MXPA99005163A - Keratinocyte growth factors and uses thereof - Google Patents

Abstract

The present invention relates to keratinocyte growth factors and to uses thereof.

Description

FACTORS OF GROWTH OF QÜERATINOCYTES AND THEIR USE IN COMBINATION WITH DERIVATIVES OF PEPTIDES LIKELY TO GLUCAGON FIELD OF THE INVENTION The present invention relates to the growth factors of keratinocytes and to the uses thereof.

BACKGROUND OF THE INVENTION The complex process of tissue generation and regeneration is mediated by several protein factors sometimes referred to as soft tissue growth factors. These molecules are generally released by a cell type and act to influence the proliferation of other cell types (Rubin et al. (1989) Proc. Nat'l Acad. Sci. USA, 86: 802-806). There are also some growth factors released from cells that themselves have the ability to respond to such growth factors. Some soft or soft growth factors are secreted by particular cell types Ref.30425 and influence the proliferation, differentiation, and / or maturation of the cells responsible for the development of multicellular organisms (Finch et al. (1989), Science, 245: 752-755). In addition to their roles in the development of organisms, some soft or soft tissue growth factors are significant in the health and ongoing maintenance of more mature systems. For example, in mammals there are many systems where rapid cell changes occur. Such systems include the skin and the gastrointestinal tract, both of which are comprised of epithelial cells. Included within this group of soft tissue growth factors is a family of fibroblast growth factor proteins (FGFs). The family of fibroblast growth factors (FGF) is now known to consist of at least fourteen members, especially FGF-1 to FGF-10 and homologous factors FHF-1 to FHF-4, which share a connection between structures primary: basic fibroblast growth factor, bFGF (Abraham et al. (1986), EMBO J., 5: 2523-2528); the growth factor of acidic fibroblasts, aFGF (Jaye et al (1986), Science, 233: 541-545); the product of the int-2 gene, int-2 (Dickson &Peters (1897), Nature, 326: 833); hst / kFGF (Delli-Bovi et al. (1987), Cell, 50: 729-737 and Yoshida et al. (1987), Proc. Nati, Acad. Sci. USA, 84: 7305-7309); FGF-5 (Zhan et al (1988), Mol Cell Cell Biol. 8: 3487-3495); FGF-6 (Marics et al (1989), Oncogene, 4: 335-340); keratinocyte growth factor, KGF (Finch et al (1989), Science, 24: 752-755); hisactofilin (Habazzettl et al. (1992), Nature, 359: 855-858); FGF-9 (Miyamoto et al. (1993), Mol Cell Cell Biol., 13 (7): 4251-4259); and fibroblast growth factor-10, also known as keratinocyte growth factor-2, KGF-2 (WO 96/25422). More recently, four homologous factors (or "FHFs") were identified from the human retina by a combination of random cDNA sequencing, searches of existing sequence databases and polymerase chain reactions based on homologies ( Smalwood et al. (1966), Proc. Nati, Acad. Sci. USA, 93: 9850-9857). It has been proposed that FHF-1, FHF-2, FHF-3 and FHF-4 should be designated as FGF-11, FGE-12, FGF-13 and FGF-14, respectively, in accordance with the recommendation of the Nomenclature Committee ( Coulier et al. (1997), Journal of Molecular Evolution, 44: 43-56).

It is an object of the present invention to provide keratinocyte growth factors and uses thereof.

Brief Description of the Invention The present invention is directed to KGF protein product (s). This product (s) of KGF proteins have (are) general applicability and may retain some or all of the biological activity of KGF. Still another aspect is related to the methods of modulation of growth and differentiation of epithelial cells. Specifically, a patient in need of stimulation (including cytoprotection, proliferation and / or differentiation) of the epithelial cells will be delivered or administered with therapeutically effective or prophylactically effective amounts of a protein product (s). of KGF. Additional aspects and advantages of the invention will be apparent to those skilled in the art upon consideration of the following description, which details the practice of the present invention.

Brief Description of the Figures Numerous aspects and advantages of the present invention will become apparent during the review of the Figures, wherein: Figure 1 shows the nucleotide (SEQ ID NO: 1) and amino acid (SEQ ID NO: 2) sequences of KGF (the nucleotides encoding the mature form of mature KGF is shown by bases 96 to 582 of SEQ ID NO: 1 and the mature form of KGF is shown by amino acid residues 32 to 194 of SEQ ID NO: 2), with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 2 shows the nucleotide (SEQ ID NO: 3) and amino acid (SEQ ID NO: 4) sequences of C (1,15) S, a KGF analog having substitutions of serine for cysteine at the amino acid positions 1 and 15 of KGF, with the initial amino acid which is Mn where n equals 0 or 1. Figure 3 shows the nucleotide sequences (SEQ ID NO. NO: 5) and amino acids (SEQ ID NO: 6) of? N3 (C (15) S, a KGF analog having a deletion of the first 3 amino acids of the amino terminal and a substitution of serine by the cysteine at position 15 of the amino acids of KGF, with the initial amino acid being Mn where n is equal to 0 or 1.

Figure 4 shows the nucleotide sequences (SEQ ID NO: 7) and amino acids (SEQ ID NO: 8) of? N3 / C (15) -, a KGF analog having a deletion of the first three amino acids of the terminal of amino and a deletion of cysteine at position 15 of the amino acids of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 5 shows the nucleotide sequences (SEQ ID NO: 9) and amino acids (SEQ ID NO: 10) of? N8 / C (15) S, a KGF analog having a deletion of the first 8 amino acids of the amino terminus and a substitution of the cysteine at position 15 of the amino acids of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 6 shows the nucleotide sequences (SEQ ID N0: 11) and amino acids (SEQ ID NO: 12) of? N8 / C ( 15) -, a KGF analog having a deletion of the first 8 amino acids of the amino terminal and a deletion of the cysteine at position 15 of KGF, with the amino acid or initial that is Mn where n is equal to -0 or 1. Figure 7 shows the nucleotide sequences (SEQ ID NO: 13) and amino acids (SEQ ID NO: 14) of? N15, a KGF analog that has a deletion of the first fifteen amino acids of the amino terminal of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 8 shows the nucleotide sequences (SEQ ID N0: 15) and amino acids (SEQ ID NO: 16) of? N16, a KGF analog having a deletion of the first 16 amino acids of the amino terminal of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 9 shows the nucleotide sequences (SEQ ID NO: 17) and amino acids (SEQ ID NO: 18) of? N17, a KGF analog having a deletion of the first 17 amino acids of the amino terminal of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 10 shows the nucleotide sequences (SEQ ID NO: 19) and amino acids (SEQ ID NO: 20) of? N 18, a KGF analog having a deletion of the first 18 amino acids of the amino terminal of KGF, with the initial amino acid being Mn where n is equal to 0 or 1. Figure 11 shows the nucleotide sequences (SEQ. ID NO: 21) and amino acids (SEQ ID NO: 22) of? N19, a KGF analog having a deletion of the first 19 amino acids of the amino terminal of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 12 shows the nucleotide sequences (SEQ ID NO: 23) and amino acids (SEQ ID NO: 24) of? N20, a KGF analog that has a deletion of the first 20 amino acids of the terminal of amino of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 13 shows the nucleotide sequences (SEQ ID NO: 25) and amino acids (SEQ ID NO: 26) of? N21, a KGF analog that has a deletion of the first 21 amino acids of the amino terminal of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 14 shows the nucleotide sequences (SEQ ID NO: 27) and amino acids (SEQ ID NO: 28) of? N22, a KGF analogue having a deletion of the first 22 amino acids of the amino terminal of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 15 shows the nucleotide sequences (SEQ ID NO: 29) and amino acids (SEQ ID NO: 30) of? N23, a KGF analog having a deletion of the first 23 amino acids of the amino terminal of KGF, with the initial amino acid being Mn where n equals 0 or 1. Figure 16 shows the nucleotide sequences (SEQ ID N0: 31) and amino acids (SEQ ID NO: 32) of? N24, a KGF analog having a deletion of the first 24 amino acids of the amino terminal of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 17 shows the nucleotide sequences (SEQ ID NO: 33) and amino acids (SEQ ID NO: 34) of C (1,15) S / R (144) E, a KGF analog having substitutions of serine for cysteine at amino acid positions 1 and 15 and a substitution of glutamic acid for arginine at the position of 144 amino acids of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 18 shows the nucleotide (SEQ ID NO: 35) and amino acid (SEQ ID NO: 36) sequences of C ( 1.15) S / R (144) Q, a KGF analog that has substitutions of serine for cysteine at amino acid positions 1 and 15 and a substitution of glutamine for arginine at the 144 amino acid position of KGF, with the amino acid initial that is Mn where n is equal to 0 or 1.

Figure 19 shows the nucleotide sequences (SEQ ID NO: 37) and amino acids (SEQ ID NO: 38) of? N23 / R (144) Q, a KGF analog having a deletion of the first 23 amino acids of the terminal of amino and a substitution of glutamine by arginine at position 144 of the amino acids of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 20 shows the nucleotide sequences (SEQ ID NO: 39 ) and amino acids (SEQ ID NO: 40) of C (1,15,40) S, a KGF analog having serine substitutions by cysteine at amino acid positions 1, 15 and 40 of KGF, with the initial amino acid is Mn wherein n is equal to 0 or 1. Figure 21 shows the nucleotide sequences (SEQ ID NO: 41) and amino acids (SEQ ID NO: 42) of C (1, 15, 102) S, an analog of KGF having substitutions of serine for cysteine at amino acid positions 1, 15 and 102 of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 22 shows the nucleotide sequences (SEQ ID NO: 43) and amino acids (SEQ ID NO: 44) of C (1,15,102,106) S, a KGF analog having serine substitutions by cysteine at amino acid positions 1, 15, 102, and 106 of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 23 shows the nucleotide sequences (SEQ ID NO: 45) and amino acids (SEQ ID NO: 46) of? N23 / N (137) E, a KGF analog having a deletion of the first 23 amino acids of the amino terminal and a substitution of glutamic acid with asparagine at position 137 of the amino acids of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 24 shows the nucleotide sequences (SEQ ID NO: 47) and amino acids (SEQ ID NO: 48) of? N23 / K (139) E, a KGF analog that has a deletion of the first 23 amino acids of the amino terminal and a substitution of glutamic acid by lysine at position 139 of KGF, with the amino acid initiated to which is Mn where n is equal to 0 or 1. Figure 25 shows the nucleotide sequences (SEQ ID NO: 49) and amino acids (SEQ ID NO: 50) of? N23 / K (139) Q, an analogue of KGF having a deletion of the first 23 amino acids of the amino terminal - and a substitution of glutamine by lysine at position 139 of KGF, with the initial amino acid being Mn where n equals 0 or 1. Figure 26 shows the nucleotide sequences (SEQ ID NO: 51) and amino acids (SEQ ID NO: 52) of? N23 / R (144) A, a KGF analog having a deletion of the first 23 amino acids of the terminal of amino and a substitution of alanine by arginine at position 144 of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 27 shows the nucleotide sequences (SEQ ID NO: 53) and amino acids ( SEQ ID NO: 54) of? N23 / K (144) E, a KGF analog having a deletion of the first 23 amino acids of the amino terminal and a substitution of acid g moat by arginine at position 144 of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 28 shows the nucleotide sequences (SEQ ID NO: 55) and amino acids (SEQ ID NO: 56 ) of? N23 / R (144) L, a KGF analog having a deletion of the first 23 amino acids of the amino terminal and a substitution of leucine for arginine at position 144 of KGF, with the initial amino acid being Mn wherein n is equal to 0 or 1. Figure 29 shows the nucleotide sequences (SEQ ID NO: 57) and amino acids (SEQ ID NO: 58) of? N23 / K (147) E, a KGF analog having a deletion of the first 23 amino acids of the amino terminal and a substitution of glutamic acid by lysine at position 147 of KGF, with the initial amino acid being Mn where n equals 0 or 1. Figure 30 shows the sequences of nucleotides (SEQ ID NO: 59) and amino acids (SEQ ID NO: 60) of? N23 / K (147) Q, a KGF analog having a deletion of the first 23 amino acids of the amino terminal and a substitution of glutamine with lysine at position 147 of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 31 shows the nucleotide sequences (SEQ ID NO: 61) and amino acids (SEQ ID NO: 62) of? N23 / K (153) E, a KGF analog having a deletion of the first 23 amino acids of the amino terminal and a substitution of glutamic acid with lysine at position 153 of KGF, with the initial amino acid which is Mn where n equals 0 or 1. Figure 32 shows the nucleotide sequences (SEQ ID NO: 63) and amino acids (SEQ ID NO: 64) of? N23 / K (153) Q, a KGF analog having a deletion of the first 23 amino acids of the amino terminal - and a substitution of glutamine for lysine at position 153 of KGF, with the initial amino acid which is Mn where n is equal to 0 or 1. Figure 33 shows the nucleotide sequences (SEQ ID NO: 65) and amino acids (SEQ ID NO: 66) of? N23 / Q (152) E / K (153) E, a KGF analog having a deletion of the first 23 amino acids of the terminal of amino and a substitution of glutamic acid by glutamine at position 152 of the amino acids of KGF and of glutamic acid by lysine at position 153 of amino acids of KGF, with the initial amino acid being Mn where n is equal to 0 or 1 .

Detailed description of the invention KGF protein (s) According to the present invention, the term "KGF protein (s)" is understood to mean the protein defined by the amino acids Cys32 to Thr194 of SEQ ID NO: 2 (mature KGF) and variable proteins thereof. (Unless otherwise indicated, the numbering of the amino acids for the molecules described herein will correspond to that presented for the mature form of the molecule (ie, minus the signal sequence), as shown by amino acids 32 to 194 for SEQ ID NO: 2, with the initial MET in each such sequence being the residual number "0"). The term "KGF protein (s)" thus includes a protein in which one or more amino acid residues have been deleted from ("deletion variant (s)") inserted in ("variant (s) of addition") , and / or substituted by ("substitution variant (s)"), the residues within the amino acid sequence of SEQ ID NO: 2 and which retain the biological activity. It will be appreciated by those skilled in the art that many combinations of deletions, insertions, and substitutions (individual or collective variant (s)) can be made, provided that the final protein is biologically active. The term "biological activity" as used herein means that a KGF protein (s) possess some but not necessarily all the same properties (and not necessarily to the same extent as) KGF. The selection of the particular properties of interest depends on the desired use of the desired KGF protein (s). There are two main variables in the construction of the variant (s) of the amino acid sequences: The location of the mutation site and the nature of the mutation. In the design of each of the variant (s), the location of each mutation site and the nature of each mutation will depend on the biochemical characteristic (s) that are to be modified. Each mutation site can be modified individually or in series, for example, (1) by deletion of the target or target amino acid residue, (2) by the insertion of one or more amino acid residues adjacent to the localized site or (3) by substitution first with the choices of conservative amino acids and, depending on the result achieved, then with more radical selections. Deletions of the amino acid sequence generally vary from about 1 to 30 amino acid residues, preferably from about 1 to 20 amino acids, more preferably from about 1 to 10 amino acid residues and even more preferably from about 1 to 5 residues. Amino-terminal, carboxy-terminal and internal intra-sequence deletions are contemplated. Deletions can be made within the amino acid sequence of KGF, for example, in the regions of reduced homology with the sequences of other members of the FGF family. Deletions within the amino acid sequence of KGF in the areas of substantial homology to the sequences of other elements of the FGF family will be more likely to significantly modify biological activity. The number of the total deletions and / or the consecutive deletions will preferably be selected to preserve the tertiary structure of KGF in the affected domain, for example, the cross-linking of the cysteine. An addition of the amino acid sequence may include the insertions of an amino- and / or carboxyl-terminal fusion of variable length from a residue to one hundred or more residues, as well as internally-internal inserts of single or multiple amino acid residues. The internal additions may generally vary from about 1 to 20 amino acid residues, preferably from about 1 to 10 amino acid residues, more preferably from about 1 to 5 amino acid residues, and even more preferably from about 1 to 3 amino acid residues. Additions within the amino acid sequence of KGF can be made in regions of low homology with the sequences of other members of the FGF family. Additions within the amino acid sequence of KGF in areas of substantial homology to the sequences of other members of the FGF family will be more likely to significantly modify biological activity. The insertions or additions preferably include the amino acid sequences derived from the sequences of other members of the FGF family.

An amino-terminal addition is contemplated to include the addition of methionine (for example, as a trick of direct expression in the bacterial recombinant cell culture) or an amino acid residue or the KGF sequence. A further example of an amino-terminal addition includes the fusion of a signal sequence to the amino-terminus of KGF to facilitate the secretion of the protein from the recombinant host cells. Such signal sequences will generally be obtained from and therefore will be homologous with respect to the species of the proposed host cell. For prokaryotic host cells that do not renoise and process the sequence of the natural signal, the signal sequence can be replaced by a sequence of the prokaryotic signal selected, for example, from the group of the alkaline phosphatase leader sequences, penicillinase. or enterotoxime II stable in the heat. For expression in the host cells, each polypeptide can have a signal sequence selected, for example, from the leader sequences of the yeast invertase group, alpha factor or acid phosphatase. In the expression of mammalian cells specifically, the sequences of the KGF signal are satisfactory, although other mammalian signal sequences may be suitable, for example sequences derived from other members of the FGF family may be suitable. An example of an amino or carboxy terminal addition includes chimeric proteins comprising the amino-terminal or carboxy-terminal fusion of a KGF protein with all or a portion of the constant domain of the light or heavy chain of human immunoglobulin ( individually or collectively, ("KGF Fc (s)"). Such chimeric polypeptides are preferred wherein the immunoglobulin portion of each comprises all of the domains except the first domain of the constant region of the heavy chain of human immunoglobulin such as IgG (for example, IgGl or IgG3), IgA, IgM or IgE. An expert artisan will appreciate that any amino acid of the immunoglobulin portion can be deleted or substituted with one or more amino acids, or one or more amino acids can always be added that the protein portion of KGF is able to stimulate the epithelial cells and the immunoglobulin portion shows one or more of its characteristic properties Another variant group (s) is (are) the substitution variant (s) of the amino acids, of the amino acid sequence of KGF. This (s) are variant (s) in which at least one amino acid residue in KGF is removed and a different residue is inserted in its place. The substitution variant (s) include the allelic variant (s)), which are characterized by changes in nucleotide sequences that occur naturally in the population of the species that may or may not they can lead to an amino acid change. One skilled in the art can use any known information about the binding or active site of the polypeptide in the selection of possible mutation sites. A method for identifying amino acid residues or regions for the mutagenesis of a protein is called "alanine scanning mutagenesis", as described by Cunningham and Wells (1989), Science, 244: 1081-1085, the description of the which is incorporated herein by reference. In this method, an amino acid residue or group of target or target residues of a protein is identified (eg, charged residues such as Arg, Asp, His-, Lys and Glu) and replaced by a neutral or charged amino acid negatively (more preferably alanine or polyalanine) to affect the interaction of the amino acids with the surrounding aqueous environment inside or outside the cell. Those domains / residues that demonstrate functional sensitivity to substitutions are then refined by the introduction of additional or alternative residues at the substitution sites. Therefore, the site for the introduction of the modification of the amino acid sequence is predetermined. To optimize the functioning of a mutation at a given site, the alanine scan or random mutagenesis can be conducted and the variant (s) can be selected for the optimal combination of the activity and the desired degree of activity. . The sites of greatest interest for substitutional mutagenesis include sites in which the particular residues within KGF are substantially different from several species or other members of the FGF family in terms of the volume of the side chain, the charge, and / or hydrophobicity. Other sites of interest include those in which particular residues within KGF are identical among several species or other members of the FGF family, because such positions are generally important for the biological activity of a protein. A skilled person will appreciate that initially these sites should be modified by the substitution in a relatively conservative manner. t > Such conservative substitutions are shown in Table 1 under the title "Preferred Substitutions." If such substitutions lead to a change in biological activity, then more substantial changes (Exemplary Substitutions) can be introduced and / or additional ones can be made and the resulting polypeptides selected.

TABLE 1: Substitutions of Amino Acids During the realization of such changes, the hydropathic index of amino acids can be considered. The importance of the hydropathic amino acid index in the case of conferring an interactive biological function on a protein, is generally understood in the art (Kyte and Doolittle (1982), J. Mol. Biol., 157: 105-131. which is incorporated herein for reference). It is known that certain amino acids can be substituted by other amino acids that have a similar hydropathic index or evaluation and still retain a similar biological activity. It is also understood in the art that substitution of similar amino acids can be effectively done based on hydrophilicity, particularly where the functionally equivalent protein or peptide created hereby is proposed for use in immunological modalities, as in the present case . The U.S. patent No. 4,554,101, the description of which is incorporated herein for reference, states that the largest local average hydrophilicity of a protein, when governed by the hydrophilicity of its adjacent amino acids, correlates with its ingenicity and antigenicity, is say, with a biological property of the protein.

