Methods of treating colorectal cancer using non-naturally occurring melanocortin analogs

Abstract

Provided herein are methods of treating, preventing, or reducing conditions and / or side effects associated with anti-cancer agents (e.g., chemotherapeutic agents) via administration of a non-naturally occurring melanocortin analog prior to, during, and / or after administration of the anti-cancer agents. The methods reduce adverse effects associated with the anti-cancer agent, such as anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite, thereby enhancing tolerance of the anti-cancer agents and survival of the subject having cancer or having a disease or condition that is not cancer but is treated, reduced, or prevented by administration of an anti-cancer agent.

Description

Docket No.: 211Z-412981-WOMETHODS OF TREATING COLORECTAL CANCER USING NON- NATURALLY OCCURRING MELANOCORTIN ANALOGSCROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] This application claims the benefit of U. S. Provisional Patent Application No. 63 / 895,268, filed October 7, 2025, and U. S. Provisional Patent Application No.63 / 756,785, filed February 10, 2025, both of which are incorporated herein by reference in their entirety.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] This application contains an ST.26 compliant Sequence Listing, which is submitted concurrently in xml format and herby incorporated by reference in its entirety. The.xml copy, created on February 10, 2026, is titled “211Z-412981-WO_SL.xml” and is 1,552,384 bytes in size.BACKGROUND

[0003] The use of anti-cancer agents, including chemotherapeutic agents, to treat patients is often restricted because the patient suffers from certain conditions such as anorexia, emesis, weight loss, fat and muscle wasting, and fatigue. These conditions may be caused by the subject’s cancer or may be side effects of the anti-cancer agents. Restrictions on anti-cancer agent use may include limited duration and dose of cancer treatment due to subject’s suffering from one or more of these conditions. Accordingly, these conditions limit treatment tolerance of a subject to an anti-cancer agent thereby reducing the overall treatment efficacy, reducing quality of life in cancer patients, and increasing risk that treatments are not as effective as they otherwise could be.SUMMARY

[0004] The present technology comprises methods of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject having colorectal cancer, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the groupDocket No.: 211Z-412981-WO consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0005] In some embodiments, the present technology comprises methods of maintaining or increasing weight in a subject having colorectal cancer, prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0006] In some embodiments, the present technology comprises methods of maintaining or increasing weight in a subject having colorectal cancer, prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0007] In some embodiments, the subject experiences an increase in weight by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% compared to baseline or a control.

[0008] In some embodiments, the present technology comprises methods of maintaining or increasing muscle mass, fat mass, or cardiac mass in a subject having colorectal cancer, prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0009] In some embodiments, the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.Docket No.: 211Z-412981-WO

[0010] In some embodiments, the present technology comprises methods of maintaining or increasing bone density in a subject having colorectal cancer, prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0011] In some embodiments, the subject experiences an increase in bone density by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

[0012] In some embodiments, the present technology comprises methods of increasing or maintaining a Functional Assessment of Anorexia / Cachexia Therapy (FAACT) score in a subject having colorectal cancer, prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

[0013] In some embodiments, the subject experiences an increase in the FAACT score compared to baseline or control by at least 1, 2, 3, 4, or 5 points.

[0014] In some embodiments, the present technology comprises methods of stimulating appetite or reducing loss of appetite induced by an anti-cancer agent in a subject having colorectal cancer, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

[0015] In some embodiments, the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.

[0016] In some embodiments, the present technology comprises methods of preventing, reducing, or restoring weight loss induced by an anti-cancer agent in a subject having colorectal cancer, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

[0017] In some embodiments, the present technology comprises methods of treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in aDocket No.: 211Z-412981-WO subject having colorectal cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0018] In some embodiments, the present technology comprises methods of preventing reduction of, maintaining, or improving Eastern Cooperative Oncology Group (ECOG) and / or Karnofsky performance status (KPS) score of a subject having colorectal cancer relative to a baseline or a control, comprising administering an anticancer agent and a non-naturally occurring melanocortin analog to the subject.

[0019] In some embodiments, the subject experiences a reduction in ECOG performance score by about 1, 2, or 3 compared to baseline or control.

[0020] In some embodiments, the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.

[0021] In some embodiments, the present technology comprises methods of preventing reduction of, maintaining, or improving overall survival (OS) or progression free survival (PFS) in a subject having colorectal cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0022] In some embodiments, the subject experiences an increase in OS or an increase in PFS compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

[0023] In some embodiments, the present technology comprises methods of reducing time to cancer treatment failure in a subject having cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0024] In some embodiments, the present technology comprises methods of increasing or maintaining body mass index (BMI) in a subject having colorectal cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0025] In some embodiments, the subject experiences an increase in BMI compared to baseline or control by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 points.Docket No.: 211Z-412981-WO

[0026] In some embodiments, the subject experiences an increase in BMI durability compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

[0027] In some embodiments, the method maintains or increases lean body mass, fat body mass, and / or weight of the subject relative to a baseline or a control.

[0028] In some embodiments, the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, loss of appetite, vomiting, diarrhea, nausea, and fatigue.

[0029] In some embodiments, the improvement, maintenance, or prevented reduction of ECOG and / or KPS score occurs by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0030] In some embodiments, the colorectal cancer is newly diagnosed colorectal cancer.

[0031] In some embodiments, the colorectal cancer is newly diagnosed colorectal adenocarcinoma.

[0032] In some embodiments, the colorectal cancer is metastatic colorectal cancer.

[0033] In some embodiments, the metastatic colorectal cancer is newly diagnosed metastatic colorectal cancer.

[0034] In some embodiments, the metastatic colorectal cancer is newly diagnosed colorectal adenocarcinoma.

[0035] In some embodiments, the anti-cancer agent comprises a chemotherapy or a monoclonal antibody.

[0036] In some embodiments, the non-naturally occurring melanocortin analog is administered in a dose of about 12.5 mg, 25 mg, 50 mg, or 75 mg.

[0037] In some embodiments, the non-naturally occurring melanocortin analog is administered daily for a period of at least about 5 days to at least about 4-weeks.Docket No.: 211Z-412981-WO

[0038] In some embodiments, the method reduces or prevents a chemotherapy induced mass loss and / or wasting in the subject and increases lean body mass and body weight of the subject relative to a baseline or a control.

[0039] In some embodiments, the methods comprise a non-naturally occurring melanocortin analog having a sequence Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2, wherein c represents cyclization between R2and R7via a lactam bond.

[0040] In some embodiments, the method maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the method reduces mass loss and / or wasting in the subject relative to a baseline or a control.

[0041] In some embodiments, the anorexia is associated with weight loss.

[0042] In some embodiments, the subject has not previously received an anticancer agent.

[0043] In some embodiments, the subject has previously received an anti-cancer agent.

[0044] In some embodiments, the subject is receiving an anti-cancer agent.

[0045] In some embodiments, the administration of the non-naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.

[0046] In some embodiments, the enhanced tolerability results in a greater dosage, an increased frequency of administration, and / or an increased duration of administration of the anti-cancer agent, relative to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0047] In some embodiments, the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.Docket No.: 211Z-412981-WO

[0048] In some embodiments, the administration of the non-naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti-cancer agent relative to a baseline or a control.

[0049] In some embodiments, the downward titration comprises a decreased dosage, a decreased frequency of administration, and / or a decreased duration of administration, compared to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0050] In some embodiments, the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration of the non-naturally occurring melanocortin analog.

[0051] In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cancer and / or the anti-cancer agent

[0052] In some embodiments, the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.

[0053] In some embodiments, the non-naturally occurring melanocortin analog is administered before and / or after the anti-cancer agent.

[0054] In some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0055] In some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0056] In some embodiments, administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anticancer agent in the subject relative to a baseline or a control.Docket No.: 211Z-412981-WO

[0057] In some embodiments, administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anticancer agent in the subject relative to a baseline or a control.

[0058] In some embodiments, administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves an ECOG score, a KPS score, a EORTC QLQ-C30 score, a RECIST 1.1 score, a median overall survival (mOS) of the subject, relative to a baseline or a control.

[0059] In some embodiments, administration of the non-naturally occurring analog reduces, maintains, or improves a mOS hazard ratio.

[0060] In some embodiments, administration of the non-naturally occurring analog prevents reduction of, maintains, or improves an immunotherapy treatment response rate.

[0061] In some embodiments, the subject’s mass and / or weight is not more than 5%-15% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0062] In some embodiments, the subject has an ECOG score of 2 or less prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0063] In some embodiments, the method lowers the ECOG score of the subject, relative to a baseline or a control.

[0064] In some embodiments, the subject has a life expectancy of at least about 9 months or more.

[0065] In some embodiments, the subject has a BMI of up to about 33 kg / m2.

[0066] In some embodiments, the subject has a BMI of about 18 kg / m2to about 33 kg / m2.

[0067] In some embodiments, the subject has a BMI of about 18 kg / m2to about 29 kg / m2.

[0068] In some embodiments, the subject has one or more of (i) an Absolute neutrophil count (ANC) > 1.5 x 109 / L; (ii) a platelet level > 100 x 109 / L; (iii) a hemoglobin level > 9 g / dL; (iv) Aspartate aminotransferase (AST) and alanine aminotransferaseg-Docket No.: 211Z-412981-WO (ALT) level < 3 x upper limit of normal (ULN), where, if the subject has liver metastases, then < 5 x ULN; (v) a Bilirubin level < 1.5 x ULN or < 3 x ULN in the presence of documented Gilbert’s Syndrome; (vi) an albumin level between 3.4 and 5.4 g / dL or within an otherwise normal limit; (vii) a creatine clearance level > 50 mL / min; (viii) a normal hemoglobin A1c level; and (ix) an N-terminal pro b-type natriuretic peptide (NT-Pro-BNP) and / or a Troponin (Tnl, TnT) level within a normal limit. In some embodiments,

[0069] In some embodiments, the subject is at least about 18 years of age or older.

[0070] In some embodiments, the method increases the subject’s cumulative mass relative to a baseline or control.

[0071] In some embodiments, the method reduces the subject’s rate of loss of cumulative mass relative to a baseline or control.

[0072] In some embodiments, the method increases a net weight gain in the subject relative to a baseline or control.

[0073] In some embodiments, the net weight gain is the change in weight between two or more time points.

[0074] In some embodiments, the net weight gain is the change in weight between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

[0075] In some embodiments, the two or more time points comprises an intermediate time point.

[0076] In some embodiments, the method increases the subject’s cumulative food intake relative to a baseline or control.

[0077] In some embodiments, the cumulative food intake is the total food intake between two or more time points.

[0078] In some embodiments, the cumulative food intake is the total in food intake between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

[0079] In some embodiments, the two or more time points comprises an intermediate time point.-22-Docket No.: 211Z-412981-WO

[0080] In some embodiments, the method increases the subject’s BMI relative to a baseline or control.

[0081] In some embodiments, the subject administered the non-naturally occurring melanocortin analog (a) does not experience a worsening of, (b) experiences an improvement of, or (b) does not experience a change in, compared to baseline, a value selected from the group consisting of (i) a complete blood count level; (ii) Blood chemistries including: sodium (Na), potassium (K), chloride (Cl), carbon dioxide (CO2), creatinine, creatinine clearance (calculated by Cockcroft-Gault formula), glucose, hemoglobin A1c, and blood urea nitrogen (BUN); (iii) Clotting parameters (prothrombin time (PT), partial thromboplastin time (PTT), International normalized ratio (INR)); (iv) Fasting lipid profile; (v) Cardiac markers (N-terminal pro b-type natriuretic peptide [NT-Pro-BNP] and Troponins [Tnl, TnT]); (vi) CT or MRI scan assessments of measurable disease by RECIST 1.1 criteria; (v) a body mass distribution; (vi) a change in the adrenal gland, heart, liver, pancreas, prostate gland, skeletal muscle, or spleen; (vii) a change or reaction at an injection site; or (viii) an organ failure.

[0082] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (II):X1X2X3R1R2R3R4R5R6R7R8R9R10Y1Y2Y3Y4Y5Y6Y7(II) wherein:R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated D-norleucine (Ac-dNIe), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), acetylated D-cysteine (Ac-dCys), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, acetylated asparagine (Ac-Asn), acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Ac-Tle), acetylated D-tert-leucine (Ac-dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;Docket No.: 211Z-412981-WO R2is selected from the group consisting of proline, histidine, D-aspartic acid, aspartic acid, glutamic acid, lysine, alanine, D-alanine, tryptophan, cysteine, D-cysteine, CO-cis-CH=CH — CO, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);R3is absent or is selected from the group consisting of histidine, D-proline, L-proline, hydroxyproline (Hyp), transPro(guan), cisPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of D-phenylalanine, L-phenylalanine, D-Nal(2'), biphenylalanine (Bip), dBip, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);R5is absent or is selected from the group consisting of arginine, ornithine, histidine, alanine, proline, transPro(guan), cisPro(guan), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, and D-glutamic acid;R6is absent or is selected from the group consisting of D-tryptophan, L-tryptophan, D-Nal(2'), Tic, histidine, D-histidine, Nal(1 ’), D-Nal(1 ’), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, alanine, and D-alanine;R7is absent or is selected from the group consisting of glycine, aspartic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), proline, D-Nal(2'), ornithine, D-ornithine, Pen, and dPen;-21-Docket No.: 211Z-412981-WO R8is absent, lysine, or arginine;R9is absent or tryptophan;R10is absent or lysine;X1is absent or is selected from the group consisting of tyrosine, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;X2is absent or is selected from the group consisting of D-proline, L-valine, phenylalanine, and norleucine;X3is absent, phenylalanine, or norleucine;Y1is selected from the group consisting of D-alanine, L-alanine, D-valine, L-valine, D-leucine, D-tert-leucine, norleucine, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, L-arginine, D-arginine, L-asparagine, D-asparagine, L-lysine, D-lysine, and L-tryptophan;Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, D-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;Y4is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;Y5is absent or D-valine;Y6is absent or D-valine;Y7is absent or D-proline;the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:a disulfide bond between R1and R7when R1and R7are each cysteine;a disulfide bond between R2and R7when R2and R7are each independently selected from D-cysteine, cysteine, Pen, and dPen;a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH— CO, and R7is lysine, D-lysine, Dap, D-ornithine, or ornithine;Docket No.: 211Z-412981-WO a side-chain lactam bridge between R2and R7when R2is lysine and R7is aspartic acid;a side-chain lactam bridge between R1or R2and R8when R1or R2is aspartic acid, R8is lysine, and R7is glycine or proline;a side-chain lactam bridge between R2and R10when R2is aspartic acid, R7is dNal(2’), and R10is lysine;X1X2X3represents an optionally present N-terminus; andY1Y2Y3Y4Y5Y6Y7represents a C-terminus.

[0083] In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3, 10, 14, 33-39, 82-96, 108-111, 119-124, 126-135, 138, 192-199, 222-295, 408 and 413.

[0084] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 3).

[0085] In some embodiments, the chemotherapy comprises at least one chemotherapeutic agent.

[0086] In some embodiments, the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of a platinum-coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, a cytotoxic antibiotic, a FOLFOX regimen, a FOLFIRI regimen, and a FOLFIRINOX regimen.

[0087] In some embodiments, the FOLFOX regimen is selected from the group consisting of a FOLFOX-4, a FOLFOX-6, a modified FOLFOX-6 (mFOLFOX-6), and a FOLFOX-7.

[0088] In some embodiments, the FOLFIRINOX regimen comprises FOLFIRINOX with or without bevacizumab.

[0089] In some embodiments, the subject is a human.

[0090] In some embodiments, the subject is an animalDocket No.: 211Z-412981-WO

[0091] In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject as a daily dose of 12.5 mg, 25 mg, or 50 mg.

[0092] In some embodiments, the non-naturally occurring melanocortin analog and / or the anti-cancer agent is formulated in a pharmaceutical composition.

[0093] In some embodiments, the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.BRIEF DESCRIPTION OF THE DRAWINGS

[0094] FIG. 1 A is a graph depicting daily food intake of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily food intakes in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0095] FIG. 1B is a graph depicting daily food consumption of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily food consumptions (i.e., daily food intake normalized to daily body weight) in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0096] FIG. 1 C is a graph depicting daily body weight of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily body weights in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125Docket No.: 211Z-412981-WO mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0097] FIG. 1 D is a graph depicting daily body weight gain of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the daily body weight gains (% initial) in the rats administered with saline (Group 1 ), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0098] FIG. 2A is a graph depicting locomotor activity in dark phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the locomotor activities in dark phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in dark phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0099] FIG. 2B is a graph depicting locomotor activity in light phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the locomotor activities in light phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in light phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0100] FIG. 2C is a graph depicting locomotor activity (% of baseline) in dark phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares-34-Docket No.: 211Z-412981-WO the locomotor activities (% of baseline) in dark phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in dark phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0101] FIG. 2D is a graph depicting locomotor activity (% of baseline) in light phase of Sprague Dawley rats in a chemotherapy dose-response study. The graph compares the locomotor activities (% of baseline) in light phase in the rats administered with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days. The locomotor activities in light phase are monitored from 5 days prior to the administration until 21 days after administration of the initial dose. Mortality was observed in rats treated with high dose of cisplatin (Group 3, 5 mg / kg / week cisplatin) or 5-FU (Group 5, 125 mg / kg / week 5-FU) after the second cycle of chemotherapy. Therefore, the third cycle of chemotherapy was discontinued to ensure survival of both high dose groups.

[0102] FIG. 3 is a bar graph depicting fat mass, lean mass, and total water changes of Sprague Dawley rats after a chemotherapy dose-response study. The graph compares the changes in fat mass, lean mass, and total water of the rats after administration with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days.

[0103] FIG. 4 is a bar graph depicting serum GDF-15 (growth differentiation factor-15) concentration of Sprague Dawley rats after a chemotherapy dose-response study. The graph compares the serum GDF-15 concentrations of the rats after administration with saline (Group 1), 2.5 mg / kg / week cisplatin (Group 2), 5 mg / kg / week cisplatin (Group 3), 62.5 mg / kg / week 5-FU (Group 4), and 125 mg / kg / week 5-FU (Group 5), respectively, for 21 days.-164-Docket No.: 211Z-412981-WO

[0104] FIG. 5 is a graph depicting the design of studies using one or more compositions of the present technology.

[0105] FIG. 6A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0106] FIG. 6B is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1 ), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0107] FIG. 6C is a graph depicting daily food consumption of Sprague Dawley rats in a combination therapy study. The graph compares the daily food consumptions (i.e., daily food intake normalized to daily body weight) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0108] FIG. 6D is a graph depicting daily food consumption of Sprague Dawley rats in a combination therapy study. The graph compares the daily food consumptions (i.e., daily food intake normalized to daily body weight) in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0109] FIG. 7A is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.Docket No.: 211Z-412981-WO

[0110] FIG. 7B is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1 ), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0111] FIG. 7C is a graph depicting weekly food intake of Sprague Dawley rats in a combination therapy study. The graph compares the weekly food intakes in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0112] FIG. 7D is a graph depicting weekly food intake of Sprague Dawley rats in a combination therapy study. The graph compares the weekly food intakes in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1 ), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0113] FIG. 8A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0114] FIG. 8B is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0115] FIG. 9A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and-34-Docket No.: 211Z-412981-WO saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0116] FIG. 9B is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline, (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0117] FIG. 10A is a graph depicting daily food intake of Sprague Dawley rats in a combination therapy study. The graph compares the daily food intakes in the rats administered cisplatin, saline, and IgG (Group 1), cisplatin plus saline plus an anti-GDF-15 monoclonal antibody (mAb) comprising a human ponsegromab Fab region (“ponsegromab”; Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0118] FIG. 10B is a graph depicting weekly food intake of Sprague Dawley rats in a combination therapy study. The graph compares the weekly food intakes in the rats administered cisplatin plus saline plus IgG (IgG (Group 1 ), cisplatin plus saline plus the anti-GDF-15 mAb (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus GDF15 the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0119] FIG. 10C is a graph depicting cumulative food intake of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative food intakes in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0120] FIG. 10D is a graph depicting total food intake of Sprague Dawley rats in a combination therapy study over 21 days. The graph compares total food intakes in the-|: W-Docket No.: 211Z-412981-WO rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0121] FIG. 11 A is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weights in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0122] FIG. 11 B is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weights in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1 ), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0123] FIG. 11 C is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% initial) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0124] FIG. 11 D is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% initial) in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0125] FIG. 11 E is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% of day 0) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plusDocket No.: 211Z-412981-WO saline (Group 3), respectively. Daily body weight gains are shown from day -10 to day 21, where day 0 signifies initiation of cisplatin administration. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0126] FIG. 12A is a graph depicting cumulative body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative body weight gains (% of initial) in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0127] FIG. 12B is a graph depicting cumulative body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the cumulative body weight gains (% of initial) in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1 ), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0128] FIG. 13A is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0129] FIG. 13B is a graph depicting daily body weight change of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% of initial) in the rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0130] FIG. 14A is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 65 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.-21-Docket No.: 211Z-412981-WO

[0131] FIG. 14B is a graph depicting daily body weight change of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gains (% of initial) in the rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 65 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0132] FIG. 15A is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb of FIG. 10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 the anti-GDF-15 mAb of FIG. 10 (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0133] FIG. 15B is a graph depicting cumulative body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the body weight change (% of initial) in the rats administered cisplatin plus saline plus (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb of FIG. 10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb of FIG. 10 (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0134] FIG. 15C is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight change (% of initial) in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb of FIG. 10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb of FIG. 10 (Group 3). Cisplatin was administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0135] FIG. 15D is a graph depicting total body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the net body weight gain (% of baseline) in the rats administered cisplatin plus saline plus IgG (Group 1), cisplatin plus saline plus the anti-GDF-15 mAb of FIG. 10 (Group 2), and cisplatin plus 3 mg / kg / day TCMCB07 plus the anti-GDF-15 mAb of FIG. 10 (Group 3). Cisplatin was-22-Docket No.: 211Z-412981-WO administered at 5 mg / kg on day 0, 3 mg / kg on day 7, and 3 mg / kg on day 14. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0136] FIG. 16A is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0137] FIG. 16B is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain (% of initial) in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0138] FIG. 16C is a graph depicting daily body weight of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 63 days. Administration occurred on days 0, 7, 14, 21, 28, and 35.

[0139] FIG. 16D is a graph depicting daily body weight gain of Sprague Dawley rats in a combination therapy study. The graph compares the daily body weight gain (% of initial) in the rats administered 2 mg / kg / week doxorubicin plus saline (Group 1), 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 63 days. Administration occurred on days 0, 7, 14, 21, 28, and 35.

[0140] FIG. 17A is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares the heart weights of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.Docket No.: 211Z-412981-WO

[0141] FIG. 17B is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares the heart weights of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0142] FIG. 17C is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares the gastrocnemius weights of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0143] FIG. 17D is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares the gastrocnemius weights of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1 ), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0144] FIG. 17E is a bar graph depicting spleen weight of Sprague Dawley rats after combination therapy. The graph compares the spleen weights of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0145] FIG. 17F is a bar graph depicting spleen weight of Sprague Dawley rats after combination therapy. The graph compares the spleen weights of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0146] FIG. 18A is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares heart weights of rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.Docket No.: 211Z-412981-WO

[0147] FIG. 18B is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares gastrocnemius weights of rats administered with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0148] FIG. 19A is a bar graph depicting heart weight of Sprague Dawley rats after combination therapy. The graph compares heart weights of rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0149] FIG. 19B is a bar graph depicting gastrocnemius weight of Sprague Dawley rats after combination therapy. The graph compares gastrocnemius weights of rats administered with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0150] FIG. 20A is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gains of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0151] FIG. 20B is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gains of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0152] FIG. 20C is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gains of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / weekDocket No.: 211Z-412981-WO cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0153] FIG. 20D is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gains of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0154] FIG. 21 A is a bar graph depicting fat mass of Sprague Dawley rats after combination therapy. The graph compares the fat mass of the rats before and after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0155] FIG. 21 B is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gain (% of initial) of the rats after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0156] FIG. 21 C is a bar graph depicting lean mass of Sprague Dawley rats after combination therapy. The graph compares the lean mass of the rats before and after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0157] FIG. 21 D is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gain (% of initial) of the rats after administration with 65 mg / kg / week cyclophosphamide plus saline (Group 1), 65 mg / kg / week cyclophosphamide plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.Docket No.: 211Z-412981-WO

[0158] FIG. 22A is a bar graph depicting fat mass of Sprague Dawley rats after combination therapy. The graph compares the fat mass of the rats before and after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0159] FIG. 22B is a bar graph depicting fat mass gain of Sprague Dawley rats after combination therapy. The graph compares the fat mass gain (% of initial) of the rats after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0160] FIG. 22C is a bar graph depicting lean mass of Sprague Dawley rats after combination therapy. The graph compares the lean mass of the rats before and after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0161] FIG. 22D is a bar graph depicting lean mass gain of Sprague Dawley rats after combination therapy. The graph compares the lean mass gain (% of initial) of the rats after administration with 0.27 mg / kg / week vincristine plus saline (Group 1), 0.27 mg / kg / week vincristine plus 3 mg / kg / day TCMCB07 (Group 2), saline plus saline (Group 3), and saline plus 3 mg / kg / day TCMCB07 (Group 4), respectively, for 21 days. The cutoffs for significance are * (or #, &)<. O5, **<.01, ***<.001 ****<.0001.

[0162] FIG. 23A is a graph depicting locomotor activity in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in dark phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1 ), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.Docket No.: 211Z-412981-WO

[0163] FIG. 23B is a graph depicting locomotor activity in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in dark phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1 ), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0164] FIG. 23C is a graph depicting locomotor activity (% of baseline) in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in dark phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), and 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0165] FIG. 23D is a graph depicting locomotor activity (% of baseline) in dark phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in dark phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), and 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0166] FIG. 24A is a graph depicting locomotor activity in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in light phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1 ), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days. The locomotor activities in light phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0167] FIG. 24B is a graph depicting locomotor activity in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities in dark phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1 ), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (GroupDocket No.: 211Z-412981-WO 3), respectively, for 21 days. The locomotor activities in dark phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0168] FIG. 24C is a graph depicting locomotor activity (% of baseline) in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in light phase in the rats administered with 2.5 mg / kg / week cisplatin plus saline (Group 1), and 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in light phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0169] FIG. 24D is a graph depicting locomotor activity (% of baseline) in light phase of Sprague Dawley rats in combination therapy. The graph compares the locomotor activities (% of baseline) in light phase in the rats administered with 70 mg / kg / week 5-FU plus saline (Group 1), and 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), respectively, for 21 days. The locomotor activities in light phase are monitored from 4 days prior to the administration until 21 days after administration of the initial dose.

[0170] FIG. 25A is a bar graph depicting leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of Sprague Dawley rats after combination therapy. The graph compares the leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0171] FIG. 25B is a bar graph depicting leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of Sprague Dawley rats after combination therapy. The graph compares the leukocyte counts (total leukocytes, neutrophils, lymphocytes, monocytes, eosinophils, and basophils) of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1 ), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0172] FIG. 25C is a bar graph depicting leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of Sprague Dawley rats afterDocket No.: 211Z-412981-WO combination therapy. The graph compares the leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0173] FIG. 25D is a bar graph depicting leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of Sprague Dawley rats after combination therapy. The graph compares the leukocyte ratios of neutrophils, lymphocytes, monocytes, eosinophils, and basophils of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0174] FIG. 26A is a bar graph depicting erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of Sprague Dawley rats after combination therapy. The graph compares the erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0175] FIG. 26B is a bar graph depicting erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of Sprague Dawley rats after combination therapy. The graph compares the erythrocytes (RBC, Hb, HCT, MCV, MCH, and MCHC) of the rats after administration with 70 mg / kg / week 5-FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0176] FIG. 26C is a bar graph depicting concentration of thrombocytes of Sprague Dawley rats after combination therapy. The graph compares the concentrations of thrombocytes of the rats after administration with 2.5 mg / kg / week cisplatin plus saline (Group 1), 2.5 mg / kg / week cisplatin plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0177] FIG. 26D is a bar graph depicting concentration of thrombocytes of Sprague Dawley rats after combination therapy. The graph compares the concentrations of thrombocytes of the rats after administration with 70 mg / kg / week 5-Docket No.: 211Z-412981-WO FU plus saline (Group 1), 70 mg / kg / week 5-FU plus 3 mg / kg / day TCMCB07 (Group 2), and saline plus saline (Group 3), respectively, for 21 days.

