MXPA00011939A - Artificial t helper cell epitopes as immune stimulators for synthetic peptideimmunogens - Google Patents

Abstract

This invention relates to a peptide immunogen comprising a novel artificial T helper cell epitope (Th) covalently linked to a desired target antigenic site comprising B cell epitopes and optionally a general immune stimulator sequence. The artificial Th epitope imparts to the peptide immunogen the capability to induce strong T helper cell-mediated immune responses and the production of antibodies directed against the"target antigenic site."The invention also provides for the advantageous replacement of carrier proteins and pathogen-derived T helper cell sites in established peptide immunogens by the novel artificial T helper cell epitopes for improved immunogenicity.

Description

ARTIFICIAL EPITOPES OF ASSISTANT CELLS AND AS IMMUNE STIMULATORS FOR PEPTIDE IMMUNOGENS SYNTHETIC FIELD OF THE INVENTION This invention relates to a peptide immunogen comprising a novel artificial epitope of helper cell T (Th) covalently linked to a desired antigenic target site comprising B cell epitopes and optionally a general immuno-stimulatory sequence. The epitope A r: if i cia I Th imparts to the peptide immunogen the ability to induce strong immune responses mediated by T-helper cells and the production of antibodies directed against "the antigenic target site". The invention also provides the Advantageous replacement of carrier proteins and T-helper cell sites derived from pathogens in peptide immunogens established by the novel artificial epitopes of T-helper cells for improved immunogenicity. Many rules have been developed to predict the amino acid sequences of T-cell epitopes. However, because there is no central unifying theory on how or which makes a pariticule amino acid sequence useful as a T-cell epitope, the rules are empirical and are not universally applicable. Being aware of these regs, you developed the novel artificial cell epitopes 3 ^^^^ s¡yg ^ ¡¡¡¡assistants T of the present invention, however, by empirical research. The peptide immunogens of the present invention are useful for evoking antibody responses in a host immunized to a desired antigenic target site, which includes sites taken from pathogenic organisms and sites normally taken from autoantigen immuno silent and targets associated with tumors. Accordingly, the peptides of the invention are useful in various medical applications and veterinarians, such as: vaccines to provide protective immunity against infectious diseases; immunotherapies to treat disorders that result from malfunction of normal physiological processes; immunotherapies to treat cancer and as agents to intervene in normal physiological processes to produce desirable results. For example, the novel artificial epitopes of T-helper cells of the present invention provide novel short peptide immunogens that produce antibodies selected for the hormone that releases the hormone.

Luteinizing (LHRH) and are useful for contraception, control of hormone-dependent tumors, prevention of non-castrated pig spot, and immunocastration. The novel artificial Th epitopes of the present invention have been found to elicit an immune response when combined with epitopes B-cell target of various microorganisms / proteins / rftftÜMMtlilta ^ MMI -M ------ ^ - * peptides. In addition to LHRH, the Th artificial epitopes of the present invention have been found to be useful when linked to other target antigenic sites including somatostatin for growth promotion in farm animals; IgE for the treatment of allergy; the CD4 receptor of the T-helper cells for the treatment and prevention of HIV infection and immune disorders; and capsid protein of foot and mouth disease virus for the prevention of foot and mouth disease; HIV virion epitopes for the prevention and treatment of HIV infection; the circumsporozoite antigen of Plasmodium falciparum for the prevention and treatment of arteriosclerosis.

BACKGROUND OF THE INVENTION It is known that most antibody immune responses are mediated by cells, which require cooperative interaction between antigen presenting cells, B cells (cells that produce antibodies which also function as antigen-presenting cells), and T cell assistants (Th). Consequently, the production of an effective antibody response requires that the B cells recognize the target antigenic site (B cell epitope) of an immunogenic subject and that the T helper cells recognize an epitope of Th. Generally, the epitope of T-helpers on a subject immunogen is different from its epitope or B cell epitopes • MM ^ M - M ---- MHW ^ HHIlMHIi ^^^^ M ^^^^^^ rtMÍ (Babbitt et al., Nature, 1985; 317: 359-361). The B cell epitope is a site on the desired target recognized by B cells which in responses produce antibodies towards the desired target site. It is understood that the natural conformation of the target determines the site to which the antibody is linked directly. The recognition of proteins by T-helper cells is, however, much more complex and less well understood. (Cornette et al., In Methods in Enzymology, vol 178, Academic Press, 1989, pp 611-634). Under present theories, the evocation of a Th cell response requires that the recipient of the T-helper cells recognize not the desired target but a complex on the membrane of the cell presenting the antigen formed between a peptide fragment processed from the protein target and a major class II associated histocompatibility complex (MHC). Thus, the peptide processing of the target protein and a recognition of three forms is required for the response of the helper cell T. The three-part complex is particularly difficult to define since the MHC class II critical contact residues are located variably within of different MHC binding peptides (Th epitopes) and these peptides are of varying lengths with different amino acid sequences (Rudensky et al., Nature, 1991; 353: 622-627). In addition, the MHC class II molecules themselves are highly diverse depending on the genetic character of the host. Immune responsiveness to a ** • Particular epitope Th is thus determined in part by the host MHC genes. In fact, it has been shown that certain peptides only bind to the products of particular MHC class II alleles. Thus, it is difficult to identify Th epitopes promiscuous, that is, those that are reactive through the species and through the individuals of a simple species. It has been found that the reactivity of Th epitopes is different even among individuals in a population. The multiple and varied factors for each of the component stages of T cell recognition: the appropriate peptide processing by the cell that propels the antigen, the presentation of the peptide by an MHC class molecule II genetically determined and the recognition of the molecular complex of MHC / peptide by the receptor on the cells assistants T has made it difficult to determine the requirements for promiscuous Th epitopes that provide extensive resposability (Bianchi et al., EP 0427347; Sinigaglia et al., Chaptér 6 in Immunological Recognition of Peptides in Medicine and Biology, ed., Zegers et al. ., CRC Press, 1995, pp. 79-87). It is clear that for the induction of antibodies, the immunogen must comprise the determinant of B cells and the determinant or determinants of mixed Th cells. Commonly, to increase the immunogenicity of an objective, the Th response is provided by the coupling of the objective to a carrier protein. The disadvantages of this technique are -p many. It is difficult to manufacture well defined, safe, and effective peptide carrier conjugates for the following reasons: 1. Chemical coupling are random reactions that introduce heterogeneity in size and composition, for example, conjugation with glutaraldehyde (Borras-Cuesta et al. al., Eur J Immunol, 1987; 17: 1213-1215); 2. the carrier protein introduces a potential for undesirable immune responses such as allergic reactions and autoimmune (Bixler et al., WO 89/06974); 3. the large peptide carrier protein produces irrelevant immune responses predominantly misdirected towards the carrier protein rather than the target site (Cease et al., Proc Nati Acad Sci USA, 1987; 84: 4249-4253); and 4. the carrier protein also introduces a potential for epitope deletion in a host which has been previously immunized with an immunogen comprising the same carrier protein. When a host is immunized subsequently with another immunogen where the same The carrier protein is coupled to a different hapten, the resulting immune response is enhanced for the carrier protein but inhibited for the hapten (Schutze et al., J Immunol, 1985; 135: 2319-2322). To avoid these risks, it is desirable to replace carrier proteins. The assistant cell T can be supplied to TO a target antigen peptide by covalent bond to a well characterized promiscuous Th determinant. Known promiscuous Th are derived from potent pathogenic agents such as the F protein of measles virus (Greenstein dt al., J 5 Immunol, 1992; 148: 3970-3977) and the surface antigen of hepatitis B virus (Matches et al., J Gen Virol 1991; 72: 1293-1299). The present inventors have shown that many of the known promiscuous Th are effective in enhancing a poorly immunogenic peptide, such as the hormone decapeptide of the The hormone that releases luteinizing hormone (LHRH) (US Patent 5,759,551). Other chimeric peptides comprising known promiscuous Th epitopes have been developed with poorly immunogenic synthetic peptides to generate potent immunogens (Borras-Cuesta et al., 1987). The peptides well-designed promiscuous B / Th cell epitopes are capable of producing mixed Th responses with resultant antibody responses selected for the B cell site in most members of a genetically diverse population (US Patent 5,759,551). A review of the known promiscuous Th epitopes shows that they vary in size from about 15 to 50 amino acid residues (US Patent 5,759 ^ 551) and frequently share common structural characteristics with specific tag sequences. For example, a The common feature is the presence of amphipathic helices. they are alpha helical structures with hydrophobic amino acid residues dominating one side of the helix and charged and polar residues dominating the surrounding faces (Cease et al., 1987). Known promiscuous Th epitopes also frequently contain additional primary amino acid patterns such as a charged residue, -Gly-, followed by two to three hydrophobic residues, followed in turn by a polar or charged residue (Rothbard and Taylor, EMBO J, 1988; 7: 93-101). Th epitopes with these patterns are called sequences of Rothbard It has also been found that promiscuous Th epitopes frequently obey the rule of 1, 4, 5, 8, where a positively charged residue is followed by hydrophobic residues at the fourth, fifth and eighth positions, consisted of an antipathetic helix having the positions 1, 4, 5 and 8 located on the same side. This pattern of hydrophobic and charged and polar amino acids can be repeated within a single Th epitope (Partidos et al., J Gen Virol, 1991; 72: 1293-99). Most, if not all, of the known promiscuous T-cell epitopes contain at least one db the periodicities described above. Thrombocytopenic epitopes derived from pathogens include hepatitis B surface epitopes and epitopes from epitope T-helper nuclei antigen (HBsAg Th and HBc Th), epithets from pertussis toxin from T-helper cells (PT Th), epitopes of the tetanus toxin of cells T i go, ...... ?? ii .ña-Mi,,? r-j ,, ir 'fi M | lll-d - M --- lla - á ---- ^^ assistants (TT Th), the epitopes of the F protein of measles virus T-helper cells (MVF Th), epitopes of the major outer membrane protein of Chlamydia trachomatis T-helper cells (CT Th), epitopes of T-cell diphtheria attendant (DT Th), epitopes of Plasmodium falciparum circumesporozoite of attendant T cells (PF Th), epitopes of Trisos phosphate isomerase of Schistosoma mansoni of T-helper cells (SM Th), and TraT epitopes of T-helper Escherichia coli (TraT Th). The sequences of these Th epitopes derived from pathogens can be found in US Pat. No. 5,759,551 as SEQ. FROM IDENT. NOS: 2-9 and 42-52 therein, incorporated herein by reference; in Stagg et al., Immunology, 1993; 79; 1-9; and in Ferrari et al., J Clin Invest, 1991; 88: 214-222, also incorporated for reference The use of such pathogen-derived sites for the immuno-potentiation of B-cell peptide sites for application to LHRH has been described in the US Pat. ,759,551, for HIV in Greenstein et al. (1992), for malaria in EP 0 427,347, for rotavirus in Borras-Cuesta et al. (1987), and for measles in Partidos et al. (1991). Useful Th epitopes may also include epitopes Th combinatorial. In Wang et al. (WO 95/11998), a particular class of combinatorial Th epitopes, "Strúctured Synthetic Antigen Library" (SSAL) is described. The SSAL epitopes comprise ^ ud Mtei? MiUM a multitude of Th epitopes with amino acid sequences organized around a residue building structure without variation with substitutions at specific positions. The sequences of the SSAL are determined by retaining relatively unchanged residues while varying other residues to provide recognition of the various MHC restriction elements. This can be achieved by aligning the primary amino acid sequence of a Th, promiscuous, selecting and retaining as the skeletal structure the residues responsible for the unique structure of the Th peptide, and varying the remaining residues according to the known MHC restriction elements. Lists of unchanged and variable positions are available with the preferred amino acids of the MHC restriction elements to obtain MHC-binding motifs. These can be consulted when designing Th SSAL epitopes (Meister et al., Vaccine, 1995; 13: 581-591). The members of the SSAL can be produced simultaneously in a simple solid phase peptide synthesis in tandem with the selected epitope of B cell and other sequences. The Th epitope library sequences are designed to maintain the structural motifs of a promiscuous Th epitope and, at the same time, accommodate the reactivity for a wider range of haplotypes. For example, the degenerated epitope Th "SSAL1 TH1" (WO 95/11998) was modeled after a promiscuous epitope of the F protein of the viifus of the »- * - • - .- ~ * -. -.- * .-. l > j .J, rf «,» - b - ^^ --..-.- ,,?,. ^ - i. .... .- • a * - ^ * measles (Partidos et al., 1991). TH1 SSAL1 was designed to be used in tandem with a target antigen, LHRH. Like the measles epitope from which it was derived, TH1 SSAL1 was designed to follow the Rothbard sequence and rules 1, 4, 5, 8: and it is a mixture of four peptides: 1 5 10 15 Asp-Leu-Ser-Asp-Leu-Lys-Gly-Leu-Leu-Leu-His-Lys-Leu-Asp Gly-Leu (SEQ ID NO: 2) Glu Me Glu Me Arg le Me Arg Me Glu lie (SEQ ID NO: 3) Val Val Val Val Val Val Val (SEQ ID NO: 4) Phe Phe Phe Phe Phe Phe Phe (SEQ ID NO: 5) A residue loaded with Glu or Asp is added in position one to increase the charge surrounding the hydrophobic face of Th. The hydrophobic face of the antipathetic helix is then maintained by hydrophobic residues in 2, 5, 8, 9, 10, 13 and 16. The positions at 2, 5, 8, 9, 10, and 13 are varied to provide a front with the ability to bind to a wide range of MHC restriction elements. The net effect on - '• * •? Lpi -' r? IÉ ----- É --- characteristic SSAL is to enlarge the range of immune responsiveness of the artificial Th (WO 95/11998). Other attempts have been made to design "idealized artificial Th epitopes" that incorporate all the properties and characteristics of the known promiscuous Th epitopes. Various peptide immunogens comprising these artificial promiscuous Th epitopes including those in the SSAL form have also been constructed. The artificial Th sites have been combined with peptide sequences taken from autoantigens and foreign antigens to provide improved antibody responses for specific target sites (WO 95 ^ 11998 Alexander et al., Immunity, 1994, 1: 751; Del Guerio et al., Vaccine, 1997, 15: 441) that have been described as highly effective. Such peptide immunogens are preferred to provide effective and safe antibody responses and for their immunopotency, which arises from a largely reactive responsiveness imparted by the described idealized promiscuous Th site.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides an immunogenic peptide composition comprising a promiscuous artificial T helper cell epitope linked to a synthetic peptide B cell epitope "target antigenic site". The immunogenic peptide comprises an epitopes of artificial T helper cells (Th) and a target antigenic site containing B cell epitopes and, optionally, a general immuno-stimulatory sequence. The presence of an artificial Th epitope in the immunogenic peptide imparts to that an ability to induce a strong immune response mediated by T-helper cells with the production of a high level of antibodies directed against the "target antigenic site." The present invention further provides for the advantageous replacement of carrier proteins and sites of T-helper cells derived from pathogens to establish peptide immunogens with epitopes of artificial T-helper cells designed specifically to improve their immunogenicity. The novel short peptide immunogens with the artificial Th epitopes of the present invention produce a high level of antibodies selected for the hormone that releases luteinizing hormone (LHRH) useful for contraception, the control of hormone-dependent tumors, the prevention of spot of uncastrated pork, and immunocastration. The artificial Th epitopes were developed empirically, attentive to the known rules for predicting promiscuous T-cell epitopes. In the absence of a unifying theory explaining the mechanism of Th epitopes, these "prediction" rules serve merely as guidelines for designing effective artificial Th epitopes. The artificial Th epitopes of the present invention have been found useful when binding to target antigenic sites and optionally to a sequence Nimmunostimulatory The immunogenic peptides of the present invention can be represented by the formulas: (A) n- (Target antigenic site) - (B) 0- (Th) mX or (A) n- (B) 0- (Th) m- ( B) 0 (Target antigenic site) -X or (A) n - (Th) m- (B) 0- (Target antigenic site) - X or (Target antigenic site) - (B) 0- (Th) m- (A) nX or (Th) m- (B) 0- (Target antigenic site) - (A) nX wherein: A is an amino acid or a general immunostimulatory sequence, for example, the invasin domain (Inv) (SEQ. DE IDENT NO: 78) where n is more than one; Individual A may be the same or different; 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) -; Th is an artificial epitope of T cells of attendants selected from the group consisting of SEC. FROM IDENT. US: 6-22, 31-35 and 105 and an analog or segment thereof; "Target antigenic site" is a desired B cell epitope, a peptide hapten, or an immunologically reactive analogue thereof; X is an amino acid a-COOH or -CONH 2 'n is from 1 to about 10; m is from 1 to about 4; and o is from 0 to about 10. An example of a peptide hapten as an antigenic target site is LHRH (SEQ ID NO: 77). The compositions of the present invention comprise peptides capable of evoking antibody responses in a host immunized to a desired target antigenic site. The target antigenic site can be derived from pathogenic organisms and usually immuno-silent autoantigens and tumor-associated targets such as LHRH. Accordingly, the compositions of the present invention are useful in many and diverse medical and veterinary applications. These include vaccines to provide an infectious disease protective unit, immunotherapies for the treatment of disorders resulting from malfunction of normal physiological processes, immunotherapies for the treatment of cancer, and agents to intervene desirably and modify normal physiological processes. Some of the target antigens that can be covalently linked to the Th epitopes of the present invention include: LHRH for contraception, the control of hormone-dependent tumors and immuno castration; somatostatin for the promotion of the growth of farm animals; IgE for the treatment of allergies; the CD4 receptor of T-helper cells for the treatment and prevention of HIV infection and immune disorders; capsid protein of the foot-and-mouth disease virus as a vaccine for the prevention of foot-and-mouth disease; the Plasmodium CS antigen for the prevention of malaria; CETP for the prevention and treatment of arteriosclerosis; and HIV virion epitopes for the prevention and treatment of HIV infection.

