BACKGROUND OF THE INVENTION The inflammatory response is a defence reaction caused by tissue damage or injury.

This may result from a variety of causes, both bacterial infections and physical and chemical factors, such as heat, ionising radiation, toxic substances, mechanical factors etc. Examples of such tissue damage or injury are abrasions, broken bones, muscle and tendon strains, sprains, joint dislocations, sunburns, fire burns etc.

The inflammatory response also may be related to and aggravate e. g. states of al- lergy, such as hay fever, bee sting, as well as autoimmune diseases, such as asthma, arthritis, Crohn's disease etc.

Since inflammation is a defence mechanism of the body in response to tissue injury or damage or as a reaction to immunological activation, the primary objective thereof is to localize and reduce or eliminate the irritant and repair the surrounding tissue. Due to different causes, an inflammatory response may be triggered by re- lease of inflammatory compounds from various sources such as injured tissue cells, lymphocytes and mast cells into the extracellular fluid, the most important being histamine, prostaglandins, and cytokines.

The triggered inflammatory response involves three major stages: dilation of capil- laries to increase blood flow; microvascular permeability changes and escape of plasma proteins from the bloodstream; and leukocyte recruitment including adhe- sion and transmigration through endothelium and accumulation at the site of in- jury. In the last stage, the leukocyte accumulation at the site of injury is the result of the so-called leukocyte adhesion cascade, which is a sequence of adhesion and activation steps involving different adhesion receptors (such as selectins and in- tegrins) on leukocytes. Those steps may be identified as capture, rolling, slow roll- ing, firm adhesion and transmigration. Each step in the leukocyte adhesion cascade is necessary for effective leukocyte recruitment into the site of inflammation, and blocking any of them would lead to a reduction of leukocyte accumulation in the tissue. Regardless of its origin, the inflammation is characterized by a number of symptoms, viz. redness, swelling, heat, pain and loss of tissue or organ function.

The inflammatory condition may be of varying severity, ranging from scarcely no- ticeable to severely disabling, and may even, in extreme cases, be life-threatening.

Various anti-inflammatory drugs are currently used to combat disabling or danger- ous states of inflammation, based on the physiological mechanisms of the inflam- matory response. They function as blockers, suppressors, or modulators thereof.

Essentially, they may be subdivided into two major groups: steroidal and nonster- oidal (NSAID) agents. Both types of agents have well-known side effects, although these are generally less severe for the NSAIDs.

For example, topically applied steroids have side effects such as dry, irritated skin, and unusual growth of hair on the face or body after prolonged use. The application of potent corticosteroids to extensive areas of the body for prolonged periods in- creases the likelihood of systemic side effects, whereas common side effects associ- ated with oral steroids include diarrhoea or constipation, headache, nervousness, just to mention a few. Other administration forms, such as inhalation, are associ- ated with still other side effects. The side effects of NSAIDs are generally less severe, however, these latter anti-inflammatory drugs are less potent. Moreover, long-term or extensive ingestion of NSAIDs can result in toxic effects for the kidney or the stomach epithelium, possibly causing ulcers.

It therefore appears that there is a continuing need of providing new anti-inflamma- tory drugs for use in methods of anti-inflammatory treatment.

SUMMARY OF THE INVENTION According to a first aspect of the present invention new anti-inflammatory drugs are provided by use of a protein or of a peptide portion thereof comprising at least one repeating unit of said protein, said protein being selected from a group of proteins designated Eap (extracellular adherence protein).

According to a second aspect, the present invention provides a method of treating a mammal suffering from an inflammatory condition.

According to a further aspect of the invention the above defined protein or polypep- tide is used in the manufacture of a medicament for use in a cancer therapy.

Further aspects of the invention are defined in the claims.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a bar diagram illustrating experimental data relating to the in vivo inhi- bition of neutrophil emigration by Eap in acute inflammation in mice; Figure 2A is a bar diagram illustrating experimental data relating to the contribu- tion of Eap to the adhesion of S. aureus to ICAM-1; and Figure 2B is a graph illustrating experimental data relating to the contribution of Eap to the adhesion of S. aureus to ICAM-1.

DETAILED DESCRIPTION OF THE INVENTION The present invention in a first aspect relates to the inhibition of inflammatory reac- tions in a mammal, such as a human, by administration of a certain protein, selec- ted from the Eap group (Extracellular adherence protein), or a suitable peptide por- tion of said protein. This aspect of the invention is based on the surprising discov- ery that proteins belonging to the Eap group, or a suitable peptide portion thereof, present anti-inflammatory effects when given to a mammal suffering from an acute or chronic inflammation.

