MXPA96005651A

MXPA96005651A - New peptides with immune regulated effects

Info

Publication number: MXPA96005651A
Application number: MXPA/A/1996/005651A
Authority: MX
Inventors: Bergstrand Hakan; Lindvall Magnus; Sarnstrand Bengt; Eriksson Tomas
Original assignee: Astra Ab
Priority date: 1995-03-24
Filing date: 1996-11-18
Publication date: 1998-02-01

Abstract

Peptides that are absorbable by coating epithelial cells in a mammal, resulting in a modulated immune response and therefore a therapeutic effect against the disease, formulations containing such peptides and their

Description

NEW PEPTIDES WITH IMMUNE-REGULATING EFFECTS FIELD OF THE INVENTION The present invention relates to the non-specific immunoregulation of the antigen, including both immunosuppression and immunostimulation. In particular, the invention relates to peptides in unregulators which are capable of inducing an immunoregulatory response in mammals, and therefore u? therapeutic effect and its uses.

BACKGROUND OF THE INVENTION The immune system, when functioning properly, protects the individual from infection and growth of cancers. To perform these functions, you must be able to recognize and mount an attack against foreign antigens (including cancer-specific antigens), but not against auto-antigens present on normal cells throughout the body. It is possible to stimulate the immune system to improve its level of protection. Vaccines, including single-protein antigens, such as diphtheria toxoid, are widely used to generate immunity against a specific antigen, and thus, a specific disease. Where general stimulation of the immune system is desired, this can sometimes be achieved with non-specific agents such as adjuvants, interleukins, interferons, and factors that stimulate colony formation. Occasionally, the immune system loses its critical capacity to distinguish from self (self) from non-self (strange). The resulting immunological assault on the individual's own tissues can take the form of autoimmune diseases, for example systemic lupus erythematosus, type 1 diabetes, or rheumatoid arthritis. In such a case or alternatively, where the individual is the recipient of a transplanted organ or tissue, suppression rather than stimulation of the immune response is desirable. Nonspecific down regulation of the immune response is typically achieved by treatment with corticosteroids, azathioprine, cyclosporine, tacrolimus (FK506), rapamycin, or mycophenolate mofetil. Certain immunoglobulins, including the monoclonal antibody OKT3, end up being used for this purpose. The suppression of immunity against a specific antigen, called "induction of tolerance" may also be possible. Methods that have been used to induce tolerance against a particular antigen include intravenous administration or repeated topical administration of the antigen in diluted form, treatment with a very high dose of the antigen and oral administration of the antigen. EP 635621 describes an oral delivery system, which is based on interalia, in that it has a cationic polysaccharide film deposited in a gellable hydrocolloid within which a drug (peptide) can be incorporated. WO 94/20136 describes a method for presenting pharmaceutically active peptides in cyclodextrin inclusion complexes. It is disclosed that the peptides are useful as receptor agonists, receptor antagonists, and as vaccines. It is established that many peptides of 3 to 20 amino acids in length are unstable and tend to lose biological activity. It is not mentioned in the described peptides that they include cysteine residues. It is intended that the use of the cyclodextrin improves the stability of such peptides. EP 566135 describes a system, whereby the peptides are presented to the mucosal coating together with a nucleotide derivative cytidine in a formulation designed for oral delivery. EP 566135 teaches that peptides or proteins, when administered orally and without some form of protection or stabilizing element, lose activity and include reference to many patent applications, which seek different solutions to the problem of stability in the oral delivery of peptides. In addition to the patient's discomfort associated with the administration of peptides or proteins by injection, the actual amount of the peptide or protein that is administered, can produce toxic side effects. It has now been found that certain peptides have activity as immunoregulators. A surprising property associated with immunoregulatory activity is that the activity has been found to be immunoinhibitory or immunostimulating in effect based on the experiments described herein and further, that the immunoregulatory activity has been shown to have some therapeutic effect on the treatment of certain diseases, such as cancer and arthritis. Furthermore, it has been found that when administration to epithelial cell lining is by oral administration, administration of the peptides has been found to correlate with a modulating or regulating effect on the growth of the tumors. Another surprising discovery is that the oral presentation of the "naked" peptides of the invention does not require the inclusion of aggregated transport agents. Thus, the peptides of the invention need not be administered in association with transport agents, such as delivery vehicles, for example, vesicular delivery systems, which are designed to improve the delivery or coating of mucosal epithelial cells of the intestine. In addition, it has also been found that the amount of peptide required to produce the therapeutic effect by oral delivery can be significantly decreased than that required to produce a similar effect, when the peptide is delivered systemically, for example, by parenteral injection. It is an object of the present invention to provide an effective means for treating the disease using immunoregulatory peptides. It is another object of the invention to provide immunoregulatory peptides, which can be used in the treatment of the disease. These and other objects of the invention will become apparent from the following description and examples.

DECLARATION OF THE INVENTION According to the present invention there is provided a physiologically active, purified peptide and comprises at least two cysteine amino acid residues, the two residues are aligned contiguous to each other or separated by no more than one amino acid, the peptides are absorbable by the coating of epithelial cells in a mammal, resulting in a regulated immune response, and therefore, a therapeutic effect against the disease. The peptides are prepared from amino acid residues independently selected from the amino acid residues having aliphatic side chains, aliphatic hydroxyl side chains, basic side chains, acid side chains, secondary amino groups, amide side chains, and sulfur containing side chains. The peptides of the invention must be physiologically active, in the sense that they must be able to induce a regulated immune response, and therefore a therapeutic effect against the disease. Suitable amino acids can be selected independently from the groups comprising amino acid residues that occur naturally and unnaturally. Examples of amino acid residues that occur naturally include isoleucine (lie), leucine (Leu), alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gln) ), glutamic acid (Glu), glycine (Gly), lysine (Lys), phenyl alanine (Phe), Proline (Pro), serine (Ser), trionine (Thr), tryptophan (Trp), tyrosine (Tyr), methionine (Met), valine (Val), and histidine (His). In this way, the peptides of the invention can include additional cysteine residues, either adjacent to, or removed from at least two cysteine amino acid residues mentioned in the above.

Naturally, the skilled person will appreciate that amino acid residues that occur naturally include those amino acid residues which are found in peptides and / or proteins of living organisms. The skilled artisan will also appreciate that such naturally occurring amino acid residues may be present in peptides of the invention in chemically modified forms, for example including aggregate protecting groups such as ethyl, trityl (Trt), allyls, t-butyl and the like. Naturally, the skilled person will appreciate that any group b protecting groups which may be present in the peptides of the invention, should be such that they do not substantially interfere with their immunoregulatory properties and therefore with their therapeutic effect. The purified peptides of the invention can be made synthetically, for example, by chemical means, or by the use of recombinant DNA technology. Alternatively, the peptides of the invention may be isolated from polypeptides or proteins and the like. A peptide of the invention can take the form of a dimer consisting of two identical or two different peptide monomers joined together via sulfur to sulfur bonds between at least one of at least two amino acid residues cysteine of the first monomer of peptide, and at least one of at least two amino acid residues cysteine of a second peptide monomer. In one aspect of the invention, the peptide monomers will be linked to each other via sulfur to sulfur bonds between at least two cysteine amino acid residues of the first peptide monomer and at least two residues of the amino acid cysteine of the second peptide monomer. The dimers of the present invention can be in parallel form, ie, two peptide monomers aligned parallel to each other, such that both peptide monomers are read in a address, for example, from the address from N-terminal to C-terminal. The peptide monomers forming the dimer may or may not be of the same length. Preferably, the peptide monomers are of the same length and the N- and C-terminal amino acid residues of a monomer are located adjacent to the N- and C-terminal amino acid residues of the second peptide monomer. Alternatively, a dimer of the / - present invention may be in antiparallel form. That is, a first monomer reads from the N-terminal amino acid residue to the C-terminal amino acid residue is aligned against a second monomer which is read from the C-terminal amino acid residue to the N-terminal amino acid residue, ie, in the opposite direction to that of the first peptide monomer; the two peptide monomers that are bound by means of sulfur to sulfur bonds by means of the residues amino acids cysteine as described above, for parallel or antiparallel dimers of the invention. Where the two peptide monomers forming a peptide dimer of the invention are different from each other, the dimer is referred to as a heterodimer. A heterodimer may be in parallel or antiparallel form. Thus, a heterodimer can be composed of two peptide monomers of the same length, differing, for example in the substitution of an amino acid residue having the L-form for an amino acid residue having the form D. Alternatively, the lengths of the monomers of the peptide that form the dimer may be different. Preferably, the first and second peptide monomers which form a dimer of the present invention are the same. The peptides of the invention also include monomers, which at least two contiguously or spaced-apart cysteine amino acid residues are essentially linked via disulfide bridges. The monomers can be linear or cyclic. Preferably, the monomers are linear. The administration of peptides of the invention by way of example, oral administration, intratracheal, nasal or parenteral administration, produce a measurable regulated immune response as indicated in the examples herein.

