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United States Patent (19) 11 Patent Number: 5,049,655 Vaughan Et Al

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United States Patent (19) 11 Patent Number: 5,049,655 Vaughan Et Al United States Patent (19) 11 Patent Number: 5,049,655 Vaughan et al. (45) Date of Patent: Sep. 17, 1991 54 MELANIN-CONCENTRATING HORMONES Nervous System of Rat, Guinea-Pig, Pig and Man', (75) Inventors: Joan Vaughan, San Diego; Wolfgang Neuroscience 25925 (1988). H. Fischer, Solano Beach; Jean E. F. Alex N. Eberle, “The Melanotropins', Chapters 15, 16, Rivier, La Jolla; Jean-Louis M. and 20, Karger Publishing Company (1988). Nahon; Francoise G. Presse, both of Primary Examiner-Margaret Moskowitz San Diego; Wylie W. Vale, Jr., La Assistant Examiner-Nina Ossanna Jolla, all of Calif. Attorney, Agent, or Firm-Fitch, Even, Tabin & (73) Assignee: The Salk Institute for Biological Flannery Studies, San Diego, Calif. 21 Appl. No.: 326,984 57 ABSTRACT Mammalian melanin-concentrating hormone (MCH) is 22 Filed: Mar. 22, 1989 isolated from rat tissue, purified and characterized. (51) Int. Cl. ......................... C07K 7/64; C12N 15/16 These MCH peptides are useful for treating skin disor 52 U.S.C. ...................................... 530/326; 536/27; ders, for suppressing the proliferation of skin tumor 530/827; 530/854; 435/69.4; 435/320.1 cells, such as melanomas in mammals, and for modulat 58 Field of Search ....................... 530/326, 827, 854; ing the secretion of ACTH. Generally, peptides are 536/27; 435/69.4, 320.1 provided which have the following formula: (56) References Cited PUBLICATIONS h–Ap-r-ap-Me-la-A-G-Me- Leu Young and Davis, "Efficient Isolation of Genes by Using Antibody Probes', Proc. Natl. Acad. Sci. U.S.A., Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Gln-Val-OH, vol. 80 pp. 1194-1198 (3/83). Zamir et al., "Melanin-Concentrating Hormone: or which are naturally occurring homologs of the pep Unique Peptide Neuronal System in the Rat Brain and tide with said formula. The peptides which are the natu Pituitary Gland', Proc. Natl. Acad. Sci. U.S.A. 83, pp. rally occurring MCH homologs of mammalian species 1528-1531, 3/86. Kawauchi et al., "Characterization of Melanin-Concen other than rat can also be obtained using the materials trating Hormone in Chum Salmon Pituitaries', Nature, disclosed, as demonstrated specifically with human vol. 305 pp. 321-323 (9/22/83). MCH, which is found to have the same structure as rat White et al., Principles of Biochemistry Sixth Ed. p. 829 MCH. Also disclosed are the amino acid sequences of, (1978). and the nucleotide sequences of the cDNAs which Scopes, Protein Purification Second Ed. pp. 167–172 encode, the putative precursors of rat MCH and human (1987). MCH. These precursors may also include one or more Wilkes, et al., "Synthesis and Biological Actions of biologically active peptides N-terminally of the mature Melanin Concentrating Hormone', Biochemical and MCH's. Among these peptides, which are thought to be Biophysical Research Communications 122, 613-619 formed from the MCH precursors, are the peptide with (1984). Baker, et al., "Further Observations on the the sequence H-Glu-Ile-Gly-Asp-Glu-Glu-Asn-Ser Distribution and Properties of Teleost Melanin Concen Ala-Lys-Phe-Pro-Ile-NH2, which is cross-reactive with trating Hormone', General and Comparative Endocrinol antibodies against alpha-MSH and CRF, and the pep ogy 50, 423 (1983). tide with the sequence H-Gly-XNGE-Phe-Pro-Ala-Glu Naito, et al., "Melanin-Concentrating Hormone-Like Asn-Gly-Val-Gln-Asn-Thr-Glu-Ser-Thr-Gln-Glu-OH, Immunoreactive Material in the Rat Hypothalamus; wherein XNGE is Pro-Ala-Val or Ser-Val-Ala, which is Characterization and Subcellular Localization', Cell cross-reactive with antibodies against GRF. and Tissue Research 253, 291-295 (1988). Sekiya, et al., "The Distribution of Melanin-Concen trating Hormone-Like Immunoreactivity in the Central 5 Claims, No Drawings 5,049,655 1 . 2 as a result of the isolation and then sequencing of the MELANIN-CONCENTRATING HORMONES cDNA's, which were made possible by the isolation and sequencing of the mature rat peptide, it was possible to This invention was made with Government support determine that the C-terminus of the native MCH pep under Grants DK-26741 and HD-13527 awarded by the tide is in the free acid form. National Institutes of Health. The Government has The amino acid sequences of the mature MCH's of rat certain rights in the invention. and human, as determined by the sequencing of the This invention relates to hormones for concentrating mature rat peptide and deduced from the sequences of melanin in mammals and to methods of treating man the cDNA segments encoding the hormones, are identi mals using such hormones. 