Methods of preventing and / or treating side effects associated with Anti-cancer agents using non-naturally occurring melanocortin analogs with Anti-gdf-15 antibodies

Abstract

Provided herein are compositions comprising a combination of a non-naturally occurring melanocortin analog, and a spiro compound and / or an antibody or antigen binding fragment thereof. The composition may further include an anti-cancer agent (e.g., a chemotherapeutic agent). Also provided herein are pharmaceutical compositions incorporating the composition, methods of using the same to regulate weight, including but not limited to increasing appetite, preventing appetite loss, promoting weight gain, preventing weight loss, and / or treating, preventing, or otherwise reducing cachexia and / or anorexia in a subject in need thereof.

Description

METHODS OF PREVENTING AND / OR TREATING SIDE EFFECTS ASSOCIATED WITH ANTI-CANCER AGENTS USING NON- NATURALLY OCCURRING MELANOCORTIN ANALOGS WITH ANTI-GDF-15 ANTIBODIES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 485,867 filed February 17, 2023, U.S. Provisional Patent Application No. 63 / 453,664, filed March 21, 2023, and U.S. Provisional Patent Application No. 63 / 514,271, filed July 18, 2023. The contents of each of these provisional applications are incorporated by reference in their entirety. SEQUENCE LISTING INCORPORATED BY REFERENCE

[0002] This application contains an ST.26 compliant Sequence Listing, which is submitted concurrently in .xml format via Patent Center and is hereby incorporated by reference in its entirety. The .xml copy, created on February 16, 2024, is named 146316_8009_WO00_SL.xml and is 1,382,825 bytes in size. TECHNICAL FIELD

[0003] Described herein are compositions comprising a combination of non- naturally occurring melanocortin analogs, and spiro compounds and / or an Anti-GDF-15 antibody or antigen binding fragments thereof, and methods of using the same. BACKGROUND

[0004] Melanocortin analogs have been synthesized for the potential regulation and treatment of many conditions, including weight regulation (e.g., obesity, anorexia, and cachexia), hormonal secretion, and hyposecretion of many exocrine glands (e.g., Sjogren's syndrome), immuno-relevant conditions, and sexual dysfunction.

[0005] Loss of appetite (e.g., anorexia), if left untreated, may lead to fatigue, malnutrition, weight loss, decreased muscle or fat mass, and decline in overall physical condition. Decreased appetite and / or weight loss are symptoms of cachexia, including cancer cachexia, and may have adverse effects on quality of life and survival of patients. -1- 146316.8009.WO00\165259190.24

[0006] Despite recent advances, there is still a need to develop more effective therapeutics for treating patients experiencing decreased appetite and / or weight loss. There is also a need for appetite stimulation therapies that are more selective, less toxic, and may effectively promote appetite, increase food consumption, and increase body weight (e.g., muscle mass, fat mass) in patients in need thereof.

[0007] The use of anti-cancer agents, including chemotherapeutic agents, is often restricted because of related side effects such as anorexia, emesis, weight loss, fat and muscle wasting, and fatigue. Such restrictions on use may include limited duration of cancer treatment and dosages of anti-cancer therapies. Accordingly, these side effects limit treatment tolerance and reduce quality of life in cancer patients. Despite recent advances in cancer treatment, there is a demand for novel therapies with robust activity that reduce adverse side effects of cancer therapies. SUMMARY

[0008] In some embodiments, the present technology comprises a composition, comprising: a first compound comprising a non-naturally occurring melanocortin analog comprising 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 cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D- asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, -2- 146316.8009.WO00\165259190.24norleucine, 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), alanine, D-alanine, D- methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4- aminophenylpiperidine-4-carboxylic acid (APPC), 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), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-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, and acetylated norleucine; -3- 146316.8009.WO00\165259190.24X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-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, 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, 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-proline, L-proline, D- valine, and L-valine; Y4is absent or is 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; a side-chain lactam bridge between R1or R2and R8when R1or R2is glutamic acid or aspartic acid, R8is lysine, and R7is proline, glycine or tryptophan; -4- 146316.8009.WO00\165259190.24a side-chain lactam bridge between R2or R4and R10when R2is glutamic acid or aspartic acid and R10is lysine; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys (SEQ ID NO: 661), then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent, and a second compound and / or a third compound, wherein the second compound comprises a structure according to Formula (X) or aRx1is H, halogen, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, 4- to 7- memberedocycloalkyl, phenyl, or Rx1a, wherein each of the C3-6 cycloalkyl and 4- to 7- memberedocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected C1-4 alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 -5- 146316.8009.WO00\165259190.24independently selected RxB, wherein RxBis halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-4cycloalkyl, or RxB1; or two adjacent RxBtogether with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; Rx1ais 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independent RxA, wherein each RxAis halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C14 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, -N(C1-4 alkyl)2, RxA1, or (C3-4 cycloalkyl)- C14alkyl-, wherein each of the C14alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; or two adjacent RxAtogether with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6- membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6- membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1- 4 alkoxy, and C1-4 haloalkoxy; RxA1is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4 haloalkoxy; RxB1is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; each of Rx2and Rx3is independently H, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4haloalkyl, (C1-4alkoxy)-C1-4alkyl-, C3-4cycloalkyl, or (C3-4cycloalkyl)-C1-4alkyl, wherein each of C3-4 cycloalkyl and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or Rx2and Rx3together with the carbon atom to which they are attached form C3-6 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; -6- 146316.8009.WO00\165259190.24each Rx4is independently H, halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4haloalkoxy, -N(C1-2alkyl)2, C3-4cycloalkyl, or (C3-4cycloalkyl)-C1-4 alkyl-, wherein each of the C1-4 alkyl, C3-4 cycloalkyl, and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy Xx1is C(RxX)2, wherein each RxXis independently H or C1-4alkyl; and each of Yx1, Yx2, Yx3, Yx4, and Yx5is independently CR4or N, provided that no more than 3 of Yx1, Yx2, Yx3, Yx4, and Yx5are N, and wherein the third compound comprises an antibody, or antigen binding fragment thereof, that specifically binds to human growth differentiation factor 15 (GDF- 15), comprising at least one of the following: a) a light chain complementarity determining region 1 (LCDR-1) comprising the amino acid sequence of SEQ ID NO:95, a LCDR-2 comprising the amino acid sequence of SEQ ID NO:28, a LCDR-3 comprising the amino acid sequence of SEQ ID NO:9, a heavy chain complementarity determining region 1 (HCDR-1) comprising the amino acid sequence of SEQ ID NO:32, a HCDR-2 comprising the amino acid sequence of SEQ ID NO:165, and a HCDR-3 comprising the amino acid sequence of SEQ ID NO:52; b) LCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) a LCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) a LCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) a HCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) a HCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) a HCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173, and 181; -7- 146316.8009.WO00\165259190.24h) the HCDR-1, HCDR-2, and HCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:163; i) the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:166, and a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:163; k) a VHcomprising the amino acid sequence of SEQ ID NO:166 and a VLcomprising the amino acid sequence of SEQ ID NO:163; l) a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:164, and a light chain (LC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:162; m) a HC comprising the amino acid sequence of SEQ ID NO:164, and a LC comprising the amino acid sequence of SEQ ID NO:162; andGDF-15 n) an antibody that competes for binding to GDF-15 with at least one antibody from (a)-(m) above.

[0009] In some embodiments, the present technology comprises a composition, comprising: a first compound comprising a non-naturally occurring melanocortin analog comprising a sequence according to Formula (I), X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8(I) R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- -8- 146316.8009.WO00\165259190.24phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D- asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, 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), alanine, D-alanine, D- methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4- aminophenylpiperidine-4-carboxylic acid (APPC), 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), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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-R20are absent; -9- 146316.8009.WO00\165259190.24X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-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, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-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, 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, 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-proline, L-proline, D- valine, and L-valine; Y4is absent or is 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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; -10- 146316.8009.WO00\165259190.24a side-chain lactam bridge between R1or R2and R7when R1or R2is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO, and R7is lysine or ornithine; 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; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent, and a second compound comprising a structure according to Formula (X) or aRx1is H, halogen, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, 4- to 7- memberedocycloalkyl, phenyl, or Rx1a, wherein each of the C3-6 cycloalkyl and 4- to 7- -11- 146316.8009.WO00\165259190.24memberedocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected C1-4alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 independently selected RxB, wherein RxBis halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-4cycloalkyl, or RxB1; or two adjacent RxBtogether with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; Rx1ais 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independent RxA, wherein each RxAis halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C14 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, -N(C1-4 alkyl)2, RxA1, or (C3-4 cycloalkyl)- C14alkyl-, wherein each of the C14alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; or two adjacent RxAtogether with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6- membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6- membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1- 4 alkoxy, and C1-4 haloalkoxy; RxA1is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4 haloalkoxy; RxB1is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; each of Rx2and Rx3is independently H, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4haloalkyl, (C1-4alkoxy)-C1-4alkyl-, C3-4cycloalkyl, or (C3-4cycloalkyl)-C1-4alkyl, wherein each of C3-4 cycloalkyl and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; -12- 146316.8009.WO00\165259190.24or Rx2and Rx3together with the carbon atom to which they are attached form C3-6cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each Rx4is independently H, halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, -N(C1-2 alkyl)2, C3-4 cycloalkyl, or (C3-4 cycloalkyl)-C1-4alkyl-, wherein each of the C1-4alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy Xx1is C(RxX)2, wherein each RxXis independently H or C1-4 alkyl; and each of Yx1, Yx2, Yx3, Yx4, and Yx5is independently CR4or N, provided that no more than 3 of Yx1, Yx2, Yx3, Yx4, and Yx5are N.

[0010] In some embodiments, the present technology comprises a composition, comprising: a first compound comprising a non-naturally occurring melanocortin analog comprising 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 cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D- asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, 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), alanine, D-alanine, D- -13- 146316.8009.WO00\165259190.24methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4- aminophenylpiperidine-4-carboxylic acid (APPC), 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), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-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, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L- leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and norleucine; -14- 146316.8009.WO00\165259190.24X3is 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, 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, 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-proline, L-proline, D- valine, and L-valine; Y4is absent or is 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; provided that: when R2is dAsp, then R7is not dLys; -15- 146316.8009.WO00\165259190.24when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent, and a third compound comprising an antibody, or antigen binding fragment thereof, that specifically binds to human growth differentiation factor 15 (GDF-15), comprising at least one of the following: a) a light chain complementarity determining region 1 (LCDR-1) comprising the amino acid sequence of SEQ ID NO:95, a LCDR-2 comprising the amino acid sequence of SEQ ID NO:28, a LCDR-3 comprising the amino acid sequence of SEQ ID NO:9, a heavy chain complementarity determining region 1 (HCDR-1) comprising the amino acid sequence of SEQ ID NO:32, a HCDR-2 comprising the amino acid sequence of SEQ ID NO:165, and a HCDR-3 comprising the amino acid sequence of SEQ ID NO:52; b) LCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) a LCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) a LCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) a HCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; -16- 146316.8009.WO00\165259190.24f) a HCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) a HCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173, and 181; h) the HCDR-1, HCDR-2, and HCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:163; i) the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:166, and a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:163; k) a VH comprising the amino acid sequence of SEQ ID NO:166 and a VL comprising the amino acid sequence of SEQ ID NO:163; l) a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:164, and a light chain (LC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:162; m) a HC comprising the amino acid sequence of SEQ ID NO:164, and a LC comprising the amino acid sequence of SEQ ID NO:162; and n) an antibody that competes for binding to GDF-15 with at least one antibody from (a)-(m) above.

[0011] In some embodiments, the present technology comprises a composition, comprising: a first compound comprising a non-naturally occurring melanocortin analog comprising a sequence according to Formula (I), X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8(I) wherein: -17- 146316.8009.WO00\165259190.24R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D- asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, 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), alanine, D-alanine, D- methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4- aminophenylpiperidine-4-carboxylic acid (APPC), 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), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; -18- 146316.8009.WO00\165259190.24R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-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, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-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, 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, 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-proline, L-proline, D- valine, and L-valine; Y4is absent or is 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; -19- 146316.8009.WO00\165259190.24the non-naturally occurring melanocortin analog is optionally cyclized through a moiety selected from the group consisting of: a disulfide bond between R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent, a second compound comprising a structure according to Formula (X): -20- 146316.8009.WO00\165259190.24or a pharm Rx1is H, halogen, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, 4- to 7- memberedocycloalkyl, phenyl, or Rx1a, wherein each of the C3-6cycloalkyl and 4- to 7- memberedocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected C1-4alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 independently selected RxB, wherein RxBis halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-4cycloalkyl, or RxB1; or two adjacent RxBtogether with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; Rx1ais 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independent RxA, wherein each RxAis halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C14 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, -N(C1-4 alkyl)2, RxA1, or (C3-4 cycloalkyl)- C14 alkyl-, wherein each of the C14 alkyl, C3-4 cycloalkyl, and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or two adjacent RxAtogether with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6- membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6- membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; RxA1is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently -21- 146316.8009.WO00\165259190.24selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4haloalkoxy; RxB1is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each of Rx2and Rx3is independently H, halogen, C1-4alkyl, C1-4hydroxyalkyl, C1-4 haloalkyl, (C1-4 alkoxy)-C1-4 alkyl-, C3-4 cycloalkyl, or (C3-4 cycloalkyl)-C1-4 alkyl, wherein each of C3-4cycloalkyl and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; or Rx2and Rx3together with the carbon atom to which they are attached form C3-6cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each Rx4is independently H, halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, -N(C1-2 alkyl)2, C3-4 cycloalkyl, or (C3-4 cycloalkyl)-C1-4alkyl-, wherein each of the C1-4alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy Xx1is C(RxX)2, wherein each RxXis independently H or C1-4 alkyl; each of Yx1, Yx2, Yx3, Yx4, and Yx5is independently CR4or N, provided that no more than 3 of Yx1, Yx2, Yx3, Yx4, and Yx5are N, and a third compound comprising an antibody, or antigen binding fragment thereof, that specifically binds to human growth differentiation factor 15 (GDF-15), comprising at least one of the following: a) a light chain complementarity determining region 1 (LCDR-1) comprising the amino acid sequence of SEQ ID NO:95, a LCDR-2 comprising the amino acid sequence of SEQ ID NO:28, a LCDR-3 comprising the amino acid sequence of SEQ ID NO:9, a heavy chain complementarity determining region 1 (HCDR-1) comprising the amino acid sequence of SEQ ID NO:32, a HCDR-2 comprising the amino acid sequence of SEQ ID NO:165, and a HCDR-3 comprising the amino acid sequence of SEQ ID NO:52; b) LCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; -22- 146316.8009.WO00\165259190.24c) a LCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) a LCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) a HCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) a HCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) a HCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173, and 181; h) the HCDR-1, HCDR-2, and HCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:163; i) the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:166, and a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:163; k) a VHcomprising the amino acid sequence of SEQ ID NO:166 and a VLcomprising the amino acid sequence of SEQ ID NO:163; l) a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:164, and a light chain (LC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:162; m) a HC comprising the amino acid sequence of SEQ ID NO:164, and a LC comprising the amino acid sequence of SEQ ID NO:162; GDF-15and n) an antibody that competes for binding to GDF-15 with at least one antibody from (a)-(m) above.

[0012] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by a functional group selected from the -23- 146316.8009.WO00\165259190.24group consisting of an acyl group, an imine group, an amide group, a urea group, a carbamate group, a sulfonamide group, and an alkylamine group.

[0013] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group.

[0014] In some embodiments, the acyl group is acetyl group.

[0015] In some embodiments, the acyl group is formyl group.

[0016] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an imine group.

[0017] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an amide group.

[0018] In some embodiments, the amide group is a pyroglutamyl (pGlu) group.

[0019] In some embodiments, the amide group is derived from a fatty acid.

[0020] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.

[0021] 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.

[0022] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group.

[0023] In some embodiments, the amide group is an -NHalkyl amide group or an -NHaryl amide group.

[0024] In some embodiments, the -NHaryl amide group is p-nitroanilide group or 7-amino-4-methylcoumarin.

[0025] In some embodiments, C-terminus of the non-naturally occurring melanocortin analog is modified by an ester group.

[0026] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified.

[0027] In some embodiments, R1is absent, and R2is D-aspartic acid.

[0028] In some embodiments, X1, X2, and X3are absent. -24- 146316.8009.WO00\165259190.24

[0029] In some embodiments, R4is not D-phenylalanine.

[0030] In some embodiments, R4is dNal(2′).

[0031] In some embodiments, Y3-Y8are absent. In some embodiments, Y1is D-valine and Y2is D-proline; or Y1is D-proline and Y2is D-valine.

[0032] In some embodiments, Y3is present and Y4-Y8are absent. In some embodiments, Y1is D-valine or D-proline; Y2is D-valine or D-proline; and / or Y3is D-valine or D-proline. In some embodiments, Y1is D-valine, Y2is D-valine, and Y3is D-proline; Y1is D-proline, Y2is D-valine, and Y3is D-valine; Y1is D-valine, Y2is D-proline, and Y3is D-valine; or Y1is D-proline, Y2is D-valine, and Y3is D-proline.

[0033] In some embodiments, Y3and Y4are present, and Y5-Y8are absent. In some embodiments, Y1is D-valine or D-proline; Y2is D-valine or D-proline; Y3is D-valine or D-proline; and / or Y4is D-valine or D-proline. In some embodiments, Y1is D-valine, Y2is D-valine, Y3is D-valine, and Y4is D-proline; Y1is D-proline, Y2is D-valine, Y3is D-valine, and Y4is D-valine; Y1is D-valine, Y2is D-proline, Y3is D-valine, and Y4is D-valine; Y1is D-valine, Y2is D-valine, Y3is D-proline, and Y4is D-valine; or Y1is D-valine, Y2is D-proline, Y3is D-valine, and Y4is D-proline.

[0034] 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; -25- 146316.8009.WO00\165259190.24R3is selected from the group consisting of proline, hydroxyproline, and hydroxy- D-proline; R4is D-Nal(2′); R5is arginine; R6is D-tryptophan or L-tryptophan; R7is lysine; Y1is D-valine; and / or Y2is D-proline.

[0035] 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: 306; B07) or Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 307; D3), wherein c represents cyclization through R2and R7via a lactam bond.

[0036] In some embodiments, R1, R2, R7, and R8are present and R9-R20are absent, and the sequence of Formula (I) is cyclized through R2and R8via a lactam bond. In some embodiments, R1is acetylated norleucine; R2is aspartic acid; R3is selected from the group consisting of proline, hydroxyproline, hydroxy-D- proline, phenylalanine, and histidine; R4is histidine or D-Nal(2′); R5is D-Nal(2′) or arginine; R6is selected from the group consisting of arginine, D-tryptophan, and L- tryptophan; R7is tryptophan or proline; R8is lysine; Y1is selected from the group consisting of D-valine, D-leucine, and D-isoleucine; and / or Y2is D-proline.

[0037] 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: 308; D1); Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 309; D1γ); -26- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO: 310; D1δ); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 311; D2); and Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO: 312; D4), wherein c represents cyclization through R2and R8via a lactam bond.

[0038] In some embodiments, R1-R2and R7-R10are present and R11-R20are absent, and the sequence of Formula (I) is cyclized through R2and R10via a lactam bond.

[0039] 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: 313; D1α), wherein c represents cyclization through R2and R10via a lactam bond.

[0040] In some embodiments, R1-R2and R7-R10are present and R11-R20are absent, and the sequence of Formula (I) is cyclized through R4and R10via a lactam bond.

[0041] 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: 314; D1β), wherein c represents cyclization through R4and R10via a lactam bond.

[0042] In some embodiments, the sequence of Formula (I) is Ac-Nle-c(Asp-Pro- dNal(2')-Arg-Trp-Lys)-dVal-dPro (SEQ ID NO: 305; B07a), wherein c represents cyclization through R2and R7via a lactam bond.

[0043] In some embodiments, the sequence of Formula (I) is linear.

[0044] In some embodiments, the sequence of Formula (I) is Ac-Nle-Asp-Pro- dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2(SEQ ID NO: 315; A1).

[0045] 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: 316); Ac-dMet-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 317); Ac-dIle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 318); Ac-dLeu-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 319); Ac-dVal-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 320); Ac-dAla-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 321); Ac-Ala-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 322); -27- 146316.8009.WO00\165259190.24Ac-Tle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 323); Ac-dTle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 324); Ac-dNle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 325); Ac-Nva-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 326); Ac-Gly-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 327); Ac-dPro-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 328); Ac-dCys-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 329); Ac-dPhe-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 330); Ac-dTyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 331); Ac-dGln-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 332); and Ac-dAsn-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 333), wherein c represents cyclization through R2and R7via a lactam bond.

[0046] 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: 334); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 335); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 336); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 337); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 338); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 339); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 340); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 341); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 342); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 343); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 344); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 345); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 346); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 347); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 348); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 349); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 350); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO: 351); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 352); -28- 146316.8009.WO00\165259190.24Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 353); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 354); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 355); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 356); Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 357); Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO: 358); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 359); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO: 360); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO: 361); Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO: 362); and Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2 (SEQ ID NO: 363), wherein c represents cyclization through R2and R6or R7via a lactam bond or a disulfide bond.

[0047] 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: 364); Ac-Nle-c(Asp-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 365); Ac-Nle-c(Asp-dPro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 366); Ac-Nle-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 367); Ac-Nle-c(Asp-dMet-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 368); Ac-Nle-c(Asp-Pro-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 369); Ac-Nle-c(Asp-Gly-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 370); Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 371); Ac-Nle-c(Asp-Leu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 372); Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 373); and Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 374), wherein c represents cyclization through R2and R7via a lactam bond.

[0048] In 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: 375); Ac-Nle-c(Asp-Pro-dNal(2’)-Lys-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 376); Ac-Nle-c(Asp-Pro-dNal(2’)-dLys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 377); Ac-Nle-c(Asp-Pro-dNal(2’)-dArg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 378); -29- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-dNal(2’)-Orn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 379); Ac-Nle-c(Asp-Pro-dNal(2’)-dOrn-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 380); Ac-Nle-c(Asp-Pro-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 381); Ac-Nle-c(Asp-Pro-dNal(2’)-Ala-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 382); Ac-Nle-c(Asp-Pro-dNal(2’)-Gly-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 383); Ac-Nle-c(Asp-Pro-dNal(2’)-Asp-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 384); and Ac-Nle-c(Asp-Pro-dNal(2’)-Glu-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 385), wherein c represents cyclization through R2and R7via a lactam bond.

[0049] 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: 386); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Nal(1’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 387); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aia-Lys)-dVal-dPro-NH2(SEQ ID NO: 388); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Phe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 389); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Tyr-Lys)-dVal-dPro-NH2(SEQ ID NO: 390); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-His-Lys)-dVal-dPro-NH2 (SEQ ID NO: 391); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Ala-Lys)-dVal-dPro-NH2(SEQ ID NO: 392), wherein c represents cyclization through R2and R7via a lactam bond.

[0050] In some embodiments, the sequence of Formula (I) is Ac-Nle-c(Asp-Pro- Bip-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 393), wherein c represents cyclization through R2and R7via a lactam bond.

[0051] 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: 394); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-OH (SEQ ID NO: 395); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-OH (SEQ ID NO: 396); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO: 397); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dHyp-NH2 (SEQ ID NO: 398); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-Hyp-NH2(SEQ ID NO: 399); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-dHyp-NH2 (SEQ ID NO: 400); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-dVal-NH2(SEQ ID NO: 401); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-dVal-NH2 (SEQ ID NO: 402); -30- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-Val-NH2 (SEQ ID NO: 403); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-Val-NH2(SEQ ID NO: 404); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-NH2 (SEQ ID NO: 405); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dPro-NH2(SEQ ID NO: 406); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-NH2 (SEQ ID NO: 407); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-NH2(SEQ ID NO: 408); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-NH2 (SEQ ID NO: 409); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Pro-NH2(SEQ ID NO: 410); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Ala-NH2 (SEQ ID NO: 411); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAla-NH2(SEQ ID NO: 412); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-NH2 (SEQ ID NO: 413); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-NH2(SEQ ID NO: 414); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAla-dAla-NH2 (SEQ ID NO: 415); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Ala-Ala-NH2(SEQ ID NO: 416); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Gly-Gly-NH2 (SEQ ID NO: 417); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Asp-NH2(SEQ ID NO: 418); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Arg-NH2 (SEQ ID NO: 419); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Asn-NH2 (SEQ ID NO: 420); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dAsp-NH2 (SEQ ID NO: 421); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dArg-NH2 (SEQ ID NO: 422); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dAsn-NH2(SEQ ID NO: 423); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asp-dPro-NH2 (SEQ ID NO: 424); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dPro-NH2(SEQ ID NO: 425); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asn-dPro-NH2 (SEQ ID NO: 426); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsp-dPro-NH2(SEQ ID NO: 427); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dPro-NH2 (SEQ ID NO: 428); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsn-dPro-NH2(SEQ ID NO: 429); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asp-NH2 (SEQ ID NO: 430); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-NH2(SEQ ID NO: 431); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asn-NH2 (SEQ ID NO: 432); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsp-NH2(SEQ ID NO: 433); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-NH2 (SEQ ID NO: 434); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsn-NH2(SEQ ID NO: 435); -31- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Pro-Val-NH2 (SEQ ID NO: 436); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-dVal-NH2(SEQ ID NO: 437); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-dVal-NH2 (SEQ ID NO: 438); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-NH2(SEQ ID NO: 439); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-NH2 (SEQ ID NO: 440); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Val-Pro-NH2(SEQ ID NO: 441); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dVal-dPro-NH2 (SEQ ID NO: 442); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dVal-dPro-NH2(SEQ ID NO: 443); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Pro-Val-NH2 (SEQ ID NO: 444); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dPro-dVal-NH2(SEQ ID NO: 445); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dPro-dVal-NH2 (SEQ ID NO: 446); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Val-Pro-NH2(SEQ ID NO: 447); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dVal-dPro-NH2 (SEQ ID NO: 448); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dVal-dPro-NH2(SEQ ID NO: 449), wherein c represents cyclization through R2and R7via a lactam bond.

[0052] 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)-dVal-dVal-dPro-NH2 (SEQ ID NO: 450); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-dPro-NH2(SEQ ID NO: 451); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 452); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2(SEQ ID NO: 453); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dVal-dVal-dVal-dPro- NH2(SEQ ID NO: 454), wherein c represents cyclization through R2and R7via a lactam bond.

[0053] In some embodiments, X1is present and is acetylated norleucine, and R1is present and is norleucine.

[0054] In some embodiments, X2is present and is norleucine.

[0055] In some embodiments, is present and is norleucine. -32- 146316.8009.WO00\165259190.24

[0056] 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: 455); Ac-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 456); and Ac-Nle-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 457), wherein c represents cyclization through R2and R7via a lactam bond.

[0057] In some embodiments, 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: 458); Ac-Nle-c(Asp-Trp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 459); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dTrp-Lys)-dVal-dPro-NH2(SEQ ID NO: 460); c(CO-cis-CH = CH-CO-Pro-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 461); Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 462); Ac-Nle-c(Asp-β-Ala-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 463); Ac-Nle-c(Asp-Mamb-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 464); Ac-Nle-c(Asp-Acpc-dNal(2′) Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 465); Ac-c(Cys-Arg-dPhe-Cys)-Trp-dVal-dPro-NH2(SEQ ID NO: 466); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Trp-NH2 (SEQ ID NO: 467), wherein c represents cyclization through R2and R7or R8via a lactam bond or through R2and R5via a disulfide bond.

[0058] In some embodiments, the sequence of Formula (I) is: Ac-Nle-c(Asp-Aic-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 468); or Ac-Nle-c(Asp-Cpe-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 469), wherein c represents cyclization through R2and R7or R8via a lactam bond.

[0059] In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 306, 428, 481-483,493-495, 528- 531, and 552-555.

[0060] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 306. -33- 146316.8009.WO00\165259190.24

[0061] In some embodiments, the second compound is a compound of Formula (Xi):

[0062] In some embodiments, the second compound is a compound of Formula (Xii):

[0063] In some embodiments, Rx1is Rx1a; and Rx1ais 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RxA, wherein each RxAis halogen, -OH, -CN, C1-4alkyl, C14 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-C4 cycloalkyl, or (C3-4 cycloalkyl)- C14 alkyl-, wherein each of the C1-4 alkyl, C3-4 cycloalkyl, and (C3-4alkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or two adjacent RxAtogether with the two ring-atoms of the 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6-membered heteroaryl, -34- 146316.8009.WO00\165259190.24each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C14 haloalkoxy.