The U.S. patent No. 4,554,101 also teaches the identification and preparation of the epitopes from the primary amino acid sequences based on hydrophilicity. By means of the methods described in U.S. Pat. No. 4,554,101 a skilled artisan could be able to identify the epitopes, for example, within the amino acid sequence of KGF. These regions are also referred to as "epitopic core regions." Numerous scientific publications have been devoted with respect to the prediction of secondary structure, and with respect to the identification of epitopes, from the analysis of amino acid sequences (Chou and Fasman (1974).) Biochemistry, 13 (2): 222-245, Chou and Fasman (1974), Biochemistry, 23 (2) .211-222, Chou and Fasman (1978), Adv. Enzymol, Relat.Areas Mol. Biol., 47: 45-148, Chou and Fasman. (1978), Ann. Rev. Biochem., 47: 251-276 and Chou and Fasman (1979), Byophys. J., 26: 367-384, the description of which is incorporated herein for reference). In addition, computer programs are now available to help with the prediction of antigenic portions and epitope core regions of proteins. Examples include those programs based on the Jameson-Wolf analysis (Jameson and Wolf (1998), Comput. Appl. Biosci., 4 (1) .181-186 and Wolf et al. (1988), Comput.

Appi. Biosci., 4 (1): 187-191, the descriptions of which are incorporated herein for reference); the PepPlot® program (Brutlag et al. (1990), CABS, 6: 237-245 and Weinberg et al. (1985), Science, 228: 740-742, the descriptions of which are incorporated herein for reference); and other programs for the prediction of the tertiary structure of proteins (Fetrow and Bryant (1993), BIOTECHNOLOGY, 11: 479-483, the description of which is incorporated herein for reference). In contrast, substantial modifications in the functional and / or chemical characteristics of KGF can be effected by selecting substitutions that differ significantly in their effect on the maintenance of (a) the structure of the polypeptide backbone in the area of substitution, e.g. , as a sheet or helical conformation, (b) the relative charge or hydrophobicity of the protein at the target site or (c) the volume of the side chain. The residues that are naturally present are divided into groups based on the properties of the common side chain: 1) hydrophobic: norleucine, Met, Ala, Val, Leu, lie; 2) neutral hydrophilic: Cys, Ser, Thr; 3) Acids: Asp, Glu; 4) Basic: Asn, Gln, His, Lys, Arg; 5) aromatics: Trp, Tyr, Phe; and 6) residues that influence the orientation of the chain: Gly, Pro. Non-conservative substitutions may involve the exchange of a member of one of these groups with each other. Such substituted residues can be introduced into the KGF regions so that, for example, they are homologous with other members of the FGF family or in non-homologous regions of the protein. A variety of amino acid substitutions or deletions can be made to modify or add N-linked or N-linked glycosylation sites, leading to a protein with altered glycosylation. The sequence can be modified to add glycosylation sites to, or to delete the N-linked or O-linked glycosylation sites of the KGF proteins. A glycosylation recognition site linked to asparagine comprises a tripeptide sequence which is specifically recognized by the appropriate cellular glycosylation enzymes. These tripeptide sequences are either Asn-Xaa-Thr or Asn-Xaa-Ser, where Xaa can be any amino acid other than Pro. Specific mutations of the KGF sequences may involve the substitution of an unnatural Asn in the position 50 and Thr at position 52 to insert an N-linked glycosylation site. Such modifications may be particularly useful in the addition of a carbohydrate, which may reduce aggregation (to increase thermal stability and in storage), increase the average life in circulation, reduce the isoelectric point, increase the solubility and reduce the antigenicity of the protein. In a specific embodiment, a variable polypeptide will preferably be substantially homologous to the amino acid sequence of KGF (SEQ ID NO: 2). The term "substantially homologous" as used herein means a degree of homology that is in excess of 80%, preferably in excess of 90%, more preferably in excess of 95% or more preferably still of 99%. The percentage of homology as described here is calculated as the percentage of amino acid residues found in the smaller of the two sequences which are aligned with identical amino acid residues in the sequence which is compared when four holes of a length of 100 amino acids can be introduced to aid this alignment, as described by Dayhoff (1972), Atlas of Protein Sequence and Structure, 5: 124, National Biochemical Research Foundation, Washington, DC, the description of which is hereby incorporated by reference . Also included within the term "substantially homologous" are variant (s) of KGF which can be isolated by virtue of cross-reactivity with the antibodies for the amino acid sequence of SEQ ID NO: 2, or whose genes can be isolated at through hybridization with the DNA of SEQ ID NO: 1 or with segments thereof. A KGF protein (s) can be selected quickly to evaluate their physical properties. For example, the level of biological activity (e.g., receptor binding and / or affinity, mitogenic, proliferative activity of cells and / or in vivo) can be tested using a variety of assays. One such assay includes a mitogenic assay to test the ability of a protein to stimulate DNA synthesis (Rubin et al (1989), supra, the description of which is incorporated herein for reference). Another such assay includes the proliferative assay of cells to test the ability of a protein to stimulate cell proliferation (Falco et al. (1988), Oncogene, 2: 573-578, the disclosure of which is incorporated herein by reference. ). The specific variant (s) of KGF are described in WO 9008771, WO 9622369, WO 9611949 and WO 9611951, the descriptions of which are incorporated herein by reference. An example of KGF includes proteins that have residues corresponding to Cys1 and Cys15 of SEQ ID NO: 2 replaced or deleted, with the resulting molecule having improved stability when compared to the original molecule (WO 96/11949). Another example of KGF includes charge-shift polypeptides wherein one or more of the amino acid residues 41-154 of the native KGF (preferably residues Arg41, Gln43, Lys55, Lys95, Lys128, Asn137, Gln138, Lys139, Arg144, Lys147 , Gln152, Lys153 or Thr154) are deleted or substituted with a neutral residue or negatively charged residue selected to effect a protein with a reduced positive charge (WO 96/11951). A still further example of KGF includes the proteins generated by the substitution of at least one amino acid having a higher loop-forming potential for at least one amino acid within the loop-forming region of Asn115-HisU6-Tyr117- Asn118-Thr119 of natural KGF (WO 96/11950). A still further example includes proteins that have one or more substitutions, deletions or additions of amino acids within a region of 123-133 (amino acids 154-164 of SEQ ID NO: 2) of natural KGF; these proteins have agonist or antagonist activity.

The proteins specifically described include the following: C (1,15) S (Figure 2); ? N3 / C (15) S (Figure 3); ? N3 / C (15) - (Figure 4); N8 / C (15) S (Figure 5); N8 / C (15) - (Figure 6); N15 (Figure 7); N16 (Figure 8); N17 (Figure 9); N18 (Figure 10); N19 (Figure 11); ? N20 (Figure 12); N21 (Figure 13); N22 (Figure 14); ? N23 (Figure 15); N24 (Figure 16); C (1, 15) S / R (14) E (Figure 17); C (1.15) S / R (144) Q (Figure 18); ? N3 / R (144) Q (Figure 19); C (1,15.40) S (Figure 20); C (1,15,102) S (Figure 21) C (1,15,102,106) S (Figure 22); ? N23 / N (137) E (Figure 23) ? N23 / K (139) E (Figure 24)? N23 / K (139) Q (Figure 25) ? N23 / R (144) A (Figure 26)? N23 / R (144) E (Figure 27) ? N23 / R (144) L (Figure 28)? N23 / K (147) E (Figure 29) ? N23 / K (147) Q (Figure 30)? N23 / K (153) E (Figure 31)? N23 / K (153) Q (Figure 32) and? N23 / Q (152) E / K (153) E (Figure 33).

Polypeptide derivatives Chemically-modified derivatives of KGF proteins in which the protein is linked to a polymer to modify the properties of the protein (referred to herein as "derivatives") are included within the scope of the present invention. Such derivatives can be prepared by a person skilled in the art given the descriptions herein. The conjugates can be prepared using glycosylated, non-glycosylated or de-glycosylated KGF proteins and the appropriate chemical moieties. Typically non-glycosylated proteins and water-soluble polymers will be used. Water soluble polymers are desirable because the protein to which each is fixed will not precipitate in an aqueous environment, such as a physiological environment. Preferably, the polymer will be pharmaceutically acceptable for the preparation of a therapeutic product or composition. A person skilled in the art will be able to select the desired polymer based on such considerations as if the polymer / protein conjugate will be used therapeutically and, if so, the therapeutic profile of the protein (e.g., the duration of the sustained release, resistance to proteolysis, effects, if any, on dosage, biological activity, ease of handling, the degree or lack of antigenicity and other known effects of the water-soluble polymer on a protein therapeutic). Suitable water-soluble, clinically acceptable water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), polyethylene glycol propionaldehyde, ethylene glycol / propylene glycol copolymers, nomomethoxy-polyoxyethylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol (PVA), polyvinyl pyrrolidone, poly-1, 3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymer, poly (β-amino acids) (either homopolymers or random copolymers), poly (n-vinyl pyrrolidone) polyethylene glycol, homopolymers of polypropylene glycol (PPG) and other polyalkylene oxides, copolymers of polypropylene oxide / ethylene oxide, polyoxyethylated polyols (POG) (for example, glycerol) and other polyoxyethylated polyols, polyoxyethylated sorbitol, or polyoxyethylated glucose, colonic acids or other polymers of carbohydrates, Ficoll or dextran and mixtures thereof. When used herein, polyethylene glycol is understood to encompass any of the forms that have been used to derive other proteins, such as mono- (C1-C10) alkoxy- or aryloxy-polyethylene glycol. Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water. The water-soluble polymers each may be of any molecular weight and may be branched or unbranched. In general, the higher the molecular weight or the more branching, the higher the polymer: protein ratio. The water-soluble polymers each typically have an average molecular weight of between about 2 kDa to about 100 kDa (the term "about" indicates that in the preparations of a water-soluble polymer, some molecules will weigh more, some less, than the molecular weight established). The average molecular weight of each water soluble polymer is preferably between about 5kDa to about 40kDa, more preferably between about 10kDa to about 35kDa and even more preferably between about 15KDa to about 30KDa. There are several attachment or attachment methods available to persons skilled in the art, including acylation reactions or alkylation reactions (preferably to generate an amino-terminal chemically modified protein) with a water-soluble, reactive molecule. See, for example, EP 0 401 384, the description of which is incorporated herein for reference; see also, Malik et al. (1992), Exp. Hematol., 20: 1028-1035; Francis (1992), Focus on Growth Factors, 3 (2): 4-10, published by Mediscript, Mountain Court, Friern Barnet Lane, London N20 OLD, UK; EP 0 154 316; EP 0 401 384; WO 92/16221; WO 95/34326; WO 95/13312; WO 96/11953; US96 / 19459; and the other publications cited herein that refer to pegylation (PEG treatment), the descriptions of which are incorporated herein by reference. A specific embodiment of the present invention is an unbranched monomethoxy-polyethylene glycol aldehyde molecule having an average molecular weight of either about 20 kDa or about 33 kDa (eg, between 30 kDa and 35 kDa), or an additive of tertiary butyl polyethylene glycol having an average molecular weight of about 33 kDa (eg, between 30 kDa and 35 kDa) conjugated by means of reductive alkylation to the KGF proteins.

Polyvalent forms Polyvalent forms, that is, molecules that comprise more than one active portion, can be constructed. In one embodiment, the molecule can possess multiple KGF protein (s). Additionally, the molecule can possess at least one KGF protein (s) and, depending on the desired characteristic of the polyvalent form, at least one other molecule. In one embodiment, the polyvalent form can be constructed, for example, by the chemically coupling of at least one KGF protein (s) and another portion with any clinically accepted linker (e.g., a water soluble polymer). Initially, the linker must not impart a new immunogenicity nor, by virtue of the new amino acid residues, alter the hydrophobicity balance and the structure load, which affects its biodistribution and spacing or clearance. The water-soluble polymers can be, based on the monomers listed above, homopolymers, block or random copolymers, straight or branched chain terpolymers, substituted or unsubstituted. The polymer can be of any length or molecular weight, but these characteristics can affect the biological properties. The polymeric average molecular weights particularly useful for reducing spacing or clearance rates in pharmaceutical applications are in the range of 2,000 to 35,000 daltons. In addition, the length of the polymer can be varied to optimize or confer the desired biological activity. The active portions can be linked using conventional coupling techniques (see WO 92/16221, WO 95/13312 and WO 95/34326, the descriptions of which are incorporated hn by refce).

Alternatively, a bivalent molecule may consist of two serial repeats of the KGF protein (s) separated by a polypeptide linker region. The design of the polypeptide linkers is similar in design to the insertion of short loop or loop sequences between the domains in the newly designed proteins (Mutter (198 8), TIBS, 13: 260-265 and Regan and DeGrado (1998), Science, 241: 976-978, the descriptions of which are incorporated hn for refce). Several difft linker constructions have been assembled and shown to be useful for forming single chain antibodies; most functional linkers range in size from 12 to 25 amino acids (amino acids having non-reactive side groups, eg, alanine, serine and glycine) which together constitute a hydrophilic sequence, have few residues charged oppositely to improve solubility and are flexible (Whitlow and Filpula (1991), Methods: A Companion to Methods in Enzymology, 2: 97-105; and Brigido et al. (1993), J. Immunol., 150: 469-479, the descriptions of the which are incorporated hn for refce). Additionally, the KGF protein (s) can be chemically bound to a biotin, and the resulting conjugate is then allowed to bind avidin, leading to the tetravalent avidin / biotin / KGF protein (s). . The KGF protein (s) can also be covalently linked to dinitrophenol (DNP) or trinitrophenol (TNP) and the resulting conjugates precipitated with anti-DNP or anti-TNP-IgM to form decamer conjugates. In still another embodiment, recombinant fusion proteins can also be produced whn each recombinant chimeric molecule has a KGF protein sequence amino-terminally or carboxy-terminally fused to all or part of the constant domains, but at least one domain constant, of the heavy or light chain of human immunoglobulin. For example, an IgG1 fusion protein / chimeric KGF protein (or IgG1 / KGF protein) can be produced from the chimeric gene containing the light chain, a chimeric agent of the human kappa light chain / KGF protein (protein of KGF / Ck) or a human kappa light chain / chimeric KGF protein (Ck / KGF protein); or a chimeric gene containing the heavy chain: a human gamma-1 heavy chain chimeric agent / KGF protein (KGF / Cg-1 protein) or a KGF protein chimeric agent / human gamma-1 heavy chain (Cg-1) / KGF protein). Following the transcription and translation of a heavy chain chimeric gene, or of a gene containing the light chain and a heavy chain chimeric gene, the gene products can be assembled into a single chimeric molecule having one (s) protein (s) exhibited bivalently. Additional details relating to the construction of such chimeric molecules are described in U.S. Patent 5,116,964, WO 89/09622, WO 91/16437 and EP 315062, the disclosures of which are incorporated herein by reference. In yet a further embodiment, recombinant fusion proteins can also be produced wherein each recombinant chimeric molecule has at least one KGF protein (s), as described above, and at least a portion of the 186- region. 401 of the osteoprotegerin (OPG), as described in European Patent Application No. 96309363.8, the disclosure of which is incorporated herein by reference. Either the KGF protein (s) or the osteoprotogerin portion may be at the amino terminus or the carboxy terminus or carboxy terminus of the chimeric molecule. The production of the KGF protein (s) is described in further detail below. Such proteins can be prepared, for example, by recombinant techniques or by in vitro chemical synthesis of the desired KGF protein (s).

Polynucleotides Based on the present disclosure and using the universal codon table, one of ordinary skill in the art can easily determine all of the nucleic acid sequences encoding the amino acid sequence of the KGF protein (s). . Recombinant expression techniques driven according to the descriptions shown below can be followed to produce these polynucleotides and to express the encoded proteins. For example, by inserting a nucleic acid sequence which encodes a KGF protein (s) into an appropriate vector, a person of ordinary skill in the art can easily produce large quantities of the desired nucleotide sequence. The sequences can then be used to generate detection probes or amplification primers. Alternatively, a polynucleotide encoding a KGF protein (s) can be inserted into an expression vector. By introducing the expression vector into an appropriate host, the desired protein (s) can also be produced in large quantities. As described further herein, there are numerous vector / host systems available for the propagation of the desired nucleic acid sequences and / or the production of the desired protein. These include, but are not limited to, plasmid, viral and insertion vectors, and prokaryotic and eukaryotic hosts. One skilled in the art can adapt a vector / host system which is capable of propagating or expressing heterologous DNA to produce or express the sequences of the present invention. Furthermore, it will be appreciated by those skilled in the art that, in view of the present disclosure, the nucleic acid sequences within the scope of the present invention include the nucleic acid sequence of Figure 1, as well as the degenerate nucleic acid sequences. thereof, the nucleic acid sequences which encode the variant (s) of KGF and those nucleic acid sequences which hybridize (under the conditions of hybridization described in the selection section of the cDNA library below) , or equivalent conditions or stricter conditions) with the nucleic acid sequence complements of Figure 1. Also provided by the present invention are recombinant DNA constructs that involve the vector DNA together with the DNA sequences encoding the desired proteins. In each such DNA construct, the nucleic acid sequence encoding a desired protein (with or without the signal peptides) is in operative association with a suitable regulatory or expression control sequence capable of directing the replication and / or expression of the desired protein in a selected host.

Preparation of Polynucleotides A nucleic acid sequence encoding a KGF protein (s) can be obtained easily in a variety of ways including, without limitation, chemical synthesis, selection of the genomic library or cDNA, expression of the selection of the library and / or PCR amplification of the cDNA. These methods and others which are useful for the isolation of such nucleic acid sequences are described in Sambrook et al. (1989), Molecular Cloning: A Laboratory Manual, Cold. Spring Harbor Laboratory Press, Cold Spring Harbor, NY; by Ausubel et al. (1994), Current Protocois in Molecular Biology, Current Protocols Press; and by Berger and Kimmel (1987), Methods in Enzymology: Guide to Molecular Cloning Techniques, Vol. 152, Academic Press, Inc., San Diego, CA, the descriptions of which are incorporated herein by reference. The chemical synthesis of a nucleic acid sequence which codes for desired proteins can be effected using methods well known in the art, such as those described by Engels et al. (1989)Angew Chem. Intl. Ed., 28: 716-734 and Wells et al. (1985), Gene, 34: 315, the descriptions of which are incorporated herein for reference. These methods include, inter alia, the phosphotriester, phosphoramidite and H-phosphonate methods of the synthesis of the nucleic acid sequence. Large nucleic acid sequences, for example those larger than about 100 nucleotides in length, can be synthesized as several fragments. The fragments can then be joined together to form a suitable nucleic acid sequence. A preferred method is the synthesis supported by a polymer using the standard phosphoramidite chemistry. Alternatively, a suitable nucleic acid sequence can be obtained by selecting an appropriate cDNA library (i.e., a library prepared from one or more of the tissue or cell sources thought to express the protein) or a genomic library (a library prepared from total genomic DNA). The source of the cDNA library is typically a tissue of any species that is believed to express a desired protein in reasonable amounts. The source of the genomic library can be any tissue or tissues of any mammal or other species that is believed to contain a gene encoding a desired protein. The hybridization medium can be selected on the basis of the presence of a DNA encoding a desired protein using one or more nucleic acid probes (oligonucleotides, cDNA or genomic DNA fragments having an acceptable level of homology to the cDNA or gene). to be cloned) that will selectively hybridize with the cDNA (s) or the gene (s) present in the library. The probes typically used for such selection encode a small region of the DNA sequence of the same species or similar species as the species from which the library is prepared. Alternatively, the probes may degenerate, as described herein.