[0178] FIG. 27A is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 7 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a percentage of baseline) of the rats after administration with saline vehicle (Group 1) 2 mg / kg / week doxorubicin (DOX) plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 7 days. N=10, 16, and 12 rats for Group 1, Group 2, and Group 3, respectively. DOX was administered by intraperitoneal injection and TCMCB07 was administered by subcutaneous injection. The cutoffs for significance are * <.05, **<.01, ***<.001 ****<.0001.

[0179] FIG. 27B is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 14 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a percentage of baseline) of the rats after administration with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 14 days. N=10, 16, and 12 rats for Group 1, Group 2, and Group 3, respectively. DOX was administered by intraperitoneal injection and TCMCB07 was administered by subcutaneous injection. The cutoffs for significance are * <.05, **<.01, ***<.001 ****<.0001.

[0180] FIG. 27C is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 21 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a percentage of baseline) of the rats after administration with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 21 days. N=10, 16, and 12 rats for Group 1, Group 2, and Group 3, respectively. DOX was administered by intraperitoneal injection and TCMCB07 was administered by subcutaneous injection.

[0181] FIG. 27D is a bar graph depicting total body weight change (as a percentage of baseline) after combination therapy for 28 days in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the total body weight gains (as a % of baseline) of the rats after administration with saline vehicle (Group 1)-21-Docket No.: 211Z-412981-WO 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 28 days. N=10, 16, and 12 rats for Group 1, Group 2, and Group 3, respectively. DOX was administered by intraperitoneal injection and TCMCB07 was administered by subcutaneous injection. The cutoffs for significance are * <.05, **<.01, ***<.001 ****<.0001.

[0182] FIG. 28A is a graph depicting daily body weight after combination therapy in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the daily body weights in the rats administered with saline vehicle (Group 1) 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 17 days.

[0183] FIG. 28B is a graph depicting daily body weight after combination therapy in a doxorubicin chemotherapy Sprague Dawley rat model. The graph compares the daily body weights in the rats administered with saline vehicle (Group 1 ), 2 mg / kg / week doxorubicin plus saline (Group 2), and 2 mg / kg / week doxorubicin plus 3 mg / kg / day TCMCB07 (Group 3), respectively, for 26 days. N = 12 rats per group. TCMCB07 was administered subcutaneously.

[0184] FIGS. 29A-C are graphs from a post treatment study (TCMCB07 post treatment after cisplatin administration) in a Sprague Dawley rat model. Rats were administered with cisplatin plus TCMCB07 followed by saline vehicle (Group 1), cisplatin plus TCMCB07 followed by TCMCB07 post treatment (Group 2), cisplatin followed by saline vehicle (Group 3), and cisplatin followed by TCMCB07 post treatment (Group 4) respectively. N = 10 rats per group. FIG. 29A depicts daily body weight. FIG.29B depicts body weight gain (% of initial). FIG. 29C depicts daily cumulative food intake (g). TCMCB07 was administered subcutaneously.

[0185] FIG. 30 illustrates proinflammatory gene expression in the hypothalamus of cancer cachectic rats administered either TCMCB07 or saline control as measured by mRNA levels.

[0186] FIGS. 31A-C illustrate changes in cAMP levels following activation of the human (FIG. 31 A), rat (FIG. 31 B), and dog (FIG. 31 C) melanocortin 1 receptor (MC1 R) under various concentrations of TCMCB07.-22-Docket No.: 211Z-412981-WO

[0187] FIG. 32 illustrates a dosing schema for administering TCMCB07 in a chronic kidney disease model.

[0188] FIG. 33 illustrates daily body weight measurements in rats having chronic kidney disease induced cachexia (G2) and control rats (G1) administered TCMCB07 under 3 different dosing schemas (G3, G4, and G5).

[0189] FIGS. 34A-G illustrate that subcutaneous administration of the non-naturally occurring melanocortin analogs of the present technology ameliorate anorexia, body weight loss, and lean mass loss in rats with chronic kidney disease (CKD) cachexia. FIG. 34A is a graph depicting design of an in vivo renal failure model (5 / 6 nephrectomy model) in rats using one or more non-naturally occurring melanocortin analogs of the present technology. FIG. 34B is a graph comparing the daily body weights in rats who received the nephrectomy according to the in vivo renal failure model of FIG. 34A administered with saline (Neph / saline) or TCMCB07 (Neph / TCMCB07), respectively, and rat on sham operation administered with saline (Sham / saline), for 28 days. FIG. 34C is a graph comparing the daily food intakes in rats who received the nephrectomy according to the in vivo renal failure model of FIG. 34A administered with saline (Neph / saline) or TCMCB07 (Neph / TCMCB07), respectively, and rat on sham operation administered with saline (Sham / saline), for 28 days. FIG.34D is a bar graph depicting fat mass gain in rats who received the nephrectomy according to the in vivo renal failure model of FIG. 34A administered with saline (Neph / saline) or TCMCB07 (Neph / TCMCB07), respectively, and rat on sham operation administered with saline (Sham / saline), for 28 days. FIG. 34E is a graph showing body weight gain (%, net gain normalized to baseline) post-nephrectomy and post-treatment. FIG. 34F is a graph showing cumulative food intake post-treatment. FIG. 34G is a graph showing lean mass were determined by MR pre- (day 14) and post- (day 28) treatment, and gain (%) was calculated (net gain normalized to baseline). All data are expressed as mean ± SEM for each group. Two-way ANOVA in (42B-42E), Unpaired Student’s t-Test in (34D & 34G), * & # p < 0.05, ## p < 0.01, ***& ### p < 0.001 and p < 0.0001. Stars in (34B & 34C): Neph / saline group versus Sham / saline group, and red pounds in (34B & 34C): Neph / TCMCB07 group versus Neph / saline group

[0190] FIGS. 35A-F illustrate effects of continued treatment with TCMCB07 in CKD model after the rat meets the equivalence point, where the weight of the rat treatedDocket No.: 211Z-412981-WO with TCMCB07 is no different from a sham rat. FIG. 35A shows a schematic diagram of the experimental method. FIG. 35B shows daily body weight of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 35C shows daily body weight gain compared to day 1 of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 35D shows body weight gain, measured as % of initial weight compared to day 1 of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 35E shows body weight gain, measured as % of initial weight compared to day 14 of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 35F shows the cumulative food intake of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point.

[0191] FIGS. 36A-F illustrate body compositions of CKD model rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 36A illustrates fat mass; FIG. 36B illustrates lean mass; FIG. 36C illustrates fluid mass; FIG. 36D illustrates fat mass gained; FIG. 36E illustrates lean mass gained; and FIG. 36F illustrates fluid mass gained.

[0192] FIGS. 37A-D illustrates tissue weight and length of the rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 37A illustrates heart weight; FIG. 37B illustrates gastrocnemii weight; FIG. 37C illustrates spleen weight; and FIG. 37D illustrates body length.

[0193] FIGS. 38A and 38B illustrate serum creatinine and urea in rats treated with TCMCB07 with a change in dosing at the equivalence point. FIG. 38A illustrates serum creatinine and FIG. 38B illustrates serum blood urea nitrogen (BUN).

[0194] FIG. 39 shows a study design for assessing the non-naturally occurring melanocortin analogs in accordance with the embodiments of the present technology.

[0195] FIG. 41 illustrates weight gain in healthy individuals administered TCMCB07 over a 5 day period compared to placebo.

[0196] FIG. 42 illustrates self-reported ease of eating during dosing days experienced by healthy individuals administered TCMCB07 over a 5 day period compared to placebo.-34-Docket No.: 211Z-412981-WO

[0197] FIG. 42 illustrates plasma levels of TCMCB07 after single-dose administration in rats at 3 mg / kg or 10 mg / kg. Data presented as mean ± SEM.

[0198] FIGS. 43A and 43B illustrate subcutaneous biodistribution of TCMCB07 in CD-1 mice administered 2.7 pCi I125labeled TCMCB07 both subcutaneously (FIG. 43A) and intravenously (FIG. 43B). Data presented as mean ± SEM. ID: injected dose.

[0199] FIG. 44 illustrates plasma levels of TCMCB07 following intraperitoneal (IP) or subcutaneous (SC) injection in male rats. Data presented as mean ± SEM.

[0200] FIG. 45 illustrates plasma protein binding levels of TCMCB07 in canine plasma. Data are presented as mean. CP = canine plasma; PA = pluronic acid F-68.DETAILED DESCRIPTION

[0201] The present technology comprises methods of treating, preventing, or reducing one or more conditions, including but not limited to side effects and iatrogenic injury, associated with an anti-cancer agent (e.g., chemotherapy agent) in a subject in need thereof using non-naturally occurring melanocortin analogs, as well as methods of treating subjects with having one or more such conditions. In some embodiments, the present technology includes methods for preventing or reducing one or more of the conditions associated with an anti-cancer agent by administering a non-naturally occurring melanocortin analog to the subject in need thereof prior to administration of the anti-cancer agent. In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject after an anti-cancer agent. In some embodiments, the non-naturally occurring melanocortin analog is administered to the subject concurrently with an anti-cancer agent or during an anti-cancer agent dosing regimen. In any of the embodiments of the present technology, the subject has cancer, or the subject has another condition (e.g., not cancer) which may be treated with an anticancer agent such as, but not limited to, a chemotherapy agent.

[0202] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration only and are not intended to limit the scope of the present technology of the presentDocket No.: 211Z-412981-WO technology. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features.

[0203] Furthermore, the detailed description of various embodiments herein makes reference to the accompanying drawing / FIGS, which show various embodiments by way of illustration. While the embodiments are described in sufficient detail to enable those skilled in the art to practice the present technology, it should be understood that other embodiments may be realized and that logical and mechanical changes may be made without departing from the spirit and scope of the present technology. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps or functions recited in descriptions, any method, system, or process, may be executed in any order and are not limited to the order presented. Moreover, any of the step or functions thereof may be outsourced to or performed by one or more third parties.Definitions

[0204] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present technology belongs. For the purposes of the present technology, the following terms are defined below.

[0205] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0206] The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by acceptable levels in the art. Typically, such variation may be as much 10% above and below a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length and such variation may be influenced by standard applicable measurement practices. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.-22-Docket No.: 211Z-412981-WO

[0207] “Melanocortin analogs,” “non-naturally occurring melanocortin analogs,” “melanocortin peptides,” “melanocortin receptor peptides,” or “melanocortins,” are used interchangeably and refer to melanocortin-receptor ligands, which are macromolecules containing at least one melanocortin pharmacophore. Melanocortin analogs are typically peptides that bind melanocortin receptors under physiological conditions. Melanocortin analogs include naturally occurring non-naturally occurring melanocortin analogs (i.e., “synthetic peptides” or “synthetic analogs”) and truncated and / or modified versions of melanocortin full-length protein or peptides. For example, the full-length proopiomelanocortin protein (POMC), prior to proteolytic cleavage of “sub-peptides,” consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC yields peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, 257-265, Academic Press (2000). Synthesized, non-naturally occurring melanocortin analogs having increased melanocortin receptor activity as discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding functionality with melanocortin receptors. The binding to the melanocortin receptor is inhibitory (antagonist). In addition to peptides, the non-naturally occurring melanocortin analogs include small molecule analogs of melanocortin or portions thereof comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule — i.e., peptide mimetics, or various combinations thereof. “Non-naturally occurring melanocortin analogs” may be structurally similar and / or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors. Further, the non-naturally occurring melanocortin analogs generally contain the pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 1) or a modified version thereof, or a structural or functional peptide mimetic thereof.

[0208] A “pharmacophore” is the minimum set of amino acid residues necessary to achieve a physiological effect; or a small molecule that is (with respect to a receptor) a structural mimic of the amino acid residues required for binding to and activation of a receptor. His-Phe-Arg-Trp (SEQ ID NO: 1) and their analogs are the pharmacophore of melanocortin for the regulated physiological effect. Therefore, non-naturally occurring melanocortin pharmacophore analogs may be small peptides or organic molecules designed to mimic the appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.Docket No.: 211Z-412981-WO

[0209] “Potentiated therapeutic activity” refers to an increase in melanocortin activity in a non-naturally occurring melanocortin analog that has undergone derivatization at the N- and / or C-terminus. Such derivatizations do not necessarily involve the pharmacophore but do imply a relative increase in in vivo biological half-life.

[0210] A melanocortin receptor “antagonist” is a naturally occurring substance or manufactured drug substance or composition that opposes the melanocortin receptor-associated responses normally induced by a melanocortin receptor agonist agent.

[0211] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.

[0212] The “peptides” of the present technology may be (a) naturally-occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of larger molecules, (e) produced by methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides.

[0213] The term “peptide” as used herein includes any structure comprised of two or more amino acids, including chemical modifications and derivatives of amino acids. The amino acids forming all or a part of a peptide may be naturally occurring amino acids, stereoisomers and modifications of such amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically modified amino acids, constructs or structures designed to mimic amino acids, and the like, so that the term “peptide” includes pseudopeptides and peptidomimetics, including structures which have a non-peptidic backbone. The term “peptide” also includes dimers or multimers of peptides. A “manufactured” peptide includes a peptide produced by chemical synthesis, recombinant DNA technology, biochemical, or enzymatic fragmentation of larger molecules, combinations of the foregoing or, in general, made by any other method. The term “peptide” includes peptides containing a variable number of amino acid residues, optionally with non-amino acid residue groups at the N- and C-termini, such groups including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups, among others.

[0214] By employing chemical synthesis, a useful means of production, it is possible to introduce various amino acids which do not naturally occur along the chain,-22-Docket No.: 211Z-412981-WO modify the N- or C-terminus, and the like, thereby providing for improved stability and formulation, resistance to protease degradation, and the like.

[0215] “Amino acids” are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N — CHR — COOH, wherein R represents a side chain group. The various a-amino acids differ in the side-chain moiety that is attached to the o-carbon. The “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A User’s Guide, G. A. Grant, editor, W. H. Freeman & Co., New York (1992), the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are described generally in Synthetic Peptides: A User’s Guide, supra; Hruby et al., Biochem. J. 268:249-262 (1990); and Toniolo, Int. J. Peptide Protein Res. 35:287-300 (1990); the teachings of all of which are incorporated herein by reference.

[0216] The phrase “amino acid side chain moiety” used herein, including as used in the specification and claims, includes any side chain of any amino acid, as the term “amino acid” is defined herein. This thus includes the side chain moiety present in naturally occurring amino acids. It further includes side chain moieties in modified naturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moieties in stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids, and the like. For example, the side chain moiety of any amino acid of the present technology is included within the definition. A “derivative” of an amino acid side chain moiety is included within the definition of an amino acid side chain moiety.Docket No.: 211Z-412981-WO

[0217] The “derivative” of an amino acid side chain moiety includes any modification to or variation in any amino acid side chain moieties, including a modification of naturally occurring amino acid side chain moieties. By way of example, derivatives of amino acid side chain moieties include straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, saturated or unsaturated, alkyl, aryl or aralkyl moieties.

[0218] In the peptides of the present technology, conventional amino acid residues have their conventional meaning as given in Chapter 2400, of the Manual of Patent Examining Procedure, 8thEd. Thus, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gin” is glutamine; “Glu” is glutamic acid; “His” is histidine; “He” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; “Phe” is phenylalanine; “Pro” is proline; “Ser” is serine; “Thr” is threonine; “Trp” is tryptophan; “Tyr” is tryosine; and “Vai” is valine. Unless otherwise indicated, all amino acids abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof may be used. Thus, for example, “L-Phe” or “IPhe” is L-phenylalanine; “D-Phe” or “dPhe” is D-phenylalanine; dVal is D-valine; dPro is D-proline; “D- / L-Phe” or “d / IPhe” is D-phenylalanine, L-phenylalanine, or combinations thereof; “Phe” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on. Non-standard amino acids are “Nle” is norleucine; “Nal” is naphthylalanine; “D-Nal” is D-naphthylalanine; D-Nal(2') or DNal(2’) is D-2'-naphthylalanine; L-Nal(2’) or LNal(2’) is L-2'-naphthylalanine; L-Nal(T) is L-1 '-naphthylalanine; D-Nal(T) or DNal(T) is D-T-naphthylalanine; Tie is tert-Leucine; Nva is norvaline; Orn is ornithine; and so on.

[0219] An alpha (a)-amino acid has the generic formula H2N—CαHR—COOH, where R is a side chain moiety and the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (i.e., the a-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom.

[0220] When 0-amino acids are incorporated into peptides, two main types of p-peptides exist: those with the side chain residue, R, on the carbon next to the amine are called β3peptides and those with the side chain residue on the carbon next to the carbonyl group are called β2amino acids. Further, p-amino acids may adopt L- or D-stereochemistry. Unless otherwise indicated, all p-amino acid abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof.Docket No.: 211Z-412981-WO

[0221] Gamma (y)-amino acids are amino acids with the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.

[0222] For additional modified and unusual amino acids, see §2422 of the MPEP, particularly Table 4 at 2400-24. Additionally, “Ac” indicates N-acetyl and “cyclo” and “c” refers to a cyclic structure. “NH2” indicates an amine group, typically added on the C-terminus of a polypeptide. Accordingly, as used herein, an — NH₂ moiety on the C-terminus of a peptide indicates an amidated C-terminus.

[0223] Additional abbreviations are used as follows: Pen is L-Penicillamine; Aib is 2-Aminoisobutyric acid; Aba is 4-amino-1,2,4,5-tetra-hydro-2-benzazepin-3-one; Pip is piperidine-2-carboxylic acid; Nip is piperidine-3-carboxylic acid; Tic is tetrahydroquinoline-3-carboxylic acid; Bip is biphenylalanine; Oic is Octohydroindole-2-carboxylic acid; Ata is 7-amino-7,8-dihydro4H-(1,2,3)triazolo( 1,5-a)(1,4)diazepin-6(5H)-one; Aia is 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one; Mamb is 3-aminomethylbenzoic acid; Ate is 2-Aminotetraline-2-carboxylic acid; APO is 1-Amino-4-phenylcyclohexane-carboxylic acid; ACC is 4-Aminophenylpiperidine-4-carboxylic acid (APPC); Acpc is 1 -aminocyclo-propane-1 -carboxylic acid; Aic is 2-aminoindone-2-carboxylic acid; D-2’-napthylalanine is dNal(2’); p(CI)Phe is para-chloro-phenylalanine (I - iodo, Br- bromo, F- fluoro, CF3 - trifluoromethyl); and p(CI)dPhe is para-chloro-D-phenylalanine (I - iodo, Br- bromo, F- fluoro, CF3 - trifluoromethyl).

[0224] The term “acyl” includes a group RCO—, where R is an organic group. An example is the acetyl group CH₃CO —, referred to herein as “Ac.”

[0225] A peptide or aliphatic moiety is “acylated” when an alkyl or substituted alkyl group as defined above is bonded through one or more carbonyl { — (C=O) — } groups. A peptide is most usually acylated at the N-terminus.

[0226] An “amine” includes compounds that contain an amine group ( — NH₂).

[0227] An “amide” includes compounds that have a trivalent nitrogen attached to a carbonyl group (i.e., — CO — NH₂), such as for example methylamide, ethylamide, propylamide, and the like. A peptide is most usually amidated at the C-terminus by the addition of an amine (— NH₂) moiety to the C-terminal carboxyl group.

[0228] Amino acids, including stereoisomers and modifications of naturally occurring amino acids, protein amino acids, non-protein amino acids, post--41-Docket No.: 211Z-412981-WO translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids (peptide mimetics), and the like, including all of the foregoing, are sometimes referred to herein as “residues.”

[0229] The terms “administering” or “administer” include delivery of therapies (e.g., combination therapies, non-naturally occurring melanocortin analogs (also referred to herein as peptides), anti-cancer agents) of the present technology to a subject either by local or systemic administration. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer), intratracheal, intranasal, epidermal and transdermal, oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.

[0230] The terms “active ingredient” and “active compound” refer to a biologically active substance, whether naturally or non-naturally occurring, that is the main component of the pharmaceutical composition which elicits the intended effect of an administered therapeutic. This may be any component that drives the pharmacological activity or direct effect in the diagnosis, cure, mitigation, treatment, or prevention of the conditions associated with the present technology, such as but not limited to, reduced appetite and weight loss.

[0231] As used herein, a “composition” or a “pharmaceutical composition” refers to a mixture of the active ingredient with other chemical components, such as pharmaceutically acceptable carriers and / or excipients.

[0232] As used herein, a “pharmaceutically acceptable carrier” of the first or the second pharmaceutical composition refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of the administered active ingredient, and / or does not interact in a deleterious manner with the other components of the composition in which it is contained. The term “carrier” encompasses any excipient, binder, diluent, filler, salt, buffer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptableDocket No.: 211Z-412981-WO carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia Pa., 2005, which is incorporated herein by reference in its entirety). Some examples of physiologically acceptable carriers include antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN® (ICI, Inc.; Bridgewater, N. J.), polyethylene glycol (PEG), and PLURONICS™ (BASF; Florham Park, N. J.). An “excipient” of the first or the second pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0233] As used herein, “a side effect associated with the anti-cancer agent”, “an adverse side-effect associated with the anti-cancer agent”, or “a side effect induced by the anti-cancer agent”, refers to any unwanted, undesirable, or deleterious biological activity occurs during or after independent use of the anti-cancer agent. Examples of such side effects include, but are not limited to, anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. Such anti-cancer agents may also be administered to subjects for therapeutic uses besides cancer, for example, to treat, reduce, or prevent a condition or disease in a subject not having cancer.

[0234] The terms “treat,” “treatment,” and “treating” refer to a manner of providing a pharmaceutical composition and / or melanocortin analog to alleviate disease outcomes. This includes utilizing administration techniques as described in the context of the present technology. Efficacy of treatment may be determined by various assessment methods as described in the context of the present technology (e.g., assessment of appetite, food consumption, body weight, muscle mass, fat mass, and measurement of biomarkers). The term “biomarker” refers to a biological output that isDocket No.: 211Z-412981-WO used as a measure of cellular response, whether that be to assess response to therapeutics, disease status, such as cachexia, or as a predictor of clinical outcomes. Biomarkers evaluated in the context of cells, tissue, or whole organisms. The term “disease” herein refers to any disorder adversely affecting biological status. This includes weight-related disorders, such as cachexia. Disease also may be in the context of human and animal health.

[0235] The terms “treat”, “treatment”, and “treating” may also refer to the reduction or inhibition of the progression and / or duration of a disease (e.g., cancer), the reduction or amelioration of the severity of the disease, and / or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies. Specifically, these terms may refer to: (1) a stabilization, reduction (e.g. by more than 10%, 20%, 30%, 40%, 50%, or more than 60% of the population of cancer cells and / or tumor size before administration), or elimination of the cancer cells, (2) inhibiting cancerous cell division and / or cancerous cell proliferation, (3) relieving to some extent (or, preferably, eliminating) one or more symptoms associated with a pathology related to or caused in part by unregulated or aberrant cellular division, (4) an increase in disease-free, relapse-free, progression-free, and / or overall survival, duration, or rate, (5) a decrease in hospitalization rate, (6) a decrease in hospitalization length, (7) eradication, removal, or control of primary, regional and / or metastatic cancer, (8) a stabilization or reduction (e.g. by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, or at least 80% relative to the initial growth rate) in the growth of a tumor or neoplasm, (9) an impairment in the formation of a tumor, (10) a reduction in mortality, (11 ) an increase in the response rate, the durability of response, or number of patients who respond or are in remission, (12) the size of the tumor is maintained and does not increase or increases by less than 10%, less than 5%, less than 4%, or less than 2%, (13) a decrease in the need for surgery (e.g. colectomy, mastectomy), (14) preventing or reducing the metastasis of cancer cells, and (15) promoting mass gain and / or mass maintenance by the subject or otherwise preventing mass loss or reducing mass loss by the subject prior to, during, or after administration of an anti-cancer agent. The terms “treat”, “treatment”, and “treating” include prophylactic and / or therapeutic treatments. If it is administered prior to clinical manifestation of a condition, the treatment is considered prophylactic. Therapeutic treatment includes, e.g., ameliorating or reducing the severity of a disease, or shortening the length or frequency of the disease.-44-Docket No.: 211Z-412981-WO

[0236] As used herein, the terms “effective amount” or “therapeutically effective amount”, refer to that amount of the active ingredient being administered which will relieve to some extent one or more of the symptoms of the disease being treated. The result may be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate “effective amount” may differ from one individual to another. An appropriate “effective amount” in any individual case may be determined using techniques, such as a dose escalation study.

[0237] The term “after administration” refers to any duration of time after the non-naturally occurring melanocortin analog or pharmaceutical composition thereof, and / or the anti-cancer agent has been administered to a subject. “After administration” may also refer to the duration of time after one dose has been completed or after more than one dose has been completed, such as two doses, three doses, four doses, and the like. In some embodiments, “after administration” refers to completion of dosing regimen that includes one or more doses. Likewise, the term “prior to” refers to any duration of time before the non-naturally occurring melanocortin analog or pharmaceutical composition thereof, and / or the anti-cancer agent has been administered to a subject. Unless otherwise specified, durations of time encompassed by “after administration” or “prior to administration” may include seconds, minutes, hours, days, weeks, months, and years.

[0238] “Appetite” in a subject and / or patient is typically assessed by their desire to eat and / or the amount of food they consume. As used herein, appetite may be assessed through a daily questionnaire given at specified or random times of the day. In the questionnaire, subjects or patients rate their hunger and / or desire to eat greater varieties of food using scales ranging from 0 (not at all) to 100 (extremely).

[0239] “Cachexia” refers to a state of general ill health and malnutrition characterized by loss of body mass including loss of weight, loss of muscle mass (skeletal, smooth, and / or cardiac muscle), loss of fat mass, or a combination thereof, and wasting. It is often associated with and induced by certain diseases or conditions such as, but not limited to, cancer, cystic fibrosis, or AIDS. The term “cancer cachexia” refers to cachexia induced by cancer. Diagnostic criterion for cachexia may include (i) weight loss of greater than 5% over past 6 months; (ii) weight loss of greater than 2%Docket No.: 211Z-412981-WO in patients with a body mass index (BMI) less than 20 kg / m2; or (iii) weight loss of greater than 2% in patients with sarcopenia (or appendicular skeletal muscle index consistent with sarcopenia). See Fearon K, et aL, Lancet Oncol. 12(5):489-95 (2011). Cachexia may be used interchangeably with the term “Protein-Energy Wasting” (i.e., PEW).

[0240] “Anorexia” refers to a loss of appetite, whether brought on by medical, physiological, or psychological factors. Anorexia is often closely associated with, and generally contributes to, cachexia seen in patients with advanced cancers and other conditions.

[0241] The term “Body Mass Index” or “BMI” refers to a value derived from an individual’s body weight and height. Specifically, BMI is determined by body weight (kilograms) divided by the square of height (m2) and is expressed in units of “kg / m2”. “Normal” BMI ranges are known to a person of ordinary skill in the art and consider factors such as patient sex, age, height, race, and body type. Typically, a normal BMI range is about 18.5 kg / m2to about 25 kg / m2.

[0242] The terms “subject” and “patient” refer to anyone being evaluated for disease or condition or being administered a therapeutic or pharmaceutical composition. This includes people without diagnosed or confirmed disease or condition. This also includes people with diagnosed or confirmed disease or condition, such as cancer, loss of appetite, nausea, emesis, anorexia, or cachexia.

[0243] The term “control,” as used herein, refers to any basis for comparison to the subject (e.g., test subject). A control includes, but is not limited to, a given measurement at baseline in a subject, any subject who has not been administered the therapeutic or pharmaceutical composition (e.g., the non-naturally occurring melanocortin analog, a therapeutically effective amount of the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof) or administered a placebo. A control may reference to a measurement from the same subject as the subject being treated (e.g., a measurement at baseline or an intermediate timepoint), or from a different subject (e.g., a subject not having the same treatment or condition as the subject being treated).

