Methods for preventing and / or treating side effects associated with anti-cancer drugs using non-naturally occurring melanocortin analogs in conjunction 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 compositions may further comprise an anti-cancer agent (e.g., a chemotherapeutic agent). Also provided herein are pharmaceutical compositions incorporating the compositions, and methods for using the compositions to regulate body weight, including, but not limited to, increasing appetite, preventing appetite loss, promoting weight gain, preventing weight loss, and / or treating, preventing, or otherwise alleviating cachexia and / or anorexia in a subject in need thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS 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 patent applications are incorporated by reference in their entirety.

[0002] SEQUENCE LISTING INCORPORATED BY REFERENCE This application contains an ST.26 compliant Sequence Listing, which was concurrently filed via the Patent Center in .xml format and is incorporated herein 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.

[0003] Described herein are compositions comprising a non-naturally occurring melanocortin analog in combination with a spiro compound and / or an anti-GDF-15 antibody or antigen-binding fragment thereof, and methods of use thereof. [Background technology]

[0004] Melanocortin analogs have been synthesized for the potential regulation and treatment of many conditions, including weight regulation (e.g., obesity, anorexia, and cachexia), hormone secretion and secretory deficiencies of many exocrine glands (e.g., Sjögren's syndrome), immune-related conditions, and sexual dysfunction.

[0005] Loss of appetite (e.g., anorexia), if left untreated, can lead to fatigue, malnutrition, weight loss, loss of muscle or fat mass, and a decline in overall physical condition. Loss of appetite and / or weight loss are symptoms of cachexia, including cancer cachexia, and can adversely affect a patient's quality of life and survival.

[0006] Despite recent advances, there remains a need to develop more effective therapeutic agents for treating patients experiencing loss of appetite and / or weight loss. There is also a need for appetite stimulating therapies that are more selective, less toxic, and can effectively stimulate 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 drugs, including chemotherapeutic agents, is often limited by associated side effects such as loss of appetite, vomiting, weight loss, fat and muscle wasting, and fatigue.Such limitations on use may include limited cancer treatment duration and anti-cancer therapy dosage.Therefore, these side effects limit treatment tolerance in cancer patients and reduce quality of life.Despite recent progress in cancer treatment, there is a need for new therapies with robust activity that can reduce the harmful side effects of cancer treatment. Summary of the Invention [Means for solving the problem]

[0008] In some embodiments, the present technology comprises: A first compound comprising a non-naturally occurring melanocortin analog comprising a sequence according to formula (I): X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y4 Y 5 Y 6 Y 7 Y 8 (I) During the ceremony, R 1 is absent or 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; R 2 is absent or 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); R 3is absent or contains 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), benzazepin-3-one (BBE), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetralin-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-cyclopentanecarboxy (Cpe), R 4 is 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); R 5 is absent or 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; R 6 is absent or selected from the group consisting of L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, NaI(1'), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R 7is absent or 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); R 8 is absent or is lysine or arginine; R 9 is absent or is tryptophan, R 10 is absent or is lysine; R 11 ~R 20 But he is absent, X 1 is absent or 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; X 2 is absent or 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; X 3 is absent or 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; Y1 is absent or 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; Y 2 is absent or 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; Y 3 is absent or selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y 4 is absent or is D-proline or D-valine; Y 5 is absent or is D-proline or D-valine; Y 6 is absent or is D-proline or D-valine; Y 7 is absent or is D-proline or D-valine; Y 8 is absent or is D-proline or D-valine; Non-naturally occurring melanocortin analogs include R 1 or R 2 is cysteine ​​and R 7 or X 1 is cysteine, R 1 or R 2 and R 7 or X 1 The disulfide bond between R 2 and R 5 ~R 20is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 and R 5 ~R 20 a disulfide bond between any one of R 1 is norleucine and R 7 is glutamic acid, R 1 and R 7 The lactam bridge between R 1 or R 2 is glutamic acid, aspartic acid, or CO-cis-CH=CH-CO, and R 7 is lysine or ornithine, R 1 or R 2 and R 7 A side chain lactam bridge between R 1 or R 2 is glutamic acid or aspartic acid, and R 8 is lysine and R 7 If is proline, glycine, or tryptophan, then R 1 or R 2 and R 8 A side chain lactam bridge between R 2 is glutamic acid or aspartic acid, and R 10 is lysine, R 2 or R 4 and R 10 and a side chain lactam bridge between however, R 2 If is dAsp, then R 7 is not dLys, R 2 ~R 4 is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, R 5 ~R 7 is not Arg-Trp-Lys, Y1 is dPro and Y 2 is dVal and Y 3 ~Y 8 If absent, R 4 is not dNal(2') or R 4 is dNal(2') and the C-terminus is unmodified; R 7 If Aia, then R 4 is dNal(2'), R 4 is p(I)dPhe and the non-naturally occurring melanocortin analog is R 1 and R 7 If the compound is cyclized via a lactam bond between R 2 is His, R 2 ~R 7 is Asp-Pro-dNal(2')-Arg-Trp-Lys (SEQ ID NO: 661); 1 ~Y 2 is not dPro-dVal, A naturally occurring melanocortin analogue is R 2 and R 8 and R 3 If is Pro, then R 7 But not Pro, but Y 1 is not dPro, and If the non-naturally occurring melanocortin analog is linear, R 2 is not absent; and a second compound and / or a third compound, The second compound has a structure according to formula (X): [ka] or a pharmaceutically acceptable salt thereof, wherein: Rx 1 But H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl, or Rx 1a and C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl is selected from 1, 2, 3, or 4 independently selected C 1-4 and optionally substituted with alkyl, and phenyl is selected from 1, 2, 3, or 4 independently selected Rx B and optionally replaced by Rx B But halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl, or Rx B1 or two adjacent Rx B together 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 is independently halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 and 1, 2, or 3 optionally substituted substituents each independently selected from haloalkoxy; Rx 1a but 1, 2, 3, or 4 independent Rx A and each Rx is a 5- or 6-membered heteroaryl optionally substituted with A But halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl, -N(C 1-4 alkyl)2, Rx A1 , or (C 3-4 Cycloalkyl)-C 14 alkyl- and C 14 Alkyl, C 3-4 Cycloalkyl, and (C 3-4 Cycloalkyl)-C 1-4Each of the alkyl- is a halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 haloalkoxy; or two adjacent Rx A together 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 selected from the group consisting of halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx A1 is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx B1 is a 5- or 6-membered heteroaryl, each of which is selected from halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx 2 and Rx 3 each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C1-4 Alkyl-, C 3-4 cycloalkyl, or (C 3-4 Cycloalkyl)-C 1-4 alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is a halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Or Rx 2 and Rx 3 together with the carbon atoms to which they are attached, halogens, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 C optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy 3-6 forming a cycloalkyl, Each Rx 4 are independently H, halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -N(C 1-2 Alkyl)2, C 3-4 cycloalkyl, or (C 3-4 Cycloalkyl)-C 1-4 alkyl- and C 1-4 Alkyl, C 3-4 Cycloalkyl, and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is a halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Xx 1 But C(Rx X )2, and each Rx X are independently H or C 1-4 is alkyl, Yx 1 , Yx 2 , Yx 3 , Yx 4 , and Yx 5 Each of these independently 4 or N, but Yx 1 , Yx 2 , Yx 3 , Yx 4 , and Yx 5 provided that no more than three of The third compound is: 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) an LCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) an LCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) an LCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) an HCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) an HCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) an HCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 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 set forth in the amino acid sequence of SEQ ID NO: 166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences 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 with the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited with the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 166 H ), and a light chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 163. L ), k) V comprising the amino acid sequence of SEQ ID NO: 166 H and V comprising the amino acid sequence of SEQ ID NO: 163 L , l) a heavy chain (HC) comprising an amino acid sequence that is at least 90% identical to the sequence of SEQ ID NO: 164, and a light chain (LC) comprising an amino acid sequence that is 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 GDF-15 and n) a second compound and / or a third compound comprising an antibody or antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), including at least one of the antibodies (a) to (m) above that compete with at least one antibody for binding to GDF-15.

[0009] In some embodiments, the present technology comprises: A first compound comprising a non-naturally occurring melanocortin analog comprising a sequence according to formula (I): X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) R 1 is absent or 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; R 2is absent or 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); R 3 is absent or contains 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), benzazepin-3-one (BBE), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetralin-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-cyclopentanecarboxy (Cpe), R 4 is 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); R 5 is absent or 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; R6 is absent or selected from the group consisting of L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, NaI(1'), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R 7 is absent or 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); R 8 is absent or is lysine or arginine; R 9 is absent or is tryptophan, R 10 is absent or is lysine; R 11 ~R 20 But he is absent, X 1 is absent or 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; X 2 is absent or 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; X 3is absent or 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; Y 1 is absent or 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; Y 2 is absent or 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; Y 3 is absent or selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y 4 is absent or is D-proline or D-valine; Y 5 is absent or is D-proline or D-valine; Y 6 is absent or is D-proline or D-valine; Y 7 is absent or is D-proline or D-valine; Y 8 is absent or is D-proline or D-valine; Non-naturally occurring melanocortin analogs include R 1 or R 2 is cysteine ​​and R7 or X 1 is cysteine, R 1 or R 2 and R 7 or X 1 The disulfide bond between R 2 and R 5 ~R 20 is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 and R 5 ~R 20 a disulfide bond between any one of R 1 is norleucine and R 7 is glutamic acid, R 1 and R 7 The lactam bridge between R 1 or R 2 is glutamic acid, aspartic acid, or CO-cis-CH=CH-CO, and R 7 is lysine or ornithine, R 1 or R 2 and R 7 A side chain lactam bridge between R 1 or R 2 is glutamic acid or aspartic acid, and R 8 is lysine and R 7 If is proline, glycine, or tryptophan, then R 1 or R 2 and R 8 A side chain lactam bridge between R 2 is glutamic acid or aspartic acid, and R 10 is lysine, R 2 or R 4 and R 10 and a side chain lactam bridge between however, R 2 If is dAsp, then R 7is not dLys, R 2 ~R 4 is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, R 5 ~R 7 is not Arg-Trp-Lys, Y 1 is dPro and Y 2 is dVal and Y 3 ~Y 8 If absent, R 4 is not dNal(2') or R 4 is dNal(2') and the C-terminus is unmodified; R 7 If Aia, then R 4 is dNal(2'), R 4 is p(I)dPhe and the non-naturally occurring melanocortin analog is R 1 and R 7 If the compound is cyclized via a lactam bond between R 2 is His, R 2 ~R 7 is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y 1 ~Y 2 is not dPro-dVal, A naturally occurring melanocortin analogue is R 2 and R 8 and R 3 If is Pro, then R 7 But not Pro, but Y 1 is not dPro, and If the non-naturally occurring melanocortin analog is linear, R 2 is not absent; and A structure according to formula (X): [ka] or a pharmaceutically acceptable salt thereof, wherein: Rx 1 But H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl, or Rx 1a and C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl is selected from 1, 2, 3, or 4 independently selected C 1-4 and optionally substituted with alkyl, and phenyl is selected from 1, 2, 3, or 4 independently selected Rx B and optionally replaced by Rx B But halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl, or Rx B1 or two adjacent Rx B together 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 is independently halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 and 1, 2, or 3 optionally substituted substituents each independently selected from haloalkoxy; Rx 1a but 1, 2, 3, or 4 independent Rx A and each Rx is a 5- or 6-membered heteroaryl optionally substituted with A But halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl, -N(C 1-4 alkyl)2, Rx A1 , or (C 3-4Cycloalkyl)-C 14 alkyl- and C 14 Alkyl, C 3-4 Cycloalkyl, and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is a halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 haloalkoxy; or two adjacent Rx A together 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 selected from the group consisting of halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx A1 is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx B1 is a 5- or 6-membered heteroaryl, each of which is selected from halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx 2 and Rx3 each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl, or (C 3-4 Cycloalkyl)-C 1-4 alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is a halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Or Rx 2 and Rx 3 together with the carbon atoms to which they are attached, halogens, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 C optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy 3-6 forming a cycloalkyl, Each Rx 4 are independently H, halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -N(C 1-2 Alkyl)2, C 3-4 cycloalkyl, or (C 3-4 Cycloalkyl)-C 1-4 alkyl- and C 1-4 Alkyl, C 3-4 Cycloalkyl, and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is a halogen, -OH, -CN, C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Xx 1 But C(Rx X )2, and each Rx X are independently H or C 1-4 is alkyl, Yx 1 , Yx 2 , Yx 3 , Yx 4 , and Yx 5 Each of these independently 4 or N, but Yx 1 , Yx 2 , Yx 3 , Yx 4 , and Yx 5 and a second compound, with the proviso that no more than three of are N.

[0010] In some embodiments, the present technology comprises: A first compound comprising a non-naturally occurring melanocortin analog comprising a sequence according to formula (I): X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y7 Y 8 (I) During the ceremony, R 1 is absent or 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; R 2 is absent or 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); R 3is absent or contains 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), benzazepin-3-one (BBE), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetralin-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-cyclopentanecarboxy (Cpe), R 4 is 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); R 5 is absent or 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; R 6 is absent or selected from the group consisting of L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, NaI(1'), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R 7is absent or 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); R 8 is absent or is lysine or arginine; R 9 is absent or is tryptophan, R 10 is absent or is lysine; R 11 ~R 20 But he is absent, X 1 is absent or 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; X 2 is absent or 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; X 3 is absent or 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; Y1 is absent or 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; Y 2 is absent or 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; Y 3 is absent or selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y 4 is absent or is D-proline or D-valine; Y 5 is absent or is D-proline or D-valine; Y 6 is absent or is D-proline or D-valine; Y 7 is absent or is D-proline or D-valine; Y 8 is absent or is D-proline or D-valine; Non-naturally occurring melanocortin analogs include R 1 or R 2 is cysteine ​​and R 7 or X 1 is cysteine, R 1 or R 2 and R 7 or X 1 The disulfide bond between R 2 and R 5 ~R 20is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 and R 5 ~R 20 a disulfide bond between any one of R 1 is norleucine and R 7 is glutamic acid, R 1 and R 7 The lactam bridge between R 1 or R 2 is glutamic acid, aspartic acid, or CO-cis-CH=CH-CO, and R 7 is lysine or ornithine, R 1 or R 2 and R 7 A side chain lactam bridge between R 1 or R 2 is glutamic acid or aspartic acid, and R 8 is lysine and R 7 If is proline, glycine, or tryptophan, then R 1 or R 2 and R 8 A side chain lactam bridge between R 2 is glutamic acid or aspartic acid, and R 10 is lysine, R 2 or R 4 and R 10 and a side chain lactam bridge between however, R 2 If is dAsp, then R 7 is not dLys, R 2 ~R 4 is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, R 5 ~R 7 is not Arg-Trp-Lys, Y1 is dPro and Y 2 is dVal and Y 3 ~Y 8 If absent, R 4 is not dNal(2') or R 4 is dNal(2') and the C-terminus is unmodified; R 7 If Aia, then R 4 is dNal(2'), R 4 is p(I)dPhe and the non-naturally occurring melanocortin analog is R 1 and R 7 If the compound is cyclized via a lactam bond between R 2 is His, R 2 ~R 7 is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y 1 ~Y 2 is not dPro-dVal, A naturally occurring melanocortin analogue is R 2 and R 8 and R 3 If is Pro, then R 7 But not Pro, but Y 1 is not dPro, and If the non-naturally occurring melanocortin analog is linear, R 2 is not absent; and a third compound, 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) an LCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) an LCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) an LCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) an HCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) an HCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) an HCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 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 set forth in the amino acid sequence of SEQ ID NO: 166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences 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 with the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited with the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 166 H ), and a light chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 163. L ), k) V comprising the amino acid sequence of SEQ ID NO: 166 Hand V comprising the amino acid sequence of SEQ ID NO: 163 L , l) a heavy chain (HC) comprising an amino acid sequence that is at least 90% identical to the sequence of SEQ ID NO: 164, and a light chain (LC) comprising an amino acid sequence that is 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 and n) a third compound comprising an antibody or antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), including at least one of antibodies that compete with at least one antibody from (a) to (m) above for binding to GDF-15.

[0011] In some embodiments, the present technology comprises: A first compound comprising a non-naturally occurring melanocortin analog comprising a sequence according to formula (I): X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) During the ceremony, R 1is absent or 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; R 2 is absent or 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); R 3is absent or contains 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), benzazepin-3-one (BBE), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetralin-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-cyclopentanecarboxy (Cpe), R 4 is 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); R 5 is absent or 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; R 6 is absent or selected from the group consisting of L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, NaI(1'), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R 7is absent or 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); R 8 is absent or is lysine or arginine; R 9 is absent or is tryptophan, R 10 is absent or is lysine; R 11 ~R 20 But he is absent, X 1 is absent or 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; X 2 is absent or 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; X 3 is absent or 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; Y1 is absent or 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; Y 2 is absent or 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; Y 3 is absent or selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y 4 is absent or is D-proline or D-valine; Y 5 is absent or is D-proline or D-valine; Y 6 is absent or is D-proline or D-valine; Y 7 is absent or is D-proline or D-valine; Y 8 is absent or is D-proline or D-valine; Non-naturally occurring melanocortin analogs include R 1 or R 2 is cysteine ​​and R 7 or X 1 is cysteine, R 1 or R 2 and R 7 or X 1 The disulfide bond between R 2 and R 5 ~R 20is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 and R 5 ~R 20 a disulfide bond between any one of R 1 is norleucine and R 7 is glutamic acid, R 1 and R 7 The lactam bridge between R 1 or R 2 is glutamic acid, aspartic acid, or CO-cis-CH=CH-CO, and R 7 is lysine or ornithine, R 1 or R 2 and R 7 A side chain lactam bridge between R 1 or R 2 is glutamic acid or aspartic acid, and R 8 is lysine and R 7 If is proline, glycine, or tryptophan, then R 1 or R 2 and R 8 A side chain lactam bridge between R 2 is glutamic acid or aspartic acid, and R 10 is lysine, R 2 or R 4 and R 10 and a side chain lactam bridge between however, R 2 If is dAsp, then R 7 is not dLys, R 2 ~R 4 is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, R 5 ~R 7 is not Arg-Trp-Lys, Y1 is dPro and Y 2 is dVal and Y 3 ~Y 8 If absent, R 4 is not dNal(2') or R 4 is dNal(2') and the C-terminus is unmodified; R 7 If Aia, then R 4 is dNal(2'), R 4 is p(I)dPhe and the non-naturally occurring melanocortin analog is R 1 and R 7 If the compound is cyclized via a lactam bond between R 2 is His, R 2 ~R 7 is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y 1 ~Y 2 is not dPro-dVal, A naturally occurring melanocortin analogue is R 2 and R 8 and R 3 If is Pro, then R 7 But not Pro, but Y 1 is not dPro, and If the non-naturally occurring melanocortin analog is linear, R 2 is not absent; and A structure according to formula (X): [ka] or a pharmaceutically acceptable salt thereof, wherein: Rx 1 But H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl, or Rx1a and C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl is selected from 1, 2, 3, or 4 independently selected C 1-4 and optionally substituted with alkyl, and phenyl is selected from 1, 2, 3, or 4 independently selected Rx B and optionally replaced by Rx B But halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl, or Rx B1 or two adjacent Rx B together 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 is independently halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 and 1, 2, or 3 optionally substituted substituents each independently selected from haloalkoxy; Rx 1a but 1, 2, 3, or 4 independent Rx A and each Rx is a 5- or 6-membered heteroaryl optionally substituted with A But halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl, -N(C 1-4 alkyl)2, Rx A1 , or (C 3-4 Cycloalkyl)-C 14 alkyl- and C 14 Alkyl, C 3-4 Cycloalkyl, and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is a halogen, -OH, -CN, C 1-4 Alkyl, C 1-4Haloalkyl, C 1-4 Alkoxy, and C 1-4 haloalkoxy; or two adjacent Rx A together 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 selected from the group consisting of halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx A1 is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx B1 is a 5- or 6-membered heteroaryl, each of which is selected from halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx 2 and Rx 3 each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl, or (C 3-4Cycloalkyl)-C 1-4 alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is a halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Or Rx 2 and Rx 3 together with the carbon atoms to which they are attached, halogens, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 C optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy 3-6 forming a cycloalkyl, Each Rx 4 are independently H, halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -N(C 1-2 Alkyl)2, C 3-4 cycloalkyl, or (C 3-4 Cycloalkyl)-C 1-4 alkyl- and C 1-4 Alkyl, C 3-4 Cycloalkyl, and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is a halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Xx 1 But C(Rx X )2, and each Rx Xare independently H or C 1-4 is alkyl, Yx 1 , Yx 2 , Yx 3 , Yx 4 , and Yx 5 Each of these independently 4 or N, but Yx 1 , Yx 2 , Yx 3 , Yx 4 , and Yx 5 a second compound, with the proviso that no more than three of a third compound, 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) an LCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) an LCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) an LCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) an HCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) an HCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) an HCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 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 set forth in the amino acid sequence of SEQ ID NO: 166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences 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 with the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited with the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 166 H ), and a light chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 163. L ), k) V comprising the amino acid sequence of SEQ ID NO: 166 H and V comprising the amino acid sequence of SEQ ID NO: 163 L , l) a heavy chain (HC) comprising an amino acid sequence that is at least 90% identical to the sequence of SEQ ID NO: 164, and a light chain (LC) comprising an amino acid sequence that is 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 and n) a third compound comprising an antibody or antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), including at least one of antibodies that compete with at least one antibody from (a) to (m) above for binding to GDF-15.

