Drug containing recombinant mistletoe lectins for treating malignant melanoma

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Mar. 8, 2016 is named 74062_0002_01_SL_ST25.txt and is 33,022 bytes in size.

The invention relates to a drug and/or pharmaceutical composition for treating metastatic tumors, in particular of malignant melanoma, above all of stage IV malignant melanoma, and to the use of said drug, in particular the use of said drug in select patient populations.

Malignant melanoma (also referred to as black skin cancer) is a rapidly and early metastazing tumor of the melanocytes, melanin-producing cells, in the basal cell layer of the epidermis. The extent of the disease is dependent on the extent of the metastasis in the regional lymph nodes and in remote regions of the body. Malignant melanoma is particularly aggressive and pernicious and is responsible for virtually 80% of all deaths due to skin tumors (Parkin D M, Bray F, Ferlay J, Pisani P. 2005. CA Cancer J Clin 55: 74-108). Cases of malignant melanoma are growing at the fastest rate of skin tumors affecting men, and are growing at the second fastest rate of skin tumors affecting women. Worldwide, an incidence of 160,000 new cases and 41,000 deaths each year is assumed (Parkin et al. 2005 (supra)).

For the year 2010, it is expected that 68,000 new cases and 8,700 deaths will occur in the USA (SEER-Statistik, www.seer.cancer.gov), and 62,000 new cases and 16,600 deaths will occur in Europe. In Australia and New Zealand, 10,000 new cases and 1,300 deaths are expected (Parkin et al. 2005 (supra)). It is expected that the seven most significant pharmaceutical markets in the world (USA, Japan, France, Germany, Italy, Spain, Great Britain) will see 138,000 new cases in the year 2010, and approximately 227,000 new cases in the year 2019 (Globocan 2002<http://www-dep.iarc.fr/> [Accessed Apr. 7, 2010], World Population Prospects 2008<http://esa.un.org/unpp/> [Accessed Apr. 7, 2010]).

If malignant melanoma is diagnosed and treated in the early stage, the five-year survival rate is 85%. The survival rate drops dramatically after metastasis (near and distant metastases) of the melanoma. A prospective analysis of eight clinical trials conducted by the Eastern Cooperative Oncology Group (ECOG) with 1362 patients having metastatic malignant melanoma, who were treated with combination chemotherapies, yielded a median survival time of 6.5 months and an assumed five-year survival rate of 6%. Significant parameters for a shortened survival time of patients with metastatic melanoma are a poor general state, visceral metastases, the number of affected organs, and elevated LDH (lactate dehydrogenase) (Manola J, Atkins M, Ibrahim J, Kirkwood J. 2000 J Clin Oncol 18: 3782-93, Balch C M, Gershenwald J E, Soong S-J et al. 2009 J Clin Oncol 27(36): 6199-6206, Korn E L, Liu P-Y, Lee S J et al. 2008 J Clin Oncol 26(4): 527-534).

Metastatic malignant melanoma (so-called stage IV) is typically an incurable disease (Balch et al 2009 (supra)). The current standard therapy for treating patients with stage IV metastatic melanoma is dacarbazine (DTIC) (Garbe C, Hauschild A, Volkenandt M et al. 2005, German guidelines: Malignant Melanoma, www.ado-homepage.de). Dacarbazine is well-tolerated, but offers little advantage to patients in terms of the response rate and survival time. The general use of dacarbazine yields a response rate of 5.3%-23%, although the duration thereof is short (Huncharek M, Caubet J F & McGarry R. 2001 Melanoma Res 11(1): 75-81, Serrone L, Zeuli M & Cognetti F 2000 J Exp Clin Res 19(1): 21-34). A phase III clinical trial yielded no additional evidence that dacarbazine prolongs the survival times of patients. The median survival time after dacarbazine in phase III trials is approximately 7.5 months (Chapman P B, Einhorn L H, Meyers M L et al. 1999 J Clin Oncol 17(9): 2745-2751, Middleton M R, Grab J J, Aaronson N et al. 2000 J Clin Oncol 18(1): 158-166, Atkins M B, Lotze M T, Dutcher J P et al. 1999 J Clin Oncol 17: 2105-2116, Falkson C I, Ibrahim J, Kirkwood J M et al. 1998 J Clin Oncol 16: 1743-1751, Avril M F, Aamdal S, Grob J J et al. 2004 J Clin Oncol 22: 1118-1125, Flaherty L E, Atkins M, Sosman J et al. 2001 J Clin Oncol 19: 3194-3202). Other cytotoxic substances such as temozolomide, which has a response rate (ORR) of 13.5-21%, the substances carboplatin, cisplatin and vindesine (ORR 12-26%) and paclitaxel and fotemustine (ORR 7.4-24.2%) exhibit activity in patients with metastatic melanoma. The clinical efficacy of these therapies is comparable to that of dacarbazine (Chapman et al. 1999 (supra), Middleton et al. 2000 (supra), Atkins et al. 1999 (supra)). For example, the use of treosulfan in a second-line therapy after dacarbazine resulted in a median survival time of 6.5 months and a one-year survival rate of 33.9%, combined with 15-18% serious hematological side effects (Neuber K, Reinhold U, Deutschmann A et al 2003 Melanoma Res 13: 81-85).

Many of these substances are used in combination therapies (polychemotherapy) with the objective of increasing the response rates and prolonging the survival time of the patients. Although polychemotherapies increased the response rate, the therapy did not affect the survival rate (OS) in comparison with the general use of dacarbazine (Agarwala S S, Glaspy J, O'Day S J et al. 2002 J Clin Oncol 20: 125-133, Eton 0, Legha S S, Bedikian A Y et al. 2002 J Clin Oncol 20: 2045-2052, Falkson et al 1998 (supra), Avril et al. 2004 (supra)). Two examples of polychemotherapies are the BHD regime (ORR: 12.7%-30.4%) and the DVP regime (ORR: 31.4%-45%).

In addition to chemotherapy, an immunotherapy with high-dose interleukin-2 (IL-2), which is approved for this therapy, has been used for a few years in patients with metastatic malignant melanoma. Reports of significant clinical effects are known, although select patient groups are affected (Danson S, Lorigan P, Arance A et al. 2003 J Clin Oncol 21: 2551-2557). The tumor response rates that were achieved (ORR: 16%-21.5%) are accompanied by extensive multiple organ toxicities, however, and therefore limit the use of IL-2. Similar results are obtained with the use of a high dosage and a moderate dosage of interferon-alpha (IFN-alpha). Treatment with GM-CSF appeared to be successful only in small studies and in clinical trials of the early phase.