[0244] The disclosure of all publications, patents, and published patent applications listed herein are hereby incorporated by reference in their entireties,Docket No.: 211Z-412981-WO including but not limited to U. S. Patent Nos. 8,541,545 and 9,534,018 and PCT Publication Nos. WO2025 / 123055 and WO2025 / 151135.Non-naturallv Occurring Melanocortin Analogs

[0245] The present technology provides non-naturally occurring melanocortin analogs that may be administered to a subject in need thereof. The present technology also provides methods of treating, preventing, or reducing unwanted side effects induced by anti-cancer agents (e.g., chemotherapeutic agents) as well as symptoms associated with cancer via administration of a non-naturally occurring melanocortin analog, which may be the non-naturally occurring melanocortin analog as of the present technology in any of its embodiments.

[0246] Non-naturally occurring melanocortin analogs described herein may be selective for the melanocortin 4 receptor and / or melanocortin 3 receptor over other melanocortin receptors, i.e., the melanocortin 1, melanocortin 2, and melanocortin 5 receptors. Some of the melanocortin analogs bind the melanocortin 3 receptor with greater affinity than the melanocortin 4 receptor, whereas other melanocortin analogs bind the melanocortin 4 receptor with greater affinity than the melanocortin 3 receptor. Certain melanocortin analogs bind the melanocortin 3 receptor with the same or generally similar affinity as the melanocortin 4 receptor.

[0247] The non-naturally occurring melanocortin analogs of the present technology may be full antagonists for one or more melanocortin receptors. A full antagonist may comprise a non-naturally occurring melanocortin analog having a maximum effect (Emax) agonist value of greater than or equal to 80%.

[0248] The non-naturally occurring melanocortin analogs of the present technology may be partial agonists or partial antagonists of one or more melanocortin receptor. A partial agonist or antagonist may comprise a non-naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 80%.

[0249] If a non-naturally occurring melanocortin analog’s Emax antagonist value is greater than it's Emaxagonist value, then the non-naturally occurring melanocortin analog may be classified as an agonist (e.g., a full agonist or a partial agonist). Similarly, if a non-naturally occurring melanocortin analog’s Emaxagonist value is greaterDocket No.: 211Z-412981-WO than it’s Emaxantagonist value, then the non-naturally occurring melanocortin analog may be classified as an antagonist (e.g., a full antagonist or a partial antagonist).

[0250] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC3R antagonist and a full MC4R antagonist; (ii) a full MC3R antagonist and a partial MC4R antagonist; (iii) a full MC3R antagonist having no MC4R agonist or antagonist activity; (iv) a full MC3R antagonist and a partial MC4R agonist; (v) a partial MC3R antagonist and a full MC4R antagonist; (vi) a partial MC3R antagonist and a partial MC4R antagonist; (vii) a partial MC3R antagonist having no MC4R agonist or antagonist activity; or (viii) a partial MC3R antagonist and a partial MC4R agonist.

[0251] The non-naturally occurring melanocortin analogs in accordance with the present technology may have structural features that impart specific properties on the analogs, such as, for example, degradation resistance, enhanced epithelial, gastrointestinal, and / or blood brain barrier transport, and binding affinity for the MC4R and / or MC3R. For example, in some embodiments, the non-naturally occurring melanocortin analogs comprise one or more of (i) blood brain barrier passage capabilities, (ii) enhanced epithelial and / or gastrointestinal transport; (iii) degradation resistance; or (iv) equipotency on MC3R and MC4R activity. In some embodiments, the non-naturally occurring melanocortin analogs comprise two or more of (i)-(iv). In some embodiments, the non-naturally occurring melanocortin analogs comprise each of (i)-(iv). Accordingly, in some embodiments, the melanocortin analogs include a stabilizing N-terminus, and / or a C-terminus that provides enhanced transport of the analog. In some embodiments, melanocortin analogs include a D-valine-D-proline (dVal-dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation Additionally, in some embodiments, the melanocortin analogs have one or more beta hairpin (p-hairpin) and / or beta turn (p-turn) structures. In general, cyclization and D-amino acids may induce and / or stabilize beta-turns.

[0252] The presence of certain structural features may impart the non-naturally occurring melanocortin analogs of the present technology with specific binding properties. For example, inclusion of large amino acids like dNal(2’) at the R4position may result in enhanced inhibition of the melanocortin 4 and the melanocortin 3 receptors. Accordingly, melanocortin analogs having amino acids like and dNal(2’) atDocket No.: 211Z-412981-WO R4may be full antagonists on MC3R and MC4R. Additionally, smaller amino acids, such as p(F)dPhe, may confer inhibitory activity on the melanocortin analogs when Pro is included at the R3position. Such melanocortin analogs may by full antagonists on MC3R and have no activity or partial activity (agonist or antagonist) on MC4R.

[0253] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I),X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8(I)wherein:R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated D-norleucine (Ac-dNIe), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), trans-4-guanidinyl-proline (transPro(guan)), c / s-4-guanidinyl-proline (c / sPro(guan)), acetylated cysteine, acetylated D-cysteine (Ac-dCys), methylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, CO-cis-CH=CH — CO, an n-pentanoyl group, an n-hexanoyl group, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated asparagine (Ac-Asn), acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Ac-Tle), acetylated D-tert-leucine (Ac-dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;R2is absent or is selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), hydroxyproline (Hyp), transPro(guan), c / sPro(guan), D-aspartic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine, tryptophan, cysteine, D-cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH=CH — CO, an n-pentanoyl group, an n-hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);Docket No.: 211Z-412981-WO R3is absent or is selected from the group consisting of histidine, histidine methylated at positions 1 or 3, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), transPro(guan), cisPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, succinic acid, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (P-Ala), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2 / 7)-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), (o-Phe)Phe, aspartic acid, biphenylalanine (Bip), dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF₃)dPhe);R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), c / sPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, D-glutamic acid, cysteine, and p(l)dPhe;R6is absent or is selected from the group consisting of D-tryptophan, L-tryptophan, D-Nal(2'), L-Nal(2’), Tic, Bip, arginine, histidine, D-histidine, cysteine, Nal(1 ’), D-Nal(1’), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine;R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap),Docket No.: 211Z-412981-WO methionine, proline, tryptophan, D-Nal(2'), ornithine, D-ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic);R8is absent or is lysine or arginine;R9is absent or is tryptophan;R10is absent or is lysine;R11-R2°are each independently absent or selected from the group consisting of cysteine, norleucine, tyrosine, aspartic acid, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, D-proline, prolylglycine (Pro-Gly), D-Nal(2'), L-Nal(2'), Bip, ornithine, and tryptophan;wherein if R2is an n-pentanoyl group or an n-hexanoyl group, then R1, X1, X2and X3are absent;X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;X2is absent or is selected from the group consisting of D-threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;X³ is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;Y1is selected from the group consisting of D-alanine, L-alanine, p-alanine, D-threonine, L-threonine, p-threonine, D-valine, L-valine, p-valine, (3-methyl)-β-valine, D-Docket No.: 211Z-412981-WO leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, D-tert-leucine, L-tert-leucine, norleucine, L-proline, D-proline, β-homo proline, a piperazin-2-one ring, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, L-arginine, D-arginine, L-asparagine, D-asparagine, L-lysine, D-lysine, and L-tryptophan;Y2is absent or is selected from the group consisting of D-proline, L-proline, p-homo proline, a piperazin-2-one ring, D-threonine, L-threonine, p-threonine, D-valine, L-valine, p-valine, (3-methyl)-β-valine, D-leucine, L-leucine, p-leucine, D-isoleucine, L-isoleucine, p-isoleucine, D-tert-leucine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, p-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, L-threonine, p-threonine, D-alanine, L-alanine, D-lysine, L-lysine, D-proline, L-proline, D-valine, L-valine, p-valine, (3-methyl)-β-valine, D-leucine, L-leucine, p-leucine, D-isoleucine, L-isoleucine, p-isoleucine, and a piperazin-2-one ring;Y4is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;Y5is absent or is D-proline or D-valine;Y6is absent or is D-proline or D-valine;Y7is absent or is D-proline or D-valine;Y8is absent or is D-proline or D-valine;the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:a disulfide bond between R1and R7or when R1and R7are each cysteine; a disulfide bond between R2and any one of R7-R20when R2and the any one of R7-R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen;a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid;a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7is lysine, D-lysine, Dap, D-ornithine, or ornithine;-22-Docket No.: 211Z-412981-WO a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid;a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is glycine, proline or tryptophan;a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine;a lactam closure between R1and R7when R1is succinic acid or o-phthalic acid and R7is lysine; anda lactam closure between R2and R7when R2is succinic acid and R7is 2,3-diamino-propionic acid;X1X2X3represents an optionally present N-terminus; andY¹Y²Y³Y⁴Y⁵Y⁶Y⁷Y⁸ represents a C-terminus.

[0254] In some embodiments of Formula (I):R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated D-norleucine (Ac-dNIe), frans-4-guanidinyl-proline (transPro(guan)), c / s-4-guanidinyl-proline (c / sPro(guan)), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), acetylated cysteine, acetylated D-cysteine (Ac-dCys), methylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, CO-cis-CH=CH— CO, an n-pentanoyl group, an n-hexanoyl group, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated asparagine (Ac-Asn), acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tie), acetylated D-tert-leucine (dTle), acetylated norvaline (Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;R2is absent or is selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), hydroxyproline (Hyp), transPro(guan), cZsPro(guan), D-asprtic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine,Docket No.: 211Z-412981-WO tryptophan, D-cysteine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH=CH — CO, an n-pentanoyl group, an n-hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);R3is absent or is selected from the group consisting of histidine, histidine methylated at positions 1 or 3, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), transPro(guan), cisPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, succinic acid, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), (o-Phe)Phe, aspartic acid, biphenylalanine (Bip), dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), c / sPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, D-glutamic acid, cysteine, and p(l)dPhe;R6is absent or is selected from the group consisting of D-tryptophan, L-tryptophan, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, histidine, D-histidine, cysteine, Nal(1 ’), D-Nal(1'), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine;Docket No.: 211Z-412981-WO R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), ornithine, D-ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic);R8is absent or is lysine or arginine;R9is absent or is tryptophan;R10is absent or is lysine;R11-R2°are each independently absent or selected from the group consisting of cysteine, norleucine, tyrosine, aspartic acid, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, D-proline, prolylglycine (Pro-Gly), D-Nal(2'), L-Nal(2'), Bip, ornithine, and tryptophan;wherein if R2is an n-pentanoyl group or an n-hexanoyl group, then R1, X1, X2and X3are absent;X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, β-alanine, D-arginine, L-arginine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;X2is absent or is selected from the group consisting of D-threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;X³ is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homo proline, D-alanine, L-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, a piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;Docket No.: 211Z-412981-WO Y1is selected from the group consisting of D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, D-tert-leucine, L-tert-leucine, norleucine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;Y4is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;Y5is absent or is D-proline or D-valine;Y6is absent or is D-proline or D-valine;Y7is absent or is D-proline or D-valine;Y8is absent or is D-proline or D-valine;the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:a disulfide bond between R1and R7when R1and R7are each cysteine;a disulfide bond between R2and any one of R7-R20when R2and the any one of R7-R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen;a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid;a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7is lysine, D-lysine, D-ornithine, or ornithine;a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid;a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan;Docket No.: 211Z-412981-WO a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine;a lactam closure between R1and R7when R1is succinic acid or o-phthalic acid and R7is lysine; anda lactam closure between R2and R7when R2is succinic acid and R7is 2,3-diamino-propionic acid;X1X2X3represents an optionally present N-terminus; andY1Y2Y3Y4Y5Y6Y7Y8represents a C-terminus.

[0255] In some embodiments of Formula (I):R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated D-norleucine (Ac-dNIe), trans-4-guanidinyl-proline (transPro(guan)), c / s-4-guanidinyl-proline (c / sPro(guan)), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated c / s-4-guanidinyl-proline (Ac-cisPro(guan)), acetylated cysteine, acetylated D-cysteine (Ac-dCys), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-asparagine (Ac-Asn), acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tertleucine (Tie), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;R2is absent or is selected from the group consisting of proline, histidine, D-hydroxyproline (dHyp), hydroxyproline (Hyp), transPro(guan), c / sPro(guan), D-aspartic acid, aspartic acid, D-glutamic acid, glutamic acid, glycine, lysine, alanine, D-alanine, tryptophan, D-cysteine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH=CH — CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);R3is absent or is selected from the group consisting of histidine, D-proline, L-proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), transPro(guan), cisPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (ProDocket No.: 211Z-412981-WO Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-phenylalanine, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of histidine, D-phenylalanine, L-phenylalanine, D-Nal(2'), aspartic acid, biphenylalanine (Bip), dBip, glycine, proline, cysteine, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, transPro(guan), cisPro(guan), Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2'), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, D-glutamic acid, cysteine, and p(l)dPhe;R6is absent or is selected from the group consisting of L-tryptophan, D-Nal(2'), L-Nal(2'), Tic, Bip, arginine, histidine, D-histidine, cysteine, Nal(T), D-Nal(1 ’), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, Pen, dPen, alanine, and D-alanine;R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), methionine, proline, tryptophan, D-Nal(2'), ornithine, D-ornithine, Pen, dPen, and tetrahydro-isoquinoline-3-carboxylic acid (Tic);R8is absent or is lysine or arginine;R9is absent or is tryptophan;Docket No.: 211Z-412981-WO R10is absent or is lysine;R11-R2°areabsent;X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, p-alanine, D-arginine, L-arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;X2is absent or is selected from the group consisting of D-threonine, D-proline, L-proline, D-alanine, L-alanine, p-alanine, D-valine, L-valine, p-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;X3is absent or is selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, D-alanine, L-alanine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine;Y1is absent or is selected from the group consisting of D-alanine, L-alanine, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan;Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, D-tert-leucine, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;Y4is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;Y5is absent or is D-proline or D-valine;Y6is absent or is D-proline or D-valine;Y7is absent or is D-proline or D-valine;Docket No.: 211Z-412981-WO Y8is absent or is D-proline or D-valine;the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:a disulfide bond between R1and R7when R1and R7are each cysteine;a disulfide bond between R2and any one of R7-R20when R2and the any one of R7-R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen;a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid;a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7is lysine, D-lysine, D-ornithine, or ornithine;a side-chain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid;a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan;a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine.

[0256] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein R11-R20and Y8are absent. Accordingly, in some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (II):X1X2X3R1R2R3R4R5R6R7R8R9R10Y1Y2Y3Y4Y5Y6Y7(II) wherein:R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated D-norleucine (Ac-dNIe), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), acetylated D-cysteine (Ac-dCys), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, acetylated asparagine (Ac-Asn), acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine -203-Docket No.: 211Z-412981-WO (Ac-Tle), acetylated D-tert-leucine (Ac-dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;R2is selected from the group consisting of proline, histidine, D-aspartic acid, aspartic acid, glutamic acid, lysine, alanine, D-alanine, tryptophan, cysteine, D-cysteine, CO-cis-CH=CH — CO, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);R3is absent or is selected from the group consisting of histidine, D-proline, L-proline, hydroxyproline (Hyp), transPro(guan), cfsPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of D-phenylalanine, L-phenylalanine, D-Nal(2'), biphenylalanine (Bip), dBip, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);R5is absent or is selected from the group consisting of arginine, ornithine, histidine, alanine, proline, transP ro (guan), cfsPro(guan), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, and D-glutamic acid;R6is absent or is selected from the group consisting of D-tryptophan, L-tryptophan, D-Nal(2'), Tic, histidine, D-histidine, Nal(1 ’), D-Nal(1 ’), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, alanine, and D-alanine;-61-Docket No.: 211Z-412981-WO R7is absent or is selected from the group consisting of glycine, aspartic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), proline, D-Nal(2'), ornithine, D-ornithine, Pen, and dPen;R8is absent, lysine, or arginine;R9is absent or tryptophan;R10is absent or lysine;X1is absent or is selected from the group consisting of tyrosine, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;X2is absent or is selected from the group consisting of D-proline, L-valine, phenylalanine, and norleucine;X3is absent, phenylalanine, or norleucine;Y1is selected from the group consisting of D-alanine, L-alanine, p-alanine, D-threonine, -threonine, D-valine, L-valine, p-valine, (3-methyl)-β-valine, D-leucine, p-isoleucine, D-tert-leucine, norleucine, D-proline, p-homo proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, L-arginine, D-arginine, L-asparagine, D-asparagine, L-lysine, D-lysine, and L-tryptophan;Y2is absent or is selected from the group consisting of D-proline, L-proline, β-homo proline, D-valine, L-valine, β-valine, D-leucine, β-leucine, D-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, β-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3is absent or is selected from the group consisting of D-threonine, β-threonine, D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;Y4is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;Y5is absent or D-valine;Y6is absent or D-valine;Y7is absent or D-proline;the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:a disulfide bond between R1and R7when R1and R7are each cysteine;Docket No.: 211Z-412981-WO a disulfide bond between R2and R7when R2and R7are each independently selected from D-cysteine, cysteine, Pen, and dPen;a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH— CO, and R7is lysine, D-lysine, Dap, D-ornithine, or ornithine;a side-chain lactam bridge between R2and R7when R2is lysine and R7is aspartic acid;a side-chain lactam bridge between R1or R2and R8when R1or R2is aspartic acid, R8is lysine, and R7is glycine or proline;a side-chain lactam bridge between R2and R10when R2is aspartic acid, R7is dNal(2’), and R10is lysine;X1X2X3represents an optionally present N-terminus; and Y1Y2Y3Y4Y5Y6Y7represents a C-terminus.

[0257] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (II), wherein:R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated D-norleucine (Ac-dNIe), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), acetylated D-cysteine (Ac-dCys), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, acetylated asparagine (Ac-Asn), acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Ac-Tle), acetylated D-tert-leucine (Ac-dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;R2is selected from the group consisting of proline, histidine, D-aspartic acid, aspartic acid, glutamic acid, lysine, alanine, D-alanine, tryptophan, cysteine, D-cysteine, CO-cis-CH=CH — CO, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);R3is absent or is selected from the group consisting of histidine, D-proline, L-proline, hydroxyproline (Hyp), transPro(guan), cfsPro(guan), alanine, D-alanine, D-Docket No.: 211Z-412981-WO methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), 1 -amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of D-phenylalanine, L-phenylalanine, D-Nal(2'), biphenylalanine (Bip), dBip, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);R5is absent or is selected from the group consisting of arginine, ornithine, histidine, alanine, proline, transP ro (guan), cfsPro(guan), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, and D-glutamic acid;R6is absent or is selected from the group consisting of D-tryptophan, L-tryptophan, D-Nal(2'), Tic, histidine, D-histidine, Nal(1 ’), D-Nal(1'), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, alanine, and D-alanine;R7is absent or is selected from the group consisting of glycine, aspartic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), proline, D-Nal(2'), ornithine, D-ornithine, Pen, and dPen;R8is absent, lysine, or arginine;R9is absent or tryptophan;R10is absent or lysine;X1is absent or is selected from the group consisting of tyrosine, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;WDocket No.: 211Z-412981-WO X2is absent or is selected from the group consisting of D-proline, L-valine, phenylalanine, and norleucine;X3is absent, phenylalanine, or norleucine;Y1is selected from the group consisting of D-alanine, L-alanine, D-valine, L-valine, D-leucine, D-tert-leucine, norleucine, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, L-arginine, D-arginine, L-asparagine, D-asparagine, L-lysine, D-lysine, and L-tryptophan;Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, D-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;Y4is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;Y5is absent or D-valine;Y6is absent or D-valine;Y7is absent or D-proline;the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:a disulfide bond between R1and R7when R1and R7are each cysteine;a disulfide bond between R2and R7when R2and R7are each independently selected from D-cysteine, cysteine, Pen, and dPen;a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7is lysine, D-lysine, Dap, D-ornithine, or ornithine;a side-chain lactam bridge between R2and R7when R2is lysine and R7is aspartic acid;a side-chain lactam bridge between R1or R2and R8when R1or R2is aspartic acid, R8is lysine, and R7is glycine or proline;Docket No.: 211Z-412981-WO a side-chain lactam bridge between R2and R10when R2is aspartic acid, R7is dNal(2’), and R10is lysine;X1X2X3represents an optionally present N-terminus; and Y1Y2Y3Y4Y5Y6Y7represents a C-terminus.

[0258] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (II), wherein R9-R10are absent. Accordingly, in some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (IIA):X1X2X3R1R2R3R4R5R6R7R8Y1Y2Y3Y4Y5Y6Y7(IIA), wherein:R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated D-norleucine (Ac-dNIe), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), acetylated D-cysteine (Ac-dCys), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, acetylated asparagine (Ac-Asn), acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Ac-Tle), acetylated D-tert-leucine (Ac-dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;R2is selected from the group consisting of proline, histidine, D-aspartic acid, aspartic acid, glutamic acid, lysine, alanine, D-alanine, tryptophan, cysteine, D-cysteine, CO-cis-CH=CH — CO, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);R3is absent or is selected from the group consisting of histidine, D-proline, L-proline, hydroxyproline (Hyp), transPro(guan), cisPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-Docket No.: 211Z-412981-WO 1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2 / - / )-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of D-Nal(2'), biphenylalanine (Bip), dBip, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF₃)dPhe);R5is absent or is selected from the group consisting of arginine, ornithine, histidine, alanine, proline, transP ro (guan), cfsPro(guan), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, and D-glutamic acid;R6is absent or is selected from the group consisting of D-tryptophan, L-tryptophan, D-Nal(2'), Tic, histidine, D-histidine, Nal(1 ’), D-Nal(1'), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, alanine, and D-alanine;R7is absent or is selected from the group consisting of glycine, aspartic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), proline, D-Nal(2'), ornithine, D-ornithine, Pen, and dPen;R8is absent or lysine;X1is absent or is selected from the group consisting of tyrosine, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;X2is absent or is selected from the group consisting of D-proline, L-valine, phenylalanine, and norleucine;X3is absent, phenylalanine, or norleucine;Y1is selected from the group consisting of D-alanine, L-alanine, D-valine, L-valine, D-leucine, D-tert-leucine, norleucine, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, L-arginine, D-arginine, L-asparagine, D-asparagine, L-lysine, D-lysine, and L-tryptophan;Docket No.: 211Z-412981-WO Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, D-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;Y4is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;Y5is absent or D-valine;Y6is absent or D-valine;Y7is absent or D-proline;the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:a disulfide bond between R1and R7when R1and R7are each cysteine;a disulfide bond between R2and R7when R2and R7are each independently selected from D-cysteine, cysteine, Pen, and dPen;a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7is lysine, D-lysine, Dap, D-ornithine, or ornithine;a side-chain lactam bridge between R2and R7when R2is lysine and R7is aspartic acid;a side-chain lactam bridge between R1or R2and R8when R1or R2is aspartic acid, R8is lysine, and R7is glycine or proline;X1X2X3represents an optionally present N-terminus; andY1Y2Y3Y4Y5Y6Y7represents a C-terminus.

[0259] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (HA), wherein:R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated D-norleucine (Ac-dNIe), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), acetylated D-cysteine (Ac-dCys), tyrosine, D-tyrosine, di-methyl tyrosineDocket No.: 211Z-412981-WO (Dmt), aspartic acid, acetylated asparagine (Ac-Asn), acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Ac-Tle), acetylated D-tert-leucine (Ac-dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;R2is selected from the group consisting of proline, histidine, D-aspartic acid, aspartic acid, glutamic acid, lysine, alanine, D-alanine, tryptophan, cysteine, D-cysteine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);R3is absent or is selected from the group consisting of histidine, D-proline, L-proline, hydroxyproline (Hyp), transPro(guan), cisPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of D-Nal(2'), para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF₃)dPhe);R5is absent or is selected from the group consisting of arginine, ornithine, histidine, alanine, proline, transPro(guan), cisPro(guan), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, and D-glutamic acid;R6is absent or is selected from the group consisting of D-tryptophan, L-tryptophan, D-Nal(2'), Tic, histidine, D-histidine, Nal(1 ’), D-Nal(1 ’), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, alanine, and D-alanine;Docket No.: 211Z-412981-WO R7is absent or is selected from the group consisting of glycine, aspartic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), proline, D-Nal(2'), ornithine, D-ornithine, Pen, and dPen;R8is absent or lysine;X1is absent or is selected from the group consisting of tyrosine, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;X2-X3are absent;Y1is selected from the group consisting of D-alanine, L-alanine, D-valine, L-valine, D-leucine, D-tert-leucine, norleucine, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, L-arginine, D-arginine, L-asparagine, D-asparagine, L-lysine, D-lysine, and L-tryptophan;Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, D-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3-Y7are absent;the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:a disulfide bond between R1and R7when R1and R7are each cysteine;a disulfide bond between R2and R7when R2and R7are each independently selected from D-cysteine, cysteine, Pen, and dPen;a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid or aspartic acid, and R7is lysine, D-lysine, Dap, D-ornithine, or ornithine;a side-chain lactam bridge between R2and R7when R2is lysine and R7is aspartic acid;a side-chain lactam bridge between R1or R2and R8when R1or R2is aspartic acid, R8is lysine, and R7is glycine or proline.

[0260] In some embodiments, the non-naturally occurring melanocortin analog has one or more beta hairpin (p-hairpin) and / or beta turn (p-turn) structures. In some embodiments, R3of the sequence according to Formula (I), which may be D-proline, L--70-Docket No.: 211Z-412981-WO proline, hydroxyproline, D-hydroxyproline, D-alanine, D-methionine, D-valine, prolylglycine (Pro-Gly), glycine, transPro(guan), cisPro(guan), provides the p-hairpin and / or p-turn structures of the non-naturally occurring melanocortin analog. In some embodiments, the disulfide bond of the sequence according to Formula (I), if present, provides the p-hairpin and / or p-turn structures of the non-naturally occurring melanocortin analog.

[0261] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is modified. The N-terminus of the melanocortin analog may be modified by any functional group known in the art, such as, for example, an acyl group, an imine group, an amide group, a urea group, a carbamate group, a sulfonamide group, and an alkylamine group.

[0262] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is modified by an acyl group. In some embodiments, the acyl group OA ^.peptideML / is acetyl group (e.g., ).

[0263] Alternatively, in some embodiments, the N-terminus of the non-naturally occurring melanocortin analog is not modified.

[0264] As discussed above, Y1Y2Y3Y4Y5Y6Y7Y8represents a C-terminus of the non-naturally occurring melanocortin analog. In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog terminates with a dVal-dPro moiety. In other embodiments the C-terminus of the non-naturally occurring melanocortin analog initiates with a dVal-dPro moiety. The dVal-dPro moiety may confer improved properties on the melanocortin analog, such as increased plasma duration and improved transport across the blood-brain-barrier, the epithelium, and / or gastrointestinal tract, or increased stability against biodegradation.

[0265] In some embodiments, Y1-Y8are absent. In some embodiments, Y1is present and Y2-Y8are absent. In some embodiments, Y2-Y8are absent and Y1is selected from dVal, dPro, Vai, Pro, Ala, dAla, Hyp, dHyp, Asp, Arg, Asn, dAsp, dArg, and dAsn.

[0266] In some embodiments, Y1and Y2are present and Y3-Y8are absent. In some embodiments, Y3-Y8are absent, and Y1is selected from dVal, dLeu, dTle, dPro,Docket No.: 211Z-412981-WO Vai, Hyp, dHyp, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, and dLys and Y2is selected from dPro, dVal, Pro, Vai, Hyp, dHyp, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle. In some embodiments, Y3-Y8are absent, and Y1is dVal and Y2is dPro.

[0267] In some embodiments, Y1-Y3are present and Y4-Y8are absent. In some embodiments, Y4-Y8are absent, and Y1is selected from dVal, dPro, dTle, Lys, dLys, Arg, and dArg, Y2is selected from dVal, dPro, Vai, Pro, and dTle, and Y3is dPro, dVal, Pro, and VaL

[0268] In some embodiments, Y1-Y4are present and Y5-Y8are absent. In some embodiments, Y5-Y8are absent, and Y1is dVal, Y2is dVal or dPro, Y3is dVal, and Y4is dVal.

[0269] In some embodiments, Y1-Y5are present and Y6-Y8are absent. In some embodiments, Y1-Y6are present and Y7-Y8are absent.

[0270] In some embodiments, Y1-Y7are present and Y8is absent. In some embodiments, Y8is absent, and Y1is dVal, Y2is dVal, Y3is dVal, Y4is dVal, Y5is dVal, Y6is dVal, and Y7is dPro.