Hybridization is typically effected by annealing an oligonucleotide probe or cDNA to the clones under stringent conditions that prevent non-specific binding but allow the binding of these clones having a significant level of homology to the probe or primer . Typical hybridization and washing under stringent conditions depend in part on the size (i.e., the number of nucleotides in length) of the cDNA or the oligonucleotide probe and whether the probe is degenerate. The probability of identifying a clone is also considered in the design of the hybridization medium (for example, if a genomic or cDNA library is being selected). Where a DNA fragment (such as a cDNA) is used as a probe, typical hybridization conditions include those as described in Ausubel et al. (1994), supra. After hybridization, the hybridization medium is washed under appropriate stringent conditions, depending on various factors such as the size of the probe, the expected homology of the probe with respect to the clone, the hybridization medium that is selected, the number of clones that are going to be selected and similar. Exemplary stringent hybridization conditions are hybridization in 6 x SSC at 62-67 ° C, followed by washing in 0.1 x SSC at 62-67 ° C for about one hour. Alternatively, the exemplary stringent hybridization conditions are hybridization in 45-55% formamide, 6 x SSC at 40-45 ° C, followed by washing in 0.1 x SSC at 62-67 ° C for about one hour. Also included are sequences which hybridize to the nucleic acid sequences described in Figure 1 under relaxed hybridization conditions and which encode the KGF protein (s). Examples of such conditions of stringent stringent hybridization conditions are 6 x SSC at 45-55 ° C or hybridization with 30-40% formamide at 40-45 ° C, followed by washing in 1-2 x SSC at 55 ° C for approximately 30 minutes. See Maniatis et al. (1982), Molecular Cloning (A Laboratory Manual), Cold Spring Harbor Laboratory, pages 387 to 389, the description of which is incorporated herein for reference. There are also exemplary protocols for stringent washing conditions wherein the oligonucleotide probes are used to select the hybridization medium. For example, a first protocol uses 6 X SSC with 0.05 percent sodium pyrophosphate at a temperature of about 35 ° C to 63 ° C, depending on the length of the probe. For example, 14 base probes are washed at 35-40 ° C, 17 base probes at 45-5 ° C, 2C base probes at 52-57 ° C, and 23 base probes at 57-63 ° C. The temperature can be increased 2-3 ° C where the binding does not specify the bottom seems high. A second protocol uses tetramethylammonium chloride (TMAC) for washing. One such wash solution under stringent conditions is 3 M TMAC, 50 mM Tris-HCl, pH 8.0 and 0.2% SDS. Another method for obtaining a suitable nucleic acid sequence encoding a KGF protein is the polymerase chain reaction (PCR). In this method, the cDNA is prepared from the poly (A) + RNA or total RNA using the reverse transcriptase of the enzyme. Two primers, typically complementary to two separate regions of cDNA (oligonucleotides) encoding the desired protein, are then added to the cDNA in the company of a polymerase such as a Taq polymerase, and the polymerase amplifies the cDNA region between the two primers. The sequences of oligonucleotides selected as probes or primers should be of suitable length and sufficiently unambiguous to minimize the amount of non-specific binding that may occur during selection or PCR amplification. The actual sequence of the probes or primers is based on sequences or conserved or highly homologous regions. Optionally, the probes or primers may degenerate totally or partially, that is, they may contain a mixture of probes / primers, all encoding the same amino acid sequence but using different codons and so on. An alternative to prepare degenerate probes is to place an inosine in some or all of those codon positions that vary by species. Oligonucleotide probes or primers can be prepared by chemical synthesis methods for DNA as described herein.

Vector The DNA encoding the desired protein can be inserted into vectors for further cloning (DNA amplification) or for expression. Suitable vectors are commercially available or can be specifically constructed. The selection or construction of an appropriate vector will depend on (1) whether it is to be used for DNA amplification or for DNA expression, (2) the size of the DNA to be inserted into the vector and (3) the proposed host cell to be transformed with the vector.

The vectors each typically involve a nucleic acid sequence which encodes a desired protein operably linked to one or more of the following control or expression regulatory sequences capable of directing, controlling or otherwise effecting the expression of a desired protein. by a selected host cell. Each vector contains several components, depending on its function (DNA amplification or DNA expression) and its compatibility with the proposed host cell. The vector components generally include, but are not limited to, one or more of the following: a signal sequence, an origin of replication, one or more marker or selection genes, a promoter, an enhancer element, a sequence of termination of transcription and the like. These components can be obtained from natural sources or can be synthesized by known methods. Examples of suitable prokaryotic cloning vectors include bacteriophages such as lambda derivatives, or E. coli plasmids (e.g., pBR322, El, pUC, factor F, and Bluescript® plasmid derivatives (Stratagene, LaJolla, CA )). Other appropriate expression vectors, of which numerous types are known in the art for the host cells described herein, may also be used for this purpose.

Signal Sequence The nucleic acid encoding a sequence of the signal can be inserted 5 'of the sequence encoding a desired protein, for example, it can be a component of a vector or it can be a part of a nucleic acid encoding a desired protein . The nucleic acid encoding the sequence of the natural KGF signal is known (WO 90/08771).

Origin of the Replication The expression and cloning vectors each generally include a nucleic acid sequence that makes it possible for the vector to replicate in one or more selected host cells. In a cloning vector, this sequence is typically one that makes it possible for the vector to replicate independently of the host chromosomal DNA and includes an origin of replication or autonomously replicating sequence. Such sequences are well known. The origin of replication of plasmid pBR322 is suitable for most Gram-negative bacteria, and several origins (eg, SV4C, polyoma, adenovirus, VSV or BPV) are useful for cloning vectors in mammalian cells. In general, the origin of replication is not necessary for the expression of mammalian vectors (for example, the origin of SV40 is frequently used only because the same contains the initial promoter).

Gen Selection The expression and cloning vectors each typically contain a selection gene. This gene encodes a "marker" protein necessary for the survival or growth of transformed host cells when grown in a selective culture medium. Host cells that are not transformed with the vector will not * contain the selection gene and, therefore, will not survive in the culture medium. Typical selection genes encode proteins that (a) confer resistance to antibiotics or other toxins, for example, ampicillin, neomycin, methotrexate or tetracycline; (b) complement auxotrophic deficiencies or (c) supply critical nutrients not available from the culture medium.

Other selection genes can be used to amplify the genes that are to be expressed. Amplification is the process in which genes which are in greater demand for the production of a protein critical for growth are serially reiterated within the chromosomes of successive generations of recombinant cells. Examples of selectable markers suitable for mammalian cells include dihydrofolate reductase (DHFR) and thymidine kinase. The transformants of the cell are placed under selection pressure which only the transformants are adapted to survive by virtue of the marker that is present in the vectors. The selection pressure imposed by the culture of the transformed cells under the conditions in which the concentration of the selection agent in the medium is successively changed, whereby leads to the amplification of both the selection gene and the DNA encoding the desired protein. As a result, the increased amounts of the desired protein are synthesized from the amplified DNA. For example, cells transformed with the DHFR selection gene are first identified by culturing all of the transformants in a culture medium containing methotrexate, a competitive antagonist of DHFR. An appropriate host cell when wild-type DHFR is used is the Chinese hamster ovary cell line deficient in DHFR activity (Urlaub and Chasin (1980), Proc. Nati. Acad. Sci., USA, 77 (7) : 4216-4220, the description of which is incorporated herein for reference). The transformed cells are then exposed to increased levels of methotrexate. This leads to the synthesis of multiple copies of the DHFR gene and, concomitantly, to multiple copies of the other DNA present in the expression vector, such as the DNA encoding a desired protein.

Promoter The expression and cloning vectors will each typically contain a promoter that is recognized by the host organism and are operably linked to a nucleic acid sequence encoding the desired protein. A promoter is an untranslated sequence located upstream (5 ') with respect to the start codon of a structural gene (generally within about 100 to 1000 bp) that controls the transcription and translation of a particular nucleic acid sequence. A promoter can be conventionally grouped into one of two classes, inducible promoters and constitutive promoters. An inducible promoter initiates the increased levels of transcription from the DNA under its control in response to some change in culture conditions, such as the presence or absence of a nutrient or a change in temperature. A large number of promoters, recognized by a variety of potential host cells, are well known. A promoter can be operably linked to the DNA encoding a desired protein by removing the promoter from the source DNA by digesting the restriction enzyme and inserting the desired promoter sequence. The promoter sequence of natural KGF can be used to direct the amplification and / or expression of the DNA encoding a desired protein. A heterologous promoter is preferred, however, if it allows a larger transcription and higher yields of the expressed protein when compared to the natural promoter and if it is compatible with the host cell system that has been selected for its use. For example, any of the natural promoter sequences of other members of the FGF family can be used to direct the amplification and / or expression of the DNA encoding a desired protein.

Promoters suitable for use with prokaryotic hosts include beta-lactamase and lactose promoter systems; alkaline phosphatase, a tryptophan (trp) promoter system; a bacterial luminescence gene (luxR) system and hybrid promoters such as the tac promoter. Other known bacterial promoters are also suitable. Their nucleotide sequences have been published, whereby it becomes possible for one skilled in the art to link them to the desired DNA sequence (s) using linkers or adapters when necessary to supply any required restriction sites. Promoter sequences suitable for use with yeast hosts are also well known in the art. Promoters suitable for use with mammalian host cells are well known and include those obtained from the genomes of viruses such as polyoma virus, chicken skin virus, adenovirus (such as Adenovirus 2), papilloma virus bovine, poultry sarcoma virus, cytomegalovirus, a retrovirus, the hepatitis B virus and, more preferably, the Simian virus 40 (SV40). Other suitable mammalian promoters include heterologous mammalian promoters, for example, thermal shock promoters and the actin promoter.

Improvement Element The expression and cloning vectors each will typically contain an enhancer sequence for increasing the transcription by the higher eukaryotes of a DNA sequence encoding a desired protein. Enhancers are cis-acting elements of DNA, usually from about 10-300 bp in length, which act on the promoter to increase its transcription. The breeders are relatively independent of orientation and position. They have been found in 5 'and 3' with respect to the transcription unit. Yeast improvers are advantageously used with the promoters of the yeast. Several available enhancer sequences of mammalian genes are known (eg, globin, elastase, albumin, alpha-keto-protein and insulin). Additionally, viral enhancers such as the SV40 enhancer, the cytomegalovirus initial promoter enhancer, the polyoma enhancer and the adenovirus enhancers are exemplary enhancing elements for the activation of eukaryotic promoters. Although an enhancer can be divided into a vector at a 5 'or 3' position with respect to a DNA encoding a desired protein, it is typically located at a 5 'site of the promoter.

Termination of the Transcript The expression vectors used in the eukaryotic host cells will each typically contain a sequence necessary for the termination of transcription and to stabilize the mRNA. Such sequences are commonly available from the 5 'and occasionally 3' untranslated regions of eukaryotic DNAs or cDNAs. These regions contain segments of nucleotides transcribed as polyadenylated fragments in the untranslated portion of the mRNA that encodes a desired protein.

Construction of the Vector The construction of a suitable vector containing one or more of the components listed above (together with the desired coding sequence) can be effected by standard binding or ligation techniques. Isolated plasmids or DNA fragments are cleaved, adapted and re-ligated in the desired order to generate the required vector. To confirm that the correct sequence has been constructed, the ligation or binding mixture can be used to transform E. coli, and successful transformants can be selected by known techniques as described herein. The amounts of the vector from the transformants are then prepared, analyzed by digestion of the restriction endonuclease and / or sequenced to confirm the presence of the desired construct. A vector that provides for the temporary expression of the DNA encoding a desired protein in mammalian cells can also be used. In general, temporal expression involves the use of an expression vector that is capable of efficiently replicating in a host cell, such that the host cell accumulates many copies of the expression vector and, in turn, synthesizes high levels of expression. the desired protein, encoded by the expression vector. Each temporal expression system, comprising a suitable expression vector and a host cell, allows convenient positive identification of the proteins encoded by the cloned DNAs as well as the rapid selection of such proteins for the desired biological or physiological properties.

Host Cells Any of a variety of recombinant host cells, each of which contains a nucleic acid sequence for use in the expression of a desired protein, is also provided by the present invention. Exemplary prokaryotic and eukaryotic host cells include bacterial, mammalian, fungal, insect, yeast or plant cells. Prokaryotic host cells include, but are not limited to, eubacteria such as Gram-negative or Gram-positive organisms (e.g., E. coli (HB101, DH5a, DH10, and MC1061); Bacilli spp. such as B. subtilis; Pseudomonas spp. such as P. aeruginosa; Streptomyces spp .; Salmonella spp. such as S. typhimurium; or Serratia spp. such as S. marcescans. In a specific embodiment, a desired protein can be expressed in E. coli. In addition to the prokaryotic host cells, a KGF protein (s) can be expressed in the glycosylated form by any of several suitable host cells derived from multicellular organisms. Such host cells are capable of complex processing and glycosylation activities. In the beginning, any culture of higher eukaryotic cells could be used, if such a culture involves vertebrate or invertebrate cells, including plant cells and insects. Eukaryotic microbes such as filamentous fungi or yeast may be suitable hosts for the expression of a desired protein. Saccharomyces cerevisiae, or common baking yeast, is the most commonly used among lower eukaryotic host microorganisms, but several other genera, species and strains are well known and commonly available. Vertebrate cells can be used, such as the propagation of vertebrate cells in culture (tissue culture), in a procedure that is well known. Examples of useful mammalian host cell lines include, but are not limited to, the CVl line of the monkey kidney transformed by SV40 (COS-7), the human embryonic kidney line (293 cells or 293 cells subcloned for growth in a suspension culture), kidney cells of the newborn hamster and cells of the ovaries of the Chinese hamster. Other suitable mammalian cell lines include, but are not limited to, Hela, mouse L-929 cells, 3T3 lines derived from Swiss, Balb-c or NIH mice, and hamster BHK or HaK cell lines. In a specific embodiment, a desired protein can be expressed in COS cells or in baculovirus cells. A cell can be transfected and preferably transformed with a desired nucleic acid under appropriate conditions that allow the expression of the nucleic acid. The selection of suitable host cells and methods for transformation, cultivation, amplification, selection and production of products and purification are well known in the art (Gething and Sambrook (1981), Nature, 293: 620-625 or, alternatively, Kaufman et al. (1985), Mol. Cell. Biol., 5 (7): 1750-1759, or Pat. U.S.

No. 4,419,446, the descriptions of which are incorporated herein for reference). For example, for mammalian cells without cell walls, the calcium phosphate precipitation method can be used. Electroporation, microinjection and other known techniques can also be used. It is also possible that a desired protein can be produced by homologous recombination or with recombinant production methods that use the control elements used in the cells that already contain the DNA encoding a KGF protein (s). Homologous recombination is a technique originally developed for the location as targets of genes to induce or correct mutations in transcriptionally active genes (Kucherlapati (1989), Prog. In Nucí, Acid Res. And Mol. Biol., 36: 301 , the description of which is incorporated herein for reference). The basic technique was developed as a method to introduce specific mutations into specific regions of the mammalian genome (Thomas et al. (1986), Cell, 44: 419-428; Thomas and Capecchi (1987), Cell, 51: 503 -512 and Doetschman et al. (1988), Proc. Nati. Acad. Sci., 85: 8583: 8587, the descriptions of which are incorporated herein for reference) or to correct specific mutations within defective genes (Doetschman et al. (1987), Nature, 330: 576-578, the disclosure of which is incorporated herein by reference). Exemplary techniques are described in U.S. Pat. No. 5,272,071; WO 92/01069; WO 93/03183; WO 94/12650 and WO 94/31560, the descriptions of which are incorporated herein by reference.

Host Cell Culture The method for cultivating each of the one or more recombinant host cells for the production of a desired protein will vary depending on many factors and considerations; The optimum production procedure for a given situation will be apparent to those skilled in the art through minimal experimentation. Such recombinant host cells are cultured in suitable media and the expressed protein is then optionally recovered, isolated and purified from the culture medium (or from the cell, if it is expressed intracellularly) by appropriate means known to those skilled in the art. Specifically, each of the recombinant cells used to produce a desired protein can be cultured in a suitable medium to induce promoters, select suitable recombinant host cells or amplify the gene encoding the desired protein. The medium can be supplemented when necessary with hormones and / or other growth factors (such as insulin, transferrin or epidermal growth factor), salts (such as sodium chloride, calcium, magnesium and phosphate). ), buffer solutions (such as HEPES), nucleosides (such as adenosine and thymidine), antibiotics (such as gentamicin), trace elements (defined as inorganic compounds usually present at final concentrations in the micromolar range), and glucose and other Energy sources. Other supplements may also be included, at appropriate concentrations, as will be appreciated by those skilled in the art. Suitable culture conditions, such as temperature, pH and the like, are also well known to those skilled in the art for use with the selected host cells. The resulting expression product can then be purified almost to homogeneity using procedures known in the art. Exemplary purification techniques are taught in WO 90/08771 and WO 96/11952, the descriptions of which are incorporated herein by reference.

Applications The KGF protein (s) and the chemically modified derivatives thereof having biological activity (collectively, "the product (s) of the KGF protein") can be used as research reagents and as therapeutic and diagnostic agents. Accordingly, one or more KGF protein product (s) can be used in in vitro and / or in vivo diagnostic assays to quantitate the amount of KGF in a tissue or organ sample. For example, one (s) product (s) of the KGF protein can be used for the identification of the receptor (s) for the KGF protein (s) in various body fluids and tissue samples. using techniques known in the art (WO 90/08771). This invention also contemplates the use of one or more KGF protein product (s) in the generation of antibodies made against the KGF protein product (s), including KGF. A person with ordinary skill in the art can use well-known published procedures to obtain polyclonal, monoclonal or recombinant antibodies. Such antibodies can then be used to purify and characterize the KGF protein product (s).

Pharmaceutical Compositions The present invention encompasses pharmaceutical preparations each containing therapeutically or prophylactically effective amounts of a KGF protein product (s). The pharmaceutical compositions each will generally include a therapeutically effective or prophylactically effective amount of one KGF protein product (s) mixed with a carrier. The carrier preferably includes one or more pharmaceutically or physiologically acceptable formulation materials blended with the KGF protein product (s). The primary solvent in a vehicle can be either aqueous or non-aqueous in nature. In addition, the carrier can contain other pharmaceutically acceptable excipients to modify or maintain the pH, preferably to maintain the pH at between about 6.5 and 7.0 (for example, buffer solutions such as citrates, phosphates and amino acids such as glycine); osmolarity (for example, mannitol and sodium chloride); viscosity; clarity; color; sterility; stability (for example, sucrose and sorbitol); odor of the formulation; dissolution rate (eg, solubilizers or solubilizing agents such as alcohols, polyethylene glycols and sodium chloride); release speed; as well as bulking agents for the lyophilized formulation (e.g., mannitol and glycine); surfactants (e.g., polysorbate 20, polysorbate 80, triton, and pluronics); antioxidants (for example, sodium sulfite and sodium acid sulfite); preservatives (for example, benzoic acid and salicylic acid), seasoning agents and diluents; emulsifying agents, suspending agents; solvents; fillers; supply vehicles; diluents and / or pharmaceutical adjuvants. Other effective forms of administration such as slow release formulations, parenterals, inhalation mists, orally active formulations, or suppositories are also contemplated. The compositions also involve particulate preparations of polymeric compounds such as volumetric erosion polymers (e.g., poly (lactic-co-glycolic acid) copolymers (PLGA), PLGA polymer blends, PEG block copolymers, and lactic and glycolic acid, poly (cyanoacrylates)); surface erosion polymers (e.g., poly (anhydrides) and poly (ortho esters)); hydrogel esters (for example, pluronic polyols, polyvinyl alcohol, polyvinylpyrrolidone, alkyl vinyl ether-maleic anhydride copolymers, cellulose, hyaluronic acid derivatives, alginate, collagen, gelatin, albumin, and starches and dextrans) and composition systems thereof; or liposome or microsphere preparations. Such compositions may influence the physical state, stability, speed of in vivo release, and the rate of clearance or in vivo spacing of the present proteins and derivatives. The optimal pharmaceutical formulation for a desired protein will be determined by one skilled in the art depending on the route of administration and the desired dosage. Exemplary pharmaceutical compositions are described in Remington's Pharmaceutical Sciences, 18 / a. Ed., (1990), Mack Publishing Co., Easton, PA 18042, pages 1435-1712; Gambotz and Pettit (1995, Bioconjugate Chem., 6: 332-351; Leone-Bay, et al. (1995), Journal of Medicinal Chemistry, 38: 4263-4269; Haas, et al. (1995), Clinical Immunology and Immunopathology, 76 (1): 93, WO 94/06457, WO 94/21275, FR 2706772 and WO 94/21235, the descriptions of which are incorporated herein by reference.Specific sustained release compositions are available from a variety of suppliers including Depotech Corp. (Depofoam®, a multivesicular iiposome) and Aikermes, Inc. (ProLease®, a PLGA microsphere.) When used here, hyaluronan is proposed to include hyaluronan, hyaluronic acid, salts thereof (such as as sodium hyaluronate), esters, ethers, enzymatic derivatives and cross-linked gels of hyaluronic acid, and chemically modified derivatives of hyaluronic acid (such as hilan.) Exemplary forms of hyaluronan are described in US Patent Nos. 4,582,865, 4,605,691, 4,636,524, 4,713, 448, 4,716,154, 4,716,224, 4,772,419, 4,851,521, 4,957,774, 4,863,907, 5,128,326, 5,202,431, 5,336,767, 5,356,883; European Patent Applications Nos. 0 507 604 A2 and 0 718 312 A2; and WO 96/05845, the descriptions of which are incorporated herein by reference. The suppliers of hyaluran include BioMatrix, Inc., Ridgefield, NJ; Fidia S.p.A., Abano Terme, Italy; Kaken Pharmaceutical Co., Ltd., Tokyo, Japan; Pharmacia AB, Stockholm, Sweden; Genzyme Corporation, Cambridge, MA; Pronova Biopolymer, Inc. Portsmourth, NH; Calbiochem-Novabiochem AB, Lautelfingen, Switzerland; Intergen Company, Purchase, NY and Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan. For the treatment and / or prevention of oral indications, a liquid solution or suspension can be used in a manner similar to a mouthwash, where the liquid is beaten or whipped around the mouth to maximize treatment of the mouths. injuries (Patents of the United States of America 5,102,870, the teachings of which are incorporated herein for reference). The most prolonged contact with the mucosal surface can be achieved by selecting a suitable vehicle which is able to coat the mucosa. Typical examples are pectin-containing formulations such as Orabase® (Colgate-Hoyt Laboratories, Norwood, MA), suspensions of sucralfate, Kaopectate and Magnesia Milk. The formulation may also be a sprayable cream, gel, lotion or ointment having a non-toxic, pharmaceutically acceptable carrier or carrier. The KGF protein product (s) can also be incorporated into a slowly dissolving lozenge or troche, a chewable gum base, or a slow delivery or buccal prosthesis hooked onto a molar skeleton, for example. Once the pharmaceutical composition has been formulated, it can be stored in sterile ampoules as a solution, suspension, gel, emulsion, solid, or a dehydrated or lyophilized powder. Such formulations can be stored either in a ready-to-use form or in a form (eg, lyophilized) that requires reconstitution prior to administration. In a specific embodiment, the present invention is directed to sets or assemblies for producing a single dose delivery unit. The sets or sets may each contain both a first container having a dry protein and a second container having an aqueous formulation. The kits or sets included within the scope of this invention are single-chamber and multi-chamber pre-filled syringes (eg syringes with liquid, and lyo-syringes such as Lyo-Ject®, a double-chamber pre-filled lyo-syringe) are available from Vetter. GmbH, Ravensburg, Germany. A KGF protein product (s) can be applied in effective amounts therapeutically and prophylactically to organs or tissues specifically characterized because they have damage to or in insufficient numbers of epithelial cells clinically. It should be noted that the formulations of the KGF protein products (s) described herein can be used for veterinary as well as human applications and that the term "patient" should not be interpreted in a limiting manner.