The combination of chemotherapy drugs and cytokines (polychemoimmunotherapy) shows partially highly response rates (ORR) in comparison to monotherapies, but the survival time is not improved. For example, the combination of IL-2 and cisplatin exhibited a high response rate, of 50%, having a short duration, although this was accompanied by strong side effects (undesired effects). In a comparison of a monotherapy with dacarbazine and a combination of dacarbazine, cisplatin, IFN- and IL-2, no differences were observed between the two methods of treatment (Flaherty et al. 2001 (supra), Danson et al. 2003 (supra), Agarwala et al. 2002 (supra), Eton et al 2002 (supra), Falkson et al 1998 (supra)). A combination of chemotherapy (cisplatin, vinblastine, dacarbazine) combined with a long-term application of biotherapeutic agents (interleukin-2, interferon alfa-2b and GM-CSF in various regimens) resulted in a median survival time of 14 months for patients with metastatic malignant melanoma. This prolongation of the general survival time was accompanied by a large number of hematological and non-hematological side effects having CTC grade 3 and CTC grade 4. (O'Day S J, Atkins M B, Boasberg P et al. 2009 J Clin Oncol 27(36): 6207-6212).

In terms of metastatic tumors, the study results for Ipilimumab (BMS, Yervoy.RTM.), a monoclonal antibody that detects human CTLA-4, are successful. The median survival time of patients with metastatic melanoma (stage III and stage IV) who were treated with Ipilimumab was significantly prolonged, specifically to 10 months versus 6.4 months in the control group (Hodi F S, O'Day S J, McDermott D F et al. 2010 N Engl J Med 363 (8): 711-723). This corresponds to a one-year survival rate of 45.6% in the Ipilimumab group compared to 25.3% in the control group. The side effects experienced by patients on Ipilimumab were considered to be very serious, however. 10-15% of the patients had serious immunological side effects (CTC grade 3 and grade 4) with effects on the skin and the intestinal tract (Hodi et al. 2010 (supra)).

Therefore, there is a great need to provide drugs that ensure better care or at least significantly increase the life expectancy of patient populations in stage III or stage IV with metastatic tumors, in particular in the event of failure of a standard therapy.

Mistletoe extracts have been used for therapeutic purposes for centuries. Mistletoe preparations have been used with varying degrees of success in cancer therapy in particular (Bocci V 1993 J Biol Regulators and Homeostatic Agents 7(1): 1-6; Gabius H-J, Gabius S, Joshi S S et al. 1993 Planta Med 60: 2-7; Gabius H-J & Gabius S 1994 PZ 139: 9-16; Ganguly C & Das S 1994 Chemotherapy 40: 272-278, Hajto T, Hostanska K, Gabius H_J 1989 Cancer Res 49: 4803-4808, Hajto T, Hostanska K, Frei K et al. 1990 Cancer Res. 50: 3322-3326). It has been shown that the therapeutic effects are attributable to so-called mistletoe lectins (viscumin, Viscum album agglutinin, VAA) in particular. Mistletoe lectins have a cytotoxic effect and induce an unspecific immunostimulation, the positive effects of which are used to treat tumor patients. Various investigations involving mistletoe lectins in vitro (Hajto et al., 1990 (supra); Mannel D N, Becker H, Gundt A et al. 1991 Cancer Immunol Immunother 33: 177-182; Beuth J, Ko K L, Tunggal L et al. 1993 Drug Res 43: 166-169) and in vivo (Hajto T 1986 Oncology 43 suppl 1: 51-65; Hajto et al., 1989 (supra), Beuth J, Ko H L, Gabius H-J et al. 1991 In Vivo 5: 29-32; Beuth J, Ko H L, Gabius H-J et al. 1992 J Clin Invest 70: 658-661), and clinical studies (Beuth et al., 1992 (supra)) showed an increased release of inflammmatory cytokines (TNF-alpha, IL-1, IL-6) and an activation of cellular components of the immune system (TH cells, NK cells).

Analysis of mistletoe extract have so far resulted in the identification of three mistletoe lectins (ML-I, ML-II, ML-III) with different molecular weights and sugar-binding specificities. It could be shown that the immunostimulating effect of mistletoe extract is attributable to ML-I. The ML-I lectin consists of two A- and two B-chains (MLA and MLB, respectively), each glycosylated. The A-chain is responsible for an enzymatic inactivation of ribosomes (Endo Y, Tsurugi K & Franz H 1988 FEBS Lett 231: 378-380), while the B-chain participates in carbohydrate binding. The two chains are linked together via disulphide bridges. The resulting mistletoe lectin monomers can associate into dimers with the formation of non-covalent bonds.

It is also possible to produce the biologically active mistletoe lectin using recombinant technology. EP 0751221 describes the isolation of mistletoe lectin polypeptides as a structurally homogeneous substance, wherein, proceeding from the genetic sequences of mistletoe lectin, recombinant, highly pure single chains (A-chain, B-chain) are produced, which can be reassociated in vitro and thereby yield a recombinant mistletoe lectin holoprotein, which is protein-chemically, enzymatically and structurally homogeneous, so-called Aviscuminum. According to EP 0751221, the recombinant mistletoe lectin polypeptide is suitable for therapeutic use as a holoprotein, a subchain, and in the form of subfragments, and is covered according to the invention.

Hitherto, recombinant mistletoe lectins were used in the treatment of tumor diseases in particular. However, the use of recombinant mistletoe lectins for the treatment of skin cancer, in particular of malignant melanoma also in the form of a metastatic tumor, is not described in the prior art.

Surprisingly, it has been shown that the survival time of tumor patients with metastatic melanoma (stage III and IV) who are treated with recombinant mistletoe lectins can be prolonged significantly, and the one-year survival rate increases significantly.

The problem addressed by the present invention is that of providing a drug and a pharmaceutical composition, by means of which a metastatic tumor, preferably skin cancer, in particular malignant melanoma, can be effectively treated in animals, mammals and humans.

The problem is solved by providing a drug and a pharmaceutical composition, wherein these contain recombinant mistletoe lectins for the treatment of metastatic tumors, preferably skin cancer, in particular malignant melanoma, wherein the recombinant mistletoe lectins have the following amino acid sequences:

The drug according to the invention preferably comprises the mistletoe lectin A-chain (MLA) and the mistletoe lectin B-chain (MLB), either individually or in combination in either case, also in the form of dimers (see, for example, EP 0 751 221 or EP 1 051 495).

The recombinant mistletoe lectin polypeptide of the mistletoe lectin A-chain comprises the following sequences: SEQ ID No. 1-3, including the isoforms thereof or a functional fragment thereof.

The recombinant mistletoe lectin polypeptide of the mistletoe lectin B-chain comprises the following sequences: SEQ ID No. 4-12, including the isoforms thereof or a functional fragment thereof.