[0271] In some embodiments, Y1-Y8are present.

[0272] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by a functional group selected from the group consisting of an amide group, an ester group, and an aldehyde group.

[0273] In some embodiments, the C-terminus of the non-naturally occurring OPeptide — melanocortin analog is modified by an amide group (e.g.,wwz). In the sequence of Formula (I), a non-naturally occurring melanocortin analog with a C-terminus modified by an amide may be represented by a terminal -NH2.

[0274] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In the sequence of Formula (I), a non-naturally occurring melanocortin analog with an unmodified C-terminus may be represented by -OH or by the absence of a C-terminal group. In some embodiments, the C-terminus of-34-Docket No.: 211Z-412981-WO the non-naturally occurring melanocortin analog is not modified, and the sequence of Formula (I) is Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 2).

[0275] In some embodiments, R1is absent, and R2is aspartic acid. In some embodiments, R1is acetylated norleucine, and R2is aspartic acid.

[0276] In some embodiments, X1, X2, and X3are absent. In some embodiments, X1is present and X2and X3are absent.

[0277] In some embodiments, the non-naturally occurring melanocortin analog of the present technology is cyclized. For example, the non-naturally occurring melanocortin analog may be cyclized through a moiety selected from the group consisting of: a disulfide bond between R1and R7or when R1and R7are each cysteine; a disulfide bond between R2and any one of R7-R20when R2and the any one of R7-R20are selected from the group consisting of D-cysteine, cysteine, Pen, and dPen; a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid; a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7is lysine, D-lysine, Dap, D-ornithine, or ornithine; a sidechain lactam bridge between R2and R7when R2is lysine, and R7is glutamic acid or aspartic acid; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is glycine, proline or tryptophan; a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine; a lactam closure between R1and R7when R1is succinic acid or o-phthalic acid and R7is lysine; and a lactam closure between R2and R7when R2is succinic acid and R7is 2,3-diamino-propionic acid.

[0278] In some embodiments, R1, R2, and R7are present and R8-R20are absent, and the sequence of Formula (I) is cyclized through R2and R7via a lactam bond. In some embodiments, R1is acetylated norleucine, R2is aspartic acid, R3is selected from the group consisting of proline, hydroxyproline, and D-hydroxyproline, R4is dNal(2'), R5is arginine, R6is D-tryptophan or L-tryptophan, R7is lysine, Y1is D-valine, and / or Y2is D-proline.

[0279] In some embodiments, the sequence of Formula (I) is: Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3; TCMCB07) or Ac-Nle-c[Asp-Hyp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 4; D3), wherein c represents cyclization through R2and R7via a lactam bond.Docket No.: 211Z-412981-WO

[0280] In some embodiments, X1or R8is present and R9-R20are absent. In further embodiments, the sequence of Formula (I) is cyclized through R1and R7or R2and R8via a lactam bond. In some embodiments, X1is absent or acetylated norleucine, R1is acetylated norleucine or aspartic acid, R2is selected from aspartic acid, proline, and phenylalanine, R3is hydroxyproline or histidine, R4is dNal(2'), R5is arginine, R6is tryptophan, R7is tryptophan or proline, and R8is lysine. In further embodiments, Y1is selected from D-valine, D-leucine, D-proline, and D-tert-leucine, and Y2is D-proline or D-valine.

[0281] In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Ac-Nle-c[Asp-Pro-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 5; D1);Ac-Nle-c[Asp-Phe-His-dNal(2')-Arg-Trp-Lys]-dLeu-dPro-NH2(SEQ ID NO: 6; D1γ); Ac-Nle-c[Asp-Phe-His-dNal(2’)-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 7; D18); Ac-Nle-c[Asp-His-dNal(2’)-Arg-Trp-Pro-Lys]-dVal-dPro-NH2(SEQ ID NO: 8; D2);Ac-Nle-c[Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys]-dVal-dPro-NH2(SEQ ID NO: 9; D4); and Ac-Nle-c[Asp-Pro-His-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-NH2(SEQ ID NO: 10; D5), wherein c represents cyclization through R1or R2and R7or R8via a lactam bond.

[0282] In some embodiments, R1-R2and R7-R10are present and R11-R20are absent. In further embodiments, the sequence of Formula (I) is cyclized through R2and R10via a lactam bond. In some embodiments, the sequence of Formula (I) is Ac-Nle-c[Asp-Phe-Phe-Pro-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 11; D1α), wherein c represents cyclization through R2and R10via a lactam bond.

[0283] In some embodiments, X1-X3are present and R8-R20are absent. In further embodiments, the sequence of Formula (I) is cyclized through R1and R7via a lactam bond. In some embodiments, the sequence of Formula (I) is Ac-Nle-Phe-Phe-c[Asp-Phe-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 12; D1β), wherein c represents cyclization through R1and R7via a lactam bond.

[0284] In some embodiments, the sequence of Formula (I) is linear. In some embodiments, the sequence of Formula (I) is Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-Docket No.: 211Z-412981-WO dVal-dPro-NH2(SEQ ID NO: 13; A1). In some embodiments, the sequence of Formula (I) is Ac-Nle-Pro-dNal(2’)-Arg-Trp-dVal-dPro-NH2(SEQ ID NO: 14; A2).

[0285] In some embodiments of the sequence of Formula (I), R1is acetylated norleucine. Alternatively, in some embodiments, R1is an acetylated amino acid other than acetylated norleucine. In some embodiments, R1is a non-acetylated amino acid. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Ac-dArg-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 15);Ac-dMet-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 16);Ac-dlle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 17);Ac-dLeu-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 18);Ac-dVal-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 19);Ac-dAla-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 20);Ac-Ala-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 21);Ac-Tle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 22);Ac-dTle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 23);Ac-dNle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 24);Ac-Nva-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 25);Ac-Gly-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 26);Ac-dPro-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 27);Ac-dCys-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 28);Ac-dPhe-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 29);Ac-dTyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 30);Ac-dGln-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 31);Ac-dAsn-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 32);Ac-transPro(guan)-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 33); Ac-cisPro(guan)-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 34);Docket No.: 211Z-412981-WO dTyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 35);Tyr-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 36);Dmt-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 37);Ac-Glu-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 38); andAc-Asn-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 39), wherein c represents cyclization through R2and R7via a lactam bond.

[0286] In some embodiments, when the sequence of Formula (I) is cyclized through R2and R7, then R2is Asp and R7is Lys. Alternatively, in some embodiments, when the sequence of Formula (I) is cyclized through R2and R7, then R2is an amino acid capable of forming a linkage to the residue at R7other than Asp and R7is an amino acid capable of forming a linkage to the residue at R2other than Lys. For example, when R2is an amino acid other than Arg and R7is an amino acid other than Lys, the residue at R2may be capable of forming a linkage such as a lactam bond or a disulfide bond with the residue at R7. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Ac-Nle-c[dAsp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 40);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-dLys]-dVal-dPro-NH2(SEQ ID NO: 41);Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 42);Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 43);Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 44);Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 45);Ac-Nle-c[Cys-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 46);Ac-Nle-c[dCys-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 47);Ac-Nle-c[Cys-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 48);Ac-Nle-c[dCys-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 49);Ac-Nle-c[Cys-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2(SEQ ID NO: 50);Ac-Nle-c[dCys-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2(SEQ ID NO: 51);Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 52);Docket No.: 211Z-412981-WO Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 53);Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2(SEQ ID NO: 54);Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2(SEQ ID NO: 55);Ac-Nle-c[dPen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2(SEQ ID NO: 56);Ac-Nle-c[Pen-Pro-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2(SEQ ID NO: 57);Ac-Nle-c[Cys-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2(SEQ ID NO: 58);Ac-Nle-c[dCys-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2(SEQ ID NO: 59);Ac-Nle-c[Pen-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 60);Ac-Nle-c[Pen-dNal(2’)-Arg-Trp-dCys]-dVal-dPro-NH2(SEQ ID NO: 61);Ac-Nle-c[Pen-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2(SEQ ID NO: 62);Ac-Nle-c[dPen-dNal(2’)-Arg-Trp-Pen]-dVal-dPro-NH2(SEQ ID NO: 63);Ac-Nle-c[dPen-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2(SEQ ID NO: 64);Ac-Nle-c[Pen-dNal(2’)-Arg-Trp-dPen]-dVal-dPro-NH2(SEQ ID NO: 65);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 66);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-dOrn]-dVal-dPro-NH2(SEQ ID NO: 67);Ac-Nle-c[Glu-Pro-dNal(2’)-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 68);Ac-Nle-c[Glu-Pro-dNal(2’)-Arg-Trp-dOrn]-dVal-dPro-NH2(SEQ ID NO: 69); and Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Dap]-dVal-dPro-NH2(SEQ ID NO: 70),wherein c represents cyclization through R2and R7via a lactam bond or a disulfide bond.

[0287] In some embodiments of the sequence of Formula (I), R3is Pro. Alternatively, in some embodiments, R3is absent or an amino acid other than Pro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Ac-Nle-c[Asp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 71);Ac-Nle-c[Asp-Ala-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 72);Ac-Nle-c[Asp-dPro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 73);Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 74);Ac-Nle-c[Asp-dMet-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 75);Ac-Nle-c[Asp-Pro-Gly-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 76);Ac-Nle-c[Asp-Gly-Gly-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 77);Ac-Nle-c[Asp-Gly-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 78);Ac-Nle-c[Asp-Leu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 79);Ac-Nle-c[Asp-Ile-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 80);Ac-Nle-c[Asp-Val-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 81);Ac-Nle-c[Asp-dLeu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 82);Ac-Nle-c[Asp-dlle-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 83);Ac-Nle-c[Asp-dVal-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 84);Ac-Nle-c[Asp-Trp-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 85);Ac-Nle-c[Asp-dTrp-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 86);Ac-Nle-c[Asp-transPro(guan)-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 87); Ac-Nle-c[Asp-cisPro(guan)-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 88); Ac-Nle-c[Asp-Val-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 89);Ac-Nle-c[Asp-lle-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 90);Ac-Nle-c[Asp-Gly-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 91);Ac-Nle-c[Asp-Glu-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 92);Ac-Nle-c[Asp-Arg-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 93);Ac-Nle-c[Asp-dLeu-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 94);Ac-Nle-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 95); and Ac-Nle-c[Asp-dMet-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 96), wherein c represents cyclization through R2and R7via a lactam bond.

[0288] In some embodiments of the sequence of Formula (I), R5is Arg. Alternatively, in some embodiments, R5is absent or an amino acid other than Arg. InDocket No.: 211Z-412981-WO some embodiments, the sequence of Formula (I) is selected from the group consisting of:Ac-Nle-c[Asp-Pro-dNal(2’)-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 97);Ac-Nle-c[Asp-Pro-dNal(2’)-Lys-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 98);Ac-Nle-c[Asp-Pro-dNal(2’)-dLys-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 99);Ac-Nle-c[Asp-Pro-dNal(2’)-dArg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 100);Ac-Nle-c[Asp-Pro-dNal(2’)-Orn-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 101);Ac-Nle-c[Asp-Pro-dNal(2’)-dOrn-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 102);Ac-Nle-c[Asp-Pro-dNal(2’)-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 103);Ac-Nle-c[Asp-Pro-dNal(2’)-Ala-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 104);Ac-Nle-c[Asp-Pro-dNal(2’)-Gly-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 105);Ac-Nle-c[Asp-Pro-dNal(2’)-Asp-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 106);Ac-Nle-c[Asp-Pro-dNal(2’)-Glu-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 107);Ac-Nle-c[Asp-Pro-dNal(2’)-dHis-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 108);Ac-Nle-c[Asp-Pro-dNal(2’)-dAla-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 109);Ac-Nle-c[Asp-Pro-dNal(2’)-dAsp-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 110); and Ac-Nle-c[Asp-Pro-dNal(2’)-dGlu-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 111), wherein c represents cyclization through R2and R7via a lactam bond.

[0289] In some embodiments of the sequence of Formula (I), R6is Trp. Alternatively, in some embodiments, R6is absent or an amino acid other than Trp. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Lys]-dVal-dPro-NH2(SEQ ID NO: 112);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Nal(1’)-Lys]-dVal-dPro-NH2(SEQ ID NO: 113);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Aia-Lys]-dVal-dPro-NH2(SEQ ID NO: 114);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Phe-Lys]-dVal-dPro-NH2(SEQ ID NO: 115);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Tyr-Lys]-dVal-dPro-NH2(SEQ ID NO: 116);Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-His-Lys]-dVal-dPro-NH2(SEQ ID NO: 117);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Ala-Lys]-dVal-dPro-NH2(SEQ ID NO: 118);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dNal(1’)-Lys]-dVal-dPro-NH2(SEQ ID NO: 119);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dPhe-Lys]-dVal-dPro-NH2(SEQ ID NO: 120);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dNal(2’)-Lys]-dVal-dPro-NH2(SEQ ID NO: 121);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dTyr-Lys]-dVal-dPro-NH2(SEQ ID NO: 122);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dHis-Lys]-dVal-dPro-NH2(SEQ ID NO: 123); and Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dAla-Lys]-dVal-dPro-NH2(SEQ ID NO: 124), wherein c represents cyclization through R2and R7via a lactam bond.

[0290] In some embodiments of the sequence of Formula (I), R4is dNal(2’). Alternatively, in some embodiments, R4is an amino acid other than dNal(2’). For example, in some embodiments, when R4is an amino acid other than dNal(2’), R4is Bip. In some embodiments, the sequence of Formula (I) is Ac-Nle-c[Asp-Pro-21-p-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 125), wherein c represents cyclization through R2and R7via a lactam bond.

[0291] In some embodiments of the sequence of Formula (I), Y1is dVal and Y2is dPro. Alternatively, in some embodiments, Y1is an amino acid other than dVal and Y2is an amino acid other than dPro. In some embodiments, Y1is dVal and Y2is an amino acid other than dPro. In some embodiments, Y1is an amino acid other than dVal and Y2is dPro.

[0292] In some embodiments, Y1is dVal, Y2is dPro, and the C-terminus is modified by NH2. In some embodiments, Y1is an amino acid other than dVal, Y2is an amino acid other than dPro, and the C-terminus is modified by NH2. In some embodiments, Y1is dVal, Y2is an amino acid other than dPro, and the C-terminus is modified by NH2. In some embodiments, Y1is an amino acid other than dVal, Y2is dPro, and the C-terminus is modified by NH2. In some embodiments, Y1is dVal, Y2is dPro, and the C-terminus is unmodified.

[0293] In embodiments of Formula (I) when Y1is an amino acid other than dVal, then Y1is selected from dPro, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, dLys, and dTle. In embodiments of Formula (I) when Y2is an aminoDocket No.: 211Z-412981-WO acid other than dPro, then Y2or selected from dVal, Vai, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, and dTle. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-Pro-NH2(SEQ ID NO: 126);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 127);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-OH (SEQ ID NO: 128);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Hyp-NH2(SEQ ID NO: 129);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dHyp-NH2(SEQ ID NO: 130);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-Hyp-NH2(SEQ ID NO: 131);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-dHyp-NH2(SEQ ID NO: 132);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-dVal-NH2(SEQ ID NO: 133);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-dVal-NH2(SEQ ID NO: 134);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-Val-NH2(SEQ ID NO: 135);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-Val-NH2(SEQ ID NO: 136);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-NH2(SEQ ID NO: 137);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dPro-NH2(SEQ ID NO: 138);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-NH2(SEQ ID NO: 139);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-NH2(SEQ ID NO: 140);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Val-NH2(SEQ ID NO: 141);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Pro-NH2(SEQ ID NO: 142);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Ala-NH2(SEQ ID NO: 143);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAla-NH2(SEQ ID NO: 144);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dHyp-NH2(SEQ ID NO: 145);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Hyp-NH2(SEQ ID NO: 146);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAla-dAla-NH2(SEQ ID NO: 147);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Ala-Ala-NH2(SEQ ID NO: 148);-21-Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Gly-Gly-NH2(SEQ ID NO: 149);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Asp-NH2(SEQ ID NO: 150);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Arg-NH2(SEQ ID NO: 151);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-Asn-NH2(SEQ ID NO: 152);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dAsp-NH2(SEQ ID NO: 153);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dArg-NH2(SEQ ID NO: 154);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dAsn-NH2(SEQ ID NO: 155);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asp-dPro-NH2(SEQ ID NO: 156);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dPro-NH2(SEQ ID NO: 157);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asn-dPro-NH2(SEQ ID NO: 158);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsp-dPro-NH2(SEQ ID NO: 159);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dPro-NH2(SEQ ID NO: 160);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsn-dPro-NH2(SEQ ID NO: 161);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asp-NH2(SEQ ID NO: 162);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-NH2(SEQ ID NO: 163);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Asn-NH2(SEQ ID NO: 164);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsp-NH2(SEQ ID NO: 165);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-NH2(SEQ ID NO: 166);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dAsn-NH2(SEQ ID NO: 167);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-Pro-Val-NH2(SEQ ID NO: 168);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dPro-dVal-NH2(SEQ ID NO: 169);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dPro-dVal-NH2(SEQ ID NO: 170); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dPro-NH2(SEQ ID NO: 171);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dPro-NH2(SEQ ID NO: 172);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-Val-Pro-NH2(SEQ ID NO: 173);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Lys-dVal-dPro-NH2(SEQ ID NO: 174);Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dLys-dVal-dPro-NH2(SEQ ID NO: 175);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-Pro-Val-NH2(SEQ ID NO: 176);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dPro-dVal-NH2(SEQ ID NO: 177);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dPro-dVal-NH2(SEQ ID NO: 178);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-Val-Pro-NH2(SEQ ID NO: 179);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Arg-dVal-dPro-NH2(SEQ ID NO: 180);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dArg-dVal-dPro-NH2(SEQ ID NO: 181);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dVal-dPro-NH2(SEQ ID NO: 182);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 183);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dVal-NH2(SEQ ID NO: 184);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-NH2(SEQ ID NO: 185);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-dPro-NH2(SEQ ID NO: 186);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 187);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dTle-NH2(SEQ ID NO: 188); and Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dTle-NH2(SEQ ID NO: 189), wherein c represents cyclization through R2and R7via a lactam bond.

[0294] In some embodiments of the sequence of Formula (I) when Y3is present and Y4-8are absent, then each of Y1, Y2, and Y3are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3and Y4are present and Y5-8are absent, then each of Y1, Y2, Y3, and Y4are independently selected from dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y5are present and Y6-8are absent, then each of Y1-Y5are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y6are present and Y7-8are absent, then each of Y1-Y6are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y7are present and Y8is absent, then each of Y1-Y7are independently selected form dVal and dPro. In some embodiments of the sequence of Formula (I) when Y3-Y8are present, then each of Y1-Y8are independently selected from dVal and dPro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dPro-NH2(SEQ ID NO: 190);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 191);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 192); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-dVal-dPro-NH2(SEQ ID NO: 193); andAc-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 194),wherein c represents cyclization through R2and R7via a lactam bond.

[0295] In some embodiments of the sequence of Formula (I), X1is present and is acetylated norleucine, and R1is present and is norleucine. In some embodiments, X2is present and is norleucine. In some embodiments, X3is present and is norleucine. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Ac-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 195);Ac-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 196); andAc-Nle-Nle-Nle-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 197),wherein c represents cyclization through R2and R7via a lactam bond.

[0296] As described above, some of the non-naturally occurring melanocortin analogs comprising the sequence of Formula (I) may bind the melanocortin 3 receptor and the melanocortin 4 receptor with the same or generally similar affinity. Other non-naturally occurring melanocortin analogs comprising the sequence of Formula (I) may bind the melanocortin 3 receptor with greater affinity than the melanocortin 4 receptor. In some embodiments, when the melanocortin antagonist of the present technology binds the melanocortin 3 receptor with greater affinity than the melanocortin 4 receptor, then the sequence of Formula (I) is selected from the group consisting of:Ac-Nle-c[Asp-Pro-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 198);Ac-Nle-c[Asp-Trp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 199);WDocket No.: 211Z-412981-WO Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-dTrp-Lys]-dVal-dPro-NH2(SEQ ID NO: 200);c[CO-cis-CH=CH-CO-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 201); Ac-Nle-c[Asp-β-Ala-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 202);Ac-Nle-c[Asp-Mamb-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 203);Ac-Nle-c[Asp-Acpc-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 204);Ac-c[Cys-Arg-dPhe-Cys]-Trp-dVal-dPro-NH2(SEQ ID NO: 205);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-Trp-NH2(SEQ ID NO: 206);Ac-Nle-c[Asp-Aba-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 207);Ac-Nle-c[Asp-Aia-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 208); and Ac-Nle-c[Asp-Ata-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 209), wherein c represents cyclization through R1or R2and R7or R8via a lactam bond or a disulfide bond.

[0297] Some non-naturally occurring melanocortin analogs comprising the sequence of Formula (I) may bind the melanocortin 4 receptor with greater affinity than the melanocortin 3 receptor. In some embodiments, when the melanocortin antagonist binds the melanocortin 4 receptor with greater affinity than the melanocortin 3 receptor, then the sequence of Formula (I) is selected from the group consisting of:Ac-Nle-c[Asp-Aic-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 210);Ac-Nle-c[Asp-Cpe-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 211);Ac-Nle-c[Asp-Che-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 212);Ac-Nle-c[Asp-Oic-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 213);Ac-Nle-c[Asp-loc-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 214);Ac-Nle-c[Asp-Tic-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 215);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Pro-Lys]-dVal-dPro-NH2(SEQ ID NO: 216);Ac-Nle-c[Asp-His-dNal(2’)-Pro-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 217);Ac-Nle-c[Asp-His-dNal(2’)-transPro(guan)-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 218); Ac-Nle-c[Asp-His-dNal(2’)-c / sPro(guan)-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 219);Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-Pro-dNal(2’)-Pro-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 220);Ac-Nle-c[Asp-Pro-dNal(2’)-?ransPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 221); Ac-Nle-c[Asp-Pro-dNal(2’)-c / sPro(guan)-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 222); Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Aba-Lys]-dVal-dPro-NH2(SEQ ID NO: 223);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Ata-Lys]-dVal-dPro-NH2(SEQ ID NO: 224);Ac-Nle-c[Asp-Glu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 225);Ac-Nle-c[Asp-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2(SEQ ID NO: 226);Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 227);Ac-Nle-c[Asp-Pro-Glu-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2(SEQ ID NO: 228); Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2(SEQ ID NO: 229);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2(SEQ ID NO: 230);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-dLys-dAsp-NH2(SEQ ID NO: 231);Ac-Glu-c[Asp-Pro-dNal(2')-Arg-Trp-Gly-Lys]-dPro-dPro-Lys-Asp-NH2(SEQ ID NO: 232); andAc-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dPro-dLys-dAsp-NH2(SEQ ID NO: 233), wherein c represents cyclization through R1or R2and R7or R8via a lactam bond.

[0298] In some embodiments of the sequence of Formula (I), when X1is present and X2and X3are absent, the sequence of Formula (I) is cyclized through a lactam bond or a disulfide bond between R1and any one of R5 8. In some embodiments, when X1is present and X2and X3are absent, the sequence of Formula (I) is cyclized through a lactam bond between R1and R6. In some embodiments, when X1is present and X2and X3are absent, the sequence of Formula (I) is cyclized through a lactam bond between R1and R7. In some embodiments, Y1and Y2are present and are dVal and dPro, respectively, and Y3-Y8are absent. In some embodiments, Y1-Y8are absent. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 234);Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-Glu-His-dNal(2')-Arg-Trp-Gly-Lys]-dVal-dPro-NH2(SEQ ID NO: 235); Ac-Nle-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 236);Ac-Arg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 237);Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 238);Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-dVal-dPro-NH2(SEQ ID NO: 239);Ac-dArg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 240); Ac-Arg-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 241);Ac-dArg-c[Asp-dAla-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 242);Ac-Nle-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 243);Ac-Arg-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 244);Ac-dArg-c[Asp-Ala-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 245);Ac-Nle-c[Asp-Trp-Arg-dNal(2’)-Pro-Lys]-dVal-dPro-NH2(SEQ ID NO: 246);Ac-Nle-c[Asp-Pro-Trp-dNal(2’)-Lys]-dVal-dPro-NH2(SEQ ID NO: 247);Ac-Nle-c[Asp-Pro-Trp-Arg-dNal(2’)-Pro-Lys]-dVal-dPro-NH2(SEQ ID NO: 248);Ac-Nle-c[Asp-Pro-Trp-Arg-dNal(2’)-Lys]-dVal-dPro-NH2(SEQ ID NO: 249);Ac-Nle-c[Lys-Trp-Arg-dNal(2’)-Pro-Asp]-dVal-dPro-NH2(SEQ ID NO: 250);Ac-Arg-c[Cys-dAla-His-dNal(2’)-Arg-Trp-Cys]-NH2(SEQ ID NO: 251);Ac-Arg-c[Asp-dAla-His-dNal(2’)-Arg-Trp-Lys]-NH2(SEQ ID NO: 252);Ac-Arg-c[Asp-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 253); and Ac-Arg-c[Asp-Glu-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 254), wherein c represents cyclization through R1or R2and R7or R8via a lactam bond or a disulfide bond.

[0299] In some embodiments of the sequence of Formula (I), when X1and X2are present and X3and R1are absent, the sequence of Formula (I) is cyclized through a lactam bond between R2and R7. In such embodiments, X1and X2are each independently selected from dVal and dPro. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Docket No.: 211Z-412981-WO Ac-dVal-dPro-c[Asp-Trp-Arg-dNal(2’)-Pro-Lys]-Nle-NH2(SEQ ID NO: 255);Ac-dVal-dPro-c[Lys-Trp-Arg-dNal(2’)-Pro-Asp]-Nle-NH2(SEQ ID NO: 256);Ac-dVal-dPro-c[Asp-Trp-Arg-dNal(2’)-Pro-Lys]-Nle-Nle-NH2(SEQ ID NO: 257);Ac-dVal-dPro-c[Lys-Trp-Arg-dNal(2’)-Pro-Asp]-Nle-Nle-NH2(SEQ ID NO: 258);Ac-dVal-dPro-c[Asp-Trp-Arg-dNal(2’)-Pro-Lys]-dVal-dPro-NH2(SEQ ID NO: 259); and Ac-dVal-dPro-c[Lys-Trp-Arg-dNal(2’)-Pro-Asp]-dVal-dPro-NH2(SEQ ID NO: 260), wherein c represents cyclization through R2and R7via a lactam bond.

[0300] In some embodiments of the sequence of Formula (I), R1is Nle and one or more of X1and X2are present. In some embodiments, R1is Nle X1is present, and X2is absent. In some embodiments, R1is Nle, and X1and X2are present. In some embodiments, the sequence of Formula (I) is:Ac-dVal-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 261); or Tyr-Val-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 262), wherein c represents cyclization through R2and R7via a lactam bond.

[0301] In some embodiments of the sequence of Formula (I), R1is Ac-Glu. In some embodiments, R1is Ac-Glu, R2is Asp, R3is Glu, His, or Arg, R4is dNal(2’), R5is Arg, R6is Trp, and R7is Lys. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Ac-Glu-c[Asp-Glu-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 263);Ac-Glu-c[Asp-His-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 264); and Ac-Glu-c[Asp-Arg-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 265), wherein c represents cyclization through R2and R7via a lactam bond.