[0012] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified with 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.

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

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

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

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

[0017] In some embodiments, the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified with 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 unmodified.

[0021] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is modified with 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 with an amide group.

[0023] In some embodiments, the amide group is an -NH alkylamide group or an -NH arylamide group.

[0024] In some embodiments, the -NH arylamide group is a p-nitroanilide group or 7-amino-4-methylcoumarin.

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

[0026] In some embodiments, the C-terminus of the non-naturally occurring melanocortin analog is unmodified.

[0027] In some embodiments, R 1 is absent, and R 2 is D-aspartic acid.

[0028] In some embodiments, X 1 , X 2 , and X 3 is absent.

[0029] In some embodiments, R 4 is not D-phenylalanine.

[0030] In some embodiments, R 4 is dNal(2').

[0031] In some embodiments, Y 3 ~Y 8 is absent. In some embodiments, Y 1 is D-valine, and Y 2 is D-proline, or Y 1 is D-proline and Y 2 is D-valine.

[0032] In some embodiments, Y 3exists and Y 4 ~Y 8 is absent. In some embodiments, Y 1 is D-valine or D-proline; Y 2 is D-valine or D-proline, and / or Y 3 is D-valine or D-proline. In some embodiments, Y 1 is D-valine, and Y 2 is D-valine, and Y 3 is D-proline, or Y 1 is D-proline, and Y 2 is D-valine, and Y 3 is D-valine, Y 1 is D-valine, and Y 2 is D-proline, and Y 3 is D-valine, or Y 1 is D-proline, and Y 2 is D-valine, and Y 3 is D-proline.

[0033] In some embodiments, Y 3 and Y 4 exists and Y 5 ~Y 8 is absent. In some embodiments, Y 1 is D-valine or D-proline; Y 2 is D-valine or D-proline; Y 3 is D-valine or D-proline, and / or Y 4 is D-valine or D-proline. In some embodiments, Y 1 is D-valine, and Y 2 is D-valine, and Y 3 is D-valine, and Y4 is D-proline, Y 1 is D-proline, and Y 2 is D-valine, and Y 3 is D-valine, and Y 4 is D-valine, Y 1 is D-valine, and Y 2 is D-proline, and Y 3 is D-valine, and Y 4 is D-valine, Y 1 is D-valine, and Y 2 is D-valine, and Y 3 is D-proline, and Y 4 is D-valine, or Y 1 is D-valine, and Y 2 is D-proline, and Y 3 is D-valine, and Y 4 is D-proline.

[0034] In some embodiments, R 1 , R 2 , and R 7 exists and R 8 ~R 20 is absent and the sequence of formula (I) is connected to R via a lactam bond 2 and R 7 It is cyclized through In some embodiments, R 1 is acetylated norleucine, R 2 is aspartic acid, R 3 is selected from the group consisting of proline, hydroxyproline, and hydroxy-D-proline; R 4 is D-Nal(2′), R 5 is arginine, R 6 is D-tryptophan or L-tryptophan, R 7 is lysine, Y 1 is D-valine, and / or Y 2 is 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 is R through a lactam bond. 2 and R 7 represents a cyclization through

[0036] In some embodiments, R 1 , R 2 , R 7 , and R 8 exists and R 9 ~R 20 is absent and the sequence of formula (I) is connected to R via a lactam bond 2 and R 8 It is cyclized through In some embodiments, R 1 is acetylated norleucine, R 2 is aspartic acid, R 3 is selected from the group consisting of proline, hydroxyproline, hydroxy-D-proline, phenylalanine, and histidine; R 4 is histidine or D-Nal(2'), R 5 is D-Nal(2') or arginine, R 6 is selected from the group consisting of arginine, D-tryptophan, and L-tryptophan; R 7 is tryptophan or proline, R 8is lysine, Y 1 is selected from the group consisting of D-valine, D-leucine, and D-isoleucine, and / or Y 2 is D-proline.

[0037] In some embodiments, the sequence of formula (I) is: 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), In the sequence, c is R via a lactam bond 2 and R 8 represents a cyclization through

[0038] In some embodiments, R 1 ~R 2 and R 7 ~R 10 exists and R 11 ~R 20 is absent and the sequence of formula (I) is connected via a lactam bond to R 2 and R 10 It is cyclized through

[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 is R via a lactam bond 2 and R 10 represents a cyclization through

[0040] In some embodiments, R 1 ~R 2 and R 7 ~R 10 exists and R 11 ~R 20 is absent and the sequence of formula (I) is connected via a lactam bond to R 4 and R 10 It is cyclized through

[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 is R through a lactam bond. 4 and R 10 represents a cyclization through

[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 is R through a lactam bond. 2 and R 7 represents a cyclization through

[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: 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), 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); In the sequence, c is R via a lactam bond 2 and R 7 represents a cyclization through

[0046] In some embodiments, the sequence of formula (I) is: 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), 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); In the sequence, c is R via a lactam bond or disulfide bond. 2 and R 6 or R 7 represents a cyclization through

[0047] In some embodiments, the sequence of formula (I) is: 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); In the sequence, c is R via a lactam bond 2 and R 7 represents a cyclization through

[0048] In some embodiments, the sequence of formula (I) is: 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), 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); In the sequence, c is R via a lactam bond 2 and R 7 represents a cyclization through

[0049] In some embodiments, the sequence of formula (I) is: 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); In the sequence, c is R via a lactam bond 2 and R 7 represents a cyclization through

[0050] In some embodiments, the sequence of formula (I) is Ac-Nle-c(Asp-Pro-Bip-Arg-Trp-Lys)-dVal-dPro-NH (SEQ ID NO: 393), wherein c is R through a lactam bond. 2 and R 7 represents a cyclization through

[0051] In some embodiments, the sequence of formula (I) is: 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), 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), 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); In the sequence, c is R via a lactam bond 2 and R 7 represents a cyclization through

[0052] In some embodiments, the sequence of formula (I) is: 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); In the sequence, c is R via a lactam bond 2 and R 7 represents a cyclization through

[0053] In some embodiments, X 1 is present, is an acetylated norleucine, and R 1 is present and is norleucine.

[0054] In some embodiments, X 2 is present and is norleucine.

[0055] In some embodiments, it is present and is norleucine.

[0056] In some embodiments, the sequence of formula (I) is: 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); In the sequence, c is R via a lactam bond 2 and R 7 represents a cyclization through

[0057] In some embodiments, the sequence of formula (I) is: 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); In the sequence, c is R via a lactam bond 2 and R 7 Or R 8 cyclization through or via a disulfide bond 2 and R 5 represents a cyclization through

[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), In the sequence, c is R via a lactam bond 2 and R 7 or R 8 represents a cyclization through

[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 the sequence of SEQ ID NO:306.

[0061] In some embodiments, the second compound is a compound of formula (Xi): [ka] or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the second compound is a compound of formula (Xii): [ka] or a pharmaceutically acceptable salt thereof.

[0063] In some embodiments, Rx 1 Rx 1a and Rx 1a is 1, 2, 3, or 4 independently selected Rx A and each Rx is a 6-membered heteroaryl optionally substituted with A are halogens, -OH, -CN, C 1-4 Alkyl, C 14 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3- C4 cycloalkyl, or (C 3-4 Cycloalkyl)-C 14 alkyl- and C 1-4 Alkyl, C 3-4 Cycloalkyl, and (C 3-4 Alkyl)-C 1-4Each of the alkyl- is a halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 or two adjacent Rx optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; A together with the two ring atoms of the six-membered heteroaryl to which they are attached form a fused benzene ring or a fused five- or six-membered heteroaryl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 14 Optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy.

[0064] In some embodiments, Rx 1a is 1, 2, or 3 independently selected Rx A and each Rx is pyrimidinyl optionally substituted with A are halogens, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, or C 3-4 It is cycloalkyl.

[0065] In some embodiments, Rx 1a is pyrimidin-2-yl.

[0066] In some embodiments, Xx 1 is CH2.

[0067] In some embodiments, Rx 2 and Rx 3 each independently is H, F, or C 1-4 It is alkyl.

[0068] In some embodiments, Rx 2is methyl and Rx 3 is H.

[0069] In some embodiments, Yx 3 is N and Yx 1 , Yx 2 , Yx 4 , and Yx 5 Each of the CRx 4 is.

[0070] In some embodiments, Rx 4 are independently H, halogen, or C 1-2 It is an alkoxy.

[0071] In some embodiments, the second compound is (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-naphthyridin-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-naphthyridin-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-naphthyridin-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-naphthyridin-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- 2 H2) 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.

[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 a 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-naphthyridin-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 has a K of 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. D It binds to human GDF-15 or cynomolgus monkey GDF-15 at 1000 kJ / s.

[0076] In some embodiments, the antibody or antigen-binding fragment thereof comprises the 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, 23 24, 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.

[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 platinum coordination complexes, antimetabolites, tubulin binding agents, alkylating antitumor agents, and cytotoxic antibiotics.

[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 anti-tumor 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 at a concentration of 0.1 mg / mL to 50 mg / mL relative to the 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.

[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 at a concentration of 0.1 mg / mL to 50 mg / mL relative to the total volume of the first pharmaceutical composition.

[0097] In some embodiments, the present technology comprises: a first compound having a primary therapeutic activity; and a second compound and / or a third compound, each having a secondary therapeutic activity; The present invention includes compositions in which a first compound is a non-naturally occurring melanocortin analog, a second compound is a spiro compound, and a third compound is an antibody or antigen-binding fragment thereof.

[0098] In some embodiments, the non-naturally occurring melanocortin analogs are melanocortin 3 receptor (MC3R) agonists and melanocortin 4 receptor (MC4R) agonists.

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

[0100] In some embodiments, the non-naturally occurring melanocortin analog comprises a sequence according to formula (I): X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) During the ceremony, R 1is absent or 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; R 2 is absent or 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); R 3is absent or contains 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), benzazepin-3-one (BBE), β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclopropane-1-carboxylic acid (Acpc), 2-aminotetralin-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-cyclopentanecarboxy (Cpe), R 4 is 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); R 5 is absent or 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; R 6 is absent or selected from the group consisting of L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, NaI(1'), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R 7is absent or 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); R 8 is absent or is lysine or arginine; R 9 is absent or is tryptophan, R 10 is absent or is lysine; R 11 ~R 20 But he is absent, X 1 is absent or 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; X 2 is absent or 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; X 3 is absent or 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; Y1 is absent or 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; Y 2 is absent or 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; Y 3 is absent or selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y 4 is absent or is D-proline or D-valine; Y 5 is absent or is D-proline or D-valine; Y 6 is absent or is D-proline or D-valine; Y 7 is absent or is D-proline or D-valine; Y 8 is absent or is D-proline or D-valine; Non-naturally occurring melanocortin analogs include R 1 or R 2 is cysteine ​​and R 7 or X 1 is cysteine, R 1 or R 2 and R 7 or X 1 The disulfide bond between R 2 and R 5 ~R 20is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, R 2 and R 5 ~R 20 a disulfide bond between any one of R 1 is norleucine and R 7 is glutamic acid, R 1 and R 7 The lactam bridge between R 1 or R 2 is glutamic acid, aspartic acid, or CO-cis-CH=CH-CO, and R 7 is lysine or ornithine, R 1 or R 2 and R 7 A side chain lactam bridge between R 1 or R 2 is glutamic acid or aspartic acid, and R 8 is lysine and R 7 If is proline, glycine, or tryptophan, then R 1 or R 2 and R 8 A side chain lactam bridge between R 2 is glutamic acid or aspartic acid, and R 10 is lysine, R 2 or R 4 and R 10 and a side chain lactam bridge between however, R 2 If is dAsp, then R 7 is not dLys, R 2 ~R 4 is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, R 5 ~R 7 is not Arg-Trp-Lys, Y1 is dPro and Y 2 is dVal and Y 3 ~Y 8 If absent, R 4 is not dNal(2') or R 4 is dNal(2') and the C-terminus is unmodified; R 7 If Aia, then R 4 is dNal(2'), R 4 is p(I)dPhe and the non-naturally occurring melanocortin analog is R 1 and R 7 If the compound is cyclized via a lactam bond between R 2 is His, R 2 ~R 7 is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y 1 ~Y 2 is not dPro-dVal, A naturally occurring melanocortin analogue is R 2 and R 8 and R 3 If is Pro, then R 7 But not Pro, but Y 1 is not dPro, and If the non-naturally occurring melanocortin analog is linear, R 2 is not absent.

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

[0102] In some embodiments, the spiro compounds are MC4R antagonists.

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

[0104] In some embodiments, the spiro compound has a structure according to formula (X): [ka] or a pharmaceutically acceptable salt thereof, wherein: Rx 1 But H, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, 4- to 7-membered cycloalkyl, phenyl, or Rx 1a and C 3-6 Each of the cycloalkyl and 4- to 7-membered cycloalkyl is selected from 1, 2, 3, or 4 independently selected C 1-4 and optionally substituted with alkyl, and phenyl is selected from 1, 2, 3, or 4 independently selected Rx B and optionally replaced by Rx B But halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl, or Rx B1 or two adjacent Rx B together 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 is independently halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 and 1, 2, or 3 optionally substituted substituents each independently selected from haloalkoxy; Rx 1a but 1, 2, 3, or 4 independent Rx A and each Rx is a 5- or 6-membered heteroaryl optionally substituted with A But halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 14 Alkoxy, C1-4 Haloalkoxy, C 3-4 Cycloalkyl, -N(C 1-4 alkyl)2, Rx A1 , or (C 3-4 Cycloalkyl)-C 14 alkyl- and C 14 Alkyl, C 3-4 Cycloalkyl, and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is a halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 haloalkoxy; or two adjacent Rx A together 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 selected from the group consisting of halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx A1 is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx B1 is a 5- or 6-membered heteroaryl, each of which is selected from halogen, —OH, —CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C1-4 optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx 2 and Rx 3 each independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, (C 1-4 Alkoxy)-C 1-4 Alkyl-, C 3-4 cycloalkyl, or (C 3-4 Cycloalkyl)-C 1-4 alkyl, C 3-4 Cycloalkyl and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is a halogen, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Or Rx 2 and Rx 3 together with the carbon atoms to which they are attached, halogens, -OH, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 C optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy 3-6 forming a cycloalkyl, Each Rx 4 are independently H, halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -N(C 1-2 Alkyl)2, C 3-4 cycloalkyl, or (C 3-4 Cycloalkyl)-C 1-4 alkyl- and C 1-4 Alkyl, C 3-4Cycloalkyl, and (C 3-4 Cycloalkyl)-C 1-4 Each of the alkyl- is a halogen, -OH, -CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, and C 1-4 optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Xx 1 But C(Rx X )2, and each Rx X are independently H or C 1-4 is alkyl, Yx 1 , Yx 2 , Yx 3 , Yx 4 , and Yx 5 Each of these independently 4 or N, but Yx 1 , Yx 2 , Yx 3 , Yx 4 , and Yx 5 The condition is that no more than three of these are 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-naphthyridin-2,3'-pyrrolidin)-1'-yl)propan-1-one, or a 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).

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

[0108] In some embodiments, the antibody or antigen-binding fragment thereof is 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) an LCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) an LCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) an LCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) an HCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) an HCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) an HCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 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 set forth in the amino acid sequence of SEQ ID NO: 166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences 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 with the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited with the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 166 H ), and a light chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 163. L ), k) V comprising the amino acid sequence of SEQ ID NO: 166 H and V comprising the amino acid sequence of SEQ ID NO: 163 L , l) a heavy chain (HC) comprising an amino acid sequence that is at least 90% identical to the sequence of SEQ ID NO: 164, and a light chain (LC) comprising an amino acid sequence that is 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 with at least one of the antibodies from (a) to (m) above for binding to GDF-15.

[0109] In some embodiments, the antibody or antigen-binding fragment thereof comprises the 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, 23 24, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10, and 162.

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

[0111] In some embodiments, the composition comprises fewer dosage units of the second compound and / or the third compound compared to dosage units of the second compound and / or the third compound that do not comprise the first compound.

[0112] In some embodiments, the composition comprises a lower dose of the second compound and / or the third compound compared to the dose of the second compound and / or the dose of the third compound without the first compound.

[0113] In some embodiments, the composition comprises a shorter dosing regimen of the second compound and / or the third compound compared to a dosing regimen of the second compound and / or the third compound that does not include the first compound.

[0114] In some embodiments, the composition comprises a lower dosage of the second compound and / or the third compound compared to the dosage of the second compound and / or the third compound without 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 without the first compound and / or the effect on MC4R of the third compound.

[0116] In some embodiments, the subject technology provides a method of increasing appetite in a subject in need thereof relative to a control, comprising: The present invention also includes methods comprising administering the compositions of the present technology.

[0117] In some embodiments, the subject experiences an increase in appetite as measured by an increase in food intake of 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 a 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 at least 2000 kcal of calories, with at least 50% of the calories coming from carbohydrates.

[0120] In some embodiments, the subject is not on a high-fat, high-calorie (HFHC) diet.

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

[0122] In some embodiments, the first compound, the second compound, and the third compound are administered simultaneously as a single composition. 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.

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

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

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

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

[0127] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered sequentially within about a 24 hour period.

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

[0129] In some embodiments, the first pharmaceutical composition and the third pharmaceutical composition are administered consecutively within about a 24 hour period.

[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 the 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 of the subject's body weight.

[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 of the subject's body weight.

[0134] In some embodiments, a therapeutically effective amount of a second compound is administered, wherein the therapeutically effective amount of the second compound is 10% to 75% less than the therapeutically effective amount of the second compound when administered alone.

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

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

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

[0138] In some embodiments, the composition is administered to a 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 a 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 decreased appetite, reduced food consumption, and / or weight loss prior to 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 the appetite of a subject, (ii) increases food consumption by a subject, (iii) prevents or alleviates nausea, vomiting, and / or anorexia in a subject, (iv) increases or maintains the body weight of a subject, (v) prevents or reduces weight loss in a subject, (vi) increases or maintains muscle mass in a subject, (vii) prevents or reduces muscle mass loss in a subject, (viii) increases or maintains fat mass in a subject, and / or (ix) prevents or reduces fat mass loss in a subject.

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

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

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

[0147] In some embodiments, the present technology provides a method of treating a subject having cancer, comprising: administering to a subject a composition of any one of embodiments 77-96, The methods include those that reduce or prevent side effects associated with the anti-cancer drugs of the combination therapy, wherein the side effects are 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 subject technology provides a method of improving survival in a subject having cancer, comprising: administering to a subject a composition of any one of embodiments 77-96, The methods include those that reduce or prevent side effects associated with the anti-cancer drugs of the combination therapy, thereby improving survival in the subject, wherein the side effects are 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 includes a method for increasing the body weight of a subject relative to a control, comprising administering to the subject a composition described in any one of embodiments 1 to 115.

[0150] In some embodiments, the subject experiences about a 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% increase in body weight compared to a control.

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

[0152] In some embodiments, the subject experiences an increase in muscle mass of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a control.

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

[0154] In some embodiments, the subject experiences an increase in fat mass of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a control.

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

[0156] In some embodiments, the subject experiences an increase in myocardial mass of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a control.

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

[0158] In some embodiments, the subject experiences an increase in bone mineral density of about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% compared to a control.

[0159] In some embodiments, the present technology includes a method of reducing fatigue in a subject compared to a control, comprising administering to the subject a composition described in any one of embodiments 1-115.

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

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

[0162] In some embodiments, the technology includes a method of increasing the cumulative amount in a subject compared to a control, comprising administering to the subject a composition described in any one of embodiments 1 to 115.

[0163] In some embodiments, the subject experiences an increase in cumulative amount of 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 includes a method for increasing net weight gain in a subject compared to a control, comprising administering to the subject a composition described in any one of embodiments 1 to 115.

[0165] In some embodiments, the subject experiences an increase in net weight gain of 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 a control.

[0166] In some embodiments, the technology includes a method of reducing the rate of decline in a subject's cumulative amount compared to a control, comprising administering to the subject a composition described in any one of embodiments 1-115.

[0167] In some embodiments, the subject experiences a reduction in the rate of cumulative dose reduction of 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 a control.

[0168] In some embodiments, the present technology includes a method of increasing a subject's cumulative food intake compared to a control, comprising administering to the subject a composition described in any one of embodiments 1-115.

