MXPA00011752A - Synthetic somatostatin immunogen for growth promotion in farm animals - Google Patents

Abstract

The invention provides peptides comprising somatostatin, or a sequence homologous to somatostatin, which is covalently linked to a helper T cell epitope and optionally to other immunostimulatory sequences. The present invention provides for the use of such peptides as immunogens to elicit the production in mammals of high titer polyclonal antibodies, which are specific to somatostatin. The peptides are expected to be useful in lowering somatostatin levels in mammals, thereby increasing growth rate and food utilization efficiency.

Description

IMMUNOGENOUS OF SYNTHETIC SOMATOSTATIN FOR PROMOTION OF THE GROWTH OF FARM ANIMALS FIELD OF THE INVENTION This invention relates to a peptide composition that is useful as an immunogen for promoting the growth of farm animals. The immunogenic peptides of the subject composition contain epitopes of helper T cells (Th) which comprise multiple MHC class II binding motifs and have somatostatin either at the C- or N-terminus. The peptides, optionally, contain an invasin domain which acts as a general immune stimulator. The attendant T cell epitopes and the invasin domain allow the immune response against the self-peptide somatostatin.

BACKGROUND OF THE INVENTION The recent understanding of the neuro-endocrine and hormonal factors involved in growth, together with the rapid advances in biotechnology, have provided potential avenues for the improvement of the rate of growth in a variety of farm animal species. A method for the promotion of animal growth that modifies the regulatory effects of growth hormones through immunoneutralization is a valuable alternative to the present methods which use antibiotics, anabolic steroids, and growth hormones as growth promoters. This application of antibiotics to the breeding of domestic animals is believed to be a driving force for the selection of antibiotic resistance in certain pathogenic bacterial species and has resulted in adverse consequences in the control of human infectious disease (Witte, Science, 1998; 279: 996). The application of anabolic steroids promotes growth in farm animals, but is not popular with consumers. The use of steroids is restricted in Europe both by legislation and by public opinion (Buttery and Dawson, Proc Nutr Soc, 1990; 49: 459). Recombinant DNA technology has allowed the production of metabolic hormones in large quantities for direct administration to animals. Such an application can promote growth. It is, however, only one of the stages that need to be taken if the somatotrophic hormones are to be used as a means of improving animal performance. The main somatotrophic hormones are: somatotropin (growth hormone, GH), somatomedin-C (insulin-like growth factor-1, IGF-1), somatocrinin (GH releasing factor, GRF) and somatostatin (factor that inhibits the release of GH). The main potential applications for somatotrophic hormones are in growth and lactation, however the hormonal control of these phenomena lies in a complex interaction between many different hormones (Spencer, Livest Prod Sci, 1985, 12:31). Thus, the simple application of a simple hormone may not be enough to improve productivity. It seems that GH plays two different roles. It has a positive effect to stimulate an increase in the synthesis of muscle protein (most, if not all, of which was measured by IGF-1) and a potent catabolic effect for its ability to break down fats. The general effects are an increase in the animal's lean corpse content and a decrease in the animal's corpse fat, often an increase in growth, and universally an improvement in feed conversion efficiency (Buttery and Dawson, Proc Nutr Soc, 1990; 49: 459; and, Spencer, Reprod Nutr Develop, 1987; 27 (2B): 581). The effects on growth with the administration of GH are not reliable for use in practice; probably due to the administration of exogenous hormones, it ignores the sensitive interrelation between different hormones and ignores the possible effect of the elevation of the plasma levels of the receptor populations. The effective application of GH requires frequent injections in such a way as to provide a continuous physiologically effective serum hormone level. This results in an increased risk of upsetting these balanced relationships and causing adverse effects. A) YesAlthough pure preparations of growth hormones can be manufactured in large quantities by recombinant DNA technology, this technology does not provide the modulated mechanism for delivery that is needed for the desired effect on growth. In addition, the use of recombinant growth hormones in edible animals, most recently in dairy cows, has resulted in widespread consumer opposition and regulatory obstacles. The use of growth hormone to promote lean deposition in ruminants and other farm animals has not received regulatory approval within the European Economic Community. The regulatory and political situation is similar for the application of IGF-1 or GRF to promote growth in farm animal species. As an alternative to increase levels of hormones that stimulate growth, it may prove to be equally, or even more effective, to eliminate endogenous growth inhibitors. The main inhibitor of total somatic growth is somatostatin. Somatostatin is a cyclic peptide of fourteen amino acids and its structure is conserved throughout the species. It is synthesized as a ninety-two amino acid prosomatostatin molecule of which it is known to derive six peptides including somatostatin itself in a form of somatostatin of twenty-eight amino acids (Reichlin, J Lab Clin Med, 1987; 109: 320). Somatostatin inhibits release in many gastrointestinal hormones as well as inhibits the release of thyroid hormones, insulin, GH, thereby affecting both the ability of the animal to absorb nutrients and its subsequent ability to direct these nutrients into tissue growth. It has been found that the use of a somatostatin antagonist stimulates growth in rats (Spencer et al., Life Sci, 1985, 37:27), but this type of treatment also suffers from the disadvantages of GH, IGF-1 and GRF. because it requires daily injections. A practical alternative is the use of the immune response to induce the immunoneutralization of somatostatin. The use of the immune system to promote growth may be more acceptable to consumers and regulatory agencies than the direct administration of hormone or synthetic steroids. The immunoneutralization of somatostatin per vaccine was first explored in sheep by Spencer et al. (Livest prod Sci, 1983, 10: 469). In a preliminary study using St. Kilda lambs, twins, active immunization against somatostatin resulted in the growth of lambs treated at 176% of the speed of control lambs (Spencer et al., Anim Prod, 1981, 32: 376 ). Subsequent studies have been unable to reproduce this value, but an improvement of 15-20% in the rate of growth is more usual. The somatostatin molecule is the same in all farm animal species, and it has now been shown that active immunization against somatostatin can stimulate growth in commercially important sheep species (Spencer et al., Livest Prod Sci, 1983, 10:25, Laarveld et al., Can J Anim Sci, 1986, 66:77), cattle (Lawrence et al., J Anim Sci, 1986, 63: (Suppl) 215), pigs and chickens (Spencer et al. al., Dom Anim Endocr, 1986, 3:55). A summary of successful examples demonstrating effective immunization against somatostatin for farm animals is shown in Table 1. In addition to stimulating the growth rate and leading to a 20% reduction in breeding time (Spencer, Reprod. Nutr Develop, 1987; 27 (2B): 581), active immunization against somatostatin also has a beneficial effect on feed conversion efficiency. In addition to saving on feed by virtue of faster growth, animals currently use their feed more efficiently during the growth period (Spencer et al., Livest Prod Sci, 1983, 10: 469), at least partially as a result of changes in bowel mobility (Fadlalla et al., J Anim Sci, 1985, 61: 234; Faichney et al., Can J Anim Sci, 1985, 64 (Suppl) 93). The treatment has no marked effect on the composition of the carcass (Spencer et al., 1983, ibid.) But there are indications that, when killed at equal weights, the treated animals may be lean. Taking all the experimental data together, active immunization seems to be a powerful, safe and effective tool to improve growth (Spencer, Dom Anim Endocr, 1986, 3:55). Various immunogenic forms of somatostatin have been designed and tested as reported in the literature. For example, somatostatin has been conjugated with protein carriers to improve immunopotency. However, protein carriers are too expensive for economical use in farm animals. Additionally, effective immunization with somatostatin depends on the conjugation site between somatostatin and the carrier. Most if not all of the somatostatin protein carrier conjugates were prepared by glutaraldehyde coupling, using crosslinking between the lysine residues present in the somatostatin and the carrier protein. the two somatostatin plants available for coupling received within a 12-part functional ripple can result in significant loss of the native structure of somatostatin and reduction in cross-reactivity to somatostatin when such conjugates are used as vaccines.