[0064] In some embodiments, Rx1ais pyrimidinyl optionally substituted with 1, 2, or 3 independently selected RxA, wherein each RxAis halogen, -OH, -CN, C1-4 alkyl, C1- 4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, or C3-4 cycloalkyl.

[0065] In some embodiments, Rx1ais pyrimidin-2-yl.

[0066] In some embodiments, Xx1is CH2.

[0067] In some embodiments, each of Rx2and Rx3is independently H, F, or C1-4 alkyl.

[0068] In some embodiments, Rx2is methyl and Rx3is H.

[0069] In some embodiments, Yx3is N, and each of Yx1, Yx2, Yx4, and Yx5is independently CRx4.

[0070] In some embodiments, Rx4is independently H, halogen, or C1-2 alkoxy.

[0071] In some embodiments, the second compound is selected from: (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-(7-methyl-6-(2-methyl-2H-tetrazol-5- yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, DIAST- 1; 2-(6-methoxy-2-methylpyrimidin-4-yl)-1-((2S)-7-methyl-6-(2-methyl-2H-tetrazol- 5-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, DIAST-1; 2-(6-(difluoromethoxy)pyridin-3-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4- dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, DIAST-2; 1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'- pyrrolidin)-1'-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one, DIAST-1; 1-(4,7-dimethyl-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)-2- (4-fluorophenyl)ethan-1-one, DIAST-1; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(2-methyl-2H- tetrazol-5-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1- one; -35- 146316.8009.WO00\165259190.24(2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4- dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one; (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4- dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(7-methyl-6-(1-methyl-1H-pyrazol-4- yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, DIAST- 1; and (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-{(2S)-7-methyl-6-((4,6-2H2)pyrimidin- 2-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl}propan-1-one, or pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the second compound is (2R)-2-(5-fluoro-2- methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8- naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, or pharmaceutically acceptable salt thereof.

[0073] In some embodiments, the second compound is a crystalline form of (2R)- 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H- spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one.

[0074] In some embodiments, the antibody or antigen binding fragment thereof comprises a human Fc domain selected from the group consisting of an Fc domain of IgA1 IgA2, IgD, IgE, IgM, IgG1, IgG2, IgG3, or IgG4.

[0075] In some embodiments, the antibody or antigen binding fragment thereof, binds human or cynomolgus monkey GDF-15 with a KD about or less than a value selected from the group consisting of about 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, and 10 pM.

[0076] In some embodiments, the antibody or antigen binding fragment thereof comprises Anti-GDF-15 antibody GDF-15_001 having one or more amino acid sequences selected from the group of amino acid sequences consisting of SEQ ID NOs: 32, 165, 52, 25, 166, 22, 2324, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10, and 162.

[0077] In some embodiments, the composition further comprises an anti-cancer agent. -36- 146316.8009.WO00\165259190.24

[0078] In some embodiments, the anti-cancer agent is at least one chemotherapeutic agent.

[0079] 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, an alkylating antineoplastic agent, and a cytotoxic antibiotic.

[0080] In some embodiments, the platinum-coordination complex is cisplatin.

[0081] In some embodiments, the antimetabolite is 5-fluorouracil (5-FU).

[0082] In some embodiments, the tubulin binding agent is vincristine.

[0083] In some embodiments, the alkylating antineoplastic agent is cyclophosphamide.

[0084] In some embodiments, the cytotoxic antibiotic is doxorubicin.

[0085] In some embodiments, the first compound and the second compound are present in a single pharmaceutical composition.

[0086] In some embodiments, the first compound and the third compound are present in a single pharmaceutical composition.

[0087] In some embodiments, the first compound, the second compound, and the third compound, if present, are present in a single pharmaceutical composition.

[0088] In some embodiments, the single pharmaceutical composition is formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, or oral administration.

[0089] In some embodiments, the single pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[0090] In some embodiments, the first compound is present in the single pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, relative to a total volume of the single pharmaceutical composition.

[0091] In some embodiments, the first compound is present in a first pharmaceutical composition; and the second compound is present in a second pharmaceutical composition. -37- 146316.8009.WO00\165259190.24

[0092] In some embodiments, the first compound is present in a first pharmaceutical composition; and the third compound is present in a third pharmaceutical composition.

[0093] In some embodiments, the first compound is present in a first pharmaceutical composition; the second compound is present in a second pharmaceutical composition; and the third compound is present in a third pharmaceutical composition.

[0094] In some embodiments, the first pharmaceutical composition is formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, or oral administration.

[0095] In some embodiments, the first pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

[0096] In some embodiments, the first compound is present in the first pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, relative to a total volume of the first pharmaceutical composition.

[0097] In some embodiments, the present technology comprises a composition, comprising: a first compound having primary therapeutic efficacy; and a second compound and / or a third compound each having secondary therapeutic efficacy, wherein the first compound is a non-naturally occurring melanocortin analog, the second compound is a spiro compound, and the third compound is an antibody or antigen binding fragment thereof.

[0098] In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin 3 receptor (MC3R) agonist and a melanocortin 4 receptor (MC4R) agonist.

[0099] In some embodiments, the primary therapeutic efficacy occurs following agonism of the MC3R and / or the MC4R.

[0100] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to Formula (I), -38- 146316.8009.WO00\165259190.24X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8(I) wherein: R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D- asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, 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), alanine, D-alanine, D- methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4- aminophenylpiperidine-4-carboxylic acid (APPC), 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), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; -39- 146316.8009.WO00\165259190.24R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-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, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-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, 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, 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-proline, L-proline, D- valine, and L-valine; Y4is absent or is D-proline or D-valine; Y5is absent or is D-proline or D-valine; -40- 146316.8009.WO00\165259190.24Y6is 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent.

[0101] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 306.

[0102] In some embodiments, the spiro compound is an MC4R antagonist. -41- 146316.8009.WO00\165259190.24

[0103] In some embodiments, the secondary therapeutic efficacy occurs following antagonism of the MC4R.

[0104] In some embodiments, the spiro compound comprises a structure according to Formula (X) or a44 64- to 7- memberedocycloalkyl, phenyl, or Rx1a, wherein each of the C3-6 cycloalkyl and 4- to 7- memberedocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected C1-4 alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 independently selected RxB, wherein RxBis halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-4cycloalkyl, or RxB1; or two adjacent RxBtogether with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; Rx1ais 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independent RxA, wherein each RxAis halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C14 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, -N(C1-4 alkyl)2, RxA1, or (C3-4 cycloalkyl)- C14alkyl-, wherein each of the C14alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; or two adjacent RxAtogether with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6- -42- 146316.8009.WO00\165259190.24membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6- membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; RxA1is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4haloalkoxy; RxB1is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each of Rx2and Rx3is independently H, halogen, C1-4alkyl, C1-4hydroxyalkyl, C1-4 haloalkyl, (C1-4 alkoxy)-C1-4 alkyl-, C3-4 cycloalkyl, or (C3-4 cycloalkyl)-C1-4 alkyl, wherein each of C3-4cycloalkyl and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; or Rx2and Rx3together with the carbon atom to which they are attached form C3-6 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each Rx4is independently H, halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4haloalkoxy, -N(C1-2alkyl)2, C3-4cycloalkyl, or (C3-4cycloalkyl)-C1-4 alkyl-, wherein each of the C1-4 alkyl, C3-4 cycloalkyl, and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy Xx1is C(RxX)2, wherein each RxXis independently H or C1-4alkyl; each of Yx1, Yx2, Yx3, Yx4, and Yx5is independently CR4or N, provided that no more than 3 of Yx1, Yx2, Yx3, Yx4, and Yx5are N.

[0105] In some embodiments, the spiro compound is (2R)-2-(5-fluoro-2- methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8- naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, or pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the antibody or antigen binding fragment thereof specifically binds to a portion of human growth differentiation factor 15 (GDF-15). -43- 146316.8009.WO00\165259190.24

[0107] In some embodiments, the antibody or antigen binding fragment thereof binds to GDF-15 thereby preventing binding of GDF-15 to a Glial-derived neurotrophic factor-family receptor α-like (GFRAL) receptor.

[0108] In some embodiments, the antibody or antigen binding fragment thereof comprises at least one of the following: a) a light chain complementarity determining region 1 (LCDR-1) comprising the amino acid sequence of SEQ ID NO:95, a LCDR-2 comprising the amino acid sequence of SEQ ID NO:28, a LCDR-3 comprising the amino acid sequence of SEQ ID NO:9, a heavy chain complementarity determining region 1 (HCDR-1) comprising the amino acid sequence of SEQ ID NO:32, a HCDR-2 comprising the amino acid sequence of SEQ ID NO:165, and a HCDR-3 comprising the amino acid sequence of SEQ ID NO:52; b) LCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) a LCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) a LCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) a HCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) a HCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) a HCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173, and 181; h) the HCDR-1, HCDR-2, and HCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:163; i) the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded -44- 146316.8009.WO00\165259190.24by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:166, and a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:163; k) a VHcomprising the amino acid sequence of SEQ ID NO:166 and a VLcomprising the amino acid sequence of SEQ ID NO:163; l) a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:164, and a light chain (LC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:162; m) a HC comprising the amino acid sequence of SEQ ID NO:164, and a LC comprising the amino acid sequence of SEQ ID NO:162; GDF-15; and n) an antibody that competes for binding to GDF-15 with at least one antibody from (a)- (m) above.

[0109] In some embodiments, the antibody or antigen binding fragment thereof comprises Anti-GDF-15 antibody GDF-15_001 having one or more amino acid sequences selected from the group of amino acid sequences consisting of SEQ ID NOs: 32, 165, 52, 25, 166, 22, 2324, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10, and 162.

[0110] In some embodiments, the secondary therapeutic efficacy is supportive therapeutic efficacy compared to the primary therapeutic efficacy.

[0111] In some embodiments, the composition comprises a lower dosage unit of the second compound and / or the third compound compared to a dosage unit of the second compound and / or a dosage unit of the third compound absent the first compound.

[0112] In some embodiments, the composition comprises a lower dose of the second compound and / or the third compound compared to a dose of the second compound and / or a dose of the third compound absent the first compound.

[0113] In some embodiments, the composition comprises a shorter dosage regimen of the second compound and / or the third compound compared to a dosage -45- 146316.8009.WO00\165259190.24regimen of the second compound and / or a dosage regimen of the third compound absent the first compound.

[0114] In some embodiments, the composition comprises fewer dosages of the second compound and / or the third compound compared to dosages of the second compound and / or dosages of the third compound absent the first compound.

[0115] In some embodiments, the composition has an improved net-effect on MC4R compared to the effect on MC4R of the second compound and / or the effect on MC4R of the third compound absent the first compound.

[0116] In some embodiments, the present technology comprises a method of increasing appetite of a subject in need thereof relative to a control, the method comprising: administering a composition of the present technology.

[0117] 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, compared to the control.

[0118] In some embodiments, the subject is not on a High Carbohydrate High Calorie (HCHC) diet.

[0119] In some embodiments, the HCHC diet comprises a daily food consumption providing calories of at least 2000 kcal and at least 50 % of the calories are from carbohydrate.

[0120] In some embodiments, the subject is not on a High Fat High Calorie (HFHC) diet.

[0121] In some embodiments, the HFHC diet comprises a daily food consumption providing calories of at least 2000 kcal and at least 50 % of the calories are from fat.

[0122] In some embodiments, , the first, the second, and the third compounds are administered simultaneously as a single composition. In some embodiments, the first compound is present in a first pharmaceutical composition; -46- 146316.8009.WO00\165259190.24the second compound, if present, is present in a second pharmaceutical composition; and the third compound, if present, is present in a third pharmaceutical composition.

[0123] In some embodiments, the first, the second, and the third pharmaceutical compositions are different and are administered simultaneously but separately.

[0124] In some embodiments, the first, the second, and the third pharmaceutical compositions are different and are administered sequentially.

[0125] In some embodiments, the first pharmaceutical composition is administered prior to initial administration of the second pharmaceutical composition.

[0126] In some embodiments, the first pharmaceutical composition is administered prior to initial administration of the third pharmaceutical composition.

[0127] In some embodiments, the first and the second pharmaceutical compositions are administered sequentially within about 24 hours.

[0128] In some embodiments, the first pharmaceutical composition is administered in the morning, and the second pharmaceutical composition is administered in the evening.

[0129] In some embodiments, the first and the third pharmaceutical compositions are administered sequentially within about 24 hours.

[0130] In some embodiments, the first pharmaceutical composition is administered in the morning, and the third pharmaceutical composition is administered in the evening.

[0131] In some embodiments, the first compound comprises a sequence of SEQ ID NO: 306.

[0132] In some embodiments, the first compound 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.

[0133] In some embodiments, the first compound 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.

[0134] In some embodiments, a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second -47- 146316.8009.WO00\165259190.24compound is 10%-75% less than that of the second compound when administered alone.

[0135] In some embodiments, a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 25%-50% less than that of the second compound when administered alone.

[0136] In some embodiments, a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 10%-75% less than that of the third compound when administered alone.

[0137] In some embodiments, a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 25%-50% less than that of the third compound when administered alone.

[0138] In some embodiments, the composition is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0139] In some embodiments, the composition is administered to the subject for 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

[0140] In some embodiments, the subject experiences loss of appetite, decreased food consumption, and / or weight loss prior to the administration.

[0141] In some embodiments, the loss of appetite, decreased food consumption, and / or weight loss is caused by cachexia.

[0142] In some embodiments, the weight loss is muscle mass loss, fat mass loss, or both.

[0143] In some embodiments, the method (i) stimulates appetite of the subject; (ii) increases food consumption by 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. -48- 146316.8009.WO00\165259190.24

[0144] In some embodiments, the present technology comprises a method of treating cancer in a subject in need thereof, the method comprising: administering the composition of any one of embodiments 77-96 to the subject.

[0145] In some embodiments, the subject experiences a decrease in tumor size by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to the control.

[0146] In some embodiments, the subject experiences a decrease in cancer metastasis as measured by a decrease in cancer cell proliferation by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to control.

[0147] In some embodiments, the present technology comprises a method of treating a subject with a cancer, the method comprising: administering the composition of any one of embodiments 77-96 to the subject, wherein: the method reduces or prevents a side effect associated with the anti-cancer agent of the combination therapy, wherein the side effect is at least one selected from the group consisting of cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

[0148] In some embodiments, the present technology comprises method of improving survival in a subject with a cancer, the method comprising: administering the composition of any one of embodiments 77-96 to the subject, wherein: the method reduces or prevents a side effect associated with the anti-cancer agent of the combination therapy, thereby improving survival of the subject, wherein the side effect is at least one selected from the group consisting of cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

[0149] In some embodiments, the present technology comprises a method of increasing body weight in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0150] In some embodiments, the subject experiences an increase in body weight by 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%, -49- 146316.8009.WO00\165259190.2495%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 350%, 400%, 450%, or 500% compared to the control.

[0151] In some embodiments, the present technology comprises a method of increasing muscle mass in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0152] In some embodiments, the subject experiences an increase in muscle mass by 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 the control.

[0153] In some embodiments, the present technology comprises a method of increasing fat mass in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0154] In some embodiments, the subject experiences an increase in fat mass by 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 the control.

[0155] In some embodiments, the present technology comprises a method of increasing cardiac mass in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0156] In some embodiments, the subject experiences an increase in cardiac mass by 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 the control.

[0157] In some embodiments, the present technology comprises a method of increasing bone density in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0158] In some embodiments, the subject experiences an increase in bone density by 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 the control.

[0159] In some embodiments, the present technology comprises a method of reducing fatigue in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject. -50- 146316.8009.WO00\165259190.24

[0160] In some embodiments, the present technology comprises a method of reducing vomiting in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0161] In some embodiments, the present technology comprises a method of reducing diarrhea in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0162] In some embodiments, the present technology comprises a method of increasing cumulative mass in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0163] In some embodiments, the subject experiences an increase in cumulative mass by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

[0164] In some embodiments, the present technology comprises a method of increasing net weight gain in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0165] In some embodiments, the subject experiences an increase in net weight gain by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

[0166] In some embodiments, the present technology comprises a method of reducing a rate of loss of cumulative mass in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0167] In some embodiments, the subject experiences a reduction in the rate of loss of cumulative mass by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

[0168] In some embodiments, the present technology comprises a method of increasing cumulative food intake in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject. -51- 146316.8009.WO00\165259190.24

[0169] In some embodiments, the subject experiences an increase in cumulative food intake by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

[0170] In some embodiments, the present technology comprises a method of increasing body mass index (BMI) in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0171] In some embodiments, the subject experiences an increase in BMI compared to the 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.

[0172] In some embodiments, the present technology comprises a method of reducing a proinflammatory transcript or protein level in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1- 115 to the subject.

[0173] In some embodiments, the subject experiences a reduction in an inflammatory transcript or protein level by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the control.

[0174] In some embodiments, the proinflammatory transcript is selected from the group consisting of an IL1b transcript, and IL1R1 transcript, an IL6 transcript, a CCL2 transcript, and a GDF-15 transcript.

[0175] In some embodiments, the proinflammatory protein is selected from the group consisting of an IL1b protein, and IL1R1 protein, an IL6 protein, a CCL2 protein, and a GDF-15 protein.

[0176] In some embodiments, the present technology comprises a method of increasing a Functional Assessment of Anorexia / Cachexia Treatment (FAACT) score in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0177] In some embodiments, the subject experiences an increase in FAACT score by at least 1, 2, 3, 4, or 5 points compared to the control. -52- 146316.8009.WO00\165259190.24

[0178] In some embodiments, the present technology comprises a method of increasing BMI durability in a subject compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0179] In some embodiments, the subject experiences an increase in BMI durability of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the control.

[0180] In some embodiments, the subject has a cancer.

[0181] In some embodiments, the present technology comprises a method of reducing or maintaining an Eastern Cooperative Oncology Group (ECOG) performance status score in a subject having cancer compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0182] In some embodiments, the subject experiences a reduction in ECOG score by about 1, 2, or 3 compared to the control.

[0183] In some embodiments, the present technology comprises a method of increasing or maintaining a Karnofsky Performance Status (KPS) grade in a subject having cancer compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0184] In some embodiments, the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to the control.

[0185] In some embodiments, the present technology comprises a method of increasing overall survival (OS) in a subject having cancer compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0186] In some embodiments, the subject experiences an increase in OS by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

[0187] In some embodiments, the present technology comprises a method of increasing progression free survival (PFS) in a subject having cancer compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject. -53- 146316.8009.WO00\165259190.24

[0188] In some embodiments, the subject experiences an increase in PFS by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

[0189] In some embodiments, the present technology comprises a method of reducing time to cancer treatment failure in a subject having cancer compared to a control, the method comprising administering the composition of any one of embodiments 1-115 to the subject.

[0190] In some embodiments, the subject experiences a reduction in time to cancer treatment failure by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

[0191] In some embodiments, the control comprises the subject at baseline or a second subject that has not received the composition of any one of embodiments 1- 115.

[0192] In some embodiments, the subject is not on a High Carbohydrate High Calorie (HCHC) diet.

[0193] In some embodiments, the HCHC diet comprises a daily food consumption providing calories of at least 2000 kcal and at least 50 % of the calories are from carbohydrate.

[0194] In some embodiments, the subject is not on a High Fat High Calorie (HFHC) diet.

[0195] In some embodiments, the HFHC diet comprises a daily food consumption providing calories of at least 2000 kcal and at least 50 % of the calories are from fat.

[0196] In some embodiments, the first, the second, the third compounds, and the anti-cancer agent are administered simultaneously as a single composition.

[0197] In some embodiments, the first compound is present in a first pharmaceutical composition; the second compound, if present, is present in a second pharmaceutical composition; the third compound, if present, is present in a third pharmaceutical composition; and the anti-cancer agent is present in a fourth pharmaceutical composition. -54- 146316.8009.WO00\165259190.24

[0198] In some embodiments, the first, the second, the third, and the fourth pharmaceutical compositions are different and are administered simultaneously but separately.

[0199] In some embodiments, the first, the second, the third, and the fourth pharmaceutical compositions are different and are administered sequentially.

[0200] In some embodiments, the first pharmaceutical composition is administered prior to initial administration of the second pharmaceutical composition.

[0201] In some embodiments, the first pharmaceutical composition is administered prior to initial administration of the third pharmaceutical composition.

[0202] In some embodiments, the first pharmaceutical composition is administered prior to initial administration of the fourth pharmaceutical composition.

[0203] In some embodiments, the first and the second pharmaceutical compositions are administered sequentially within about 24 hours.

[0204] In some embodiments, the first pharmaceutical composition is administered in the morning, and the second pharmaceutical composition is administered in the evening.

[0205] In some embodiments, the first and the third pharmaceutical compositions are administered sequentially within about 24 hours.

[0206] In some embodiments, the first pharmaceutical composition is administered in the morning, and the third pharmaceutical composition is administered in the evening.

[0207] In some embodiments, the first compound 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.

[0208] In some embodiments, the first compound 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.

[0209] In some embodiments, a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 10-75% less than that of the second compound when administered alone. -55- 146316.8009.WO00\165259190.24

[0210] In some embodiments, a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 25-50% less than that of the second compound when administered alone.

[0211] In some embodiments, a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 10-75% less than that of the third compound when administered alone.

[0212] In some embodiments, a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 25-50% less than that of the third compound when administered alone.

[0213] In some embodiments, the composition is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

[0214] In some embodiments, the composition is administered to the subject for 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

[0215] In some embodiments, the subject is a human.

[0216] In some embodiments, the subject is an animal.

[0217] In some embodiments, the present technology does not reduce efficacy of the anti-cancer agent.

[0218] In some embodiments, the cancer is at least one selected from the group consisting of bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colon cancer, oral cancer, skin cancer, and melanoma.

[0219] In some embodiments, the cancer is at least one selected from the group consisting of bone cancer, lung cancer, testicular cancer, breast cancer, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer. -56- 146316.8009.WO00\165259190.24

[0220] In some embodiments, the subject with a cancer has previously undergone a treatment with the anti-cancer agent.

[0221] In some embodiments, 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 cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

[0222] In some embodiments, the one or more anti-cancer agents are dosed at a higher amount when present in the composition comprising the first compound and the third compound compared to the composition comprising the one or more anti-cancer agents and the first compound or the one or more anti-cancer agents and the third compound.

[0223] In some embodiments, dosing the one or more anti-cancer agents at a higher amount comprises increased dose amounts, administering more frequent doses, extending the duration of the dosing regimen, and / or increasing the total number of doses administered to the subject.

[0224] In some embodiments, the one or more anti-cancer agents is dosed at least at about 6 mg / mL, 7 mg / mL, or 8 mg / mL in combination with the first compound and the third compound compared to about 2 mg / mL or about 3 mg / mL with the first compound or the third compound.

[0225] In some embodiments, the one or more anti-cancer agents is dosed at least at about 6 mg / mL, in combination with the first compound and the third compound compared to about 2 mg / mL with the first compound or the third compound.

[0226] In some embodiments, the one or more anti-cancer agents is dosed at least at about 7 mg / mL, in combination with the first compound and the third compound compared to about 2 mg / mL with the first compound or the third compound.

[0227] 229. The method of embodiment 226, wherein the one or more anti- cancer agents is dosed at least at about 8 mg / mL, in combination with the first compound and the third compound compared to about 2 mg / mL with the first compound or the third compound. -57- 146316.8009.WO00\165259190.24

[0228] In some embodiments, the one or more anti-cancer agents is dosed at least at about 6 mg / mL, in combination with the first compound and the third compound compared to about 3 mg / mL with the first compound or the third compound.

[0229] In some embodiments, the one or more anti-cancer agents is dosed at least at about 7 mg / mL, in combination with the first compound and the third compound compared to about 3 mg / mL with the first compound or the third compound.

[0230] In some embodiments, the one or more anti-cancer agents is dosed at least at about 8 mg / mL, in combination with the first compound and the third compound compared to about 3 mg / mL with the first compound or the third compound.

[0231] In some embodiments, the one or more anti-cancer agents comprises cisplatin.

[0232] In some embodiments, the method reduces or prevents one or more side effects in the subject and further comprises dosing the one or more anti-cancer agents at a higher amount thereby increasing efficacy of the one or more anti-cancer agents in the subject.

[0233] In some embodiments, the method increases efficacy of the anti-cancer agent. BRIEF DESCRIPTION OF THE DRAWINGS

[0234] FIGS. 1A-WW illustrate percent activation of the melanocortin 3 receptor (MC3R) following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Graphs displaying cAMP data for selected example non-naturally occurring melanocortin analogs from Table 3 and Table 4 are provided.

[0235] FIGS.2A-Y illustrate percent activation of the MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Graphs displaying cAMP data for selected example non-naturally occurring melanocortin analogs from Tables 5- 7 are provided.

[0236] FIGS.3A-ZZ illustrate percent inhibition of the MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in -58- 146316.8009.WO00\165259190.24accordance with embodiments of the present technology. Graphs displaying cAMP data for selected example non-naturally occurring melanocortin analogs from Table 8 are provided.

[0237] FIGS. 4A-H illustrate percent inhibition of the MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Graphs displaying cAMP data for selected example non-naturally occurring melanocortin analogs from Table 9 are provided.

[0238] FIGS. 5A-AAA illustrate percent activation of the melanocortin 4 receptor (MC4R) following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Graphs displaying cAMP data for selected example non-naturally occurring melanocortin analogs from Table 3 and Table 4 are provided.

[0239] FIGS.6A-HH illustrate percent activation of the MC4R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Graphs displaying cAMP data for selected example non-naturally occurring melanocortin analogs from Tables 5- 7 are provided.

[0240] FIGS.7A-JJJ illustrate percent inhibition of the MC4R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Graphs displaying cAMP data for selected example non-naturally occurring melanocortin analogs from Table 8 are provided.

[0241] FIGS. 8A-N illustrate percent inhibition of the MC4R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels in accordance with embodiments of the present technology. Graphs displaying cAMP data for selected example non-naturally occurring melanocortin analogs from Table 9 are provided.

[0242] FIG.9 shows (i) a comparison of binding curves of compound A1 (SEQ ID NO: 315) and TCMCB07 (“B07”) to human melanocortin 1 receptor (hMC1R; Gene ID: 4157), human melanocortin 3 receptor (hMC3R; Gene ID: 4159), and human -59- 146316.8009.WO00\165259190.24melanocortin 4 receptor (hMC4R; Gene ID: 4160), respectively; (ii) a summary of IC50 values for ligand binding of SM-001 to hMC1R, hMC3R, and hMC4R, respectively; and (iii) a summary of IC50 values for ligand binding of B07 to hMC1R, hMC3R, and hMC4R, respectively.

[0243] FIG. 10 provides a table summarizing the SEQ ID NOs corresponding to some GDF-15 antibodies of the present technology.

[0244] FIGS. 11A-D show graphs depicting daily food intake (FIG. 11A), weekly food intake (FIG. 11B), daily cumulative food intake (FIG. 11C), and total food intake after 21 days (FIG.11D) of Sprague Dawley rats. The graphs compare the food intakes in three groups of rats. Group 1 rats were administered cisplatin, saline, and IgG; Group 2 rats were administered cisplatin, saline, and an anti-GDF-15 monoclonal antibody (mAb) comprising a human ponsegromab Fab region having SEQ ID NOs: 288 and 289 and a murine Fc region; and Group 3 rats were administered cisplatin, TCMCB07 (SEQ ID NO: 306), and the anti-GDF-15 murine mAb. Cisplatin was administered at 5mg / kg on day 0 and 3mg / kg on days 7 and 14.

[0245] FIGS.12A-D show graphs depicting daily body weight (FIG.12A), weekly cumulative body weight (FIG.12B), daily body weight gain (FIG.12C), and total body weight gain after 21 days (FIG.12D) of Sprague Dawley rats. The graphs compare the body weight and body weight gain in three groups of rats. Group 1 rats were administered cisplatin, saline, and IgG; Group 2 rats were administered cisplatin, saline, and anti-GDF-15 murine mAb (murine mAb comprising SEQ ID NOs: 288 and 289; and Group 3 rats were administered cisplatin, TCMCB07 (SEQ ID NO: 306), and anti-GDF- 15 murine mAb. Cisplatin was administered at 5mg / kg on day 0 and 3mg / kg on days 7 and 14.