[0169] In some embodiments, the subject experiences an increase in cumulative food intake of 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 a control.

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

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

[0172] In some embodiments, the technology includes a method of reducing pro-inflammatory transcript or protein levels in a subject compared to a control, comprising administering to the subject a composition described in any one of embodiments 1-115.

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

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

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

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

[0177] In some embodiments, the subject experiences an increase in FAACT score of at least 1, 2, 3, 4, or 5 points compared to the control.

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

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

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

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

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

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

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

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

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

[0187] In some embodiments, the technology includes a method of increasing progression-free survival (PFS) in a subject having cancer compared to a control, comprising administering to the subject a composition described in any one of embodiments 1-115.

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

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

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

[0191] In some embodiments, the control includes the subject at baseline or a second subject who does not receive 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 at least 2000 kcal of calories, with at least 50% of the calories coming from carbohydrates.

[0194] In some embodiments, the subject is not on a high-fat, high-calorie (HFHC) diet.

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

[0196] In some embodiments, the first compound, the second compound, the third compound, 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; The anti-cancer drug is present in a fourth pharmaceutical composition.

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

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

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

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

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

[0203] In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered sequentially within about a 24 hour period.

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

[0205] In some embodiments, the first pharmaceutical composition and the third pharmaceutical composition are administered consecutively within about a 24 hour period.

[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 of the subject's body weight.

[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 of the subject's body weight.

[0209] In some embodiments, a therapeutically effective amount of a second compound is administered, wherein the therapeutically effective amount of the second compound is 10% to 75% less than the therapeutically effective amount of the second compound when administered alone.

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

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

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

[0213] In some embodiments, the composition is administered to a 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 a 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 technology does not reduce the effectiveness of the anti-cancer drug.

[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.

[0220] In some embodiments, the subject with cancer has previously been treated with an anti-cancer agent.

[0221] In some embodiments, the subject has previously experienced one or more adverse side effects when treated with an anti-cancer agent, the adverse side effects being 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 in a higher amount when present in a composition comprising a first compound and a third compound compared to a composition comprising one or more anti-cancer agents and a first compound or one or more anti-cancer agents and a third compound.

[0223] In some embodiments, dosing one or more anticancer agents at higher amounts includes administering increased doses, 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 are dosed at at least 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 are dosed at at least 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 are dosed at at least 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 anticancer agents are dosed at at least 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.

[0228] In some embodiments, the one or more anti-cancer agents are dosed at at least 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 are dosed at at least 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 are dosed at at least 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 anticancer agents comprises cisplatin.

[0232] In some embodiments, the method further includes reducing or preventing one or more side effects in the subject and administering a higher amount of the one or more anti-cancer agents, thereby increasing the effectiveness of the one or more anti-cancer agents in the subject.

[0233] In some embodiments, the method increases the effectiveness of an anti-cancer drug. [Brief explanation of the drawings]

[0234] [Figure 1A]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1B]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1C]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1D]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1E]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1F]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1G]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1H]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1I]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1J]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1K]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1L]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1M]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1N]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1O]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1P]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1Q]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1R]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1S]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1T]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1U]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1V]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1W]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1X]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1Y]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1Z]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1AA]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1BB]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1CC]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1DD]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1EE]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1FF]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1GG]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1HH]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1II]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1JJ]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1KK]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1LL]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1MM]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1NN]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 100]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1PP]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1QQ]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1RR]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1SS]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1TT]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1UU]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1VV]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 1WW]

[0023] Figure 1 illustrates percent activation of the melanocortin 3 receptor (MC3R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 2A]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2B]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2C]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2D]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2E]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2F]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2G]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2H]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2I]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2J]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2K]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2L]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2M]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2N]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2O]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2P]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2Q]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2R]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2S]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2T]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2U]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2V]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2W]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2X]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 2Y]

[0023] Figure 1 illustrates the percent activation of MC3R following stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary non-naturally occurring melanocortin analogs selected from Tables 5-7. [Figure 3A] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3B] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3C] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3D] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3E]1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3F] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3G] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3H] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3I] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3J] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3K]1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3L] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3M] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3N] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3O] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3P] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3Q]1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3R] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3S] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3T] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3U] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3V] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3W]1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3X] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3Y] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3Z] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3AA] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3BB] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3CC]1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3DD] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3EE] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3FF] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3GG] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3HH] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3II]1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3JJ] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3KK] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3LL] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3MM] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3NN] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3OO]1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3PP] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3QQ] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3RR] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3SS] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3TT] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3UU]1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3VV] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3WW] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3XX] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3YY] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 3ZZ] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 4A]1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 4B] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 4C] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 4D] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 4E] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 4F] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 4G]1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 4H] 1 illustrates the percent inhibition of MC3R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 5A]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5B]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5C]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5D]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5E]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5F]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5G]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5H]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5I]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5J]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5K]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5L]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5M]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5N]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5O]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5P]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5Q]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5R]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5S]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5T]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5U]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5V]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5W]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5X]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5Y]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5Z]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5AA]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5BB]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5CC]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5DD]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5EE]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5FF]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5GG]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5HH]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5II]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5JJ]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5KK]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5LL]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5MM]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5NN]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5OO]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5PP]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5QQ]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5RR]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5SS]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5TT]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5UU]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5VV]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5WW]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5XX]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5YY]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5ZZ]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 5AAA]

[0023] Figure 1 illustrates percent activation of the melanocortin 4 receptor (MC4R) after stimulation with non-naturally occurring melanocortin analogs, as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Tables 3 and 4. [Figure 6A]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6B]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6C]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6D]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6E]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6F]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6G]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6H]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6I]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6J]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6K]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6L]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6M]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6N]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6O]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6P]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6Q]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6R]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6S]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6T]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6U]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6V]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6W]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6X]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6Y]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6Z]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6AA]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6BB]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6CC]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6DD]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6EE]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6FF]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6GG]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 6HH]

[0023] Figure 1 illustrates the percent activation of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. Graphs are provided presenting cAMP data for exemplary melanocortin analogs selected from Tables 5-7. [Figure 7A] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7B] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7C] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7D]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7E] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7F] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7G] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7H] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7I] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7J]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7K] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7L] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7M] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7N] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7O] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7P]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7Q] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7R] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7S] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7T] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7U] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7V]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7W] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7X] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7Y] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7Z] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7AA] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7BB]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7CC] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7DD] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7EE] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7FF] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7GG] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7HH]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7II] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7JJ] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7KK] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7LL] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7MM] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7NN]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7OO] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7PP] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7QQ] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7RR] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7SS] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7TT]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7UU] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7VV] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7WW] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7XX] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7YY] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7ZZ]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7AAA] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7BBB] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7CCC] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7DDD] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7EEE] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7FFF]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7GGG] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7HHH] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7III] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 7JJJ] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 8 is provided. [Figure 8A] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8B]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8C] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8D] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8E] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8F] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8G] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8H]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8I] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8J] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8K] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8L] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8M] 1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 8N]1 illustrates the percent inhibition of MC4R after stimulation with non-naturally occurring melanocortin analogs as measured by cAMP levels, according to embodiments of the present technology. A graph presenting cAMP data for selected exemplary non-naturally occurring melanocortin analogs from Table 9 is provided. [Figure 9] 1 shows (i) a comparison of the binding curves of Compound A1 (SEQ ID NO: 315) and TCMCB07 ("B07") to the human melanocortin 1 receptor (hMC1R, Gene ID: 4157), human melanocortin 3 receptor (hMC3R, Gene ID: 4159), and human melanocortin 4 receptor (hMC4R, Gene ID: 4160), respectively; (ii) a summary of the IC50 values ​​for ligand binding of SM-001 to hMC1R, hMC3R, and hMC4R, respectively; and (iii) a summary of the IC50 values ​​for ligand binding of B07 to hMC1R, hMC3R, and hMC4R, respectively. [Figure 10] A table summarizing the SEQ ID NOs corresponding to several GDF-15 antibodies of the present technology is provided. [Figure 11A] 1 shows the daily food intake of Sprague Dawley rats. The graph compares the food intake of three groups of rats. Group 1 rats received cisplatin, saline, and IgG; Group 2 rats received cisplatin, saline, and an anti-GDF-15 monoclonal antibody (mAb) comprising a human ponsegromab Fab region and a mouse Fc region having SEQ ID NOs: 288 and 289; and Group 3 rats received cisplatin, TCMCB07 (SEQ ID NO: 306), and an anti-GDF-15 mouse mAb. Cisplatin was administered at 5 mg / kg on day 0 and 3 mg / kg on days 7 and 14. [Figure 11B]1 shows a graph depicting the weekly food intake of Sprague Dawley rats. The graph compares the food intake of 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 and a mouse Fc region having SEQ ID NOs: 288 and 289; and Group 3 rats were administered cisplatin, TCMCB07 (SEQ ID NO: 306), and an anti-GDF-15 mouse mAb. Cisplatin was administered at 5 mg / kg on day 0 and 3 mg / kg on days 7 and 14. [Figure 11C] 1 shows a graph depicting the cumulative daily food intake of Sprague Dawley rats. The graph compares the food intake of 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 and a mouse Fc region having SEQ ID NOs: 288 and 289; and Group 3 rats were administered cisplatin, TCMCB07 (SEQ ID NO: 306), and an anti-GDF-15 mouse mAb. Cisplatin was administered at 5 mg / kg on day 0 and 3 mg / kg on days 7 and 14. [Figure 11D] 1 shows a graph depicting total food intake in Sprague Dawley rats after 21 days. The graph compares food intake 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 and a mouse Fc region having SEQ ID NOs: 288 and 289; and Group 3 rats were administered cisplatin, TCMCB07 (SEQ ID NO: 306), and an anti-GDF-15 mouse mAb. Cisplatin was administered at 5 mg / kg on day 0 and 3 mg / kg on days 7 and 14. [Figure 12A]1 shows a graph depicting the daily body weight of Sprague Dawley rats. The graph compares the body weight and weight gain of three groups of rats. Group 1 rats were administered cisplatin, saline, and IgG; Group 2 rats were administered cisplatin, saline, and anti-GDF-15 mouse mAb (mouse mAb comprising SEQ ID NOs: 288 and 289); and Group 3 rats were administered cisplatin, TCMCB07 (SEQ ID NO: 306), and anti-GDF-15 mouse mAb. Cisplatin was administered at 5 mg / kg on day 0 and at 3 mg / kg on days 7 and 14. [Figure 12B] 1 shows a graph depicting the weekly cumulative body weight of Sprague Dawley rats. The graph compares the body weight and weight gain of three groups of rats. Group 1 rats were administered cisplatin, saline, and IgG; Group 2 rats were administered cisplatin, saline, and anti-GDF-15 mouse mAb (mouse mAb comprising SEQ ID NOs: 288 and 289); and Group 3 rats were administered cisplatin, TCMCB07 (SEQ ID NO: 306), and anti-GDF-15 mouse mAb. Cisplatin was administered at 5 mg / kg on day 0 and at 3 mg / kg on days 7 and 14. [Figure 12C] 1 shows a graph depicting the daily weight gain of Sprague Dawley rats. The graph compares the weight and weight gain of three groups of rats. Group 1 rats were administered cisplatin, saline, and IgG; Group 2 rats were administered cisplatin, saline, and anti-GDF-15 mouse mAb (mouse mAb comprising SEQ ID NOs: 288 and 289); and Group 3 rats were administered cisplatin, TCMCB07 (SEQ ID NO: 306), and anti-GDF-15 mouse mAb. Cisplatin was administered at 5 mg / kg on day 0 and at 3 mg / kg on days 7 and 14. [Figure 12D]1 shows a graph depicting total weight gain after 21 days in Sprague Dawley rats. The graph compares the weight and weight gain of three groups of rats. Group 1 rats were administered cisplatin, saline, and IgG; Group 2 rats were administered cisplatin, saline, and anti-GDF-15 mouse mAb (mouse mAb comprising SEQ ID NOs: 288 and 289); and Group 3 rats were administered cisplatin, TCMCB07 (SEQ ID NO: 306), and anti-GDF-15 mouse mAb. Cisplatin was administered at 5 mg / kg on day 0 and at 3 mg / kg on days 7 and 14. [Figure 13A] 1 shows a graph depicting the relative quantification (RQ) of mRNA expression of the cytokine IL1b in the hypothalamus of Sprague Dawley rats, as measured by quantitative polymerase chain reaction (qPCR). The graph compares mRNA expression in five groups of rats. Group 1 rats received cisplatin and an IgG light chain (IgG-L), Group 2 rats received cisplatin and an IgG heavy chain (IgG-H), Group 3 rats received cisplatin and a ponsegromab light chain (GDF-15Ab-L, SEQ ID NO: 289), Group 4 rats received cisplatin and a ponsegromab heavy chain (GDF-15Ab-H, SEQ ID NO: 288), and Group 5 rats received saline (saline / saline). [Figure 13B] 1 shows a graph depicting the relative quantification (RQ) of IL1R1 mRNA expression in the hypothalamus of Sprague Dawley rats, as measured by quantitative polymerase chain reaction (qPCR). The graph compares mRNA expression in five groups of rats. Group 1 rats received cisplatin and an IgG light chain (IgG-L), Group 2 rats received cisplatin and an IgG heavy chain (IgG-H), Group 3 rats received cisplatin and a ponsegromab light chain (GDF-15Ab-L, SEQ ID NO: 289), Group 4 rats received cisplatin and a ponsegromab heavy chain (GDF-15Ab-H, SEQ ID NO: 288), and Group 5 rats received saline (saline / saline). [Figure 13C]1 shows a graph depicting the relative quantification (RQ) of IL6 mRNA expression in the hypothalamus of Sprague Dawley rats, as measured by quantitative polymerase chain reaction (qPCR). The graph compares mRNA expression in five rat groups. 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 heavy chain (GDF-15Ab-H, SEQ ID NO: 288), and Group 5 rats were administered saline (saline / saline). [Figure 13D] 1 shows a graph depicting the relative quantification (RQ) of CCL2 mRNA expression in the hypothalamus of Sprague Dawley rats, as measured by quantitative polymerase chain reaction (qPCR). The graph compares mRNA expression in five rat groups. 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 heavy chain (GDF-15Ab-H, SEQ ID NO: 288), and Group 5 rats were administered saline (saline / saline). [Figure 13E] 1 shows a graph depicting the relative quantification (RQ) of GDF-15 mRNA expression in the hypothalamus of Sprague Dawley rats, as measured by quantitative polymerase chain reaction (qPCR). The graph compares mRNA expression in five rat groups. 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 heavy chain (GDF-15Ab-H, SEQ ID NO: 288), and Group 5 rats were administered saline (saline / saline). DETAILED DESCRIPTION OF THE INVENTION

[0235] Described herein are compositions comprising a first compound comprising a non-naturally occurring melanocortin analog, a second compound having a spiro structure, and / or a third compound comprising an antibody or antigen-binding fragment thereof. The compositions may further comprise an anti-cancer agent(s). Also described herein are methods for regulating body weight using the compositions, including, but not limited to, increasing appetite, preventing appetite loss, promoting weight gain, preventing weight loss, and / or treating, preventing, or otherwise alleviating cachexia and / or anorexia in a subject in need thereof, and / or increasing the effectiveness of an anti-cancer agent by administering the compounds to the subject. Also described are methods for treating a subject with cancer without causing one or more side effects.

[0236] The following description is merely exemplary in nature and is not intended to limit the present technology, its application, or its uses. It should be understood that corresponding reference numerals indicate like or corresponding parts and features throughout the drawings. The descriptions of specific examples shown in various embodiments of the present technology are for illustrative purposes only and are not intended to limit the scope of the present technology. Furthermore, the recitation of multiple embodiments having described features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the described features.

[0237] Furthermore, the detailed description of various embodiments herein refers to the accompanying drawings / figures, which illustrate various embodiments by way of example. These embodiments are described in sufficient detail to enable those skilled in the art to practice the present technology, but 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. Accordingly, the detailed description herein is presented for purposes of illustration only, and not limitation. For example, the steps or functions listed in the description, any method, system, or process, may be performed in any order and are not limited to the order presented. Furthermore, any of the steps or functions may be outsourced to or performed by one or more third parties.

[0238] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this technology belongs. For purposes of the present technology, the following terms are defined below.

[0239] 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. Similarly, any reference to a singular element may include plural embodiments, and any reference to plural elements may include singular embodiments.

[0240] The term "about" means that a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length varies by a level accepted in the art. In some embodiments, such variation can be as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% of 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 stated numerical values.

[0241] The term "administering" or "administering" includes delivering a therapy of the present technology (e.g., combination therapy, non-naturally occurring melanocortin analogs (also referred to herein as peptides), anti-cancer agents) to a subject by either local or systemic administration. Administration can be topical (including ocular and mucosal membranes, including vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including nebulizers), 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.

[0242] As used herein, a "pharmaceutically acceptable carrier" of a first, second, or third pharmaceutical composition refers to a carrier or diluent that does not cause significant irritation to an organism, does not inhibit the biological activity and properties of the administered active ingredient, and / or does not adversely interact with other components of the composition in which it is contained. The term "carrier" includes any excipient, binder, diluent, filler, salt, buffer, solubilizer, lipid, stabilizer, or other material known in the art for use in pharmaceutical formulations. The choice of carrier for use in a composition depends on the intended route of administration of the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described, for example, in 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, proteins such as low molecular weight (less than about 10 residues) polypeptides, 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 dextrin, chelating agents such as EDTA, sugar alcohols such as mannitol or sorbitol, salt-forming counterions such as sodium, and / or non-ionic surfactants such as TWEEN® (ICI, Inc., Bridgewater, NJ), polyethylene glycol (PEG), and PLURONICS™ (BASF, Florham Park, NJ). An "excipient" of a first or second pharmaceutical composition refers to an inert substance added to a composition to further facilitate administration of a compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

[0243] As used herein, "anti-cancer drug-associated side effects" or "anti-cancer drug-associated adverse side effects" refer to any unwanted, undesired, or adverse biological activity that occurs during or after the independent use of an anti-cancer drug.

[0244] 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 disease severity, and / or the amelioration of one or more symptoms thereof resulting from the administration of one or more therapies. Specifically, these terms refer to (1) the stabilization, reduction (e.g., a 10%, 20%, 30%, 40%, 50%, or greater than 60% reduction in the cancer cell population and / or tumor size pre-administration), or elimination of cancer cells; (2) the inhibition of cancerous cell division and / or cancerous cell proliferation; (3) the alleviation to some extent (or elimination) of one or more symptoms associated with pathologies associated with, or caused in part by, uncontrolled or aberrant cell division; (4) an increase in disease-free, recurrence-free, progression-free, and / or overall survival duration or rate; (5) a decrease in hospitalization rates; (6) a decrease in hospitalization duration; (7) the treatment of primary, regional, and / or metastatic cancer. (8) eradication, removal, or control of tumor or neoplasm growth (e.g., at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, or at least an 80% reduction compared to the initial growth rate); (9) impaired tumor formation; (10) reduced mortality; (11) increased response rate, durability of response, or number of patients responding or in remission; (12) tumor size maintained and increasing or decreasing by less than 10%, 5%, 4%, or 2%; (13) reduced need for surgery (e.g., colectomy, mastectomy); and (14) prevention or reduction of metastasis of cancer cells. The terms "treat," "treatment," and "treating" include prophylactic and / or therapeutic treatment. Treatment is considered prophylactic if administered before the onset of clinical symptoms of a condition. Therapeutic treatment includes, for example, amelioration or reduction of disease severity or shortening of disease duration or frequency.

[0245] As used herein, the term "effective amount" or "therapeutically effective amount" refers to that amount of active ingredient administered that will relieve to some extent one or more of the symptoms of the disease being treated. That result can be reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. An appropriate "effective amount" can vary from individual to individual. An appropriate "effective amount" in any individual case can be determined using techniques such as a dose escalation study.

[0246] The term "post-administration" refers to any period of time after a combination therapy, a non-naturally occurring melanocortin analog or pharmaceutical composition thereof, and / or an anti-cancer agent is administered to a subject. Unless otherwise specified, the period encompassed by "post-administration" can include seconds, minutes, hours, days, weeks, months, and years.

[0247] "Cachexia" refers to a state of generalized ill health and malnutrition characterized by loss of body mass, including weight loss, loss of muscle mass (skeletal, smooth, and / or cardiac), loss of fat mass, or a combination thereof, and wasting. Cachexia 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 criteria for cachexia include (i) weight loss of more than 5% in the past 6 months, (ii) a body weight of 20 kg / m 2 These may include (iii) weight loss of more than 2% in patients with a body mass index (BMI) of less than 100 mg / kg, or (iv) weight loss of more than 2% in patients with sarcopenia (or an 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).

[0248] "Anorexia" simply refers to a loss of appetite, whether caused by medical, physiological, or psychological factors. Anorexia is often closely associated with and commonly contributes to the cachexia seen in patients with advanced cancer and other conditions.