(referred to comprehensively in the following as "recombinant mistletoe lectins")

Further, a recombinant mistletoe lectin according to the invention is preferred, a heterodimer comprising sequences of SEQ ID No. 1 and SEQ ID No. 4; see, for example, EP 0 751 221 (so-called Aviscuminum).

In the context of this invention, the expression "functional fragment" defines fragments of the stated polypeptides that have the same biological function as the polypeptide presented above comprising the particular amino acid sequence.

In this context, the expression "the same biological function" means, for example, that fragments or derivatives of the polypeptides induce the same signals in a cell as the stated peptides. Examples of fragments are peptide domains having defined functions. The "same biological function" also comprises the cytotoxicity, immunostimulation (of the native and the adaptive immune system), stimulation of the release of cytokines, antigenicity, the induction of expression or the activation of surface markers, the induction of apoptosis or endorphin stimulation.

In this case, the expression "biological activity of the recombinant mistletoe lectin" refers to any biological activity from the spectrum of the totality of biological activities of recombinant mistletoe lectin. A function of this type is the pharmacological effect of recombinant mistletoe lectin, for example.

Investigations of ML-I monomers yielded 25 different isoforms, which result from different combinations of various A- and B-chains and different states of glycosylation of the chains.

With respect to the present invention, a mistletoe lectin polypeptide or a fragment thereof that comprises the sequence variability of the various MLA and MLB chains is therefore also considered, according to the invention, for the sequences of SEQ ID No. 1-12.

The drug according to the invention preferably contains a recombinant mistletoe lectin polypeptide comprising sequences of SEQ ID No. 1-12 or a functional fragment thereof, or any combination thereof.

Further, it is preferable for recombinant mistletoe lectins according to the invention to be used in patient populations that do not respond to tumor preparations by means of a standard therapy, or in patient populations that include non-responders or therapeutic failures.

Therefore, the invention also relates to patients or patient populations of non-responders and therapeutic failures having metastatic tumors, in particular malignant melanomas and skin cancer, particularly preferably in stages III and IV, for whom a standard tumor therapy is unsuccessful.

The invention therefore relates to that selection of patients or patient populations who, after an initial treatment of tumors, in particular of malignant melanomas and skin cancer, with a tumor preparation as described above using malignant melanoma as an example, are then treated with the recombinant mistletoe lectins according to the invention. Therefore, those patients or patient populations are preferably treated with the recombinant mistletoe lectins according to the invention who are in the advanced or end stage of a tumor disease, wherein metastasis (stage III and IV), in particular involving malignant melanoma, has occurred. The invention therefore also relates to a combination therapy of a patient, for example to treat malignant melanoma, wherein, firstly, a first anti-tumor preparation, such as dacarbazine, dacarbazine combined with interferon-alpha, dacarbazine combined with vindesine, treosulfan combined with gemcitabine, imatinib is administered, followed by the additional administration of recombinant mistletoe lectins according to the invention exclusively or in combination.

Particularly preferably, the drug according to the invention is suitable for treating malignant melanomas in stage III and IV, since, surprisingly, a significant prolongation of the life of a single patient or a corresponding patient population can be achieved.

This result is completely unexpected, and this special suitability and advantage cannot be expected from a tumor drug per se.

The drug therefore relates to a new anti-tumorigenic preparation for the treatment of metastatic tumors, in particular of malignant melanomas, preferably in stage III and IV.

Within the meaning of this invention, a "malignant melanoma" refers to that which was intially described, wherein stages III and IV describe the forms of malignant melanoma that represent a metastasis of the tumor according to the invention (see, for example, the description in Pschyrembel.RTM., De Gruyter Verlag, Berlin).

The invention also relates to a drug for the treatment of malignant melanoma, which contains the recombinant mistletoe lectin polypeptide, possibly together with a pharmaceutically compatible carrier, with the formation of a pharmaceutical composition. Examples of particularly suitable pharmacologically compatible carriers are known to a person skillled in the art in the field of tumor medical science and comprise buffered sodium chloride solutions, water, inter alia, various types of detergents, sterile solutions, etc. Drugs that comprise such carriers can be formulated using conventional methods. These drugs can be administered to an individual in a suitable dosage. The administration can take place locally, orally, or parenterally, for example, intravenously, intraperitoneally, subcutaneously, intramuscularly, locally, intranasally, intrabronchially or intradermally, or via a catheter at a point in an artery. The type of dosing is determined by the treating physician in accordance with the clinical factors. A person skilled in the art knows that the type of dosing is dependent on various factors, such as the body height and weight, the body surface area, age, gender, or the general health of the patient, and on the preparation to be administered in particular, the duration and type of administration, and on other medications that may be administered in parallel.

The pharmaceutical composition that comprises the recombinant mistletoe polypeptides according to the invention can be administered locally or systemically.

The pharmaceutical composition is used, according to the invention, in the treatment of malignant melanoma.

A dosage of the mistletoe lectins according to the invention for human application of 2-10 ng/kg (body weight) has proven advantageous. The dosage in a range of 3-7 ng/kg is particularly advantageous. The quantity administered is preferably 5 ng/kg body weight. The preferred human dosage that is independent of body weight is 350 ng.

The drug according to the invention is applied over a period of at least 8 weeks at intervals of 1.times. day up to 1.times. per week. Preferably, the drug is administered 2 to 3.times. per week, while 2.times. per week is particularly preferred.

The invention therefore relates to a method for dosing the recombinant mistletoe lectins according to the invention or the drug according to the invention, wherein the dosage is 2 to 10 ng/kg (body weight). In particular, the invention relates to a method for dosing the recombinant mistletoe lectins according to the invention or the drug according to the invention, wherein the dosage is 200-500 ng, in particular 350 ng, and is administered to the patient at least 1.times. per week. The patient is preferably a patient in the advanced or end stage of a tumor disease, wherein metastasis (stage III and IV), in particular involving malignant melanoma, has occurred.

The following examples and figures are provided to explain the invention, although the invention is not limited to these examples.