[0246] FIGS.13A-E show graphs depicting relative quantification (RQ) of mRNA expression of cytokines IL1b (FIG.13A), IL1R1 (FIG.13B), IL6 (FIG.13C), CCL2 (FIG. 13D), and GDF-15 (FIG. 13E) in the hypothalamus of Sprague Dawley rats, as measured by quantitative polymerase chain reaction (qPCR). The graphs compare mRNA expression in five groups of rats. Group 1 rats were administered cisplatin and IgG light chain (IgG-L); Group 2 rats were administered cisplatin and IgG heavy chain (IgG-H; Group 3 rats were administered cisplatin and ponsegromab light chain (GDF- 15Ab-L, SEQ ID NO: 289); Group 4 rats were administered cisplatin and ponsegromab -60- 146316.8009.WO00\165259190.24heavy chain (GDF-15Ab-H, SEQ ID NO: 288); and Group 5 rats were administered saline (saline / saline). DETAILED DESCRIPTION

[0247] Described herein are compositions comprising a first compound comprising a non-naturally occurring melanocortin analog, and a second compound which has spiro structure, and / or a third compound that comprises an antibody, or antigen binding fragment thereof. The composition may further comprise anti-cancer agent(s). Also described herein are methods of using the same to regulate weight, including but not limited to increasing appetite, preventing appetite loss, promoting weight gain, preventing weight loss, treating, preventing, or otherwise reducing cachexia and / or anorexia in a subject in need thereof, and / or increasing efficacy of the anti-cancer agent by administering the composition to the subject. Methods of treating subjects with cancer without causing one or more side effects are also described.

[0248] 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. 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.

[0249] 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 -61- 146316.8009.WO00\165259190.24order presented. Moreover, any of the step or functions thereof may be outsourced to or performed by one or more third parties.

[0250] 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.

[0251] 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. Likewise, any reference to singular includes plural embodiments, and any reference to more than one component may include a singular embodiment.

[0252] 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. In some embodiments, such variation may be as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. 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.

[0253] 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.

[0254] As used herein, a “pharmaceutically acceptable carrier” of the first, the second, or the third 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 -62- 146316.8009.WO00\165259190.24contained. 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 acceptable 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.

[0255] As used herein, “a side effect associated with the anti-cancer agent” or “an adverse side effect associated with the anti-cancer agent” refers to any unwanted, undesirable, or deleterious biological activity occurs during or after independent use of the anti-cancer agent.

[0256] As used herein, the terms “treat”, “treatment”, and “treating” 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 -63- 146316.8009.WO00\165259190.24(or 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), and (14) preventing or reducing the metastasis of cancer cells. 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.

[0257] 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.

[0258] The term “after administration” refers to any duration of time after the combination therapy, 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” may include seconds, minutes, hours, days, weeks, months, and years. -64- 146316.8009.WO00\165259190.24

[0259] “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% 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).

[0260] “Anorexia” refers simply 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.

[0261] “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 pro-opiomelanocortin 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 -65- 146316.8009.WO00\165259190.24compounds, 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: 304) or a modified version thereof, or a structural or functional peptide mimetic thereof.

[0262] A peptide or amino acid “mimetic” is a non-amino acid molecule that mimics a peptide (a chain of amino acids) or one amino acid residue.

[0263] “Substantial degradation” refers to the degradation of the N-terminal extension, the C-terminal extension, both N- and C-terminal degradation or degradation to other regions of the non-naturally occurring melanocortin analog by physiological enzymes and other factors, in such a manner or to a degree that side effects appear. According to one aspect, a non-naturally occurring melanocortin analog having a C- terminal extension that resists substantial degradation is one where no more than 50% of the administered peptide causes side effects and / or displays a low half-life. In some aspects, no more than 25% of the administered peptide causes side effects and / or displays a low half-life. More, in some aspects, less than 10% of the administered peptide causes side effects and / or displays a low half-life, as compared to a non- naturally occurring melanocortin analog that lacks a C-terminal extension.

[0264] The “peptides” described herein 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.

[0265] 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 -66- 146316.8009.WO00\165259190.24peptides. 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.

[0266] “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 α-amino acids differ in the side-chain moiety that is attached to the α-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 Non-naturally occurring melanocortin analogs: 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 Non- naturally occurring melanocortin analogs: 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.

[0267] 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 -67- 146316.8009.WO00\165259190.24structures 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.

[0268] 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.

[0269] In the peptides described herein, 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; “Gln” is glutamine; “Glu” is glutamic acid; “His” is histidine; “Ile” 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 “Val” 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” is L-phenylalanine; “D- Phe” is D-phenylalanine; “D- / L-Phe” 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′) is D-2′-naphthylalanine; L- Nal(2') is L-2′-naphthylalanine; L-Nal(1') is L-1′-naphthylalanine; D-Nal(1') is D-1′- naphthylalanine; Tle is tert-Leucine; Nva is norvaline; Orn is ornithine; Bip is biphenyl amino acid; and so on.

[0270] An alpha (α)-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 α-carbon). Other types of amino acid exist when the amino group is attached to a different carbon atom. For example, beta (β)-amino acids, the carbon atom to which the amino group is attached is separated from the carboxylate group by one carbon atom, Cβ. For example, α-alanine -68- 146316.8009.WO00\165259190.24has the formula H2N—CαH(CH3)—COOH. In contrast, β-alanine has the general formula H2N—CβH2—CαH2—COOH (i.e., 3-aminopropanoic acid).

[0271] When β-amino acids are incorporated into peptides, two main types of β- 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. As a non-limiting example, “β-valine” may refer to: —NH—CβH2—CαH(CH3)2—CO—, i.e., β2-valine (R on carboxy side); —NH—CβH(CH3)2—CαH2—CO—, i.e., β3-valine (R on amino side); or —NH—CβH(CH3)2—CαH(CH3)2—CO—, i.e., β2,3-valine (R at both positions).

[0272] Further, β-amino acids may adopt L- or D- stereochemistry. Unless otherwise indicated, all β-amino acid abbreviations represent either isomer, i.e., the L- isomer, the D-isomer, or a combination thereof.

[0273] Gamma (γ)-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. For example, γ-amino butyric acid has the formula, H2N—CγH2—CβH2—CαH2—COOH.

[0274] 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” refers to a cyclic structure, which is also shown in the literature as “c” or referred to as a “lactam.” “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 amide, i.e., —CO—NH2. In addition, the following abbreviations are used herein: Harg is Homo arginine; Hlys is Homo lysine.

[0275] Additional abbreviations are used as follows: tBu is tert-butyl; Hyp(Bzl) is benzyl-L-hydroxy-proline; glutaric acid linker is CO—(CH2)3—CO; 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; Phg is α- Phenyl-glycine; Sar is Sarcosine; Azt is 3′-azido-3′-deoxythymidine; 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)- -69- 146316.8009.WO00\165259190.24one; Aba is 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one; Mamb is 3- aminomethylbenzoic acid; Atc is 2-Aminotetraline-2-carboxylic acid; APC is 1-Amino-4- phenylcyclohexane-carboxylic acid; APPC is 4-Aminophenylpiperidine-4-carboxylic acid; Acpc is 1-aminocyclo-propane-1-carboxylic acid; Aic is 2-aminoindone-2- carboxylic acid; p(Cl)Phe is para-chloro-phenylalanine (I – iodo, Br- bromo); and p(Cl)dPhe is para-chloro-D-phenylalanine (I – iodo, Br- bromo).

[0276] The term “alkene” includes unsaturated hydrocarbons that contain one or more double carbon-carbon bonds. Examples of such alkene groups include ethylene, propene, and the like.

[0277] The term “alkenyl” includes a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one double bond; examples thereof include ethenyl, 2-propenyl, and the like.

[0278] The term “alkynal” includes a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms containing at least one triple bond; examples thereof include ethynyl, propynal, butynyl, and the like.

[0279] The term “aryl” includes a monovalent or bicyclic aromatic hydrocarbon radical of 6-to-12 ring atoms, and optionally substituted independently with one or more substituents selected from alkyl, haloalkyl, cycloalkyl, alkoxy, alkythio, halo, nitro, acyl, cyano, amino, monosubstituted amino, disubstituted amino, hydroxy, carboxy, or alkoxy-carbonyl. Examples of an aryl group include phenyl, biphenyl, naphthyl, 1- naphthyl, and 2-naphthyl, derivatives thereof, and the like.

[0280] The term “aliphatic” includes compounds with hydrocarbon chains, such as for example alkanes, alkenes, alkynes, and derivatives thereof.

[0281] 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.”

[0282] The term “fatty acid” describes a carboxylic acid with an aliphatic chain, which may be fully saturated or partially unsaturated, and optionally attached to a functional group such as a hydroxyl group or a carboxyl group. The aliphatic chain may contain e.g., from 6 to 26 carbon atoms and hydrogen atoms. -70- 146316.8009.WO00\165259190.24

[0283] 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.

[0284] An “omega amino derivative” includes an aliphatic moiety with a terminal amino group. Examples of omega amino derivatives include aminoheptanoyl and the amino acid side chain moieties of ornithine and lysine.

[0285] The term “heteroaryl” includes mono- and bicyclic aromatic rings containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. Five- or six- membered heteroaryl are monocyclic heteroaromatic rings; examples thereof include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and the like. Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazole, indole, benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline, purine, furopyridine, and thienopyridine.

[0286] An “amine” includes compounds that contain an amine group (—NH2).

[0287] 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.

[0288] An “imine” includes compounds that have a carbon-nitrogen double bond, with the nitrogen also attached to a hydrogen (NH═CH—R).

[0289] An “imide” includes compounds containing an imido group (—OC—NH— CO—).

[0290] A “nitrile” includes compounds that are carboxylic acid derivatives and contain a (—CN) group bound to an organic group.

[0291] The term “halogen” is intended to include the halogen atoms fluorine, chlorine, bromine and iodine, and groups including one or more halogen atoms, such as —CF3and the like.

[0292] Amino acids, including stereoisomers and modifications of naturally occurring amino acids, protein amino acids, non-protein amino acids, post- -71- 146316.8009.WO00\165259190.24translationally 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.”

[0293] A melanocortin receptor “agonist” is a naturally occurring substance or manufactured drug substance or composition that may interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor. By 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. A melanocortin receptor “inverse agonist” is a drug or a compound that stabilizes the inactive conformation of the melanocortin receptor and inhibits basal activity.

[0294] “Compound” when used herein includes any pharmaceutically acceptable derivative or variation, including conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic, diastereomeric and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. The expression “prodrug” refers to compounds that are drug precursors which following administration, release the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).

[0295] The term “alkyl” means an acyclic, saturated aliphatic hydrocarbon group which may be straight / linear or branched. Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, sec-butyl, isobutyl and tert-butyl. The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by a prefix designating a lower and upper number of carbon atoms in the moiety, that is, the prefix Ci-j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive. Thus, for example, C1-4 alkyl refers to alkyl of one to four carbon atoms, inclusive. Representative examples of C1-4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. For another example, C1-4 alkyl refers to alkyl of one to two carbon atoms, inclusive (i.e., methyl or ethyl). The alkyl group optionally may be substituted by 1 or more (e.g., 1 to 5) suitable substituents, -72- 146316.8009.WO00\165259190.24when so specified. The “alkyl” groups specified herein include those alkyl radicals of the designated length in either a straight or branched configuration. Examples of such alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.

[0296] At various places in the present specification regarding the second compound, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the present technology include each and every individual sub- combination of the members of such groups and ranges. For example, the term “C1-4 alkyl” is specifically intended to include C1 alkyl (methyl), C2 alkyl (ethyl), C3 alkyl, and C4 alkyl. For another example, the term “4- to 7-membered heterocycloalkyl” is specifically intended to include any 4-, 5-, 6-, or 7-membered heterocycloalkyl group.

[0297] As used herein, the term “n-membered”, where n is an integer, typically describes the number of ring-forming atoms in a moiety where the number of ring- forming atoms is n. For example, pyridinyl is an example of a 6-membered heteroaryl ring and pyrazolyl is an example of a 5-membered heteroaryl group.

[0298] As used herein, the term “alkoxy” or “alkyloxy” refers to an -O-alkyl group. For example, the term “C1-4 alkoxy” or “C1-4 alkyloxy” refers to an -O-(C1-4 alkyl) group; For another example, the term “C1-2 alkoxy” or “C1-2 alkyloxy” refers to an -O- (C1-2 alkyl) group. Examples of alkoxy include methoxy, ethoxy, propoxy (e.g., n- propoxy and isopropoxy), tert-butoxy, and the like. The alkoxy or alkyloxy group optionally may be substituted by 1 or more (e.g., 1 to 5) suitable substituents when so specified.

[0299] The term "halo" or "halogen" as used herein, means -F, -Cl, -Br, or -I.

[0300] As used herein, the term “haloalkyl” refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom). For example, the term “C1-4 haloalkyl” refers to a C1-4 alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom); and the term “C1-2 haloalkyl” refers to a C1-2 alkyl group (i.e., methyl or ethyl) having one or more halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a halogen atom). Examples of haloalkyl groups include - CF3, -CHF2, -CH2F, -CH2CF3, -C2 F5, -CH2Cl and the like. -73- 146316.8009.WO00\165259190.24

[0301] “Fluoroalkyl” means an alkyl as defined herein substituted with one or more fluoro (-F) substituents (up to perfluoroalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a fluorine atom). The term “C1-2 fluoroalkyl” refers to a C1-2 alkyl group (i.e., methyl or ethyl) having one or more fluorine substituents (up to perfluoroalkyl, i.e., every hydrogen atom of the alkyl group has been replaced by a fluorine atom); and the term “C1 fluoroalkyl” refers to methyl having 1, 2, or 3 fluorine substituents. Examples of C1 fluoroalkyl include fluoromethyl, difluoromethyl and trifluoromethyl; some examples of C2 fluoroalkyl include 1- fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2- trifluoroethyl, and the like.

[0302] As used here, the term “haloalkoxy” refers to an -O-haloalkyl group. For example, the term “C1-4 haloalkoxy” refers to an -O-(C1-4 haloalkyl) group; and the term “C1-2 haloalkoxy” refers to an -O-(C1-2 haloalkyl) group. For yet another example, the term “C1 haloalkoxy” refers to a methoxy group having one, two, or three halogen substituents. An example of haloalkoxy is -OCF3 or –OCHF2.

[0303] As used here, the term “fluoroalkoxy” refers to an -O-fluoroalkyl group. For example, the term “C1-2 fluoroalkoxy” refers to an -O-(C1-2 fluoroalkyl) group; and the term “C1 fluoroalkoxy” refers to an -O-(C1 fluoroalkyl) group. Examples of C1 fluoroalkoxy include -O-CH2F, -O-CHF2, and -O-CF3. Some examples of C2 fluoroalkoxy include -O-CH2CHF2, -O-CH2–- CHF2, -O-CH2 CF3, -O-CF2CH3, and - O-CF2CF3.

[0304] As used herein, the term “hydroxylalkyl” or “hydroxyalkyl” refers to an alkyl group having one or more (e.g., 1, 2, or 3) OH substituents. The term “C1-4 hydroxylalkyl” or “C1-4 hydroxyalkyl” refers to a C1-4 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents; and the term “C1-2 hydroxylalkyl” or “C1-2 hydroxyalkyl” refers to a C1-2 alkyl group having one or more (e.g., 1, 2, or 3) OH substituents. An example of hydroxylalkyl is -CH2OH or -CH2CH2OH.

[0305] As used herein, the term "cycloalkyl” refers to saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclics such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclics including spiro, fused, or bridged systems (such as bicyclo(1.1.1)pentanyl, bicyclo(2.2.1)heptanyl, bicyclo(3.2.1)octanyl or bicyclo(5.2.0)nonanyl, decahydronaphthalenyl, etc.). The cycloalkyl group has 3 to 15 -74- 146316.8009.WO00\165259190.24(e.g., 3 to 14, 3 to 10, 3 to 6, 3 to 4, or 4 to 6) carbon atoms. In some embodiments the cycloalkyl may optionally contain one, two, or more non-cumulative non- aromatic double or triple bonds and / or one to three oxo groups. In some embodiments, the bicycloalkyl group has 6 to 14 carbon atoms. The term“"C3-4 cycloalky”" as used herein, means a saturated cyclic hydrocarbon group containing from 3 to 4 carbons. Examples of C3-4 cycloalkyl include cyclopropyl and cyclobutyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings (including aryl and heteroaryl) fused to the cycloalkyl ring, for example, benzo or pyridinyl derivatives of cyclopentane (a 5-membered cycloalkyl), cyclopentene, cyclohexane (a 6-membered cycloalkyl), and the like, for example, 6,7-dihydro-5H-cyclopenta(b)pyridinyl, 5,6,7,8- tetrahydroquinolinyl, or 15,6,7,8- tetrahydroisoquinolinyl, each of which includes a 5- membered or 6-membered cycloalkyl moiety that is fused to a heteroaryl ring (i.e. the pyridinyl ring). The cycloalkyl or C3-4 cycoalkyl group optionally may be substituted by 1 or more (e.g., 1 to 5) suitable substituents when so specified.

[0306] The term“" C3-4 cycloalkyl-C1-4 alkyl“" as used herein, means a C3-4 cycloalkyl as defined herein, appended to the parent molecular moiety through a C3-4 alkyl group, as defined herein. Some examples of C3-4 cycloalkyl-C1-4 alkyl- include cyclopropylmethyl, 2-cyclopropylethyl, 2-cyclopropylpropyl, 3-cyclopropylpropyl, cyclobutylmethyl, 2-cyclobutylethyl, 2-cyclobutylpropyl, and 3-cyclobutylpropyl.

[0307] As used herein, the term “heterocycloalkyl” refers to a monocyclic or polycyclic (including 2 or more rings that are fused together, including spiro, fused, or bridged systems, for example, a bicyclic ring system), saturated or unsaturated, non- aromatic 4- to 15-membered ring system (such as a 4- to 14-membered ring system, 4- to 12-membered ring system, 5- to 10-membered ring system, 4- to 7-membered ring system, 4- to 6-membered ring system, or 5- to 6-membered ring system), including 1 to 14 ring-forming carbon atoms and 1 to 10 ring- forming heteroatoms each independently selected from O, S and N (and optionally P or B when present). The heterocycloalkyl group may also optionally contain one or more oxo (i.e., =O) or thiono (i.e., =S) groups. For example, the term“"4- to 7-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4- to 7-membered ring system that comprises one or more ring-forming heteroatoms each independently selected from O, S and N. For another example, the term“"5- or 6-membered heterocycloalkyl” refers to a monocyclic or polycyclic, saturated or unsaturated, non- -75- 146316.8009.WO00\165259190.24aromatic 5- or 6-membered ring system that comprises one or more ring-forming heteroatoms each independently selected from O, S and N. The heterocycloalkyl group optionally may be substituted by 1 or more (e.g., 1 to 5) suitable substituents, when so specified.

[0308] Some examples of 4- to 7-membered heterocycloalkyl include azetidinyl, oxetanyl, tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl, morpholinyl, tetrahydrodiazinyl, and tetrahydropyranyl (also known as oxanyl). Some further examples of 4- to 7-heterocycloalkyl include tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydropyranyl (e.g., tetrahydro-2H-pyran- 4-yl), imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, 1,3-oxazolidin-3-yl, 1,4-oxazepan-2-yl, isothiazolidinyl, 1,3- thiazolidin-3- yl, 1,2-pyrazolidin-2-yl, 1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl, 1,2- tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-4-yl, oxazolidinonyl, 2-oxo- piperidinyl (e.g., 2-oxo-piperidin-1-yl), 2-oxoazepan-3-yl, and the like.

[0309] As used herein, the term “heteroaryl” refers to monocyclic or fused-ring polycyclic aromatic heterocyclic groups with one or more heteroatom ring members (ring-forming atoms) each independently selected from O, S and N in at least one ring. The heteroaryl group has 5 to 14 ring-forming atoms, including 1 to 13 carbon atoms, and 1 to 8 heteroatoms selected from O, S, and N. In some embodiments, the heteroaryl group has 5 to 10 ring-forming atoms including one to four heteroatoms. The heteroaryl group may also contain one to three oxo or thiono (i.e., =S) groups. In some embodiments, the heteroaryl group has 5 to 8 ring-forming atoms including one, two or three heteroatoms. For example, the term "5-membered heteroaryl” refers to a monocyclic heteroaryl group as defined above with 5 ring-forming atoms in the monocyclic heteroaryl ring; the term“"6-membered heteroaryl” refers to a monocyclic heteroaryl group as defined above with 6 ring-forming atoms in the monocyclic heteroaryl ring; and the term“"5- or 6-membered heteroaryl” refers to a monocyclic heteroaryl group as defined above with 5 or 6 ring-forming atoms in the monocyclic heteroaryl ring. A heteroaryl group optionally may be substituted by 1 or more (e.g., 1 to 5) suitable substituents, when so specified. Examples of monocyclic heteroaryls include those with 5 ring-forming atoms including one to three heteroatoms or those -76- 146316.8009.WO00\165259190.24with 6 ring-forming atoms including one, two or three nitrogen heteroatoms. Examples of fused bicyclic heteroaryls include two fused 5- and / or 6-membered monocyclic rings including one to four heteroatoms.

[0310] Some examples of heteroaryl groups include pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridine-4-yl), pyrazinyl, pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, or pyrimidin-5-yl), pyridazinyl (e.g., pyridazin-3-yl, or pyridazin-4-yl), thienyl, furyl, imidazolyl (e.g., 1H-imidazol-4- yl), pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g., 1,2-thiazolyl, 1,3- thiazolyl), pyrazolyl (e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl), tetrazolyl (e.g., 2H-tetrazol-5- yl), triazolyl (e.g., 1,2,3-triazolyl, 1,2,4- triazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4- oxadiazolyl or 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl, or 1,2,4-thiadiazolyl), quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, benzothiazolyl, 1,2-benzoxazolyl, 1H- imidazo(4,5- c)pyridinyl, imidazo(1,2-a)pyridinyl, 1H-pyrrolo(3,2-c)pyridinyl, imidazo(1,2- a)pyrazinyl, imidazo(2,1-c)(1,2,4)triazinyl, imidazo(1,5-a)pyrazinyl, imidazo(1,2-a)pyrimidinyl, 1H- indazolyl, 9H-purinyl, imidazo(1,2-a)pyrimidinyl, (1,2,4)triazolo(1,5-a)pyridinyl, (1,2,4)triazolo(1,5-a)pyrimidinyl, (1,2,4)triazolo(4,3-b)pyridazinyl, isoxazolo(5,4- c)pyridazinyl, isoxazolo(3,4-c)pyridazinyl, pyrazolo(1,5-a)pyrimidinyl, 6,7-dihydro-5H- pyrrolo(1,2- b)(1,2,4)triazolyl,77yridinee, pyrimidone, pyrazinone, pyrimidinone, 1H- imidazol-2(3H)-one, 1H- pyrrole-2,5-dione, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl, 2,4(1H,3H)- dioxo-pyrimidinyl, 1H-2-oxo-pyrazinyl, and the like.

[0311] An “antibody” or “Ab” is an immunoglobulin molecule capable of recognizing and binding to a specific target or antigen (Ag), such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” may encompass any type of antibody, including but not limited to monoclonal antibodies, polyclonal antibodies, antigen-binding fragments (or portion), of intact antibodies that retain the ability to specifically bind to a given antigen (e.g., GDF-15).

[0312] The term “antigen” refers to the molecular entity used for immunization of an immunocompetent vertebrate to produce the antibody that recognizes the Ag or to screen an expression library (e.g., phage, yeast or ribosome display library, among others). Herein, Ag is termed more broadly and is generally intended to include target molecules that are specifically recognized by the Ab, thus including fragments or mimics -77- 146316.8009.WO00\165259190.24of the molecule used in an immunization process for raising the Ab or in library screening for selecting the Ab. Thus, for antibodies of the present technology binding to GDF-15, full-length GDF-15 from mammalian species (e.g., human, monkey, mouse and rat GDF-15), including monomers and multimers, such as dimers, trimers, etc. thereof, as well as truncated and other variants of GDF-15, are referred to as an antigen.

[0313] An “antigen-binding fragment” of an antibody refers to a fragment of a full- length antibody that retains the ability to specifically bind to an antigen (with substantially the same binding affinity). Examples of an antigen-binding fragment includes (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab′)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VHand CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., 1989 Nature 341:544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR), disulfide-linked Fvs (dsFv), and anti-idiotypic (anti-Id) antibodies and intrabodies. Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they may be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VHregions pair to form monovalent molecules (known as single chain Fv (scFv)); see e.g., Bird et al. Science 242:423-426 (1988) and Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883. Other forms of single chain antibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which VHand VLdomains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen-binding sites (see e.g., Holliger et al, 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak et al., 1994, Structure 2:1121-1123).

[0314] An antibody “variable domain” refers to the variable region of the antibody light chain (VL) or the variable region of the antibody heavy chain (VH), either alone or in combination. As known in the art, the variable regions of the heavy and light chains each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs) and contribute to the formation of the antigen-binding site of antibodies. -78- 146316.8009.WO00\165259190.24

[0315] “Complementarity Determining Regions” (CDRs) may be identified according to the definitions of Kabat, Chothia, the accumulation of both Kabat and Chothia, AbM, contact, North, and / or conformational definitions or any method of CDR determination well known in the art. See, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed. (hypervariable regions); Chothia et al., 1989, Nature 342:877-883 (structural loop structures). The identity of the amino acid residues in a particular antibody that make up a CDR may be determined using methods well known in the art. The AbM definition of CDRs is a compromise between Kabat and Chothia and uses Oxford Molecular's AbM antibody modeling software (Accelrys®). The “contact” definition of CDRs is based on observed antigen contacts, set forth in MacCallum et al., 1996, J. Mol. Biol., 262:732-745. The “conformational” definition of CDRs is based on residues that make enthalpic contributions to antigen binding (see, e.g., Makabe et al., 2008, J. Biol. Chem., 283:1156-1166). North has identified canonical CDR conformations using a different preferred set of CDR definitions (North et al., 2011, J. Mol. Biol.406: 228-256). In another approach, referred to herein as the “conformational definition” of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding (Makabe et al., 2008, J Biol. Chem.283:1156-1166). Still other CDR boundary definitions may not strictly follow one of the above approaches but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. As used herein, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches. For any given embodiment containing more than one CDR, the CDRs (or other residue of the antibody) may be defined in accordance with any of Kabat, Chothia, North, extended, AbM, contact, and / or conformational definitions.

[0316] “Framework” (FR) residues are antibody variable domain residues other than the CDR residues. A VH or VL domain framework comprises four framework sub- regions, FR1, FR2, FR3 and FR4, interspersed with CDRs in the following structure: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. -79- 146316.8009.WO00\165259190.24

[0317] As known in the art, a “constant region” of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination.

[0318] The terms “Fc region”, “Fc domain” and “Fc”, as interchangeably used herein refer to the portion of an immunoglobulin (Ig) molecule that correlates to a crystallizable fragment obtained by papain digestion of an Ig molecule. As used herein, the terms relate to the constant region of an antibody excluding the first constant region immunoglobulin domain and further relates to portions of that region. Thus, Fc refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, and the last three constant region immunoglobulin domains of IgE and IgM, and the flexible hinge N-terminal to these domains, or portions thereof. For IgA and IgM, Fc may include the J chain.

[0319] For IgG, Fc comprises immunoglobulin domains Cy2 and Cy3 (C gamma 2 and C gamma 3) and the hinge between Cy1 (C gamma 1) and Cy2 (C gamma 2). Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is usually defined to comprise residues C226 or P230 to its carboxyl-terminus, wherein the numbering is according to the EU index of Edelman et al., 1969, Proc. Natl. Acad. Sci. USA 63(1):78-85 as described in Kabat et al., 1991. Typically, the Fc domain comprises from about amino acid residue 236 to about 447 of the human IgG1 constant domain. An exemplary human wild type IgG1 Fc domain amino acid sequence is set forth in SEQ ID NO:31. Fc polypeptide may refer to this region in isolation, or this region in the context of an antibody, or an antigen-binding portion thereof, or Fc fusion protein.

[0320] The heavy chain constant domain comprises the Fc region and further comprises the CH1 domain and hinge as well as the CH2 and CH3 (and, optionally, CH4 of IgA and IgE) domains of the IgG heavy chain.

[0321] In certain embodiments, the antibody, or antigen-binding fragment thereof, described herein comprises an Fc domain. The Fc domain may be derived from IgA (e.g., IgA1or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0322] An “Fc fusion” protein is a protein wherein one or more polypeptides are operably linked to an Fc polypeptide. An Fc fusion combines the Fc region of an immunoglobulin with a fusion partner. -80- 146316.8009.WO00\165259190.24

[0323] An “epitope” refers to the area or region of an antigen to which an antibody specifically binds, e.g., an area or region comprising residues that interact with the antibody. Epitopes may be linear or conformational.