DETAILED DESCRIPTION OF THE INVENTION Idealized artificial Th epitopes are provided. These are modeled on two known natural Th epitopes and SSAL peptide prototypes, described in WO 95/1199ß. SSALS incorporate binding motifs of combinatorial MHC molecules (Meister et al., 1995) that attempt to produce broad immune responses among members of a genetically diverse population. The SSÁL peptide prototypes were designed based on the Th epitopes of the measles virus and hepatitis B virus antigens, modified by introducing multiple MHC binding motifs. The design of the other Th epitopes was modeled after other known Th epitopes by simplifying, adding, and / or modifying the multiple MHC binding motifs to produce a series of novel artificial Th epitopes. The newly adapted promiscuous artificial Th sites were incorporated into synthetic peptide immunogens carrying a variety of objective antigenic sites. The resulting chimeric peptides were able to stimulate effective antibody responses to the target antigenic sites The artificial prototype epitope of T helper cells (Th) shown in Table 1a as "SSAL1 TH1" (SEQ ID NOS: 2.3 , 4,5) is an idealized Th epitope modeled on a promiscuous Th epitope of the F protein of measles virus (Partidos et al., 1991). The Th epitope model, shown in Table 1a as "MVF Th" (SEQ ID NO: 1) corresponds to residues 288-302 of the F protein of the measles virus. The Th MVF (SEQ ID NO: 1) was modified in the prototype Th1 SSAL1 (SEQ ID NOS: 2,3,4,5) by adding a Glu / Asp loaded residue at position 1 to increase the charge surrounding the hydrophobic face of the epitope; adding or retaining a charged residue or Gly at positions 4, 6, 12 and 14; and adding or retaining a charged or Gly residue at positions 7 ^ 11 in accordance with the "Rothbard Rule". The hydrophobic face of the Th epitope comprises residues at positions 2, 5, 8, 9, 10, 13 and 16. The hydrophobic residues commonly associated with the promiscuous epitopes were substituted at these positions to provide the combinatorial Th SSAL epitopes, Th1 SSAL1 ( SEQ ID NO: 2,3,4,5). The hydrophobic residues conforming to the Rothbard sequence rule are shown in bold type (Table 1a, SEQ ID NO: 1). The positions in the sequence that obey rule 1, 4, 5, 8 are underlined. Other significant feature of the prototype Th1 SSAL1 (SEQ ID NOS: 2,3,4,5) is that positions 1 and 4 are imperfectly repeated as a palindrome on each side of position 9, to mimic a binding motif to MHC. That palindromic pattern "1, 4, 9" of Th1 SSAL1 was further modified in SEC. FROM IDENT. NO: 3 (Table 1a) to more closely reflect the sequence of the original MVF Th model (SEQ ID NO: 1). Also, the hydrophobicity of the Th1 SSAL1 prototype (SEQ ID NO: 2,3,4,5) was modulated in SEC. FROM IDENT. NOS: 6,7, and 8 by the addition of methionine residues at variable positions 1, 12, and 14. Experimental data show that SEC. FROM IDENT. NOS: 6,7,8 coupled to a target antigenic site, improves the antibody response in animals immunized at the target antigenic sites. The SEC. FROM IDENT. NOS: 6,7,8 was simplified in SEC. FROM IDENT. US Nos: 6,9,10 and 11 (Table 1a) to provide additional immunogenic Th SSAL epitopes. The SEC. FROM IDENT. NOS: 6,7,8 was further simplified in the SEC. FROM IDENT. NOS: 6, 12-14 (Table 1a) to provide a series of single-sequence epitopes. The Th SSAL SEC. FROM IDENT. NOS: 4j9, 10 and 11 and the Th epitopes of single sequence SEC. FROM IDENT. NOS: 6, 12-14, coupled to the target antigenic sites also provided improved immunogenicity. It was found that the immunogenicity of SEC. FROM IDENT. NOS: 6,7,8 can be improved by extending the N-terminal with _ ^^ ..------ i- i -.aJ + - -. --I -------------- S- an uncharged nonpolar amino acid and a polar one, for example, e and Ser, and extending the C terminal for a charged and hydrophobic ammonia, for example, Lys and Phe. This is shown in Table 1a as SEC. FROM IDENT. NOs: 15,16,17 from which the simplified Th SSAL epitopes were derived SEC. FROM IDENT. US Nos. 15 and 18, 105 and 19. Peptide immunogens comprising a target antigenic site and a Th epitope selected from SEQ. FROM IDENT. US Nos. 15-17, 15 and 18, 105 and 19, and 123, 124 showed improved immunogenicity. Sequence-chain peptides such as SEC. FROM IDENT. NOS: 15, 20-22 were also synthesized and tested for immunogenicity in animals. These were also found to be effective Th epitopes. The artificial helper epitope SSAL shown in Table 1b as "SSAL2 Th2" (SEQ ID NOS: 26-30) was modeled following a promiscuous epitope of the surface antigen of hepatitis B virus SEC. FROM IDENT. NO: 23 corresponding to residues 19-33 of hepatitis B surface antigen (HBsAg) (Greenstein et al., 1992). The model Th derived from a pathogen was modified in SEC. FROM IDENT. NO: 24 when adding three Lysines to improve water solubility; The C-terminal Asp was deleted in the SEC. FROM IDENT. NO: 25 to facilitate the synthesis of chimeric peptides where Gly-Gly was introduced as spacers. The Th2 SSAL2 (SEQ ID NOS: 26-30) was further modified from the SEC. FROM IDENT. NO: 24 by varying the residues positively charged therein in positions 1, 2, 3 and 5 to vary the load that surrounds the hydrophobic face of the helical structure. An amino acid loaded in variable position 3 also contributes to a residue required to generate the idealized Th epitope, Th2 SSAL2 (SEQ ID NOS: 26-30), which obeys rule 1, 4, 5, 8 (residues underlined). The hydrophobic face of the antipathetic helix consists of hydrophobic residues at positions 4, 6, 7, 10, 11, 13, 15 and 17 of the SEC. FROM IDENT. NOS: 26-30. The Rothbard residue sequence is shown in black letters for the Th2 SSAL2 prototype (SEQ ID NOS: 26-30). The SEC. FROM IDENT. NOS: 31-35 was simplified from the idealized Th2 SSAL2 prototype (SEQ ID NOS: 26.30) as described above. For example, variable hydrophobic residues were replaced with simple amino acids, such as Me or Met (SEQ ID NOS: 31-35). The hydrophobic Phe at position 4 was incorporated as a characteristic of the SEC. FROM IDENT. NO: 34 at the same time that the three lysines are removed. The elimination of C-terminal Asp was incorporated as a characteristic of SEC. FROM IDENT. NOS: 32, 34 and 35. Additional modifications include the substitution of C-terminal for a common MHC binding motif AxTxIL (Meister et al, 1995). Each of the novel artificial Th epitopes, SEC. FROM IDENT. US. 6,12-19, 105, 123, 124 20-22 and 31-35 were coupled to a variety of target antigenic sites for • -• ME-------------------------------------. I-I --------- provide peptide immunogens. Target antigenic sites include the peptide hormones, LHRH and somatostatin, B-cell epitopes of immunoglobulin IgE, the CD4 receptor of the T-cell, and the capsid protein of VP1 of the foot-and-mouth disease virus; the plasmodium falciparum cs antigen; and the cholesteryl ester transport protein (CETP); and the B cell epitopes of HIV. The results show that effective cross-reactive anti-target site antibodies are produced in a diverse group of autoantigens and foreign antigens. Most importantly, the antibody responses are targeted to the target antigenic sites and not to the novel Th epitopes.

The results for the novel peptide immunogens for LHRH are shown in Tables 2 and 3. The immunogenicity results also show that the produced antibodies are effective against LHRH but not against the Th epitopes themselves. It is emphasized that LHRH is an objective antigenic site devoid of T-cell epitopes (Sad et al., Immunology, 1992; 76: 599-603 and U.S. Patent 5,759,551). Thus, the novel artificial Th epitopes of the present invention represent a new class of promiscuous assistant epitopes T. The artificial Th epitopes of the present invention are contiguous sequences of amino acids (natural or unnatural amino acids) comprising a binding site to the MHC class II molecule. They are sufficient to improve or stimulate an antibody response to the target antigenic site. Since a Th epitope may consist of discontinuous continuous amino acid segments, not all of the amino acids of the Th epitope are necessarily involved with MHC recognition. The Th epitopes of the invention additionally include immunologically functional homologues. Functional Th homologs include homologs that enhance immunity, cross-reactive homologs, and segments of any of these Th epitopes. Functional Th homologs further include conservative substitutions, additions, deletions, and insertions of from 1 to about 10 amino acid residues and provide the Th stimulating function of the Th epitope. The promiscuous Th epitopes of the invention are covalently linked to the N- or C-terminus of the target antigenic site, to produce chimeric peptides of Th / B cell site. The term "peptide immunogen" as used herein refers to molecules comprising Th epitopes covalently linked to a target antigenic site, either through conventional peptide bonds to form a single larger peptide, or through other forms of covalent bonding, such as a thioester. Accordingly, the Th epitopes (eg, SEQ ID NOS: 6, 12-19, 105, 123, 124,20-22 and 31-35) are covalently linked to the target antigenic site (eg, SEC. FROM IDENTITY NO: 77) either by means of n-r-ir1? i •, •• f »< ljaea chemical coupling or by means of direct synthesis. The Th epitopes can be directly linked to the target site through a spacer, for example, Gly-Gly.o (e-N) Lys. In addition to physically separating the Th epitope from the B cell epitope (e.g., SEQ ID NOS: 41-64, 77-76, 84-90, 92-94, 96-102, 103, 104, 106, 126 -129, and 135-153), the spacer can disrupt any secondary artifact structure created by the Th epitope binding or its functional homologue to the target antigenic site and thereby eliminate any interference with the Th and / or B cell responses. A flexible spacer hinge that improves the separation of the Th and IgE domains can also be useful. The flexible hinge sequences are frequently rich in proline. A particularly useful flexible hinge is provided by the sequence Pro-Pro-Xaa-Pro-Xaa-Pro (SEQ ID NO: 79) patterned from the flexible hinge region found in the immunoglobulin heavy chains. The Xaa in it is any amino acid, preferably aspartic acid. The conformational separation provided by the spacer (see SEQ ID NOS: 80 and 82) allows more efficient interactions between the presented peptide immunogen and the Th cells and the appropriate B cells. Thus, immune responses to the Th epitope are increased to provide improved immune reactivity. The peptide conjugated immunogens of the invention may also optionally comprise a sequence general immunostimulatory peptide. For example, a domino of an invasin protein (Inv) of the Yersinia spp. Bacterium (B rett et al., Eur J Inmunol, 1993, 23: 1608-1614). 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. A preferred embodiment of the invasin domain (Inv) for binding to a promiscuous Th epitope has been previously described in U.S. 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-GI n-Phe (SEQ ID NO: 78) ) or is an immunostimulatory homologue thereof of the corresponding region in another invasion 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 immunostimulatory properties. The general immunostimulatory sequence can optionally be linked to the Th epitope with a spacer sequence. The peptide conjugates of this invention, ie, peptide immunogens comprising the described artificial Th epitopes can be represented by the formulas: (A) n- (Target antigenic site) - (B) 0- (Th) m-X (A) n- (B) 0- (TH) m- (B) 0 - (Target antigenic site) -X or (A) n- (Th) m- (B) 0- (Target antigenic site) -X o (Target antigenic site) - (B) 0- (Th) m- (A) nX (Th) m- (B) 0- (Target antigenic site) - (A) n-X wherein: A is optional and is an amino acid or a general immunostimulatory sequence, wherein n > 1, each A can be the same or different; B is selected from the group consisting of amino acids, -NHCH (X) CH2SCH2CO-, -NHCH (X) CH2SCH2CO (eN) Lys-, NHCH (X) CH2S-succ? Nimidyl (eN) Lys-, and -NHCH (X CH2S- (succinimidyl) -; Th is an artificial helper T-cell epitope (SEQ ID NOS: 6,12-19,105,20-22 and 31-35) or a homolog enhancing immunity or a segment thereof; "Target antigenic site" is a desired B cell epitope or a peptide hapten, or an analog thereof); X is an amino acid a-COOH or -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 immunogens of the present invention comprise from about 25 to about 100 amino acid residues, preferably from about 25 to about 80 amino acid residues. When A is an amino acid, it can be any amino acid that occurs not naturally or that occurs naturally.

Amino acids that do not occur naturally include, but are not limited to, D-amino acids, β-alanine, ornithine, norleucine, norvaline, hydroxyproline, thyroxine, α-aminobutyric acid, homoserine, citrulline, and the like. Naturally occurring amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. In addition, when n 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 sequence, it is preferably an immunostimulatory epitope of the invasin protein of a Yersinia species described herein as SEC. FROM IDENT. NO: 77 In a modality where n is 3, each A is in turn a sequence of invasin (Inv), glycine and glycine. B is optional and is a spacer comprising one or more naturally occurring or non-naturally occurring amino acids. In (B) 0, where 0 > 1, each B can be the same or different. B can be Gly-Gly or Pro-Pro-Xaa-Pro-Xaa-Pro (SEQ ID NO: 79) or -NHCH (X) CH2SCH2CO-, NHCH (X) CH2SCH2CO (e-NLys) -, -NHCH (X) CH2S-succinimidyl eNLys-, and -NHCH (X) CH2S- (succinimidyl) -. Th is a promiscuous T helper cell epitope selected from the group of SECs. FROM IDENT. US: 6,12- 19,105,123,124,20-22 and 31-35 and homologs thereof. The peptide immunogens of this invention can be made by chemical methods 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. The peptides can be synthesized using Merrifield solid phase peptide synthesis automated with t-Boc or Fmoc to protect the a-NH2 or the secondary chain amino acids. The equipment for peptide synthesis is commercially available. An example is an Applied Biosystems Peptide Synthesizer Model 430A or 431. 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 groups on the secondary chains of amino acids. . The free peptide is purified by CLAP and characterized biochemically, for example, by amino acid analysis, by sequencing, or by mass spectrometry.

