ANTIBODIES RECOGNIZING THE FOURTH IMMUNOGLOBULIN-LIKE DOMAIN OF VCAM1

Abstract: Monoclonal antibodies recognizing immunoglobulin domain 4 of Vascular Cell Adhesion Molecule-1 (VCAM1) are described. Such antibodies are useful, e.g., in the treatment of acute inflammation and disorders characterized by VCAM1-mediated adhesion of leukocytes and in purification methods, diagnostic methods and diagnostic kits, especially where distinguishing between the six-domain and seven-domain forms of VCAM1 is advantageous.

Description: ANTIBODIES RECOGNIZING THE FOURTH IMMUNOGLOBULIN-LIKE DOMAIN OF VCAMl FIELD OF THE INVENTION This invention relates to monoclonal antibodies (MAbs) , specifically monoclonal antibodies that bind to the domain 4 of Vascular Cell Adhesion Molecule-1 (VCAMl) . BACKGROUND OF THE INVENTION VCAMl (also known as INCAM-110) was first identified as an adhesion molecule induced on endothelial cells by inflammatory cytokines (TNF and IL-1) and LPS (Rice et al., 1989 [1]; Osborn et al., 1989 [2]). VCAMl binds to cells exhibiting the integrin VLA-4 (α 4 3 j ) , including T and B lymphocytes, monocytes, and eosinophils, but not neutrophils, and is thought to participate in recruitment of these cells from the bloodstream to areas of infection and inflammation (Elices et al, 1990 [3]; Osborn, 1990 [4]). The VCAM1/VLA-4 adhesion pathway has been associated with a number of physiological and pathological processes. Although VLA-4 is normally restricted to hematopoietic lineages, it is found on melanoma cell lines, and thus it has been suggested that VCAMl may participate in metastasis of such tumors (Rice et al., 1989 [1]) . In vivo, VCAMl is found on areas of arterial endothelium representing early atherosclerotic plaques in a rabbit model system (Cybulsky and Gimbrone, 1991 [5]). VCAMl is also found on follicular dendritic cells in human lymph nodes (Freed an et al. , 1990 [6]). It is also present on bone marrow stromal cells in the mouse (Miyake et al. , 1991 [7]), thus VCAMl appears to play a role in B- cell development. VCAMl belongs to the immunoglobulin (Ig) superfamily. The major form on endothelial cells, referred to herein as VCAM-7D, has seven Ig homology units or domains; domains 4, 5 and 6 are similar in amino acid sequence to domains 1, 2 and 3, respectively, suggesting an intergenic duplication event in the evolutionary history of the gene (Osborn et al. , 1989 [2]; Polte et al. 1990 [8]; Hession et al. , 1991 [9]). There is also a minor 6-domain form (referred to as VCAM-6D herein) generated by alternative splicing, in which the fourth domain is deleted (Osborn et al. , 1989 [2]; Hession et al. 1991 [9], Cybulsky et al. , 1991 [10]). The biological significance of this alternate splicing is not known, however as shown below VCAM-6D can bind VLA-4-expressing cells and thus clearly has potential functionality in vivo. The apparent involvement of the VCAM1/VLA-4 adhesion pathway in infection, inflammation and possibly atherosclerosis has led to continuing intensive research to understand the mechanisms of cell-cell adhesion on a molecular level and has led investigators to propose intervention in this adhesion pathway as a treatment for diseases, particularly inflammation (Osborn et al. , 1989 [2]). Monoclonal antibodies that inhibit VCAMl binding to VLA-4 are known. For example, anti-VLA-4 MAbs HP2/1 and HP1/3 have been shown to block attachment of VLA-4- expressing Ramos cells to human umbilical vein cells and VCAMl-transfected COS cells (Elices et al., 1990 [3]). Also, anti-VCAMl antibodies such as the monoclonal antibody 4B9 (Carlos et al., 1990 [11]) have been shown to inhibit adhesion of Ramos (B-cell-like) , Jurkat (T-cell- like) and HL60 (granulocyte-like) cells to COS cells transfected to express VCAM-6D and VCAM-7D (Hession et al., 1991 [9]) . Although blocking antibodies that might be potential therapeutics are known, new monoclonal antibodies recognizing epitopes on other, non-binding domains of VCAMl would be important research tools to map the portion(s) of VCAMl essential for binding to VLA-4. Antibodies that bind to VCAMl without competing for the epitope of a blocking antibody such as 4B9 would also have important diagnostic uses. For instance, a radiolabeled anti-VCAMl antibody recognizing an epitope not essential to VLA-4 binding could be used to monitor the course and location of acute inflammatory events but would not interfere with the action of a later-administered therapeutic that interacts with the VLA-4-binding domain of VCAMl. SUMMARY OF THE INVENTION We have now isolated a panel of monoclonal antibodies which bind to VCAM-7D but not to VCAM-6D, and therefore presumably recognize an epitope in domain 4 of VCAMl. We have surprisingly discovered that some of these domain 4 antibodies inhibit Ramos binding to VCAM-7D- expressing cells, and through the use of these antibodies we have demonstrated that domain 4 of VCAM-7D contains a site involved in VLA-4 binding, which is in addition to the site recognized and blocked by MAb 4B9 (domain 1) . Thus, VCAMl is identified as the first known adhesion molecule to have two binding sites for a single receptor (VLA-4) ; and the domain 4 monoclonal antibodies according to this invention are useful not only in mapping the molecular functionality of VCAMl but also in at least partially inhibiting VCAMl recognition by VLA-4. Accordingly, it is an object of this invention to provide monoclonal antibodies recognizing VCAM-7D but not VCAM-6D. It is a further object of this invention to provide antibodies recognizing an epitope dependent on the fourth immunoglobulin-like domain ("domain 4") of VCAM-7D ("domain 4 antibodies") , and particularly domain 4 antibodies that do not cross-block the anti-VCAMl MAb 4B9. It is a further object of the present invention to provide domain 4 antibodies capable of blocking adhesion of VLA-4-expressing cells to VCAMl. These and other objects are accomplished by the monoclonal antibodies described and claimed herein. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a schematic diagram of VCAM-7D, showing the linear arrangement of functional domains from the amino terminus to the carboxyl terminus. These are the signal peptide ("sig") , immunoglobulin-like domains 1 through 7, the transmembrane sequence ("tm") , and the cytoplasmic domain or "tail" ("cyt") . Also indicated are the relative positions of several restriction enzyme recognition sites, which were used to prepare additional VCAMl constructs having one or more altered domains (described infra) . In the examples set forth below, cDNA encoding VCAM-7D having the diagrammed conformation was used to transfect COS7 cells to produce COS7 cells exhibiting VCAM-7D on their surfaces. Figure 2 is a schematic diagram of VCAM-6D, showing the linear arrangement of functional domains from the amino terminus to the carboxyl terminus —the signal peptide ("sig") , immunoglobulin-like domains 1, 2, 3, 5, 6 and 7, the transmembrane sequence ("tm") , and the cytoplasmic domain or "tail" ("cyt") . In the examples set forth below, cDNA encoding VCAM-6D having the diagrammed conformation was used to transfect C0S7 cells to produce COS7 cells exhibiting VCAM-6D on their surfaces. Figure 3 is a schematic diagram of a chimeric VCAMl, designated VCAM/ICAM-1, showing the linear arrangement of functional domains. This polypeptide has the general structure of VCAM-7D, except the cDNA encoding VCAM-7D was modified so that a segment encoding most of domain 1 and part of domain 2 was excised and replaced by cDNA encoding analogous portions of Intercellular Adhesion Molecule-l (ICAMl) . The modified portion of the VCAM-7D molecule is indicated by shading. Figure 4 is a schematic diagram of another chimeric VCAMl, designated VCAM/ICAM-2, showing the linear arrangement of functional domains. This polypeptide has the general structure of VCAM-7D, except as indicated by the shaded area, the cDNA coding for most of domain 1 and a large part of domain 2 was excised and replaced with ICAMl cDNA. Figure 5 is a schematic diagram of another chimeric VCAMl, designated VCAM/ICAM-3, showing the linear arrangement of functional domains. This polypeptide has the general structure of VCAM-7D, except as indicated by the shaded area, the cDNA coding for part of domain 1, all of domains 2 and 3, and a small N-terminal part of domain 4 was excised and replaced with ICAMl cDNA. Figure 6 is a graph showing relative levels of expression in COS7 cells transfected with either cDNA encoding VCAM-6D or cDNA encoding VCAM-7D. Expression of either VCAM-6D or VCAM-7D was analyzed by flow cytofluorometry following indirect immunofluorescent staining with MAb 4B9. The number of cells with fluorescent intensity greater than that shown by 99% of control transfectants (pCDM8 vector only) was determined. The data depicted combines the results of two experiments; standard deviation is indicated by error bars. Figure 7 is a graph showing the extent of Ramos cell binding to COS cells separately tranfected with cDNA encoding VCAM-7D, VCAM-6D, VCAM/ICAM-1, VCAM/ICAM-2, and VCAM/ICAM-3. In addition, the effects on Ramos binding of preincubation of the transfected COS cells with 20 g/ml of MAb 4B9 (anti-VCAMl) and 10 g/ml of MAb HP1/2 (anti- VLA-4) are shown. In addition, the negligible Ramos binding to cells transfected with pCDMδ (expression vector only; negative control) and cells transfected to exhibit surface ICAMl is shown. Binding is expressed as Ramos cells bound per square millimeter ("Ramos cells bound/mm" in the figures) . Figure 8 is a schematic diagram of another chimeric VCAMl, designated VCAM6D/ICAM-1, showing the linear arrangement of functional domains. This polypeptide has the general structure of VCAM-6D (no domain 4) , however, as indicated by the shaded area, the cDNA coding for most of domain 1 and a small part of domain 2 was excised and replaced with ICAMl cDNA. Figure 9 is a schematic diagram of another chimeric VCAMl, designated VCAM6D/ICAM-2, showing the linear arrangement of functional domains. This polypeptide has the general structure of VCAM-6D (no domain 4) , however, as indicated by the shaded area, the cDNA coding for most of domain 1 and a large part of domain 2 was excised and replaced with ICAMl cDNA. Figure 10 is a graph depicting the extent of Ramos cell binding to COS cells separately tranfected wit CDNA encoding VCAM/ICAM-1, VCAM6D/ICAM-1, VCAM/ICAM-2, an VCAM6D/ICAM-2. In addition, the negligible Ramos binding to cells transfected with pCDM8 (expression vector only; negative control) and cells transfected to exhibit surfac ICAMl is shown. Figure 11 is a schematic diagram of another chimeric VCAMl, designated VCAM6D/VCAM4-1, showing the linear arrangement of functional domains. This polypeptide has the general structure of VCAM-6D (no domain 4) , however, as indicated by the shaded area, the cDNA coding for domain 1 and a small part of domain 2 was excised and replaced with cDNA encoding domain 4 (and one amino acid of domain 5) of VCAM-7D. Figure 12 is a graph depicting the extent of Ramos cell binding of COS cells separately tranfected wit cDNA encoding VCAM/ICAM-1, VCAM6D/ICAM-1, and VCAM6D/VCAM4-1. Negligible Ramos binding to ICAMl and negative (pCDMδ) controls is also shown. Figure 13 is a graph depicting the extent of Ramos cell binding to transfectants expressing various chimeric VCAMl constructs in the absence of any interfering antibody or in the presence of MAb 4B9 or MAb GH12 (this invention) . Figure 14 is a graph depicting the extent of Ramos cell binding to transfectants expressing various chimeric VCAMl constructs in the absence• of any interfering antibody or in the presence of MAb 4B9 or MAb ED11 (this invention) . Figure 15 is a graph depicting the extent of Ramos cell binding to transfectants expressing various chimeric VCAMl constructs in the absence of any interfering antibody or in the presence of MAb 4B9 or MAb GE4 (this invention) . Figures 16, 17, 18 and 19 are graphs showing Ramos cell binding to cultured HUVECs treated with 20 ng/ml of recombinant human TNF for 4 hours (Fig. 16) , 24 hours (Fig. 17), 48 hours (Fig. 18), and 72 hours (Fig. 19) . Binding of Ramos cells to uninduced HUVECs (control) , induced (TNF-treated) HUVECs alone, and in the presence of HP1/2 (anti-VLA-4 α 4 MAb) , 4B9 (anti-VCAMl MAb) , ED11 (anti-VCAMl MAb, this invention) , and GH12 (anti-VCAMl MAb, this invention) is compared. DETAILED DESCRIPTION OF THE INVENTION The technology for producing monoclonal antibodies is well known. Briefly, an immortal cell line (typically murine myeloma cells) is fused to lymphocytes (typically splenocytes) from a mammal immunized with whole cells expressing a given antigen, e.g., VCAMl, and/or with purified antigen, and the culture supernatants of the resulting hybrido a cells are screened for antibodies against the antigen. See, generally, Kohler and Milstein, 1975 [12]. Immunization may be accomplished using standard procedures. The unit dose and immunization regimen depend on the species of mammal immunized, its immune status, the body weight of the mammal, etc. Typically, the immunized mammals are bled and the serum from each blood sample is assayed for particular antibodies using appropriate screening assays. For example, anti-VCAMl antibodies according to the present invention were identified by testing the ability of the immune serum to block Ramos binding to plates coated with a recombinant soluble form of VCAM-7D (rsVCAM-7D) . The lymphocytes used in the production of hybridoma cells typically are isolated from immunized mammals whose sera have already tested positive for the presence of anti-VCAMl antibodies using such screening assays. Typically, the immortal cell line (e.g., a myeloma cell line) is derived from the same mammalian species as the lymphocytes. Preferred immortal cell line are mouse myeloma cell lines that are sensitive to cultur medium containing hypoxanthine, aminopterin and thymidine ("HAT medium") . Typically, HAT-sensitive mouse myeloma cells ar fused to mouse splenocytes using polyethylene glycol (e.g., PEG 3350). Hybridoma cells resulting from the fusion are then selected using HAT medium, which kills unfused and unproductively fused myeloma cells (unfused splenocytes die after several days because they are not transformed) . Hybridomas producing a desired antibody ar detected by screening the hybridoma culture supernatants using assays which detect MAbs having the desired specificity. For example, hybridomas according to the invention were identified by their ability to bind to VCAM-7D-expressing cells but not to VCAM-6D-expressing cells. (See Example 1, supra.) To produce anti-VCAMl antibodies, hybridoma cells that tested positive in such screening assays were cultured in a nutrient medium under conditions and for a time sufficient to allow the hybridoma cells to secrete the monoclonal antibodies into the culture medium. Tissue culture techniques and culture media suitable for hybridoma cells are well known. The conditioned hybridoma culture supernatant may be collected and the anti-VCAMl antibodies optionally further purified by well-known methods. Alternatively, the desired antibody may be produced by injecting the hybridoma cells into the peritoneal cavity of a mouse primed with 2,6,10,14- tetramethylpentadecane (PRISTANE; Sigma Chemical Co., St. Louis MO) . The hybridoma cells proliferate in the peritoneal cavity, secreting the antibody which accumulates as ascites fluid. The antibody may be harvested by withdrawing the ascites fluid from the peritoneal cavity with a syringe. The monoclonal antibodies of the present invention recognize epitopes dependent on the fourth Ig domain of the seven-Ig-domain form of VCAMl, i.e., VCAM- 7D. That is, the MAbs of the present invention bind to epitopes that either are contained within the fourth Ig domain of VCAM-7D or are partly contained within the fourth Ig domain, such that elimination of the fourth Ig domain eliminates their ability to recognize the VCAMl structure. These MAbs are referred to as "domain 4 MAbs" herein. The domain 4 MAbs bind to VCAM-7D but do not bind to VCAM-6D. All of the antibodies of this invention are distinct from known VCAMl/VLA-4 blocking antibodies such as 4B9. We show