A. In addition, the protein binding to somatostatin is problematic because most immune responses are directed to the carrier rather than somatostatin (the mass of the carrier molecule (s) is much larger than the mass of the carrier molecule. somatostatin) and immunization with hapten carrier conjugates frequently leads to carrier-induced immunosuppression (Schutz et al., J ^ Immunol, 1985, 135: 2319). Consequently, an immuno-improver that is suitable for use in cattle, cheap and capable of stimulating an early and strong immune response to somatostatin has been sought. This immuno-enhancer must avoid carrier-induced suppression. An important factor affecting the immunogenicity of a synthetic peptide for a somatostatin immunogen is their presentation to the immune system by epitopes of T-helper cells. Previously, these were provided by a carrier protein with the related disadvantages discussed above. These can also be supplied as hybrid polypeptides by DNA expression systems Recombinant (Riggs, US 4,812,554, US 4,563,424, and Xu et al., Science in China (Series B), 1994; 37: 1234). These may also be simpler and less expensive provided by a synthetic peptide comprising the target B cell hapten site and attendant T (Th) epitopes appropriate for the guest. Such peptides react with helper T-cell receptors and MHC class II molecules, in addition to the anty binding sites (Babbitt et al., Nature, 1985, 317: 359) and thus closely stimulate a specific anty response at the site. , for the anty binding target site (target site). A fully synthetic peptide immunogen for somatostatin would enjoy the following advantages over carrier conjugates and recombinant polypeptides: the product is chemically defined for ease of quality control, is stable, an elaborate downstream process is not required, a plant is not required. elaborate production, and the engendered immune response is site-specific so that undesirable responses such as epitopic suppression are avoided. The immunogenicity of synthetic somatostatin immunogens can be optimized by (1) combining somatostatin with selected promiscuous Th sites for which the majority of a population is responsive; (2) combining somatostatin with an enlarged repertoire of Th through combination chemistry and thereby accommodating the variable immunoresponsibility of a population, and (3) stabilizing a desirable conformational characteristic of somatostatin by cyclic restriction. Epitopes called promiscuous Th evoke sufficient assistance of T cells and can be combined with B cell epitopes that by themselves are poorly immunogenic to provide potent immunogens. Well-designed promiscuous Th / epitope B epitope peptides are capable of producing Th responses and resulting anty responses in the majority of members of a genetically diverse population that express diverse MHC halotypes. Promiscuous Th may be provided by specific sequences derived from potent immunogens that include measles virus F protein and hepatitis B virus surface antigen. Many known promiscuous Th have been shown to be effective in potentiating a poorly immunogenic peptide corresponding to the hormone. Decapeptide LHRH (U.S. Patent 5,759,551). Th potent epitopes vary in size from approximately 15-30 amino acid residues in length, frequently share common structural features, and may contain specific tag sequences. For example, a common characteristic are amphipathic helices, which are alpha-helix structures with hydrophobic amino acid residues that dominate one side of the helix and with charged polar residues that dominate the surrounding faces (Cease et al., Proc Nati Acad Sci USA, 1987; 84: 4249-4253). Th epitopes often contain additional primary amino acid patterns such as a Gly or charged residue followed by two to three hydrophobic residues, followed in turn by a charged or polar residue. This film pattern what are called Rothbard sequences. Also, Th epitopes frequently obey rule 1, 4, 5, 8, where a positively charged residue is followed by hydrophobic residues at the fourth, fifth and eighth positions after the charged residue. Since all these structures are composed of common hydrophobic charged and polar amino acids, each structure can exist simultaneously within a single Th epitope (Partidos et al., J Gen Virol, 1991; 72: 1293). Most, if not all, of the promiscuous T-cell epitopes fit into at least one of the perioricities described above. These characteristics can be incorporated within the designs of idealized artificial Th sites, which include combinatorial Th epitopes. Regarding the design of the combinatorial Th sites, lists of variable positions and preferred amino acids are available for MHC binding motifs (Meister et al., Vaccine, 1995, 13: 581-591); and, a method for producing combinatorial Th for structured synthetic antigen library or SSAL library peptides has been described (Wang et al., WO 95/11998). Thus, the 1,4,5,8 rule can be applied together with the combinatorial MHC binding motifs in the assignment of positions for the unchanged and degenerated sites of an SSAL and for the selection of residues for these sites, in such a way that they vastly enlarge the range of immunoresponsibility to an artificial Th (WO 95/11998). Peptide immunogens are generally more flexible than proteins and do not tend to retain any preferred structure. Therefore it is useful to stabilize a peptide immunogen by the introduction of cyclic constraints. A properly cyclized peptide immunogen can mimic and preserve the selected epitope conformation and thereby evoke antibody with cross-reactivities at that site on the authentic molecule (Moore, Chapter 2 in Synthetic Peptides A User's guide, ed Grant, WH Freeman and Company: New York, 1992, pp. 63-67). Peptide immunogens that have been designed with the peptide technologies and peptide design elements discussed above, eg, the design of potent promiscuous Th epitopes, TH SSAL combinatorial peptides, and cyclic constraints, are the basis for effective synthetic somatostatin immunogens. Such peptides are preferred for their presentation of somatostatin by optimized position and cyclization, and for the responsiveness of widely reactive Th. Accordingly, it has been found that peptides that contain particular structural arrangements of a Th epitope alone or linked to a general immunogenitor, e.g., an invasin domain (U.S. Patent 5,759,551) and somatostatin in its intact form wherein the functional site within the undulated 12-part structure is not disturbed (as a target antigen), they are effective in stimulating the production of antibodies against somatostatin.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to an immunogenic peptide composition comprising synthetic peptides, which are capable of inducing antibodies against somatostatin which leads to the suppression of somatostatin levels, promote growth and improve the efficiency of conversion of food into farm animals. In particular, the peptides of this invention have a Th epitope attached to a carboxylic or amino terminal somatostatin (SEQ ID NO: 1) or a somatostatin analogue peptide. Optionally, the peptides have an invasin domain (SEQ ID NO: 2) as a general immunostimulator. These peptides are effective as immunogens, capable of increasing the serum level of growth hormone in immunized hosts to promote daily weight gain in farm animals. Another aspect of this invention provides an antigenic composition comprising an immunologically effective amount of a peptide composition according to this invention and one or more pharmaceutically acceptable vaccine formulations and instructions for dosing such that immunotherapeutic antibodies directed against the site. of somatostatin target are generated. Such peptide compositions are useful for the promotion of growth in farm animals. A further aspect of the invention relates to a method for increasing circulating somatotropic hormone levels in a mammal by administering one or more of the peptides subject to the mammal for a time and under conditions sufficient to induce functional antibodies directed against somatostatin. . Yet another aspect of the invention relates to an immunogenic synthetic peptide of about 30 to about 90 amino acids which contains an epitope (Th) of helper T cells, somatostatin (SEQ ID NO: 1) or a somatostatin analogue peptide. , spacers for separating the immunogenic domains and optionally the general immunostimulatory sites, for example, an invasin domain (SEQ ID NO: 2). These three immunogenic domain elements of the peptide and the spacer can be covalently linked in any order with the proviso that any of the peptide hapten immunoreactivity is substantially retained or that immunostaining to the somatostatin self-peptide can be generated.