The methods of purification and peptide characterization are well known to one of skill in the art. Other chemical means for generating peptide immunogens comprising the Th epitopes of the invention include the ligation of haloacetylated and cysteinylated peptides through the formation of a "thioether" bond. For example, a cysteine can be added to the C terminus of a Th-containing peptide and the thiol group of the cysteine can be used to form a covalent bond for an electrophilic group such as a modified N-chloroacetyl group or a maleimide-a -derived or e- ^ H2 of a lysine residue, which in turn binds to the N terminus of a target antigenic site peptide.In this form, Th / Cell B epitope site conjugates can be obtained. The immunogenic subject can also be The polymerization can be achieved for example by reaction between the glutaraldehyde and -NH2 groups of the lysine residues using routine methodology.For another method, the Th / Cell B site immunogen can be polymerized or copolymerized by the use of an additional cysteine. added to the N-terminus of the linear constructs The thiol group of the N-terminal cysteine can be used for the formation of a "thioether" bond with a haloacetyl-amino acid group modified or a derivative maleimide- or e-NH2 of a lysine residue that binds to the N-terminus of a branched poly-lysyl core molecule (e.g., K2K, K4K2K or K8K4K2K). The immunogenic subject also ^^^ l ^ g can be polymerized as a branched structure through the synthesis of the desired peptide construction directly on a branched poly-lysyl core resin (Wang, et al., Science, 1991; 254: 285-288). The larger synthetic peptide conjugates can alternatively be synthesized by well-known nucleic acid cloning techniques. Any standard manual or molecular cloning technology provides detailed protocols for producing peptides comprising the Th epitopes of the invention by expression of recombinant DNA and RNA. To construct a gene expressing a Th / peptide of the target antigenic site of this invention (for example, SEQ ID NOS: 36-64,106,71-76 and 80-82), the amino acid sequence is inversely translated into a nucleic acid sequence, preferably using codons optimized for the organism in which the gene will be expressed. Then, a gene encoding the peptide is typically made by synthesizing overlapping oligonucleotides which encode the peptide and the necessary regulatory elements. The synthetic gene is assembled and inserted into the desired expression vector. The synthetic nucleic acid sequences encompassed in this invention include those encoding the Th epitopes of the invention and the peptides comprising those Th epitopes, the immunologically functional homologs thereof, and the nucleic acid constructs characterized by changes in the non-coding sequence that does not alter the immunogenic properties of the peptide or the Th epitope encoded thereby. The synthetic gene is inserted into a suitable cloning vector and the recombinants are obtained and characterized. The Th epitopes and the peptides comprising the Th epitopes are then expressed under conditions appropriate for the selected expression system and the host. The Th epitope or peptide is purified and characterized by standard methods. The peptide immunogens of the invention can be used alone or in combination to produce antibody responses to the Luteinizing Hormone Releasing Hormone. The hormone that releases the Luteinizing Hormone (LHRH) or the hormone that releases Gonadotropin (GnRH) is a master hormone for the regulation of sexual reproduction in males and females. The LHRH regulates the release of LH and FSH which in turn control spermatogenesis, ovulation and estrus, sexual development. LHRH ultimately controls the secretion of male hormones androgen and testosterone, and the secretion of female hormones, estrogen and progesterone, which in and of themselves are essential for fertility in males and females, respectively. (Basic and Clinical Endocrinology, eds FS Greenspan and JD Baxter, Appleton &Lange: Norwalk CT, 1994). It has long been known that active immunization against LHRH exerts multiple effects on males that • * - * - > - »-" • - "* - •" * - - -------- M includes decrease in serum and LH and pituitary FSH, reduction of serum testosterone, suppression of spermatogenesis and reversible atrophy of the gonads and accessory sex organs (See, for example, Fraser et al., J. Endocrinol., 1974; 63: 399-405; Gip et al., Exp. Molec. Pathol., 1991; 54: 255-264; Ladd et al. al., J. Reprod. Immunol., 1989; 15: 85-101, and references cited therein.) Immunization against LHRH has proven useful as a contraceptive in males and has potential as a treatment for the prostate cancer (Thau, Scand J Immunol, 1992; 36 Suppl 11 127-130; and US 5,759,551) Immuno-intervention on the hypothallopituitary gonadal axis by active immunization against LHRH can also be used to inhibit hormones In women, since LHRH regulates the production of FSH by the anterior pituitary which in turn regulates the production of estrogen by the ovaries, b Locking the action of LHRH is a therapy for sex hormone dependent diseases in women. For example, ectopic development and maintenance of endometrial tissues outside the uterine musculature was measured by estrogen. Therefore, blocking the action of LHRH is useful as a treatment for endometriosis. In addition, by analogy to prostate cancer, breast tumors driven by estrogen must also be responsive to LHRH immunotherapy. Actually, a vaccine that induces anti-LHRH has been shown to effectively reduce serum levels of LH and FSH in women, an illustration of the potential of this method to perform contraception and the treatment of hormone-dependent disorders (Gual et al., Fertility and Sterility, 1997; 67: 404-407). In addition to providing treatment for a number of important diseases and reversible infertility in men and women, LHRH-based immunotherapy provides a means for reversible contraception in male and female animals (for example dogs, cats, horses and rabbits) as well as mitigate the undesirable behavior driven by androgen such as heat, territorial signaling and aggression. Finally, immunological castration (for example, the inhibition of the action of LHRH based on antibodies) has application in the livestock industry. The meat of the male animals is not processed in the most chosen cuts due to the presence of an offensive aroma and taste, known as unneutrated pork stain. The unneutrated pork stain is conventionally removed by mechanical castration; however, castration of male food animals is no longer considered human. In addition, mechanical castration results in poorer growth performance and lesions in the body part, also referred to as sample resit qualities, compared to non-castrated animals. While the growth performance and carcass qualities of the immunocastrated animals are less affected than those of the castrated animals (Bonneau et al., J Anim Sci, 1994; 72: -i.- . . > .l. «*. i ........ - 14-20 and North American Patent 5,573,767). Therefore, immunological castration is preferable to mechanical castration. LHRH (or GnRH) is a self-molecule that must be linked to a Th component to generate anti-LHRH antibodies (Sad et al., Immunology, 1992; 76: 599-603). Such various immunogenic forms of LHRH have been tested. For example, LHRH immunogens have been produced by conjugation to carrier proteins or are linked by peptide synthesis to potent Th sites derived from pathogenic organisms (WO 94/07530, US Pat. No. 5,759,551, Sad et al., 1992). Enhanced LHRH peptide immunogens comprising epitopes of LHRH and Th artificial are exemplified in EXAMPLES 1-3. This invention also provides compositions comprising pharmaceutically acceptable delivery systems for the administration of peptide immunogens. The compositions comprise an immunologically effective amount of one or more of the peptide immunogens of this invention. When formulated thus, the compositions of the present invention comprising LHRH or a homologue thereof as a target antigenic site, are used for the treatment of prostate cancer, prevention of unneutrated pig spot, immunocastration of animals, treatment of endometriosis, breast cancer and other gynecological cancers affected by gonadal steroid hormones, and for contraception in males and females. The utility for the peptides of the invention have objective antigen sites other than LHRH will vary according to the specificity of the subject antigenic site. The peptide immunogens of the invention can be formulated as immunogenic compositions using adjuvants, emulsifiers, pharmaceutically acceptable carriers or other ingredients routinely provided in vaccine compositions. Adjuvants or emulsifiers that can be used in this invention include alum, incomplete Fround adjuvant (IFA), liposine, saponin, squalene, L121, emulsifier, monophosphoryl lipid A (MPL), dimethyldioctadecylammonium bromide (DDA), QS21, and ISA 720 , ISA 51, ISA 35 or ISA 206 as well as the other effective adjuvants and emulsifiers. Such formulations are readily determined by one of ordinary skill in the art and also include formulations for immediate release and / or sustained release. The present vaccines can be administered by any convenient route that includes subcutaneous, oral, intramuscular, intraperitoneal, or other parenteral or erlteric route. Similarly, immunogens can be administered in a single dose or multiple doses. Immunization schedules are easily determined by the commonly skilled artisan. The 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 g to about 1 mg of the peptide immunogen per kg body weight. When supplied in multiple doses, it can conveniently be divided into an appropriate amount per dose. For example, the dose, 0.2-2.5 mg; preferably 1 mg, can be administered by injection, preferably intramuscularly. This can be followed by repeated dose (driver). The dosage will depend on the age, weight and general health of the subject how well it is known in the therapeutic and vaccine techniques. Vaccines comprising mixtures of the subject peptide immunogens, particularly mixtures comprising Th sites derived from MVF Th, ie, SEC. FROM IDENT. US: 6, 12-19,105,123,124,20-22, and Th HBsAg, ie, SEC. FROM IDENT. NOS: 31-35, can provide increased immunoefficiency in a larger population and thus provide an improved immune response to LHRH or another target antigenic site. The immune response to peptide conjugates of Th / LHRH or other Th / target antigenic site conjugates can be improved by delivery through capture in or on biodegradable microparticles of the type described by O'Hagar) et al. (Vaccine, 1991; 9: 768). Immunogens can be encapsulated with or without an adjuvant, and such microparticles can carry a immunostimulatory adjuvant. The microparticles can also be co-administered with peptide immunogens to enhance immune responses. As a specific example, the invention provides a method for inducing anti-LHRH antibody by administering pharmaceutical compositions comprising Th / LHRH peptide immunogens to a mammal for a time and under conditions to produce an infertile state in the mammal. As used herein an infertile state is that state which prevents conception. Infertility can be measured by methods known in the art, for example the evaluation of spermatogenesis or ovulation, as well as by statistical modeling of experimental data from animals. Other indicators of infertility in males include the reduction of serum testosterone to levels of castration and involution of the testicles. The appropriate dose of the composition is about 0.5 μg to about 1 mg of each peptide per kg of body weight. This dosage can be conveniently divided into appropriate amounts per dose when delivered in multiple doses. Similarly, the LHRH modalities of this invention relate to a method for treating androgen-dependent carcinoma by administering the peptide compositions subject to the mammal for a time and under conditions to prevent further growth of the carcinoma. The appropriate unit dose is about 0.5 μg to about 1 mg of each peptide per kg of body weight. This is conveniently divided into the appropriate amounts per application when administered in multiple doses. Additionally, the LHRH modalities refer to a method for improving the organoleptic qualities and softness of the meat of male domestic animals while maintaining the advantageous growth performance of intact males. The androgenic steroid hormones of intact males are responsible for rapid growth but their presence is accompanied by non-androgenic steroids (eg, daandrostenone) and skatole (a product of the microbial metabolism of tryptophan) which imparts unpleasant taste and aroma to the meat. This condition, known as pork njiancha without castrating in the case of pigs, reduces the quality of the meat. However, by the active immunization of young males with compositions comprising LHRH peptides of the invention, on a Plan that effects immunocastration in the weeks just before slaughter, many of the growth benefits of non-castrated males can be retained. instead, it provides meat with improved flavor and smoothness. The efficiency of the peptide composition of the present invention comprising the target antigenic site, LHRH, can be tested by the procedure described in Examples 1-3. ^? ^^^ ámu *****? ^ * iHtui * ß * í ??? tÉík ** Wt * * l ^^ Other target antigenic sites that have also had to be used in peptide immunogens of the present invention are described in Examples 4-9. The peptide immunogen compositions are useful for the immune response induced in mammals against the specific target antigens and provide for the prevention or treatment of the disease or intervening in the normal physiologically useful conditions modified.

EXAMPLE 1 IMMUNIZATION OF RATS WITH PEPTIDE IMMUNOGENS CONTAINING LHRH The peptides listed in Tables 2a and 2b were synthesized and tested as described below. A. Peptide synthesis. The peptides listed in Tables 2a and 2b 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 (SSALs), for example, the artificial Th site designated SEC. FROM IDENT. NO: 6-8, was achieved by providing a mixture of the desired amino acids selected for a given position. After complete assembly of the desired peptide or combinatorial ppptidos, the resin was 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. The cleaved, extracted and washed peptides were purified with CLAP and characterized by mass spectrometry and reverse phase CLAP. The peptides were synthesized to have the target antigenic peptide LHRH (SEQ ID NO: 77) in tandem with each of the Th epitopes as listed in Tables 2a and 2b. The Th epitopes are those shown in Tables 1a and 1b (SEQ ID NOS: 6,12-19,105,20-22 and 31-35). For comparison purposes, the peptide immunogens of the prior art comprising model Th sites (SEQ ID NOS: 36 and 65), and prototype Th sites (SEQ ID NOS: 37-40 and 66-70) and a peptide / carrier protein conjugate, KLH-LHRH (Table 2b) was also tested and synthesized. Th / LHRH and Inv / Th / LHRH peptide constructs were synthesized with gly-gly as a spacer between the target antigenic site and the Th epitope, and with or without gly-gly as a spacer between the Th epitope and the immunostimulatory sequence Inv . In addition, SEC. FROM IDENT. NOS: 80-82 were synthesized with the SEC. FROM IDENT. NO: 79 as a space between the Th site and the antigenic site object. The results for peptide immunogens SEC. FROM IDENT. NOS: 80-82 are not yet available.

B. Protocols for immunization. The LHRH peptide immunogens shown in Tables 2a and 2b were evaluated in groups of 5 to 10 rats as specified by the experimental immunization protocol summarized below and by serological tests for the determination of immunogenicity in serum samples: Animals: male Sprague rats -Dawley Group size: 5-10 rats / group Immunogen: individual peptide immunogen Dosage: amount in μg as specified, in 0.5 mL Adjuvants: (1) Freund's Incomplete Adjuvant (IFA); or (2) Alum (Aluminum hydroxide); One adjuvant per immunogen per group Dose schedule: 0, 3, and 6 weeks or 3 weeks as specified Route: intramuscular Blood was collected and processed in serum and stored before ELISA and radioimmunoassay (RIA) for determination of serum testosterone values. C. Method for the determination of immunogenicity. Antibody activities were determined by ELISA (enzyme-linked immunosorbent assays) using 96 well flat bottom microtitre plates which were coated with the LHRH peptide (SEQ ID NO: 77) as an immunosorbent. The aliquots (100 μL) of the peptide immunogen solution at a concentration of 5 μg / mL were incubated for 1 hour at 37 ° C. Plates were blocked by another incubation at 37 ° C for 1 hour with a 3% gelatin / PBS solution. The blocked plates were then dried and used for the test. Aliquots (100 μL) of the immune serum test, they started with a 1: 100 dilution in a sample dilution regulator and then ten-fold serial dilutions 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% Tween® in PBS. 100 μL of horseradish peroxidase labeled in goat IgG ganti-rat antibody was added to the appropriate dilutions in conjugate dilution buffer (Phosphate buffer containing 0.5M NaCl, and normal goat serum). Plates were incubated for 1 hour at 37 ° C before being washed as above. Aliquots (100 μL) of o-phenylenediamine substrate solution were then added. The color was allowed to develop for 5-15 minutes before the colorful enzymatic reaction was stopped by the addition of 50 μL of 2N 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 absorbances, with cut A492nm set at 0.5. This cutoff value was rigorous since the values for the normal diluted control samples run with each test were less than 0.15. D. Determination of immunogen efficiency. The immunogens were evaluated for efficiency by RIA for serum testosterone values. Serum testosterone levels were measured using a RIA equipment from Diagnostic Products (Los Angeles, CA) according to the manufacturer's instructions. The lower limit of detection for testosterone ranged from 0.01 to 0.03 nmol / L. Each sample was analyzed in duplicate. The serum samples were counted as being at castration level when the testosterone level was below the detection limits and as "near castration" as < 0.1 nMol / L. The results were verified by comparison with the serum testosterone levels of mechanically castrated rats. E. Results. The results of the serum samples collected in weeks 10 or 12 are presented in Tables 2a and 2b. (The peptides of the Tables are ordered by derivation of their Th epitopes, as was done in Tables 1a and 1b). ELISA data (not shown) demonstrated that immunization of all listed immunogens resulted in antibody responses in all animals. The efficiency of anti-peptide antibody responses, consistent with cross-reactivity to natural LHRH, was established by determining serum testosterone levels. These results are summarized in the right column of Tables 2a and 2b as the number of ^ Ajiy ^^ ** animals that have serum testosterone castration level by total animals in the group. The results show that the peptides of the invention, either with a strong IFA adjuvant and administered 3 times at a high dose, or with a weak adjuvant Alur? Bre and administered twice at a low dose were effective to produce immunocastration. The immunogenicity of Th SEC sites. FROM IDENT. NOS: 6,9 and 15 were improved by the addition of the Inv domain sequence. See comparisons between SEC. FROM IDENT. NOS: 41.44 and 45 and SEC. FROM IDENT. NOS: 53 and 60. Although, the addition of the Inv domain sequence did not always result in the improvement of immunogenicity, for example, compare SEC. FROM IDENT. NOS: 51 and 52, SEC. FROM IDENT. NOS: 61 and 62, and, SEC. FROM IDENT. NOS: 74 and 75. Two peptides of the invention (SEQ ID NOS: 50 and 76) were tested only at low dose with the weak adjuvant and failed to cause immunocastration, but the results with other peptides, e.g. . FROM IDENT. NO: 73, indicate that they would have been effective at a higher dose with a strong adjuvant. Many of the peptide immunogens LHRH of the present invention were significantly more effective in inducing immunocastration than the conjugate of KLH / peptide carrier protein LHRH or peptide immunogens having Th HbsAg (SEQ ID NOS: 65 and 66-70). See Table 2b.

Also, the peptide immunogens of the present invention were more readily synthesized than the carrier peptide / protein conjugate or the peptide immunogens having the more complex Th prototype epitopes of the prior art (SEQ ID NOS: 2-5 or 26). -30). Still, enhanced equivalent immunogenicity was obtained with lower and lower doses with the peptide immunogens comprising the artificial Th epitopes of the present invention. A serological analysis of the antibody responses of rats that had received the LHRH peptides of the invention demonstrated that the antibody responses to the peptides were directed specifically to the target antigenic site and not to the novel artificial Th sites. This is a unique advantage of these peptide immunogens over conventional peptide / carrier protein conjugates. Serum samples from rats that had been immunized with the peptide immunogens shown in Table 3, with doses of 25 μg on Alum at 0 and 3 weeks, were compared by reactivities to the LHRH target site and the Th epitope by ELISA using the peptide LHRH (SEQ ID NO: 77) and the appropriate Th epitope (SEQ ID NO: 15 and 18, 31 or 34) as solid phase substrates in peptide-based ELISA. The results for these ELISAs are presented in Table 3 which show that despite the high titer responsiveness to the LHRH portion of the Th / LHRH peptide conjugates, the reactivities for the artificial Th sites were at basic levels.

EXAMPLE 2 PEPTIDE MIXTURE LHRH FOR INDUCTION OF WIDER IMMUNOCASTRATION IN RATS Relative efficiencies of the various Th / LHRH epitope constructs were established as shown above in Example 1, allowing the selection of the most effective to assemble within a peptide mixture of increased immunogenicity. A mixture of Th / LHRH peptide immunogens is more effective than any individual peptide within the mixture (U.S. Patent 5,795,551). In addition, a mixture of individual constructs carrying promiscuous Th epitopes derived from Th MVF (SEQ ID NO: 1) and Th HBsAg (SEQ ID NOS: 23-25) provides a broader response in a genetically diverse population than a peptide composition having Th epitopes derived from only one promiscuous Th epitope. Therefore, a peptide composition comprising a mixture of peptides of the invention derived from Th MVF and HbSAg Th was assembled and the efficiency of the mixture was tested and compared to the compositions comprising the individual peptides of the mixture. The groups of 6 or 8 male rats were immunized with doses of 25 μg (total dose) of the peptide compositions indicated in Table 4. The peptides in the mixture were combined in equimolar proportions. Peptides were formulated with 0.4% Alum and were administered intramuscularly at weeks 0 and 3. Serum testosterone levels were followed for 22 weeks and the results were counted as number of animals with testosterone castration level by total number of animals in the group. These results are presented in Table 4. It is shown that low doses of peptide compositions, given with a relatively ineffective adjuvant, achieved testosterone castration levels by week 5, and that this response was maintained until week 22. In addition, the peptide mixture performed significantly better than one of the peptide compositions comprising an individual peptide. It can be assumed that the mixture would have shown improved immunogenicity over the other individual peptide composition if the numbers of experimental animals had been larger and more representative of a true population.

EXAMPLE 3 PEPTIDE MIXTURE LHRH AND FORMULATIONS FOR PIG IMMUNOCASSATION A group of test animals have been shown to be more broadly responsive to a mixture of peptide immunogens with different Th epitopes than to a composition containing a single peptide immunogen. However, for the prevention of swine stain, it is necessary that the immunopotent LHRH peptide immunogens be sufficiently potent to produce the desired response in most animals while being acceptable for use in food animals. It is important that there is no immediate effect adverse to the rate of growth and that no residue of peptide immunogen or adjuvant is left in the meat or cause injury in the commercial parts of the carcass. To evaluate the useful immunogenicity of a mixture of LHRH peptides of the invention, the mixture was administered to the pig in three formulations in either 0.4% of Alum, IFA, or ISA 206 / DDA. ISA 206 / DDA is an oil / water emulsion in which dimetidioctadecylammonium bromide (DDA) is dispersed in MONTANIDE® ISA 206 at 30 mg / ml (MONTANIDE® ISA 206 is an oily metabolizable solution supplied by SEPPIC Inc. of Fairfield, NJ). The oil suspension was then emulsified at a 1: 1 volume ratio within an aqueous peptide solution which had been adjusted for a peptide concentration to provide the desired dose of peptide in 0.5 mL of the final preparation.

'• - - - * - "-" - "^ - *" Immunization protocol Animals: male Yorkshire hybrid hybrids Hampshire Cross Swine, 3-4 weeks old not neutered Group size: 2-3 animals / group Immunogen: Equimolar mixture of SEC. OF IDENTI. NOS: 5758, 71 and 75, Dosage: 400 μg of peptide (s) in 0.5 mL Adjuvants: (1) 0.4% alum, (2) IFA, (3) ISA 206 / DDA Plan: 0.4, and 13 weeks or 0 , 4 weeks, Route: Intramuscular The efficiency of the immuno peptide formulations was monitored by testing the pig serum samples collected through the course of the study, the results are presented graphically in Figures 1-3. The tests include a RIA for the determination of the presence of cross-reacting antibodies to native LHRH in solution as described below, and an RIA for testosterone as described in EXAMPLE 1. In addition, the cross-sectional area of testes average was determined by palpitation with a calibrator. The antiserum for the anti-LHRH RIA was diluted 1: 100 in 1% bovine serum albumin (BSA), pH 7.4. An equal volume of diluted serum was added to 100 μL of [125 I] -LHRH (New England Nuclear Company, Boston, MA) diluted in 1% BSA to contain approximately 15,000 cpm for 5.25 pg LHRH. The solution was incubated overnight at room temperature and the antibody bound to LHRH was precipitated with 400 μL of 25% polyethylene glycol (Molecular Weight 8,000) in 0.01 M phosphate buffer solution (PBS), pH 7.6, and 200 μL of 5 mg / mL bovine gammaglobulin in PBS. Anti-LHRH antibody concentrations are expressed as iodinated nmol bound to LHRH per liter of serum (Ladd et al., 1988, Am J Reprod Immunol, 17: 121-127). The results are represented graphically in Figures 1-3 for the three tests. The intervals at which the immunogens were administered are shown by rows at the bottom of the graphs. The determinations for the individual experimental ariimals in each figure are represented by circles, triangles, and solid squares. The pig responded immunologically to the three formulations, as shown by the presence of anti-LHRH antibody and the concomitant suppression of testosterone. The alum preparation (Figure 1) was less effective in producing a lower level of antibody responses. An animal of this group did not achieve the level of castration of testosterone until week 11 and both animals in this group did not manifest the complete involution of the testicles. The animals in the alum group did not receive immunizations at week 13, and the effects of the treatment were reversed. The animals of the IFA group (Fig. 2) exhibited higher levels of antibody responses, with two of three reaching and maintaining a castration level of testosterone by week 6. However, with the administration of a booster dose in week 13 , the less responsive pig of the three failed to respond and reverted to a normal level of testosterone and uninvolved testes. The two responsive animals of this group achieved complete involution of the testicles by week 23. Both pigs of group ISA 206 / DDA (Fig. 3) provided high and relatively uniform levels of antibody responses. Testosterone immunocastration levels in this group were achieved by week 9 and remained stable through week 12. Both animals were responsive to the impulse at week 13 and maintained testosterone castration levels. The testes of both animals were undetectable by week 23. From the results obtained from the ISA formulation 206 / DDA, thus, most preferred for the prevention of pig spot. High and uniform effects on the two animals were achieved with the ISA 206 / DDA formulation. In addition, the formulation is more acceptable in pigs compared to the IFA formulation which caused lesions apparently due to the fact that the IFA formulation is not readily metabolized.