[0324] At its most detailed level, the epitope for the interaction between the Ag and the Ab may be defined by the spatial coordinates defining the atomic contacts present in the Ag-Ab interaction, as well as information about their relative contributions to the binding thermodynamics. At a less detailed level, the epitope may be characterized by the spatial coordinates defining the atomic contacts between the Ag and Ab. At a further less detailed level the epitope may be characterized by the amino acid residues that it comprises as defined by a specific criterion, e.g., by distance between atoms (e.g., heavy, i.e., non-hydrogen atoms) in the Ab and the Ag. At a further less detailed level the epitope may be characterized through function, e.g., by competition binding with other Abs. The epitope may also be defined more generically as comprising amino acid residues for which substitution by another amino acid will alter the characteristics of the interaction between the Ab and Ag (e.g. using alanine scanning).

[0325] From the fact that descriptions and definitions of epitopes, dependent on the epitope mapping method used, are obtained at different levels of detail, it follows that comparison of epitopes for different Abs on the same Ag may similarly be conducted at different levels of detail.

[0326] Epitopes described at the amino acid level, e.g., determined from an X-ray structure, are said to be identical if they contain the same set of amino acid residues. Epitopes are said to overlap if at least one amino acid is shared by the epitopes. Epitopes are said to be separate (unique) if no amino acid residue is shared by the epitopes.

[0327] Epitopes characterized by competition binding are said to be overlapping if the binding of the corresponding antibodies are mutually exclusive, i.e., binding of one antibody excludes simultaneous or consecutive binding of the other antibody. The epitopes are said to be separate (unique) if the antigen is able to accommodate binding of both corresponding antibodies simultaneously.

[0328] An antibody that “preferentially binds” or “specifically binds” (used interchangeably herein) to an epitope is a term well understood in the art, and methods to determine such specific or preferential binding are also well known in the art. A -81- 146316.8009.WO00\165259190.24molecule is said to exhibit “specific binding” or “preferential binding” if it reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with a particular cell or substance than it does with alternative cells or substances. An antibody “specifically binds” or “preferentially binds” to a target if it binds with greater affinity, avidity, more readily, and / or with greater duration than it binds to other substances. For example, an antibody that specifically or preferentially binds to a GDF-15, PD-1 or PD-L1 epitope is an antibody that binds this epitope with greater affinity, avidity, more readily, and / or with greater duration than it binds to other GDF-15, PD-1 or PD-L1 epitopes or non-GDF-15, PD-1, PD-L1 epitopes. Generally, but not necessarily, reference to binding means preferential binding. “Specific binding” or “preferential binding” includes a compound, e.g., a protein, a nucleic acid, an antibody, and the like, which recognizes and binds to a specific molecule in a sample, but does not substantially recognize or bind other molecules in the sample. For instance, an antibody or a peptide receptor which recognizes and binds to a cognate ligand or binding partner (e.g., an anti-GDF-15 antigen antibody that binds a GDF-15 antigen, a molecule that binds GDF-15, etc.) in a sample but does not substantially recognize or bind other molecules in the sample, specifically binds to that cognate ligand or binding partner. Thus, under designated assay conditions, the specified binding moiety (e.g., an antibody or an antigen-binding portion thereof or a receptor or a ligand binding portion thereof) binds preferentially to a particular target molecule and does not bind in a significant amount to other components present in a test sample.

[0329] A variety of assay formats may be used to select an antibody or peptide that specifically binds a molecule of interest. For example, solid-phase ELISA immunoassay, immunoprecipitation, BIAcore™ (GE Healthcare, Piscataway, N.J.), fluorescence-activated cell sorting (FACS), Octet™ (ForteDo, Inc., Menlo Park, Calif.) and Western blot analysis are among many assays that may be used to identify an antibody that specifically reacts with an antigen or a receptor, or ligand binding portion thereof, that specifically binds with a cognate ligand or binding partner. Typically, a specific or selective reaction will be at least twice background signal or noise and more typically more than 10 times background, even more specifically, an antibody is said to “specifically bind” an antigen when the equilibrium dissociation constant (KD) is 1 pM, 100 nM, more 10 nM, even more , 100 pM, yet more , 10 pM, and even more , 1 pM. -82- 146316.8009.WO00\165259190.24

[0330] The term “compete”, as used herein with regard to an antibody, means that binding of a first antibody, or an antigen-binding portion thereof, to an antigen reduces the subsequent binding of the same antigen by a second antibody or an antigen-binding portion thereof. In general, the binding a first antibody creates steric hindrance, conformational change, or binding to a common epitope (or portion thereof), such that the binding of the second antibody to the same antigen is reduced. Standard competition assays may be used to determine whether two antibodies compete with each other. One suitable assay for antibody competition involves the use of the Biacore technology, which may measure the extent of interactions using surface plasmon resonance (SPR) technology, typically using a biosensor system (such as a BIACORE system). For example, SPR may be used in an in vitro competitive binding inhibition assay to determine the ability of one antibody to inhibit the binding of a second antibody. Another assay for measuring antibody competition uses an ELISA-based approach.

[0331] The antibodies of the present technology further comprise antibody variants thereof. A variant antibody may comprise 1, 2, 3, 4, 5, up to 10, up to 20, up to 30 or more amino acid substitutions and / or deletions and / or insertions from the specific sequences and fragments discussed above. “Deletion” variants may comprise the deletion of individual amino acids, deletion of small groups of amino acids such as 2, 3, 4 or 5 amino acids, or deletion of larger amino acid regions, such as the deletion of specific amino acid domains or other features. “Insertion” variants may comprise the insertion of individual amino acids, insertion of small groups of amino acids such as 2, 3, 4 or 5 amino acids, or insertion of larger amino acid regions, such as the insertion of specific amino acid domains or other features. “Substitution” variants involve the replacement of one or more amino acids with the same number of amino acids and making conservative amino acid substitutions. For example, an amino acid may be substituted with an alternative amino acid having similar properties, for example, another basic amino acid, another acidic amino acid, another neutral amino acid, another charged amino acid, another hydrophilic amino acid, another hydrophobic amino acid, another polar amino acid, another aromatic amino acid or another aliphatic amino acid. Some properties of the 20 main amino acids which may be used to select suitable substituents are as follows.

[0332] In a process known as “germlining”, certain amino acids in the VH and VL sequences may be mutated to match those found naturally in germline VHand VL-83- 146316.8009.WO00\165259190.24sequences. In particular, the amino acid sequences of the framework regions in the VH and VLsequences may be mutated to match the germline sequences to reduce the risk of immunogenicity when the antibody is administered. As used herein, the term “germline” refers to the nucleotide sequences and amino acid sequences of the antibody genes and gene segments as they are passed from parents to offspring via the germ cells. This germline sequence is distinguished from the nucleotide sequences encoding antibodies in mature B cells which have been altered by recombination and hypermutation events during the course of B cell maturation. An antibody that “utilizes” a particular germline has a nucleotide or amino acid sequence that most closely aligns with that germline nucleotide sequence or with the amino acid sequence that it specifies. Such antibodies frequently are mutated compared with the germline sequence. Germline DNA sequences for human VHand VLgenes are known in the art.

[0333] The disclosure of all publications, patents, and published patent applications listed herein are hereby incorporated by reference, including but not limited to U.S. Patent No. 9,534,018, U.S. Patent Application No. 16 / 541,817; WIPO International Application No. PCT / IB2021 / 054970. Compositions

[0334] The present technology comprises compositions having (i) a first compound having primary therapeutic efficacy, and (ii) a second compound and / or (iii) a third compound each having secondary therapeutic efficacy. The first compound may comprise a non-naturally occurring melanocortin analog. The second compound may comprise a spiro compound. The third compound may comprise an antibody or antigen binding fragment thereof. First Compounds: Non-Naturally Occurring Melanocortin Analogs

[0335] The first compounds of the present technology may comprise a non- naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin 3 receptor (MC3R) and / or a melanocortin 4 receptor (MC4R) antagonist, agonist, or inverse agonist. The first compound may exert therapeutic effects following antagonism of the MC3R and / or the MC4R. Non-naturally Occurring Melanocortin Analog Formulas -84- 146316.8009.WO00\165259190.24

[0336] In some embodiments, the first compound present in the composition of the present technology comprises a non-naturally occurring melanocortin analog comprising 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 cysteine, methylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, 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 D-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 (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D- tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, 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), alanine, D-alanine, D-methionine, valine, D-valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, succinic acid, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4- carboxylic acid (APPC), 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), proline, -85- 146316.8009.WO00\165259190.24cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D- Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)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, cysteine, Nal(1’), 4-amino- 1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one (Aia), phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of glycine, glutamic acid, cysteine, lysine, 2,3-diamino-propionic acid, methionine, proline, tryptophan, D-Nal(2′), 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-R20are 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, 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, 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- -86- 146316.8009.WO00\165259190.24leucine, 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; X3is 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, β-alanine, D- threonine, L-threonine, β-threonine, D-valine, L-valine, β-valine, (3-methyl)-β-valine, D- leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, L-proline, D- proline, β-homo proline, a piperazin-2-one ring, 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, β- homo proline, a piperazin-2-one ring, D-threonine, L-threonine, β-threonine, D-valine, L-valine, β-valine, (3-methyl)-β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L- isoleucine, β-isoleucine, 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, L- threonine, D-alanine, L-alanine, D-proline, L-proline, D-valine, L-valine, β-valine, (3- methyl)-β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β- isoleucine, and a piperazin-2-one ring; Y4is absent or is 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: -87- 146316.8009.WO00\165259190.24a disulfide bond between R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; X1X2X3represents an optionally present N-terminus; and Y1Y2Y3Y4Y5Y6Y7Y8represents a C-terminus.

[0337] In some embodiments of Formula (I): R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, methylated D-phenylalanine, succinic acid, o-phthalic acid, tyrosine, 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 D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D- leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert- leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Nva), acetylated glycine, acetylated D-proline, acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, cysteine, norleucine, arginine, succinic acid, -88- 146316.8009.WO00\165259190.24glutaric 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), alanine, D-alanine, D-methionine, valine, D-valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, succinic acid, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4- carboxylic acid (APPC), 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), proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D- Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)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, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of glycine, aspartic acid, glutamic acid, cysteine, lysine, 2,3-diaminopropionic acid, methionine, proline, tryptophan, D-Nal(2′), 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-R20are each independently absent or selected from the group consisting of cysteine, norleucine, tyrosine, aspartic acid, leucine, isoleucine, valine, norvaline, -89- 146316.8009.WO00\165259190.24alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, arginine, histidine, hydroxyproline, D-hydroxyproline, 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, 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; X3is 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, D-valine, L- valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, 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, 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; -90- 146316.8009.WO00\165259190.24Y5is 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; 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.

[0338] In some embodiments of Formula (I): R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, tyrosine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, acetylated D- methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert- leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, -91- 146316.8009.WO00\165259190.24acetylated D-phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D-asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, 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), alanine, D-alanine, D- methionine, valine, D-valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4-aminophenylpiperidine-4-carboxylic acid (APPC), 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), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, proline, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D- Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, D-Nal(2′), L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of glycine, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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; -92- 146316.8009.WO00\165259190.24R11-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-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, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-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, 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, 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: -93- 146316.8009.WO00\165259190.24a disulfide bond between R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified.

[0339] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein: R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D- asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, -94- 146316.8009.WO00\165259190.24norleucine, 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), alanine, D-alanine, D- methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4- aminophenylpiperidine-4-carboxylic acid (APPC), 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), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-alanine, D-arginine, L- -95- 146316.8009.WO00\165259190.24arginine, D-valine, L-valine, D-leucine, L-leucine, D-isoleucine, L-isoleucine, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-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, 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, 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-proline, L-proline, D- valine, and L-valine; Y4is absent or is 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; -96- 146316.8009.WO00\165259190.24a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent.

[0340] In some embodiments, the non-naturally occurring melanocortin analog has one or more beta hairpin (β-hairpin) and / or beta turn (β-turn) structures. In some embodiments, R3of the sequence according to Formula (I), which may be hydroxyproline, hydroxy-D-proline, D-alanine, D-methionine, D-valine, prolylglycine (Pro-Gly), glycine, provides the β-hairpin and / or β-turn structures of the non-naturally occurring melanocortin analog. In some embodiments, the disulfide bond of the -97- 146316.8009.WO00\165259190.24sequence according to Formula (I), if present, provides the β-hairpin and / or β-turn structures of the non-naturally occurring melanocortin analog.

[0341] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by a functional group selected from the group consisting of an acyl group, an imine group, an amide group, a urea group, a carbamate group, a sulfonamide group, and an alkylamine group.

[0342] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group. In some embodiments,melanocortin analog, if present, is modified by an imine group.

[0344] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an amide group. In some embodiments, the amide group is a pyroglutamyl (pGlu) ). In some embodiments, the amide group).are not limitednd ing melanocortin analog, if present, is not modified.

[0347] As discussed above, Y1Y2Y3Y4Y5Y6Y7Y8represents a C-terminus of the non-naturally occurring melanocortin analog. In some embodiments, Y1-Y8are absent. In some embodiments, Y1is present and Y2-Y8are absent.

[0348] In some embodiments, Y3-Y8are absent. In some embodiments, Y3-Y8are absent, and Y1is D-valine and Y2is D-proline, or Y1is D-proline and Y2is D-valine.

[0349] In some embodiments, Y3is present and Y4-Y8are absent. In some embodiments, Y3is present and Y4-Y8are absent, and (i) Y1is D-valine or D-proline, (ii) Y2is D-valine or D-proline, and / or (iii) Y3is D-valine or D-proline. In some embodiments, Y3is present and Y4-Y8are absent, and (i) Y1is D-valine, Y2is D-valine, and Y3is D- proline, (ii) Y1is D-proline, Y2is D-valine, and Y3is D-valine, or (iii) Y1is D-valine, Y2is D-proline, and Y3is D-valine.

[0350] In some embodiments, Y3and Y4are present, and Y5-Y8are absent. In some embodiments, Y3and Y4are present, and Y5-Y8are absent, and (i) Y1is D-valine or D-proline, (ii) Y2is D-valine or D-proline, (iii) Y3is D-valine or D-proline, and / or (iv) Y4is D-valine or D-proline. In some embodiments, Y3and Y4are present, and Y5-Y8are absent, and (i) Y1is D-valine, Y2is D-valine, Y3is D-valine, and Y4is D-proline, (ii) Y1is D-proline, Y2is D-valine, Y3is D-valine, and Y4is D-valine, (iii) Y1is D-valine, Y2is D- proline, Y3is D-valine, and Y4is D-valine, or (iv) Y1is D-valine, Y2is D-valine, Y3is D- proline, and Y4is D-valine.

[0351] In some embodiments, the C-terminus includes additional derivatives to extend the length of C-terminus of the non-naturally occurring melanocortin analog. Exemplary additional C-terminus include, but are not limited to, Y1Y2Y3Y4Y5Y6Y7Y8Y9, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14, -99- 146316.8009.WO00\165259190.24Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20Y21, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20Y21Y22, Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20Y21Y22Y23, and Y1Y2Y3Y4Y5Y6Y7Y8Y9Y10Y11Y12Y13Y14Y15Y16Y17Y18Y19Y20Y21Y22Y23Y24, etc., wherein Y9- Y24, if present, are each independently D-proline or D-valine.

[0352] 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.

[0353] In some embodiments, the C-terminus of the non-naturally occurring ,aryl amide group. In some embodiments, the N-arylor

[0354] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified by an ester group ,). embodiments, the C-terminus of the non-naturally occurringmelanocortin analog is modified by an aldehyde (e.g., ).

[0356] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is not modified. In some embodiments, the C-terminus of 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 (SEQ ID NO: 305; B07a).

[0357] In some embodiments, R1is absent, and R2is D-aspartic acid. In some embodiments, R1is acetylated norleucine, and R2is D-aspartic acid.

[0358] In some embodiments, X1, X2, and X3are absent. In some embodiments, X1is present and X2and X3are absent.

[0359] In some embodiments, R4is not D-phenylalanine. In some embodiments, R4is D-Nal(2′).

[0360] In some embodiments, the non-naturally occurring melanocortin analog described herein 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-R20are selected from the group consisting of cysteine, Pen, and dPen; a lactam bridge between R1and R7when R1is norleucine and R7is glutamic acid; a side-chain lactam bridge between R1and any of R5-8when R1is aspartic acid and any of R5-8are lysine; a side-chain lactam bridge between R1and R6when R1is lysine and R6is aspartic acid; a side-chain lactam bridge between R2and R7when R2is glutamic acid, aspartic acid, or CO-cis-CH═CH—CO, and R7is lysine or ornithine; a side-chain lactam -101- 146316.8009.WO00\165259190.24bridge between R2and R8when R2is glutamic acid or aspartic acid, R8is lysine, and R7is glycine, proline or tryptophan; a side-chain lactam bridge between R2or R4and any R10when R2or R4is 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 / or a lactam closure between R2and R7when R2is succinic acid and R7is 2,3-diamino- propionic acid. Cyclization may also occur from any of the X residues (optional stabilizing N-terminus residues). For example, X2may be an aspartic acid that may be used for cyclization.

[0361] 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 hydroxy-D-proline, R4is dNal(2′), R5is arginine, R6is D-tryptophan or L-tryptophan, R7is lysine, Y1is D-valine, and / or Y2is D-proline.

[0362] 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: 306; B07) or Ac-Nle-c(Asp-Hyp- dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 307; D3), wherein c represents cyclization through R2and R7via a lactam bond.

[0363] In some embodiments, R1, R2, R7, and R8are present and R9-R20are absent, and the sequence of Formula (I) is cyclized through R2and R8via a lactam bond. In some embodiments, R1is acetylated norleucine, R2is aspartic acid, R3is selected from the group consisting of proline, hydroxyproline, hydroxy-D-proline, phenylalanine, and histidine, R4is histidine or dNal(2′), R5is dNal(2′) or arginine, R6is selected from the group consisting of arginine, D-tryptophan, and L-tryptophan, R7is tryptophan or proline, R8is lysine, Y1is selected from the group consisting of D-valine, D-leucine, and D-isoleucine, and / or Y2is D-proline.

[0364] 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: 308; D1); Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 309; D1γ); Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2(SEQ ID NO: 310; D1δ); -102- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 311; D2); and Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO: 312; D4), wherein c represents cyclization through R2and R8via a lactam bond.

[0365] In some embodiments, R1-R2and R7-R10are present and R11-R20are absent, and 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: 313; D1α), wherein c represents cyclization through R2and R10via a lactam bond. In some embodiments, R1-R2and R7-R10are present and R11-R20are absent, and the sequence of Formula (I) is cyclized through R4and R10via 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: 314; D1β), wherein c represents cyclization through R4and R10via a lactam bond.

[0366] 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- dVal-dPro-NH2 (SEQ ID NO: 315; A1).

[0367] 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: 316); Ac-dMet-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 317); Ac-dIle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 318); Ac-dLeu-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 319); Ac-dVal-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 320); Ac-dAla-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 321); Ac-Ala-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 322); Ac-Tle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 323); -103- 146316.8009.WO00\165259190.24Ac-dTle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 324); Ac-dNle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 325); Ac-Nva-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 326); Ac-Gly-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 327); Ac-dPro-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 328); Ac-dCys-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 329); Ac-dPhe-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 330); Ac-dTyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 331); Ac-dGln-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 332); and Ac-dAsn-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 333), wherein c represents cyclization through R2and R7via a lactam bond.

[0368] 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: 334); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dLys)-dVal-dPro-NH2 (SEQ ID NO: 335); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 336); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 337); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 339); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 340); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 341); -104- 146316.8009.WO00\165259190.24Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 342); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 343); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 344); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 345); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 346); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 347); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 348); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 349); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 350); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 351); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 352); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 353); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 354); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 355); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 356); Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 357); Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 358); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 359); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO: 360); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2(SEQ ID NO: 361); Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2(SEQ ID NO: 362); and Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2(SEQ ID NO: 363), wherein c represents cyclization through R2and R6or R7via a lactam bond or a disulfide bond.

[0369] 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 -105- 146316.8009.WO00\165259190.24some 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: 364); Ac-Nle-c(Asp-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 365); Ac-Nle-c(Asp-dPro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 366); Ac-Nle-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 367); Ac-Nle-c(Asp-dMet-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 368); Ac-Nle-c(Asp-Pro-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 369); Ac-Nle-c(Asp-Gly-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 370); Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 371); Ac-Nle-c(Asp-Leu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 372); Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 373); and Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 374), wherein c represents cyclization through R2and R7via a lactam bond.

[0370] In some embodiments of the sequence of Formula (I), R5is Arg. Alternatively, in some embodiments, R5is absent or an amino acid other than Arg. In 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: 375); Ac-Nle-c(Asp-Pro-dNal(2’)-Lys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 376); Ac-Nle-c(Asp-Pro-dNal(2’)-dLys-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 377); Ac-Nle-c(Asp-Pro-dNal(2’)-dArg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 378); Ac-Nle-c(Asp-Pro-dNal(2’)-Orn-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 379); Ac-Nle-c(Asp-Pro-dNal(2’)-dOrn-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 380); Ac-Nle-c(Asp-Pro-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 381); Ac-Nle-c(Asp-Pro-dNal(2’)-Ala-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 382); Ac-Nle-c(Asp-Pro-dNal(2’)-Gly-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 383); -106- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-dNal(2’)-Asp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 384); and Ac-Nle-c(Asp-Pro-dNal(2’)-Glu-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 385), wherein c represents cyclization through R2and R7via a lactam bond.

[0371] 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: 386); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Nal(1’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 387); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aia-Lys)-dVal-dPro-NH2(SEQ ID NO: 388); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Phe-Lys)-dVal-dPro-NH2(SEQ ID NO: 389); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Tyr-Lys)-dVal-dPro-NH2(SEQ ID NO: 390); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-His-Lys)-dVal-dPro-NH2 (SEQ ID NO: 391); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Ala-Lys)-dVal-dPro-NH2 (SEQ ID NO: 392), wherein c represents cyclization through R2and R7via a lactam bond.

[0372] 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-Bip-Arg- Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 393), wherein c represents cyclization through R2and R7via a lactam bond.

[0373] 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.

[0374] 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 -107- 146316.8009.WO00\165259190.24embodiments, 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.

[0375] In embodiments of Formula (I) when Y1is an amino acid other than dVal, then Y1is selected from dPro, Val, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, dAsn, Lys, and dLys. In embodiments of Formula (I) when Y2is an amino acid other than dPro, then Y2or selected from dVal, Val, Hyp, dHyp, Pro, Ala, dAla, Gly, Asp, Arg, Asn, dAsp, dArg, and dAsn. 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: 394); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-OH (SEQ ID NO: 395); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-OH (SEQ ID NO: 396); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Hyp-NH2(SEQ ID NO: 397); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dHyp-NH2 (SEQ ID NO: 398); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-Hyp-NH2 (SEQ ID NO: 399); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-dHyp-NH2 (SEQ ID NO: 400); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-dVal-NH2 (SEQ ID NO: 401); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-dVal-NH2 (SEQ ID NO: 402); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-Val-NH2(SEQ ID NO: 403); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-Val-NH2(SEQ ID NO: 404); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-NH2(SEQ ID NO: 405); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dPro-NH2(SEQ ID NO: 406); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-NH2 (SEQ ID NO: 407); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-NH2 (SEQ ID NO: 408); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-NH2 (SEQ ID NO: 409); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Pro-NH2 (SEQ ID NO: 410); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Ala-NH2 (SEQ ID NO: 411); -108- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAla-NH2 (SEQ ID NO: 412); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-NH2(SEQ ID NO: 413); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-NH2(SEQ ID NO: 414); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAla-dAla-NH2(SEQ ID NO: 415); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Ala-Ala-NH2(SEQ ID NO: 416); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Gly-Gly-NH2 (SEQ ID NO: 417); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Asp-NH2 (SEQ ID NO: 418); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Arg-NH2 (SEQ ID NO: 419); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Asn-NH2 (SEQ ID NO: 420); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dAsp-NH2 (SEQ ID NO: 421); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dArg-NH2(SEQ ID NO: 422); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dAsn-NH2(SEQ ID NO: 423); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asp-dPro-NH2(SEQ ID NO: 424); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dPro-NH2 (SEQ ID NO: 425); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asn-dPro-NH2 (SEQ ID NO: 426); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsp-dPro-NH2 (SEQ ID NO: 427); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dPro-NH2 (SEQ ID NO: 428); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsn-dPro-NH2 (SEQ ID NO: 429); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asp-NH2(SEQ ID NO: 430); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-NH2(SEQ ID NO: 431); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asn-NH2(SEQ ID NO: 432); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsp-NH2(SEQ ID NO: 433); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-NH2 (SEQ ID NO: 434); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsn-NH2 (SEQ ID NO: 435); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Pro-Val-NH2 (SEQ ID NO: 436); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-dVal-NH2 (SEQ ID NO: 437); -109- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-dVal-NH2 (SEQ ID NO: 438); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-NH2(SEQ ID NO: 439); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-NH2(SEQ ID NO: 440); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Val-Pro-NH2(SEQ ID NO: 441); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dVal-dPro-NH2(SEQ ID NO: 442); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dVal-dPro-NH2 (SEQ ID NO: 443); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Pro-Val-NH2 (SEQ ID NO: 444); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dPro-dVal-NH2 (SEQ ID NO: 445); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dPro-dVal-NH2 (SEQ ID NO: 446); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Val-Pro-NH2 (SEQ ID NO: 447); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dVal-dPro-NH2(SEQ ID NO: 448); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dVal-dPro-NH2(SEQ ID NO: 449), wherein c represents cyclization through R2and R7via a lactam bond.

[0376] 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 from 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 from 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: Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dPro-NH2(SEQ ID NO: 450); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-dPro-NH2(SEQ ID NO: 451); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 452); -110- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2 (SEQ ID NO: 453); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH2 (SEQ ID NO: 454), wherein c represents cyclization through R2and R7via a lactam bond.

[0377] In some embodiments, 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: 455); Ac-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 456); and Ac-Nle-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 457), wherein c represents cyclization through R2and R7via a lactam bond.

[0378] 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 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 non-naturally occurring melanocortin analog 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: 458); Ac-Nle-c(Asp-Trp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 459); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dTrp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 460); c(CO-cis-CH = CH-CO-Pro-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 461); Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 462); Ac-Nle-c(Asp-β-Ala-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 463); -111- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Mamb-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 464); Ac-Nle-c(Asp-Acpc-dNal(2′) Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 465); Ac-c(Cys-Arg-dPhe-Cys)-Trp-dVal-dPro-NH2(SEQ ID NO: 466); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Trp-NH2(SEQ ID NO: 467), wherein c represents cyclization through R1or R2and R7or R8via a lactam bond or through R2and R5via a disulfide bond.

[0379] Some 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 non-naturally occurring melanocortin analog binds the melanocortin 4 receptor with greater affinity than the melanocortin 3 receptor, then the sequence of Formula (I) is: Ac-Nle-c(Asp-Aic-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 468); or Ac-Nle-c(Asp-Cpe-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 469), wherein c represents cyclization through R2and R7via a lactam bond.

[0380] 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.

[0381] Alternatively, in some embodiments, the non-naturally occurring melanocortin analog comprises a sequence selected from the group consisting of: Ac-Nle-c(Asp-His-Arg-p(I)dPhe-Arg-Tic-Lys)-dVal-dPro-NH2 (SEQ ID NO: 470); Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 471); Ac-Nle-c(Asp-Atc-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 472); Ac-Nle-c(Asp-APC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 473); Ac-Nle-c(Asp-APPC-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 474); -112- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 475); Ac-Nle-c(Asp-Pro-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 476); Ac-Nle-c(Asp-His-p(I)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 478); Ac-Nle-c(Asp-Pro-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 479); Ac-Nle-c(Asp-Pro-dPhe-Arg-dTrp-Lys)-dVal-dPro-NH2(SEQ ID NO: 480); Ac-Nle-c(Asp-Pro-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 481); Ac-Nle-c(Asp-His-p(Cl)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 482); Ac-Nle-c(Asp-His-p(Br)dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 483); Ac-Nle-c(Asp-Trp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 484), wherein c represents cyclization through R1or R2and R7via a lactam bond.