The "epithelial cell lining" is defined as the cell lining and cells associated with it, which covers the internal and external surfaces of the body, including the lining of vessels and other small cavities. For the purposes of the present invention, epithelial cell lining is considered to be at least one layer of cells in depth and as many as several deep cell layers. Cells included within the scope of "epithelial cell lining" also include those specialized lymphoid cells and tissues which are located in or associated with the lining of epithelial cells and which influence the immune response such as T lymphocytes, B lymphocytes, enterocytes , NK cells, monocytes, dendritic cells and cells comprising a mucosal associated lymphoid tissue (MALT), such as Peyer's patches and the like. In this way, the skilled person will appreciate that the so-called migratory cells such as T and B lymphocytes, which can be considered as transient resident cells of the epithelial cell lining as defined above are included within the scope of the definition of the cell lining epithelial The peptides of the invention can be absorbed by coating epithelial cells in a passive or active sense. For example, peptides can be absorbed on the surface of the cell or actively or passively incorporated by cells located on the side of the lumen surface of epithelial cell lining, or they can pass between cells located on the surface side of the cell. lumen of epithelial cell lining and are incorporated by cells located deeper in the lining of epithelial cells, e.g., T lymphocytes or Peyer's patches. The skilled person will also appreciate that "uptake" as defined herein also includes the situation in which the peptides of the invention initiate an immune response by interaction with surface receptors found in or on the membranes of certain specialized cells. located in the lining of epithelial cells, such as enterocytes, intraepithelial lymphocytes, without physically penetrating the lining of epithelial cells. In this way, the skilled person will understand that the peptides of the invention can interact with, bind to, pass through or penetrate the epithelial cell lining. The peptides of the invention are preferably administered by oral, nasal or intratracheal administration in the form of an oral, nasal or intratracheal dose. It has been found that the amount of a peptide of the invention required to produce a given therapeutic effect, when administered orally may be significantly less than that required to produce the same effect with other types of administration, such as parenteral administration. In another aspect of the invention, there is provided an oral dosage form comprising an immunoregulatory peptide comprising at least two amino acid residues cysteine, the two residues are aligned contiguous with each other or separated by no more than one amino acid residue, the peptide is absorbable by the lining of epithelial cells of the gastrointestinal tract in a mammal, resulting in a regulated immune response and therefore in a therapeutic effect against the disease. The peptide may be in the form of a monomer or a dimer. In another aspect of the invention, there is provided an oral dosage form comprising at least one immunoregulatory peptide, each of which comprises at least two cysteine amino acid residues, the two cysteine residues being aligned contiguous with each other or separated by no more than one amino acid residue, at least one peptide that is absorbable by the epithelial cell lining of the gastrointestinal tract in a mammal resulting in a modulated immune response and therefore a therapeutic effect against the disease, wherein the amount of at least one peptide administered parenterally and in need of inducing an observable level of modulated immune response in a mammal is less than the amount thereof in at least one peptide administered parenterally and necessary to achieve a similar observable level of regulated or modulated immune response in the mammal. In another aspect of the invention, there is provided a nasal dose form of an immunoregulatory peptide comprising at least two residues of the amino acid cysteine, two residues that are aligned contiguous with each other or separated by no more than one amino acid residue, the peptide which it is absorbable by the coating of epithelial cells of the nasal passages in a mammal resulting in a modulated immune response and therefore a therapeutic effect against the disease. In another aspect of the invention there is provided a nasal dose form, comprising at least one immunoregulatory peptide, each of which comprises at least two cysteine amino acid residues, the two cysteine amino acid residues being aligned contiguous with each other or separated by no more than one amino acid residue, the peptide is absorbable by the lining of nasal conductor epithelial cells in a mammal, which results in a modulated immune response and therefore a therapeutic effect against the disease, in that the amount of the peptide administered nasally necessary to induce an observable level of modulated immune response in a mammal is less than the amount of the same peptide administered parenterally and necessary to achieve a similar observable level of the modulated immune response in the mammal. In another aspect of the invention, there is provided an intra-tracheal dosage form comprising an immunoregulatory peptide comprising by the hands two cysteine amino acid residues, the two residues being aligned contiguous with each other or separated by no more than one amino acid residue, the peptide is absorbable by the lining of epithelial cells of the lung in a mammal, which results in a modulated immune response and therefore a therapeutic effect against the disease. In another aspect of the invention, there is provided an intratracheal dose form comprising at least one immunoregulatory peptide each of which comprises at least two amino acid residues cysteine, the two cysteine residues are aligned contiguous with each other or separated by no more than one amino acid residue, at least one peptide that is absorbable by the lining of epithelial cells of the lung in a mammal, which results in a modulated immune response, and therefore a therapeutic effect against the disease, in which the amount of at least one peptide administered intratracheally necessary to induce an observable level of modulated immune response in a mammal is less than the amount thereof in at least one peptide administered parenterally and necessary to achieve a similar observable level of modulated immune response in the mammal. The peptides of the invention can be of any length, provided that they are capable of inducing a modulated immune response and a therapeutic effect therefor. Generally, the peptides of the invention are short peptides of 4 amino acid residues up to about 30 amino acid residues in length. Preferably, the peptides are from 4 amino acid residues to about 20 amino acid residues in length. More preferably, the peptides of the invention are 4 to 15 peptides in length (e.g., 4 to 10 or 4 to 9), and most preferably, 4 to 7 amino acids in length. For example, the peptide may be 4, 5, 6, 7, or 8 amino acid residues in length, with or without protecting groups. The peptides of the invention may or may not be associated with transport agents as defined herein. Preferably, the peptides of the invention are administered in "bare" form, ie, free of aggregated transport agents. Aggregated transport agents are those with which the peptides of the invention are intentionally placed in contact or in association, either before, during or immediately after administration, and which may serve to improve absorption and / or improve peptide stability.

Thus, in preference there is provided a physiologically active, purified peptide, free of aggregated transport agents, of 4 to 15 amino acid residues in length, comprising two amino acid residues cysteine, the residues being aligned contiguous with each other or separated by no more than one amino acid residue, the peptide is absorbable by the coating of epithelial cells in a mammal, which results in a modulated immune response and therefore a therapeutic effect against the disease. The peptide may be in the form of a monomer or dimer of the same or different peptides or peptides. Suitable peptides of the invention will now be described with reference to the following formulas: Formula (I) (A) nX-Cys-Cys-Y- (B) m (I) wherein Each A is independently selected from H, a protective group, for example ethyl, trityl (Trt), allyl, and t-butyl, or at least one amino acid residue independently selected from the group of amino acid residues having aliphatic side chains, hydroxyl aliphatic side chains, basic side chains, acid side chains, aminose secondary groups, amide side chains, aromatic side chains, and side chains containing sulfur; n is an integer selected from the group consisting of the set of 1 to 11; X is selected from the group consisting of NH, and the group of amino acid residues having secondary amino groups, amide side chains, and aliphatic side chains. Preferably, X is selected from the group Gly, Pro, Gln, Lie, Val, Asp, Leu, Ala or NH. Y is selected from the group consisting of NH, and the group of amino acid residues having secondary amino groups, aliphatic side chains, acid side chains, aliphatic hydroxyl side chains, aromatic side chains and amide side chains. Preferably, Y is selected from the group Pro, Gly, Leu, Glu, Val, Lie, Ser, Phe, Tyr, Thr, Asp, Gln or NH; Each B is independently selected from the group consisting of H, OH, NH2, a protecting group, such as ethyl, trilyl (Trt), allyl or t-butyl, or at least one amino acid residue selected from the group of amino acid residues having aliphatic side chains, hydroxyl aliphatic side chains, basic side chains, acid side chains, secondary amino groups, amide side chains, aromatic side chains, and side chains containing sulfur; m is an integer selected from the group consisting of the set of 1 to 11; with the proviso that when A is not at least one amino acid residue, n is 1 and when B is not at least one amino acid residue, m is 1; and the complete peptide sequence contains no more than 15 amino acid residues. When A and / or B represent an amino acid residue or a sequence of amino acid residues, the amino acid residue or sequence of amino acid residues may include naturally occurring amino acid residues, such as those described in the foregoing or their analogues or may include amino acid residues that do not occur naturally such as synthetic amino acid residues and their analogs, or amino acid residues or amino acid residue sequences that include both amino acid residues that occur naturally and / or their analogs and amino acid residues that do not they occur naturally and / or their analogues. The skilled artisan will also appreciate that included within the scope of formula (I) are peptides in which intramolecular disulfide bridges are present between the two amino acid residues Cys. Such peptides represent an oxidized form of the peptides of the formula (I) The skilled artisan will also appreciate that the peptides of Formula (I) may be in the form of homodimers or heterodimers which may be in parallel or antiparallel form. Such homodimers or heterodimers are formed of monomers of Formula (I) and can be linked via sulfur to sulfur bonds via cysteine residues. Also included within the scope of the invention are the pharmaceutically acceptable areas of peptides of Formula (I) or their physiologically functional derivatives together with a pharmaceutically acceptable carrier therefor. The preferred peptides of the invention agreed with Formula (I) are those in which: XesGly and YesGly; XesPro and YTSPTO; XesProy YesVal; Xeßlle and Yes Leu; XesPro and YesGlu; XesGlu and YsTyp XesPro and YeßPhc; XesGluy YsPhe; XesAla and YesVal; XesVal and YesDe; XßsGLn and YeßSep XesBe and Y is Thr; X is Leu and Yes Asp; X is Asp and Y is; X is Leu and Ye Gln; X is Gly and Y is Asn; XesGly and Y is Pro and XesAla and YesGly; and in which A and B are as defined in the above. The most preferred peptides according to Formula (I) of the invention are: Gly-Pro-Cys-Cys-Pro-Gly; Ala-Pro-Cys-Cys-Val-Pro; Lys-Pro-Cys-Cys-Glu-Arg; PTO-Asp-Cys-Cys-De-Pro; Ac Ala Pro Cys Cys Val Pro; Arg Cys Ser Gly Cys Cys Asn; Pro-Gly-Cys-Cys-Gly-Pro: Pro-Gly-Cys-Cys-Gly-Pro; Gly-Pro-Cys-Cys-Pro-Gly; l_J Trp-Pro-Cys-Cys-Pro-Trp; I I Val-De-Cys-Cys-Lcu-TTir; Thr-Pro-Cys-Cys-Phe-Ala; Glu-Glu-Cys-Cys-Phe-Typ Lys-Leu-Cys-Cys-Asp-üe; Lys-Glu-Cys-Cys-Tyr-Val; The most preferred peptides according to Formula (I) of the invention are the peptides: Gly-Pro-Cys-Cys-Pro-Gly; Pro-Gly-Cys-Cys-Gly-Pro; Ala-Pro-Cys-Cys-Val-Pro; Lys-Pro-Cys-Cys-Glu-Arg; Arg Cys Ser Gly Cys Cys Asn; Pro-Gly-Cys-Cys-Gly-Pro; Val-De-Cy Ds-Cys-Leu-Tlir.