herein that 4B9 recognizes an epitope in domain 1 of VCAMl, and thus recognizes both VCAM-7D and VCAM-6D. The monoclonal antibodies of the present invention recognize VCAM-7D but do not cross-block MAb 4B9. Some of the monoclonal antibodies described herein are effective to inhibit adhesion of Ramos and other VLA-4-expressing cells to VCAMl-expressing cells. Some of the domain 4 monoclonal antibodies described herein bind to epitopes of VCAMl which are not involved i the adhesion pathway between mononuclear leukocytes and VCAMl-expressing cells that is mediated by VCAMl. This latter type of antibody may be useful, for example, to detect the presence of VCAMl, in particular VCAM-7D, in vitro or in vivo without interference with the binding of VCAMl. Using the monoclonal antibodies of the present invention and other anti-VCAMl MAbs obtained from other investigators, we have discovered that binding of VLA-4 to VCAMl can occur via two separate sites, one requiring domain 1, and the other requiring domain 4. The fact that some of the anti-VCAMl domain 4 MAbs of this invention can inhibit domain 4-dependent cell binding and can inhibit cell binding to VCAMl on cultured endothelial cells, indicates that binding through domain 4 is a significant functional component of the VCAMl/VLA-4 interaction .in vivo. The monoclonal antibodies of the present invention may be produced naturally as outlined above or may be synthesized using recombinant DNA techniques. Suitable recombinant antibodies include antibodies produced, e.g., by transforming a host cell with a suitable expression vector containing DNA encoding the light and heavy immunoglobulin chains of the desired antibody, and recombinant chimeric antibodies, wherein some or all of the hinge, constant and/or variable regions of the heavy and/or the light chains of the anti-VCAMl antibody have been substituted with corresponding regions of an immunoglobulin light or heavy chain of a different species. This includes so-called "humanized" antibodies. (See, e.g., Jones et al. , 1986 [13], Ward et al., 1989 [14], and U.S. Patent 4,816,397 (Boss et al.) [15], all incorporated herein by reference.) Furthermore, domain 4-binding fragments of anti- VCAMl antibodies, such as Fab, Fab', F(ab) 2 , and F(v) fragments; heavy chain monomers or di ers; light chain monomers or dimers; and dimers consisting of one heavy chain and one light chain are also contemplated herein. Such antibody fragments may be produced by chemical methods, e.g., by cleaving an intact antibody with a protease, such as papain or pepsin, or via recombinant DNA techniques, e.g., by using host cells transformed with truncated heavy and/or light chain genes. Heavy and light chain monomers may similarly be produced by treating t an intact antibody with a reducing agent such as dithiothreitol or 3-mercaptoethanol or by using host cells transformed with DNA encoding either the desired heavy chain or light chain or both. As an alternative to hybridoma technology, antibody fragments having similar specificities may be isolated by phage cloning methods. (See, e.g., Clackson et al. (1991) [16].) Monoclonal antibodies of the present invention may be used in any application where antibody recognition of domain 4 of VCAMl is advantageous, including applications where inhibiting binding between VCAMl and its ligand, VLA-4, is desired. For example, monoclonal antibodies of the present invention may be used in the treatment of inflammation or diseases characterized by leukocyte binding to endothelium, such as post-reperfusion injury, microbial infections or other cell migration (e.g., metastasis) dependent on a VCAMl-mediated binding pathway, vasculitis, etc. The monoclonal antibodies of the present invention may also be used in combination with other antibodies, bioactive agents or materials for various purposes. For example, the present monoclonal antibodies may be used in combination with 4B9 or other anti-VCAMl antibodies in the treatment of disorders characterized by VCAMl expression in endothelium. Alternatively, the present monoclonal antibodies may be used in combination with antibodies recognizing other endothelial cell receptors identified in inflammatory events (e.g., ELAM1, ICAMl, etc.) in a combination therapy designed to suppres a range of leukocyte-endothelial cell binding pathways. Also, the antibodies of the present invention, or VCAM1- recognizing fragments thereof, may be combined or linked to cytotoxic molecules such as TNF, ricin or the A chain of diphtheria toxin, in order to provide antibody/toxin conjugates capable of targeting cytotoxic elements to VCAMl-expressing cells. The antibodies of the present invention may also be immobilized on a chromatographic substrate (e.g., Protein A-sepharose) to provide an affinity chromatography resin useful, for example, for separating or purifying VCAM-7D preferentially over VCAM- 6D. Detectably labeled antibodies according to the present invention may also be used in screening methods o diagnostic methods for detecting VCAMl protein in a sampl or VCAMl-expressing endothelial cells in vitro or in vivo. For example, samples may be screened for the presence of VCAMl or VCAMl-expressing cells by contacting the sample with a labeled antibody according to the present inventio and detecting whether a VCAMl/anti-VCAMl antibody complex is formed. Suitable labels can be radioactive, enzymatic, fluorescent, magnetic or chemiluminescent. Radiolabeled antibodies are prepared in known ways by coupling a radioactive isotope such as 3 H, 32 P, 3i S, ^Fe, 12S I, which can then be detected by gamma counter, scintillation counter or by autoradiography. Antibodies of this invention may be suitably labeled with enzymes such as yeast alcohol dehydrogenase, horseradish peroxidase, alkaline phosphatase, and the like, then developed and detected spectrophotometrically or visually. Suitable fluorescent labels include fluorescein isothiocyanate, fluorescamine, rhodamine, and the like. Suitable chemiluminescent labels include luminol, imidazole, oxalate ester, luciferin, and the like. For therapeutic uses, the monoclonal antibodies of the present invention may be formulated as a pharmaceutical composition comprising an effective amount of the antibody admixed with a pharmaceutically acceptable carrier. Typically, the antibodies of the present invention will be suspended in a sterile saline solution for therapeutic uses. The pharmaceutical compositions may alternatively be formulated to control release of the active ingredients or to prolong their presence in a patient's system. Numerous suitable drug delivery systems are known and include, e.g., hydrogels, hydroxymethylcellulose, microcapsules, liposomes, microemulsions, microspheres, and the like. The pharmaceutical compositions contemplated herein may be administered by any suitable means such as orally, intranasally, subcutaneously, intramuscularly, intravenously, intra-arterially, or parenterally. Ordinarily, intravenous (i.v.) or parenteral administration will be preferred. Example l MAbs Recognizing VCAM-7D But Not VCAM-6D Monoclonal antibodies according to the inventio that recognize domain 4 of VCAM-7D were prepared in the following manner. We injected four BALB/c mice with whol CHO cells that express VCAM-6D on their surfaces ("VCAM- 6D/CHO" cells) . The CHO culture was a Chinese Hamster Ovary cell line stably transfected with cDNA encoding VCAM-6D and was obtained from Biogen, Inc. (Cambridge, MA) . Initially, each mouse received approximately 10 7 cells in PBS intraperitoneally (i.p.). We injected complete Freund's adjuvant i.p. at a different site 2-24 hours later. We boosted the mice twice i.p. with VCAM- 6D/CHO cells, without adjuvant. We then immunized each of the mice with 55 μg of a recombinant soluble form of VCAM- 7D (rsVCAM-7D, consisting of the N-terminal 674 amino acids of mature VCAM-7D and lacking the transmembrane and cytoplasmic regions; obtained from Biogen, Inc. , Cambridge, MA) injected intraperitoneally with incomplete Freund's adjuvant. We boosted the mice twice with rsVCAM- 7D i.p. without adjuvant. Four days after the rsVCAMl injections, we removed the spleen from one mouse and fused the splenocytes with P3/X63-Ag8.653 murine myeloma cells according to the method described by Lerner [17]. Supernatants of cultures of individual clones of fused cells were screened for their ability to bind to rsVCAM-7D-coated plates. ELISA plates (Corning) were coated with rsVCAM-7D (0.1 μg/ml, 50 μl/well) and incubated overnight at 4° C. The coating solution was aspirated and blocking buffer was added (phosphate buffered saline (PBS) with 5% fetal calf serum (FCS) , pH 7.2) to block the remaining sites, and the plates were incubated for 2 hrs. at room temperature. The blocking buffer was removed, and 50 μl of hybridoma culture supernatants (or supernatant diluted into blocking buffer) were added to the plates and then incubated for 1 hr. at room temperature. Next, the plates were washed with PBS containing 0.05% detergent (Tween-20) to remove unbound antibody and incubated with a horseradish peroxidase- conjugated goat anti-mouse immunoglobulin for 1 hr. at room temperature. The plates were washed with the PBS/Tween-20 solution and developed with the chromogenic horseradish peroxidase substrate, TMB (3,3',5,5'- tetramethylbenzidine; ICN, Lisle IL) 42mM in 0.1M sodium acetate-citric acid, pH 4.9. The reaction was initiated by addition of hydrogen peroxide (15 l, 30% solution) and quenched by addition of 2N sulfuric acid. The colored product was quantified at 450 nm using a Thermofax plate reader (Molecular Devices; Palo Alto CA) . The cells in positive culture wells were subcloned by limiting dilution and re-evaluated using the screening assay described above. We then evaluated the hybridoma supernatants for their ability to stain, by FACS analysis, C0S7 cells transiently expressing VCAM-6D or VCAM-7D. In these experiments cDNA encoding VCAM-6D or VCAM-7D was inserted into an expression vector (pCDM8) and subsequently transfected into COS7 cells by electroporation, as described in Osborn et al. 1989 [2] and Hession et al. 1991 [9], The COS7 cells, transfected with either VCAM-6D or VCAM-7D cDNA, were washed and suspended in suspension buffer (PBS/5mM EDTA/2% FCS/0.05% sodium azide) and incubated 45 min. at 4° C with supernatant from hybridoma cultures. The transfected cells were then washed with suspension buffer and incubated with a fluoresceinated goat anti-mouse Ig (Jackson Immunoresearch, West Grove PA) for 45 min. at 4° C. The cells were washed, fixed with 0.2% paraformaldehyde in PBS and evaluated using a FACSta (Becton Dickinson, Mountain View CA) . FACS analysis showed that the isolated anti- VCAMl monoclonal antibodies bound to VCAM-7D but not to VCAM-6D. The binding data for these antibodies are summarized in Table I (infra p. 28) . Example 2 Ramos Cell Binding Assay Ramos is a B-lymphoblastoid cell line that expresses VLA-4 and thus binds to VCAMl but does not bind to other induced endothelial cell molecules such as ICAM-I or ELAM-1 (Osborn et al., 1989 [2]). Ramos is therefore a convenient model cell line with which to assay VLA-4- dependent binding. Ramos cells bind to both recombinant VCAM-6D and recombinant VCAM-7D when these molecules are expressed on COS cells. We had previously noted that binding to VCAM-7D was somewhat (less than 2 fold) greater than to VCAM-6D in transient transfection assays of a single preparation of each plasmid (Hession et al., 1991 [9]). To determine if this quantitative difference in binding activity was reproducible, several preparations of each plasmid were made and electroporated in parallel into COS cells. Repeated transfections revealed that although expression of the two plasmids is similar, VCAM-7D on average binds significantly more cells per square millimeter than does VCAM-6D. (Cf. Figure 6 and Figure 7.) Binding to both six- and seven-domain forms of VCAMl was inhibited by the anti-VLA-4 MAb HP1/2 or by anti-VCAM MAb 4B9 (Figure 7). In all of our procedures, the binding of Ramos cells was measured as follows: Confluent monolayers of the target cells (e.g., COS transfectants or induced HUVECs) in 48-well plastic tissue culture plates were washed with RPMI/10% fetal calf serum (FCS) , and an amount (e.g., 10 g/ml, varying per MAb and per experiment) of the test MAb (e.g., 4B9, HP1/2, GH12, etc.) in a volume of 0.15 ml was added. In the case of HUVECs, the cells were preincubated 4, 24, 48 or 72 hours at 37° C with 20 ng/ml recombinant human TNF (Biogen, Inc.) to induce expression of VCAMl. Ramos cells were fluorescently labeled by adding 2',7'-bis(2-carboxyethyl)- 5(and 6)-carboxy-fluorescein ("BCECF", Molecular Probes, Eugene OR) according to the manufacturer's instructions. The cells were first centrifuged and then resuspended in RPMI/10% fetal calf serum (FCS) to a concentration of 5 x 10 6 cells ml. The BCECF was added to 2 μM and the suspension incubated for 30 min. at 37° C. The cells were washed twice in RPMI/10% FCS and then resuspended in the same solution at 3 x 10 6 cells/ml. 4.5 X 10 s labeled Ramos cells were added to each well of the 48-well tissue culture plates (final volume, 0.3 ml) and incubated 10 minutes at 37° C. The plates were then emptied by inversion with gentle shaking and washed 3X with HANKS Buffered Salt Solution (HBSS) with Ca " * " and Mg ++ . Adherent cells were lysed by addition of 0.12 ml of a 1% detergent solution (Nonidet P-40) , followed by incubation for 5 min. at 37° C. The lysate was transferred to 96-well microtiter plates by multichannel micropipette, and the number of adherent Ramos cells was calculated by reading the plate in a Titertek Fluorskan II ELISA reader (Flow Laboratories) . (See, also, Gimbrone et al. , 1989 [18].) Antibody Staining Assay The antibodies were tested for their ability to bind to VCAM-7D, VCAM-6D and various VCAM/ICAM constructs exhibiting domain 4-dependent cell binding (see Figures l 13 and Example 3, infra) . COS7 cells transfected with a particular VCAM, ICAM (control) or chimeric VCAM/ICAM (or VCAM/VCAM, see Fig. 11) cDNA construct were removed from 100 mm culture dishes by incubation in HBSS/5 mM EDTA for 15 min. at 37° C, followed by vigorous pipetting. Aliquots of 3-5 x 10 5 cells were incubated individually with 2 μg/ml of the MAb being tested, or with rabbit polyclonal antiserum raised against rsVCAM-7D (diluted 1:500), in PNF (PBS/0.1% sodium azide/2% FCS) for 20 min. at room temperature. After incubation the cells were washed twice with PNF and incubated 20 min. at room temperature with 0.2 g/ml of a secondary fluoresceinated antibody (rabbit anti-mouse immunoglobulin or goat anti- rabbit immunoglobulin) in PNF. Cells were then washed 3X with PBS, suspended in PBS/1% formaldehyde, stored dark at 4° C, and analyzed using a FACStar (Becton Dickinson; Mountain View CA) . The number of cells versus fluorescen intensity was plotted, and the number of positive cells in each sample was determined from the FACS histograms. Fluorescence peaks for each transfectant and for negative controls (pCDM8 vector only) run in parallel were compared and the peaks marked to exclude 99% of the negative cells. The number of positive cells (to the right of the marker) was determined for each transfectant. This method results in a slight underestimate of the number of positive cells in each case, since weakly positive cells that overlap the negative control fluorescence peak are excluded. Example 3 Construction and Expression of Chimeric VCAM/ICAM Polypeptides In order to identify regions of VCAMl involved in recognition of VLA-4-expressing cells, recombinant genes encoding VCAM/ICAM chimeras were constructed by excising portions of the VCAM-7D and VCAM-6D cDNAs and replacing them with analogous regions of ICAM-1, using unique restriction endonuclease sites in the VCAMl cDNA (see Fig. 1) and polymerase chain reaction (PCR)-generated fragments of ICAMl. Substitution of the excised VCAMl regions was done to eliminate as much as possible the structural distortions that would accompany deletion of one or more domains of the VCAMl molecules. ICAMl was selected as a source of substituent structures because it is also a member of the Ig superfamily and has