WO2016073733A1

WO2016073733A1 - Methods of treating cancer using lipopeptides

Info

Publication number: WO2016073733A1
Application number: PCT/US2015/059263
Authority: WO
Inventors: Alexander Shakhov; Elena Feinstein
Original assignee: Cleveland Biolabs, Inc.
Priority date: 2014-11-06
Filing date: 2015-11-05
Publication date: 2016-05-12

Abstract

This invention relates to, in part, methods and compositions that are useful for the treatment of various diseases, including cancer and side effects of cancer treatments, for example. The invention relates to, in part, combination therapeutic strategies to increase the effectiveness of chemotherapy and radiotherapy.

Description

METHODS OF TREATING CANCER USING LIPOPEPTIDES

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Nos. 62/076,143, filed November 6, 2014 and 62/191 ,053, filed July 10, 2015, the contents of which are hereby incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

[0002] This invention relates to, in part, methods, compositions, and doses that are useful for the treatment of various diseases, including cancer. Particularly, the invention relates to, in part, the use of lipopeptides for the treatment of cancer. In addition, the invention relates to combination therapeutic strategies for increasing the effectiveness of anti-cancer therapies such as chemotherapy and radiotherapy.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

[0003] The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: CLE-017PC- SequenceListing.txt; date recorded: November 5, 2015; file size: 12 KB).

BACKGROUND

[0004] Cancer affects approximately 20 million adults and children worldwide. According to the American Cancer Society, more than 500,000 Americans are expected to die of cancer each year, which amounts to more than 1 ,500 people a day.

[0005] Currently, cancer therapy typically involves surgery, chemotherapy and/or radiotherapy to eradicate neoplastic cells in a patient. All of these approaches pose significant drawbacks for the patient. Surgery, for example, may be contraindicated due to the health of the patient or may be unacceptable to the patient. Additionally, surgery may not completely remove the neoplastic tissue. Radiotherapy is effective only when the irradiated neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue, and radiotherapy often elicits serious side effects. With respect to chemotherapy, there are a variety of chemotherapeutic agents available for treatment of neoplastic disease. However, despite the availability of a variety of chemotherapeutic agents, chemotherapy has many drawbacks. Almost all chemotherapeutic agents are toxic, and chemotherapy causes significant, and often dangerous, side effects, including, for example, severe pain, nausea, or bone marrow suppression. Such side effects can have the effect of dramatically reducing a patient's quality of life. Additionally, the side effects can limit the ability of a patient to receive treatment and therefore lower the likelihood of recovery. [0006] There remains a need for novel and effective anti-cancer therapeutics. There also remains a need for agents that can increase the effectiveness while reducing the side effects of existing standard of care cancer therapies such as surgery, chemotherapy, and radiotherapy.

SUMMARY OF THE INVENTION

[0007] Accordingly, in one aspect, the present invention provides for methods of treating cancer comprising administering to a subject an effective amount of a lipopeptide of Formula I.

[0008] In another aspect, the present invention provides for methods of treating cancer, comprising administering to a subject undergoing chemotherapy and/or radiotherapy a lipopeptide of Formula I. In various embodiments, the administration of the lipopeptide increases the effectiveness and/or reduces side effects associated with the chemotherapy or radiotherapy, e.g. chemotherapy-induced myelosuppression. In an embodiment, the lipopeptide is administered to the subject after administration of the chemotherapy or radiotherapy.

[0009] In another aspect, the present invention provides for methods of treating cancer, comprising administering to a human patient a lipopeptide of Formula I, including without limitation CBLB612, in a safe and effective dose as described herein. In another aspect, the present invention provides for methods of treating chemotherapy-induced myelosuppression, comprising administering to a human patient a lipopeptide of Formula I, including without limitation CBLB612, in a safe and effective dose as described herein. For instance, in various embodiments, the methods described herein pertain to a dose of CBLB612 of about 0.5 μg to about 5 μg, or about 4 μg, which may be administered by subcutaneous injection. Further, in various embodiments, suitable formulations of a lipopeptide of Formula I, including without limitation CBLB612 are provided.

[0010] In various embodiments, administration of the lipopeptide mitigates the side effects of chemotherapy or radiotherapy. In an embodiment, administration of the lipopeptide mitigates the loss of white blood cells in the subject undergoing chemotherapy or radiotherapy.

[0011] In various embodiments, administration of the lipopeptide expands the therapeutic window of the chemotherapy or radiotherapy. For example, administration of the lipopeptide increases the ability of a subject to receive an adequate dose, and/or an increased or complete regimen of the chemotherapy and/or radiotherapy and/or increased or complete maintenance regimen of the chemotherapy or radiotherapy. In addition, administration increases the tolerance and patient compliance of these treatments.

[0012] In another aspect, the present invention provides for a method of reducing in the duration of neutropenia in a cancer patient, comprising administering an effective amount of a lipopeptide of formula I in which the patient is receiving one or more anti-cancer drugs, for example an myelosuppressive anti-cancer drug (by way of non-limiting example one or more of cyclophosphamide, doxorubicin, etoposide, ifosfamide, mesna, methotrexate, vinblastine, and cisplatin). In various embodiments, the lipopeptide reduces or prevents infection in the patient and/or increases absolute neutrophil count (ANC) in the patient (e.g. to greater than about 500/mm³, or about 750/mm³, or about 1000/mm³, or about 1250/mm³, or about 1500/mm³, or about 2000/mm³. In some embodiments, the patient is elderly (e.g. greater than about 60, or about 65, or about 70, or about 75 years of age).

[0013] In various aspects, the lipopeptide of formula I is:

wherein, Ri represents H or -CO-R4, R2, Rs and R4 independently are H or optionally substituted aliphatic; X is H or a peptide; and Z is S or CH₂.

[0014] In various embodiments, X is a peptide comprising an amino acid sequence selected from SEQ ID NOs: 1-52. In one embodiment, X is a peptide comprising an amino acid sequence selected from SEQ ID NOs: 8, 16, 17, 18, and 21. In another embodiment, X is a peptide comprising an amino acid sequence of SEQ ID NO: 21.

[0015] In various embodiments, Ri is H. In some embodiments, Ri is -CO-R4.

[0016] In various embodiments, one or more of R2, R3 and R4 are aliphatics. In some embodiments, one or more of R2, Rs and R4 are C7 to C19, or Ce to C20, or C7 to C15, or Ce to C16, or C7 to Cn, or Ce to C12 aliphatics. In some embodiments, one or more of R2, Rs and R₄ is a C5, or Ce, or C7, or Ce, or Cg, or C10, or Cn , or C12, or C13, or Ci4, or Ci5, or C16, or C17, or Cie, or C19, or C20 aliphatics.

[0017] In some embodiments, R2, R3 and R4 are identical aliphatics. In some embodiments, In some embodiments, R2, R3 and R4 are non-identical aliphatics. In some embodiments, R2 and R3 are identical aliphatics. In some embodiments, In some embodiments, R2 and R3 are non-identical aliphatics.

[0018] In some embodiments, Z is S. In some embodiments, Z is CH2.

[0019] In some embodiments, the lipopeptide is of Formula la:

wherein X is a peptide. In some embodiments, X is a peptide comprising an amino acid sequence comprising one of SEQ ID NOs: 8 or 21.

[0020] In some embodiments, the lipopeptide is (VQGEESNDK is SEQ ID NO: 21).

BRIEF DESCRIPTION OF THE FIGURES

[0021] Figure 1 shows Kaplan-Meier survival curves for p53^+/- mice irradiated with 4 Gy of total body irradiation. Starting at 4 weeks after irradiation, the mice were treated with either vehicle (phosphate buffered saline - PBS) or CBLB612 (0.1 mg/kg) by subcutaneous injection once per week for 4 weeks (N=70 mice/group). The top curve is the CBLB612 treated group and the bottom curve is the PBS group.

[0022] Figure 2 shows the effects of CBLB612 treatment (with or without cyclophosphamide treatment) on tumor volume in a B16 melanoma model.

[0023] Figure 3 shows the effects of CBLB612 treatment on white blood cell counts in the peripheral blood of cyclophosphamide-treated mice. At each time point, the left bar is CBLB612 and the right bar is PBS.

[0024] Figure 4 shows the dynamics of changes in absolute neutrophil count in response to administration of various doses of CBLB612 (0.5 - 8 μς) or placebo in human patients. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention is based, in part, on the discovery that a lipopeptide as described herein effectively reduced tumor growth. Further still, the lipopeptide mitigated the side effects of certain chemotherapies and radiotherapies, and therefore expanded the therapeutic window of these treatments. Even further still, the present inventors have discovered a safe and effective dose of a lipopeptide, such as CBLB612, in human patients, as well as suitable formulations for clinical uses.. Accordingly, the present invention provides novel methods for treating cancer. The present invention further provides improved methods of treating cancers with standard of care cancer therapies such as chemotherapy and radiotherapy.

Lipopeptides and Pharmaceutical Compositions

[0026] In some aspects, the present invention provides use of a lipopeptide as described herein for the treatment of cancer. In some aspects, the present invention provides methods of treating cancer with a lipopeptide as described herein, in a patient undergoing treatment with another anti-cancer therapy, including, for example, chemotherapy or radiotherapy. In various aspects, the present lipopeptides reduce the side effects of various anti-cancer therapies, including, for example, reducing or preventing leukopenia, including neutropenia and/or infections.

[0027] In various embodiments, the present invention provides lipopeptides as described herein and pharmaceutical compositions comprising the same. The lipopeptide may be isolated from part of the outer membrane of a Gram-negative bacteria, Gram-positive bacteria, or mycoplasma. Bacterial lipopeptides may have no shared sequence homology, but may be characterized by the unusual N-terminal amino acid S-(2,3- dihydroxypropyl)-L-cysteine that is acylated by two or three fatty acids. Bacterial lipopeptides may be strong immune modulators that activate early host responses after infection by signaling through Toll-Like Receptor 2 (TLR2)-TLR1 or TLR2-TLR6 heterodimers, leading to the activation of NF-κΒ and cytokine production. Synthetic analogues of the N-terminal lipopeptides of natural lipopeptides may be potent activators of TLRs and NF-κΒ, as well as being immunoadjuvants in vivo and in vitro.

[0028] The lipopeptide may be a compound of formula (I):

wherein, Ri represents H or -CO-R4, R2, R3 and R4 independently are H or optionally substituted aliphatic; X is H or a peptide; and Z is S or CH2.

[0029] In various embodiments, Ri is H. In some embodiments, Ri is -CO-R4.

[0030] In various embodiments, one or more of R2, R3 and R4 are aliphatics In some embodiments, one or more of R2, Rs and R4 are C7 to C19, or Ce to C20, or C7 to C15, or Ce to C16, or C7 to Cn, or Ce to C12 aliphatics. In some embodiments, one or more of R2, Re and R₄ is a C5, or C6, or C7, or Ce, or Cg, or C10, or Cn , or C12, or C13, or Ci4, or Ci5, or C16, or C17, or Cie, or C19, or C20 aliphatics.