[0302] In some embodiments of the sequence of Formula (I), R5is His. In some embodiments, when R5is His, then R3is His and the sequence of Formula (I) is cyclized via a lactam bond through R1or R2and R7. In some embodiments, X1is Ac-Arg, Ac-Nle, or absent, R1is Ac-Nle, Ac-Arg, or Asp, R2is Asp or Pro, R3is His, R4is dNal(2’), R5is His, R6is Trp, and R7is Lys or Dap. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-Pro-His-dNal(2’)-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 266);Ac-Nle-c[Asp-His-dNal(2’)-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 267);Ac-Arg-c[Asp-Pro-His-dNal(2’)-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 268);Ac-Arg-c[Asp-His-dNal(2’)-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 269);Ac-Nle-c[Asp-Pro-His-dNal(2’)-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 270);Ac-Nle-c[Asp-His-dNal(2’)-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 271);Ac-Nle-c[Asp-Pro-His-dNal(2’)-His-Trp-Lys]-dVal-Hyp-NH2(SEQ ID NO: 272);Ac-Nle-c[Asp-His-dNal(2’)-His-Trp-Lys]-dVal-Hyp-NH2(SEQ ID NO: 273);Ac-Arg-c[Asp-Pro-His-dNal(2’)-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 274);Ac-Arg-c[Asp-His-dNal(2’)-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 275);Ac-Arg-c[Asp-Pro-His-dNal(2’)-His-Trp-Lys]-dVal-Hyp-NH2(SEQ ID NO: 276);Ac-Arg-c[Asp-His-dNal(2’)-His-Trp-Lys]-dVal-Hyp-NH2(SEQ ID NO: 277);Ac-Nle-c[Asp-Pro-His-dNal(2’)-His-Trp-Dap]-dVal-dPro-NH2(SEQ ID NO: 278);Ac-Nle-c[Asp-His-dNal(2’)-His-Trp-Dap]-dVal-dPro-NH2(SEQ ID NO: 279);Ac-Arg-c[Asp-Pro-His-dNal(2’)-His-Trp-Dap]-dVal-dPro-NH2(SEQ ID NO: 280); and Ac-Arg-c[Asp-His-dNal(2’)-His-Trp-Dap]-dVal-dPro-NH2(SEQ ID NO: 281), wherein c represents cyclization through R1or R2and R7via a lactam bond.

[0303] In some embodiments of the sequence of Formula (I), R1is Ac-Nle, R2is Asp and dAsp, R3is Pro or His, R4is dNal(2’), R5is Arg, R6is Trp, and R7is Lys and dLys. In such embodiments, Y1, Y2, and Y3are varied. In some embodiments, the sequence of Formula (I) is selected from the group consisting of:Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dThr-dPro-dThr-NH2(SEQ ID NO: 282); Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dThr-dPro-dThr (SEQ ID NO: 283);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-dThr-dPro-dThr (SEQ ID NO: 284);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-dThr-dPro-dThr (SEQ ID NO: 285);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dVal-NH2(SEQ ID NO: 286);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dPro-dVal-NH2(SEQ ID NO: 287);Docket No.: 211Z-412981-WO Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-dPro-dVal-NH2(SEQ ID NO: 288);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-dPro-dVal-NH2(SEQ ID NO: 289);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 290);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 291);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-dVal-dPro-NH2(SEQ ID NO: 292);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-dVal-dPro-NH2(SEQ ID NO: 293);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-β-Pro-β-Val-NH2(SEQ ID NO: 294);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-p-Pro-p-Val-NH2(SEQ ID NO: 295);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-p-Pro-p-Val-NH2(SEQ ID NO: 296);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-β-Pro-β-Val-NH2(SEQ ID NO: 297);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-β-Pro-β-Val-NH2(SEQ ID NO: 298);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-β-Pro-β-Val-NH2(SEQ ID NO: 299);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-β-Val-β-Pro-NH2(SEQ ID NO: 300);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-p-Val-p-Pro-NH2(SEQ ID NO: 301);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-p-Val-p-Pro-NH2(SEQ ID NO: 302);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-β-Val-β-Pro-NH2(SEQ ID NO: 303);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-β-Val-β-Pro-NH2(SEQ ID NO: 304);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-β-Val-β-Pro-NH2(SEQ ID NO: 305);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-β-Pro-β-Pro-NH2(SEQ ID NO: 306);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-p-Pro-p-Pro-NH2(SEQ ID NO: 307);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-β-Pro-β-Pro-NH2(SEQ ID NO: 308);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-β-Pro-β-Pro-NH2(SEQ ID NO: 309);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-β-Pro-β-Pro-NH2(SEQ ID NO: 310);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-β-Val-β-Val-NH2(SEQ ID NO: 311);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-β-Val-β-Val-NH2(SEQ ID NO: 312);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-β-Val-β-Val-NH2(SEQ ID NO: 313);Docket No.: 211Z-412981-WO Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-p-Val-p-Val-NH2(SEQ ID NO: 314);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Val-NH₂ (SEQ ID NO: 315); Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Val-NH₂ (SEQ ID NO: 316); Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Val-NH2(SEQ ID NO: 317);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Val-NH₂ (SEQ ID NO: 318)Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Pro-NH2(SEQ ID NO: 319);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Pro-NH₂ (SEQ ID NO: 320); Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Pro-NH2(SEQ ID NO: 321);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Pro-NH2(SEQ ID NO: 322);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-p-Thr-p-Pro-p-Thr (SEQ ID NO: 323);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-p-Thr-p-Pro-p-Thr (SEQ ID NO: 324);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-p-Thr-p-Pro-p-Thr (SEQ ID NO: 325);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-p-Thr-p-Pro-p-Thr (SEQ ID NO: 326);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dAla-NH2(SEQ ID NO: 327);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dPro-dAla-NH2(SEQ ID NO: 328);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-dPro-dAla-NH2(SEQ ID NO: 329);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dPro-dAla-NH2(SEQ ID NO: 330);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dAla-dPro-NH₂ (SEQ ID NO: 331);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dAla-dPro-NH2(SEQ ID NO: 332);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-dAla-dPro-NH2(SEQ ID NO: 333);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-dAla-dPro-NH2(SEQ ID NO: 334);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-p-Pro-p-Ala-NH2(SEQ ID NO: 335);-21-Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-p-Pro-p-Ala-NH2(SEQ ID NO: 336);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-p-Pro-p-Ala-NH2(SEQ ID NO: 337);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-p-Pro-p-Ala-NH2(SEQ ID NO: 338);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-p-Ala-p-Pro-NH2(SEQ ID NO: 339);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-p-Ala-p-Pro-NH2(SEQ ID NO: 340);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-p-Ala-p-Pro-NH2(SEQ ID NO: 341);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-p-Ala-p-Pro-NH2(SEQ ID NO: 342);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-p-Val-p-Ala-NH2(SEQ ID NO: 343);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-p-Val-p-Ala-NH2(SEQ ID NO: 344);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-p-Val-p-Ala-NH2(SEQ ID NO: 345);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-p-Val-p-Ala-NH2(SEQ ID NO: 346);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Ala-NH2(SEQ ID NO: 347); Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Ala-NH2(SEQ ID NO: 348); Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Ala-NH2(SEQ ID NO: 349);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Ala-NH2(SEQ ID NO: 350)Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dLeu-NH2(SEQ ID NO: 351);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dPro-dLeu-NH2(SEQ ID NO: 352);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-Lys]-dPro-dLeu-NH2(SEQ ID NO: 353);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dPro-dLeu-NH2(SEQ ID NO: 354);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dLeu-dPro-NH2(SEQ ID NO: 355);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-dLeu-dPro-NH2(SEQ ID NO: 356);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-dLeu-dPro-NH2(SEQ ID NO: 357);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-dLeu-dPro-NH2(SEQ ID NO: 358);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-p-Pro-p-Leu-NH2(SEQ ID NO: 359);Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-p-Pro-p-Leu-NH2(SEQ ID NO: 360);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-p-Pro-p-Leu-NH2(SEQ ID NO: 361);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-p-Pro-p-Leu-NH2(SEQ ID NO: 362);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-p-Leu-p-Pro-NH2(SEQ ID NO: 363);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-p-Leu-p-Pro-NH2(SEQ ID NO: 364);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-p-Leu-p-Pro-NH2(SEQ ID NO: 365);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-p-Leu-p-Pro-NH2(SEQ ID NO: 366);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-p-Val-p-Leu-NH2(SEQ ID NO: 367);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-p-Val-p-Leu-NH2(SEQ ID NO: 368);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-p-Val-p-Leu-NH2(SEQ ID NO: 369);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-p-Val-p-Leu-NH2(SEQ ID NO: 370);Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Leu-NH2(SEQ ID NO: 371);Ac-Nle-c[Asp-His-dNal(2')-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Leu-NH2(SEQ ID NO: 372);Ac-Nle-c[dAsp-Pro-dNal(2')-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Leu-NH2(SEQ ID NO: 373); andAc-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Leu-NH2(SEQ ID NO: 374),wherein c represents cyclization through R2and R7via a lactam bond.

[0304] Alternatively, in some embodiments, the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of: Ac-Nle-c[Asp-Pro-dPhe-Arg-dTrp-Lys]-dVal-dPro-NH2(SEQ ID NO: 375);Ac-Nle-c[Asp-His-Arg-p(l)dPhe-Arg-Tic-Lys]-dVal-dPro-NH2(SEQ ID NO: 376);Ac-Nle-c[Asp-His-Arg-dBip-Arg-Tic-Lys]-dVal-dPro-NH2(SEQ ID NO: 377);Ac-Nle-c[Asp-Pro-Arg-p(l)dPhe-Arg-Tic-Lys]-dVal-dPro-NH2(SEQ ID NO: 378);Ac-Nle-c[Asp-Pro-Arg-dBip-Arg-Tic-Lys]-dVal-dPro-NH2(SEQ ID NO: 379);Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-Arg-Pro-p(I)dPhe-Arg-Tic-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 380); Ac-Nle-c[Asp-Arg-Pro-dBip-Arg-Tic-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 381);Ac-Nle-c[Asp-Aba-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 382);Ac-Nle-c[Asp-Aia-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 383);Ac-Nle-c[Asp-Ata-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 384);Ac-Nle-c[Asp-Aba-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 385);Ac-Nle-c[Asp-Aia-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 386);Ac-Nle-c[Asp-Ata-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 387);Ac-Nle-c[Asp-Atc-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 388);Ac-Nle-c[Asp-APC-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 389);Ac-Nle-c[Asp-APPC-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 390);Ac-Nle-c[Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 391);Ac-Nle-c[Asp-Pro-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 392);Ac-Nle-c[Asp-Pro-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 393);Ac-Nle-c[Asp-Pro-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 394);Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 395);Ac-Nle-c[Asp-His-p(CI)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 396);Ac-Nle-c[Asp-His-p(l)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 397);Ac-Nle-c[Asp-His-p(Br)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 398);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 399);Ac-Nle-c[Asp-His-p(CF3)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 400);Ac-Nle-c[Asp-Pro-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 401);Ac-Nle-c[Asp-Trp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 402);Ac-Nle-c[Asp-His-dPhe-Pro-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 403);Ac-Nle-c[Asp-His-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 404); Ac-Nle-c[Asp-His-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 405);-S4-Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-Pro-dPhe-Pro-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 406);Ac-Nle-c[Asp-Pro-dPhe-transPro(guan)-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 407); Ac-Nle-c[Asp-Pro-dPhe-cisPro(guan)-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 408); Ac-Nle-c[Asp-Pro-dPhe-Arg-Aia-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 409);Ac-Nle-c[Asp-Pro-dPhe-Arg-Aba-Lys]-dVal-dPro-NH2(SEQ ID NO: 410);Ac-Nle-c[Asp-Pro-dPhe-Arg-Ata-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 411);Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aia-Lys]-dVal-dPro-NH2(SEQ ID NO: 412);Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Aba-Lys]-dVal-dPro-NH2(SEQ ID NO: 413);Ac-Nle-c[Asp-Pro-p(CF3)dPhe-Arg-Ata-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 414); and Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH₂ (SEQ ID NO: 415),wherein c represents cyclization through R1or R2and R7via a lactam bond.

[0305] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of:Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dThr-dPro-dThr (SEQ ID NO: 416);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dThr-dPro-dThr (SEQ ID NO: 417);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-dThr-dPro-dThr (SEQ ID NO: 418);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-dThr-dPro-dThr (SEQ ID NO: 419);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dVal-NH₂ (SEQ ID NO: 420);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-dPro-dVal-NH2(SEQ ID NO: 421);Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-NH2(SEQ ID NO: 422);Ac-Nle-c[Asp-His-dNal(2’)-Arg-Trp-Lys]-dPro-dVal-NH2(SEQ ID NO: 423);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 424);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 425);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-dVal-dPro-NH2(SEQ ID NO: 426);Ac-Nle-c[dAsp-His-dNal(2’)-Arg-Trp-dLys]-dVal-dPro-NH2(SEQ ID NO: 427);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p-Pro-p-Val-NH2(SEQ ID NO: 428);Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-p-Pro-p-Val-NH2(SEQ ID NO: 429);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-p-Pro-p-Val-NH2(SEQ ID NO: 430);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-p-Pro-p-Val-NH2(SEQ ID NO: 431);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p-Val-p-Pro-NH2(SEQ ID NO: 432);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-p-Val-p-Pro-NH2(SEQ ID NO: 433);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-p-Val-p-Pro-NH2(SEQ ID NO: 434);Ac-Nle-c[dAsp-His-dNal(2’)-Arg-Trp-dLys]-p-Val-p-Pro-NH2(SEQ ID NO: 435);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p-Pro-p-Pro-NH2(SEQ ID NO: 436);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-p-Pro-p-Pro-NH2(SEQ ID NO: 437);Ac-Nle-c[dAsp-Pro-dNal(2’)-Arg-Trp-dLys]-p-Pro-p-Pro-NH2(SEQ ID NO: 438);Ac-Nle-c[dAsp-His-dNal(2’)-Arg-Trp-dLys]-p-Pro-p-Pro-NH2(SEQ ID NO: 439);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p-Val-p-Val-NH2(SEQ ID NO: 440);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-p-Val-p-Val-NH2(SEQ ID NO: 441);Ac-Nle-c[dAsp-Pro-Phe-Arg-Trp-dLys]-p-Val-p-Val-NH2(SEQ ID NO: 442);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-p-Val-p-Val-NH2(SEQ ID NO: 443);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Val-NH2(SEQ ID NO: 444); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Val-NH2(SEQ ID NO: 445); Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Val-NH2(SEQ ID NO: 446); Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Val-NH2(SEQ ID NO: 447); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Pro-NH2(SEQ ID NO: 448); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Pro-NH2(SEQ ID NO: 449); Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Pro-NH2(SEQ ID NO: 450); Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Pro-NH2(SEQ ID NO: 451); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p-Thr-p-Pro-p-Thr (SEQ ID NO: 452);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-p-Thr-p-Pro-p-Thr (SEQ ID NO: 453);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-p-Thr-p-Pro-p-Thr (SEQ ID NO: 454);Docket No.: 211Z-412981-WO Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-p-Thr-p-Pro-p-Thr (SEQ ID NO: 455);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dAla-NH2 (SEQ ID NO: 456);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dAla-NH2 (SEQ ID NO: 457);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-dPro-dAla-NH₂ (SEQ ID NO: 458);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-dPro-dAla-NH2 (SEQ ID NO: 459);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dAla-dPro-NH2 (SEQ ID NO: 460);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dAla-dPro-NH2(SEQ ID NO: 461);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-dAla-dPro-NH2 (SEQ ID NO: 462);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-dAla-dPro-NH2(SEQ ID NO: 463);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p-Pro-p-Ala-NH2 (SEQ ID NO: 464);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-p-Pro-p-Ala-NH2 (SEQ ID NO: 465);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-p-Pro-p-Ala-NH₂ (SEQ ID NO: 466);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-p-Pro-p-Ala-NH2(SEQ ID NO: 467);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p-Ala-p-Pro-NH2 (SEQ ID NO: 468);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-p-Ala-p-Pro-NH2 (SEQ ID NO: 469);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-p-Ala-p-Pro-NH2 (SEQ ID NO: 470);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-p-Ala-p-Pro-NH2(SEQ ID NO: 471);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p-Val-p-Ala-NH2(SEQ ID NO: 472);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-p-Val-p-Ala-NH2(SEQ ID NO: 473);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-p-Val-p-Ala-NH2 (SEQ ID NO: 474);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-p-Val-p-Ala-NH2(SEQ ID NO: 475);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Ala-NH2 (SEQ ID NO: 476); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Ala-NH2(SEQ ID NO: 477); Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Ala-NH2 (SEQ ID NO: 478); Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Ala-NH2(SEQ ID NO: 479); Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dPro-dLeu-NH2 (SEQ ID NO: 480);Docket No.: 211Z-412981-WO Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dLeu-NH2 (SEQ ID NO: 481);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-dPro-dLeu-NH2 (SEQ ID NO: 482);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dLeu-NH2 (SEQ ID NO: 483);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-dLeu-dPro-NH₂ (SEQ ID NO: 484);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dLeu-dPro-NH2 (SEQ ID NO: 485);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-dLeu-dPro-NH2 (SEQ ID NO: 486);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-dLeu-dPro-NH2 (SEQ ID NO: 487);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p-Pro-p-Leu-NH2 (SEQ ID NO: 488);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-p-Pro-p-Leu-NH2 (SEQ ID NO: 489);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-p-Pro-p-Leu-NH2 (SEQ ID NO: 490);Ac-Nle-c[dAsp-His-dNal(2')-Arg-Trp-dLys]-p-Pro-p-Leu-NH2(SEQ ID NO: 491);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p-Leu-p-Pro-NH2 (SEQ ID NO: 492);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-p-Leu-p-Pro-NH2 (SEQ ID NO: 493);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-p-Leu-p-Pro-NH2 (SEQ ID NO: 494);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-p-Leu-p-Pro-NH2 (SEQ ID NO: 495);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-p-Val-p-Leu-NH2 (SEQ ID NO: 496);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-p-Val-p-Leu-NH2(SEQ ID NO: 497);Ac-Nle-c[dAsp-Pro-dPhe-Arg-Trp-dLys]-p-Val-p-Leu-NH2 (SEQ ID NO: 498);Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-p-Val-p-Leu-NH2(SEQ ID NO: 499);Ac-Nle-c[Asp-Pro-dPhe-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Leu-NH2 (SEQ ID NO: 500); Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-(3-methyl)-p-Val-p-Leu-NH2 (SEQ ID NO: 501); Ac-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Leu-NH2(SEQ ID NO: 502); andAc-Nle-c[dAsp-His-dPhe-Arg-Trp-dLys]-(3-methyl)-p-Val-p-Leu-NH2(SEQ ID NO: 503), wherein c represents cyclization through R2and R7via a lactam bond.Docket No.: 211Z-412981-WO

[0306] In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 2-374. In some embodiments, the non-naturally occurring melanocortin antagonist analog comprises any one of the sequences of SEQ ID NOs: 2-281. In some embodiments, the non-naturally occurring melanocortin antagonist analog comprises any one of the sequences of SEQ ID NOs: 3, 20, 29-32, 67-70, 99-102, 127-130, 159, 163-166, 187-190, 387, 391, 394, 396, 398 and 399. In some embodiments, the non-naturally occurring melanocortin antagonist analog comprises any one of the sequences of SEQ ID NOs: 10, 14, 33-39, 82-96, 108-111, 119-124, 128, 182-189, 212-281, 394 and 399.

[0307] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 3 (TCMCB07). The structure of TCMCB07 (“B07”), which comprises Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys[-dVal-dPro-NH2, is shown below:TCMCB07.Anti-cancer Agents

[0308] The anti-cancer agent of the present technology is a therapeutic agent useful for the treatment or prevention of neoplasm, of tumor or cancer cell division, growth, proliferation and / or metastasis in a subject; induction of death or apoptosis of tumor and / or cancer cells; and / or any other forms of proliferative disorder. In some embodiments, such anti-cancer agents may be effective to treat, reduce, prevent, or otherwise be useful for a subject having a disease or condition that is not cancer, or besides cancer. The present technology is expected to be useful for subjects that mayDocket No.: 211Z-412981-WO receive, have received, or are receiving one or more doses of an anti-cancer agent regardless of the underlying disease or condition that the subject has or develops.

[0309] Conventional anti-cancer agents include chemotherapeutic agents such as platinum-based chemotherapeutic agents and non-platinum-based chemotherapeutic agents. Conventional cancer therapies may include more than one anti-cancer agent, for example, a combination of two or more chemotherapeutic agents (e.g., 5-FU plus leucovorin (FOLFOX), sunitinib plus oxaliplatin), a combination of chemotherapeutic agent and immunotherapy, as well as a combination of two or more immunotherapies. In contrast, the methods of the present technology are directed to administration of a non-naturally occurring melanocortin analog prior to, during, and / or after administration of an anti-cancer agent.

[0310] Exemplary chemotherapeutic agents include, but are not limited to, (i) alkylating antineoplastic agents such as cyclophosphamide (CYTOXAN), thiotepa, busulfan, carmustine, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, mercaptopurine, and procarbazine; (ii) antimetabolites such as 5-fluorouracil (5-FU), cladribine, cytarabine, fludarabine, gemcitabine (GEMZAR), tegafur (UFTORAL), pentostatin, clofarabine, capecitabine (XELODA), methotrexate, pemetrexed, and thioguanine; (iii) cytotoxic antibiotics such as doxorubicin (including ADRIAMYCIN, morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin, a doxorubicin salt (e.g., hydrochloride salt), doxorubicin HCI liposome injection (DOXIL), and deoxydoxorubicin), daunorubicin, idarubicin, mitomycins such as mitomycin C, actinomycin, epirubicin, calicheamicin, dynemicin, including dynemicin A, aclacinomysins, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, detorubicin, 6-diazo-5-oxo-L-norleucine, esorubicin, idarubicin, marcellomycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; (iv) tubulin binding agents such as vincristine (ONCOVIN), paclitaxel, epothilone, docetaxel, discodermolide, etoposide, vinblastine, teniposide, vinorelbine, and vindesine; and (v) platinum-coordination complexes such as cisplatin, oxaliplatin, carboplatin, and nedaplatin.Docket No.: 211Z-412981-WO

[0311] Additional examples of chemotherapeutic agents include, but are not limited to, tyrosine-kinase inhibitors such as imatinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, and sunitinib; topoisomerase inhibitors such as CPT-11 (irinotecan, CAMPTOSAR), mitoxantrone, and topotecan (HYCAMTIN); thymidine phosphorylase (TPase) inhibitors such as tipiracil, and trifluridine; mitotic inhibitors; cell cycle inhibitors; enzymes; biological response modifiers; antiangiogenic agents such as MMP-2, MMP-9, and COX-2 inhibitor; anti-androgens such as fiutamide, nilutamide and bicalutamide; a substituted urea such as hydroxyurea; adrenocortical suppressants such as mitotane, aminoglutethimide, and trilostane; anti-hormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), e.g., tamoxifen (including NOLVADEX tamoxifen), raloxifene (EVISTA), droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 11 7018, onapristone, and toremifene (FARESTON®); hormone and / or hormone antagonists such as the adrenocorticosteriods (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate), and estrogens (e.g., diethylstilbestrol); androgens, such as testosterone propionate; and aromatase inhibitors, such as anastrozole (ARIMIDEX), exemestane (AROMASIN), 4(5)-imidazoles, aminoglutethimide, megestrol acetate (MEGASE), formestanie, fadrozole, vorozole (RJVISOR), and letrozole (FEMARA).

[0312] In some embodiments, the anti-cancer agent comprises a chemotherapy and the chemotherapy comprises at least one chemotherapeutic agent. In some embodiments, the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of a platinum-coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, and a cytotoxic antibiotic. In some embodiments, the chemotherapeutic agent is an antimetabolite, a pyrimidine antagonist, an alkylating agent, a topoisomerase inhibitor, a mitotic inhibitor, an antitumor antibiotic, a protein kinase inhibitor, a proteosome inhibitor, a poly(ADP-ribose) polymerase inhibitor, a plant alkaloid, an antimicrotubule agent, an antineoplastic agent, or an enzyme.

[0313] In some embodiments, the chemotherapeutic agent is an antimetabolite. Nonlimiting examples of antimetabolites include fluorouracil, 5-fluorouracil, 6-mercaptopurine, azacytidine, capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil. In some embodiments, the chemotherapeutic -101-Docket No.: 211Z-412981-WO agent comprises an antimetabolite selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil.

[0314] In some embodiments, the chemotherapeutic agent is a pyrimidine antagonist. Nonlimiting examples of pyrimidine antagonists include vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and topotecan.

[0315] In some embodiments, the chemotherapeutic agent is an alkylating agent. Nonlimiting examples of alkylating agents include altretamine, bendamustine, busulfan, carboplatin, carmustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.

[0316] In some embodiments, the chemotherapeutic agent is a topoisomerase inhibitor. Nonlimiting examples of topoisomerase inhibitors include irinotecan, camptothecin, etoposide, doxorubicin, topotecan, mitoxantrone, teniposide, daunorubicin, idarubicin, epirubicin, SN-38, dexrazoxane, belotecan, levofloxacin, anthracycline, rubitecan, sacituzumab govitecan, moxifloxacin, gatifloxacin, rubitecan, nalidixic acid, nalidixic acid, novobiocin, enoxacin, flumequine, clinafloxacin.

[0317] In some embodiments, the chemotherapeutic agent is a mitotic inhibitor. Nonlimiting examples of mitotic inhibitors include paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, ixabepilone, colchicine, demecolcine, etoposide, teniposide, alisertib, barasertib, volasertib, paclitaxel protein-bound particles, albumin-bound paclitaxel, ispinesib, and eribulin.

[0318] In some embodiments, the chemotherapeutic agent is an antitumor antibiotic. Nonlimiting examples of antitumor antibiotics include daunorubicin, doxorubicin, liposomal doxorubicin, epirubicin, idarubicin, mitomycin, and valrubicin.

[0319] In some embodiments, the chemotherapeutic agent is a protein kinase inhibitor. Nonlimiting examples of protein kinase inhibitors include imatinib, dasatinib, nilotinib, bosutinib, ponatinib, sorafenib, sunitinib, pazopanib, cabozantinib, vandetanib, crizotinib, ceritinib, alectinib, brigatinib, osimertinib, larotrectinib, entrectinib, dabrafenib, trametinib, and cobimetinib.Docket No.: 211Z-412981-WO

[0320] In some embodiments, the chemotherapeutic agent is a proteosome inhibitor. Nonlimiting examples of proteosome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib, delanzomib, oprozomib, delanzomib, belinostat, panobinostat, romidepsin, vorinostat, belinostat, pracinostat, resminostat, givinostat, quisinostat, mocetinostat, chidamide, rocilinostat, and tucidinostat.

[0321] In some embodiments, the chemotherapeutic agent is a poly(ADP-ribose) polymerase inhibitor. Nonlimiting examples of poly(ADP-ribose) polymerase inhibitors include olaparib, rucaparib, niraparib, talazoparib, veliparib, pamiparib, ceralasertib, talazoparib, iniparib, niraparib, olaparib, rucaparib, veliparib, talazoparib, pamiparib, iniparib, veliparib, olaparib, talazoparib, and rucaparib.

[0322] In some embodiments, the chemotherapeutic agent is a plant alkaloid. Nonlimiting examples of plant alkaloids include vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and topotecan.

[0323] In some embodiments, the chemotherapeutic agent is an antimicrotubule agent. Nonlimiting examples of antimicrotubule agents include docetaxel, paclitaxel, vinblastine, vincristine, vinorelbine, eribulin, ixabepilone, and cabazitaxel.

[0324] In some embodiments, the chemotherapeutic agent is an antineoplastic agent. Nonlimiting examples of antineoplastic agents include estramustine, mitomycin, hydroxydaunorubicin, chlorambucil, cisplatin, carboplatin, oxaliplatin, methotrexate, 5-fluorouracil, capecitabine, doxorubicin, epirubicin, idarubicin, daunorubicin, bleomycin, etoposide, teniposide, mitoxantrone, irinotecan, topotecan, gemcitabine, pemetrexed, paclitaxel, and docetaxel.

[0325] In some embodiments, the chemotherapeutic agent is an enzyme. Nonlimiting examples of enzymes include L-asparaginase, pegaspargase, glucarpidase, carboxypeptidase G2, methioninase, arginine deiminase, ADI-PEG 20, protease-activated receptor 1 (PAR-1) inhibitors, thymidylate synthase inhibitors, topoisomerase I inhibitors, topoisomerase II inhibitors, dihydrofolate reductase inhibitors, ribonucleotide reductase inhibitors, hypoxanthine-guanine phosphoribosyltransferase inhibitors, DNA polymerase inhibitors, telomerase inhibitors, histone deacetylase inhibitors, protein kinase C inhibitors, sirtuin inhibitors, and matrix metalloproteinase inhibitors.Docket No.: 211Z-412981-WO

[0326] In some embodiments, the at least one chemotherapeutic agent comprises a platinum-coordination complex. In some embodiments, the platinum-coordination complex is carboplatin and / or cisplatin.

[0327] In some embodiments, the at least one chemotherapeutic agent comprises a tubulin binding agent or a plant alkaloid. In some embodiments, the tubulin binding agent or the plant alkaloid is at least one selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and Topotecan.