It should be understood that amino acid residues located at N and C terminals, respectively of the above peptides, do not contain modifications.

Formula (II) (A) nX-Cys-Z-Cys-Y- (B) m (II) wherein Each A is independently selected from the group consisting of H, A protective group such as ethyl, trityl (Trt), allyl or t -bitulo, or at least one amino acid residue selected from the group of amino acids in any L, or D form having aliphatic side chains, aliphatic hydroxyl side chains, basic side chains, acid side chains, secondary amino groups, amide side chains, and side chains containing sulfur; n is an integer selected from the group consisting of the set of 1 to 10; X is selected from the group of NH, and the group of amino acid residues having aliphatic side chains, secondary amino groups, acid side chains, aromatic side chains, and amide side chains. Preferably, X is selected from the group consisting of Gly, Pro, Gln, Lie, Val, Asp, Leu, Glu, Ala, Lys or NH. Z is selected from the group consisting of amino acid residues having aliphatic side chains, hydroxyl aliphatic side chains and basic side chains. Preferably, Z is selected from the group lie, Gly, Thr, Ala and Lys. And it is selected from the group consisting of amino acid residues having amide side chains, basic side chains, aliphatic side chains, acid side chains and secondary amino groups. Preferably Y is selected from the group consisting of Pro, Gly, Glu, Val, Gln, and Arg; B is independently selected from the group consisting of H, OH, NH2, a protecting group such as ethyl, trityl (Trt), allyl or t-butyl or at least one amino acid residue selected from the group of amino acid residues having aliphatic side chains , aliphatic hydroxyl side chains, basic side chains, acid side chains, secondary amino groups, amide side chains and side chains containing sulfur; m is an integer selected from the set of 1 to 10; with the proviso that A is not at least one amino acid residue, n is 1, and when B is not at least one amino acid residue, m is 1; and each peptide sequence contains no more than 15 amino acid residues. As for Formula (I), the skilled artisan will appreciate that when A and / or B represent an amino acid residue or amino acid residue sequence, the amino acid residue or a sequence of amino acid residues may include amino acid residues that occur naturally, such as those described in the above or their analogues or may include amino acid residues that do not occur naturally, such as synthetic amino acid residues and their analogs, or amino acid residues or sequences of amino acid residues that include amino acid residues that occur naturally and / or their analogs and amino acid residues that do not occur naturally and / or their analogues. The experts will also appreciate that included within the scope of Formula (II) are peptides in which the intramolecular disulfide bridges between the two Cys amino acid residues contiguously aligned or separated are present. Such peptides represent an oxidized form of peptides of Formula (II). The skilled person will also appreciate that the dimers of Formula (II) may be in parallel or antiparallel and may include heterodimers and may be linked via sulfur to sulfur bonds via the amino acid residues cysteine. Also included within the scope of the invention are the pharmaceutically acceptable peptide salts of Formula (II) or their physiologically functional derivatives with a pharmaceutically acceptable carrier therefor. Preferred peptides of the invention, according to Formula (II) include the following: Val Cys He Cys Gln Val Cys Gly Cys Arg; Asp Cys De Cys Qlp; From Cys Thr Cys Glu; Phe Cys De Cys Lys; Ala Cys Lys Cys Gln; Lys Cys Arg Cys Lys; From Cys Thr Cys Glu; I I Leu Cys Ala Cys Val; I (Asp Cys lie Cys Gln: I I Gly Pro Cys De Cys Pro Gly Gly Pro Cys De Cys Pro Gly; The peptides of the invention can be administered with or without transport agents. Preferably, the peptides of the invention are administered orally, intra-tracheally, nasally or systematically free of aggregated transport agents. More preferably, the peptides of the invention are administered intra-tracheally, nasally or orally. More preferably, the peptides of the invention are administered orally. "Transport agents" include aggregate media for delivery such as vesicular delivery systems, microparticles, liposomes and similar systems, which are designed to transport drugs (e.g., peptides) to epithelial cell lining or endothelial cell lining. The "transport agents" also include chemical agents or additional peptide sequences, which can form an association with, or fuse to, or complex with the peptides and which help maintain the physiological integrity of the peptide sequences of the invention, for example, by presenting the peptides in a prepro- or pro forma or by fusing the peptides to the carrier proteins, for example glucosyltransferase or complexing with chemical agents such as cyclodextrins and the like. Preferably, the peptides of the invention are administered to the receptor as free peptides together with customary adjuvants, excipients and diluents commonly found in pharmaceutical formulations. In this way, the peptides of the invention can be delivered by oral or systemic administration in simple oral or systemic formulations comprising adjuvants, diluents and excipients commonly employed in oral and systemic dosage forms. Preferably, the peptides are administered in a free oral dosage form of the aggregated transport agents. Lymphoid tissue associated with the mucosa (MALT) are also found in the coatings of epithelial cells of the gastrointestinal tract, that is, esophagus, stomach, duodenum, ileum and colon; coatings of the bronchioles in the lung; and in the linings of the nasal passages. Without intending to be bound by theory, it is believed that the peptides of the invention interact with MALT and therefore train a sequence of immunoregulatory events which results in a therapeutic effect against certain diseases. The immunoregulatory response can be immunoinhibitory or immunostimulatory in the effect. The immunomodulatory response has been shown to be an indicator for cancer therapy. Peptides of the invention which have an immunoregulatory effect are indicated to be advantageous in the treatment of cancers of mesenchymal origin such as sarcoma, for example, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma or cordosarcoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, synoviosarcoma or mesotheliomas, leukemias, and lympholas such as granulocytic leukemia, monocytic leukemia, lymphocytic leukemia, malignant lymphoma, plasmacytoma, reticulum cell sarcoma, or Hodgkins disease; sarcomas such as leomyosarcoma or rhabdomisarcoma, tumors of epithelial origin (carcinomas) such as squamous cell carcinoma, basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, carcinoma without differentiate, bronchogenic carcinoma, melanoma, renal cell carcinoma, liver-hepatoma cell carcinoma, bile duct carcinoma, cholangiocarcinoma, papillary carcinoma, choriocarcinoma, transitional cell carcinoma, * semonoma or embryonal carcinoma; and tumors of the central nervous system, such as glioma, menigoma, medulloblastoma, schwannoma or ependymoma. The peptides of the invention are indicated on the basis of their activity for the treatment of malignancies such as melanoma, mammary carcinoma, gastrointestinal carcinoma such as colonic carcinomas, glioma, carcinoma of the bladder, and squamous cell carcinoma of the neck region and the head. In addition, peptides that produce an immunoregulatory effect in the tests described herein, are indicated for therapy in the treatment of acute and / or chronic infections associated with autoimmune disease and autoimmune disease per se such as non-obese diabetes, lupus. erythematosus, scleroderma, Sjögren's syndrome, dermatomyositis or multiple sclerosis or rheumatoid arthritis, arteriosclerosis, and psoriasis, asthma, rhinitis, fibrosis, chronic bronchitis, hepatitis, post-infectious anergy, diseases of acquired immune deficiency, such as AIDS and immune anergy post -traumatic In addition, the peptides according to the present invention are immunoregulators in action, they can be advantageously used as adjuvants in various forms of vaccine preparations and in formulations designed to inhibit the rejection of organs in transplants. In another aspect of the invention, there is provided a method for inducing a modulated immune response in a mammal, which comprises administering to the mammalian epithelial cell coat a purified, physiologically active dose of the immunoregulatory peptide comprising at least two amino acid residues. cysteine, the two residues are aligned contiguous with each other or separated by no more than one amino acid residue, sufficient to induce the modulated immune response and therefore a therapeutic effect. In another aspect of the invention, there is provided a method for inducing a modulated immune response in a mammal, which comprises 1) identifying a mammal in need of modulation of its immune response and 2) administering to at least one cell coat mammalian epithelial a dose of a purified, physiologically active peptide free of transport agent aggregates of 4 to 15 amino acid residues in length, comprising two cysteine amino acid residues, which are aligned contiguous with each other, or separated by no more than one residue enough amino acid to induce the immunoregulatory response and therefore a therapeutic effect. Preferably, the coating of epithelial cells to which the peptide is administered is the coating of epithelial cells of the gastrointestinal tract. Most preferably, the peptide is administered to MALT. In one embodiment, a method for inducing a modulated immune response in a mammal is provided, which comprises administering to MALT of the mammal a dose of a physiologically active peptide of Formula (I), the peptide is free of aggregated transport agents and is sufficient to induce the modulated immune response and therefore a therapeutic effect. The peptide may be in the form of a monomer or dimer. One embodiment provides a method for inducing a modulated immune response in a mammal, which comprises administering to MALT of the mammal a dose of a physiologically active peptide of Formula (II), the peptide is free of aggregated transport agents and is enough to induce the immune-regulated response and so - > - • both a therapeutic effect. The monomer may be in the form of a monomer or dimer. In another aspect of the invention, there is provided the use of a physiologically active peptide of 4 to 15 residues 5 amino acids in length comprising two cysteine residues that are aligned contiguous with each other or separated by no more than one amino acid residue, the peptide is free of aggregated transport agents, in the preparation of a suitable drug for the treatment of the disease. The forms Individuals of the cancer which can be treated with the peptides of the invention are listed in the foregoing. In one embodiment, the use of a physiologically active peptide of Formula (I) free of aggregated transport agents in the preparation of a medicament is provided. suitable for the treatment of the disease, in particular cancer and rheumatoid arthritis. Also encompassed as another aspect of the invention, is the use of a physiologically active peptide of Formula (II) free of aggregated transport agents in the preparation of a medicament. suitable for the treatment of the disease, in particular cancer and rheumatoid arthritis. In another embodiment of the invention, there is provided a method for preparing a peptide of the invention by a chemical process, in which amino acid residues The individual or fragments of peptides of the invention are linked to form peptide bonds and in which the protecting groups are used at the beginning and / or end of the process. In another embodiment of the invention, provided as another alternative aspect of the invention, a physiologically active peptide free of aggregated transport agents of 4 to 15 amino acid residues in length, comprising two cysteine residues, the amino acid residues are separated by no more of an amino acid residue for use in therapy, for example in cancer or rheumatoid arthritis therapy. In one embodiment, a peptide of Formula (I) or Formula (II) is provided for use in therapy, for example in cancer therapy or rheumatoid arthritis therapy. The amount of peptides of Formula (I) or Formula (II) which are required in cancer therapy or rheumatoid arthritis therapy will, of course, vary and is ultimately at the discretion of the physician or veterinarian. Factors to be considered include the condition being treated, the route of administration and nature of the formulation, the mammalian body weight, the surface area, age and general condition and the particular peptide to be administered. An adequate effective dose of peptides of the invention is generally placed in the range of about 0.0001 μmol / kg to about 1000 μmol / kg of body weight, preferably from about 0.003 to about 300 μmol / kg of body weight, for example in the range from about 0.001 to 100 μmoles / kg of body weight, for example from 0.03 to 3.0 μmoles / kg of body weight. The total dose can be given as a single dose or multiple doses, for example 2 to 6 times a day. For example, for a 75 kg mammal (e.g. a human) the dose range would be about 2.25 pmol / kg / day to 225 pmol / kg / day and a typical dose could be about 100 pmol of the peptide. If discrete multiple doses are indicated in the treatment, they should normally be 25 μmol of a peptide of the invention, given up to 4 times per day. In an alternative administrative regimen, the peptides of the invention may be given on alternate days or even once or twice a week. The expert will appreciate that an appropriate administrative regime would be at the discretion of the doctor or veterinarian. Although it is possible for the active peptide to be administered alone, it may be preferable to present the active peptide in a pharmaceutical formulation. The formulations of the present invention, for medical use, consist of a peptide of Formula (I) or Formula (II) or its salt together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients. The carrier or carriers must be pharmaceutically acceptable, in the sense that they are compatible with the other ingredients of the formulation and substantially not harmful to the recipient thereof. The skilled artisan will appreciate that the free acid addition salts (for example hydrohalo salts) of the peptides mentioned herein as well as base salts are encompassed within the scope of the invention. Most preferred, the salts will be pharmaceutically acceptable. Suitable acid addition salts include those formed from hydrochloric, hydrobromic, nitric, perchloric, sulfuric, citric, tartaric, phosphoric, lactic, benzoic, glutamic, oxalic, aspartic, pyruvic, acetic, succinic, fumaric, maleic, oxaloacetic acids. , isotonic, stearic, phthalic, methanesulfonic, p-toluenesulfonic, benzenesulfonic, lactobionic, and glucuronic. Suitable base salts include salts of inorganic bases such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium); salts of organic bases, for example phenylethylbenzylamine salts, dibenzylethylenediamine, ethanolamine and diethanolamine; and salts of amino acids, for example glycine and arginine. More preferably, the salts will be pharmaceutically acceptable. Therefore, the present invention further provides a pharmaceutical formulation comprising a peptide of Formula (I) or Formula (II) together with a carrier therefor, pharmaceutically acceptable. Of course, the skilled artisan will appreciate that any pharmaceutical formulation comprising a peptide of Formula (I) can include more than one peptide of Formula (I). Thus, a pharmaceutical formulation may comprise at least two peptides of Formula (I) or (II) or a mixture of peptides of Formula (I) or (II). In an alternative, the pharmaceutical formulation may consist of at least two peptides, at least one which is selected from Formula (I) and at least one which is selected from Formula (II) and may consist of a mixture of peptides selected from formulas (I) and (II). A method for the preparation of a pharmaceutical formulation is also provided, which comprises bringing in association a peptide of the invention, for example, at least one peptide of Formula (I) and / or at least one peptide of the Formula (I). II) or a physiologically functional derivative thereof and a pharmaceutically acceptable carrier therefor. The peptides of the invention and their physiologically functional derivatives can be administered by any route appropriate for the condition to be treated, the routes include oral, intra-tracheal, rectal, nasal, topical (which includes buccal and sublingual), vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, intraperitoneal and epidural). It will be appreciated that the route may vary, for example, with the condition of the receiver. Preferred formulations are those suitable for oral, nasal or intra-tracheal administration. The most preferred formulations are those suitable for oral administration. Formulations for topical administration in the mouth include lozenges comprising the peptide or peptides in a flavored basis, usually sucrose and acacia and tragacanth; pills comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes comprising the peptide or peptides in a suitable liquid carrier. The formulations of the present invention, suitable for oral administration may be present as discrete units such as capsules, cachets, tablets, lozenges comprising the peptide or peptides in a flavored base usually sucrose and gum acacia and gum tragacanth; pills comprising the active ingredient or ingredients in an inert base, such as gelatin and glycerin or sucrose and acacia gum; and mouthwashes comprising the active ingredient or ingredients in a suitable liquid carrier. Each formulation generally contains a predetermined amount of the active peptide or peptides; as a powder or granules; or a solution or suspension in an aqueous or non-aqueous liquid such as a syrup, an elixir, an emulsion or spray and the like. A tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active peptide or peptides in free flowing form, such as powder or granules, optionally mixed with a binder, (for example povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative , disintegrant (eg sodium starch glycolate, crosslinked povidone, crosslinked sodium carboxymethylcellulose) surface active or dispersing agent. The molded tablets can be prepared by molding in a suitable machine a mixture of the peptide or powdered peptides moistened with an inert liquid diluent. The tablets may optionally be coated or etched and may be formulated to provide slow or controlled release of the active ingredient therein., using for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. A syrup can be prepared by adding the active peptide or peptides to a concentrated aqueous solution of a sugar, for example sucrose, to which any of the necessary ingredients can also be added. Such an accessory ingredient or ingredients may include flavors, an agent for retarding the crystallization of sugar or an agent for increasing the solubility of any other ingredients, such as a polyhydric alcohol, for example glycerol or sorbitol. In addition to the ingredients mentioned in the foregoing, the formulations of this invention may further include one or more accessory ingredients selected from diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. The emulsion formers and stabilizers of the Suitable emulsions for use in the formulation of the present invention include Tweed 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of 'oils or fats suitable for The formulation is based on achieving the desired therapeutic properties, since the solubility of the active compound in most oils is likely to be used in pharmaceutical emulsion formulations. In this way, the cream should preferably be non-greasy, without staining and a washable product with adequate consistency to prevent leakage of tubes or other containers. Straight or branched, mono- or di-basic chain alkylesters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, palmitate 2- ethylhexyl, or a mixture of branched chain esters known as Crodamol CAP can be used, with the last three esters being preferred. These can be used alone or in combination depending on the required properties. Alternatively, high melting point lipids such as white soft paraffin and / or liquid paraffin or other mineral oils may be used. Formulations for rectal administration may be presented in any suitable form, for example as a suppository with a suitable base comprising the peptide or peptides of the invention in admixture with a neutral fat base, for example cocoa butter, or for example, in a mixture with a salicylate, or in the form of solutions and suspensions. In an alternative, formulations in the form of rectal gelatin capsules comprising the peptide or active peptides of the invention in admixture with oil or vegetable oils, or paraffin oil may be used.