[0031] In some embodiments, R2, R3 and R4 are identical aliphatics. In some embodiments, In some embodiments, R2, R3 and R4 are non-identical aliphatics. In some embodiments, R2 and R3 are identical aliphatics. In some embodiments, In some embodiments, R2 and R3 are non-identical aliphatics.

[0032] The lipopeptide may comprise two or three fatty acids. The aliphatic substituents of R2, R3 and R4 may comprise from 6 to 20 carbon atoms. R2, R3 and R4 may be C6-C20 alkyl, C6-C20 alkenyl, or C6-C20 alkynyl. Representative examples of alkyl substituents at R₂, R3 and R4 include C6, Ce, Cg, C10, C12, C14, and C16. Representative examples of alkenyl substituents at R₂, Re and R₄ include Cio:i^{D1 trans}, Cie_:i^D9, and Ci8:2^D9' ¹²-

[0033] In some embodiments, Z is S. In some embodiments, Z is CH2.

[0034] In various embodiments, X is a peptide comprising an amino acid sequence selected from SEQ ID NOs: 1-52. In one embodiment, X is a peptide comprising an amino acid sequence selected from SEQ ID NOs: 8, 16, 17, 18, and 21. In another embodiment, X is a peptide comprising an amino acid sequence of SEQ ID NO: 21.

[0035] The peptide may comprise between at least 4 or 5 amino acids and no more than 20, 30 or 40 amino acids. The peptide moiety may be essential for activity and the activity of the lipopeptide may be modulated by the amino acid sequence, but biological activity may be insensitive to most peptide sequences (Spohn ef a/., Vaccine, 22(19):2494-9, 2004), the contents of which are incorporated by reference in their entirety. In an embodiment, the peptide may comprise a sequence as set forth in Table 1. In another embodiment, the peptide may comprise a sequence that is at least about 70%, about 71 %, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81 %, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to a sequence as set forth in Table 1 , or any analog, derivative, fragment, homolog, variant or substitution thereof. The peptide may carry a net negative charge.

Table t

SEQUENCE LENGTH SEQ ID NO.

GNNDESNISFKEKSPPPP 18 41

SSNKSTTGSGETTTAAGT 18 42

CGNNDESNISFKEKSKKKK 19 43

GSPLSFESSVQLIVSDNSS 19 44

SNYAKKWKQKNHVYTPVY 19 45

ADVI AKIVEIVKGLI DQFTQK 21 46

GAASSLTYESSVQLWSDNSS 21 47

GGEPAAQAPAETPAAAAEAAS 21 48

GQTDNNSSQSQQPGSGTTNT 21 49

SGALAATSDDDVKKAATVAIVA 22 50

SIVSTIIEWKTIVDIVKKFKK 22 51

SSGGGGVAADIGAGLADALTAP 22 52

[0036] The first four to five amino acids of the peptide moiety of a lipopeptide may be selected from those listed for each position in Table 2. This table is based upon Spohn ei a/., Vaccine, 22(19):2494-9, 2004; and Reutter ei a/., J. Peptide Res., 65, 375-383, 2005, the entire contents of which are incorporated herein by reference in their entirety.

Table 2.

[0037] The lipopeptide may be an RR- or RS-stereoisomer, or mixture thereof, with respect to the stereochemistry of the N-terminal lipoamino acid. The lipopeptide may be water-soluble.

[0038] In a specific embodiment, the lipopeptide has the formula (la):

[0039] In some embodiments, the lipopeptide is

an agent described as "CBLB612" (VQGEESNDK is SEQ ID NO: 21).

[0040] The lipopeptides are further described in International Patent Publication Nos. WO 2006/138238 and WO 2008/086426, the entire contents of which are incorporated herein by reference.

[0041] In some embodiments, the lipopeptide (and/or additional therapeutic agent, such as chemotherapeutic agent (e.g., cyclophosphamide)) described herein, include derivatives that are modified, i.e., by the covalent attachment of any type of molecule to the composition such that covalent attachment does not prevent the activity of the composition. For example, but not by way of limitation, derivatives that have been modified by, inter alia, glycosylation, lipidation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, etc. Additionally, a derivative can contain one or more non-classical amino acids.

[0042] In still other embodiments, the lipopeptide (and/or additional therapeutic agent) described herein may be modified to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and radioactive materials.

[0043] In some embodiments, the lipopeptide (and/or additional therapeutic agent) described herein can possess a sufficiently basic functional group, which can react with an inorganic or organic acid, or a carboxyl group, which can react with an inorganic or organic base, to form a pharmaceutically acceptable salt. A pharmaceutically acceptable acid addition salt is formed from a pharmaceutically acceptable acid, as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in, for example, Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H. Stahl and C. G. Wermuth (eds.), Verlag, Zurich (Switzerland) 2002, which are hereby incorporated by reference in their entirety.

[0044] Pharmaceutically acceptable salts include, by way of non-limiting example, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, pamoate, phenylacetate, trifluoroacetate, acrylate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, isobutyrate, phenylbutyrate, a-hydroxybutyrate, butyne-1 ,4- dicarboxylate, hexyne-1 ,4-dicarboxylate, caprate, caprylate, cinnamate, glycollate, heptanoate, hippurate, malate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, phthalate, teraphthalate, propiolate, propionate, phenyl propionate, sebacate, suberate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, naphthalene-1 ,5-sulfonate, xylenesulfonate, and tartarate salts.

[0045] The term "pharmaceutically acceptable salt" also refers to a salt of the lipopeptide (and/or additional therapeutic agent) of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base. Suitable bases include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-lower alkylamines), such as mono-; bis-, or tris-(2-hydroxyethyl)amine, 2- hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxyl-lower alkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such as arginine, lysine, and the like.

[0046] In some embodiments, the pharmaceutical compositions described herein are in the form of a pharmaceutically acceptable salt.

[0047] Further, any lipopeptide (and/or additional therapeutic agent) described herein can be administered to a subject as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. Such compositions can optionally comprise a suitable amount of a pharmaceutically acceptable excipient so as to provide the form for proper administration.

[0048] Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any agent described herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Any agent described herein, if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents.

Formulations, Administration, Dosing, and Treatment Regimens

[0049] The present invention includes the described lipopeptide or lipopeptide composition (and/or additional therapeutic agent) in various formulations. Any lipopeptide or lipopeptide composition (and/or additional therapeutic agent) described herein can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the lipopeptide or lipopeptide composition is in the form of a capsule {see, e.g., U.S. Patent No. 5,698,155). Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.

[0050] Where necessary, the lipopeptide or lipopeptide composition (and/or additional therapeutic agent) can also include a solubilizing agent. Also, the agents can be delivered with a suitable vehicle or delivery device as known in the art. Combination therapies outlined herein can be co-delivered in a single delivery vehicle or delivery device. Compositions for administration can optionally include a local anesthetic such as, for example, lignocaine to lessen pain at the site of the injection.

[0051] The formulations comprising the lipopeptide or lipopeptide composition (and/or additional therapeutic agent) may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, eic, followed by tableting using conventional methods known in the art).

[0052] In some embodiments, the lipopeptide or lipopeptide composition (and/or additional therapeutic agent) is formulated with one or more of sodium chloride, potassium chloride, disodium hydrogen phosphate, anhydrous, and potassium dihydrogen phosphate.

[0053] In some embodiments, there is provided a formulation of the lipopeptide or lipopeptide composition, e.g. CBLB612. In some embodiments, the formulation comprises the lipopeptide or lipopeptide composition, e.g. CBLB612 as well as sodium chloride, potassium chloride, disodium hydrogen phosphate, anhydrous, and potassium dihydrogen phosphate. [0054] In some embodiments, the formulation comprises the lipopeptide or lipopeptide composition, e.g. CBLB612 as well as sodium chloride, potassium chloride, disodium hydrogen phosphate, anhydrous, and potassium dihydrogen phosphate and the lipopeptide or lipopeptide composition, e.g. CBLB612 is present at a dose disclosed herein (without limitation about 0.5 μg to about 5 μg, e.g. about 4 μς); sodium chloride .at about 6 mg to about 10 mg, potassium chloride at about 0.1 mg to about 0.3 mg, disodium hydrogen phosphate, anhydrous at about 0.9 mg to about 1.3 mg, and potassium dihydrogen phosphate at about 0.1 mg to about 0.3 mg.

[0055] In some embodiments, the formulation comprises the lipopeptide or lipopeptide composition, e.g. CBLB612 as well as sodium chloride, potassium chloride, disodium hydrogen phosphate, anhydrous, and potassium dihydrogen phosphate and the lipopeptide or lipopeptide composition, e.g. CBLB612 is present at a dose disclosed herein (without limitation about 0.5 μg to about 5 μg, e.g. about 4 μς); sodium chloride .at about 8 mg, potassium chloride at about 0.2 mg, disodium hydrogen phosphate, anhydrous at about 1.1 mg, and potassium dihydrogen phosphate at about 0.2 mg.

[0056] In some embodiments, the following formulation of the lipopeptide or lipopeptide composition is used:

In some embodiments, any of the above components may be altered as needed to not effect pharmaceutical properties, e.g. by using ± 5%, or ± 10%, or ± 15%, or ± 20%, or ± 25%, of the above values in formulation.

[0057] In some embodiments, the following formulation is used:

[0058] In one embodiment, the lipopeptide or lipopeptide composition (and/or additional therapeutic agent) described herein is formulated in accordance with routine procedures as a composition adapted for a mode of administration described herein.

[0059] Routes of administration include, for example: intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin. In some embodiments, the administering is effected orally or by parenteral injection.

[0060] In an embodiment, the routes of administration is subcutaneous, e.g. by injection.

[0061] In an embodiment, the lipopeptide or lipopeptide composition (and/or additional therapeutic agent) described herein can be administered orally. The lipopeptide or lipopeptide composition (and/or additional therapeutic agent) can also be administered by any other convenient route, for example, by intravenous infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and can be administered together with another biologically active agent. Administration can be systemic or local. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, eic, and can be used for administration. In specific embodiments, it may be desirable to administer locally to the area in need of treatment.

[0062] In one embodiment, the lipopeptide or lipopeptide composition (and/or additional therapeutic agent) described herein is formulated in accordance with routine procedures as a composition adapted for oral administration to humans. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally administered lipopeptide or lipopeptide composition (and/or additional therapeutic agent) can comprise one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the lipopeptide or lipopeptide composition can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active compound driving any lipopeptide or lipopeptide composition (and/or additional therapeutic agent) are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule is imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be useful. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade. Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, eic, and mixtures thereof.

[0063] Dosage forms suitable for parenteral administration (e.g. intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g. lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art.

[0064] In another embodiment, delivery can be in a vesicle, in particular a liposome (see Langer, 1990, Science 249:1527-1533; Treat ef a/., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989).