[0382] 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 (SEQ ID NO: 485); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 486); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 487); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dThr-dPro-dThr (SEQ ID NO: 488); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO: 489); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO: 490); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 491); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dPro-dVal-NH2 (SEQ ID NO: 492); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 306); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 493); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO: 494); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO: 495); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Val-NH2(SEQ ID NO: 496); -113- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Val-NH2 (SEQ ID NO: 497); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Val-NH2(SEQ ID NO: 498); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Val-NH2(SEQ ID NO: 499); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Pro-NH2(SEQ ID NO: 500); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Pro-NH2(SEQ ID NO: 501); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Pro-NH2 (SEQ ID NO: 502); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Pro-NH2 (SEQ ID NO: 503); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Pro-NH2 (SEQ ID NO: 504); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Pro-NH2 (SEQ ID NO: 505); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Pro-NH2 (SEQ ID NO: 506); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Pro-NH2(SEQ ID NO: 507); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Val-NH2(SEQ ID NO: 508); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Val-NH2(SEQ ID NO: 509); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Val-NH2 (SEQ ID NO: 510); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Val-NH2 (SEQ ID NO: 511); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Val-NH2 (SEQ ID NO: 512); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Val-NH2(SEQ ID NO: 513); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Val-NH2(SEQ ID NO: 514); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Val-NH2(SEQ ID NO: 515); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO: 516); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Pro-NH2(SEQ ID NO: 517); -114- 146316.8009.WO00\165259190.24Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO: 518); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Pro-NH2 (SEQ ID NO: 519); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 520); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 521); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 522); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Thr-β-Pro-β-Thr (SEQ ID NO: 523); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 524); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 525); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dPro-dAla-NH2 (SEQ ID NO: 526); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 527); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO: 528); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO: 529); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dAla-dPro-NH2(SEQ ID NO: 530); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dAla-dPro-NH2 (SEQ ID NO: 531); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Ala-NH2 (SEQ ID NO: 532); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Ala-NH2 (SEQ ID NO: 533); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Ala-NH2 (SEQ ID NO: 534); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Ala-NH2 (SEQ ID NO: 535); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Ala-β-Pro-NH2(SEQ ID NO: 536); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Ala-β-Pro-NH2(SEQ ID NO: 537); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Ala-β-Pro-NH2(SEQ ID NO: 538); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Ala-β-Pro-NH2(SEQ ID NO: 539); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Ala-NH2 (SEQ ID NO: 540); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Ala-NH2 (SEQ ID NO: 541); -115- 146316.8009.WO00\165259190.24Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Ala-NH2 (SEQ ID NO: 542); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Ala-NH2(SEQ ID NO: 543); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Ala-NH2(SEQ ID NO: 544); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO: 545); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO: 546); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO: 547) Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO: 548); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO: 549); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO: 550); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 551); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 552); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 553); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 554); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 555); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO: 556); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Pro-β-Leu-NH2(SEQ ID NO: 557); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO: 558); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Leu-NH2(SEQ ID NO: 559); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 560); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 561); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 562); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 563); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Leu-NH2 (SEQ ID NO: 564); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-β-Val-β-Leu-NH2(SEQ ID NO: 565); -116- 146316.8009.WO00\165259190.24Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 566); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Val-β-Leu-NH2(SEQ ID NO: 567); Ac-Nle-c(Asp-Pro-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 568); Ac-Nle-c(Asp-His-dNal(2′)-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 569); Ac-Nle-c(dAsp-Pro-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 570); and Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 571), wherein c represents cyclization through R1and R7via a lactam bond.

[0383] 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-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 572); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dThr-dPro-dThr (SEQ ID NO: 573); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dThr-dPro-dThr (SEQ ID NO: 574); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-Dlys)-dThr-dPro-dThr (SEQ ID NO: 575); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 576); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-dPro-dVal-NH2 (SEQ ID NO: 577); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2 (SEQ ID NO: 578); Ac-Nle-c(Asp-His-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-NH2(SEQ ID NO: 579); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 580); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 581); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dVal-dPro-NH2(SEQ ID NO: 582); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-DLys)-dVal-dPro-NH2 (SEQ ID NO: 583); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βVal-NH2 (SEQ ID NO: 584); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βVal-NH2 (SEQ ID NO: 585); -117- 146316.8009.WO00\165259190.24Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βPro-βVal-NH2 (SEQ ID NO: 586); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βPro-βVal-NH2(SEQ ID NO: 587); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βPro-NH2(SEQ ID NO: 588); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βPro-NH2(SEQ ID NO: 589); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βVal-βPro-NH2(SEQ ID NO: 590); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-DLys)-βVal-βPro-NH2 (SEQ ID NO: 591); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βPro-NH2 (SEQ ID NO: 592); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βPro-NH2 (SEQ ID NO: 593); Ac-Nle-c(dAsp-Pro-dNal(2’)-Arg-Trp-DLys)-βPro-βPro-NH2 (SEQ ID NO: 594); Ac-Nle-c(dAsp-His-dNal(2’)-Arg-Trp-DLys)-βPro-βPro-NH2 (SEQ ID NO: 595); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βVal-NH2(SEQ ID NO: 596); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βVal-NH2(SEQ ID NO: 597); Ac-Nle-c(dAsp-Pro-Phe-Arg-Trp-DLys)-βVal-βVal-NH2(SEQ ID NO: 598); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βVal-βVal-NH2 (SEQ ID NO: 599); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO: 600); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO: 601); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO: 602); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βVal-NH2 (SEQ ID NO: 603); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βPro-NH2(SEQ ID NO: 604); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βPro-NH2(SEQ ID NO: 605); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βPro-NH2(SEQ ID NO: 606); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βPro-NH2(SEQ ID NO: 607); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βThr-βPro-βThr (SEQ ID NO: 608); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βThr-βPro-βThr (SEQ ID NO: 609); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βThr-βPro-βThr (SEQ ID NO: 610); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βThr-βPro-βThr (SEQ ID NO: 611); -118- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2 (SEQ ID NO: 612); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dAla-NH2(SEQ ID NO: 613); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dPro-dAla-NH2(SEQ ID NO: 614); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-dPro-dAla-NH2(SEQ ID NO: 615); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2(SEQ ID NO: 616); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dAla-dPro-NH2 (SEQ ID NO: 617); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-dAla-dPro-NH2 (SEQ ID NO: 618); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-dAla-dPro-NH2 (SEQ ID NO: 619); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βPro-βAla-NH2 (SEQ ID NO: 620); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βPro-βAla-NH2 (SEQ ID NO: 621); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βPro-βAla-NH2(SEQ ID NO: 622); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βPro-βAla-NH2(SEQ ID NO: 623); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βAla-βPro-NH2(SEQ ID NO: 624); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βAla-βPro-NH2 (SEQ ID NO: 625); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βAla-βPro-NH2 (SEQ ID NO: 626); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βAla-βPro-NH2 (SEQ ID NO: 627); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-βVal-βAla-NH2 (SEQ ID NO: 628); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-βVal-βAla-NH2 (SEQ ID NO: 629); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-βVal-βAla-NH2(SEQ ID NO: 630); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-DLys)-βVal-βAla-NH2(SEQ ID NO: 631); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βAla-NH2(SEQ ID NO: 632); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-βVal-βAla-NH2(SEQ ID NO: 633); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-DLys)-(3-methyl)-βVal-βAla-NH2 (SEQ ID NO: 634); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Ala-NH2 (SEQ ID NO: 635); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 636); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2 (SEQ ID NO: 637); -119- 146316.8009.WO00\165259190.24Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dPro-dLeu-NH2 (SEQ ID NO: 638); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dPro-dLeu-NH2(SEQ ID NO: 639); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2(SEQ ID NO: 640); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-dLeu-dPro-NH2(SEQ ID NO: 641); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2(SEQ ID NO: 642); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-dLeu-dPro-NH2 (SEQ ID NO: 643); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 644); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 645); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 646); Ac-Nle-c(dAsp-His-dNal(2′)-Arg-Trp-dLys)-β-Pro-β-Leu-NH2 (SEQ ID NO: 647); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Leu-β-Pro-NH2(SEQ ID NO: 648); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Leu-β-Pro-NH2(SEQ ID NO: 649); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Leu-β-Pro-NH2(SEQ ID NO: 650); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-β-Leu-β-Pro-NH2 (SEQ ID NO: 651); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-β-Val-β-Leu-NH2 (SEQ ID NO: 652); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-β-Val-β-Leu-NH2 (SEQ ID NO: 653); Ac-Nle-c(dAsp-Pro-dPhe-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 654); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-β-Val-β-Leu-NH2 (SEQ ID NO: 655); Ac-Nle-c(Asp-Pro-dPhe-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 656); Ac-Nle-c(Asp-His-dPhe-Arg-Trp-Lys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 657); Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2(SEQ ID NO: 658); and Ac-Nle-c(dAsp-His-dPhe-Arg-Trp-dLys)-(3-methyl)-β-Val-β-Leu-NH2 (SEQ ID NO: 659), wherein c represents cyclization through R1and R7via a lactam bond.

[0384] In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin receptor antagonist, such as a melanocortin 3 receptor and / or a -120- 146316.8009.WO00\165259190.24melanocortin 4 receptor antagonist. In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin receptor agonist, such as a melanocortin 1 receptor, melanocortin 3 receptor, melanocortin 4 receptor, and / or melanocortin 5 receptor agonist. For example, in some embodiments, the melanocortin analog has agonist activity at the melanocortin 3 receptor and / or the melanocortin 4 receptor, as well as the melanocortin 1 and melanocortin 5 receptors. In other embodiments, the melanocortin analog has antagonist activity at the melanocortin 3 receptor and / or the melanocortin 4 receptor, as well as agonist activity at the melanocortin 1 and melanocortin 5 receptors.

[0385] In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 305-659. In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID Nos: 305-469, 481-483, and 485-571. In some embodiments, the non- naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID Nos: 305-469 and 481-483. In some embodiments, the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID Nos: 306, 428, 481-483,493-495, 528-531, and 552-555.

[0386] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO: 306 (TCMCB07). The structure of TCMCB07 (“B07”), which comprises Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2, is shown below: -121- 146316.8009.WO00\165259190.24. Additional Embodiments of Melanocortin Analogs

[0387] Additional aspects of melanocortin analogs that may be used in the compositions are described below.

[0388] The non-naturally occurring melanocortin analog is represented by Formula (I), as shown above, and comprises a non-naturally occurring melanocortin analog coupled to a degradation-resistant C-terminal extension and an optional N-terminal extension.

[0389] Collectively, R1to R20 maybe one of many known melanocortin analogs, wherein each of the seven residues is independently an amino acid or peptide mimetic. Some melanocortin analogs have less than seven residues. In one aspect, R1to R7, collectively, represent alpha (α)-melanocortin analogs. In another aspect, R1to R7, collectively, represent melanocortin analogs, which bind to MC3, MC4, and / or MC5 receptors as agonists, inverse agonists, or antagonists.

[0390] Presence of a C-terminal extension on the non-naturally occurring melanocortin analog of the present technology may confer degradation-resistance to the sequence, prevent exposure of the RFamide sequence, and / or facilitate trans- epithelial transport. -122- 146316.8009.WO00\165259190.24

[0391] In some embodiments, a proline mimetic (piperazin-2-one ring) is substituted for D-Pro at the C-terminal extension. In one approach, a proline mimetic is synthesized as described in Teixido et al., Brain Res Bull, 2007, 73(1-3): 103-107. The piperazin-2-one ring is also discussed in Bhatt and Just, Helvetica Chimica Acta 83: 722-727 (2000). For the replacement of proline with a piperazin-2-one ring, an ethylene bridge is incorporated between the nitrogen molecules of two adjacent α-amino groups. This produces a six-membered ring, containing two nitrogen and four carbon atoms, a structure that is similar to a proline ring (albeit six-membered) between the two adjacent amino acid residue functional groups.

[0392] The C-terminal extension of the non-naturally occurring melanocortin analog is resistant to substantial degradation prior to the peptide being cleared from the bloodstream in the human or animal body. Further, the C-terminal extension has sufficient stability such that the non-naturally occurring melanocortin analog does not cause cardiovascular effects or has minimized cardiovascular effects when administered to a human or animal. As stability of peptides, amino acids, and small molecules varies widely, melanocortin analogs described herein have variable length C-terminal extensions in the extracellular physiological environment. The C-terminal extension is of sufficient stability (e.g., length, steric structure) such that any degradation in the body prior to clearance from the bloodstream will not re-expose the cardiovascular (RFamide) pharmacophore to achieve the effect. Cyclization Variants

[0393] Cyclized melanocortin analogs have shown improved efficacy and stability. See Balse-Srinivasan et al., J. Med. Chem.46(17): 3728-3733 (2003) and Bednarek et al., Biochem. Biophys. Res. Com.286(3): 641-645 (2001); Kavarana, et al., J. Med. Chem.45(12): 2644-2650 (2002). In one aspect, the non-naturally occurring melanocortin analog represented by Formula (I) is cyclized. The following represents a non-limiting list of examples of how the non-naturally occurring melanocortin analog represented by Formula I may be cyclized:

[0394] In Formula (I), disulfide bond between R1or R2and R7or Y1, when R1or R2is cysteine and R7or Y1is cysteine as described in Balse-Srinivasan et al., J. Med. Chem., 2003, 46(23): 4965-4973. When Y1is cysteine, Y2is not absent, but is selected -123- 146316.8009.WO00\165259190.24from the group consisting of D-threonine, L-threonine, D-proline, L-proline and a piperazin-2-one ring.

[0395] A lactam bridge between R1and R7, when R1is norleucine and R7is glutamic acid, as described in Mayorov et al. J. Med. Chem.49: 1946-1952 (2006) and Bednarek et al., Biochem. Biophys. Res. Com.286(3): 641-645 (2001).

[0396] A side-chain lactam bridge between R2and R7, when R2is glutamic acid or aspartic acid and R7is lysine, as described in Bednarek et al., Biochem. Biophys. Res. Com.286(3): 641-645 (2001).

[0397] A lactam bridge between R1and R7, when R1is succinic acid or o-pthalic acid and R7is lysine, as described in Bednarek et al., Biochem. Biophys. Res. Com.286(3): 641-645 (2001) and Kavarana et al., J. Med. Chem.45(12): 2644-2650 (2002).

[0398] A lactam bridge between R2or R3and R7, when R2or R3is succinic acid and R7is 2,3-diamino-propionic acid as described in Bednarek et al., Biochem. Biophys. Res. Com.286(3): 641-645 (2001).

[0399] A “backbone” cyclized peptide is formed by covalent bond formation between the C- and / or N-terminus of a linear peptide of interest. An example of this is described in the bonding of two amide nitrogens via a bridge consisting of alkyl groups and an amide, as described by Hess et al., J. Med. Chem.50: 6201-6211 (2007). Amino Acids—Isomers and Non-Standard Amino Acids

[0400] In some embodiments, the amino acid residues, provided herein for the non-naturally occurring melanocortin analogs of the present technology, may be either D- or L-amino acids or may be substituted with their non-standard, isomeric counterparts. For example, α-amino acids may be substituted with β-amino acids, and L-amino acids may be substituted with D-amino acids. An amino acid of the present technology that is not designated as a D- or L-isomer, may be either isomer. All amino acids are α-amino acids, unless specifically indicated as β-amino acids. A β-amino acid may be either a β2-amino acid or a β3-amino acid, or both β2and β3in some cases, unless a specific designation is provided. Receptor Agonist and Antagonists -124- 146316.8009.WO00\165259190.24

[0401] In some embodiments, the non-naturally occurring melanocortin analog is an MC4 receptor agonist, an MC4 receptor antagonist, an MC3 receptor agonist, an MC3 receptor antagonist, and / or an MC5 receptor agonist, of the α-melanocyte- stimulating hormone (MSH) group.

[0402] In some embodiments, the non-naturally occurring melanocortin analog is an MC3 receptor antagonist of the gamma melanocyte-stimulating hormone group.

[0403] In some embodiments, the non-naturally occurring melanocortin analog is an MC3 receptor agonist of the gamma melanocyte-stimulating hormone group. Peptide Synthesis

[0404] The non-naturally occurring melanocortin analogs described herein may be readily synthesized by any known conventional procedure for the formation of a peptide linkage between amino acids. Such conventional procedures include, for example, any solution phase procedure permitting a condensation between the free alpha amino group of an amino acid or residue thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or residue thereof having the amino group or other reactive groups protected. In an exemplary procedure, the peptides described herein may be synthesized by solid-phase synthesis and purified according to methods known in the art. Any of a number of well-known procedures utilizing a variety of resins and reagents may be used to prepare the peptides described herein.

[0405] The process for synthesizing the peptides may be carried out by a procedure whereby each amino acid in the desired sequence is added one at a time in succession to another amino acid or residue thereof or by a procedure whereby peptide fragments with the desired amino acid sequence are first synthesized conventionally and then condensed to provide the desired peptide. The resulting peptide is then cyclized to yield a cyclic peptide.

[0406] Solid phase peptide synthesis methods are well known and practiced in the art. In such methods, the synthesis of peptides may be carried out by sequentially incorporating the desired amino acid residues one at a time into the growing peptide chain according to the general principles of solid phase methods. These methods are disclosed in numerous references, including Merrifield, Angew Chem.24:799-810 -125- 146316.8009.WO00\165259190.24(1985) and Barany et al., The Peptides, Analysis, Synthesis and Biology, Vol.2, Gross E. and Meienhofer J., Eds. Academic Press 1-284 (1980).

[0407] In chemical syntheses of peptides, reactive side chain groups of the various amino acid residues are protected with suitable protecting groups, which prevent a chemical reaction from occurring at that site until the protecting group is removed. Also common is the protection of the alpha amino group of an amino acid residue or fragment while that entity reacts at the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site. Specific protecting for solid phase synthesis methods and solution phase synthesis methods groups are known to those having ordinary skill in the art.

[0408] Alpha amino groups may be protected by a suitable protecting group, including a urethane-type protecting group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-biphenyl-isopropoxycarbonyl, 9- fluorenylmethoxycarbonyl (Fmoc) and p-methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc is useful for alpha amino protection.

[0409] Guanidino groups may be protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc is a useful protecting group for Arg.

[0410] Solid phase synthesis is commenced from the C-terminal end of the peptide by coupling a protected alpha amino acid to a suitable resin. Such starting material is prepared by attaching an alpha amino-protected amino acid by an ester linkage to a p- benzyloxybenzyl alcohol (Wang) resin or a 2-chlorotrityl chloride resin, by an amide bond between an Fmoc-Linker, such as p-((R,S)-α-(1-(9H-fluor-en-9-yl)- methoxyformamido)-2,4-dimethyloxybenzyl)-phenoxyacetic acid (Rink linker) to a benzhydrylamine (BHA) resin, or by other means well known in the art. Fmoc-Linker- BHA resin supports are commercially available and generally used when feasible. The resins are carried through repetitive cycles as necessary to add amino acids sequentially. The alpha amino Fmoc protecting groups are removed under basic -126- 146316.8009.WO00\165259190.24conditions. Piperidine, piperazine, diethylamine, or morpholine (20-40% v / v) in N,N- dimethylformamide (DMF) may be used for this purpose.

[0411] Following removal of the alpha amino protecting group, the subsequent protected amino acids are coupled stepwise in the desired order to obtain an intermediate, protected peptide-resin. The activating reagents used for coupling of the amino acids in the solid phase synthesis of the peptides are well known in the art. After the peptide is synthesized, if desired, the orthogonally protected side chain protecting groups may be removed using methods well known in the art for further derivatization of the peptide.

[0412] Reactive groups in a peptide may be selectively modified, either during solid phase synthesis or after removal from the resin. For example, peptides may be modified to obtain N-terminus modifications, such as acetylation, while on resin, or may be removed from the resin by use of a cleaving reagent and then modified. Methods for N-terminus modification, such as acetylation, and for C-terminus modification, such as amidation, are known in the art. Similarly, methods for modifying side chains of amino acids are well known to those skilled in the art of peptide synthesis. The choice of modifications made to reactive groups present on the peptide will be determined, in part, by the characteristics that are desired in the peptide.

[0413] The peptide may be cyclized prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains are deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents include, for example DMF, dichloromethane (DCM) or 1-methyl-2-pyrrolidone (NMP). Suitable cyclic coupling reagents include, for example, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1H- benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), benzotriazole-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1-yl-oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2- (7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TATU), 2- (2-oxo-1 (2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or N,N′- dicyclohexylcarbodiimide / 1-hydroxybenzotriazole (DCCl / HOBt). Coupling is convention initiated by use of a suitable base, such as N,N-diispropylethylamine (DIPEA), sym- collidine or N-methylmorpholine (NMM). -127- 146316.8009.WO00\165259190.24

[0414] Following cleavage of peptides from the solid phase following their synthesis, the peptide may be purified by any number of methods, such as reverse phase high performance liquid chromatography (RP-HPLC), using a suitable column, such as a C18column. Other methods of separation or purification, such as methods based on the size or charge of the peptide, may also be employed. Once purified, the peptide may be characterized by any number of methods, such as high-performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like. Salt Forms of Peptides

[0415] The non-naturally occurring melanocortin analog peptides described herein may be in the form of any pharmaceutically acceptable salt. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Exemplary salts are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0416] When the peptides described herein are basic, acid addition salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, carboxylic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p- toluenesulfonic acid, trifluoroacetic acid, and the like. Acid addition salts of the peptides described herein are prepared in a suitable solvent from the peptide and an excess of -128- 146316.8009.WO00\165259190.24an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, tartaric, maleic, succinic or methanesulfonic acid. The acetate salt form is especially useful. Where the peptides described herein include an acidic moiety, suitable pharmaceutically acceptable salts may include alkali metal salts, such as sodium or potassium salts, or alkaline earth metal salts, such as calcium or magnesium salts. Second Compounds: Spiro Compounds

[0417] The second compounds of the present technology may comprise a spiro compound. In some embodiments, the spiro compound is an MC4R antagonist. The second compound may exert therapeutic effects following antagonism of the MC4R.

[0418] The spiro compound may be the compound of formula (X) of the present technology, e.g., (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin- 2-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, or pharmaceutically acceptable salt thereof.

[0419] As used herein, the compound of Formula X as described herein includes optional substitutions and variables. It is understood that the normal valency of each of the designated (optionally substituted) atom or moiety is not exceeded, and that any of the optional substitution results in a stable compound. It is also understood that combinations of optional substituents and / or variables are permissible only if such combinations result in a stable compound.

[0420] As used herein, unless otherwise specified, the point of attachment of a substituent may be from any suitable position of the substituent. For example, piperidinyl may be piperidin-1-yl (attached through the N atom of the piperidinyl), piperidin-2-yl (attached through the C atom at the 2-position of the piperidinyl), piperidin- 3-yl (attached through the C atom at the 3-position of the piperidinyl), or piperidin-4-yl (attached through the C atom at the 4-position of the piperidinyl). For another example, pyridinyl (or pyridyl) may be 2-pyridinyl (or pyridin-2-yl), 3- pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).

[0421] As used herein, the point of attachment of a substituent may be specified to indicate the position where the substituent is attached to another moiety. For -129- 146316.8009.WO00\165259190.24example, “(C3-4 cycloalkyl)-C1- 4 alkyl-” means the point of attachment occurs at the “C1-4 alkyl” part of the “(C3-4 cycloalkyl)-C1-4 alkyl-.”

[0422] When a substituted or optionally substituted moiety is described without indicating the atom via which such moiety is bonded to a substituent, then the substituent may be bonded via any appropriate atom in such moiety. For example in a substituted “(C3-4 cycloalkyl)-C1-4 alkyl-”, a substituent on the cycloalkylalkyl (i.e., (C3- 4 cycloalkyl)-C1-4 alkyl-) may be bonded to any carbon atom on the alkyl part or on the cycloalkyl part of the cycloalkylalkyl. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0423] As used herein, the term “adjacent” in describing the relative positions of two substituent groups on a ring structure refers to two substituent groups that are respectively attached to two ring-forming atoms of the same ring, wherein the two ring- forming atoms are directly connected through a chemical bond. Spiro Compounds of Formula (X)

[0424] In some embodiments, the composition of the present technology comprises a second compound comprising a structure according to Formula (X): or aRx1is H, halogen, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, 4- to 7- memberedocycloalkyl, phenyl, or Rx1a, wherein each of the C3-6cycloalkyl and 4- to 7- memberedocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected C1-4alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 independently selected RxB, wherein RxBis halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-4cycloalkyl, or RxB1; or two adjacent -130- 146316.8009.WO00\165259190.24RxBtogether with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; Rx1ais 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independent RxA, wherein each RxAis halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, -N(C1-4 alkyl)2, RxA1, or (C3-4 cycloalkyl)- C1-4 alkyl-, wherein each of the C1-4 alkyl, C3-4 cycloalkyl, and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or two adjacent RxAtogether with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6- membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6- membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; RxA1is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4haloalkoxy; RxB1is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; each of Rx2and Rx3is independently H, halogen, C1-4alkyl, C1-4hydroxyalkyl, C1-4 haloalkyl, (C1-4 alkoxy)-C1-4 alkyl-, C3-4 cycloalkyl, or (C3-4 cycloalkyl)-C1-4 alkyl, wherein each of C3-4cycloalkyl and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; or Rx2and Rx3together with the carbon atom to which they are attached form C3-6 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; -131- 146316.8009.WO00\165259190.24each Rx4is independently H, halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4haloalkoxy, -N(C1-2alkyl)2, C3-4cycloalkyl, or (C3-4cycloalkyl)-C1-4 alkyl-, wherein each of the C1-4 alkyl, C3-4 cycloalkyl, and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy Xx1is C(RxX)2, wherein each RxXis independently H or C1-4 alkyl; and each of Yx1, Yx2, Yx3, Yx4, and Yx5is independently CR4or N, provided that no more than 3 of Yx1, Yx2, Yx3, Yx4, and Yx5are N.

[0425] In some embodiments, the second compound is a compound of Formula (Xi):

[0426] In some embodiments, the second compound is a compound of Formula (Xii):-132- 146316.8009.WO00\165259190.24

[0427] In some embodiments, Rx1is Rx1a; and Rx1ais 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RxA, wherein each RxAis halogen, -OH, -CN, C1-4 alkyl, C14 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-C4 cycloalkyl, or (C3-4cycloalkyl)-C14alkyl-, wherein each of the C1-4alkyl, C3-4cycloalkyl, and (C3-4alkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4 haloalkoxy; or two adjacent RxAtogether with the two ring-atoms of the 6- membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C14 haloalkoxy.

[0428] In some embodiments, Rx1ais pyrimidinyl optionally substituted with 1, 2, or 3 independently selected RxA, wherein each RxAis halogen, -OH, -CN, C1-4alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, or C34 cycloalkyl.

[0429] In some embodiments, Rx1ais pyrimidin-2-yl.

[0430] In some embodiments, Xx1is CH2.

[0431] In some embodiments, each of Rx2and Rx3is independently H, F, or C1-4 alkyl. In some embodiments, Rx2is methyl and Rx3is H.

[0432] In some embodiments, Yx3is N, and each of Yx1, Yx2, Yx4, and Yx5is independently CRx4. In some embodiments, Rx4is independently H, halogen, or C1-2 alkoxy.

[0433] In some embodiments, the second compound is selected from: (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-(7-methyl-6-(2-methyl-2H-tetrazol-5- yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, DIAST- 1; 2-(6-methoxy-2-methylpyrimidin-4-yl)-1-((2S)-7-methyl-6-(2-methyl-2H-tetrazol- 5-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3’-pyrrolidin)-1’-yl)propan-1-one, DIAST-1; 2-(6-(difluoromethoxy)pyridin-3-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4- dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, DIAST-2; -133- 146316.8009.WO00\165259190.241-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'- pyrrolidin)-1'-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one, DIAST-1; 1-(4,7-dimethyl-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)-2- (4-fluorophenyl)ethan-1-one, DIAST-1; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(2-methyl-2H- tetrazol-5-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1- one; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4- dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one; (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4- dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(7-methyl-6-(1-methyl-1H-pyrazol-4- yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, DIAST- 1; and (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-{(2S)-7-methyl-6-((4,6-2H2)pyrimidin- 2-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl}propan-1-one, or a pharmaceutically acceptable salt thereof.

[0434] In some embodiments, the second compound is (2R)-2-(5-fluoro-2- methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8- naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, or a pharmaceutically acceptable salt thereof. The chemical structure of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7- methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'- yl)propan-1-one (also referred herein as “Compound A1”, or “A1”) is shown below: -134- 146316.8009.WO00\165259190.241.

[0435] In some embodiments, the second compound is a crystalline form of (2R)- 2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H- spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one.