EXAMPLES and FIGURES

Example 1 of a Composition of the Drug

TABLE-US-00001 Solution for injection: 1 mL ampule with 0.5 mL/1.0 mL injection solution Aviscuminum 200-500 ng Sodium monohydrogen phosphate 2.8 mg 5.6 mg dihydrate Sodium dihydrogen phosphate 0.078 mg 0.155 mg dihydrate Sodium chloride 3.3 mg 6.7 mg Polyoxyethylene sorbitan ester 0.1 mg 0.1 mg (polysorbate) Glutaminic acid 0.1 mg 0.1 mg Water for injection to make 0.5 ml to make 1.0 mL

Example 2 of a Composition of the Drug

TABLE-US-00002 Powder for making a solution for injection, 2R glass vial with Aviscuminum 200-500 ng Trehalose 40.0 mg Sodium chloride 1.0 mg Tris(hydroxymethyl)aminomethane (TRIS) 0.6 mg Polyoxyethylene sorbitan ester (polysorbate) 0.1 mg Hydrochloric acid for adjusting the pH value for administration, the powder is dissolved in 0.5 mL or 1.0 mL water for injection

A clinical study was conducted to investigate whether recombinant mistletoe lectin (Aviscumin, "rML" according to EP 0 751 221) can halt the progression of the disease in patients with stage IV metastatic malignant melanoma after failure of standard therapy, or whether the survival of the patient can be prolonged. The study involved 31 evaluatable patients. Although the progression-free survival was changed, surprisingly, the survival of the patients was significantly increased. The median survival of the patients was 11.0 months, and the one-year survival rate was 45.0%. The prolongation of the survival time was independent of the number of pretreatments and independent of the general condition (ECOG status 0 or 1). The one-year survival rate of a comparable control group, which can be calculated on the basis of the criteria of gender, brain metastases present/not present, the type of metastases (visceral/non-visceral), and general condition (ECOG) according to the data of Korn et al. 2008 (supra), is 33.1%. No side effects occurred over the course of treatment with rML that had a severity of >2 according to the CTC criteria. Therefore, the use of rML is very well tolerated.

TABLE-US-00003 TABLE 1 Demographic data Patients, n = 31 Sex n (%) Male 16 (51.6) female 15 (48.4) ECOG n (%) 0 17 (54.8) 1 14 (45.2) Age Mean 65.32 (yrs) SD 13.53 Median 67.00 Range 20-86 Weight Mean 76.53 (kg) SD 12.42 Median 77.50 Type of n (%) cutaneous 26 (83.9) melanoma mucosal 3 (9.7) occult 1 (3.2) other 1 (3.2) No. of metastatic n (%) 1 13 (41.9) sites 2 13 (41.9) 3 4 (12.9) 4 1 (3.2) LDH (U/L) Mean 262.71 at BL SD 89.17 Median 245.00 LDH elevation n (%) yes 17 (54.8) no 14 (45.2) ECOG = Eastern Cooperative Oncology Group, LDH = Lactate dehydrogenase

Case Study 1: Patient, female, age: 78 years, stage IV malignant melanoma, ECOG: 1, Metastases in lymph nodes and lungs, 2 pretreatments with dacarbazine, 15 cycles (420 days) therapy with Aviscuminum (rML) 350 ng, 2.times.per week, Stabilization of the disease (no tumor growth) for a period of 433 days, survival time: 453 days Case Study 2: Patient, male, age: 79 years, stage IV malignant melanoma, ECOG: 0, multiple metastases in the liver and lungs, 5 pretreatments with dacarbazine, dacarbazine combined with interferon-alpha, dacarbazine combined with vindesine, treosulfan combined with gemcitabine, imatinib 4 cycles (112 days) therapy with Aviscuminum (rML) 350 ng, 2.times.per week, Stabilization of the disease (no tumor growth) for a period of 116 days, survival time: 435 days Description of the Figures

FIG. 1 describes the survival curve according to the Kaplan-Meier method that was evaluated with respect to the study data.