[0328] In some embodiments, the at least one chemotherapeutic agent comprises an alkylating antineoplastic agent. In some embodiments, the alkylating antineoplastic agent is at least one selected from the group consisting of altretamine, busulfan, carmustine, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.

[0329] In some embodiments, the at least one chemotherapeutic agent comprises a cytotoxic antibiotic. In some embodiments, the cytotoxic antibiotic is at least one selected from the group consisting of daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, and valrubicin.

[0330] In some embodiments, the platinum-coordination complex is cisplatin. In some embodiments, the chemotherapy comprises cisplatin, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3).

[0331] In some embodiments, the antimetabolite is 5-fluorouracil (5-FU). In some embodiments, the chemotherapy comprises 5-FU, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3).

[0332] In some embodiments, the tubulin binding agent or the plant alkaloid is vincristine. In some embodiments, the chemotherapy comprises vincristine, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3).

[0333] In some embodiments, the alkylating antineoplastic agent is cyclophosphamide. In some embodiments, the chemotherapy comprisesDocket No.: 211Z-412981-WO cyclophosphamide, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3).

[0334] In some embodiments, the cytotoxic antibiotic is doxorubicin. In some embodiments, the chemotherapy comprises doxorubicin, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3).

[0335] The present technology further encompasses combinations of two or more anti-cancer agents, including the above chemotherapeutic agents, as the anti-cancer agent of the combination therapy. Non-limiting examples include gemcitabine in combination with cisplatin; carboplatin in combination with pemetrexed; CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin combined with 5-FU and leucovovin.

[0336] In some embodiments, the method further comprises administering an antibody, or antigen binding fragment thereof, that specifically binds to human growth differentiation factor 15 (GDF15) such as, but not limited to, ponsegromab. See U. S. Patent No. 11,566,066 (or U. S. Patent Application No. 16 / 541,817, incorporated herein by reference). In some embodiments, the non-naturally occurring melanocortin analog treats, prevents, and / or reduces one or more side effects that an antibody, or antigen binding fragment thereof, that specifically binds to GDF15 may also treat, prevent, and / or reduce.Formulations

[0337] The compositions comprising the carriers and / or excipients described in the present technology facilitate delivery of the non-naturally occurring melanocortin analog and / or one or more anti-cancer agents of the present technology in any of its embodiments to a subject.

[0338] In some embodiments, the one or more anti-cancer agents is present in a composition.

[0339] In some embodiments, the non-naturally occurring melanocortin analog is present in a composition.-105-Docket No.: 211Z-412981-WO

[0340] In some embodiments, the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the composition. For example, the non-naturally occurring melanocortin analog is present in the composition in a concentration of 0.1 mg / mL to 500 mg / mL, 0.5 mg / mL to 250 mg / mL, 1 mg / mL to 100 mg / mL, 2.5 mg / mL to 50 mg / mL, or 5 mg / mL to 25 mg / mL, relative to a total volume of the composition. In some embodiments, the non-naturally occurring melanocortin analog is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0341] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3), and the non-naturally occurring melanocortin analog is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the composition. For example, the non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 3) is present in the composition in a concentration of 5 mg / mL to 100 mg / mL, 10 mg / mL to 75 mg / mL, 15 mg / mL to 50 mg / mL, 20 mg / mL to 40 mg / mL, or 25 mg / mL to 30 mg / mL, relative to a total volume of the composition. In some embodiments, the non-naturally occurring melanocortin analog comprising a sequence of Ac-Nle-c[Asp-Pro-dNal(2')-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3) is present in the composition in a concentration of about 50 mg / mL, relative to a total volume of the composition.

[0342] In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally. In some embodiments, the composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.

[0343] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises the non-naturally occurring melanocortin analog of Formula (I) at a concentration at about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or even more, depending on the specific peptide selected, the desired response, the route of administration, the formulation and other factors known to thoseDocket No.: 211Z-412981-WO of skill in the art. In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 3).

[0344] In some embodiments, the compositions of the present technology are administered to the subject at a dose that is based on the subject’s BML In some embodiments, two or more doses of the compositions of the present technology are administered to the subject, wherein the two or more doses are titrated (e.g., inversely titrated) based on the subject’s BMI at the time of each administration.

[0345] The compositions comprising the carriers and / or excipients described in the present technology facilitate delivery (e.g., parenteral administration, in particular subcutaneous injection) of the non-naturally occurring melanocortin analog of the present technology in any of its embodiments to a subject. Other purposes of the compositions comprising the carriers and / or excipients are to enhance dispersion, solubility, and stability of the non-naturally occurring melanocortin analog, and to reduce adverse injection site reactions.

[0346] The carriers and / or excipients of the composition may generally include one or more of the following components: a pH buffered aqueous solution comprising (a) sodium acetate, (b) Tris, and (c) water. In some embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.

[0347] In some embodiments, the carrier and / or excipient is isotonic.

[0348] In order to achieve a desirable tonicity, the composition of the present technology may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salt is present in the composition in a concentration of 0.1 mg / mL to 50 mg / mL, 1 mg / mL to 25 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0349] The carriers and / or excipients of the composition also includes a pH buffered aqueous solution which comprises (a) sodium acetate, (b) Tris, and (c) water.Docket No.: 211Z-412981-WO

[0350] The water used herein may act as a diluent and include, without limitation, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffered aqueous solution is water for injection.

[0351] In some embodiments, the composition includes water in an amount of about 1 wt% to about 90 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 50 wt%, relative to a total weight of the composition.

[0352] In some embodiments, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0353] In some embodiments, sodium acetate is present in the composition in a concentration of about 6 mg / mL to about 8 mg / mL, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a concentration of 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.1 mg / mL, 7.5 mg / mL, or 8 mg / mL, relative to a total volume of the composition.

[0354] In some embodiments, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, 10 mM to 600 mM, 20 mM to 500 mM, 30 mM to 400 mM, 40 mM to 300 mM, 50 mM to 200 mM, 60 mM to 100 mM, or 70 mM to 80 mM, relative to a total volume of the composition.

[0355] In some embodiments, sodium acetate is present in the composition in a molar concentration of about 80 mM to about 100 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 80 mM, 85 mM, 87 mM, 90 mM, 95 mM, or 100 mM, relative to a total volume of the composition.Docket No.: 211Z-412981-WO

[0356] The term “Tris” represents tris(hydroxymethyl)aminomethane also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, Trizma®, Trisamine, Trometamol, Tromethane, Trisaminol, orTHAM. In some embodiments, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0357] In some embodiments, Tris is present in the composition in a concentration of about 6 mg / mL to about 8 mg / mL, relative to a total volume of the composition. For example, Tris is present in the composition in a concentration of 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.3 mg / mL, 7.6 mg / mL, or 8 mg / mL, relative to a total volume of the composition.

[0358] In some embodiments, Tris is present in the composition in a molar concentration of 2 mM to 500 mM, relative to a total volume of the composition. For example, Tris is present in the composition in a molar concentration of 2 mM to 500 mM, 5 mM to 400 mM, 10 mM to 300 mM, 20 mM to 200 mM, 30 mM to 150 mM, 40 mM to 100 mM, 50 mM to 80 mM, or 60 mM to 70 mM, relative to a total volume of the composition.

[0359] In some embodiments, Tris is present in the composition in a molar concentration of about 50 mM to about 70 mM, relative to a total volume of the composition. For example, Tris is present in the composition in a molar concentration of 50 mM, 55 mM, 60 mM, 65 mM, or 70 mM, relative to a total volume of the composition.

[0360] In some embodiments, the pH buffered aqueous solution provides the composition with a pH equivalent or close to the physiological pH levels. This may reduce adverse injection site reactions and also provide the non-naturally occurring melanocortin analog with enhanced stability and resistance to aggregation and degradation.

[0361] In addition to sodium acetate and Tris, the composition may include other buffering agents. Non-limiting examples of additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid,-109-Docket No.: 211Z-412981-WO ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, malate, imidazole, and mixtures thereof. In some embodiments, the composition comprises acetic acid as an additional buffering agent.

[0362] In some embodiments, a weight ratio of sodium acetate to Tris is 1:4 to 4:1, 2:7 to 7:2, 1:3 to 3:1, 2:5 to 5:2, 1:2 to 2:1, 2:3 to 3:2, or about 1:1. In some embodiments, the weight ratio of sodium acetate to T ris is about 1:1.

[0363] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is 1:1 to 20:1, 3:2 to 15:1, 2:1 to 12:1, 3:1 to 10:1, 4:1 to 9:1, 5:1 to 8:1, or 6:1 to 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to sodium acetate is about 7:1.

[0364] In some embodiments, a weight ratio of the non-naturally occurring melanocortin analog to Tris is 1:1 to 20:1, 3:2 to 15:1, 2:1 to 12:1, 3:1 to 10:1, 4:1 to 9:1, 5:1 to 8:1, or 6:1 to 7:1. In some embodiments, the weight ratio of the non-naturally occurring melanocortin analog to Tris is about 7:1.

[0365] The composition may also comprise a preservative agent. Exemplary preservative agents include, but are not limited to, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, phenol, m-cresol, benzyl alcohol, alpha-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, benzalkonium chloride, phenoxyethanol, and methyl paraben.

[0366] If present, the concentration of the preservative agent may range from 0.001 mg / mL to 50 mg / mL, 0.01 mg / mL to 25 mg / mL, 0.1 mg / mL to 10 mg / mL, or 1 mg / mL to 5 mg / mL, relative to a total volume of the composition.

[0367] In some embodiments, the composition is in the form of an aqueous solution or a suspension. In some embodiments, the composition is in the form of an emulsion. In some embodiments, the composition is in the form of an aqueous solution. In some embodiments, the composition is in the form of an aqueous solution which is clear, colorless, and / or free of visible foreign matter.Docket No.: 211Z-412981-WO

[0368] In some embodiments, the composition has a pH ranging from 6.5 to 8.5. In some embodiments, the composition has a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5.

[0369] In some embodiments, the composition is basic and has a pH of about 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, or 8.5. In some embodiments, the composition has a pH ranging from about 7.3 to about 7.4. In some embodiments, the composition has a pH of 7.3 or 7.4.

[0370] In some embodiments, the composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the composition has an osmolality ranging from 250 mOsm / kg to 360 mOsm / kg, 260 mOsm / kg to 340 mOsm / kg, 270 mOsm / kg to 330 mOsm / kg, 280 mOsm / kg to 320 mOsm / kg, 290 mOsm / kg to 310 mOsm / kg, or about 300 mOsm / kg. In some embodiments, the composition has an osmolarity of about 250 mOsm / kg, about 260 mOsm / kg, about 270 mOsm / kg, about 280 mOsm / kg, about 290 mOsm / kg, about 300 mOsm / kg, about 310 mOsm / kg, about 320 mOsm / kg, about 330 mOsm / kg, about 340 mOsm / kg, about 350 mOsm / kg, or about 360 mOsm / kg. In some embodiments, the composition has an osmolality ranging from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the composition has an osmolality of about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg.

[0371] In some embodiments, the composition has a viscosity ranging from 0.5 cP to 5 cP. For example, the composition has a viscosity ranging from 0.5 cP to 5 cP, 0.75 cP to 4.5 cP, 1.0 cP to 4 cP, 1.2 cP to 3.5 cP, 1.3 cP to 3 cP, 1.4 cP to 2.5 cP, 1.5 cP to 2 cP, or 1.6 cP to 1.8 cP. In some embodiments, the composition has a viscosity of about 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5 cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, or 2.0 cP. In some embodiments, the composition has a viscosity of about 1.4 cP or 1.6 cP.

[0372] The composition of the present technology in any of its embodiments may be formulated for parenteral administration, such as, for example, in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. The term “parenteral”, as used herein, includes subcutaneous, intravenous, intraperitoneal, intramuscular, and intralesional, or infusion techniques.

[0373] The active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) may be dissolved or suspended in the aforementioned carrier and / or excipient.Docket No.: 211Z-412981-WO Additional aqueous or non-aqueous carriers that may facilitate dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and / or various buffers.

[0374] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises a non-naturally occurring melanocortin analog at a concentration at about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or even more, depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.

[0375] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises sodium acetate at a concentration at about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 76 mM, 77 mM, 78 mM, 79 mM, 80 mM, 81 mM, 82 mM, 83 mM, 84 mM, 85 mM, 86 mM, 87 mM, 88 mM, 89 mM, 90 mM, 91 mM, 92 mM, 93 mM, 94 mM, 95 mM, 96 mM, 97 mM, 98 mM, 99 mM, 100 mM, 105 mM, 110 mM, 120 mM, 130 mM, 140 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, or 200 mM.

[0376] In some embodiments, the composition formulated for parenteral administration (e.g., subcutaneous administration) comprises Tris at a concentration at about 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35mM, 40 mM, 45 mM, 50 mM, 55 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, or 120 mM.

[0377] The compositions of the present technology may be formulated for intranasal delivery. In some embodiments, the intranasal composition comprises a non-naturally occurring melanocortin analog of the present technology and a carrier and / or excipient.

[0378] The carriers and / or excipients of the composition may generally include one or more of the following components: (i) one or more antioxidants, (ii) one or more preservatives, (iii) one or more buffers, (iv) one or more tonicity adjustors, (v) one or more surfactants, (vi) flavor, (vii) propellants, and / or (viii) a vehicle or solvent. In someDocket No.: 211Z-412981-WO embodiments, all components are compatible with the non-naturally occurring melanocortin analog (i.e., do not react or cause the non-naturally occurring melanocortin analog to react) and are homogeneously dispersed or dissolved uniformly in the composition.

[0379] In some embodiments, the carrier and / or excipient is isotonic to nasal fluids.

[0380] In order to achieve a desirable tonicity, the composition of the present technology may further include a salt such as sodium chloride, sodium succinate, sodium sulfate, potassium chloride, magnesium chloride, magnesium sulfate, and calcium chloride. In some embodiments, the salt is present in the composition in a concentration of 0.1 mg / mL to 50 mg / mL, 1 mg / mL to 25 mg / mL, or 5 mg / mL to 10 mg / mL, relative to a total volume of the composition. In some aspects, the salt is sodium chloride at a concentration of 0.9% wt.

[0381] The carriers and / or excipients of the composition also includes a pH buffered aqueous solution which comprises sodium acetate, Tris, and / or a phosphate buffer.

[0382] The water used herein may act as a diluent and include, without limitation, water for injection (WFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pH buffered aqueous solution is water for injection.

[0383] In some embodiments, the composition includes water (e.g., water for injection) in an amount of about 1 wt% to about 90 wt%, about 10 wt% to about 75 wt%, or about 25 wt% to about 50 wt%, relative to a total weight of the composition.

[0384] In some embodiments, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0385] In some embodiments, sodium acetate is present in the composition in a molar concentration of about 80 mM to about 100 mM, relative to a total volume of theDocket No.: 211Z-412981-WO composition. For example, sodium acetate is present in the composition in a molar concentration of 80 mM, 85 mM, 87 mM, 90 mM, 95 mM, or 100 mM, relative to a total volume of the composition.

[0386] The term “Tris” represents tris(hydroxymethyl)aminomethane also known as Tris buffer, Tris base, TRIS, tromethamine, tromethamine buffer, Trizma®, Trisamine, Trometamol, Tromethane, Trisaminol, orTHAM. In some embodiments, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, relative to a total volume of the composition. For example, Tris is present in the composition in a concentration of 0.5 mg / mL to 50 mg / mL, 1 mg / mL to 40 mg / mL, 2 mg / mL to 30 mg / mL, 4 mg / mL to 20 mg / mL, 5 mg / mL to 15 mg / mL, 6 mg / mL to 12 mg / mL, or 8 mg / mL to 10 mg / mL, relative to a total volume of the composition.

[0387] In some embodiments, the pH buffered aqueous solution provides the composition with a pH equivalent or close to the physiological pH levels. This may reduce adverse injection site reactions and also provide the non-naturally occurring melanocortin analog with enhanced stability and resistance to aggregation and degradation.

[0388] In addition to sodium acetate and Tris, the composition may include other buffering agents. Non-limiting examples of additional buffering agents include saline, phosphate, phosphoric acid, citrate, succinate, gluconate, histidine, acetic acid, ascorbate, tartartic acid, maleic acid, glycine, lactate, lactic acid, ascorbic acid, imidazole, bicarbonate, carbonic acid, succinic acid, sodium benzoate, benzoic acid, gluconate, edetate, malate, imidazole, and mixtures thereof. In some embodiments, the composition comprises acetic acid as an additional buffering agent.

[0389] In some embodiments, sodium phosphate is present in the composition in a molar concentration of 5 mM to 700 mM, relative to a total volume of the composition. For example, sodium acetate is present in the composition in a molar concentration of 5 mM to 700 mM, 10 mM to 600 mM, 20 mM to 500 mM, 30 mM to 400 mM, 40 mM to 300 mM, 50 mM to 200 mM, 60 mM to 100 mM, or 70 mM to 80 mM, relative to a total volume of the composition.

[0390] The composition may also comprise a preservative agent. Exemplary preservative agents include, but are not limited to, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, ascorbyl palmitate, butylatedDocket No.: 211Z-412981-WO hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, phenol, m-cresol, benzyl alcohol, benzalkonium chloride, alpha-tocopherol, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, benzalkonium chloride, phenoxyethanol, and methyl paraben.

[0391] If present, the concentration of the preservative agent may range from 0.001 mg / mL to 50 mg / mL, 0.01 mg / mL to 25 mg / mL, 0.1 mg / mL to 10 mg / mL, or 1 mg / mL to 5 mg / mL, relative to a total volume of the composition.

[0392] In some embodiments, the composition is in the form of an aqueous solution or a suspension. In some embodiments, the composition is in the form of an emulsion. In some embodiments, the composition is in the form of an aqueous solution. In some embodiments, the composition is in the form of an aqueous solution which is clear, colorless, and / or free of visible foreign matter.

[0393] In some embodiments, the composition has a pH approximating the normal pH range of the nasal fluid. In some embodiments, the composition has a pH ranging from 5.5 to 6.5. In some embodiments, the composition has a pH of about 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5.

[0394] In some embodiments, the composition has an osmolality ranging from 250 mOsm / kg to 350 mOsm / kg. For example, the composition has an osmolality ranging from 250 mOsm / kg to 360 mOsm / kg, 260 mOsm / kg to 340 mOsm / kg, 270 mOsm / kg to 330 mOsm / kg, 280 mOsm / kg to 320 mOsm / kg, 290 mOsm / kg to 310 mOsm / kg, or about 300 mOsm / kg. In some embodiments, the composition has an osmolarity of about 250 mOsm / kg, about 260 mOsm / kg, about 270 mOsm / kg, about 280 mOsm / kg, about 290 mOsm / kg, about 300 mOsm / kg, about 310 mOsm / kg, about 320 mOsm / kg, about 330 mOsm / kg, about 340 mOsm / kg, about 350 mOsm / kg, or about 360 mOsm / kg. In some embodiments, the composition has an osmolality ranging from about 275 mOsm / kg to about 330 mOsm / kg. In some embodiments, the composition has an osmolality of about 279 mOsm / kg, about 314 mOsm / kg, or about 329 mOsm / kg.

[0395] In some embodiments, the composition has a viscosity ranging from 0.5 cP to 5 cP. For example, the composition has a viscosity ranging from 0.5 cP to 5 cP, 0.75 cP to 4.5 cP, 1.0 cP to 4 cP, 1.2 cP to 3.5 cP, 1.3 cP to 3 cP, 1.4 cP to 2.5 cP, 1.5 cP to 2 cP, or 1.6 cP to 1.8 cP. In some embodiments, the composition has a viscosity of about 0.5 cP, 0.6 cP, 0.7 cP, 0.8 cP, 0.9 cP, 1.0 cP, 1.1 cP, 1.2 cP, 1.3 cP, 1.4 cP, 1.5Docket No.: 211Z-412981-WO cP, 1.6 cP, 1.7 cP, 1.8 cP, 1.9 cP, or 2.0 cP. In some embodiments, the composition has a viscosity of about 1.4 cP or 1.6 cP.

[0396] In some embodiments, the composition comprises one or more antioxidants. For example, the composition may comprise ascorbic acid, cysteine, sodium metabisulfite, propyl gallate, butylated hydroxytoluene, and / or butylated hydroxyanisole.

[0397] In some embodiments, the composition comprises a surfactant, such as a sorbitan ester.

[0398] In some embodiments, the composition comprises a flavoring or scent, such as an aromatic oil.

[0399] The active ingredient(s) (e.g., the non-naturally occurring melanocortin analog) may be dissolved or suspended in the aforementioned carrier and / or excipient. Additional aqueous or non-aqueous carriers that may facilitate dissolution of the active ingredient include, but are not limited to, ethanol, benzyl alcohol, DMSO, polyethylene glycol, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, and / or various buffers.

[0400] In some embodiments, the non-naturally occurring melanocortin analog is solubilized or suspended in a solvent or vehicle. In some aspects, the solvent or vehicle is purified water, ethyl alcohol, propylene glycol. The composition may comprise between 0.03% wt and 1% wt melanocortin solubilized or suspended in a solvent or vehicle. The composition may comprise about 0.03% wt, 0.05% wt, 0.1 % wt, 0.15% wt, 0.2% wt, 0.25% wt, 0.3% wt, 0.35% wt, 0.4% wt, 0.45% wt, 0.5% wt, 0.55% wt, 0.6% wt, 0.65% wt 0.7% wt, 0.75% wt, 0.8% wt, 0.85% wt, 0.9% wt, 0.95% wt, or 1% wt melanocortin.

[0401] In some embodiments, the composition formulated for intranasal administration comprises a non-naturally occurring melanocortin analog at a concentration at about 0.001 nmol, 0.005 nmol, 0.01 nmol, 0.02 nmol, 0.05 nmol, 0.1 nmol, 0.25 nmol, 0.5 nmol, 1 nmol, 2.5 nmol, 5 nmol, 10 nmol, 20 nmol, 25 nmol, 50 nmol, 100 nmol, 250 nmol, 500 nmol, or 1000 nmol, or even more, depending on the specific peptide selected, the desired therapeutic response, the route of administration, the formulation and other factors known to those of skill in the art.Docket No.: 211Z-412981-WO

[0402] The composition may be formulated to be delivered by nose drop, spray device, or topical solution. In some embodiments, the pharmaceutical composition may be formulated as an aerosol, atomizer, inhalation, insufflation, metered-dose inhaler, nebulizer, or hydrobromide. In some embodiments, the composition includes a propellant, such as hydrofluoroalkane.

[0403] In some embodiments, the composition may be configured to be administered using a spray device or nasal inhaler. The spray device or nasal inhaler may be configured to deliver 1 ug to 10Oug per spray. In some embodiments, the spray device or nasal inhaler may be configured to deliver 1ug to 100ug, 5ug to 90ug, 10ug to 80ug, 15ug to 70ug, 20ug to 60ug, 25ug, to 50ug, or 30ug to 40ug per spray.Pharmacokinetics and Pharmacodynamics

[0404] The non-naturally occurring melanocortin analogs of the present technology exhibit pharmacokinetic (pK) and / or pharmacodynamic (pD) parameters. Such pK and / or pD may be expressed or otherwise determined relative to a control, which, in some instances, may be a non-naturally occurring melanocortin analog lacking one or more features of the non-naturally occurring melanocortin analogs of the present technology.

[0405] In some embodiments, the pK and / or pD of the non-naturally occurring melanocortin analogs may be assessed using concentration and / or temporal measurements (e.g., Tfinal, Cmax, T ½ (h)), AUC, or TmaxIn some embodiments, the non-naturally occurring melanocortin analogs have reduced clearance and / or metabolism, increased uptake, absorption, and / or stability, relative to a control.Clearance

[0406] “Clearance” may refer to the elimination, absorption, and / or metabolism of the non-naturally occurring melanocortin analogs in the subject’s plasma. Clearance may be assessed as volume of plasma cleared of the non-naturally occurring melanocortin analogs over time (e.g., mL / min, L / hr, or L / day) and / or may be normalized to body weight of the subject (e.g., mL / min / kg). Reduced clearance may also be represented by an increase in half-life or volume of distribution (Vd). In some embodiments, measuring clearance comprises measuring a terminal elimination rate constant (Az) or an inter-compartmental clearance (Q).Docket No.: 211Z-412981-WO

[0407] In some embodiments, the reduction in clearance comprises a measurement about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0408] In some embodiments, the reduction in clearance comprises a measurement during administration of the non-naturally occurring melanocortin analogs. In some embodiments, the reduction in clearance comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs.Concentration

[0409] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased tissue, plasma, and / or serum concentration relative to a control. “Concentration” may comprise a measurement reflecting one or more of the absolute amounts of the non-naturally occurring melanocortin analogs, the absorption of the non-naturally occurring melanocortin analogs, the metabolism of non-naturally occurring melanocortin analogs, or the elimination of non-naturally occurring melanocortin analogs.

[0410] The increased tissue, plasma, and / or serum concentration may be an increase in concentration of the non-naturally occurring melanocortin analogs at a given time point relative to a control administered at the same dose and measured at the same time point. The concentration may be measured at an intermediate time point or a final time point and may be measured as a mean residence time (MRT), an average concentration (Cavg), a trough concentration (Ctrough), or a concentration at the end of administration (e.g., infusion) time (CT).

[0411] In some embodiments, the increased concentration is reflected by an increase in peak plasma concentration (Cmax). An increase in Cmax may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. In some embodiments, Cmax comprises a dose normalized Cmax (DNCmax).

[0412] In some embodiments, the increased concentration is reflected by an increase in minimum plasma concentration (Cmin). An increase in Cmin may suggestDocket No.: 211Z-412981-WO increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. In some embodiments, Cmin comprises a dose normalized Cmin (DNCmin).

[0413] In some embodiments, the increased concentration is reflected by a reduction in time to reach Cmax (Tmax). A reduced Tmax may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0414] In some embodiments, the increased concentration is reflected by a final measurable concentration (Tfinal). An increased Tfinalmay suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control.

[0415] In some embodiments, the increased concentration is reflected by an increase in area under the curve (AUC). An increase in AUC may signify increased exposure to the non-naturally occurring melanocortin analogs and / or may suggest increased absorption, reduced metabolism, or slower elimination of the non-naturally occurring melanocortin analogs, relative to a control. The AUG measurement may comprise an Area Under the Curve for Concentration of Drug in Non-Compartmental Analysis (DNAUC).

[0416] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0417] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0418] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours,Docket No.: 211Z-412981-WO 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0419] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0420] In some embodiments, the increase in tissue, plasma, and / or serum concentration comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs.Distribution

[0421] In some embodiments, the non-naturally occurring melanocortin analogs of the present technology comprise an increased distribution relative to a control. The increased distribution may be an increase in distribution of the non-naturally occurring melanocortin analogs at a given time point relative to a control administered at the same dose and measured at the same time point. The distribution may be measured at an intermediate time point or a final time point.

[0422] In some embodiments, the measurement of distribution comprises measuring a volume of distribution at the terminal phase (Vdor Vdβ), a central volume of distribution (V), a peripheral volume of distribution (V2), an apparent volume of distribution (Vz), or a measurement of distribution comprises measuring a volume of distribution at steady state (Vss). A high or increased Vd, Vdβ, Vz, and / or Vssmay suggest large distribution beyond the tissue, plasma, and / or serum compartment, relative to the control.

[0423] In some embodiments, the increase in distribution comprises a measurement about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0424] In some embodiments, the increase in distribution comprises a measurement at least 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3Docket No.: 211Z-412981-WO days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0425] In some embodiments, the increase in distribution comprises a measurement at least about 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 day, 6 days, or 1 week after administration of the non-naturally occurring melanocortin analogs.

[0426] In some embodiments, the increase in distribution comprises a measurement during administration of the non-naturally occurring melanocortin analogs.

[0427] In some embodiments, the increase in distribution comprises a measurement at the completion of administration of the non-naturally occurring melanocortin analogs.Additional pD and pK Embodiments

[0428] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following:(a) an increase in half-life relative to a control;(b) a reduction in clearance relative to a control;(c) an increase in tissue concentration relative to a control;(d) an increase in plasma concentration relative to a control;(e) an increase in serum concentration relative to a control;(f) an increase in distribution relative to a control;(g) an increase in an AUC measurement relative to a control;(h) an increase in a DNAUC measurement relative to a control;(i) an increase in Tfinalrelative to a control;(j) an increase in Cmax relative to a control;(k) an increase in Cmin relative to a control;(l) an increase in DNCmin relative to a control;Docket No.: 211Z-412981-WO (m) an increase in MRT relative to a control;(n) an increase in Cavg relative to a control;(o) an increase in Ctrough relative to a control;(p) an increase in CT relative to a control;(q) an increase in Vd relative to a control;(r) a reduction in Tmax relative to a control; or(s) a reduction in Q relative to a control.