[0436] Other non-limiting embodiments describing the second compound of Formula (X) may be found in WIPO International Application No. PCT / IB2021 / 054970, the entire contents of which are herein incorporated by reference. Third Compounds: Antibodies and Antigen Binding Fragments

[0437] The third compounds of the present technology may comprise an antibody or an antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof specifically binds to a portion of human growth differentiation factor 15 (GDF-15). In some embodiments, the antibody or antigen binding fragment thereof binds to GDF-15 thereby preventing binding of GDF-15 to a Glial-derived neurotrophic factor-family receptor α-like (GFRAL) receptor.

[0438] The antibody or antigen binding fragment thereof may specifically bind to a portion of human growth differentiation factor 15 (GDF-15). The antibody or antigen binding fragment thereof of the present technology may comprise an anti-GDF-15 antibody, an anti-GDF-15 mab, an anti-GDF-15 ab, or the like. Table 1 provides the sequences of human GDF-15 and several exemplary anti-GDF-15 antibodies that may be included in the present technology. Table 1. Sequences of GDF15 peptides and anti-GDF15 antibodies. -135- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence A P H D Q T E F H C R C F V E G S P V S IQ D Q T E F H C R C D Q T-136- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence E F H C R C P P P V K Q S P P D Y-137- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence E KL S TI W K T P S N IS DI Y G S T S TI W-138- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence P P P V K P P S Y A G S P P A K E V V-139- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence S Y A P P P V K P P S TI W K T P S N IS DI-140- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence LY G S TI W P P P V K P P S TI W K T P S N IS-141- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence DI Y G S TI W P P P V K P P S Y A G S P P A K E V V-142- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence S Y A P P P V K P P FT Y A G S P P A K E V V FT Y-143- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence A P P P V K P P FT Y A G S P P A K E V V FT Y A P P P V K-144- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence P P S Y A G S P P A K E V V S Y A P P P V K P P S TI W K T P-145- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence S N IS DI Y G S TI W P P V V K P P S Y A G S P P A K E V V-146- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence FS Y A P P P V K P P S Y V G S P P A K E V V S Y V P P P V-147- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence K P P S FF A G S P P A K E V V S FF A P P P V K P P-148- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence FS Y A G S P P A K E V V S Y A P P P V K P P FT TI W K T P S N-149- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence IS DI Y G FT TI W P P P V K P P S TI W K T P S N IS DI Y G-150- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence FS TI W P P P V K P P FT Y F G S P P A K E V V FT Y F P P-151- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence P V K P P S Y A G S P P A K E V V S Y A P P P V K P P S Y-152- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence A G S P P A K E V V S Y A P P P V K P P FT Y Q G S P P A K E-153- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence V V FT Y Q P P P V K P P S TI W K T P S N IS DI Y G S TI W-154- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence P P P V K P P S TI W K T P S N IS DI Y G S TI W C C T G T A-155- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence AT G G G A G C G T T G A T G A C C T G T A T G G G G A C T G G C G A C-156- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence C A G C G T T G A T G A A T G C G C T A A G G G T C T C G C C C T C G C-157- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence A G T T G A A G C X7V or is FT FF A P P-158- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence E H D E H D PL W T P V L P N FT LL A-159- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence TP LL A P F D PI E H V E H V S DL D V E K P K LL A P LL A P F D PI-160- 146316.8009.WO00\165259190.24SEQ ID NO Description Sequence FE H V E H V PL W Y P Y V V E Q N S N S K F SLeof specifically binds at least a portion of a sequence about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% identical to SEQ ID NO: 1.

[0440] In some embodiments, the antibody or antigen binding fragment thereof specifically binds at least a portion of a sequence at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO: 1. -161- 146316.8009.WO00\165259190.24

[0441] In some embodiments, the antibody or antigen binding fragment thereof specifically binds at least about a portion of a sequence at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% identical to SEQ ID NO: 1.

[0442] In some embodiments, the antibody or antigen binding fragment thereof comprises an amino acid a sequence about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% identical to SEQ ID NO: 2-166 or 171-196.

[0443] In some embodiments, the antibody or antigen binding fragment thereof comprises an amino acid a sequence at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO: 2-166 or 171-196.

[0444] In some embodiments, the antibody or antigen binding fragment thereof comprises an amino acid a sequence at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% identical to SEQ ID NO: 2-166 or 171-196.

[0445] In some embodiments, the antibody or antigen binding fragment thereof is encoded by a polynucleotide sequence about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% identical to SEQ ID NO: 167-170.

[0446] In some embodiments, the antibody or antigen binding fragment thereof is encoded by a polynucleotide sequence at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO: 167-170.

[0447] In some embodiments, the antibody or antigen binding fragment thereof is encoded by a polynucleotide sequence at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% identical to SEQ ID NO: 167-170. -162- 146316.8009.WO00\165259190.24

[0448] In some embodiments, the anti-GDF-15 antibody is GDF-15_001 (ponsegromab) having one or more amino acid sequences selected from the group of amino acid sequences consisting of SEQ ID NOs: 32, 165, 52, 25, 166, 22, 2324, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10, 162, 288 and 289.

[0449] In some embodiments the antibody or antigen binding fragment thereof is an anti-GDF-15 antibody or antigen binding fragment thereof which comprises any one of the antibodies or a fragment thereof selected from Table 2. In some embodiments, the composition comprises one or more anti-GDF-15 antibodies or antigen binding fragments thereof selected from Table 2. In some embodiments, the composition comprises two or more anti-GDF-15 antibodies or antigen binding fragments thereof selected from Table 2.

[0450] In some embodiments, the anti-GDF-15 antibody or antigen binding fragment thereof comprises an amino acid sequence about 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to any one of the VHsequences in Table 2. In some embodiments, the anti-GDF-15 antibody or antigen binding fragment thereof comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to any one of the VH sequences in Table 2. In some embodiments, the anti-GDF-15 antibody or antigen binding fragment thereof comprises an amino acid sequence at least about 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to any one of the VH sequences in Table 2.

[0451] In some embodiments, the anti-GDF-15 antibody or antigen binding fragment thereof comprises an amino acid sequence about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to any one of the VLsequences in Table 2. In some embodiments, the anti-GDF-15 antibody or antigen binding fragment thereof comprises an amino acid sequence at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to any one of the VL sequences in Table 1. In some embodiments, the anti-GDF-15 antibody or antigen binding fragment thereof comprises an amino acid sequence at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to any one of the VLsequences in Table 2.

[0452] In some embodiments, the anti-GDF-15 antibodies or antigen binding fragments thereof selected from Table 2 constitute means for binding GDF-15. In some embodiments, the anti-GDF-15 antibody or antigen binding fragment thereof comprises -163- 146316.8009.WO00\165259190.24one or more complementary determining regions (CDR) such as CDRs 1, 2, and / or 3 of the anti-GDF-15 antibodies or antigen binding fragments thereof selected from Table 2. In certain embodiments, the anti-GDF-15 antibody or antigen binding fragment thereof comprises CDR 3 of the anti-GDF-15 antibodies or antigen binding fragments thereof selected from Table 2.

[0453] In some embodiments, the antibody or antigen binding fragment thereof comprises an amino acid a sequence about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100% identical to SEQ ID NO: 197-303.

[0454] In some embodiments, the antibody or antigen binding fragment thereof comprises an amino acid a sequence at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100% identical to SEQ ID NO: 197-303.

[0455] In some embodiments, the antibody or antigen binding fragment thereof comprises an amino acid a sequence at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100% identical to SEQ ID NO: 197-303. Table 2: Anti-GDF-15 Antibodies Antibody VH Sequence VL sequence VH SEQ VL SEQ Source ID NO: ID NO:-164- 146316.8009.WO00\165259190.24AYMELRSLRSDDTAVY FATYYCQHFWSDPYTF YCAREAITTVGAMDYW GQGTKLEIK GQGTLVTVSS-165- 146316.8009.WO00\165259190.24Anti-GDF-15 QVQLVQSGAEVKKPG DIQMTQSPSSLSASVG 216 217 EP2934584 ASVKVSCKASGYTFTD DRVTITCRTSENLHNYL YNMDWVRQAPGQSLE AWYQQKPGKSPKLLIY-166- 146316.8009.WO00\165259190.24Anti-GDF-15 QVQLVQSGAEVKKPG DIQMTQSPSSLSASVG 220 221 EP2934584 SSVKVSCKASGYTFSD DRVTITCRTSENLHNYL YNMDWVRQAPGQGLE AWYQQKPGKAPKLLIY-167- 146316.8009.WO00\165259190.24Anti-GDF-15 QVQLVQSGAEVKKPG DIQMTQSPSSLSASVG 224 225 EP2934584 SSVKVSCKASGYTFSD DRVTITCRTSENLHNYL YNMDWVRQAPGQGLE AWYQQKPGKAPKLLIY-168- 146316.8009.WO00\165259190.24Anti-GDF-15 QVQLVQSGAEVKKPG DIQMTQSPSSLSASVG 228 229 EP2934584 ASVKVSCKASGYTFTD DRVTITCRTSENLHNYL YNMDWVRQAPGKSLE AWYQQKPGKSPKLLVY-169- 146316.8009.WO00\165259190.24Anti-GDF-15 QVQLVQSGSELKKPGA DIQMTQSPSSLSASVG 232 233 US20220281965 SVKVSCKASGYTFTDY DRVTITCRASENIYSYL NMDWIRQSPGKGLEWI AWYQQKPGKAPKLLVY 65 65 65 65 65-170- 146316.8009.WO00\165259190.24AREEKLYFGLMDYWG DFGNYYCQHQYGSPP QGTSVTVSS TFGGGTKLEIK AB1170028 DVKLVESGEGLVKPGG SIVMTQTPKFLPVSAG 244 245 US20220281965 65 65 65 65 65 65-171- 146316.8009.WO00\165259190.24AB1170072 QVTLKESGPGILQPSQ DIVMTQSQKFMSTSVG 258 259 US20220281965 TLSLTCSFSGFSLSTYG DRVSVTCKASQNMDT MGVGWIRQPSGKGLE NVAWYQQKPGQSPKA 65 65 65 65 65 65 65-172- 146316.8009.WO00\165259190.24GDINPNQGGTFYNQKF NAKTLAEGVPSRFSGS KDRATLTVDKSTSTAY GSGIDFTLTISSLQPED MELRSLRSDDTAVYYC FATYYCQHQYGSPPTF 65 65 65 65 65 65 65-173- 146316.8009.WO00\165259190.24FCARGGTTVVLDYWG DLAEYFCQQYSSSPWT QGTTLTVSS FGGGTKLELK Anti-GDF-15 QVQLVQSGAEVKKPG EIVLTQSPATLSLSPGE 288 289 US20220380448 24 24 24 24 24-174- 146316.8009.WO00\165259190.24VKFNWYVDGVEVHNA KTKPREEQYNSTYRW SVLTVLHQDWLNGKEY 24 24

[0456] In some embodiments, the antibodies of the present technology comprise an amino acid sequence about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% identical to any one of SEQ ID NOs 2-303, including one or more substitution variants. Substitution variants have at least one amino acid residue in the antibody molecule removed and a different residue inserted in its place. The sites of greatest interest for substitutional mutagenesis include the hypervariable regions, but -175- 146316.8009.WO00\165259190.24framework alterations are also contemplated. Conservative substitutions are shown in Table 3. If such substitutions result in a change in biological activity, then more substantial changes, denominated “exemplary substitutions” shown below, or as further described below in reference to amino acid classes, may be introduced and the products screened.

[0457] A high throughput process for “binning” antibodies based upon their competition is described in International Patent Application No. WO2003 / 48731, the contents of which are incorporated herein by reference in their entirety. Competition is present if one antibody (or fragment) reduces the binding of another antibody (or fragment) to GDF-15. For example, a sequential binding competition assay may be used, with different antibodies being added sequentially. The first antibody may be added to reach binding that is close to saturation. Then, the second antibody is added. If the binding of second antibody to GDF-15 is not detected, or is significantly reduced (e.g., at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% reduction) as compared to a parallel assay in the absence of the first antibody (which value may be set as 100%), the two antibodies are considered as competing with each other. Table 3. Conservative Amino Acid Substitutions Amino Acids and Substitutions-176- 146316.8009.WO00\165259190.24Amino Acids and Substitutions ConservativeSubstantial modifications in the biological properties of the antibody are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a beta-sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into groups based on common side-chain properties: i. Non-polar: Norleucine, Met, Ala, Val, Leu, Ile; ii. Polar without charge: Cys, Ser, Thr, Asn, Gln; iii. Acidic (negatively charged): Asp, Glu; iv. Basic (positively charged): Lys, Arg; ...

Claims

CLAIMS I / We claim:

1. A composition, comprising: a first compound comprising a non-naturally occurring melanocortin analog comprising 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 cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D- asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, 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), alanine, D-alanine, D- methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4- aminophenylpiperidine-4-carboxylic acid (APPC), 2-aminoindone-2-carboxylic acid (Aic), and 1-amino-1-cyclopentane carboxylic (Cpe); -340- 146316.8009.WO00\165259190.24R4is selected from the group consisting of histidine, D-phenylalanine, L- phenylalanine, D-Nal(2′), aspartic acid, biphenylalanine (Bip), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-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, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-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, L-proline, D-proline, Hyp, dHyp, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, D-asparagine, lysine, D-lysine, and tryptophan; -341- 146316.8009.WO00\165259190.24Y2is absent or is selected from the group consisting of D-proline, L-proline, D- valine, L-valine, 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-proline, L-proline, D- valine, and L-valine; Y4is absent or is 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; -342- 146316.8009.WO00\165259190.24when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys (SEQ ID NO: 661), then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent, and a second compound and / or a third compound, wherein the second compound comprises a structure according to Formula (X) or aRx1is H, halogen, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, 4- to 7- memberedocycloalkyl, phenyl, or Rx1a, wherein each of the C3-6 cycloalkyl and 4- to 7- memberedocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected C1-4 alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 independently selected RxB, wherein RxBis halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-4cycloalkyl, or RxB1; or two adjacent RxBtogether with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; Rx1ais 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independent RxA, wherein each RxAis halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C14 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, -N(C1-4 alkyl)2, RxA1, or (C3-4 cycloalkyl)- C14alkyl-, wherein each of the C14alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected -343- 146316.8009.WO00\165259190.24from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or two adjacent RxAtogether with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6- membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6- membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; RxA1is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4 haloalkoxy; RxB1is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; each of Rx2and Rx3is independently H, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4haloalkyl, (C1-4alkoxy)-C1-4alkyl-, C3-4cycloalkyl, or (C3-4cycloalkyl)-C1-4alkyl, wherein each of C3-4 cycloalkyl and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1- 4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or Rx2and Rx3together with the carbon atom to which they are attached form C3-6cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each Rx4is independently H, halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, -N(C1-2 alkyl)2, C3-4 cycloalkyl, or (C3-4 cycloalkyl)-C1-4alkyl-, wherein each of the C1-4alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy Xx1is C(RxX)2, wherein each RxXis independently H or C1-4 alkyl; and each of Yx1, Yx2, Yx3, Yx4, and Yx5is independently CR4or N, provided that no more than 3 of Yx1, Yx2, Yx3, Yx4, and Yx5are N, and wherein the third compound comprises an antibody, or antigen binding fragment thereof, that specifically binds to human growth differentiation factor 15 (GDF- 15), comprising at least one of the following: -344- 146316.8009.WO00\165259190.24a) a light chain complementarity determining region 1 (LCDR-1) comprising the amino acid sequence of SEQ ID NO:95, a LCDR-2 comprising the amino acid sequence of SEQ ID NO:28, a LCDR-3 comprising the amino acid sequence of SEQ ID NO:9, a heavy chain complementarity determining region 1 (HCDR-1) comprising the amino acid sequence of SEQ ID NO:32, a HCDR-2 comprising the amino acid sequence of SEQ ID NO:165, and a HCDR-3 comprising the amino acid sequence of SEQ ID NO:52; b) LCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) a LCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) a LCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) a HCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) a HCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) a HCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173, and 181; h) the HCDR-1, HCDR-2, and HCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:163; i) the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:166, and a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:163; k) a VH comprising the amino acid sequence of SEQ ID NO:166 and a VL comprising the amino acid sequence of SEQ ID NO:163; -345- 146316.8009.WO00\165259190.24l) a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:164, and a light chain (LC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:162; m) a HC comprising the amino acid sequence of SEQ ID NO:164, and a LC comprising the amino acid sequence of SEQ ID NO:162; andGDF-15 n) an antibody that competes for binding to GDF-15 with at least one antibody from (a)-(m) above.

2. A composition, comprising: a first compound comprising a non-naturally occurring melanocortin analog comprising a sequence according to Formula (I), X1X2X3R1R2R3R4R5R6R7R8R9R10R11R12R13R14R15R16R17R18R19R20Y1Y2Y3Y4Y5Y6Y7Y8(I) R1is absent or is selected from the group consisting of cysteine, norleucine (Nle), acetylated norleucine (Ac-Nle), acetylated cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D- asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, 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), alanine, D-alanine, D- methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4- -346- 146316.8009.WO00\165259190.24aminophenylpiperidine-4-carboxylic acid (APPC), 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), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-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, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-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; -347- 146316.8009.WO00\165259190.24Y1is absent or is selected from the group consisting of D-alanine, L-alanine, D- valine, L-valine, 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, 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-proline, L-proline, D- valine, and L-valine; Y4is absent or is 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); -348- 146316.8009.WO00\165259190.24when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent, and a second compound comprising a structure according to Formula (X) or aRx1is H, halogen, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, 4- to 7- memberedocycloalkyl, phenyl, or Rx1a, wherein each of the C3-6 cycloalkyl and 4- to 7- memberedocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected C1-4 alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 independently selected RxB, wherein RxBis halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-4cycloalkyl, or RxB1; or two adjacent RxBtogether with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; Rx1ais 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independent RxA, wherein each RxAis halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C14 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, -N(C1-4 alkyl)2, RxA1, or (C3-4 cycloalkyl)- C14alkyl-, wherein each of the C14alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected -349- 146316.8009.WO00\165259190.24from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or two adjacent RxAtogether with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6- membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6- membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; RxA1is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4 haloalkoxy; RxB1is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; each of Rx2and Rx3is independently H, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4haloalkyl, (C1-4alkoxy)-C1-4alkyl-, C3-4cycloalkyl, or (C3-4cycloalkyl)-C1-4alkyl, wherein each of C3-4 cycloalkyl and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1- 4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or Rx2and Rx3together with the carbon atom to which they are attached form C3-6cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each Rx4is independently H, halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, -N(C1-2 alkyl)2, C3-4 cycloalkyl, or (C3-4 cycloalkyl)-C1-4alkyl-, wherein each of the C1-4alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy Xx1is C(RxX)2, wherein each RxXis independently H or C1-4 alkyl; and each of Yx1, Yx2, Yx3, Yx4, and Yx5is independently CR4or N, provided that no more than 3 of Yx1, Yx2, Yx3, Yx4, and Yx5are N. -350- 146316.8009.WO00\165259190.

243. A composition, comprising: a first compound comprising a non-naturally occurring melanocortin analog comprising 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 cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D- asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, 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), alanine, D-alanine, D- methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4- aminophenylpiperidine-4-carboxylic acid (APPC), 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), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); -351- 146316.8009.WO00\165259190.24R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-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, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-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, 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, L-tert-leucine, norleucine, Hyp, dHyp, D-alanine, L-alanine, glycine, aspartic acid, D-aspartic acid, arginine, D-arginine, asparagine, and D-asparagine; -352- 146316.8009.WO00\165259190.24Y3is absent or is selected from the group consisting of D-proline, L-proline, D- valine, and L-valine; Y4is absent or is 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and -353- 146316.8009.WO00\165259190.24when the non-naturally occurring melanocortin analog is linear, R2is not absent, and a third compound comprising an antibody, or antigen binding fragment thereof, that specifically binds to human growth differentiation factor 15 (GDF-15), comprising at least one of the following: a) a light chain complementarity determining region 1 (LCDR-1) comprising the amino acid sequence of SEQ ID NO:95, a LCDR-2 comprising the amino acid sequence of SEQ ID NO:28, a LCDR-3 comprising the amino acid sequence of SEQ ID NO:9, a heavy chain complementarity determining region 1 (HCDR-1) comprising the amino acid sequence of SEQ ID NO:32, a HCDR-2 comprising the amino acid sequence of SEQ ID NO:165, and a HCDR-3 comprising the amino acid sequence of SEQ ID NO:52; b) LCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) a LCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) a LCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) a HCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) a HCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) a HCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173, and 181; h) the HCDR-1, HCDR-2, and HCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:163; i) the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125039; -354- 146316.8009.WO00\165259190.24j) a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:166, and a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:163; k) a VH comprising the amino acid sequence of SEQ ID NO:166 and a VL comprising the amino acid sequence of SEQ ID NO:163; l) a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:164, and a light chain (LC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:162; m) a HC comprising the amino acid sequence of SEQ ID NO:164, and a LC comprising the amino acid sequence of SEQ ID NO:162; and n) an antibody that competes for binding to GDF-15 with at least one antibody from (a)-(m) above.

4. A composition, comprising: a first compound comprising a non-naturally occurring melanocortin analog comprising 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 cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D- asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, tryptophan, D-cysteine, cysteine, norleucine, arginine, succinic acid, glutaric acid, CO-cis-CH═CH—CO, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); -355- 146316.8009.WO00\165259190.24R3is absent or is selected from the group consisting of histidine, D-proline, L- proline, hydroxyproline (Hyp), D-hydroxyproline (dHyp), alanine, D-alanine, D- methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, 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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4- aminophenylpiperidine-4-carboxylic acid (APPC), 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), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-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, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L- -356- 146316.8009.WO00\165259190.24leucine, 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, 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, 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-proline, L-proline, D- valine, and L-valine; Y4is absent or is 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; provided that: -357- 146316.8009.WO00\165259190.24when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent, a second compound comprising a structure according to Formula (X): or aRx1is H, halogen, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, 4- to 7- memberedocycloalkyl, phenyl, or Rx1a, wherein each of the C3-6 cycloalkyl and 4- to 7- memberedocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected C1-4 alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 independently selected RxB, wherein RxBis halogen, -OH, -CN, C1-4alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, or RxB1; or two adjacent RxBtogether with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; -358- 146316.8009.WO00\165259190.24Rx1ais 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independent RxA, wherein each RxAis halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C14 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, -N(C1-4 alkyl)2, RxA1, or (C3-4 cycloalkyl)- C14alkyl-, wherein each of the C14alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; or two adjacent RxAtogether with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6- membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6- membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; RxA1is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4haloalkoxy; RxB1is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each of Rx2and Rx3is independently H, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4haloalkyl, (C1-4alkoxy)-C1-4alkyl-, C3-4cycloalkyl, or (C3-4cycloalkyl)-C1-4alkyl, wherein each of C3-4 cycloalkyl and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or Rx2and Rx3together with the carbon atom to which they are attached form C3-6 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; each Rx4is independently H, halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4alkoxy, C1-4haloalkoxy, -N(C1-2alkyl)2, C3-4cycloalkyl, or (C3-4cycloalkyl)-C1-4 alkyl-, wherein each of the C1-4 alkyl, C3-4 cycloalkyl, and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy Xx1is C(RxX)2, wherein each RxXis independently H or C1-4alkyl; -359- 146316.8009.WO00\165259190.24each of Yx1, Yx2, Yx3, Yx4, and Yx5is independently CR4or N, provided that no more than 3 of Yx1, Yx2, Yx3, Yx4, and Yx5are N, and a third compound comprising an antibody, or antigen binding fragment thereof, that specifically binds to human growth differentiation factor 15 (GDF-15), comprising at least one of the following: a) a light chain complementarity determining region 1 (LCDR-1) comprising the amino acid sequence of SEQ ID NO:95, a LCDR-2 comprising the amino acid sequence of SEQ ID NO:28, a LCDR-3 comprising the amino acid sequence of SEQ ID NO:9, a heavy chain complementarity determining region 1 (HCDR-1) comprising the amino acid sequence of SEQ ID NO:32, a HCDR-2 comprising the amino acid sequence of SEQ ID NO:165, and a HCDR-3 comprising the amino acid sequence of SEQ ID NO:52; b) LCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) a LCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) a LCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) a HCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) a HCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) a HCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173, and 181; h) the HCDR-1, HCDR-2, and HCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:163; i) the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125039; -360- 146316.8009.WO00\165259190.24j) a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:166, and a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:163; k) a VH comprising the amino acid sequence of SEQ ID NO:166 and a VL comprising the amino acid sequence of SEQ ID NO:163; l) a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:164, and a light chain (LC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:162; m) a HC comprising the amino acid sequence of SEQ ID NO:164, and a LC comprising the amino acid sequence of SEQ ID NO:162; GDF-15and n) an antibody that competes for binding to GDF-15 with at least one antibody from (a)-(m) above.

5. The composition of any one of claims 1-4, wherein the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by a functional group selected from the group consisting of an acyl group, an imine group, an amide group, a urea group, a carbamate group, a sulfonamide group, and an alkylamine group.

6. The composition of claim 5, wherein the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an acyl group.

7. The composition of claim 6, wherein the acyl group is acetyl group.

8. The composition of claim 6, wherein the acyl group is formyl group.

9. The composition of claim 5, wherein the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an imine group.

10. The composition of claim 5, wherein the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified by an amide group. -361- 146316.8009.WO00\165259190.2411. The composition of claim 10, wherein the amide group is a pyroglutamyl (pGlu) group.

12. The composition of claim 10, wherein the amide group is derived from a fatty acid.

13. The composition of any one of claims 1-4, wherein the N-terminus of the non-naturally occurring melanocortin analog, if present, is not modified.

14. The composition of any one of claims 1-4, wherein 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.

15. The composition of claim 14, wherein the C-terminus of the non-naturally occurring melanocortin analog is modified by an amide group.

16. The composition of claim 15, wherein the amide group is an -NHalkyl amide group or an -NHaryl amide group.

17. The composition of claim 16, wherein the -NHaryl amide group is p- nitroanilide group or 7-amino-4-methylcoumarin.

18. The composition of claim 14, wherein the C-terminus of the non-naturally occurring melanocortin analog is modified by an ester group.

19. The composition of any one of claims 1-4, wherein the C-terminus of the non-naturally occurring melanocortin analog is not modified.

20. The composition of any one of claims 1-4, wherein R1is absent, and R2is D-aspartic acid.

21. The composition of claim 20, wherein X1, X2, and X3are absent. -362- 146316.8009.WO00\165259190.2422. The composition of any one of claims 1-4, wherein R4is not D- phenylalanine.

23. The composition of any one of claims 1-4, wherein R4is dNal(2′).

24. The composition of any one of claims 1-4, wherein Y3-Y8are absent.

25. The composition of claim 24, wherein: Y1is D-valine and Y2is D-proline; or Y1is D-proline and Y2is D-valine.

26. The composition of any one of claims 1-4, wherein Y3is present and Y4- Y8are absent.

27. The composition of claim 26, wherein: Y1is D-valine or D-proline; Y2is D-valine or D-proline; and / or Y3is D-valine or D-proline.

28. The composition of claim 26, wherein: Y1is D-valine, Y2is D-valine, and Y3is D-proline; Y1is D-proline, Y2is D-valine, and Y3is D-valine; Y1is D-valine, Y2is D-proline, and Y3is D-valine; or Y1is D-proline, Y2is D-valine, and Y3is D-proline.

29. The composition of any one of claims 1-4, wherein Y3and Y4are present, and Y5-Y8are absent.

30. The composition of claim 29, wherein: Y1is D-valine or D-proline; Y2is D-valine or D-proline; Y3is D-valine or D-proline; and / or Y4is D-valine or D-proline. -363- 146316.8009.WO00\165259190.2431. The composition of claim 29, wherein: Y1is D-valine, Y2is D-valine, Y3is D-valine, and Y4is D-proline; Y1is D-proline, Y2is D-valine, Y3is D-valine, and Y4is D-valine; Y1is D-valine, Y2is D-proline, Y3is D-valine, and Y4is D-valine; Y1is D-valine, Y2is D-valine, Y3is D-proline, and Y4is D-valine; or Y1is D-valine, Y2is D-proline, Y3is D-valine, and Y4is D-proline.

32. The composition of any one of claims 1-4, wherein R1, R2, and R7are present and R8-R20are absent, and the sequence of Formula (I) is cyclized through R2and R7via a lactam bond.