EXAMPLE 4 SOMATOSTATINE IMMUNOGENS FOR THE PROMOTION OF I GROWTH IN FARM ANIMALS The immunogens of the invention may be used in combination or in combination to produce antibodies to somatostatin. Somatostatin is a major inhibitor of total somatic growth. It is a typical peptide hormone of 14 amino acids (SEQ ID NO: 80, Table 5) and its structure is conserved throughout the species. Somatostatin inhibits the release of many gastrointestinal hormones as well as inhibits the release of growth hormone, insulin, and thyroid hormones thereby affecting the animal's ability to absorb nutrients and its subsequent ability to direct these nutrients into tissue growth. The neutralization of somatostatin. For immunization to been shown to stimulate growth in sheep, goats, chickens and pigs (Spencer, Dom Anim Endocr, 1986; 3:55; Spencer et al., Reprod Nutr Develop, 1987; 27 (2B): 581; Laarveld et al., Can J Anim Sci, 1986, 66:77), and Cattle (Lawrence et al., J Anim Sci, 1986, 63 (Suppl): 215). In addition to stimulating the growth rate and driving a 20% reduction in breeding time (Spencer, 1986; Spencer et al., 1987), active immunization against somatostatin also has a beneficial effect on the conversion efficiency of food ie, in addition to saving on feed by virtue of faster growth, animals currently use their feed more efficiently during the growing period, at least partially as a result of changes in bowel motility (Fadlalla et al., J Anim Sci, 1985, 61: 234). The treatment has no marked effect on the composition of the dead net (Spencer et al., 1987) but there were indications that, when killed at equal weights, the treated animals may be less fatty and lean. Taking all the experimental data together, effective active immunization for somatostatin (as evidenced by the presence of antisomatostatin antibodies) is a powerful, safe, and effective tool for improving growth (Spencer, 1986). However, somatostatin is a corf peptide and an autoantigen and is non-immunogenic by itself (see Table 5). However, 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 economic use in farm animals. In addition, effective immunization with somatostatin is highly dependent on how the carrier is conjugated to somatostatin. In most cases, glutaraldehyde is used as the carrier to couple with the glycine residues present on somatostatin and glutaraldehyde. The two lysine on somatostatin available for coupling reside within a functional 12-mer ripple. The conjugation of these lysines can result in significant losses of the native somatostatin structure. As a result, cross-reactivity to natural somatostatin with antibodies is reduced. In addition, with protein carriers, most immune responses are directed to the carrier rather than to somatostatin (the mass of the carrier molecule (s) is much larger than that of somatostati? A). Immunization with a small peptide carrier conjugate often leads to carrier-induced immune suppression (Schutz et al., J Immunol, 1985, 135: 2319). In consecuense, there is a need for a different way of improving immunogenicity that is more suitable for the pso of farm animals. The vaccine should be inexpensive and able to stimulate an early and strong immune response to somatostatin and avoid carrier-induced suppression. The peptide immunogens or somatostatin / Th epitope shown in Table 5 were synthesized and administered to rats. The effect of the immunization was determined by peptide ELISA as described in EXAMPLE 1. Cyclicized somatostatin was used in one of the peptide immunogens (SEQ ID NO: 80) tested and in the test as the solid phase substrate in ELISA - Oa 3 -., - A? T. * To fully cyclize somatostatin, the split peptide was dissolved in 15% DMSO in water for 48 hours to facilitate intradisulfide bond formation. From the results shown in Table 5, it is clear that somatostatin alone is devoid of immunogenicity while the peptide immunogens of the present invention produced high titers of somatostatin-specific antibodies in the immunized hosts. The antisomatostatin response generated for SEC. FROM IDENT. NO: 81-83, SEC. FROM IDENT. NO: 84-86 and SEC. FROM IDENT. NO: 87, with Th epitopes (SEQ ID NOS: 6,7,8 and 31) shows the effectiveness of Th epitopes. However, a close comparison of antibody titers for immunogenicity shows that it is preferable to place the Th epitope on the C-terminal. Results for SEC. FROM IDENT. NOS: 84-86, with the epitope Th as SEC. FROM IDENT. NOS: 6,7,8 shows that there was an earlier higher level of antibodies. The results of Table 5 illustrate the strong antibody response to immunization with the artificial Th / somatostatin compositions, thereby establishing the utility of these peptides of this invention for the promotion of growth in farm animals.

EXAMPLE 5 PEPTIDE COMPOSITION FOR PREVENTION FOR THE HIV INFECTION The peptide immunogens comprise idealized artificial Th sites of the present invention and a cross-reactive target antigenic site to an HIV host / co-receptor host cell complex can be used to produce antibodies to that host cell complex in the immunized host. The complex which is located on the surface of host lymphocytes expressing CD4 comprises CD4 associated with a chemokine receptor domain. This complex is the primary receptor for the entry of HIV into T cells. Antibodies directed to this CD4 complex block the interactions between HIV and its receptor, and the interactions between T cells expressing CD4 and CD-4. and other activated T cells. Thus, antibodies directed to this complex have broad neutralizing activities against primary isolates of HIV-1 HIV-2, and SIV and are involved in the immunosuppression of immune responses mediated by CD4 + cells (WO 97/46697). Peptide immunogenic relevant to the CD4 complex antigenic site can be formulated simply or in combination for generation, by active immunization in mammals including humans, high titers of serum antibodies to the CD4 complex these antibodies are useful for . -S¡. " ".. -1.. prevention and treatment of immunodeficiency virus infection as well as for the treatment of undesirable immune responses such as transplant rejection, rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. An epitope Th peptide / target antigenic site immunogen was engineered with a modified sequence of the CDR2- like domain of CD4 as the target antigenic site. The modified site comprises a peptide sequence taken from the CDR2-like domain of human CD4 (amino acids 39-66 according to the numbering system of Maddon et al., Cell, 1985; 42:93; and Littman et al., Cell, 1988; 55: 541) modified as follows: (1) the insertion of cysteine residue on the N-terminal side of position 39 of the naturally occurring CD4 sequence, (2) the insertion of a cysteine residue on the C-terminal side at position 66 thereof, and (3) the formation of a disulfide bond between the inserted cysteine to produce a cyclic structure. The optimized and modified (i.e. cyclized) site for CD4-CDR2 of the following sequences is provided: 1. Cys-Asn-Gln-Gly-Ser-Phe-Leu-Thr-Lys-Gly-Pro-S er-Lys -Leu -Asn -Asp-Arg -Al a-As p-Ser-Arg -Arg -Ser-Leu -Trp- As p-Gln-Gly-Asn-Cys (SEQ ID NO: 88) To complete the cyclization, the modified peptide was dissolved in 15% DMSO in water for 48 hours to facilitate the formation of the intra-disulfide bond between the cysteine SEQ. FROM IDENT. NO: 84 was incorporated into the peptide immunogen: (SEQ ID NO: 6,7,8) -GG- (SEQ ID NO: 88) (SEQ ID NO: 89-91) Immunogenicity in SEC guinea pigs. FROM IDENT.

NO: 85 formulated in ISA 206 / DDA, 100 μg / dose, given at week 0, 3, 6, was evaluated. Immunogenicity was determined by peptide ELISA as described in EXAMPLE 1 The cyclized target antigenic site peptide was used as the solid phase substrate in the ELISA. The labeled conjugate was specific for guinea pig and IgG. Six of six guinea pigs were successfully seroconverted by the ELISA reactivity obtained. It is significant that SEC. FROM IDENT. NO: 85 has been found to be highly immunogenic and is functional in a large animal. An immunogenic composition comprising SEC. FROM IDENT. NO: 85 was formulated in IFA, 300μg / dose, and administered to a pig by intramuscular injection for week 0, 3, and 6. The seroconverted pig and week 8 serum was tested for neutralization activity against of a primary isolate of HIV-1. Neutralization activity was tested on HIV-1 VL135, a primary isolate of subtype B, by MT-2 Microplate Neutralization Test (Hanson et al., J Clin Microbiol, 1990; 28: 2030; WO 97/46697) . The pig serum sample provided 50% neutralization of virus at a dilution of 1: 249, and 90% neutralization at 1:97. Therefore, immunization of a large host animal with a peptide immunogen composition of the present invention produces antibodies that bind to the host cell receptor that comprises CD4 and neutralizes HIV.

EXAMPLE 6 PEPTIDE COMPOSITION FOR THE TREATMENT OF ALLERGY The peptide immunogens comprising the idealized artificial Th sites of the invention and a target antigenic site cross-reactive with a vector site on the third constant domain (CH3) of the epsilon heavy chain (e) of IgE is provided. The immunogens can be used to produce antibodies to the IgE effector site in the immunized host. That effector site lgE-CH3 is modified from a segment of the CH3 domain of the human IgE epsilon heavy chain (amino acids 413-435 (Dorrington and Bennich, 1978, 41: 3) .It is modified from those naturally occurring IgE sequence as follows : (1) insertion of a cysteine residue on the N-terminal side at position 413 (2) substitution of the native cysteine at position 418 of the native porcerin IgE sequence, (3) insertion of cysteine on the C side -terminal at position 435, and (4) formation of a disulfide bond between the cysteines in the N- and C- terms to produce a cyclic structure.For this process the target alpigen site for human IgE is optimized. 2. Cys-Gly-Glu-Thr-Tyr-Gln-Ser-Arg-Val-Thr-His-Pro-His- 3. Leu-Pro-Arg-Ala-Leu-Met-Arg-Ser-Thr-Thr-Lys- Cys (SEQ ID NO: 92) The amino acid substitutions of the natural sequence are shown in bold. The results show that the polyclonal antibodies produced have specificity for the CH3 site of IgE in the immunized host. They avoid sensitization of mast and basophilic cells by IgE, thus preventing the triggering and activation of mast / basophil cells and leading to the down regulation of IgE synthesis. In addition, the antibodies produced by peptides shown in Table 6 with which they comprise this target antigenic site are cross-reactive with human IgE, and these antibodies are safe and non-anaphylactogenic. In addition, the antibodies do not crosslink the IgE binding to the high affinity cell receptor to induce degranulation. Peptide conjugates relevant to the IgE-C3 antigenic site may be formulated simply or in combination and used to immunize mammals including humans to generate high serum antibody titers, which are useful for the prevention and treatment of allergic symptoms. The peptide immunogens that incorporate the modified IgE-CH3 target site (SEQ ID NO: 92) are shown in Table 6 as SEC. FROM IDENT. NOS: 87-90. These peptide immunogens were used to immunize groups of 3 ^^ fe ^^ g ^ guinea pigs using 100μg / dose, formulated in CFA in week 0, IFA in week 3 and 6, and administered intramuscularly. For comparison, a 2 an conjugate group of similarly administered peptide / KLH carrier protein was immunized. The ELISA results of serum samples collected in week 8 are shown. In the ELISA, a human IgE myeloma protein (American Biosystem, Inc. cat.No. A113) was used as the solid phase immunosorbent. The procedure used was identical to the peptide-based ELISAs previously described, except that the myeloma I g E was used as the solid phase immunoabsorbent. Thus, the results demonstrate cross-reactivity with human IgE. The ELISA results also showed that all constructs were immunogenic with cross-reactivity to human IgE, with the peptide immunogens of the present invention providing superior immunogenicity. Inclusion of the Inv domain sequence (SEQ ID NO: 78) increased immunogenicity, as shown by increased immunogenicity SEC. FROM IDENT. NO: 99 on SEC. FROM IDENT. NO: 98 To test anti-human IgE antibodies in tests for biological activity and safety, guinea pig hyperimmune serum was produced against SEC. FROM IDENT. NO: 98 and 99. The procedure is as described above, except that the animals also received a driving dose of the peptide immunogen in IFA at week 10. Antibodies Guinea pig IgE were purified and the ability of purified antibodies to inhibit sensitization of human basophils by specific IgE-allergens was determined as follows: Guinea pig IgG antibodies were purified by Protein A affinity chromatography (ImmunoPure® Immobilized Recomb). ® Protein A, Pierce) of serum collected in weeks 8 and 12. The serum of animals immunized with SEC. FROM IDENT. NOS 98, 99 met. The eluted antibodies were prepared at a standard concentration of 8mg / mL in 25mM PIPES regulator, 0.15M NaCl, pH 7.2. A control antibody preparation of the assembled serum of guinea pig immunized with an irrelevant peptide immunogen was prepared. These antibodies were used in tests that measured the reduction in Ige-mediated sensitization of human basophils. Human basophils were prepared from the venous blood of volunteers using centrifugation through Percoll density gradients (MacGlashan, J Allergy Clin Innmunol, 1993; 91: 605-615). The leukosite bands were harvested, washed, and resuspended in 0 1mL of PAGCM buffer as described (MacGlashan, 1993) except that the PAGCM buffer used to suspend the cells was made with water containing 44% D20. The IgE used for the test was a specific allergen, either human BPO specific IgE or chimeric human IgE having variable domains inserted with specificity for HIV gp120 glycoprotein. The specific IgE allergen at 0.25 μg / mL was pre-incubated for 15 minutes at 37 ° C with an equal volume of purified antibody at 8mg / mL. The total volume was 0.1mL. The antibody mixture was added to it and incubated for 20 minutes to allow the sensitization of the basophils by IgE not complexed. The sensitized was then stimulated by the addition of the allergen, either BP021-HSA or a gp120 polypeptide as described. (MacGlashan, 1993). After an appropriate incubation period (usually 45 minutes), the basophils were separated from the supernatant and the supernatant was tested for histamine content by an automated fluorometric technique (Siraganian, Anal Biochem, 1974; 57: 383-394). All reactions were performed in duplicate. The percent histamine release was calculated from the ratio of the sample to the total histamine minus both of the amounts of spontaneous histamine release. The release of histamine by experimental antibodies for the release of histamine by the control antibody of irrelevant specificity was compared and the ratio was obtained. (Histamine release tests on human basophils were performed gently under conditions codified by Dr. Donald W. MacGlashan, The Johns Hopkins Uni versity School of Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore). The specific inhibition of histamine release by the site-specific anti-IgE was 61% and 71% for purified antibodies from the indentations taken at weeks 8 and 12, respectively.

These actively induced polyclonal antibodies were further tested for safety. They were tested for the ability or inability to cross-link IgE bound to the receptor and induce the spontaneous release of histamine in the absence of allergen. This establishes and is or is not anti-non-anaphylactogenic IgE antibodies. An anti-SEC preparation. FROM IDENT. NO: 98 guinea pig was tested by direct challenge of basophils sensitized to IgE-in the absence of allergen, to assess their ability to cross-link IgE to the receptor and induce degranulation. The release of histamine by anti-SEC. FROM IDENT. NO: 98 was equivalent to the level of spontaneous histamine release by the donor cells. Based on this result, it was concluded that the specificity antibody for the target antigenic site of SEC. FROM IDENT. NO: 98, that is, SEC. FROM IDENT. NO: 92, it is not anaphylactogenic. The anti-SEC preparation. FROM IDENT. NO: 98 of 12 weeks was also evaluated for IgE specificity to determine the potency of these antibodies for immunosuppression isotype specification. The cross-reactivity of anti-SEC. FROM IDENT. NO: 98 antibodies for human guinea pig IgE and for IgG was compared by ELISA. The procedure is described for human IgG. For human IgG ELISA, human IgG was used as the solid phase immunosorbent. IgE ELISA plates were coated with human I g E myeloma at 5μg / mL. For the IgG ELISA, the plates were coated with purified human IgG (Sigma human grade IgG reagent), also at 5μg / mL. The anti-SEC. FROM IDENT. NO: 98 of purified guinea pig was tested by reactivity in both ELISAs at concentrations of 0.5 and 0.1 μg / mL. The results were compared to the antibodies purified from control guinea-pigry and to a "non-antibody" control. The A490 values obtained for anti-SEC. FROM IDENT. NO: 98 antibody on IgE were 1.126 at 0.5μg / mL and 0.344 at 0.1μg / mL. The A490 values obtained for SEC antibody. FROM IDENT. NO: 98 on IgG were equal to the control antibody and background values. This shows that there was no cross-reactivity of the anti-SEC. FROM IDENT. NO: 98 from guinea pig to human IgG. The immunogenic peptide composition of the present invention does not produce antibodies that recognize IgG antibodies, and therefore are isotype specific for I g E. Thus, it can be concluded that active immunization with mixed Th / IgE target antigenic site immunogens produces safe non-anaphylactogenic IgE anti-IgE antibodies. The antibodies were effective in inhibiting IgE-mediated sensitization, and had a specific immunosuppressive potential for the isotype Ige antibodies.