[0065] Any lipopeptide or lipopeptide composition (and/or additional therapeutic agent) described herein can be administered by controlled-release or sustained-release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591 ,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the agents described herein. The invention thus provides single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.

[0066] Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, stimulation by an appropriate wavelength of light, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

[0067] In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 ; see also Levy ef a/., 1985, Science 228:190; During ef a/., 1989, Ann. Neurol. 25:351 ; Howard ef a/., 1989, J. Neurosurg. 71 :105).

[0068] In another embodiment, a controlled-release system can be placed in proximity of the target area to be treated, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussed in the review by Langer, 1990, Science 249:1527-1533) may be used.

[0069] The dosage of any lipopeptide or lipopeptide composition (and/or additional therapeutic agent) as well as the dosing schedule can depend on various parameters, including, but not limited to, the disease being treated, the subject's general health, and the administering physician's discretion. Any lipopeptide or lipopeptide composition described herein can be administered prior to (e.g., about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about weeks, or about 12 weeks before), concurrently with, or subsequent to (e.g., about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 24 hours, about 48 hours, about 72 hours, about 96 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about weeks, or about 12 weeks after) the administration of an additional therapeutic agent or a chemotherapy or a radiotherapy, to a subject in need thereof. In various embodiments any agent or therapy described herein can be administered about 1 minute apart, about 10 minutes apart, about 30 minutes apart, less than about 1 hour apart, about 1 hour apart, about 1 hour to about 2 hours apart, about 2 hours to about 3 hours apart, about 3 hours to about 4 hours apart, about 4 hours to about 5 hours apart, about 5 hours to about 6 hours apart, about 6 hours to about 7 hours apart, about 7 hours to about 8 hours apart, about 8 hours to about 9 hours apart, about 9 hours to about 10 hours apart, about 10 hours to about 11 hours apart, about 11 hours to about 12 hours apart, no more than about 24 hours apart or no more than about 48 hours apart.

[0070] In various aspects, the present invention relates to specific doses of lipopeptides described herein, including CBLB612, found to be effective and tolerated in human. In some embodiments, the dose is up to about 4 μg, or up to about 5 μg. In some embodiments, the dose is between about 0.5 μg to about 5 μg, 0.5 μg to about 4 μg, or about 1 μg to about 4 μg, or about 2 μg to about 4 μg, or about 3 μg to about 4 μg, or about 0.5 μg to about 3 μg, or about 0.5 μg to about 2 μg, or about 0.5 μg to about 1 μg. In some embodiments the dose of CBLB612 is about 0.5 μg, or about 1 μg, or about 1.5 μg, or about 2 μg, or about 2.5 μg, or about 3 μg, or about 3.5 μg, or about 4 μg, or about 5 μg. In various embodiments, these doses are used in subcutaneous administration, e.g. via injection. In various embodiments, unit dosage forms of CBLB612 in amounts of about 0.5 μg, or about 1 μg, or about 1.5 μg, or about 2 μg, or about 2.5 μg, or about 3 μg, or about 3.5 μg, or about 4 μg, or about 5 μg are provided. For example, the present invention includes a pre-loaded syringe, which can be sterile, of amounts of about 0.5 μg, or about 1 μg, or about 1.5 μg, or about 2 μg, or about 2.5 μg, or about 3 μg, or about 3.5 μg, or about 4 μg, or about 5 μg. The pre-loaded syringe may be unit dose form, e.g. a preloaded (a.k.a. pre-dosed or pre-filled) syringe or a pen needle injector (injection pen).

[0071] In various embodiments, the dose is expressed as μg/kg, for instance about 0.0075μ9 Ι 9, or about 0.015 μg/kg, or about 0.03 μg/kg, or about 0.6 μg/kg, or about 0.7 μg/kg, or about 0.8 μg/kg.

[0072] With regard to additional therapeutic agents, the doses that are useful are known to those in the art. For example, doses may be determined with reference Physicians' Desk Reference, 66th Edition, PDR Network; 2012 Edition (December 27, 2011), the contents of which are incorporated by reference in its entirety.

[0073] The dosage of any additional therapeutic agent described herein can depend on several factors including the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the subject to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular subject may affect dosage used. Furthermore, the exact individual dosages can be adjusted somewhat depending on a variety of factors, including the specific combination of the agents being administered, the time of administration, the route of administration, the nature of the formulation, the rate of excretion, the particular disease being treated, the severity of the disorder, and the anatomical location of the disorder. Some variations in the dosage can be expected.

[0074] Generally, individual doses of the additional therapeutic agent can be administered in unit dosage forms containing, for example, from about 0.01 mg to about 5,000 mg, about 0.01 mg to about 4,000 mg, about 0.01 mg to about 3,000 mg, about 0.01 mg to about 2,000 mg, about 0.01 mg to about 1 ,000 mg, about 0.01 mg to about 900 mg, about 0.01 mg to about 800 mg, about 0.01 mg to about 700 mg, about 0.01 mg to about 600 mg, about 0.01 mg to about 500 mg, about 0.01 mg to about 400 mg, about 0.01 mg to about 300 mg, about 0.01 mg to about 200 mg, from about 0.1 mg to about 100 mg, from about 0.1 mg to about 90 mg, from about 0.1 mg to about 80 mg, from about 0.1 mg to about 70 mg, from about 0.1 mg to about 60 mg, from about 0.1 mg to about 50 mg, from about 0.1 mg to about 40 mg, from about 0.1 mg to about 30 mg, from about 0.1 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.1 mg to about 5 mg, from about 0.1 mg to about 3 mg, from about 0.1 mg to about 1 mg per unit dosage form, or from about 5 mg to about 80 mg per unit dosage form. For example, a unit dosage form can be about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 ,000 mg, about 2,000 mg, about 3,000 mg, about 4,000 mg, or about 5,000 mg, inclusive of all values and ranges therebetween.

[0075] In one embodiment, the additional therapeutic agent is administered at an amount of from about 0.01 mg to about 5,000 mg daily, about 0.01 mg to about 4,000 mg daily, about 0.01 mg to about 3,000 mg daily, about 0.01 mg to about 2,000 mg daily, about 0.01 mg to about 1 ,000 mg daily, about 0.01 mg to about 900 mg daily, about 0.01 mg to about 800 mg daily, about 0.01 mg to about 700 mg daily, about 0.01 mg to about 600 mg daily, about 0.01 mg to about 500 mg daily, about 0.01 mg to about 400 mg daily, about 0.01 mg to about 300 mg daily, about 0.01 mg to about 200 mg daily, from about 0.01 mg to about 100 mg daily, from about 0.1 mg to about 90 mg daily, from about 0.1 mg to about 80 mg daily, from about 0.1 mg to about 70 mg daily, from about 0.1 mg to about 60 mg daily, from about 0.1 mg to about 50 mg daily, from about 0.1 mg to about 40 mg daily, from about 0.1 mg to about 30 mg daily, from about 0.1 mg to about 20 mg daily, from about 0.1 mg to about 10 mg daily, from about 0.1 mg to about 5 mg daily, from about 0.1 mg to about 3 mg daily, from about 0.1 mg to about 1 mg daily, or from about 5 mg to about 80 mg daily. In various embodiments, additional therapeutic agent is administered at a daily dose of about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 ,000 mg, about 2,000 mg, about 3,000 mg, about 4,000 mg, or about 5,000 mg, inclusive of all values and ranges therebetween.

[0076] In some embodiments, a suitable dosage of additional therapeutic agent is in a range of about 0.01 mg/kg to about 500 mg/kg of body weight of the subject, for example, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, 1.9 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg body weight, about 200 mg/kg body weight, about 300 mg/kg body weight, about 400 mg/kg body weight, about 500 mg/kg body weight, inclusive of all values and ranges therebetween. In other embodiments, a suitable dosage of additional therapeutic agent is in a range of about 0.01 mg/kg to about 10 mg/kg of body weight, in a range of about 0.01 mg/kg to about 9 mg/kg of body weight, in a range of about 0.01 mg/kg to about 8 mg/kg of body weight, in a range of about 0.01 mg/kg to about 7 mg/kg of body weight, in a range of 0.01 mg/kg to about 6 mg/kg of body weight, in a range of about 0.05 mg/kg to about 5 mg/kg of body weight, in a range of about 0.05 mg/kg to about 4 mg/kg of body weight, in a range of about 0.05 mg/kg to about 3 mg/kg of body weight, in a range of about 0.05 mg/kg to about 2 mg/kg of body weight, in a range of about 0.05 mg/kg to about 1.5 mg/kg of body weight, or in a range of about 0.05 mg/kg to about 1 mg/kg of body weight.

[0077] When orally administered to a mammal, the dosage of any additional therapeutic agent described herein may be 0.001 mg/kg/day to 100 mg/kg/day, 0.01 mg/kg/day to 50 mg/kg/day, or 0.1 mg/kg/day to 10 mg/kg/day. When orally administered to a human, the dosage of any agent described herein is normally 0.001 mg to 1000 mg per day, 1 mg to 600 mg per day, or 5 mg to 30 mg per day.

[0078] For administration of any additional therapeutic agent described herein by parenteral injection, the dosage is may be 0.1 mg to 250 mg per day, 1 mg to 20 mg per day, or 3 mg to 5 mg per day. Injections may be given up to four times daily. Generally, when orally or parenterally administered, the dosage of any agent described herein is normally 0.1 mg to 1500 mg per day, or 0.5 mg to 10 mg per day, or 0.5 mg to 5 mg per day.

A dosage of up to 3000 mg per day can be administered. [0079] Administration of any lipopeptide or lipopeptide composition (and/or additional therapeutic agent) described herein can, independently, be one to ten times daily, one to six times daily, one to four times daily or one to four times per month or one to six times per year or once every two, three, four or five years. Administration can be for the duration of one day, one month, two months, three months, six months, one year, two years, three years, and may even be for the life of the subject. Chronic, long-term administration will be indicated in many cases. The dosage may be administered as a single dose or divided into multiple doses. In general, the desired dosage should be administered at set intervals for a prolonged period, usually at least over several weeks or months, although longer periods of administration of several months or years or more may be needed.

[0080] The dosage regimen utilizing any lipopeptide or lipopeptide composition (and/or additional therapeutic agent) described herein can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the subject; the pharmacogenomic makeup of the individual; and the specific compound of the invention employed. Any lipopeptide or lipopeptide composition (and/or additional therapeutic agent) described herein can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three, four, five, six, seven, eight, nine, or ten times daily. Furthermore, any lipopeptide or lipopeptide composition (and/or additional therapeutic agent) described herein can be administered continuously rather than intermittently throughout the dosage regimen.