Formulations suitable for nasal administration, wherein the carrier is a solid include a coarse powder having a particle size, for example in the range of 20 to 500 microns. Where the particle size is related to an active substance in the form of a particle per se, the particle size may be in the range of 2 to 500 microns. The coarse powder formulations can be administered by rapid inhalation through the nasal passage of a powder container held close to the nose. Suitable formulations in which the carrier is a liquid, for administration for example, as a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. In this way, the peptides of the invention can be formulated in pressurized metered dose inhalers or dry powder inhalers for oral or nasal inhalation or in liquid formulations for nebulization. The active peptide or peptides are micronized or processed in any other form at a particle size suitable for inhalation therapy (mean mass diameter <10 μm). In the case of pressurized metered dose inhalers, the micronized peptide or peptides can be suspended in a liquefied propellant or a mixture of liquefied propellants. Such propellants can also, but not necessarily, act as solvents. In any case, the micronized peptide or peptides can be filled in a container equipped, for example with a metering or metering valve. Suitable propellants include those commonly employed in the art, such as hydrofluoroalkanes (HFA). The HFA propellants may be present in any mixture, which is suitable for delivering the peptide or peptides of the invention for MALT mixtures. Examples of HFA suitable for use in the invention include tetrafluoroethane (e.g., propellant 134a (Hoechst)) and heptafluoropropane (for example propellant 227 (Hoechst)). Naturally, the skilled person will appreciate that appropriate concentrations of the surfactants may also be present in such formulations, for example sorbitan triolate, lecithin, oleic acid and the like, the use of surfactants that increase the physical stability of the peptide or peptide preparation. The formulation may also contain solvents, such as ethanol, to improve the solubility of the peptide or peptides in the chosen propellant. The active peptides of the invention can be delivered by means of inhalation devices suitable for inhalation of dry powder, such as portable inhalation devices and the like. In such dry powder formulations, the active peptide or peptides of the invention can be used either alone or in combination with a carrier, such as lactose, mannitol, or glucose. The selection of the carrier is not critical with the proviso that the physiological action of the peptide or peptides of the invention is substantially undama Other additives may also be included in the powder formulations as required, for example to maintain stability, etc. Again, such additives should be such as not to substantially interfere with the physiological effect and therefore the therapeutic effect of the peptide or peptides of the invention. The inhalation device may be of any type known in the art, such as a single dose inhaler having a predetermined dose or a multiple dose inhaler, wherein the dose is measured by a unit of measurement inside the inhaler or it is supplied from a set of predetermined doses. Formulations suitable for parenteral administration conveniently consist of a sterile aqueous preparation of the active compound, which is preferably isotonic with the blood of the recipient. Such formulations suitably consist of a solution of the pharmaceutical and pharmacologically acceptable acid addition salt of a peptide or peptides of the invention, which is isotonic with the blood of the recipient.