It has been shown that proteins belonging to the Eap group are produced by the bacterium Staphylococcus aureus. S. aureus is a persistent pathogen that causes serious community-acquired and nosocomial infections. The range of disease pro- duced by S. aureus is broad, including endocarditis, osteomyelites and septic shock. Eap has a wide binding repertoire; it has affinity for at least seven plasma proteins, including fibrinogen, fibronectin and prothrombin. The protein also has an ability to bind to cells of S. aureus, to form oligomers and to agglutinate S. aureus.

The Eap group of proteins should be considered as a family of proteins, here termed the Eap-family, or just Eap, since minor variations in sequence occur between dif- ferent strains of S. aureus. It comprises an extracellular 60 kDa protein secreted by the bacterium (1). This family also comprises a protein designated Map (Major his- tocompatibility complex class II Analogous Protein) (2) (3). Another member of the family is a cationic protein termed p70 (4,5). In a recent study, Eap was found to be present in 98 % of clinical isolates from 240 strains of S. aureus. Table 1 identi- fies proteins within the Eap family and illustrates the relationship between them.

TABLE 1: C-terminal and N-terminal sequences of proteins belonging to the Eap group Pro-Source of N-terminal C-terminal Data-Accession Version Date Ref. tein the protein; amino amino base Number Number bacterial acid se-acid sequence (AC) (SV) strain quence Eap S. aureus, N-AAKQIDKSSS KVDIEIKF-C Gen-AJ132841 AJ132841. 1 March 25, 1999 (8) Newman Bank GI : 4454323 Map S. aureus, Not determined QYTKSKKNK-C Gen-AJ223806 AJ223806.1 Jan 7,1999 (6) Newman Bank GI : 4138455 Map S. aureus, N-AAKQIDKSSS KVDIEIKF-C Gen-U20503 U20503.1 Sept 30,1995 (3) FDA 574 Bank GI : 1001960 P70 S. aureus, N-AAKPLDKSSS TKSKKNK-C Gen-Y10419 Y10419.1 June 8,1997 (7) wood 46 Bank GI : 2190506 It appears that the proteins partly differ in their terminal sequences; the proteins are more or less isoforms. A typical amino acid sequence example of a protein of the Eap group or protein family is the following (8) : <BR> <BR> AAKPLDKSSSTLHHGHSNTQIPYTITVNGTSQ1VILSSLTFNKNQNISYKDIENKVKSVL YFNRG<BR> ISDIDLRLSKQAEYTVHFKNGTKRVIDLKSGTYTADLINTSDIKAISVNVDTKKQPKDKA KANV<BR> QVPYTITVNGTSQNILSNLTFNKNQMSYKDLEDRVKSVLESNRGITDVDLRLSKQAKYTV NF<BR> KNGTKKVIDLKAGIYTANLINSSDIKSININVDTKKHIENKAKRNYQVPYSINLNGTSTN ILSNLS<BR> FSNKPWTNYKNLTSQIKSVLKHDRGISEQDLKYAKKAYYTVYFKNGGKRILQLNSKNYTA NLV<BR> HVKDVKRIEITVKTGTKAKADRYVPYTLAVNGTSTPILSDLRFTGDPRVGYKDITKKVKS VLK<BR> HDRGIGERELKYAKKATYTVHFKNGKKKVINLNSKISQLNLLYVQDIKKIDID VKTGSKAKAD<BR> SYVPYTIA VNGTSTPILSKLKTSNKQLISYKYLNDKVKSVLKNERGISDLDLKFAKQAKYTVYF< BR> KNGKKQWNLKSDIFTPNLFSAKDIKKIDID VKTGSKAKADSYVPYTIAVNGTSTPILSKLKIS<BR> NKQLISYKYLNDKVKSVLKSERGISDLHLKFAKQAKYTVYFKNGKKQVVNLKSDIFTPNL FSAK<BR> DIKKIDIDVKQYTKSKKNK Another similar sequence has been described (3). When used herein below, the term Eap will be understood to be any of the proteins within the Eap family. Eap has several repeating units of about 30 amino acids or more, which may differ in a few amino acids between different members of the family. For example, in the above sequence, several repeating units may be identified, such as e. g.

PYTITVNGTSQNILSSLTFNKNQNISYK or VKTGTKAKADRYVPYTIAVNGTSTPILSDLK, with only one or two amino acids varying. Examples of repeating units are high- lighted in bold characters, and a partial overlap of both repeating units with each other can be recognized as well. It is likely that several of the described characteris- tics of Eap can be found within a single repeating unit. Therefore, what is said here- in about Eap is valid also for peptide portions of shorter length but comprising at least one repeating unit thereof. In other words, a peptide fraction of Eap suitable for use according to the invention should comprise at least one repeating unit of the amino acid sequence of the protein. For the purpose of the invention the word pep- tide fraction or peptide portion or peptide is used as synonymous with polypeptide.