The frequency of dosing of the KGF protein products to a patient will depend on the disease and condition of the patient, as well as on the pharmacokinetic parameters of the KGF protein products (s) as formulated, and the route of administration. The KGF protein product (s) can be administered once, administered daily, or administered with an initial dose of bolus followed by a continuous dose or sustained delivery. It is also contemplated that other modes of continuous or quasi-continuous dosing can be practiced. For example, the chemical derivation can lead to sustained release forms of the protein which have the effect of a continuous presence in the bloodstream, in predictable amounts, based on a given dosage regimen. A patient having a need for stimulation (including cytoprotection, proliferation and / or differentiation) of the epithelial cells can be administered with an effective amount of one or more KGF protein product (s) to cause the desired response in the patient. The dosage regimen involved in a method to prevent or treat a condition specifically will generally be determined by the doctor providing the care, considering several factors which modify the action of the drugs, eg, age, condition, body weight. , the sex and diet of the patient, the severity of any infection, the time of administration and other clinical factors. Appropriate dosages can be ascertained through the use of established assays to determine the dosages used in conjunction with the appropriate dose response data. Typical dosages will vary from 0.001 mg / kg of body weight to 500 mg / kg of body weight, preferably up to 200 mg / kg of body weight, more preferably 100 mg / kg of body weight. The KGF protein product (s) can be administered by means of topical, enteral or parenteral administration including, without limitation, infusion, intraarterial, intraarticular, intracapsular, intracardiac, intradermal, intramuscular, intraorbital, intrathecal, intravenous, intraperitoneal, intraspinal, intrasternal, intraventricular, subcutaneous, subcuticular, subcapsular, subarachnoid and transtracheal injection. The KGF protein product (s) can be administered by oral administration or administered by means of mucous membranes, i.e., buccal, intranasal, rectal or sublingually for systemic delivery. The KGF protein product (s) can be used once or administered repeatedly, depending on the disease and the condition of the patient. In some cases, the KGF protein product (s) can be administered as an adjuvant for another therapy and also with other pharmaceutical preparations. In another embodiment, cell therapy is also contemplated, for example, the implantation of cells that produce KGF protein (s). This embodiment of the present invention may include implanting into patient cells which are capable of synthesizing and secreting a biologically active form of the KGF protein (s). Such cells that produce KGF protein (s) may be cells which normally do not produce KGF protein (s) but which have been modified to produce KGF (s) proteins, or which may be cells whose ability to produce protein (s) of KGF has been increased for transformation with a suitable polynucleotide for the expression and secretion of the KGF protein (s). To minimize a potential immunological reaction in patients who are administered with the KGF protein (s) of foreign species, it is preferred that the cells are from the same species as the patient (eg, human), or that the cells can be encapsulated with material that provides a barrier against immune recognition, or that the cells are placed in an immunologically privileged anatomical site, as such in the testes, the eye and the central nervous system. Human or non-human animal cells can be implanted in patients in semi-permeable, biocompatible polymeric membranes or enclosures, to allow the release of a KGF protein (s) but preventing the destruction of the cells by the patient's immune system or by other damaging factors of the surrounding tissue. Alternatively, the patient's own cells, transformed ex vivo to produce the KGF protein (s), could be implanted directly into the patient without such encapsulation. The methodology for encapsulating the membrane of living cells is familiar to those of ordinary skill in the art, and the preparation of the encapsulated cells and their implantation in patients can be effected with known techniques (U.S. Patent Nos. 4,892,538; 5,011,472; and 5,106,627, the descriptions of which are hereby incorporated by reference).

In still another embodiment, in vivo gene therapy is also contemplated, wherein a nucleic acid sequence encoding a KGF protein (s) is introduced directly into a patient. The transfer of the gene of prolonged and efficient duration to the hepatocytes is required for the therapy of the gene effective for the local expression of the protein to prevent and / or treat diseases of the liver and / or for the secretion of the protein, to prevent and / or treat diseases in other organs or tissues. The DNA construct can be injected directly into the tissue of the organ to be treated, where it can be received in vivo and expressed, provided that the DNA is operably linked to a promoter that is active in such tissue. The DNA construct can also additionally include the sequence of the vector, of vectors such as an adenovirus vector, a retroviral vector, a papilloma virus and / or herpes virus vector, to aid in cell reception. The physical transfer can be accomplished in vivo by local injection of the desired nucleic acid construct or other appropriate delivery vector containing the desired nucleic acid sequence, such as liposome-mediated transfer, direct injection (naked DNA), transfer mediated by the receptor (DNA-ligand complex), or microparticle bombardment (gene gun). For the in vivo regeneration of hepatocytes in the liver, the use of Moloney retroviral vectors can be especially effective (Bosch, et al. (1996), Cold Springer Harbor, Gene Therapy Meeting, 25-29 September 1996, and Bosch , et al. (1996), Journal of Clinical Investigation, 98 (12): 2683-2687, the description of which are incorporated herein for reference). A KGF protein product (s) can be applied in effective amounts therapeutically and prophylactically to organs or tissues specifically characterized because they have a damage with respect to, or insufficient, numbers of epithelial cells. It should be noted that one or more KGF protein product (s) can be used for veterinary as well as human applications and that the term "patient" should not be interpreted in a limiting manner. According to the present invention, a KGF protein product (s) can be used in vivo to induce stimulation (including cytoprotection, proliferation and / or differentiation), proliferation and / or differentiation of epithelial cells. which include, but are not limited to, the eye, ear, gums, hair, lungs, skin, pancreas (endocrine and exocrine), the thymus, the thyroid, the urinary bladder, the liver, and the gastrointestinal tract including cells in the oral cavity, in the esophagus, in the large stomach and small intestine, in the colon and intestinal mucosa, in the rectum and in the anal canal. The indications in which one or more KGF protein product (s) can be administered successfully include, but are not limited to: burns and other partial and full thickness lesions that have a need for stimulation of adnexal structures such like the hair follicles, the sweat glands; the lesions caused by epidermolysis bullosa, which is a defect in the adherence of the epidermis to the underlying dermis, leading to painful, frequently open blisters, which cause severe morbidity; alopecia induced by chemotherapy and male pattern baldness, or progressive hair loss in men and women; gastric and duodenal ulcers; the toxicity of the intestine in the treatment regimens with radiation and chemotherapy; Erosions of the gastrointestinal tract (eg, esophagus, stomach, and intestines) include erosive gastritis, esophagitis, esophageal reflux, or inflammatory bowel diseases, such as Crohn's disease (which mainly affects the small intestine) and colitis ulcerative (which mainly affects the large intestine); disorders or damage to tissue of the salivary gland including the effects of radiation / chemotherapy, autoimmune diseases such as Sjogren's Syndrome which can cause salivary gland insufficiency (Sicca syndrome); the insufficient production of mucus in the entire gastrointestinal tract; adult respiratory distress syndrome (ARDS), pneumonia, hyaline membrane disease (ie, respiratory distress syndrome in children and bronchopulmonary dysplasia) in preterm infants; chronic or acute lung damage or insufficiency due to inhalation injuries (including elevated oxygen levels), emphysema, damage to the lungs of chemotherapeutic substances, trauma of the ventilator or other circumstances of damage to the lungs; liver cirrhosis, fulminating liver failure, damage caused by acute viral hepatitis and / or toxic liver attacks and / or bile duct disorders, and virally mediated gene transfer to the liver, corneal abrasion and / or corneal ulcerations due to chemical substances, bacteria or viruses; the progressive disease of the gums; the damage to the eardrum; ulcerations and / or inflammations that include conditions resulting from chemotherapy and / or infection; pancreatic disorders and pancreatic insufficiencies including diabetes (Type I and Type II), pancreatitis, cystic fibrosis, and as an adjuvant in islet cell transplantation. Therapeutic agents such as analgesics and anesthetics can also be administered to alleviate pain and anti-infective, antibacterial, antifungal and / or antiseptic agents can also be administered to prevent and / or treat secondary infection of the lesions. This invention therefore has significant implications in terms of making possible the application of the KGF protein product (s) specifically characterized by its prophylactic and / or therapeutic use of KGF to reduce, retard and / or block the start of the damage to, or deficiencies in, these particular types of cells. The following is a more specific description of the diseases and medical conditions which can be treated with KGF protein product (s) according to the invention. The KGF protein product (s) is (are) useful (s) to increase cytoprotection, proliferation and / or differentiation of hepatocytes to increase liver function. The KGF protein product (s) are useful for treating and / or preventing liver cirrhosis, fulminating liver failure, damage caused by acute viral hepatitis, toxic liver attacks and bile duct disorders. . Liver cirrhosis, secondary to viral hepatitis and chronic alcohol ingestion, is a significant cause of morbidity and mortality. The KGF protein product (s) are useful for treating and / or preventing the development of cirrhosis. A standard in vivo model of liver cirrhosis is already known (Tomaszewski et al. (1991), J. Appl. Toxicol., 11: 229-231, the disclosure of which is hereby incorporated by reference). Fulminant failure of the liver is a life-threatening condition that occurs with cirrhosis in the terminal stage and which is currently treatable only with liver transplantation. The KGF protein product (s) are useful for treating and / or preventing fulminant failure of the liver. Standard in vivo models of fulminant liver failure are already known (Mitchell et al. (1973), J. Pharmacol. Exp. Ther., 187: 185-194; Thakore and Mehendale (1991), Toxicologic Pathol., 19 : 47-58; and Havill et al. (1994), FASEB Journal, 8 (4-5): A930, Abstract 5387, the descriptions of which are incorporated herein for reference). Acute viral hepatitis is often subclinical and self-limiting. However, in a minority of patients severe liver damage may result over several weeks. The KGF protein product (s) are useful in the prevention and / or treatment of viral hepatitis. Standard in vivo models of hepatocyte proliferation are already known (Housley et al. (1994), Journal of Clinical Investigation, 94 (5): 1764-1777; and Havill et al. (1994), supra, descriptions of which are incorporated herein by reference, toxic liver attacks caused by acetaminophen, halothane, carbon tetrachloride and other toxins can be prevented and / or treated by KGF protein product (s). Liver toxicity is already known (Mitchell et al. (1973), supra, Thakore and Mehendale (1991), supra, and Havill et al. (1994), supra, the descriptions of which are incorporated herein for reference). (the) KGF protein product (s) are useful for increasing the cytoprotection, proliferation and / or differentiation of epithelial cells in the gastrointestinal tract (e.g., the oral cavity, esophagus, stomach, small intestine, the colon, the rectum and the anal canal The terms "gastrointestinal tract", as defined herein, and "gut" are terms well recognized in the art and are used interchangeably herein. Specifically, the KGF protein product (s) are useful for treating and / or preventing gastric ulcers, duodenal ulcers, inflammatory bowel disease, bowel toxicity, and erosions of the gastrointestinal tract. Gastric ulcers cause significant morbidity, have a relatively high rate of recurrence, and heal by scar formation on the lining of the mucosa. The KGF protein product (s) are useful to prevent degeneration of the grandular mucosa and to regenerate the grandular mucosa more rapidly, for example, offering a significant therapeutic improvement in the treatment of gastric ulcers. Standard in vivo models of gastric ulcers are already known (Tarnawski et al. (1991), "Indomethacin Impairs Quality of Experimental Gastric Ulcer Healing: A Quantitative Histological and Ultrastructural Analysis", In: Mechanisms of Injury, Protection and Repair of the Upper Gastrointestinal Tract, (Eds) Garner and O'brien, Wiley & amp;; Sons; Brodie (1968), Gastroenterology, 55:25; and Ohning et al. (1994), Gastroenterology, 106 (4 Suppl.): A624, the descriptions of which are incorporated herein for reference). Duodenal ulcers, similar to gastric ulcers, cause significant morbidity and have a relatively high rate of recurrence. The KGF protein product (s) are useful to prevent degeneration of the mucosal lining and to rapidly regenerate the lining of the duodenum mucosa to heal these ulcers and reduce their recurrence. Standard in vivo models of duodenal ulcers are already known (Berg et al. (1949), Proc. Soc. Exp. Biol. Med., 7: 374-376; Szabo and Pihan, Cronobiol. Int. (1987), 6: 31-42; and Robert et al. (1970), Gastroenterology, 59: 95-102, the descriptions of which are incorporated herein for reference). Intestinal toxicity is a major limiting factor associated with the treatment of cancer, both in radiation (abdominal, whole or local body, for example, head and neck) and chemotherapy. Patients suffering from it are of primary interest; chemotherapy for cancer such as leukemia, breast cancer or as an adjuvant for tumor removal; Radiation therapy for cancer of the head and neck; and combined chemotherapy and radiation therapy for bone marrow transplants. The severity of the damage is related to the type and dosage of the chemotherapeutic agent (s) and concomitant therapy such as radiotherapy. Mucositis in portions of the gastrointestinal tract can be taken into account for the significant pain and discomfort of these patients, and the variation in the severity of redness and swelling of frank ulcerative lesions. The lesions frequently become secondarily infected and become much more difficult to heal. Standard in vivo models of radiation-induced bowel toxicity are already known (Withers and Elkind (1970), Int. J. Radiat., 17 (3): 261-267, the description of which is incorporated herein for reference). Standard in vivo models of bowel toxicity induced by chemotherapy are already known (Farrel et al., The American Society of Hematology, 38th Annual Meeting (Orlando, FL), 6-8 December 1996, Sonis et al. 1990), Oral Surg. Med. &Oral Pathol., 69 (4): 437-443; and Moore (1985), Cancer Chemotherapy Pharmacol., 15: 11-15, the descriptions of which are incorporated herein for reference ).

Exemplary chemotherapeutic agents include, but are not limited to, BCNU, busulfan, carboplatin, cyclophosphamide, cisplatin, cytosine arabinoside, daunorubicin, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, ifosfamide, irinotecan, melphalan, methotrexate, navelbine, topotecan, taxol and taxotere, and exemplary treatment regimens include, but are not limited to, BEAM (busulfan, etoposide, cytosine arabinoside, methotrexate); cyclophosphamide and complete irradiation of the body; cyclophosphamide, the total irradiation of the body and the etoposide; cyclophosphamide and busulfan; and 5-fluorouracil with leucovorin or levamisole. The treatment, pretreatment and / or aftercare, with the KGF protein product (s) are useful to generate a cytoprotective effect or regeneration or both, for example, on the mucosa of the small intestine, allowing increased dosages of such therapies while the potential fatal side effects of bowel toxicity are reduced. The KGF protein product (s) can be preferably administered in the following environments. Colon-rectal patients are routinely administered with 5-fluorouracil with leucovorin on days 1 to 5; the KGF protein product (s) can be administered on days -2, -1, and 0. Patients with cancer of the head and neck are commonly administered with hypofractionated radiation therapy plus 5-fluorouracil and cisplatin over a period of seven weeks, the protein products of KGF can be administered on days -2, -1 and 0 and after that once a week until the end of radiation therapy. In lymphoma transplant patients they are frequently administered by BEAM therapy for 6 days (days 1 to 6); the protein product (s) of KGF can be administered during days -2, -1 and 0 and as a three-day aftercare (days 7 to 9). In specific embodiments, the KGF protein product (s) can be administered prophylactically and / or therapeutically to reduce, retard and / or block the onset of mucositis (due to chemotherapy and / or radiotherapy), in combination with one or more cytokines to delay and / or block the onset of cytopenia. Typically, cells from the bone marrow, blood progenitor cells, peripheral or stem cells (McNiece et al. (1989), Blood, 74: 609-612 and Moore et al. (1979), Blood Cells, 5: 297-311, the descriptions of which are hereby incorporated by reference) are removed from a patient prior to myelosuppressive cytoreductive therapy (chemotherapy alone or with radiation therapy) and are then administered to the patient concurrently with or subsequent to cytoreductive therapy to counteract the sympathetic effects of such therapy. Many different approaches have been undertaken to protect an organism from the side effects of radiation or toxic chemicals. One approach is to replace the cells in the bone marrow before the toxicity has developed. Another approach is to use peripheral blood progenitor cells (PBPC). These PBPCs can be collected by apheresis or phlebotomy following therapy alone (G-CSF or GM-CSF), or with chemotherapy or cytokines. They can be fresh or cytopreserved again. If desired, the cells can be CD34 + selected, free or depleted of Tn cells, free or depleted of tumorigenic cells, or the progenitor cells can be expanded (caused to multiply) by means known in the art, prior to administration . The benefits of reinfusion of autologous or allogeneic progenitors following myelosuppressive therapy have been described in the literature (Morse et al. (1992), Ann. Clin. Lab. Sci., 22: 221-225; Kessinger and Ar. itage (1991), Blood, 77: 211-213, Kessinger et al. (1989), Blood, 74: 1260-1265; Takam et al. (1989), Blodd, 74: 1245-1245 and Kessinger et al. (1988), Blood: 723-727, the descriptions of which are incorporated herein for reference). When used here, the term "cytokine" is a generic term for proteins released by a population of cells which act on another cell as intercellular mediators. Examples of such cytokines without the lymphokines, the onocins and the traditional polypeptide hormones. Included among the cytokines are growth factors similar to insulin; the human growth hormone; the human growth hormone of N-methionyl; bovine growth hormone, the hormone of the parathyroid; thyroxine; insulin; proinsulin; relaxin; Prorrelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH) and leutinizing hormone (LH); the hemopoietic growth factor; the liver growth factor; the fibroblast growth factor; prolactin; the placental lactogen, the alpha and -beta factor of tumor necrosis, the peptide associated with mouse gonadotropin; inhibin; activin; the vascular endothelial growth factor; the integrin; thrombopoietin; nerve growth factors such as beta-NGF; platelet growth factors such as TPO and MGDF; transforming growth factors (TGFs) such as TGF-alpha and TGF-beta; growth factor I and II similar to insulin; erythropoietin; the osteoinductive factors; interferons such as interferon-alpha, beta and gamma, colony-stimulating factors (CSFs) such as macrophages-CSF (M-CSF), granulocytes-macrophages-CSF (GM-CSF), and granulocytes-CSF (C -CSF); interleukins (lis) such as IL-1, IL-2, 11-3, IL-4, IL-5, IL-6, IL-7, IL-8, 11-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15 and IL-16; and other polypeptide factors. The cytokines can be used alone or in combination to provide protection against, mitigate and / or reverse the myeloid or hematopoietic toxicity associated with cytotoxic agents. The mode of administration of the KGF protein product (s), as well as the cytokine, must be coordinated and optimized. Depending on the circumstances, an appropriate dose of the KGF protein products may be administered prior to or subsequent to the administration of the therapeutic agent (s). For example, a parameter that is to be considered is whether the cytokine is administered in a single dose or in multiple doses during the course of therapy. Certain cytokines are rapidly cleared or cleared from the body and will require periodic or continuous administration to maximize their effectiveness. The manner of administration may differ, depending on whether a pretreatment or post-treatment of the cytokine occurs. For example, if the cytokine is provided prior to the cytotoxic agent, it is preferable to administer the cytokine by intravenous bolus injection for several hours and, optionally, repeat such administration for one or more days while and after the cytotoxic therapy is supplemented. In a specific embodiment, the KGF protein product (s) are administered (e.g., intravenously) at 0.1 to 500 micrograms / kg / dose, preferably up to about 200 micrograms / kg / dose, prior to (e.g. 1 to 3 days) and / or after radiation therapy or chemotherapy, and G-CSF (Neupogen® - or Lenograstim®) or GM-CSF (Sargramostim®) is administered (eg, subcutaneously) at 5 micrograms kg / kg / dose for 1 to 10 days (preferably 7 to 10 days) after chemotherapy.