the highest degree of amino acid homology to VCAMl among Ig superfamily members (Osborn et al. , 1989 [2]). Schematic diagrams of the VCAMl/ICAMl chimeric polypeptides are shown in Figures 1-5, 8, 9 and 11. The cDNA constructs coding for each of these were prepared as ollows: Aliquots of the parent plasmids VCAM1E11/CDM8 (encoding VCAM-7D; see, Hession et al., 1991 [9]) or VCAM41/CDM8 (encoding VCAM-6D; Osborn et al. , 1989 [2]) were digested using restriction endonucleases at the appropriate sites indicated in Figure 1 and agarose gel purified. ICAMl inserts were made by PCR from an ICAMl/CDM8 plasmid isolated from an endothelial cDNA library previously described (Osborn et al. , 1989 [2]), using oligonucleotide probes based on the published sequence of ICAMl (Simmons et al., 1988 [19]; Staunton et al., 1988 [20]). The PCR primers were designed as follows: Primer P-l (SEQ ID NO:l) EcoRV 5'-TCTAGATATC TTCTGCCCCG GGAGGCTCCG TGCTG-3' The first twelve nucleotides correspond to the coding region for VCAMl amino acid residues 9-12; the following twenty-three nucleotides correspond to the coding region for ICAMl amino acid residues 11-18. Primer P-2 (SEQ ID NO: 2 ) Bgl2 5'-GGTGGAGATC TACTGGACTC CAGAACGGGT GGAA-3' The first thirteen nucleotides correspond to the coding region for VCAMl amino acid residues 86-89; the following twenty-one nucleotides correspond to the coding region for ICAMl amino acid residues 84-90. Primer P-3 (SEQ ID NO:3) Hind3 5'-TCTCAAGCTT TTACTGTTGA GATCTCCCCT GG-3' The first twelve nucleotides correspond to the coding region for VCAMl amino acid residues -3-1; the following twenty nucleotides correspond to the coding region for ICAMl amino acid residues 300-306. Primer P-4 fSEO ID NO:4) BSU361 5'-CTGGATCCTT AGGAGTCCAG TACACGGTGA GGAAGG-3' The first fourteen nucleotides correspond to the coding region for VCAMl amino acid residues 92-96; the following twenty-two nucleotides correspond to the coding region for ICAMl amino acid residues 79-85. Primer P-5 fSEO ID NO:5) BspHl 5'-CTCTTCATGA GCTTCTCCC CACGGAGCAG CACCAC-3' The first eleven nucleotides correspond to the coding region for VCAMl amino acid residues 134-137; the following twenty-four nucleotides correspond to the codin region for ICAMl amino acid residues 121-128. Primer P-6 fSEO ID NO:6) Bgl2 5'-GGGGAGATCT CGGGCGCCGG AAAGCTGTAG ATGGT-3' The first eleven nucleotides correspond to the coding region for VCAMl amino acid residues 302-305; the following twenty-four nucleotides correspond to the coding region for ICAMl amino acid residues 279-286. Primer P-7 fSEO ID NO:7) Bsu361 5'-CTGGATCCTT AGGGAATGAG TAGAGCTCCA C-3' The first thirteen nucleotides correspond to the coding region for VCAMl amino acid residues 92-96; the following eighteen nucleotides correspond to the coding region for VCAMl amino acid residues 385-394. PCR synthesis for inserts for construct VCAM/ICAM-1 (Fig. 3) was primed with P-l and P-4; for construct VCAM/ICAM-2 (Fig. 4) , P-l and P-5; for construct VCAM/ICAM-3 (Fig. 5), P-2 and P-6; for construct VCAM6D/VCAM4-1 (Fig. 11), P-3 and P-7. VCAM6D/ICAM-1 and VCAM6D/ICAM-2 (Figs. 8 and 9) were made using the same inserts as for VCAM/ICAM-1 and VCAM/ICAM-2, respectively, cloned into the VCAM-6D expression vector (VCAM41/CDM8) instead of the VCAM-7D expression vector (VCAM1E11/CDM8) . After PCR synthesis, performed as described in Hession et al. (1991) [9], the insert fragments were digested with the appropriate restriction endonucleases and gel purified. Expression vectors and insert fragments were ligated using NEB ligase and buffer, ethanol precipitated, then electroporated into bacterial host strain MC1061/p3 using a Biorad Gene Pulser. Clones were screened by PCR and restriction digests, and at least one isolate of each clone was sequenced across cloning junctions and insert using a Sequenase kit (United States Biochemical Corp.). The complete cDNA sequences for VCAM-7D, VCAM-6D, and each of the chimeric constructs VCAM/ICAM-1, VCAM/ICAM-2, VCAM/ICAM-3, VCAM6D/ICAM-1, VCAM6D/ICAM-2, and VCAM6D/VCAM4-1 are set forth in the Sequence Listing belo (in order, SEQ ID NOS: 8 through 15) . The diagrammed constructs were transfected into COS7 cells and found to be well expressed when tested by FACS analysis after staining with polyclonal antiserum to VCAMl. In constructs VCAM/ICAM-1 (Fig. 3) and VCAM/ICAM-2 (Fig. 4), most of VCAM domain 1, or most of domain 1 and the first half of domain 2, were replaced by ICAMl sequence (see shaded areas, Figs. 3 and 4, respectively) . In construct VCAM/ICAM-3 (Fig. 5) , VCAM domains 2 and 3, and small portions of domains 1 and 4, were replaced by ICAMl sequence (see shaded area, Fig. 5) . Example 4 MAb 4B9 Binding to VCAMl domain 1. It has been previously shown that the N-terminal three domains of VCAMl support adhesion to VLA-4 (Taichman et al., 1991 [21]) and that the anti-VCAMl MAb 4B9 significantly inhibits binding of VLA-4-bearing cells to induced HUVECs or VCAMl transfectants (Carlos et al., 1990 [22]). These results suggested that the binding site of VCAMl recognized by VLA-4 and obstructed by 4B9 is in the N-terminal portion of the VCAMl molecule. Using the MAb binding assay described above (Example 2) , we confirmed that MAb 4B9 recognizes an epitope in VCAMl domain 1. It was found that 4B9 bound readily to COS7 transfectants expressing both seven- and six-domain forms of VCAMl. Furthermore, chimeric constructs VCAM/ICAM-1 and VCAM/ICAM-2 (Figs. 3 and 4, respectively) , wherein most of domain 1 was replaced by ICAMl amino acid residues, did not bind to 4B9 (see. Table 1 infra) . These results indicated that the epitope to which 4B9 binds requires domain 1 for recognition. Finally, construct VCAM/ICAM-3 (see, Fig. 5, domain 1 mostly intact) did bind 4B9, confirming that domain 1 contains the 4B9 epitope. The binding and Ramos blocking characteristics of 4B9 are summarized in Table I, infra. Although constructs VCAM/ICAM-1 and VCAM/ICAM-2 did not bind MAb 4B9, both bound Ramos cells at about 30% of the level seen with intact VCAM-7D (Figure 7) . This binding was mediated by VLA-4/VCAMl, since anti-VLA-4 mAb HP1/2 completely inhibited the interaction, while a blocking antibody to the ICAM-1 pathway (MAb 60.3) did not affect binding (data not shown) . Construct VCAM/ICAM-3 bound Ramos cells weakly but measurably, at about 10% of the level seen with intact VCAM-7D (Figure 7) . Ramos Cells Bind At Two Regions On VCAMl To determine whether Ramos cell binding to constructs VCAM/ICAM-1 and VCAM/ICAM-2 was due to residual portions of the domain 1-dependent binding site, or to domain 4 (which is structurally similar to domain 1) , constructs analogous to VCAM/ICAM-1 and VCAM/ICAM-2 were made, except that cDNA coding for VCAM-6D (no domain 4) instead of VCAM-7D was used as the substrate or backbone for the substituted ICAMl inserts (see. Figs. 8 and 9). These constructs, designated VCAM6D/ICAM-1 and VCAM6D/ICAM-2, respectively, were well expressed in COS7 cells as measured by anti-VCAMl polyclonal antiserum staining, but were unable to bind Ramos cells (Figure 10) . These results indicated that the binding of Ramos cells t constructs VCAM/ICAM-l and VCAM/ICAM-2 appears to be due to the presence of domain 4. We next prepared a construct designated VCAM6D/VCAM4-1, in which domain 4 of VCAM-7D was substituted for domain 1 of VCAM-6D (Fig. 11) . Referring to the results depicted in Figures 7 and 12, Ramos bindin of VCAM6D/VCAM4-1 was comparable to that of VCAM-6D (see Fig. 2, intact domain 1) and VCAM/ICAM-l (see Fig. 3, intact domain 4) , indicating that domain 4 can indeed bind cells. This result was somewhat surprising in light of the fact that MAb 4B9, which binds to domain 1 but not to domain 4, can completely inhibit binding of Ramos cells to VCAM-7D. Stearic hindrance is one possible explanation; it is also possible that binding of 4B9 to domain 1 perturbs the structure of the molecule so that domain 4 is no longer in the proper conformation to bind cells. Example 5 Monoclonal Antibodies That Block Domain 4-dependent Cell Adhesion According to the procedure set forth in Example 1, three monoclonal antibodies were produced that recognize VCAM-7D but not VCAM-6D, indicating that they bind domain 4, or a domain 4-dependent epitope. These MAbs were designated GE4, ED11 and GH12. All three MAbs were of IgGl isotype. The binding and Ramos blocking characteristics of each antibody were determined using the antibody and Ramos binding assays described above (Example 2) . MAb GH12 bound to COS7 transfectants expressing VCAM-7D, VCAM/ICAM-l and 2, and VCAM6D/VCAM4-1 but did not bind to transfectants expressing VCAM-6D or VCAM/ICAM-3. Referring to Figure 13, Ramos binding experiments showed that MAb GH12 at 10 μg/ml inhibited Ramos binding to COS7 transfectants expressing the VCAM/ICAM-l, VCAM/ICAM-2 and VCAM6D/VCAM4-1 constructs but did not bind to the VCAM/ICAM-3-expressing tranfectants, indicating that the small portion of domain 4 eliminated from the VCAM/ICAM-3 construct was important to GH12 binding. MAb GH12 did not block Ramos cell binding to VCAM-6D or VCAM-7D. Binding experiments showed that MAb ED11 bound to COS7 cells expressing VCAM-7D, VCAM/ICAM-l and VCAM/ICAM-2 but not to cells expressing VCAM-6D, VCAM/ICAM-3 or VCAM6D/VCAM4-1. Referring to Figure 14, Ramos binding experiments showed that MAb ED11 at 5 μg/ml inhibited Ramos binding to COS7 transfectants expressing the VCAM/ICAM-l and VCAM/ICAM-2 constructs but did not inhibit VCAM-6D-expressing, VCAM/ICAM-3-expressing or VCAM6D/VCAM4-l-expressing tranfectants. Surprisingly, MAb ED11 did partially block Ramos cell binding to VCAM-7D- expressing COS7 cells. Binding experiments showed that MAb GE4 bound to COS7 cells expressing VCAM-7D, VCAM/ICAM-l, VCAM/ICAM-2 and VCAM/ICAM-3 but not to cells expressing VCAM-6D or VCAM6D/VCAM4-1. Referring to Figure 15, Ramos binding experiments showed that MAb GE4 at 10 μg/ml did not inhibit Ramos binding to COS7 transfectants expressing VCAM/ICAM-l and VCAM/ICAM-2. MAb GE4 did not block Ramos adhesion to transfectants expressing VCAM6D/VCAM4-1, VCAM/ICAM-3 or VCAM-6D, and also did not inhibit Ramos binding to VCAM-7D-expressing COS7 cells at the single concentration tested. The binding and blocking data are summarized below in Table I. From these results it can be concluded that each of the three domain 4 antibodies recognize distinct epitopes, and two are capable of blocking domain 4-dependent adhesion of VLA-4 to VCAMl. These antibodies represent a new class of anti-VCAMl blocking antibody. Table I constructs* MAb VCAM-7D VCAM-6D A B c D GH12 binding + + + + blocking + + + EDll binding + + + blocking +/- + + GE4 binding + blocking - 4B9 (control) binding + + + blocking + + + * A = VCAM/ICAM-l C = VCAM/ICAM-3 B = VCAM/ICAM-2 D = VCAM6D/VCAM4-1 Example 6 Domain 4 MAb Inhibition of Ramos Binding to Cytokine-activated Endothelial Cells To determine whether the domain-4-dependent MAbs EDll or GH12 were capable of blocking adhesion to VCAMl on endothelial cells (which is predominantly VCAM-7D) , human umbilical vein endothelial cells (HUVECs) were treated with 20 ng/ml human recombinant TNF for 4, 24, 48, or 72 hours, and binding of Ramos cells and the ability of the antibodies to block binding was measured. All MAbs were added at a concentration of 10 μg/ml. The results are shown for each activation period in Figures 16-19. The results indicate overall that MAb GH12 did not block HUVEC/Ramos binding reliably at the single concentration tested (10 μg/ml) , but MAb EDll blocked more than 80% of Ramos cell binding to induced HUVECs at all time points tested. MAb 4B9 blocked HUVEC/Ramos binding by greater than 90%. These results suggest that although the two cell binding sites of VCAMl (domain 1- and domain- 4-dependent) can be separated and remain functional, antibodies to each can interfere with Ramos cell binding to the other. This is so even though the antibodies do not cross-react with each other's binding sites (shown by the antibody binding data to constructs, above) . In contrast to stimulated endothelial cells, as in this Example, where VCAM-7D is the predominantly expressed (RNA and protein) form of VCAM-1, VCAM-6D (RNA) may be the predominant species of VCAM-1 in bone marrow stromal cells and tonsillar follicular dendritic cells. This suggests a potential therapeutic advantage of domain 4 specific anti-VCAMl antibodies over domain 1 specific anti-VCAMl antibodies, in that domain 4 antibodies according to the present invention might potentially block the recruitment of leukocytes via stimulated endothelial cells into sites of inflammation, without blocking lymphopoiesis, which is the role that VCAM-1 plays in bone marrow (Miyake et al. , 1977 [7]). Such an inhibition of B-cell lymphopoiesis may be undesirable in longer term therapy with anti-VCAMl antibodies. The foregoing examples are intended as an illustration of the present invention and are not presented as a limitation of the invention as claimed hereinafter. From the foregoing disclosure, numerous modi ications and additional embodiments of the invention will be apparent to and easily practiced by those experienced in this art. All such modifications and additional embodiments are within the contemplation of this application and within the scope of the appended claims. We deposited subclones of hybridomas producing EDll, GE4 and GH12 monoclonal antibodies under the Budapest Treaty with the American Type Culture Collection (ATCC) , 12301 Parklawn Dr., Rockville, MD (US) on January 9, 1992. The cultures were identified as follows: designation ATCC accession no. MAb CB.ED11.AG3 HB 10962 MAb CB.GE4.BG5 HB 10961 MAb CB.GH12.AA12 HB 10963 CITED PUBLICATIONS [1] Rice, G.E. and Bevilacqua, M.P. (1989), "An inducible endothelial cell surface glycoprotein mediates melanoma adhesion," Science. 246, 1303-1306. [2] Osborn, L., Hession, C., Tizard, R., Vassallo, C. , Luhowskyj, S., Chi-Rosso, G. , and Lobb, R. (1989), "Direct expression cloning of vascular cell adhesion molecule 1, a cytokine-induced endothelial protein that binds to lymphocytes," Cell, 59, 1203-1211. [3] Elices, M.J., Osborn, L. , Takada, Y. , Crouse, C. , Luhowskyj, S., Hemler, M.E., and Lobb, R.R. (1990), "VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site," Cell, 60, 577-584. [4] Osborn, L. (1990) , "Leukocyte adhesion in inflammation," Cell, 62, 3-6. [5] Cybulsky, M.I. and Gimbrone, M.A. , Jr. (1991), "Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis," Science, 251. 788-791. [6] Freedman, A.S., Munro, J.M. , Rice, G.E., Bevilacqua, M.P., Morimoto, C. , Mclntyre, B.W. , Rhynhart, K. , Pober, J.S., and Nadler, L.M. (1990), "Adhesion of human B cells to germinal centers in vitro involves VLA-4 and INCAM-110," Science. 249. 1030-1033. [7] Miyake, K. , Medina, K. , Ishihara, K. , Kimoto, M. , Auerbach, R. and Kincade, P.W. (1991), "A VCAM-like adhesion molecule on murine bone marrow stromal cells mediates binding of lymphocyte precursors in culture," J. Cell Biol.. 114. 557-565. [8] Polte, T., Newman, W. , and Gopal, T.V. (1990), "Full length vascular cell adhesion molecule 1 (VCAM-1)," Nuc. Ac. Res. F 18, 5901. [9] Hession, C, Tizard, R. , Vassallo, C, Schiffer, S.B., Goff, D. , Moy, P., Chi-Rosso, G. , Luhowskyj, S., Lobb, R. , and Osborn, L. (1991), "Cloning of an alternate form of vascular cell adhesion molecule-1 (VCAMl)", J. Biol. Chem.. 266. 6682-6685. [10] Cybulsky, M.I., Fries, J.W.U., Williams, A.J., Sultan, P., Eddy, R. , Byers, M. , Shows, T., Gimbrone, M.A. , Jr., and Collins, T. (1991), "Gene structure, chromosomal location, and basis for alternative mRNA splicing of the human VCAMl gene," Proc. Natl. Acad. Sci. USA. 88. 7859-7863. [11] Carlos, T.M. , Schwartz, B.R., Kovach, N.L., Yee, E. , Russo, M. , Osborn, L. , Chi-Rosso, G. , Newman, Lobb, R. , and Harlan, J.M. (1990) , "Vascular cell adhesion molecule-1 mediates lymphocyte adherence to cytokine- activated cultured human endothelial cells. Blood, 16 , 965-970. [12] Kohler, G. and Milstein, C. (1975) , "Continuous Cultures of Fused Cells Secreting Antibody of Predefined Specificity", Nature, 256, pp. 495-497. [13] Jones, P. T., et al. (1986), "Replacing the Complementarity-Determining Regions in a Human Antibody with Those From a Mouse," Nature, 321, 522- 525. [14] Ward, E. S., et al. (1989), "Binding Activities of a Repertoire of Single Immunoglobulin Variable Domains Secreted From Escherichia coli." Nature. 