[0249] The terms "melanocortin analog," "non-naturally occurring melanocortin analog," "melanocortin peptide," "melanocortin receptor peptide," or "melanocortin" 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 to melanocortin receptors under physiological conditions. Melanocortin analogs include naturally occurring and non-naturally occurring melanocortin analogs (i.e., "synthetic peptides" or "synthetic analogs"), as well as truncated and / or modified forms of full-length melanocortin proteins or peptides. For example, the full-length proopiomelanocortin protein (POMC), prior to proteolytic cleavage of "subpeptides," consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC results in peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, pp. 257-265, Academic Press (2000). The synthetic, non-naturally occurring melanocortin analogs with increased melanocortin receptor activity discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding function with melanocortin receptors. Binding to melanocortin receptors is inhibitory (antagonist). In addition to peptides, non-naturally occurring melanocortin analogs include small molecule analogs of melanocortin or portions thereof, consisting of organic compounds, inorganic compounds, or combinations of peptides and small molecules, i.e., peptidomimetics, or various combinations thereof. "Non-naturally occurring melanocortin analogs" may be structurally and / or functionally similar to biological melanocortin proteins in their ability to bind to melanocortin receptors. Additionally, non-naturally occurring melanocortin analogs generally include the pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 304) or modified versions thereof, or structural or functional peptidomimetics thereof.

[0250] A peptide or amino acid "mimetic" is a non-amino acid molecule that mimics a peptide (a chain of amino acids) or a single amino acid residue.

[0251] "Substantial degradation" refers to degradation of the N-terminal extension, the C-terminal extension, both the N- and C-termini, or other regions of a non-naturally occurring melanocortin analog by physiological enzymes and other factors in such a manner or to such an extent that side effects are manifested. According to one embodiment, a non-naturally occurring melanocortin analog having a C-terminal extension that resists substantial degradation is one that causes side effects in 50% or less of the administered peptide and / or exhibits a reduced half-life. In some embodiments, no more than 25% of the administered peptide causes side effects and / or exhibits a reduced half-life. Furthermore, in some embodiments, less than 10% of the administered peptide causes side effects and / or exhibits a reduced half-life compared to a non-naturally occurring melanocortin analog lacking the C-terminal extension.

[0252] The "peptides" described herein may (a) occur naturally, (b) be produced by chemical synthesis, (c) be produced by recombinant DNA technology, (d) be produced by biochemical or enzymatic fragmentation of a larger molecule, (e) be produced by a method resulting from a combination of methods (a)-(d) above, or (f) be produced by any other means for producing a peptide.

[0253] As used herein, the term "peptide" includes any structure composed of two or more amino acids, including chemical modifications and derivatives of amino acids. The amino acids forming all or 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, etc., so that the term "peptide" includes pseudopeptides and peptidomimetics, including structures with non-peptide backbones. The term "peptide" also includes peptide dimers or multimers. "Manufactured" peptides include peptides generated by chemical synthesis, recombinant DNA technology, biochemical or enzymatic fragmentation of larger molecules, combinations of the above, or generally peptides produced by any other method. The term "peptide" includes peptides containing a variable number of amino acid residues, optionally containing non-amino acid residues at the N- and C-termini, including, inter alia, acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups.

[0254] An "amino acid" is a molecule containing an amine group, a carboxylic acid group, and a side chain specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen, and have the general formula HN-CHR-COOH, where R represents the side chain group. Various α-amino acids differ in the side chain moiety attached to the α-carbon. The "amino acids" of the present technology include known naturally occurring protein amino acids, which are referred to by both their common three-letter and one-letter abbreviations. See generally, "Non-naturally occurring melanocortin analogs: A User's Guide," GAGrant, editor, W.H. Freeman & Co., New York (1992) (including the text and tables in paragraphs 11-24), the teachings of which are incorporated herein by reference. As noted 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 generally described in Non-naturally occurring melanocortin analogs: A User's Guide (see above), 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.

[0255] The phrase "amino acid side chain moiety" as used herein, including in the specification and claims, includes any side chain of any amino acid, as the term "amino acid" is defined herein. Thus, it includes side chain moieties 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 of stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. For example, any amino acid side chain moiety of the present technology is included within this definition. A "derivative" of an amino acid side chain moiety is included within the definition of an amino acid side chain moiety.

[0256] A "derivative" of an amino acid side chain moiety includes any modification to or any variation of any amino acid side chain moiety, including modifications of naturally occurring amino acid side chain moieties. By way of example, derivatives of amino acid side chain moieties include linear or branched, cyclic or acyclic, substituted or unsubstituted, saturated or unsaturated alkyl, aryl, or aralkyl moieties.

[0257] In the peptides described herein, conventional amino acid residues have their conventional meanings as provided in Chapter 2400 of the Manual of Patent Examining Procedure (8th Edition). 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 treptophan, "Tyr" is trypsin, and "Val" is valine. Unless otherwise indicated, all amino acid abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or a combination 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 a combination thereof, "Phe" is D-phenylalanine, L-phenylalanine, or a combination thereof, etc. Non-standard amino acids are "Nle" for norleucine, "Nal" for naphthylalanine, "D-Nal" for D-naphthylalanine, D-Nal(2') for D-2'-naphthylalanine, L-Nal(2') for L-2'-naphthylalanine, L-Nal(1') for L-1'-naphthylalanine, D-Nal(1') for D-1'-naphthylalanine, Tle for tert-leucine, Nva for norvaline, Orn for ornithine, Bip for biphenyl amino acid, etc.

[0258] Alpha (α)-amino acids have the general formula H2N-C αThey have the formula HR-COOH, where R is the 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 acids exist where the amino group is attached to a different carbon atom. For example, in beta (β)-amino acids, the carbon atom to which the amino group is attached is carbon atom C β It is separated from the carboxylate group by one atom. For example, α-alanine has the formula H2N-C α H(CH3)-COOH. In contrast, β-alanine has the general formula H2N-C β H2-C α H2-COOH (i.e., 3-aminopropanoic acid).

[0259] When β-amino acids are incorporated into peptides, two main types of β-peptides exist: those with a side chain residue R on the carbon next to the amine, and those with a side chain residue R on the carbon next to the amine. 3 Peptides are called β-peptides, and those with a side chain residue on the carbon next to the carbonyl group are called β-peptides. 2 As a non-limiting example, "β-valine" is -NH-C β H2-C α H(CH3)2-CO-, i.e., β 2 -valine (R on the carboxyl side), -NH-C β H(CH3)2-C α H2-CO-, i.e., β 3 - valine (R on the amino side), or -NH-C β H(CH3)2-C α H(CH3)2-CO-, i.e., β 2,3 -Can refer to valine (R in both positions).

[0260] Additionally, β-amino acids can be of L- or D-stereochemistry. Unless otherwise indicated, all β-amino acid abbreviations represent either isomer, i.e., L-isomer, D-isomer, or a combination thereof.

[0261] Gamma (γ)-amino acids are amino acids in which the carbon atom to which the amino group is attached is separated from the carboxylate moiety by two carbon atoms. For example, γ-aminobutyric acid has the formula HN-C γ H2-C β H2-C α It has H2-COOH.

[0262] For additional modified and unusual amino acids, see MPEP Article 2422, especially Table 4 in 2400-24. Additionally, "Ac" refers to N-acetyl, and "cyclo" refers to a cyclic structure, designated in the literature as "c" or referred to as a "lactam." "NH2" refers to an amine group typically added to the C-terminus of a polypeptide. Thus, as used herein, the -NH2 moiety at the C-terminus of a peptide refers to an amide, i.e., -CO-NH2. Additionally, the following abbreviations are used herein: Harg is homoarginine, and Hlys is homolysine.

[0263] Additional abbreviations are used as follows: tBu is tert-butyl, Hyp(Bzl) is benzyl-L-hydroxy-proline, the 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, and Ata is 7-amino-7,8-dihydro-4H-(1,2,3)triazolo(1,5-a)(1,4)dicarboxylic acid. Aia is 4-amino-1,4,5,6-tetrahydroazepino(4,3-b)indol-3(2H)-one, Aba is 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one, Mamb is 3-aminomethylbenzoic acid, Atc is 2-aminotetralin-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).

[0264] The term "alkene" includes unsaturated hydrocarbons containing one or more double carbon-carbon bonds. Examples of such alkene groups include ethylene, propene, and the like.

[0265] The term "alkenyl" includes linear monovalent hydrocarbon radicals of two to six carbon atoms or branched monovalent hydrocarbon radicals of three to six carbon atoms containing at least one double bond, examples of which include ethenyl, 2-propenyl, and the like.

[0266] The term "alkynal" includes linear monovalent hydrocarbon radicals of two to six carbon atoms or branched monovalent hydrocarbon radicals of three to six carbon atoms containing at least one triple bond, examples of which include ethynyl, propynal, butynyl, and the like.

[0267] The term "aryl" includes monovalent or bicyclic aromatic hydrocarbon radicals of 6 to 12 ring atoms, 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 aryl groups include phenyl, biphenyl, naphthyl, 1-naphthyl, and 2-naphthyl, derivatives thereof, and the like.

[0268] The term "aliphatic" includes compounds having hydrocarbon chains such as, for example, alkanes, alkenes, alkynes, and derivatives thereof.

[0269] The term "acyl" includes the group RCO-, where R is an organic group. An example is the acetyl group CHCO-, referred to herein as "Ac".

[0270] The term "fatty acid" refers to a carboxylic acid having an aliphatic chain that may be fully saturated or partially unsaturated and optionally attached to a functional group such as a hydroxyl or carboxyl group. The aliphatic chain may contain, for example, 6 to 26 carbon and hydrogen atoms.

[0271] A peptide or aliphatic moiety is "acylated" when an alkyl or substituted alkyl group, as defined above, is attached through one or more carbonyl {-(C=O)-} groups. Peptides are most often acylated at the N-terminus.

[0272] An "omega amino derivative" comprises an aliphatic moiety having a terminal amino group. Examples of omega amino derivatives include aminoheptanoyl and the amino acid side chain moieties of ornithine and lysine.

[0273] The term "heteroaryl" includes monocyclic and bicyclic aromatic rings containing one to four heteroatoms selected from nitrogen, oxygen, and sulfur. Five- or six-membered heteroaryls are monocyclic heteroaromatic rings, examples of which 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.

[0274] "Amine" includes compounds that contain an amine group (-NH2).

[0275] "Amide" includes compounds having a trivalent nitrogen attached to a carbonyl group (i.e., -CO-NH), e.g., methylamide, ethylamide, propylamide, etc. Peptides are most often amidated at the C-terminus by the addition of an amine (-NH) moiety to the C-terminal carboxyl group.

[0276] "Imine" includes compounds with a carbon-nitrogen double bond, where the nitrogen is also bonded to a hydrogen (NH=CH-R).

[0277] "Imide" includes compounds containing the imide group (-OC-NH-CO-).

[0278] "Nitrile" includes compounds that are carboxylic acid derivatives and contain a (-CN) group attached to an organic group.

[0279] The term "halogen" is intended to include the halogen atoms fluorine, chlorine, bromine, and iodine, as well as groups containing one or more halogen atoms, such as -CF3.

[0280] Amino acids, including stereoisomers and modifications of naturally occurring amino acids, 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 (peptidomimetics), etc., including all of the foregoing, may be referred to herein as "residues."

[0281] A melanocortin receptor "agonist" is a naturally occurring substance or manufactured drug substance or composition that can interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor. A melanocortin receptor "antagonist" is a naturally occurring substance or manufactured drug substance or composition that opposes the melanocortin receptor-associated response normally induced by a melanocortin receptor agonist. A melanocortin receptor "inverse agonist" is a drug or compound that stabilizes the inactive conformation of the melanocortin receptor and inhibits basal activity.

[0282] As used herein, "compound" includes conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomers, and other mixtures of such isomers, as well as any pharmaceutically acceptable derivatives or variants, including solvates, hydrates, isomorphs, polymorphs, tautomers, esters, salt forms, and prodrugs. The term "prodrug" refers to a compound that is a drug precursor that releases a drug in vivo after administration through some chemical or physiological process (e.g., a prodrug brought to physiological pH or converted to the desired drug form via enzymatic action).

[0283] The term "alkyl" refers to an acyclic saturated aliphatic hydrocarbon group, which may be straight-chained 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 prefixes specifying the lower and upper number of carbon atoms in the moiety; i.e., the prefix Ci-j indicates a moiety having from integer "i" to integer "j" carbon atoms (inclusive). Thus, for example, C1-4 alkyl refers to an alkyl having 1 to 4 carbon atoms. Representative examples of C1-4 alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. In another example, C1-4 alkyl refers to an alkyl having 1 to 2 carbon atoms (i.e., methyl or ethyl). An alkyl group can be optionally substituted (where so specified) with one or more (e.g., 1 to 5) suitable substituents. The "alkyl" groups specified herein include 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.

[0284] In various places herein relating to second compounds, substituents of the compounds are disclosed in groups or ranges. It is specifically intended that the present technology include any and all individual subcombinations 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. In another example, the term "4- to 7-membered heterocycloalkyl" is specifically intended to include any 4-, 5-, 6-, or 7-membered heterocycloalkyl group.

[0285] As used herein, the term "n-membered," where n is an integer, typically refers to the number of ring-forming atoms in a moiety where n is the number of ring-forming atoms. For example, pyridinyl is an example of a 6-membered heteroaryl ring, and pyrazolyl is an example of a 5-membered heteroaryl group.

[0286] As used herein, the term "alkoxy" or "alkyloxy" refers to an -O-alkyl group. For example, the term "C alkoxy" or "C alkyloxy" refers to an -O-(C alkyl) group, and as another example, the term "C alkoxy" or "C alkyloxy" refers to an -O-(C alkyl) group. Examples of alkoxy include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), tert-butoxy, and the like. An alkoxy or alkyloxy group can be optionally substituted (where so specified) with one or more (e.g., 1 to 5) suitable substituents.

[0287] As used herein, the term "halo" or "halogen" means -F, -Cl, -Br, or -I.

[0288] As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., all hydrogen atoms of the alkyl group are replaced by halogen atoms). 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., all hydrogen atoms of the alkyl group are replaced by halogen atoms), 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., all hydrogen atoms of the alkyl group are replaced by halogen atoms). Examples of haloalkyl groups include -CF3, -CHF2, -CH2F, -CH2CF3, -CF5, -CH2Cl, and the like.

[0289] "Fluoroalkyl" refers to an alkyl, as defined herein, substituted with one or more fluoro (-F) substituents (up to perfluoroalkyl, i.e., all hydrogen atoms of the alkyl group are replaced with fluorine atoms). 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., all hydrogen atoms of the alkyl group are replaced with fluorine atoms), and the term "C1 fluoroalkyl" refers to a methyl having one, two, or three fluorine substituents. Examples of C1 fluoroalkyl include fluoromethyl, difluoromethyl, and trifluoromethyl, and some examples of C2 fluoroalkyl include 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, etc.

[0290] As used herein, 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. In yet another example, the term "C1 haloalkoxy" refers to a methoxy group having one, two, or three halogen substituents. An example of a haloalkoxy is -OCF3 or -OCHF2.

[0291] As used herein, the term "fluoroalkoxy" refers to an -O-fluoroalkyl group. For example, the term "C fluoroalkoxy" refers to an -O-(C fluoroalkyl) group, and the term "C fluoroalkoxy" refers to an -O-(C fluoroalkyl) group. Examples of C fluoroalkoxy include -O-CH F, -O-CHF, and -O-CF. Some examples of C fluoroalkoxy include -O-CH CHF, -O-CH-CHF, -O-CH CF, -O-CF CH, and -O-CF CF.

[0292] 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 a hydroxylalkyl is -CH2OH or -CH2CH2OH.

[0293] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (including bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.), or bicyclic, including spiro, fused, or bridged systems (e.g., bicyclo(1.1.1)pentanyl, bicyclo(2.2.1)heptanyl, bicyclo(3.2.1)octanyl, or bicyclo(5 .2.0) nonanyl, decahydronaphthalenyl, etc.). Cycloalkyl groups have 3 to 15 (e.g., 3 to 14, 3 to 10, 3 to 6, 3 to 4, or 4 to 6) carbon atoms. In some embodiments, cycloalkyl can optionally contain one, two, or more non-cumulative non-aromatic double or triple bonds and / or one to three oxo groups. In some embodiments, bicycloalkyl groups have 6 to 14 carbon atoms. As used herein, When used herein, the term "C3-4 cycloalkyl" refers to a saturated cyclic hydrocarbon group containing 3 to 4 carbons. Examples of C3-4 cycloalkyl include cyclopropyl and cyclobutyl. Also included within the definition of cycloalkyl are moieties having one or more aromatic rings (including aryl and heteroaryl) fused to the cycloalkyl ring, e.g., benzo or pyridinyl derivatives such as cyclopentane (5-membered cycloalkyl), cyclopentene, cyclohexane (6-membered cycloalkyl), and the like, e.g., 6,7-dihydro-5H-cyclopenta(b)pyridinyl, 5,6,7,8-tetrahydroquinolinyl, or 15,6,7,8-tetrahydroisoquinolinyl, each of which contains a 5- or 6-membered cycloalkyl moiety fused to a heteroaryl ring (i.e., a pyridinyl ring). A cycloalkyl group or C3-4 cycloalkyl group can be optionally substituted (where so specified) with one or more (e.g., 1 to 5) suitable substituents.

[0294] As used herein, the term "C3-4 cycloalkyl-C1-4 alkyl" 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.

[0295] As used herein, the term "heterocycloalkyl" refers to a monocyclic or polycyclic (spiro, fused, or bridged system, e.g., containing two or more rings fused together, including bicyclic systems), saturated or unsaturated, non-aromatic 4- to 15-membered ring system (such as a 4- to 14-membered ring system, a 4- to 12-membered ring system, a 5- to 10-membered ring system, a 4- to 7-membered ring system, a 4- to 6-membered ring system, or a 5- to 6-membered ring system) containing 1 to 14 ring-forming carbon atoms and 1 to 10 ring-forming heteroatoms, each independently selected from O, S, and N (optionally P or B, if present). Heterocycloalkyl groups can 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 containing one or more ring-forming heteroatoms, each independently selected from O, S, and N. In another example, the term "5- or 6-membered heterocycloalkyl" refers to a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 5- or 6-membered ring system that contains one or more ring-forming heteroatoms each independently selected from O, S, and N. A heterocycloalkyl group can be optionally substituted (where so specified) by one or more (e.g., 1 to 5) suitable substituents.

[0296] Some examples of 4-7 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 4-7 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.

[0297] As used herein, the term "heteroaryl" refers to a monocyclic or fused-ring polycyclic aromatic heterocyclic group having one or more heteroatom ring members (ring-forming atoms) each independently selected from O, S, and N in at least one ring. Heteroaryl groups have 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, heteroaryl groups have 5 to 10 ring-forming atoms, including 1 to 4 heteroatoms. Heteroaryl groups may also contain 1 to 3 oxo or thiono (i.e., ═S) groups. In some embodiments, heteroaryl groups have 5 to 8 ring-forming atoms, including 1, 2, or 3 heteroatoms. For example, the term "5-membered heteroaryl" refers to a monocyclic heteroaryl group as defined above having 5 ring-forming atoms in the monocyclic heteroaryl ring; the term "6-membered heteroaryl" refers to a monocyclic heteroaryl group as defined above having 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 having 5 or 6 ring-forming atoms in the monocyclic heteroaryl ring. Heteroaryl groups can be optionally substituted (where so specified) with one or more (e.g., 1 to 5) suitable substituents. Examples of monocyclic heteroaryls include those having 5 ring-forming atoms, including 1 to 3 heteroatoms, or those having 6 ring-forming atoms, including 1, 2, or 3 nitrogen heteroatoms. Examples of fused bicyclic heteroaryls include two fused 5- and / or 6-membered monocyclic rings, including 1 to 4 heteroatoms.

[0298] Some examples of heteroaryl groups include pyridinyl (e.g., pyridin-2-yl, pyridin-3-yl, pyridin-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, etc.

[0299] 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, or polypeptide, via at least one antigen recognition site located in the variable region of the immunoglobulin molecule. As used herein, the term "antibody" can encompass any type of antibody, including, but not limited to, monoclonal antibodies, polyclonal antibodies, and antigen-binding fragments (or portions) of intact antibodies that retain the ability to specifically bind to a given antigen (e.g., GDF-15).

[0300] The term "antigen" refers to a molecular entity used to immunize an immunocompetent vertebrate to produce antibodies that recognize the Ag, or to screen an expression library (e.g., a phage, yeast, or ribosome display library, among others). In this specification, Ag is used more broadly and is generally intended to include the target molecule specifically recognized by Ab (and therefore includes fragments or mimics of the molecule used in the immunization process to raise Abs or library screening to select Abs). Thus, in the case of the antibody of the present technology that binds to GDF-15, full-length GDF-15 from mammalian species (e.g., human, monkey, mouse, and rat GDF-15) (including its monomers and multimers, such as dimers, trimers, etc.), as well as truncated forms and other variants of GDF-15, are referred to as antigens.