Erosions of the gastrointestinal tract (eg, esophagus, stomach, and intestine) include erosive gastritis, esophagitis, esophageal reflux, and inflammatory bowel diseases. Inflammatory diseases of the intestine, such as Cron's disease (which mainly affects the small intestine) and ulcerative colitis (which mainly affects the large intestine), are chronic diseases of unknown etiology that lead to the destruction of the mucosal surface , inflammation, scar formation and adhesion during repair, and significant morbidity with respect to affected individuals. The KGF protein product (s) are useful for regenerating the mucosal lining and decreasing the recurrence of these erosions, leading to faster healing, and may be beneficial in controlling the progression of the disease. Standard in vivo models of gastrointestinal tract erosion are already known (Geisinger et al. (1990), Mod-Pathol., 3 (5): 619-624; Carlborg et al. (1983), Laryngoscope, 93 (2) ): 184-187; Carlborg et al. (1980), Eur-Surg-Res., 12 (4): 270-282; Keshavarzian et al., 81991), Alcohol-Clin-Exp-Res., 15 (1) : 116-121; Katz et al. (1988), Dig-Dis-Sci-., 33 (2): 217-224; and Zeeh et al. (1996), Gastroenterology, 110 (4): 1077-1083, the descriptions of which are incorporated herein for reference). Standard in vivo models of inflammatory bowel disease are well known (Morris et al. (1989), Gastroenterology, 96: 795-803, Rachmilewitz et al. (1989), Gastroenterology, 97: 326-327; Allgayer et al. (1989), Gastroenterology, 96: 1290-1300, and Kim and Borstad (1992), Scand J. Gastroenterol, 27 (7): 529-537, the descriptions of which are incorporated herein for reference). Animal studies have established the relationship between total parenteral nutrition (TPN) and atrophy of the intestinal mucosa (Buch et al. (1195), Journal of Parenteral and Enteral Nutrition, 19: 453-460). The decrease in the height of intestinal hair is attributed to the lack of growth stimuli provided through the oral intake of nutrients. This is reflected in a reduction in the Labeling Index, a measure of growth. Reductions in hair height are also correlated with reductions in the specific activities of the enzymes involved in the absorption of nutrients. The KGF protein product (s) are useful either to provide protection against atrophy during fasting and / or to facilitate regrowth during the reintroduction of oral nutrients.

In a specific embodiment, the present invention is directed to the method of using the KGF protein products and the GLP-2 protein products in combination to increase cytoprotection, proliferation and / or differentiation of epithelial cells in the gastrointestinal tract. Specifically, the combination therapy is useful to treat and / or prevent gastric ulcers, duodenal ulcers, inflammatory bowel disease, bowel toxicity and erosions of the gastrointestinal tract. The term "GLP-2 peptide" refers collectively herein to human GLP-2 (SEQ ID NO: 67) and variants thereof (defined, for example, in WO 96/32414 and, for example, hGLP-2 (g2), a GLP-2 variant in which glycine is replaced by asparagine in position 2 (SEQ ID NO: 68) and hGLP-2 (S2), a variant GLP-2 in which serine is substituted by asparagine in position 2 (SEQ ID NO: 69, described herein) GLP-2 and variants thereof can be produced and purified by standard techniques (see, for example, WO 96/31414, the description of which is incorporated herein by reference.) WO 96/32414 reported that GLP-2 has effects on the small intestine and pancreatic islets.

Hyaline membrane disease of premature infants leads to the absence of surfactant production by the type of pneumocytes II within the lung, leading to the collapse of the alveoli. The KGF protein product (s) are useful for treating and / or preventing hyaline membrane disease. Smoke inhalation is a significant cause of morbidity and mortality in the week following burn injury, due to necrosis of the bronchiolar epithelium and alveoli. The KGF protein products are useful for treating and / or preventing inhalation injuries. Emphysema results from the progressive loss of the alveoli. The KGF protein product (s) are useful for treating and / or preventing emphysema. Pancreatic disorders may be endocrine related such as Type I or Type II diabetes, or may be related exocrine such as pancreatitis and pancreatic inefficiencies or cystic fibrosis. Patients with diagnosed Type I diabetes require administration of constant exogenous insulin. Patients with Type II diabetes progression diagnosed through the variable stages of insulin resistance / insufficiency to this day also require the administration of exogenous insulin. The KGF protein product (s) are useful for improving, retarding and / or preventing the permanent manifestation of diabetes mellitus or as an adjuvant in the fixation or adjustment of islet cell transplantation by induction of the pancreatic beta cell function to normalize blood glucose levels during variable metabolic demands, still avoiding frequent or deep hypoglycemia. The standard models of diabetes are already known (Junod et al. (1967), Proc. Soc. Exp. Bio. Med. 126 (1): 201-205; Rerup (1970), Pharm. Rev., 22: 485-518; Rossini et al. (1977), P.N.A.S., 74: 2485-2489; and Ar'Rajab and Ahren (1993), Pancreas, 8: 50-57, the descriptions of which are incorporated herein for reference). A standard model of pancreatic cell proliferation is already known (Yi et al. (1994), American Journal of Pathology, 145 (1): 80-85, the description of which is incorporated herein for reference). Corneal cells can be damaged by abrasion of the cornea and / or ulcerations of the cornea due to chemical substances, bacteria or viruses. The KGF protein product (s) are useful for treating and / or preventing degeneration of the cornea.

Standard in vivo models of regeneration of corneal cells are already known (Inatomi et al. (1994), Investigative Opthalmology and Visual Science, 35 (4): 1318, Abstract 299, Sotozono et al. (1994), Investigative Opthamology and Visual Science, 35 (4): 1941, Abstract 317, Wilson et al. (1994), Investigative Opthalmology and Visual Science, 35 (4): 1319, Abstract 301, Wilson et al. (1993), The FASEB Journal, 7 (3): A493, Abstract 2857, Inatomi et al. (1994), Investigative Ophthalmology &Visual Science, 35 (4): 1318, Wilson et al. (1994), Experimental Eye Research, 59 (6): 665-678; Y Sotozono et al. (1995), Investigative Ophthalmology & Visual Science, 36 (8): 1524-1529, the descriptions of which are hereby incorporated by reference). The KGF protein product (s) are useful for treating and / or preventing gum disease. Standard in vivo models of gum disease are already known. The KGF protein product (s) are useful for treating and / or preventing ulceration and / or inflammatory conditions that include conditions related to chemotherapy (as described above) and / or infection. Standard in vivo models of urinary bladder damage are already known (Ford and Hess (1976), Arch. Intern. Med., 136: 616-619 and Droller, et al. (1982), Urol., 20: 256 -258, the descriptions of which are incorporated herein for reference). The KGF protein product (s) are useful for treating and / or preventing damage to the eardrum. Standard in vivo models of tympanic membrane perforations are already known (Clymer et al. (1996), Laryngoscope (USA), 106 (3): 280-285, the description of which is incorporated herein for reference). The KGF protein product (s) are useful for treating and / or preventing disorders or tissue damage of the salivary glands, including the effects of radiation / chemotherapy (as described above) and autoimmune diseases such as Sjogren's syndrome which can cause salivary glandinsufficiency (sicca syndrome). Standard in vivo models of tissue damage to the salivary gland are already known. The following examples are included to more fully illustrate the present invention. It is understood that modifications can be made to the described procedures without departing from the spirit of the invention.

EXAMPLES Standard methods for many of the methods described in the following examples, or suitable alternative procedures, are provided in widely recognized molecular biology manuals such as, for example, Molecular Cloning, Second Edition, Sambrook et al., Cold Spring Harbor Laboratory Press (1987) and Current Protocols in Molecular Biology, Ausabel et al. (1990), Greene Publishing Associates / Wiley Interscience, New York. All chemical substances are either analytical or USP grade. materials The test materials used in the following in vivo studies were a KGF having a deletion of the first 23 amino acids of the amino terminal of KGF (ie,? N23 KGF) using standard techniques (WO 96/11946). All proteins were produced by recombinant expression in E. coli and purified to homogeneity. Each protein was administered as a subcutaneous formulation. The polypeptide of hGLP-2 (G2) was synthesized by the method of solid phase peptide chemistry based on Fmoc (fluorenylmethoxycarbonyl) / t-butyl. An ABI 431A peptide synthesizer (Perkin Elmer Corp., Foster City, CA) using a unique coupling program to carry out the assembly of the chain. The commercially available pre-filled Fmoc-amino acid-HMP (hydroxymethyl-phenylacetyl) derived polystyrene resin was used to prepare the carboxy-terminal acid peptides. The amino acids were subsequently coupled or bound as esters of HOBT (hydroxybenzotriazole). The protection of the side chain was used as follows: Arg (PMC (2, 2, 5, 7, 8-pentamethylchroman-6-sulfonyl), Asn (TrT), Asp (OtBu), Cys (Trt), Gln (Trt), Glu (OtBu), His (Trt), Ser (tBu) ), Thr (tBu), and Tyr (tBu). The Gly (FmocHmb) was incorporated to eliminate the risk of the formation of byproducts of aspartimide or piperidine. During the removal of the final N-terminal Fmoc, the protective groups of the side chain were removed and the peptides were cleaved from the resin by the treatment for 4 hours with TFA: triisopropylsilane: water: phenol (85: 5: 5: 5). The resulting suspension is filtered, and the volume of the filtrate reduced by roto-evaporation. The crude peptide is precipitated and washed with ether, then dried in vacuo overnight. All peptides were purified to >95% homogeneity by reverse phase HPLC on a preparative Vydac C18 (2.5 cm x 25 cm) column with linear gradients of 99.95% acetonitrile plus 0.05% TFA against 0.1% aqueous TFA. The mass spectra for the synthetic peptides were obtained on a Sciex API single quadrupole mass spectrometer (Perkin Elmer Corp.).

All mass spectral samples were fractions outside the purification by preparative HPLC. The amino acid analyzes were carried out on an ABI 420A derivatizer / hydrolyzer with a 130A separation system (Perkin Elmer Corp.). The peptides were hydrolyzed using 6N HCl at 200 ° C for 30 minutes and then derivatives as the PTC derivative (phenyl isothiocinate). The amino acid mixture was then separated by HPLC on a Brownlee PTC Cis column, 5 micron pore size, 2.1 x 220 mm with a linear gradient of 70% acetonitrile against water. Both solvents were buffered with sodium acetate until pH = 5.4. The amino acid determinations were quantified by comparing the relationships of unknown peaks with a standard equimolar amino acid.

EXAMPLE 1: Intestinal Growth in Normal Animals Normal BDFl mice were treated with? N23 KGF given as a single daily injection of 5 mg / kg / day alone, hGLP-2 (G2) given as a twice daily injection of 30 ug / injection, or both. The mice were treated for 6 days and euthanized for the removal of the intestines on day 7. The total length of the small intestine was removed, and hung under 5 g of tension for length measurement and subdivision into 3 segments. The first 10 cm were designated the duodenum, the last 10 cm were designated as the ileus and the remaining central portion the jejunum. The segments were flooded in salt solution cooled with ice, dried with taps and heavy. The values of the average wet weight were converted to percentage increases in relation to the control and the data are presented in Table 2, which is given below.

Table 2 As seen in Table 2, treatment with hGLP-2 (G2) or? N23 KGF administered alone had a significant effect on wet weight in the intestine. Surprisingly, pretreatment with? N23 KGF and hGLP (G2) showed a synergistic effect on the increase of wet weight in the intestine.

EXAMPLE 2 Model of Mucositis induced by Chemotherapy An animal model of mucositis induced by chemotherapy was used to investigate the combination therapy of? N23 KGF and hGLP-2 (G2). Mice (15 / group) treated with 5-fluorouracil (Roche Laboratories, Nutley NJ), were administered with the vehicle alone (brine), and with? N23 KGF (formulated in brine and / or hGLP-2 (G2) in bicarbonate ammonium 0.1 M according to the following schedule: Control group: On days -2 to 0, a group of mice were given brine on days -2 to 0, and injected intraperitoneally with 5-fluorouracil (5-FU, 60 mg / kg / day) in the days 1 to 4.

Pretreatment with? N23 KGF: On days -2 to 0, a group of mice were injected subcutaneously with N23 KGF (5 mg / kg). On days 1 to 4, the mice were injected intraperitoneally with 5-fluorouracil (5-FU, 60 mg / kg / day).

Pretreatment with hGLP-2 (G2): On days -5 to 0, a group of mice were injected subcutaneously with hGLP-2 (G2) (3 mg / kg) (divided dose). On days 1 to 4, the mice were injected intraperitoneally with -fluorouracil (5-FU, 60 mg / kg / day).

Pretreatment with? N23 and hGLP-2 (G2): On days -2 to 0, a group of mice were injected subcutaneously with hGLP-2 (G2) (3 mg / kg (divided dose) -.) And injected subcutaneously with N23 KGF (5 mg / kg). On days 1 to 4, the mice were injected intraperitoneally with 5-fluorouracil (5-FU, 60 mg / kg / day).

The effects on body weights and the survival of several groups were analyzed. The body weights were taken daily from day 0 to completion on day 30. The mice were visually examined twice a day to verify signs of morbidity for 30 days and all dying animals were euthanized. The percentage change in body weight in the nadir of day 6 is shown in table 3.

As seen in Table 3, the pretreatment with hGLP2 (G2) administered alone did not provide protection against weight loss, but the treatment with? N23 KGF administered only had a significant effect. Pretreatment with? N23 KGF and hGLP-2 (G2) showed a relative improvement with respect to pretreatment with? N23 KGF or hGLP-2 (G2) alone. Liver abscesses are commonly found in the control, but surviving mice, not pretreated with? N23 KGF, indicate that their 5-FU toxicity is partly due to the weight of the gastrointestinal barrier function. In addition, mice pretreated with? N23 KGF lost less weight and consumed more food and water during the period of 5-FU treatment. The pretreatment with? N23 KGF increased the survival capacity in 30 days in relation to the brine (75% versus 35%), but not the concurrent treatment (0% versus 35%). The pretreatment with? N23 KGF and hGLP-2 (G2) led to all the animals surviving during the 30 days. The hGLP-2 (2) given concurrently with the? N23 KGF as a pretreatment significantly improved survival compared to survival in the group given only? N23 KGF as a pretreatment.

Although the present invention has been described above both generally and in terms of the preferred embodiments, it is understood that other variations and modifications will occur to those skilled in the art in light of the foregoing description.