EXAMPLE 7 PEPTIDE COMPOSITION FOR THE PREVENSION OF THE FOOT AND MOUTH DISEASE The peptide immunogens comprising idealized artificial Th sites of the invention and a cross-reactive target antigenic site to the "GH wave" on the capsid protein VP1 of the foot and mouth disease virus (FMDV) , can be used to produce neutralizing antibodies for FMDV. Foot and mouth disease (FMD) is the most economically important disease of domestic livestock. The species of split leg that include cattle, pigs, sheep and goats are susceptible. Seven different serotypes have been described: A, O, C, Asia, and the South African types SAR-1, 2, and 3 each of which can be subdivided into multiple subtypes. Serotype A, O, and Asia-1 viruses are the most common. Serotype A viruses are the most variable, having more than 30 subtypes. There is no cross-protection between serotypes so that animals recovered from infection with or vaccinated against a virus of one serotype are still susceptible to infection with viruses from the remaining six serotypes. In addition, the degree of antigenic variation of a serotype is such that a vaccine made against one subtype may not be protective for another subtype within the same serotype (Brown, Vaccine, 1992; 10: 1022-1026). - * - "- - • * - • • ** • ....". .i ..., Mf. ^ - The peptides specific for serotypes corresponding to the region 141-160 (the GH ripple) of the VP1 capsid proteins of isolates belonging to all seven FMDV serotypes have been shown to produce protective levels of specific type neutralizing antibodies in guinea pigs (Francis et al., Immunology, 1990; 69171-176) Clearly this region contains an immunogenic site The initial observations of immunity for these 141-160 VP1 peptides were achieved using synthetic peptides conjugated to the carrier protein KLH (slotted limpet hemocyanin), a procedure that negates the advantage of manufacturing a well-defined synthetic immunogen, however, the development of the synthetic immunogens VP1 was developed by DiMarchi and Brook (US Patent No. 4,732,971) which showed that the two VP1 sequences of an isolate of subtype O, linked in a chimeric construction 200-213 Pro-Pro-Ser-141-158-Pro-Cys-Gly (SEQ. FROM IDENT. NO: 100) protected the cattle against the challenge. However, the efficiency of this effect was limited by the low immunogenicity of the peptide immunogen and by its narrow serotype specificity. The practical application demands that a vaccine formulation provide protection from homotypic and heterotypic exposure, with small amounts of peptide immunogen. The immunodominant site ripple G-H optimized for immunogenicity and ability to induce antibodies The broadly neutralizing HBsAg is broadly incorporated as an objective antigenic site within the peptide immunogens of the present invention. The site is homologous to amino acid positions 134-169 on the FMDV VP1 protein of A12 (Robertson et al, J Virol, 1985; 54: 651-660) and extends beyond the end of the G-H ripple. The target site was further modified by: (1) substitution of Asp at position 134 and Gln at position 157 with cysteines, (2) formation of a disulfide bond between the substituent cysteines to produce a cyclic structure, and (3) construction of an SSAL thereof using the corresponding VP1 sequences of a selection of subtypes. The target antigen sites optimized for the FMDV VP1 are exemplified by the peptides listed in Table 7. The two peptide immunogens, SEQ. FROM IDENT. NO: 101 and SEC. FROM IDENT. NO: 102, are SSAL target antigenic sites compiled from serotypes or FMDV and Asia respectively. The target antigenic sites both serotype I and Asia were coupled to the Rh epitopes of the present invention SEC. FROM IDENT. NO: 31 The mixed domain sequences (SEQ ID NO: 78) were also incorporated into the SEC. FROM IDENT. NO: 102. These SSAL peptide immunogens were synthesized and used to hyperimmunize groups of three guinea pigs (Duncan Hartley (of 9-week-old females, 450 gm, free of virus). Each animal was immunized with 100μg per dose of the indicated synthetic construct emulsified in CFA at week 9 or IFA at weeks 3 and 6. Animals were bled at weeks 0, 5 and 10 for testing. The serum samples were obtained from bleeding of five and 10 weeks and were collected from each group. The pooled serum was evaluated by reactivity to the epitope that neutralizes VP1 by peptide based on ELISA using a peptide having the sequences for the neutralizing epitope (VP1 134-169) as the i. By absorbing phase s6, ida- Its capacity to neutralize FMDV A1 A1 A12FP, AFL, A23, 0-1JH, 0-1P2, and Asia-1 was also determined. The virus-neutralizing activity of a 1: 100 dilution of a serum sample was determined by observing the neutralization over a series of increasing viral load loads, using aliquots (10,000 MPD50) of the above-mentioned virus samplings. The results are shown in Table 7. The test method performed (Morgan and Moore, Am J Vet Res, 1990; 51: 40-45), demonstrated that immunization with the peptide antigens of the present invention provides serum which reduced in 2.5 log10 microplates FMDV to a dilution of 1: 100 The results are also highly predictive of protective immunity against FMDV infection. As shown in Table 7, high antipeptide titers against the target antigenic sites (> 5 Log10) occurred in week 5. Wide and effective neutralization of all seven proven strains belonging to the three was observed. different serotypes of FMDV (ie, A, O, Asia) despite the wide variations between sepals and serotypes. This further demonstrates the efficiency of the artificial Th epitopes of the present invention to stimulate effective antibody responses against an epitope of a foreign pathogen.

EXAMPLE 8 PEPTHIDIC COMPOSITION OF A MALARIA SPOROZOITE VACCINE Peptide immunogens are provided comprising the idealized artificial Ph sites and a circumsporozoite (CS) target antigen of Plasmodium falciparum, a human malaria parasite. The CS protein is the main surface antigen of the sporozoite stage of the parasite. Immunological studies and sequence data from a large number of human plasmodium, simian, and rodent CS genes have been documented showing that all CS proteins contain a central region, consisting of a series of tandem repeats, spanning copies multiple of an immunodominant B-cell epitope. In P. falciparum the repeating epitope is represented as (Ans-Ala-Asn-Pro) n (SEQ ID NO: 103) Antibodies directed against the repeats of the CS protein of the human malaria parasite , P. falciparum and P vivax, inhibit the invasion of hepatocytes by sporozoites and cancel their ineffectiveness. Therefore, repeats of the CS epitope have been the target antigen of the subunit vaccines used in various human malaria vaccine tests (Nussenzweig et al., Adv. Immunol., 1989, 45: 283; Hoffman et al., Science , 1991, 252: 520). However, one of the disadvantages of the various synthetic malarial vaccines commonly in clinical trials is their low immunogenicity. Thus, a potential malaria vaccine remains to be developed. (Calvo-Calle et al., J Inmunol, 1994, 150: 1403) To overcome the problem of immunogenicity associated with the repetitions of the P. falciparum CS protein, the artificial Th epitopes shown in Table 1 are incorporated into the CS peptide immunogens. for example, the peptide construct (SEQ ID NOS: 15, 18) -eNLys- (Asn-Ala-Ash-Pro) 4 (SEQ ID NO: 10, 105) is synthesized and used as the key immunogen in a malaria vaccine to produce potent protective antibodies in small animals, primates (eg, baboons) and humans against P. falciparum sporozoites.

EXAMPLE 9 PEPTIDE COMPOSITION FOR PREVENSION AND TREATMENT OF ATEROESCLEROIS AND DISEASE CARDIOVASCULAR The cholesteryl ester transport protein (CETP) measured the transfer of cholesteryl esters from HDL to TG-rich lipoproteins such as VLDL and LDL, and also the reciprocal exchange of TG of VLDL and LDL (Tall, J Internal Med, 1995, 237: 5-12; Tall, J Lipid Res, 1993, 34: 1255; Hesler et al., J Biol Chem, 1987, 262: 2275; Quig et al., Ann Rev Nutr, 1990, 10: 169). CETP may play a role in the modulation of cholesteryl ester and triglyceride levels associated with various classes of lipoproteins. A high transfer activity of cholesteryl ester CETP has been correlated with increasing levels of cholesterol associated with LDL and cholesterol associated with VDLD, which in turn correlates with the increased risk of cardiovascular disease (see, for example Tato et al., Arterioscler Thromb Vascular Biol, 1995, 15: 112). CETP isolated from human plasma is a hydrophobic glycoprotein that has 476 amino acids. A human CETP that encodes cDNA has been cloned and sequenced (Drayna et al., Nature, 1987, 237: 632). A TP2 monoclonal antibody (formerly designated 5C7) which, completely inhibits the transfer activity of the CETP triglyceride and cholesteryl ester and to a lesser extent, the transfer activity of ii ^ g i phospholipids (Hesler et al., J Biol Chem, 1998, 263: 5020). The epitope of TP2 was located at the terminal carboxyl of 26 amino acids, that is, the amino acids of Arg451 to Ser476 of Human CETP (see, Hesler et al., 1988): Arg Asp Gly Phe Leu Leu Leu Gln Met Asp Phe Gly Phe Pro Glu His Leu Leu Val Asp Phe Leu Gln Ser Leu Ser (SEQ ID NO: 106) reported that TP2 inhibits the activity of human and rabbit CETP in vitro and rabbit CETP in vivo (Yen et al., J Clin Invest, 1989, 83: 2018). The additional analysis of the region of CETP bound by Tp2 revealed that the amino acids between Phe463 and Leu475 Phe Gly Phe Pro Glu His Leu Leu Val Asp Phe Leu Gln Ser Leu Ser (SEQ ID NO: 107) are required for the TP2 linkage and to neutralize the neutral lipid binding and transfer activity of CETP (see , Wang et al., J Biol Chem, 1992, 270: 612). An in vivo study number using animal or human models have indicated that CETP activity may affect the level of circulating cholesterol containing HDL. The increased transfer activity of cholesteryl ester CETP can produce a decrease in the levels of HDL-C relative to the levels of LDLC and / or VLDLC and low HDL which in turn correlates with an increased susceptibility to arteriosclerosis. Therefore, the discovery of compounds and methods to control the activity of CETP will be advantageous to prevent or treat cardiovascular disease. Rittershaus et al., WO 96/34888, proposes the use of a peptide composition comprising a "universal" or "broad range" immunogenic attendant T cell epitope linked, preferably and covalently to a B cell epitope portion such as the found in the carboxyl terminal portion of human CETP involved in a neutral lipid bond or CETP transfer activity. To improve the immunogenicity of the human CETP functional site, ie, the carboxyl terminal amino acids of human CETP (SEQ ID NOS: 96 and 97) and peptide analogs thereof linked to antigenic peptides comprising epitopes were synthesized. Th artificial of Table 1 and peptides antigen target CETP. These peptide antigens, shown in Table 8, are used to produce antibodies to CETP in small, primate and human animals. Anti-CETOP antibodies control CETP. Therefore, it is expected that CETP antigenic peptides cause reduced plasma accumulation of LDL-associated cholesterol to provide protection and treatment of arteriosclerosis and coronary heart disease.

EXAMPLE 10 PEPTIDAL COMPOSITION AS A VACCINE COMPONENT HIV FOR THE PRODUCTION OF NEUTRALIZATION ANTIBODIES AGAINST HIV Progress in the development of an effective vaccine for HIV-1 has been largely evaluated by measuring the ability to induce neutralizing antibodies and cytotoxic T lymphocytes CD8 + specific for viruses (CTLs). The leading indicators of a protective immune response. A strong correlation was observed between protection against infection and neutralization Abs levels in non-human primates infected with HIV-1 and simian HIV (SHIV). However, progress has been made to generate neutralizing antibodies over the past decades. Part of the problem is the weak neutralization antibody response generated by the candidate HIV-1 vaccines. A recent article entitled "Toward an HIV Type 1 vaccine, which broadly cross-reactive neutralizing antibodies" by Montefiori et al (AIDS Res and Hum Retrovir, 1999. 15: 689-698) provides a review of the state of the art. the difficulties encountered in the development of the HIV vaccine. In an effort to improve the neutralization antibody response against HIV, we embarked on targeted synthetic antigen designs to produce potent neutralizing antibodies. Synthetic antigens employ specially designed artificial Th epitopes as the construct-stimulating immune element covalently linked to B-cell epitopes that neutralize HIV (eg, Korber et al, HIV Immunol D atabase 1997, Part III Antibody Binding Sites) or neutralization methods (for example, Scala et al, J Immunol 1999, 162: 6155-6161) previously recognized by monoclonal or polyclonal antibodies. Among the B cell epitopes that neutralize HIV, an artificial V3 consensus sequence (SEQ ID NO: 125) comprising an optimal structure of the HIV gp120 main V3 neutralization determinant (Wang, CY, US 5,763,160) was designed. . These include the most frequent amino acids for each of the amino acid positions within the structure based on analysis of the amino acid sequences of about 1,000 HIV isolates of subtypes A to G, together with the sequence derived from linear epitopes or of the HIV gp120 / gp41 regions shown here in Tables 9 and 10 in SEC. FROM IDENT. NOS: 125, 126-129, 148-153. The neutralization mimetics of Scala et al (SEQ ID NOS: 130-135) are also synthesized as peptides of the invention, SEQ. FROM IDENT. NOS: 136-147, as shown in Table 9. The immunogenic peptide constructs of the invention shown in Table 10 are completely synthetic and were synthesized by the solid phase method delineated in Example 1. These immunogenic peptide constructions illustrate .1.. additionally the utility of the artificial Ph of the present invention in the development of HIV vaccines. Each peptide in Table 10 can be represented by the formula (A) n- (Th) m - (B) 0- (neutralization epitope B VI lj-l) -X or (HIV neutralization epitope) - (B) 0 - (Th) m- (A) nX. Epitopes that neutralize HIV include SEC. FROM IDENT. NOS: 125 and 130-135. Immunogenic peptides comprise one or more of the Th sites derived from artificial Th (as shown in Table 1). Each peptide of this example has Gly-Gly or (e-N) Lys spacers between the immunogenic elements, but the peptides of the invention may have other spacers or no spacer. The peptides of these examples may comprise an optional Inv immunostimulatory site (SEQ ID NO: 27). It is understood, however, that the invention is not limited to the use of Inv as an additional immunostimulatory element. Representative peptide constructs of the invention as listed in Table 10 (SEQ ID NOS: 148-153) were synthesized, cleaved, cyclized and purified as described in Example 1. Each peptide construct was formulated for immunization within of small animals such as guinea pigs, or within larger animals such as pigs or Baboon for evaluation of their immunogenicity, each of the peptides was suspended in a volume of 0.5 mL containing representative emulsifiers and adjuvants such as ISA51, ISA720, DDA or monophosphoryl lipid A (MPL). The dose was 100 μg of peptide for guinea pigs or 300 μg of peptide for pigs or baboons and the animals were immunized intramuscularly. The animals received injections at week 0, 3 and 6 as specified in Table 10. Test bleeds at 5, 8, 10 and 11 weeks after the initial immunization were evaluated for the reactivities with target epitopes by the ELISA. B-cell epitope peptide as described in Example 1, and was further tested for its ability to neutralize HIV-1 as described in detail in Example 5. All the peptides tested yielded crossed reactivities directed to the strong site to the target peptide corresponding, as shown by the Log10 titers in anti-B epitope peptide ELISAs greater than 4. HIV-1 neutralization was also observed for immune serum obtained from guinea pigs and baboons. This functional reactivity by Babuino serum is worthy of mention since the neutralization of human HIV by Babuino serum is almost a human system. The results are strong indicators of the efficiency of a peptide construct of the invention as an agent for the prevention and / or immunotherapy of HIV infection by active immunization.

Table 1 Model, Prototype, and Idealized Artificial Th epitopes a. Th and Th MVF epitopes derived from them Th Amino Acid Sequence Identifier MVFTh SEC. FROM IDENT. NO: 1 LSEIKGVIVHRLEGV SEC. FROM IDENT. NO: 2 DLSDLKGLLLHKLDGL SSAL1 Th1 SEC. FROM IDENT. NO: 3 The EIR lll RÍE I SEC. FROM IDENT. NO: 4 V V VVV V V SEC. FROM IDENT. NO: 5 F F FFF F F SEC. OF IDE NT. NO: 6 ISEIKGVIVHKIEGI SEC. FROM IDENT. NO: 7 MT RT TRMTM SEC. FROM IDENT. NO: 8 L L V SEC. FROM IDENT. NO: 6 ISEIKGVIVHKIEGI SEC. FROM IDENT. NO: 9 T RT TR T SEC. DEIDENT NO: 10 MSEIKGVIVHKLEGM SEC. DEIDENT NO: 11 LTMRT TRMTV SEC. FROM IDENT. NO: 6 ISEIKGVIVHKIEGI SEC. DEIDENT NO: 12 ITEIRTVIVTRIETI SEC. DEIDENT NO: 13 MSEMKGVIVHKMEGM SEC. FROM IDENT. NO: 14 LTEIRTVIVTRLETV SEC. DEIDENT NO: 15 ISISEIKGVIVHKIEGILF SEC. DEIDENT NO: 16 MT RT TRMTM SEC. DEIDENT NO: 17 L L V SEC. DEIDENT NO: 15 ISISEIKGVIVHKIEGILF SEC. DEIDENT NO: 18 T RT TR T SEC. DEIDENT NO: 19 ISLSEIKGVIVHKLEGMLF SEC. DEIDENT NO: 105 MTMRT TRMTV SEC. DEIDENT NO: 123 ISLTEIRTVIVTRLETVLF SEC. DEIDENT NO: 124 I I I igjSg ^. ^^^ »gjg ^ b. HBsAg Th, Prototype and derivatives Or Table 2 Immunochemistry of LHRH Peptides Derivative MVF Th Table 2 (Cont'd) b. HBsAg Th Derivative LHRH = EHWSYGLRPG (ID SECTION NO: 77) b INV = Invasin Domain (SEQ ID NO: 78) c KLH = Slotted Limpet Hemocyanin d Hinge Spacer = PPXPXP (SEQ ID NO: 79) ) Table 3 Antibody Specificity Evaluation for the Target Anti-Cancer Site a Number of animals with anti-LHRH titers > 1: 1000 / total of immunized animals. The ELISA peptide was SEC. FROM IDENT. NO: 77 Number of animals with anti-Th reactivida > 0.100 A490 / total of immunized animals. The sera were diluted 1: 100 and all A490 values were in base values for the respective Th peptides.

: The ELISA peptide was a mixture of two peptides of: SEC. FROM IDENT. NOS: 15 and 18.

The Peptide ELISA was SEC. FROM IDENT. NO: 31 The ELISA peptide was SEC. FROM IDENT. NO: 34 ^^ * j¡gjj # ^ & ^^ Table 4 Evaluation of Artificial Th / LHRH Peptide Compositions that Include Mixing Individual LHRH peptide compositions or the mixed LHRH peptide composition were formulated in alum. Immunization plan: 25μg / dose at 0 and 3 wpi.