DETAILED DESCRIPTION OF THE INVENTION This invention is directed to a novel peptide composition for the generation of high titer polyclonal antibodies with specificity for somatostatin. The high specificity of sites of the peptide composition minimizes the generation of antibodies that are directed to irrelevant sites on carrier proteins. Therefore, the invention is directed to an effective method for the promotion of growth in farm animals. Somatostatin (SEQ ID NO: 1) is a short cyclized peptide hormone which, by itself, is not immunogenic, to a greater degree because it is an autoantigen. This short peptide can be immunopotentiated by chemical coupling to a carrier protein, for example, slotted limpet hemocyanin (KLH) or by fusion to a carrier polypeptide through the expression of recombinant DNA, for example, hepatitis B surface antigen. The main shortcomings of such "somatostatin carrier" vaccines is that the largest portion of antibodies generated by the combinations are non-functional antibodies directed against the carrier protein or polypeptide and the potential for epitope deletion. The immunogens of the present invention are completely synthetic peptides which minimize the generation of irrelevant antibodies to produce a more focused immune response to somatostatin. However, because somatostatin is not an immunogenic T cell-dependent antigen, it is completely dependent on Th extrinsic epitopes for immunogenicity. These are provided for the peptides of the invention as promiscuous, covalently bonded Th epitopes. The immunogens of the invention are all site-specific immunoreactivity to provide effective growth promotion in cattle. Specific examples are provided in the present invention as embodiments of the peptides of the invention. These examples provide the binding of synthetic immunostimulatory elements to the somatostatin peptide in such a way that potent somatostatin-reactive antibodies are generated, in a genetically diverse host population. These antibodies, in turn, lead to the inhibition of somatostatin function resulting in effective promotion of the growth of cattle. For active immunization, the term "immunogen" referred to herein refers to a peptide composition that is capable of inducing antibody against somatostatin, which leads to the inhibition or suppression of somatostatin levels in a mammal. The peptide composition of the present invention includes peptides which contain promiscuous helper T cell epitopes (Th epitope). The peptides are covalently linked to the somatostatin peptide, with a spacer (eg, Gly-Gly), such that it is adjacent to either the N- or C-terminus of the target somatostatin peptide, to evoke efficient antibody responses. The immunogen can also comprise a generalized immunostimulatory element, for example, a domain of an invasive protein of the bacterium Yersinia spp (Brett et al., Eur J Immunol, 1993, 23: 1608-1614) (SEQ ID NO: 2). The invasin domain binds via a spacer to a Th peptide. The peptides of this invention can be represented by the formulas: H2N- (A) n- (somatostatin a peptide) - (B) 0- (Th) mX or H2N - (A) n- (Th) m- (B) 0- (somatostatin peptide) -X wherein H2N is the N-terminal a-NH2 of the peptide conjugate, each A is independently an amino acid or a general immunostimulatory sequence; each B is selected from the group consisting of amino acids, -NHCH (X) CH2SCH2CO-, -NHCH (X) CH2SCH2CO (e-N) Lys-, -NHCH (X) CH2S-succinimidyl (e-N) Lis-, and -NHCH (X) CH2S- (succinimidyl) -; each Th is independently an amino acid sequence comprising an attendant T cell epitope, or an immunomodulatory analog or segment thereof; the somatostatin peptide is somatostatin or an immunologically functional cross-reactive analogue thereof; X is an amino acid a-COOH or a-CONH2; n is from 1 to about 10; m is from 1 to about 4; and o is from 0 to about 10. The peptide immunogen of the present invention comprises from about 20 to about 100 amino acid residues, preferably from about 25 to about 80 amino acid residues and more preferably from about 25 to about 65 amino acid residues. When A is an amino acid or a general immunostimulatory element, for example Inv, it can be covalently linked to either the N-terminal peptide immunogen as shown by the formulas, or the C-terminal (not shown). When A is an amino acid, it can be any amino acid that occurs naturally or does not occur naturally. Amino acids that do not occur naturally include, but are not limited to β-alanine, ornithine, norleucine, norvaline, hydroxyproline, tyrosine, α-aminobutyric acid, homoserine, citrulline and the like. The naturally occurring amino acids include alanine, arginine, aspargine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, Usina, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. In addition, when m is larger than one, and two or more of groups A are amino acids, then each amino acid can be independently the same or different. When A is an invasin domain, it is an immunostimulatory epitope of the invasin protein of a Yersinia species. This immunostimulatory property results from the ability of this invasin domain to interact with the β1 integrin molecules present in T cells, particularly memory T cells or immunoactivated cells. The specific sequence for an invasin domain that has been found to interact with the β1 integrins has been described by Brett et al (Eur J Immunol, 1993). A preferred embodiment of the invasin domain (Inv) for binding to a promiscuous Th epitope has previously been described in US Patent 5,759,551 and is incorporated herein by reference. The Inv domain has the sequence: Thr-Ala-Lys-Ser-Lys-Lys-Phe-Pro-Ser-Tyr-Thr-Ala-Thr-Tyr-Gln-Phe (SEQ ID NO: 2) or is an immunostimulatory homologue thereof. corresponding region in another invasive protein of the Yersinia species. Such homologs may thus contain substitutions, deletions or insertions of amino acid residues to accommodate variation from strain to strain, with the proviso that the homologs retain the immunostimulatory properties. In one embodiment, n is 1 and A is a-NH2. In another embodiment, n is 4 and A is a-NH2, an invasin domain (Inv), glycine and glycine, in that order. B is a spacer and is an amino acid which can occur naturally or amino acids that do not occur naturally as described above. Each B is independently the same or different. The amino acids of B can also provide a spacer, eg, Gly-Gly, between the promiscuous Th epitope and the somatostatin peptide (e.g., SEQ ID NO: 1) and functional and cross-reactive immunological analogues thereof . In addition to physically separating the Th epitope from the B-cell epitope, ie, the somatostatin peptide and the immunological analogues thereof, the Gly-Gly spacer can disrupt any secondary artifact structure created by the binding of the Th epitope with the peptide. of somatostatin and the functional and cross-reactive immunological analogs thereof and thus eliminate the interference between the Th and / or B cell responses. The amino acids can also form a spacer which acts as a flexible hinge that improves the separation of Th and IgE domains. Examples of the sequences encoding flexible hinges are found in the immunoglobulin heavy chain hinge region. The sequences of flexible hinges are frequently rich in proline. A particularly useful flexible hinge is provided by the sequence Pro-Pro-Xaa-Pro-Xaa-Pro (SEQ ID NO: 3), wherein Xaa is any amino acid and preferably aspartic acid. The conformational separation provided by the amino acids of B allows more efficient interactions between the presented peptide immunogen and the appropriate Th cells and B cells and thus improves the immune responses to the Th epitope and the epitope that produces antibodies and their functional and cross-reactive immunological analogues thereof. Th is a sequence of amino acids (natural or non-natural amino acids) comprising a Th epitope. A Th epitope can consist of a continuous or discontinuous epitope. Therefore, not any Th amino acid is necessarily part of the epitope. Accordingly, Th epitopes, which include analogs and segments of Th epitopes are capable of enhancing or stimulating an immune response to the somatostatin peptide and immunological analogues thereof. Th epitopes that are immunodominant and promiscuous are highly and extensively reactive in animal and human populations with widely divergent MHC types (Partidos et al., 1991; U.S. Patent 5,759,551). The Th domain of the subject peptides has from about 10 to about 50 amino acids and preferably from about 10 to about 30 amino acids. When multiple Th epitopes are present (ie, m> 2), then each Th epitope is independently the same or different. The Th segments are contiguous portions to a Th epitope that are sufficient to enhance or stimulate an immune response to the somatostatin peptide (SEQ ID NO: 1) and immunological analogues thereof. Th epitopes of the present invention include those derived from foreign pathogens including, but not limited to, as examples, T-cell epitopes, hepatitis B surface antigen and core antigen (HBsTh and HBcTh), T-cell epitopes, toxin assistants. of pertussis (PT Th), T-cell epitopes attendant of tetanus toxin (TT Th), epitopes of T-cell assistants of measles virus F protein (MVF Th), T-cell epitopes attendant of the outer main membrane protein Chlamydia trachomatis (CT Th), diphtheria toxin attendant T cell epitopes (DT Th), attendant T cell epitopes of Plasmodium falciparum circumesporozoite (PF Th), epitopes of Triosa phosphate isomerase isomerase T cells from Schistosoma mansoni (SM Th), and epitopes of T helper T cells of Escherichia coli (TraT Th). The Th derivatives of pathogens selected herein as representative examples of promiscuous Th are listed as SEC. FROM IDENT. NO: 2-9 and 42-52 in U.S. Patent 5,759,551; as CT Th P11 in Stagg et al., Immunology, 1993; 79; 1-9; and as peptide HBc 50-69 in Ferrari et al., J Clin Invest, 1991; 88: 214-222; and incorporated herein by reference. Additionally, Th epitopes include idealized artificial Th (e.g., SEQ ID NO: 14) and artificial SSAL Th (e.g., SEQ ID NO: 7, 30, 31). Peptides comprising Th SSAL are produced simultaneously in a simple solid phase peptide synthesis in tandem with somatostatin and other sequences. Th sites also include functional immunological analogues. Functional Th analogues include immunomodulatory analogs, cross-reactive analogs and segments of any of these Th epitopes. Functional Th analogues additionally include conservative substitutions, additions, deletions and insertions of one to about 10 amino acid residues in the Th epitope which do not essentially modifies the Th-stimulating function of the Th epitope.

The synthetic peptides of this invention, as described by the formulas (A) n- (Th) m- (B) 0- (somatostatin peptide) or (A) n- (somatostatin peptide) - (B) 0- (Th) m, have Th epitope covalently linked through spacer B to any of the N-terminal or C-terminus of the somatostatin peptide and functional and cross-reactive immunological analogues thereof. Functional and cross-reactive immunological analogues of the somatostatin peptide (e.g., SEC.

IDENT. NO: 1) according to the invention, may additionally comprise conservative substitutions, additions, deletions, or insertions from one to about four amino acid residues with the proviso that the peptide analogs are capable of producing a cross-reactive immune response with the peptides of somatostatin. Conservative substitutions, additions, and insertions can be achieved with natural or non-natural amino acids as defined herein. The preferred peptide immunogens of this invention are peptides containing the somatostatin peptides or functional and cross-reactive immunological analogs thereof; a spacer (for example, Gly-Gly); an epitope Th which is a Th HBS (SEQ ID.