[0301] 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 antigen-binding fragments include: (i) V L , V H (ii) a Fab fragment, which is a monovalent fragment consisting of the CL, CL, and CH1 domains; (iii) a F(ab′)2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; and (iv) a V H(iv) a Fd fragment consisting of a V domain and a CH1 domain of a single arm of an antibody; L Domains and V H Fv fragment consisting of domains, (v) V H (vi) isolated complementarity-determining regions (CDRs), disulfide-linked Fvs (dsFvs), and anti-idiotypic (anti-Id) antibodies and intracellular antibodies. In addition, two domains of the Fv fragment, V, and V, are also included. L and V H are encoded by separate genes, they can be synthesized using recombinant methods L Area and V H The domains may be linked by a synthetic linker that allows them to be produced as a single protein chain (known as single-chain Fv (scFv)) that pairs to form a monovalent molecule. See, for example, 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 comprised of V H Domains and V L Bivalent, bispecific antibodies in which the domains are expressed on a single polypeptide chain, but with a linker that is too short to allow pairing between the two domains on the same chain, thereby allowing them to pair with complementary domains on another chain and create 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).

[0302] An antibody "variable domain" refers to the variable region of an antibody light chain (V L ) or the variable region of an antibody heavy chain (V HAs is 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), which contribute to the formation of the antigen-binding site of an antibody.

[0303] "Complementarity-determining regions" (CDRs) can be identified according to Kabat, Chothia, a combination of both Kabat and Chothia, AbM, contact, North, and / or conformational definitions, or any CDR determination method known to those skilled in the art. See, for example, Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th ed. (hypervariable regions); Chothia et al., 1989, Nature 342:877-883 (structural loop structure). The identity of amino acid residues in a particular antibody that constitute a CDR can 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 the observed antigen contacts described in MacCallum et al., 1996, J. Mol. Biol., 262:732-745. The "conformational" definition of CDRs is based on the residues that contribute enthalpily to antigen binding (see, for example, 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 CDRs can be identified as residues that contribute enthalpily 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 still overlap with at least a portion of the Kabat CDRs, but they may be shortened or extended in light of predictions or experimental results that particular residues or groups of residues, or even entire CDRs, do not significantly affect antigen binding. As used herein, CDR may refer to a CDR defined by any approach known in the art, including a combination 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 residues of the antibody) may be defined according to any of the Kabat, Chothia, North, extension, AbM, contact, and / or conformation definitions.

[0304] "Framework" (FR) residues are those antibody variable domain residues other than the CDR residues. H Domain or V L The domain framework comprises four framework subregions, FR1, FR2, FR3, and FR4, interspersed with CDRs in the following structure: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0305] 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.

[0306] The terms "Fc region," "Fc domain," and "Fc," used interchangeably herein, refer to a portion of an immunoglobulin (Ig) molecule that correlates to the crystallizable fragment obtained by papain digestion of the Ig molecule. As used herein, these terms refer to the constant region of an antibody, excluding the first constant region immunoglobulin domain, and also 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, as well as the flexible hinges at the N-terminus of these domains, or portions thereof. In the case of IgA and IgM, Fc may include the J chain.

[0307] In the case of IgG, Fc comprises the immunoglobulin domains Cy2 and Cy3 (Cgamma2 and Cgamma3) and the hinge between Cy1 (Cgamma1) and Cy2 (Cgamma2). Although the boundaries of the Fc region can vary, the human IgG heavy chain Fc region is usually defined to include residues C226 or P230 at its carboxyl terminus, with numbering 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 amino acid residues from about 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 can refer to this region in isolation or in the context of an antibody, an antigen-binding portion thereof, or an Fc fusion protein.

[0308] The heavy chain constant domain comprises the Fc region, and further comprises the CH1 domain and hinge, and CH2 and CH3 domains of an IgG heavy chain (and optionally the CH4 domain of IgA and IgE).

[0309] In certain embodiments, the antibodies or antigen-binding fragments thereof described herein comprise an Fc domain, which can be derived from IgA (e.g., IgA1 or IgA2), IgD, IgE, IgM, or IgG (e.g., IgG1, IgG2, IgG3, or IgG4).

[0310] An "Fc fusion" protein is a protein in which 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.

[0311] "Epitope" refers to the area or region of an antigen to which an antibody specifically binds, e.g., the area or region that contains residues that interact with the antibody. Epitopes can be linear or conformational.

[0312] At its most detailed level, an epitope for an interaction between an Ag and an Ab can be defined by spatial coordinates defining the atomic contacts present in the Ag-Ab interaction, as well as information regarding their relative contribution to binding thermodynamics. At a less detailed level, an epitope can be characterized by spatial coordinates defining the atomic contacts between the Ag and the Ab. At an even less detailed level, an epitope can be characterized by the amino acid residues it contains, as defined by specific criteria, such as the distance between atoms (e.g., heavy atoms, i.e., non-hydrogen atoms) in the Ab and the Ag. At an even less detailed level, an epitope can be characterized by function, such as competitive binding with other Abs. An epitope can also be more generally defined as including amino acid residues whose substitution with another amino acid (e.g., using alanine scanning) alters the characteristics of the interaction between the Ab and the Ag.

[0313] The fact that epitope description and definition can be obtained at different levels of detail depending on the epitope mapping method used means that comparisons of epitopes of different Abs on the same Ag can likewise be made at different levels of detail.

[0314] Epitopes described at the amino acid level, for example, as determined from X-ray structures, 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 distinct (unique) if no amino acid residues are shared by the epitopes.

[0315] Epitopes characterized by competitive binding are said to overlap if the binding of the corresponding antibodies is mutually exclusive, i.e., if the binding of one antibody precludes the simultaneous or sequential binding of the other. Epitopes are said to be distinct (unique) if the antigen can simultaneously accept the binding of both corresponding antibodies.

[0316] An antibody that "preferentially binds" or "specifically binds" (used interchangeably herein) to an epitope is a term well understood in the art, and methods for determining such specific or preferential binding are also well known in the art. A molecule is said to exhibit "specific binding" or "preferential binding" if it reacts or associates with a particular cell or substance more frequently, rapidly, for longer duration, and / or with greater affinity than with alternative cells or substances. An antibody "specifically binds" or "preferentially binds" to a target if it binds with greater affinity, avidity, ease, and / or for longer 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 to this epitope with greater affinity, greater affinity, ease, and / or for longer duration than it binds to other GDF-15, PD-1, or PD-L1 epitopes, or non-GDF-15, PD-1, PD-L1 epitopes. Generally, reference to binding refers to preferential binding, but this is not necessarily the case. "Specific binding" or "preferential binding" includes compounds, such as proteins, nucleic acids, antibodies, etc., that recognize and bind to a specific molecule in a sample but do not substantially recognize or substantially bind to other molecules in the sample. For example, an antibody or peptide receptor that recognizes and binds to its cognate ligand or binding partner in a sample (e.g., an anti-GDF-15 antigen antibody that binds to a GDF-15 antigen, a molecule that binds to GDF-15, etc.) but does not substantially recognize or substantially bind to other molecules in the sample specifically binds to its cognate ligand or binding partner. Thus, under specified assay conditions, a specified binding moiety (e.g., an antibody or its antigen-binding portion, or a receptor or its ligand-binding portion) preferentially binds to a specific target molecule and does not bind to a significant amount to other components present in the test sample.

[0317] A variety of assay formats can be used to select antibodies or peptides that specifically bind to a molecule of interest. For example, solid-phase ELISA immunoassays, immunoprecipitation, BIAcore™ (GE Healthcare, Piscataway, NJ), fluorescence-activated cell sorting (FACS), Octet™ (ForteDo, Inc., Menlo Park, Calif.), and Western blot analysis are among the many assays that can be used to identify antibodies that specifically react with an antigen or receptor, or a ligand-binding portion thereof, that specifically binds to its cognate ligand or binding partner. Typically, a specific or selective reaction is at least 2-fold background signal or noise, more typically more than 10-fold background, and even more specifically, is characterized by an equilibrium dissociation constant (K D An antibody is said to "specifically bind" to an antigen when the binding affinity (Ig) is 1 pM, 100 nM, even 10 nM, even 100 pM, even 10 pM, or even 1 pM.

[0318] As used herein with respect to antibodies, the term "compete" means that the binding of a first antibody, or antigen-binding portion thereof, to an antigen reduces subsequent binding of the same antigen by a second antibody, or antigen-binding portion thereof. Generally, binding of a first antibody causes steric hindrance, conformational change, or binding to a common epitope (or portion thereof) such that binding of the second antibody to the same antigen is reduced. Standard competition assays can be used to determine whether two antibodies compete with each other. One suitable assay for antibody competition involves the use of Biacore technology, which typically uses a biosensor system (such as a BIACORE system) to measure the degree of interaction using surface plasmon resonance (SPR) technology. For example, SPR can be used in an in vitro competitive binding inhibition assay to determine the ability of one antibody to inhibit binding of a second antibody. Another assay for measuring antibody competition uses an ELISA-based approach.

[0319] The antibodies of the present technology further include antibody mutants thereof. Mutant antibodies may contain 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 of the above-mentioned specific sequences and fragments. "Deletion" mutants may include the deletion of individual amino acids, the deletion of small groups of amino acids, for example, 2, 3, 4, or 5 amino acids, or the deletion of larger amino acid regions, for example, the deletion of specific amino acid domains or other features. "Insertion" mutants may include the insertion of individual amino acids, the insertion of small groups of amino acids, for example, 2, 3, 4, or 5 amino acids, or the insertion of larger amino acid regions, for example, the insertion of specific amino acid domains or other features. "Substitution" mutants involve replacing one or more amino acids with the same number of amino acids, making conservative amino acid substitutions. For example, an amino acid can be substituted with an alternative amino acid having similar properties, such as 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 that can be used to select suitable replacements are as follows:

[0320] In a process known as "germlinization," V H Array and V L Certain amino acids in the sequence are germline V H Array and V L The V may be mutated to match that found in nature in the sequence. Specifically, to reduce the risk of immunogenicity when the antibody is administered, H Array and V LThe amino acid sequence of the framework region in the sequence may be mutated to match the germline sequence. As used herein, the term "germline" refers to the nucleotide and amino acid sequences of antibody genes and gene segments that are passed from parents to offspring via germ cells. This germline sequence is distinct from the nucleotide sequence encoding the antibody in mature B cells, which is modified by recombination and hypermutation events during the B cell maturation process. An antibody that "utilizes" a particular germline has a nucleotide or amino acid sequence that most closely aligns with the germline nucleotide sequence or amino acid sequence it specifies. Such antibodies are frequently mutated compared to the germline sequence. Human V H and V L The germline DNA sequence of the gene is known in the art.

[0321] The disclosures of all publications, patents, and published patent applications cited herein, including but not limited to U.S. Patent No. 9,534,018, U.S. Patent Application No. 16 / 541,817, and WIPO International Application No. PCT / IB2021 / 054970, are hereby incorporated by reference.

[0322] composition The present technology includes compositions having (i) a first compound having a primary therapeutic benefit, and (ii) a second compound and / or (iii) a third compound, each having a secondary therapeutic benefit. The first compound may include a non-naturally occurring melanocortin analog. The second compound may include a spiro compound. The third compound may include an antibody or an antigen-binding fragment thereof.

[0323] First compound: a non-naturally occurring melanocortin analogue The first compound of the present technology may include a non-naturally occurring melanocortin analog. In some embodiments, the non-naturally occurring melanocortin analog is a melanocortin 3 receptor (MC3R) and / or melanocortin 4 receptor (MC4R) antagonist, agonist, or inverse agonist. The first compound may exert a therapeutic effect after antagonizing MC3R and / or MC4R.

[0324] Formulas for non-naturally occurring melanocortin analogs 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): X 1 X 2 X 3 R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 R 12 R 13 R 14 R 15 R 16 R 17 R 18 R 19 R 20 Y 1 Y 2 Y 3 Y 4 Y 5 Y 6 Y 7 Y 8 (I) During the ceremony, R 1is absent or contains 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, n-pentanoyl group, n-hexanoyl group, leucine, isoleucine, valine, norvaline, alanine, glycine, proline, methionine, lysine, phenylalanine, glutamic acid, asparagine, acetylated D-arginine, a selected from the group consisting of cetylated 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; R 2 is absent or 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, n-pentanoyl group, n-hexanoyl group, methionine, phenylalanine, penicillamine (Pen), and D-penicillamine (dPen); R 3is absent or is selected from the group consisting of histidine, histidine methylated at position 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-tetrahydrofuran, -2-benzazepin-3-one (Aba), beta-alanine (β-Ala), 3-aminomethylbenzoic acid (Mamb), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetralin-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-cyclopentanecarboxy (Cpe); R 4 is 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); R 5 is absent or 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; R 6is absent or 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; R 7 is absent or 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); R 8 is absent or is lysine or arginine; R 9 is absent or is tryptophan, R 10 is absent or is lysine; R 11 ~R 20 are each independently 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; R 2 is an n-pentanoyl group or an n-hexanoyl group, R 1 , X 1 , X 2 , and X 3 is absent, X 1is absent or selected from the group consisting of D-cysteine, L-cysteine, D-threonine, D-proline, L-proline, β-homoproline, 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, piperazin-2-one ring, norvaline, glycine, methionine, lysine, phenylalanine, tyrosine, glutamic acid, asparagine, aspartic acid, and acetylated norleucine; X 2 is absent or selected from the group consisting of D-threonine, D-proline, L-proline, β-homoproline, D-alanine, L-alanine, β-alanine, D-valine, L-valine, β-valine, D-leucine, L-leucine, β-leucine, D-isoleucine, L-isoleucine, β-isoleucine, piperazin-2-one ri...

Claims

1. A composition comprising a first compound and a second compound and / or a third compound, the first compound comprises a non-naturally occurring melanocortin analog comprising a sequence according to formula (I); X １ X ２ X ３ R １ R ２ R ３ R ４ R ５ R ６ R ７ R ８ R ９ R １０ R １１ R １２ R １３ R １４ R １５ R １６ R １７ R １８ R １９ R ２０ Y １ Y ２ Y ３ Y ４ Y ５ Y ６ Y ７ Y ８ (I) During the ceremony, R １ is absent or 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; R ２ is absent or 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); R ３ is 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), benzazepin-3-one (Bbe ... β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mam), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetralin-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-cyclopentanecarboxy (Cpe), R ４ is 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); R ５ is absent or 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; R ６ is absent or selected from the group consisting of L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, NaI(1'), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R ７ is absent or 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); R ８ is absent or is lysine or arginine; R ９ is absent or is tryptophan, R １０ is absent or is lysine; R １１ ~R ２０ But he is absent, X １ is absent or 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; X ２ is absent or 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; X ３ is absent or 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; Y １ is absent or 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; Y ２ is absent or 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; Y ３ is absent or selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y ４ is absent or is D-proline or D-valine; Y ５ is absent or is D-proline or D-valine; Y ６ is absent or is D-proline or D-valine; Y ７ is absent or is D-proline or D-valine; Y ８ is absent or is D-proline or D-valine; the naturally occurring melanocortin analog is R １ or R ２ is cysteine ​​and R ７ or X １ is cysteine, R １ or R ２ and R ７ or X １ The disulfide bond between R ２ and R ５ ~R ２０ is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, then R ２ and the above R ５ ~R ２０ a disulfide bond between any one of R １ is norleucine, and R ７ is glutamic acid, R １ and R ７ The lactam bridge between R １ or R ２ is glutamic acid, aspartic acid, or CO-cis-CH=CH-CO, and R ７ is lysine or ornithine, R １ or R ２ and R ７ A side chain lactam bridge between R １ or R ２ is glutamic acid or aspartic acid, and R ８ is lysine and R ７ is proline, glycine, or tryptophan, R １ or R ２ and R ８ A side chain lactam bridge between R ２ is glutamic acid or aspartic acid, and R １０ is lysine, R ２ or R ４ and R １０ and a side chain lactam bridge between however, R ２ If is dAsp, then R ７ is not dLys, R ２ ~R ４ is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then R ５ ~R ７ is not Arg-Trp-Lys; Y １ is dPro, and Y ２ is dVal, and Y ３ ~Y ８ If is absent, R ４ is not dNal(2') or R ４ is dNal(2') and the C-terminus is unmodified; R ７ If Aia, then R ４ is dNal(2'), R ４ is p(I)dPhe and the non-naturally occurring melanocortin analog is R １ and R ７ When the compound is cyclized via a lactam bond between R ２ is His, R ２ ~R ７ is Asp-Pro-dNal(2')-Arg-Trp-Lys (SEQ ID NO: 661), then Y １ ~Y ２ is not dPro-dVal, The naturally occurring melanocortin analog is R ２ and R ８ and R ３ If is Pro, then R ７ But not Pro, Y １ is not a dPro, and When the naturally occurring melanocortin analog is linear, R ２ is not absent; the second compound comprises a structure according to formula (X) or a pharmaceutically acceptable salt thereof; 【Chemistry 1】 During the ceremony, Rx １ H, halogen, C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ cycloalkyl, 4- to 7-membered cycloalkyl, phenyl, or Rx １ａ and said C ３－６ cycloalkyl and each of said 4- to 7-membered cycloalkyls is selected from 1, 2, 3, or 4 independently selected C １－４ and wherein said phenyl is optionally substituted with 1, 2, 3, or 4 independently selected Rx Ｂ and Rx is optionally substituted with Ｂ But halogen, -OH, -CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C ３－４ Cycloalkyl, or Rx Ｂ１ or two adjacent Rx Ｂ together with the two ring-forming atoms of said phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which is independently halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ and 1, 2, or 3 optionally substituted substituents each independently selected from haloalkoxy; Rx １ａ but 1, 2, 3, or 4 independent Rx Ａ and each Rx is a 5- or 6-membered heteroaryl optionally substituted with Ａ But halogen, -OH, -CN, C １－４ Alkyl, C １－４ Haloalkyl, C １４ Alkoxy, C １－４ Haloalkoxy, C ３－４ Cycloalkyl, —N(C １－４ alkyl) ２ , Rx Ａ１ , or (C ３－４ Cycloalkyl)-C １４ alkyl-, and １４ alkyl, the C ３－４ Cycloalkyl, and the above (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ haloalkoxy, or two adjacent Rx Ａ are taken together with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached to 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 selected from the group consisting of halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx Ａ１ is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx Ｂ１ is a 5- or 6-membered heteroaryl, each of which is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx ２ and Rx ３ each independently represents H, halogen, C １－４ Alkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkyl, (C １－４ Alkoxy)-C １－４ Alkyl-, C ３－４ cycloalkyl, or (C ３－４ Cycloalkyl)-C １－４ alkyl, C ３－４ Cycloalkyl and (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Or Rx ２ and Rx ３ together with the carbon atoms to which they are attached, halogens, -OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ C optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy ３－６ forming a cycloalkyl, Each Rx ４ are independently H, halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, —N(C １－２ alkyl) ２ , C ３－４ cycloalkyl, or (C ３－４ Cycloalkyl)-C １－４ alkyl-, and １－４ alkyl, the C ３－４ Cycloalkyl, and the above (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Xx １ But C(Rx Ｘ ) ２ and each Rx Ｘ are independently H or C １－４ is alkyl, Yx １ , Yx ２ , Yx ３ , Yx ４ , and Yx ５ Each of the ４ or N, with the proviso that Yx １ , Yx ２ , Yx ３ , Yx ４ , and Yx ５ provided that no more than three of are N; The third compound is: 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) an LCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) an LCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) an LCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) an HCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) an HCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) an HCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 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 set forth in the amino acid sequence of SEQ ID NO: 166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences 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 with the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited with the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 166 Ｈ ), and a light chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:

163. Ｌ ), k) V comprising the amino acid sequence of SEQ ID NO: 166 Ｈ and V comprising the amino acid sequence of SEQ ID NO: 163 Ｌ , 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 GDF-15 n) A composition comprising an antibody or antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), including at least one of the following: an antibody that competes with at least one antibody from (a) to (m) above for binding to GDF-15.

