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WO1997011966A1 - Polypeptides and their use in treatment and prophylaxis of auto-immune disease - Google Patents

Polypeptides and their use in treatment and prophylaxis of auto-immune disease Download PDF

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Publication number
WO1997011966A1
WO1997011966A1 PCT/GB1996/002382 GB9602382W WO9711966A1 WO 1997011966 A1 WO1997011966 A1 WO 1997011966A1 GB 9602382 W GB9602382 W GB 9602382W WO 9711966 A1 WO9711966 A1 WO 9711966A1
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gly
seq
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PCT/GB1996/002382
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French (fr)
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James Stephen Thompson
Christopher John Elson
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Peptide Therapeutic Limited
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Priority to AU70912/96A priority Critical patent/AU7091296A/en
Publication of WO1997011966A1 publication Critical patent/WO1997011966A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/35—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Mycobacteriaceae (F)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the present invention relates to polypeptides and fragments thereof, to their use in the prevention, diagnosis and treatment of auto-immune disease such as rheumatoid arthritis, and to methods of preparing these fragments.
  • Autoimmune diseases are thought to arise as a result of similarities between a foreign molecule or antigen and a molecular structure of the organism itself. Chronic forms of arthritis are thought to involve autoimmunity to constituents of the joints in particular of the connective tissues of the body.
  • RA ⁇ Rheumatoid arthritis
  • the disease is the third most common of the elderly and causes a tremendous burden of pain and suffering. It has been known for some time that an association exists between HLA-DR4 and RA suggesting a T-cell involvement [Stasney, New Eng. J. Med. (1978) 298:869 and Watanabe et al, J. exp. Med. (1989) 169:2263] and a genetic contribution to the disease.
  • recent twin studies [Silman ⁇ t al, Brit. J. Rheumatol.
  • pristane-induced arthritis This model is based upon the finding that a proportion of mice injected intraperitoneally with the paraffin oil pristane (2, 6, 10, 14-tetramethylpentadecane) develop a chronic T-cell dependent inflammatory arthritis between 60 and 200 days later depending on the strain of mice [Potter M, J. Immunol. (1981) 127:1591, Bedwell et al, J. Immunol. (1987) 25:393, Wooley et al, Arthritis. Rheum. (1987) 32:1022, Wooley et al. Arthritis. Rheum.
  • Chat heat shock proteins are immunodominant antigens in a number of infectious diseases, such as tuberculosis and leishmania. These infectious diseases can have similar abnormalities as observed in RA such as raised agalactosyl-IgG levels, the organs involved and range of autoantibodies present. Since environmental factors are clearly important in RA, microbial agents and hence hsp's were implicated.
  • Hsps are grouped in gene families according co their molecular weight and sequence homology within individual groups.
  • hsp60 (60KD) gene family includes members hsp65 (mycobacterial) and hsp5 ⁇ (mammalian) .
  • mice become sensitised to hsp by exDOsure to microbial flora in the environment and that this process is necessary for the induction of arthritis by pristane injection. If so, it would be predicted that there is a relationship between sensitisation to hsp65 and susceptibility to PIA. Experiments carried out by the applicants suggest that this hypothesis is correct.
  • hsp 58 has been detected in the joints of patients with RA [Karlsson-Parra et al, Scand. J. Immunol. (1990) 31:283] and T-cells from mice with PIA react with joint extracts [Thompson et al, Eur. J. Immunol. (1990) 20:2479] it seems reasonable to postulate that hsp58 could be a target antigen in the joints of mice developing PIA.
  • mice with PIA and animals protected from the development of arthritis by hps65 preim unisatiOn exhibit elevated immune responses to the 65kD mycobacterial heat shock protein. It would be expected that only mice with PIA should develop autoimmune responses to the 60kD family of hsps whereas the response of mice pre-immunised with hsp65 should be restricted to microbial specific determinants. In other words, the response elicted by immunisation with hps65 in IFA differs from that induced by sensitisation with environmental/bowel microorganisms.
  • T cell-mediated response to mycobacterial antigens has been implicated in the pathogenesis of inflammatory arthritis both in experimental animal models and in man. In adjuvant arthritis in rats, it has been established that the disease can be initiated by T cell clones specific for the 65-kDa mycobacterial heat-shock protein.
  • Rats may also be protected to subsequent adjuvant arthritis induction by pre-immunisation with either a 65 KDa specific T cell line cr with the hsp itself (Van Eden et al., Nature, 1988, 331:171 and Holoshitz et al. , Science 1983, 219:56) .
  • EP-A-322990 describes polypeptides having amino acid sequence 172-192 of a bacterial hsp 64 and their use as immunogens for inducing resistance to auto-immune disease.
  • WO 92/04049 discloses that a peptide comprising the amino acid sequence corresponding to positions 180-186 of the Mycobacterium tuberculosis protein hsp65 is effective in the prevention and treatment of immune-related disease such as autoimmune arthritis.
  • the present invention provides a polypeptide of up to 21 amino acid residues which comprises or consists of the sequence
  • VGLTLENADLSL (SEQ ID 107) or a homologue or functional equivalent or mimetic thereof.
  • the above described polypeptide sequence corresponds to amino acids 302-314 of microbial (mycobacterial) hsp65.
  • the invention also provides che use of such a polypeptide in the prophylaxis or treacment of auto-immune disease such as RA. 8
  • T H 1 cells are induced which leads to pristane induced arthritis due to determinant spreading
  • T H 2 cells are induced which leads to protection due to repertoire limitation.
  • type II collagen another potential joint antigen
  • RA trans-mucosal memorane mode of administration
  • Full sequence information in respect of human hsp58 is known for example from Jindal et al . Mol . Cell Biol . 1989 , 9 : 2279 -2283 . It is therefore proposed that human hsp58 or fragments thereof are useful in the prophylaxis or treatment of RA.
  • the present invention provides the use of human hsp58 or a fragment thereof containing or consisting of the amino acid sequence
  • VLNRLKVGLQV (SEQ ID 108 ) or a homologue or functional equivalent or mimetic thereof in the prophylaxis or treatment of auto- immune disease such as RA; and provides novel polypeptide fragments of up to 21 amino acid residues , per se .
  • This region is a non-conserved region and is mammalian specific . This means that the region will not cross - react with the bacterial form of the protein and administered transmucosally, would induce T-cell tolerance to it and thus prevent arthritis .
  • the present invention further provides a polypeptide of up to 21 amino acid residues comprising or consisting of the sequence
  • polypeptides include fragments of human hsp58 protein, in particular those including the amino acid residues corresponding to 271-257 of hsp65 or homologues thereof; i.e. the amino acid sequence
  • a particularly preferred polypeptide will consist only of the amino acids VLNRLKVGLQV.
  • hsp58 containing amino acid residues corresponding to 302-314 of hsp65 is also important for this application. This region is also a non- conserved region and is mammalian specific.
  • the present invention further provides the use of human hsp58 fragment containing or consisting of the amino acid sequence
  • LTLNLEDVQPHD (SEQ ID 110) or a homologue or functional equivalent or mimetic thereof in the prophylaxis or treatment of auto-immune disease such as RA; and provides novel polypeptide fragments of up to 21 amino acid residues, per se.
  • the invention further provides a polypeptide of up to 21 amino acid residues comprising or consisting of the sequence
  • LTLNLEDVQPHD (SEQ ID 110 ) or a homologue or functional equivalent or mimetic thereof .
  • a parcicularly preferred polypeptide will consist only of the amino acids
  • polypeptides of the invention have been found to have a prophylactic or therapeutic effect when applied immunogenically in the treatment of RA .
  • the invention further provides a vaccine for the prophylactic or therapeutic treatment of RA which vaccine comprises a polypeptide as described above .
  • the polypeptide is suitably administered in a trans -mucosal membrane manner for example , orally or nasally .
  • the polypeptide may be formulated as a suppository .
  • polypeptides of the invention are suitably administered in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition in combination with a pharmaceutically acceptable carrier or excipient.
  • Suitable carriers include solid or liquid carriers.
  • formulations including solid carriers include tablets or suspensions for oral administration or suppositories.
  • Suitable liquid carriers include oils or water.
  • the compositions may be adapted for nasal administration by inhalers, atomizers or sprays as are available in the art.
  • polypeptide or a pharmaceutical composition including the polypeptide, parenterally, for example sub ⁇ cutaneously, intramuscularly, intravenously or intra peritoneally.
  • polypeptides of the invention can be produced using various techniques which would be apparent to the skilled person. For example, they may be obtained by fragmentation of human hsp58 using conventional techniques after which the desired fragments obtained by purification, again using techniques which are known in the art. However peptides obtained by this method are less likely to have the precisely the desired length.
  • polypeptides may be obtained using recombinant DNA technology.
  • the nucleotide sequence encoding the desired polypeptide can be incorporated into a suitable host using a vector system which causes expression of the polypeptide.
  • polypeptides sequences may be generated entirely synthetically using standard chemical methods or peptide synthesizers available in the art.
  • the expression 'homologue' refers to peptides having an amino acid sequence which is are at least 60%, preferably 70 and most preferably at least 80V homologous tc the described polypeptide.
  • the expression 'functional equivalent' or 'mimetic' relates to any chemical, which may be a peptide or other organic chemical which produces similar effects in vivo to the compounds of the present invention. In particular, such compounds will produce a protective immunogenic response against RA when applied in pristane-induced arthritis model using tests as described in the examples hereinafter.
  • Figure 1 is the peptide library comprising eleven pools of overlapping peptides corresponding to the entire sequence of microbial hsp65. (SEQ IDs Nos. 1-106)
  • Figure 2 shows a comparison of the proliferative response of T cells from each of 6 arthritic mice (top panel) , 6 protected mice (middle panel) and 6 normal mice (n-6) to the eleven pools of overlapping peptides defined in Figure 1;
  • Figure 3 shows the results of studies to determine the protection against PIA of mice pre-immunised with microbial hsp65 polypeptides
  • Figure 4 shows the entire amino acid sequence of human hsp58 (top line) in corresponding relationship to the entire sequence of microbial hsp65 (lower line) ; (SEQ IDs Nos. 107-109)
  • Figure 5 shows the sequences and % homology of 5 peptides in the region hsp65 m 251-312 and the corresponding sequences of hsp58; (SEQ IDs Nos. 110-117) 15
  • Figure 7 shows the prophylactic effect of pre-immunisation with polypeptides of the invention at 10 days prior to pristane injection (D---10) .
  • CBA/Igb mice Male CBA/Igb mice aged between 4 and 8 weeks were used unless otherwise specified. CBA/Igb mice were obtained by back-crossing (101 strain x CBA) Fl hybrids to CBA mice and selecting those mice with Igb allotype in their serum.
  • Completed peptides were extracted from the resin using trifluoroacetic acid and suitable scavengers, and isolated by solvent evaporation and precipitation with methanol and diethylether. Purity was checked by amino acid analysis and by HPLC. Irrelevant control antigens BSA and human IgG were also used along with the mitogen ConA.
  • the nonadherent cells were then gently aspirated followed by washing with medium. These cells were then used as the T cell enriched fractions. A purity of .85V was achieved as assessed by anti-Thy 1.2 staining using flow cytometry (FACScan, Becton Dickinson Ltd. , Oxford, GB) . Normal mouse spleen cells were used as antigen presenting cells. In these experiments the APC were irradiated 1000 rads from a caesium source (Gravatom Industries, Gosport, GB) .
  • the cultures consisted of 1.25 x 10 s purified splenic T-cells plus 1.25 x 10 s APC per ml, in a volume of 2ml in a 24 well plate (Flow) in the presence or absence of the various antigens 92.5-10 ⁇ g/ml). Alternatively, some cultures were set up in a volume of 200 ⁇ l in round bottom 96 well plates (Flow) . All cultures were incubated at 37°C in a humidified atmosphere of 5V C02 and 95V air.
  • mice against PIA Protection of mice against PIA by immunisation with microbial Hsp65 fragments
  • mice were immunised intraperitoneally 10 days before pristane challenge as follows :
  • each polypeptide was administered as an emulsion in IFA.
  • the polypeptide fragment used in the pre-immunisation of group 3 was manufactured by Cambridge Research Biochemicals of Northwich, Cheshire UK.
  • VGLTLENADLSL is effective in producing a beneficial effect.
  • amino acids 261-271 of microbial hsp 6 5 can be useful in prophylaxis or treatment of auto-immune d isease.
  • Figure 4 shows the two complete sequences in corresponding alignment, with hspS ⁇ above hsp ⁇ S. Note that the numbering of hsp65 amino acids is used herein. References herein to amino acid sequence numbers for human fragments (from hsp58) are the numbers of the corresponding hsp60 sequence region. Thus, for example, reference herein to human hsp58 region h 261-271 corresponds to microbial m 261-271 but is, in fact, amino acid 287-297 of the upper sequence of Figure 4. Likewise, h 302-314 corresponds to m 302-314 but is, in fac t amino acids 330-341 of the upper sequence of Figure 4 .
  • Figure 5 tabulates the V homology of 5 sequences of the complete region covered by hsp65 m 251-312.
  • mice against PIA Protection of mice against PIA by oral immunisation with human hsp58 fragment.
  • the eleven amino acid polypeptide of sequence VLNRLKVGLQV (h 261-271) :SEQ ID 108) was prepared for use in the Example by Cambridge Research Biochemicals, Gadbrook Par, Nothwich,
  • mice Male CBA/Igb mice aged between 4 and 8 weeks are suitably used. Arthritis can be induced by two intraperitoneal injections of 0.5ml of pristane 50 days apart as described above. Mice which are to be subjected to an immunisation regime are given oral doses of polypeptide dissolved in saline, administered orally with 23
  • Each animal should receive a single dose on 5 consecutive days (up to and including the day of challenge with pristane) of 50 micrograms of polypeptide.
  • mice can be examined visually for the incidence of arthritis in the tarsal (ankle) joints at various time points. This may be assessed for example using a micrometer and comparing enlarged joints with normal joints. In this way, the protective effect of the polypeptide can be demonstrated.
  • the experiment is terminated 200 days after pristane injection.
  • stifle (knee) joints may be dissected out, fixed in neutral-buffered formalin and decalicified. If longitudinal sections are prepared and stained with haematoxylin and eosin, arthritis may be further assessed, for example by a veterinary pathologist.
  • the assessment is carried out blind and joint changes graded according to the following system:
  • Synovial hyperplasia with pannus formation and mild inflammation (polymorphonuclear leucocytes-PMN) or non-inflammatory mild articular cartilage degeneration.
  • a proliferative T-cell assay may be carried out as described in Experiment 1 above which will further confirm the effectiveness of this polypeptide.
  • Example 1 Protection of mice against PIA by nasal immunisation with human hso65 fragment.
  • Example 1 may be repeated except that instead of oral administration, the polypeptide is given nasally.
  • the animal is first anaesthetized and then laid on its back.
  • a 50 microlitre drop of solution containing 50micrograms of the polypeptide described in Example 1 are then placed on the nostrils. As soon as the animal becomes conscious, the drop is rapidly inhaled. This procedure is repeated five times on five consecutive days in the same way as the oral dosing described in Example 1.
  • Monitoring of the animals may be carried out in the same way as described above, whereupon a protective effect is shown.
  • Figure 6 shows the therapeutic effect of administration of polypeptides according to the invention 60 days after first administration of pristane. 50 milligrams of peptide was administered ip as an emulsion IFA to each mouse at day 60. This was after two pristane injections, 50 days apart, one at day 0 and one at day 50. This timing is judged to be just prior to the development/onset phase of PIA. The percentage arthritis was assessed by visual scoring with the assessment being made at the 210th day (D-210) . As can be seen from the figure, each of the peptides according to the invention pro d uces a reduc t ion in percentage arthritis in comparison to the control (IPP only) .
  • Figure 7 shows the prophylactic effect of pre-immunisation with peptides according to the invention 10 days prior to the first pristane injection. From these results it appears that h 261-271 may actually increase the incidence of PIA whereas h 302-314 may have little or no effect reduction of arthritis. However, m 302-314 clearly appears to give a significant reduction or nearly 4 fold in the percentage arthritis.
  • polypeptides of the invention may be useful prophylaxis, some may be useful in treatment, and some may have both prophylactic and therapeutic activity although not all polypeptides of the invention are expected to show both activities.
  • MOLECULE TYPE peptide (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 12 :
  • MOLECULE TYPE peptide (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 54 :
  • MOLECULE TYPE peptide
  • SEQUENCE DESCRIPTION SEQ ID NO: 59:
  • MOLECULE TYPE peptide (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 62 :
  • MOLECULE TYPE peptide
  • SEQUENCE DESCRIPTION SEQ ID NO: 96:

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Abstract

The invention relates to polypeptides and fragments thereof, to their use in the prevention, diagnosis and treatment of auto-immune disease such as rheumatoid arthritis (RA), and to methods of preparing these fragments. Examples of such polypeptides include fragments of human heat shock protein hsp58. The invention provides a polypeptide of up to 21 amino acid residues which comprises or consists of the following sequences: (1) VGLTLENADLSL (SEQ ID 107), (2) VLNRLKVGLQV (SEQ ID 108), (3) LTLNLEDVQPHD (SEQ ID 110) or a homologue or functional equivalent or mimetic thereof. The invention provides a vaccine for the prophylactic or therapeutic treatment of RA which comprises a polypeptide as described above.

Description

POLYPEPTIDES AND THEIR USE IN TREATMENT AND PROPHYLAXIS OF
AUTO-IMMUNE DISEASE
The present invention relates to polypeptides and fragments thereof, to their use in the prevention, diagnosis and treatment of auto-immune disease such as rheumatoid arthritis, and to methods of preparing these fragments.
Autoimmune diseases are thought to arise as a result of similarities between a foreign molecule or antigen and a molecular structure of the organism itself. Chronic forms of arthritis are thought to involve autoimmunity to constituents of the joints in particular of the connective tissues of the body.
Rheumatoid arthritis (RA} is the most common of the arthritides which exhibit autoimmune manifestations [reviewed in Elson et al, Autoimmunity (1992) 13:327] . The disease is the third most common of the elderly and causes a tremendous burden of pain and suffering. It has been known for some time that an association exists between HLA-DR4 and RA suggesting a T-cell involvement [Stasney, New Eng. J. Med. (1978) 298:869 and Watanabe et al, J. exp. Med. (1989) 169:2263] and a genetic contribution to the disease. However, recent twin studies [Silman εt al, Brit. J. Rheumatol. (1993) 32:903] have suggested that the upper limit of the genetic contribution is only 15%. It follows that the main factors contributing to the induction of RA are environmental. This contention is supported by the increased incidence of RA in South Africans as they move from villages to towns [Solomon et al, Ann, rheum. Dis. (1975) 34:128] and the increasing evidence of abnormal immune responses to microbes in patients with the disease [Deighton et al, Brit. J. Rheumatol. (1992) 31:241] . Such considerations have led to the suggestion that RA is triggered by bacterial or viral antigens which may share a'high degree of homology with self protein [reviewed in reference McCulloch et al, Clin. Exp. Immunol. (1993) 92:1] .
One model has proved useful in investigating environmental factors which contribute to the disease is pristane-induced arthritis (PIA) . This model is based upon the finding that a proportion of mice injected intraperitoneally with the paraffin oil pristane (2, 6, 10, 14-tetramethylpentadecane) develop a chronic T-cell dependent inflammatory arthritis between 60 and 200 days later depending on the strain of mice [Potter M, J. Immunol. (1981) 127:1591, Bedwell et al, J. Immunol. (1987) 25:393, Wooley et al, Arthritis. Rheum. (1987) 32:1022, Wooley et al. Arthritis. Rheum. (1989) 32:1022 and Levitt et al, J. Rheumatol. (1992) 19:1342] . The time course of PIA thus distinguishes it from other established animal models resembling RA such as adjuvant arthritis, streptococcal cell wall arthritis and collagen-induced arthritis. Histolopathologically the arthritis is characterised by cell infiltration and sy oviocyte hyperplasia with cartilage erosions and the formation of pannus [Bedwell et al, J. Immunol. (1987) 25:393, Hopkins et al, Rheumatol. Int. (1984) 5:21 and Thompson et al, Imm. Let. (1993) 36:227] .
Recent work has demonstrated that the microbial environment influences the development of PIA. Specific pathogen free (SPF) mice maintained under sterile conditions in an isolator are resistant to the development of PIA whilst the return of such animals to a conventional environment restores their susceptibility to the induction of the disease [Thompson et al, Imm. Let. (1993) 36:227] . Although the resident bowel flora differs between susceptible and refractory mice [Thompson et al, Imm. Let. (1993) 36:227], it is not known if this change affects susceptibility to the disease or indeed how exposure to microbes renders mice susceptible to the development of PIA. However, it is known that serum of mice with PIA contains raised levels of antibodies to the immunodominant mycobacterial 65kD heat shock protein (hsp65) as compared with age matched normal animals or pristane injected mice which failed to develop the disease.
It has long been recognised Chat heat shock proteins (hsp's) are immunodominant antigens in a number of infectious diseases, such as tuberculosis and leishmania. These infectious diseases can have similar abnormalities as observed in RA such as raised agalactosyl-IgG levels, the organs involved and range of autoantibodies present. Since environmental factors are clearly important in RA, microbial agents and hence hsp's were implicated.
Hsps are grouped in gene families according co their molecular weight and sequence homology within individual groups. For example, hsp60 (60KD) gene family includes members hsp65 (mycobacterial) and hsp5θ (mammalian) .
It was found that splenic T-cells from arthritic mice proliferate more vigorously in vitro in response to hsp65. than T-cells from age matched normal or non-arthritic mice. Furthermore, if the mice are immunised with hsp65 in incomplete Freud's adjuvant (IFA) prior to pristane challenge, the disease will not develop [Thompson et al, Eur. J. Immunol. (1990) 20:2479 and Thompson et al, Autoimmunity, (1991) 11:89] . This protective effect is specific to hsp65 and is not induced by the E.coli equivalent GroEl or other unrelated antigens [Thompson et al, Eur. J. Immunol. (1990) 20:2479] and cannot be attributed to antigenic competition [Barker et al, Autoimmunity. (1992) 14:73] . These findings raise the possibility that mice become sensitised to hsp by exDOsure to microbial flora in the environment and that this process is necessary for the induction of arthritis by pristane injection. If so, it would be predicted that there is a relationship between sensitisation to hsp65 and susceptibility to PIA. Experiments carried out by the applicants suggest that this hypothesis is correct.
One possibility which would explain how PIA could develop from such sensitisation is that pristane promotes an immune response to epitopes on microbial hsp65 which cross react with self (mammalian) hsp58 [Thompson et al, Imm. Let. (1993) 36:227 and Thompson et al, Eur. J. Immunol. (1990) 20:2479] . This suggestion gains credence from the fact that hsps are dominant antigens in the immune response to microorganisms, despite their extraordinarily high sequence conservation throughout the eukaryotic and prokaryotic kingdoms [Cohen et al, Immunol. Today, (1991) 12 105] . Thus, every microbial hsp is studded with self epitopes for any animal with an immune system. Moreover, they are normal constituents of all cells although their synthesis is increased by many different forms of cellular stress. Since hsp 58 has been detected in the joints of patients with RA [Karlsson-Parra et al, Scand. J. Immunol. (1990) 31:283] and T-cells from mice with PIA react with joint extracts [Thompson et al, Eur. J. Immunol. (1990) 20:2479] it seems reasonable to postulate that hsp58 could be a target antigen in the joints of mice developing PIA. This hypothesis may explain the paradox that both mice with PIA and animals protected from the development of arthritis by hps65 preim unisatiOn exhibit elevated immune responses to the 65kD mycobacterial heat shock protein. It would be expected that only mice with PIA should develop autoimmune responses to the 60kD family of hsps whereas the response of mice pre-immunised with hsp65 should be restricted to microbial specific determinants. In other words, the response elicted by immunisation with hps65 in IFA differs from that induced by sensitisation with environmental/bowel microorganisms.
T cell-mediated response to mycobacterial antigens has been implicated in the pathogenesis of inflammatory arthritis both in experimental animal models and in man. In adjuvant arthritis in rats, it has been established that the disease can be initiated by T cell clones specific for the 65-kDa mycobacterial heat-shock protein.
Rats may also be protected to subsequent adjuvant arthritis induction by pre-immunisation with either a 65 KDa specific T cell line cr with the hsp itself (Van Eden et al., Nature, 1988, 331:171 and Holoshitz et al. , Science 1983, 219:56) .
The epitope recognised by the arthritogenic T cell clone has been localized to amino acids 180-188. EP-A-322990 describes polypeptides having amino acid sequence 172-192 of a bacterial hsp 64 and their use as immunogens for inducing resistance to auto-immune disease. WO 92/04049 discloses that a peptide comprising the amino acid sequence corresponding to positions 180-186 of the Mycobacterium tuberculosis protein hsp65 is effective in the prevention and treatment of immune-related disease such as autoimmune arthritis.
Using the PIA model, it has been found (Tho oson et al. Eur. J. Immunology, 1990, 20: 2479-2484) that autoimmune reactions to an antigen which cross-reacts with hsp65 are generated in pristane-induced arthritis. Furthermore, pre-immunisation with hsp65 has been shown to protect mice from the development of pristane-induced arthritis by altering the specificity or quality of the immune response to this antigen.
On further study using the PIA model, the applicants were surprised to find that a region of the microbial protein hsp65 quite different and remote from that described in for example WO 92/04049 is effective in providing a protective response against arthritis.