As briefly outlined herein above, in relation to the inflammatory response, leuko- cytes emigrating from the blood-stream into sites of inflammation or injury, un- dergo a complex sequence of adhesion and locomotion steps. These highly co- ordinated processes require the expression and upregulation of various adhesion receptors on the surface of leukocytes and vascular cells. Different receptor systems direct the interaction of leukocytes with the endothelium. Whereas leukocyte rolling depends on selectins, firm adhesion to and transmigration through the endothelium is mediated by the ß2-integrins Mac-1 (CDllb/CD18, aMp2, CR3) and LFA-1 (CDlla/CD18, aLß2), that interact with their counter-receptor ICAM-1 on the en- dothelial cells.

The present inventors have investigated whether Eap by binding to the different proteins of the extracellular matrix could regulate the adhesion and recruitment of leukocytes. The results indicate that the secreted bacterial protein Eap specifically interacts with ICAM-1 on endothelial cells, thereby inhibiting Mac-1 and LFA-1 me- diated leukocyte adhesion to endothelial cells.

Thus, the present inventors have found that Eap binding to host (adhesive) proteins in the connective tissue (extracellular matrix, ECM) and on cell surfaces leads to inhibition of host (inflammatory) cell adhesion and migration and thereby blocks inflammatory defence mechanisms of the infected host organism. This anti-adhesive function of Eap was established for different types of leukocyte cells including granulocytes and monocytes, but can also be extended to lymphocytes, which all share several adhesive processes and characteristics including the existence of fus2- integrins, the major class of adhesion receptors. Thus, by binding to different ligands of 62-integrins in the ECM (such as fibrinogen or vitronectin) and on cells (such as ICAM-1), Eap can inhibit the mobility, infiltration and activities of acute inflammatory cells (granulocytes), of monocytes and macrophages (relevant for phagocytosis) and of immune cells (such as lymphocytes).

By experiments as detailed in the experimental section herein below, the present inventors subsequently were able to show that Eap in vivo inhibits recruitment of neutrophils into a site of inflammation. It is on the basis of these findings that the invention has been made.

EXPERIMENTAL 1. Inhibition of neutrophil recruitment in the mouse model of acute thioglycollate- induced peritonitis by Eap (Fig. 1) Methods: Bacterial strains and purification of Eap. Previously, we have characterized the polymorphism of S. aureus type strains and clinical isolates (8) of which three dif- ferent S. aureus strains were used in this study: Strain Newman D2C (ATCC 25904) is a laboratory strain rich in Clf, strain Wood 46 (ATCC 10832) is rich in protein A and S. aureus clinical isolate 7 from a patient with S. aureus soft tissue infection have been characterized as producer of a representative group of Eap. Eap of these strains, namely Eap N, Eap W and Eap 7, respectively, were purified by affinity chromatography on FBG-Sepharose followed by ion-exchange chromatography us- ing a MonoS column (Pharmacia, Uppsala, Sweden) as described before (1). More- over, Eap N, Eap W and Eap 7 were also recombinantly expressed in E. coli and iso- lated on Ni-NTA column. Bacteria were propagated in appropriate standard media (tryptic soy, brain heart infusion, Muller-Hinton, or Luria-Bertani) In vivo peritonitis model: Experiments were performed according to a previously described protocol (9,10), in which 1 ml thioglycollate bouillon (Merck, Darmstadt, Germany) was administered intraperitoneally to female 8-10-week old NMRI mice (Charles River Wiga, Sulzfeld, Germany) to induce peritonitis. For inhibition studies, 30 min prior to the injection of thioglycollate 100 ug of mAb against mouse Mac-1 or mouse LFA-1 in PBS or 50-100 llg of Eap in PBS were administered intrave- nously. Control mice were treated with the same volume of PBS and some mice ob- tained isotype-matched control antibodies. All reagents were endotoxin-free. At 1 h and 4 h after injection of thioglycollate, mice were sacrificed and the peritoneal lav- age was generated by injecting 10 ml PBS, massaging the peritoneal wall and re- moving the fluid. Total cell numbers were determined in a Casy Counter (Scharfe System, Germany) and 5x104 cells were then transferred onto adhesion slides (Bio- rad, Munich, Germany), fixed and stained (Diff-Quick, DADE-Behring, Munich, Germany). Cells were differentially counted by microscopy, evaluating 300 cells per slide. From the total cell count in the peritoneal lavage and the percentage of neu- trophils determined microscopically, the absolute number of emigrated neutrophils in the peritoneal lavage was calculated. Analysis of blood smears revealed that pe- ripheral neutrophil counts were not affected by any of the antibodies or reagents injected.