[0081] In various aspects, the present invention relates to specific doses of CBLB612 found to be effective and tolerated in human. In some embodiments, the dose is up to about 4 μg, or up to about 5 μg. In some embodiments, the dose is between about 0.5 μg to about 4 μg, or about 1 μg to about 4 μg, or about 2 μg to about 4 μg, or about 3 μg to about 4 μg, or about 0.5 μg to about 3 μg, or about 0.5 μg to about 2 μg, or about 0.5 μg to about 1 μg. In some embodiments the dose of CBLB612 is about 0.5 μg, or about 1 μg, or about 1.5 μg, or about 2 μg, or about 2.5 μg, or about 3 μg, or about 3.5 μg, or about 4 μg, or about 5 μg. In various embodiments, these doses are used in subcutaneous administration, e.g. via injection.

Methods of Treatment

[0082] In various embodiments, the present invention relates, in part, to the treatment or prevention of cancers and/or tumors using the lipopeptide or lipopeptide composition (and/or additional therapeutic agent) as described herein.

[0083] As used herein, "cancer" or "tumor" refers to an uncontrolled growth of cells and/or abnormal increased cell survival and/or inhibition of apoptosis which interferes with the normal functioning of the bodily organs and systems. Included are benign and malignant cancers, polyps, hyperplasia, as well as dormant tumors or micro metastases. Also, included are cells having abnormal proliferation that is not impeded by the immune system (e.g. virus infected cells). A subject that has a cancer or a tumor is a subject having objectively measurable cancer cells present in the subject's body. Cancers which migrate from their original location and seed vital organs can eventually lead to the death of the subject through the functional deterioration of the affected organs. Hematopoietic cancers, such as leukemia, are able to out-compete the normal hematopoietic compartments in a subject, thereby leading to hematopoietic failure (e.g. in the form of anemia, thrombocytopenia and neutropenia) ultimately causing death.

[0084] The cancer may be a primary cancer or a metastatic cancer. The primary cancer may be an area of cancer cells at an originating site that becomes clinically detectable, and may be a primary tumor. In contrast, the metastatic cancer may be the spread of a disease from one organ or part to another non-adjacent organ or part. The metastatic cancer may be caused by a cancer cell that acquires the ability to penetrate and infiltrate surrounding normal tissues in a local area, forming a new tumor, which may be a local metastasis. "Metastasis" refers to the spread of cancer from a primary site to other places in the body. Cancer cells can break away from a primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow in a distant focus (metastasize) in normal tissues elsewhere in the body. Metastasis can be local or distant. Metastasis is a sequential process, contingent on tumor cells breaking off from the primary tumor, traveling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life -threatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cell regulate this behavior, and interactions between the tumor cell and host cells in the distant site are also significant. Metastases may be detected through the sole or combined use of magnetic resonance imaging (MRI) scans, computed tomography (CT) scans, blood and platelet counts, liver function studies, chest X-rays and bone scans in addition to the monitoring of specific symptoms.

[0085] The cancer may also be caused by a cancer cell that acquires the ability to penetrate the walls of lymphatic and/or blood vessels, after which the cancer cell is able to circulate through the bloodstream (thereby being a circulating tumor cell) to other sites and tissues in the body. The cancer may be due to a process such as lymphatic or hematogeneous spread. The cancer may also be caused by a tumor cell that comes to rest at another site, re-penetrates through the vessel or walls, continues to multiply, and eventually forms another clinically detectable tumor. The cancer may be this new tumor, which may be a metastatic (or secondary) tumor.

[0086] The cancer may be caused by tumor cells that have metastasized, which may be a secondary or metastatic tumor. The cells of the tumor may be like those in the original tumor. As an example, if a breast cancer or colon cancer metastasizes to the liver, the secondary tumor, while present in the liver, is made up of abnormal breast or colon cells, not of abnormal liver cells. The tumor in the liver may thus be a metastatic breast cancer or a metastatic colon cancer, not liver cancer.

[0087] The cancer may have an origin from any tissue. The cancer may originate from melanoma, colon, breast, or prostate, and thus may be made up of cells that were originally skin, colon, breast, or prostate, respectively. The cancer may also be a hematological malignancy, which may be lymphoma. The cancer may invade a tissue such as liver, lung, bladder, or intestinal. [0088] Also provided herein is a method of reducing cancer recurrence using any lipopeptide or lipopeptide composition (and/or additional therapeutic agent) described herein. The method may also prevent cancer recurrence. The cancer may be an oncological disease. The cancer may be a dormant tumor, which may result from the metastasis of a cancer. The dormant tumor may also be left over from surgical removal of a tumor. The cancer recurrence may be tumor regrowth, a metastasis such as a lung metastasis or a liver metastasis.

[0089] Representative cancers and/or tumors that may be treated or prevented include, but are not limited to, a basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblasts leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.

[0090] In one aspect, the present invention provides a method for treating cancer, comprising administering an effective amount of a lipopeptide or lipopeptide composition described herein to a subject as a monotherapy.

[0091] In another aspect, the present invention provides a method for treating cancer, comprising administering an effective amount of a lipopeptide or lipopeptide composition described herein as an adjuvant therapy to a subject undergoing treatment with an anti-cancer therapy such as chemotherapy or radiotherapy. In an embodiment, an effective amount of a lipopeptide or lipopeptide composition is administered sequentially or simultaneously with an effective amount of a chemotherapeutic agent to a subject in need thereof. In another embodiment, an effective amount of a lipopeptide or lipopeptide composition is administered sequentially or simultaneously with an effective amount of radiation to a subject in need thereof.

[0092] For example, the lipopeptide or lipopeptide composition may be administered simultaneously (including co-administration and/or co-formulation) with administration of one or more chemotherapeutic agents (or radiation) to a cancer patient in need thereof. The term "simultaneously" as used herein, means that the chemotherapeutic agent (or radiation) and the lipopeptide or lipopeptide composition are administered with a time separation of, for example, no more than about 60 minutes, such as no more than about 30 minutes, no more than about 20 minutes, no more than about 10 minutes, no more than about 5 minutes, or no more than about 1 minute. In an embodiment, administration of the chemotherapeutic agent and the lipopeptide or lipopeptide composition can be by simultaneous administration of a single formulation (e.g., a formulation comprising the chemotherapeutic agent and the lipopeptide or lipopeptide composition) or of separate formulations (e.g., a first formulation including the chemotherapeutic agent and a second formulation including the lipopeptide or lipopeptide composition).

[0093] Co-administration does not require the chemotherapeutic agent (or radiation) and the lipopeptide or lipopeptide composition to be administered simultaneously, if the timing of their administration is such that the pharmacological activities of the chemotherapeutic agent (or radiation) and the lipopeptide or lipopeptide composition overlap in time, thereby exerting a combined therapeutic effect. For example, the chemotherapeutic agent (or radiation) and the lipopeptide or lipopeptide composition can be administered sequentially. The term "sequentially" as used herein means that the chemotherapeutic agent (or radiation) and the lipopeptide or lipopeptide composition are administered with a time separation of more than about 60 minutes. For example, the time between the sequential administration of the chemotherapeutic agent (or radiation) and the lipopeptide or lipopeptide composition can be more than about 60 minutes, more than about 2 hours, more than about 5 hours, more than about 10 hours, more than about 1 day, more than about 2 days, more than about 3 days, more than about 1 week, more than about 2 weeks, more than about 3 weeks, more than about 4 weeks, more than about 2 months, more than about 3 months apart, more than about 4 months, more than about 5 months, or more than about 6 months apart. The optimal administration times will depend on the rates of metabolism, excretion, and/or the pharmacodynamic activity of the chemotherapeutic agent (or radiation) and the lipopeptide or lipopeptide composition being administered. Either the chemotherapeutic agent (or radiation) or the lipopeptide or lipopeptide composition may be administered first.

[0094] In various embodiments, the present invention provides for compositions of, and anti-cancer uses of, co-formulations of a lipopeptide or lipopeptide composition as described herein and one or more chemotherapeutic agents. In other embodiments, provided are lipopeptide or lipopeptide composition as described herein and chemotherapeutic agents for use in treating, or in the manufacture of a medicament for the treatment of, various cancers.

[0095] In various embodiments, the subject may be undergoing chemotherapy using chemotherapeutic agents including, but not limited to, alkylating agents such as thiotepa and CYTOXAN cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (e.g., bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (e.g., cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB 1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g.,

Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, ADRIAMYCIN doxorubicin (including morpholino- doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifl uridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as minoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK polysaccharide complex (JHS Natural

Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2', 2"- trichlorotriethylamine; trichothecenes (e.g., T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.),

ABRAXANE Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American

Pharmaceutical Partners, Schaumberg, 111), and TAXOTERE doxetaxel (Rhone-Poulenc Rorer, Antony,

France); chloranbucil; GEMZAR gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE. vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (Camptosar, CPT-11) (including the treatment regimen of irinotecan with 5-FU and leucovorin); topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; combretastatin; leucovorin (LV); oxaliplatin, including the oxaliplatin treatment regimen (FOLFOX); lapatinib (Tykerb); inhibitors of PKC-a, Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva)) and VEGF-A such as Bl- 2356, Sutent, PF-562271 , AMG706, dasatinib, sorafenib, GSK461364A, and Bez-235 that reduce cell proliferation and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0096] In an embodiment, the subject may be undergoing chemotherapy using cyclophosphamide (e.g. ENDOXAN, CYTOXAN, NEOSAR, PROCYTOX, REVIMMUNE). In some embodiments, including those in which the subject is undergoing chemotherapy using cyclophosphamide, the cancer may be Hodgkin's lymphoma (Hodgkin's disease) and non-Hodgkin's lymphoma; cutaneous T-cell lymphoma (CTCL); leukemia (including without limitation chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute myeloid leukemia (AML, ANLL), and acute lymphoblastic leukemia (ALL)); retinoblastoma; neuroblastoma; ovarian cancer; and breast cancer

[0097] In various embodiments, the lipopeptide or lipopeptide composition described herein when used in the context of a subject undergoing treatment with chemotherapy and/or radiotherapy or when administered as a co-formulation or co-administration (e.g. sequentially or simultaneously) with chemotherapy and/or radiotherapy increases the therapeutic window of the chemotherapeutic agent and/or radiation.

[0098] In various embodiments, the administration of the lipopeptide or lipopeptide composition disclosed herein eliminates and/or reduces and/or mitigates one or more side effects of a subject's anti-cancer therapy such as chemotherapy or radiotherapy. For example, certain subjects may require dose-reduction of the chemotherapeutic agent or radiation because of side effects. In some embodiments, the present methods prevent the need for such dose reduction.

[0099] In various embodiments, methods of the invention allow a sub-therapeutic dose of any of the agents to be administered. In various embodiments, a sub-therapeutic dose of the chemotherapeutic agent or radiation is less than about 50%, less than about 55%, or less than about 60%, less than about 65%, less than about 70%, less than about 75%, less than about 80%, less than about 85%, or less than about 90% of an approved label dose and/or a maximum tolerated dose (MTD). In various embodiments, the use of a sub-therapeutic dose does not appreciably affect the extent of the therapeutic benefit of any of the agents or the combination of agents. This in turn may improve patient compliance. For example, the present invention may allow for a full dose of a chemotherapeutic agent or radiation to be taken once daily thus avoiding the patient compliance problems associated with a twice or more daily administration regimen. In such embodiments, the administration of the lipopeptide or lipopeptide composition disclosed herein allows for dose-reduction which accordingly provides for a reduction of side effects.