SEQUENCE LISTINGS

1

121253PRTArtificial sequenceEP0751221 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deletedmisc_feature(5)..(5)Xaa can be Ile or Leumisc_feature(16)..(16)Xaa can be Glu or Asp 1Xaa Tyr Glu Arg Xaa Arg Leu Arg Val Thr His Gln Thr Thr Gly Xaa 1 5 10 15 Glu Tyr Phe Arg Phe Ile Thr Leu Leu Arg Asp Tyr Val Ser Ser Gly 20 25 30 Ser Phe Ser Asn Glu Ile Pro Leu Leu Arg Gln Ser Thr Ile Pro Val 35 40 45 Ser Asp Ala Gln Arg Phe Val Leu Val Glu Leu Thr Asn Gln Gly Gly 50 55 60 Asp Ser Ile Thr Ala Ala Ile Asp Val Thr Asn Leu Tyr Val Val Ala 65 70 75 80 Tyr Gln Ala Gly Asp Gln Ser Tyr Phe Leu Arg Asp Ala Pro Arg Gly 85 90 95 Ala Glu Thr His Leu Phe Thr Gly Thr Thr Arg Ser Ser Leu Pro Phe 100 105 110 Asn Gly Ser Tyr Pro Asp Leu Glu Arg Tyr Ala Gly His Arg Asp Gln 115 120 125 Ile Pro Leu Gly Ile Asp Gln Leu Ile Gln Ser Val Thr Ala Leu Arg 130 135 140 Phe Pro Gly Gly Ser Thr Arg Thr Gln Ala Arg Ser Ile Leu Ile Leu 145 150 155 160 Ile Gln Met Ile Ser Glu Ala Ala Arg Phe Asn Pro Ile Leu Trp Arg 165 170 175 Ala Arg Gln Tyr Ile Asn Ser Gly Ala Ser Phe Leu Pro Asp Val Tyr 180 185 190 Met Leu Glu Leu Glu Thr Ser Trp Gly Gln Gln Ser Thr Gln Val Gln 195 200 205 His Ser Thr Asp Gly Val Phe Asn Asn Pro Ile Arg Leu Ala Ile Pro 210 215 220 Pro Gly Asn Phe Val Thr Leu Thr Asn Val Arg Asp Val Ile Ala Ser 225 230 235 240 Leu Ala Ile Met Leu Phe Val Cys Gly Glu Arg Pro Ser 245 250 2256PRTArtificial sequenceEP1051495 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deletedmisc_feature(16)..(16)Xaa can be Asp or Glumisc_feature(64)..(64)Xaa can be Gly or Glnmisc_feature(67)..(67)Xaa can be Ile or Valmisc_feature(76)..(76)Xaa can be Leu or Alamisc_feature(108)..(108)Xaa can be Asp-Arg or can be deletedmisc_feature(114)..(114)Xaa can be Asn or Thrmisc_feature(118)..(118)Xaa can be Pro or Thrmisc_feature(135)..(135)Xaa can be Asp or Glumisc_feature(142)..(142)Xaa can be Ser or Thrmisc_feature(146)..(146)Xaa can be Phe or Tyrmisc_feature(153)..(153)Xaa can be Ala or Thrmisc_feature(178)..(178)Xaa can be Ala or Tyrmisc_feature(181)..(181)Xaa can be Tyr or Aspmisc_feature(186)..(186)Xaa can be Ala or Glumisc_feature(192)..(192)Xaa can be Val or Metmisc_feature(220)..(220)Xaa can be Ile or Phemisc_feature(225)..(226)Xaa can be Pro-Ser or Pro-Thrmisc_feature(233)..(233)Xaa can be Thr or Sermisc_feature(237)..(237)Xaa can be Asp or Sermisc_feature(255)..(256)Xaa can be Ser-Ser or can be deleted 2Xaa Tyr Glu Arg Leu Arg Leu Arg Val Thr His Gln Thr Thr Gly Xaa 1 5 10 15 Glu Tyr Phe Arg Phe Ile Thr Leu Leu Arg Asp Tyr Val Ser Ser Gly 20 25 30 Ser Phe Ser Asn Glu Ile Pro Leu Leu Arg Gln Ser Thr Ile Pro Val 35 40 45 Ser Asp Ala Gln Arg Phe Val Leu Val Glu Leu Thr Asn Gln Gly Xaa 50 55 60 Asp Ser Xaa Thr Ala Ala Ile Asp Val Thr Asn Xaa Tyr Val Val Ala 65 70 75 80 Tyr Gln Ala Gly Asp Gln Ser Tyr Phe Leu Arg Asp Ala Pro Arg Gly 85 90 95 Ala Glu Thr His Leu Phe Thr Gly Thr Thr Arg Xaa Ser Ser Leu Pro 100 105 110 Phe Xaa Gly Ser Tyr Xaa Asp Leu Glu Arg Tyr Ala Gly His Arg Asp 115 120 125 Gln Ile Pro Leu Gly Ile Xaa Gln Leu Ile Gln Ser Val Xaa Ala Leu 130 135 140 Arg Xaa Pro Gly Gly Ser Thr Arg Xaa Gln Ala Arg Ser Ile Leu Ile 145 150 155 160 Leu Ile Gln Met Ile Ser Glu Ala Ala Arg Phe Asn Pro Ile Leu Trp 165 170 175 Arg Xaa Arg Gln Xaa Ile Asn Ser Gly Xaa Ser Phe Leu Pro Asp Xaa 180 185 190 Tyr Met Leu Glu Leu Glu Thr Ser Trp Gly Gln Gln Ser Thr Gln Val 195 200 205 Gln His Ser Thr Asp Gly Val Phe Asn Asn Pro Xaa Arg Leu Ala Ile 210 215 220 Xaa Xaa Gly Asn Phe Val Thr Leu Xaa Asn Val Arg Xaa Val Ile Ala 225 230 235 240 Ser Leu Ala Ile Met Leu Phe Val Cys Gly Glu Arg Pro Ser Xaa Xaa 245 250 255 3257PRTArtificial sequenceEP1051495 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deleted 3Xaa Tyr Glu Arg Leu Arg Leu Arg Val Thr His Gln Thr Thr Gly Asp 1 5 10 15 Glu Tyr