Number of animals in one hatched / total number of animals in the group. Animals were counted as immunocastrated when the serum testosterone values were < 0.1 nmol / L to undetectable. -% í., »» iaa¿¿'j.g Table 5 Immunogenicity of Somatostatin Antigenic Peptides a Somatostatin sequence: AGCKNFF KTFTSC (SEQ ID NO: 80; b PI = Weeks after immunization c) Test results for the pooled sera of the animals reactive to ELISA.

Table 6 Immunogenicity of IgE-CH3 Antigenic Peptides Modified IgE-CH3 site (SEQ ID NO: 92) Average of animals of the invasive domain C-peptide group (SEQ ID NO: 7) Hemocyanin of Lapa Slotted Table 7 Antigenic Th and Artificial SSAL Peptides for Improved Immunogenicity and Amplitude of Nutricization FMDV T158 of native sequence was replaced by C. T134 of native sequence was replaced by C. Ri of native sequence was replaced by C. Reactivities of the pooled sera of reactive aniumales to ELISA. Sueron for neutralization tests diluted 1: 100.

TABLE 8 CETP ANTIGENIC PEPTIDES Note. Phe Gly Phe Pro Lys His Leu Leu Val Asp Phe Leu Gln Ser Leu Ser (SEQ ID NO: 108) b _ Leu Asp Gly Cys Leu Leu Leu Gln Met Asp Phe Gly Phe Pro Lys His Leu Leu Val Asp Phe Leu Gln Ser Leu Ser (SEC DEIDENT NO: 109) • ** - »> * »-.- Table 10 Immunogenicity of Representative Peptides of the Invention LIST OF SEQUENCES (1) GENERAL INFORMATION: (i) APPLICANT: UNITED BIOMEDICAL INC., ET AL. (ii) TITLE OF THE INVENTION: ARTIFICIAL EPITOPES OF ASSISTANT CELLS AND AS IMMUNO STIMULATORS FOR PEPTIDE IMMUNOGENS SYNTHETIC (ii) NUMBER OF SEQUENCES: 151 (iv) DIRECT CORRESPONDENCE: (A) RECIPIENT: Morgan & Finnegan, L.L.P. (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 MEDIUM: Flexible disk (B) COMPUTER: compatible with an IBM PC (C) OPERATING SYSTEM: Windows PC (D) SOFTWARE: Word 97 (vi) DATA OF THE CURRENT APPLICATION: (A) APPLICATION NUMBER: TO BE ASSIGNED ( B) DATE OF SUBMISSION: June 21, 1999 (C) CLASSIFICATION: (vii) DATA FROM THE PREVIOUS APPLICATION: (A) APPLICATION NUMBER: 09 / 100,414 (B) DATE OF SUBMISSION: June 20, 1998 (viii) ) EMPLOYEE / AGENT INFORMATION: (A) NAME: Maria H. Lin (B) REGISTRATION NUMBER: 29,323 (C) REFERENCE / FILE NUMBER: 1151- 4157F ^ C1 (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: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 1: 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: 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. N0: 2: Asp Leu As Asp Leu Lys Gly Leu Leu Leu His Lys 1 5 10 Leu Asp Gly Leu 15 (2) INFORMATION FOR SEC. IDENT. NO: 3: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 16 amino acids (B) TYPE: amino acid (C) TOPOLOGY: LINEAR (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 3: Glu lie Ser Glu lie Arg Gly Me Me Me His Arg 1 5 10 Me Glu Gly Me 15 (2) INFORMATION FOR SEC. IDENT. NO: 4: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 16 amino acids (B) TYPE: amino acid ,? attt-- '(C) TOPOLOGY: LINEAR (¡i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

N0: 4: Asp Val Ser Asp Val Lys Gly Val Val Val His Lys 1 5 10 Val Asp Gly Val 15 (2) INFORMATION FOR SEC. IDENT. NO: 5: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 16 amino acids (B) TYPE: amino acid (C) TOPOLOGY: LINEAR (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 5: Asp Phe Ser Asp Phe Lys Gly Phe Phe Phe His Lys 1 5 10 Phe Asp Gly Phe 15 (2) INFORMATION FOR SEC. IDENT. NO: 6: (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.

Me Ser Glu Me Lys Gly Val Me Val His Lys Me 1 5 10 Glu Gly Me 15 (2) INFORMATION FOR SEC. IDENT. NO: 7: (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.

Met Thr Glu Me Arg Thr Val Me Val Thr Arg Met 1 5 10 Glu Thr Met 15 (2) INFORMATION FOR SEC. IDENT. NO: 8: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 15 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide ií ------------------- l ---------____- (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

N0: 8: Leu Ser Glu Me Lys Gly Val e Val His Lys 1 5 10 Leu Glu Gly Val 15 (2) INFORMATION FOR SEC. IDENT. N0: 9: (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: 9: Me Thr Glu Me Arg Thr Val Me Val Thr Arg Me 1 5 10 Glu Thr Me 15 (2) INFORMATION FOR SEC. IDENT. NO: 10: (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: 10: Met Ser Glu Me Lys Gly Val Me Val His Lys Leu 1 5 10 Glu Gly Met 15 (2) INFORMATION FOR SEC. IDENT. NO: 11: (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: 11 Leu Thr Glu Met Arg Thr Val Me Val Thr Arg Met 1 5 10 Glu Thr Val 15 (2) INFORMATION FOR SEC. IDENT. NO: 12: (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.

N0: 12: Me Thr Glu Me Arg Thr Val Me Val Thr Arg Me 1 5 10 Glu Thr Me 15 (2) INFORMATION FOR SEC. IDENT. NO: 13: (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: 13: Met Ser Glu Met Lys Gly Val Me Val His Lys Met 1 5 10 Glu Gly Met 15 (2) INFORMATION FOR SEC. IDENT. NO: 14: (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: 14: Leu Thr Glu Me Arg Thr Val Me Val Thr Arg Leu 1 5 10 Glu Thr Val 15 (2) INFORMATION FOR SEC. IDENT. NO: 15: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 19 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 15: Me Being Me Glu Me Lys Gly Val Me Val His 1 5 10 Lys lie Glu Gly Me Leu Phe 15 (2) INFORMATION FOR SEC. IDENT. NO: 16: (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: 16: Me Met Met Thr Glu Me Arg Thr Val e Val Thr 1 5 10 Arg Met Glu Thr Met Leu Phe 15 (2) INFORMATION FOR SEC. IDENT. NO: 17: (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: 17: Me Ser Leu Ser Glu Me Lys Gly Val Me Val His 1 5 10 Lys Leu Glu Gly Val Leu Phe 15 (2) INFORMATION FOR SEC. IDENT. NO: 18: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 19 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide a-E-M-i-M-M-Ma (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 18: Me Being Thr Glu Me Arg Thr Val Me Val Thr 1 5 10 Arg Me Glu Thr Me Leu Phe 15 (2) INFORMATION FOR SEC. IDENT. NO: 19: (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: 19: Me Ser Leu Ser Glu Me Lys Gly Val Me Val His 1 5 10 Lys Leu Glu Gly Met Leu Phe 15 (2) INFORMATION FOR SEC. IDENT. NO: 20: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 19 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 20: Me Being Thr Glu Me Arg Thr Val Me Val Thr 1 5 10 Arg Me Glu Thr Me Leu Phe (2) INFORMATION FOR SEC. IDENT. NO: 21: (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: 21 Me Being Met Met Glu Met Lys Gly Val Me Val His 1 5 10 Lys Met Glu Gly Met Leu Phe 15 (2) INFORMATION FOR SEC. IDENT. NO: 22: (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 THE SEQUENCE: SEC. IDENT.

NO: 22: Me Ser Leu Thr Glu Me Arg Thr Val Me Val Thr 1 5 10 Arg Leu Glu Thr Val Leu Phe 15 (2) INFORMATION FOR SEC. IDENT. NO: 23: (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: 23: Phe Phe Leu Leu Thr Arg Me Leu Thr Me Pro Gln 1 5 10 Ser Leu Asp 15 (2) INFORMATION FOR SEC. IDENT. NO: 24: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 24: Lys Lys Lys Phe Phe Leu Leu Thr Arg Me Leu Thr 1 5 10 Me Pro Gln Ser Leu Asp 15 (2) INFORMATION FOR SEC. IDENT. NO: 25: (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: 25: Phe Phe Leu Leu Thr Arg Me Leu Thr e Pro Gln 1 5 10 Ser Leu (2) INFORMATION FOR SEC. IDENT. NO: 26: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 26: . .. ^ - ..

Lys Lys Lys Leu Phe Leu Leu Thr Lys Leu Leu Thr 1 5 10 Leu Pro Gln Ser Leu Asp 15 (2) INFORMATION FOR SEC. IDENT. NO: 27: (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: 27: Arg Arg Arg Me Lys He Me Thr Arg Me Me Thr 1 5 10 Me Pro Leu Ser Me Arg 15 (2) INFORMATION FOR SEC. IDENT. NO: 28: (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. I'DENT.

NO: 28: «Ri.n1-.rir i .., .ti- He 'i III M lt ^ áhl > É ------ l ---- É ------- M ^ ---- Í - ^^ Lys Lys Lys Val Arg Val Val Thr Lys Val Val Thr 1 5 10 Val Pro lie Ser Val Asp 5 15 (2) INFORMATION FOR SEC. IDENT. NO: 29: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 18 amino acids (B) TYPE: amino acid 10 (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 29: Lys Lys Lys Phe Phe Phe Phe Thr Lys Phe Phe Thr 15 1 5 10 Phe Pro Val Ser Phe Asp 15 (2) INFORMATION FOR SEC. IDENT. NO: 30: (i) CHARACTERISTICS OF THE SEQUENCE: 20 (A) LENGTH: 18 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. 25 NO: 30: - • * - • Mii '< a.ha ,,? t, «. * ... - ....« - ... > -.-.-, * - * .- r..a »---------- ^ ---. «-. -, - i ..----- ,. -_. "_ .., ._...-_., --- Lys Lys Lys Leu Phe Leu Leu Thr Lys Leu Leu Thr 1 5 10 Leu Pro Phe Ser Leu Asp 15 (2) INFORMATION FOR SEC. IDENT. NO: 31: (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: 31: Lys Lys Lys Me Me Thr Me Thr Arg Me Me Thr 1 5 10 Me He Thr Thr He Asp 15 (2) INFORMATION FOR 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: ._ ---- _-. - .. - ^ --- á.-u -, - -. -, --- Mi-ü - ii Lys Lys Lys He He Thr He Thr Arg He He Thr 1 5 10 He He Thr Thr He 15 (2) INFORMATION FOR SEC. IDENT. NO: 33: (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: 33: Lys Lys Lys Met Met Met Thr Met Thr Arg Met He Thr 1 5 10 Met He Thr Thr He Asp 15 (2) INFORMATION FOR SEC. IDENT. NO: 34: (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 THE SEQUENCE: SEC. IDENT. NO: 34: ah? hi Phe He Thr Met Asp Thr Lys Phe Leu Leu Wing Ser 1 5 10 Thr His He Leu 15 (2) INFORMATION FOR SEC. IDENT. NO: 35: (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 THE SEQUENCE: SEC. IDENT.

NO: 35: Lys Lys Lys Phe He Thr Met Asp Thr Lys Phe Leu 1 5 10 Leu Ala Ser Thr His Me Leu 15 (2) INFORMATION FOR SEC. IDENT. NO: 36: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 27 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 36: ^ JÉ = IHta Leu Ser Glu He Lys Gly Val He Val His Arg Leu 1 5 10 Glu Gly Val Gly Gly Glu His Trp Ser Tyr Gly Leu 15 20 Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 37: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 28 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 37: Asp Leu Ser Asp Leu Lys Gly Leu Leu Leu His Lys 1 5 10 Leu Asp Gly Leu Gly Gly Glu His Trp Ser Tyr Gly 15 20 Leu Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 38: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 28 amino acids (B) TYPE: amino acid ---- and ^^ U ^ (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 38: Glu He Ser Glu He Arg Gly He He He He His Arg 1 5 10 He Glu Gly He Gly Gly Glu His Trp Ser Tyr Gly 15 20 Leu Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 39: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 28 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 39: Asp Val Ser Asp Val Lys Gly Val Val Val His Lys 1 5 10 Val Asp Gly Val Gly Gly Glu His Trp Ser Tyr Gly 15 20 Leu Arg Pro Gly 25 i '' i? .. ,, i, i *? tfu * u * LátÍ? iá * Li (2) INFORMATION FOR SEC. IDENT. NO: 40: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 28 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 40: Asp Phe Ser Asp Phe Lys Gly Phe Phe Phe His Lys 1 5 10 Phe Asp Gly Phe Gly Gly Glu His Trp Ser Tyr Gly 15 20 Leu Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 41: (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 SEQUENCE: SEC. I'DENT. NO: 41 He Ser Glu He Lys Gly Val He Val His Lys He 1 5 10 ^ wAAIlUi? a > IÉU > É? U ^ al ^ UMíto Glu Gly He Gly Gly Glu His Trp Ser Tyr Gly Leu 15 20 Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 42: (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: 42: Met Thr Glu He Arg Thr Val He Val Thr Arg Met 1 5 10 Glu Thr Met Gly Gly Glu His Trp Ser Tyr Gly Leu 15 20 Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 43: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 27 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide ttflátri '- - IIÉIIII mi l-l ------------- lL ---------- M ^ h «- (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 43: Leu Ser Glu He Lys Gly Val He Val His Lys Leu 1 5 10 Glu Gly Val Gly Gly Glu His Trp Ser Tyr Gly Leu 15 20 Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 44: (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 SEQUENCE: SEC. IDENT. NO: 44: He Thr Glu He Arg Thr Val He Val Thr Arg He 1 5 10 Glu Thr He Gly Gly Glu His Trp Ser Tyr Gly Leu 15 20 Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 45: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 45 amino acids • • * - • - - * - * - ^ m ^ ..

(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 45: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Ala 1 5 10 Thr Tyr Gln Phe Gly Gly He Ser Glu He Lys Gly 15 20 Val He Val His Lys He Glu Gly He Gly Gly Glu 25 30 35 His Trp Ser Tyr Gly Leu Arg Pro Gly 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 46: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 45 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 46: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Ala 1 5 10 Thr Tyr Gln Phe Gly Gly He Thr Glu He Arg Thr 15 20 ,. ,. ^^ fc Val He Val Thr Arg He Glu Thr He Gly Gly Glu 25 30 35 His Trp Ser Tyr Gly Leu Arg Pro Gly 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 47: (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: 47: Met Ser Glu He Lys Gly Val He Val His Lys Leu 1 5 10 Glu Gly Met Gly Gly Glu His Trp Ser Tyr Gly Leu 15 20 Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 48: (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: 48: Leu Thr Glu Met Arg Thr Val He Val Thr Arg Met 1 5 10 Glu Thr Val Gly Gly Glu His Trp Ser Tyr Gly Leu 15 20 Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 49: (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 SEQUENCE: SEC. IDENT. NO: 49: He Thr Glu He Arg Thr Val He Val Thr Arg He 1 5 10 Glu Thr He Gly Gly Glu His Trp Ser Tyr Gly Leu 15 20 Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 50: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 27 amino acids . ^. or "> , «A --- J (»?. «, .-- u-. -. ^. - -. - ... -» .... .-- «i -». - ".. • - * ¿-t - '= (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC.

NO: 50: Met Ser Glu Met Lys Gly Val He Val His Lys Met 1 5 10 Glu Gly Met Gly Gly Glu His Trp Ser Tyr Gly Leu 15 20 Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO-51: (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: 51 Leu Thr Glu He Arg Thr Val He Val Thr Arg Leu 1 5 10 Glu Thr Val Gly Gly Glu His Trp Ser Tyr Gly Leu 15 20 Arg Pro Gly 25 ^ -.- - * .. * (2) INFORMATION FOR SEC. IDENT. NO: 52: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 45 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 52: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Wing 1 5 10 Thr Tyr Gln Phe Gly Gly Leu Thr Glu He Arg Thr 15 20 Val He Val Thr Arg Leu Glu Thr Val Gly Gly Glu 25 30 35 His Trp Ser Tyr Gly Leu Arg Pro Gly 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 53: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 53: I've Been Glu He Lys Gly Val He Val His 1 5 10 Lys He Glu Gly He Leu Phe Gly Gly Glu His Trp 15 20 Ser Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 54: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE 'SEC. IDENT.