2. A composition comprising a first compound and a second compound, the first compound comprises a non-naturally occurring melanocortin analog comprising a sequence according to formula (I), X １ X ２ X ３ R １ R ２ R ３ R ４ R ５ R ６ R ７ R ８ R ９ R １０ R １１ R １２ R １３ R １４ R １５ R １６ R １７ R １８ R １９ R ２０ Y １ Y ２ Y ３ Y ４ Y ５ Y ６ Y ７ Y ８ (I) During the ceremony, R １ is absent or 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; R ２ is absent or 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); R ３ is 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), benzazepin-3-one (Bbe ... β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mam), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetralin-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-cyclopentanecarboxy (Cpe), R ４ is 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); R ５ is absent or 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; R ６ is absent or selected from the group consisting of L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, NaI(1'), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R ７ is absent or 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); R ８ is absent or is lysine or arginine; R ９ is absent or is tryptophan, R １０ is absent or is lysine; R １１ ~R ２０ But he is absent, X １ is absent or 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; X ２ is absent or 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; X ３ is absent or 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; Y １ is absent or 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; Y ２ is absent or 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; Y ３ is absent or selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y ４ is absent or is D-proline or D-valine; Y ５ is absent or is D-proline or D-valine; Y ６ is absent or is D-proline or D-valine; Y ７ is absent or is D-proline or D-valine; Y ８ is absent or is D-proline or D-valine; the naturally occurring melanocortin analog is R １ or R ２ is cysteine ​​and R ７ or X １ is cysteine, R １ or R ２ and R ７ or X １ The disulfide bond between R ２ and R ５ ~R ２０ is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, then R ２ and the above R ５ ~R ２０ a disulfide bond between any one of R １ is norleucine, and R ７ is glutamic acid, R １ and R ７ The lactam bridge between R １ or R ２ is glutamic acid, aspartic acid, or CO-cis-CH=CH-CO, and R ７ is lysine or ornithine, R １ or R ２ and R ７ A side chain lactam bridge between R １ or R ２ is glutamic acid or aspartic acid, and R ８ is lysine and R ７ is proline, glycine, or tryptophan, R １ or R ２ and R ８ A side chain lactam bridge between R ２ is glutamic acid or aspartic acid, and R １０ is lysine, R ２ or R ４ and R １０ and a side chain lactam bridge between however, R ２ If is dAsp, then R ７ is not dLys, R ２ ~R ４ is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then R ５ ~R ７ is not Arg-Trp-Lys; Y １ is dPro, and Y ２ is dVal, and Y ３ ~Y ８ If is absent, R ４ is not dNal(2') or R ４ is dNal(2') and the C-terminus is unmodified; R ７ If Aia, then R ４ is dNal(2'), R ４ is p(I)dPhe and the non-naturally occurring melanocortin analog is R １ and R ７ When the compound is cyclized via a lactam bond between R ２ is His, R ２ ~R ７ is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y １ ~Y ２ is not dPro-dVal, The naturally occurring melanocortin analog is R ２ and R ８ and R ３ If is Pro, then R ７ But not Pro, Y １ is not a dPro, and When the naturally occurring melanocortin analog is linear, R ２ is not absent; said second compound having a structure according to formula (X) or a pharmaceutically acceptable salt thereof; 【Chemistry 2】 During the ceremony, Rx １ H, halogen, C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ cycloalkyl, 4- to 7-membered cycloalkyl, phenyl, or Rx １ａ and said C ３－６ cycloalkyl and each of said 4- to 7-membered cycloalkyls is selected from 1, 2, 3, or 4 independently selected C １－４ and wherein said phenyl is optionally substituted with 1, 2, 3, or 4 independently selected Rx Ｂ and Rx is optionally substituted with Ｂ But halogen, -OH, -CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C ３－４ Cycloalkyl, or Rx Ｂ１ or two adjacent Rx Ｂ together with the two ring-forming atoms of said phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which is independently halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ and 1, 2, or 3 optionally substituted substituents each independently selected from haloalkoxy; Rx １ａ but 1, 2, 3, or 4 independent Rx Ａ and each Rx is a 5- or 6-membered heteroaryl optionally substituted with Ａ But halogen, -OH, -CN, C １－４ Alkyl, C １－４ Haloalkyl, C １４ Alkoxy, C １－４ Haloalkoxy, C ３－４ Cycloalkyl, —N(C １－４ alkyl) ２ , Rx Ａ１ , or (C ３－４ Cycloalkyl)-C １４ alkyl-, and １４ alkyl, the C ３－４ Cycloalkyl, and the above (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ haloalkoxy, or two adjacent Rx Ａ are taken together with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached to 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 selected from the group consisting of halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx Ａ１ is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx Ｂ１ is a 5- or 6-membered heteroaryl, each of which is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx ２ and Rx ３ each independently represents H, halogen, C １－４ Alkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkyl, (C １－４ Alkoxy)-C １－４ Alkyl-, C ３－４ cycloalkyl, or (C ３－４ Cycloalkyl)-C １－４ alkyl, C ３－４ Cycloalkyl and (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Or Rx ２ and Rx ３ together with the carbon atoms to which they are attached, halogens, -OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ C optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy ３－６ forming a cycloalkyl, Each Rx ４ are independently H, halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, —N(C １－２ alkyl) ２ , C ３－４ cycloalkyl, or (C ３－４ Cycloalkyl)-C １－４ alkyl-, and １－４ alkyl, the C ３－４ Cycloalkyl, and the above (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Xx １ But C(Rx Ｘ ) ２ and each Rx Ｘ are independently H or C １－４ is alkyl, Yx １ , Yx ２ , Yx ３ , Yx ４ , and Yx ５ Each of the ４ or N, with the proviso that Yx １ , Yx ２ , Yx ３ , Yx ４ , and Yx ５ provided that no more than three of are N.

3. A composition comprising a first compound and a third compound, the first compound comprises a non-naturally occurring melanocortin analog comprising a sequence according to formula (I), X １ X ２ X ３ R １ R ２ R ３ R ４ R ５ R ６ R ７ R ８ R ９ R １０ R １１ R １２ R １３ R １４ R １５ R １６ R １７ R １８ R １９ R ２０ Y １ Y ２ Y ３ Y ４ Y ５ Y ６ Y ７ Y ８ (I) During the ceremony, R １ is absent or 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; R ２ is absent or 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); R ３ is 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), benzazepin-3-one (Bbe ... β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mam), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetralin-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-cyclopentanecarboxy (Cpe), R ４ is 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); R ５ is absent or 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; R ６ is absent or selected from the group consisting of L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, NaI(1'), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R ７ is absent or 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); R ８ is absent or is lysine or arginine; R ９ is absent or is tryptophan, R １０ is absent or is lysine; R １１ ~R ２０ But he is absent, X １ is absent or 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; X ２ is absent or 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; X ３ is absent or 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; Y １ is absent or 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; Y ２ is absent or 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; Y ３ is absent or selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y ４ is absent or is D-proline or D-valine; Y ５ is absent or is D-proline or D-valine; Y ６ is absent or is D-proline or D-valine; Y ７ is absent or is D-proline or D-valine; Y ８ is absent or is D-proline or D-valine; the naturally occurring melanocortin analog is R １ or R ２ is cysteine ​​and R ７ or X １ is cysteine, R １ or R ２ and R ７ or X １ The disulfide bond between R ２ and R ５ ~R ２０ is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, then R ２ and the above R ５ ~R ２０ a disulfide bond between any one of R １ is norleucine, and R ７ is glutamic acid, R １ and R ７ The lactam bridge between R １ or R ２ is glutamic acid, aspartic acid, or CO-cis-CH=CH-CO, and R ７ is lysine or ornithine, R １ or R ２ and R ７ A side chain lactam bridge between R １ or R ２ is glutamic acid or aspartic acid, and R ８ is lysine and R ７ is proline, glycine, or tryptophan, R １ or R ２ and R ８ A side chain lactam bridge between R ２ is glutamic acid or aspartic acid, and R １０ is lysine, R ２ or R ４ and R １０ and a side chain lactam bridge between however, R ２ If is dAsp, then R ７ is not dLys, R ２ ~R ４ is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then R ５ ~R ７ is not Arg-Trp-Lys; Y １ is dPro, and Y ２ is dVal, and Y ３ ~Y ８ If is absent, R ４ is not dNal(2') or R ４ is dNal(2') and the C-terminus is unmodified; R ７ If Aia, then R ４ is dNal(2'), R ４ is p(I)dPhe and the non-naturally occurring melanocortin analog is R １ and R ７ When the compound is cyclized via a lactam bond between R ２ is His, R ２ ~R ７ is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y １ ~Y ２ is not dPro-dVal, The naturally occurring melanocortin analog is R ２ and R ８ and R ３ If is Pro, then R ７ But not Pro, Y １ is not a dPro, and When the naturally occurring melanocortin analog is linear, R ２ is not absent; The third compound is as follows: 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) an LCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) an LCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) an LCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) an HCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) an HCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) an HCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 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 set forth in the amino acid sequence of SEQ ID NO: 166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences 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 with the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited with the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 166 Ｈ ), and a light chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:

163. Ｌ ), k) V comprising the amino acid sequence of SEQ ID NO: 166 Ｈ and V comprising the amino acid sequence of SEQ ID NO: 163 Ｌ , 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) A composition comprising an antibody or antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), including at least one of the following: an antibody that competes with at least one antibody from (a) to (m) above for binding to GDF-15.

4. A composition comprising a first compound, a second compound, and a third compound, the first compound comprises a non-naturally occurring melanocortin analog comprising a sequence according to formula (I), X １ X ２ X ３ R １ R ２ R ３ R ４ R ５ R ６ R ７ R ８ R ９ R １０ R １１ R １２ R １３ R １４ R １５ R １６ R １７ R １８ R １９ R ２０ Y １ Y ２ Y ３ Y ４ Y ５ Y ６ Y ７ Y ８ (I) During the ceremony, R １ is absent or 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; R ２ is absent or 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); R ３ is 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), benzazepin-3-one (Bbe ... β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mam), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetralin-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-cyclopentanecarboxy (Cpe), R ４ is 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); R ５ is absent or 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; R ６ is absent or selected from the group consisting of L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, NaI(1'), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R ７ is absent or 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); R ８ is absent or is lysine or arginine; R ９ is absent or is tryptophan, R １０ is absent or is lysine; R １１ ~R ２０ But he is absent, X １ is absent or 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; X ２ is absent or 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; X ３ is absent or 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; Y １ is absent or 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; Y ２ is absent or 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; Y ３ is absent or selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y ４ is absent or is D-proline or D-valine; Y ５ is absent or is D-proline or D-valine; Y ６ is absent or is D-proline or D-valine; Y ７ is absent or is D-proline or D-valine; Y ８ is absent or is D-proline or D-valine; the naturally occurring melanocortin analog is R １ or R ２ is cysteine ​​and R ７ or X １ is cysteine, R １ or R ２ and R ７ or X １ The disulfide bond between R ２ and R ５ ~R ２０ is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, then R ２ and the above R ５ ~R ２０ a disulfide bond between any one of R １ is norleucine, and R ７ is glutamic acid, R １ and R ７ The lactam bridge between R １ or R ２ is glutamic acid, aspartic acid, or CO-cis-CH=CH-CO, and R ７ is lysine or ornithine, R １ or R ２ and R ７ A side chain lactam bridge between R １ or R ２ is glutamic acid or aspartic acid, and R ８ is lysine and R ７ is proline, glycine, or tryptophan, R １ or R ２ and R ８ A side chain lactam bridge between R ２ is glutamic acid or aspartic acid, and R １０ is lysine, R ２ or R ４ and R １０ and a side chain lactam bridge between however, R ２ If is dAsp, then R ７ is not dLys, R ２ ~R ４ is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then R ５ ~R ７ is not Arg-Trp-Lys; Y １ is dPro, and Y ２ is dVal, and Y ３ ~Y ８ If is absent, R ４ is not dNal(2') or R ４ is dNal(2') and the C-terminus is unmodified; R ７ If Aia, then R ４ is dNal(2'), R ４ is p(I)dPhe and the non-naturally occurring melanocortin analog is R １ and R ７ When the compound is cyclized via a lactam bond between R ２ is His, R ２ ~R ７ is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y １ ~Y ２ is not dPro-dVal, The naturally occurring melanocortin analog is R ２ and R ８ and R ３ If is Pro, then R ７ But not Pro, Y １ is not a dPro, and When the naturally occurring melanocortin analog is linear, R ２ is not absent; said second compound having a structure according to formula (X) or a pharmaceutically acceptable salt thereof; 【Transformation 3】 During the ceremony, Rx １ H, halogen, C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ cycloalkyl, 4- to 7-membered cycloalkyl, phenyl, or Rx １ａ and said C ３－６ cycloalkyl and each of said 4- to 7-membered cycloalkyls is selected from 1, 2, 3, or 4 independently selected C １－４ and wherein said phenyl is optionally substituted with 1, 2, 3, or 4 independently selected Rx Ｂ and Rx is optionally substituted with Ｂ But halogen, -OH, -CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C ３－４ Cycloalkyl, or Rx Ｂ１ or two adjacent Rx Ｂ together with the two ring-forming atoms of said phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which is independently halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ and 1, 2, or 3 optionally substituted substituents each independently selected from haloalkoxy; Rx １ａ but 1, 2, 3, or 4 independent Rx Ａ and each Rx is a 5- or 6-membered heteroaryl optionally substituted with Ａ But halogen, -OH, -CN, C １－４ Alkyl, C １－４ Haloalkyl, C １４ Alkoxy, C １－４ Haloalkoxy, C ３－４ Cycloalkyl, —N(C １－４ alkyl) ２ , Rx Ａ１ , or (C ３－４ Cycloalkyl)-C １４ alkyl-, and １４ alkyl, the C ３－４ Cycloalkyl, and the above (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ haloalkoxy, or two adjacent Rx Ａ are taken together with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached to 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 selected from the group consisting of halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx Ａ１ is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx Ｂ１ is a 5- or 6-membered heteroaryl, each of which is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx ２ and Rx ３ each independently represents H, halogen, C １－４ Alkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkyl, (C １－４ Alkoxy)-C １－４ Alkyl-, C ３－４ cycloalkyl, or (C ３－４ Cycloalkyl)-C １－４ alkyl, C ３－４ Cycloalkyl and (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Or Rx ２ and Rx ３ together with the carbon atoms to which they are attached, halogens, -OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ C optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy ３－６ forming a cycloalkyl, Each Rx ４ are independently H, halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, —N(C １－２ alkyl) ２ , C ３－４ cycloalkyl, or (C ３－４ Cycloalkyl)-C １－４ alkyl-, and １－４ alkyl, the C ３－４ Cycloalkyl, and the above (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Xx １ But C(Rx Ｘ ) ２ and each Rx Ｘ are independently H or C １－４ is alkyl, Yx １ , Yx ２ , Yx ３ , Yx ４ , and Yx ５ Each of the ４ or N, with the proviso that Yx １ , Yx ２ , Yx ３ , Yx ４ , and Yx ５ provided that no more than three of are N; The third compound is as follows: 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) an LCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) an LCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) an LCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) an HCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) an HCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) an HCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 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 set forth in the amino acid sequence of SEQ ID NO: 166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences 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 with the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited with the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 166 Ｈ ), and a light chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:

163. Ｌ ), k) V comprising the amino acid sequence of SEQ ID NO: 166 Ｈ and V comprising the amino acid sequence of SEQ ID NO: 163 Ｌ , 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) A composition comprising an antibody or antigen-binding fragment thereof that specifically binds to human growth differentiation factor 15 (GDF-15), including at least one of the following: an antibody that competes with at least one antibody from (a) to (m) above for binding to GDF-15.

5. 5. The composition of any one of claims 1 to 4, wherein the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified with 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. 6. The composition of claim 5, wherein the N-terminus of the non-naturally occurring melanocortin analog, if present, is modified with an acyl group.

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

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

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

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

11. 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 to 4, wherein the N-terminus of the non-naturally occurring melanocortin analog, if present, is unmodified.

14. 5. The composition of any one of claims 1 to 4, wherein the C-terminus of the non-naturally occurring melanocortin analog is modified with a functional group selected from the group consisting of an amide group, an ester group, and an aldehyde group.

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

16. The composition of claim 15, wherein the amide group is an -NH alkylamide group or an -NH arylamide group.

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

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

19. The composition of any one of claims 1 to 4, wherein the C-terminus of the non-naturally occurring melanocortin analog is unmodified.

20. R １ is absent, and R ２ The composition according to any one of claims 1 to 4, wherein is D-aspartic acid.

21. X １ , X ２ , and X ３ 21. The composition of claim 20, wherein is absent.

22. R ４ The composition of any one of claims 1 to 4, wherein is not D-phenylalanine.

23. R ４ The composition according to any one of claims 1 to 4, wherein is dNal(2').

24. Y ３ ~Y ８ The composition of any one of claims 1 to 4, wherein:

25. Y １ is D-valine, and Y ２ is D-proline, or Y １ is D-proline, and Y ２ The composition of claim 24, wherein is D-valine.

26. Y ３ exists and Y ４ ~Y ８ The composition of any one of claims 1 to 4, wherein:

27. Y １ is D-valine or D-proline; Y ２ is D-valine or D-proline, and / or Y ３ The composition of claim 26, wherein is D-valine or D-proline.

28. Y １ is D-valine, and Y ２ is D-valine, and Y ３ is D-proline, Y １ is D-proline, and Y ２ is D-valine, and Y ３ is D-valine, Y １ is D-valine, and Y ２ is D-proline, and Y ３ is D-valine, or Y １ is D-proline, and Y ２ is D-valine, and Y ３ The composition of claim 26, wherein is D-proline.

29. Y ３ and Y ４ exists and Y ５ ~Y ８ The composition of any one of claims 1 to 4, wherein:

30. Y １ is D-valine or D-proline; Y ２ is D-valine or D-proline; Y ３ is D-valine or D-proline, and / or Y ４ 30. The composition of claim 29, wherein is D-valine or D-proline.

31. Y １ is D-valine, and Y ２ is D-valine, and Y ３ is D-valine, and Y ４ is D-proline, Y １ is D-proline, and Y ２ is D-valine, and Y ３ is D-valine, and Y ４ is D-valine, Y １ is D-valine, and Y ２ is D-proline, and Y ３ is D-valine, and Y ４ is D-valine, Y １ is D-valine, and Y ２ is D-valine, and Y ３ is D-proline, and Y ４ is D-valine, or Y １ is D-valine, and Y ２ is D-proline, and Y ３ is D-valine, and Y ４ 30. The composition of claim 29, wherein is D-proline.

32. R １ , R ２ , and R ７ exists and R ８ ~R ２０ is absent and said sequence of formula (I) is connected to R via a lactam bond ２ and R ７ The composition of any one of claims 1 to 4, wherein the compound is cyclized through

33. R １ is acetylated norleucine, R ２ is aspartic acid, R ３ is selected from the group consisting of proline, hydroxyproline, and hydroxy-D-proline; R ４ is D-Nal(2'), R ５ is arginine, R ６ is D-tryptophan or L-tryptophan; R ７ is lysine, Y １ is D-valine, and / or Y ２ The composition of claim 32, wherein is D-proline.

34. The sequence of formula (I) is Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 306, B07), or Ac-Nle-c(Asp-Hyp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 307, D3), wherein c is R ２ and R ７ 33. The composition of claim 32, which exhibits cyclization through:

35. R １ , R ２ , R ７ , and R ８ exists and R ９ ~R ２０ is absent and said sequence of formula (I) is connected to R via a lactam bond ２ and R ８ The composition of any one of claims 1 to 4, wherein the compound is cyclized through

36. R １ is acetylated norleucine, R ２ is aspartic acid, R ３ is selected from the group consisting of proline, hydroxyproline, hydroxy-D-proline, phenylalanine, and histidine; R ４ is histidine or D-Nal(2'), R ５ is D-Nal(2') or arginine; R ６ is selected from the group consisting of arginine, D-tryptophan, and L-tryptophan; R ７ is tryptophan or proline, R ８ is lysine, Y １ is selected from the group consisting of D-valine, D-leucine, and D-isoleucine, and / or Y ２ The composition of claim 35, wherein is D-proline.