Results: Peritonitis was induced by thioglycollate injection, and after 4 h there was an ex- pected increase in the total leukocyte count, mostly attributable to emigrated neu- trophils: The percentage of neutrophils among all leukocytes after 4 h was 50-60% as compared with 3-10% lh after stimulation (9,10). The use of blocking antibod- ies against LFA-1 or Mac-1 30 min prior to the induction of peritonitis resulted in a 50-75% inhibition of neutrophil extravasation into the inflamed peritoneum at 4 h following thioglycollate injection (Fig. 1), whereas isotype-matched control antibody had no effect at all (not shown). At 1 h and 4 h following thioglycollate injection neutrophil recruitment to the peritoneum was significantly reduced in mice that were pre-treated with Eap 7 (50,75, 100 pg/mouse). The maximal inhibition (>75%) was obtained at 4 h with 100 pg of Eap. Thus, Eap inhibits ß2-integrin- dependent neutrophil emigration in vivo.

The results are illustrated in Fig. 1, where: - dotted bars represent values obtained for mice treated with PBS prior to thiogly- collate administration; - hatched bars represent values obtained for mice treated with a blocking mAb against mouse a-subunit of LFA-1 prior to thioglycollate administration; - filled bars represent values obtained for mice treated with a blocking mAb against mouse a-subunit of Mac-1 prior to thioglycollate administration; and - bars with horizontal lines represent values obtained for mice treated with Eap7 prior to thioglycollate administration.

Data are mean SEM (n=4 mice per treatment) of a typical experiment; similar re- sults were obtained in three separate sets of experiments.

2. Interaction of Eap with endothelial cell ICAM-1 (Fig. 2) Methods: Adherence of S. aureus : Polystyrene microtiter plate wells were coated with FBG or ICAM-1 (5 Hg/ml each), respectively, dissolved in bicarbonate buffer, pH 9.6 and blocked with 3% (wt/vol) BSA. Formalin-inactivated S. aureus strain Newman or Eap-deficient mutant AH12 in PBS were adjusted to an OD (578 nm) of 1.0 (ap- proximately 109 cells/ml), and 100 ul of the bacterial suspension was added per well. After incubation for lh at 37°C the wells were washed and the number of ad- herent bacteria was quantified by crystal violet staining at 590 nm.

Results: Fig. 2 (A and B) illustrates the contribution of Eap to the adhesion of S. aureus to ICAM-1. In Fig. 2A the adhesion of S. aureus strain Newman and the Newman Eap- deficient mutant strain AH 12 to immobilized FBG (filled bars) or ICAM-1 (hatched bars) (each 5 gug/ml) is shown. In Fig. 2B the adhesion of S. aureus strain Newman to immobilized ICAM-1 in the absence or presence of increasing concentrations of EapN is shown. Adhesion is expressed as absorbance at 590 nm and data are mean SEM (n=3) of a typical experiment; similar results were obtained in at least three separate experiments.

One consequence of the described direct binding interaction between ICAM-1 and Eap is the possible contribution of Eap in S. aureus adhesion to ICAM-1 on endo- thelial cells. Although Eap binds to FBG, Eap does not mediate S. aureus adhesion to FBG; here, bacterial adhesion is predominantly dependent on clumping factor.

When the adhesion of S. aureus strain Newman and mutant AH 12 to FBG was compared, no difference between both strains was observed (Fig. 2A); addition of soluble clumping factor blocked adhesion of both strains to FBG by > 50-60% (not shown). On the other hand, S. aureus Newman adhered to ICAM-1 and endothelial cells and this adhesion was markedly reduced in Eap-deficient strain AH 12 (Fig.

2A). Moreover, the exogenous addition of Eap dose-dependently inhibited the adhe- sion of strain Newman to immobilized ICAM-1 (Fig. 2B). These data indicate that Eap secreted from S. aureus and rebound to the bacterial surface plays an impor- tant role for the ICAM-1-dependent adhesion of S. aureus to endothelial cells.

The inflammatory situations treated in accordance with the present invention in- clude acute and allergic inflammatory reactions, including responses to radiation, infection, chemicals, allergins, and injury. Examples of specific conditions that can be treated include allergy, asthma, arthritis, psoriasis, skin sunburn, inflammatory pelvic disease, inflammatory bowel disease, urethritis, uvitis, sinusitis, pneumoni- tis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepati- tis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitis, and cholangititis.