[00100] In some embodiments, the administration of the lipopeptide composition may permit a subject to receive a specific mode of administration of the chemotherapeutic agent or radiation by reducing side effects. For example, the administration of the lipopeptide or lipopeptide composition may offset the side effects associated with bolus doses of a chemotherapeutic agent. In another example, the administration of the lipopeptide or lipopeptide composition may offset the side effects associated with continuous infusion of a chemotherapeutic agent.

[00101] Illustrative side effects of chemotherapy and/or radiotherapy include, but are not limited to, fatigue, nausea, vomiting, loss of appetite, pain, hair loss, blood disorders, infection, mouth, gum and throat complications, diarrhea, constipation, nerve and muscle complications, effects on skin and nails, radiation recall, kidney and bladder complications, flu-like symptoms, fluid retention, and effects on sexual organs and sexuality. For example, blood disorders may include leukopenia and/or reduced white blood count and reduction of other types of blood cells, including neutrophils, lymphocytes, platelets, red blood cells as well as blood clotting complications. In another example, nerve and muscle complications may include tingling, burning, weakness or numbness in the hands or feet, weak, sore, or achy muscles, loss of balance, shaking, stiff neck, headache, visual problems, walking problems, hearing problems, and clumsiness. In a further example, mouth, gum and throat complications may include sores or difficulty in swallowing.

[00102] In certain embodiments, exemplary side effects include those associated with administration of, for example, an alkylating agent such as cyclophosphamide. These side effects include, but are not limited to, coughing, fever or chills, lower back or side pain, amenorrhea, painful or difficult urination, blood in the urine, dizziness, confusion, agitation, fast heartbeat, joint pain, shortness of breath, swelling of the feet or lower legs, tiredness, weakness, unusual bleeding or bruising, red spots on the skin, black stools, frequent urination, sores, shortness of breath, unusual thirst, yellow eyes or skin, darkening of the skin and fingernails, loss of appetite, nausea or vomiting, diarrhea, flushing or redness of the face, headache, increased sweating, skin rash, hives, or itching, stomach pain, swollen lips, hematologic side effects such as myelosuppression, leukopenia, neutropenia (including without limitation febrile neutropenia), anemia, and cystitis.

[00103] In certain embodiments, exemplary side effects include those associated with administration of, for example, an anti-metabolite such as 5-FU. These side effects include, but are not limited to, stomatitis, esophagopharyngitis, leukopenia and/or reduced white blood count, risk of infection, vomiting, diarrhea, nausea, poor appetite, damage to the Gl tract, including gastrointestinal ulceration and/or bleeding, thrombocytopenia, hand-foot syndrome, alopecia, mucositis, impaired hepatic function, and hemorrhage.

[00104] In certain embodiments, exemplary side effects include those associated with administration of, for example, a topoisomerase I inhibitor such as irinotecan. These side effects include, but are not limited to, diarrhea, dehydration, suppression of the immune system, hematological damage, lowered white blood cell counts, neutropenia, cholinergic syndrome, blood clots, infection, and abdominal pain. In some embodiments, hematological damage is one or more of leukopenia and/or reduced white blood count and reduction of other types of blood cells, including neutrophils, lymphocytes and platelets.

[00105] In certain embodiments, exemplary side effects include those associated with administration of, for example, a nucleoside analog such as gemcitabine. These side effects include, but are not limited to, flu-like symptoms (e.g. muscle pain, fever, headache, chills, and fatigue), fever (e.g. within 6-12 hours of first dose), fatigue, nausea, vomiting, poor appetite, skin rash, allergic reaction, diarrhea, weakness, hair loss, mouth sores, difficulty sleeping, and shortness of breath.

[00106] In certain embodiments, exemplary side effects include those associated with administration of, for example, a kinase inhibitor such as sorafenib. These side effects include, but are not limited to, lymphopenia, hypophosphataemia, haemorrhage, hypertension, diarrhea, rash, alopecia, hand-foot syndrome, pruritus, erythema, increased amylase, increased lipase, fatigue, pain, nausea, vomiting, leucopenia, neutropenia, anaemia, thrombocytopenia, anorexia, weight loss, hypocalcaemia, hypokalaemia, depression, peripheral sensory neuropathy, tinnitus, congestive heart failure, myocardial infarction, myocardial ischemia, hoarseness, constipation, stomatitis, dyspepsia, dysphagia, dry skin, exfoliative dermatitis, acne, skin desquamation, arthralgia, myalgia, renal failure, proteinuria, erectile dysfunction, asthenia, fever, and influenza-like illness.

[00107] In an embodiment, a subject is administered the chemotherapeutic agent (or radiation) and is subsequently evaluated for side effects. If side effects are present, the patient is subsequently administered the lipopeptide or lipopeptide composition described herein. Alternatively, if side effects are absent, the lipopeptide or lipopeptide composition is not administered to the subject.

[00108] In an exemplary embodiment, the administration of the lipopeptide or lipopeptide composition disclosed herein eliminates or reduces or mitigates blood disorders associated with chemotherapy or radiotherapy. In an embodiment, the administration of the lipopeptide or lipopeptide composition eliminates or reduces or mitigates leukopenia and/or reduced white blood count and reduction of other types of blood cells, including neutrophils, lymphocytes, platelets, and red blood cells. The blood disorder may be assessed by a blood test well-established in the art. For example, the blood test may involve a cell count, such as a complete blood count (CBC). The blood test may further include a blood differential test which measures the percentage of each type of white blood cell as well as revealing any abnormal or immature cells. In some embodiments, a patient is classified as being afflicted with neutropenia if he or she presents with an absolute neutrophil count (ANC) of less than about 1700/mm³. In some embodiments, a patient is classified as being severely afflicted with neutropenia if he or she presents with an absolute neutrophil count (ANC) of less than about 500/mm³.

[00109] In another aspect, the present invention provides for a method of reducing in the duration of neutropenia in a cancer patient, comprising administering an effective amount of a lipopeptide of formula I in which the patient is receiving one or more anti-cancer drugs, for example any of the drugs described herein, including myelosuppressive anti-cancer drug (by way of non-limiting example one or more of cyclophosphamide, doxorubicin, etoposide, ifosfamide, mesna, methotrexate, vinblastine, and cisplatin). In various embodiments, the lipopeptide of formula I provides for a recovery of white blood cell levels in a neutropenia-afflicted cancer patient. In various embodiments, the cancer is any of those described herein, including cancers that effects bone marrow directly, for example, leukemia, lymphoma, and myeloma, or metastatic cancer.

[00110] In various embodiments, the lipopeptide reduces or prevents infection in the patient and/or increases absolute neutrophil count (ANC) in the patient (e.g. to greater than about 500/mm³, or about 600/mm³, or about 700/mm³, or about 800/mm³, or about 900/mm³, or about 1000/mm³, or about 1100/mm³, or about 1200/mm³, or about 1300/mm³, or about 1400/mm³, or about 1500/mm³, or about 1600/mm³, or about 1700/mm³, or about 1800/mm³, or about 1900/mm³, or about 2000/mm³, or about 2100/mm³, or about 2200/mm³, or about 2300/mm³, or about 2400/mm³, or about 2500/mm³).

[00111] In various embodiments, the lipopetide may treat a leukopenia including neutropenia in combination with granulocyte colony-stimulating factor (G-CSF) or an analog thereof (e.g. filgrastim (e.g. EMGRAST, FILCAD, GRAFEEL, IMUMAX, NEUKINE, NEUPOGEN, NUFIL, RELIGRAST, and ZARZIO)).

[00112] In some embodiments, the lipopeptide reduces or prevents delay and/or a dose reduction in one or more scheduled cycles of chemotherapy. Such delays or dose reductions are often used to allow hematopoietic activity to recover in cancer patients and can reduce the efficacy of treatment. The present lipopeptides, in some embodiments, spare the patient such delays or reductions and therefore improve the quality of the cancer treatment. For instance, such treatment improvements, in some embodiments, may manifest as increased long- term survival and/or periods of remission.

[00113] In some embodiments, the patient is elderly (e.g. greater than about 60, or about 65, or about 70, or about 75 years of age).

[00114] In certain embodiments, the increased therapeutic window of the chemotherapeutic agent or radiation comprises increasing a cancer patient's likelihood of receiving a complete regimen of the chemotherapy or radiotherapy. In an embodiment, the increased therapeutic window of the chemotherapy and/or radiotherapy comprises increasing a cancer patient's likelihood of receiving more than a complete regimen of the chemotherapy or radiotherapy.

[00115] In certain embodiments, the increased therapeutic window of the chemotherapy and/or radiotherapy comprises increasing the dose or length of the chemotherapy or radiotherapy. In some embodiments, use of the lipopeptide or lipopeptide composition allows for a cancer patient to receive dose-dense chemotherapy or radiotherapy. In various embodiments, use of the lipopeptide or lipopeptide composition allows for a cancer patient to avoid dose delay.

[00116] In various examples, the present methods may open the therapeutic window such that a full regimen or more than a full regimen of the chemotherapy and/or radiotherapy can be completed without having to cease treatment due to, for example, side effects. In another example, the present methods may open the therapeutic window such that increased dosages or administration at higher frequencies can be tolerated by the patient. In a further example, the present methods may open the therapeutic window such that the periods without treatment are shortened or eliminated, or the number of cycles reduced or increased.

[00117] In certain embodiments, the increased therapeutic window of the chemotherapeutic agent or radiation comprises increasing a cancer patient's likelihood receiving the chemotherapeutic agent or radiation maintenance therapy. In an embodiment, the increased therapeutic window of the chemotherapeutic agent or radiation comprises allowing a patient to be administered a greater maintenance therapy (e.g. more frequently and/or at a larger dose).

[00118] In certain embodiments, the present invention provides for use of the lipopeptide or lipopeptide composition to increase an ability of a cancer patient to receive a combination therapy including a chemotherapeutic agent (or radiation) and another therapeutic agent. In some embodiments, use of the lipopeptide or lipopeptide composition described herein increases the ability of a cancer patient to receive a complete regimen of a combination therapy including a chemotherapeutic agent (or radiation) and another therapeutic agent and not have to cease treatment due to, for example, side effects. In some embodiments, the use of the lipopeptide or lipopeptide composition increases the ability of a cancer patient to receive a greater dose or longer duration of combination therapy including a chemotherapeutic agent (or radiation) and another therapeutic agent. In some embodiments, the methods of the present invention allows for an increased dose and/or frequency of the regiment of the combination therapy. The combination therapy may include any of the chemotherapeutic agents or radiation agents described herein.