341, 544- 546. [15] U.S. Patent No. 4,816,397, Boss et al., "Multichain Polypeptides Or Proteins And Processes For Their Production", issued March 28, 1989. [16] Clackson, T., Hoogenboom, H. R. , Griffiths, A. D. , and Winter, G. (1991) , "Making antibody fragments using phage display libraries," Nature. 352. 624-628. [17] Lerner, L.A. (1981), "How to Make a Hybridoma," Yale J. Biol. Med.. 54. 387-402. [18] Gimbrone, M.A., Jr., Obin, M.S., Brock, A.F., Luis, W.A. , Hass, P.E., Hebert, CA. , Yip, Y.K. , Leung, D.W. , Lowe, D.G., Kohr, W.J., Darbonne, W.C., Bachtol, K.B., and Baker, J.B. (1989), "Endothelial interleukin-8: A novel inhibitor of leukocyte- endothelial interactions," Science. 246, 1601-1603. [19] Simmons, D., Makgoba, M.W. , and Seed, B. (1988), "ICAM, an adhesion ligand of LFA-1, is homologous to the neural cell adhesion molecule NCAM," Nature, 331, 624-627. [20] Staunton, D.E., Dustin, M.L., Erickson, H.P., and Springer, T.A. (1990) , "The arrangement of the immunoglobulin-like domains of ICAM-1 and the binding sites for LFA-1 and rhinovirus," Cell, 61, 243-254. [21] Taichman, D.B., Cybulsky, M.I., Djaffar, I., Longenecker, B.M. , Teixido, J. , Rice, G.E., Aruffo, A., and Bevilacqua, M.P. (1991), "Tumor cell surface a*βj_ integrin mediates adhesion to vascular endothelium: Demonstration of an interaction with the N-terminal domains of IΝCAM-110/VCAM-1," Cell Regulation, 2., 347-355. [22] Carlos, T.M. , Schwartz, B.R. , Kovach, N.L., Yee, E. , Rosso, M. , Osborn, L. , Chi-Rosso, G. , Newman, B. , Lobb, R. , and Harlan, J.M. (1990), "Vascular cell adhesion molecule-l mediates lymphocyte adherence to cytokine-activated cultured human endothelial cells," Blood. 7615 , 965-970. The foregoing publications are incorporated herein by reference. SEQUENCE LISTING (1) GENERAL INFORMATION: (i) APPLICANT: Osbαrn, Laurelee Benjamin, Christopher D. (ii) TITLE OF INVENTION: ANTIBODIES RECOGNIZING THE FOURIH Df -IOGLOBUIJN-IJKE DOMAIN OF VCAMl (iii) NUMBER OF SEQUENCES: 23 (iv) CORRESPONDENCE ADDRESS: (A) ADDRESSEE: Allegretti & Witcoff, Ltd. (B) STREET: 10 South Wacker Drive (C) CITY: Chicago (D) STATE: IL (E) COUNTRY: US (F) ZIP: 60606 (v) COMPUTER READABLE FORM: (A) MEDIUM TYPE: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS/MS-DOS (D) SOFTWARE: Pateπtin Release #1.0, Version #1.25 (vi) CURRENT APPLICATION DATA: (A) APPLICATION NUMBER: (B) FILING DATE: (C) CLASSIFICATION: (viii) AΠORNEY/ACTNT INFORMATION: (A) NAME: McNicholas, Janet M. (B) REGISTRATION NUMBER: 32, 918 (C) REFERENCE/DOCKEΠ? NUMBER: 92, 306-A; DOOl CIP PCT (ix) TELEmMUOTCATION INFORMATION: (A) TELEPHONE: (312) 715-1000 (B) TELEFAX: (312) 715-1234 (2) INFORMATION FOR SEQ ID NO: l: (i) SEQUENCE CHARACTERISTICS: (A) LENGIH: 35 base pairs (B) TYPE: nucleic acid (C) SERANDEENESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTI-ON: SEQ ID NO:1: TCTAGATATC TTCTGOOCOG GGAGGCTCOG TGCTG 35 (2) INFORMATION FOR SEQ ID N0:2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 34 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear ( I) SEQUENCE DESCRIPTION: SEQ ID NO: 2: GGΓGGAGATC TACTGGACTC CAGAAOGGGΓ GGAA 34 (2) INFORMATION EUR SEQ ID N0:3: (i) SEQUENCE CHARACTERISTICS: (A) LENSIH: 32 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear ( I) SEQUENCE DESCRIPNCN: SEQ ID NO: 3: TCTCAAGCΓΓ TΓACΓGΠGA GA CΓCCOCΓ GG 32 (2) INF05MATICN FOR SEQ ID NO:4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 36 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: CIGGATCCIT AGGAGTCCAG TACACGGIGA GGAAGG 36 (2) INFORMATION FOR SEQ ID NO:5: (i) SEQUENCE CHARACTERISTICS: (A) LENGIH: 35 base pairs (B) TYPE: nucleic acid (C) STRANDEI»IESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPπαJ: SEQ ID NO: 5: CTCTTCATGA GCTTCTQOOC AOGGAGCAGC AOCAC 35 (2) INFORMATION FOR SEQ ID NO: 6: (i) SEQUENCE C3ffiRACIERISTICS: (A) LENGTH: 35 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6: GGGGAGATCT CGGGOGCOGG AAAGCIGTAG ATGGT 35 (2) INFORMATION FOR SEQ ID NO: 7 : (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 31 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear (XI) SEQUENCE DESCRIPTION: SEQ ID NO: 7: CTGGATCCΓΓ AGGGAATGAG TAGAGCTOCA C 31 (2) INFORMATION FOR SEQ ID NO:8: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2217 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..2217 (ix) FEATURE: (A) NAME/KEY: matjpeptide (B) LOCATION: 73..2217 (ix) FEATURE: (A) NAME/KEY: sig_peptide (B) LOCATION: 1. .72 (xi) SEQUENCE DESCRIPTICN: SEQ ID NO:8: ATG CCT GGG AAG ATG GTC GIG ATC CTT GGA GOC TCA AAT ATA C T TGG 48 Mat Pro Gly Lys Met Val Val lie Leu Gly Ala Ser Asn lie Leu Trp -24 -20 -15 -10 ATA ATG TTT GCA GCT TCT CAA GCT TTT AAA ATC GAG ACC ACC CCA GAA 96 lie M≥t Hie Ala Ala Ser Gin Ala Phe Lys lie Glu Thr Thr Pro Glu -5 1 5 TCT AGA TAT CTT GCT CAG ATT GGT GAC TCC GTC TCA TIG ACT TGC AGC 144 Ser Arg Tyr Leu Ala Gin lie Gly Asp Ser Val Ser Leu Thr Cys Ser 10 15 20 ACC ACA GGC TGT GAG TGC CCA TTT TTC TCT TGG AGA ACC CAG ATA GAT 192 Thr Thr Gly Cys Glu Ser Pro Phe Phe Ser Trp Arg Thr Gin lie Asp 25 30 35 40 ACT CCA CTG AAT GGG AAG G G AOG AAT GAG GGG ACC ACA TCT ACG CTG 240 Ser Pro Leu Asn Gly Lys Val Thr Asn Glu Gly Thr Thr Ser Thr Leu 45 50 55 ACA ATG AAT CCT CTT ACT TTT GGG AAC GAA CAC TCT TAC CTG TGC ACA 288 Thr Met Asn Pro Val Ser Phe Gly Asn Glu His Ser Tyr Leu Cys Thr 60 65 70 GCA ACT TGT GAA TCT AGG AAA TIG GAA AAA GGA ATC CAG GTG GAG ATC 336 Ala Thr Cys Glu Ser Arg Lys Leu Glu Lys Gly lie Gin Val Glu lie 75 80 85 TAC TCT TTT CCT AAG GAT CCA GAG AIT CAT TTG ACT GGC CCT CTG GAG 384 Tyr Ser Hie Pro Lys Asp Pro Glu lie His Leu Ser Gly Pro Leu Glu 90 95 100 GCT GGG AAG COG ATC ACA GTC AAG TCT TCA GTT GCT GAT GTA TAC CCA 432 Ala Gly Lys Pro lie Thr Val Lys Cys Ser Val Ala Asp Val Tyr Pro 105 110 115 120 TIT GAC AGG CTG GAG ATA GAC TTA CTG AAA GGA GAT CAT CTC ATG AAG 480 Hie Asp Arg Leu Glu lie Asp Leu Leu Lys Gly Asp His Leu Met Lys 125 130 135 ACT CAG GAA TTT CTG GAG GAT GCA GAC AGG AAG TCC CTG GAA ACC AAG 528 Ser Gin Glu Phe Leu Glu Asp Ala Asp Arg Lys Ser Leu Glu Thr Lys 140 145 150 ACT TTG GAA GTA ACC TTT ACT CCT GTC ATT GAG GAT ATT GGA AAA GTT 576 Ser Leu Glu Val Thr Phe Thr Pro Val lie Glu Asp lie Gly Lys Val 155 160 165 CTT GTT TGC CGA GCT AAA TTA CAC ATT GAT GAA ATG GAT TCT GTG OCC 624 Leu Val Cys Arg Ala Lys Leu His lie Asp Glu Met Asp Ser Val Pro 170 175 180 ACA CTA. AGG CAG GCT GTA AAA G^TIG CAAGTC TACAIATCACCC AAG 672 Thr Val Arg Gin Ala Val Lys Glu Leu Gin Val Tyr lie Ser Pro Lys 185 190 195 200 AAT ACA GTT ATT TCT GTG AAT CCA TCC ACA AAG CTG CAA GAA GCT GGC 720 Asn Thr Val lie Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly 205 210 215 TCT GTG ACC ATG ACC TGT TCC AGO GAG GCT CTA CCA GCT CCA GAG ATT 768 Ser Val Thr Met Thr Cys Ser Ser Glu Gly Leu Pro Ala Pro Glu lie 220 225 230 TTC TGG ACT AAG AAA TTA GAT AAT GGG AAT CTA CAG CAC CTT TCT GGA 816 Phe Trp Ser Lys Lys Leu Asp Asn Gly Asn Leu Gin His Leu Ser Gly 235 240 245 AAT GCA ACT CTC ACC TTA ATT GCT ATG AGG ATG GAA GAT TCT GGA ATT 864 Asn Ala Thr Leu Thr Leu lie Ala Met Arg Met Glu Asp Ser Gly lie 250 255 260 TAT GTG TGT GAA GGA GTT AAT TTG ATT GGG AAA AAC AGA AAA GAG GTG 912 Tyr Val Cys Glu Gly Val Asn Leu lie Gly Lys Asn Arg Lys Glu Val 265 270 275 280 GAA TTA ATT GTT CAA GAG AAA CCA TTT ACT GTT GAG ATC TCC CCT GGA 960 Glu Leu lie Val Gin Glu Lys Pro Phe T r Val Glu lie Ser Pro Gly 285 290 295 CCC CGG ATT GCT GCT CAG ATT GGA GAC TCA GTC ATG T G ACA TCT ACT 1008 Pro Arg lie Ala Ala Gin lie Gly Asp Ser Val Mat Leu Thr Cys Ser 300 305 310 GTC ATG GGC TGT GAA TCC CCA TCT TTC TCC TGG AGA ACC CAG ATA GAC 1056 Val Met Gly Cys Glu Ser Pro Ser Phe Ser Trp Arg Thr Gin lie Asp 315 320 325 AGC CCT CTG AGC GGG AAG GTG AGG ACT GAG GGG ACC AAT TCC ACG CTG 1104 Ser Pro Leu Ser Gly Lys Val Arg Ser Glu Gly Thr Asn Ser Thr Leu 330 335 340 ACC CTG AGC <XT GTGACTTTT GAGAAC GA CaCTCT. TAT CTGTGC ACA 1152 Thr Leu Ser Pro Val Ser Phe Glu Asn Glu His Ser Tyr Leu cys Thr 345 350 355 360 CTG ACT TCT GGA CAT AAG AAA CTG GAA AAG GGA ATC CAG CTG GAG CDC 1200 Val Thr Cys Gly His Lys Lys Leu Glu Lys Gly lie Gin Val Glu Leu 365 370 375 TAC TCA TTC CCT AGA GAT CCA GAA ATC GAG ATG ACT GCT GGC CTC CTG 1248 Tyr Ser Phe Pro Arg Asp Pro Glu lie Glu Met Ser Gly Gly Leu Val 380 385 390 AAT GGG AGC TCT CTC ACT CTA AGC TGC AAG GTT CCT AGC GTG TAC CCC 1296 Asn Gly Ser Ser Val Thr Val Ser Cys Lys Val Pro Ser Val Tyr Pro 395 400 405 CTT GAC GGG CTG GAG ATT GAA TTA CTT AAG GGG GAG ACT ATT CTG GAG 1344 Leu Asp Arg Leu Glu lie Glu Leu Leu Lys Gly Glu Thr lie Leu Glu 410 415 420 AAT ATA GAG TTT TTG GAG GAT AGG GAT ATG AAA TCT CTA GAG AAC AAA 1392 Asn lie Glu Phe Leu Glu Asp Thr Asp Met Lys Ser Leu Glu Asn Lys 425 430 435 440 ACT TTG GAA ATG ACC TTC ATC CCT ACC ATT GAA GAT ACT GGA AAA GCT 1440 Ser Leu Glu Met Thr Phe lie Pro Thr lie Glu Asp Thr Gly Lys Ala 445 450 455 CTT CTT TCT CAG GCT AAG TEA CAT ATT GAT GAC ATG GAA TTC GAA CCC 1488 Leu Val Cys Gin Ala Lys Leu His lie Asp Asp Met Glu Hie Glu Pro 460 465 470 AAA CAA AGG CAG ACT ACG CAA ACA CTT TAT CTC AAT CTT GOC CCC AGA 1536 Lys Gin Arg Gin Ser Thr Gin Thr Leu Tyr Val Asn Val Ala Pro Arg 475 480 485 GAT ACA ACC CTC TTG GTC AGC CCT TCC TCC ATC CTG GAG GAA GGC ACT 1584 Asp Thr Thr Val Leu Val Ser Pro Ser Ser lie Leu Glu Glu Gly Ser 490 495 500 TCT CTG AAT ATG ACA TGC TIG AGC CAG GGC TTT CCT GCT COS AAA ATC 1632 Ser Val Asn Met Thr Cys Leu Ser Gin Gly Phe Pro a Pro Lys lie 505 510 515 520 CTG TGG AGC AGG CAG CTC CCT AAC GGG GAG CTA CAG CCT CTT TCT GAG 1680 Leu Trp Ser Arg Gin Leu Pro Asn Gly Glu Leu Gin Pro Leu Ser Glu 525 530 535 AAT GCA ACT CTC ACC TTA ATT TCT ACA AAA ATG GAA GAT TCT GGG GTT 1728 Asn Ala Thr Leu Thr Leu lie Ser Thr Lys Mat Glu Asp Ser Gly Val 540 545 550 TAT TTA TCT GAA GGA ATT AAC CAG GCT GGA AGA AGC AGA AAG GAA GTG 1776 Tyr Leu Cys Glu Gly lie Asn Gin Ala Gly Arg Ser Arg Lys Glu Val 560 565 GAA TEA ATT ATC CAA GTT ACT CCA AAA GAC ATA AAA CTT ACA GCT TTT 1824 Glu Leu lie lie Gin Val Thr Pro Lys Asp lie Lys Leu Thr Ma Phe 570 575 580 CCT TCT GAG ACT GTC .AAA GAA GGA GAC ACT GTC ATC ATC TCT TCT ACA 1872 Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val lie lie Ser Cys Thr 585 590 595 600 TCT GGA AAT CTT CCA GAA ACA TGG ATA ATC CTG AAG AAA AAA GCG GAG 1920 Cys Gly Asn Val Pro Glu Thr Trp lie lie Leu Lys Lys Lys Ma Glu 605 610 615 ACA GGA GAC ACA GTA CTA AAA TCT ATA GAT GGC GCC TAT ACC ATC CGA 1968 Thr Gly Asp Thr Val Leu Lys Ser lie Asp Gly Ma Tyr Thr lie Arg 620 625 630 AAG GCC CAG TTG AAG GAT GOG GGA GTA TAT GAA TCT GAA TCT AAA AAC 2016 Lys Ma Gin Leu Lys Asp Ma Gly Val Tyr Glu Cys Glu Ser Lys Asn 635 640 645 AAA CTT GGC TCA CAA TTA AGA ACT TTA ACA CTT GAT GTT CAA GGA AGA 2064 Lys Val Gly Ser Gin Leu Arg Ser Leu Thr Leu Asp Val Gin Gly Arg 650 655 660 GAA AAC AAC AAA GAC TAT TIT TCT CCT GAG CIT CTC GTG CTC TAT TTT 2112 Glu Asn Asn Lys Asp Tyr Phe Ser Pro Glu Leu Leu Val Leu Tyr Phe 665 670 675 680 GCA TCC TCC TTA ATA ATA CCT GCC A T GGA ATG ATA ATT TAC TTT GCA 2160 Ma Ser Ser Leu He He Pro Ma He Gly Met He He Tyr Hie Ma 685 690 695 AGA AAA GCC AAC ATG AAG GGG TCA TAT ACT CIT CTA GAA GCA CAG AAA 2208 Arg Lys Ma Asn Met Lys Gly Ser Tyr Ser Leu Val Glu Ma Gin Lys 700 705 710 TCA AAA GIG 2217 Ser Lys Val 715 (2) INFORMATION FOR SEQ ID NO:9: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 739 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: M≥t Pro Gly Lys Ifet Val Val He Leu Gly Ma Ser Asn He Leu Trp -24 -20 -15 -10 lie Met Phe Ma Ma Ser Gin Ma Hie Lys He Glu Thr Thr Pro Glu -5 1 5 Ser Arg Tyr Leu Ala Gin lie Gly Asp Ser Val Ser Leu Thr Cys Ser 10 15 20 Thr Thr Gly Cys Glu Ser Pro Phe Phe Ser Trp Arg Thr Gin He Asp 25 30 35 40 Ser Pro Leu Asn Gly Lys Val Thr Asn Glu Gly Thr Thr Ser Thr Leu 45 50 55 Thr Met Asn Pro Val Ser Phe Gly Asn Glu His Ser Tyr Leu Cys Thr 60 65 70 Ma Thr Cys Glu Ser Arg Lys Leu Glu Lys Gly lie Gin Val Glu He 75 80 85 Tyr Ser Hie Pro Lys Asp Pro Glu He His Leu Ser Gly Pro Leu Glu 90 95 100 Ma Gly Lys Pro lie Thr Val Lys cys Ser Val Ma Asp Val Tyr Pro 105 110 115 120 Hie Asp Arg Leu Glu He Asp Leu Leu Lys Gly Asp His Leu Met Lys 125 130 135 Ser Gin Glu he Leu Glu Asp Ma Asp Arg Lys Ser Leu Glu Thr Lys 140 145 150 Ser Leu Glu Val Thr Phe Thr Pro Val He Glu Asp He Gly Lys Val 155 160 165 Leu Val Cys Arg Ma Lys Leu His He Asp Glu Met Asp Ser Val Pro 170 175 180 Thr Val Arg Gin Ma Val Lys Glu Leu Gin Val Tyr He Ser Pro Lys 185 190 195 200 Asn Thr Val lie Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly 205 210 215 Ser Val Thr Met Thr cys Ser Ser Glu Gly Leu Pro Ma Pro Glu He 220 225 230 Phe Tip Ser Lys Lys Leu Asp Asn Gly Asn Leu Gin His Leu Ser Gly 235 240 245 . Asn Ala Thr Leu Thr Leu He Ma Met Arg Met Glu Asp Ser Gly He 250 255 260 Tyr Val Cys Glu Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val 265 270 275 280 Glu Leu lie Veil Gin Glu Lys Pro Phe Thr Val Glu He Ser Pro Gly 285 290 295 Pro Arg He Ma Ma Gin He Gly Asp Ser Val Met Leu Thr Cys Ser 300 305 310 Val Met Gly Cys Glu Ser Pro Ser Phe Ser Trp Arg Thr Gin He Asp 315 320 325 Ser Pro Leu Ser Gly Lys Val Arg Ser Glu Gly Thr Asn Ser Thr Leu 330 335 340 Thr Leu Ser Pro Val Ser Hie Glu Asn Glu His Ser Tyr Leu Cys Thr 345 350 355 360 Val Thr Cys Gly His Lys Lys Leu Glu Lys Gly He Gin Val Glu Leu 365 370 375 Tyr Ser Phe Pro Arg Asp Pro Glu He Glu Met Ser Gly Gly Leu Val 380 385 390 Asn Gly Ser Ser Val Thr Val Ser cys Lys Val Pro Ser Val Tyr Pro 395 400 405 Leu Asp Arg Leu Glu He Glu Leu Leu Lys Gly Glu Thr He Leu Glu 410 415 420 Asn He Glu Phe Leu Glu Asp Thr Asp Met Lys Ser Leu Glu Asn Lys 425 430 435 440 Ser Leu Glu Met Thr Phe He Pro Thr He Glu Asp Thr Gly Lys Ma 445 450 455 Leu Val Cys Gin Ma Lys Leu His He Asp Asp Met Glu Phe Glu Pro 460 465 470 Lys Gin Arg Gin Ser Thr Gin Thr Leu Tyr Val Asn Val Ma Pro Arg 475 480 485 Asp Thr Thr Val Leu Val Ser Pro Ser Ser He Leu Glu Glu Gly Ser 490 495 500 Ser Val Asn Met Thr Cys Leu Ser Gin Gly Phe Pro Ma Pro Lys He 505 510 515 520 Leu Trp Ser Arg Gin Leu Pro Asn Gly Glu Leu Gin Pro Leu Ser Glu 525 530 535 Asn Ma Thr Leu Thr Leu He Ser Thr Lys Ifet Glu Asp Ser Gly Val 540 545 550 Tyr Leu Cys Glu Gly lie Asn Gin Ma Gly Arg Ser Arg Lys Glu Val 555 560 565 Glu Leu He He Gin Val Thr Pro Lys Asp lie Lys Leu Thr Ma Phe 570 575 580 Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val He He Ser Cys Thr 585 590 595 600 Cys Gly Asn Val Pro Glu Thr Trp lie He Leu Lys Lys Lys Ma Glu 605 610 615 Thr Gly Asp Thr Val Leu Lys Ser lie Asp Gly Ma Tyr Thr He Arg 620 625 630 Lys Ma Gin Leu Lys Asp Ma Gly Val Tyr Glu Cys Glu Ser Lys Asn 635 640 645 Lys Val Gly Ser Gin Leu Arg Ser Leu Thr Leu Asp Val Gin Gly Arg 650 655 660 Glu Asn Asn Lys Asp Tyr Phe Ser Pro Glu Leu Leu Val Leu Tyr Phe 665 670 675 680 Ma Ser Ser Leu He He Pro Ma He Gly Met He He Tyr Phe Ma 685 690 695 Arg Lys Ma Asn Met Lys Gly Ser Tyr Ser Leu Val Glu Ma Gin Lys 700 705 710 Ser Lys Val 715 (2) INFORMATION FOR SEQ ID NO:10: (i) SEQUENCE CHARACTERISTICS: (A) LENGIH: 1941 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..1941 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) LOCATION: 73. .1941 (ix) FEATURE: (A) NAME/KEY: sig_pεptide (B) LOCATION: 1..72 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: ATG CCT GGG AAG ATG GTC GTG ATC CTT GGA GCC TCA AAT ATA CIT TGG 48 Met Pro Gly Lys Met Val Val He Leu Gly Ala Ser Asn He Leu Trp -24 -20 -15 -10 ATA ATG TTT GCA GCT TCT CAA GCT TTT AAA ATC GAG ACC ACC CCA GAA 96 He Met Phe Ma Ma Ser Gin Ma Hie Lys He Glu Thr Thr Pro Glu -5 1 5 TCT AGA TAT CTT GCT CAG A T GCT GAC TCC GTC TCA TTG ACT TGC AGC 144 Ser Arg Tyr Leu Ma Gin He Gly Asp Ser Val Ser Leu Thr Cys Ser 10 15 20 ACC ACA GGC TGT GAG TCC CCA TTT TTC TCT TGG AGA ACC CAG ATA GAT 192 Thr Thr Gly Cys Glu Ser Pro Phe Phe Ser Trp Arg Thr Gin He Asp 25 30 35 40 ACT CCA CTG AAT GGG AAG GTG ACG AAT GAG GGG ACC ACA TCT ACG CTG 240 Ser Pro Leu Asn Gly Lys Val Thr Asn Glu Gly Thr Thr Ser Thr Leu 45 50 55 ACA ATG AAT CCT CTT ACT TTT GGG AAC GAA CAC TCT TAC CTG TGC ACA 288 Thr Met Asn Pro Val Ser Hie Gly Asn Glu His Ser Tyr Leu Cys Thr 60 65 ' 70 GCA ACT TCT GAA TCT AGG AAA TTG GAA AAA GGA ATC CAG CTG GAG ATC 336 Ma Thr Cys Glu Ser Arg Lys Leu Glu Lys Gly He Gin Val Glu He 75 80 85 TAC TCT TTT CCT AAG GAT CCA GAG ATT