Phe Arg Phe Ile Thr Leu Leu Arg Asp Tyr Val Ser Ser Gly 20 25 30 Ser Phe Ser Asn Glu Ile Pro Leu Leu Arg Gln Ser Thr Ile Pro Val 35 40 45 Ser Asp Ala Gln Arg Phe Val Leu Val Glu Leu Thr Asn Gln Gly Gln 50 55 60 Asp Ser Ile Thr Ala Ala Ile Asp Val Thr Asn Ala Tyr Val Val Ala 65 70 75 80 Tyr Gln Ala Gly Asp Gln Ser Tyr Phe Leu Arg Asp Ala Pro Arg Gly 85 90 95 Ala Glu Thr His Leu Phe Thr Gly Thr Thr Arg Asp Arg Ser Ser Leu 100 105 110 Pro Phe Thr Gly Ser Tyr Thr Asp Leu Glu Arg Tyr Ala Gly His Arg 115 120 125 Asp Gln Ile Pro Leu Gly Ile Glu Gln Leu Ile Gln Ser Val Ser Ala 130 135 140 Leu Arg Tyr Pro Gly Gly Ser Thr Arg Ala Gln Ala Arg Ser Ile Leu 145 150 155 160 Ile Leu Ile Gln Met Ile Ser Glu Ala Ala Arg Phe Asn Pro Ile Leu 165 170 175 Trp Arg Tyr Arg Gln Asp Ile Asn Ser Gly Glu Ser Phe Leu Pro Asp 180 185 190 Met Tyr Met Leu Glu Leu Glu Thr Ser Trp Gly Gln Gln Ser Thr Gln 195 200 205 Val Gln His Ser Thr Asp Gly Val Phe Asn Asn Pro Phe Arg Leu Ala 210 215 220 Ile Ser Thr Gly Asn Phe Val Thr Leu Ser Asn Val Arg Ser Val Ile 225 230 235 240 Ala Ser Leu Ala Ile Met Leu Phe Val Cys Gly Glu Arg Pro Ser Ser 245 250 255 Ser 4264PRTArtificial sequenceEP0751221 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deleted 4Xaa Asp Asp Val Thr Cys Ser Ala Ser Glu Pro Thr Val Arg Ile Val 1 5 10 15 Gly Arg Asn Gly Met Cys Val Asp Val Arg Asp Asp Asp Phe Arg Asp 20 25 30 Gly Asn Gln Ile Gln Leu Trp Pro Ser Lys Ser Asn Asn Asp Pro Asn 35 40 45 Gln Leu Trp Thr Ile Lys Arg Asp Gly Thr Ile Arg Ser Asn Gly Ser 50 55 60 Cys Leu Thr Thr Tyr Gly Tyr Thr Ala Gly Val Tyr Val Met Ile Phe 65 70 75 80 Asp Cys Asn Thr Ala Val Arg Glu Ala Thr Leu Trp Gln Ile Trp Gly 85 90 95 Asn Gly Thr Ile Ile Asn Pro Arg Ser Asn Leu Val Leu Ala Ala Ser 100 105 110 Ser Gly Ile Lys Gly Thr Thr Leu Thr Val Gln Thr Leu Asp Tyr Thr 115 120 125 Leu Gly Gln Gly Trp Leu Ala Gly Asn Asp Thr Ala Pro Arg Glu Val 130 135 140 Thr Ile Tyr Gly Phe Arg Asp Leu Cys Met Glu Ser Asn Gly Gly Ser 145 150 155 160 Val Trp Val Glu Thr Cys Val Ser Ser Gln Lys Asn Gln Arg Trp Ala 165 170 175 Leu Tyr Gly Asp Gly Ser Ile Arg Pro Lys Gln Asn Gln Asp Gln Cys 180 185 190 Leu Thr Cys Gly Arg Asp Ser Val Ser Thr Val Ile Asn Ile Val Ser 195 200 205 Cys Ser Ala Gly Ser Ser Gly Gln Arg Trp Val Phe Thr Asn Glu Gly 210 215 220 Ala Ile Leu Asn Leu Lys Asn Gly Leu Ala Met Asp Val Ala Gln Ala 225 230 235 240 Asn Pro Lys Leu Arg Arg Ile Ile Ile Tyr Pro Ala Thr Gly Lys Pro 245 250 255 Asn Gln Met Trp Leu Pro Val Pro 260 5268PRTArtificial sequenceEP0751221 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deleted 5Xaa Asp Asp Val Thr Cys Ser Ala Ser Glu Pro Thr Val Arg Ile Val 1 5 10 15 Gly Arg Asn Gly Met Cys Val Asp Val Arg Asp Asp Asp Phe Arg Asp 20 25 30 Gly Asn Gln Ile Gln Leu Trp Pro Ser Lys Ser Asn Asn Asp Pro Asn 35 40 45 Gln Leu Trp Thr Ile Lys Arg Asp Gly Thr Ile Arg Ser Asn Gly Ser 50 55 60 Cys Leu Thr Thr Tyr Gly Tyr Thr Ala Gly Val Tyr Val Met Ile Phe 65 70 75 80 Asp Cys Asn Thr Ala Val Arg Glu Ala Thr Leu Trp Gln Ile Trp Gly 85 90 95 Asn Gly Thr Ile Ile Asn Pro Arg Ser Asn Leu Val Leu Ala Ala Ser 100 105 110 Ser Gly Ile Lys Gly Thr Thr Leu Thr Val Gln Thr Leu Asp Tyr Thr 115 120 125 Leu Gly Gln Gly Trp Leu Ala Gly Asn Asp Thr Ala Pro Arg Glu Val 130 135 140 Thr Ile Tyr Gly Phe Arg Asp Leu Cys Met Glu Ser Asn Gly Gly Ser 145 150 155 160 Val Trp Val Glu Thr Cys Val Ser Ser Gln Lys Asn Gln Arg Trp Ala 165 170 175 Leu Tyr Gly Asp Gly Ser Ile Arg Pro Lys Gln Asn Gln Asp Gln Cys 180 185 190 Leu Thr Cys Gly Arg Asp Ser Val Ser Thr Val Ile Asn Ile Val Ser 195 200 205 Cys Ser Ala Gly Ser Ser Gly Gln Arg Trp Val Phe Thr Asn Glu Gly 210 215 220 Ala Ile Leu Asn Leu Lys Asn Gly Leu Ala Met Asp Val Ala Gln Ala 225 230 235 240 Asn Pro Lys Leu Arg Arg Ile Ile Ile Tyr Pro Ala Thr Gly Lys Pro 245 250 255 Asn Gln Met Trp Leu Pro Val Pro Gly Gly Tyr His 260 265 6265PRTArtificial sequenceEP1051495 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deletedmisc_feature(19)..