LIST OF SEQUENCES (1. GENERAL INFORMATION: (I) APPLICANT: Amgen Inc. (ii) TITLE OF THE INVENTION: Keratinocyte Growth Factors and their Use in Combination with Glucagon-like Peptide Derivatives (iii) SEQUENCE NUMBER: 69 (iv) ADDRESS FOR CORRESPONDENCE: (A) RECIPIENT: Amgen Inc. (B) STREET: 1840 Dehavilland Drive (C) CITY: Thousand Oaks (D) STATE: California (E) COUNTRY: E.U.A. (F) POSTAL CODE: 91320-1789 (v) READABLE FOR THE COMPUTER: (A) TYPE OF MEDIUM: Flexible magnetic disk (B) COMPUTER: Compatible with IBM PC (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) PROGRAM: Patentln Relay # 1.0 , Version # 1.30 (vi) DATA OF THIS APPLICATION: (A) APPLICATION NUMBER: STILL NOT KNOWN (B) DATE OF SUBMISSION: 08-DEC-1997 (C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: US 60 / 032,533 (B) DATE OF SUBMISSION: 06-DEC-1996 (vii) PRIOR APPLICATION DATA: (A) APPLICATION NUMBER: US 60 / 062,074 (B) SUBMISSION DATE: OCT 15, 1997 (viii) EMPLOYEE INFORMATION / MANDATORY: (A) NAME: Zindrick, Thomas D. (B) REGISTRATION NUMBER: 32,185 (C) REFERENCE NUMBER / REGISTRATION: A-481B (2) INFORMATION FOR SECTION ID NO: l: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 862 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 108..692 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: l: CAATCTACAA TTCACAGATA GGAAGAGGTC AATGACCTAG GAGTAACAAT CAACTCAAGA so TTCATTTTCA TTATGTTATT CATGAACACC CGGAGCACTA CACTATA ATG CAC AAA 116 Mee His Lys 1 TGG ATA CTG ACA TGG ATC CTG CCA ACT TTG CTC TAC AGA TCA TGC TTT 164 Trp lie Leu Thr Trp lie Leu Pro Thr Leu Leu Tyr Arg Ser Cys = he 5 10 15 CAC ATT ATC TGT CTA GTG GGT ACT ATA TCT TTA GCT TGC AAT GAC ATG 212 His lie lie Cys Leu Val Gly Thr lie Ser Leu Wing Cys Asn Asp Met 20 25 30 35 ACT CCA GAG CAG ATG GCT ACAT AAT GTG AAC TGT TCC AGC CCT GAG CGA 260 Thr Pro Glu Gln Met Wing Thr Asn Val Asn Cys Ser Ser Pro Glu Arg 40 45 50 CAC ACA AGA AGT TAT GAT TAC ATG GAA GGA GGG GAT ATA AGA GTG AGA 308 His Tr Arg Ser Tyr Asp Tyr Met Glu Gly Gly Asp lie Arg Val Arg 55 60 65 AGA CTC TTC TGT CGA ACA CAG TGG TAC CTG AGG ATC GAT AAA AGA GGC 356 Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg lie Asp Lys Arg Gly 70 75 80 AAA GTA AAA GGG ACC CAA GAG ATG AAG AAT AAT TAC AAT ATC ATG GAA 404 Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn lie Mee Glu 85 90 95 ATC AGG ACA GTG GCA GTT GGA ATT GTG GCA ATC AAA GGG GTG GAA AGT 452 lie Arg Thr Val Wing Val Gly lie Val Ala lie Lys Gly Val Glu Ser 100 105 110 H5 GAA TTC TAT CTT GCA ATG AAC AAG GAA GGA AAA CTC TAT GCA AAG AAA 500 Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys 120 125 130 GAA TGC AAT GAA GAT TGT AAC TTC AAA GAA CTA ATT CTG GAA AAC CAT 548 Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu lie Leu Glu Asn His 135 140 145 TAC AAC ACAT TAT GCA TCA GCT AAA TGG ACÁ CAC AAC GGA GGG GAA ATG 596 Tyr Asn Thr Tyr Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu Met 150 155 160 TTT GTT GCC TTA AAT CAA AAG GGG ATT CCT GTA AGA GGA AAA AAA ACG 644 Phe Val Ala Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr 165 170 175 AAG AAA GAA CAA AAA ACA GCC CAC TTT CTT CCT ATG GCA ATA ACT TAA 692 Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 180 185 190 135 TTGCATATGG TATATAAAGA ACCCAGTT CC AGCAGGGAGA TTTCTTTAAG TGGACTGTTT 752 TCTTTCTTCT CAAAATTTTC TTTCCTTTTA TTTTTTAGTA ATCAAGAAAG GCTGGAAAAA 812 CTACTGAAAA ACTGATCAAG CTGGACTTGT GCATTTATGT TTGTTTTAAG 862 (2) INFORMATION FOR SEQ ID NO: 2: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 195 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 2 Met His Lys Trp He Leu Thr Trp He Leu Pro Thr Leu Leu v Ring 1 5 10 Í5 Be Cys Phe His He He Cys Leu Val Gly Thr He Ser Leu Wing Cvs 20 25 3rd Asn Asp Met Thr Pro Glu Gln Met Wing Thr Asn Val Asn Cys Ser Ser 40 40 45 Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Mee Glu Gly Gly Asp He 50 55 60 Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp 65 70 75 80 Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn 85 90 95 He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He Lys Gly 100 105 Not Val Glu Ser Glu Phe Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tvr 115 120 125 Ala Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu 130 135 1 or Glu Asn His Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly 145 150 155 160 Gly Glu Met Phe Val Ala Leu Asn Gln Lys Gly He Pro Val Ars Glv 165 170 175 Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Mee Wing 180 185 190 He Thr * 195 (2) INFORMATION FOR SEQ ID NO: 3: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 495 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTIC: (A) NAME / KEY: CDS (B) LOCATION: 1. . 495 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 3: ATG TCT AAT GAT ATG ACT CCG GAA CAG ATG GCT ACC AAC GTT AAC TCC 48 Met Ser Asn Asp Met Thr Pro Glu Gln Met Ala Thr Asn Val Asn Ser 1 5 10 15 TCC TCC CCG GAA CGT CAC ACG CGT TCC TAC GAC TAC ATG GAA GGT GGT 96 Ser Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly 20 25 30 GAC ATC CGC GTA CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT 144 Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg 35 40 45 ATC GAC AAA CGC GGC AAA GTC AAG GGC ACC CAA GAG ATG AAA AAC AAC 192 He Asp Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn 50 55 60 TAC AAT ATT ATG GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC 240 Tyr Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He 65 70 75 80 AAA GGT GTT GAA TCT GAA TTC CTG GCA ATG AAC AAA GAA GGT AAA 288 Lys Gly Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys 85 90 95 CTG GCA AAA AAA GAA TGC AAC GAA GAC TGC AAC TTC AAA GAA CTG 136 Leu Tyr Ala Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu 100 105 110 ATC CTG GAA AAC CAC TAC AAC ACC TAC GCA TCT GCT AAA TGG ACC CAC 384 He Leu Glu Asn His Tyr Asn Thr Tyr Wing Ser Wing Lys Trp Thr His 115 120 125 AAC GGT GGT GAA ATG TTC GTT GCT CTG AAC CAG AAA GGT ATC CCG GTT 432 Asn Gly Gly Glu Met Phe Val Ala Leu Asn Gln Lys Gly He Pro Val 130 135 140 CGT GGT AAA AAA ACC AAA AAA GAA CAG AAA ACC GCT CAC TTC CTG CCG 480 Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro 145 150 155 160 495 ATG GCA ATC ACT TAA Met Wing He Thr • 165 (2) INFORMATION FOR SEQ ID NO: 4: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 165 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 4 Met Ser Asn Asp Met Thr Pro Glu Gln Met Ala Thr Asn Val Asn Ser 1 5? O 15 Ser Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Glv 20 25 30 Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg 35 40 45 He Asp Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn 50 55 60 Tyr Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He 65 70 75 80 Lys Gly Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys 85 90 95 Leu Tyr Ala Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu 100 105 no He Leu Glu Asn His Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr His 115 120 125 Asn Gly Gly Glu Met Phe Val Ala Leu Asn Gln Lys Gly He Pro Val 130 135 140 Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Ala His Phe Leu Pro 145 150 155 160 Met Ala He Thr * 165) INFORMATION FOR SEQ ID NO: 5: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 483 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (iii) CHARACTERISTIC: (A) NAME / KEY: CDS (B) LOCATION: 1..483 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 5: ATG ACT CCG GAA CAG ATG GCT ACC AAC GTT AAC TCC TCC TCC CCG GAA 48 Met Thr Pro Glu Gln Met Wing Thr Asn Val Asn Ser Ser Pro Glu 1 5 10 15 CGT CAC ACG CGT TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA 96 . Arg His Thr Arg Ser Tyr Asp Tyr Mee Glu Gly Gly Asp He Arg Val 20 25 30 CGT CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC 144 Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg 35 40 45 GGC AAA GTC AAG GGC ACC CAG GAG ATG AAA AAC AAC TAC AAT ATT ATG 192 Gly Lys Val Lys Gly Thr Gln Glu Mee Lys Asn Asn Tyr Asn He Met 50 55 60 GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA 240 Glu He Arg Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu 65 70 75 80 TCT GAA TTC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA 286 Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys 85 90 95 AAA GAA TGC AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC 336 Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn 100 • 105 no CAC TAC AAC ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA 384 His Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu 115 120 125 ATG TTC GTT GCT CTG AAC CAG AAA GGT ATC CCG GTT CGT GGT AAA AAA 432 Met Phe Val Ala Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys 130 135 140 ACC AAA AAA GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT 480 Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr 145 150 155 160 TAA 483 (2) INFORMATION FOR SEQ ID NO: 6: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 161 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 6: Met Thr Pro Glu Gln Met Wing Thr Asn Val Asn Being Ser P ^ o Glu 1 5 10 15 Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val 20 25 30 Arer Arg Leu Phe cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg 35 40 45 Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met 50 55 60 Glu He Arg Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu 65 70 75 80 Ser Glu Phe Tyr Leu Wing Met Asn Lys Glu Gly Lye Leu Tyr Wing Lys 85 90 95 Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu lie Leu Glu Asn His Tyr Asn Thr Tyr Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu 115 120 25 Met P e Val Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lvs 130 135 140 3 * uy * ^ y * Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr 150 155 160 (2) INFORMATION FOR SEQ ID NO: 7: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 480 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA iii) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..480 [xi) DESCRIPTION OF SEQUENCE SEQ ID NO: ATG ACT CCG GAA CAG ATG GCT ACC AAC GTT AAC TCT TCT CCT GAA CGT 48 Met Thr Pro Glu Gln Met Ala Thr Asn Val Asn Ser Ser Pro Glu Arg 1 5 10 15 CAT ACG CGT TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT 96 His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg 20 25 30 CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC 144 Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly 35 40 45 AAA GTC AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA 192 Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu 50 55 60 ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT 240 He Arg Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser 65 70 75 80 GAA TTC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA 288 Glu Phe Tyr Leu Ala Mee Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys 85 90 95 GAA TGC AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC 336 Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu As His 100 105 110 TA C AAC ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG 384 Tyr Asn Thr Tyr Wing Sez Wing Lys Trp Thr His Asn Gly Gly Glu Met 115 120 125 TTC GTT GCT CTG AAC CAG AAA GGT ATC CCG GTT CGT GGT AAA AAA ACC 4-32 Phe Val Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr 130 135 140 AAA AAA GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 480 Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 145 150 155 160 (2) INFORMATION FOR SEQ ID NO: 8 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 160 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 8 Met Thr Pro Glu Gln Met Wing Thr Asn Val Asn Ser Ser Pro Glu Ars 1 5 10 15 His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Ars 20 25 30 Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys? Rs Glv 35 40 45 Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu 50 55 60 He Arg Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser 65 70 75 80 Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys 85 90 95 Glu Cye Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His 100 105 no Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met 115 120 125 Phe Val Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr 130 135 140 Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 145 150 155 160 (2) INFORMATION FOR SEQ ID NO: 9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 468 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1.488 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9; ATG GCT ACT AAT GTT AAC TCC TCT TCT CCT GAA CGT CAT ACG CGT TCC 48 Met Ala Thr Asn Val Asn Ser Ser Pro Glu Arg His Thr Arg Ser 1 5 10 15 TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG TTC TGC 96 Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu Phe Cys 20 25 30 CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC AAG GGC 144 Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val Lys Gly 35 40 45 ACC CAÁ GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT ACT GTT - 192 Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg Thr Val 50 55 60 GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC TAC CTG 240 Wing Val Gly He Val Ala He Lys Gly Val Glu Ser Glu Phe Tyr Leu 65 70 75 80 GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC AAC GAA 288 Wing Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys Asn Glu 85 90 95 GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC ACC TAC 336 Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn HIS Tyr Asn Thr Tyr 100 105 110 GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT GCT CTG 38 Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val Wing Leu 115 120 125 AAC CAG AAA GGT ATC CCG GTT CGT GGT AAA AAA AAA AAAA GAA CAG 43 Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys Glu Gln 130 135 140 AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 46 Lys Thr Ala His Phe Leu Pro Mee Wing He Thr * 145 150 155 ) INFORMATION FOR SEQ ID NO: 10: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 156 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 10: Met Ala Thr Asn Val Asn Ser Ser Ser Pro Glu Arg His Thr Arg Ser 1 5 10 15 Tyr Asp Tyr Met Glu Gly Gly Asp He Arg "Val Arg Arg- eu Phe Cys 20 25 30 Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val Lys Gly 35 40 45 Thr Gln Glu Met Lys Asn Tyr Asn He Met Glu He Arg Thr Val 50 55 60 Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe Tyr Leu 65 70 75 80 Wing Met Asn Lys Glu Gly Lys Leu Tyr Wing Lye Lys Glu Cys Asn Glu 35 90 95 Asp Cys Asn Phe Lys Giu Leu He Leu Giu Asn His Tyr Asn Thr Tyr 100 105 not Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu Mee Phe Val Wing Leu 115 120 125 Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys Glu Gln 130 135 140 Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 145 150 155) INFORMATION FOR SEQ ID NO: 11: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 465 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1.4665 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 11: ATG GCT ACT AAT GTT AAC TCT TCT CCT GAA CG CF.T ACG CGT TCC TAC 48 Mee? Ia. Thr Asn Val Asn Ser Ser Pro Glu Arg His Tr.r Arg Ser Tyr 1 5 10 15 GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG TTC TGC CGT 96 Asp Tyr Met Glu Giy Gly Asp He Arg Val Arg Arg Leu Phe Cys Arg 20 25 30 ACC CAG TGG TAC CTG CCT ATC GAC AAA COZ GGC AAA GTC AAG GGC ACC 144 Thr Cln Trp Tyr Leu Arq lie Asp Lys Ars Gly Lys Val Lys Gly Thr 35 40 45 CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT ACT GTT GCT 192 Gln Glu Met Lys A = n Asn Tyr Asn He Met Glu He Arg Thr Val Wing 50 55 60 GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC TAC CTG GCA 240 Val Gly He Val Ala He Lys Gly Val Glu Ser Giu Phe Tyr Leu Ala 65 70 75 80 ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC AAC GAA GAC 288 Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys Asn Glu Asp 85 90 95 TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC ACC CT GCA 336 Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn Thr Tyr Wing 100 105 HO TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT GCT CTG AAC 384 Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met Phe Val Ala Leu Asn 115 120 125 CAG AAA GGT ATC CCG GTT CGT GGT AAA AAA ACC AAA AAA GAA CAG AAA 432 Gln Lye Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys 130 135 140 ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 465 Thr Ala His Phe Leu Pro Met Ala He Thr * 145 150 155 (2) INFORMATION FOR SEQ ID NO: 12: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 155 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 12 Met Ala Thr Asn Val Asn Ser Ser Pro Glu Arg His Thr Arg Ser Tyr 1 5 10 15 Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu Phe Cys Ring 20 25 30 Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val Lys Gly Thr 40 45 Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg Thr Val Wing 50 55 60 Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe Tyr Leu Wing 65 70 75 80 Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys Asn Glu Asp 85 90 95 Cys Asn Phe Lys Glu Leu He Leu Glu Asn Kis Tyr Asn Thr Tvr Wing 100 105 no " Be Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val Wing Leu Asn 115 120 125 Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys Glu G1 !. Lys 130 135 140 Thr Wing His Phe Leu Pro Met Wing He Thr * 145 150 155 (2) INFORMATION FOR SEQ ID NO: 13: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 450 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..450 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 13: ATG TCT TCT CCT GAA CGT CAT ACG CGT TCC TAC GAC TAC ATG GAA GGT 48 Mee Ser Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly 1 5 10 15 GGT GAC ATC CGC GTA CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG 96 Gly Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu 20 25 30 CGT ATC GAC AAA CGC GGC AAA GTC AAG GGC ACC CAG GAG ATG AAA AAC 144 Arg He Asp Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Mee Lys Asn 35 40 45 AAC TAC AAT ATT ATG GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA 192 Asn Tyr Asn He Mee Glu He Arg Thr Val Wing Val Gly He Val Wing 50 55 60 'ATC AAA GGT GTT GAA TCT GAA TTC TAC CTG GCA ATG AAC AAA GAA GGT 240 He Lys Gly Val Glu Ser Glu Phe Tyr Leu Ala Mee Asn Lys Glu Gly 65 70 75 80 AAA CTG GCA AAA AAA GAA TGC AAC GAA GAC TGC AAC TTC AAA GAA 288 Lys Leu Tyr Ala Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu 85 90 95 CTG ATC CTG GAA AAC CAC TAC AAC ACC TAC GCA TCT GCT AAA TGG ACC 336 Leu He Leu Glu Asn His Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr 100 105 '110 CAC AAC GGT GGT GAA ATG TTC GTT GCT CTG AAC CAG AAA GGT ATC CCG 384 His Asn Gly Gly Glu Mee Phe Val Ala Leu Asn Gln Lys Gly He Pro 115 120 125 GTT CGT GGT AAA AAA ACC AAA AAA GAA CAG AAA ACC GCT CAC TTC CTG 432 Val Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu 130 135 140 CCG ATG GCA ATC ACT TAA 450 Pro Met Wing He Thr * 145 150 (2) INFORMATION FOR SEQ ID NO: 14 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 150 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 14 Met Ser Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly 1 5 10 15 Gly Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu 20 25 30 Arg He Asp Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn 35 40 45 Asn Tyr Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing 50 55 60 He Lys Gly Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly 65 70 75 80 Lys Leu Tyr Ala Lys Lys Glu Cye Asn Glu Asp Cys Asn Phe Lys Glu 85 90 95 Leu He Leu Glu Asn His Tyr A = n Thr Tyr Wing Ser Wing Lye Trp Thr 100 105 no His Asn Gly Gly Glu Met Phe Val Wing Leu A = n Gln Lys Gly He Pro 115 120 125 Val Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu 130 135 140 Pro Met Wing He Thr * 145 150 NFORMATION FOR SEQ ID NO: 15: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 447 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1.447 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 15 ATG TCT CCT GAA CGT CAT ACG CGT TCC TAC GAC TAC ATG GAA GGT GGT 48 Met Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Glv 1 5 10 15 GAC ATC CGC GTA CGT CGT CTG TTC TGC CGT ACC CAG TGG CT CTG CGT 96 Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Glr. Trp Tyr Leu Arg 20 25 30 ATC GAC AAA CGC GGC AAA GTC AAG GGC ACC CAG GAG ATG AAA AAC AAC 144 He Asp Lys Arg Gly Lys Val Lys Gly Thr Gin Glu Mee Lys Asn Asn 35 40 45 TAC AAT ATT ATG GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC 192 Tyr Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He 50 55 60 AAA GGT GTT GAA TCT GAA TTC CTG GCA ATG AAC AAA GAA GGT AAA 240 Lys Gly Val Glu Be Glu Phe Tyr Leu Wing Met Asn Lys Glu Gly Lye 65 70 75 80 CTG GCA AAA AAA GAA TGC AAC GAA GAC TGC AAC TTC AAA GAA CTG 288 Leu Tyr Ala Lys Lys Giu Cye Asn Glu Asp Cys Asn Phe Lys Glu Leu 85 90 95 ATC CTG GAA AAC CAC TAC AAC ACC TAC GCA TCT GCT AAA TGG ACC CAC 336 He Leu Glu Asn His Tyr Asn Thr Tyr Wing Ser Wing Lys Trp Thr Hie 100 105 HO AAC GGT GGT GAA ATG TTC GTT GCT CTG AAC CAG AAA GGT ATC CCG GTT Asn Gly Glu Glu Met Phe Val Wing Leu Asn Gln Lys Gly He Pro Val 384 115 120 125 CGT GGT AAA AAA AA AAA AAA GAA CAG AAA ACC GCT CAC TTC CTG CCG Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Ala His Phe Leu Pro 432 130 135 1 0 ATG GCA ATC ACT TAA Met Wing He Thr * 447 145 (2) INFORMATION FOR SEQ ID NO: 16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 149 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein ixi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 16: Met Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly 1 5 10 15 Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg 20 25 30 He Asp Lye Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn 35 40 45 Tyr Asn He Met Glu Xle Arg Thr Val Wing Val Gly He Val Wing He 50 55 60 Lys Gly Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys 65 70 75 80 Leu Tyr Ala Lys Lys Glu Cys Asn Glu ASD Cys Asn Phe Lys Glu Leu 85 90 95 He Leu Glu Asn His Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr His 100 105 HO Asn Gly Gly Glu Met Phe Val Ala Leu Asn Gln Lys Gly He Pro Val 115 120 12S Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro 130 135 140 Met Wing He Thr * 145 (2) INFORMATION FOR SEQ ID NO: 17: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 444 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1.444 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 17 GAC 48 Asp ATC CGC GTA CGT CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC 96 He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Aro He 20 25 30 GAC AAA CGC GGC AAA GTC AAG GGC ACC CAÁ GAG ATG AAA AAC AAC TAC 144 Asp Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Mee Lys Asn Asn Tyr 35 40 45 AAT ATT ATG GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA 192 Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He Lys 50 55 60 GGT GTT GAA TCT GAA TTC CTG GCA ATG AAC AAA GAA GGT AAA CTG 240 Gly Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu 65 70 75 80 TAC GCA AAA AAA GAA TGC AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC 288 Tyr Ala Lys Lys Glu Cys Asn Glu A = p Cye A = n Phe Lys Glu Leu He 85 90 95 CTG GAA AAC CAC TAC AAC ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC 336 Leu Glu Asn His Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr Kis Asn 100 105 110 GGT GGT GAA ATG TTC GTT GCT CTG AAC CAG AAA GGT AmC CCG GTT CGT 384 Gly Gly Glu Met Phe Val Ala Leu Asn Gln Lye Gly lie Pro Val Arg 115 120 125 GGT AAA AAA ACC AAA AAA GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG 437 Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Mee 130 135 1 0 GCA ATC ACT TAA Wing He Thr * 44 145 (2) INFORMATION FOR SEQ ID NO: 18: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 148 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein , 'xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 18: Met Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Glv ASD 1 5 10 15 He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He 20 25 30 Asp Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr 35 40 45 Asn He Mee Glu He Arg Thr Val Wing Val Gly He Val Wing tle Lys 50 55 60 Gly Val Glu Ser Glu Phe Tyr Leu Ala Mee Asn Lys Glu Gly Lys Leu 65 70 75 80 Tyr Ala Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He 85 90 95 Leu Glu Asn His Tyr Asn Thr Tyr Wing Being Wing Lys Trp Thr His Asn 100 105 HO Gly Gly Glu Mee Phe Val Wing Leu Asn Gln Lys Gly He Pro Val Arg 115 120 125 Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Prc Mee 130 135 140 Wing He Thr 145 (2) INFORMATION FOR SEQ ID NO: 19: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 441 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1.441 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: ATG GAA CGT CAT ACG CGT TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC 4 Mee Glu Arg His Thr Arg Ser Tyr Asp Tyr Mee Glu Gly Gly Asp He 1 5 10 15 CGC GTA CGT CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC 9 Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp 20 25 30 AAA CGC GGC AAA GTC AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT 14 Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn 35 40 45 ATT ATG GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT 19 He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He Lys Gly 50 55 60 GTT GAA TCT GAA TTC TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC 24 Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr 65 70 75 80 GCA AAA GAA GAA TGC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG 28 Wing Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu 85 90 95 GAA AAC CAC TAC AAC ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT 33 Glu Asn His Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly 100 105 110 GGT GAA ATG TTC GTT GCT CTG AAC CAG AAA GGT ATC CCG GTT CGT GGT 384 Gly Glu Met Phe Val Ala Leu Asn Gln Lys Gly He Pro Val Arg Gly 115 120 125 AAA AAA ACC AAA AAA GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA 43 Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing 130 135 140 ATC ACT TAA 44 He Thr * 145 (2) INFORMATION FOR SEQ ID NO: 20: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 147 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 20: Met Glu Arg His Thr Arg Ser Tyr Asp Tyr Mee Glu Gly Gly Asp He 10 15 Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp 20 25 30 Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys A = n Asn Tyr Asn 35 40 45 He Met Glu He Arg Thr Val Wing Val Gly He Val Ala He Lvs Glv 50 55 60 Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr 65 70 75 8o Ala Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu 85 90 95 Glu Asn His Tyr Asn Thr Tyr Wing Ser Wing Lys Trp Thr His Asn Gly 100 105 not Gly Glu Met Phe Val Wing Leu Asn Gln Lys Gly He Pro Val Aro Glv 115 120 125 Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing 130 135 140 He Thr * 145 (2) INFORMATION FOR SEQ ID NO: 21 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 438 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1 .. 38 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 21 ATG CGT CAT ACG CGT TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC 4 Mee Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg 1 5 10 15 GTA CGT CGT CTG TTC TGC CGT ACC CAG TGG CT CTG CGT ATC GAC AAA 9 Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys 20 25 30 CGC GGC AAA GTC AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT 144 Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He 35 40 45 ATG GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT 19 Met Glu He Arg Thr Val Wing Val Gly He Val Wing He Lys Gly Val 50 55 60 GAA TCT GAA TTC TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA 24 Glu Ser Glu Phe Tyr Leu Wing Mee Asn Lys Glu Gly Lys Leu Tyr Wing 65 70 75 80 AAA AAA GAA TGC AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA 28 Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu 85 90 95 AAC CAC TAC AAC ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT -.33 Asn His Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly 100 105 no GAA ATG TTC GTT GCT CTG AAC CAG AAA GGT ATC CCG GTT CGT GGT AAA 384 Glu Met Phe Val Ala Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys 115 120 125 AAA ACC AAA AAA GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC 432 Lys Thr Lys Lys Glu Gln Lys Thr Wing Hie Phe Leu Pro Met Wing He 130 135 140 ACT TAA 438 Thr * 145 (2) INFORMATION FOR SEQ ID NO: 22: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 146 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 22: Met Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg 1 5 10 15 Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys 20 25 30 Arg Gly Lys Val Lys Gly Thr Gln Glu Mee Lys Asn Asn Tyr Asn He 35 40 45 Met Glu He Arg Thr Val Wing Val Gly He Val Wing He Lys Gly Val 50 55 60 Glu Ser Glu Phe Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tyr Wing 65 70 75 80 Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu 85 90 95 Asn His Tyr Asn Thr Tyr Wing Ser Wing Lys Trp Thr His Asn Gly Gly 100 105 no Glu Met Phe Val Ala Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys 115 120 125 LyS xa © yS LVS Glu Gln? 13? 5 Thr Ala His Phe Leu Pro Met Wing He 140 Thr 145; 2) INFORMATION FOR SEQ ID NO: 23: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 435 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1. . 435 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 23: ATG CAT ACT CGT TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA 4 Met His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val 1 5 - 10 15 CGT CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC 9 Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg 20 25 30 GGC AAA GTC AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG 14 Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met 35 40 45 GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA 19 Glu He Arg Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu 50 55 60 TCT GAA TTC TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA 24 Ser Glu Phe Tyr Leu Wing Mee Asn Lys Glu Gly Lys Leu Tyr Wing Lys 65 70 75 80 £ K SE £ ffi S 35 £ £ £ £ ffi SS 2? S 28S S Sf S S S? s E S £ S S K j- «? 336 u: > 110 S tí f E? E SS S S «g¡ e -j« JJJ «384 ACC AAA AAA GAA CAG AAA Arr rr > * > r »-. i J »^ -. «X. ííí S S Sí S ™ S ™ g «c« r 432 140 TAA * 145 435 (2) INFORMATION FOR SEQ ID NO: 24 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 145 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 24: -t Thr Arg be tyr ssp ^ Met cly 01y Asp ne ^ ^^? o 15 Arg Arg Leu Phe Cys Arg Thr Gln Trp Tvr Leu »m * 20 P 2? 5 ?? r le Ar9 He Asp Lys Arg 30 Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met 35 40 45 Glu He Arg Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu 50 55 55 60 Ser Glu Phe Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys 65 70 75 80 Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn 85 90 95 Kis Tyr Asn Thr Tyr Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu 100 105 Not Met Phe Val Wing Leu Asn Gln Lys Gly He Pro Val Arg-Gly Lys Lys 115 120 125 Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr 130 135 140 * 145 (2) INFORMATION FOR SEQ ID NO: 25: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 432 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) FEATURE: (A) NAME / KEY: CDS (B) LOCATION: 1..432 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 25: ATG ACT CGT TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT 48 Met Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Aro 1 5 10 15 CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC 96 Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly 20 25 30 AAA GTC AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA 144 Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu 35 40 45 ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT 192 He Arg Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser 50 55 60 GAA TTC TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA 240 Glu Phe Tyr Leu Ala Mee Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys 65 70 75 80 GAA TGC AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC 288 Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His 85 9 ° 95 TAC AAC ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG 336 Tyr Aen Thr Tyr Ala Ser Ala Lye Trp Thr His Asn Gly Gly Glu Met 100 105 110 TTC GTT GCT CTG AAC CAG AAA GGT ATC CCG GTT CGT GGT AAA AAA ACC 384 Phe Val Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Thr 115 120 125 AAA AAA GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 432 Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 26: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 144 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear ii) TYPE OF MOLECULE: protein xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 26 Met Thr Arg Ser Tyr A = p Tyr Met Glu Gly Gly Asp He Arg Val Arg 1 5 10 15 Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Aso Lys Arg Gly 20 25"30 Lys Val Lys Gly Thr Gln Glu Mee Lys Asn Asn Tyr Asn He Met Glu 35 40 45 He Arg Thr Val Wing Val Gly He Val Wing He Lvs Gly Val Glu Ser 50 55 60 Glu Phe Tyr Leu Wing Met Asn Lys Glu Gly Lye Leu Tyr Wing Lys Lvs 65 70 75 and Q Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn HAS 85 or 95 Tyr Asn Thr Tyr Wing Being Wing Lys Trp Thr His Asn Gly Glv Glu Met 100 105 uj¡ Mec Phe Val Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 130 135 1 0 (2) INFORMATION FOR SEQ ID NO: 27: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 429 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..429 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 27 ATG CGT TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT 48 Met Arg Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg 1 5 10 15 CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA 96 Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys 20 25 30 GTC AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC 144 Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Met Glu He 35 40 45 CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA 192 Arg Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu 50 55 60 TTC TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA 240 Phe Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tyr Wing Lys Lys Glu 65 70 75 80 TGC AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC 288 Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr 85 90 95 AAC ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC 336 Asn Thr Tyr Wing Ser Wing Lys Trp Thr His Asn Gly Gly Met Phe 100 105 HO GTT GCT CTG AAC CAG AAA GGT ATC CCG GTT CGT GGT AAA AAA ACC AAA 384 Val Ala Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys 115 120 125 AAA GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 429 Lys Glu Gln Lys Thr Wing His Phe Leu Pro Mee Wing He Thr * 130 135 140 2) INFORMATION FOR SEQ ID NO: 28 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 143 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 28 Met Arg Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg 1 5? O 15 Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys 20 25 3rd Val Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He 35 40 45 Arg Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu 50 55 60 Phe Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tyr Wing Lys Lys Glu 65 70 75 80 Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tvr 85 90 95 Asn Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Met Phe 100 105 no Val Ala Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lye Thr Lys 115 120 125 Lys Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 130 135 140 2) INFORMATION FOR SEQ ID NO: 29: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..426 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 29: ATG TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG 48 Met Ser Tyr Asp Tyr Met Glu Gly Gly A = p He Arg Val Arg Arg Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC 96 Phe Cys Arg Thr Gln Trp Tyr Leu Aro He Asp Lys Arg Gly Lys Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT 144 Lys Gly Thr Gln Glu Met Lys Asn A = n Tyr Asn He Met Glu He Arg 35 40 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 192 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC 240 Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys 65 70 75 80 AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC 288 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 ACC TAC GCT TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 336 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 HO GCT CTG AAC CAG AAA GGT ATC CCG GTT CGT GGT AAA AAA ACC AAA AAA 384 Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys 115 120 125 GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 426 Glu Gln Lys Thr Ala His Phe Leu Pro Met Ala He Thr * 130 135 140) INFORMATION FOR SEQ ID NO: 30: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 30: Mee Ser Tyr Asp Tyr Mee Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 Phe Cye Arg Thr Gln Trp Tyr Leu Arg He AeD Lye Arg Gly Lys Val 20 25 30 Lye Gly Thr Gln Glu Met Lye Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Ala Mee Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cvs 65 70 75 80 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 Thr Tyr Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 no Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys 115 120 125 Glu Gln Lys Thr Wing His Phe Leu Pro Mee Wing He Thr * 130 135 1 0 ) INFORMATION FOR SEQ ID NO: 31: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 423 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..423 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 31 ATG TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CGT CTG TTC 48 Mee Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu Phe 1 5 10 15 TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC AAG 96 Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val Lys 20 25 30 GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT ACT 144 Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Mee Glu He Arg Thr 35 40 45 GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC TAC 192 Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe Tyr 50 55 60 CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC AAC 240 Leu Ala Mee Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys Asn 65 70 75 80 GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC ACC 288 Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn Thr 85 90 95 TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT GCT 336 Tyr Wing Ser Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val Wing 100 105 110 CTG AAC CAG AAA GGT ATC CCG GTT CGT GGT AAA AAA ACC AAA AAA GAA 364 Leu A = n Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys Glu 115 120 125 CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 423 Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 32: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 141 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 32 Met Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu Phe 1 5 10 15 Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val Lys 20 25 30 Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg Thr 35 40 45 Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe Tyr 50 55 60 Leu Ala Mee Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys Asn 65 70 75 80 Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu A = n His Tyr Asn Thr 85 90 95 Tyr Ala Ser Wing Lys Trp Thr His Asn Gly Gly Glu MeC Phe Val Wing 100 105 not Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys Glu 115 120 125 Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 33: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 495 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1.495 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 33: ATG TCT AAT GAT ATG ACT CCG GAA CAG ATG GCT ACC AAC GTT AAC TCC 48 Met As As Asp Met Thr Pro Glu Gln Mee Ala Thr Asn Val Asn Ser 1 5 10 15 TCC TCC CCG GAA CGT CAC ACG CGT TCC TAC GAC TAC ATG GAA GGT GGT 96 Ser Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly 20 25 30 GAC ATC CGC GTA CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT 144 Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg 35 40 45 ATC GAC AAA CGC GGC AAA GTC AAG GGC ACC CAA GAG ATG AAA AAC AAC 192 He Asp Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn 50 55 60 TAC AAT ATT ATG GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC 240 Tyr Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He 65 70 75 80 AAA GGT GTT GAA TCT GAA TTC TAT CTT GCA ATG AAC AAG GAA GGA AAA Lye Gly Val Glu Ser Glu Phe Tyr Leu Wing Met Asn Lys Glu Gly Lys 85 90 95 CTC TAT GCA AAG AAA GAA TGC AAT GAA TGAT AAT TTC AAA GAA CTA Leu Tyr Ala Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu 100 105 no ATT CTG GAA AAC CAT TAC AAC ACA TAT GCA TCT GCT AAA TGG ACC CAC He Leu Glu Asn His Tyr A = n Thr Tyr Ala Ser Ala Lys Trp Thr His 115 120 125 AAC GGT GGT GAA ATG TTC GTT GCT CTG AAC CAG AAA GGT ATC CCT GTT A = n Gly Gly Glu Met Phe Val Ala Leu Asn Gln Lys Gly He Pro Val 130 135 140 GAA GGT AAG AAA ACC AAG AAA GAA CAG AAA ACC GCT CAC TTC CTG CCG Glu Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro 145 150 155 160 ATG GCA ATC ACT TAA Met Wing He Thr * 165 INFORMATION FOR SEQ ID NO: 34: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 165 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 34 Met Ser Asn Asp Met Thr Pro Glu Gln Met Ala Thr Aen Val Asn Ser 1 5 10 15 Being Ser Pro Glu Arg His Thr Arg Being Tyr Asp Tyr Met Glu Gly Gly 20 25 30 Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg 45 He Asp Lys Arg Giy Lys Val Lys Gly Thr Gln Glu 55 Mee Lys Asn Asn 60 TVr A * "n. Met Glu. " »- thr V l A1 > = iy ^ ^ Ala He - «and v.! G1 S || 01ü Ph. ^ ^ ^ T5 ^ ^ ^ ^ 8 »0 - »* r? L. ^, ys ". cys ^ Asp ^ Asn phe ^ »110 He Leu Glu Asn His Tyr Asn Thr Tyr Ala 115 120 Ser Ala Lys Trp Thr His 125 Asn Gly Gly Met Phe Val Ala Leu 130 135 Asn Gln Lys Gly He Pro Val 140 Glu Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro 145 150 155 160 Mee Ala He Thr * 165 (2) INFORMATION FOR SEQ ID NO: 35: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 495 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1.495 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35: ATG TCT AAT GAT ATG ACT CCG GAA CAG ATG GCT ACC AAC GTT AAC TCC 48 Met Ser Asn Asp Met Thr Pro Glu Gln Met Ala Thr Asn Val Asn Ser 1 5 10 15 TCC TCC CCG GAA CGT CAC ACG CGT TCC TAC GAC TAC ATG GAA GGT GGT 96 Ser Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly 20 25 30 GAC ATC CGC CTA CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT 144 Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg 35 40 45 ATC GAC AAA CGC GGC AAA GTC AAG GGC ACC CAG GAG ATG AAA AAC AAC 192 He Aep Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn 50 55 60 TAC AAT ATT ATG GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC 240 Tyr Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He 65 70 75 80 AAA GGT GTT GAA TCT GAA TTC TAT CTT GCA ATG AAC AAG GAA GGA AAA 288 Lys Gly Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys 85 90 95 CTC TAT GCA AAG AAA GAA TGC AAT GAA GAT TGT AAC TTC AAA GAA CTA 336 Leu Tyr Ala Lye Lys Glu Cys Asn Glu Asp Cys Aen Phe Lye Glu Leu 100 105 no ATT CTG GAA AAC CAT TAC AAC ACA TAT GCA TCT GCT AAA TGG ACC CAC 384 He Leu Glu Asn His Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr His 115 120 125 AAC GGT GGT GAA ATG TTC GTT GCT CTG AAC CAG AAA GGT ATC CCT GTT 432 A = n Gly Gly Glu Met Phe Val Wing Leu Asn Gln Lys Gly He Pro Val 130 135 140 CAA GGT AAG AAA ACC AAA GAA CAG AAA ACC GCT CAC TTC CTG CCG 480 Gln Gly Lye Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro 145 150 155 160 ATG GCA ATC ACT TAA 4-95 Met Ala He Thr * 165 \ 2) INFORMATION FOR SEQ ID NO: 36: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 165 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 36: Met Ser Asn Asp Met Thr Pro Glu Gln Met Ala Thr Asn Val Asn Ser 1 5 10 15 Being Ser Pro Glu Arg His Thr Arg Being Tyr Asp Tyr Met Glu Gly Gly 20 25 30 Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg 35 40 45 He Asp Lys Ars Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn 50 55 60 Tyr Aen He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He 65 70 75 80 Lye Gly Val Giu Ser Glu Phe Tyr Leu Ala Mee Asn Lye Glu Gly Lye 85 90 95 Leu Tyr Ala Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu 100 105 no He Leu Glu Asn His Tyr Asn Thr Tyr Ala Ser Ala Lys Trp Thr His 115 120 125 Asn Gly Gly Met Phe Val Ala Ala Asu Gln Lys Gly He Pro Val 130 135 140 Gln Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro 145 150 155 160 Met Ala He Thr * 165 ) INFORMATION FOR SEQ ID NO: 37 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..426 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 37.