Finally, it is known that non-regulated adhesiveness of leukocytes circulating tu- mour cells and/or endothelial cells may result in uncontrolled cellular extravasa- tion causing atherosclerosis, rheumatoid arthritis or leading to tumour metastasis.

In such pathological processes Eap derived sequences could be devised as ICAM-1 blocking agents to achieve an antiadhesive potential during therapeutic interven- tions. Therefore, in a further aspect the invention also provides a method of treating a mammal suffering from a cancer, or susceptible of developing a tumour metasta- sis, e. g. after a cancer therapy including a surgical removal of a tumour, by admin- istering Eap or a suitable peptide portion thereof to said mammal. Accordingly, in relation to this further aspect, Eap or a suitable peptide fraction thereof is used in the manufacture of a medicament to be given as part of a cancer therapy.

The protein or peptide of the invention may be produced by chemical synthesis or by recombinant expression according to conventional methods. For example, the proteins and peptides according to the invention can be obtained by using a host organism transformed or transfected with an expression vector obtained by inser- tion of a gene according to the invention, or part thereof, into a vector in a conven- tional manner. The vector which is used to construct the expression vector is not particularly limited, but specific examples include plasmids such as pET (Stratagen) and the like; and phages such as M13 (NEB), phage display libraries and the like.

As expression regulatory sequence can among others T7 promotors and lac promo- tors be used.

An appropriate host to be transformed or transfected with the expression vector can be chosen among for example E. coli, or Bacillus subtilus. The transformed or trans- fected host is cultured and proliferated under suitable conditions, as known to the person skilled in the art.

After culturing, the peptides of the present invention may be purified by, for exam- ple, chromatography, precipitation, and/or density gradient centrifugation. The purified preparation containing one or several proteins according to the inven- tion, or parts thereof, is then formulated as a pharmaceutical composition, as for example a vaccine, or in a mixture with adjuvants. If desired the proteins are frag- mented by standard chemical or enzymatic techniques to produce peptide seg- ments.

The protein or peptide according to the invention can be formulated as pharmaceu- tical compositions and administered to a mammal subject, e. g. a human patient, in any suitable form, depending on the subject and the specific condition being treated. The compositions may be adapted for local or systemic, oral or parenteral administration, i. e. by intravenous, intramuscular, topical or subcutaneous routes.

Administration may be e. g. by inhalation or insufflation, topically, vaginally, rec- tally, by intracavitary administration, transdermally, intradermally, intraperito- neally or nasally.

By oral administration the protein or peptide compositions may comprise a phar- maceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier, and any suitable excipient. Any suitable dosage form may be used, such as hard or soft shell gelatin capsules, tablets, buccal compositions, troches, capsules, elixirs, suspensions, syrups, wafers, and the like, or by direct incorporation in the food of the patient's diet.

The tablets and the like also may contain any suitable constituents, e. g, binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dical- cium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose or aspartame, flavouring agents such as peppermint, oil of winter- green, or cherry flavouring. Additionally, capsules may contain, a liquid carrier, e. g. a vegetable oil. Also, coating materials may be provided, such as gelatin, wax, shel- lac or sugar and the like. A syrup or elixir may contain the peptide compositions, a sweetening agent, preservatives, such as methyl and propylparabens, and flavour- ings. Sustained-release preparations and devices, such as sustained release cap- sules or patches, may also be used.

The protein or peptide compositions according to the invention also may be solu- tions or dispersions to be administered intravenously or intraperitoneally by infu- sion or injection. The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the protein or peptide composition according to the invention for the extemporane- ous preparation of sterile injectable or infusible solutions or dispersions. Also it may be encapsulated in liposomes. Any suitable liquid carrier or vehicle may be used, e. g. water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, and mixtures thereof. Other con- ventional additives are e. g. preservatives.

For topical administration, including also e. g. vaginal, rectal, intracavitary and buc- cal administration, it generally will be desirable to administer the protein or peptide compositions according to the invention in combination with a dermatologically ac- ceptable solid or liquid carrier, well-known to the man skilled in the art. Liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area, and may include any suit- able viscosity modifiers or thickeners to form gels, ointments, and the like.

The amount of the protein or peptide composition according to the invention re- quired for use in treatment will vary with the route of administration, the nature of the condition being treated and the age and condition of the patient. In general, however, a suitable dose will be in the range of from about 0.2 mg/kg of body weight to 20 mg/kg of body weight by systemic administration and from about 0.2 mg/kg of body weight to 100 mg/kg body weight by local administration.

The protein or peptide composition according to the invention conveniently may be presented in a single dose or as multiple doses administered at appropriate time intervals over the day.

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