NO: 15), Th HBC Th (SEQ ID NO: 4), MVF Th (SEQ ID NO: 21.29), PT Th (SEQ ID NO: 6), TT Th ( ID SECTION NO: 5); CT Th (SEQ ID NO: 27), DT Th (SEQ ID NO: 28), an artificial Th (eg, SEQ ID NO: 7,14,30,31) or a analogous thereof; and, optionally, an Inv domain (SEQ ID NO: 2) or analogous thereof. Peptide compositions containing cocktails of the peptide immunogens of the subject with two or more of the Th epitopes can improve immunoefficiency in a larger population and thus provide an improved immune response to the somatostatin peptide. The peptide immunogens of this invention can be manufactured by chemical synthesis methods which are well known to the ordinarily skilled artisan. See, for example, Fields et al., Chapter 3 in Synthetic Peptides: A User's Guide, ed. Grant, W. H. Freeman & Co., New York, NY, 1992, p. 77. Thus, peptides can be synthesized using automated Mereld solid phase synthesis techniques with α-NH2 protected by either t-Boc or F-moc chemistry using protected secondary chain amino acids on, for example with an Applied Biosystems Peptide Synthesizer Model 430A or 431. The preparation of the peptide constructs comprising the SSALs for Th epitopes can be achieved by providing a mixture of alternative amino acids for coupling at a given variable position. After the complete assembly of the desired peptide immunogen, the resin is treated according to standard procedures to unfold the peptide from the resin and unblock the functional residues on the secondary chains of amino acids. The free peptide is pued by CLAP and characterized biochemically, for example, by amino acid analysis or by sequencing. The methods of pucation and characterization for peptides are well known to one of common experience in the art. The subject immunogen can also be polymerized.

Polymerization can be achieved for example by the reaction between glutaraldehyde and the -NH2 groups of the Usin residues using routine methodology. By another method, the synthetic immunogen "A-Th-spacer- (somatostatin peptide)" or "(somatostatin peptide) -spacer- (Th) mA" can be polymerized or copolymerized by the use of an additional cysteine added to the N- terminal of the synthetic immunogen "A-Th-spacer- (somatostatin peptide) or" (somatostatin peptide) -spacer- (Th) m- (A) n "The subject immunogen can also be prepared as a branched polymer through the synthesis of the desired peptide construction directly on a branched poly-lysyl resin core (Wang, et al., Science, 1991; 254: 285-288). Alternatively, the longer synthetic peptide immunogens can be synthesized by well known recombinant DNA techniques. Any standard manual on DNA technology provides detailed protocols for producing the peptides of the invention. To construct a gene encoding a peptide of this invention, the amino acid sequence is translated inversely into a nucleic acid sequence and preferably using the codon optimized for the organism in which the gene will be expressed. Next, a synthetic gene is made, typically by synthesizing overlapping oligonucleotides which encode the peptide and any regulatory element if necessary. The synthetic gene is inserted into a suitable cloning vector and the recombinants are obtained and characterized. The peptide is then expressed under suitable conditions appropriate for the selected expression system and the host. The peptide is purified and characterized by standard methods. The efficiency of the peptide composition of the present invention can be established by injecting an animal, for example, rats, with an immunogenic composition comprising peptides of the invention, for example, SEC. FROM IDENT. NO: 8-13, 16-20, 22 followed by observation of the immune and moral response to somatostatin and functional and cross-reactive immunological homologs thereof, as detailed in the examples. Another aspect of this invention provides a peptide composition comprising an immunologically effective amount of one or more of the peptide immunogens of this invention in a pharmaceutically acceptable delivery system. Accordingly, the subject peptides can be formulated as a peptide composition using adjuvants, pharmaceutically acceptable carriers or other ingredients routinely provided in peptide compositions. Among the ingredients that may be used in this invention are adjuvants or emulsifiers including alum, incomplete Freund's adjuvant, liposine, saponin, squalene, L121, lipid A monophosphoryl emulsifier (MPL), QS21, ISA51, ISA35, ISA206 and ISA 720 as well like the other effective adjuvants and emulsifiers. The formulations include formulations for immediate release and / or sustained release, and induction of systemic immunity, which can be achieved, for example, by capture of immunogen by or co-administration with microparticles. Such formulations are easily determined by one of common experience in the art. The present immunogens can be administered by any convenient route including subcutaneous, oral, intramuscular, or other parenteral or enteral route. Similarly, immunogens can be administered as a single dose or multiple doses. Immunization plans are easily determined by the commonly experienced expert. The peptide composition of the present invention contains an effective amount of one or more of the peptide immunogens of the present invention and a pharmaceutically acceptable carrier. Such a composition in a suitable unit dosage form generally contains about 0.5 μg to about 1 mg of the immunogen per kg of body weight. When supplied in multiple doses, it can be conveniently divided into an appropriate amount per unit dosage form. For example, an initial dose, for example 0.2-2.5 mg; preferably 1 mg, of immunogen represented as a peptide composition of the present invention, is administered by injection, preferably intramuscularly followed by repeated doses (booster). The dosage will depend on the age, weight and general health of the animal as it is well known in the therapeutic and vaccine techniques. The immune response to the peptide immunogens of synthetic somatostatin can be improved by delivery through capture in or on biodegradable microparticles of the type described by O'Hagan et al. (Vaccina, 1991; 9: 768-771). The immunogens can be encapsulated with or without an adjuvant in biodegradable microparticles, to enhance immune responses, and to provide controlled time release for sustained or periodic responses, and for oral administration, (O'Hagan et al, 1991; and, Eldridge et al. ., 1991; 28: 287-294). Specific peptide immunogens and compositions are provided in the following examples to illustrate the invention. These examples are for the purpose of illustration only, and should not be construed as limiting the scope of the invention in any way.

EXAMPLE 1 TYPICAL METHODS FOR SYNTHESIZING SOMATOSTATINE PEPTIDE CONSTRUCTS The peptides listed in Tables 2 and 3 were individually synthesized by the Merrifield solid phase synthesis technique on Applied Biosystems automated peptide synthesizers (Models 430, 431 and 433A) using Fmoc chemistry. The preparation of peptide constructs comprising libraries of structured synthetic antigens (SSAL), for example, artificial Th site called "1,4,9 PALINDROMIC" (SEQ ID NO: 7), can be achieved by providing a mixture of the amino acids desired for chemical coupling at a given position as specified in the design. After complete assembly of the desired peptide, the resin is treated according to the standard procedure using trifluoroacetic acid to unfold the peptide from the resin and unblock the protecting groups on the secondary amino acid chains. For cyclic peptides, the split peptide was dissolved in 15% DMSO in water for 48 hours to facilitate the formation of the intradisulfide bond between the cisterns. The cleaved, extracted and washed peptides were purified by CLAP and characterized by mass spectrometry and reverse phase CLAP. The peptides labeled by "b" in the column of peptide codes were synthesized as target antigenic peptides in tandem with the Th sites as shown. The Th sites used include, for example, Th HB taken from the hepatitis B virus (SEQ ID NO: 15), and the novel artificial Th site designated "1,4,9 PALINDROMIC" (SEQ ID NO. : 7). The peptides marked by "c" are variants of the "b" constructs synthesized in tandem with the immunostimulatory peptide Inv domain (SEQ ID NO: 2). The peptides marked by "d" are inverse of the "b" constructs (eg, somatostatin-Th) and the peptides marked by "e" are the inverse of the "c" constructs (eg, somatostatin-Th-lnv) . Constructs "b", "c", "d" and "e" were synthesized with gly-gly spacers for the separation of the target antigenic site from the Th site, and the Th separation from the immunostimulatory site Inv.

EXAMPLE 2 TYPICAL METHODS FOR EVALUATING THE IMMUNOGENICITY OF SOMATOSTATIN PEPTIDES Somatostatin peptide immunogens (eg, SEQ ID NO: 8-13, 16-20, 22 and 24 as shown in Tables 2 and 3) they were evaluated in groups of 4 or 5 rats as specified by the experimental immunization protocol delineated later and by serological tests for the determination of immunogenicity. Standard Experimental Design: Immunogens: (1) individual peptide immunogen; or (2) mixtures comprising equimolar peptide immunogens as specified in each sample. Dosage: 100 μg in 0.5 mL per immunization unless otherwise specified Route: intramuscular unless otherwise specified Adjuvant: (1) Complete Freund's Adjuvant (CFA) / Incomplete Adjuvant (IFA); or (2) 0.4% alum (aluminum hydroxide); The CFA / IFA groups received CFA week 0, IFA in subsequent weeks.