CAT TTG ACT GGC CCT CTG GAG 384 Tyr Ser Hie Pro Lys Asp Pro Glu He His Leu Ser Gly Pro Leu Glu 90 95 100 GCT GGG AAG COG ATC ACA GTC AAG TGT TCA CTT GCT GAT GTA TAC CCA 432 Ma Gly Lys Pro He Thr Val Lys Cys Ser Val Ma Asp Val Tyr Pro 105 110 115 120 TTT GAC AGG CTG GAG ATA GAC TTA CTG AAA GGA GAT CAT CTC ATG AAG 480 Phe Asp Arg Leu Glu He Asp Leu Leu Lys Gly Asp His Leu Met Lys 125 130 135 ACT CAG GAA TTT CTG GAG GAT GCA GAC AGG AAG TCC CTG GAA ACC AAG 528 Ser Gin Glu Hie Leu Glu Asp Ala Asp Arg Lys Ser Leu Glu Thr Lys 140 145 150 ACT TIG GAA CTA ACC TTT ACT CCT GTC ATT GAG GAT ATT GGA AAA CTT 576 Ser Leu Glu Val Thr Phe Thr Pro Val He Glu Asp He Gly Lys Val 155 160 165 CTT GTT TGC CGA GCT AAA TTA CAC ATT GAT GAA ATG GAT TCT CTG CCC 624 Leu Val Cys Arg Ma Lys Leu His He Asp Glu Met Asp Ser Val Pro 170 175 180 ACA GTA AGG CAG GCT CTA AAA GAA TTG CAA GTC TAC ATA TCA CCC AAG 672 Thr Val Arg Gin Ma Val Lys Glu Leu Gin Val Tyr lie Ser Pro Lys 185 190 195 200 AAT ACA CTT ATT TCT GTG AAT CCA TCC ACA AAG CTG CAA GAA GCT GGC 720 Asn Thr Val He Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly 205 210 215 TCT CTG ACC ATG ACC TCT TCC AGC GAG GCT CIA CCA GCT CCA GAG ATT 768 Ser Val Thr Met Thr Cys Ser Ser Glu Gly Leu Pro Ma Pro Glu He 220 225 230 TTC TGG ACT AAG AAA TTA GAT AAT GGG AAT CTA CAG CAC CTT TCT GGA 816 Hie Trp Ser Lys Lys Leu Asp Asn Gly Asn Leu Gin His Leu Ser Gly 235 240 245 AAT GCA ACT CTC ACC TTA ATT GCT ATG AGG ATG GAA GAT TCT GGA ATT 864 Asn Ma Thr Leu Thr Leu He Ma Met Arg Ifet Glu Asp Ser Gly He 250 255 2.60 TAT CTG TCT GAA GGA GTT AAT TTG AIT GGG AAA AAC AGA AAA GAG CTG 912 Tyr Val Cys Glu Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val 265 270 275 280 GAA TTA ATT GTT CAA GCA TTC CCT AGA GAT CCA GAA ATC GAG ATG ACT 960 Glu Leu lie Val Gin Ma Hie Pro Arg Asp Pro Glu He Glu Met Ser 285 290 295 GCT GGC CTC CTG AAT GGG AGC TCT CTC ACT GTA AGC TGC AAG GTT CCT 1008 Gly Gly Leu Val Asn Gly Ser Ser Val Thr Val Ser Cys Lys Val Pro 300 305 310 AGC CTG TAC CCC CIT GAC CGG CTG GAG ATT GAA TTA CTT AAG GGG GAG 1056 Ser Val Tyr Pro Leu Asp Arg Leu Glu lie Glu Leu Leu Lys Gly Glu 315 320 325 ACT ATT CTG GAG AAT ATA GAG TIT TIG GAG GAT ACG GAT ATG AAA TCT 1104 Thr He Leu Glu Asn lie Glu Hie Leu Glu Asp Thr Asp Met Lys Ser 330 335 340 CTA GAG AAC AAA ACT TTG GAA ATG ACC TTC ATC CCT ACC ATT GAA GAT 1152 Leu Glu Asn Lys Ser Leu Glu Met Thr Phe He Pro Thr He Glu Asp 345 350 355 360 ACT GGA AAA GCT CTT CTT TCT CAG GCT AAG TTA CAT ATT GAT GAC ATG 1200 Thr Gly Lys Ala Leu Val Cys Gin Ma Lys Leu His He Asp Asp Met 365 370 375 GAATTCGAAαrAAA O-AAGG CAGACTACEα-AACΑ Cπ^ 1248 Glu Hie Glu Pro Lys Gin Arg Gin Ser Thr Gin Thr Leu Tyr Val Asn 380 385 390 GTT GCC CCC AGA GAT ACA ACC GTC TIG GTC AGC CCT TCC TCC ATC CTG 1296 Val Ma Pro Arg Asp Thr Thr Val Leu Val Ser Pro Ser Ser He Leu 395 400 405 GAG GAA GGC ACT TCT GIG AAT ATG ACA TGC TTG AGC CAG GGC TTT CCT 1344 Glu Glu Gly Ser Ser Val Asn Met Thr Cys Leu Ser Gin Gly Hie Pro 410 415 420 GCT COG AAA ATC CTG TGG AGC AGG CAG CTC CCT AAC GGG GAG CTA CAG 1392 Ma Pro Lys He Leu Trp Ser Arg Gin Leu Pro Asn Gly Glu Leu Gin 425 430 435 440 CCT CTT TCT GAG AAT GCA ACT CTC ACC TTA ATT TCT ACA AAA ATG GAA 1440 Pro Leu Ser Glu Asn Ma Thr Leu Thr Leu He Ser Thr Lys Met Glu 445 450 455 GAT TCT GGG GTT TAT TTA TCT GAA GGA ATT AAC CAG GCT GGA AGA AGC 1488 Asp Ser Gly Val Tyr Leu Cys Glu Gly He Asn Gin Ma Gly Arg Ser 460 465 470 AGA AAG GAA CTG GAA TTA ATT ATC CAA GTT ACT CCA AAA GAC ATA AAA 1536 Arg Lys Glu Val Glu Leu He He Gin Val Thr Pro Lys Asp He Lys 475 480 485 CTT ACA GCT TTT CCT TCT GAG ACT GTC AAA GAA GGA GAC ACT GTC ATC 1584 Leu Thr Ma Phe Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val He 490 495 500 ATC TCT TCT ACA TCT GGA AAT GTT CCA GAA ACA TGG ATA ATC CTG AAG 1632 He Ser Cys Thr Cys Gly Asn Val Pro Glu Thr Trp He He Leu Lys 505 510 515 520 AAA AAA GOG GAG ACA GGA GAC ACA GTA CTA AAA TCT ATA GAT GGC GCC 1680 Lys Lys Ma Glu Thr Gly Asp Thr Val Leu Lys Ser He Asp Gly Ma 525 530 535 TAT ACC ATC CGA AAG GCC CAG TTG AAG GAT GOG GGA GTA TAT GAA TCT 1728 Tyr Thr He Arg Lys Ma Gin Leu Lys Asp Ma Gly Val Tyr Glu Cys 540 545 550 GAA TCT AAA AAC AAA CTT GGC TCA CAA TTA AGA ACT TTA ACA CTT GAT 1776 Glu Ser Lys Asn Lys Val Gly Ser Gin Leu Arg Ser Leu Thr Leu Asp 555 560 565 CTT CAA GGA AGA GAA AAC AAC AAA GAC TAT TTT TCT CCT GAG CTT CTC 1824 Val Gin Gly Arg Glu Asn Asn Lys Asp Tyr Phe Ser Pro Glu Leu Leu 570 575 580 CTG CTC TAT TTT GCA TCC TCC TTA ATA ATA CCT GCC ATT GGA ATG ATA 1872 Val Leu Tyr Hie Ala Ser Ser Leu lie lie Pro Ma He Gly Met He 585 590 595 600 ATT TAC T T GCA AGA AAA GOC AAC ATG AAG GGG TCA TAT ACT CTT CTA 1920 He Tyr Hie Ma Arg Lys Ma Asn Met Lys Gly Ser Tyr Ser Leu Val 605 610 615 GAA GCA CAG AAA TCA AAA CTG 1941 Glu Ala Gin Lys Ser Lys Val 620 (2) .INFORMATION FOR SEQ ID NO:11: (i) SEQUENCE CHARACTERISTTCS: (A) LENCTH: 647 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:ll: Met Pro Gly Lys Met Val Val He Leu Gly Ma Ser Asn He Leu Trp -24 -20 -15 -10 He Ifet Hie Ma Ma Ser Gin Ma Hie Lys lie Glu Thr Thr Pro Glu -5 1 5 Ser Arg Tyr Leu Ma Gin He Gly Asp Ser Val Ser Leu Thr cys Ser 10 15 20 Thr Thr Gly Cys Glu Ser Pro Phe Phe Ser Trp Arg Thr Gin He Asp 25 30 35 40 Ser Pro Leu Asn Gly Lys Val Thr Asn Glu Gly Thr Thr Ser Thr Leu 45 50 55 Thr Met Asn Pro Val Ser Phe Gly Asn Glu His Ser Tyr Leu Cys Thr 60 65 70 Ma Thr Cys Glu Ser Arg Lys Leu Glu Lys Gly He Gin Val Glu He 75 80 85 Tyr Ser Hie Pro Lys Asp Pro Glu lie His Leu Ser Gly Pro Leu Glu 90 95 100 Ma Gly Lys Pro He Thr Val Lys Cys Ser Val Ma Asp Val Tyr Pro 105 110 115 120 Phe Asp Arg Leu Glu He Asp Leu Leu Lys Gly Asp His Leu Met Lys 125 130 135 Ser Gin Glu Phe Leu Glu Asp Ma Asp Arg Lys Ser Leu Glu Thr Lys 140 145 150 Ser Leu Glu Val Thr Fhe Thr Pro Val He Glu Asp He Gly Lys Val 155 160 165 Leu Val cys Arg Ma Lys Leu His He Asp Glu Met Asp Ser Val Pro 170 175 180 Thr Val Arg Gin Ma Val Lys Glu Leu Gin Val Tyr He Ser Pro Lys 185 190 195 200 Asn Thr Val He Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly 205 210 215 Ser Val Thr Met Thr Cys Ser Ser Glu Gly Leu Pro Ma Pro Glu He 220 225 230 Phe Trp Ser Lys Lys Leu Asp Asn Gly Asn Leu Gin His Leu Ser Gly 235 240 245 Asn Ma Thr Leu Thr Leu He Ma Met Arg Met Glu Asp Ser Gly He 250 255 260 Tyr Val Cys Glu Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val 265 270 275 280 Glu Leu He Val Gin Ma Phe Pro Arg Asp Pro Glu He Glu Met Ser 285 290 295 Gly Gly Leu Val Asn Gly Ser Ser Val Thr Val Ser Cys Lys Val Pro 300 305 310 Ser Val Tyr Pro Leu Asp Arg Leu Glu He Glu Leu Leu Lys Gly Glu 315 320 325 Thr He Leu Glu Asn He Glu Hie Leu Glu Asp Thr Asp Met Lys Ser 330 335 340 Leu Glu Asn Lys Ser Leu Glu Met Thr Hie He Pro Thr He Glu Asp 345 350 355 360 Thr Gly Lys Ala Leu Val cys Gin Ala Lys Leu His He Asp Asp Met 365 370 375 Glu Phe Glu Pro Lys Gin Arg Gin Ser Thr Gin Thr Leu Tyr Val Asn 380 385 390 Val Ma Pro Arg Asp Thr Thr Val Leu Val Ser Pro Ser Ser lie Leu 395 400 405 Glu Glu Gly Ser Ser Val Asn Met Thr Cys Leu Ser Gin Gly Hie Pro 410 415 420 Ala Pro Lys He Leu Trp Ser Arg Gin Leu Pro Asn Gly Glu Leu Gin 425 430 435 440 Pro Leu Ser Glu Asn Ma Thr Leu Thr Leu He Ser Thr Lys Met Glu 445 450 455 Asp Ser Gly Val Tyr Leu cys Glu Gly He Asn Gin Ma Gly Arg Ser 460 465 470 Arg Lys Glu Val Glu Leu He lie Gin Val Thr Pro Lys Asp He Lys 475 480 485 Leu Thr Ma Hie Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val He 490 495 500 lie Ser cys Thr Cys Gly Asn Val Pro Glu Thr Trp lie He Leu Lys 505 510 515 520 Lys Lys Ma Glu Thr Gly Asp Thr Val Leu Lys Ser He Asp Gly Ma 525 530 535 Tyr Thr He Arg Lys Ala Gin Leu Lys Asp Ma Gly Val Tyr Glu Cys 540 545 550 Glu Ser Lys Asn Lys Val Gly Ser Gin Leu Arg Ser Leu Thr Leu Asp 555 560 565 Val Gin Gly Arg Glu Asn Asn Lys Asp Tyr Phe Ser Pro Glu Leu Leu 570 575 580 Val Leu Tyr Phe Ma Ser Ser Leu He He Pro Ma lie Gly Met lie 585 590 595 600 lie Tyr Phe Ma Arg Lys Ma Asn Ifet Lys Gly Ser Tyr Ser Leu Val 605 610 615 Glu Ma Gin Lys Ser Lys Val 620 (2) INEOFMAnON FOR SEQ ID N0:12: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2205 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ix) FEATURE: (A) NAME/KEY: CDS (B) IXXAΠCN: 1. .2205 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) LOCATION: 73. .2205 (ix) FEATURE: (A) NAME/KEY: sig_pεptide (B) LOCATION: 1. .72 (xi) SEQUENCE DESCRIPTION: SEQ 3D NO:12: ATG CCT GGG AAG ATG GTC CTG ATC CIT GGA GCC TCA AAT ATA CIT TGG 48 Met Pro Gly Lys Met Val Val He Leu Gly Ma Ser Asn He Leu Trp -24 -20 -15 -10 ATA ATG TTT GCA GCT TCT CAA GCT TTT AAA ATC GAG ACC ACC CCA GAA 96 He Met Phe Ala Ma Ser Gin Ma Phe Lys He Glu Thr Thr Pro Glu -5 1 5 TCT AGA TAT CIT CTG CCC CGG GGA GGC TCC CTG CTG CTG ACA TGC AGC 144 Ser Arg Tyr Leu Leu Pro Arg Gly Gly Ser Val Leu Val Thr Cys Ser 10 15 20 ACC TCC TCT GAC CAG CCC AAG TTG TTG GGC ATA GAG ACC COG TTG CCT 192 Thr Ser Cys Asp Gin Pro Lys Leu Leu Gly He Glu Thr Pro Leu Pro 25 30 35 40 AAA AAG GAG TTG CTC CTG CCT GGG AAC AAC CGG AAG CTG TAT GAA CTG 240 Lys Lys Glu Leu Leu Leu Pro Gly Asn Asn Arg Lys Val Tyr Glu Leu 45 50 55 AGC AAT CTG CAA GAA GAT AGC CAA CCA ATG TGC TAT TCA AAC TGC CCT 288 Ser Asn Val Gin Glu Asp Ser Gin Pro Met Cys Tyr Ser Asn Cys Pro 60 65 70 GAT GGG CAG TCA ACA GCT AAA ACC TTC CTC ACC CTG TAC TGG ACT CCT 336 Asp Gly Gin Ser Thr Ma Lys Thr Phe Leu Thr Val Tyr Trp Thr Pro 75 80 85 AAG GAT OCA GAG ATT CAT TTG ACT GGC CCT CTG GAG GCT GGG AAG COG 384 Lys Asp Pro Glu lie His Leu Ser Gly Pro Leu Glu Ma Gly Lys Pro 90 95 100 ATC ACA GTC AAG TCT TCA GTE GCT GAT CTA TAC CCA T T GAC AGG CTG 432 He Thr Val Lys Cys Ser Val Ala Asp Val Tyr Pro Hie Asp Arg Leu 105 HO H5 120 GAG ATA GAC TTA CTG AAA GGA GAT CAT CTC ATG AAG ACT CAG GAA TTT 480 Glu lie Asp Leu. Leu Lys Gly Asp His LeuMet Lys Ser Gin Glu Hie 125 130 135 CTG GAG GAT GCA GAC AGG AAG TCC CTG GAA ACC AAG ACT TTG GAA GTA 528 Leu Glu Asp Ala Asp Arg Lys Ser Leu Glu Thr Lys Ser Leu Glu Val 140 145 150 ACC TTT ACT OCT GTC ATT GAG GAT ATT GGA AAA GTT CTT CTT TGC CGA 576 Thr Hie Thr Pro Val He Glu Asp He Gly Lys Val Leu Val cys Arg 155 160 165 GCT AAA TTA CAC ATT GAT GAA ATG GAT TCT GTG CCC ACA CTA AGG CAG 624 Ma Lys Leu His He Asp Glu Ifet Asp Ser Val Pro Thr Val Arg Gin 170 175 180 GCT CTAAAA GAA TTG CAA CTC TAC ATA TCA CCC AAG AAT ACA CTT ATT 672 Ma Val Lys Glu Leu Gin Val Tyr lie Ser Pro Lys Asn Thr Val He 185 190 195 200 TCT CTG AAT CCA TCC ACAAAG CTG CAA GAA GCT GGC TCT GTG ACC ATG 720 Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly Ser Val Thr Met 205 210 215 ACC TCT TCC AGC GAG GCT CTA CCA GCT CCA GAG ATT TTC TGG ACT AAG 768 Thr cys Ser Ser Glu Gly Leu Pro Ma Pro Glu He Hie Trp Ser Lys 220 225 230 AAA TTA GAT AAT GGG AAT CTA CAG CAC CIT TCT GGA AAT GCA ACT CTC 816 Lys Leu Asp Asn Gly Asn Leu Gin His Leu Ser Gly Asn Ma Thr Leu 235 240 245 ACC TTA ATT GCT A G AGG ATG GAA GAT TCT GGA ATT TAT GTG TCT GAA 864 Thr Leu He Ma Ifet Arg Met Glu Asp Ser Gly He Tyr Val Cys Glu 250 255 260 GGA GTT AAT TTG ATT GGG AAA AAC AGA AAA GAG GTG GAA TTA ATT GEE 912 Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val Glu Leu lie Val 265 270 275 280 CAA GAG AAA CCA TTT ACT CTT GAG ATC TCC CCT GGA CCC CGG A T GCT 960 Gin Glu Lys Pro Hie Thr Val Glu He Ser Pro Gly Pro Arg He Ala 285 290 295 GCT CAG ATT GGA GAC TCA GTC ATG TTG ACA TGT AC CTC ATG GGC TCT 1008 Ma Gin He Gly Asp Ser Val Met Leu Thr Cys Ser Val Met Gly Cys 300 305 310 GAA TCC CCA TCT TTC TCC TGG AGA ACC CAG ATA GAC AGC CCT CTG AGC 1056 Glu Ser Pro Ser Hie Ser Trp Arg Thr Gin He Asp Ser Pro Leu Ser 315 320 325 GGG AAG CTG AGG ACT GAG GGG ACC AAT TCC ACG CTG ACC CTG AGC CCT 1104 Gly Lys Val Arg Ser Glu Gly Thr Asn Ser Thr Leu Thr Leu Ser Pro 330 335 340 CTG ACT TTT GAG AAC GAA CAC TCT TAT CTG TGC ACA GTG ACT TCT GGA 1152 Val Ser Hie Glu Asn Glu His Ser Tyr Leu Cys Thr Val Thr Cys Gly 345 350 355 360 CAT AAG AAA CTG GAA AAG GGA ATC CAG GTG GAG CTC TAC TCA TTC OCT 1200 His Lys Lys Leu Glu Lys Gly He Gin Val Glu Leu Tyr Ser Phe Pro 365 370 375 AGA GAT <XAGAAATCGAGATCACTGCTGGC CTCCTGAATGGG AGC TCT 1248 Arg Asp Pro Glu He Glu Met Ser Gly Gly Leu Val Asn Gly Ser Ser 380 385 390 GTC ACT GTA AGC TGC AAG GTT CCT AGC GTG TAC CCC CTT GAC CGG CTG 1296 Val Thr Val Ser Cys Lys Val Pro Ser Val Tyr Pro Leu Asp Arg Leu 395 400 405 GAG AIT GAA TTA CIT AAG GGG GAG ACT ATT CTG GAG AAT ATA GAG TTT 1344 Glu He Glu Leu Leu Lys Gly Glu Thr He Leu Glu Asn He Glu Hie 410 415 420 TTG GAG GAT ACG GAT ATG AAA TCT CTA GAG AAC AAA ACT TTG GAA ATG 1392 Leu Glu Asp Thr Asp Met Lys Ser Leu Glu Asn Lys Ser Leu Glu Met 425 430 435 440 ACC TTC ATC CCT ACC ATT GAA GAT ACT GGA AAA GCT CTT GTT TCT CAG 1440 Thr Phe He Pro Thr He Glu Asp Thr Gly Lys Ma Leu Val Cys Gin 445 450 455 GCT AAG TTA CAT ATT GAT GAC ATG GAA TTC GAA CCC AAA CAA AGG CAG 1488 Ma Lys Leu His He Asp Asp Met Glu Phe Glu Pro Lys Gin Arg Gin 460 465 470 ACT ACG CAA ACA CTT TAT GTC AAT GTT GCC CCC AGA GAT ACA ACC GTC 1536 Ser Thr Gin Thr Leu Tyr Val Asn Val Ma Pro Arg Asp Thr Thr Val 475 480 485 TTG GTC AGC CCT TCC TCC ATC CTG GAG GAA GGC ACT TCT CTG AAT ATG 1584 Leu Val Ser Pro Ser Ser He Leu Glu Glu Gly Ser Ser Val Asn Met 490 495 500 ACA TGC TTG AGC CAG GGC TTT CCT GCT COG AAA ATC CTG TGG AGC AGG 1632 Thr Cys Leu Ser Gin Gly Hie Pro Ala Pro Lys He Leu Trp Ser Arg 505 510 515 520 CAG CTC CCT AAC GGG GAG CTA CAG CCT CTT TCT GAG AAT GCA ACT CTC 1680 Gin Leu Pro Asn Gly Glu Leu Gin Pro Leu Ser Glu Asn Ma Thr Leu 525 530 535 ACC TTA ATT TCT ACA AAA ATG GAA GAT TCT GGG GTT TAT TTA TCT GAA 1728 Thr Leu lie Ser Thr Lys Met Glu Asp Ser Gly Val Tyr Leu Cys Glu 540 545 550 GGA AIT AAC CAG GCT GGA AGA AGC AGA AAG GAA GTG GAA TTA ATT ATC 1776 Gly He Asn Gin Ala Gly Arg Ser Arg Lys Glu Val Glu Leu He lie 555 560 565 CAA CTT ACT CCA AAA GAC ATA AAA CTT ACA GCT TTT CCT TCT GAG ACT 1824 Gin Val Thr Pro Lys Asp lie Lys Leu Thr Ma Phe Pro Ser Glu Ser 570 575 580 CTC AAA GAA GGA GAC ACT CTC ATC ATC TCT TCT ACA TCT GGA AAT GTT 1872 Val Lys Glu Gly Asp Thr Val lie He Ser Cys Thr Cys Gly Asn Val 585 590 595 600 CCA GAA ACA TGG ATA ATC CTG AAG AAA AAA GOG GAG ACA GGA GAC ACA 1920 Pro Glu Thr Trp lie lie Leu Lys Lys Lys Ma Glu Thr Gly Asp Thr 605 610 615 CTA CTA AAA TCT ATA GAT GGC GCC TAT ACC ATC CGA AAG GOC CAG TIG 1968 Val Leu Lys Ser lie Asp Gly Ma Tyr Thr He Arg Lys Ma Gin Leu 620 625 630 AAG GAT GOG GGA GTA TAT GAA TCT GAA TCT AAA AAC AAA CTT GGC TCA 2016 Lys Asp Ma Gly Val Tyr Glu Cys Glu Ser Lys Asn Lys Val Gly Ser 635 640 645 CAA TTA AGA ACT TEA ACA CTT GAT CTT CAA GGA AGA GAA AAC AAC AAA 2064 Gin leu Arg Ser Leu Thr Leu Asp Val Gin Gly Arg Glu Asn Asn Lys 650 655 660 GAC TAT TTT TCT CCT GAG CIT CTC CTG CTC TAT TTT GCA TCC TCC TTA 2112 Asp Tyr Phe Ser Pro Glu Leu LeuVal Leu Tyr Phe Ma Ser Ser Leu 665 670 675 680 ATA ATA CCT GOC ATT GGA ATG ATAATT TAC TTT GCAAGA AAA GOC AAC 2160 lie lie Pro Ma He Gly Ifet lie He Tyr Phe Ma Arg Lys Ala Asn 685 690 695 ATG AAG GGG TCA TAT ACT CTT GTA GAA GCA CAG AAA TCA AAA GTG 2205 Ifet Lys Gly Ser Tyr Ser Leu Val Glu Ala Gin Lys Ser Lys Val 700 705 710 (2) INFORMATION FOR SEQ ID NO:13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 735 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: Met Pro Gly Lys Met Val Val He Leu Gly Ala Ser Asn He Leu Trp -24 -20 -15 -10 He Met Phe Ma Ma Ser Gin Ma Phe Lys He Glu Thr Thr Pro Glu -5 1 5 Ser Arg Tyr Leu Leu Pro Arg Gly Gly Ser Val Leu Val Thr Cys Ser 10 15 20 Thr Ser Cys Asp Gin Pro Lys Leu Leu Gly He Glu Thr Pro Leu Pro 25 30 35 40 Lys Lys Glu Leu Leu Leu Pro Gly Asn Asn Arg Lys Val Tyr Glu Leu 45 50 55 Ser Asn Val Gin Glu Asp Ser Gin Pro Met Cys Tyr Ser Asn Cys Pro 60 65 70 Asp Gly Gin Ser Thr Ma Lys Thr Phe Leu Thr Val Tyr Trp Thr Pro 75 80 85 Lys Asp Pro Glu He His Leu Ser Gly Pro Leu Glu Ma Gly Lys Pro 90 95 100 He Thr Val Lys Cys Ser Val Ma Asp Val Tyr Pro Phe Asp Arg Leu 105 110 115 120 Glu He Asp Leu Leu Lys Gly Asp His Leu Met Lys Ser Gin Glu Hie 125 130 135 Leu Glu Asp Ma Asp Arg Lys Ser Leu Glu Thr Lys Ser Leu Glu Val 140 145 150 Thr Hie Thr Pro Val He Glu Asp He Gly Lys Val Leu Val Cys Arg 155 160 165 Ma Lys Leu His He Asp Glu Met Asp Ser Val Pro Thr Val Arg Gin 170 175 180 Ma Val Lys Glu Lai Gin Val Tyr lie Ser Pro Lys Asn Thr Val He 185 190 195 200 Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly Ser Val Thr Met 205 210 215 Thr Cys Ser Ser Glu Gly Leu Pro Ma Pro Glu lie Phe Trp Ser Lys 220 225 230 Lys LeuAsp Asn Gly Asn Leu Gin His Leu Ser Gly Asn Ma Thr