Useful formulations also comprise concentrated or solid solutions containing the peptide or peptides of the invention, which upon dilution with an appropriate solvent give a solution for parenteral administration as in the above. Now the invention will be described by the following non-limiting examples. 1. Synthesis of peptides It should be understood that where no group is shown in the N- and C-terminus of the peptides of the invention herein, they describe that the N-terminus is in the amino (NH2) form and that the C-terminus is in the form carboxyl (-COOH). The numbering system of the peptides in the following examples is that used in Table 1, which shows the results obtained from Example 43.

Example 1: Synthesis of Pro-Gly-Cys-Cys-Glv-Pro.

Fmoc-proline bound to a resin (1.11 g, 0. 18 mmoles / g, 0.20 mmoles) consists of a cross-linked polystyrene skeleton grafted with polyethylene glycol chains, functionalized with the p-carboxy-triphenylmethanol linker (Sheppard, RC, Williams, BJ Acid-labile < * - Resin Linkage Agents for Use in Solid Phase Peptide Synthesis, Int. J. Peptide Protein Res. 1982, 20, 451-454) from Rapp Polymer was used for synthesis. The pentafluorophenyl esters of the L-amino acid Na-Fmoc-protected used, were purchased from Bachem and Millipore and Cys was protected with a triphenylmethyl group (Trt). DMF and 20% piperidine / DMF as peptide reagent was purchased from Millipore. The coupling reagent 1-hydroxybenzothiazole (HOBT) came from Fluka. The synthesis is done in a Millopore Pepper 9050 Plus Peppersetter. The C-terminal amino acid, Tentagel S trt-Pro-Fmoc (1.11 g, 0.18 mmole / g, 0.20 mmole) in resin (from Rapp Polymer) is allowed to expand in DMF for 30 minutes before adding the suspension to the column. synthesizer. He Synthesizer operates with consecutive unblocking, washing and copying cycles consisting of 8 minutes of recycling with 20% piperidine / DMF for each Fmoc unlocking followed, then by washing by activation of the pentafluorophenyl ester of the L-amino acid Na-Fmoc-protected (0.8 mmole) with HOBT (0.9 mmol). The activated amino acids are added to the column and recycled every 30 minutes. The synthesizer finished the synthesis with an unblocking of the N-terminal Fmoc group and a final wash with DMF. The resulting peptide on the resin was transferred to a glass funnel sintered, where it is washed twice with MeOH (2 x 10 ml) and three times with CH2Cl2 (3 x 10 ml). The resin is allowed to dry under vacuum overnight after which the peptide is deprotected from the side chain and cleaved from the resin using ethanedithiol / TFA 5/95 (20 ml) at room temperature for 3 h. The resin is removed by filtration and washed with 3 x 10 ml of acetic acid. The combined acid fraction is evaporated after which the residue is triturated three times with ether. The unpurified peptide is dissolved in H20 / CH3CN 1/1 and lyophilized. The resulting material is purified in CLAP using a Gilson CLAP system 305 and 306 with a reverse phase column Kromasil 100-5C18 25 cm x 22 mm di (A = 0.1% TFA / H20 - B = 0.1% TFA / CH3CN: 5 -80% / 25 min; 10 ml / min, 220 nm). The combined CLAP fraction is lyophilized leaving 84 mg of the title compound. MH + (m / z) = 533.

Example 2 Synthesis te kvs-lrfH-CTS'CYS-GlivMrt I I Lys-Leu-Cys-Cys-Gln-Met (39.6 mg, 54.7 μmoles) are prepared following a similar protocol as for Example 1. Lys-Leu-Cys-Cys-Gln-Met are dissolved in 5% aqueous acetic acid (80 ml) and the pH of the solution is adjusted to 6 with ammonium carbonate. Dimethyl sulfoxide (60 ml) is added and the mixture is stirred at room temperature for 24 h. At the end, the reaction mixture is concentrated in vacuo to about 8 ml remaining. The solution is purified by semipreparative CLAP (APEX Prep Sil ODS, 8 μm, 25 cm x 20 mm di, eluted with a linear gradient of CH 3 CN, 5-60% 50 min, in 0.1% aqueous TFA, flow rate 10 ml / min, UV detection at 220 nm) and then lyophilized to give the title peptide (19.7 mg, 50% as a white powder) EMAR (FAB +) the exact mass calculated for C2gH51NgOgS3: 723.299, found: 723302.

Example 3: Synthesis of the intermolecularly oxidized parallel dimer: Pro. (.lt.Cvs.Cw.Glt.Pry.rlfinern parallel) Pro _lT.Ctj, .Cv'5.Glt Pr «.

To prepare the parallel homodimer a single peptide chain with a protective group Acm (acetamidomethyl) in one of the cysteines and with the other unprotected cysteine (Pro-Gly-Cys-Cys (Acm) -Gly-Pro) was synthesized using the Same protocol as for Example 1. The monomer was dimerized by the oxidation of the free cysteines using the same protocol as for Example 2. The second disulfide bond is made using the Ruiz-Gayo protocol (Ruiz-Gayo et al, 1988 , Tetrahedron Letters, 29, 3845-3848) in which the monooxidized dimer (100 mg, 83 μmol) was dissolved in MeOH (16 ml). I2 is added 0. 2M / CH3OH freshly prepared (8.2 ml, 1.64 mmol) and the mixture is stirred at room temperature for 2 h. H20 is added (20 ml) after which the 0.5 M ascorbic acid (aqueous) is slowly added to the mixture until the iodine color disappears. The mixture is carefully evaporated at room temperature to half the volume. The unpurified product is lyophilized and then purified in CLAP.

Example 4: Synthesis of antiparallel dimer Pro-Gly-Cys-Cys-Gly-Pro (antiparallel dimer) Pro.Gly-Cys-c GIJ * PTO To prepare the antiparallel homodimer, the general procedure of Ruiz-Gayo (Ruiz-Gayo et al, 1988, Tetrahedron Letters, 29, 3845-3848) was used. Two chains of individual peptides each with an Acm protecting group (acetamidomethyl) in one of the cysteines and with the other unprotected cysteine (Pro-Gly-Cys-Cys (Acm) -Gly-Pro and Pro-Gly-Cys (Acm) -Cys-Gly-Pro) was synthesized using the Same protocol as Example 1. The unprotected cysteine in one of the monomers was activated with dithiopyridine by the r "- dissolution of one of the monomers (62 μmoles) in isopropanol / 2M acetic acid (50/50, 20 ml) and adding 2,2'-dithiopyridine (205 μmol dissolved in 15 ml of isopropanol / acetic acid 2M 50/50) The mixture is allowed to stir at room temperature overnight.The mixture is evaporated, then CH 3 CN (25 ml) is added. ) and the mixture is evaporated one more time The remaining unpurified product is triturated with ether (4 x 25 ml) and the resulting S-pyridyl derivative of Pro-Gly-Cys (SPyr) -Cys (Acm) -Gly-Pro it was used directly without another purification. This activated derivative was reacted with the second peptide chain (62 μmoles) by means of the activated chain solution in 0.01M ammonium acetate solution (50 ml, pH-6.5) and the other chain (dissolved in 17 ml of 0.01M ammonium acetate (aqueous)) allowing the mixture to stir for 30 minutes. The reaction mixture is lyophilized and the unpurified product is purified in resulting CLAP in monodisulfide dimer. The second disulfide bond is made using the same protocol as in Example 3 with iodine in CH30H, which after the purification in CLAP, resulted in the final product.

Example 5: Synthesis of Gly-Pro-Cys-Cvs-Pro-Glv.

The synthesis was carried out following a similar protocol as for Example 1.

Example 6: Synthesis of Ala-Pro-Cys-Cvs-Val-Pro.

The synthesis was carried out following a similar protocol as for Example 1.

Example 7: Synthesis of Phe-Cys-Ile-Cvs-Lys.

The synthesis was carried out following a similar protocol as for Example 1.

Example 8: Synthesis of Lvs-Pro-Cys-Cys-Glu-Ara.

The synthesis was carried out following a similar protocol as for Example 1.

Example 9: Synthesis of Ara-Cys-Ser-Glv-Cys-Cys-Asn.

The synthesis was carried out following a similar protocol as for Example 1.

Example 10; Synthesis of oxidized Gly-Pro-Cys-Cys-Pro-Gly intrapnisculannente L_J The synthesis was carried out following a similar protocol as for Example 2.

Eiemolo; Synthesis of intravenously oxidized Val-Ue-Cys-Cys-Leu-Thr L_l The synthesis was carried out following a similar protocol as for Example 2.

Example 12; Synthesis of Lys-Leu-Cys-Cys-Asp-lle oxidized intram? S ilapnente LJ The synthesis was carried out following a similar protocol as for Example 2.

Example 13; Synthesis of Thr-Pro-Cys-Cys-Prie-Ala oxidized intrapinsculatively LJ The synthesis was carried out following a similar protocol as for Example 2.

Example 14; Synthesis of Lys-Ghi-Cys-Cys-Tyr-Val oxidized intramuscularly LJ The synthesis was carried out following a similar protocol as for Example 2.