The alum groups received the same formulations for all doses. Dose plan: 0, 2 and 4 weeks; 0, 3, and 6 weeks or otherwise specified. Bleeding plan: week 0, 3, 6 and 8 or otherwise specified Species: Sprague-Dawley rats Group size: 4 or 5 rats / group Test: ELISA specific for each antipeptide activity of the immune serum, the solid phase substrate was the cyclized somatostatin peptide (SEQ ID NO: 1). The blood was collected and processed in serum, and stored before titration by ELISA with the target antigenic peptides. Anti-somatostatin antibody activities were determined by ELISA (immunosorbent assays bound to the enzyme) using 96 well flat bottom microtiter plates which were coated with the cyclised somatostatin peptide (SEQ ID NO: 1) as immunosorbent . Aliquots (100 μL) of the peptide immunogenic solution were incubated at a concentration of 5 μg / mL for 1 hour at 37 ° C. The plates were blocked by another incubation at 37 ° C for 1 hour with a 3% solution of gelatin / PBS. The blocked plates were then dried and used for the test. Aliquots (100 μL) of the immune serum test, starting with a 1: 100 dilution in a sample dilution regulator and serial dilutions ten times thereafter, were added to the peptide-coated plates. The plates were incubated for 1 hour at 37 ° C. The plates were washed six times with 0.05% PBS / Tween® regulator. Added 100 μL of horseradish peroxidase labeling goat antispecies specific antibody at appropriate dilutions in conjugate dilution buffer (phosphate buffer containing 0.5M NaCl, and normal goat serum). The plates were incubated for 1 hour at 37 ° C before washing as above. Aliquots (100 μL) of o-phenylenediamine substrate solution was then added. The color was allowed to develop for 5-15 minutes before the enzymatic color reaction was stopped by the addition of 50 μL 2N of H2SO4. The A492nm of the contents of each well was read on a plate reader. The ELISA titers were calculated based on linear regression analysis of the absorbencies, with a cut of A492nm set at 0.5. This cut-off value was rigorous since the values for the normal diluted control samples run with each test were less than 0.15. Peptide Th based on ELISA. The Th peptide based on ELISA was performed in essentially the same way as the ELISA somatostatin described herein above except for the antigen coating steps, where the microtiter wells were coated for 1 hour at 37 ° with the individual designated Th peptide derived from its corresponding somatostatin vaccine construct (eg, peptides with SEQ ID NO: 14 and 15) at 5 μg / mL.

EXAMPLE 3 PEPTIDE IMMUNOGENICITY STUDIES SOMATOSTATINE ANTIGENICOS THAT INCORPORATE VARIOUS IMMUNOESTIMULATOR ELEMENTS The somatostatin peptide immunogens shown in Table 2 illustrate the variations of the peptides of this invention represented by the formulas: (A) n- (Th) m- (B) 0- (somatostatin peptide) or (A) ) n (somatostatin peptide) - (B) 0- (Th) m wherein: A is an amino acid, aNH2, or Inv (SEQ ID NO: 2); when A is an amino acid or Inv can be linked to the N-terminal or the C-terminal; B is glycine; Th is an attendant T cell epitope derived from foreign pathogens, for example, HBc50-69Th (SEQ ID NO: 4), TT6? 5-63? Th (SEQ ID NO: 5), PT149- 176Th (SEQ ID NO: 6), or / and an artificial Th for example, 1.4.9 PALIDROMIC Th (SEQ ID NO: 7); n is 1, m is 1 and o is 2 These peptides were synthesized among others and the immune serum was generated for evaluation of immunogenicity. Most of the peptides shown in Table 2, which incorporate various forms and orientations of Th epitopes, produced high titer-specific somatostatin antibodies in immunized hosts. In contrast, the somatostatin peptide (p1348a, SEQ ID NO: 1) lacking Th is devoid of immunogenicity. However, certain Th are preferred over others. For example, in Table 2, p2134b (SEQ ID NO: 8) having HBc Th (SEQ ID NO: 4), p2384b (SEQ ID NO: 20) having SynTh (1) , 2.3) (SEQ ID NO: 14), an artificial Th site, and p2138b (SEQ ID NO: 10) having PT149-176 Th (SEQ ID NO: 6) are more immunogenic than p2135b (SEQ ID NO: 9) having TT Th (SEQ ID NO: 5) and all of these are preferable to p2136b (SEQ ID NO: 24) having CTA8 Th ( SEQ ID NO: 23) which is slightly immunogenic. Also, for optimal immunogenicity, the orientation of the Th site to the somatostatin target site should be specified. Compare the kinetics of the antibody response for p2253b (SEQ ID NO: 11) for p2255d (SEQ ID NO: 12). It is preferable to place 1, 4.9 PALINDROMIC Th (SEQ ID NO: 7) on the C-terminus of somatostatin. From the comparison of p1344b (SEQ ID NO: 16) to p1349b (SEQ ID NO: 22), the best location for MVF258.277 (SEQ ID NO: 21) is about the N- terminal of somatostatin. It is clear that the selection and arrangement of each Th site must be specified for the preferred peptides of the invention. For the somatostatin peptides shown in Table 3, where the somatostatin constructs comprise a promiscuous Th epitope already d to be immunogenic, the binding of Inv to the "Th" constructs may improve the immunogenicity of the somatostatin peptide. Comparisons of immunogenicities for p1344b (SEQ ID NO: 16) with p1343c (SEQ ID NO: 17) and p1346b (SEQ ID NO: 18) with p1345c (SEQ ID NO. : 19) shows that the addition of the Inv domain (SEQ ID NO: 2) to the N-terminus of Th constructs improves immunogenicity in terms of the percentage of animals that respond, in the intensity of the somatostatin-specific antibody titer, and in the longevity of that antibody response (>35 weeks). However, the comparison of immunogenicities of p2134b (SEQ ID NO: 8) with p2134c (SEQ ID NO: 25) and with p2134d (SEQ ID NO: 26) illustrates that in combination with the Particular Th sites Inv may not be immunostimulatory, and that a particular orientation on the N-terminus is preferred over the orientation of the C-terminus for the combination of Inv with the Th HBc site (SEQ ID NO: 4). For example, from p2135e (SEQ ID NO: 13), the combination of Inv with TT615-63? Th (SEQ ID NO: 5) on C-terminal resulted in an effective immunogen. Thus, the addition of Inv and the orientation of Th and Inv should be specified for the preferred peptides of the invention. For constructs having potent site-directed immunogenicity for somatostatin, antibody titers directed to the immunostimulatory elements, eg, lnv-MVF258-277 Th from p1343c (SEQ ID NO: 17) and KKK-HBs19-32 Th- GG of p1346b (SEQ ID NO: 18) of Table 3, were < 1 Log10 compared to those of > 3 Log10 for somatostatin. Thus, the immune response generated for the synthetic peptides of the present invention was directed almost exclusively to the somatostatin target site.

EXAMPLE 4 ADDITIONAL ANTIGENIC PEPTIDES OF THE INVENTION Somatostatin peptide antigens illustrate variations of the peptides of this invention represented by the formulas: (A) n- (Th) m- (B) 0- (somatostatin peptide) (A) n- (somatostatin peptide) - (B) 0- (Th) m wherein: Th is a T cell epitope assistant derived from any of the foreign pathogens as shown in Table 4; or, a helper T cell epitope of any of the Th artificial epitopes as shown in Table 5; A is an amino acid, aNH2, or an invasin domain (SEQ ID NO: 2); when A is an amino acid or Inv can be linked to either the N-terminal or the C-terminal; B is glycine; n is 1, m is 1 and o is 2 are synthesized and serum-immune generated.

Table 1. Immunization against Somatostatin for Growth Promotion Somatostatin-carrier protein conjugates were used as vaccines for immunization.

Table 2 a Somatostatin sequence: AGCKNFFWKTFTSC bResults of the test for pooled serum of reactive animals to ELISA.

Table 3. Improvement of the Immunogenicity of the Somatostatin Antigenic Peptides with the binding of a a Somatostatin sequence: AGCKNFFWKTFTSC (Seq ID No.1) "Inv sequence (ie adjuvant invasin domain): TAKSKKFPSYTATYQF (Seq ID No.2) c Test result for pooled serum from ELISA-reactive animals.