Lai 235 240 245 Thr Lai He Ala Met Arg Met Glu Asp Ser Gly lie Tyr Val Cys Glu 250 255 260 Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val Glu Leu He Val 265 270 275 280 Gin Glu Lys Pro Phe Thr Val Glu He Ser Pro Gly Pro Arg lie Ala 285 290 295 Ma Gin He Gly Asp Ser Val Met Leu Thr Cys Ser Val Met Gly Cys 300 305 310 Glu Ser Pro Ser Phe Ser Trp Arg Thr Gin He Asp Ser Pro Leu Ser 315 320 325 Gly Lys Val Arg Ser Glu Gly Thr Asn Ser Thr Leu Thr Leu Ser Pro 330 335 340 Val Ser Phe Glu Asn Glu His Ser Tyr Leu Cys Thr Val Thr Cys Gly 345 350 355 360 His Lys Lys Leu Glu Lys Gly lie Gin Val Glu Leu Tyr Ser Hie Pro 365 370 375 Arg Asp Pro Glu He Glu Met Ser Gly Gly Leu Val Asn Gly Ser Ser 380 385 390 Val Thr Val Ser Cys Lys Val Pro Ser Val Tyr Pro Leu Asp Arg Leu 395 400 405 Glu He Glu Leu Leu Lys Gly Glu Thr He Leu Glu Asn lie Glu Phe 410 415 420 Leu Glu Asp Thr Asp Ifet Lys Ser Leu Glu Asn Lys Ser Leu Glu Met 425 430 435 440 Thr Hie lie Pro Thr lie Glu Asp Thr Gly Lys Ma Leu Val Cys Gin 445 450 455 Ma Lys Leu His He Asp Asp Met Glu Phe Glu Pro Lys Gin Arg Gin 460 465 470 Ser Thr Gin Thr Leu Tyr Val Asn Veil Ma Pro Arg Asp Thr Thr Val 475 480 485 Leu Val Ser Pro Ser Ser He Leu Glu Glu Gly Ser Ser Val Asn Met 490 495 500 Thr Cys Leu Ser Gin Gly Phe Pro Ma Pro Lys He Leu Trp Ser Arg 505 510 515 520 Gin Leu Pro Asn Gly Glu Leu Gin Pro Leu Ser Glu Asn Ma Thr Leu 525 530 535 Thr Leu He Ser Thr Lys Met Glu Asp Ser Gly Val Tyr Leu Cys Glu 540 545 550 Gly He Asn Gin Ma Gly Arg Ser Arg Lys Glu Val Glu Leu He He 555 560 565 Gin Val Thr Pro Lys Asp He Lys leu Thr Ala Hie Pro Ser Glu Ser 570 575 580 Val Lys Glu Gly Asp Thr Val He He Ser Cys Thr Cys Gly Asn Val 585 590 595 600 Pro Glu Thr Trp He He Leu Lys Lys Lys Ma Glu Thr Gly Asp Thr 605 610 615 Val Leu Lys Ser He Asp Gly Ma Tyr Thr He Arg Lys Ma Gin Leu 620 625 630 Lys Asp Ma Gly Val Tyr Glu Cys Glu Ser Lys Asn Lys Val Gly Ser 635 640 645 Gin Leu Arg Ser Leu Thr Leu Asp Val Gin Gly Arg Glu Asn Asn Lys 650 655 660 Asp Tyr Phe Ser Pro Glu Leu Leu Val Leu Tyr Phe Ma Ser Ser Leu 665 670 675 680 He He Pro Ma He Gly Met He He Tyr Hie Ma Arg Lys Ma Asn 685 690 695 Met Lys Gly Ser Tyr Ser Leu Val Glu Ma Gin Lys Ser Lys Val 700 705 710 (2) INFORMATION FOR SEQ ID NO: 14: (i) SEQUENCE CHARACTERISTICS: (A) LENCTH: 2208 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 1..2208 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) LOCATION: 73..2208 (ix) FEATURE: (A) NAME/KEY: sig_peptide (B) IOCATIC-N: 1..72 ( i) SEQUENCE DESCRIPTION: SEQ ID NO:14: ATG OCT GGG AAG ATG GTC GTG ATC CTT GGA GCC TCA AAT ATA CTT TGG 48 Ifet Pro Gly Lys Met Val Val He Leu Gly Ma Ser Asn He Leu Trp -24 -20 -15 -10 ATA ATG TTT GCA GCT TCT CAA GCT TTT AAA ATC GAG ACC ACC CCA GAA 96 He Ifet Hie Ala Ma Ser Gin Ma Phe Lys He Glu Thr Thr Pro Glu -5 1 5 TCT AGA TAT CTT CTG CCC CGG GGA GGC TCC CTG CTG GTG ACA TGC AGC 144 Ser Arg Tyr Leu Leu Pro Arg Gly Gly Ser Val Leu Val Thr cys Ser 10 15 20 ACC TCC TCT GAC CAG CCC AAG TTG TTG GGC ATA GAG ACC CCG TTG CCT 192 Thr Ser cys Asp Gin Pro Lys Leu Leu Gly lie Glu Thr Pro Leu Pro 25 30 35 40 AAA AAG GAG TTG CTC CTG OCT GGG AAC AAC CGG AAG CTG TAT GAA CTG 240 Lys Lys Glu Leu Leu Leu Pro Gly Asn Asn Arg Lys Val Tyr Glu Leu 45 50 55 AGC AAT GTG CAA GAA GAT AGC CAA CCA ATG TGC TAT TCA AAC TGC CCT 288 Ser Asn Val Gin Glu Asp Ser Gin Pro Ifet Cys Tyr Ser Asn Cys Pro 60 65 70 GAT GGG CAG TCA ACA GCT AAA ACC TTC CTC ACC CTG TAC TGG ACT CCA 336 Asp Gly Gin Ser Thr Ala Lys Thr Hie Leu Thr Val Tyr Trp Thr Pro 75 80 85 GAA OGG G G GAA CTG GCA CCC CTC CCC TCT TGG CAG CCA CTG GGC AAG 384 Glu Arg Val Glu Leu Ala Pro Leu Pro Ser Trp Gin Pro Val Gly Lys 90 95 100 AAC CTT ACC CEA OGC TGC CAG GTG GAG GCT GGG GCA CCC CGG GCC AAC 432 Asn Leu Thr Leu Arg Cys Gin Val Glu Gly Gly Ma Pro Arg Ma Asn 105 110 115 120 CTC ACC GTG GTG CTG CTC CCT GGG GAG AAG CTC ATG AAG ACT CAG GAA 480 Leu Thr Val Val Lai Leu Arg Gly Glu Lys Lai Met Lys Ser Gin Glu 125 130 135 T T CTG GAG GAT GCA GAC AGG AAG TCC CTG GAA ACC AAG ACT TTG GAA 528 Phe Leu Glu Asp Ala Asp Arg Lys Ser Leu Glu Thr Lys Ser Leu Glu 140 145 150 GTA ACC TTT ACT CCT GTC A T GAG GAT ATT GGA AAA GTT CTT CTT TGC 576 Val Thr Phe Thr Pro Val He Glu Asp He Gly Lys Veil Leu Val Cys 155 160 165 OGA GCT AAA TTA CAC AT GAT GAA ATG GAT TCT CTG CCC ACA CTA AGG 624 Arg Ma Lys Leu His lie Asp Glu Met Asp Ser Val Pro Thr Val Arg 170 175 180 CAG GCT GTA AAA GAA TTG CAA GTC TAC ATA TCA CCC AAG AAT ACA GTT 672 Gin Ala Val Lys Glu Lai Gin Veύ. Tyr He Ser Pro Lys Asn Thr Val 185 190 195 200 ATT TCT GTG AAT CCA TCC ACA AAG CTG CAA GAA GCT GGC TCT GTG ACC 720 lie Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly Ser Val Thr 205 210 215 ATG ACC TGT TCC AGC GAG GCT CTA CCA GCT CCA GAG ATT TTC TGG ACT 768 Met Thr Cys Ser Ser Glu Gly Leu Pro Ala Pro Glu He Phe Trp Ser 220 225 230 AAG AAA TTA GAT AAT GGG AAT CTA CAG CAC CIT TCT GGA AAT GCA ACT 816 Lys Lys Leu Asp Asn Gly Asn Leu Gin His Leu Ser Gly Asn Ma Thr 235 240 245 CT A∞ T AOT GCT ATG AGG ATG G GAT TCT GGA ATT TAT GTG TGT 864 Leu Thr Leu He Ma Met Arg Met Glu Asp Ser Gly He Tyr Val Cys 250 255 260 GAA GGA CTT AAT TTG ATT GGG AAA AAC AGA AAA GAG GTG GAA TTA ATT 912 Glu Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val Glu Leu He 265 270 275 280 CTT CAA GAG AAA CCA TTT ACT CTT GAG ATC TCC CCT GGA CCC CGG ATT 960 Val Gin Glu Lys Pro Phe Thr Val Glu He Ser Pro Gly Pro Arg He 285 290 295 GCT GCT CAG ATT GGA GAC TCA GTC ATG TTG ACA TCT ACT CTC ATG GGC 1008 Ma Ma Gin He Gly Asp Ser Val Ifet Lai Thr Cys Ser Val Ifet Gly 300 305 310 TCT GAA TCC OCA TCT TTC TCC TGG AGA ACC CAG ATA GAC AGC CCT CTG 1056 Cys Glu Ser Pro Ser Phe Ser Trp Arg Thr Gin He Asp Ser Pro Leu 315 320 325 AGC GGG AAG CTG AGG ACT GAG GGG ACC AAT TCC ACG CTG ACC CTG AGC 1104 Ser Gly Lys Val Arg Ser Glu Gly Thr Asn Ser Thr Leu Thr Leu Ser 330 335 340 CCT GTG ACT TTT GAG AAC GAA CAC TCT TAT CTG TGC ACA CTG ACT TCT 1152 Pro Val Ser Phe Glu Asn Glu His Ser Tyr Leu Cys Thr Val Thr Cys 345 350 355 360 GGA CAT AAG AAA CTG GAAAAG GGA ATC CAG GTG GAG CTC TAC TCA TTC 1200 Gly His Lys Lys Leu Glu Lys Gly lie Gin Val Glu Leu Tyr Ser Phe 365 370 375 OCT AGA GAT CCA GAAATC GAG ATG ACT GCT GGC CTC GTG AAT GGG AGC 1248 Pro Arg Asp Pro Glu He Glu Ifet Ser Gly Gly Leu Val Asn Gly Ser 380 385 390 TCT CTC ACT CTA AGC TGC AAG CTT CCT AGC GTG TAC CCC CTI GAC CGG 1296 Ser Val Thr Val Ser cys Lys Val Pro Ser Val Tyr Pro leu Asp Arg 395 400 405 CTG GAG AT GAA TTA CTT AAG GGG GAG ACT ATT CTG GAG AAT ATA GAG 1344 Leu Glu He Glu Leu Leu Lys Gly Glu Thr He Leu Glu Asn He Glu 410 415 420 TTT TTG GAG GAT ACG GAT ATG AAA TCT CTA GAG AAC AAA ACT T G GAA 1392 Hie Leu Glu Asp Thr Asp Met Lys Ser Leu Glu Asn Lys Ser Leu Glu 425 430 435 440 ATG ACC TTC ATC CCT ACC ATT GAA GAT ACT GGA AAA GCT CTT CTT TCT 1440 Ifet Thr Hie He Pro Thr He Glu Asp Thr Gly Lys Ma Leu Val Cys 445 450 455 CAG GCT AAG TTA CAT ATT GAT GAC ATG GAA TTC GAA CCC AAA CAA AGG 1488 Gin Ala Lys Leu His lie Asp Asp Met Glu Hie Glu Pro Lys Gin Arg 460 465 470 CAG ACT AGG CAA ACA CTT TAT CTC AAT GET GCC CCC AGA GAT ACA ACC 1536 Gin Ser Thr Gin Thr Leu Tyr Val Asn Val Ma Pro Arg Asp Thr Thr 475 480 485 GTC T G GTC AGC CCT TCC TCC ATC CTG GAG GAA GGC ACT TCT CTG AAT 1584 Val Leu Val Ser Pro Ser Ser lie Leu Glu Glu Gly Ser Ser Val Asn 490 495 500 ATG ACA TGC TTG AGC CAG GGC TTT CCT GCT COG AAA ATC CTG TGG AGC 1632 Met Thr Cys Leu Ser Gin Gly Hie Pro Ma Pro Lys He Leu Trp Ser 505 510 515 520 AGG CAG CTC CCT AAC GGG GAG CTA CAG CCT CTT TCT GAG AAT GCA ACT 1680 Arg Gin Leu Pro Asn Gly Glu Leu Gin Pro Lai Ser Glu Asn Ma Thr 525 530 535 CTC ACC TTA ATT TCT ACA AAA ATGGAAGATTCTGGGGITTAT TTATCT 1728 Leu Thr Leu He Ser Thr Lys Met Glu Asp Ser Gly Val Tyr Leu Cys 540 545 550 GAA GGA ATT AAC CAG GCT GGA AGA AGC AGA AAG GAA CTG GAA TTA ATT 1776 Glu Gly He Asn Gin Ala Gly Arg Ser Arg Lys Glu Val Glu Leu He 555 560 565 ATC CAA GTT ACT CCA AAA GAC ATA AAA C T ACA GCT TTT OCT TCT GAG 1824 He Gin Val Thr Pro Lys Asp He Lys Leu Thr Ma Phe Pro Ser Glu 570 575 580 ACT GTC AAA GAA GGA GAC ACT CTC ATC ATC TCT TCT ACA TCT GGA AAT 1872 Ser Val Lys Glu Gly Asp Thr Val He He Ser Cys Thr Cys Gly Asn 585 590 595 . 600 CTT OCA GAA ACA TGG ATA ATC CTG AAG AAA AAA GOG GAG ACA GGA GAC 1920 Val Pro Glu Thr Trp He He Leu Lys Lys Lys Ma Glu Thr Gly Asp 605 610 615 ACA GTA C A AAA TCT ATA GAT GGC GCC TAT ACC ATC CGA AAG GOC CAG 1968 Thr Val Leu Lys Ser He Asp Gly Ala Tyr Thr He Arg Lys Ma Gin 620 625 630 TTG AAG GAT GOG GGA GTA TAT GAA TCT GAA TCT AAA AAC AAA GTT GGC 2016 Leu Lys Asp Ma Gly Val Tyr Glu Cys Glu Ser Lys Asn Lys Val Gly 635 640 645 TCA CAA TTA AGA ACT TTA ACA CTT GAT CTT CAA GGA AGA GAA AAC AAC 2064 Ser Gin Leu Arg Ser Leu Thr Leu Asp Val Gin Gly Arg Glu Asn Asn 650 655 660 AAA GAC TAT TTT TCT OCT GAG CIT CTC GTG CTC TAT TTT GCA TCC TCC 2112 Lys Asp Tyr Phe Ser Pro Glu Leu Leu Val Leu Tyr Phe Ma Ser Ser 665 670 675 680 TTA ATA ATA OCT GCC AIT GGA ATG ATA ATT TAC TTT GCA AGA AAA GCC 2160 Leu He He Pro Ma He Gly Met He He Tyr Hie Ma Arg Lys Ma 685 690 695 AAC ATG AAG GGG TCA TAT ACT CTT CTA GAA GCA CAG AAA TCA AAA GTG 2208 Asn Met Lys Gly Ser Tyr Ser Leu Val Glu Ma Gin Lys Ser Lys Val 700 705 710 (2) INFORMATION FOR SEQ ID NO:15: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 736 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ 3D NO:15: Met Pro Gly Lys Met Val Val He Leu Gly Ala Ser Asn He Leu Trp -24 -20 -15 -10 lie Met Hie Ma Ma Ser Gin Ma Hie Lys He Glu Thr Thr Pro Glu -5 1 5 Ser Arg Tyr La Lai Pro Arg Gly Gly Ser Val Leu Val Thr Cys Ser 10 15 20 Thr Ser cys Asp Gin Pro Lys Leu Leu Gly He Glu Thr Pro Leu Pro 25 30 35 40 Lys Lys Glu Leu Leu Leu Pro Gly Asn Asn Arg Lys Val Tyr Glu leu 45 50 55 Ser Asn Val Gin Glu Asp Ser Gin Pro Met Cys Tyr Ser Asn Cys Pro 60 65 70 Asp Gly Gin Ser Thr Ala Lys Thr Hie lieu Thr Val Tyr Trp Thr Pro 75 80 85 Glu Arg Val Glu Leu Ma Pro Leu Pro Ser Trp Gin Pro Val Gly Lys 90 95 100 Asn Leu Thr Leu Arg Cys Gin Val Glu Gly Gly Ma Pro Arg Ma Asn 105 HO 115 120 Leu Thr Val Val Leu Leu Arg Gly Glu Lys Leu Met Lys Ser Gin Glu 125 130 135 Hie Leu Glu Asp Ala Asp Arg Lys Ser Leu Glu Thr Lys Ser Leu Glu 140 145 150 Val Thr Hie Thr Pro Val lie Glu Asp lie Gly Lys Val Leu Val Cys 155 160 165 Arg Ma Lys Lai His He Asp Glu Met Asp Ser Val Pro Thr Val Arg 170 175 180 Gin Ala Val Lys Glu Leu Gin Val Tyr He Ser Pro Lys Asn Thr Val 185 190 195 200 He Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly Ser Val Thr 205 210 215 et Thr Cys Ser Ser Glu Gly Leu Pro Ma Pro Glu He Hie Trp Ser 220 225 230 Lys Lys Leu Asp Asn Gly Asn Leu Gin His Leu Ser Gly Asn Ma Thr 235 240 245 Leu Thr Leu He Ma Met Arg Met Glu Asp Ser Gly He Tyr Val Cys 250 255 260 Glu Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val Glu Leu He 265 270 275 280 Val Gin Glu Lys Pro Phe Thr Val Glu He Ser Pro Gly Pro Arg He 285 290 295 Ma Ma Gin He Gly Asp Ser Val Met Leu Thr Cys Ser Val Met Gly 300 305 310 Cys Glu Ser Pro Ser Phe Ser Trp Arg Thr Gin He Asp Ser Pro Leu 315 320 325 Ser Gly Lys Val Arg Ser Glu Gly Thr Asn Ser Thr Leu Thr Leu Ser 330 335 340 Pro Val Ser Phe Glu Asn Glu His Ser Tyr Leu Cys Thr Val Thr Cys 345 350 355 360 Gly His Lys Lys Leu Glu Lys Gly He Gin Val Glu Leu Tyr Ser Phe 365 370 375 Pro Arg Asp Pro Glu He Glu Met Ser Gly Gly Leu Val Asn Gly Ser 380 385 390 Ser Val Thr Val Ser Cys Lys Val Pro Ser Val Tyr Pro Leu Asp Arg 395 400 405 Leu Glu He Glu Leu Leu Lys Gly Glu Thr He Leu Glu Asn He Glu 410 415 420 Phe Leu Glu Asp Thr Asp Met Lys Ser Leu Glu Asn Lys Ser Leu Glu 425 430 435 440 Met Thr Phe He Pro Thr He Glu Asp Thr Gly Lys Ma Leu Val Cys 445 450 455 Gin Ma Lys Leu His He Asp Asp Met Glu Phe Glu Pro Lys Gin Arg 460 465 470 Gin Ser Thr Gin Thr Leu Tyr Val Asn Val Ma Pro Arg Asp Thr Thr 475 480 485 Val leu Val Ser Pro Ser Ser He Leu Glu Glu Gly Ser Ser Val Asn 490 495 500 Met Thr Cys Lai Ser Gin Gly Hie Pro Ala Pro Lys He Leu Trp Ser 505 510 515 520 Arg Gin Leu Pro Asn Gly Glu Leu Gn Pro Leu Ser Glu Asn Ma Thr 525 530 535 Lai Thr Lai lie Ser Thr Lys Ifet Glu Asp Ser Gly Val Tyr Leu Cys 540 545 550 Glu Gly He Asn Gin Ala Gly Arg Ser Arg Lys Glu Val Glu Leu He 555 560 565 He Gin Val Thr Pro Lys Asp He Lys Leu Thr Ala Phe Pro Ser Glu 570 575 580 Ser Val Lys Glu Gly Asp Thr Val lie lie Ser Cys Thr Cys Gly Asn 585 590 595 600 Val Pro Glu Thr Trp He He Leu Lys Lys Lys Ma Glu Thr Gly Asp 605 610 615 Thr Val Lai Lys Ser He Asp Gly Ma Tyr Thr He Arg Lys Ma Gin 620 625 630 Leu Lys Asp Ma Gly Val Tyr Glu Cys Glu Ser Lys Asn Lys Val Gly 635 640 645 Ser Gin Leu Arg Ser Leu Thr Leu Asp Val Gin Gly Arg Glu Asn Asn 650 655 660 Lys Asp Tyr Phe Ser Pro Glu Leu Leu Val Leu Tyr Hie Ma Ser Ser 665 670 675 680 Leu lie lie Pro Ala He Gly Met lie He Tyr Hie Ma Arg Lys Ala 685 690 695 Asn Ifet Lys Gly Ser Tyr Ser Leu Val Glu Ma Gin Lys Ser Lys Val 700 705 710 (2) INFORMATION FOR SEQ 3D NO:16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2220 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ix) FEATURE: (A) NAME/KEY: CDS (B) IOCAITON: 1..2220 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) LOCATIC^: 73..2220 (ix) FEATURE: (A) NAME/KEY: sig_peptide (B) LOCATION: 1..72 (xi) SEQUENCE DESCRIPTION: SEQ 3D NO: 16: ATG CCT GGG AAG ATG GTC CTG ATC CTT GGA GCC TCA AAT ATA CIT TGG 48 Met Pro Gly Lys Met Val Val He Leu Gly Ma Ser Asn He Leu Trp -24 -20 -15 -10 ATA ATG TIT GCA GCT TCT CAA GCT TTT AAA ATC GAG ACC ACC CCA GAA 96 He Met Hie Ma Ma Ser Gin Ma Hie Lys He Glu Thr Thr Pro Glu -5 1 5 TCT AGA TAT CTT GCT CAG ATT GCT GAC TCC GTC TCA TTG ACT TGC AGC 144 Ser Arg Tyr Leu Ma Gin He Gly Asp Ser Val Ser Leu Thr Cys Ser 10 15 20 ACC ACA GGC TCT GAG TOC < A TTT TTC TCT TGG AGA ACC CAG ATA GAT 192 Thr Thr Gly Cys Glu Ser Pro Hie Hie Ser Trp Arg Thr Gin He Asp 25 30 35 40 ACT CCA CTG AAT GGG AAG GIG ACG AAT GAG GGG ACC ACA TCT ACG CTG 240 Ser Pro Leu Asn Gly Lys Val Thr Asn Glu Gly Thr Thr Ser Thr Leu 45 50 55 ACA ATG AAT CCT CTT ACT TTT GGG AAC GAA CAC TCT TAC CTG TGC ACA 288 Thr Met Asn Pro Val Ser Phe Gly Asn Glu His Ser Tyr Leu cys Thr 60 65 70 GCA ACT TGT GAA TCT AGG AAA TTG GAA AAA GGA ATC CAG GTG GAG ATC 336 Ma Thr Cys Glu Ser Arg Lys Leu Glu Lys Gly He Gin Val Glu lie 75 80 85 TAC TGG ACT CCA GAA CGG CTG GAA CTG GCA CCC CTC CCC TCT TGG CAG 384 Tyr Trp Thr Pro Glu Arg Val Glu Lai Ma Pro leu Pro Ser Trp Gin 90 95 100 OCA GTG GGC AAG AAC CTT ACC CTA OGC TGC CAG GTG GAG GCT GGG GCA 432 Pro Val Gly Lys Asn Leu Thr Leu Arg Cys Gin Val Glu Gly Gly Ma 105 HO 115 120 CCC OGG GCC AAC CTC ACC GTG CTG CTG CTC CCT GGG GAG AAG GAG CTG 480 Pro Arg Ma Asn Lai Thr Val Val Leu Lai Arg Gly Glu Lys Glu lieu 125 130 135 AAA CGG GAG CCA GCT CTG GGG GAG CCC GCT GAG CTC ACG ACC ACG GTG 528 Lys Arg Glu Pro Ala Val Gly Glu Pro Ma Glu Val Thr Thr Thr Val 140 145 150 CTG GTG AGG AGA GAT CAC CAT GGA GCC AAT TTC TOG TGC OGC ACT GAA 576 Leu Val Arg Arg Asp His His Gly Ala Asn Hie Ser Cys Arg Thr Glu 155 160 165 CTG GAC CTG CGG CCC CAA GGG CTG GAG CTG TTT GAG AAC ACC TOG GOC 624 Leu Asp Leu Arg Pro Gin Gly Leu Glu Leu Hie Glu Asn Thr Ser Ala 170 175 180 CCC TAC CAG CTC CAG ACC TTT GTC CTG CCA GOG ACT CCC CCA CAA CTT 672 Pro Tyr Gin Leu Gin Thr Phe Val Leu Pro Ma Thr Pro Pro Gin Leu 185 190 195 200 GTC AGC CCC CGG GTC CTA GAG CTG GAC ACG CAG GGG ACC CTG GTC TCT 720 Val Ser Pro Arg Val Leu Glu Val Asp Thr Gin Gly Thr Val Val Cys 205 210 215 TCC CTG GAC GGG CTG TTC OCA CTC TOG GAG GCC CAG GTC CAC CTG GCA 768 Ser Leu Asp Gly Leu Hie Pro Val Ser Glu Ma Gin Val His Leu Ma 220 225 230 CTG GGG GAC CAG AGG TTG AAC CCC ACA GTC ACC TAT GGC AAC GAC TCC 816 Leu Gly Asp Gin Arg Leu Asn Pro Thr Val Thr Tyr Gly Asn Asp Ser 235 240 245 TTC TOG GCC AAG GCC TCA CTC ACT CTG ACC GCA GAG GAC GAG GGC ACC 864 Phe Ser Ma Lys Ma Ser Val Ser Val Thr Ala Glu Asp Glu Gly Thr 250 255 260 CAG CGG CTG ACG TCT GCA CTA ATA CTG GGG AAC CAG AGC CAG GAG ACA 912 Gin Arg Leu Thr Cys Ala Val He Leu Gly Asn Gin Ser Gin Glu Thr 265 270 275 280 CTG CAGACA CTG ACC ATC TAC AGC TTT COG GOG CCC GAG ATC TCC CCT 960 Lai Gin Thr Val Thr He Tyr Ser Phe Pro Ma Pro Glu He Ser Pro 285 290 295 GGA CCC CGG ATT GCT GCT CAG ATT GGA GAC TCA GTC ATG TTG ACA TGT 1008 Gly Pro Arg He Ma Ma Gin He Gly Asp Ser Val Met Leu Thr Cys 300 305 310 ACT GTC ATG GGC TGT GAA TCC CCA TCT TTC TCC TGG AGA ACC CAG ATA 1056 Ser Val Met Gly Cys Glu Ser Pro Ser Hie Ser Trp Arg Thr Gin He 315 320 325 GACAGC CCT C SAGC GGGAAGGTGAGGACT GAGGGGACCAAT TCCACG 1104 Asp Ser Pro Leu Ser