33. The composition of claim 32, wherein: R1is acetylated norleucine; R2is aspartic acid; R3is selected from the group consisting of proline, hydroxyproline, and hydroxy- D-proline; R4is D-Nal(2′); R5is arginine; R6is D-tryptophan or L-tryptophan; R7is lysine; Y1is D-valine; and / or Y2is D-proline.

34. The composition of claim 32, wherein the sequence of Formula (I) is: Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 306; B07) or Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 307; D3), wherein c represents cyclization through R2and R7via a lactam bond.

35. The composition of any one of claims 1-4, wherein R1, R2, R7, and R8are present and R9-R20are absent, and the sequence of Formula (I) is cyclized through R2and R8via a lactam bond. -364- 146316.8009.WO00\165259190.2436. The composition of claim 35, wherein: R1is acetylated norleucine; R2is aspartic acid; R3is selected from the group consisting of proline, hydroxyproline, hydroxy-D- proline, phenylalanine, and histidine; R4is histidine or D-Nal(2′); R5is D-Nal(2′) or arginine; R6is selected from the group consisting of arginine, D-tryptophan, and L- tryptophan; R7is tryptophan or proline; R8is lysine; Y1is selected from the group consisting of D-valine, D-leucine, and D-isoleucine; and / or Y2is D-proline.

37. The composition of claim 35, wherein 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: 308; D1); Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH2 (SEQ ID NO: 309; D1γ); Ac-Nle-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH2 (SEQ ID NO: 310; D1δ); Ac-Nle-c(Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2 (SEQ ID NO: 311; D2); and Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH2(SEQ ID NO: 312; D4), wherein c represents cyclization through R2and R8via a lactam bond.

38. The composition of any one of claims 1-4, wherein R1-R2and R7-R10are present and R11-R20are absent, and the sequence of Formula (I) is cyclized through R2and R10via a lactam bond.

39. The composition of claim 38, wherein 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: 313; D1α), wherein c represents cyclization through R2and R10via a lactam bond. -365- 146316.8009.WO00\165259190.2440. The composition of any one of claims 1-4, wherein R1-R2and R7-R10are present and R11-R20are absent, and the sequence of Formula (I) is cyclized through R4and R10via a lactam bond.

41. The composition of claim 40, wherein 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: 314; D1β), wherein c represents cyclization through R4and R10via a lactam bond.

42. The composition of claim 19, wherein the sequence of Formula (I) is Ac- Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro (SEQ ID NO: 305; B07a), wherein c represents cyclization through R2and R7via a lactam bond.

43. The composition of any one of claims 1-4, wherein the sequence of Formula (I) is linear.

44. The composition of claim 43, wherein the sequence of Formula (I) is Ac- Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH2 (SEQ ID NO: 315; A1).

45. The composition of any one of claims 1-4, wherein 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: 316); Ac-dMet-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 317); Ac-dIle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 318); Ac-dLeu-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 319); Ac-dVal-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 320); Ac-dAla-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 321); Ac-Ala-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 322); Ac-Tle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 323); Ac-dTle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 324); Ac-dNle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 325); Ac-Nva-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 326); Ac-Gly-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 327); Ac-dPro-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 328); -366- 146316.8009.WO00\165259190.24Ac-dCys-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 329); Ac-dPhe-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 330); Ac-dTyr-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 331); Ac-dGln-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 332); and Ac-dAsn-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 333), wherein c represents cyclization through R2and R7via a lactam bond.

46. The composition of any one of claims 1-4, wherein 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: 334); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dLys)-dVal-dPro-NH2(SEQ ID NO: 335); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 336); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 337); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 338); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 339); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 340); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 341); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 342); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 343); Ac-Nle-c(Cys-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 344); Ac-Nle-c(dCys-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 345); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2 (SEQ ID NO: 346); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2(SEQ ID NO: 347); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 348); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 349); Ac-Nle-c(dPen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 350); Ac-Nle-c(Pen-Pro-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO: 351); Ac-Nle-c(Cys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 352); Ac-Nle-c(dCys-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 353); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Cys)-dVal-dPro-NH2(SEQ ID NO: 354); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dCys)-dVal-dPro-NH2 (SEQ ID NO: 355); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2(SEQ ID NO: 356); Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-Pen)-dVal-dPro-NH2 (SEQ ID NO: 357); -367- 146316.8009.WO00\165259190.24Ac-Nle-c(dPen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2 (SEQ ID NO: 358); Ac-Nle-c(Pen-dNal(2’)-Arg-Trp-dPen)-dVal-dPro-NH2(SEQ ID NO: 359); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 360); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2(SEQ ID NO: 361); Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-Orn)-dVal-dPro-NH2 (SEQ ID NO: 362); and Ac-Nle-c(Glu-Pro-dNal(2’)-Arg-Trp-dOrn)-dVal-dPro-NH2(SEQ ID NO: 363), wherein c represents cyclization through R2and R6or R7via a lactam bond or a disulfide bond.

47. The composition of any one of claims 1-4, wherein 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: 364); Ac-Nle-c(Asp-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 365); Ac-Nle-c(Asp-dPro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 366); Ac-Nle-c(Asp-dAla-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 367); Ac-Nle-c(Asp-dMet-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 368); Ac-Nle-c(Asp-Pro-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 369); Ac-Nle-c(Asp-Gly-Gly-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 370); Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 371); Ac-Nle-c(Asp-Leu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 372); Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 373); and Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 374), wherein c represents cyclization through R2and R7via a lactam bond.

48. The composition of any one of claims 1-4, wherein 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: 375); Ac-Nle-c(Asp-Pro-dNal(2’)-Lys-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 376); Ac-Nle-c(Asp-Pro-dNal(2’)-dLys-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 377); Ac-Nle-c(Asp-Pro-dNal(2’)-dArg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 378); Ac-Nle-c(Asp-Pro-dNal(2’)-Orn-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 379); Ac-Nle-c(Asp-Pro-dNal(2’)-dOrn-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 380); Ac-Nle-c(Asp-Pro-dNal(2’)-His-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 381); -368- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-dNal(2’)-Ala-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 382); Ac-Nle-c(Asp-Pro-dNal(2’)-Gly-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 383); Ac-Nle-c(Asp-Pro-dNal(2’)-Asp-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 384); and Ac-Nle-c(Asp-Pro-dNal(2’)-Glu-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 385), wherein c represents cyclization through R2and R7via a lactam bond.

49. The composition of any one of claims 1-4, wherein 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: 386); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Nal(1’)-Lys)-dVal-dPro-NH2 (SEQ ID NO: 387); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Aia-Lys)-dVal-dPro-NH2(SEQ ID NO: 388); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Phe-Lys)-dVal-dPro-NH2 (SEQ ID NO: 389); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Tyr-Lys)-dVal-dPro-NH2(SEQ ID NO: 390); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-His-Lys)-dVal-dPro-NH2 (SEQ ID NO: 391); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Ala-Lys)-dVal-dPro-NH2(SEQ ID NO: 392), wherein c represents cyclization through R2and R7via a lactam bond.

50. The composition of any one of claims 1-4, wherein the sequence of Formula (I) is Ac-Nle-c(Asp-Pro-Bip-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 393), wherein c represents cyclization through R2and R7via a lactam bond.

51. The composition of any one of claims 1-4, wherein 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: 394); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-OH (SEQ ID NO: 395); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-OH (SEQ ID NO: 396); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Hyp-NH2 (SEQ ID NO: 397); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dHyp-NH2 (SEQ ID NO: 398); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-Hyp-NH2(SEQ ID NO: 399); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-dHyp-NH2 (SEQ ID NO: 400); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-dVal-NH2(SEQ ID NO: 401); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-dVal-NH2 (SEQ ID NO: 402); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-Val-NH2(SEQ ID NO: 403); -369- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-Val-NH2 (SEQ ID NO: 404); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-NH2(SEQ ID NO: 405); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dPro-NH2 (SEQ ID NO: 406); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-NH2(SEQ ID NO: 407); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-NH2 (SEQ ID NO: 408); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Val-NH2(SEQ ID NO: 409); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Pro-NH2 (SEQ ID NO: 410); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Ala-NH2(SEQ ID NO: 411); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAla-NH2 (SEQ ID NO: 412); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dHyp-NH2(SEQ ID NO: 413); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Hyp-NH2 (SEQ ID NO: 414); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAla-dAla-NH2(SEQ ID NO: 415); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Ala-Ala-NH2 (SEQ ID NO: 416); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Gly-Gly-NH2(SEQ ID NO: 417); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Asp-NH2 (SEQ ID NO: 418); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Arg-NH2(SEQ ID NO: 419); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-Asn-NH2 (SEQ ID NO: 420); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dAsp-NH2 (SEQ ID NO: 421); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dArg-NH2 (SEQ ID NO: 422); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dAsn-NH2 (SEQ ID NO: 423); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asp-dPro-NH2(SEQ ID NO: 424); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dPro-NH2 (SEQ ID NO: 425); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asn-dPro-NH2(SEQ ID NO: 426); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsp-dPro-NH2 (SEQ ID NO: 427); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dPro-NH2(SEQ ID NO: 428); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsn-dPro-NH2 (SEQ ID NO: 429); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asp-NH2(SEQ ID NO: 430); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-NH2 (SEQ ID NO: 431); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Asn-NH2(SEQ ID NO: 432); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsp-NH2 (SEQ ID NO: 433); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-NH2(SEQ ID NO: 434); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dAsn-NH2 (SEQ ID NO: 435); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Pro-Val-NH2(SEQ ID NO: 436); -370- 146316.8009.WO00\165259190.24Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-dVal-NH2 (SEQ ID NO: 437); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-dVal-NH2(SEQ ID NO: 438); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dPro-NH2 (SEQ ID NO: 439); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dPro-NH2(SEQ ID NO: 440); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-Val-Pro-NH2 (SEQ ID NO: 441); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Lys-dVal-dPro-NH2(SEQ ID NO: 442); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dLys-dVal-dPro-NH2 (SEQ ID NO: 443); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Pro-Val-NH2(SEQ ID NO: 444); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dPro-dVal-NH2 (SEQ ID NO: 445); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dPro-dVal-NH2(SEQ ID NO: 446); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-Val-Pro-NH2 (SEQ ID NO: 447); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Arg-dVal-dPro-NH2(SEQ ID NO: 448); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dArg-dVal-dPro-NH2 (SEQ ID NO: 449), wherein c represents cyclization through R2and R7via a lactam bond.

52. The composition of any one of claims 1-4, wherein the sequence of Formula (I) is selected from the group consisting of: Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dPro-NH2 (SEQ ID NO: 450); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dPro-dVal-dPro-NH2(SEQ ID NO: 451); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 452); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH2(SEQ ID NO: 453); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dVal-dVal-dVal-dVal-dVal-dPro- NH2 (SEQ ID NO: 454), wherein c represents cyclization through R2and R7via a lactam bond.

53. The composition of any one of claims 1-4, wherein X1is present and is acetylated norleucine, and R1is present and is norleucine.

54. The composition of claim 53, wherein X2is present and is norleucine. -371- 146316.8009.WO00\165259190.2455. The composition of claim 53, wherein X3is present and is norleucine.

56. The composition of claim 53, wherein 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: 455); Ac-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 456); and Ac-Nle-Nle-Nle-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 457), wherein c represents cyclization through R2and R7via a lactam bond.

57. The composition of any one of claims 1-4, wherein 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: 458); Ac-Nle-c(Asp-Trp-Pro-dNal(2’)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 459); Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-dTrp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 460); c(CO-cis-CH = CH-CO-Pro-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 461); Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 462); Ac-Nle-c(Asp-β-Ala-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 463); Ac-Nle-c(Asp-Mamb-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 464); Ac-Nle-c(Asp-Acpc-dNal(2′) Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 465); Ac-c(Cys-Arg-dPhe-Cys)-Trp-dVal-dPro-NH2(SEQ ID NO: 466); and Ac-Nle-c(Asp-Pro-dNal(2’)-Arg-Trp-Lys)-Trp-NH2 (SEQ ID NO: 467), wherein c represents cyclization through R2and R7or R8via a lactam bond or through R2and R5via a disulfide bond.

58. The composition of any one of claims 1-4, wherein the sequence of Formula (I) is: Ac-Nle-c(Asp-Aic-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2(SEQ ID NO: 468); or Ac-Nle-c(Asp-Cpe-dNal(2′)-Arg-Trp-Lys)-dVal-dPro-NH2 (SEQ ID NO: 469), wherein c represents cyclization through R2and R7or R8via a lactam bond. -372- 146316.8009.WO00\165259190.2459. The composition of any one of claims 1-4, wherein the non-naturally occurring melanocortin analog comprises any one of the sequences of SEQ ID NOs: 306, 428, 481-483,493-495, 528-531, and 552-555.

60. The composition of any one of claims 1-4, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO:

306.

61. The composition of any one of claims 1-2 and 4-60, wherein the second compound is a compound of Formula (Xi): or a62. The composition of any one of claims 1-2 and 4-61, wherein the second compound is a compound of Formula (Xii): or a-373- 146316.8009.WO00\165259190.2463. The composition of any one of claims 1-2 and 4-62, wherein: Rx1is Rx1a; and Rx1ais 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected RxA, wherein each RxAis halogen, -OH, -CN, C1-4 alkyl, C14haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-C4cycloalkyl, or (C3-4cycloalkyl)- C14 alkyl-, wherein each of the C1-4 alkyl, C3-4 cycloalkyl, and (C3-4alkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; or two adjacent RxAtogether with the two ring-atoms of the 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C14haloalkoxy.

64. The composition of claim 63, wherein Rx1ais pyrimidinyl optionally substituted with 1, 2, or 3 independently selected RxA, wherein each RxAis halogen, - OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, or C3-4 cycloalkyl.

65. The composition of claim 64, wherein Rx1ais pyrimidin-2-yl.

66. The composition of any one of claims 1-2, 4-61, and 63-65, wherein Xx1is CH2.

67. The composition of any one of claims 1-2 and 4-66, wherein each of Rx2and Rx3is independently H, F, or C1-4 alkyl.

68. The composition of any one of claims 1-2 and 4-67, wherein Rx2is methyl and Rx3is H.

69. The composition of any one of claims 1-2 and 4-68, wherein Yx3is N, and each of Yx1, Yx2, Yx4, and Yx5is independently CRx4.

70. The composition of claim 69, wherein Rx4is independently H, halogen, or C1-2alkoxy. -374- 146316.8009.WO00\165259190.2471. The composition of any one of claims 1-2 and 4, wherein the second compound is selected from: (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-(7-methyl-6-(2-methyl-2H-tetrazol-5- yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, DIAST- 1; 2-(6-methoxy-2-methylpyrimidin-4-yl)-1-((2S)-7-methyl-6-(2-methyl-2H-tetrazol- 5-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, DIAST-1; 2-(6-(difluoromethoxy)pyridin-3-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4- dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, DIAST-2; 1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'- pyrrolidin)-1'-yl)-2-(4-(trifluoromethyl)phenyl)propan-1-one, DIAST-1; 1-(4,7-dimethyl-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)-2- (4-fluorophenyl)ethan-1-one, DIAST-1; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(2-methyl-2H- tetrazol-5-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1- one; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4- dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one; (2R)-2-(5-chloro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4- dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one; (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-(7-methyl-6-(1-methyl-1H-pyrazol-4- yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, DIAST- 1; and (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-{(2S)-7-methyl-6-((4,6-2H2)pyrimidin- 2-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl}propan-1-one, or pharmaceutically acceptable salt thereof.

72. The composition of any one of claims 1-2 and 4, wherein the second compound is (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2- yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, or pharmaceutically acceptable salt thereof. -375- 146316.8009.WO00\165259190.2473. The composition of any one of claims 1-2 and 4, wherein the second compound is a crystalline form of (2R)-2-(5-fluoro-2-methoxypyridin-4-yl)-1-((2S)-7- methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'- yl)propan-1-one.

74. The composition of any one of claims 1 and 3-73, wherein the antibody or antigen binding fragment thereof comprises a human Fc domain selected from the group consisting of an Fc domain of IgA1IgA2, IgD, IgE, IgM, IgG1, IgG2, IgG3, or IgG4.

75. The composition of any one of claims 1 and 3-74, wherein the antibody or antigen binding fragment thereof, binds human or cynomolgus monkey GDF-15 with a KD about or less than a value selected from the group consisting of about 10 nM, 5 nM, 2 nM, 1 nM, 900 pM, 800 pM, 700 pM, 600 pM, 500 pM, 400 pM, 300 pM, 250 pM, 200 pM, 150 pM, 100 pM, 50 pM, 40 pM, 30 pM, 25 pM, 20 pM, 15 pM, and 10 pM.

76. The composition of any one of claims 1 and 3-75, wherein the antibody or antigen binding fragment thereof comprises Anti-GDF-15 antibody GDF-15_001 having one or more amino acid sequences selected from the group of amino acid sequences consisting of SEQ ID NOs: 32, 165, 52, 25, 166, 22, 2324, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10, and 162.

77. The composition of any one of claims 1-76, further comprising an anti- cancer agent.

78. The composition of claim 77, wherein the anti-cancer agent is at least one chemotherapeutic agent.

79. The composition of claim 78, 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, an alkylating antineoplastic agent, and a cytotoxic antibiotic. -376- 146316.8009.WO00\165259190.2480. The composition of claim 79, wherein the platinum-coordination complex is cisplatin.

81. The composition of claim 79, wherein the antimetabolite is 5-fluorouracil (5-FU).

82. The composition of claim 79, wherein the tubulin binding agent is vincristine.

83. The composition of claim 79, wherein the alkylating antineoplastic agent is cyclophosphamide.

84. The composition of claim 79, wherein the cytotoxic antibiotic is doxorubicin.

85. The composition of any one of claims 1-2 and 4, wherein the first compound and the second compound are present in a single pharmaceutical composition.

86. The composition of any one of claims 1 and 3-4, wherein the first compound and the third compound are present in a single pharmaceutical composition.

87. The composition of claim 1 or 4, wherein the first compound, the second compound, and the third compound, if present, are present in a single pharmaceutical composition.

88. The composition of any one of claims 85-87, wherein the single pharmaceutical composition is formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, or oral administration.

89. The composition of any one of claims 85-87, wherein the single pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient. -377- 146316.8009.WO00\165259190.2490. The composition of any one of claims 85-89, wherein the first compound is present in the single pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, relative to a total volume of the single pharmaceutical composition.

91. The composition of any one of claims 1-2 and 4, wherein: the first compound is present in a first pharmaceutical composition; and the second compound is present in a second pharmaceutical composition.

92. The composition of any one of claims 1 and 3-4, wherein: the first compound is present in a first pharmaceutical composition; and the third compound is present in a third pharmaceutical composition.

93. The composition of claim 1 or 4, wherein: the first compound is present in a first pharmaceutical composition; the second compound is present in a second pharmaceutical composition; and the third compound is present in a third pharmaceutical composition.

94. The composition of any one of claims 91-93, wherein the first pharmaceutical composition is formulated for intraperitoneal, intravenous, parenteral, subcutaneous, intramuscular, intracerebroventricular, or oral administration.

95. The composition of any one of claims 91-94, wherein the first pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

96. The composition of any one of claims 91-95, wherein the first compound is present in the first pharmaceutical composition in a concentration of 0.1 mg / mL to 50 mg / mL, relative to a total volume of the first pharmaceutical composition.

97. A composition, comprising: a first compound having primary therapeutic efficacy; and a second compound and / or a third compound each having secondary therapeutic efficacy, -378- 146316.8009.WO00\165259190.24wherein the first compound is a non-naturally occurring melanocortin analog, the second compound is a spiro compound, and the third compound is an antibody or antigen binding fragment thereof.

98. The composition of claim 97, wherein the non-naturally occurring melanocortin analog is a melanocortin 3 receptor (MC3R) agonist and a melanocortin 4 receptor (MC4R) agonist.

99. The composition of claim 97 or 98, wherein the primary therapeutic efficacy occurs following agonism of the MC3R and / or the MC4R.

100. The composition of any one of claims 97-99, wherein 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 cysteine, aspartic acid, glutaric acid, leucine, isoleucine, valine, norvaline (Nva), alanine, glycine, proline, methionine, lysine, phenylalanine, asparagine, acetylated D-arginine, acetylated D-methionine, acetylated D-isoleucine, acetylated D-leucine, acetylated D-valine, acetylated alanine, acetylated D-alanine, acetylated tert-leucine (Tle), acetylated D-tert-leucine (dTle), acetylated norvaline (Ac-Nva), acetylated glycine, acetylated D-proline, acetylated D- phenylalanine, acetylated D-tyrosine, acetylated D-glutamine, and acetylated D- asparagine; R2is absent or is selected from the group consisting of proline, aspartic acid, D- aspartic acid, glutamic acid, glycine, lysine, 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), alanine, D-alanine, D- methionine, valine, prolylglycine (Pro-Gly), glycylglycine (Gly-Gly), glycine, phenylalanine, D-phenylalanine, leucine, isoleucine, arginine, 4-amino-1,2,4,5- -379- 146316.8009.WO00\165259190.24tetrahydro-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 (Atc), 1-amino-4-phenylcyclohexane-carboxylic acid (APC), 4- aminophenylpiperidine-4-carboxylic acid (APPC), 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), glycine, proline, cysteine, para-chloro-D-phenylalanine (p(Cl)dPhe), para-bromo-D-phenylalanine (p(Br)dPhe), and para-iodo-D-phenylalanine (p(I)dPhe); R5is absent or is selected from the group consisting of arginine, homoarginine, ornithine, histidine, alanine, Pip, Nip, Tic, Phg, Sar, Azt, phenylalanine, D-Nal(2′), lysine, glycine, aspartic acid, glutamic acid, cysteine, and p(I)dPhe; R6is absent or is selected from the group consisting of L-tryptophan, D- tryptophan, L-Nal(2′), Tic, Bip, arginine, histidine, cysteine, Nal(1’), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R7is absent or is selected from the group consisting of aspartic acid, glutamic acid, cysteine, lysine, methionine, proline, tryptophan, D-Nal(2′), 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-R20are absent; X1is absent or is selected from the group consisting of D-cysteine, L-cysteine, D- threonine, D-proline, L-proline, D-alanine, L-alanine, β-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, and acetylated norleucine; X2is absent or is selected from the group consisting of D-threonine, D-proline, L- proline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-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- -380- 146316.8009.WO00\165259190.24leucine, 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, 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, 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-proline, L-proline, D- valine, and L-valine; Y4is absent or is 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 R1or R2and R7or X1when R1or R2is cysteine and R7or X1is cysteine; a disulfide bond between R2and any one of R5-R20when R2and the any one of R5-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 or ornithine; 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; provided that: when R2is dAsp, then R7is not dLys; when R2-R4is Asp-His-dNal(2’), Asp-Pro-dNal(2’) or Asp-Pro-dPhe, then R5-R7is not Arg-Trp-Lys; and -381- 146316.8009.WO00\165259190.24when Y1is dPro, Y2is dVal, and Y3-Y8are absent, then R4is not dNal(2’) or R4is dNal(2’) and the C-terminus is not modified; when R7is Aia, R4is dNal(2’); when R4is p(I)dPhe and the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R1and R7, then R2is His; when R2-R7is Asp-Pro-dNal(2’)-Arg-Trp-Lys, then Y1-Y2is not dPro-dVal; when the non-naturally occurring melanocortin analog is cyclized through a lactam bond between R2and R8, and R3is Pro, then R7is not Pro and Y1is not dPro; and when the non-naturally occurring melanocortin analog is linear, R2is not absent.

101. The composition of claim 100, wherein the non-naturally occurring melanocortin analog comprises a sequence of SEQ ID NO:

306.

102. The composition of any one of claims 97-101, wherein the spiro compound is an MC4R antagonist.

103. The composition of any one of claims 97-102, wherein the secondary therapeutic efficacy occurs following antagonism of the MC4R.

104. The composition of any one of claims 97-103, wherein the spiro compound comprises a structure according to Formula (X) or aRx1is H, halogen, C1-4alkyl, C1-4haloalkyl, C3-6cycloalkyl, 4- to 7- memberedocycloalkyl, phenyl, or Rx1a, wherein each of the C3-6 cycloalkyl and 4- to 7- -382- 146316.8009.WO00\165259190.24memberedocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected C1-4alkyl, and wherein the phenyl is optionally substituted with 1, 2, 3, or 4 independently selected RxB, wherein RxBis halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, C1-4haloalkoxy, C3-4cycloalkyl, or RxB1; or two adjacent RxBtogether with the two ring-forming atoms of the phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which each is optionally substituted 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; Rx1ais 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independent RxA, wherein each RxAis halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C14 alkoxy, C1-4 haloalkoxy, C3-4 cycloalkyl, -N(C1-4 alkyl)2, RxA1, or (C3-4 cycloalkyl)- C14alkyl-, wherein each of the C14alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; or two adjacent RxAtogether with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached form a fused benzene ring or a fused 5- or 6- membered heteroaryl or a fused 5- or 6-membered heterocycloalkyl or a fused 5- or 6- membered cycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4 haloalkyl, C1- 4 alkoxy, and C1-4 haloalkoxy; RxA1is 5- or 6-membered heteroaryl or 5- or 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4 haloalkoxy; RxB1is 5- or 6-membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents each independently selected from halogen, -OH, -CN, C1-4 alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy; each of Rx2and Rx3is independently H, halogen, C1-4 alkyl, C1-4 hydroxyalkyl, C1-4haloalkyl, (C1-4alkoxy)-C1-4alkyl-, C3-4cycloalkyl, or (C3-4cycloalkyl)-C1-4alkyl, wherein each of C3-4 cycloalkyl and (C3-4 cycloalkyl)-C1-4 alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; -383- 146316.8009.WO00\165259190.24or Rx2and Rx3together with the carbon atom to which they are attached form C3-6cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, and C1-4 haloalkoxy; each Rx4is independently H, halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, -N(C1-2 alkyl)2, C3-4 cycloalkyl, or (C3-4 cycloalkyl)-C1-4alkyl-, wherein each of the C1-4alkyl, C3-4cycloalkyl, and (C3-4cycloalkyl)-C1-4alkyl- is optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from halogen, -OH, -CN, C1-4alkyl, C1-4haloalkyl, C1-4alkoxy, and C1-4haloalkoxy Xx1is C(RxX)2, wherein each RxXis independently H or C1-4 alkyl; each of Yx1, Yx2, Yx3, Yx4, and Yx5is independently CR4or N, provided that no more than 3 of Yx1, Yx2, Yx3, Yx4, and Yx5are N.

105. The composition of claim 104, wherein the spiro compound is (2R)-2-(5- fluoro-2-methoxypyridin-4-yl)-1-((2S)-7-methyl-6-(pyrimidin-2-yl)-3,4-dihydro-1H- spiro(1,8-naphthyridine-2,3'-pyrrolidin)-1'-yl)propan-1-one, or pharmaceutically acceptable salt thereof.

106. The composition of any one of claims 97-105, wherein the antibody or antigen binding fragment thereof specifically binds to a portion of human growth differentiation factor 15 (GDF-15).

107. The composition of any one of claims 97-106, wherein the antibody or antigen binding fragment thereof binds to GDF-15 thereby preventing binding of GDF- 15 to a Glial-derived neurotrophic factor-family receptor α-like (GFRAL) receptor.

108. The composition of any one of claims 97-107, wherein the antibody or antigen binding fragment thereof comprises at least one of the following: a) a light chain complementarity determining region 1 (LCDR-1) comprising the amino acid sequence of SEQ ID NO:95, a LCDR-2 comprising the amino acid sequence of SEQ ID NO:28, a LCDR-3 comprising the amino acid sequence of SEQ ID NO:9, a heavy chain complementarity determining region 1 (HCDR-1) comprising the amino acid sequence of SEQ ID NO:32, a HCDR-2 comprising the amino acid sequence of SEQ ID NO:165, and a HCDR-3 comprising the amino acid sequence of SEQ ID NO:52; -384- 146316.8009.WO00\165259190.24b) LCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) a LCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) a LCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) a HCDR-1 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) a HCDR-2 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) a HCDR-3 amino acid sequence selected from the group consisting of the sequence of SEQ ID NO:1, 19, 43, 52, 79, 111, 119, 135, 147, 154, 160, 173, and 181; h) the HCDR-1, HCDR-2, and HCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences as set forth in the amino acid sequence of SEQ ID NO:163; i) the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited at the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:166, and a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:163; k) a VH comprising the amino acid sequence of SEQ ID NO:166 and a VL comprising the amino acid sequence of SEQ ID NO:163; l) a heavy chain (HC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:164, and a light chain (LC) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:162; m) a HC comprising the amino acid sequence of SEQ ID NO:164, and a LC comprising the amino acid sequence of SEQ ID NO:162; GDF-15; and -385- 146316.8009.WO00\165259190.24n) an antibody that competes for binding to GDF-15 with at least one antibody from (a)-(m) above.