ATG TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG 4 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC 9 Phe Cys Arg Thr Gln Trp Tyr Leu Ara He Asp Lys Arg Gly Lys Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA "ATC CGT 14 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 19 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 TAT CTT GCA ATG AAC AAG GAA GGA AAA CTC TAT GCA AAG AAA GAA TGC 24 Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys 65 70 75 80 AAT GAA GAT TGT AAC TTC AAA GAA CTA ATT CTG GAA AAC CAT TAC AAC 28 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 ACÁ TAT GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 33 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 110 GCT CT G AAC CAG AAA GGT ATC CCT GTT CAA GGT AAG AAA ACC AAG AAA 384 A a Leu Asn Gln Lys Gly He Pro Val Gln Gly Lys Lys Thr Lys Lye 115 120 125 GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 426 Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 130 135 140 \ 2) INFORMATION FOR SEQ ID NO: 38: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 38 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tyr Wing Lys Lys Glu Cys 65 70 75 80 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 110 Ala Leu Asn Gln Lys Gly He Pro Val Gln Gly Lys Lys Thr Lys Lys 115 120 125 Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr • 130 135 140 (2) INFORMATION FOR SEQ ID NO: 39: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 495 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1.495 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 39: ATG TCT AAT GAT ATG ACT CCG GAA CAG ATG GCT ACC AAC GTT AAC TCC 46 Met As As Asp Met Thr Pro Glu Gln Met Ala Thr Asn Val Asn Ser 1 5 10 15 TCC TCC CCG GAA COT CAC ACG CGT TCC TAC GAC TAC ATG GAA GGT GGT 96 Ser Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly 20 25 30 GAC ATC CGC GTA CGC TTG TTC TCT CGT ACC CAG TGG TAC CTG CGT 144 Asp He Arg Val Arg Arg Leu Phe Ser Arg Thr Gln Trp Tyr Leu Arg 35 40 45 ATC GAC AAA CGC GGC AAA GTC AAG GGC ACC CAA GAG ATG AAA AAC AAC 192 He Asp Lys Arg Gly Lys Val Lys Glv Thr Gln Glu Met Lys Asn Asn 50 55 60 TAC AAT ATT ATG GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC 240 Tyr Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He 65 70 75 80 AAA GGT GTT GAA TCT GAA TTC TAT CTT GCA ATG AAC AAG GAA GGA AAA 288 Lys Gly Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys 85 90 95 CTC TAT GCA AAG AAA GAA TGC AAT GAA GAT TGT AAC TTC AAA GAA CTA 336 Leu Tyr Ala Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu 100 105 110 ATT CTG GAA AAC CAT TAC AAC ACÁ TAT GCA TCA GCT AAA TGG ACÁ CAC 384 He Leu Glu Asn His Tyr Asn Thr Tyr Wing Ser Wing Lys Trp Thr His 115 120 125 AAC GGA GGG GAA ATG TTT GTT GCC TTA AAT CAA AAG GGG ATT CCT GTA 432 Asn Gly Glu Glu Met Phe Val Wing Leu Asn Gln Lys Gly He Pro Val 130 135 140 AGA GGA AAA AAA AAA AAA GAA CAA AAA AAA AAA CCCC TTT CTT CCT 480 AAA Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro 145 150 155 160 ATG GCA ATA ACT TAA 495 Met Ala He Thr * 165 (2) INFORMATION FOR SEQ ID NO: 40: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 165 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 40: Met Ser Asn Asp Me Thr Pro Glu Gln Mee Wing Thr Asn Val Asn Ser 1 5 10 15 Being Ser Pro Glu Arg Hie Thr Arg Being Tyr Asp Tyr Met Glu Gly Gly 20 25 30 Asp He Arg Val Arg Arg Leu Phe Being Arg Thr Gln Trp Tyr Leu Arg -3-1 40 45 He Asp Lye Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Aen? 55 60 Ty Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He 65 70 75 80 Lye Gly Val Glu Ser Glu Phe Tyr Leu Ala Mee Asn Lys Glu Gly Lys 85 90 95 Leu Tyr Ala Lys Lys Glu Cys Asn Glu Asp Cys Asn Phe Lys Glu Leu 100 105 iio He Leu Glu Asn His Tyr Asn Thr Tyr Ala Ser Ala Lys p Thr His 115 120 125 Asn Gly Gly Met Phe Val Ala Leu Asn Gln Lys Gly He Pro Val 130 135 140 Arg Gly Lys Lys Thr Lye Lye Glu Gln Lye Thr Wing His Phe Leu Pro 45 150 155 160 Met Wing He Thr * 165 (2) INFORMATION FOR SEQ ID NO: 41: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 495 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1.495 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 41: ATG TCT AAT GAT ATG ACT CCG GAA CAG ATG GCT ACC AAC GTT AAC TCC 48 Met Ser Asn Asp Mee Thr Pro Glu Gln Met Wing Thr Asn Val Asn Ser 1 5 10 15 TCC TCC CCG GAA CGT CAC ACG CGT TCC TAC GAC TAC ATG GAA GGT GGT 96 Ser Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Mee Glu Gly Gly 20 25 30 GAC ATC CGC GTA CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT 144 Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg 35 40 45 ATC GAC AAA CGC GGC AAA GTC AAG GGC ACC CAG GAG ATG AAA AAC AAC 192 He Aep Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn 50 55 60 TAC AAT ATT ATG GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC 240 Tyr Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He 65 70 75 80 AAA GGT GTT GAA TCT GAA TTC CTG GCT ATG AAC AAA GAA GGT AAA 288 Lys Gly Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys 85 90 95 CTG TAC GCT AAA AAA GAA TCC AAT GAA GAT TGT AAC TTC AAA GAA CTA 336 Leu Tyr Ala Lys Lys Glu Ser Asn Glu Asp Cys Asn Phe Lys Glu Leu 100 105 110 ATT CTG GAA AAC CAT TAC AAC ACÁ TAT GCA TCA GCT AAA TGG ACA CAC 384 He Leu Glu Asn His Tyr Asn Thr Tyr Ala Ser Wing Lys Trp Thr His 115 120 125 AAC GGA GGG GAA ATG TTT GTT GCC TTA AAT CAA AAG GGG ATT CCT GTA 432 A = n Gly Gly Glu Met Phe Val Wing Leu Asn Gln Lys Gly He Pro Val 130 135 140 AGA GGA AAA AAA ACG AAA GAA CAA AAA ACA GCC CAC TTT CTT CCT 480 Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro 145 150 155 160 ATG GCA ATA ACT TAA 495 Met Ala He Thr * 165 [2) INFORMATION FOR SEQ ID NO: 42: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 165 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 2: Met Ser Asn Asp Mee Thr Pro Glu Gln Mee Wing Thr Asn Val Asn Ser 1 5 10 15 Being Ser Pro Glu Arg His Thr Arg Being Tyr Asp Tyr Mee Glu Gly Gly 20 25 30 Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg 35 40 45 He Asp Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Mee Lys Aen Asn 50 55 60 Tyr Asn He Mee Glu He Arg Thr Val Wing Val Gly He Val Wing He 65 70 75 80 Lys Gly Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Giy Lys 85 90 95 Leu Tyr Ala Lys Lys Glu Ser Asn Glu ASD Cys Asn Phe Lys Glu Leu 100 105 no He Leu Glu Asn His Tyr Asn Thr Tyr Ala Ser Wing Lys Trp Thr His 115 120 1 5 Asn Gly Gly Met Phe Val Ala Leu Asn Gln Lys Gly He Pro Val 130 135 1 0 Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro 145 150 155? 60 Met Ala He Thr * 165 ) INFORMATION FOR SEQ ID NO: 43: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 495 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1.495 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 3 ATG TCT AAT GAT ATG ACT CCG GAA CAG ATG GCT ACC AAC GTT AAC TCC 48 Met Ser Asn Asp Met Thr Pro Glu Gln Met Ala Thr Asn Val Asn Ser 1 5 10 15 TCC TCC CCG GAA CGT CAC ACG CGT TCC TAC GAC TAC ATG GAA GGT GGT 96 Ser Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Gly 20 25 30 GAC ATC CGC GTA CGT CGT CTG TTC TGC CGT ACC CAG TGG TAC CTG CGT 144 Asp He Arg Val Arg Arg Leu Phe Cye Arg Thr Gln Trp Tyr Leu Arg 35 40 45 ATC GAC AAA CGC GGC AAA GTC AAG GGC ACC CAA GAG ATG AAA AAC AAC 192 He Asp Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn 50 55 60 TAC AAT ATT ATG GAA ATC CGT ACT GTT GCT GTT GGT ATC GTT GCA ATC 240 Tyr Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He 65 70 75 80 AAA GGT GTT GAA TCT GAA TTC TAC CTG GCT ATG AAC AAA GAA GGT AAA 288 Lys Gly Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Glv Lys 85 90 95 CTG TAC GCT AAA AAA GAA TCC AAT GAA GAT TCT AAC TTC AAA GAA CTA 336 Leu Tyr Ala Lys Lys Glu Ser Asn Glu Asp Ser Asn Phe Lys Glu Leu 100 105 110 ATT CTG GAA AAC CAT TAC AAC ACÁ TAT GCA TCA GCT AAA TGG ACÁ CAC - 38 He Leu Glu Asn His Tyr Asn Thr Tyr Ala Ser Wing Lys Trp Thr His 115 120 125 AAC GGA GGG GAA ATG TTT GTT GCC TTA AAT CAÁ AAG GGG ATT CCT GTA 43 Asn Gly Glu Glu Met Phe Val Wing Leu Asn Gln Lys Gly He Pro Val 130 135 140 AGA GGA AAA AAA AAA AAA GAA CAA AAA AAA GCC CAC TTT CTT CCT 48 Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro 145 150 155 160 ATG GCA ATA ACT TAA 49 Met Wing He Thr * 165, 2) INFORMATION FOR SEQ ID NO: 44: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 165 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein 10 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 44 Met Ser As Asp Met Thr Pro Glu Gln Met Wing Thr A = n Val Asn Ser 1 5? Or 15 Ser Ser Pro Glu Arg His Thr Arg Ser Tyr Asp Tyr Met Glu Gly Glv 20 25 30 15 Asp He Arg Val Arg Arg Leu Phe Cys Arg Thr Gln Trp Tyr Leu Arg 35 40 45 He Asp Lys Arg Gly Lys Val Lys Gly Thr Gln Glu Met Lys Asn Asn 50 55 60 Tyr Asn He Met Glu He Arg Thr Val Wing Val Gly He Val Wing He 65 70 75 80 Lys Gly Val Glu Ser Glu Phe Tyr Leu Ala Met Asn Lys Glu Gly Lys 85 90 95 Leu Tyr Ala Lys Lys Glu Ser A = n Glu Aep Ser Aen Phe Lys Glu Leu 100 105 no He Leu Glu Asn His Tyr Asn Thr Tyr Ala Ser Wing Lys Trp Thr His 115 120 125 Asn Gly Glu Mee Phe Val Ala Leu Asn Gln Lys Gly He Pro Val 130 135 140 Arg Gly Lys Lys Thr Lys Lys Glu Gln Lys Thr Wing His Phe Leu Pro 145 150 155 160 Met Ala He Thr * 165 (2) INFORMATION FOR SEQ ID NO: 45: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..426 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 5: ATG TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Ara Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT 1 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 1 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC 2 Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tyr Wing Lys Lys Glu Cys 65 70 75 80 AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC 2 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 336 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 110 GCT CTG GAA CAG AAA GGT ATC CCT GTT CGT GGT AAG AAA ACC AAG AAA 384 Wing Leu Glu Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys 115 120 125 GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 426 Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 46: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 46: Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 Lys Giy Thr Glr. Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Ala Mee Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cvs 65 70 75 80 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 no Ala Leu Glu Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys 115 120 125 Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr 130 135 140 ) INFORMATION FOR SEQ ID NO: 7: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..426 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 47 ATG TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG 4 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC 9 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT 14 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 19 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 * T £ AC - CT.G MGC-A «ATG" AA_C £ AAA SGAíA gGGjT &»*» ™ ".-." T? C gj £ ^ ^ "c 240 SO AAC GAA GAC TGC Air t-rr» »» - .. A = n Glu Asp J £ "J ™ JJC CTG CAA AAC CAC TAC AAC 85 U" * Leu Glu Asn His Tyr Asn 288 «A < _rC, T * AC AG1C-A JTJCJT "GC.T LAyAAs ^ Tr-« »rr -», - «« jc = t gj "_" 336 110 GCT CTG AAC CAG GAA GGT ATC CCT GTT CCT GG * Ala Leu Asn Gln Glu Gly He ££ ^ 1 AS Glv ° ** ACC "* *** 115 120 val Ar9 Gly Lys Lys Thr Lys Lye 384 GAA CAG AAA ACC GCT CAC TC GTG r > nn «" "« u gn, ys ». I. a .. £ S S K S ÍS ÍS ^ 426 (2) INFORMATION FOR SEQ ID NO: 48: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 48 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Mee Glu He Arg 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Ala Mee Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys 65 70"> Asn Glu A = p Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu MeC Phe Val 100 105 110 Ala Leu Asn Gln Glu Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys 115 120 125 Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr 130 135 140 (2) INFORMATION FOR SEQ ID NO: 49: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown 'ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..426 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 49: CTG Leu 48 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 96 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT 14 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 19 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC 24 Tyr Leu Ala Met Asn Lye Glu Gly Lye Leu Tyr Ala Lys Lys Glu Cys 65 70 75 BO AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC 28 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 33 Thr Tyr Wing Ser Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 110 GCT CTG AAC CAG CAA GGT ATC CCT GTT CGT GGT AAG AAA ACC AAG AAA 38 Ala Leu Asn Gln Gln Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys 115 120 125 GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 426 Glu Gln Lys Thr Ala His Phe Leu Pro Met Ala He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 50: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 50; Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Aro Leu 1 5 10 15 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 Lys Gly Thr Gln Glu Met Lye Asn Asn Tyr Asn He Mee Glu He Arg 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Wing Met A = n Lys Glu Gly Lys Leu Tyr Wing Lys Lys Glu Cys 65 70 75 80 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn Hie Tyr Asn 85 90 95 Thr Tyr Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 110 Wing Leu Asn Gln Gln Gly He Pro Val Arg Gly Lys Lys Thr Lys Lye 115 120 125 Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 51: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1. 426 'xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51 ATG TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG 48 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Ars Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC 96 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT i 44 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Mee Glu He Ars 35 40 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 192 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC 2 0 Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tyr Wing Lye Lys Glu Cye 65 70 75 80 AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC 288 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu A = n His Tyr Asn 85 90 95 ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 336 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 110 GCT CTG AAC CAG AAA GGT ATC CCT GTT GCT GGT AAG AAA ACC AAG AAA 384 Wing Leu Asn Gln Lys Gly He Pro Val Wing Gly Lys Lye Thr Lys Lys 115 120 125 GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 426 Glu Gln Lys Thr Ala His Phe Leu Pro Met Ala He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 52: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear; ii) TYPE OF MOLECULE: protein 'xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 52: Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5? O 15 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Ars 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tyr Wing Lys Lys Glu Cys 65 70 75 BO Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 Thr Tyr Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 no Wing Leu Asn Gln Lys Gly He Pro Val Wing Gly Ly = Lys Thr Lys Lys 115 120 125 Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 130 135 140 NFORMATION FOR SEQ ID NO: 53: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTIC: (A) NAME / KEY: CDS (B) LOCATION: 1..426 Xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 53: ATG TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG 48 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC 96 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lye Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT 144 Lys Gly Thr Gln Glu Met Lye Asn Asn Tyr A = n He Met Glu He Arg 35 40 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 192 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 TAT CTT GCA ATG AAC AAG GAA GGA AAA CTC TAT GCA AAG AAA GAA TGC 240 Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys 65 70 75 80 AAT GAA GAT TGT AAC TTC AAA GAA CTA ATT CTG GAA AAC CAT TAC AAC 288 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 ACÁ TAT GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 336 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 no GCT CTG AAC CAG AAA GGT ATC CCT GTT GAA GGT AAG AAA ACC AAG AAA 384 Wing Leu Asn Gln Lys Gly He Pro Val Glu Gly Lys Lys Thr Lys Lys 115 120 125 GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 426 Glu Gln Lys Thr Ala His Phe Leu Pro Met Ala He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 54: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 54 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tyr Wing Lys Lys Glu Cvs 65 70 75 80 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Met Phe Val 100 105 no Ala Leu Asn Gln Lys Gly He Pro Val Glu Gly Lys Lys Thr Lys Lys 115 120 125 Glu Gln Lys Thr Wing His Phe Leu Pro Met Wing He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 55: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..426 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 55 ATG TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG 48 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Ars Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC 96 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lvs Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT 144 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr A = n He Met Glu He Arg 35 40 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 192 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC 240 Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Wing Lye Lys Glu Cye 65 70 75 80 AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC 288 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 336 Thr Tyr Wing Ser Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 HO GCT CTG AAC CAG AAA GGT ATC CCT GTT CTG GGT AAG AAA ACC AAG AAA 384 Ala Leu Asn Gln Lys Gly He Pro Val Leu Gly Lys Lys Thr Lys Lys 115 120 125 GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 426 Glu Gln Lys Thr Ala His Phe Leu Pro Mee Ala He Thr * 130 135 140 | 2) INFORMATION FOR SEQ ID NO: 56: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 56: Mee Ser Tyr Asp Tyr Mee Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 Lys Gly Thr Gln Glu Mee Lys Asn Asn Tyr Asn He Mee Glu He Arg 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys 65 70 75 80 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 Thr Tyr Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 no Wing Leu Asn Gln Lys Gly He Pro Val Leu Gly Lys Lye Thr Lye Lye 115 120 125 Glu Gln Lys Thr Al a His Phe Leu Pro Met Wing He Thr 130 135 140 (2) INFORMATION FOR SEQ ID NO: 57 (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..426 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 57 ATG TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG 48 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC 96 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT 1 4 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 192 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC 240 Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys 65 70 75 80 AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC 288 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 336 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 110 GCT CTG AAC CAG AAA GGT ATT CCT GTT CGT GGT AAG GAA ACC AAG AAA 384 Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Glu Thr Lys Lys 115 120 125 GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 4 Glu Gln Lys Thr Wing His Phe Leu Pro Mee Wing He Thr * 130 135 140 INFORMATION FOR SEQ ID NO: 58: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 58: Mee Ser Tyr Asp Tyr Mee Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 2 25 30 Lys Gly Thr Gln Glu Mee Lys Asn Asn Tyr Asn He Met Glu He Ars 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Ala Mee Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cvs 65 70 75 so Asn Glu Asp Cys Aen Phe Lye Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 no Ala Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Glu Thr Lys Lvs 115 120 125 Glu Gln Lys Thr Wing His Phe Leu Pro Mee Wing He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 59: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..426 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 59: ATG TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG 48 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTO CGT ATC GAC AAA CGC GGC AAA GTC 96 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT .144 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 192 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC 240 Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys 65 70 75 80 AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC 288 Asn Glu A = p Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 ACC TAC GCT TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 336 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Mee Phe Val 100 105 no GCT CTG AAC CAG AAA GGT ATC CCT GTT CGT GGT AAG CAA ACC AAG AAA 384 Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Gln Thr Lys Lys 115 120 125 GAA CAG AAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 426 Glu Gin Lys Thr Ala Hxs Phe Leu Pro Mee Ala He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 60: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ü) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 60: Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Aen He Met Glu He Arg 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tyr Wing Lys Lys Glu Cys 65 70 75 80 Asn Glu ASD Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 or 95 Thr Tyr Ala Be Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 110 Wing Leu Asn Gln Lvs Gly He Pro Val Arg Gly Lys Gln Thr Lys Lys 115"120 125 Glu Gln Lys Thr Ala His Phe Leu Pro Met Ala He Thr 130 135 140 (2) INFORMATION FOR SEQ ID NO: 61: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..426 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 61.

