hodgkin's lymphoma, polycythemia vera, post-transplant lymphoproliferative disorder, Sezary's syndrome, small lymphocytic leukemia, T-cell lymphoma, Waldenstrom's macroglobulinemia, and any subtype thereof.

27. The method of claim 17, wherein said hematological malignancy or neoplasm is myeloma or a leukemia.

28. The method of claim 17, which further comprises administering a second agent, wherein said agent is an antineoplastic agent.

29. The method of claim 28, wherein said antineoplastic agent is selected from the group consisting of surgery, radiation, nitrogen mustards, azihdine, alkyl sulfonate, nitrosoureas, platinum complexes, nonclassic alkylators, folate analogs, purine analogs, adenosine analogs, pyrimidine analogs, substituted ureas, antitumor antibiotics, epipodophyllotoxins, taxanes, epothilones, vinca alkaloids, camptothecin analogs, anticancer enzymes, imidazotetrazinone analogs, oligonucleotides, integrin inhibitors, glutarimide analogs, 17AAG analogs, retinoids, PDGFR inhibitors, RAF-1 inhibitors, EGFR Inhibitors, mTOR inhibitors, 26S proteasome inhibitors, quinolinones, anti-CD20 antibody agents, HER2 mediators, anti-CD52 antibody agents, VEGF inhibitors, EGFR inhibitors, TRAIL receptor agonists, and any combination thereof.

30. The method of claim 28, wherein said peptide agent and said antineoplastic agent are administered separately.

31. The method of claim 29, wherein said peptide agent and said antineoplastic agent are administered together.

32. The method of claim 30, wherein said antineoplastic agent is administered subsequent to administering said peptide agent.