(19)Xaa can be Asn or Sermisc_feature(22)..(22)Xaa can be Cys or Argmisc_feature(57)..(57)Xaa can be Gly or Asnmisc_feature(96)..(96)Xaa can be Gly or Asnmisc_feature(158)..(158)Xaa can be Gly or Glnmisc_feature(167)..(167)Xaa can be Val or Aspmisc_feature(171)..(171)Xaa can be Gln or Lysmisc_feature(174)..(175)Xaa can be Gly or can be deleted or can be Gly- Arg or Gly-Lys or Arg or Lysmisc_feature(196)..(196)Xaa can be Cys or Val or Sermisc_feature(212)..(213)Xaa can be Ala-Ala or Ala-Gly or Gly-Ala or Gly- Glymisc_feature(215)..(216)Xaa can be Ser-Ser or Ser-Gly or Gly-Ser or Gly- Glymisc_feature(225)..(225)Xaa can be Gly or Tyrmisc_feature(232)..(236)Xaa232 can be Asn, Ser, Thr or Lys, Xaa233 can be Ser or Gly, Xaa234 can be Leu or Pro, Xaa235 can be Ala or Met, Xaa 236 can be Met or Valmisc_feature(265)..(265)Xaa can be Pro or Phe 6Xaa Asp Asp Val Thr Cys Ser Ala Ser Glu Pro Thr Val Arg Ile Val 1 5 10 15 Gly Arg Xaa Gly Met Xaa Val Asp Val Arg Asp Asp Asp Phe His Asp 20 25 30 Gly Asn Gln Ile Gln Leu Trp Pro Ser Lys Ser Asn Asn Asp Pro Asn 35 40 45 Gln Leu Trp Thr Ile Lys Arg Asp Xaa Thr Ile Arg Ser Asn Gly Ser 50 55 60 Cys Leu Thr Thr Tyr Gly Tyr Thr Ala Gly Val Tyr Val Met Ile Phe 65 70 75 80 Asp Cys Asn Thr Ala Val Arg Glu Ala Thr Ile Trp Gln Ile Trp Xaa 85 90 95 Asn Gly Thr Ile Ile Asn Pro Arg Ser Asn Leu Val Leu Ala Ala Ser 100 105 110 Ser Gly Ile Lys Gly Thr Thr Leu Thr Val Gln Thr Leu Asp Tyr Thr 115 120 125 Leu Gly Gln Gly Trp Leu Ala Gly Asn Asp Thr Ala Pro Arg Glu Val 130 135 140 Thr Ile Tyr Gly Phe Arg Asp Leu Cys Met Glu Ser Asn Xaa Gly Ser 145 150 155 160 Val Trp Val Glu Thr Cys Xaa Ser Ser Gln Xaa Asn Gln Xaa Xaa Trp 165 170 175 Ala Leu Tyr Gly Asp Gly Ser Ile Arg Pro Lys Gln Asn Gln Asp Gln 180 185 190 Cys Leu Thr Xaa Gly Arg Asp Ser Val Ser Thr Val Ile Asn Ile Val 195 200 205 Ser Cys Ser Xaa Xaa Ser Xaa Xaa Gln Arg Trp Val Phe Thr Asn Glu 210 215 220 Xaa Ala Ile Leu Asn Leu Lys Xaa Xaa Xaa Xaa Xaa Asp Val Ala Gln 225 230 235 240 Ala Asn Pro Lys Leu Arg Arg Ile Ile Ile Tyr Pro Ala Thr Gly Lys 245 250 255 Pro Asn Gln Met Trp Leu Pro Val Xaa 260 265 7264PRTArtificial sequenceEP1051495 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deleted 7Xaa Asp Asp Val Thr Cys Ser Ala Ser Glu Pro Thr Val Arg Ile Val 1 5 10 15 Gly Arg Asn Gly Met Cys Val Asp Val Arg Asp Asp Asp Phe His Asp 20 25 30 Gly Asn Gln Ile Gln Leu Trp Pro Ser Lys Ser Asn Asn Asp Pro Asn 35 40 45 Gln Leu Trp Thr Ile Lys Arg Asp Gly Thr Ile Arg Ser Asn Gly Ser 50 55 60 Cys Leu Thr Thr Tyr Gly Tyr Thr Ala Gly Val Tyr Val Met Ile Phe 65 70 75 80 Asp Cys Asn Thr Ala Val Arg Glu Ala Thr Ile Trp Gln Ile Trp Gly 85 90 95 Asn Gly Thr Ile Ile Asn Pro Arg Ser Asn Leu Val Leu Ala Ala Ser 100 105 110 Ser Gly Ile Lys Gly Thr Thr Leu Thr Val Gln Thr Leu Asp Tyr Thr 115 120 125 Leu Gly Gln Gly Trp Leu Ala Gly Asn Asp Thr Ala Pro Arg Glu Val 130 135 140 Thr Ile Tyr Gly Phe Arg Asp Leu Cys Met Glu Ser Asn Gly Gly Ser 145 150 155 160 Val Trp Val Glu Thr Cys Val Ser Ser Gln Gln Asn Gln Arg Trp Ala 165 170 175 Leu Tyr Gly Asp Gly Ser Ile Arg Pro Lys Gln Asn Gln Asp Gln Cys 180 185 190 Leu Thr Cys Gly Arg Asp Ser Val Ser Thr Val Ile Asn Ile Val Ser 195 200 205 Cys Ser Ala Gly Ser Ser Gly Gln Arg Trp Val Phe Thr Asn Glu Gly 210 215 220 Ala Ile Leu Asn Leu Lys Asn Gly Leu Ala Met Asp Val Ala Gln Ala 225 230 235 240 Asn Pro Lys Leu Arg Arg Ile Ile Ile Tyr Pro Ala Thr Gly Lys Pro 245 250 255 Asn Gln Met Trp Leu Pro Val Pro 260 8265PRTArtificial sequenceEP1051495 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deleted 8Xaa Asp Asp Val Thr Cys Ser Ala Ser Glu Pro Thr Val Arg Ile Val 1 5 10 15 Gly Arg Asn Gly Met Arg Val Asp Val Arg Asp Asp Asp Phe His Asp