Gly Lys Val Arg Ser Glu Gly Thr Asn Ser Thr 330 335 340 CTG ACC CTG AGC CCT GTG ACT TTT GAG AAC GAA CAC TCT TAT CTG TGC 1152 Leu Thr Leu Ser Pro Val Ser Phe Glu Asn Glu His Ser Tyr Leu Cys 345 350 355 360 ACA GTG ACT TGT GGA CAT AAG AAA CTG GAA AAG GGA ATC CAG CTG GAG 1200 Thr Val Thr Cys Gly His Lys Lys Leu Glu Lys Gly He Gin Val Glu 365 370 375 CTC TAC TCA TTC CCT AGA GAT CCA GAA ATC GAG ATG ACT GCT GGC CTC 1248 Leu Tyr Ser Hie Pro Arg Asp Pro Glu He Glu Met Ser Gly Gly Leu 380 385 390 GIG AAT GGG AGC TCT GTC ACT CTA AGC TGC AAG GTT CCT AGC GTG TAC 1296 Val Asn Gly Ser Ser Val Thr Val Ser Cys Lys Val Pro Ser Val Tyr 395 400 405 CCC CTT GAC CGG CTG GAG ATT GAA TTA CTT AAG GGG GAG ACT A T CTG 1344 Pro Leu Asp Arg Leu Glu He Glu Leu Leu Lys Gly Glu Thr He Leu 410 415 420 GAG AAT ATA GAG TTT TTG GAG GAT AOG GAT ATG AAA TCT CTA GAG AAC 1392 Glu Asn He Glu Phe Leu Glu Asp Thr Asp Met Lys Ser Leu Glu Asn 425 430 435 440 AAA ACT TTG GAA ATG ACC TTC ATC CCT ACC ATT GAA GAT ACT GGA AAA 1440 Lys Ser Leu Glu Met Thr Phe He Pro Thr He Glu Asp Thr Gly Lys 445 450 455 GCT CTT CTT TCT CAG GCT AAG TTA CAT ATT GAT GAC ATG GAA TTC GAA 1488 Ma Leu Val Cys Gin Ma Lys Leu His He Asp Asp Met Glu Phe Glu 460 465 470 CCC AAA CAA AGG CAG ACT ACG CAA ACA CTT TAT CTC AAT GTT GOC CCC 1536 Pro Lys Gin Arg Gin Ser Thr Gin Thr Leu Tyr Val Asn Val Ma Pro 475 480 485 AGA GAT ACA ACC GTC TTG GTC AGC CCT TCC TCC ATC CTG GAG GAA GGC 1584 Arg Asp Thr Thr Val leu Val Ser Pro Ser Ser He Leu Glu Glu Gly 490 495 500 ACT TCT CTG AAT ATG ACA TGC TTG AGC CAG GGC TTT CCT GCT CGG AAA 1632 Ser Ser Val Asn Met Thr cys leu Ser Gin Gly Hie Pro Ala Pro Lys 505 510 515 520 ATC CTG TGG AGC AGG CAG CTC CCT AAC GGG GAG CTA CAG CCT CTT TCT 1680 lie Lai Trp Ser Arg Gin Leu Pro Asn Gly Glu Leu Gin Pro Leu Ser 525 530 535 GAGAAT GCAACT CTC ACC TTAATT TCT ACAAAA ATG GAA GAT TCT GGG 1728 Glu Asn Ala Thr Leu Thr .Leu lie Ser Thr Lys Ifet Glu Asp Ser Gly 540 545 550 GTT TAT TTA TCT GAA GGAATT AAC CAG GCT GGA AGA AGC AGA AAG GAA 1776 Val Tyr Leu cys Glu Gly He Asn Gin Ma Gly Arg Ser Arg Lys Glu 555 560 565 CTG GAA TTAATT ATC CAA GTE ACT OCA AAA GAC ATA AAA CTT ACA GCT 1824 Val Glu leu He He Gin Val Thr Pro Lys Asp He Lys Leu Thr Ma 570 575 580 TTT CCT TCT GAG ACT GTC AAA GAA GGA GAC ACT CTC ATC ATC TCT TGT 1872 Phe Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val He lie Ser Cys 585 590 595 600 ACA TCT GGAAAT GTT CCA GAAACA TGG ATA ATC CTG AAG AAA AAA GCG 1920 Thr Cys Gly Asn Val Pro Glu Thr Trp lie lie Leu Lys Lys Lys Ma 605 610 615 GAG ACA GGA GAC ACA GTA CEA AAA TCT ATA GAT GGC GCC TAT ACC ATC 1968 Glu Thr Gly Asp Thr Val Leu Lys Ser lie Asp Gly Ma Tyr Thr He 620 625 630 CGAAAG GCC CAG TTG AAG GAT GOG GGA CTA TAT GAA TCT GAA TCT AAA 2016 Arg Lys Ma Gin Leu Lys Asp Ma Gly Val Tyr Glu Cys Glu Ser Lys 635 640 645 AAC AAA CTT GGC TCA CAA TTA AGA ACT TTA ACA CTT GAT GTT CAA GGA 2064 Asn Lys Val Gly Ser Gin Leu Arg Ser leu Thr Leu Asp Val Gin Gly 650 655 660 AGA GAA AAC AAC AAA GAC TAT TTT TCT CCT GAG CTT CTC CTG CTC TAT 2112 Arg Glu Asn Asn Lys Asp Tyr Hie Ser Pro Glu leu Leu Val leu Tyr 665 670 675 680 TTT GCA TCC TCC TTA ATA ATA OCT GCC ATT GGA ATG ATA ATT TAC T T 2160 Phe Ala Ser Ser Leu He He Pro Ma lie Gly Ifet lie He Tyr Hie 685 690 695 GCAAGA AAA GCC AAC ATG AAG GGG TCA TAT ACT CTT CTA GAA GCA CAG 2208 Ala Arg Lys Ma Asn Ifet Lys Gly Ser Tyr Ser Leu Val Glu Ma Gin 700 705 710 AAA TCA AAA GTG 2220 Lys Ser Lys Val 715 (2) INFORMATION FOR SEQ 3D NO:17: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 740 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ 3D NO:17: Met Pro Gly Lys Met Val Val He Leu Gly Ma Ser Asn He lieu Trp -24 -20 -15 -10 He Met Hie Ma Ma Ser Gin Ma Phe Lys He Glu Thr Thr Pro Glu -5 1 5 Ser Arg Tyr Leu Ma Gin He Gly Asp Ser Val Ser Leu Thr Cys Ser 10 15 20 Thr Thr Gly Cys Glu Ser Pro Phe Hie Ser Tip Arg Thr Gin He Asp 25 30 35 40 Ser Pro Leu Asn Gly Lys Val Thr Asn Glu Gly Thr Thr Ser Thr Leu 45 50 55 Thr Met Asn Pro Val Ser Phe Gly Asn Glu His Ser Tyr Leu cys Thr 60 65 70 Ma Thr Cys Glu Ser Arg Lys Leu Glu Lys Gly He Gin Val Glu He 75 80 85 Tyr Trp Thr Pro Glu Arg Val Glu Leu Ma Pro Leu Pro Ser Trp Gin 90 95 100 Pro Val Gly Lys Asn Leu Thr Leu Arg Cys Gin Val Glu Gly Gly Ma 105 110 115 120 Pro Arg Ma Asn Leu Thr Val Val Leu Leu Arg Gly Glu Lys Glu Leu 125 130 135 Lys Arg Glu Pro Ma Val Gly Glu Pro Ma Glu Val Thr Thr Thr Val 140 145 150 Leu Val Arg Arg Asp His His Gly Ma Asn Ihe Ser Cys Arg Thr Glu 155 160 165 leu Asp Lai Arg Pro Gin Gly Lai Glu La Hie Glu Asn Thr Ser Ma 170 175 180 Pro Tyr Gin Leu Gin Thr Hie Val leu Pro Ma Thr Pro Pro Gin Leu 185 190 195 200 Val Ser Pro Arg Val Lai Glu Val Asp Thr Gin Gly Thr Val Val Cys 205 210 215 Ser Leu Asp Gly Jjeu Phe Pro Val Ser Glu Ala Gin Val His Leu Ma 220 225 230 lieu Gly Asp Gin Arg leu Asn Pro Thr Val Thr Tyr Gly Asn Asp Ser 235 240 245 Phe Ser Ma Lys Ma Ser Val Ser Val Thr Ma Glu Asp Glu Gly Thr 250 255 260 Gin Arg Leu Thr Cys Ala Val He Leu Gly Asn Gin Ser Gin Glu Thr 265 270 275 280 Leu Gin Thr Val Thr lie αyr Ser Hie Pro Ala Pro Glu He Ser Pro 285 290 295 Gly Pro Arg lie Ma Ma Gin lie Gly Asp Ser Val Met Leu Thr Cys 300 305 310 Ser Val Ifet Gly Cys Glu Ser Pro Ser Phe Ser Trp Arg Thr Gin lie 315 320 325 Asp Ser Pro leu Ser Gly Lys Val Arg Ser Glu Gly Thr Asn Ser Thr 330 335 340 leu Thr Leu Ser Pro Val Ser Phe Glu Asn Glu His Ser Tyr Leu Cys 345 350 355 360 Thr Val Thr Cys Gly His Lys Lys Leu Glu Lys Gly He Gin Val Glu 365 370 375 Leu Tyr Ser Hie Pro Arg Asp Pro Glu lie Glu Ifet Ser Gly Gly Leu 380 385 390 Val Asn Gly Ser Ser Val Thr Val Ser Cys Lys Val Pro Ser Val Tyr 395 400 405 Pro I-eu Asp Arg Leu Glu He Glu Leu Leu Lys Gly Glu Thr He Leu 410 415 420 Glu Asn lie Glu Phe Leu Glu Asp Thr Asp Met Lys Ser Leu Glu Asn 425 430 435 440 Lys Ser Leu Glu Met Thr Hie He Pro Thr He Glu Asp Thr Gly Lys 445 450 455 Ma Leu Val cys Gin Ma Lys Leu His He Asp Asp Met Glu Hie Glu 460 465 470 Pro Lys Gin Arg Gin Ser Thr Gin Thr lieu Tyr Val Asn Val Ma Pro 475 480 485 Arg Asp Thr Thr Val Leu Val Ser Pro Ser Ser He Leu Glu Glu Gly 490 495 500 Ser Ser Val Asn Met Thr Cys .Lai Ser Gin Gly Hie Pro Ma Pro Lys 505 510 515 520 He Leu Trp Ser Arg Gin Leu Pro Asn Gly Glu leu Gin Pro Leu Ser 525 530 535 Glu Asn Ma Thr Leu Thr Leu He Ser Thr Lys Met Glu Asp Ser Gly 540 545 550 Val Tyr lieu Cys Glu Gly He Asn Gin Ma Gly Arg Ser Arg Lys Glu 555 560 565 Val Glu Leu He He Gin Val Thr Pro Lys Asp He Lys Leu Thr Ma 570 575 580 Hie Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val He He Ser Cys 585 590 595 600 Thr Cys Gly Asn Val Pro Glu Thr Trp He He leu Lys Lys Lys Ma 605 610 615 Glu Thr Gly Asp Thr Val Leu Lys Ser He Asp Gly Ma Tyr Thr He 620 625 630 Arg Lys Ma Gin Leu Lys Asp Ma Gly Val Tyr Glu Cys Glu Ser Lys 635 640 645 Asn Lys Val Gly Ser Gin Leu Arg Ser Leu Thr Leu Asp Val Gin Gly 650 655 660 Arg Glu Asn Asn Lys Asp Tyr Hie Ser Pro Glu leu Leu Val Leu Tyr 665 670 675 680 Hie Ma Ser Ser Leu He He Pro Ma He Gly Met He He Tyr Hie 685 690 695 Ma Arg Lys Ma Asn Met Lys Gly Ser Tyr Ser .Leu Val Glu Ma Gin 700 705 710 Lys Ser Lys Val 715 (2) INFORMATION FOR SEQ 3D NO:18: (i) SEQUENCE CHARACTERISTICS: (A) LENCTH: 1929 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ix) FEATURE: (A) NAME/KEY: CDS (B) IOCATICN: 1. .1929 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) .LOCATION: 73. .1929 (ix) FEATURE: (A) NAME/KEY: sig_peptide (B) LOCATION: 1. .72 (Xi) SEQUENCE DESCRIPTION: SEQ 3D NO:18: ATG CCT GGG AAG ATG GTC CTG ATC CTT GGA GCC TCA AAT ATA CTT TGG 48 Met Pro Gly Lys Ifet Val Val He Leu Gly Ma Ser Asn He Leu Trp -24 -20 -15 -10 ATA ATG TTT GCA GCT TCT CAA GCT TTT AAA ATC GAG ACC ACC CCA GAA 96 lie Ifet Hie Ma Ma Ser Gin Ma Hie Lys He Glu Thr Thr Pro Glu -5 1 5 TCT AGA TAT CTE CTG CCC CGG GGA GGC TCC CTG CTG CTG ACA TGC AGC 144 Ser Arg Tyr Leu Leu Pro Arg Gly Gly Ser Val Leu Val Thr cys Ser 10 15 20 ACC TCC TCT GAC CAG CCC AAG TTG TTG GGC ATA GAG ACC COG TTG CCT 192 Thr Ser Cys Asp Gin Pro Lys Leu Leu Gly lie Glu Thr Pro leu Pro 25 30 35 40 AAA AAG GAG TTG CTC CTG CCT GGG AAC AAC OGG AAG GTG TAT GAA CTG 240 Lys Lys Glu Leu Leu Leu Pro Gly Asn Asn Arg Lys Val Tyr Glu Leu 45 50 55 AGC AAT CTG CAA GAA GAT AGC CAA CCA ATG TGC TAT TCA AAC TGC CCT 288 Ser Asn Val Gin Glu Asp Ser Gin Pro Ifet Cys Tyr Ser Asn Cys Pro 60 65 70 GAT GGG CAG TCA ACA GCT AAA ACC TTC CTC ACC GTG TAC TGG ACT CCT 336 Asp Gly Gin Ser Thr Ala Lys Thr Phe leu Thr Val Tyr Trp Thr Pro 75 80 85 AAG GAT OCA GAG ATT CAT TTG ACT GGC OCT CTG GAG GCT GGG AAG COG 384 Lys Asp Pro Glu He His Leu Ser Gly Pro Leu Glu Ma Gly Lys Pro 90 95 100 ATC ACA GTC AAG TGT TCA CTT GCT GAT GTA TAC CCA TTT GAC AGG CTG 432 He Thr Val Lys Cys Ser Val Ma Asp Val Tyr Pro Phe Asp Arg Leu 105 110 H5 120 GAG ATA GAC TTA CTG AAA GGA GAT CAT CTC ATC AAG ACT CAG GAA TTT 480 Glu He Asp Lai Leu Lys Gly Asp His Leu Met Lys Ser Gin Glu Hie 125 130 135 CTG GAG GAT GCA GAC AGG AAG TCC CTG GAA ACC AAG ACT TTG GAA GTA 528 Leu Glu Asp Ma Asp Arg Lys Ser Leu Glu Thr Lys Ser Leu Glu Val 140 145 150 ACC TIT ACT CCT GTC AIT GAG GAT ATT GGA AAA GTT C T GTT TGC GGA 576 Thr Phe Thr Pro Val He Glu Asp He Gly Lys Val Leu Val Cys Arg 155 160 165 GCT AAA TTA CAC ATT GAT GAA ATG GAT TCT GTG CCC ACA GTA AGG CAG 624 Ma Lys Leu His He Asp Glu Met Asp Ser Val Pro Thr Val Arg Gin 170 175 180 GCT CTA AAA GAA TTG CAA GTC TAC ATA TCA CCC AAG AAT ACA GTT ATT 672 Ma Val Lys Glu .Leu Gin Val Tyr He Ser Pro Lys Asn Thr Val He 185 190 195 200 TCT GTG AAT CCA TCC ACA AAG CTG CAA GAA GCT GGC TCT CTG ACC ATG 720 Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly Ser Val Thr Met 205 210 215 ACC TGT TCC AGC GAG GCT CTA CCA GCT OCA GAG ATT TTC TGG ACT AAG 768 Thr Cys Ser Ser Glu Gly Leu Pro Ma Pro Glu He Phe Trp Ser Lys 220 225 230 AAA T GM AAT GGG AAT CTA CS^ CAC CTT TCT GGA AAT GCA ACT CTC 816 Lys Leu Asp Asn Gly Asn Leu Gin His Lai Ser Gly Asn Ma Thr Leu 235 240 245 ACC TTA ATT GCT ATG AGG ATG GAA GAT TCT GGA ATT TAT GTG TCT GAA 864 Thr Leu He Ma Met Arg Met Glu Asp Ser Gly He Tyr Val Cys Glu 250 255 260 GGA CTT AAT TTG ATT GGG AAA AAC AGA AAA GAG GTG GAA TEA AIT GTT 912 Gly Val Asn lieu lie Gly Lys Asn Arg Lys Glu Val Glu Lai He Val 265 270 275 280 CAA GCA TTC CCT AGA GAT OCA GAA ATC GAG ATG ACT GCT GGC CTC GTG 960 Gin Ma Hie Pro Arg Asp Pro Glu lie Glu Met Ser Gly Gly .Leu Val 285 290 295 AAT GGG AGC TCT CTC ACT CTA AGC TGC AAG CTT CCT AGC GTG TAC CCC 1008 Asn Gly Ser Ser Val Thr Val Ser Cys Lys Val Pro Ser Val Tyr Pro 300 305 310 CT GAC CGG CTG GAG ATT GAA TTA C3T AAG GGG GAG ACT ATT CTG GAG 1056 Leu Asp Arg Leu Glu He Glu Leu L u Lys Gly Glu Thr He Leu Glu 315 320 325 AAT ATA GAG TTT TTG GAG GAT ACG GAT ATG AAA TCT CTA GAG AAC AAA H04 Asn lie Glu Hie leu Glu Asp Thr Asp Met Lys Ser leu Glu Asn Lys 330 335 340 ACT TTG GAA ATG ACC TTC ATC CCT ACC ATT GAA GAT ACT GGA AAA GCT 1152 Ser leu Glu Met Thr Phe He Pro Thr He Glu Asp Thr Gly Lys Ma 345 350 355 360 CTT CTT TCT CAG GCT AAG TTA CAT ATT GAT GAC ATG GAA TTC GAA CCC 1200 leu Val cys Gin Ma Lys Lai His lie Asp Asp Met Glu Hie Glu Pro 365 370 375 AAA CAA AGG CAG ACT ACG CAA ACA CIT TAT GTC AAT CTT GCC CCC AGA 1248 Lys Gin Arg Gin Ser Thr Gin Thr Leu Tyr Val Asn Val Ma Pro Arg 380 385 390 GAT ACA ACC GTC TIG GTC AGC OCT TCC TCC ATC CTG GAG GAA GGC ACT 1296 Asp Thr Thr Val leu Val Ser Pro Ser Ser He leu Glu Glu Gly Ser 395 400 * 405 TCT CTG AAT ATG ACA TGC TTG AGC CAG GGC TTT CCT GCT COG AAA ATC 1344 Ser Val Asn Met Thr Cys Leu Ser Gin Gly Hie Pro Ma Pro Lys lie 410 415 420 CTG TGG AGC AGG CAG CTC CCT AAC GGG GAG CTA CAG CCT CTT TCT GAG 1392 Leu Trp Ser Arg Gin Leu Pro Asn Gly Glu leu Gin Pro Leu Ser Glu 425 430 435 440 AAT GCA ACT CTC ACC TTA ATT TCT ACA AAA.ATG GAA GAT TCT GGG CTT 1440 Asn Ma Thr leu Thr leu He Ser Thr Lys Ifet Glu Asp Ser Gly Val 445 450 455 TAT TTA TGT GAA GGA ATT AAC CAG GCT GGA AGA AGC AGA AAG GAA GTG 1488 Tyr leu cys Glu Gly lie Asn Gin Ma Gly Arg Ser Arg Lys Glu Val 460 465 470 GAA TTA ATT ATC CAA CTT ACT CCA AAA GAC ATA AAA CTT ACA GCT TTT 1536 Glu le He He Gin Val Thr Pro Lys Asp He Lys Leu Thr Ma Hie 475 480 485 CCT TCT GAG ACT GTC AAA GAA GGA GAC ACT GTC ATC ATC TCT TCT ACA 1584 Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val He He Ser Cys Thr 490 495 500 TGT GGA AAT GTT CCA GAA ACA TGG ATA ATC CTG AAG AAA AAA GOG GAG 1632 Cys Gly Asn Val Pro Glu Thr Trp He He Leu Lys Lys Lys Ma Glu 505 510 515 520 ACA GGA GAC ACA GTA CTA AAA TCT ATA GAT GGC GCC TAT ACC ATC GGA 1680 Thr Gly Asp Thr Val Leu Lys Ser He Asp Gly Ma Tyr Thr He Arg 525 530 535 AAG GCC CAG TTG AAG GAT GOG GGA GTA TAT GAA TCT GAA TCT AAA AAC 1728 Lys Ma Gin Leu Lys Asp Ma Gly Val Tyr Glu Cys Glu Ser Lys Asn 540 545 550 AAA GTT GGC TCA CAA TTA AGA ACT TTA ACA CTT GAT CTT CAA GGA AGA 1776 Lys Val Gly Ser Gin Leu Arg Ser Leu Thr Leu Asp Val Gin Gly Arg 555 560 565 GAA AAC AAC AAA GACTATTTTTCT CCT G^ CTT CTC GTG CTC TAT T^ 1824 Glu Asn Asn Lys Asp Tyr Phe Ser Pro Glu Leu Leu Val Leu Tyr Hie 570 575 580 GCA TCC TCC TTA ATA ATA CCT GOC ATT GGA ATG ATA ATT TAC TTT GCA 1872 Ma Ser Ser Leu He He Pro Ma He Gly Met He He Tyr Hie Ma 585 590 595 600 AGA AAA GCC AAC ATG AAG GGG TCA TAT ACT CTT CTA GAA GCA CAG AAA 1920 Arg Lys Ma Asn Met Lys Gly Ser Tyr Ser Leu Val Glu Ma Gin Lys 605 610 615 TCA AAA GTG 1929 Ser Lys Val (2) INFORMATiαi FOR SEQ 3D NO:19: (i) SEQUENCE CHARACTERISTICS: (A) LENCTH: 643 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ 3D NO:19: Met Pro Gly Lys Met Val Val He Leu Gly Ma Ser Asn He Leu Trp -24 -20 -15 -10 He Met Hie Ala Ala Ser Gin Ma Phe Lys He Glu Thr Thr Pro Glu -5 1 5 Ser Arg Tyr leu Leu Pro Arg Gly Gly Ser Val lieu Val Thr cys Ser 10 15 20 Thr Ser cys Asp Gin Pro Lys Lai Lai Gly He Glu Thr Pro Leu Pro 25 30 35 40 Lys Lys Glu Lsu Leu Leu Pro Gly Asn Asn Arg Lys Val Tyr Glu Leu 45 50 55 Ser Asn Val Gin Glu Asp Ser Gin Pro Met Cys Tyr Ser Asn Cys Pro 60 65 70 Asp Gly Gin Ser Thr Ma Lys Thr Phe Leu Thr Val Tyr Trp Thr Pro 75 80 85 Lys Asp Pro Glu He His Leu Ser Gly Pro Leu Glu Ma Gly Lys Pro 90 95 100 He Thr Val Lys Cys Ser Val Ma Asp Val Tyr Pro Phe Asp Arg leu 105 HO 115 120 Glu He Asp Leu Lu Lys Gly Asp His Lai Met Lys Ser Gin Glu Hie 125 130 135 leu Glu Asp Ala Asp Arg Lys Ser Lai Glu Thr Lys Ser Leu Glu Val 140 145 150 Thr Phe Thr Pro Val lie G1U Asp He Gly Lys Val Leu Val Cys Arg 155 160 165 Ala Lys Leu His He Asp Glu Met Asp Ser Val Pro Thr Val Arg Gin 170 175 180 Ma Val Lys Glu Leu Gin Val Tyr He Ser Pro Lys Asn Thr Val He 185 190 195 200 Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly Ser Val Thr Met 205 210 215 Thr Cys Ser Ser Glu Gly .Leu Pro Ma Pro Glu He Phe Trp Ser Lys 220 225 230 Lys leu Asp Asn Gly Asn Leu Gin His Leu Ser Gly Asn Ma Thr Leu 235 240 245 Thr Leu He Ma Met Arg et Glu Asp Ser Gly He Tyr Val Cys Glu 250 255 260 Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val Glu leu He Val 265 270 275 280 Gin Ma Phe Pro Arg Asp Pro Glu He Glu Met Ser Gly Gly Leu Val 285 290 295 Asn Gly Ser Ser Val Thr Val Ser Cys Lys Val Pro Ser Val Tyr Pro 300 305 310 Leu Asp Arg lieu Glu He Glu lieu Leu Lys Gly Glu Thr He Leu Glu 315 320 325 Asn lie Glu Hie leu Glu Asp Thr Asp Met Lys Ser leu Glu Asn Lys 330 335 340 Ser Leu Glu Met Thr Hie He Pro Thr He Glu Asp Thr Gly Lys Ma 345 350 355 360 Leu Val Cys Gin Ma Lys Leu His He Asp Asp Met Glu Phe Glu Pro 365 370 375 Lys Gin Arg Gin Ser Thr Gin Thr Leu Tyr Val Asn Val Ma Pro Arg 380 385 390 Asp Thr Thr Val Leu Val Ser Pro Ser Ser He leu Glu Glu Gly Ser 395 400 405 Ser Val Asn Met Thr Cys Leu Ser Gin Gly Hie Pro Ma Pro Lys He 410 415 420 Leu Trp Ser Arg Gin leu Pro Asn Gly Glu Leu Gin Pro Leu Ser Glu 425 430 435 " 440 Asn Ma Thr Leu Thr leu He Ser Thr Lys Met Glu Asp Ser Gly Val 445 450 455 Tyr Leu Cys Glu Gly He Asn Gin Ma Gly Arg Ser Arg Lys Glu Val 460 465 470 Glu Leu He He Gin Val Thr Pro Lys Asp He Lys Leu Thr Ma Hie 475 480 485 Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val He He Ser Cys Thr 490 495 500 Cys Gly Asn Val Pro Glu Thr Trp He He Leu Lys Lys Lys Ma Glu 505 510 515 520 Thr Gly Asp Thr Val .Leu Lys Ser He Asp Gly Ma Tyr Thr He Arg 525 530 535 Lys Ala Gin Lai Lys Asp Ala Gly Val Tyr Glu Cys Glu Ser Lys Asn 540 545 550 Lys Val Gly Ser Gin Leu Arg Ser Leu Thr Lai Asp Val Gin Gly Arg 560 565 Glu Asn Asn Lys Asp Tyr Phe Ser Pro Glu Leu Leu Val leu Tyr Hie 570 575 580 Ma Ser Ser Leu He He Pro Ma He Gly Met He He Tyr Phe Ma 585 590 595 600 Arg Lys Ala Asn Met Lys Gly Ser Tyr Ser Lai Val Glu