37. The sequence of formula (I) is Ac-Nle- ｃ (Asp-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 308, D1), Ac-Nle- ｃ (Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dLeu-dPro-NH ２ (SEQ ID NO: 309, D1γ), Ac-Nle- ｃ (Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dTle-dPro-NH ２ (SEQ ID NO: 310, D1δ), Ac-Nle- ｃ (Asp-His-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 311, D2), and Ac-Nle- ｃ (Asp-Hyp-dNal(2')-Arg-Trp-Pro-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 312, D4), In the sequence, c is R via a lactam bond ２ and R ８ 36. The composition of claim 35, which exhibits cyclization through:

38. R １ ~R ２ and R ７ ~R １０ exists and R １１ ~R ２０ is absent and said sequence of formula (I) is connected to R via a lactam bond ２ and R １０ The composition of any one of claims 1 to 4, wherein the compound is cyclized through

39. The sequence of formula (I) is Ac-Nle- ｃ (Asp-Phe-Phe-Pro-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 313, D1α), wherein c is R via a lactam bond ２ and R １０ 39. The composition of claim 38, which exhibits cyclization through:

40. R １ ~R ２ and R ７ ~R １０ exists and R １１ ~R ２０ is absent and said sequence of formula (I) is connected to R via a lactam bond ４ and R １０ The composition of any one of claims 1 to 4, wherein the compound is cyclized through

41. The sequence of formula (I) is Ac-Nle-Phe-Phe-c(Asp-Phe-His-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 314, D1β), wherein c is R via a lactam bond ４ and R １０ 41. The composition of claim 40, which exhibits cyclization through:

42. 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 is an R bond via a lactam bond. ２ and R ７ 20. The composition of claim 19, which exhibits cyclization through:

43. The composition according to any one of claims 1 to 4, wherein said sequence of formula (I) is linear.

44. The sequence of formula (I) is Ac-Nle-Asp-Pro-dNal(2')-Arg-Trp-Lys-dVal-dPro-NH ２ (SEQ ID NO: 315, A1).

45. The sequence of formula (I) is Ac-dArg- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 316), Ac-dMet- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 317), Ac-dIle- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 318), Ac-dLeu- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 319), Ac-dVal- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 320), Ac-dAla- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 321), Ac-Ala- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 322), Ac-Tle- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 323), Ac-dTle- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 324), Ac-dNle- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 325), Ac-Nva- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 326), Ac-Gly- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 327), Ac-dPro- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 328), Ac-dCys- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 329), Ac-dPhe- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 330), Ac-dTyr- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 331), Ac-dGln- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 332), and Ac-dAsn- ｃ (Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 333), In the sequence, c is R via a lactam bond ２ and R ７ The composition of any one of claims 1 to 4, which exhibits cyclization through

46. The sequence of formula (I) is Ac-Nle-c(dAsp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 334), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-dLys)-dVal-dPro-NH ２ (SEQ ID NO: 335), Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH ２ (SEQ ID NO: 336), Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH ２ (SEQ ID NO: 337), Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH ２ (SEQ ID NO: 338), Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH ２ (SEQ ID NO: 339), Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH ２ (SEQ ID NO: 340), Ac-Nle-c(dCys-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH ２ (SEQ ID NO: 341), Ac-Nle-c(Cys-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH ２ (SEQ ID NO: 342), Ac-Nle-c(dCys-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH ２ (SEQ ID NO: 343), Ac-Nle-c(Cys-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH ２ (SEQ ID NO: 344), Ac-Nle-c(dCys-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH ２ (SEQ ID NO: 345), Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH ２ (SEQ ID NO: 346), Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH ２ (SEQ ID NO: 347), Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH ２ (SEQ ID NO: 348), Ac-Nle-c(dPen-Pro-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH ２ (SEQ ID NO: 349), Ac-Nle-c(dPen-Pro-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH ２ (SEQ ID NO: 350), Ac-Nle-c(Pen-Pro-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH ２ (SEQ ID NO: 351), Ac-Nle-c(Cys-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH ２ (SEQ ID NO: 352), Ac-Nle-c(dCys-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH ２ (SEQ ID NO: 353), Ac-Nle-c(Pen-dNal(2')-Arg-Trp-Cys)-dVal-dPro-NH ２ (SEQ ID NO: 354), Ac-Nle-c(Pen-dNal(2')-Arg-Trp-dCys)-dVal-dPro-NH ２ (SEQ ID NO: 355), Ac-Nle-c(Pen-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH ２ (SEQ ID NO: 356), Ac-Nle-c(dPen-dNal(2')-Arg-Trp-Pen)-dVal-dPro-NH ２ (SEQ ID NO: 357), Ac-Nle-c(dPen-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH ２ (SEQ ID NO: 358), Ac-Nle-c(Pen-dNal(2')-Arg-Trp-dPen)-dVal-dPro-NH ２ (SEQ ID NO: 359), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Orn)-dVal-dPro-NH ２ (SEQ ID NO: 360), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-dOrn)-dVal-dPro-NH ２ (SEQ ID NO: 361), Ac-Nle-c(Glu-Pro-dNal(2')-Arg-Trp-Orn)-dVal-dPro-NH ２ (SEQ ID NO: 362), and Ac-Nle-c(Glu-Pro-dNal(2')-Arg-Trp-dOrn)-dVal-dPro-NH ２ (SEQ ID NO: 363), In the sequence, c is R via a lactam bond or a disulfide bond ２ and R ６ or R ７ The composition of any one of claims 1 to 4, which exhibits cyclization through

47. The sequence of formula (I) is Ac-Nle-c(Asp-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 364), Ac-Nle-c(Asp-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 365), Ac-Nle-c(Asp-dPro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 366), Ac-Nle-c(Asp-dAla-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 367), Ac-Nle-c(Asp-dMet-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 368), Ac-Nle-c(Asp-Pro-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 369), Ac-Nle-c(Asp-Gly-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 370), Ac-Nle-c(Asp-Gly-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 371), Ac-Nle-c(Asp-Leu-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 372), Ac-Nle-c(Asp-Ile-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 373), and Ac-Nle-c(Asp-Val-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 374), In the sequence, c is R via a lactam bond ２ and R ７ The composition of any one of claims 1 to 4, which exhibits cyclization through

48. The sequence of formula (I) is Ac-Nle-c(Asp-Pro-dNal(2')-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 375), Ac-Nle-c(Asp-Pro-dNal(2')-Lys-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 376), Ac-Nle-c(Asp-Pro-dNal(2')-dLys-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 377), Ac-Nle-c(Asp-Pro-dNal(2')-dArg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 378), Ac-Nle-c(Asp-Pro-dNal(2')-Orn-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 379), Ac-Nle-c(Asp-Pro-dNal(2')-dOrn-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 380), Ac-Nle-c(Asp-Pro-dNal(2') -His-Trp-Lys)-dVal-dPro-NH ２ (Allocation number 381), Ac-Nle-c(Asp-Pro-dNal(2')-Ala-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 382), Ac-Nle-c(Asp-Pro-dNal(2')-Gly-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 383), Ac-Nle-c(Asp-Pro-dNal(2')-Asp-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 384), and Ac-Nle-c(Asp-Pro-dNal(2')-Glu-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 385), In the sequence, c is R via a lactam bond ２ and R ７ The composition of any one of claims 1 to 4, which exhibits cyclization through

49. The sequence of formula (I) is Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 386), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Nal(1')-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 387), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Aia-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 388), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Phe-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 389), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Tyr-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 390), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-His-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 391), and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Ala-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 392), In the sequence, c is R via a lactam bond ２ and R ７ The composition of any one of claims 1 to 4, which exhibits cyclization through

50. The sequence of formula (I) is Ac-Nle-c(Asp-Pro-Bip-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 393), wherein c is R ２ and R ７ The composition of any one of claims 1 to 4, which exhibits cyclization through

51. The sequence of formula (I) is Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Pro-NH ２ (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-NH ２ (SEQ ID NO: 397), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dHyp-NH ２ (SEQ ID NO: 398), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-Hyp-NH ２ (SEQ ID NO: 399), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-dHyp-NH ２ (SEQ ID NO: 400), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-dVal-NH ２ (SEQ ID NO: 401), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-dVal-NH ２ (SEQ ID NO: 402), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-Val-NH ２ (SEQ ID NO: 403), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-Val-NH ２ (SEQ ID NO: 404), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-NH ２ (SEQ ID NO: 405), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dPro-NH ２ (SEQ ID NO: 406), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-NH ２ (SEQ ID NO: 407), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-NH ２ (SEQ ID NO: 408), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Val-NH ２ (SEQ ID NO: 409), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Pro-NH ２ (SEQ ID NO: 410), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-NH ２ (SEQ ID NO: 411), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-NH ２ (SEQ ID NO: 412), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dHyp-NH ２ (SEQ ID NO: 413), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Hyp-NH ２ (SEQ ID NO: 414), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAla-dAla-NH ２ (SEQ ID NO: 415), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Ala-Ala-NH ２ (SEQ ID NO: 416), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Gly-Gly-NH ２ (SEQ ID NO: 417), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asp-NH ２ (SEQ ID NO: 418), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Arg-NH ２ (SEQ ID NO: 419), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-Asn-NH ２ (SEQ ID NO: 420), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsp-NH ２ (SEQ ID NO: 421), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dArg-NH ２ (SEQ ID NO: 422), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dAsn-NH ２ (SEQ ID NO: 423), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-dPro-NH ２ (SEQ ID NO: 424), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dPro-NH ２ (SEQ ID NO: 425), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-dPro-NH ２ (SEQ ID NO: 426), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-dPro-NH ２ (SEQ ID NO: 427), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dPro-NH ２ (SEQ ID NO: 428), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-dPro-NH ２ (SEQ ID NO: 429), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asp-NH ２ (SEQ ID NO: 430), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-NH ２ (SEQ ID NO: 431), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Asn-NH ２ (SEQ ID NO: 432), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsp-NH ２ (SEQ ID NO: 433), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-NH ２ (SEQ ID NO: 434), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dAsn-NH ２ (SEQ ID NO: 435), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-Pro-Val-NH ２ (SEQ ID NO: 436), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dPro-dVal-NH ２ (SEQ ID NO: 437), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dPro-dVal-NH ２ (SEQ ID NO: 438), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dPro-NH ２ (SEQ ID NO: 439), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dPro-NH ２ (SEQ ID NO: 440), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-Val-Pro-NH ２ (SEQ ID NO: 441), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Lys-dVal-dPro-NH ２ (SEQ ID NO: 442), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dLys-dVal-dPro-NH ２ (SEQ ID NO: 443), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-Pro-Val-NH ２ (SEQ ID NO: 444), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dPro-dVal-NH ２ (SEQ ID NO: 445), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dPro-dVal-NH ２ (SEQ ID NO: 446), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-Val-Pro-NH ２ (SEQ ID NO: 447), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Arg-dVal-dPro-NH ２ (SEQ ID NO: 448), and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dArg-dVal-dPro-NH ２ (SEQ ID NO: 449), In the sequence, c is R via a lactam bond ２ and R ７ The composition of any one of claims 1 to 4, which exhibits cyclization through

52. The sequence of formula (I) is Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dPro-NH ２ (SEQ ID NO: 450), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dPro-dVal-dPro-NH ２ (SEQ ID NO: 451), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dVal-dPro-NH ２ (SEQ ID NO: 452), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-dVal-dPro-NH ２ (SEQ ID NO: 453), and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dVal-dVal-dVal-dVal-dVal-dPro-NH ２ (SEQ ID NO: 454), In the sequence, c is R via a lactam bond ２ and R ７ The composition of any one of claims 1 to 4, which exhibits cyclization through

53. X １ is present, is an acetylated norleucine, and R １ The composition of any one of claims 1 to 4, wherein:

54. X ２ is present and is norleucine.

55. X ３ is present and is norleucine.

56. The sequence of formula (I) is Ac-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 455), Ac-Nle-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 456), and Ac-Nle-Nle-Nle-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 457), In the sequence, c is R via a lactam bond ２ and R ７ 54. The composition of claim 53, which exhibits cyclization through:

57. The sequence of formula (I) is Ac-Nle-c(Asp-Pro-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 458), Ac-Nle-c(Asp-Trp-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 459), Ac-Nle-c(Asp-Pro-dNal(2')-Arg-dTrp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 460), c(CO-cis-CH=CH-CO-Pro-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 461), Ac-Nle-c(Asp-Aba-dPhe-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 462), Ac-Nle-c(Asp-β-Ala-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 463), Ac-Nle-c(Asp-Mab-dNal(2′) -Arg-Trp-Lys)-dVal-dPro-NH ２ (Allocation number 464), Ac-Nle-c(Asp-Acpc-dNal(2')Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 465), Ac-c(Cys-Arg-dPhe-Cys)-Trp-dVal-dPro-NH ２ (SEQ ID NO: 466), and Ac-Nle-c(Asp-Pro-dNal(2')-Arg-Trp-Lys)-Trp-NH ２ (SEQ ID NO: 467), In the sequence, c is R via a lactam bond ２ and R ７ Or R ８ or via a disulfide bond ２ and R ５ The composition of any one of claims 1 to 4, which exhibits cyclization through

58. The sequence of formula (I) is Ac-Nle-c(Asp-Aic-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 468), or Ac-Nle-c(Asp-Cpe-dNal(2')-Arg-Trp-Lys)-dVal-dPro-NH ２ (SEQ ID NO: 469), In the sequence, c is R via a lactam bond ２ and R ７ or R ８ The composition of any one of claims 1 to 4, which exhibits cyclization through

59. 5. 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 to 4, wherein the non-naturally occurring melanocortin analog comprises the sequence of SEQ ID NO:

306.

61. 61. The composition of any one of claims 1-2 and 4-60, wherein the second compound is a compound of formula (Xi), or a pharmaceutically acceptable salt thereof: 【Chemistry 4】

62. 62. The composition of any one of claims 1-2 and 4-61, wherein the second compound is a compound of formula (Xii), or a pharmaceutically acceptable salt thereof: 【Transformation 5】

63. Rx １ But Rx １ａ and Rx １ａ is 1, 2, 3, or 4 independently selected Rx Ａ and each Rx is a 6-membered heteroaryl optionally substituted with Ａ But halogen, -OH, -CN, C １－４ Alkyl, C １４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C ３－ C ４ cycloalkyl, or (C ３－４ Cycloalkyl)-C １４ alkyl-, and １－４ alkyl, the C ３－４ Cycloalkyl, and the above (C ３－４ alkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ haloalkoxy, or two adjacent Rx Ａ together 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 selected from the group consisting of halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １４ 63. The composition of any one of claims 1-2 and 4-62, optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy.

64. Rx １ａ is 1, 2, or 3 independently selected Rx Ａ and each Rx is pyrimidinyl optionally substituted with Ａ But halogen, -OH, -CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy, or C ３－４ 64. The composition of claim 63, wherein the alkyl is cycloalkyl.

65. Rx １ａ 65. The composition of claim 64, wherein is pyrimidin-2-yl.

66. Xx １ is CH ２ The composition of any one of claims 1 to 2, 4 to 61, and 63 to 65,

67. Rx ２ and Rx ３ each independently is H, F, or C １－４ The composition of any one of claims 1 to 2 and 4 to 66, wherein the alkyl is alkyl.

68. Rx ２ is methyl, and Rx ３ The composition of any one of claims 1-2 and 4-67, wherein is H.

69. Yx ３ is N and Yx １ , Yx ２ , Yx ４ , and Yx ５ each independently being CRx ４ The composition of any one of claims 1 to 2 and 4 to 68, wherein

70. Rx ４ are independently H, halogen, or C １－２ 70. The composition of claim 69, wherein the alkoxy group is alkoxy.

71. The second compound is (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-naphthyridin-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-naphthyridin-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-naphthyridin-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-naphthyridin-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-naphthyridin-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-naphthyridin-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-naphthyridin-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-naphthyridin-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-naphthyridin-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- ２ H ２ ) pyrimidin-2-yl)-3,4-dihydro-1H-spiro(1,8-naphthyridin-2,3′-pyrrolidin)-1′-yl}propan-1-one, The composition according to any one of claims 1 to 2 and 4, wherein the compound is selected from the group consisting of:

72. The composition of any one of claims 1 to 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-naphthyridin-2,3'-pyrrolidin)-1'-yl)propan-1-one, or a pharmaceutically acceptable salt thereof.

73. 5. The composition of any one of claims 1-4, 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-naphthyridin-2,3'-pyrrolidin)-1'-yl)propan-1-one.

74. The antibody or antigen-binding fragment thereof is IgA １ , IgA ２ , IgD, IgE, IgM, IgG １ , IgG ２ , IgG ３ , or IgG ４ 74. The composition of any one of claims 1 and 3 to 73, comprising a human Fc domain selected from the group consisting of the Fc domains of:

75. The antibody or antigen-binding fragment thereof has a K of 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. Ｄ 75. The composition of any one of claims 1 and 3 to 74, which binds to human GDF-15 or cynomolgus GDF-15 at 1000 ribonucleotides.

76. 76. The composition of any one of claims 1 and 3-75, wherein the antibody or antigen-binding fragment thereof comprises the 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, 23 24, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10, and 162.

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

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

79. 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 platinum coordination complexes, antimetabolites, tubulin binding agents, alkylating antitumor agents, and cytotoxic antibiotics.

80. 80. The composition of claim 79, wherein the platinum coordination complex is cisplatin.

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

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

83. 80. The composition of claim 79, wherein the alkylating anti-tumor agent is cyclophosphamide.

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

85. The composition of any one of claims 1 to 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. 10. 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. 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 to 87, wherein the single pharmaceutical composition further comprises a pharmaceutically acceptable carrier and / or excipient.

90. 90. The composition of any one of claims 85 to 89, wherein the first compound is present in the single pharmaceutical composition at a concentration of 0.1 mg / mL to 50 mg / mL relative to the total volume of the single pharmaceutical composition.

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

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

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

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

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

97. 1. A composition comprising: a first compound having a primary therapeutic activity; and a second compound and / or a third compound, each having a secondary therapeutic activity; A composition, 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.

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

100. The naturally occurring melanocortin analog comprises a sequence according to formula (I): X １ X ２ X ３ R １ R ２ R ３ R ４ R ５ R ６ R ７ R ８ R ９ R １０ R １１ R １２ R １３ R １４ R １５ R １６ R １７ R １８ R １９ R ２０ Y １ Y ２ Y ３ Y ４ Y ５ Y ６ Y ７ Y ８ (I) During the ceremony, R １ is absent or 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; R ２ is absent or 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); R ３ is 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), benzazepin-3-one (Bbe ... β-alanine (β-Ala), 3-aminomethylbenzoic acid (Mam), 1-aminocyclo-propane-1-carboxylic acid (Acpc), 2-aminotetralin-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-cyclopentanecarboxy (Cpe), R ４ is 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); R ５ is absent or 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; R ６ is absent or selected from the group consisting of L-tryptophan, D-tryptophan, L-Nal(2'), Tic, Bip, arginine, histidine, cysteine, NaI(1'), Aia, phenylalanine, tyrosine, Pen, dPen, and alanine; R ７ is absent or 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); R ８ is absent or is lysine or arginine; R ９ is absent or is tryptophan, R １０ is absent or is lysine; R １１ ~R ２０ But he is absent, X １ is absent or 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; X ２ is absent or 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; X ３ is absent or 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; Y １ is absent or 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; Y ２ is absent or 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; Y ３ is absent or selected from the group consisting of D-proline, L-proline, D-valine, and L-valine; Y ４ is absent or is D-proline or D-valine; Y ５ is absent or is D-proline or D-valine; Y ６ is absent or is D-proline or D-valine; Y ７ is absent or is D-proline or D-valine; Y ８ is absent or is D-proline or D-valine; the naturally occurring melanocortin analog is R １ or R ２ is cysteine ​​and R ７ or X １ is cysteine, R １ or R ２ and R ７ or X １ The disulfide bond between R ２ and R ５ ~R ２０ is selected from the group consisting of D-cysteine, cysteine, Pen, and dPen, then R ２ and the above R ５ ~R ２０ a disulfide bond between any one of R １ is norleucine, and R ７ is glutamic acid, R １ and R ７ The lactam bridge between R １ or R ２ is glutamic acid, aspartic acid, or CO-cis-CH=CH-CO, and R ７ is lysine or ornithine, R １ or R ２ and R ７ A side chain lactam bridge between R １ or R ２ is glutamic acid or aspartic acid, and R ８ is lysine and R ７ is proline, glycine, or tryptophan, R １ or R ２ and R ８ A side chain lactam bridge between R ２ is glutamic acid or aspartic acid, and R １０ is lysine, R ２ or R ４ and R １０ and a side chain lactam bridge between however, R ２ If is dAsp, then R ７ is not dLys, R ２ ~R ４ is Asp-His-dNal(2'), Asp-Pro-dNal(2'), or Asp-Pro-dPhe, then R ５ ~R ７ is not Arg-Trp-Lys; Y １ is dPro, and Y ２ is dVal, and Y ３ ~Y ８ If is absent, R ４ is not dNal(2') or R ４ is dNal(2') and the C-terminus is unmodified; R ７ If Aia, then R ４ is dNal(2'), R ４ is p(I)dPhe and the non-naturally occurring melanocortin analog is R １ and R ７ When the compound is cyclized via a lactam bond between R ２ is His, R ２ ~R ７ is Asp-Pro-dNal(2')-Arg-Trp-Lys, then Y １ ~Y ２ is not dPro-dVal, The naturally occurring melanocortin analog is R ２ and R ８ and R ３ If is Pro, then R ７ But not Pro, Y １ is not a dPro, and When the naturally occurring melanocortin analog is linear, R ２ 100. The composition of any one of claims 97 to 99, provided that:

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

306.