In a first aspect, the present invention provides a polypeptide of up to 21 amino acid residues which comprises or consists of the sequence
VGLTLENADLSL (SEQ ID 107) or a homologue or functional equivalent or mimetic thereof. The above described polypeptide sequence corresponds to amino acids 302-314 of microbial (mycobacterial) hsp65. The invention also provides che use of such a polypeptide in the prophylaxis or treacment of auto-immune disease such as RA. 8
Most of the previous work in this area has been carried out using hsp from microbial sources since there are obvious dangers in considering the administration of 'self-antigens' in the treatment of auto-immune disease in that such antigens may increase the harmful T cell response, to the detriment of the patient.
The applicants formed a view that the role of microbial hsp's in both the induction of arthritis and protection against the disease may be due to the form of antigen presentation. Depending upon this, either TH1 cells are induced which leads to pristane induced arthritis due to determinant spreading, or TH2 cells are induced which leads to protection due to repertoire limitation. Assuming this to be correct, the mode of application of the immunogenic agent would have a considerable effect on this. Indeed, it has been shown (Thompson et al., Immunology 1993, 79 152-157) that type II collagen (another potential joint antigen) when administered orally, lowered both the incidence and severity of pristane-induced arthritis whereas intraperitoneally administered type II collagen exacerbated both.
The applicants decided to investigate whether the human homologue of microbial hsp65, hsp58, and fragments thereof may be employed in the prophylaxis or therapy of 9
RA. A trans-mucosal memorane mode of administration would preferably be employed. Full sequence information in respect of human hsp58 is known for example from Jindal et al . Mol . Cell Biol . 1989 , 9 : 2279 -2283 . It is therefore proposed that human hsp58 or fragments thereof are useful in the prophylaxis or treatment of RA.
Hence the present invention provides the use of human hsp58 or a fragment thereof containing or consisting of the amino acid sequence
VLNRLKVGLQV (SEQ ID 108 ) or a homologue or functional equivalent or mimetic thereof in the prophylaxis or treatment of auto- immune disease such as RA; and provides novel polypeptide fragments of up to 21 amino acid residues , per se .
It is believed by analogy with work carried out using microbial hsp65 ; that the region of hsp58 containing amino acid residues corresponding to 261-271 of hsp65 is important for this application.
This region is a non-conserved region and is mammalian specific . This means that the region will not cross - react with the bacterial form of the protein and administered transmucosally, would induce T-cell tolerance to it and thus prevent arthritis .
Hence the present invention further provides a polypeptide of up to 21 amino acid residues comprising or consisting of the sequence
VLNRLKVGLQV (SEQ ID 108)
or a homologue or functional equivalent or mimetic thereof.
Examples of such polypeptides include fragments of human hsp58 protein, in particular those including the amino acid residues corresponding to 271-257 of hsp65 or homologues thereof; i.e. the amino acid sequence
DVDGEALSTLVLNRLKV (SEQ ID 109)
A particularly preferred polypeptide will consist only of the amino acids VLNRLKVGLQV.
It is believed by analogy with work carried out using microbial hsp65, that the region of hsp58 containing amino acid residues corresponding to 302-314 of hsp65 is also important for this application. This region is also a non- conserved region and is mammalian specific.
The present invention further provides the use of human hsp58 fragment containing or consisting of the amino acid sequence
LTLNLEDVQPHD (SEQ ID 110) or a homologue or functional equivalent or mimetic thereof in the prophylaxis or treatment of auto-immune disease such as RA; and provides novel polypeptide fragments of up to 21 amino acid residues, per se. Hence the invention further provides a polypeptide of up to 21 amino acid residues comprising or consisting of the sequence
LTLNLEDVQPHD (SEQ ID 110 ) or a homologue or functional equivalent or mimetic thereof .
A parcicularly preferred polypeptide will consist only of the amino acids
LTLNLEDVQPHD
The polypeptides of the invention have been found to have a prophylactic or therapeutic effect when applied immunogenically in the treatment of RA .
Hence the invention further provides a vaccine for the prophylactic or therapeutic treatment of RA which vaccine comprises a polypeptide as described above . For use in the treatment , the polypeptide is suitably administered in a trans -mucosal membrane manner for example , orally or nasally . Alternatively the polypeptide may be formulated as a suppository .
Administration in this way should cause the polypeptide to act in a prophylactic or therapeutic way to reduce the symptoms of RA. The mechanism by which this effect is produced is not understood . It is possible that these polypeptides act as non-specific dσwnregulatcrs of the immune resnonse . The mechanism of oral tolerance has not been fully elucidated but antigen-driven bystander suppression after oral administration of antigens has been proposed (Miller et al., J. Exp. Med. (1991) 144 791-798) .
The polypeptides of the invention are suitably administered in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier or excipient. Such compositions form a further aspect of the invention.
Suitable carriers include solid or liquid carriers. Examples of formulations including solid carriers include tablets or suspensions for oral administration or suppositories. Suitable liquid carriers include oils or water. The compositions may be adapted for nasal administration by inhalers, atomizers or sprays as are available in the art.
In suitable circumstances it may be desirable or necessary to administer the polypeptide, or a pharmaceutical composition including the polypeptide, parenterally, for example sub¬ cutaneously, intramuscularly, intravenously or intra peritoneally.
The polypeptides of the invention can be produced using various techniques which would be apparent to the skilled person. For example, they may be obtained by fragmentation of human hsp58 using conventional techniques after which the desired fragments obtained by purification, again using techniques which are known in the art. However peptides obtained by this method are less likely to have the precisely the desired length.
Alternatively, the polypeptides may be obtained using recombinant DNA technology. The nucleotide sequence encoding the desired polypeptide can be incorporated into a suitable host using a vector system which causes expression of the polypeptide.
Preferably however, polypeptides sequences may be generated entirely synthetically using standard chemical methods or peptide synthesizers available in the art.
As used herein, the expression 'homologue' refers to peptides having an amino acid sequence which is are at least 60%, preferably 70 and most preferably at least 80V homologous tc the described polypeptide. The expression 'functional equivalent' or 'mimetic' relates to any chemical, which may be a peptide or other organic chemical which produces similar effects in vivo to the compounds of the present invention. In particular, such compounds will produce a protective immunogenic response against RA when applied in pristane-induced arthritis model using tests as described in the examples hereinafter. The observations and deductions which led to the present invention will now be outlined with reference to the accompanying drawings in which:
Figure 1 is the peptide library comprising eleven pools of overlapping peptides corresponding to the entire sequence of microbial hsp65. (SEQ IDs Nos. 1-106)
Figure 2 shows a comparison of the proliferative response of T cells from each of 6 arthritic mice (top panel) , 6 protected mice (middle panel) and 6 normal mice (n-6) to the eleven pools of overlapping peptides defined in Figure 1;
Figure 3 shows the results of studies to determine the protection against PIA of mice pre-immunised with microbial hsp65 polypeptides;
Figure 4 shows the entire amino acid sequence of human hsp58 (top line) in corresponding relationship to the entire sequence of microbial hsp65 (lower line) ; (SEQ IDs Nos. 107-109)
Figure 5 shows the sequences and % homology of 5 peptides in the region hsp65 m 251-312 and the corresponding sequences of hsp58; (SEQ IDs Nos. 110-117) 15
Figure 6 shows the therapeutic effect of immunisation with polypeptides of the invention at 60 days post pristane injection (D=60) ; and
Figure 7 shows the prophylactic effect of pre-immunisation with polypeptides of the invention at 10 days prior to pristane injection (D---10) .
Experiment 1
Proliferation of T cells in-vi tro from PIA mice, hsp65 protected mice and normal age-matched mice.
Animals. Male CBA/Igb mice aged between 4 and 8 weeks were used unless otherwise specified. CBA/Igb mice were obtained by back-crossing (101 strain x CBA) Fl hybrids to CBA mice and selecting those mice with Igb allotype in their serum.
Arthri is induction by pristane . One group of six mice were immunised intraperitoneally with 50 micrograms of mycobacterial hsp65 administered as an emulsion in incomplete Freuds adjuvant (IFA) . This group formed the protected group of mice. After ten days, this group and a further group of 6 mice received two intraperitoneal injections of 0.5ml of pristane 50 days apart (Aldrich Chemical Co., Milwaukee, WIJ in order to induce arthritis. A final group of 'normal' mice were maintained as controls.