Table 4 Amino acid sequences of Th epitopes derived from pathogens Table 5 Amino Acid Sequence of Artificial Thyroid Epitopes LIST 0 SEQUENCES (1) GENERAL INFORMATION: (i) APPLICANT: UNITED BIOMEDICAL INC. (ii) TITLE OF THE INVENTION: IMMUNOGENOUS OF SYNTHETIC SOMATOSTATIN FOR PROMOTION GROWTH OF FARM ANIMALS (iii) SEQUENCE NUMBER: 45 (iv) DIRECT CORRESPONDENCE: (A) RECIPIENT: Morgan & Finnegan (B) STREET: 345 Park Avenue (C) CITY: New York (D) STATE: NY (E) COUNTRY: USA (F) POSTAL CODE: 10154-0054 (v) 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 # 1.25 (vi) DATA FROM THE PREVIOUS REQUEST : (A) APPLICATION NUMBER: US (B) SUBMISSION DATE: (C) CLASSIFICATION: (vii) DATA OF THE CURRENT APPLICATION: (A) APPLICATION NUMBER: TBA (B) DATE OF SUBMISSION: June 18, 1999 (C) CLASSIFICATION: (viii) INFORMATION OF THE EMPLOYEE / AGENT: (A) NAME: MARÍA C.H. LIN (B) REGISTRATION NUMBER: 29,323 (C) REFERENCE / FILE NUMBER: 1151-4155PC1 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 212-758-4800 (B) TELEFAX: 212-751-6849 ( 2) INFORMATION FOR SEC. IDENT. NO: 1: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 1: Wing Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr 1 5 10 Ser Cys (2) INFORMATION FOR SEC. IDENT. NO: 2: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 16 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 2: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Ala 1 5 10 Thr Tyr Gln Phe 15 (2) INFORMATION FOR SEC. IDENT. NO: 3: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 3: Pro Pro Xaa Pro Xaa Pro 1 5 (2) INFORMATION FOR SEC. IDENT. NO: 4: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 4: Ser Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp 1 5 10 Thr Ala Ser Ala Leu Tyr Arg Glu 15 20 (2) INFORMATION FOR SEC. IDENT. NO: 5: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 5: Trp Val Arg Asp lie Asp Asp Phe Thr Asn Glu 1 5 10 Be Ser Gln Lys Thr 15 (2) INFORMATION FOR SEC. IDENT. NO: 6: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 30 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 6: Lys Lys Leu Arg Arg Leu Leu Tyr Met lie Tyr Met 1 5 10 Ser Gly Leu Ala Val Arg Val His Val Ser Lys Glu 15- 20 Glu Gln Tyr Tyr Asp Tyr 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 7: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTICS: (A) NAME / KEY : Modified site (B) LOCATION: 1 (D) OTHER INFORMATION: / note = "lie, Met or Leu " (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 2 (D) OTHER INFORMATION: / note = "Ser or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) ) LOCATION: 4 (D) OTHER INFORMATION: / note = "Me or Arg" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 5 (D) OTHER INFORMATION: / note = "Lys o Thr "(ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 10 (D) OTHER INFORMATION: / note *" His or Thr "(ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 11 (D) OTHER INFORMATION: / note = "Lys or Arg" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 12 (D) OTHER INFORMATION: / note = " Me, Met or Leu "(ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 14 (D) OTHER INFORMATION: / note =" Gly or Thr "(ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 15 (D) OTHER INFORMATION: / note = "Me, Met or Val" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 7: Xaa Xaa Glu Xaa Xaa Gly Val Me Val Xaa Xaa Xaa 1 5 10 Glu Xaa Xaa 15 (2) INFORMATION FOR SEC. IDENT. NO: 8: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 36 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 8: Be Asp Phe Phe Pro Ser Val Arg Asp Leu Leu Asp 1 5 10 Thr Wing Being Wing Leu Tyr Arg Glu Gly Gly Wing Gly 15 20 Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys 25 30 35 (2 ) INFORMATION FOR SEC. IDENT. NO: 9: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 33 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 9: Trp Val Arg Asp Me Me Asp Asp Phe Thr Asn Glu 1 5 10 Be Ser Gln Lys Thr Gly Gly Wing Gly Cys Lys Asn 15 20 Phe Phe Trp Lys Thr Phe Thr Ser Cys 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 10: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 46 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 10: Lys Lys Leu Arg Arg Leu Leu Tyr Met Me Tyr Met 1 5 10 Ser Gly Leu Wing Val Arg Val His Val Ser Lys Glu 15 20 Glu Gln Tyr Tyr Asp Tyr Gly Gly Wing Gly Cys Lys 25 30 35 Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 11: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY : Modified site (B) LOCATION: 1 (D) OTHER INFORMATION: / note = "Me, Met or Leu" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 2 (D) OTHER INFORMATION : / note = "Ser or Thr" (ix) CHARACTERISTICS: (A) NAME / KEY: Modified site (B) LOCATION: 4 (D) OTHER INFORMATION: / note = "Me or Arg" (ix) FEATURE: (A) ) NAME / KEY: Modified site (B) LOCATION: 5 (D) OTHER INFORMATION: / note = "Lys or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 10 (D) OTHER INFORMATION: / note = "His or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) ) LOCATION: 11 (D) OTHER INFORMATION: / note = "Lys or Arg" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 12 (D) OTHER INFORMATION: / note = "Me, Met or Leu "(ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 14 (D) OTHER INFORMATION: / note =" Gly or Thr "(ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 15 (D) OTHER INFORMATION: / note = "Me, Met or Val" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 11 Xaa Xaa Glu Xaa Xaa Gly Val Me Val Xaa Xaa Xaa 1 5 10 Glu Xaa Xaa Gly Gly Wing Gly Cys Lys Asn Phe Phe 15 20 Trp Lys Thr Phe Thr Ser Cys 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY : Modified site (B) LOCATION: 17 (D) OTHER INFORMATION: / note = "Me, Met or Leu "(ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 18 (D) OTHER INFORMATION: / note =" Ser or Thr "(ix) FEATURE: (A) NAME / KEY : Modified site (B) LOCATION: 21 (D) OTHER INFORMATION: / note = "Me or Arg" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 22 (D) OTHER INFORMATION: / note = "Lys or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 26 (D) OTHER INFORMATION: / note = "His or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 27 (D) OTHER INFORMATION: / note = "Lys or Arg" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 28 (D) OTHER INFORMATION : / note = "Me, Met or Leu" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 30 (D) OTHER INFORMATION: / note = "Gly or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 31 (D) OTHER INFORMATION: / note = "Me, Met or Val" (xi) DESC RIPTION OF THE SEQUENCE: SEC. IDENT. NO: 12: Wing Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr 1 5 10 Ser Cys Gly Gly Xaa Xaa Glu Me Xaa Xaa Val He 15 20 Val Xaa Xaa Xaa Glu Xaa Xaa 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 13: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 13: Wing Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr 1 5 10 Ser Cys Gly Gly Trp Val Arg Asp Me Me Asp Asp 15 20 Phe Thr Asn Glu Be Ser Gln Lys Thr Gly Gly Thr 25 30 35 Wing Lys Ser Lys Lys Phe Pro Ser Tyr Thr Wing Thr 40 45 Tyr Gln Phe 50 (2) INFORMATION FOR SEC. IDENT. NO: 14: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 14: Lys Lys Lys Me Me Thr He Thr Arg He Me Thr 1 5 10 He He Thr Thr He Asp 15 (2) INFORMATION FOR SEC. IDENT. NO: 15: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 15: Phe Phe Leu Leu Thr Arg He Leu Thr Me Pro Gln 1 5 10 Ser Leu Asp 15 (2) INFORMATION FOR SEC. IDENT. NO: 16: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 36 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 16: Gly Me Leu Glu Ser Arg Gly He Lys Wing Arg Me 1 5 10 Thr His Val Asp Thr Glu Ser Tyr Gly Gly Wing Gly 15 20 Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys 25 30 35 (2 ) INFORMATION FOR SEC. IDENT. NO: 17: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 