NO: 54: He Met Met Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg Met Glu Thr Met Leu Phe Gly Gly Glu His Trp 15 20 Ser Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT NO: 55: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear fete_ÜA ^ .Mi .------------ b ------ ^ ----------- l (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 55: Be Ser Leu Be Glu He Lys Gly Val He Val His 1 5 10 Lys Leu Glu Gly Val Leu Phe Gly Gly Glu His Trp 15 20 Ser Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 56: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 56: I have to be He Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg He Glu Thr He Leu Phe Gly Gly Glu His Trp 15 20 Ser Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 57: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 49 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 57: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Wing 1 5 10 Thr Tyr Gln Phe Gly Gly He Ser Be Ser Glu He 15 20 Lys Gly Val He Val His Lys He Glu Gly He Leu 25 30 35 Phe Gly Gly Glu His Trp Ser Tyr Gly Leu Arg Pro 40 45 Gly (2) INFORMATION FOR SEC. IDENT. NO: 58: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 49 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 58: - ...-. »..« .- i.-. -TO".-.* . -i ... , j _. 1 - j ^ _L _ :: ^ j | ^ ß Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Wing 1 5 10 Thr Tyr Gln Phe Gly Gly He Ser He Thr Glu He 15 20 Arg Thr Val He Val Thr Arg He Glu Thr He Leu 25 30 35 Phe Gly Gly Glu His Trp Ser Tyr Gly Leu Arg Pro 40 45 Gly (2) INFORMATION FOR SEC. IDENT. NO: 59: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 59: I've Ser Leu Ser Glu He Lys Gly Val He Val His 1 5 10 Lys Leu Glu Gly Met Leu Phe Gly Gly Glu His Trp 15 20 Ser Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 60: • - "" --- «- ¿•" -i - * - j * ..- «« & * ,. (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 47 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 60: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Wing 1 5 10 Thr Tyr Gln Phe He Ser Ser Glu He Lys Gly 15 20 Val He Val His Lys He Glu Gly He Leu Phe Gly 25 30 35 Gly Glu His Trp Ser Tyr Gly Leu Arg Pro Gly 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 61: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 61 I Have To Be Thr Glu He Arg Thr Val He Val Thr 1 5 10 ntini i iF, a? au? a ^ »i ^ - -?? ----? 1A ------» -------? MaM? MlMta ------ Arg He Glu Thr He Leu Phe Gly Gly Glu His Trp 15 20 Ser Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 62: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 49 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear 0 (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 62: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Wing 1 5 10 5 Thr Tyr Gln Phe Gly Gly He Ser He Thr Glu He 15 20 Arg Thr Val He Val Thr Arg He Glu Thr He Leu 25 30 35 0 Phe Gly Gly Glu His Trp Ser Tyr Gly Leu Arg Pro 40 45 Gly (2) INFORMATION FOR SEC. IDENT. NO: 63: (i) CHARACTERISTICS OF THE SEQUENCE: 5 (A) LENGTH: 47 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 63: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Ala 1 5 10 Thr Tyr Gln Phe He Ser Met Ser Glu Met Lys Gly 15 20 10 Val He Val His Lys Met Glu Gly Met Leu Phe Gly 25 30 35 Gly Glu His Trp Ser Tyr Gly Leu Arg Pro Gly 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 64: 15 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide 20 (xi) DESCRIPTION OF THE SEQUENCE: SEC . IDENT. NO: 64: I've been Leu Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg Leu Glu Thr Val Leu Phe Gly Gly Glu His Trp 25 15 20 ? ^ ddliiM - i ------ ----- U -----------. tr ^ tiS ^^^^^^ ii M-Ü ^^ A Ser Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 65 (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 SEQUENCE: SEC. IDENT. NO: 65 Phe Phe Leu Leu Thr Arg He Leu Thr He Pro Gln 1 5 10 Ser Leu Asp Gly Gly Glu His Trp Ser Tyr Gly Leu 15 20 Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 66 (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: 66"* -" '.'- iJWJU. -. . < - - i- *, ". . ^ "~ - Lys Lys Lys Leu Phe Leu Leu Thr Lys Leu Leu Thr 1 5 10 Leu Pro Gln Ser Leu Asp Gly Gly Glu His Trp Ser 15 20 Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SECTION IDENT NO: 67 (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 THE SEQUENCE: SEC. NO: 67 Arg Arg Arg He Lys He He Thr Arg He He Thr 1 5 10 He Pro Leu Ser He Arg Gly Gly Glu His Trp Ser 15 20 Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SECTION IDENT NO: 68 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 30 amino acids (B) TYPE, amino acid «.-.-.---, ..-., -.

(D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 68 Lys Lys Lys Val Val Val Val Thr Lys Val Val Thr Val 1 1 10 Val Pro He Ser Val Asp Gly Gly Glu His Trp Ser 15 20 Tyr Gly Leu Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 69 (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: 69 Lys Lys Lys Phe Phe Phe Phe Thr Lys Phe Phe Thr 1 5 10 Phe Pro Val Ser Phe Asp Gly Gly Glu His Trp Ser 15 20 Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 70 (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: 70 Lys Lys Lys Leu Phe Leu Leu Thr Lys Leu Leu Thr 1 5 10 Leu Pro Phe Ser Leu Asp Gly Gly Glu His Trp Ser 15 20 Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 71: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 30 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 71 Lys Lys Lys He He Thr He Thr Arg He He Thr 1 5 10 '- - **** -,, - -.... < vM ^, He He Thr Thr He Asp Gly Gly Glu His Trp Ser 15 20 Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 72: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 72 Lys Lys Lys He He Thr He Thr Arg He He Thr 1 5 10 He He Thr Thr He Gly Gly Glu His Trp Ser Tyr 15 20 Gly Leu Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 73: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 30 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide ^ ÜÜÉÉMÜIMMMI (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 73: Lys Lys Met Met Met Thr Met Thr Arg Met He Thr 1 5 10 Met He Thr Thr He Asp Gly Gly Glu His Trp Ser 15 20 Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 74: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 28 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. I DENT. NO: 74: Phe He Thr Met Asp Thr Lys Phe Leu Leu Wing Ser 1 5 10 Thr His He Leu Gly Gly Glu His Trp Ser Tyr Gly 15 20 Leu Arg Pro Gly 25 (2) INFORMATION FOR SEC. IDENT. NO: 75: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 46 amino acids - ^ ¡^ Sj "* &a ~ ¿(B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SECTION ID: NO: 75: Thr Wing Lys Ser Lys Lys Phe Pro Ser Tyr Thr Wing 1 5 10 Thr Tyr Gln Phe Gly Gly Phe He Thr Met Asp Thr 15 20 Lys Phe Leu Leu Wing Ser Thr His He Leu Gly Gly 25 30 35 Glu His Trp Ser Tyr Gly Leu Arg Pro Gly 40 45 (2) INFORMATION FOR SECTION ID: NO: 76: '(i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 76: Lys Lys Lys Phe He Thr Met Asp Thr Lys Phe Leu 1 5 10 Leu Ala Ser Thr His He Leu Gly Gly Glu His Trp 15 20"f - * - • 'tf *" 1H ___' a? Mt Ser Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 77: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 10 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 77: Glu His Trp Ser Tyr Gly Leu Arg Pro Gly 1 5 10 (2) INFORMATION FOR SEC. IDENT. NO: 78: (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: 78: 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: 79: - ..!,. , -, »---. j ^ J ^^^ MUIW Ufe (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 6 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 79: Pro Pro Xaa Pro Xaa Pro 1 5 (2) INFORMATION FOR SEC. IDENT. NO: 80: (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: 80: Wing Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr 1 5 10 Ser Cys (2) INFORMATION FOR SEC. IDENT. NO: 81: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (I) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. N0: 81 He Ser Glu He Lys Gly Val He Val His Lys He 1 5 10 Glu Gly He 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: 82: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 82: Met Thr Glu He Arg Thr Val He Val Thr Arg Met 1 5 10 Glu Thr Met 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: 83: (i) CHARACTERISTICS OF THE SEQUENCE: III II LILI II II HÉÉÍMÍ Ht-Éá-ii-i I ------------------- (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 83: Leu Ser Glu He Lys Gly Val He Val His Lys Leu 1 5 10 Glu Gly Val 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: 84: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 84: Wing Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr 1 5 10 Ser Cys Gly Gly He Ser Glu He Lys Gly Val He 15 20 ti *? á * ¡?? t *? ^? me *** * Val His Lys He Glu Gly He 25 30 (2) INFORMATION FOR THE SEC. IDENT. NO: 85: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 85: Wing Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr 1 5 10 Ser Cys Gly Gly Met Thr Glu He Arg Thr Val He 15 20 Val Thr Arg Met Gly Thr Met 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 86: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 86: -----yes----------. * ----------------- Wing Gly Cys Lys Asn Phe Phe Trp Lys Thr Phe Thr 1 5 10 Ser Cys Gly Gly Leu Ser Glu He Lys Gly Val He 15 20 Val His Lys Leu Glu Gly Val 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 87: (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: 87: Lys Lys Lys He He Thr He Thr Arg He He Thr 1 5 10 He He 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: 88: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 30 amino acids (B) TYPE-amino acid (D) TOPOLOGY: linear ---- g ^ gj ^ l ^ j ^ itg (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 88: Cys Asn Gln Gly Ser Phe Leu Thr Lys Gly Pro Ser 1 5 10 Lys Leu Asn Asp Arg Wing Asp Ser Arg Arg Ser Leu 15 20 Trp Asp Gln Gly Asn Cys 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 89: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 47 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 89: He Ser Glu He Lys Gly Val He Val His Lys He January 5 10 Glu Gly He Gly Gly Cys Asn Gln Gly Ser Phe Leu 15 20 Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala Asp 25 30 35 Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Cys 40 45 - «MiHu ^ aau? I (2) INFORMATION FOR THE SEC. IDENT. NO: 90: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 47 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ. IDENT. NO: 90: Met Thr Glu He Arg Thr Val He Val Thr Arg Met 10 January 5 10 Glu Thr Met Gly Gly Cys Asn Gln Gly Ser Phe Leu 15 20 Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala Asp 25 30 35 15 Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Cys 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 91: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 47 amino acids 20 (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC . IDENT. NO: 91: i * 143 Leu Ser Glu He Lys Gly Val He Val His Lys Leu 1 5 10 Glu Gly Val Gly Gly Cys Asn Gln Gly Ser Phe Leu 15 20 Thr Lys Gly Pro Ser Lys Leu Asn Asp Arg Ala Asp 25 30 35 Ser Arg Arg Ser Leu Trp Asp Gln Gly Asn Cys 40 45 10 (2) INFORMATION FOR SEC. IDENT. NO: 92: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 25 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear 15 (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 92: Cys Gly Glu Thr Tyr Gln Ser Arg Val Thr His Pro 1 5 10 20 His Leu Pro Arg Ala Leu Met Arg Ser Thr Thr Lys 15 20 Cys 25 (2) INFORMATION FOR SEC. IDENT. NO: 93: 25 (i) CHARACTERISTICS OF THE SEQUENCE: What is it? "Miiniiir lül lrahi- i i fc i? '? , * Élm &A ^ m ^ m ^^^ - ^ * á & ??? ^^^^^ (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: 93: I've Ser Glu He Lys Gly Val He Val His 1 5 10 Lys He Glu Gly He Leu Phe Gly Gly Cys Gly Glu 15 20 Thr Tyr Gln Ser Arg Val Thr His Pro His Leu Pro 25 30 35 Arg Ala Leu Met Arg Ser Thr Thr Lys Cys 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 94: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 46 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ. IDENT. NO: 94: I have been Thr Glu He Arg Thr Val He Val Thr 1 5 10 ------------- H-t-i-a ---- FÉ ------- l-l? HHMÉHMlkl trt IÉ i, g & tm Arg lie Glu Thr He Leu Phe Gly Gly Cys Gly Glu 15 20 Thr Tyr Gln Ser Arg Val Thr His Pro His Leu Pro 25 30 35 Arg Ala Leu Met Arg Ser Thr Thr Lys Cys 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 95: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 42 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 95: I've Glu He Lys Gly Val He Val His Lys He 1 5 10 Glu Gly He Gly Gly Cys Gly Glu Thr Tyr Gln Ser 15 20 Arg Val Thr His Pro His Leu Pro Arg Ala Leu Met 25 30 35 Arg Ser Thr Thr Lys Cys 40 (2) INFORMATION FOR SEC. IDENT. NO: 96: (i) CHARACTERISTICS OF THE SEQUENCE: ^^^^^^^^^ --- TIFFÉ-uafiíf (A) LENGTH: 42 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE : SEC. IDENT.

NO: 96: Met Thr Glu He Arg Thr Val He Val Thr Arg Met 1 5 10 Glu Thr Met Gly Gly Cys Gly Glu Thr Tyr Gln Ser 15 20 Arg Val Thr His Pro His Leu Pro Arg Ala Leu Met 25 30 35 Arg Ser Thr Thr Lys Cys 40 (2) INFORMATION FOR SEC. IDENT. NO: 97: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 42 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ. I'DENT.

NO: 97: Leu Ser Glu He Lys Gly Val He Val His Lys Leu 1 5 10 Glu Gly Val Gly Gly Cys Gly Glu Thr Tyr Gln Ser 15 20 Arg Val Thr His Pro His Leu Pro Arg Ala Leu Met 25 30 35 Arg Ser Thr Thr Lys Cys 40 (2) INFORMATION FOR SEC. IDENT. NO: 98: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 45 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 98: Lys Lys Lys He He Thr He Thr Arg He He Thr 1 5 10 He He Thr Thr He Asp Gly Gly Cys Gly Glu Thr 15 20 Tyr Gln Ser Arg Val Thr His Pro His Leu Pro Arg 25 30 35 Ala Leu Met Arg Ser Thr Thr Lys Cys 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 99: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 63 amino acids f ^ M-í ^ g- (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 99: Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Ala 1 5 10 Thr Tyr Gln Phe Gly Gly Lys Lys He He Thr 15 20 He Thr Arg He He Thr He He Thr Thr He Asp 25 30 35 Gly Gly Cys Gly Glu Thr Tyr Gln Ser Arg Val Thr 40 45 His Pro His Leu Pro Arg Ala Leu Met Arg Ser Thr 50 55 60 Thr Lys Cys (2) INFORMATION FOR SEC. IDENT. NO: 100: (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: 100: - ^^ and ^^ ------------------ Í ---- U _-- h ------ lt ------ > ---- --- t-Jü-ÜÉ-ni-i Arg His Lys Gln Lys He Val Pro Wing Val Lys Gln 1 5 10 Thr Leu Pro Pro Ser Val Pro Asn Leu Arg Gly Asp 15 20 Leu Gln Val Leu Ala Gln Lys Val Wing Arg Thr Pro 25 30 35 Cys Gly (2) INFORMATION FOR SEC. IDENT. NO: 101: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 56 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE SEC. IDENT. NO: 101 Lys Lys Lys He He Thr He Thr Arg He He Thr 1 5 10 He He Thr Thr He Asp Gly Gly Cys Lys Tyr Gly 15 20 Glu Asn Wing Val Thr Asn Val Arg Gly Asp Leu Gln 25 30 35 Val Leu Wing Gln Lys Ala Ala Arg Cys Leu Pro Thr 40 45 Ser Phe Asn Tyr Gly Ala He Lys 50 55 rfud > > ^ uu? * Hi? ^ aribtiM? uaiBÉau? aiHiÉ? ^ á? ií ^ Mi? (2) INFORMATION FOR SEC. IDENT. NO: 102 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 72 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 102 Thr Ala Lys Ser Lys Lys Phe Pro Ser Tyr Thr Ala 1 5 10 Thr Tyr Gln Phe Gly Gly Lys Lys He He Thr 15 20 He Thr Arg He He Thr He He Thr Thr He Asp 25 30 35 Gly Gly Cys Thr Tyr Gly Thr Gln Pro Ser Arg Arg 40 45 Gly Asp Met Wing Wing Leu Wing Gln Arg Leu Being Arg 50 55 60 Cys Leu Pro Thr Ser Phe Asn Tyr Gly Wing Val Lys 65 70 (2) INFORMATION FOR SEC. IDENT. NO: 103 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear UÉÉM ^ M l (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 103 Asn Ala Asn Pro 1 (2) INFORMATION FOR SEC. IDENT. NO: 104 (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: 104 I've Been Glu He Lys Gly Val He Val His 1 5 10 Lys He Glu Gly He Leu Phe Lys Asn Wing Asn Pro 15 20 Asn Wing Asn Pro Asn Wing Asn Pro Asn Wing Asn Pro 25 30 35 (2) INFORMATION FOR SEC. IDENT. NO: 105 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 36 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide • j¿afc ^ (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 105 I've been Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg He Glu Thr He Leu Phe Lys Asn Wing Asn Pro 15 20 Asn Wing Asn Pro Asn Wing Asn Pro Asn Wing Asn Pro 25 30 35 (2) INFORMATION FOR SEC. IDENT. NO: 106 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 26 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 106 Arg Asp Gly Phe Leu Leu Leu Gln Met Asp Phe Gly 1 5 10 Phe Pro Glu His Leu Leu Val Asp Phe Leu Gln Ser 15 20 Leu Ser 25 (2) INFORMATION FOR SEC. IDENT. NO: 107 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 16 amino acids * '** - - - * - • - ~ -i - r - * »-" «* - * - (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 107 Phe Gly Phe Pro Glu His Leu Leu Val Asp Phe Leu 1 5 10 Gln Ser Leu Ser 15 (2) INFORMATION FOR SEC. IDENT. NO: 108 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 16 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 108 Phe Gly Phe Pro Lys His Leu Leu Val Asp Phe Leu 1 5 10 Gln Ser Leu Ser 15 (2) INFORMATION FOR SEC. IDENT. NO: 109 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 26 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 109 Leu Asp Gly Cys Leu Leu Leu Gln Met Asp Phe Gly 1 5 10 Phe Pro Lys His Leu Leu Val Asp Phe Leu Gln Ser 15 20 Leu Ser 25 (2) INFORMATION FOR SEC. IDENT. NO: 110 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 46 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 110 I have to be Glu He Lys Gly Val He Val His 1 5 10 Lys He Glu Gly He Leu Phe Lys Arg Asp Gly Phe 15 20 Leu Leu Gluc Met Asp Phe Gly Phe Pro Glu His 25 30 35 155 Leu Leu Val Asp Phe Leu Gln Ser Leu Ser 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 111 5 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 46 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide 10 (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 111 Be He Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg He Glu Thr He Leu Phe Lys Arg Asp Gly Phe 15 15 20 Leu Leu Leu Gln Met Asp Phe Gly Phe Pro Glu His 25 30 35 Leu Leu Val Asp Phe Leu Gln Ser Leu Ser 40 45 20 (2) INFORMATION FOR SEC. IDENT. NO: 112 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 36 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear 25 (ii) TYPE OF MOLECULE: peptide - "• - '-.- ^ nn,! - ----.-. - .- ..... - _ ....... .. - .. ^» ^ - - ^. (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. N0: 112 I Have To Be Glu He Lys Gly Val He Val His 1 5 10 Lys He Glu Gly He Leu Phe Lys Phe Gly Phe Pro 15 20 Glu His Leu Leu Val Asp Phe Leu Gln Ser Leu Ser 25 30 35 (2) INFORMATION FOR SEC. IDENT. NO: 113 (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: 113 Be Ser Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg He Glu Thr He Leu Phe Lys Phe Gly Phe Pro 15 20 Glu His Leu Leu Val Asp Phe Leu Gln Ser Leu Ser 25 30 35 (2) INFORMATION FOR SEC. IDENT. NO: 114 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 35 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