109. The composition of claim 108, wherein the antibody or antigen binding fragment thereof comprises Anti-GDF-15 antibody GDF-15_001 having one or more amino acid sequences selected from the group of amino acid sequences consisting of SEQ ID NOs: 32, 165, 52, 25, 166, 22, 2324, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10, and 162.

110. The composition of any one of claims 97-109, wherein the secondary therapeutic efficacy is supportive therapeutic efficacy compared to the primary therapeutic efficacy.

111. The composition of any one of claims 97-110, wherein the composition comprises a lower dosage unit of the second compound and / or the third compound compared to a dosage unit of the second compound and / or a dosage unit of the third compound absent the first compound.

112. The composition of any one of claims 97-111, wherein the composition comprises a lower dose of the second compound and / or the third compound compared to a dose of the second compound and / or a dose of the third compound absent the first compound.

113. The composition of any one of claims 97-112, wherein the composition comprises a shorter dosage regimen of the second compound and / or the third compound compared to a dosage regimen of the second compound and / or a dosage regimen of the third compound absent the first compound.

114. The composition of any one of claims 97-113, wherein the composition comprises fewer dosages of the second compound and / or the third compound compared to dosages of the second compound and / or dosages of the third compound absent the first compound. -386- 146316.8009.WO00\165259190.24115. The composition of any one of claims 97-114, wherein the composition has an improved net-effect on MC4R compared to the effect on MC4R of the second compound and / or the effect on MC4R of the third compound absent the first compound.

116. A method of increasing appetite of a subject in need thereof relative to a control, the method comprising: administering the composition of any one of claims 1-115 to the subject.

117. The method of claim 116, 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, compared to the control.

118. The method of claim 116, wherein the subject is not on a High Carbohydrate High Calorie (HCHC) diet.

119. The method of claim 118, wherein the HCHC diet comprises a daily food consumption providing calories of at least 2000 kcal and at least 50 % of the calories are from carbohydrate.

120. The method of any one of claims 116-119, wherein the subject is not on a High Fat High Calorie (HFHC) diet.

121. The method of claim 120, wherein the HFHC diet comprises a daily food consumption providing calories of at least 2000 kcal and at least 50 % of the calories are from fat.

122. The method of any one of claims 116-121, the first, the second, and the third compounds are administered simultaneously as a single composition.

123. The method of any one of claims 116-122, wherein: the first compound is present in a first pharmaceutical composition; -387- 146316.8009.WO00\165259190.24the second compound, if present, is present in a second pharmaceutical composition; and the third compound, if present, is present in a third pharmaceutical composition.

124. The method of claim 123, wherein the first, the second, and the third pharmaceutical compositions are different and are administered simultaneously but separately.

125. The method of claim 123, wherein the first, the second, and the third pharmaceutical compositions are different and are administered sequentially.

126. The method of claim 125, wherein the first pharmaceutical composition is administered prior to initial administration of the second pharmaceutical composition.

127. The method of claim 125, wherein the first pharmaceutical composition is administered prior to initial administration of the third pharmaceutical composition.

128. The method of claim 125, wherein the first and the second pharmaceutical compositions are administered sequentially within about 24 hours.

129. The method of claim 128, wherein the first pharmaceutical composition is administered in the morning, and the second pharmaceutical composition is administered in the evening.

130. The method of claim 125, wherein the first and the third pharmaceutical compositions are administered sequentially within about 24 hours.

131. The method of claim 130, wherein the first pharmaceutical composition is administered in the morning, and the third pharmaceutical composition is administered in the evening.

132. The method of any one of claims 116-131, wherein the first compound comprises a sequence of SEQ ID NO:

306. -388- 146316.8009.WO00\165259190.24133. The method of any one of claims 116-132, wherein the first compound 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.

134. The method of any one of claims 116-133, wherein the first compound 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.

135. The method of any one of claims 116-134, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 10%-75% less than that of the second compound when administered alone.

136. The method of any one of claims 116-135, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 25%-50% less than that of the second compound when administered alone.

137. The method of any one of claims 116-136, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 10%-75% less than that of the third compound when administered alone.

138. The method of any one of claims 116-137, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 25%-50% less than that of the third compound when administered alone.

139. The method of any one of claims 116-138, wherein the composition is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years. -389- 146316.8009.WO00\165259190.24140. The method of any one of claims 116-138, wherein the composition is administered to the subject for 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

141. The method of any one of claims 116-140, wherein the subject experiences loss of appetite, decreased food consumption, and / or weight loss prior to the administration.

142. The method of claim 141, wherein the loss of appetite, decreased food consumption, and / or weight loss is caused by cachexia.

143. The method of claim 141 or 142, wherein the weight loss is muscle mass loss, fat mass loss, or both.

144. The method of any one of claims 116-143, wherein the method (i) stimulates appetite of the subject; (ii) increases food consumption by 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.

145. A method of treating cancer in a subject in need thereof, the method comprising: administering the composition of any one of claims 77-96 to the subject.

146. The method of claim 145, wherein the subject experiences a decrease in tumor size by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to the control.

147. The method of claim 145, wherein the subject experiences a decrease in cancer metastasis as measured by a decrease in cancer cell proliferation by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to control. -390- 146316.8009.WO00\165259190.24148. A method of treating a subject with a cancer, the method comprising: administering the composition of any one of claims 77-96 to the subject, wherein: the method reduces or prevents a side effect associated with the anti-cancer agent of the combination therapy, wherein the side effect is at least one selected from the group consisting of cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

149. A method of improving survival in a subject with a cancer, the method comprising: administering the composition of any one of claims 77-96 to the subject, wherein: the method reduces or prevents a side effect associated with the anti-cancer agent of the combination therapy, thereby improving survival of the subject, wherein the side effect is at least one selected from the group consisting of cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

150. A method of increasing body weight in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

151. The method of claim 150, wherein the subject experiences an increase in body weight by 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 the control.

152. A method of increasing muscle mass in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject. -391- 146316.8009.WO00\165259190.24153. The method of claim 152, wherein the subject experiences an increase in muscle mass by 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 the control.

154. A method of increasing fat mass in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

155. The method of claim 154, wherein the subject experiences an increase in fat mass by 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 the control.

156. A method of increasing cardiac mass in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

157. The method of claim 156, wherein the subject experiences an increase in cardiac mass by 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 the control.

158. A method of increasing bone density in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

159. The method of claim 158, wherein the subject experiences an increase in bone density by 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 the control.

160. A method of reducing fatigue in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject. -392- 146316.8009.WO00\165259190.24161. A method of reducing vomiting in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

162. A method of reducing diarrhea in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

163. A method of increasing cumulative mass in a subject compared to a control, the method comprising administering the composition of any one of claims 1- 115 to the subject.

164. The method of claim 163, wherein the subject experiences an increase in cumulative mass by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

165. A method of increasing net weight gain in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

166. The method of claim 165, wherein the subject experiences an increase in net weight gain by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

167. A method of reducing a rate of loss of cumulative mass in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

168. The method of claim 167, wherein the subject experiences a reduction in the rate of loss of cumulative mass by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control. -393- 146316.8009.WO00\165259190.24169. A method of increasing cumulative food intake in a subject compared to a control, the method comprising administering the composition of any one of claims 1- 115 to the subject.

170. The method of claim 169, wherein the subject experiences an increase in cumulative food intake by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

171. A method of increasing body mass index (BMI) in a subject compared to a control, the method comprising administering the composition of any one of claims 1- 115 to the subject.

172. The method of claim 171, wherein the subject experiences an increase in BMI compared to the 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.

173. A method of reducing a proinflammatory transcript or protein level in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

174. The method of claim 173, wherein the subject experiences a reduction in an inflammatory transcript or protein level by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the control.

175. The method of claim 173 or 174, wherein the proinflammatory transcript is selected from the group consisting of an IL1b transcript, and IL1R1 transcript, an IL6 transcript, a CCL2 transcript, and a GDF-15 transcript.

176. The method of claim 173 or 174, wherein the proinflammatory protein is selected from the group consisting of an IL1b protein, and IL1R1 protein, an IL6 protein, a CCL2 protein, and a GDF-15 protein. -394- 146316.8009.WO00\165259190.24177. A method of increasing a Functional Assessment of Anorexia / Cachexia Treatment (FAACT) score in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

178. The method of claim 177, wherein the subject experiences an increase in FAACT score by at least 1, 2, 3, 4, or 5 points compared to the control.

179. A method of increasing BMI durability in a subject compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

180. The method of claim 179, wherein the subject experiences an increase in BMI durability of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the control.

181. The method of any one of claims 150-180, wherein the subject has a cancer.

182. A method of reducing or maintaining an Eastern Cooperative Oncology Group (ECOG) performance status score in a subject having cancer compared to a control, the method comprising administering the composition of any one of claims 1- 115 to the subject.

183. The method of claim 182, wherein the subject experiences a reduction in ECOG score by about 1, 2, or 3 compared to the control.

184. A method of increasing or maintaining a Karnofsky Performance Status (KPS) grade in a subject having cancer compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

185. The method of claim 184, wherein the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to the control. -395- 146316.8009.WO00\165259190.24186. A method of increasing overall survival (OS) in a subject having cancer compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

187. The method of claim 186, wherein the subject experiences an increase in OS by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

188. A method of increasing progression free survival (PFS) in a subject having cancer compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

189. The method of claim 188, wherein the subject experiences an increase in PFS by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

190. A method of reducing time to cancer treatment failure in a subject having cancer compared to a control, the method comprising administering the composition of any one of claims 1-115 to the subject.

191. The method of claim 190, wherein the subject experiences a reduction in time to cancer treatment failure by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

192. The method of any one of claims 116-191, wherein the control comprises the subject at baseline or a second subject that has not received the composition of any one of claims 1-115.

193. The method of claim 148 or 149, wherein the subject is not on a High Carbohydrate High Calorie (HCHC) diet. -396- 146316.8009.WO00\165259190.24194. The method of claim 193, wherein the HCHC diet comprises a daily food consumption providing calories of at least 2000 kcal and at least 50 % of the calories are from carbohydrate.

195. The method of any one of claims 148-194, wherein the subject is not on a High Fat High Calorie (HFHC) diet.

196. The method of claim 195, wherein the HFHC diet comprises a daily food consumption providing calories of at least 2000 kcal and at least 50 % of the calories are from fat.

197. The method of any one of claims 148-196, wherein the first, the second, the third compounds, and the anti-cancer agent are administered simultaneously as a single composition.

198. The method of any one of claims 148-197, wherein: the first compound is present in a first pharmaceutical composition; the second compound, if present, is present in a second pharmaceutical composition; the third compound, if present, is present in a third pharmaceutical composition; and the anti-cancer agent is present in a fourth pharmaceutical composition.

199. The method of claim 198, wherein the first, the second, the third, and the fourth pharmaceutical compositions are different and are administered simultaneously but separately.

200. The method of claim 198, wherein the first, the second, the third, and the fourth pharmaceutical compositions are different and are administered sequentially.

201. The method of claim 198, wherein the first pharmaceutical composition is administered prior to initial administration of the second pharmaceutical composition. -397- 146316.8009.WO00\165259190.24202. The method of claim 198, wherein the first pharmaceutical composition is administered prior to initial administration of the third pharmaceutical composition.

203. The method of claim 198, wherein the first pharmaceutical composition is administered prior to initial administration of the fourth pharmaceutical composition.

204. The method of claim 200, wherein the first and the second pharmaceutical compositions are administered sequentially within about 24 hours.

205. The method of claim 204, wherein the first pharmaceutical composition is administered in the morning, and the second pharmaceutical composition is administered in the evening.

206. The method of claim 200, wherein the first and the third pharmaceutical compositions are administered sequentially within about 24 hours.

207. The method of claim 206, wherein the first pharmaceutical composition is administered in the morning, and the third pharmaceutical composition is administered in the evening.

208. The method of any one of claims 148-207, wherein the first compound comprises a sequence of SEQ ID NO:

306.

209. The method of any one of claims 148-208, wherein the first compound 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.

210. The method of any one of claims 148-209, wherein the first compound 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.

211. The method of any one of claims 148-210, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically -398- 146316.8009.WO00\165259190.24effective amount of the second compound is 10-75% less than that of the second compound when administered alone.

212. The method of any one of claims 148-211, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 25-50% less than that of the second compound when administered alone.

213. The method of any one of claims 148-212, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 10-75% less than that of the third compound when administered alone.

214. The method of any one of claims 148-213, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 25-50% less than that of the third compound when administered alone.

215. The method of any one of claims 148-214, wherein the composition is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

216. The method of any one of claims 148-214, wherein the composition is administered to the subject for 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

217. The method of any one of claims 148-216, wherein the subject is a human.

218. The method of any one of claims 148-216, wherein the subject is an animal.

219. The method of any one of claims 148-218, which does not reduce efficacy of the anti-cancer agent. -399- 146316.8009.WO00\165259190.24220. The method of any one of claims 148-219 or 181-191, wherein the cancer is at least one selected from the group consisting of bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colon cancer, oral cancer, skin cancer, and melanoma.

221. The method of any one of claims 148-220, wherein the cancer is at least one selected from the group consisting of bone cancer, lung cancer, testicular cancer, breast cancer, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.

222. The method of any one of claims 148-221, wherein the subject with a cancer has previously undergone a treatment with the anti-cancer agent.

223. The method of claim 222, 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 cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

224. The method of any one of claims 148-223, wherein the one or more anti- cancer agents are dosed at a higher amount when present in the composition comprising the first compound and the third compound compared to the composition comprising the one or more anti-cancer agents and the first compound or the one or more anti-cancer agents and the third compound.

225. The method of claim 224, wherein dosing the one or more anti-cancer agents at a higher amount comprises increased dose amounts, administering more frequent doses, extending the duration of the dosing regimen, and / or increasing the total number of doses administered to the subject. -400- 146316.8009.WO00\165259190.24226. The method of any one of claims 148-225, wherein the one or more anti- cancer agents is dosed at least at about 6 mg / mL, 7 mg / mL, or 8 mg / mL in combination with the first compound and the third compound compared to about 2 mg / mL or about 3 mg / mL with the first compound or the third compound.

227. The method of claim 226, wherein the one or more anti-cancer agents is dosed at least at about 6 mg / mL, in combination with the first compound and the third compound compared to about 2 mg / mL with the first compound or the third compound.

228. The method of claim 226, wherein the one or more anti-cancer agents is dosed at least at about 7 mg / mL, in combination with the first compound and the third compound compared to about 2 mg / mL with the first compound or the third compound.

229. The method of claim 226, wherein the one or more anti-cancer agents is dosed at least at about 8 mg / mL, in combination with the first compound and the third compound compared to about 2 mg / mL with the first compound or the third compound.

230. The method of claim 226, wherein the one or more anti-cancer agents is dosed at least at about 6 mg / mL, in combination with the first compound and the third compound compared to about 3 mg / mL with the first compound or the third compound.

231. The method of claim 226, wherein the one or more anti-cancer agents is dosed at least at about 7 mg / mL, in combination with the first compound and the third compound compared to about 3 mg / mL with the first compound or the third compound.

232. The method of claim 226, wherein the one or more anti-cancer agents is dosed at least at about 8 mg / mL, in combination with the first compound and the third compound compared to about 3 mg / mL with the first compound or the third compound.

233. The method of any one of claims 226-232, wherein the one or more anti- cancer agents comprises cisplatin. -401- 146316.8009.WO00\165259190.24234. The method of any one of claims 148-233, wherein the method reduces or prevents one or more side effects in the subject and further comprises dosing the one or more anti-cancer agents at a higher amount thereby increasing efficacy of the one or more anti-cancer agents in the subject.

235. The method of any one of claims 148-234, wherein the method increases efficacy of the anti-cancer agent.

236. Use of the composition of any one of claims 1-115 to increase appetite of a subject in need thereof.

237. The use of claim 236, wherein the increase in appetite comprises an increase 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 the control.

238. Use of the composition of any one of claims 1-115 for treating a subject with a cancer compared to a control.

239. The use of claim 238, wherein the subject experiences a decrease in tumor size by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to the control.

240. The use of claim 238, wherein the subject experiences a decrease in cancer metastasis as measured by a decrease in cancer cell proliferation by about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to control.

241. Use of the composition of any one of claims 1-115 for increasing survival in a subject with a cancer compared to a control.

242. Use of the composition of any one of claims 1-115 for increasing body weight in a subject compared to a control. -402- 146316.8009.WO00\165259190.24243. The use of claim 242, wherein the subject experiences an increase in body weight by 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 the control.

244. Use of the composition of any one of claims 1-115 for increasing muscle mass in a subject compared to a control.

245. The use of claim 244, wherein the subject experiences an increase in muscle mass by 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 the control.

246. Use of the composition of any one of claims 1-115 for increasing fat mass in a subject compared to a control.

247. The use of claim 246, wherein the subject experiences an increase in fat mass by 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 the control.

248. Use of the composition of any one of claims 1-115 for increasing cardiac mass in a subject compared to a control.

249. The use of claim 248, wherein the subject experiences an increase in cardiac mass by 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 the control.

250. Use of the composition of any one of claims 1-115 for increasing bone density in a subject compared to a control. -403- 146316.8009.WO00\165259190.24251. The use of claim 250, wherein the subject experiences an increase in bone density by 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 the control.

252. Use of the composition of any one of claims 1-115 for reducing fatigue in a subject compared to a control.

253. Use of the composition of any one of claims 1-115 for reducing vomiting in a subject compared to a control.

254. Use of the composition of any one of claims 1-115 for reducing diarrhea in a subject compared to a control.

255. Use of the composition of any one of claims 1-115 for increasing cumulative mass in a subject compared to a control.

256. The use of claim 255, wherein the subject experiences an increase in cumulative mass by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

257. Use of the composition of any one of claims 1-115 for increasing net weight gain in a subject compared to a control.

258. The use of claim 257, wherein the subject experiences an increase in net weight gain by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

259. Use of the composition of any one of claims 1-115 for reducing a rate of loss of cumulative mass in a subject compared to a control.

260. The use of claim 259, wherein the subject experiences a reduction in the rate of loss of cumulative mass by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, -404- 146316.8009.WO00\165259190.248%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

261. Use of the composition of any one of claims 1-115 for increasing cumulative food intake in a subject compared to a control.

262. The use of claim 261, wherein the subject experiences an increase in cumulative food intake by at least about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,10%, 2%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to the control.

263. Use of the composition of any one of claims 1-115 for increasing BMI in a subject compared to a control.

264. The use of claim 263, wherein the subject experiences an increase in BMI compared to the 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.

265. Use of the composition of any one of claims 1-115 for reducing a proinflammatory transcript or protein level in a subject compared to a control.

266. The use of claim 265, wherein the subject experiences a reduction in an inflammatory transcript or protein level by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the control.

267. The use of claim 265 or 266, wherein the proinflammatory transcript is selected from the group consisting of an IL1b transcript, and IL1R1 transcript, an IL6 transcript, a CCL2 transcript, and a GDF-15 transcript.

268. The use of claim 265 or 266, wherein the proinflammatory protein is selected from the group consisting of an IL1b protein, and IL1R1 protein, an IL6 protein, a CCL2 protein, and a GDF-15 protein. -405- 146316.8009.WO00\165259190.24269. Use of the composition of any one of claims 1-115 for increasing an FAACT score in a subject compared to a control.

270. The use of claim 269, wherein the subject experiences an increase in FAACT score by at least 1, 2, 3, 4, or 5 points compared to the control.

271. Use of the composition of any one of claims 1-115 for increasing BMI durability in a subject compared to a control.

272. The use of claim 271, wherein the subject experiences an increase in BMI durability of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to the control.

273. The use of any one of claims 242-272, wherein the subject has a cancer.

274. Use of the composition of any one of claims 1-115 for reducing or maintaining an ECOG performance status score in a subject having cancer compared to a control.

275. The use of claim 274, wherein the subject experiences a reduction in ECOG score by about 1, 2, or 3 compared to the control.

276. Use of the composition of any one of claims 1-115 for increasing or maintaining a KPS score in a subject having cancer compared to a control.

277. The use of claim 276, wherein the subject experiences an increase in KPS score by about 100, 90, 80, 70, 60, 50, 40, or 30 compared to the control.

278. Use of the composition of any one of claims 1-115 for increasing OS in a subject having cancer compared to a control. -406- 146316.8009.WO00\165259190.24279. The use of claim 278, wherein the subject experiences an increase in OS by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

280. Use of the composition of any one of claims 1-115 for increasing PFS in a subject having cancer compared to a control.

281. The use of claim 280, wherein the subject experiences an increase in PFS by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

282. Use of the composition of any one of claims 1-115 for reducing time to cancer treatment failure in a subject having cancer compared to a control.

283. The use of claim 282, wherein the subject experiences a reduction in time to cancer treatment failure by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

284. The use of any one of claims 236-283, wherein the control comprises the subject at baseline or a second subject that has not received the composition of any one of claims 1-115.

285. The use of any one of claims 236-241, wherein the subject is not on a High Carbohydrate High Calorie (HCHC) diet.

286. The use of any one of claims 236-285, wherein the HCHC diet comprises a daily food consumption providing calories of at least 2000 kcal and at least 50 % of the calories are from carbohydrate.

287. The use of any one of claims 236-286, wherein the subject is not on a High Fat High Calorie (HFHC) diet. -407- 146316.8009.WO00\165259190.24288. The use of claim 287, wherein the HFHC diet comprises a daily food consumption providing calories of at least 2000 kcal and at least 50% of the calories are from fat.

289. The use of any one of claims 236-288, wherein the first, the second, and the third compounds are administered simultaneously as a single composition.

290. The use of any one of claims 236-289, wherein: the first compound is present in a first pharmaceutical composition; the second compound, if present, is present in a second pharmaceutical composition; and the third compound, if present, is present in a third pharmaceutical composition.

291. The use of claim 290, wherein the first, the second, and the third pharmaceutical compositions are different and are administered simultaneously but separately.

292. The use of claim 290, wherein the first, the second, and the third pharmaceutical compositions are different and are administered sequentially.

293. The use of claim 292, wherein the first pharmaceutical composition is administered prior to initial administration of the second pharmaceutical composition.

294. The use of claim 292, wherein the first pharmaceutical composition is administered prior to initial administration of the third pharmaceutical composition.

295. The use of claim 292, wherein the first and the second pharmaceutical compositions are administered sequentially within about 24 hours.

296. The use of claim 295, wherein the first pharmaceutical composition is administered in the morning, and the second pharmaceutical composition is administered in the evening. -408- 146316.8009.WO00\165259190.24297. The use of claim 292, wherein the first and the third pharmaceutical compositions are administered sequentially within about 24 hours.

298. The use of claim 297, wherein the first pharmaceutical composition is administered in the morning, and the third pharmaceutical composition is administered in the evening.

299. The use of any one of claims 236-298, wherein the first compound comprises a sequence of SEQ ID NO:

306.

300. The use of any one of claims 236-299, wherein the first compound 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.

301. The use of any one of claims 236-300, wherein the first compound 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.

302. The use of any one of claims 236-301, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 10%-75% less than that of the second compound when administered alone.

303. The use of any one of claims 236-302, wherein a therapeutically effective amount of the second compound is administered, and the therapeutically effective amount of the second compound is 25%-50% less than that of the second compound when administered alone.

304. The use of any one of claims 236-303, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 10%-75% less than that of the third compound when administered alone. -409- 146316.8009.WO00\165259190.24305. The use of any one of claims 236-304, wherein a therapeutically effective amount of the third compound is administered, and the therapeutically effective amount of the third compound is 25%-50% less than that of the third compound when administered alone.

306. The use of any one of claims 236-305, wherein the composition is administered to the subject for at least 1 day, 1 week, 1 month, 3 months, 6 months, 1 year, or 5 years.

307. The use of any one of claims 236-306, wherein the composition is administered to the subject for 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 40 days, 45 days, 50 days, 60 days, 75 days, 90 days, 100 days, 110 days, or 120 days.

308. The use of any one of claims 236-307, wherein the subject experiences loss of appetite, decreased food consumption, and / or weight loss prior to the administration.

309. The use of claim 308, wherein the loss of appetite, decreased food consumption, and / or weight loss is caused by cachexia.

310. The use of claim 308 or 309, wherein the weight loss is muscle mass loss, fat mass loss, or both.

311. The use of any one of claims 236-310, wherein the use (i) stimulates appetite of the subject; (ii) increases food consumption by 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.

312. The use of any one of claims 236-311, wherein the use reduces or prevents a side effect associated with the anti-cancer agent of the combination therapy, -410- 146316.8009.WO00\165259190.24wherein the side effect is at least one selected from the group consisting of cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

313. The use of any one of claims 236-312, wherein the use reduces or prevents a side effect associated with the anti-cancer agent of the combination therapy, thereby improving survival of the subject, wherein the side effect is at least one selected from the group consisting of cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

314. The use of any one of claims 236-313, wherein the subject is a human.

315. The use of any one of claims 236-314, wherein the subject is an animal.

316. The use of any one of claims 236-315, which does not reduce efficacy of the anti-cancer agent.

317. The use of any one of claims 236-316, wherein the cancer is at least one selected from the group consisting of bone cancer, testicular cancer, gastric cancer, sarcoma, lymphoma, Hodgkin's lymphoma, leukemia, head and neck cancer, squamous cell head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, stomach cancer, thyroid cancer, lung cancer, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, leukemia, multiple myeloma, renal cell carcinoma, bladder cancer, cervical cancer, choriocarcinoma, colon cancer, oral cancer, skin cancer, and melanoma.

318. The use of any one of claims 236-317, wherein the cancer is at least one selected from the group consisting of bone cancer, lung cancer, testicular cancer, breast cancer, ovarian cancer, cervical cancer, bladder cancer, and head and neck cancer.

319. The use of any one of claims 236-318, wherein the subject with a cancer has previously undergone a treatment with the anti-cancer agent. -411- 146316.8009.WO00\165259190.24320. The use of claim 319, 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 cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

321. The use of any one of claims 236-320, wherein the one or more anti- cancer agents are dosed at a higher amount when present in the composition comprising the first compound and the third compound compared to the composition comprising the one or more anti-cancer agents and the first compound or the one or more anti-cancer agents and the third compound.

322. The use of claim 321, wherein dosing the one or more anti-cancer agents at a higher amount comprises increased dose amounts, administering more frequent doses, extending the duration of the dosing regimen, and / or increasing the total number of doses administered to the subject.

323. The use of any one of claims 236-322, wherein the one or more anti- cancer agents is dosed at least at about 6 mg / mL, 7 mg / mL, or 8 mg / mL in combination with the first compound and the third compound compared to about 2 mg / mL or about 3 mg / mL with the first compound or the third compound.

324. The use of claim 323, wherein the one or more anti-cancer agents is dosed at least at about 6 mg / mL, in combination with the first compound and the third compound compared to about 2 mg / mL with the first compound or the third compound.

325. The use of claim 323, wherein the one or more anti-cancer agents is dosed at least at about 7 mg / mL, in combination with the first compound and the third compound compared to about 2 mg / mL with the first compound or the third compound.

326. The use of claim 323, wherein the one or more anti-cancer agents is dosed at least at about 8 mg / mL, in combination with the first compound and the third compound compared to about 2 mg / mL with the first compound or the third compound. -412- 146316.8009.WO00\165259190.24327. The use of claim 323, wherein the one or more anti-cancer agents is dosed at least at about 6 mg / mL, in combination with the first compound and the third compound compared to about 3 mg / mL with the first compound or the third compound.

328. The use of claim 323, wherein the one or more anti-cancer agents is dosed at least at about 7 mg / mL, in combination with the first compound and the third compound compared to about 3 mg / mL with the first compound or the third compound.

329. The use of claim 323, wherein the one or more anti-cancer agents is dosed at least at about 8 mg / mL, in combination with the first compound and the third compound compared to about 3 mg / mL with the first compound or the third compound.

330. The use of any one of claims 236-329, wherein the one or more anti- cancer agents comprises cisplatin.

331. The use of any one of claims 236-330, wherein the use reduces or prevents one or more side effects in the subject and further comprises dosing the one or more anti-cancer agents at a higher amount thereby increasing efficacy of the one or more anti-cancer agents in the subject.

332. The use of any one of claims 236-331, wherein the use increases efficacy of the anti-cancer agent. -413- 146316.8009.WO00\165259190.24

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