ATG TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG 48 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC 96 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT 144 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 192 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC 240 Tyr Leu Wing Met Asn Lvs Glu Gly Lys Leu Tyr Wing Lys Lye Glu Cye 65 70 75 80 AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC 288 A = n Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 ACC TAC GCT TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 336 Thr Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Mee Phe Val 100 105 no GCT CTG AAC CAG AAA GGT ATC CCT GTT CGT GGT AAG AAA ACC AAG AAA 384 Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys 115 120 125 GAA CAG GAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 426 Glu Gln Glu Thr Ala His Phe Leu Pro Mee Wing He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 62: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 62 Mee Ser Tyr Asp Tyr Mee Glu Gly Gly Asp He Arg Val Ars Arg Leu 1 5 10 - is Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 Lys Gly Thr Gln Glu Met Lys Asn A = n Tyr Asn He Met Glu He Arg 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Wing Met Asn Lys Glu Gly Lys Leu Tyr Wing Lys Lys Glu Cys 65 70 75 80 Asn Glu Asp Cys Asn Phe Lys Giu Leu He Leu Glu Asn His Tyr Asn 85 90 95Thr Tyr Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 110 Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys 115 120 125 Glu Gln Glu Thr Wing His Phe Leu Pro Met Wing He Thr 130 135 140 ) INFORMATION FOR SEQ ID NO: 63: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ií) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..426 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 63: ATG TCC TAC GAC TAC ATG GAA GGT GGT GAC ATC CGC GTA CGT CTG 46 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC 96 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT 144 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 192 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 TAC CTG GCA ATG AAC AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC 240 Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cye 65 70 75 80 AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC 288 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 ACC TAC GCT TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 336 Thr Tyr Ala Ser Wing Lys Trp Thr His Asn Gly Gly Glu Mee Phe Val 100 105 110 GCT CTG AAC CAG AAA GGT ATC CCT GTT CGT GGT AAG AAA ACC AAG AAA 384 Wing Leu A = n Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys 115 120 125 GAA CAG CAAC ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 426 Glu Gln Gln Thr Ala His Phe Leu Pro Met Wing He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 64: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: protein [xi) SEQUENCE DESCRITION: SEQ ID NO: 64 Met Ser Tyr A = p Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lye Arg Gly Lys Val 20 25 30 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Arg 35 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Ala Met Asn Lys Glu Gly Lys Leu Tyr Ala Lys Lys Glu Cys 65 70 75 80 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 Thr Tyr Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 110 Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lye Thr Lys Lys 115 120 125 Glu Gln Gln Thr Wing Hie Phe Leu Pro Met Wing He Thr * 130 135 140 INFORMATION FOR SEQ ID NO: 65: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 426 base pairs (B) TYPE: nucleic acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: cDNA (ix) CHARACTERISTICS: (A) NAME / KEY: CDS (B) LOCATION: 1..426 (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 65: 4 Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 TTC TGC CGT ACC CAG TGG TAC CTG CGT ATC GAC AAA CGC GGC AAA GTC 9 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He Asp Lys Arg Gly Lys Val 20 25 30 AAG GGC ACC CAA GAG ATG AAA AAC AAC TAC AAT ATT ATG GAA ATC CGT 144 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Met Glu He Arg 35 40 - 45 ACT GTT GCT GTT GGT ATC GTT GCA ATC AAA GGT GTT GAA TCT GAA TTC 192 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 'TAC CTG GCA ATG AAA GAA GGT AAA CTG TAC GCA AAA AAA GAA TGC 240 Tyr Leu Ala Met Asn Lys Glu Gly Lys. Leu Tyr Ala Lys Lys Glu Cys 65 70 75 80 AAC GAA GAC TGC AAC TTC AAA GAA CTG ATC CTG GAA AAC CAC TAC AAC 288 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 ACC TAC GCA TCT GCT AAA TGG ACC CAC AAC GGT GGT GAA ATG TTC GTT 336 Thr Tyr Wing Ser Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 110 GCT CTG AAC CAG AAA GGT ATC CCT GTT CGT GGT AAG AAA ACC AAG AAA 384 Ala Leu Asn Gln Lys Gly He Pro Val Arg Gly Lys Lys Thr Lys Lys 115 120 125 GAA GAG GAA ACC GCT CAC TTC CTG CCG ATG GCA ATC ACT TAA 426 Glu Glu Glu Thr Ala His Phe Leu Pro Met Aia He Thr * 130 135 140 (2) INFORMATION FOR SEQ ID NO: 66: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 142 amino acids (B) TYPE: amino acid [D) TOPOLOGY: linear ii) TYPE OF MOLECULE: protein; xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 66: Met Ser Tyr Asp Tyr Met Glu Gly Gly Asp He Arg Val Arg Arg Leu 1 5 10 15 Phe Cys Arg Thr Gln Trp Tyr Leu Arg He A = p Lye Arg Gly Lys Val 20 25 30 Lys Gly Thr Gln Glu Met Lys Asn Asn Tyr Asn He Met Glu He Ara 40 45 Thr Val Wing Val Gly He Val Wing He Lys Gly Val Glu Ser Glu Phe 50 55 60 Tyr Leu Wing Met Asn Lye Glu Gly Lye Leu Tyr Wing Lys Lys Glu Cys 65 70 75 80 Asn Glu Asp Cys Asn Phe Lys Glu Leu He Leu Glu Asn His Tyr Asn 85 90 95 Thr Tyr Wing Being Wing Lys Trp Thr His Asn Gly Gly Glu Met Phe Val 100 105 no Wing Leu Asn Gln Lys Gly He Pro Val Arg Gly Lye Lys Thr Lye Lys 115 120 125 Glu Glu Glu Thr Wing His Phe Leu Pro Met Wing He Thr * 130 135 140 INFORMATION FOR SEQ ID NO: 67 (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 33 amino acids (B) TYPE: amino acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: protein Ixi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 67 His Wing Asp Gly Ser Phe Ser Asp Glu Met Asn Thr He Leu Asp Asn 1 5 10 is Leu Wing Wing Arg Asp Phe He Asn Trp Leu He Gln Thr Lys He Thr 20 25 30 Asp (2) INFORMATION FOR SEQ ID NO: 68: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 33 amino acids (B) TYPE: amino acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 68 His Gly Asp Gly Ser Phe Ser A = p Glu Mee A = n Thr He Leu Asp Asn 1 5? Or 15 Leu Ala Wing Arg Asp Phe [le A = n Trp Leu He Gln Thr Lys He Thr 20 25 30 Asp (2) INFORMATION FOR SEQ ID NO: 69: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 33 amino acids (B) TYPE: amino acid (C) TYPE OF HEBRA: unknown (D) TOPOLOGY: unknown (ii) TYPE OF MOLECULE: protein (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 69; H. Being A = p Gly Being Phe Being Asp Glu Mee Asn Thr He Leu Asp Asn Leu Ala Ala Arg Asp Phe He Asn Trp Leu He Gln Thr Lys He Thr U 25 30 Asp It is noted that in relation to this date the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following

Claims (5)

1. A method for increasing cytoprotection, proliferation and / or differentiation of epithelial cells in the gastrointestinal tract, characterized in that it comprises administering to the patient an effective amount of a KGF protein product (s) and an LPG product. -2.

2. The method according to claim 1, characterized in that the product of the KGF protein is selected from the group consisting of C (1,15) S,? N15,? N16,? N17,? N18,? N19,? N20 ,? N21,? N22,? N23,? N24,? N3 / C (15) S,? N3 / C (15) -,? N8 / C (15) S,? N8 / C (15) -, C (1.15) S / R (144) E, C (1, 15) S / R (144) Q and? N23 / R (144) Q.

3. The method according to claim 1, characterized in that the GLP-2 product is selected from the group consisting of human GLP-2, hGLP-2 (G2) and hGLP-2 (S2).

4. The method according to claim 1, characterized in that the product of GLP-2 and the (products) of KGF-2 protein are administered in effective amounts prophylactically to treat mucositis.

5. The method according to claim 1, characterized in that the product of GLP-2 is selected from the group consisting of human GLP-2, hGLP-2 (G2) and hGLP-2 (S2).