[0429] In some embodiments, the non-naturally occurring melanocortin analog of the present technology exhibits one or more of the following, relative to a control: (a) an increase in half-life by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(b) a reduction in clearance by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control;(c) an increase in tissue concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(d) an increase in plasma concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(e) an increase in serum concentration by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(f) an increase in distribution by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(g) an increase in an AUC by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% measurement relative to a control;Docket No.: 211Z-412981-WO (h) an increase in a DNAUC measurement by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(i) an increase in Tfinalby at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(j) an increase in Cmax by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(k) an increase in Cmin by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(l) an increase in DNCmin by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(m) an increase in MRT by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(n) an increase in Cavg by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(o) an increase in Ctroughby at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(p) an increase in CT by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;(q) an increase in Vdby at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900%, or 1000% relative to a control;-123-Docket No.: 211Z-412981-WO (r) a reduction in Tmaxby at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control; or(s) a reduction in Q by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% relative to a control.Therapeutic Methods

[0430] The present technology provides methods of treating, preventing, or reducing one or more conditions and / or side effects induced by anti-cancer agents (e.g., chemotherapeutic agents) as well as symptoms or conditions associated with cancer via administration of a non-naturally occurring melanocortin analog to a subject in need thereof. The methods may promote appetite and food consumption, and increase or maintain body weight, muscle mass, and / or fat mass of the subject. The methods are also effective in treating anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, loss of appetite, nausea, emesis, and symptoms associated with hypermetabolic immunoinflammatory syndrome. In some embodiments, the methods are effective in improving quality of life and / or increasing life expectancy. The methods of the present technology include administration of a non-naturally occurring melanocortin analog to a subject in need thereof prior to onset, during, and / or after onset of such conditions and / or side effects. These methods also include administration of a non-naturally occurring melanocortin analog to a subject in need thereof prior to, during, and / or after administration of an anti-cancer agent to the subject who may have cancer or may have another condition which is not cancer, but administration of the anticancer agent provides therapeutic benefit to the non-cancer condition.

[0431] The subject applicable to the methods of the present technology may be any subject who experiences involuntary loss of appetite, reduced appetite, decreased food consumption, and / or weight loss. For example, the subject may be a cancer patient, including those that have received, are receiving, or will receive anti-cancer treatment (e.g., chemotherapy) and a subject having another condition which is not cancer but administration of the anti-cancer agent provides therapeutic benefit to the non-cancer condition.

[0432] In some aspects, the present technology comprises a method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent-124-Docket No.: 211Z-412981-WO in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects associated with the anti-cancer agent are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, the method maintains or increases lean body mass, fat body mass, and / or weight of the subject. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents or reduces the one or more side effects associated with an anti-cancer agent in a subject.

[0433] In some aspects, the present technology comprises a method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

[0434] In some aspects, the present technology comprises a method of maintaining or increasing weight in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anticancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject by preventing or reducing one or more side effects associated with the anticancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.-109-Docket No.: 211Z-412981-WO

[0435] In some aspects, the present technology comprises a method of stimulating appetite or reducing loss of appetite induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent. In some embodiments, the method maintains or increases lean body mass, fat body mass, and / or body weight of the subject. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anti-cancer agent in the subject.

[0436] In some aspects, the present technology comprises a method of preventing, reducing, or restoring weight loss induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anti-cancer agent in the subject.

[0437] In some aspects, the present technology comprises a method of increasing, maintaining, reducing rate of loss, or otherwise ameliorating loss of body mass index (BMI) in a subject prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the BMI of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases BMI in the subject by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0438] In some aspects, the present technology comprises a method of increasing, maintaining, reducing rate of loss, or otherwise ameliorating loss of BMI durability in a subject prior to, during, and / or after administration of an anti-cancer agent, comprisingDocket No.: 211Z-412981-WO administering a non-naturally occurring melanocortin analog to the subject, wherein the BMI durability of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog maintains or increases BMI durability in the subject by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

[0439] In some aspects, the present technology comprises a method of preventing, reducing rate of loss, or otherwise ameliorating BMI reduction induced by an anti-cancer agent in a subject, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores BMI reduction induced by an anti-cancer agent in the subject.

[0440] In some aspects, the present technology comprises a method of treating, preventing, reducing, or otherwise ameliorating one or more side effects associated with an anti-cancer agent in a subject who failed to respond to an antiemetic treatment, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects associated with the anti-cancer agent are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, the failure to respond to an antiemetic treatment further comprises clinically and / or therapeutically insufficient weight gain, muscle mass gain, fat mass gain, increased appetite, and / or increased food intake. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects associated with an anti-cancer agent in the subject who failed to respond to an antiemetic treatment.Docket No.: 211Z-412981-WO

[0441] In some aspects, the present technology comprises a method of treating, preventing, reducing, or otherwise ameliorating one or more side effects associated with an anti-cancer agent in a subject who failed to respond to nutritional intervention, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects associated with the anti-cancer agent are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite, wherein the nutritional intervention further comprises nutritional supplementation. In some embodiments, the subject has a cancer. In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the one or more side effects associated with an anti-cancer agent in the subject who failed to respond to nutritional intervention.

[0442] In some aspects, the present technology comprises a method of preventing, reducing, or otherwise ameliorating an anti-cancer agent induced side effect in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject. In some embodiments, the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, administration of the non-naturally occurring melanocortin analog prevents or reduces the anti-cancer agent induced side effect in the subject having cancer.

[0443] In some aspects, the present technology comprises a method of treating, preventing, reducing, or otherwise ameliorating iatrogenic injury caused by an anticancer agent in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject. In some embodiments, the iatrogenic injury is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite. In some embodiments, administration of the non-naturally occurring melanocortin analog treats, prevents, or reduces the iatrogenic injury caused by an anticancer agent in the subject having cancer.

[0444] In some aspects, the present technology comprises a method of reducing time to cancer treatment failure in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.-109-Docket No.: 211Z-412981-WO In some embodiments, the time to cancer treatment failure is the interval from initiation of administration of the anti-cancer agent to its premature discontinuation. In some embodiments, the premature discontinuation is a discontinuation in anti-cancer administration due to cancer progression, adverse events associated with administration of the anti-cancer agent, or death of the subject. In some embodiments, the premature discontinuation is a change in a primary anti-cancer agent treatment.

[0445] In some aspects, the present technology comprises a method increasing, maintaining, reducing rate of loss, or otherwise ameliorating loss of Eastern Cooperative Oncology Group (ECOG) score, a Functional Assessment of Anorexia / Cachexia Therapy (FAACT) score, overall survival (OS) (e.g., a median overall survival (mOS)), progression-free survival (PFS), Karnofsky performance status (KPS) score, a wellbeing level, a European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) score, and / or a Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 score of a subject having cancer, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject. In some embodiments, the ECOG score, FAACT score, OS (e.g., a mOS), PFS, KPS, well-being level, the EORTC QLQ-C30 score, and / or the RECIST 1.1 score is improved, maintained, and / or reduction of is prevented or otherwise ameliorated by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject. In some embodiments, administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves ECOG score, FAACT score, OS, PFS, KPS, well-being level, the EORTC QLQ-C30 score, and / or the RECIST 1.1 score of the subject having cancer.

[0446] In some embodiments, the present technology comprises methods of reducing, maintaining, or otherwise improving a mOS hazard ratio in a subject having cancer, comprising administering the anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

[0447] In any of the foregoing aspects, the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration of the non-naturally occurring melanocortin analog. In some embodiments, the loss of appetite, reduced appetite, decreased food consumption,Docket No.: 211Z-412981-WO and / or weight loss is caused by the cancer. In some embodiments, the present technology prevents, reduces, or otherwise ameliorates loss of appetite, reduced appetite, decreased food consumption, and / or weight loss. In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cachexia. Nonlimiting examples of cachexia include cancer cachexia, cachexia in chronic obstructive pulmonary disease, cachexia in congestive heart failure, cachexia in chronic renal failure, and cachexia in inflammatory bowel disease. In some embodiments, the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the anti-cancer agent.

[0448] In any of the foregoing aspects, the anti-cancer agent may comprise a chemotherapy. In some embodiments, the method reduces chemotherapy induced mass loss and / or wasting in the subject and increases lean body mass and body weight of the subject. In some embodiments, the method maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the method reduces mass loss and / or wasting in the subject.

[0449] The methods of the present technology using anti-cancer agents (e.g., chemotherapy) may inhibit, remove, eradicate, reduce, regress, diminish, arrest or stabilize a cancerous tumor, including at least one of the tumor growth, tumor cell viability, tumor cell division and proliferation, tumor metabolism, blood flow to the tumor and metastasis of the tumor. In some embodiments, the size of a tumor, whether by volume, weight or diameter, is reduced after the treatment by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100%, relative to the tumor size before treatment. In some embodiments, the size of a tumor after treatment does not reduce but is maintained the same as the tumor size before treatment. Methods of assessing tumor size and / or presence include, but are not limited to, CT scan, MRI, DCE-MRI, PET scan, assessing circulating tumor DNA (ctDNA) levels, and assessing a RECIST 1.1 score.

[0450] In some embodiments, the subject with a cancer has previously undergone a treatment with the anti-cancer agent. In related embodiments, the subject has previously experienced one or more adverse side effects when treated with the anticancer agent. In some embodiments, such adverse side effects are selected from the-130-Docket No.: 211Z-412981-WO group consisting of nausea, emesis, anorexia, weight loss, fatigue, fat mass loss, and muscle mass loss.

[0451] The subject may be any subject already with the disease or condition (e.g., cancer). In some embodiments, the subject may be a subject which does not yet experience or exhibit symptoms of the disease or condition, or a subject predisposed to the disease or condition. In some embodiments, the subject is a person who is predisposed to cancer, e.g., a person with a family history of cancer.

[0452] In some embodiments, the method of the present technology in any of its aspects (i) stimulates appetite of the subject; (ii) increases food consumption of the subject; (iii) prevents or alleviates nausea, emesis, and / or anorexia in the subject; (iv) increases or maintains body weight of the subject; (v) prevents or reduces weight loss of the subject; (vi) increases or maintains muscle mass of the subject; (vii) prevents or reduces muscle mass loss of the subject; (viii) increases or maintains fat mass of the subject; and / or (ix) prevents or reduces fat mass loss of the subject.

[0453] In any of the foregoing aspects, the anorexia may be associated with weight loss.

[0454] In any of the foregoing aspects, the subject’s mass and / or weight is not more than 5% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0455] In any of the foregoing aspects, the subject’s mass and / or weight is not more than 10% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

[0456] In any of the foregoing aspects, the muscle mass loss may be cardiac muscle mass loss, skeletal muscle mass loss, or both. In some embodiments, the cardiac muscle mass loss is determined by measuring change in heart weight. In some embodiments, the cardiac muscle mass loss is determined by cardiac echocardiography. In some embodiments, the skeletal muscle mass loss is determined by measuring change in gastrocnemius tissue weight. In some embodiments, the skeletal muscle mass loss is determined by computed tomography scan. In some embodiments, the skeletal muscle mass loss is determined by dual-energy X-ray absorptiometry.Docket No.: 211Z-412981-WO

[0457] In some embodiments, muscle mass of the subject is increased by at least 1% to 100% after the administration of the non-naturally occurring melanocortin analog or the pharmaceutical composition thereof. For example, muscle mass of the subject is increased by at least 1% to 100%, at least 5% to 75%, at least 10% to 50%, or at least 20% to 35%, after the administration.

[0458] In some embodiments, muscle mass of the subject is increased by at least 5% to 15% after the administration. For example, muscle mass of the subject is increased by at least 5% to 15%, at least 6% to 14%, at least 7% to 12%, or at least 8% to 9%, after the administration.

[0459] In some embodiments, muscle mass of the subject is increased by at least 25% to 50% after the administration. For example, muscle mass of the subject is increased by at least 25% to 50%, at least 28% to 48%, at least 25% to 45%, or at least 30% to 40%, after the administration.

[0460] In some embodiments, the increased muscle mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 4 months, 6 months, 1 year, or 5 years, after the administration is stopped.

[0461] In some embodiments, the method prevents, reduces, or otherwise ameliorates muscle mass loss (e.g., involuntary muscle mass loss) in the subject.

[0462] In some embodiments, the muscle mass is cardiac muscle mass, skeletal muscle mass, or both. In some embodiments, the cardiac muscle mass is determined by measuring change in heart weight. In some embodiments, the skeletal muscle mass is determined by measuring change in gastrocnemius tissue weight. In related embodiments, the muscle mass change is cardiac muscle mass change, skeletal muscle mass change, or both. In some embodiments, cardiac muscle is determined by heart weight. In some embodiments, skeletal muscle mass is determined by gastrocnemius tissue weight. In some embodiments, the muscle mass changes may be assessed by using magnetic resonance imaging (MRI) and / or nuclear magnetic resonance (NMR).

[0463] In any of the foregoing aspects, anorexia may be determined by daily food intake, daily food consumption, and / or weekly food intake. In some embodiments, the daily food intake is determined by total calories (kcal) consumed in 1 day or mass ofDocket No.: 211Z-412981-WO food (grams or kilograms) consumed in 1 day. In some embodiments, the daily food consumption is determined by the daily food intake normalized to daily body weight of the subject. In some embodiments, the weekly food intake is determined total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 week.

[0464] In any of the foregoing aspects, the weight loss may be determined by daily body weight, and / or daily body weight gain.

[0465] In any of the foregoing aspects, the fat mass of the subject treated with the method may be at least 10% to 100% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0466] In some embodiments, fat mass of the subject is increased by at least 1% to 100% after the administration (e.g., administration of the therapeutically effective amount of the non-naturally occurring melanocortin analog or the pharmaceutical composition thereof). For example, fat mass of the subject is increased by at least 1% to 100%, at least 5% to 75%, at least 10% to 50%, or at least 20% to 35%, after the administration.

[0467] In some embodiments, fat mass of the subject is increased by at least 5% to 15% after the administration. For example, fat mass of the subject is increased by at least 5% to 15%, at least 6% to 14%, at least 7% to 12%, or at least 8% to 9%, after the administration.

[0468] In some embodiments, fat mass of the subject is increased by at least 25% to 50% after the administration. For example, fat mass of the subject is increased by at least 25% to 50%, at least 28% to 48%, at least 25% to 45%, or at least 30% to 40%, after the administration.

[0469] In some embodiments, the increased fat mass is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 4 months, 6 months, 1 year, or 5 years, after the administration is stopped.

[0470] In some embodiments, the method prevents or reduces fat mass loss (e.g., involuntary fat mass loss) in the subject.-133-Docket No.: 211Z-412981-WO

[0471] In some embodiments, the fat mass may be determined by the fat fold technique. In some embodiments, the fat mass changes may be assessed by using magnetic resonance imaging (MRI) and / or nuclear magnetic resonance (NMR).

[0472] In any of the foregoing aspects, the heart weight of the subject treated with the method may be at least 0.1 % to 10% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0473] In any of the foregoing aspects, the daily food intake of the subject treated with the method may be at least 5% to 50% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0474] In any of the foregoing aspects, the daily body weight of the subject treated with the method may be at least 1% to 15% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

[0475] In some embodiments, body weight of the subject is increased by at least 5% to 200% after the administration of the non-naturally occurring melanocortin analog or the pharmaceutical composition thereof. For example, body weight of the subject is increased by at least 5% to 200%, at least 10% to 150%, at least 25% to 100%, or at least 50% to 75%, after the administration.

[0476] In some embodiments, body weight of the subject is increased by at least 5% to 25% after the administration. For example, body weight of the subject is increased by at least 5% to 25%, at least 10% to 20%, or at least 12% to 15%, after the administration.

[0477] In some embodiments, body weight of the subject is increased by at least 20% to 100% after the administration. For example, body weight of the subject is increased by at least 20% to 100%, at least 35% to 90%, at least 50% to 80%, or at least 60% to 70%, after the administration.-105-Docket No.: 211Z-412981-WO

[0478] In some embodiments, the increased body weight is maintained for at least 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 4 months, 6 months, 1 year, or 5 years, after the administration is stopped.

[0479] In some embodiments, the method prevents or reduces weight loss (e.g., involuntary weight loss) in the subject.

[0480] In some embodiments, the body weight (or weight loss) is determined by monitoring daily body weight. In some embodiments, the body weight (or weight loss) is determined by monitoring daily body weight gain (or loss). In some embodiments, the body weight (or weight loss) is determined by monitoring cumulative body weight for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 3 months, 4 months, 6 months, 1 year, or 5 years.

[0481] In any of the foregoing aspects, appetite of the subject is increased by at least 10% to 200% after the administration of the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof. For example, appetite of the subject is increased by at least 10% to 200%, at least 20% to 175%, at least 30 to 150%, at least 40% to 125%, at least 50% to 100%, or at least 60% to 75%, after the administration.

[0482] In some embodiments, appetite of the subject is increased by at least 25% to 100% after the administration of the non-naturally occurring melanocortin analog or a pharmaceutical composition thereof. For example, appetite of the subject is increased by at least 25% to 100%, at least 30% to 90%, at least 35 to 80%, at least 40% to 70%, at least 45% to 60%, or at least 50% to 55%, after the administration.

[0483] In some embodiments, appetite is increased for ...

Claims

Docket No.: 211Z-412981-WO CLAIMSI / We claim:

1. A method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject having colorectal cancer, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent, wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

2. A method of maintaining or increasing weight in a subject having colorectal cancer, prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

3. A method of maintaining or increasing weight in a subject having colorectal cancer, prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject, wherein the weight of the subject is maintained or increased by preventing or reducing one or more side effects associated with the anti-cancer agent selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

4. The method of claim 2 or 3, wherein the subject experiences an increase in weight by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,Docket No.: 211Z-412981-WO 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% compared to baseline or a control.

5. A method of maintaining or increasing muscle mass, fat mass, or cardiac mass in a subject having colorectal cancer, prior to, during, and / or after administration of an anticancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

6. The method of claim 5, wherein the subject experiences an increase in muscle mass, fat mass, or cardiac mass by at least about 0.5%, 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

7. A method of maintaining or increasing bone density in a subject having colorectal cancer, prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

8. The method of claim 7, wherein the subject experiences an increase in bone density by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a baseline or a control.

9. A method of increasing or maintaining a Functional Assessment of Anorexia / Cachexia Therapy (FAACT) score in a subject having colorectal cancer, prior to, during, and / or after administration of an anti-cancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

10. The method of claim 9, wherein the subject experiences an increase in the FAACT score compared to baseline or control by at least 1, 2, 3, 4, or 5 points.

11. A method of stimulating appetite or reducing loss of appetite induced by an anti-cancer agent in a subject having colorectal cancer, comprising administering a nonDocket No.: 211Z-412981-WO naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

12. The method of claim 11, wherein the subject experiences an increase in appetite as measured by an increased food intake by about 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2500, 3000, or more calories compared to baseline a control.

13. A method of preventing, reducing, or restoring weight loss induced by an anticancer agent in a subject having colorectal cancer, comprising administering a non-naturally occurring melanocortin analog to the subject prior to, during, and / or after administration of the anti-cancer agent.

14. A method of preventing or reducing an anti-cancer agent induced side effect in a subject having cancer having colorectal cancer, comprising administering the anticancer agent and a non-naturally occurring melanocortin analog to the subject.

15. A method of treating, preventing, or reducing iatrogenic injury caused by an anti-cancer agent in a subject having colorectal cancer, comprising administering the anticancer agent and a non-naturally occurring melanocortin analog to the subject.

16. A method of preventing reduction of, maintaining, or improving Eastern Cooperative Oncology Group (ECOG) and / or Karnofsky performance status (KPS) score of a subject having colorectal cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

17. The method of claim 16, wherein the subject experiences a reduction in ECOG performance score by about 1, 2, or 3 compared to baseline or control.Docket No.: 211Z-412981-WO 18. The method of claim 16, wherein the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to baseline or control.

19. A method of preventing reduction of, maintaining, or improving overall survival (OS) or progression free survival (PFS) in a subject having colorectal cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

20. The method of claim 19, wherein the subject experiences an increase in OS or an increase in PFS compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

21. A method of reducing time to cancer treatment failure in a subject having cancer relative to a baseline or a control, comprising administering an anti-cancer agent and a non-naturally occurring melanocortin analog to the subject.

22. A method of increasing or maintaining body mass index (BMI) in a subject having colorectal cancer relative to a baseline or a control, comprising administering an anticancer agent and a non-naturally occurring melanocortin analog to the subject.

23. The method of claim 22, wherein the subject experiences an increase in BMI compared to baseline or control by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 points.

24. The method of claim 22 or 23, wherein the subject experiences an increase in BMI durability compared to baseline or control by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100%.

25. The method of any one of claims 1-24, wherein the method maintains or increases lean body mass, fat body mass, and / or weight of the subject relative to a baseline or a control.Docket No.: 211Z-412981-WO 26. The method of claim 14, wherein the side effect is selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, loss of appetite, vomiting, diarrhea, nausea, and fatigue.

27. The method of claim 16, wherein the improvement, maintenance, or prevented reduction of ECOG and / or KPS score occurs by inhibiting or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

28. A method of maintaining or increasing muscle mass, fat mass, or cardiac mass in a subject having colorectal cancer, prior to, during, and / or after administration of an anticancer agent, comprising administering a non-naturally occurring melanocortin analog to the subject.

29. The method of any one of claims 1-28, wherein the colorectal cancer is newly diagnosed colorectal cancer.

30. The method of any one of claims 1-28, wherein the colorectal cancer is newly diagnosed colorectal adenocarcinoma.

31. The method of any one of claims 1-28, wherein the colorectal cancer is metastatic colorectal cancer.

32. The method of claim 31, wherein the metastatic colorectal cancer is newly diagnosed metastatic colorectal cancer.

33. The method of claim 31, wherein the metastatic colorectal cancer is newly diagnosed colorectal adenocarcinoma.Docket No.: 211Z-412981-WO 34. The method of any one of claims 1-33, wherein the anti-cancer agent comprises a chemotherapy or a monoclonal antibody.

35. The method of any one of claims 1-34, wherein the non-naturally occurring melanocortin analog is administered in a dose of about 12.5 mg, 25 mg, 50 mg, or 75 mg.

36. The method of any one of claims 1-35, wherein the non-naturally occurring melanocortin analog is administered daily for a period of at least about 5 days to at least about 4-weeks.

37. A method of treating, preventing, or reducing one or more side effects associated with an anti-cancer agent in a subject having newly diagnosed colorectal adenocarcinoma, comprising administering a non-naturally occurring melanocortin analog having a sequence Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 in an amount of 12.5 mg, about 25 mg, or about 50 mg daily to the subject prior to, during, and / or after administration of the anti-cancer agent,wherein the one or more side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.

38. A method of maintaining or increasing weight in a subject having newly diagnosed colorectal adenocarcinoma, comprising administering a non-naturally occurring melanocortin analog having a sequence Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 in an amount of 12.5 mg, about 25 mg, or about 50 mg daily to the subject prior to, during, and / or after administration of the anti-cancer agent,wherein the weight of the subject is maintained or increased by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

39. A method of maintaining or increasing muscle mass, fat mass, cardiac mass, or bone density in a subject having newly diagnosed colorectal adenocarcinoma, comprisingDocket No.: 211Z-412981-WO administering a non-naturally occurring melanocortin analog having a sequence Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 in an amount of 12.5 mg, about 25 mg, or about 50 mg daily to the subject prior to, during, and / or after administration of the anti-cancer agent.

40. A method of increasing or maintaining a Functional Assessment of Anorexia / Cachexia Therapy (FAACT) score in a subject having newly diagnosed colorectal adenocarcinoma, comprising administering a non-naturally occurring melanocortin analog having a sequence Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 in an amount of 12.5 mg, about 25 mg, or about 50 mg daily to the subject prior to, during, and / or after administration of the anti-cancer agent.

41. A method of stimulating appetite or reducing loss of appetite induced by an anticancer agent in a subject having newly diagnosed colorectal adenocarcinoma, comprising administering a non-naturally occurring melanocortin analog having a sequence Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 in an amount of 12.5 mg, about 25 mg, or about 50 mg daily to the subject prior to, during, and / or after administration of the anti-cancer agent.

42. A method of preventing, reducing, or restoring weight loss induced by an anticancer agent in a subject having newly diagnosed colorectal adenocarcinoma, comprising administering a non-naturally occurring melanocortin analog having a sequence Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 in an amount of 12.5 mg, about 25 mg, or about 50 mg daily to the subject prior to, during, and / or after administration of the anti-cancer agent.

43. A method of preventing or reducing an anti-cancer agent induced side effect in a subject having newly diagnosed colorectal adenocarcinoma, comprising administering a non-naturally occurring melanocortin analog having a sequence Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-T rp-Lys]-dVal-dPro-NH2 in an amount of 12.5 mg, about 25 mg, or about 50 mg daily to the subject prior to, during, and / or after administration of the anti-cancer agent.Docket No.: 211Z-412981-WO 44. A method of preventing reduction of, maintaining, or improving Eastern Cooperative Oncology Group (ECOG), a Karnofsky performance status (KPS) score, an EORTIC QLQ-30 score, or a RECIST 1.1 score of in a subject having newly diagnosed colorectal adenocarcinoma, comprising administering a non-naturally occurring melanocortin analog having a sequence Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 in an amount of 12.5 mg, about 25 mg, or about 50 mg daily to the subject prior to, during, and / or after administration of the anti-cancer agent.

45. A method of preventing reduction of, maintaining, or improving overall survival (OS) or progression free survival (PFS) in a subject having newly diagnosed colorectal adenocarcinoma, comprising administering a non-naturally occurring melanocortin analog having a sequence Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 in an amount of 12.5 mg, about 25 mg, or about 50 mg daily to the subject prior to, during, and / or after administration of the anti-cancer agent.

46. A method of increasing or maintaining body mass index (BMI) in a subject having newly diagnosed colorectal adenocarcinoma, comprising administering a non-naturally occurring melanocortin analog having a sequence Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-T rp-Lys]-dVal-dPro-NH2 in an amount of 12.5 mg, about 25 mg, or about 50 mg daily to the subject prior to, during, and / or after administration of the anti-cancer agent.

47. The method of any one of claims 1-46, wherein the method reduces or prevents a chemotherapy induced mass loss and / or wasting in the subject and increases lean body mass and body weight of the subject relative to a baseline or a control.

48. The method of claim 47, wherein the method maintains or increases weight of the subject prior to, during, or after administration of the chemotherapy, and wherein the method reduces mass loss and / or wasting in the subject relative to a baseline or a control.

49. The method of any one of claims 1 -48, wherein the anorexia is associated with weight loss.Docket No.: 211Z-412981-WO 50. The method of any one of claims 1-49, wherein the subject has not previously received an anti-cancer agent.

51. The method of any one of claims 1-50, wherein the subject has previously received an anti-cancer agent.

52. The method of any one of claims 1 -51, wherein the subject is receiving an anticancer agent.

53. The method of any one of claims 1-52, wherein the administration of the non-naturally occurring melanocortin analog enhances tolerability of the anti-cancer agent.

54. The method of claim 53, wherein the enhanced tolerability results in a greater dosage, an increased frequency of administration, and / or an increased duration of administration of the anti-cancer agent, relative to a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

55. The method of claim 53, wherein the anti-cancer agent comprises a chemotherapy comprising at least two chemotherapeutic agents, and wherein the enhanced tolerability results in a second chemotherapeutic agent being administered to the subject during or after administration of a first chemotherapeutic agent.

56. The method of any one of claims 1-55, wherein the administration of the non-naturally occurring melanocortin analog prevents or reduces a downward titration in dosing regimen of the anti-cancer agent relative to a baseline or a control.