Synthetic peptides used as antigens in iiτt unisa tion studies . A library consisting of 106 overlapping peptides, -representing the complete sequence of microbial hsp65, of between 15 and 19 amino acids in length, was synthesised using a simultaneous multiple-peptide solid phase synthetic method [Houghton R.A. Proc. Natl. Acad. Sci. USA. (1985) 82:5131] using a polyamide resin [Arshady et al, J. Chem. Soc. Perkin Trans. (1981) 1.529] and FMOC chemistry. The complete library is shown in Figure 1. Completed peptides were extracted from the resin using trifluoroacetic acid and suitable scavengers, and isolated by solvent evaporation and precipitation with methanol and diethylether. Purity was checked by amino acid analysis and by HPLC. Irrelevant control antigens BSA and human IgG were also used along with the mitogen ConA.
Eleven antigens were prepared, each comprising a pool of the groups of polypeptides, set out in Figure 1 as groups 1-11.
Preparation of T-cells and APC for cul ture . After 200 days, spleens of individual mice were aseptically removed and single cell suspensions made in a Petri dish containing RPMI-1540 medium supplemented with 20mM HEPES (pH 7.2, Flow Labs) . Erythrocytes were removed by 17 treating the spleen cells wich 0.83V (w/v) NH4C1 solution buffered with Tris (pH 7.2) . After washing, cells were suspended in RPMI-1S40 HEPES at 1.25 x 107cells/ml. Responder T cells were enriched according to the panning method of Engleman et al [Engleman et al. J. Immunol. (1981) 127:2124] . Briefly, 10cm diameter Petri dishes (Sterilin Ltd., Hounslow, GB) were coated with 5ml of 0.5 mg/ml mouse γ-globulin in PBS at room temperature for 2 hrs. After washing once with PBS, Petri dishes were incubated with 5ml of a 1/100 dilution of rabbit anti- mouse Ig serum at 4°C overnight. After washing, 8ml of the spleen cell suspensions (lxlO'cells) were poured into the mouse Ig-rabbit anti-mouse Ig coated Petri dishes and incubated at room temperature for 40 mins. The nonadherent cells were then gently aspirated followed by washing with medium. These cells were then used as the T cell enriched fractions. A purity of .85V was achieved as assessed by anti-Thy 1.2 staining using flow cytometry (FACScan, Becton Dickinson Ltd. , Oxford, GB) . Normal mouse spleen cells were used as antigen presenting cells. In these experiments the APC were irradiated 1000 rads from a caesium source (Gravatom Industries, Gosport, GB) .
Culture and assay of prolifera ion . This was carried out as described in Thompson et al. , supra. The medium employed was alpha modification of Eagle's medium (alpha MEM) (Flow) supplemented with 4mM L-glutamine (Flow) , lOOU/ml benzyl penicillin (Glaxo Ltd., Green ford, GB) , lOOμg/ml streptomycin sulphate (Evans Medical Ltd., Greenford, GB) , 5 x 10" SM2-mercaptoethanol (Sigma) , 20 mM HEPES and 0.5V fresh normal mouse serum. The cultures consisted of 1.25 x 10s purified splenic T-cells plus 1.25 x 10s APC per ml, in a volume of 2ml in a 24 well plate (Flow) in the presence or absence of the various antigens 92.5-10μg/ml). Alternatively, some cultures were set up in a volume of 200μl in round bottom 96 well plates (Flow) . All cultures were incubated at 37°C in a humidified atmosphere of 5V C02 and 95V air.
After the periods of incubation indicated, triplicate lOOmicrolitre samples of each of the 2 ml cultures were transferred to 96 well, round bottom culture plates (Flow) and pulsed with 2mCi of 3H-Thymidine (specific activity 70-85 Ci/tπMol; Amersham International Ltd., Amersham, GB) per well for 6 hours. The cells were then harvested onto glass fibre filter mats (Whatman Ltd., Maidstone, GB) using a multiple sample harvester (Skatron AS, Lier, Norway) and the 3H-Thymidine incorporated into newly synthesized DNA measured using conventional liquid scintillation procedures with a LKB rackbeta counter (LKB-Wallac Ltd., Pharmacia, Uppsala, Sweden) . The results are presented (Figure 2) as stimulation indices (S.I.= cpm test divided by cpm control without antigen). Positive stimulation resulted in maximal 3H-Thymidine uptake of -30,000 counts per minute. Experiment 2
Protection of mice against PIA by immunisation with microbial Hsp65 fragments
AniπΛals . Male CBA/Igb mice aged between 4 and 8 weeks as described in Experiment 1 were used unless otherwise specified.
Immunisation of animals . Groups of mice were immunised intraperitoneally 10 days before pristane challenge as follows :
:cup No. pre-immunisatio: polypeptide
21 (6 weeks old)
21 (10 weeks old)
21 polypeptide corresponding to amino acids 302-314 of microbial hsp 65
15 whole microbial hsp65
50 Micrograms of each polypeptide was administered as an emulsion in IFA. The polypeptide fragment used in the pre-immunisation of group 3 was manufactured by Cambridge Research Biochemicals of Northwich, Cheshire UK.
Arthritis induction by pristane. Arthritis was then induced as described in Experiment 1 by two intraperitoneal injections of 0.5ml of pristane 50 days apart. The -animals were examined for the incidence of arthritis in the ankle joints at various time points. The final incidence was assessed 200 days post pristane injection. The arthritis was assessed by measuring the ankle joints with a micrometer. In C3A/Igb mice the swollen joints ranged in size from 3.0-4.0mm compared with normal joints which had a range from 2.5-2.8mm. However, this difference could easily be distinguished, and in most experiments the joints were assessed visually, arthritis being scored at present or absent [Thompson et al, Eur. J. Immunol. (1990) 20:2479 and Barker et al, Autoimmunity. (1992) 14:73] .
The percentage of animals in each group which developed arthritis after a period of 200 days is shown in Figure 3. It is clear that the peptide region corresponding to 302-314 of hsp65 generates an improved protective effect against RA in mice than when whole hsp65 is applied and confirms that this sequence, which is
VGLTLENADLSL is effective in producing a beneficial effect.
The present inventors have shown in a co-pending application that amino acids 261-271 of microbial hsp65 can be useful in prophylaxis or treatment of auto-immune disease.
In view of the above-mentioned results it is clear that another region of microbial hsp65 which can effectively be used in an immunisation programme is that corresponding to amino acids 302-314 in the sequence. On looking at the corresponding regions of the human homologue hsp58 which, as mentioned above, is non-conserved and so will not cross-react with microbial hsp65, it appears that these will also have a useful effect, providedthey can be administered in a 'safe' manner. By analogy with the work using type II collagen, it would seem that administration using a trans-mucosal membrane route, such as oral or nasal application could be appropriate.
To assist comparison between the amino acid sequence of microbial hsp65 (Figure 1) and the sequence of human hsp58, Figure 4 shows the two complete sequences in corresponding alignment, with hspSΘ above hspδS. Note that the numbering of hsp65 amino acids is used herein. References herein to amino acid sequence numbers for human fragments (from hsp58) are the numbers of the corresponding hsp60 sequence region. Thus, for example, reference herein to human hsp58 region h 261-271 corresponds to microbial m 261-271 but is, in fact, amino acid 287-297 of the upper sequence of Figure 4. Likewise, h 302-314 corresponds to m 302-314 but is, in fact amino acids 330-341 of the upper sequence of Figure 4.
In order to highlight the non-conserved nature of the regions 261-271 and m 302-314 in comparison to the corresponding regions of the human hsp58 sequence, Figure 5 tabulates the V homology of 5 sequences of the complete region covered by hsp65 m 251-312.
Example 1
Protection of mice against PIA by oral immunisation with human hsp58 fragment.
The eleven amino acid polypeptide of sequence VLNRLKVGLQV (h 261-271) :SEQ ID 108) was prepared for use in the Example by Cambridge Research Biochemicals, Gadbrook Par, Nothwich,
Cheshire, UK. This polypeptide can then be used to demonstrate the invention using the following methods.
Male CBA/Igb mice aged between 4 and 8 weeks are suitably used. Arthritis can be induced by two intraperitoneal injections of 0.5ml of pristane 50 days apart as described above. Mice which are to be subjected to an immunisation regime are given oral doses of polypeptide dissolved in saline, administered orally with 23
the aid of a rigid cannula inserted via the oesoohagus directly into the stomach. Each animal should receive a single dose on 5 consecutive days (up to and including the day of challenge with pristane) of 50 micrograms of polypeptide.
The mice can be examined visually for the incidence of arthritis in the tarsal (ankle) joints at various time points. This may be assessed for example using a micrometer and comparing enlarged joints with normal joints. In this way, the protective effect of the polypeptide can be demonstrated.
Suitably the experiment is terminated 200 days after pristane injection. After death, stifle (knee) joints may be dissected out, fixed in neutral-buffered formalin and decalicified. If longitudinal sections are prepared and stained with haematoxylin and eosin, arthritis may be further assessed, for example by a veterinary pathologist. Suitably the assessment is carried out blind and joint changes graded according to the following system:
0 . Normal .
1. Synovial hyperplasia with pannus formation and mild inflammation (polymorphonuclear leucocytes-PMN) or non-inflammatory mild articular cartilage degeneration.
2. Articular cartilage degeneration with synovial hyperplasia and pannus formation. Moderate to severe inflammation (PMN and macrophages) .
3. Articular cartilage degeneration with synovial hyperplasia and pannus formation. Severe inflammation (PMN and macrophages) . Significant inflammation in joint space with PMN, macrophages and debris.
In addition, a proliferative T-cell assay may be carried out as described in Experiment 1 above which will further confirm the effectiveness of this polypeptide.
Example 2