N0: 114 Lys Lys Lys He He Thr He Thr Arg He He Thr 1 5 10 He He Thr Thr He Asp Lys Phe Gly Phe Pro Glu 15 20 His Leu Leu Val Asp Phe Leu Gln Ser Leu Ser 25 30 35 (2) INFORMATION FOR THE SEC. IDENT. NO: 115 (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: 115 I've been Leu Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg Leu Glu Thr Val Leu Phe Lys Phe Gly Phe Pro 15 20 Glu His Leu Leu Val Asp Phe Leu Gln Ser Leu Ser 25 30 35 - «---.- *. . . - "-.», -. , i ~ - »s - * • * • -" • * • - * "(2) INFORMATION FOR SEC. IDENT. NO: 116 (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: 116 I Have Been Glu He Lys Gly Val He Val His 1 5 10 Lys He Glu Gly He Leu Phe Lys Phe Gly Phe Pro 15 20 Lys His Leu Leu Val Asp Phe Leu Gln Ser Leu Ser 25 30 35 (2) INFORMATION FOR SEC. IDENT. NO: 117 (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: 117 I have been Thr Glu He Arg Thr Val He Val Thr 1 5 10 * - • »-» * * • - Arg He Glu Thr He Leu Phe Lys Phe Gly Phe Pro 15 20 Lys His Leu Leu Val Asp Phe Leu Gln Ser Leu Ser 25 30 35 (2) INFORMATION FOR SEC. IDENT. NO: 118 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 46 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 118 I've Been Glu He Lys Gly Val He Val His 1 5 10 Lys He Glu Gly He Leu Phe Lys Leu Asp Gly Cys 15 20 Leu Leu Leu Gln Met Asp Phe Gly Phe Pro Lys His 25 30 35 Leu Leu Val Asp Phe Leu Gln Ser Leu Ser 40 45 (2) INFORMATION FOR SEC. IDENT. NO: 119 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 46 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear - - * ••• "• ------- tiUlt- ------- (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SECTION ID: NO 119 Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg He Glu Thr He Leu Phe Lys Leu Asp Gly Cys 15 20 Leu Leu Gln Met Asp Phe Gly Phe Pro Lys His 25 30 35 Leu Leu Val Asp Phe Leu Gln Ser Leu Ser 40 45 (2) INFORMATION FOR SECTION ID: NO: 120: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 35 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (xi) DESCRIPTION OF THE SEQUENCE: SECTION ID: NO: 120: He Ser Be He Glu He Lys Gly Val He Val His 1 5 10 Lys He Glu Gly He Leu Phe Pro Pro Xaa Pro Xaa 15 20 Pro Glu His Trp Ser Tyr Gly Leu Arg Pro Gly 25 30 35 - "* - * - * - -» • - »** - '* -" *** - (2) INFORMATION FOR SEC. IDENT. NO: 121: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 35 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. N0: 121 Be Ser Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg He Glu Thr He Leu Phe Pro Pro Xaa Pro Xaa 15 20 Pro Glu His Trp Ser Tyr Gly Leu Arg Pro Gly 25 30 35 (2) INFORMATION FOR THE SEC. IDENT. NO: 122: (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 THE SEQUENCE: SEC. IDENT. NO: 122: Lys Lys Lys He He Thr He Thr Arg He He Thr 1 5 10 liliit '1.MB ^ ié ^ ah- He He Thr Thr He Asp Pro Pro Xaa Pro Xaa Pro 15 20 Glu His Trp Ser Tyr Gly Leu Arg Pro Gly 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 123: (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: 123: I've been Leu Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg Leu Glu Thr Val Leu Phe 15 (2) INFORMATION FOR SEC. IDENT. NO: 124: (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 THE SEQUENCE: SEC. IDENT. NO: 124: ------------------- • "-" • '"- .¡ .. .. a .... -. -.» J »Sti.ií.

He Be He Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg He Glu Thr He Leu Phe 15 (2) INFORMATION FOR SEC. IDENT. NO: 125: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 125: Glu Ser Val Glu He Asn Cys Thr Arg Pro Asn Asn 1 5 10 Asn Thr Arg Lys Ser He Arg He Gly Pro Gly Gln 15 20 Wing Phe Tyr Wing Thr Gly Asp 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 126: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTICS: - t t i uji ft iii1 í -fti > n - * - * - "~ ^ * - (A) NAME / KEY: Modified site (B) LOCATION: 22 (C) OTHER INFORMATION: / note =" (eN) Lys "(xi) DESCRIPTION OF THE SEQUENCE: SEC IDENT.

NO: 126: I have to be Glu He Lys Gly Val He Val His 1 5 10 Lys He Glu Gly He Leu Phe Xaa Glu Ser Val Glu 15 20 He Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys 25 30 35 Ser He Arg He Gly Pro Gly Gln Wing Phe Tyr Wing 40 48 Thr Gly Asp 50 (2) INFORMATION FOR SEC. IDENT. N0 127: (i) CHARACTERISTICS OF THE SEQUENCE. (A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTICS: (A) NAME / KEY: Modified site (B) LOCATION: 22 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 127: I have been Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg He Glu Thr He Leu Phe Xaa Glu Ser Val Glu 15 20 He Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys 25 30 35 Ser He Arg He Gly Pro Gly Gln Wing Phe Tyr Wing 40 48 Thr Gly Asp 50 (2) INFORMATION FOR SEC. IDENT. NO: 128: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTICS: (A) NAME / KEY : Modified site (B) LOCATION: 20 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 128: I Ser Leu Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg Leu Glu Thr Val Leu Phe Xaa Glu Ser Val Glu 15 20 He Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys 25 30 35 Ser He Arg He Gly Pro Gly Gln Wing Phe Tyr Wing 40 48 Thr Gly Asp 50 (2) INFORMATION FOR SEC. IDENT. NO: 129: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 51 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY: Modified site (B) LOCATION: 20 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 129: I have been Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg He Glu Thr Val He Phe Xaa Glu Ser Val Glu 15 20 He Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys 25 30 35 Ser He Arg He Gly Pro Gly Gln Wing Phe Tyr Wing 40 48 Thr Gly Asp 50 (2) INFORMATION FOR SEC. IDENT. NO: 130: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 130: Lys Ser Ser Gly Lys Leu He Ser Leu 1 5 (2) INFORMATION FOR THE SEC. IDENT. NO: 131: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 131: Cys Asn Gly Arg Leu Tyr Cys Gly Pro 1 5 (2) INFORMATION FOR SEC. IDENT. NO: 132: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 10 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 132: Cys Gly Thr Lys Leu Val Cys Phe Ala Ala 1 5 10 (2) INFORMATION FOR SEC. IDENT. NO: 133: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 133: Lys Arg He Val He Gly Pro Gln Thr 1 5 (2) INFORMATION FOR SEC. IDENT. NO: 134: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 9 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 134: Cys Ala Gly Gly Leu Thr Cys Ser Val 1 5 (2) INFORMATION FOR SEC. IDENT. NO: 135: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 11 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 135: Cys Ser Gly Arg Leu Tyr Cys His Glu Ser Trp 1 5 10 (2) INFORMATION FOR SEC. IDENT. NO: 136: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY : Modified site (B) LOCATION: 10 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 136: Lys Ser Gly Lys Leu He Ser Leu Xaa He Ser 1 5 10 He Ser Glu He Lys Gly Val He Val His Lys He 15 20 Glu Gly He Leu Phe 25 (2) INFORMATION FOR SEC. IDENT. NO: 137: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTICS: (A) NAME / KEY : Modified site (B) LOCATION: 10 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 137: Lys Being Ser Gly Lys Leu He Ser Leu Xaa He Ser 1 5 10 He Thr Glu He Arg Thr Val He Val Thr Arg He 15 20 Glu Thr He Leu Phe 25 (2) INFORMATION FOR SEC. IDENT. NO: 138: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTICS: (A) NAME / KEY : Modified site (B) LOCATION: 10 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 138: Cys Asn Gly Arg Leu Tyr Cys Gly Pro Xaa He Ser 1 5 10 He Ser Glu He Lys Gly Val He Val His Lys He 15 20 Glu Gly He Leu Phe 25 (2) INFORMATION FOR SEC. IDENT. NO: 139: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY: Modified site (B) LOCATION: 10 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 139: Cys Asn Gly Arg Leu Tyr Cys Gly Pro Xaa He Ser 1 5 10 He Thr Glu He Arg Thr Val He Val Thr Arg He 15 20 Glu Thr He Leu Phe 25 (2) INFORMATION FOR SEC. IDENT. NO: 140: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 30 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY : Modified site (B) LOCATION: 11 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE. SEC. IDENT.

NO: 140: Cys Gly Thr Lys Leu Val Cys Phe Ala Ala Xaa He 1 5 10 Ser He Ser Glu He Lys Gly Val He Val His Lys 15 20 He Glu Gly He Leu Phe 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 141: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 30 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY : Modified site (B) LOCATION: 11 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF SEQUENCE SEC. IDENT.

NO: 141 Cys Gly Thr Lys Leu Val Cys Phe Ala Ala Xaa He 1 5 10 Ser He Thr Glu He Arg Thr Val He Val Thr Arg 15 20 He Glu Thr He Leu Phe 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 142: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY : Modified site (B) LOCATION: 10 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 142: Lys Arg He Val He Gly Pro Gln Thr Xaa He Ser 1 5 10 He Ser Glu He Lys Gly Val He Val His Lys He 15 20 Glu Gly He Leu Phe 25 (2) INFORMATION FOR SEC. IDENT. NO: 143 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY: Modified site (B) LOCATION: 10 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 143: Lys Arg He Val He Gly Pro Gln Thr Xaa He Ser 1 5 10 He Thr Glu lie Arg Thr Val He Val Thr Arg He 15 20 Glu Thr He Leu Phe 25 (2) INFORMATION FOR SEC. IDENT. NO: 144: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY : Modified site (B) LOCATION: 10 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 144: Cys Wing Gly Gly Leu Thr Cys Ser Val Xaa He Ser 1 5 10 He Ser Glu He Lys Gly Val He Val His Lys He 15 20 Glu Gly He Leu Phe 25 (2) INFORMATION FOR SEC. IDENT. NO: 145: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 29 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY : Modified site (B) LOCATION: 10 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 145: Cys Ala Gly Gly Leu Thr Cys Ser Val Xaa He Ser 1 5 10 He Thr Glu He Arg Thr Val He Val Thr Arg He 15 20 Glu Thr He Leu Phe 25 (2) INFORMATION FOR SEC. IDENT. NO: 146: (i) CHARACTERISTICS OF THE SEQUENCE: (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: 12 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 146: Cys Ser Gly Arg Leu Tyr Cys His Glu Ser Trp Xaa 1 5 10 I Have To Be Glu Me Lys Gly Val I Have Val His 15 20 Lys He Glu Gly He Leu Phe 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 147 (i) SEQUENCE CHARACTERISTICS: . , 1, (A) LENGTH: 31 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTICS: (A) NAME / KEY: Modified site (B) LOCATION: 12 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT. NO: 147: Cys Ser Gly Arg Leu Tyr Cys His Glu Ser Trp Xaa 1 5 10 He Ser He Thr Glu He Arg Thr Val He Val Thr 15 20 Arg He Glu Gly He Leu Phe 25 30 (2) INFORMATION FOR SEC. IDENT. NO: 148: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 52 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT.

NO: 148: I've Been Glu He Lys Gly Val He Val His 1 5 10 Lys He Glu Gly He Leu Phe Gly Gly Glu Ser Val 15 20 Glu He Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg 25 30 36 Lys Ser He Arg He Gly Pro Gly Gln Wing Phe Tyr 40 45 Wing Thr Gly Asp 50 (2) INFORMATION FOR SEC. IDENT. NO: 149: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 52 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF SEQUENCE: SEC. IDENT. NO: 149: He Be He Thr Glu He Arg Thr Val lie Val Thr 1 5 10 Arg He Glu Thr He Leu Phe Gly Gly Glu Ser Val 15 20 Glu He Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg 25 30 36 • ^ «to Lys Ser lie Arg He Gly Pro Gly Gln Wing Phe Tyr 40 45 Wing Thr Gly Asp 50 (2) INFORMATION FOR SEC. IDENT NO 150: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 50 amino acids (B) TYPE of amino acid (D) TOPOLOGY: linear (i) TYPE OF MOLECULE: peptide (ix) CHARACTERISTIC: (A) NAME / KEY : Modified site (B) LOCATION: 20 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE- SEC. IDENT. NO: 150 I Ser Leu Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg Leu Glu Thr Val Leu Phe Xaa Glu Ser Val Glu 15 20 He Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys 25 30 35 Ser He Arg He Gly Pro Gly Gln Wing Phe Tyr Wing 40 48 .Item .._". - "-« * »« "• Thr Gly 50 (2) INFORMATION FOR SECTION ID NO: 151 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 50 amino acids (B) TYPE: amino acid (D) TOPOLOGY : linear (ii) TYPE OF MOLECULE: peptide (ix) CHARACTERISTICS: (A) NAME / KEY: Modified site (B) LOCATION: 20 (C) OTHER INFORMATION: / note = "(eN) Lys" (xi) DESCRIPTION OF THE SEQUENCE: SEC. IDENT.

NO: 151 I have been Thr Glu He Arg Thr Val He Val Thr 1 5 10 Arg He Glu Thr Val He Phe Xaa Glu Ser Val Glu 15 20 He Asn Cys Thr Arg Pro Asn Asn Asn Thr Arg Lys 25 30 35 Ser He Arg He Gly Pro Gly Gln Wing Phe Tyr Wing 40 48 Thr Gly 50 ^^ ¿^ ¿¡¿^ ^^^

Claims (13)

1. CLAIMS 1. A helper cell epitope T selected from the group characterized by consisting of SEC. FROM IDENT. NOS: 6-22, 105, 123, 124, 31-35. 2. The helper cell epitope T according to claim 1, characterized in that it prepares a peptide immunogen represented by the formulas (A) n- (thio antigen target) - (B) 0- (Th) mX or (A ) n- (Th) m- (B) 0- (target antigenic site) -X or (A) n - (B) 0 (Th) m- (B) 0- (target antigenic site) -X or ( target antigenic site) - (B) 0- (Th) m- (A) nX or (Th) m- (B) 0- (target antigenic site) - (A) nX where: A is an amino acid or a sequence general immunostimulatory, where n is more than one, individual A's can be the same or different; B is selected from the group consisting of amino acids, -HCH (X) CH2SCH2CO-, -NHCH (X) CH2SCH2CO (e-N) Lys-,
2. -NHCH (X) CH2S-succinimidyl (e-N) Lys-, and -NHCH (X) CH2S- (succinimidyl) -;
3. Th is an artificial helper T cell epitope selected from the group consisting of SEC. FROM IDENT. NOS: 6-22, 105.31-35 or an analogue thereof; "Target antigenic site" is a B cell epitope, a peptide hapten, or an immunologically reactive analogue thereof; X is an amino acid a-COOH or -CONH2; n is from 1 to about 10; m is from 1 to about 4; and o is from 0 to approximately 10. 3. The peptide immunogen according to claim 2, characterized in that the immunostimulatory sequence is SEQ. FROM IDENT. NO: 78 4. The peptide immunogen according to claim 2, characterized in that B is selected from the group consisting of Gly-Gly, (eN) Lys-, Pro-Pro-Xaa-Pro-Pro, -NHCH (X) CH2SCH2CO-, -NHCH (X) CH2SCH2CO (eN) Lys-,
4. -NHCH (X) CH2S-succinimidyl (e-N) Lys-, and -NHCH (X) CH2S- (succinimidyl) -. 5. The peptide immunogen according to claim 4, characterized in that B is Gly-Gly. 6. The peptide immunogen according to claim 4, characterized in that B is (e-N) Lys. 7. The peptide immunogen according to claim 1, 2, 3, 4, 5 or 6, characterized in that the target antigen site is the repeat antigen of (Asn-Ala-Asn-Pro) p (SEQ ID NO. NO: 103) 8. The peptide immunogen according to claim 7, characterized in that p = 4. 9. The peptide immunogen according to claim 7, characterized in that it is selected from the group consisting of SEC. FROM IDENT. Nos. 104, 105. 10. The peptide immunogen according to claim 1, 2, 3, 4, 5, or 6, characterized in that the site
5. Target Antigen is selected from the group consisting of SEC. FROM IDENT. NOS: 106, 107, 108 and 109, an epitope of CETP. 11. The peptide immunogen according to claim 10, selected from the group consisting of d ^ SEC. FROM IDENT. NOS: 110-119. 12. The peptide immunogen according to claim 1, 2, 3, 4, 5, or 6, characterized in that the site
6. Target Antigen is selected from the group consisting of SEC. FROM IDENT. NOS: 125, 131, 132, 133, 134 and 135 an HIV epitope. 13. The peptide immunogen according to claim 12, characterized in that it is selected from the group consisting of SEC. FROM IDENT. NOS: 126-129, 136-151. 14. The peptide immunogen according to claim 13, characterized in that it is selected from | group consisting of SEC. FROM IDENT. NOS: 148-151.
7. A ^ y * 'm? 15. A method for producing a peptide immunogen by covalently binding a helper cell epitope to a target antigenic site selected from the group consisting of B cell epitopes of an antigen and a peptide hapten. 16. The method for producing a peptide immunogen according to claim 15, characterized in that it additionally binds the helper cell epitope T linked covalently and a target antigenic site to an immunostimulatory sequence. 17. The method for producing a peptide immunogen according to claim 16, characterized in that the nmuestimulating sequence is SEC. FROM IDENT. NO: 78 18. The method for producing a peptide immunogen according to claim 17, characterized in that B is selected from the group consisting of Gly-Gly, (eN) Lys, Pro-Pro-Xaa-Pro-Pro, -NHCH (X) CH2SCH2CO-, -NHCH (X) CH2SCH2CO (eN) Lys-, -NHCH (X) CH2S-succinimidyl (eN) Lys-, and -NHCH (X) CH2S- (succinimidyl) -19. The method for producing a peptide immunogen according to claim 18, characterized in that B is
8. Gly-Gly. 20. The method for producing a peptide immunogen according to claim 19, characterized in that B is (e-N) Lys. 21. The method for inducing a helper cell response T by employing a peptide immunogen according to claim 1. 22. The method for inducing a helper cell response T by employing a peptide immunogen of confo rmity with claim 2. 23 The method for inducing an attendant T cell response by employing a peptide immunogen in accordance with claim 3. 24. The method for inducing a helper cell response T by employing a peptide immunogen of confo rmity with claim 4. The method for inducing a helper cell response T by employing a peptide immunogen of confo rmity with claim 5. 26. The method for inducing a helper cell response T by employing a peptide immunogen of confo rmity with claim 6. 27 The method for inducing a helper T cell response by employing a peptide immunogen in accordance with the claim 7. The method for inducing a helper cell response T by employing a peptide immunogen in accordance with claim 8. 29. The method for inducing a helper cell response T by employing a peptide immunogen in confo rmity with the claim
9. 9. 30. The method for inducing a helper cell response T by employing a peptide immunogen according to claim
10. 10. 31. The method for inducing a helper cell response T by employing a peptide immunogen according to claim
11. 11. 32. The method for inducing an assistant cell response T by employing a peptide immunogen according to claim
12. 12. 33. The method for inducing a helper cell response T by employing a peptide immunogen according to claim
13. 13.