Example 15: Synthesis of intramuscularly oxidized Lys-Cys-Arg-Cys-Lys I I The synthesis was carried out following a similar protocol as for Example 2.

Example 16j Synthesis of intermolecularly oxidized antiparallel dimer; (antiparallel dimer) The synthesis was carried out following a similar protocol as for Example 4.

Example 17: Synthesis of Pro-Gly-Cys-Cys-Gly-Pro oxidized intra-usculannente LJ The synthesis was carried out following a similar protocol as for Example 2.

Example 18: Synthesis of Trp-Pro-Cys-Cys-Gly-Pro-Trp oxidized intramuscularly LJ The synthesis was carried out following a similar protocol as for Example 2.

Example 19: Synthesis of intramuscularly oxidized Leu-Leu-Phe-Gly-Pro-Cys-Cys-NH2 | } The synthesis was carried out following a similar protocol as for Example 2.

Example 20: Synthesis of intramuscularly oxidized Clu-Ghi-Cys-Cys-Phe-Tyr The synthesis was carried out following a similar protocol as for Example 2.

Example 21: Synthesis of Pro-Val-Cvs-Cvs-Ile-Gly.

The synthesis was carried out following a similar protocol as for Example 1.

Example 22; Synthesis of intramuscularly oxidized Pro-Val-Cys-Cys-Tle-Gly The synthesis was carried out following a similar protocol as for Example 2.

Example 23; Synthesis of Ser-Gln-Cys-Cys-Ser-Leu oxidized intramuscularly The synthesis was carried out following a similar protocol as for Example 2.

Example 24; Synthesis of intramuscularly oxidized Ser-Ile-Cys-Cys-Thys-Lys I I The synthesis was carried out following a similar protocol as for Example 2.

Example 25: Synthesis of Pro-Asp-Cys-Cvs-Ile-Pro.

The synthesis was carried out following a similar protocol as for Example 1.

Example 26: Synthesis of Leu-Ala-Cys-Cys-Val-Val.

The synthesis was carried out following a similar protocol as for Example 1.

Example 27; Synthesis of Pro-Gly-Cys-Cys-Pro-Gly The synthesis was carried out following a similar protocol as for Example 2.

Example 28: Synthesis of Ac-Ala-Pro-Cys-Cys-Val-Pro.

The synthesis was performed following a similar protocol as for Example 1 with an additional methylation step at the end of the synthetic sequence in the PlusPep Millipore 9050 synthesizer consisting of the addition of 0.3M N-acetylimidazole in DMF to the resin and allowing the solution circulates through the synthetic column for 2h followed by washing with DMF.

Example 29: Synthesis of Lvs-Glu-C? S-C? S-Tyr-Val.

The synthesis was carried out following a similar protocol as for Example 1.

Example 30: Synthesis of Lys-Leu-Cys-Cvs-Gln-Me.

The synthesis was carried out following a similar protocol as for Example 1.

Example 31; Synthesis of Ala-Pro-Cys-Cys-Glu-Ser The synthesis was carried out following a similar protocol as for Example 2.

Example 32; Synthesis of Pro-Ala-Cys-Cys-Gly-Pro The synthesis was carried out following a similar protocol as for Example 2.

Example 33: Synthesis of Val-Cvs-Ile-Cvs-Gln.

The synthesis was carried out following a similar protocol as for Example 1.

Example 34; Synthesis of Gly-Pro-Cys-Tle-Cys-Pro-Gly Gly-Pro-Cys-lle-Cys-Pro-Gly The synthesis was carried out following a similar protocol as for Example 3.

Example 35: Synthesis of Val-Cys-Gly-Cys-Arcr.

The synthesis was carried out following a similar protocol as for Example 1.

Example 36; Synthesis of Val-Cys-Gly-Cys-Arg Val-Cys-Gly-Cys-Arg The synthesis was carried out following a similar protocol as for Example 3.

Example 37: Synthesis of Ile-Cys-Thr-Cvs-Glu.

The synthesis was carried out following a similar protocol as for Example 1.

Example 38; Synthesis of lle-C.vs-Thr-Cys-G or I The synthesis was carried out following a similar protocol as for Example 2.

Example 39; Synthesis of Leu-Cys-Ala-Cys-Val i i The synthesis was carried out following a similar protocol as for Example 2.

Example 40: Synthesis of Asp-Cys-Ile-Cvs-Gln.

The synthesis was carried out following a similar protocol as for Example 1.

Example 41; Synthesis of Asp-Cys-Ile-Cys-Cln i i The synthesis was carried out following a similar protocol as for Example 2.

Example 42: Synthesis of Ala-Cvs-Lvs-C? S-Gln.

The synthesis was carried out following a similar protocol as for Example 1.

Example 43: Delayed type hypersensitivity test (DTH).

The ability of the peptides according to the invention to modulate the immune responses can be illustrative by their effect on the delayed-type hypersensitivity (DTH) test in mice. The DTH test is used to illustrate immunoregulation, the protocol for which it was described, for example, by Carlsten H., et al (1986) Int. Arch. Allergy Appl. Immunol 81: 322, incorporated herein by reference. The peptides were tested in one or more of the following doses: 0.0003 μmol / kg, 0.003 μmol / kg, 0.03 μmol / kg, 0.3 μmol / kg and 3.0 μmol / kg. Male and female Balb / c mice were obtained from Bomholtsgaard (Denmark) weighing 18-20 grams each. 4-Ethoxymethylene-2-phenyloxazolin-5-one (OXA) (Sigma Chemicals) is used as the antigen in the DTH test. The mice were sensitized, Day 0, by epicutaneous application of 150 μl of an absolute ethanol-acetone (3: 1) solution containing 3% OXA in the shaved abdomen. Treatment with peptides 1 to 41 inclusive, or the vehicle (phosphate buffer, PHI 7.4, containing a mixture of Shock Absorber A and Shock Absorber B in the proportion of 63%: 37% B (Shock Absorber A: Na2PHI4, 0.89 g / lOOml, EDTA 0.05 g / lOOml; Buffer B: NaH2P04, 0.69 g / lOOml, EDTA 0.05 g / lOOml) was started by oral feeding immediately after sensitization and was continued once a day (am) until Day 6. Seven days after sensitization, both ears of the mice were stimulated on both sides by topical application of 20 μl of 1% OXA dissolved in peanut oil, the thickness of the ear was measured before 24 hours or 48 hours after of the stimulus, using an Oditest spring gauge The stimuli and measurements were performed under light anesthesia with pentobarbital: The intensity of the DTH reactions was measured according to the method described by van Loveren H., et al (1984) J. Immunol. Methods 67: 311 and expressed according to the formula tt24 / 48 ~ Tt0 ^ m units, where tO, t24 and t48 represents the thickness of the ear at time 0, +24 hours or +48 hours after the stimulus respectively, in individual tests (T ). The results are expressed as the mean +/- S.E.M. The level of significance between the means of the groups is obtained by the t test of two Student tails. The immunoregulatory effect of the peptide is reflected in a significant difference in the increase or decrease in the thickness of the ear when compared to the control (phosphate buffer). Table 1 shows the structure of peptides 1-41 tested in the DTH test. The peptides show a significant difference in the immunostimulatory and immunoinhibitory effect compared to the control in at least one of the doses tested.

Table 1: Peptides 1 to 41 increase an Immunoregulatory response in the test DTH "" Example 44: Comparison of the immunosuppressive effect of the peptide by means of different routes of administration The peptide (Peptide No. 4 derived from SEQUENCE OF IDENTIFICATION No. 2) was administered to mice (groups of 10) orally and by parenteral injection (intravenous and subcutaneous injection) at doses of 0.0003 μmol / kg of body weight to 3.0 μmol / kg of body weight as for example 43. animals were examined as for Example 43; changes in the thickness of the ear are noted. The mean and standard error of the mean for each group of mice (10 per group) is recorded. It was found that the administration of the peptide by means of oral administration increases to a more marked immunoregulatory response than that observed, when the peptide is administered by other parenteral means.

Example 45: Comparison of the Immunoregulatory Effect in the Administration of Peptide Dimer (Peptide No. 36 - Derived from SEQUENCE OF IDENTIFICATION No. 2) by Different Ways of Administration The peptide (peptide No. 36) is administered to mice (groups of 10) at a dose of 0.03 μmol / kg body weight and 3. 0 μmol / kg body weight. The animals are examined as for Example 43; Changes in the thickness of the ear is observed. The mean and standard error of the mean for each group of mice (10 per group) was calculated. It was found that the peptide dimer produces a significant immunoregulatory effect in the DTH test in relation to the control and that the oral route of administration produces a stronger reaction in relation to the reactions observed in the administration of peptides of the same dose given via parenteral Example 46: Effects of Peptides (Peptide No. 1, Peptide No. 2, Peptide No. 7 and Peptide No. 4 and Peptide No. 8) on Tumor Growth 104 rats spontaneously developed mammary carcinoma cells in isotonic saline and 5% serum from normal syngeneic rats were inoculated in the right extremities of Wistar rats (8 per group). The size of the tumor was calculated by palpation and measurements with a calibrator of a first diameter (a), that the largest diameter and one (b) perpendicular to the first. The volume of the tumor is calculated using the formula: V = 0.4 ab2 The volume of the tumor is given in tn ^ as a mean for each group of rats (8 per group). The drug and control (isotonic saline) are administered per drink (esophasic tube) once a day (am) on each of days 4-8 and 11-15 for the peptides i) Gly Pro Cys Pro Gly (Peptide) No. 1 (SEQUENCE OF IDENTIFICATION NO 1)): 3 μmol / kg / day); ii) Pro Cys Cys Val Pro Wing (Peptide No. 7 (SEQUENCE OF IDENTIFICATION NO. 5)): 0.03 and 0.3 μmol / kg / day); iii) Val He Cys Cys Leu Thr (Peptide No. 8 (SEQ ID NO: 6)): and 0.3 μiuol / kg / day); iv) Pro Gly Cys Cys Gly Pro (Peptide No. 4 (derived from SEQ ID NO: 2)): 0.03 and 0.3 μmol / kg / day); μmol / kg / day); and on each of the 6-9 and 13-20 days for the peptide Gly Pro Cys Cys Pro Gly (Peptide No. 2 (derived from SEQ ID NO: 1)): 0.003, 0.03, 0.3 and 3.0 μmol / kg / day); and 3.0 μmol / kg / day). The results for peptides 1, 2 and 4 show a marked decrease in tumor volume compared to the control at all dose levels tested.