Protection of mice against PIA by nasal immunisation with human hso65 fragment. Example 1 may be repeated except that instead of oral administration, the polypeptide is given nasally. For this purpose, the animal is first anaesthetized and then laid on its back. A 50 microlitre drop of solution containing 50micrograms of the polypeptide described in Example 1 are then placed on the nostrils. As soon as the animal becomes conscious, the drop is rapidly inhaled. This procedure is repeated five times on five consecutive days in the same way as the oral dosing described in Example 1.
Monitoring of the animals may be carried out in the same way as described above, whereupon a protective effect is shown.
Figure 6 shows the therapeutic effect of administration of polypeptides according to the invention 60 days after first administration of pristane. 50 milligrams of peptide was administered ip as an emulsion IFA to each mouse at day 60. This was after two pristane injections, 50 days apart, one at day 0 and one at day 50. This timing is judged to be just prior to the development/onset phase of PIA. The percentage arthritis was assessed by visual scoring with the assessment being made at the 210th day (D-210) . As can be seen from the figure, each of the peptides according to the invention produces a reduction in percentage arthritis in comparison to the control (IPP only) . Figure 7 shows the prophylactic effect of pre-immunisation with peptides according to the invention 10 days prior to the first pristane injection. From these results it appears that h 261-271 may actually increase the incidence of PIA whereas h 302-314 may have little or no effect reduction of arthritis. However, m 302-314 clearly appears to give a significant reduction or nearly 4 fold in the percentage arthritis.
These data indicate that some polypeptides of the invention may be useful prophylaxis, some may be useful in treatment, and some may have both prophylactic and therapeutic activity although not all polypeptides of the invention are expected to show both activities.
SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT:
(A) NAME: PEPTIDE THERAPEUTICS LIMITED
(B) STREET: 321 CAMBRIDGE SCIENCE PARK
(C) CITY: CAMBRIDGE
(D) STATE: CAMBRIDGE
(E) COUNTRY: ENGLAND
(F) POSTAL CODE (ZIP) : CB4 4WG
(G) TELEPHONE: 01223 423333 (H) TELEFAX: 01223 423111
(ii) TITLE OF INVENTION: Polypeptides and their use in the Treatment and Prophylaxis of Auto-immune Disease
(iii) NUMBER OF SEQUENCES: 117
(iv) COMPUTER READABLE FORM:
(A) MEDIUM TYPE: Floppy disk
(B) COMPUTER: IBM PC compatible
(C) OPERATING SYSTEM: PC-DOS/MS-DOS
(D) SOFTWARE: Patentin Release #1.0, Version #1.30 (EPO)
(2) INFORMATION FOR SEQ ID NO: 1:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
( i) SEQUENCE DESCRIPTION: SEQ ID NO: 1:
Met Ala Lys Thr lie Ala Tyr Asp Glu Glu Ala Arg Arg Gly Leu 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 2:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid (C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2:
Ala Tyr Asp Glu Glu Ala Arg Arg Gly Leu Glu Arg Gly Leu Asn Ser 1 5 10 15
Leu
(2) INFORMATION FOR SEQ ID NO: 3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3:
Ala Arg Arg Gly Leu Glu Arg Gly Leu Asn Ser Leu Ala Asp Ala Val
1 5 10 15
Lys
(2) INFORMATION FOR SEQ ID NO: 4:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4 Glu Arg Gly Leu Asn Ser Leu Ala Asp Ala Val Lys Val Thr Leu Gly 1 5 10 15
Pro Lys Gly
(2) INFORMATION FOR SEQ ID NO: 5:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5:
Ser Leu Ala Asp Ala Val Lys Val Thr Leu Gly Pro Lys Gly Arg Asn 1 5 10 15
Val
(2) INFORMATION FOR SEQ ID NO: 6:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6:
Val Lys Val Thr Leu Gly Pro Lys Gly Arg Asn Val Val Leu Glu Lys 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 7:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid (C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7:
Gly Pro Lys Gly Arg Asn Val Val Leu Glu Lys Lys Trp Gly Ala 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 8:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8:
Asn Val Val Leu Glu Lys Lys Trp Gly Ala Pro Thr He Thr Asn Asp 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 9:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
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(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9:
Lys Lys Trp Gly Ala Pro Thr He Thr Asn Asp Gly Val Ser He 1 5 10 15
[ 2 ) INFORMATION FOR SEQ ID NO: 10: (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10:
Pro Thr He Thr Asn Asp Gly Val Ser He Ala Lys Glu He Glu Leu 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 11:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
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(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11:
Asp Gly Tyr Ser He Ala Lys Glu He Glu Leu Glu Asp Pro Tyr Glu 1 5 10 15
Lys
(2) INFORMATION FOR SEQ ID NO: 12:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 12 :
Ala Lys Glu He Glu Leu Glu Asp Pro Tyr Glu Lys He Gly Ala Glu 1 5 10 15
Leu Val Lys
(2) INFORMATION FOR SEQ ID NO: 13:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE.: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13:
Leu Glu Asp Pro Tyr Glu Lys He Gly Ala Glu Leu Val Lys Glu Val 1 5 10 15
Ala Lys
(2) INFORMATION FOR SEQ ID NO: 14:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14:
Glu Lys He Gly Ala Glu Leu Val Lys Glu Val Ala Lys Lys Thr Asp 1 5 10 15
Asp Val Ala
(2 ) INFORMATION FOR SEQ ID NO : 15 : (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15:
Glu Leu Val Lys Glu Val Ala Lys Lys Thr Asp Asp Val Ala Gly Asp 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 16:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16:
Val Ala Lys Lys Thr Asp Asp Val Ala Gly Asp Gly Thr Thr Thr Ala 1 5 10 15
Thr Val Leu
(2) INFORMATION FOR SEQ ID NO: 17:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: 1inear
(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17:
Asp Asp Val Ala Gly Asp Gly Thr Thr Thr Ala Thr Val Leu Ala Gin 1 5 10 15
Ala Leu Val
(2) INFORMATION FOR SEQ ID NO: 18:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18:
Asp Gly Thr Thr Thr Ala Thr Val Leu Ala Gin Ala Leu Val Lys Glu 1 5 10 15
Gly Leu
(2) INFORMATION FOR SEQ ID NO: 19:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19:
Gin Ala Leu Val Lys Glu Gly Leu Arg Asn Val Ala Ala Gly Ala Asn
1 5 10 15
Pro Leu Gly
(2) INFORMATION FOR SEQ ID NO: 20 (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20:
Glu Gly Leu Arg Asn Val Ala Ala Gly Ala Asn Pro Leu Gly Leu Lys 1 5 10 15
Arg Gly
(2) INFORMATION FOR SEQ ID NO: 21:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21:
Val Ala Ala Gly Ala Asn Pro Leu Gly Leu Lys Arg Gly He Glu Lys 1 5 10 15
Ala
(2) INFORMATION FOR SEQ ID NO: 22:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22:
Asn Pro Leu Gly Leu Lys Arg Gly He Glu Lys Ala Val Asp Lys Val 1 5 10 15
[2) INFORMATION FOR SEQ ID NO: 23:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
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(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23:
Lys Arg Gly He Glu Lys Ala Val Asp Lys Val Thr Glu Thr Leu 1 5 10 15
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(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
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Lys Ala Val Asp Lys Val Thr Glu Thr Leu Leu Lys Asp Ala Lys 1 5 10 15
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(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
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Val Thr Glu Thr Leu Leu Lys Asp Ala Lys Glu Val Glu Thr Lys 1 5 10 15
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(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
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Leu Lys Asp Ala Lys Glu Val Glu Thr Lys Glu Gin He Ala Ala 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 27:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27:
Glu Val Glu Thr Lys Glu Gin He Ala Ala Thr Ala Ala He Ser Ala 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 28:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids (B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
( i) SEQUENCE DESCRIPTION: SEQ ID NO: 28:
Gin He Ala Ala Thr Ala Ala He Ser Ala Gly Asp Gin Ser He Gly 1 - 5 10 15
Asp
(2) INFORMATION FOR SEQ ID NO: 29:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 29:
Thr Ala Ala He Ser Ala Gly Asp Gin Ser He Gly Asp Leu He 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 30:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30: Ala Gly Asp Gin Ser He Gly Asp Leu He Ala Glu Ala Met Asp Lys 10 15
Val Gly
[ 2 ) INFORMATION FOR SEQ ID NO: 31:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31:
He Gly Asp Leu He Ala Glu Ala Met Asp Lys Val Gly Asn Glu Gly 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 32:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
[ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32:
Ala Glu Ala Met Asp Lys Val Gly Asn Glu Gly Val He Thr Val 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 33:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33:
Lys Val Gly Asn Glu Gly Val He Thr Val Glu Glu Ser Asn Thr Phe 1 5 10 15
Gly Leu
(2) INFORMATION FOR SEQ ID NO: 34:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
( ii) MOLECULE TYPE : peptide
(xi) SEQUENCE DESCRIPTION : SEQ ID NO : 34 :
Gly Val He Thr Val Glu Glu Ser Asn Thr Phe Gly Leu Gin Leu 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 35:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35:
Glu Glu Ser Asn Thr Phe Gly Leu Gin Leu Glu Leu Thr Glu Gly
1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 36:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids (B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36:
Phe Gly Leu Gin Leu Glu Leu Thr Glu Gly Met Arg Phe Asp Lys Gly 1 * 5 10 15
(2) INFORMATION FOR SEQ ID NO: 37:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37:
Glu Leu Thr Glu Gly Met Arg Phe Asp Lys Gly Tyr He Ser Gly 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 38:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
( ii ) MOLECULE TYPE : peptide
(xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 38 :
Met Arg Phe Asp Lys Gly Tyr He Ser Gly Tyr Phe Val Thr Asp Ala
1 5 10 15 (2) INFORMATION FOR SEQ ID NO: 39:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39:
Gly Tyr He Ser Gly Tyr Phe Val Thr Asp Ala Glu Arg Gin Glu Ala 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 40:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 40:
Tyr Phe Val Thr Asp Ala Glu Arg Gin Glu Ala Val Leu Glu Glu Pro
1 5 10 15
Tyr He
(2) INFORMATION FOR SEQ ID NO: 41:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41:
Ala Glu Arg Gin Glu Ala Val Leu Glu Glu Pro Tyr He Leu Leu 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 42:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42:
Ala Val Leu Glu Glu Pro Tyr He Leu Leu Val Ser Ser Lys Val Ser 1 5 10 15
Thr Val Lys
(2) INFORMATION FOR SEQ ID NO: 43:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43:
Pro Tyr He Leu Leu Val Ser Ser Lys Val Ser Thr Val Lys Asp 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 44:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44:
Val Ser Ser Lys Val Ser Thr Val Lys Asp Leu Leu Pro Leu Leu Glu 1 5 10 15
Lys Val
(2) INFORMATION FOR SEQ ID NO: 45:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45:
Ser Thr Val Lys Asp Leu Leu Pro Leu Leu Glu Lys Val He Gin Ala 1 5 10 15
Gly Lys
(2) INFORMATION FOR SEQ ID NO: 46:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46 Leu Leu Pro Leu Leu Glu Lys Val He Gin Ala Gly Lys Ser Leu Leu 1 5 10 15
He He Ala
(2) INFORMATION FOR SEQ ID NO: 47:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47:
Glu Lys Val He Gin Ala Gly Lys Ser Leu Leu He He Ala Glu Asp 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 48:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48:
Ala Gly Lys Ser Leu Leu He He Ala Glu Asp Val Glu Gly Glu Ala 1 5 10 15
Leu
(2) INFORMATION FOR SEQ ID NO: 49:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid (C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49:
Leu He He Ala Glu Asp Val Glu Gly Glu Ala Leu Ser Thr Leu 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 50:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50:
Asp Val Glu Gly Glu Ala Leu Ser Thr Leu Val Val Asn Lys He Arg 1 5 10 15
Gly
(2) INFORMATION FOR SEQ ID NO: 51:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
( ii) MOLECULE TYPE : peptide
( i ) SEQUENCE DESCRIPTION : SEQ ID NO : 51 :
Val Val Asn Lys He Arg Gly Thr Phe Lys Ser Val Ala Val Lys Ala
1 5 10 15 (2) INFORMATION FOR SEQ ID NO: 52:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52:
Arg Gly Thr Phe Lys Ser Val Ala Val Lys Ala Pro Gly Phe Gly Asp 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 53:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 53:
Ser Val Ala Val Lys Ala Pro Gly Phe Gly Asp Arg Arg Lys Ala Met 1 5 10 15
Leu Gin Asp
(2) INFORMATION FOR SEQ ID NO: 54:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 54 :
Ala Pro Gly Phe Gly Asp Arg Arg Lys Ala Met Leu Gin Asp Met Ala 1 5 10 15
He
(2) INFORMATION FOR SEQ ID NO: 55:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 55:
Asp Arg Arg Lys Ala Met Leu Gin Asp Met Ala He Leu Thr Gly Ala 1 5 10 15
Gin Val
(2) INFORMATION FOR SEQ ID NO: 56:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56:
Met Leu Gin Asp Met Ala He Leu Thr Gly Ala Gin Val He Ser Glu 1 5 10 15
Glu Val Gly (2) INFORMATION FOR SEQ ID NO: 57:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57:
Ala He Leu Thr Gly Ala Gin Val He Ser Glu Glu Val Gly Leu 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 58:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
( ii ) MOLECULE TYPE : peptide
(xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 58 :
Ala Gin Val He Ser Glu Glu Val Gly Leu Thr Leu Glu Asn Thr Asp 1 5 10 15
Leu
(2) INFORMATION FOR SEQ ID NO: 59:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide ( i) SEQUENCE DESCRIPTION: SEQ ID NO: 59:
Glu Glu Val Gly Leu Thr Leu Glu Asn Thr Asp Leu Ser Leu Leu 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 60:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 60:
Thr Leu Glu Asn Thr Asp Leu Ser Leu Leu Gly Lys Ala Arg Lys 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 61:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61:
Asp Leu Ser Leu Leu Gly Lys Ala Arg Lys Val Val Met Thr Lys 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 62:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide (xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 62 :
Gly Lys Ala Arg Lys Val Val Met Thr Lys Asp Glu Thr Thr He Val 1 5 10 15
Glu Gly
[2) INFORMATION FOR SEQ ID NO: 63:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63:
Val Val Met Thr Lys Asp Glu Thr Thr He Val Glu Gly Ala Gly 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 64:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
( i) SEQUENCE DESCRIPTION: SEQ ID NO: 64:
Asp Glu Thr Thr He Val Glu Gly Ala Gly Asp Thr Asp Ala He Ala 1 5 10 15
Gly
(2) INFORMATION FOR SEQ ID NO: 65: (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65:
Val Glu Gly Ala Gly Asp Thr Asp Ala He Ala Gly Arg Val Ala 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 66:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii ) MOLECULE TYPE : peptide
(Xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 66 :
Asp Thr Asp Ala He Ala Gly Arg Val Ala Gin He Arg Thr Glu He
1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 67:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67: Ala Gly Arg Val Ala Gin He Arg Thr Glu He Glu Asn Ser Asp 10 15
(2) INFORMATION FOR SEQ ID NO: 68:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
( ii ) MOLECULE TYPE : peptide
(xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 68 :
Gin He Arg Thr Glu He Glu Asn Ser Asp Ser Asp Tyr Asp Arg Glu 1 5 10 15
Lys Leu
(2) INFORMATION FOR SEQ ID NO: 69:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69:
He Glu Asn Ser Asp Ser Asp Tyr Asp Arg Glu Lys Leu Gin Glu Arg 1 5 10 15
Leu
(2) INFORMATION FOR SEQ ID NO: 70:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 70:
Ser Asp Tyr Asp Arg Glu Lys Leu Gin Glu Arg Leu Ala Lys Leu
Figure imgf000056_0001
(2) INFORMATION FOR SEQ ID NO: 71:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 71:
Glu Lys Leu Gin Glu Arg Leu Ala Lys Leu Ala Gly Gly Val Ala Val 1 5 10 15
He Lys
(2) INFORMATION FOR SEQ ID NO: 72:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
( ii ) MOLECULE TYPE : peptide
(xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 72 :
Arg Leu Ala Lys Leu Ala Gly Gly Val Ala Val He Lys Ala Gly 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 73: (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73:
Ala Gly Gly Val Ala Val He Lys Ala Gly Ala Ala Thr Glu Val 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 74:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 74:
Val He Lys Ala Gly Ala Ala Thr Glu Val Glu Leu Lys Glu Arg Lys 1 5 10 15
His Arg He
(2) INFORMATION FOR SEQ ID NO: 75:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 75 Ala Ala Thr Glu Val Glu Leu Lys Glu Arg Lys His Arg He Glu Asp 1 5 10 15
Ala
(2) INFORMATION FOR SEQ ID NO: 76:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 76:
Glu Leu Lys Glu Arg Lys His Arg He Glu Asp Ala Val Arg Asn Ala 1 5 10 15
Lys
(2) INFORMATION FOR SEQ ID NO: 77:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77:
Lys His Arg He Glu Asp Ala Val Arg Asn Ala Lys Ala Ala Val Glu 1 5 10 15
Glu Gly
(2) INFORMATION FOR SEQ ID NO: 78: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 78:
Asp Ala Val Arg Asn Ala Lys Ala Ala Val Glu Glu Gly He Val Ala 1 5 10 15
Gly
(2) INFORMATION FOR SEQ ID NO: 79:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79:
Ala Lys Ala Ala Val Glu Glu Gly He Val Ala Gly Gly Gly, Val 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 80:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 80 Glu Glu Gly He Val Ala Gly Gly Gly Val Thr Leu Leu Gin Ala Ala 1 5 10 15
Pro Ala Leu
(2) INFORMATION FOR SEQ ID NO: 81:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 81:
Ala Gly Gly Gly Val Thr Leu Leu Gin Ala Ala Pro Ala Leu Asp Lys 1 5 10 15
Leu
(2) INFORMATION FOR SEQ ID NO: 82:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
( i) SEQUENCE DESCRIPTION: SEQ ID NO: 82:
Thr Leu Leu Gin Ala Ala Pro Ala Leu Asp Lys Leu Lys Leu Thr Gly 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 83:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid (C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 83:
Ala Pro Ala Leu Asp Lys Leu Lys Leu Thr Gly Asp Glu Ala Thr Gly 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 84:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 84:
Lys Leu Lys Leu Thr Gly Asp Glu Ala Thr Gly Ala Asn He Val Lys 1 5 10 15
Val Ala
(2) INFORMATION FOR SEQ ID NO: 85:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 85: Gly Asp Glu Ala Thr Gly Ala Asn He Val Lys Val Ala Leu Glu Ala 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 86:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 86:
Gly Ala Asn He Val Lys Val Ala Leu Glu Ala Pro Leu Lys Gin He 1 5 10 15
Ala
(2) INFORMATION FOR SEQ ID NO: 87:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 87:
Lys Val Ala Leu Glu Ala Pro Leu Lys Gin He Ala Phe Asn Ser Gly 1 5 10 15
[ 2 ) INFORMATION FOR SEQ ID NO: 88:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 88:
Ala Pro Leu Lys Gin He Ala Phe Asn Ser Gly Met Glu Pro Gly Val 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 89:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 89:
He Ala Phe Asn Ser Gly Met Glu Pro Gly Val Val Ala Glu Lys Val 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 90:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 90:
Gly Met Glu Pro Gly Val Val Ala Glu Lys Val Arg Asn Leu Ser Val 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 91: (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 91:
Val Val Ala Glu Lys Val Arg Asn Leu Ser Val Gly His Gly Leu 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 92:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 92:
Val Arg Asn Leu Ser Val Gly His Gly Leu Asn Ala Ala Thr Gly 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 93:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 93:
Val Gly His Gly Leu Asn Ala Ala Thr Gly Glu Tyr Glu Asp Leu 1 5 10 15 (2) INFORMATION FOR SEQ ID NO: 94:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 94:
Asn Ala Ala Thr Gly Glu Tyr Glu Asp Leu Leu Lys Ala Gly Val Ala 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 95:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 95:
Glu Tyr Glu Asp Leu Leu Lys Ala Gly Val Ala Asp Pro Val Lys Val 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 96:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 96:
Leu Lys Ala Gly Val Ala Asp Pro Val Lys Val Thr Arg Ser Ala Leu 1 5 10 15
[2) INFORMATION FOR SEQ ID NO: 97:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 19 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
( i) SEQUENCE DESCRIPTION: SEQ ID NO: 97:
Ala Asp Pro Val Lys Val Thr Arg Ser Ala Leu Gin Asn Ala Ala Ser 1 5 10 15
He Ala Gly
(2) INFORMATION FOR SEQ ID NO: 98:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 98:
Val Thr Arg Ser Ala Leu Gin Asn Ala Ala Ser He Ala Gly Leu 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 99:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 99:
Leu Gin Asn Ala Ala Ser He Ala Gly Leu Phe Leu Thr Thr Glu Ala 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 100:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 100:
Ser He Ala Gly Leu Phe Leu Thr Thr Glu Ala Val Val Ala Asp 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 101:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 101:
Phe Leu Thr Thr Glu Ala Val Val Ala Asp Lys Pro Glu Lys Thr Ala 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 102 (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 102:
Ala Val Val Ala Asp Lys Pro Glu Lys Thr Ala Ala Pro Ala Ser Asp 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 103:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 103:
Lys Pro Glu Lys Thr Ala Ala Pro Ala Ser Asp Pro Thr Gly Gly 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 104:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 104: Ala Ala Pro Ala Ser Asp Pro Thr Gly Gly Met Gly Gly Met Asp Phe 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 105:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 573 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 105:
Met Leu Arg Leu Pro Thr Val Phe Arg Gin Met Arg Pro Val Ser Arg 1 5 10 15
Val Leu Ala Pro His Leu Thr Arg Ala Tyr Ala Lys Asp Val Lys Phe 20 25 30
Gly Ala Asp Ala Arg Ala Leu Met Leu Gin Gly Val Asp Leu Leu Ala 35 40 45
Asp Ala Val Ala Val Thr Met Gly Pro Lys Gly Arg Thr Val He He 50 55 60
Glu Gin Ser Trp Gly Ser Pro Lys Val Thr Lys Asp Gly Val Thr Val 65 70 75 80
Ala Lys Ser He Asp Leu Lys Asp Lys Tyr Arg Asn He Gly Ala Lys
85 90 95
Leu Val Gin Asp Val Ala Asn Asn Thr Asn Glu Glu Ala Gly Asp Gly 100 105 110
Thr Thr Thr Ala Thr Val Leu Ala Arg Ser He Ala Lys Glu Gly Phe 115 120 125
Glu Lys He Ser Lys Gly Ala Asn Pro Val Glu He Arg Arg Gly Val 130 135 140
Met Leu Ala Val Asp Ala Val He Ala Glu Leu Lys Lys Gin Ser Lys 145 150 155 160
Pro Val Thr Thr Pro Glu Glu He Ala Gin Val Ala Thr He Ser Ala
165 170 175 Asn Gly Asp Lys Glu He Gly Asn He He Ser Asp Ala Met Lys Lys 180 185 190
Val Gly Arg Lys Gly Val He Thr Val Lys Asp Gly Lys Thr Leu Asn 195 200 205
Asp Glu Leu Glu He He Glu Gly Met Lys Phe Asp Arg Gly Tyr He 210 215 220
Ser Pro Tyr Phe He Asn Thr Ser Lys Gly Gin Lys Cys Glu Phe Gin 225 230 235 240
Asp Ala Tyr Val Leu Leu Ser Glu Lys Lys He Ser Ser He Gin Ser
245 250 255
He Val Pro Ala Leu Glu He Ala Asn Ala His Arg Lys Pro Leu Val 260 265 270
He He Ala Glu Asp Val Asp Gly Glu Ala Leu Ser Thr Leu Val Leu 275 280 285
Asn Arg Leu Lys Val Gly Leu Gin Val Val Ala Val Lys Ala Pro Gly 290 295 300
Phe Gly Asp Asn Arg Lys Asn Gin Leu Lys Asp Met Ala He Ala Thr 305 310 315 320
Gly Gly Ala Val Phe Gly Glu Glu Gly Leu Thr Leu Asn Leu Glu Asp
325 330 335
Val Gin Pro His Asp Leu Gly Lys Val Gly Glu Val He Val Thr Lys 340 345 350
Asp Asp Ala Met Leu Leu Lys Gly Lys Gly Asp Lys Ala Gin He Glu 355 360 365
Lys Arg He Gin Glu He He Glu Gin Leu Asp Val Thr Thr Ser Glu 370 375 380
Val Glu Lys Glu Lys Leu Asn Glu Arg Leu Ala Lys Leu Ser Asp Gly 385 390 395 400
Val Ala Val Leu Lys Val Gly Gly Thr Ser Asp Val Glu Val Asn Glu
405 410 415
Lys Lys Asp Arg Val Thr Asp Ala Leu Asn Ala Thr Arg Ala Ala Val 420 425 430
Glu Glu Gly He Val Leu Gly Gly Gly Cys Ala Leu Leu Arg Cys He 435 440 445 Pro Ala Leu Asp Ser Leu Thr Pro Ala Asn Glu Asp Gin Lys He Gly 450 455 460
He Glu He He Lys Arg Thr Leu Lys He Pro Ala Met Thr He Ala 465 470 475 480
Lys Asn Ala Gly Val Glu Gly Ser Leu He Val Glu Lys He Met Gin
485 490 495
Ser Ser Ser Glu Val Gly Tyr Asp Ala Met Ala Gly Asp Phe Val Asn 500 505 510
Met Val Glu LΫs Gly He He Asp Pro Thr Lys Val Val Arg Thr Ala 515 520 525
Leu Leu Asp Ala Ala Gly Val Ala Ser Leu Leu Thr Thr Ala Glu Val 530 535 540
Val Val Thr Glu He Pro Lys Glu Glu Lys Asp Pro Gly Met Gly Ala 545 550 555 560
Met Gly Gly Met Gly Gly Gly Met Gly Gly Gly Met Phe 565 570
(2) INFORMATION FOR SEQ ID NO: 106:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 544 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106:
Met Ala Lys Thr He Ala Tyr Asp Glu Glu Ala Arg Arg Gly Leu Glu 1 5 10 15
Arg Gly Leu Asn Ala Leu Ala Asp Ala Val Lys Val Thr Leu Gly Pro 20 25 30
Lys Gly Arg Asn Val Val Leu Glu Lys Lys Trp Gly Ala Pro Thr He 35 40 45
Thr Asn Asp Gly Val Ser He Ala Lys Glu He Glu Leu Glu Asp Pro 50 55 60 Tyr Glu Lys He Gly Ala Glu Leu Val Lys Glu Val Ala Lys Lys Thr 65 70 75 80
Asp Asp Val Ala Gly Asp Gly Thr Thr Thr Ala Thr Val Leu Ala Gin
85 90 95
Ala Leu Val Arg Glu Gly Leu Arg Asn Val Ala Ala Gly Ala Asn Pro 100 105 110
Leu Gly Leu Lys Arg Gly He Glu Lys Ala Val Glu Lys Val Thr Glu 115 120 125
Thr Leu He Lys Gly Ala Lys Glu Val Glu Thr Lys Glu Gin He Ala 130 135 140
Ala Thr Ala Ala He Ser Ala Gly Asp Gin Ser He Gly Asp Ser He 145 150 155 160
Gly Asp Leu He Ala Glu Ala Met Asp Lys Val Gly Asn Glu Gly Val
165 170 175
He Thr Val Glu Glu Ser Asn Thr Phe Gly Leu Gin Leu Glu He Thr 180 185 190
Glu Gly Met Arg Phe Asp Lys Gly Tyr He Ser Gly Tyr Phe Val Thr 195 200 205
Asp Pro Glu Arg Gin Glu Ala Val Leu Glu Asp Pro Tyr He Leu Leu 210 215 220
Val Ser Ser Lys Val Ser Thr Val Lys Asp Leu Leu Pro Leu Leu Glu 225 230 235 240
Lys Val He Gly Ala Gly Lys Pro Leu Leu He He Ala Glu Asp Val
245 250 255
Glu Gly Glu Ala Leu Ser Thr Leu Val Val Asn Lys He Arg Gly Thr 260 265 270
Phe Lys Ser Val Ala Val Lys Ala Pro Gly Phe Gly Asp Arg Arg Lys 275 280 285
Ala Met Leu Gin Asp Met Ala He Leu Thr Gly Gly Gin Val He Ser 290 295 300
Glu Glu Val Gly Leu Thr Leu Glu Asn Ala Asp Leu Ser Leu Leu Gly 305 310 315 320
Lys Ala Arg Lys Val Val Val Thr Lys Asp Glu Thr Thr He Val Glu
325 330 335 Gly Ala Gly Asp Thr Asp Ala He Ala Gly Arg Val Ala Gin He Arg 340 345 350
Gin Glu He Glu Asn Ser Asp Ser Asp Tyr Asp Arg Glu Lys Leu Gin 355 360 365
Glu Arg Leu Ala Lys Leu Ala Gly Gly Val Ala Val He Lys Ala Gly 370 375 380
Ala Ala Thr Glu Val Glu Leu Lys Glu Arg Lys His Arg He Glu Asp 385 390 395 400
Ala Val Arg A≤n Ala Lys Ala Ala Val Glu Glu Gly He Val Ala Gly
405 410 415
Gly Gly Val Thr Leu Leu Gin Ala Ala Pro Thr Leu Asp Ala Leu Lys 420 425 430
Leu Glu Gly Asp Glu Ala Thr Gly Ala Asn He Val Lys Val Ala Leu 435 440 445
Glu Ala Pro Leu Lys Gly He Ala Phe Asn Ser Gly Leu Glu Pro Gly 450 455 460
Val Val Ala Glu Lys Val Arg Asn Leu Pro Ala Gly His Gly Leu Asn 465 470 475 480
Ala Gin Thr Gly Val Tyr Glu Asp Leu Leu Ala Ala Gly Val Ala Asp
485 490 495
Pro Val Lys Val Thr Arg Ser Ala Leu Gin Asn Ala Ala Ser He Ala 500 505 510
Gly Leu Phe Leu Thr Thr Glu Ala Val Val Ala Asp Lys Pro Glu Lys 515 520 525
Glu Lys Ala Ser Val Pro Gly Gly Gly Asp Met Gly Gly Met Asp Phe 530 535 540
[2) INFORMATION FOR SEQ ID NO: 107:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 17 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 107:
Thr Ala Ala Pro Ala Ser Asp Pro Thr Gly Gly Met Gly Gly Met Asp 1 5 10 15
Phe
(2) INFORMATION FOR SEQ ID NO: 108:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 108:
Asp Val Glu Gly Glu Ala Leu Ser Thr Leu Val 1 5 10
(2) INFORMATION FOR SEQ ID NO: 109:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 109:
Asp Val Asp Gly Glu Ala Leu Ser Thr Leu Val 1 5 10
(2) INFORMATION FOR SEQ ID NO: 110:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 110:
Val Val Asn Lys He Arg Gly Thr Phe Lys Ser 1 5 10
(2) INFORMATION FOR* SEQ ID NO: 111:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111:
Phe Leu Thr Thr Glu Ala Val Val Ala Asp Lys Pro Glu Lys Thr Ala 1 5 10 15
[2) INFORMATION FOR SEQ ID NO: 112:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 10 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
[ii) MOLECULE TYPE: peptide
(Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 112
Val Ala Val Lys Ala Pro Gly Phe Gly Asp 1 5 10
(2) INFORMATION FOR SEQ ID NO: 113: (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 113:
Arg Arg Lys Ala Met Leu Gin Asp Met Ala He Leu Thr Gly Gly 1 5 10 15
(2) INFORMATION FOR SEQ ID NO: 114:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 12 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 114:
Val Gly Leu Thr Leu Glu Asn Ala Asp Leu Ser Leu 1 5 10
(2) INFORMATION FOR SEQ ID NO: 115:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 12 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 115:
Leu Thr Leu Asn Leu Glu Asp Val Gin Pro His Asp 1 5 10 (2) INFORMATION FOR SEQ ID NO: 116:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 12 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 116:
Val Gly Leu Thr Leu Glu Asn Ala Asp Leu Ser Leu 1 5 10
(2) INFORMATION FOR SEQ ID NO: 117:
(i. SEQUENCE CHARACTERISTICS:
(A) LENGTH: 12 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: single
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 117:
Leu Thr Leu Asn Leu Glu Asp Val Gin Pro His Asp 1 5 10