38 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 17: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Ala 1 5 10 Thr Tyr Gln Phe Gly lie Leu Glu Ser Arg Gly He 15 20 Lys Ala Arg Me Thr His Val Asp Thr Glu Ser Tyr 25 * v 30 35 Gly Gly (2) INFORMATION FOR SEC. IDENT. NO: 18: (i) CHARACTERISTICS OF. THE SEQUENCE: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 18: Lys Lys Lys Phe Phe Leu Leu Thr Arg Me Leu Thr 1 5 10 Me Pro Gln Ser Leu Asp Gly Gly 15 20 (2) INFORMATION FOR SEC. IDENT. NO: 19: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 38 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 19: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Ala 1 5 10 Thr Tyr Gln Phe Gly Gly Lys Lys Phe Phe Leu 15 20 Leu Thr Arg Me Leu Thr Me Pro Gln Ser Leu Asp 25 * 30 35 Gly Gly (2) INFORMATION FOR SEC. IDENT. NO: 20: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 34 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 20: Lys Lys Me Thr Me Thr Arg He He Thr 1 5 10 lie Me Thr Thr He Asp Gly Gly Wing Gly Cys Lys 15 20 Asn Phe Phe Trp Lys Thr Phe Thr Ser Cys 25 30 (2) INFORMATION THE SEC. IDENT. NO: 21: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 21: Gly Me Leu Glu Ser Arg Gly Me Lys Ala Arg Me 1 5 10 Thr His Val Asp Thr Glu Ser Tyr 15 20 (2) INFORMATION FOR SEC. IDENT. NO: 22: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 36 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 22: Wing Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr 1 5 10 Ser Cys Gly Gly He Leu Glu Ser Arg Gly He 15 20 Lys Wing Arg He Thr His Val Asp Thr Glu Ser Tyr 25 30 35 (2) INFORMATION FOR SEC. IDENT. NO: 23: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 25 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 23: Wing Leu Asn He Trp Asp Arg Phe Asp Val Phe Ser 1 5 10 Thr Leu Gly Wing Thr Ser Gly Tyr Leu Lys Gly Asn 15 20 Ser 25 (2) INFORMATION FOR THE SEC. IDENT. NO: 24: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 41 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 24: Ala Leu Asn He Trp Asp Arg Phe Asp Val Phe Ser 1 5 10 Thr Leu Gly Wing Thr Ser Gly Tyr Leu Lys Gly Asn 15 20 Ser Gly Gly Wing Gly Cys Lys Asn Phe Phe Trp Lys 25 30 35 Thr Phe Thr Ser Cys 40 (2) INFORMATION FOR SEC. IDENT. NO: 25: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 54 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 25: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Wing 1 5 10 Thr Tyr Gln Phe Gly Gly Ser Asp Phe Phe Pro Ser 15 20 Val Arg Asp Leu Leu Asp Thr Ala Ser Ala Leu Tyr 25 30 35 Arg Glu Gly Gly Wing Gly Cys Lys Asn Phe Phe Trp 40 45 Lys Thr Phe Thr Ser Cys 50 (2) INFORMATION FOR SEC. IDENT. NO: 26: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 54 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 26: Wing Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr 1 5 10 Ser Cys Gly Gly Ser Asp Phe Phe Pro Ser Val Arg 15 20 Asp Leu Leu Asp Thr Ala Ser Ala Leu Tyr Arg Glu 25 30 35 Gly Gly Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr 40 45 Thr Wing Thr Tyr Gln Phe 50 (2) INFORMATION FOR SEC. IDENT. NO: 27: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 27: Thr He Asn Lys Pro Lys Gly Tyr Val Gly Lys Glu 1 5 10 (2) INFORMATION FOR SEC. IDENT. NO: 28: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 28: Asp Ser Glu Thr Wing Asp Asn Leu Glu Lys Thr Val 1 5 10 Ala Ala Leu Ser He Leu Pro Gly His Gly 15 20 (2) INFORMATION FOR SEC. IDENT. NO: 29: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 29: Leu Ser Glu Me Lys Gly Val Me Val His Arg Leu 1 5 10 Glu Gly Val 15 (2) INFORMATION FOR SEC. IDENT. NO: 30: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY : Modified site (B) LOCATION: 2 (D) OTHER INFORMATION: / note = "Ser or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 5 (D) OTHER INFORMATION: / note = "Lys or Arg" (¡x) CHARACTERISTICS: (A) NAME / KEY: Modified site (B) LOCATION: 6 (D) OTHER INFORMATION AND / note = "Gly or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 10 (D) OTHER INFORMATION: / note = "His or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 11 (D) OTHER INFORMATION : / note = "Lys or Arg" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 14 (D) OTHER INFORMATION: / note = "Gly or Thr" (xi) DESCRIPTION OF THE SEQUENCE : SEC. IDENT. NO: 30: He Xaa Glu He Xaa Xaa Val Me Val Xaa Xaa Me 1 5 10 Glu Xaa He 15 (2) INFORMATION FOR SEC. IDENT. NO: 31: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 19 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY : Modified site (B) LOCATION: 4 (D) OTHER INFORMATION: / note = "Ser or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 7 (D) OTHER INFORMATION: / note = "Lys or Arg" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 8 (D) OTHER INFORMATION: / note = "Gly or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 12 (D) OTHER INFORMATION: / note = "His or Thr" (ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 13 (D) OTHER INFORMATION: / note = "Lys or Arg" ( ix) FEATURE: (A) NAME / KEY: Modified site (B) LOCATION: 16 (D) OTHER INFORMATION: / note = "Gly or Thr" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 31 I Have Been Xaa Glu Me Xaa Xaa Val Me Val Xaa 1 5 10 Xaa He Glu Xaa He Leu Phe 15 (2) INFORMATION FOR THE SEC. IDENT. NO: 32: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 32 Lys Lys Gln Tyr He Lys Wing Asn Ser Lys Phe He 1 5 10 Gly He Thr Glu Leu 15 (2) INFORMATION FOR SEC. IDENT. NO: 33: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 22 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 33: Lys Lys Phe Asn Asn Phe Thr Val Ser Phe Trp Leu 1 5 10 Arg Val Pro Lys Val Ser Wing Ser His Leu 15 20 (2) INFORMATION FOR SEC. IDENT. NO: 34: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 27 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 34: Tyr Asp Pro Asn Tyr Leu Arg Thr Asp Ser Asp Lys 1 5 10 Asp Arg Phe Leu Gln Thr Met Val Lys Leu Phe Asn 15 20 Arg He Lys 25 (2) INFORMATION FOR SEC. IDENT. NO: 35: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 24 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 35: Gly Ala Tyr Ala Arg Cys Pro Asn Gly Thr Arg Ala 1 5 10 Leu Thr Val Ala Glu Leu Arg Gly Asn Ala Giu Leu 15 20 (2) INFORMATION FOR SEC. IDENT. NO: 36: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 21 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 36: Val Ser Phe Gly Val Trp Me Arg Thr Pro Pro Wing 1 5 10 Tyr Arg Pro Pro Asn Ala Pro Me Leu 15 20 (2) INFORMATION FOR SEC. IDENT. NO: 37: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 37: Pro His His Thr Wing Leu Arg Gln Wing Me Leu Cys 1 5 10 Trp Gly Glu Leu Met Thr Leu Wing 15 20 (2) INFORMATION FOR SEC. IDENT. NO: 38: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 19 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 38: Arg Ala Gly Arg Ala He Leu His Me Pro Thr Arg 1 5 10 Me Arg Gln Gly Leu Glu Arg 15 (2) INFORMATION FOR SEC. IDENT. NO: 39: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 21 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 39: Wing Val Wing Glu Gly Thr Asp Arg Val Me Glu Val 1 5 10 Leu Gln Arg Wing Gly Arg Wing Me Leu 15 20 (2) INFORMATION FOR SEC. IDENT. NO: 40: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 39 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 40: Glu Glu He Val Wing Gln Being Me Wing Leu Being 1 5 10 Leu Met Val Wing Gln Wing He Pro Leu Val Gly Glu 15 20 Leu Val Asp Me Gly Phe Wing Wing Thr Asn Phe Val 25 30 35 Glu Ser Cys (2) INFORMATION FOR SEC. IDENT. NO: 41: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 21 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 41: Asp Me Glu Lys Lys He Ala Lys Met Glu Lys Ala 1 5 10 Ser Ser Val Phe Asn Val Val Asn Ser 15 20 (2) INFORMATION FOR SEC. IDENT. NO: 42: (i) CHARACTERISTICS OF THE SEQUENCE: • ^ Aátt ^ h-ata-bA.