LIST OF SEQUENCES (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: ASTRA AB (B) STREET: Vaestra Maelarehamnen 9 (C) CITY: Soedertaelje (E) COUNTRY: S eden (F) POSTAL CODE (ZIP): S- 151 85 (G) TELEPHONE: + 46-8-553 260 00 (H) TELFAX: + 46-8-553 288 20 (I) TELEX: 19237 astra s (ii) TITLE OF THE INVENTION: Immunomodulatory Peptides (iii) SEQUENCE NUMBER: 30 (iv) READING FORM ON THE COMPUTER: (A) TYPE OF MEDIUM: flexible disk (B) COMPUTER: compatible with an IBM PC (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) SOFTWARE: Patentln Relay # 1.0, Version # 1.30 (EPO) (2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) CHAIN FORM: (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..6 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 1 Gly Pro Cys Cys Pro Gly 1 5 (2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 2: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..6 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 2 Pro Gly Cys Cys Gly Pro 1 5 (2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 3: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..6 (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide (B) LOCATION: 3..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 3 Trp Pro Cys Cys Pro Trp 1 5 (2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 4 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acids (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Peptide (B) LOCATION: 1..7 (ix) FEATURE: (A) NAME / KEY: Site-modified (B) LOCATION: 7 (C) OTHER INFORMATION: / products = "OTHER" / note = "Cys-NH2" (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide (B) LOCATION: 6..7 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 4 S- Leu Leu Phe Gly Pro Cys Xaa (2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 5: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear 10 ( xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 5 Wing Pro Cys Cys Val Pro 1 5 15 (2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 6: (i) CHARACTERISTICS OF SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid 20 (C) FORM OF LA CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide 25 (B) LOCATION: 3..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO 6: Val lie Cys Cys Leu Thr 1 5 (2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 7: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide (B) LOCATION: 3..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 7 Thr Pro Cys Cys Phe Wing 1 5 (2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 8: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide (B) LOCATION: 3..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 8 Glu Glu Cys Cys Phe Tyr 1 5 (2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 9: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 9 Pro Val Cys Cys lie Gly 1 5 (2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 10: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 10: Val Cys He Cys Gln 1 5 (2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 11: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 11 Leu Ala Cys Cys Val Val 1 5 (2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 12: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 12 Val Cys Gly Cys Arg 1 5 (2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 13: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide (B) LOCATION: 3..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 13 / "Ser Gln Cys Cys Ser Leu 2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 14: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear 10 (xi) ) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 14 Lys Pro Cys Cys Glu Arg 1 5 15 (2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 15: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid 20 (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide 25 (B) LOCATION: 2..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 15: Lys Cys Arg Cys Lys 1 5 (2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 16: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 16 Lys Glu Cys Cys Tyr Val 1 5 (2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 17: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide (B) LOCATION: 3..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 17 Ser He Cys Cys Thr Lys 1 5 (2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 18: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide (B) LOCATION: 3..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 18 Lys Leu Cys Cys Asp He 1 5 (2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 19: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 19: Pro Asp Cys Cys He Pro 1 5 (2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 20: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 20 Asp Cys He Cys Gln 1 5 (2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 21: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 21: He Cys Thr Cys Glu 1 5 (2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 22: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide (B) LOCATION: 2..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 22 Leu Cys Ala Cys Val 1 5 (2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 23: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 23 Lys Leu Cys Cys Gln Met 1 5 (2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 24: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 24 Phe Cys He Cys Lys 1 5 (2) INFORMATION FOR IDENTIFICATION SEQUENCE NO: 25: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) CHAIN FORM: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 25 Arg Cys Ser Gly Cys Cys Asn 1 5 (2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 26: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 26 Ala Cys Lys Cys Gln 1 5 (2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 27: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 27: Gly Pro Cys He Cys Pro Gly 1 5 (2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 28: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide (B) LOCATION: 3..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 28 Pro Gly Cys Cys Pro Gly 1 5 (2) INFORMATION FOR THE SEQUENCE OF IDENTIFICATION NO: 29: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide (B) LOCATION: 3..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 29 Wing Pro Cys Cys Glu Ser 1 5 (2) INFORMATION FOR THE IDENTIFICATION SEQUENCE NO: 30: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (C) FORM OF THE CHAIN: (D) TOPOLOGY: linear (ix) CHARACTERISTICS: (A) NAME / KEY: Link-disulfide (B) LOCATION: 3..4 (xi) DESCRIPTION OF THE SEQUENCE: SEC. FROM IDENT. NO: 30: Pro Ala Cys Cys Gly Pro 1 5 It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims

1. A physiologically active peptide, purified, characterized in that it comprises at least two cysteine amino acid residues, the two residues are aligned contiguous with each other or separated by no more than 1 amino acid residue, the peptides are absorbable by the epithelial cell lining in a mammal that it results in a modulated immune response and therefore a therapeutic effect against the disease.

2. The peptide according to the claim 1, characterized in that it is in the form of a dimer, in which the second peptide of the dimer is linked to the first peptide by means of sulfur to sulfur bonds between at least two cysteine amino acid residues of the first peptide and at least two residues Cysteine amino acids of the second peptide.

3. The peptide according to the claim 2, characterized in that the dimer is selected from the group consisting of parallel dimers, antiparallel dimers and heterodimers.

4. The peptide according to any of claims 1 to 3, characterized in that it is of the length of 4 amino acids to about 30 amino acids.

5. The peptide according to any of claims 1 to 4 characterized in that it is of a length of 4 amino acids to about 20 amino acids. "-

6. The peptide according to any of claims 1 to 5 characterized in that it is of a length of 4 to 15 amino acids.

7. The peptide according to any of claims 1 to 6, characterized in that it comprises amino acids that occur naturally and / or amino acids that do not occur naturally.

8. The peptide according to any one of claims 1 to 7, characterized in that the peptide consists of amino acid residues independently selected from He, Leu, Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, Lys, Phe, Pro, Ser, Thr, Trp, Tyr, Met, His and Val.

9. The peptide according to any of claims 1 to 8 of Formula (I): (A) n-X-Cys-Cys-Y- (B) m. (I) characterized in that each A is independently selected from the group consisting of H, a protecting group or at least one amino acid residue independently selected from the group of amino acid residues in any L or D form having aliphatic side chains, hydroxyl aliphatic side chains, basic side chains, acid side chains, aminosecundaria groups, amide side chains, aromatic side chains and side chains containing sulfur; n is an integer selected from the group consisting of the set of 1 to 11; X is selected from the group consisting of NH, and the group of amino acid residues having aliphatic side chains, secondary amino groups, amide side chains, acid side chains and aliphatic side chains; Y is selected from the group consisting of NH and amino acid residues having aminosecundarial groups, aliphatic side chains, acid side chains, aliphatic hydroxyl side chains, aromatic side chains and amide side chains; Each B is independently selected from the group consisting of H, OH, NH2, a protecting group or at least one amino acid residue selected from the group of amino acid residues having aliphatic side chains, aliphatic hydroxyl side chains, basic side chains, acid side chains , secondary amino groups, amide side chains, aromatic side chains and side chains containing sulfur; m is a whole number selected from the set of 1 to 11; with the proviso that when A is not at least one amino acid residue, n is 1 and when B is not at least one amino acid residue, m is 1; and each peptide sequence contains no more than 15 amino acid residues.

10. A peptide according to claim 9, characterized in that: X is selected from the group consisting of Gly, Pro, Gln, He, Val, Asp, Leu, Glu, Ala and NH; and Y is selected from the group consisting of Pro, Gly, Leu, Glu, Val, He, Ser, Phe, Tyr, Thr, Asp, Gln and NH.

11. The peptide according to claim 9 or claim 19, characterized in that: Xes Gly and YßsGly; X is Pro and Yes Pro; Xes ro and Y is Val; X is líe and Yes Leu; Xes Pro YßsGlu; X is Glu Y Yes Tyr; X is Pro and Y is Phe; X is Glu and Yes Phe; X is Ala and Y is Val; X is Val and Yeslle; X is Gln and Yes Being, X is Of and Y is Thr, X is Leu and Yes Asp; X is Asp and Yes De; X is Leu and YesGln; X esdy and Y is Asn; X is Gly and Y is Pro; or X is Ala and Y is Gly.

12. The peptide according to any of claims 9-1. in the form of a dimer prepared from up to 2 peptide sequences, wherein the second peptide is linked to the first peptide by means of sulfur to sulfur bonds between the two amino acid residues cysteine of the first peptide at the two amino acid residues cysteine of the second peptide .

13. The peptide in dimeric form according to claim 12, characterized in that it consists of two similar peptide sequences.

14. The peptide according to the claim 11, characterized in that it is selected from the group of: Gly-Pro-Cys-Cys-Pro-Oly; Pro-Gly-Cys-Cys-Gly-Pro; Ala-Pro-Cys-Cys-Val-Pro; Lys-Pro-Cys-Cys-Glu-Arg; Pro-Asp-Cys-Cys-De-Pro: and Arg Cys Ser Gly Cys Cys Asn.