Claims

Claims
1. A polypeptide of up to 21 amino acid residues which comprises or consists of the sequence
VGLTLENADLSL (SEQ ID 107) or a homologue or functional equivalent or mimetic thereof.
2. The polypeptide of claim 1 for use in prophylaxis or treatment of auto-immune disease such as rheumatoid arthritis.
3. A polypeptide of up to 21 amino acid residues comprising or consisting of the sequence
VLNRLKVGLQV (SEQ ID 108) or a homologue or functional equivalent or mimetic thereof.
4. Human hsp58 polypeptide or a fragment thereof containing or consisting of the amino acid sequence of claim 3 for use in the prophylaxis or treatment of auto-immune disease such as rheumatoid arthritis.
5. A polypeptide of up to 21 amino acid residues comprising or consisting of the sequence
LTLNLEDVQPHD (SEQ ID 110) or a homologue or functional equivalent or mimetic thereof.
6. A polypeptide according to claim 5 for use in the prophylaxis or treatment of auto-immune disease such as rheumatoid arthritis.
7. A pharmaceutical composition comprising at least one polypeptide according to any of claims 1, 3 and 5 in combination with a pharmaceutically acceptable carrier or excipient.
8. A method of prophylaxis or treatment of auto-immune disease such as rheumatoid arthritis, which method comprises administering to a patient an effective amount of a polypeptide according to any one of claims 1, 3 and 5 or a pharmaceutical compositions according to claim 7.
PCT/GB1996/002382 1995-09-27 1996-09-26 Polypeptides and their use in treatment and prophylaxis of auto-immune disease WO1997011966A1 (en)

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GBGB9519737.2A GB9519737D0 (en) 1995-09-27 1995-09-27 Polypeptides and their use in treatment and prophylaxis of auto-immune

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0947524A1 (en) * 1998-03-30 1999-10-06 Upither B.V. Novel peptides for the treatment of autoimmune diseases
WO2001016174A3 (en) * 1999-08-30 2002-01-17 Rolf Kiessling Induction of cytotoxic t lymphocyte response by hla class ia restricted epitopes of mycobacterial heat shock protein 65
WO2002012286A3 (en) * 2000-08-09 2003-07-31 Univ California San Diego Stress proteins and peptides and methods of use thereof
EP1652856A1 (en) * 2000-08-09 2006-05-03 The Regents of The University of California San Diego Stress proteins-derived peptides and method of use thereof
WO2006032216A3 (en) * 2004-09-24 2007-05-18 Ct Ingenieria Genetica Biotech Peptides and apl-type derivatives of hsp60 and pharmaceutical compositions
US7576177B2 (en) 2002-01-31 2009-08-18 Andromeda Biotech Ltd. Hsp peptides and analogs for modulation of immune responses via antigen presenting cells
US7608683B2 (en) 2000-08-09 2009-10-27 The Regents Of The University Of California Stress proteins and peptides and methods of use thereof
US8691772B2 (en) 2005-01-04 2014-04-08 Yeda Research And Development Co. Ltd. HSP60, HSP60 peptides and T cell vaccines for immunomodulation
US10703784B2 (en) * 2011-09-30 2020-07-07 La Jolla Institute For Allergy And Immunology Antigens and epitopes derived from Mycobacterium tuberculosis

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CN112724238B (en) * 2021-01-21 2022-05-31 浙江辉肽生命健康科技有限公司 Bioactive peptide with amino acid structure FREGTTPKPK, and preparation method and application thereof

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WO1989012455A1 (en) * 1988-06-15 1989-12-28 Whitehead Institute For Biomedical Research Stress proteins and uses therefor
WO1994029459A1 (en) * 1993-06-04 1994-12-22 Whitehead Institute For Biomedical Research Stress proteins and uses therefor
WO1995025744A1 (en) * 1994-03-21 1995-09-28 Rijksuniversiteit Utrecht Peptide fragments of microbial stress proteins and pharmaceutical composition made thereof for the treatment and prevention of inflammatory diseases
WO1996018646A2 (en) * 1994-12-16 1996-06-20 Regents Of The University Of Minnesota Heat shock protein peptides and methods for modulating autoimmune central nervous system disease

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WO1989012455A1 (en) * 1988-06-15 1989-12-28 Whitehead Institute For Biomedical Research Stress proteins and uses therefor
WO1994029459A1 (en) * 1993-06-04 1994-12-22 Whitehead Institute For Biomedical Research Stress proteins and uses therefor
WO1995025744A1 (en) * 1994-03-21 1995-09-28 Rijksuniversiteit Utrecht Peptide fragments of microbial stress proteins and pharmaceutical composition made thereof for the treatment and prevention of inflammatory diseases
WO1996018646A2 (en) * 1994-12-16 1996-06-20 Regents Of The University Of Minnesota Heat shock protein peptides and methods for modulating autoimmune central nervous system disease

Cited By (20)

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Publication number Priority date Publication date Assignee Title
WO1999050282A3 (en) * 1998-03-30 2001-03-29 Upither B V Peptides for the treatment, prophylaxis, diagnosis and monitoring of autoimmune diseases
US6673770B1 (en) * 1998-03-30 2004-01-06 Upither B.V. Peptides for the treatment, prophylaxis, diagnosis and monitoring of autoimmune diseases
EP0947524A1 (en) * 1998-03-30 1999-10-06 Upither B.V. Novel peptides for the treatment of autoimmune diseases
WO2001016174A3 (en) * 1999-08-30 2002-01-17 Rolf Kiessling Induction of cytotoxic t lymphocyte response by hla class ia restricted epitopes of mycobacterial heat shock protein 65
WO2002012286A3 (en) * 2000-08-09 2003-07-31 Univ California San Diego Stress proteins and peptides and methods of use thereof
JP2004518430A (en) * 2000-08-09 2004-06-24 ザ レジェンツ オブ ザ ユニバーシティー オブ カリフォルニア サン ディエゴ Stress proteins and peptides and methods of using the same
US6989146B2 (en) 2000-08-09 2006-01-24 The Regents Of The University Of California Stress proteins and peptides and methods of use thereof
EP1652856A1 (en) * 2000-08-09 2006-05-03 The Regents of The University of California San Diego Stress proteins-derived peptides and method of use thereof
AU2001285427B2 (en) * 2000-08-09 2007-03-22 The Regents Of The University Of California, San Diego Stress proteins and peptides and methods of use thereof
US7608683B2 (en) 2000-08-09 2009-10-27 The Regents Of The University Of California Stress proteins and peptides and methods of use thereof
US7576177B2 (en) 2002-01-31 2009-08-18 Andromeda Biotech Ltd. Hsp peptides and analogs for modulation of immune responses via antigen presenting cells
EP2157101A1 (en) 2002-01-31 2010-02-24 Andromeda Bio Tech Ltd. HSP peptides and analogs for modulation of immune responses via antigen presenting cells
JP2008514553A (en) * 2004-09-24 2008-05-08 セントロ デ インジエニエリア ジエネテイカ イ バイオテクノロジア HSP60 peptide and APL type derivatives and pharmaceutical compositions
RU2361877C2 (en) * 2004-09-24 2009-07-20 Сентро Де Инженьериа Генетика И Биотекнологиа Hsp60 peptides and their apl-derivatives and pharmaceutical compositions
WO2006032216A3 (en) * 2004-09-24 2007-05-18 Ct Ingenieria Genetica Biotech Peptides and apl-type derivatives of hsp60 and pharmaceutical compositions
KR101054332B1 (en) 2004-09-24 2011-08-04 센트로 데 인제니에리아 제네티카 와이 바이오테크놀로지아 Peptides of HSP60 and their inducible APLs and pharmaceutical compositions
EP2371847A1 (en) 2004-09-24 2011-10-05 Centro De Ingenieria Genetica Y Biotecnologia Peptides and their derived type APL of the HSP60 and pharmaceutical compositions
CN101935345B (en) * 2004-09-24 2013-12-11 遗传工程与生物技术中心 Peptides and APL-type derivatives of HSP60 and pharmaceutical compositions
US8691772B2 (en) 2005-01-04 2014-04-08 Yeda Research And Development Co. Ltd. HSP60, HSP60 peptides and T cell vaccines for immunomodulation
US10703784B2 (en) * 2011-09-30 2020-07-07 La Jolla Institute For Allergy And Immunology Antigens and epitopes derived from Mycobacterium tuberculosis

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GB9519737D0 (en) 1995-11-29
AU7091296A (en) 1997-04-17

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