57. The method of claim 56, wherein the downward titration comprises a decreased dosage, a decreased frequency of administration, and / or a decreased duration of administration, compared to a baseline or control, wherein the baseline or control is theDocket No.: 211Z-412981-WO subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

58. The method of any one of claims 1-57, wherein the subject experiences loss of appetite, reduced appetite, decreased food consumption, and / or weight loss prior to the administration of the non-naturally occurring melanocortin analog.

59. The method of claim 58, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by cancer.

60. The method of claim 58, wherein the loss of appetite, reduced appetite, decreased food consumption, and / or weight loss is caused by the anti-cancer agent.

61. The method of any one of claims 1-60, wherein the non-naturally occurring melanocortin analog and the anti-cancer agent are administered concurrently.

62. The method of any one of claims 1-61, wherein the non-naturally occurring melanocortin analog is administered before and / or after the anti-cancer agent.

63. The method of any one of claims 1-62, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and / or loss of appetite in the subject.

64. The method of any one of claims 1-63, wherein administration of the non-naturally occurring melanocortin analog maintains or increases weight in the subject relative to a baseline or a control by preventing or reducing one or more side effects selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, reduced appetite, and loss of appetite.Docket No.: 211Z-412981-WO 65. The method of any one of claims 1-64, wherein administration of the non-naturally occurring melanocortin analog stimulates appetite or reduces loss of appetite induced by an anti-cancer agent in the subject relative to a baseline or a control.

66. The method of any one of claims 1-65, wherein administration of the non-naturally occurring melanocortin analog prevents, reduces, or restores weight loss induced by an anti-cancer agent in the subject relative to a baseline or a control.

67. The method of any one of claims 1-66, wherein administration of the non-naturally occurring melanocortin analog prevents reduction of, maintains, or improves an ECOG score, a KPS score, a EORTC QLQ-C30 score, a RECIST 1.1 score, a median overall survival (mOS) of the subject, relative to a baseline or a control.

68. The method of any one of claims 1-67, wherein administration of the non-naturally occurring analog reduces, maintains, or improves a mOS hazard ratio.

69. The method of any one of claims 1-68, wherein administration of the non-naturally occurring analog prevents reduction of, maintains, or improves an immunotherapy treatment response rate.

70. The method of any one of claims 1-69, wherein the subject’s mass and / or weight is not more than 5%-15% reduced from baseline prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

71. The method of any one of claims 1-70, wherein the subject has an ECOG score of 2 or less prior to administration of the non-naturally occurring melanocortin analog and / or the anti-cancer agent.

72. The method of claim 71, wherein the method lowers the ECOG score of the subject, relative to a baseline or a control. / / ilDocket No.: 211Z-412981-WO 73. The method of any one of claims 1-72, wherein the subject has a life expectancy of at least about 9 months or more.

74. The method of any one of claims 1 -73, wherein the subject has a BMI of up to about 33 kg / m2.

75. The method of any one of claims 1 -73, wherein the subject has a BMI of about 18 kg / m2to about 33 kg / m2.

76. The method of any one of claims 1 -73, wherein the subject has a BMI of about 18 kg / m2to about 29 kg / m2.

77. The method of any one of claims 1-76, wherein the subject has one or more of (i) an Absolute neutrophil count (ANC) > 1.5 x 109 / L; (ii) a platelet level > 100 x 109 / L; (iii) a hemoglobin level > 9 g / dL; (iv) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) level < 3 x upper limit of normal (ULN), where, if the subject has liver metastases, then < 5 x ULN; (v) a Bilirubin level < 1.5 x ULN or < 3 x ULN in the presence of documented Gilbert’s Syndrome; (vi) an albumin level between 3.4 and 5.4 g / dL or within an otherwise normal limit; (vii) a creatine clearance level > 50 mL / min; (viii) a normal hemoglobin A1c level; and (ix) an N-terminal pro b-type natriuretic peptide (NT-Pro-BNP) and / or a Troponin (Tnl, TnT) level within a normal limit.

78. The method of any one of claims 1 -77, wherein the subject is at least about 18 years of age or older.

79. The method of any one of claims 1-78, wherein the method increases the subject’s cumulative mass relative to a baseline or control.

80. The method of any one of claims 1-78, wherein the method reduces the subject’s rate of loss of cumulative mass relative to a baseline or control.Docket No.: 211Z-412981-WO 81. The method of any one of claims 1-78, wherein the method increases a net weight gain in the subject relative to a baseline or control.

82. The method of claim 81, wherein the net weight gain is the change in weight between two or more time points.

83. The method of claim 81 or 82, wherein the net weight gain is the change in weight between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

84. The method of claim 82, wherein the two or more time points comprises an intermediate time point.

85. The method of any one of claims 1-84, wherein the method increases the subject’s cumulative food intake relative to a baseline or control.

86. The method of claim 85, wherein the cumulative food intake is the total food intake between two or more time points.

87. The method of claim 85 or 86, wherein the cumulative food intake is the total in food intake between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

88. The method of claim 86, wherein the two or more time points comprises an intermediate time point.

89. The method of any one of claims 1-88, wherein the method increases the subject’s BMI relative to a baseline or control.Docket No.: 211Z-412981-WO 90. The method of claim 89, wherein the increase in BMI is the change in BMI between two or more time points.

91. The method of claim 89 or 90, wherein the increase in BMI is a change in BMI between the start of treatment and the end of treatment with the non-naturally occurring melanocortin analog or the anti-cancer agent.

92. The method of claim 90, wherein the two or more time points comprises an intermediate time point.

93. The method of any one of claims 89-92, wherein the non-naturally occurring melanocortin analog is administered to the subject based on the subject’s BMI at the time of administration.

94. The method of claim 93, wherein the subject is administered the non-naturally occurring melanocortin analog at two or more doses based on the subject’s BMI at the time of each administration.

95. The method of claim 94, wherein the two or more doses are inversely titrated based on the subject’s BMI at the time of each administration.

96. The method of any one of claims 1-95, wherein the subject administered the non-naturally occurring melanocortin analog (a) does not experience a worsening of, (b) experiences an improvement of, or (b) does not experience a change in, compared to baseline, a value selected from the group consisting of (i) a complete blood count level; (ii) Blood chemistries including: sodium (Na), potassium (K), chloride (Cl), carbon dioxide (CO2), creatinine, creatinine clearance (calculated by Cockcroft-Gault formula), glucose, hemoglobin A1c, and blood urea nitrogen (BUN); (iii) Clotting parameters (prothrombin time (PT), partial thromboplastin time (PTT), International normalized ratio (INR)); (iv) Fasting lipid profile; (v) Cardiac markers (N-terminal pro b-type natriuretic peptide [NT-Pro-BNP] and Troponins [Tnl, TnT]); (vi) CT or MRI scan assessments of measurable disease by RECISTliBilDocket No.: 211Z-412981-WO 1.1 criteria; (v) a body mass distribution; (vi) a change in the adrenal gland, heart, liver, pancreas, prostate gland, skeletal muscle, or spleen; (vii) a change or reaction at an injection site; or (viii) an organ failure.

97. The method of any one of claims 1-36 and 47-96, wherein the non-naturally occurring melanocortin analog comprises a sequence according to Formula (II),X1X2X3R1R2R3R4R5R6R7R8R9R10Y1Y2Y3Y4Y5Y6Y7(II) wherein:R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated D-norleucine (Ac-dNIe), acetylated trans-4-guanidinyl-proline (Ac-transPro(guan)), acetylated cis-4-guanidinyl-proline (Ac-cisPro(guan)), acetylated D-cysteine (Ac-dCys), tyrosine, D-tyrosine, di-methyl tyrosine (Dmt), aspartic acid, acetylated asparagine (Ac-Asn), acetylated D-arginine, acetylated arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Ac-Tle), acetylated D-tert-leucine (Ac-dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated glutamic acid, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine;R2is selected from the group consisting of proline, histidine, D-aspartic acid, aspartic acid, glutamic acid, lysine, alanine, D-alanine, tryptophan, cysteine, D-cysteine, CO-cis-CH=CH — CO, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen);R3is absent or is selected from the group consisting of histidine, D-proline, L-proline, hydroxyproline (Hyp), transPro(guan), cisPro(guan), alanine, D-alanine, D-methionine, valine, D-valine, glutamic acid, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), tryptylarginine (Trp-Arg), glycine, phenylalanine, D-leucine, leucine, D-isoleucine, isoleucine, tryptophan, D-tryptophan, arginine, 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba), beta-alanine ((3-Ala), 3-aminomethylbenzoic acid (Mamb), 1 -aminocyclopropane-1 -carboxylic acid (Acpc), 2-aminotetraline-2-carboxylic acid (Ate), 7-amino-7,8-dihydro-4H-(1,2,3)triazolo-(1,5-a)(1,4)diazepin-6(5H)-one (Ata), 4-amino-1,4,5,6-lililDocket No.: 211Z-412981-WO tetrahydroazepino(4,3-b)indol-3(2 / - / )-one (Aia), 1 -amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), octohydroindole-2-carboxylic acid (Oic), 1-amino-1 -cyclohexanecarboxylic acid (Che), tetrahydro-isoquinoline-3-carboxylic acid (Tic), indoline-2-carboxylic acid (loc), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1 -cyclopentane carboxylic (Cpe);R4is selected from the group consisting of D-phenylalanine, L-phenylalanine, D-Nal(2'), biphenylalanine (Bip), dBip, para-chloro-D-phenylalanine (p(CI)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), para-iodo-D-phenylalanine (p(l)dPhe), para-fluoro-D-phenylalanine (p(F)dPhe), and para-trifluoromethyl-D-phenylalanine (p(CF3)dPhe);R5is absent or is selected from the group consisting of arginine, ornithine, histidine, alanine, proline, transPro(guan), cisPro(guan), lysine, D-arginine, D-ornithine, D-histidine, D-alanine, D-lysine, glycine, aspartic acid, D-aspartic acid, glutamic acid, and D-glutamic acid;R6is absent or is selected from the group consisting of D-tryptophan, L-tryptophan, D-Nal(2'), Tic, histidine, D-histidine, Nal(1 ’), D-Nal(1 ’), Aia, D-phenylalanine, phenylalanine, Aba, Ata, tyrosine, D-tyrosine, alanine, and D-alanine;R7is absent or is selected from the group consisting of glycine, aspartic acid, cysteine, lysine, D-cysteine, D-lysine, 2,3-diamino-propionic acid (Dap), proline, D-Nal(2'), ornithine, D-ornithine, Pen, and dPen;R8is absent, lysine, or arginine;R9is absent or tryptophan;R10is absent or lysine;X1is absent or is selected from the group consisting of tyrosine, acetylated D-arginine, acetylated L-arginine, acetylated D-valine, and acetylated norleucine;X2is absent or is selected from the group consisting of D-proline, L-valine, phenylalanine, and norleucine;X3is absent, phenylalanine, or norleucine;liBllDocket No.: 211Z-412981-WO Y1is selected from the group consisting of D-alanine, L-alanine, D-valine, L-valine, D-leucine, D-tert-leucine, norleucine, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, L-arginine, D-arginine, L-asparagine, D-asparagine, L-lysine, D-lysine, and L-tryptophan;Y2is absent or is selected from the group consisting of D-proline, L-proline, D-valine, L-valine, D-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine;Y3is absent or is selected from the group consisting of D-lysine, L-lysine, D-proline, L-proline, D-valine, and L-valine;Y4is absent or is D-aspartic acid, aspartic acid, D-proline or D-valine;Y5is absent or D-valine;Y6is absent or D-valine;Y7is absent or D-proline;the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of:a disulfide bond between R1and R7when R1and R7are each cysteine;a disulfide bond between R2and R7when R2and R7are each independently selected from D-cysteine, cysteine, Pen, and dPen;a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH=CH — CO, and R7is lysine, D-lysine, Dap, D-ornithine, or ornithine;a side-chain lactam bridge between R2and R7when R2is lysine and R7is aspartic acid;a side-chain lactam bridge between R1or R2and R8when R1or R2is aspartic acid, R8is lysine, and R7is glycine or proline;a side-chain lactam bridge between R2and R10when R2is aspartic acid, R7is dNal(2’), and R10is lysine;liiilDocket No.: 211Z-412981-WO X1X2X3represents an optionally present N-terminus; andY1Y2Y3Y4Y5Y6Y7represents a C-terminus.

98. The method of any one of claims 1-36 and 47-97, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 3, 10, 14, 33-39, 82-96, 108-111, 119-124, 126-135, 138, 192-199, 222-295, 408 and 413.

99. The method of any one of claims 1-36 and 47-98, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-T rp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3).

100. The method of claim 33, wherein the chemotherapy comprises at least one chemotherapeutic agent.

101. The method of claim 100, wherein the at least one chemotherapeutic agent comprises one or more chemotherapeutic agents selected from the group consisting of a platinum-coordination complex, an antimetabolite, a tubulin binding agent or a plant alkaloid, an alkylating antineoplastic agent, a cytotoxic antibiotic, a FOLFOX regimen, a FOLFIRI regimen, and a FOLFIRINOX regimen.

102. The method of claim 101, wherein the FOLFOX regimen is selected from the group consisting of a FOLFOX-4, a FOLFOX-6, a modified FOLFOX-6 (mFOLFOX-6), and a FOLFOX-7103. The method of claim 101, wherein the FOLFIRINOX regimen comprises FOLFIRINOX with or without bevacizumab.

104. The method of claim 101, wherein the at least one chemotherapeutic agent comprises a platinum-coordination complex.Docket No.: 211Z-412981-WO 105. The method of claim 101, wherein the at least one chemotherapeutic agent comprises an antimetabolite.

106. The method of claim 101, wherein the at least one chemotherapeutic agent comprises a tubulin binding agent or a plant alkaloid.

107. The method of claim 101, wherein the at least one chemotherapeutic agent comprises an alkylating antineoplastic agent.

108. The method of claim 101, wherein the at least one chemotherapeutic agent comprises a cytotoxic antibiotic.

109. The method of claim 104, wherein the platinum-coordination complex is carboplatin and / or cisplatin.

110. The method of claim 105, wherein the antimetabolite is at least one selected from the group consisting of 5-fluorouracil (5-FU), 6-mercaptopurine, azacitidine, capecitabine, clofarabine, cytarabine, floxuridine, fludarabine, gemcitabine, methotrexate, pemetrexed, pentostatin, pralatrexate, trifluridine, and tipiracil.

111. The method of claim 106, wherein the tubulin binding agent or the plant alkaloid is at least one selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide, teniposide, irinotecan, and Topotecan.

112. The method of claim 107, wherein the alkylating antineoplastic agent is at least one selected from the group consisting of altretamine, busulfan, carmustine, cyclophosphamide, dacarbazine, ifosfamide, lomustine, melphalan, temozolomide, and trabectedin.Docket No.: 211Z-412981-WO 113. The method of claim 108, wherein the cytotoxic antibiotic is at least one selected from the group consisting of daunorubicin, doxorubicin, doxorubicin liposomal, epirubicin, idarubicin, and valrubicin.

114. The method of claim 104, wherein the platinum-coordination complex is cisplatin.

115. The method of claim 114, wherein the chemotherapy comprises cisplatin, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3).

116. The method of claim 105, wherein the antimetabolite is 5-fluorouracil (5-FU).

117. The method of claim 116, wherein the chemotherapy comprises 5-FU, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3).

118. The method of claim 106, wherein the tubulin binding agent or the plant alkaloid is vincristine.

119. The method of claim 107, wherein the alkylating antineoplastic agent is cyclophosphamide.

120. The method of claim 108, wherein the cytotoxic antibiotic is doxorubicin.

121. The method of claim 120, wherein the chemotherapy comprises doxorubicin, and the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3).Docket No.: 211Z-412981-WO 122. The method of any one of claims 1-121, wherein the method does not reduce efficacy of the anti-cancer agent.

123. The method of any one of claims 28-32, wherein the subject with a cancer has previously undergone a treatment with the anti-cancer agent.

124. The method of claim 123, wherein the subject has previously experienced one or more adverse side effects when treated with the anti-cancer agent, wherein the adverse side effects are selected from the group consisting of anorexia, weight loss, muscle mass loss, fat mass loss, wasting, and appetite reduction or loss of appetite.

125. The method of any one of claims 1-124, wherein the subject is a human.

126. The method of any one of claims 1-124, wherein the subject is an animal.

127. The method of any one of claims 1-27, wherein the muscle mass loss is cardiac muscle mass loss, skeletal muscle mass loss, or both.

128. The method of claim 127, wherein the cardiac muscle mass loss is determined by measuring change in heart weight.

129. The method of claim 128, wherein the skeletal muscle mass loss is determined by measuring change in gastrocnemius tissue weight.

130. The method of any one of claims 1 -27, wherein anorexia is determined by daily food intake, daily food consumption, and / or weekly food intake.

131. The method of claim 130, wherein the daily food intake is determined by total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 day.Docket No.: 211Z-412981-WO 132. The method of claim 130, wherein the daily food consumption is determined by the daily food intake normalized to daily body weight of the subject.

133. The method of claim 130, wherein the weekly food intake is determined total calories (kcal) consumed in 1 day or mass of food (grams or kilograms) consumed in 1 week.

134. The method of any one of claims 1 -27, wherein the weight loss is determined by daily body weight, and / or daily body weight gain.

135. The method of any one of claims 1-27, wherein the fat mass of the subject treated with the method is at least 10% to 100% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

136. The method of any one of claims 1 -27, wherein the heart weight of the subject treated with the method is at least 0.1% to 10% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

137. The method of any one of claims 1-27, wherein the gastrocnemius tissue weight of the subject treated with the method is at least 0.1 % to 10% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anti-cancer agent without the non-naturally occurring melanocortin analog.

138. The method of any one of claims 1-27, wherein the daily food intake of the subject treated with the method is at least 5% to 50% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturallyDocket No.: 211Z-412981-WO occurring melanocortin analog and / or a subject who is receiving or has received the anticancer agent without the non-naturally occurring melanocortin analog.

139. The method of any one of claims 1-27, wherein the daily body weight of the subject treated with the method is at least 1% to 15% greater than a baseline or control, wherein the baseline or control is the subject prior to the administration of the non-naturally occurring melanocortin analog and / or a subject who is receiving or has received the anticancer agent without the non-naturally occurring melanocortin analog.

140. The method of any one of claims 1-27, wherein appetite of the subject is increased by at least 10% to 200% after the administration of the non-naturally occurring melanocortin analog.

141. The method of any one of claims 1-27, wherein appetite of the subject is increased by at least 25% to 100% after the administration of the non-naturally occurring melanocortin analog.

142. The method of claim 140 or 141, wherein appetite is increased for at least 1 day, 1 week, 1 month, 3 months, 4 months, 6 months, 1 year, or 5 years during the administration.

143. The method of claim 140 or 141, wherein appetite is increased for at least 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 84 days, 90 days, 100 days, 110 days, or 120 days during the administration.

144. The method of any one of claims 140-143, wherein the increased appetite is maintained for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 1 month, 3 months, 4 months, 6 months, 1 year, or 5 years, after the administration is stopped.Docket No.: 211Z-412981-WO 145. The method of any one of claims 140-144, wherein the appetite is assessed by a scale for measuring desire to eat, feeling of hunger, and / or level of satiety.

146. The method of claim 145, wherein the appetite is assessed between meals.

147. The method of any one of claims 140-145, wherein the subject comprises two or more subjects, and wherein the appetite is an average appetite of the two or more subjects.

148. The method of any one of claims of 1 -58, wherein the non-naturally occurring melanocortin analog is administered to the subject as a daily dose of about 0.5 mg to about 100 mg.

149. The method of claim 148, wherein the non-naturally occurring melanocortin analog is administered to the subject as a daily dose of 12.5 mg, 25 mg, or 50 mg.

150. The method of claim 149, wherein the non-naturally occurring melanocortin analog is administered to the subject for a period of at least about 4 weeks.

151. The method of any one of claims 1-150, wherein the anti-cancer agent is administered to the subject every 2-weeks.

152. The method of any one of claims 1-151, wherein the non-naturally occurring melanocortin analog is present in a pharmaceutical composition.

153. The method of claim 152, wherein the pharmaceutical composition further comprises a pharmaceutical salt.

154. The method of claim 152, wherein the pharmaceutical composition further comprises a pharmaceutical carrier.Docket No.: 211Z-412981-WO 155. The method of claim 152, wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the pharmaceutical composition.

156. The method of claim 155, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-l_ys]-dVal-dPro-NH2(SEQ ID NO: 3), and wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the pharmaceutical composition.

157. The method of claim 156, wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the pharmaceutical composition.

158. The method of claim 157, wherein the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the pharmaceutical composition.

159. The method of any one of claims 1-158, wherein the non-naturally occurring melanocortin analog is administered via intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, intranasal, or oral administration.

160. The method of any one of claims 152-158, wherein the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is administered to the subject parenterally.

161. The method of any one of claims 152-158, wherein the pharmaceutical composition comprising the non-naturally occurring melanocortin analog is administered to the subject subcutaneously.Docket No.: 211Z-412981-WO 162. The method of any one of claims 1-161, wherein the non-naturally occurring melanocortin analog crosses the blood-brain-barrier of the subject.

163. The method of claim 154, wherein the pharmaceutical carrier comprises water.

164. The method of any one of claims 1-163, wherein the non-naturally occurring melanocortin analog is administered to a subject prior to or after a meal.

165. The method of any one of claims 1-163, wherein the non-naturally occurring melanocortin analog is administered to a subject with a meal.

166. The method of any one of claims 1-165, wherein a therapeutically effective amount of the non-naturally occurring melanocortin analog is administered, and wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

167. The method of any one of claims 1 -166, wherein the therapeutically effective amount of the non-naturally occurring melanocortin analog is from 0.5 mg / kg to 10 mg / kg per body weight of the subject.

168. The method of any one of claims 1-167, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

169. The method of any one of claims 1-167, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg per body weight of the subject.

170. The method of claim 169, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2Docket No.: 211Z-412981-WO (SEQ ID NO: 3), and the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

171. The method of claim 169, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-l_ys]-dVal-dPro-NH₂ (SEQ ID NO: 3), and the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.5 mg / kg to 10 mg / kg per body weight of the subject.

172. The method of any one of claims 1-171, wherein the non-naturally occurring melanocortin analog is administered to the subject for at least 1 day, 1 week, 28 days, 1 month, 3 months, 4 months, 6 months, 1 year, or 5 years.

173. The method of any one of claims 1-171, wherein the non-naturally occurring melanocortin analog is administered to the subject for 1 day, 5 days, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 84 days, 90 days, 100 days, 110 days, or 120 days.

174. The method of any one of claims 1 -173, wherein the anti-cancer agent and the non-naturally occurring melanocortin analog are administered simultaneously as a single composition.

175. The method of claim 174, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the single composition.

176. The method of claim 175, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3), and wherein the non-naturally occurring melanocortin analog is present inDocket No.: 211Z-412981-WO the single composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the single composition.

177. The method of claim 176, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the single composition.

178. The method of claim 176, wherein the non-naturally occurring melanocortin analog is present in the single composition in a concentration of about 50 mg / mL, relative to a total volume of the single composition.

179. The method of claim 176, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

180. The method of claim 176, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

181. The method of claim 176, wherein the non-naturally occurring melanocortin analog is present in the single composition at a dose of about 75 mg in a dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

182. The method of any one of claims 179-181, wherein the administration is performed once per day.Docket No.: 211Z-412981-WO 183. The method of any one of claims 1-182, wherein:the anti-cancer agent is present in a first pharmaceutical composition; and the non-naturally occurring melanocortin analog is present in a second pharmaceutical composition.

184. The method of claim 183, wherein the first and the second pharmaceutical compositions are different and are administered sequentially.

185. The method of claim 183, wherein the first and the second pharmaceutical compositions are different and are administered simultaneously but separately.

186. The method of any one of claims 183-185, wherein the second pharmaceutical composition is administered subcutaneously.

187. The method of any one of claims 183-186, wherein the anti-cancer agent comprises a chemotherapy, and the chemotherapy is present in the first pharmaceutical composition in a concentration of 0.001 mg / mL to 1,000 mg / mL, relative to a total volume of the first pharmaceutical composition.

188. The method of claim 187, wherein the chemotherapy is cisplatin, and cisplatin is present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 50 mg / mL, relative to a total volume of the first pharmaceutical composition.

189. The method of claim 187, wherein the chemotherapy is 5-FU, and 5-FU is present in the first pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the first pharmaceutical composition.

190. The method of claim 187, wherein the chemotherapy is doxorubicin, and doxorubicin is present in the first pharmaceutical composition in a concentration of 0.01 mg / mL to 50, relative to a total volume of the first pharmaceutical composition.Docket No.: 211Z-412981-WO 191. The method of claim 183, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 0.1 mg / mL to 500 mg / mL, relative to a total volume of the second pharmaceutical composition.

192. The method of claim 191, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 3), and wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of 5 mg / mL to 100 mg / mL, relative to a total volume of the second pharmaceutical composition.

193. The method of claim 192, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, or about 60 mg / mL, relative to a total volume of the second pharmaceutical composition.

194. The method of claim 192, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition in a concentration of about 50 mg / mL, relative to a total volume of the second pharmaceutical composition.

195. The method of claim 183, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 5 mg to about 500 mg in a dose volume of about 1 mL to 20 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

196. The method of claim 183, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 50 mg to about 100 mg in a dose volume of about 2 mL to 10 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

197. The method of claim 183, wherein the non-naturally occurring melanocortin analog is present in the second pharmaceutical composition at a dose of about 75 mg in aDocket No.: 211Z-412981-WO dose volume of about 5 mL, and wherein the administration is performed once, twice, 3 times, 4 times, 5 times, or 10 times per day.

198. The method of any one of claims 195-197, wherein the administration is performed once per day.

199. The method of claim 183, wherein the anti-cancer agent comprises cisplatin, and wherein cisplatin is administered orally and / or intraperitoneally.

200. The method of claim 183, wherein the anti-cancer agent comprises 5-FU, and wherein 5-FU is administered orally and / or intraperitoneally.

201. The method of claim 183, wherein the anti-cancer agent comprises doxorubicin, and wherein doxorubicin is administered intraperitoneally.

202. The method of claim 183, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NOS).

203. The method of any one of claims 183-202, wherein a therapeutically effective amount of the anti-cancer agent is administered at least once per week.

204. The method of claim 203, wherein the anti-cancer agent comprises cisplatin, and the therapeutically effective amount of cisplatin is from 0.01 mg / kg to 25 mg / kg per body weight of the subject.

205. The method of claim 204, wherein the therapeutically effective amount of cisplatin is about 2.5 mg / kg per body weight of the subject.Docket No.: 211Z-412981-WO 206. The method of claim 203, wherein the anti-cancer agent comprises 5-FU, and the therapeutically effective amount of 5-FU is from 0.1 mg / kg to 700 mg / kg per body weight of the subject.

207. The method of claim 206, wherein the therapeutically effective amount of 5-FU is about 70 mg / kg per body weight of the subject.

208. The method of claim 203, wherein the anti-cancer agent comprises doxorubicin, and the therapeutically effective amount of doxorubicin is from 0.005 mg / kg to 50mg / kg per body weight of the subject.

209. The method of claim 208, wherein the therapeutically effective amount of doxorubicin is about 2 mg / kg per body weight of the subject.

210. The method of any one of claims 203-209, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg per body weight of the subject.

211. The method of any one of claims 203-209, wherein the non-naturally occurring melanocortin analog is administered at least once daily in an amount ranging from about 0.5 mg / kg to about 10 mg / kg per body weight of the subject.

212. The method of claim 183, wherein the anti-cancer agent comprises cisplatin, and cisplatin is administered at a dose of 0.01 mg / kg to 25 mg / kg per body weight of the subject at intervals of about 7 days, about 14 days, about 21 days, or about 28 days.

213. The method of claim 183, wherein the anti-cancer agent comprises 5-FU, and 5-FU is administered at a dose of 0.1 mg / kg to 700 mg / kg per body weight of the subject at intervals of about 7 days, about 14 days, about 21 days, or about 28 days.Docket No.: 211Z-412981-WO 214. The method of claim 183, wherein the non-naturally occurring melanocortin analog comprises a sequence of Ac-Nle-c[Asp-Pro-dNal(2’)-Arg-Trp-Lys]-dVal-dPro-NH₂ (SEQ ID NO: 3), and the non-naturally occurring melanocortin analog is administered at a daily dose of 0.001 mg / kg to 25 mg / kg per body weight of the subject.

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