15. The peptide according to the claim 11, characterized in that it is selected from the group: Gly-Pro-Cys-Cys-Pro-Gly; I 1 Pro-Gly-Cys-Cys-Gly-Pro; I I Trp-Pro-Cys-Cys-Pro-Trp; Val-pe-Cys-Cys-Leu-Thr, I I Thr-Pro-Cys-Cvs-Phe-Ala; l_J Glu-Glu-Cys-Cys-Phe-Tyr, I I Lys-Leu-Cys-Cys-Asp-Hr, Lys-Glu-Cys-Cys-Tyr-Val; Y Pro Ala Cys Cys Gly Pro.

16 The peptide: Pro Gly Cys Cys Gly Pro

17. the peptide in accordance with the claim 14, characterized in that it is selected from the group: Gly-Pro-Cys-Cys-Pro-Gly; Pro-Gly-Cys-Cys-Gly-Pro; Ala-Pro-Cys-Cys-Val-Pro; Lys-Pro-Cys-Cys-Glu-Arg; and Arg Cys Ser Gly Cys Cys Asn.

18. The peptide according to the claim 15, characterized in that it is selected from the group: Pto-Gly-Cys-Cys-Gly-Pro; LJ Val-De-Cys-Cys-Leu-Thr, Lys-Glu-Cys-Cys-Tyr-Val; Gly-Pro-Cys-Cys-Pro-Gly; and i 1 ProAla Cys Cys Gly Pro

19. The peptide according to any of claims 1 to 8 of Formula (II): (A) nX-Cys-Z-Cys-Y- (B) m (II) characterized in that each A is independently selected from the group consisting of of H, a protecting group or an amino acid residue selected from the group of amino acid residues in any L or D form having aliphatic side chains, aliphatic hydroxyl side chains, basic side chains, acid side chains, secondary amino groups, amide side chains, and side chains containing sulfur; n is an integer selected from the set of 1 to 10; X is selected from the group consisting of NH, and the group of amino acid residues having aliphatic side chains, secondary amino groups, aromatic side chains, acid side chains and amide side chains; Z is selected from the group consisting of amino acid residues having aliphatic side chains, aliphatic hydroxyl side chains and acid side chains; And it is selected from the group consisting of amino acid residues which have amide side chains, basic side chains, aliphatic side chains, acid side chains and secondary amino groups; Each B is independently selected from H, OH, NH2, a protecting group or an amino acid residue selected from the group of amino acid residues having aliphatic side chains, aliphatic hydroxyl side chains, basic side chains, acid side chains, secondary amino groups, amide side chains, and side chains containing sulfur; m is a whole number selected from the set of 1 to 10; with the proviso that when A is not at least one amino acid residue, n is 1 and when B is not at least one amino acid residue, m is: and each peptide sequence contains no more than 15 amino acid residues.

20. The peptide according to claim 19, characterized in that: X is selected from the group consisting of Gly, Pro, Gln, He, Phe, Val, Asp, Leu, Glu, Ala, Lys or NH; And it is selected from the group consisting of Pro, Gly, Glu, Val, Lys, Gln and Arg; and Z is selected from the group consisting of He, Arg, Gly, Phr, Ala and Lys.

21. The peptide according to claim 19 or claim 20, characterized in that it is in the form of a dimer formed of two peptide sequences, wherein the second peptide is linked to the first peptide by means of sulfur to sulfur bonds between the two cysteine amino acid residues of the first peptide to the two cysteine amino acid residues of the second peptide.

22. The peptide in dimeric form according to claim 21, characterized in that it consists of two similar peptide sequences. 23. The peptide according to claim 19 or claim 20, selected from the group consisting of:

Val Cys De Cys Gln; Val Cys Gly Cys Arg; Asp Cys De Cys Gln; From Cys Thr Cys Glu; Phe Cys De Cys Lys; and AJa C s Lys CysOln.

24. The peptide selected from the group consisting of From Cys Thr Cys Glu; Lys Cys Arg Cys Lys; Leu Cys Ala Cys Val; and I I Asp Cys De Cys Gln. i i

25. The peptide selected from the group:

26. The peptide according to any of claims 1-25 characterized in that it is free of an aggregate transport agent.

27. The acid addition salts of peptides according to any of claims 1-26.

28. The acid addition salts according to claim 27, characterized in that they are selected from the group consisting of hydrochloric, hydrobromic, nitric, perchloric, sulfuric, citric, tartaric, phosphoric, lactic, benzoic, glutamic, oxalic, aspartic acid, pyruvic, acetic, succinic, fumaric, maleic, oxaloacetic, isotonic, static, phthalic, methanesulfonic, p-toluenesulfonic, benzenesulfonic, lactobionic, and glucuronic.

29. The basic peptide salts according to any of claims 1-26.

30. The basic salts according to claim 29, characterized in that they are selected from the group consisting of alkali metal and alkaline earth metal salts, salts of organic bases and salts of amino acids.

31. An oral dosage form characterized in that it comprises an immunoregulatory peptide according to any of claims 1 to 26.

32. An oral dose form according to claim 31, characterized in that the amount of the immunoregulatory peptide necessary to induce an observable level of modulated immune response in a mammal, when administered orally is less than the amount of the same immunoregulatory peptide when administered parenterally , which is necessary to achieve a similar observable level of modulated immune response in the mammal.

33. An oral dosage form according to claim 32, which does not include an aggregated transport agent.

34. An intra-tracheal dose form characterized in that it comprises an immunoregulatory peptide according to any of claims 1 to 26.

35. An intra-tracheal dose form according to claim 34, characterized in that the amount of the immunoregulatory peptide necessary to induce an observable level of modulated immune response in a mammal, when administered intratracheally, is less than the amount of the same peptide immunoregulatory, when administered parenterally, which is necessary to achieve a similar observable level of modulated immune response in the mammal.

36. An intra-tracheal dosage form according to claim 35, which does not include an aggregated transport agent.

37. A nasal dose form characterized in that it comprises an immunoregulatory peptide according to any of claims 1 to 26.

38. A nasal dose form according to claim 37, characterized in that the amount of the immunoregulatory peptide necessary to induce an observable level of regulated immune response in a mammal, when administered nasally, is less than the amount of the same immune regulatory peptide when administered parenterally, which is necessary to achieve a similar observable level of modulated immune response in the mammal.

39. The nasal dosage form according to claim 38, characterized in that it does not include an aggregate transport agent.

40. The pharmaceutical formulation characterized in that it comprises at least one peptide according to any one of claims 1 to 26 or a salt thereof, together with a pharmaceutically acceptable carrier.

41. The pharmaceutical formulation according to claim 40, characterized in that the pharmaceutical formulation is for oral administration.

42. The pharmaceutical formulation according to claim 40 or 41, characterized in that it comprises at least one peptide of the Formula (I) or its physiological derivative together with a pharmaceutical carrier.

43. The pharmaceutical formulation according to any of claims 40 to 42, characterized in that it comprises at least one peptide of the Formula (I) or a salt thereof and at least one peptide of the Formula (II) or a salt thereof along with a pharmaceutical carrier for it.

44. The peptide according to any one of claims 1 to 26 or a salt thereof in an oral dosage form for use in therapy.

45. The peptide according to any one of claims 1 to 26 or a salt thereof in oral dosage form for use in cancer therapy.

46. The peptide according to any one of claims 1 to 26 or a salt thereof in an oral dosage form for use in therapy of an autoimmune disease.

47. The peptide according to any one of claims 1 to 26 or a salt thereof for use in therapy.

48. The peptide according to any one of claims 1 to 26 or a salt thereof for use in cancer therapy.

49. The peptide according to any one of claims 1 to 26 or a salt thereof, for use in the therapy of rheumatoid arthritis.

50. The use of a physiologically active peptide according to any one of claims 1 to 26 or a salt thereof, in the preparation of a medicament suitable for the treatment of the disease.

51. The use of a physiologically active peptide according to any one of claims 1 to 26 or a salt thereof, in the preparation of a medicament suitable for the treatment of cancer.

52. The use of a physiologically active peptide according to any one of claims 1 to 26, or a salt thereof, in the preparation of a medicament suitable for the treatment of autoimmune disease.

53. The use of a physiologically active peptide according to any one of claims 1 to 26 or a salt thereof, free of an added transport agent in the preparation of a medicament suitable for the treatment of rheumatoid arthritis.

54. A method for preparing a pharmaceutical formulation, comprising bringing in association at least one peptide according to any one of claims 1 to 26 or at least one salt thereof and a pharmaceutically acceptable carrier therefor.

55. The method according to claim 54, characterized in that it comprises carrying in association at least one peptide of the formula (I) and / or at least one peptide of the formula (II) or its salts and a pharmaceutically acceptable carrier therefor. .

56. The method for inducing an immunoregulatory response in a mammal, characterized in that it comprises identifying a mammal in need of an immunoregulatory response; and administering to the mammalian epithelial cell liner a dose of the physiologically active peptide according to any one of claims 1 to 26 or a salt thereof, sufficient to induce the modulated immune response and therefore a therapeutic effect.

57. The method in accordance with the claim 56, characterized in that it comprises administering to the MALT of the mammal a dose of a physiologically active peptide of the Formula (I) or a salt thereof in an amount sufficient to induce a modulated immune response and therefore a therapeutic effect.

58. The method according to claim 56 or claim 57, characterized in that it comprises administering to the MALT of the mammal a dose of a physiologically active peptide of the Formula (II) or a salt thereof in an amount sufficient to induce a modulated immune response and therefore a therapeutic effect.

59. A method for making a peptide according to any of claims 1-26 by a chemical process, in which individual amino acid residues or fragments of peptides of the invention, bind to form peptide bonds and in which the protecting groups are used at the beginning and / or at the end of the process.