[00119] In various embodiments, a combination of the lipopeptide or lipopeptide composition and/or the chemotherapeutic agent (or radiation) produces a synergistic effect. In an embodiment, the synergistic effect is a tumor growth slowing effect.

[00120] In various embodiments, the present invention relates to the treatment or prevention of a blood- based disease, including but limited to a leukopenia such as neutropenia with the lipopeptides of formula I. various embodiments, the present invention relates to the treatment or prevention of a blood-based disease, including but limited to myelosuppression, including without limitation, chemotherapy-induced myelosuppression. Such embodiments pertain to treatment regardless of whether in the context of cancer.

[00121] In various embodiments, the present invention relates to the treatment or prevention of a blood- based disease, including but limited to any myelosuppression and/or any leukopenia such as neutropenia with the lipopeptides of formula I in various patient populations. For example, patients receiving various medications may be suited to the present methods, including: clozapine (an antipsychotic medication with a rare adverse effect leading to the total absence of all granulocytes (neutrophils, basophils, eosinophils)), the antidepressant and smoking addiction treatment drug bupropion HCI (e.g. WELLBUTRIN) minocycline, a commonly prescribed antibiotic, divalproex sodium or valproic acid (e.g. DEPAKOTE) (e.g. a patient afflicted with epilepsy (seizures), mania (with bipolar disorder) and migraine), the anticonvulsant drug, lamotrigine, metronidazole, and various immunosuppressive drugs, such as sirolimus, mycophenolate mofetil, tacrolimus, cyclosporine, Leflunomide (e.g. ARAVA) and TNF inhibitors, and interferons (e.g. patients with multiple sclerosis, such as those receiving, for example, REBIF, AVONEX, and BETASERON, can also cause leukopenia). Further, patients may have inherited neutropenia, cyclic, or severe neutropenia.

[00122] In various embodiments, the present invention relates to any of the methods of treatment described herein where the lipopeptide of Formula I, including without limitation CBLB612 is administered in a safe and effective dose as described herein. In various aspects, the safe and effective dose of the lipopeptide of Formula I, including without limitation CBLB612, is up to about 4 μς, or up to about 5 μg. In some embodiments, the dose is between about 0.5 to about 4 μς, or about 1 μς to about 4 μς, or about 2 μς to about 4 μς, or about 3 μς to about 4 μς, or about 0.5 μς to about 3 μς, or about 0.5 μς to about 2 μς, or about 0.5 μς to about 1 μς. In some embodiments the safe and effective dose of CBLB612 is about 0.5 μς, or about 1 μς, or about 1.5 μς, or about 2 μς, or about 2.5 μς, or about 3 μς, or about 3.5 μς, or about 4 μς. In various embodiments, these doses are used in subcutaneous administration, e.g. via injection.

[00123] In another aspect, the present invention provides for methods of treating cancer, comprising administering to a human patient a lipopeptide of Formula I, including without limitation CBLB612, in a safe and effective dose as described herein. In another aspect, the present invention provides for methods of treating chemotherapy-induced myelosuppression, comprising administering to a human patient a lipopeptide of Formula I, including without limitation CBLB612, in a safe and effective dose as described herein. In various aspects, the safe and effective dose of the lipopeptide of Formula I, including without limitation CBLB612, is up to about 4 μg, or up to about 5 μg. In some embodiments, the dose is between about 0.5 μg to about 4 μg, or about 1 μg to about 4 μg, or about 2 μg to about 4 μg, or about 3 μg to about 4 μg, or about 0.5 μg to about 3 μg, or about 0.5 μg to about 2 μg, or about 0.5 μg to about 1 μg. In some embodiments the safe and effective dose of CBLB612 is about 0.5 μg, or about 1 μg, or about 1.5 μg, or about 2 μg, or about 2.5 μg, or about 3 μg, or about 3.5 μg, or about 4 μg. In various embodiments, these doses are used in subcutaneous administration, e.g. via injection.

[00124] In some embodiments, the subject or patient is a human. In some embodiments, the human is a pediatric human. In other embodiments, the human is an adult human. In other embodiments, the human is a geriatric human. In other embodiments, the human may be referred to as a patient.

[00125] In certain embodiments, the human has an age in a range of from about 0 months to about 6 months old, from about 6 to about 12 months old, from about 6 to about 18 months old, from about 18 to about 36 months old, from about 1 to about 5 years old, from about 5 to about 10 years old, from about 10 to about 15 years old, from about 15 to about 20 years old, from about 20 to about 25 years old, from about 25 to about 30 years old, from about 30 to about 35 years old, from about 35 to about 40 years old, from about 40 to about 45 years old, from about 45 to about 50 years old, from about 50 to about 55 years old, from about 55 to about 60 years old, from about 60 to about 65 years old, from about 65 to about 70 years old, from about 70 to about 75 years old, from about 75 to about 80 years old, from about 80 to about 85 years old, from about 85 to about 90 years old, from about 90 to about 95 years old or from about 95 to about 100 years old

[00126] In other embodiments, the subject is a non-human animal, and therefore the invention pertains to veterinary use. In a specific embodiment, the non-human animal is a household pet. In another specific embodiment, the non-human animal is a livestock animal. [00127] The invention provides kits that can simplify the administration of any agent described herein. An exemplary kit of the invention comprises any composition described herein in unit dosage form. In one embodiment, the unit dosage form is a container, such as a pre-filled syringe (e.g. an injector pen), which can be sterile, containing any agent described herein and a pharmaceutically acceptable carrier, diluent, excipient, or vehicle. The kit can further comprise a label or printed instructions instructing the use of any agent described herein. The kit may also include a lid speculum, topical anesthetic, and a cleaning agent for the administration location. In one embodiment, the kit comprises a lipopeptide or lipopeptide composition. The kit can also further comprise one or more additional therapeutic agents described herein. In one embodiment, the kit comprises a container containing an effective amount of a composition of the invention and an effective amount of another composition, such those described herein. This invention is further illustrated by the following non-limiting examples.

EXAMPLES

Example 1. CBLB612 Promotes Cancer Survival

[00128] A critical issue for the medical use of the lipopeptides disclosed herein for the protection or stimulation of the hematopoietic system in the context of cancer treatment is whether the effect is specific for normal cells versus tumor cells. In this regard, the effect of lipopeptides on tumor growth was tested using a tumor-prone p53 heterozygous (p53^+/") mouse model in which sublethal total body irradiation (e.g., 4 Gy) leads to animal death due to tumor development. Specifically, irradiated p53 heterozygous (p53^+A) mice were treated with either phosphate buffered saline (PBS) or with an exemplary lipopeptide of formula I having a peptide sequence of SEQ ID: NO: 21 {i.e., CBLB612). As shown in Figure 1 , treatment with CBLB612 (4 weekly injections) increased median survival time from 327 days (with PBS treatment) to 345 days (P=0.0289 by Log rank test) - compare top line (CBLB612) to bottom line (PBS). This reduction in tumor-dependent mortality indicates that CBLB612 does not promote tumor growth, but rather has a tumor suppressive effect as a monotherapy.

[00129] This finding also suggests that the protective/stimulatory effects of CBLB612 are limited to normal (non-tumor) cells. Without wishing to be bound by theory, it is believed that the differential effects of CBLB612 (a TLR agonist) in normal versus tumor cells is likely due, at least in part, to common tumor-specific changes in signaling pathways (e.g., constitutive activation of NF-κΒ) which leave tumor cells unaffected by additional TLR agonist-driven changes.

Example 2. Efficacies of CBLB612 Against Tumor Growth and the Side Effects of Chemotherapy

[00130] The effect of CBLB612 (alone or in combination with the chemotherapeutic agent, cyclophosphamide) on tumor growth was tested in a murine melanoma model. Specifically, C57BL/6 mice bearing subcutaneous B16 melanoma tumors were treated with either CBLB612, cyclophosphamide, or both drugs in combination. [00131] As shown in Figure 2, CBLB612 did not enhance tumor growth in this model, but rather, like cyclophosphamide, demonstrated substantial antitumor efficacy as a single agent. Further, CBLB612 treatment did not reduce the sensitivity of B16 melanoma tumors to cyclophosphamide, suggesting that CBLB612 can be safely used as an adjuvant in combination with other anticancer therapies such as chemotherapy or radiotherapy.

Example 3. Efficacies of CBLB612 Against the Side Effects of Chemotherapy

[00132] Additional experiments were conducted to further investigate the use of CBLB612 as an adjuvant therapy for other anticancer therapies such as chemotherapy. In these experiments, non-tumor-bearing mice were treated with 500 mg/kg cyclophosphamide on days 0 and 7. Subsequently, one group of eight mice was administered CBLB612 (400 Mg/kg) on days 1 and 8 (i.e., 24 hour after each cyclophosphamide treatment) and a second group of eight mice was administered PBS at the same times. White blood cell concentrations were determined by automated complete blood cell count (CBC) analysis of peripheral blood samples before and after treatment initiation. As shown in Figure 3, CBLB612 ameliorated the loss of and promoted the restoration of circulating white blood cells following cyclophosphamide treatment. Particularly, treatment of mice with CBLB612 after cyclophosphamide reduced the extent of leukopenia and led to more rapid recovery of white blood cell levels.

[00133] Taken together, these data strongly suggest that CBLB612 is an effective anticancer agent when administered alone. Further still, the data also indicates that CBLB612 can be an effective anticancer adjuvant capable of reducing the adverse side effects of standard chemotherapies or radiotherapies while not compromising (and potentially, enhancing) tumor suppression.

Example 4. Phase 1 Study of CBLB612

[00134] A Phase 1 single-blinded, randomized, placebo-controlled, healthy-subject study of CBLB612 was undertaken. The objectives of the study were to evaluate the safety profile of CBLB612, establish the maximum tolerated dose (MTD) and characterize the magnitude and timing of CBLB612 effects on several biomarkers of activity including circulating absolute neutrophil counts (ANC) and concentrations of plasma cytokines (granulocyte colony-stimulating factor [G-CSF], interleukin [IL]-6 IL-8, IL-10 and interferon-alfa [IFN-a]).

[00135] The primary study aim was to assess safety and tolerability of various doses of CBLB612 following single subcutaneous (s/c) administration to healthy volunteers and secondary aims included assessing pharmacodynamics (PD) following various doses of CBLB612 in healthy volunteers and determining biomarkers typical for the product's mode of action. Volunteers were enrolled to the study in cohorts. In each cohort, volunteers were randomized in ratio 3:1 to CBLB612 group or placebo group, respectively. 56 volunteers took part in the study.

[00136] Escalation of the study dose, transfer to higher dose level occurred based on the conclusion of expert commission being part as of the Independent Data and Safety Monitoring Board, based on dose-limiting toxicity of the product. The following doses were studied: 0.5 μς, 1 μς, 2 μς, 4 μς, and 8 μς. The decision on achieved maximum dose 8 μg for healthy volunteers in the study was based, in part, on interim safety data, AE reported in volunteers (e.g. acute keratitis (resolved without sequelae), increased severity of flu-like syndrome), and interim pharmacodynamic data.