20 25 30 Gly Asn Gln Ile Gln Leu Trp Pro Ser Lys Ser Asn Asn Asp Pro Asn 35 40 45 Gln Leu Trp Thr Ile Lys Arg Asp Gly Thr Ile Arg Ser Asn Gly Ser 50 55 60 Cys Leu Thr Thr Tyr Gly Tyr Thr Ala Gly Val Tyr Val Met Ile Phe 65 70 75 80 Asp Cys Asn Thr Ala Val Arg Glu Ala Thr Ile Trp Gln Ile Trp Asp 85 90 95 Asn Gly Thr Ile Ile Asn Pro Arg Ser Asn Leu Val Leu Ala Ala Ser 100 105 110 Ser Gly Ile Lys Gly Thr Thr Leu Thr Val Gln Thr Leu Asp Tyr Thr 115 120 125 Leu Gly Gln Gly Trp Leu Ala Gly Asn Asp Thr Ala Pro Arg Glu Val 130 135 140 Thr Ile Tyr Gly Phe Arg Asp Leu Cys Met Glu Ser Asn Gly Gly Ser 145 150 155 160 Val Trp Val Glu Thr Cys Asp Ser Ser Gln Lys Asn Gln Gly Lys Trp 165 170 175 Ala Leu Tyr Gly Asp Gly Ser Ile Arg Pro Lys Gln Asn Gln Asp Gln 180 185 190 Cys Leu Thr Ser Gly Arg Asp Ser Val Ser Thr Val Ile Asn Ile Val 195 200 205 Ser Cys Ser Gly Ala Ser Gly Ser Gln Arg Trp Val Phe Thr Asn Glu 210 215 220 Gly Ala Ile Leu Asn Leu Lys Asn Gly Leu Ala Met Asp Val Ala Gln 225 230 235 240 Ala Asn Pro Lys Leu Arg Arg Ile Ile Ile Tyr Pro Ala Thr Gly Lys 245 250 255 Pro Asn Gln Met Trp Leu Pro Val Phe 260 265 9265PRTArtificial sequenceEP1051495 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deleted 9Xaa Asp Asp Val Thr Cys Ser Ala Ser Glu Pro Thr Val Arg Ile Val 1 5 10 15 Gly Arg Ser Gly Met Arg Val Asp Val Arg Asp Asp Asp Phe His Asp 20 25 30 Gly Asn Gln Ile Gln Leu Trp Pro Ser Lys Ser Asn Asn Asp Pro Asn 35 40 45 Gln Leu Trp Thr Ile Lys Arg Asp Asn Thr Ile Arg Ser Asn Gly Ser 50 55 60 Cys Leu Thr Thr Tyr Gly Tyr Thr Ala Gly Val Tyr Val Met Ile Phe 65 70 75 80 Asp Cys Asn Thr Ala Val Arg Glu Ala Thr Ile Trp Gln Ile Trp Asp 85 90 95 Asn Gly Thr Ile Ile Asn Pro Arg Ser Asn Leu Val Leu Ala Ala Ser 100 105 110 Ser Gly Ile Lys Gly Thr Thr Leu Thr Val Gln Thr Leu Asp Tyr Thr 115 120 125 Leu Gly Gln Gly Trp Leu Ala Gly Asn Asp Thr Ala Pro Arg Glu Val 130 135 140 Thr Ile Tyr Gly Phe Arg Asp Leu Cys Met Glu Ser Asn Gln Gly Ser 145 150 155 160 Val Trp Val Glu Thr Cys Asp Ser Ser Gln Lys Asn Gln Gly Lys Trp 165 170 175 Ala Leu Tyr Gly Asp Gly Ser Ile Arg Pro Lys Gln Asn Gln Asp Gln 180 185 190 Cys Leu Thr Val Gly Arg Asp Ser Val Ser Thr Val Ile Asn Ile Val 195 200 205 Ser Cys Ser Gly Ala Ser Gly Ser Gln Arg Trp Val Phe Thr Asn Glu 210 215 220 Tyr Ala Ile Leu Asn Leu Lys Ser Gly Leu Ala Met Asp Val Ala Gln 225 230 235 240 Ala Asn Pro Lys Leu Arg Arg Ile Ile Ile Tyr Pro Ala Thr Gly Lys 245 250 255 Pro Asn Gln Met Trp Leu Pro Val Phe 260 265 10265PRTArtificial sequenceEP1051495 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deleted 10Xaa Asp Asp Val Thr Cys Ser Ala Ser Glu Pro Thr Val Arg Ile Val 1 5 10 15 Gly Arg Asn Gly Met Arg Val Asp Val Arg Asp Asp Asp Phe His Asp 20 25 30 Gly Asn Gln Ile Gln Leu Trp Pro Ser Lys Ser Asn Asn Asp Pro Asn 35 40 45 Gln Leu Trp Thr Ile Lys Arg Asp Gly Thr Ile Arg Ser Asn Gly Ser 50 55 60 Cys Leu Thr Thr Tyr Gly Tyr Thr Ala Gly Val Tyr Val Met Ile Phe 65 70 75 80 Asp Cys Asn Thr Ala Val Arg Glu Ala Thr Ile Trp Gln Ile Trp Asp 85 90 95 Asn Gly Thr Ile Ile Asn Pro Arg Ser Asn Leu Val Leu Ala Ala Ser 100 105 110 Ser Gly Ile Lys Gly Thr Thr Leu Thr Val Gln Thr Leu Asp Tyr Thr 115 120 125 Leu Gly Gln Gly Trp Leu Ala Gly Asn Asp Thr Ala Pro Arg Glu Val 130 135 140 Thr Ile Tyr Gly Phe Arg Asp Leu Cys Met Glu Ser Asn Gly Gly Ser 145 150 155 160 Val Trp Val Glu Thr Cys Asp Ser Ser Gln Lys Asn Gln Gly Lys Trp 165 170 175 Ala Leu Tyr Gly Asp Gly Ser Ile Arg Pro Lys Gln Asn Gln Asp Gln 180 185 190 Cys Leu Thr Ser Gly Arg Asp Ser Val Ser Thr Val Ile Asn Ile Val 195 200 205 Ser Cys Ser Gly Ala Ser Gly Ser Gln Arg Trp Val Phe Thr Asn Glu 210 215 220 Gly Ala Ile Leu Asn Leu Lys Thr Gly Leu Ala Met Asp Val Ala Gln 225 230 235 240 Ala Asn Pro Lys Leu Arg Arg Ile Ile Ile Tyr Pro Ala Thr Gly Lys 245 250 255 Pro Asn Gln Met Trp Leu Pro Val Phe 260 265 11265PRTArtificial sequenceEP1051495 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deleted 11Xaa Asp Asp Val Thr Cys Ser Ala Ser Glu Pro Thr Val Arg Ile Val 1 5 10 15 Gly Arg Asn Gly Met Arg Val Asp Val Arg Asp Asp Asp Phe His Asp 20 25 30 Gly Asn Gln Ile Gln Leu Trp Pro Ser Lys Ser Asn Asn Asp Pro Asn 35 40 45 Gln Leu Trp Thr Ile Lys Arg Asp Gly Thr Ile Arg Ser Asn Gly Ser 50 55 60 Cys Leu Thr Thr Tyr Gly Tyr Thr Ala Gly Val Tyr Val Met Ile Phe 65 70 75 80 Asp Cys Asn Thr Ala Val Arg Glu Ala Thr Ile Trp Gln Ile Trp Asp 85 90 95 Asn Gly Thr Ile Ile Asn Pro Arg Ser Asn Leu Val Leu Ala Ala Ser 100 105 110 Ser Gly Ile Lys Gly Thr Thr Leu Thr Val Gln Thr Leu Asp Tyr Thr 115 120 125 Leu Gly Gln Gly Trp Leu Ala Gly Asn Asp Thr Ala Pro Arg Glu Val 130 135 140 Thr Ile Tyr Gly Phe Arg Asp Leu Cys Met Glu Ser Asn Gly Gly Ser 145 150 155 160 Val Trp Val Glu Thr Cys Asp Ser Ser Gln Lys Asn Gln Gly Lys Trp 165 170 175 Ala Leu Tyr Gly Asp Gly Ser Ile Arg Pro Lys Gln Asn Gln Asp Gln 180 185 190 Cys Leu Thr Ser Gly Arg Asp Ser Val Ser Thr Val Ile Asn Ile Val 195 200 205 Ser Cys Ser Gly Ala Ser Gly Ser Gln Arg Trp Val Phe Thr Asn Glu 210 215 220 Gly Ala Ile Leu Asn Leu Lys Lys Gly Pro Ala Met Asp Val Ala Gln 225 230 235 240 Ala Asn Pro Lys Leu Arg Arg Ile Ile Ile Tyr Pro Ala Thr Gly Lys 245 250 255 Pro Asn Gln Met Trp Leu Pro Val Phe 260 265 12265PRTArtificial sequenceEP1051495 recombinant Proteinmisc_feature(1)..(1)Xaa can be Met or can be deleted 12Xaa Asp Asp Val Thr Cys Ser Ala Ser Glu Pro Thr Val Arg Ile Val 1 5 10 15 Gly Arg Asn Gly Met Arg Val Asp Val Arg Asp Asp Asp Phe His Asp 20 25 30 Gly Asn Gln Ile Gln Leu Trp Pro Ser Lys Ser Asn Asn Asp Pro Asn 35 40 45 Gln Leu Trp Thr Ile Lys Arg Asp Gly Thr Ile Arg Ser Asn Gly Ser 50 55 60 Cys Leu Thr Thr Tyr Gly Tyr Thr Ala Gly Val Tyr Val Met Ile Phe 65 70 75 80 Asp Cys Asn Thr Ala Val Arg Glu Ala Thr Ile Trp Gln Ile Trp Asp 85 90 95 Asn Gly Thr Ile Ile Asn Pro Arg Ser Asn Leu Val Leu Ala Ala Ser 100 105 110 Ser Gly Ile Lys Gly Thr Thr Leu Thr Val Gln Thr Leu Asp Tyr Thr 115 120 125 Leu Gly Gln Gly Trp Leu Ala Gly Asn Asp Thr Ala Pro Arg Glu Val 130 135 140 Thr Ile Tyr Gly Phe Arg Asp Leu Cys Met Glu Ser Asn Gly Gly Ser 145 150 155 160 Val Trp Val Glu Thr Cys Asp Ser Ser Gln Lys Asn Gln Gly Lys Trp 165 170 175 Ala Leu Tyr Gly Asp Gly Ser Ile Arg Pro Lys Gln Asn Gln Asp Gln 180 185 190 Cys Leu Thr Ser Gly Arg Asp Ser Val Ser Thr Val Ile Asn Ile Val 195 200 205 Ser Cys Ser Gly Ala Ser Gly Ser Gln Arg Trp Val Phe Thr Asn Glu 210 215 220 Gly Ala Ile Leu Asn Leu Lys Asn Ser Leu Met Val Asp Val Ala Gln 225 230 235 240 Ala Asn Pro Lys Leu Arg Arg Ile Ile Ile Tyr Pro Ala Thr Gly Lys 245 250 255 Pro Asn Gln Met Trp Leu Pro Val Phe 260 265