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

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

104. The composition of any one of claims 97-103, wherein the spiro compound comprises a structure according to formula (X) or a pharmaceutically acceptable salt thereof: 【Transformation 6】 During the ceremony, Rx １ H, halogen, C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ cycloalkyl, 4- to 7-membered cycloalkyl, phenyl, or Rx １ａ and said C ３－６ cycloalkyl and each of said 4- to 7-membered cycloalkyls is selected from 1, 2, 3, or 4 independently selected C １－４ and wherein said phenyl is optionally substituted with 1, 2, 3, or 4 independently selected Rx Ｂ and Rx is optionally substituted with Ｂ But halogen, -OH, -CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C ３－４ Cycloalkyl, or Rx Ｂ１ or two adjacent Rx Ｂ together with the two ring-forming atoms of said phenyl to which they are attached form a fused 5- or 6-membered heteroaryl, each of which is independently halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ and 1, 2, or 3 optionally substituted substituents each independently selected from haloalkoxy; Rx １ａ but 1, 2, 3, or 4 independent Rx Ａ and each Rx is a 5- or 6-membered heteroaryl optionally substituted with Ａ But halogen, -OH, -CN, C １－４ Alkyl, C １－４ Haloalkyl, C １４ Alkoxy, C １－４ Haloalkoxy, C ３－４ Cycloalkyl, —N(C １－４ alkyl) ２ , Rx Ａ１ , or (C ３－４ Cycloalkyl)-C １４ alkyl-, and １４ alkyl, the C ３－４ Cycloalkyl, and the above (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ haloalkoxy, or two adjacent Rx Ａ are taken together with the two ring-forming atoms of the 5- or 6-membered heteroaryl to which they are attached to 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 selected from the group consisting of halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx Ａ１ is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocycloalkyl, each of which is selected from the group consisting of halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx Ｂ１ is a 5- or 6-membered heteroaryl, each of which is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, or 3 substituents each independently selected from haloalkoxy; Rx ２ and Rx ３ each independently represents H, halogen, C １－４ Alkyl, C １－４ Hydroxyalkyl, C １－４ Haloalkyl, (C １－４ Alkoxy)-C １－４ Alkyl-, C ３－４ cycloalkyl, or (C ３－４ Cycloalkyl)-C １－４ alkyl, C ３－４ Cycloalkyl and (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Or Rx ２ and Rx ３ together with the carbon atoms to which they are attached, halogens, -OH, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ C optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy ３－６ forming a cycloalkyl, Each Rx ４ are independently H, halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, —N(C １－２ alkyl) ２ , C ３－４ cycloalkyl, or (C ３－４ Cycloalkyl)-C １－４ alkyl-, and １－４ alkyl, the C ３－４ Cycloalkyl, and the above (C ３－４ Cycloalkyl)-C １－４ Each of the alkyl- is selected from halogen, —OH, —CN, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, and C １－４ optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from haloalkoxy; Xx １ But C(Rx Ｘ ) ２ and each Rx Ｘ are independently H or C １－４ is alkyl, Yx １ , Yx ２ , Yx ３ , Yx ４ , and Yx ５ Each of the ４ or N, with the proviso that Yx １ , Yx ２ , Yx ３ , Yx ４ , and Yx ５ The condition is that no more than three of the

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-naphthyridin-2,3'-pyrrolidin)-1'-yl)propan-1-one, or a pharmaceutically acceptable salt thereof.

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

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

108. the antibody or antigen-binding fragment thereof comprising: 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) an LCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 27, 36, 46, 55, 62, 82, 88, 95, 101, 129, 138, 150, 157, 174, and 184; c) an LCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 28, 37, 47, 70, 108, 114, 122, 130, 175, and 185; d) an LCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 9, 29, 38, 48, 63, 76, 89, 102, 176, and 186; e) an HCDR-1 amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 32, 41, 58, 66, 117, 125, 133, 153, 171, and 179; f) an HCDR-2 amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 33, 42, 51, 59, 67, 85, 92, 98, 105, 118, 126, 134, 141, 146, 165, 172, and 180; g) an HCDR-3 amino acid sequence selected from the group consisting of SEQ ID NOs: 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 set forth in the amino acid sequence of SEQ ID NO: 166, and the LCDR-1, LCDR-2, and LCDR-3 amino acid sequences 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 with the ATCC and having ATCC Accession No. PTA-125038, and the amino acid sequence encoded by the insert of the plasmid deposited with the ATCC and having ATCC Accession No. PTA-125039; j) a heavy chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 166 Ｈ ), and a light chain variable domain (V) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO:

163. Ｌ ), k) V comprising the amino acid sequence of SEQ ID NO: 166 Ｈ and V comprising the amino acid sequence of SEQ ID NO: 163 Ｌ , 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 with at least one antibody from (a) to (m) above for binding to GDF-15.

109. The composition of claim 108, wherein the antibody or antigen-binding fragment thereof comprises the 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, 23 24, 20, 13, 14, 15, 164, 95, 28, 9, 12, 163, 10, and 162.

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

111. 111. The composition of any one of claims 97-110, wherein the composition comprises fewer dosage units of the second compound and / or the third compound compared to dosage units of the second compound and / or dosage units of the third compound without the first compound.

112. 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 the dose of the second compound and / or the dose of the third compound without the first compound.

113. 113. The composition of any one of claims 97-112, wherein the composition comprises a shorter dosing regimen of the second compound and / or the third compound compared to a dosing regimen of the second compound and / or the third compound without the first compound.

114. 114. The composition of any one of claims 97-113, wherein the composition comprises a lower dosage of the second compound and / or the third compound compared to a dosage of the second compound and / or the third compound without the first compound.

115. 115. The composition of any one of claims 97 to 114, wherein the composition has an improved net effect on MC4R compared to the effect on MC4R of the second compound without the first compound and / or the effect on MC4R of the third compound.

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

117. 117. The method of claim 116, wherein the subject experiences an increase in appetite as measured by an increase in food intake of 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. 117. The method of claim 116, wherein the subject is not on a high carbohydrate, high calorie (HCHC) diet.

119. 119. The method of claim 118, wherein said HCHC diet comprises a daily food consumption providing at least 2000 kcal of calories, with at least 50% of said calories coming from carbohydrates.

120. 120. The method of any one of claims 116-119, wherein the subject is not on a high-fat, high-calorie (HFHC) diet.

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

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

123. the first compound is present in a first pharmaceutical composition; said second compound, if present, is present in a second pharmaceutical composition; 123. The method of any one of claims 116 to 122, wherein the third compound, if present, is in a third pharmaceutical composition.

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

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

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

127. 126. The method of claim 125, wherein the first pharmaceutical composition is administered before the first administration of the third pharmaceutical composition.

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

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

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

306.

133. 133. 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 of the subject's body weight.

134. 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 of body weight of the subject.

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

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

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

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

139. 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.

140. 139. 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. 141. The method of any one of claims 116-140, wherein the subject experiences a decreased appetite, reduced food consumption, and / or weight loss prior to said administration.

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

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

144. 144. The method of any one of claims 116-143, wherein the method (i) stimulates the appetite of the subject, (ii) increases food consumption by the subject, (iii) prevents or alleviates nausea, vomiting, and / or anorexia in the subject, (iv) increases or maintains the body weight of the subject, (v) prevents or reduces weight loss in the subject, (vi) increases or maintains muscle mass in the subject, (vii) prevents or reduces muscle mass loss in the subject, (viii) increases or maintains fat mass in the subject, and / or (ix) prevents or reduces fat mass loss in the subject.

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

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

147. 146. The method of claim 145, wherein the subject experiences a reduction in cancer metastasis as measured by a reduction in cancer cell proliferation of about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% compared to a control.

148. 1. A method of treating a subject having cancer, comprising: administering to the subject a composition according to any one of claims 77 to 96; The method reduces or prevents side effects associated with the anticancer agents of the combination therapy, wherein the side effects are at least one selected from the group consisting of cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

149. 1. A method of improving survival in a subject having cancer, comprising: administering to the subject a composition according to any one of claims 77 to 96; The method reduces or prevents side effects associated with the anticancer drugs of the combination therapy, thereby improving survival of the subject, wherein the side effects are at least one selected from the group consisting of cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

150. 116. A method of increasing the body weight of a subject relative to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

151. 151. The method of claim 150, wherein the subject experiences 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% increase in body weight compared to the control.

152. 116. A method of increasing muscle mass in a subject relative to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

153. 153. The method of claim 152, wherein the subject experiences an increase in muscle mass of 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. 116. A method of increasing fat mass in a subject relative to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

155. 155. The method of claim 154, wherein the subject experiences an increase in fat mass of 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. 116. A method of increasing myocardial mass in a subject compared to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

157. 157. The method of claim 156, wherein the subject experiences an increase in myocardial mass of 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. 116. A method of increasing bone mineral density in a subject relative to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

159. 159. The method of claim 158, wherein the subject experiences an increase in bone mineral density of 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. 116. A method of reducing fatigue in a subject relative to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

161. 116. A method of reducing vomiting in a subject relative to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

162. 116. A method of reducing diarrhea in a subject relative to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

163. 116. A method of increasing the cumulative amount in a subject compared to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

164. 164. The method of claim 163, wherein the subject experiences an increase in cumulative amount of 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. 116. A method of increasing net weight gain in a subject relative to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

166. 166. The method of claim 165, wherein the subject experiences an increase in net weight gain of 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. 116. A method of reducing the rate of cumulative mass decline in a subject compared to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

168. 168. The method of claim 167, wherein the subject experiences a reduction in the rate of decline in cumulative dose of 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.

169. 116. A method of increasing cumulative food intake in a subject relative to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

170. 170. The method of claim 169, wherein the subject experiences an increase in cumulative food intake of 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. 116. A method of increasing the body mass index (BMI) of a subject relative to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

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

173. 116. A method of reducing pro-inflammatory transcript or protein levels in a subject relative to a control, comprising administering to said subject a composition of any one of claims 1 to 115.

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

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

176. 175. The method of claim 173 or 174, wherein the pro-inflammatory protein is selected from the group consisting of IL1b protein, IL1R1 protein, IL6 protein, CCL2 protein, and GDF-15 protein.

177. 116. A method of increasing the Functional Assessment of Anorexia / Cachexia Therapy (FAACT) score in a subject compared to a control, comprising administering to the subject a composition according to any one of claims 1 to 115.

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

179. 116. A method of improving BMI endurance in a subject compared to a control, comprising administering to said subject a composition according to any one of claims 1 to 115.

180. 180. The method of claim 179, wherein the subject experiences an improvement 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. 181. The method of any one of claims 150 to 180, wherein the subject has cancer.

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

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

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

185. 185. The method of claim 184, wherein the subject experiences an increase in KPS score of about 100, 90, 80, 70, 60, 50, 40, or 30 compared to the control.

186. 116. A method of increasing overall survival (OS) in a subject having cancer compared to a control, comprising administering to said subject a composition of any one of claims 1 to 115.

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

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

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

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

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

192. 192. The method of any one of claims 116 to 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 to 115.

193. 150. The method of claim 148 or 149, wherein the subject is not on a high carbohydrate, high calorie (HCHC) diet.

194. 194. The method of claim 193, wherein said HCHC diet comprises a daily food consumption providing at least 2000 kcal of calories, with at least 50% of said calories coming from carbohydrates.

195. 195. The method of any one of claims 148-194, wherein the subject is not on a high-fat, high-calorie (HFHC) diet.

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

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

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

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

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

201. 200. The method of claim 198, wherein the first pharmaceutical composition is administered before the first administration of the second pharmaceutical composition.

202. 200. The method of claim 198, wherein the first pharmaceutical composition is administered before the first administration of the third pharmaceutical composition.

203. 200. The method of claim 198, wherein the first pharmaceutical composition is administered before the first administration of the fourth pharmaceutical composition.

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

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

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

306.

209. 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 of the subject's body weight.

210. 209. 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 of the subject's body weight.

211. 211. The method of any one of claims 148-210, wherein a therapeutically effective amount of the second compound is administered, wherein the therapeutically effective amount of the second compound is 10% to 75% less than the therapeutically effective amount of the second compound when administered alone.

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

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

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

215. 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. 215. 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 to 216, wherein the subject is a human.

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

219. 219. The method of any one of claims 148 to 218, wherein the method does not reduce the effectiveness of the anti-cancer agent.

220. The method of any one of claims 148 to 219 or 181 to 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 to 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. 222. The method of any one of claims 148-221, wherein the subject with cancer has previously been treated 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, the adverse side effects being selected from the group consisting of cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

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

225. 225. The method of claim 224, wherein administering one or more of the anticancer agents in higher amounts comprises administering increased doses, more frequent doses, extending the duration of the dosing regimen, and / or increasing the total number of doses administered to the subject.

226. 226. The method of any one of claims 148-225, wherein the one or more anti-cancer agents are dosed at at least 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. 227. The method of claim 226, wherein the one or more anti-cancer agents are dosed at at least 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. 227. The method of claim 226, wherein the one or more anti-cancer agents are dosed at at least 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. 227. The method of claim 226, wherein the one or more anti-cancer agents are dosed at at least 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. 227. The method of claim 226, wherein the one or more anti-cancer agents are dosed at at least 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. 227. The method of claim 226, wherein the one or more anti-cancer agents are dosed at at least 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. 227. The method of claim 226, wherein the one or more anti-cancer agents are dosed at at least 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. 233. The method of any one of claims 226-232, wherein the one or more anti-cancer agents comprises cisplatin.

234. 234. The method of any one of claims 148-233, wherein the method further comprises reducing or preventing one or more side effects in the subject and administering one or more of the anti-cancer agents in higher amounts, thereby increasing the effectiveness of the one or more anti-cancer agents in the subject.

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

236. 116. Use of a composition according to any one of claims 1 to 115 for increasing appetite in a subject in need thereof.

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

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

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

241. 116. Use of a composition according to any one of claims 1 to 115 to increase the survival rate of a subject with cancer compared to a control.

242. 116. Use of a composition according to any one of claims 1 to 115 to increase the body weight of a subject compared to a control.

243. 243. The use of claim 242, wherein the subject experiences about a 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% increase in body weight compared to the control.

244. 116. Use of a composition according to any one of claims 1 to 115 to increase muscle mass in a subject compared to a control.

245. The use of claim 244, wherein the subject experiences an increase in muscle mass of 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. 116. Use of a composition according to any one of claims 1 to 115 to increase fat mass in a subject compared to a control.

247. The use of claim 246, wherein the subject experiences an increase in fat mass of 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. 116. Use of a composition according to any one of claims 1 to 115 to increase myocardial mass in a subject compared to a control.

249. The use of claim 248, wherein the subject experiences an increase in myocardial mass of 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. 116. Use of a composition according to any one of claims 1 to 115 for increasing bone mineral density in a subject compared to a control.

251. The use of claim 250, wherein the subject experiences an increase in bone mineral density of 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. 116. Use of a composition according to any one of claims 1 to 115 to reduce fatigue in a subject compared to a control.

253. 116. Use of a composition according to any one of claims 1 to 115 to reduce vomiting in a subject compared to a control.

254. 116. Use of a composition according to any one of claims 1 to 115 to reduce diarrhea in a subject compared to a control.

255. Use of a composition according to any one of claims 1 to 115 to increase the cumulative amount in a subject compared to a control.

256. The use of claim 255, wherein the subject experiences an increase in cumulative amount of 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. 116. Use of a composition according to any one of claims 1 to 115 to increase 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 of 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 a composition according to any one of claims 1 to 115 to reduce the rate of decline in 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 decline in cumulative dose of 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.

261. 116. Use of a composition according to any one of claims 1 to 115 to increase the cumulative food intake of a subject compared to a control.

262. The use of claim 261, wherein the subject experiences an increase in cumulative food intake of 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. 116. Use of a composition according to any one of claims 1 to 115 to increase the BMI of a subject compared to a control.

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

265. 116. Use of a composition according to any one of claims 1 to 115 to reduce pro-inflammatory transcript or protein levels in a subject compared to a control.

266. The use of claim 265, wherein the subject experiences a reduction in inflammatory transcript or protein levels of 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 pro-inflammatory transcript is selected from the group consisting of an IL1b transcript, and an IL1R1 transcript, an IL6 transcript, a CCL2 transcript, and a GDF-15 transcript.

268. The use of claim 265 or 266, wherein the pro-inflammatory protein is selected from the group consisting of IL1b protein, IL1R1 protein, IL6 protein, CCL2 protein, and GDF-15 protein.

269. 116. Use of a composition according to any one of claims 1 to 115 to increase the FAACT score of a subject compared to a control.

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

271. 116. Use of a composition according to any one of claims 1 to 115 to improve BMI durability in a subject compared to a control.

272. The use of claim 271, wherein the subject experiences an improvement in BMI endurance 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 to 272, wherein the subject has cancer.

274. 116. Use of a composition according to any one of claims 1 to 115 to reduce or maintain the ECOG performance status score of a subject with cancer compared to a control.

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

276. 116. Use of a composition according to any one of claims 1 to 115 to increase or maintain the KPS score of a subject with cancer compared to a control.

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

278. 116. Use of a composition according to any one of claims 1 to 115 to increase OS in a subject with cancer compared to a control.

279. The use of claim 278, wherein the subject experiences an increase in OS of at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, or 100% compared to a control.

280. 116. Use of a composition according to any one of claims 1 to 115 for increasing PFS in a subject with cancer compared to a control.

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

282. 116. Use of a composition according to any one of claims 1 to 115 to reduce the time to cancer treatment failure in a subject with cancer compared to a control.

283. The use of claim 282, wherein the subject experiences a reduction in time to cancer treatment failure of 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 to 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 to 115.

285. 242. The use of any one of claims 236 to 241, wherein the subject is not on a high carbohydrate, high calorie (HCHC) diet.

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

287. The use of any one of claims 236 to 286, wherein the subject is not on a high-fat, high-calorie (HFHC) diet.

288. 288. The use of claim 287, wherein the HFHC diet comprises a daily food consumption providing at least 2000 kcal of calories, with at least 50% of the calories coming from fat.

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

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

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

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

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

294. 293. The use of claim 292, wherein the first pharmaceutical composition is administered before the first administration of the third pharmaceutical composition.

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

296. 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.

297. 293. The use of claim 292, wherein the first pharmaceutical composition and the third pharmaceutical composition are administered sequentially within about 24 hours.

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

306.

300. 300. The use of any one of claims 236 to 299, wherein the first compound is administered at least once daily in an amount ranging from 0.001 mg / kg to 25 mg / kg of body weight of the subject.

301. 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 of body weight of the subject.

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

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

304. 304. The use of any one of claims 236 to 303, wherein a therapeutically effective amount of the third compound is administered, wherein the therapeutically effective amount of the third compound is 10% to 75% less than the therapeutically effective amount of the third compound when administered alone.

305. 305. The use of any one of claims 236 to 304, wherein a therapeutically effective amount of the third compound is administered, wherein the therapeutically effective amount of the third compound is 25% to 50% less than the therapeutically effective amount of the third compound when administered alone.

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

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

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

311. 311. The use of any one of claims 236 to 310, wherein the use (i) stimulates the appetite of the subject, (ii) increases food consumption by the subject, (iii) prevents or alleviates nausea, vomiting, and / or anorexia in the subject, (iv) increases or maintains the body weight of the subject, (v) prevents or reduces weight loss in the subject, (vi) increases or maintains muscle mass in the subject, (vii) prevents or reduces muscle mass loss in the subject, (viii) increases or maintains fat mass in the subject, and / or (ix) prevents or reduces fat mass loss in the subject.

312. The use of any one of claims 236 to 311, wherein the use reduces or prevents side effects associated with the anticancer agents of the combination therapy, and the side effects are 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 to 312, wherein the use reduces or prevents side effects associated with the anticancer agents of the combination therapy, thereby improving survival of the subject, and the side effects are at least one selected from the group consisting of cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

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

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

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

317. The use of any one of claims 236 to 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 to 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. 319. The use of any one of claims 236 to 318, wherein the subject with cancer has previously been treated with the anti-cancer agent.

320. The use of claim 319, wherein the subject has previously experienced one or more adverse side effects when treated with the anti-cancer agent, the adverse side effects being selected from the group consisting of cachexia, anorexia, weight loss, fat mass loss, and muscle mass loss.

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

322. The use of claim 321, wherein administering one or more of the anticancer agents in higher amounts comprises administering increased doses, more frequent doses, extending the duration of the dosing regimen, and / or increasing the total number of doses administered to the subject.

323. 323. The use of any one of claims 236-322, wherein the one or more anti-cancer agents are dosed at at least 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. 324. The use of claim 323, wherein the one or more anti-cancer agents are dosed at at least 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. 324. The use of claim 323, wherein the one or more anti-cancer agents are dosed at at least 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. 324. The use of claim 323, wherein the one or more anti-cancer agents are dosed at at least 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.

327. 324. The use of claim 323, wherein the one or more anti-cancer agents are dosed at at least 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. 324. The use of claim 323, wherein the one or more anti-cancer agents are dosed at at least 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. 324. The use of claim 323, wherein the one or more anti-cancer agents are dosed at at least 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. 330. The use of any one of claims 236 to 329, wherein the one or more anti-cancer agents comprises cisplatin.

331. 331. The use of any one of claims 236 to 330, wherein said use further comprises reducing or preventing one or more side effects in said subject, allowing one or more of said anti-cancer agents to be administered in higher amounts, thereby increasing the effectiveness of one or more of said anti-cancer agents in said subject.

332. 332. The use of any one of claims 236 to 331, wherein said use increases the effectiveness of said anti-cancer agent.

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