[00137] Safety assessment criteria included the following parameters: adverse events, laboratory tests (complete blood count, coagulogram, blood biochemistry and urinalysis), vital signs, physical and ophthalmological examination, electrocardiography (ECG).

[00138] Criteria for pharmacodynamic assessment included the following parameters: blood immune CD34+ cells and other lymphocyte populations (Th1 , Th2, Th17, Treg, NK, NKT, MDSCs), cytokines (G-CSF, IL -8, IL- 6, IL-10, TNF-a, INF-γ, IL-1 β, IL-2, IL-12p70, IL-13), complete blood count values (including neutrophiles).

[00139] For safety evaluations, the following parameters were evaluated: presence/absence of dose-limiting toxicity, frequency and severity of adverse events (AE) and serious adverse events (SAE) in study groups with gradual dose escalation which are, according to investigators, related to the study product, premature study withdrawals due to AE and SAE, and assessment of changes in clinical, laboratory and instrumental test results.

[00140] With respect to the safety study of CBLB612, it was found that, in general, single subcutaneous injection of CBLB612 in dosages 0.5-4 μg was well-tolerated by healthy volunteers. Most AEs were of mild and moderate severity, related to the product mode of action and were transient. Frequently reported AEs (ADR) of CBLB612 included flu-like syndrome, local reaction in the injection site, laboratory abnormalities - increase of CRP and ESR levels, hyperkaliemia, as well as ophthalmologic manifestations as keratitis and conjunctivitis. These AEs were minor and expected for the drug being evaluated. No SAE were observed. Dosage of CBLB612 4μg is MTD for healthy volunteers and recommended for investigation in patients in subsequent clinical studies.

[00141] The MTD was determined as 4μg - the dose which was 1 dose level lower than the dose which induces dose-limiting toxicity (DTR) and is observed at least in one third of volunteers. The initial determination of the DTR was based, in part, on the appearance of ophthalmic AEs, namely moderate keratitis for healthy volunteers, which were considered unacceptable for the study.

[00142] With respect to the CBLB612 pharmacodynamics study, single CBLB612 injection induced dose- dependent increase of absolute neutrophil count up to about 10x10⁹, and the effect persisted for at least 20 hours. As shown in Figure 4, the maximum effect was achieved in doses 4 and 8 μg and registered 4 hours after the product administration. The effect persisted at least for 24 hours, if not longer. Absolute neutrophil count returned to normal levels up to 36 hours.

[00143] CBLB612 administration resulted in rapid, dose-dependent increase of plasma levels of several cytokines including G-CSF and IL-6, IL-8, IL-10 and INFa. Cytokine levels were rapidly decreased returning to baseline levels within 16 (+/- 8) hours after the drug product. [00144] In summary, analysis of data from the 56 healthy volunteers enrolled in the study indicates that single subcutaneous injections of CBLB612 in doses ranging from 0.5 to 4 micrograms were generally well-tolerated, with the 4 microgram dose identified as the MTD. Observed adverse events were typically mild or moderate in severity, transient, and related to the drug's mechanism of action. Single injections of CBLB612 induced dose- dependent increases in ANC lasting approximately 20 hours. Administrations of CBLB612 also resulted in rapid, dose-dependent increases of plasma levels of the specified cytokines. Cytokine levels returned to baseline levels several hours after administration of the drug

Definitions

[00145] The following definitions are used in connection with the invention disclosed herein. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of skill in the art to which this invention belongs.

[00146] As used herein, the terms "subject" and "patient" are used interchangeably irrespective of whether the subject has or is currently undergoing any form of treatment. As used herein, the terms "subject" and "subjects" refer to any vertebrate, including, but not limited to, a mammal (e.g., cow, pig, camel, llama, horse, goat, rabbit, sheep, hamsters, guinea pig, cat, dog, rat, and mouse, a non-human primate (for example, a monkey, such as a cynomolgous monkey, chimpanzee, etc) and a human).

[00147] As used herein, "a," "an," or "the" can mean one or more than one.

[00148] Further, the term "about" when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10% of that referenced numeric indication. For example, the language "about 50" covers the range of 45 to 55.

[00149] An "effective amount," when used in connection with medical uses is an amount that is effective for providing a measurable treatment, prevention, or reduction in the rate of pathogenesis of a disease of interest.

[00150] As referred to herein, all compositional percentages are by weight of the total composition, unless otherwise specified. As used herein, the word "include," and its variants, is intended to be non-limiting, such that recitation of items in a list is not to the exclusion of other like items that may also be useful in the compositions and methods of this technology. Similarly, the terms "can" and "may" and their variants are intended to be non- limiting, such that recitation that an embodiment can or may comprise certain elements or features does not exclude other embodiments of the present technology that do not contain those elements or features.

[00151] Although the open-ended term "comprising," as a synonym of terms such as including, containing, or having, is used herein to describe and claim the invention, the present invention, or embodiments thereof, may alternatively be described using alternative terms such as "consisting of or "consisting essentially of."

[00152] As used herein, the words "preferred" and "preferably" refer to embodiments of the technology that afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the technology.

[00153] The amount of compositions described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g. CBLB612 (and/or additional therapeutic agents described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A "pharmacologically effective amount," "pharmacologically effective dose," "therapeutically effective amount," or "effective amount" refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a patient suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.

[00154] Effective amounts, toxicity, and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to about 50% of the population) and the ED50 (the dose therapeutically effective in about 50% of the population). The dosage can vary depending upon the dosage form employed and the route of administration utilized. The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50. In some embodiments, compositions and methods that exhibit large therapeutic indices are preferred. A therapeutically effective dose can be estimated initially from in vitro assays, including, for example, cell culture assays. Also, a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture, or in an appropriate animal model. Levels of the described compositions in plasma can be measured, for example, by high performance liquid chromatography. The effects of any particular dosage can be monitored by a suitable bioassay. The dosage can be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.

[00155] In certain embodiments, the effect will result in a quantifiable change of at least about 10%, at least about 20%, at least about 30%, at least about 50%, at least about 70%, or at least about 90%. In some embodiments, the effect will result in a quantifiable change of about 10%, about 20%, about 30%, about 50%, about 70%, or even about 90% or more. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder or reduction in toxicity, regardless of whether improvement is realized. [00156] In certain embodiments, a pharmacologically effective amount that will treat cancer will modulate the symptoms typically by at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%. In exemplary embodiments, such modulations will result in, for example, statistically significant and quantifiable changes in the numbers of cancerous cells or indicia of toxicity as described herein (e.g. number of certain cells in a blood test, number of liver enzymes in a blood test, etc.)

EQUIVALENTS

[00157] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

[00158] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

INCORPORATION BY REFERENCE

[00159] All patents and publications referenced herein are hereby incorporated by reference in their entireties.

[00160] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

[00161] As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections.

Claims

[00162] CLAIMS What is claimed is:

1. A method of treating cancer, comprising administering to a subject an effective amount of a lipopeptide of formula I:

wherein,

Ri represents H or -CO-R4,

R2, R3 and R4 independently are H or optionally substituted aliphatic;

X is a peptide; Z is S or Chb; and

the effective amount of the lipopeptide of formula I is about 0.5 μg to about 5 μg.

2. The method of claim 1 , wherein the peptide comprises an amino acid sequence of any one of SEQ ID NOs: 1 -52 and substitutions thereof.

3. The method of claim 2, wherein the peptide comprises an amino acid sequence selected from SEQ ID NOs: 8, 16, 17, 18, and 21.

4. The method of claim 2, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 21.

5. The method of any one of claims 1 -4, wherein Ri is H.

6. The method of any one of claims 1-5, wherein any one of R2, R3 and R4 independently is a C5, or C6, or C7, or Ce, or Cg, or C10, or Cn, or C12, or C13, or C14, or C15, or C16, or C17, or C18, or C19, or C20 aliphatic and substitutions thereof.

7. The method of any one of claims 1-6, wherein Z is S.

8. The method of claim 1, wherein the lipopeptide is:

9. The method of any one of claims 1-8, wherein the cancer is selected from a basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and central nervous system cancer, breast cancer, cancer of the peritoneum, cervical cancer, choriocarcinoma, colon and rectum cancer, connective tissue cancer, cancer of the digestive system, endometrial cancer, esophageal cancer, eye cancer, cancer of the head and neck, gastric cancer (including gastrointestinal cancer), glioblastoma, hepatic carcinoma, hepatoma, intra-epithelial neoplasm, kidney or renal cancer, larynx cancer, leukemia, liver cancer, lung cancer (including small-cell lung cancer, non- small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), melanoma, myeloma, neuroblastoma, oral cavity cancer (including lip, tongue, mouth, and pharynx), ovarian cancer, pancreatic cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, rectal cancer, cancer of the respiratory system, salivary gland carcinoma, sarcoma, skin cancer, squamous cell cancer, stomach cancer, testicular cancer, thyroid cancer, uterine or endometrial cancer, cancer of the urinary system, vulval cancer, lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low grade/follicular non- Hodgkin's lymphoma (NHL), small lymphocytic (SL) NHL, intermediate grade/follicular NHL, intermediate grade diffuse NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-cleaved cell NHL, bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom's Macroglobulinemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), Hairy cell leukemia, chronic myeloblastic leukemia, as well as other carcinomas and sarcomas, and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.

10. A method of treating cancer comprising administering to a subject undergoing chemotherapy and/or radiotherapy an effective amount of a lipopeptide of formula I:

wherein,

Ri represents H or -CO-R4,

R2, R3 and R4 independently are H or optionally substituted aliphatic;

X is a peptide;

Z is S or Chb; and

11. The method of claim 10, wherein the peptide comprises an amino acid sequence of any one of SEQ ID NOs: 1-52 and substitutions thereof.

12. The method of claim 11 , wherein the peptide comprises an amino acid sequence selected from SEQ ID NOs: 8, 16, 17, 18, and 21.

13. The method of claim 12, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 21.

14. The method of any one of claims 10-13, wherein Ri is H.

15. The method of any one of claims 10-14, wherein any one of R2, R3 and R4 independently is a C5, or C6, or C7, or Ce, or Cg, or C10, or Cn, or C12, or C13, or C14, or C15, or C16, or C17, or Cis, or C19, or C20 aliphatic and substitutions thereof.