10 cal. Further, of the 54 base pairs in these DNA seg ments, differences in sequence occur at only three posi BACKGROUND OF THE INVENTION tions. The identity of amino acid sequences and close A cyclic heptadecapeptide which induces melano homology in cDNA sequences indicate that all mamma Some aggregation within fish melanophores was iso lian mature MCH's have sequences that are closely lated from salmon pituitary glands, see Kawauchi, H. et 15 similar. al., Nature, 305, 321-323 (1983), and it was named mela Further, from the sequencing of the cDNAs encod nin concentrating hormone (MCH). Fish MCH has ing the MCH precursors, it has been found that there is been reported to have the opposite effect, i.e., causing very close homology between the cDNA sequences and dispersal of melanosomes, in amphibians, Wilkes, B. C. the corresponding amino acid sequences. Indeed, both et al., B. B.R.C., 122, 613-619 (1984). MCH is believed 20 the rat and the human precursors have the same number to be synthesized in the neurons of the hypothalamus of amino acids, 165. and translocated into the neurohypophysial tissues. Inasmuch as it appears that there is very close homol MCH immunoactivity has been reported in hypothala ogy between the mature MCHs, MCH precursors, and mic extracts of the rat: Baker et al., Gen. Comp. Endo mRNAs enoding these proteins of mammalian species, crinol, 50, 423-431 (1983) ) and Naito, N. et al., Cell 25 it is believed that the DNA probes which are based Tissue Res., 253,291-295 (1988). Very crude extracts of upon the actual rat mature MCH peptide sequence (or an MCH-like substance from the rat hypothalamus other sequences provided herein using probes based on showed a generally parallel response to fish MCH in a that rat peptide sequence) will be effective in identify radioimmunoassay (RIA) using an antiserum directed ing clones with MCH-encoding or MCH precursor against salmon MCH, even though the material ap encoding cDNAs in libraries made with mRNAs ob peared to have distinct chromatographic properties and tained from appropriate tissue (e.g., hypothalamus) or showed multiple immunoreactive peaks, not all of cell lines of other mammalian species and thus will which showed bioactivity, Zamir, N. et al., P.N.A.S. permit the determination of the sequences, and conse USA. 83, 1,428-1,531 (1986); Sekiya, K. et al., Neurosci quently the synthesis and use, of the mature MCH of ence, 25, 925-930 (1988); Naito, N. et al., (1988) supra. 35 every mammalian species. Despite all of this work over a period of several Among the mammalian MCH's, the present invention years, the mammalian hormone remains unisolated and is especially concerned with the mature MCH having uncharacterized, and as a result, true testing of the bio the following structure: H-Asp-Phe-Asp-Met-Leu-Arg-Cys-Met Leu-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Gln-Val-OH- logical activity of mammalian MCH has not heretofore been possible. As a result, great efforts were made to 45 isolate, purify and then characterize and test mamma Reference in the present application to a "mammalian lian MCH. MCH' is to a mammalian mature MCH, unless the term is explicitly qualified to refer to a mammalian MCH SUMMARY OF THE INVENTION precursor. A mammalian MCH has now been isolated and puri Mammalian MCH is useful to treat humans and other fied from rat hypothalamus. Characterization of the mammals to lighten skin color, as by local or topical purified peptide shows that it is 19 amino acid residues application. It is also useful to suppress the proliferation in length and in cyclic form. of certain skin tumor cells, such as melanomas, when By the preparation of DNA probes based upon the suitably applied as by topical application or the like. It characterized sequence of the peptide, it was possible to 55 is also found that mammalian MCH can be used to locate cDNAs coding for mammalian MCH from li modulate the secretion of ACTH in humans and other braries made using rat and human hypothalamic mes mammals and thus can be used to modify the effects of senger RNA. By isolating the cDNAs from the positive stress, as by systemically administering an effective clones (i.e., those identified with the DNA probes as amount of mammalian MCH. harboring desired cDNAs) of the libraries, it was possi 60 The invention also comprehends a mammalian pep ble to obtain the sequences of the cDNAs and, by read tide, designated "NEI," for "neuropeptide N-terminal ing the sequences, confirm the precise sequence for the E C-terminal I" (E being the abbreviation for glutamic mature peptide of the rat, determine the precise se acid and I being the abbreviation for isoleucine), which quence for the mature peptide of the human, and also has as its sequence Glu-Ile-Gly-Asp-Glu-Glu-Asn-Ser deduce the sequences for the precursor peptides that are 65 Ala-Lys-Phe-Pro-Ile-NH2. A mammalian NEI is appar apparently originally expressed from the gene in the rat ently made in vivo in a mammal by processing begin and human cells of interest prior to (or simultaneously ning with the MCH precursor of the mammal.
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