(A) LENGTH: 17 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 42: Lys Trp Phe Lys Thr Asn Wing Pro Asn Gly Val Asp 1 5 10 Glu Lys He Arg He 15 (2) INFORMATION FOR SEC. IDENT. NO: 43: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 14 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 43: Gly Leu Gln Gly Lys He Wing Asp Wing Val Lys Wing 1 5 10 Lys Gly (2) INFORMATION FOR SEC. IDENT. NO: 44: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 19 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 44: Gly Leu Wing Wing Gly Leu Val Gly Met Wing Wing Asp 1 5 10 Wing Met Val Glu Asp Val Asn 15 (2) INFORMATION FOR SEC. IDENT. NO: 45: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 20 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 45: Ser Thr Glu Thr Gly Asn Gln His His Tyr Gln Thr 1 5 10 Arg Val Val Ser Asn Wing Asn Lys 15 20

Claims (29)

1. CLAIMS 1. A peptide conjugate, characterized in that it comprises an attendant T cell epitope sequence (Th) covalently linked to somatostatin or a cross-reactive and immunologically functional analogue thereof.
2. 2. The peptide conjugate according to claim 1, characterized in that the peptide conjugate is represented by the formula H2N- (A) n- (somatostatin peptide) - (B) 0- (Th) mX or H2N- (A) n- (Th) m- (B) 0- (somatostatin peptide) -X wherein H2N is the α-NH2 of the N-terminus of the peptide conjugate, each A is independently an amino acid or a general immunostimulatory sequence; each B is selected from the group consisting of amino acids, -NHCH (X) CH2SCH2CO-, -NHCH (X) CH2SCH2CO (eN) Lys-, -NHCH (X) CH2S-succinimidyl (eN) Lys-, and -NHCH (X) CH2S- (succinimidyl) -; each Th is independently an amino acid sequence comprising an attendant T cell epitope, or an immunomodulatory analog or segment thereof; the somatostatin peptide is somatostatin or an immunologically functional cross-reactive analogue thereof; X is an amino acid a-COOH or a-CONH2; n is from 1 to about 10; m is from 1 to about 4; I is from 0 to approximately 10.
3. 3. The peptide conjugate according to claim 1, characterized in that the peptide conjugate is represented by the formula H2N- (somatostatin peptide) - (B) 0- (Th) m- (A ) nX or H2N- (Th) m- (B) 0- (somatostatin peptide) - (A) nX where H2N is the N-terminal a-NH2 of the peptide conjugate, each A is independently an amino acid or a sequence general immunostimulatory; each B is selected from the group consisting of amino acids, -NHCH (X) CH2SCH2CO-, -NHCH (X) CH2SCH2CO (eN) Lys-, -NHCH (X) CH2S-succinimidyl (eN) Lis-, and -NHCH (X CH2S- (succinimidyl) -; each Th is independently an amino acid sequence comprising a T cell epitope, or an immunomodulatory analog or segment thereof; - '- • * - the somatostatin peptide is somatostatin or an immunologically functional cross-reactive analogue thereof; X is an amino acid a-COOH or a-CONH2; n is from 1 to about 10; m is from 1 to about 4; and o is from 0 to about 10.
4. The peptide conjugate according to claim 2 or claim 3, characterized in that each B is selected from the group consisting of natural and non-natural amino acids.
5. 5. The peptide conjugate according to any of claims 1-4, characterized in that the somatostatin peptide is somatostatin.
6. 6. The peptide conjugate according to any of claims 1-4, characterized in that the Th is an SSAL epitope.
7. 7. The peptide conjugate according to any of claims 1-4, characterized in that the Th has an amino acid sequence selected from the group consisting of SEC. FROM IDENT. NO: 4, SEC. FROM IDENT. NO: 5, SEC. FROM IDENT. NO: 6, SEC. FROM IDENT. NO: 7, SEC. FROM IDENT. NO: 14, SEC. FROM IDENT. NO: 15, SEC. FROM IDENT. NO: 21, SEC. FROM IDENT. NO: 23, SEC. FROM IDENT. NO: 27, SEC. FROM IDENT. NO: 28, and SEC. FROM IDENT. NO: 29 SEC. FROM IDENT. NO: 30, and SEC. FROM IDENT. N0: 31 8. The peptide conjugate according to claim 2, characterized in that the peptide conjugate has an amino acid sequence selected from the group consisting of SEC. FROM IDENT. NO:
8. 8, SEC. FROM IDENT. NO: 9, SEC. FROM IDENT. NO: 10, SEC. FROM IDENT. NO: 11, SEC. FROM IDENT. NO: 12, SEC. FROM IDENT. NO: 13, SEC. FROM IDENT. NO: 16, SEC. FROM IDENT. NO: 17, SEC. FROM IDENT. NO: 18, SEC. FROM IDENT. NO: 19, SEC. FROM IDENT. NO: 20, SEC. FROM IDENT. NO: 22, SEC. FROM IDENT. NO: 24, SEC. FROM IDENT. NO: 25, and SEC. FROM IDENT. NO: 26
9. 9. The peptide conjugate according to claim 2 or claim 3, characterized in that at least one A is an invasin domain.
10. 10. The peptide conjugate according to claim 2, characterized in that n is 3, and (A) 3 is (invasin domain) -Gly-Gly.
11. 11. The peptide conjugate according to claim 9 or claim 10, characterized in that the invasin domain has the amino acid sequence of SEC. FROM IDENT. NO: 2
12. 12. A synthetic peptide of about 25 to about 90 amino acids, characterized in that it comprises the amino acid sequences of (a) an invasin domain, (b) an attendant T cell epitope (Th), and (c) somatostatin or an analogue of cross reaction and immunologically functional thereof.
13. 13. The peptide, characterized in that it comprises an amino acid sequence selected from the group consisting of SEC. FROM IDENT. NO: 17, SEC. FROM IDENT. NO: 19 and SEC. FROM IDENT. NO: 25
14. 14. The peptide or peptide conjugate according to any of claims 1 to 13, characterized in that the peptide stimulates an immune response to somatostatin in a mammal.
15. 15. The peptide or peptide conjugate according to claim 14, characterized in that immunization of a mammal with the peptide conjugate causes a reduction in somatostatin levels in the mammal.
16. 16. The pharmaceutical composition, characterized in that it comprises an immunologically effective amount of a peptide or peptide conjugate according to any of claims 1-15, and a pharmaceutically acceptable carrier.
17. 17. The pharmaceutical composition according to claim 16, characterized in that the immunologically effective amount of the peptide or peptide conjugate is about 0.5 μg to about 1 mg per kilogram of body weight per dose.
18. 18. The method for inducing production of anti-somatostatin antibodies in a mammal, characterized in that it comprises administering to the mammal a pharmaceutical composition according to claim 16 or claim 17.
19. 19. The method for increasing the growth rate in a mammal characterized in that comprises administering a pharmaceutical composition according to claim 16 or claim 17 to the mammal.
20. 20. The method for increasing the growth rate in a mammal, characterized in that it comprises administering to a mammal an amount of a pharmaceutical composition according to claim 16 or claim 17 sufficient to reduce somatostatin levels.
21. 21. The composition, characterized in that it comprises a mixture of two or more peptides or peptide conjugates according to any of claims 1-15.
22. 22. The pharmaceutical composition, characterized in that it comprises an immunologically effective amount of a composition according to claim 21 and a pharmaceutically acceptable carrier. *
23. 23. The pharmaceutical composition according to claim 22, characterized in that the immunologically effective amount of the composition is about 0.5 μg to about 1 mg per 5 kilograms of body weight per dose.
24. 24. The method for inducing the production of anti-somatostatin antibodies in a mammal which comprises administering to the mammal a pharmaceutical composition according to claim 22 or 10 claim 23.
25. 25. The method for increasing the growth rate in a mammal, characterized in that it comprises administering a pharmaceutical composition according to claim 22 or claim 23 to the mammal.
26. 26. The method for increasing the growth rate, characterized in that it comprises administering to a mammal an amount of a pharmaceutical composition according to claim 22 or claim 23 sufficient to reduce somatostatin levels.
27. 27. The branched polymer, characterized in that it comprises a nucleus of Usin, trilisin, or heptalisin, covalently linked to two, four or eight peptide conjugates, respectively, of any of claims 1-15.
28. 28. The polymer, characterized in that it comprises one 25 or more peptide conjugates according to any of claims 1-3 and claims 5-15, crosslinked by a bifunctional crosslinking agent.
29. 29. A Th epitope peptide selected from the group consisting of SEC. FROM IDENT. NO: 4, SEC. FROM IDENT. NO: 5, SEC. FROM IDENT. NO: 6, SEC. FROM IDENT. NO: 7, SEC. FROM IDENT. NO: 14, SEC. FROM IDENT. NO: 15, SEC. FROM IDENT. NO: 21, SEC. FROM IDENT. NO: 23, SEC. FROM IDENT. NO: 27, SEC. FROM IDENT. NO: 28, and SEC. FROM IDENT. NO: 29 SEC. FROM IDENT. NO: 30, and SEC. FROM IDENT. NO: 31