16. The method of any one of claims 1-15, wherein Z is S.

17. The method of claim 10, wherein the lipopeptide is:

18. The method of any one of claims 10-17, wherein the subject is undergoing chemotherapy.

19. The method of claim 18, wherein the subject is undergoing chemotherapy with a chemotherapeutic agent selected from alkylating agents such as thiotepa and CYTOXAN cyclosphosphamide, alkyl sulfonates such as busulfan, improsulfan and piposulfan, aziridines such as benzodopa, carboquone, meturedopa, and uredopa, ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine, acetogenins (e.g., bullatacin and bullatacinone), a camptothecin (including the synthetic analogue topotecan), bryostatin, cally statin, CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues), cryptophycins (e.g., cryptophycin 1 and cryptophycin 8), dolastatin, duocarmycin (including the synthetic analogues, KW-2189 and CB 1-TM1), eleutherobin, pancratistatin, a sarcodictyin, spongistatin, nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine, antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gammall and calicheamicin omegall (see, e.g., Agnew, Chem. Intl. Ed. Engl., 33: 183-186 (1994)), dynemicin, including dynemicin A, bisphosphonates, such as clodronate, an esperamicin, as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, ADRIAMYCIN doxorubicin (including morpholino- doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, anti-metabolites such as methotrexate and 5-fluorouracil (5-FU), folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate, purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, anti-adrenals such as minoglutethimide, mitotane, trilostane, folic acid replenisher such as frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, demecolcine, diaziquone, elformithine, elliptinium acetate, an epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansinoids such as maytansine and ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, PSK polysaccharide complex (JHS Natural Products, Eugene, Oreg.), razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone, 2,2', 2"- trichlorotriethylamine, trichothecenes (e.g., T-2 toxin, verracurin A, roridin A and anguidine), urethan, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside ("Ara-C"), cyclophosphamide, thiotepa, taxoids, e.g., TAXOL paclitaxel (Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE Cremophor-free, albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, 111.), and TAXOTERE doxetaxel (Rhone-Poulenc Rorer, Antony, France), chloranbucil, GEMZAR gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum analogs such as cisplatin, oxaliplatin and carboplatin, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, NAVELBINE. vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan (Camptosar, CPT-11) (including the treatment regimen of irinotecan with 5-FU and leucovorin), topoisomerase inhibitor RFS 2000, difluoromethylornithine (DMFO), retinoids such as retinoic acid, capecitabine, combretastatin, leucovorin (LV), oxaliplatin, including the oxaliplatin treatment regimen (FOLFOX), lapatinib (Tykerb), inhibitors of PKC-a, Raf, H-Ras, EGFR (e.g., erlotinib (Tarceva)) and VEGF-A such as Bl- 2356, Sutent, PF-562271 , AMG706, dasatinib, sorafenib, GSK461364A, and Bez-235.

20. The method of claim 19, wherein the chemotherapeutic agent is cyclophosphamide.

21. The method of any one of claims 10-20, wherein the subject is undergoing radiotherapy.

22. The method of any one of claims 10-21 , wherein the lipopeptide is administered after administration of chemotherapy or radiotherapy.

23. The method of any one of claims 10-22, wherein the patient experiences one or more side effects of chemotherapy and/or radiotherapy.

24. The method of claim 23, wherein the side effects of chemotherapy and/or radiotherapy prevent the patient from receiving a full dose or regimen of chemotherapy and/or radiotherapy.

25. The method of any one of claims 10-24, wherein the lipopeptide reduces and/or mitigates one or more side effects of chemotherapy or radiotherapy.

26. The method of any one of claims 23-25, wherein the side effects are selected from one or more of fatigue, nausea, vomiting, loss of appetite, pain, hair loss, leukopenia, neutropenia, anemia, lymphopenia, thrombocytopenia, infection, mouth, gum and throat complications, diarrhea, constipation, nerve and muscle complications, effects on skin and nails, radiation recall, kidney and bladder complications, flu-like symptoms, fluid retention, and effects on sexual organs and sexuality

27. The method of claim 26, wherein the side effect is leukopenia.

28. The method of claim 27, wherein the lipopeptide mitigates the loss of white blood cell in the subject undergoing chemotherapy or radiotherapy.

29. The method of any one of claims 10-28, wherein administration of the lipopeptide increases a therapeutic window of a chemotherapeutic agent or radiation.

30. The method of claim 29, wherein the increased therapeutic window comprises one or more of increasing the subject's likelihood receiving chemotherapeutic or radiation maintenance therapy, increasing the subject's likelihood of receiving a complete regimen of chemotherapy or radiotherapy, increasing the subject's likelihood of receiving more than a complete regimen of chemotherapy or radiotherapy, and increasing the dose or length of chemotherapy or radiotherapy.

31. The method of any one of claims 10-30, wherein administering an effective amount of the lipopeptide increases the ability of the subject to receive a combination therapy with the existing chemotherapy or radiotherapy.

32. The method of any one of claims 10-31 , wherein the cancer is selected from a basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and central nervous system cancer, breast cancer, cancer of the peritoneum, cervical cancer, choriocarcinoma, colon and rectum cancer, connective tissue cancer, cancer of the digestive system, endometrial cancer, esophageal cancer, eye cancer, cancer of the head and neck, gastric cancer (including gastrointestinal cancer), glioblastoma, hepatic carcinoma, hepatoma, intraepithelial neoplasm, kidney or renal cancer, larynx cancer, leukemia, liver cancer, lung cancer (including small- cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), melanoma, myeloma, neuroblastoma, oral cavity cancer (including lip, tongue, mouth, and pharynx), ovarian cancer, pancreatic cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, rectal cancer, cancer of the respiratory system, salivary gland carcinoma, sarcoma, skin cancer, squamous cell cancer, stomach cancer, testicular cancer, thyroid cancer, uterine or endometrial cancer, cancer of the urinary system, vulval cancer, lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL), small lymphocytic (SL) NHL, intermediate grade/follicular NHL, intermediate grade diffuse NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-cleaved cell NHL, bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom's Macroglobulinemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), Hairy cell leukemia, chronic myeloblastic leukemia, as well as other carcinomas and sarcomas, and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.

33. A method of preventing or reducing the duration of neutropenia and/or preventing or reducing the duration of chemotherapy-induced myelosuppression in a cancer patient, comprising administering an effective amount of a lipopeptide of formula I:

wherein,

Ri represents H or -CO-R4,

R2, R3 and R4 independently are H or optionally substituted aliphatic;

X is a peptide;

Z is S or CH₂,

the patient is receiving one or more myelosuppressive anti-cancer drug; and

34. The method of claim 33, wherein the peptide comprises an amino acid sequence of any one of SEQ ID NOs: 1-52 and substitutions thereof.

35. The method of claim 34, wherein the peptide comprises an amino acid sequence selected from SEQ ID NOs: 8, 16, 17, 18, and 21.

36. The method of claim 35, wherein the peptide comprises an amino acid sequence of SEQ ID NO: 21.

37. The method of any one of claims 33-36, wherein Ri is H.

38. The method of any one of claims 33-37, wherein any one of R2, R3 and R4 independently is a C5, or C§, or C7, or Ce, or Cg, or C10, or Cn , or C12, or C13, or C14, or C15, or C16, or C17, or Cis, or C19, or C20 aliphatic.

39. The method of claim 32, wherein the lipopeptide is:

40. The method of any one of claims 33-39, wherein the patient has an infection.

41. The method of any one of claims 33-40, wherein the patient is being administered GM-CSF or an analog thereof.

42. The method of any one of claims 33-41 , wherein the patient has febrile neutropenia.

43. The method of any one of claims 33-42, wherein the myelosuppressive anti-cancer drug is one or more of cyclophosphamide, doxorubicin, etoposide, ifosfamide, mesna, methotrexate, vinblastine, and cisplatin.

44. The method of any one of claims 33-43, wherein the cancer is selected from a basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and central nervous system cancer, breast cancer, cancer of the peritoneum, cervical cancer, choriocarcinoma, colon and rectum cancer, connective tissue cancer, cancer of the digestive system, endometrial cancer, esophageal cancer, eye cancer, cancer of the head and neck, gastric cancer (including gastrointestinal cancer), glioblastoma, hepatic carcinoma, hepatoma, intraepithelial neoplasm, kidney or renal cancer, larynx cancer, leukemia, liver cancer, lung cancer (including small- cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), melanoma, myeloma, neuroblastoma, oral cavity cancer (including lip, tongue, mouth, and pharynx), ovarian cancer, pancreatic cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, rectal cancer, cancer of the respiratory system, salivary gland carcinoma, sarcoma, skin cancer, squamous cell cancer, stomach cancer, testicular cancer, thyroid cancer, uterine or endometrial cancer, cancer of the urinary system, vulval cancer, lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL), small lymphocytic (SL) NHL, intermediate grade/follicular NHL, intermediate grade diffuse NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-cleaved cell NHL, bulky disease NHL, mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom's Macroglobulinemia, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), Hairy cell leukemia, chronic myeloblastic leukemia, as well as other carcinomas and sarcomas, and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.

45. The method of claim 44, wherein the cancer is one the effects bone marrow directly, selected from leukemia, lymphoma, and myeloma, and metastatic cancer.

46. The method of any one of claims 33-45, wherein the lipopeptide reduces or prevents infection in the patient.

47. The method of any one of claims 33-46, wherein the lipopeptide increases absolute neutrophil count (ANC) in the patient.

48. The method of any one of claims 33-47, wherein the lipopeptide increases absolute neutrophil count (ANC) to greater than about 500/mm³.

49. The method of any one of claims 33-48, wherein the patient is elderly (e.g. greater than about 60, or about 65, or about 70, or about 75 years of age).

50. The method of any one of claims 1 -9, wherein the lipopeptide is administered in a dose of about 1 to about 4 μg.

51. The method of claim 50, where the dose is about 0.5 μg, or about 1 μg, or about 1.5 μg, or about 2 μg, or about 2.5 μg, or about 3 μg, or about 3.5 μg, or about 4 μg.

52. The method of claims 50 or 51 , wherein the lipopeptide is administered in a dose of about 4 μg.

53. The method of one of claims 50-52, wherein the lipopeptide is administered via subcutaneous injection.

54. The method of any one of claims 10-32, wherein the lipopeptide is administered in a dose of about 1 to about 4 μg.

55. The method of claim 54, where the dose is about 0.5 μg, or about 1 μg, or about 1.5 μg, or about 2 μg, or about 2.5 μg, or about 3 μg, or about 3.5 μg, or about 4 μg.

56. The method of claims 54 or 55, wherein the lipopeptide is administered in a dose of about 4 μg.

57. The method of one of claims 54-56, wherein the lipopeptide is administered via subcutaneous injection.

58. The method of any one of claims 33-49, wherein the lipopeptide is administered in a dose of about 1 to about 4 μg.

59. The method of claim 58, where the dose is about 0.5 μg, or about 1 μg, or about 1.5 μg, or about 2 μg, or about 2.5 μg, or about 3 μg, or about 3.5 μg, or about 4 μg.

60. The method of claims 58 or 59, wherein the lipopeptide is administered in a dose of about 4 μg.

61. The method of one of claims 58-60, wherein the lipopeptide is administered via subcutaneous injection.