Ma Gin Lys 605 610 615 Ser Lys Val (2) INFDKdATION FOR SEQ 3D N0:20: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1932 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ix) FEATURE: (A) NAME/KEY: CDS (B) IOCATION: 1. .1932 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) lOCATION: 73. .1932 (ix) FEATURE: (A) NAME/KEY: sig_peptide (B) IJOCATICN: 1. .72 (xi) SEQUENCE DESCRIPTION: SEQ 3D NO: 20: ATG CCT GGG AAG ATG CTC CTG ATC CIT GGA GOC TCA AAT ATA CTT TGG 48 Met Pro Gly Lys Ifet Val Val He leu Gly Ma Ser Asn He Leu Trp -24 -20 -15 -10 ATA ATG TTT GCA GCT TCT CAA GCT TTT AAA ATC GAG ACC ACC CCA GAA 96 He Met Phe Ala Ma Ser Gin Ma Phe Lys lie Glu Thr Thr Pro Glu -5 1 5 TCT AGA TAT CIT CTG CCC CGG GGA GGC TCC CTG CTG GIG ACA TGC AGC 144 Ser Arg Tyr Leu Leu Pro Arg Gly Gly Ser Val Leu Val Thr Cys Ser 10 15 20 ACC TCC TCT GAC CAG CCC AAG TTG TTG GGC ATA GAG ACC COG TTG CCT 192 Thr Ser Cys Asp Gin Pro Lys Leu Leu Gly He Glu Thr Pro Leu Pro 25 30 35 40 AAA AAG GAG TTG CTC CTG OCT GGG AAC AAC OGG AAG GTG TAT GAA CTG 240 Lys Lys Glu Leu Lai .Lai Pro Gly Asn Asn Arg Lys Val Tyr Glu leu 45 50 55 AGC AAT CTG CAA GAA GAT AGC CAA CCA ATG TGC TAT TCA AAC TGC CCT 288 Ser Asn Val Gin Glu Asp Ser Gin Pro Met Cys Tyr Ser Asn Cys Pro 60 65 70 GAT GGG CAG TCA ACA GCT AAA ACC TTC CTC ACC GTG TAC TGG ACT CCA 336 Asp Gly Gin Ser Thr Ma Lys Thr Phe Leu Thr Val Tyr Trp Thr Pro 75 80 85 GAA CGG GTG GAA CTG GCA CCC CTC CCC TCT TGG CAG OCA GTG GGC AAG 384 Glu Arg Val Glu Lai Ma Pro Leu Pro Ser Trp Gin Pro Val Gly Lys 90 95 100 AAC CTΓ AOC CTA CGC TGC CAG GTC GAG GCT GGG GCΆ OCC CGG GCC AAC 432 Asn Leu Thr Leu Arg cys Gin Val Glu Gly Gly Ma Pro Arg Ma Asn 105 110 115 120 CTC ACC GTG GTG CTG CTC OCT GGG GAG AAG CTC ATG AAG ACT CAG GAA 480 Leu Thr Val Val Leu Leu Arg Gly Glu Lys Leu Met Lys Ser Gin Glu 125 130 135 TTT CTG GAG GAT GCA GAC AGG AAG TCC CTG GAA ACC AAG ACT TTG GAA 528 Phe Leu Glu Asp Ma Asp Arg Lys Ser Leu Glu Thr Lys Ser Leu Glu 140 145 150 CTA ACC TTT ACT OCT GTC ATT GAG GAT ATT GGA AAA GTT CTT CTT TGC 576 Val Thr Phe Thr Pro Val He Glu Asp He Gly Lys Val Leu Val Cys 155 160 165 CGA GCT AAA TTA CAC ATT GAT GAA ATG GAT TCT CTG CCC ACA GTA AGG 624 Arg Ma Lys Leu His He Asp Glu Met Asp Ser Val Pro Thr Val Arg 170 175 180 CAG GCT GTA AAA GAA TTG CAA GTC TAC ATA TCA CCC AAG AAT ACA CTT 672 Gin Ma Val Lys Glu leu Gin Val Tyr He Ser Pro Lys Asn Thr Val 185 190 195 200 AIT TCT GTG AAT OCA TCC ACA AAG CTG CAA GAA GCT GGC TCT GTG ACC 720 He Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly Ser Val Thr 205 210 215 ATG ACC TCT TCC AGC GAG GCT CTA CCA GCT CCA GAG ATT TTC TGG ACT 768 Met Thr Cys Ser Ser Glu Gly .Leu Pro Ma Pro Glu He Phe Trp Ser 220 225 230 AAG AAA TTA GAT AAT GGG AAT CTA CAG CAC CTT TCT GGA AAT GCAACT 816 Lys Lys Leu Asp Asn Gly Asn Leu Gin His leu Ser Gly Asn Ala Thr 235 240 245 CTC ACC TTA ATT GCT ATG AGG ATG GAA GAT TCT GGA ATT TAT CTG TCT 864 Leu Thr leu lie Ala Met Arg Met Glu Asp Ser Gly He Tyr Val Cys 250 255 260 GAA GGA CTT AAT T G AIT GGG AAA AAC AGAAAA GAG GTG GAA TTAATT 912 Glu Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val Glu Leu He 265 . 270 275 280 CTT CAA GCA TTC CCT AGA GAT CCA GAA ATC GAG ATG ACT GCT GGC CTC 960 Val Gin Ala Hie Pro Arg Asp Pro Glu lie Glu Met Ser Gly Gly Leu 285 290 295 GTG AAT GGG AGC TCT GTC ACT CTA AGC TGC AAG CTT CCT AGC GTG TAC 1008 Val Asn Gly Ser Ser Val Thr Val Ser cys Lys Val Pro Ser Val Tyr 300 305 310 CCC CTT GAC CGG CTG GAG ATT GAA TTA CIT AAG GGG GAG ACT ATT CTG 1056 Pro Leu Asp Arg Leu Glu He Glu Leu Leu Lys Gly Glu Thr lie Leu 315 320 325 GAG AAT ATA GAG TTT TEG GAG GAT ACG GAT ATG AAA TCT CTA GAG AAC 1104 Glu Asn lie Glu Phe leu Glu Asp Thr Asp et Lys Ser Lai Glu Asn 330 335 340 AAAACT TTG GAAATG ACC TTC ATC CCT ACC ATT GAA GAT ACT GGA AAA 1152 Lys Ser Leu Glu Met Thr Phe He Pro Thr He Glu Asp Thr Gly Lys 345 350 355 360 GCT CTT GTT TGT CAG GCT AAG TEA CAT AIT GAT GAC ATG GAA TTC GAA 1200 Ma Leu Val Cys Gin Ala Lys Leu His lie Asp Asp Met Glu Hie Glu 365 370 375 CCC AAA CAA AGG CAG ACT ACG CAA ACA CIT TAT CTC AAT GET GCC CCC 1248 Pro Lys Gin Arg Gin Ser Thr Gin Thr Leu Tyr Val Asn Val Ala Pro 380 385 390 AGA GAT ACA ACC GTC TTG GTC AGC CCT TCC TCC ATC CTG GAG GAA GGC 1296 Arg Asp Thr Thr Val leu Val Ser Pro Ser Ser He Leu Glu Glu Gly 395 400 405 ACT TCT GTG AAT ATG ACA TGC TTG AGC CAG GGC TTT CCT GCT COG AAA 1344 Ser Ser Val Asn Met Thr Cys leu Ser Gin Gly Phe Pro Ma Pro Lys 410 415 420 ATC CTG TGG AGC AGG CAG CTC CCT AAC GGG GAG CTA CAG CCT CTT TCT 1392 lie Leu Trp Ser Arg Gin Leu Pro Asn Gly Glu leu Gin Pro Leu Ser 425 430 435 440 GAG AAT GCA ACT CTC ACC TTA ATT TCT ACA AAA ATG GAA GAT TCT GGG 1440 Glu Asn Ma Thr Lai Thr Leu He Ser Thr Lys Met Glu Asp Ser Gly 445 450 455 CTT TAT TTA TCT GAA GGA ATT AAC CAG GCT GGA AGA AGC AGA AAG GAA 1488 Val Tyr Leu Cys Glu Gly He Asn Gin Ma Gly Arg Ser Arg Lys Glu 460 465 470 GTG GAA TTA ATT ATC CAA CTT ACT CCA AAA GAC ATA AAA CTT ACA GCT 1536 Val Glu Leu He He Gin Val Thr Pro Lys Asp He Lys Leu Thr Ma 475 480 485 TTT OCT TCT GAG ACT CTC AAA GAA GGA GAC ACT CTC ATC ATC TCT TCT 1584 Hie Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val He He Ser Cys 490 495 500 ACA TCT GGA AAT CTT CCA GAA ACA TGG ATA ATC CTG AAG AAA AAA GGG 1632 Thr Cys Gly Asn Val Pro Glu Thr Trp He He Leu Lys Lys Lys Ma 505 510 515 520 GAG ACA GGA GAC ACA GTA CTA AAA TCT ATA GAT GGC GCC TAT ACC ATC 1680 Glu Thr Gly Asp Thr Val Leu Lys Ser He Asp Gly Ma Tyr Thr He 525 530 535 OGA AAG GCC CAG TTG AAG GAT GOG GGA CTA TAT GAA TGT GAA TCT AAA 1728 Arg Lys Ma Gin Leu Lys Asp Ma Gly Val Tyr Glu Cys Glu Ser Lys 540 545 550 AAC AAA GTT GGC TCA CAA TTA AGA ACT TTA ACA CTT GAT GTT CAA GGA 1776 Asn Lys Val Gly Ser Gin Leu Arg Ser Leu Thr Leu Asp Val Gin Gly 555 560 565 AGA GAA AAC AAC AAA GAC TAT TTTTCT OCT GAG CTT CTC GTC CTCTAT 1824 Arg Glu Asn Asn Lys Asp Tyr Phe Ser Pro Glu Leu Leu Val Leu Tyr 570 575 580 TTT GCA TCC TCC TTA ATA ATA CCT GCC ATT GGA ATG ATA ATT TAC TTT 1872 Phe Ma Ser Ser Leu He He Pro Ma He Gly Met He He Tyr Hie 585 590 595 600 GCA AGA AAA GCC AAC ATG AAG GGG TCA TAT ACT CTT CTA GAA GCA CAG 1920 Ma Arg Lys Ma Asn Met Lys Gly Ser Tyr Ser Leu Val Glu Ma Gin 605 610 615 AAA TCA AAA CTG 1932 Lys Ser Lys Val 620 (2) INFORMATION FOR SEQ 3D NO:21: (i) SEQUENCE CHARACTERISTICS: (A) LENCTH: 644 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: Met Pro Gly Lys Ifet Val Val He Leu Gly Ala Ser Asn lie Leu Trp -24 -20 -15 -10 lieMet Hie Ma Ma Ser Gin Ala Hie Lys He Glu Thr Thr Pro Glu -5 1 5 Ser Arg Tyr Lai Lai Pro Arg Gly Gly Ser Val leu Val Thr Cys Ser 10 15 20 Thr Ser Cys Asp Gin Pro Lys Leu Leu Gly He Glu Thr Pro Leu Pro 25 30 35 40 Lys Lys Glu Leu Leu Leu Pro Gly Asn Asn Arg Lys Val Tyr Glu Leu 45 50 55 Ser Asn Val Gin Glu Asp Ser Gin Pro Met Cys Tyr Ser Asn Cys Pro 60 65 70 Asp Gly Gin Ser Thr Ala Lys Thr Hie Leu Thr Val Tyr Trp Thr Pro 75 80 85 Glu Arg Val Glu Leu Ma Pro Leu Pro Ser Trp Gin Pro Val Gly Lys 90 95 100 Asn Leu Thr Leu Arg Cys Gin Val Glu Gly Gly Ma Pro Arg Ma Asn 105 HO H5 120 Leu Thr Val Val Leu Lai Arg Gly Glu Lys Leu Met Lys Ser Gin Glu 125 130 135 Phe Leu Glu Asp Ma Asp Arg Lys Ser Leu Glu Thr Lys Ser Leu Glu 140 145 150 Val Thr Hie Thr Pro Val He Glu Asp lie Gly Lys Val Leu Val Cys 155 160 165 Arg Ala Lys Leu His lie Asp Glu Ifet Asp Ser Val Pro Thr Val Arg 170 175 180 Gin Ala Val Lys Glu Leu Gin Val Tyr lie Ser Pro Lys Asn Thr Val 185 190 195 200 He Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly Ser Val Thr 205 210 215 Met Thr Cys Ser Ser Glu Gly Leu Pro Ala Pro Glu He Hie Trp Ser 220 225 230 Lys Lys Leu Asp Asn Gly Asn Leu Gin His Leu Ser Gly Asn Ma Thr 235 240 245 Leu Thr Leu He Ma Met Arg Met Glu Asp Ser Gly He Tyr Val Cys 250 255 260 Glu Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val Glu Leu He 265 270 275 280 Val Gin Ma Hie Pro Arg Asp Pro Glu He Glu Met Ser Gly Gly Leu 285 290 295 Val Asn Gly Ser Ser Val Thr Val Ser Cys Lys Val Pro Ser Val Tyr 300 305 310 Pro Leu Asp Arg Leu Glu He Glu Leu Leu Lys Gly Glu Thr He Leu 315 320 325 Glu Asn He Glu Phe Leu Glu Asp Thr Asp Met Lys Ser Leu Glu Asn 330 335 340 Lys Ser Leu Glu Met Thr Hie He Pro Thr He Glu Asp Thr Gly Lys 345 350 355 360 Ma Leu Val Cys Gin Ma Lys Leu His He Asp Asp Met Glu Hie Glu 365 370 375 Pro Lys Gin Arg Gin Ser Thr Gin Thr Leu Tyr Val Asn Val Ma Pro 380 385 390 Arg Asp Thr Thr Val Leu Val Ser Pro Ser Ser He Leu Glu Glu Gly 395 400 405 Ser Ser Val Asn Met Thr Cys Leu Ser Gin Gly Hie Pro Ma Pro Lys 410 415 420 He Leu Trp Ser Arg Gin Leu Pro Asn Gly Glu Leu Gin Pro Leu Ser 425 430 435 440 Glu Asn Ma Thr Leu Thr Leu He Ser Thr Lys Met Glu Asp Ser Gly 445 450 455 Val Tyr Leu Cys Glu Gly He Asn Gin Ma Gly Arg Ser Arg Lys Glu 460 465 470 Val Glu Lai He He Gin Val Thr Pro Lys Asp He Lys Leu Thr Ala 475 480 485 Hie Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val He He Ser Cys 490 495 500 Thr Cys Gly Asn Val Pro Glu Thr Trp He lie Lai Lys Lys Lys Ala 505 510 515 520 Glu Thr Gly Asp Thr Val Lai Lys Ser lie Asp Gly Ala Tyr Thr lie 525 530 535 Arg Lys Ala Gin Leu Lys Asp Ala Gly Val Tyr Glu Cys Glu Ser Lys 540 545 550 Asn Lys Val Gly Ser Gin Leu Arg Ser Leu Thr Leu Asp Val Gin Gly 555 560 565 Arg Glu Asn Asn Lys Asp Tyr Phe Ser Pro Glu Leu Leu Val Leu Tyr 570 575 580 Hie Ala Ser Ser Leu lie He Pro Ma lie Gly Met He He Tyr Hie 585 590 595 600 Ala Arg Lys Ala Asn Met Lys Gly Ser Tyr Ser Leu Val Glu Ala Gin 605 610 615 Lys Ser Lys Val 620 (2) INFORMATION FOR SEQ 3D N0:22: (i) SEQUENCE CHARACTERISTICS: (A) LENCTH: 1941 base pairs (B) TYPE: nucleic acid (C) STRANDEDNESS: double (D) TOPOLOGY: linear (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCAIiαT: 1. .1941 (ix) FEATURE: (A) NAME/KEY: mat_peptide (B) LDCSTION: 73. .1941 (ix) FEATURE: (A) NAME/KEY: sig_peptide (B) IOCAIICNϊ 1. .72 (Xi) SEQUENCE DESCRIPTION: SEQ 3D NO: 22: ATG CCT GGG AAG ATG GTC GTG ATC CTT GGA GCC TCA AAT ATA CTT TGG 48 Met Pro Gly Lys Met Val Val He Leu Gly Ma Ser Asn He Leu Trp -24 -20 -15 -10 ATA ATG TTT GCA GCT TCT CAA GCT TTT ACT CTT GAG ATC TCC CCT GGA 96 He Ifet Phe Ma Ma Ser Gin Ma Phe Thr Val Glu He Ser Pro Gly -5 1 5 CCC CGG A T GCT GCT CAG ATT GGA GAC TCA GTC ATG TTG ACA TCT ACT 144 Pro Arg He Ma Ma Gin He Gly Asp Ser Val Met Lai Thr Cys Ser 10 15 20 GTC ATG GGC TGT GAA TCC CCA TCT TTC TCC TGG AGA ACC CAG ATA GAC 192 Val Met Gly Cys Glu Ser Pro Ser Phe Ser Trp Arg Thr Gin He Asp 25 30 35 40 AGC CCT CTG AGC GGG AAG GTC AGG ACT GAG GGG ACC AAT TCC ACG CTG 240 Ser Pro Leu Ser Gly Lys Val Arg Ser Glu Gly Thr Asn Ser Thr Leu 45 50 55 AOC CTG AGC CCT GTG ACT T T GAG AAC GAA CAC TCT TAT CTG TGC ACA 288 Thr Leu Ser Pro Val Ser Phe Glu Asn Glu His Ser Tyr Leu Cys Thr 60 65 70 GTG ACT TCT GGA CAT AAG AAA CTG GAA AAG GGA ATC CAG CTG GAG CTC 336 Val Thr Cys Gly His Lys Lys Leu Glu Lys Gly He Gin Val Glu Leu 75 80 85 TAC TCA TTC CCT AAG GAT CCA GAG ATT CAT TTG ACT GGC CCT CTG GAG 384 Tyr Ser Phe Pro Lys Asp Pro Glu He His Leu Ser Gly Pro Leu Glu 90 95 100 GCT GGG AAG COG ATC ACA GTC AAG TGT TCA GTT GCT GAT GTA TAC CCA 432 Ma Gly Lys Pro He Thr Val Lys cys Ser Val Ma Asp Val Tyr Pro 105 110 115 120 TTT GAC AGG CTG GAG ATA GAC TTA CTG AAA GGA GAT CAT CTC ATG AAG 480 Phe Asp Arg Leu Glu He Asp Leu Leu Lys Gly Asp His Leu Met Lys 125 130 135 ACT CAG GAA TTT CTG GAG GAT GCA GAC AGG AAG TCC CTG GAA ACC AAG 528 Ser Gin Glu Hie Leu Glu Asp Ma Asp Arg Lys Ser Leu Glu Thr Lys 140 145 150 ACT TTG GAA GTA ACC TTT ACT OCT GTC ATT GAG GAT ATT GGA AAA CTT 576 Ser Leu Glu Val Thr Hie Thr Pro Val He Glu Asp He Gly Lys Val 155 160 165 CTT CTT TGC CGA GCT AAA TTA CAC ATT GAT GAA ATG GAT TCT GIG CCC 624 leu Val Cys Arg Ala Lys Lai His He Asp Glu Met Asp Ser Val Pro 170 175 180 ACA GEA AGG CAG GCT GTA AAA GAA T G CAA CTC TAC ATA TCA CCC AAG 672 Thr Val Arg Gin Ala Val Lys Glu Lai Gin Val Tyr He Ser Pro Lys 185 190 195 200 AAT ACA CTT AIT TCT CTG AAT CCA TCC ACA AAG CTG CftA GAA GCT GGC 720 Asn Thr Val He Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly 205 210 215 TCT GTG ACC ATG ACC TGT TCC AGC GAG GCT CTA CCA GCT CCA GAG ATT 768 Ser Val Thr Met Thr cys Ser Ser Glu Gly Leu Pro Ma Pro Glu He 220 225 230 TTC TGG ACT AAG AAA TTA GAT AAT GGG AAT CTA CAG CAC CTT TCT GGA 816 Hie Trp Ser Lys Lys Leu Asp Asn Gly Asn Leu Gin His Leu Ser Gly 235 240 245 AAT GCA ACT CTC ACC TTAATT GCT ATG AGG ATG GAA GAT TCT GGA ATT 864 Asn Ma Thr Lai Thr Lai lie Ma Met Arg Met Glu Asp Ser Gly He 250 255 260 TAT CTG TGT GAA GGA GTT AAT TTG ATT GGG AAA AAC AGA AAA GAG GTG 912 Tyr Val Cys Glu Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val 265 270 275 280 GAA TTA ATT CTT CAA GCA TIC CCT AGA GAT CCA GAAATC GAG ATG ACT 960 Glu Leu lie Val Gin Ala Hie Pro Arg Asp Pro Glu lie Glu Met Ser 285 290 295 GCT GGC CTC CTG AAT GGG AGC TCT GTC ACT CTA AGC TGC AAG GTE CCT 1008 Gly Gly Leu Val Asn Gly Ser Ser Val Thr Val Ser Cys Lys Val Pro 300 305 310 AGC CTG TAC CCC CTT GAC CGG CTG GAG ATT GAA TTA CTT AAG GGG GAG 1056 Ser Val Tyr Pro Leu Asp Arg Leu Glu He Glu Leu Leu Lys Gly Glu 315 320 325 ACT AIT CTG GAG AAT ATA GAG TTT TG GAG GAT ACG GAT ATG AAA TCT 1104 Thr He Leu Glu Asn lie Glu Phe Leu Glu Asp Thr Asp Met Lys Ser 330 335 340 CIA GAG AAC AAAACT TTG GAA ATG ACC TTC ATC CCT ACC ATT GAA GAT 1152 Lai Glu Asn Lys Ser Leu Glu Met Thr Fhe He Pro Thr He Glu Asp 345 350 355 360 ACT GGAAAA GCT CTT GTT TCT CAG GCT AAG TTA CAT ATT GAT GAC ATG 1200 Thr Gly Lys Ala Lai Val Cys Gin Ala Lys Leu His He Asp Asp Met 365 370 375 GAA TTC GAA CCC AAA CAA AGG CAG ACT ACG CAA ACA CTT TAT GTC AAT 1248 Glu Fhe Glu Pro Lys Gin Arg Gin Ser Thr Gin Thr Lai Tyr Val Asn 380 385 390 GTT GOC CCC AGA GAT ACA ACC GTC TTC GIC AGC CCT TOC TOC ATC CTG 1296 Val Ma Pro Arg Asp Thr Thr Val leu Vεύ. Ser Pro Ser Ser He Leu 395 400 405 GAG GAA GGC ACT TCT CTG AAT ATG ACA TGC TTG AGC CAG GGC TTT CCT 1344 Glu Glu Gly Ser Ser Val Asn Met Thr cys Leu Ser Gin Gly Fhe Pro 410 415 420 GCT COG AAA ATC CTG TGG AGC AGG CAG CTC CCT AAC GGG GAG C A CAG 1392 Ma Pro Lys He Leu Trp Ser Arg Gin .Leu Pro Asn Gly Glu Lai Gin 425 430 435 440 OCT CTT TCT GAG AAT GCA ACT CTC ACC TTA ATT TCT ACA AAA ATG GAA 1440 Pro Leu Ser Glu Asn Ala Thr lieu Thr Leu He Ser Thr Lys Met Glu 445 450 455 GAT TCT GGG CTT TAT TTA TCT GAA GGA ATT AAC CAG GCT GGA AGA AGC 1488 Asp Ser Gly Val Tyr Leu cys Glu Gly He Asn Gin Ma Gly Arg Ser 460 465 470 AGA AAG GAA CTG GAA TTA ATT ATC CAA GTT ACT CCA AAA GAC ATA AAA 1536 Arg Lys Glu Val Glu Lai He He Gin Val Thr Pro Lys Asp He Lys 475 480 485 CTT ACA GCT TTT CCT TCT GAG ACT CTC AAA GAA GGA GAC ACT GTC ATC 1584 Lai Thr Ma Hie Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val He 490 495 500 ATC TCT TCT ACA TCT GGA AAT CTT CCA GAA ACA TGG ATA ATC CTG AAG 1632 He Ser Cys Thr Cys Gly Asn Val Pro Glu Thr Trp He He Leu Lys 505 510 515 520 AAA AAA GOG GAG ACA GGA GAC ACA GTA CTA AAA TCT ATA GAT GGC GCC 1680 Lys Lys . la Glu Thr Gly Asp Thr Val Leu Lys Ser He Asp Gly Ma 525 530 535 TAT ACC ATC CGA AAG GCC CAG TTG AAG GAT GOG GGA CTA TAT GAA TCT 1728 Tyr Thr He Arg Lys Ma Gin Leu Lys Asp Ma Gly Val Tyr Glu Cys 540 545 550 GAA TCT AAA AAC AAA CTT GGC TCA CAA TTA AGA ACT TTA ACA CTT GAT 1776 Glu Ser Lys Asn Lys Val Gly Ser Gin Leu Arg Ser Leu Thr Leu Asp 555 560 565 CTT CAA GGA AGA GAA AAC AAC AAA GAC TAT TIT TCT CCT GAG CTr CTC 1824 Val Gin Gly Arg Glu Asn Asn Lys Asp Tyr Fhe Ser Pro Glu lieu Leu 570 575 580 GTG CTC TAT TTT GCA TCC TCC TTAATAATA CCT GCC ATT GGA ATG ATA 1872 Val Leu Tyr Hie Ala Ser Ser Leu lie He Pro Ma lie Gly Ifet He 585 590 595 600 AIT TAC TTT GCAAGA AAA GOC AAC ATG AAG GGG TCA TAT AGT C T GTA 1920 He Tyr Phe Ala Arg Lys Ala Asn Met Lys Gly Ser Tyr Ser Leu Val 605 610 615 GAA GCA CAG AAA TCAAAA GTG 1941 Glu Ma Gin Lys Ser Lys Val 620 (2) INFORMATION FOR SEQ 3D NO:23: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 647 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ 3D NO:23: Met Pro Gly Lys Met Val Val He Leu Gly Ma Ser Asn He Leu Trp -24 -20 -15 -10 He Met Ihe Ma Ma Ser Gin Ma Phe Thr Val Glu He Ser Pro Gly -5 1 5 Pro Arg He Ma Ma Gin He Gly Asp Ser Val Met Leu Thr Cys Ser 10 15 20 Val Met Gly Cys Glu Ser Pro Ser Phe Ser Trp Arg Thr Gin He Asp 25 30 35 40 Ser Pro Lai Ser Gly Lys Val Arg Ser Glu Gly Thr Asn Ser Thr Leu 45 50 55 Thr Lai Ser Pro Val Ser Phe Glu Asn Glu His Ser Tyr Leu Cys Thr 60 65 70 Val Thr cys Gly His Lys Lys Leu Glu Lys Gly He Gin Val Glu Leu 75 80 85 Tyr Ser Hie Pro Lys Asp Pro Glu He His Leu Ser Gly Pro Leu Glu 90 95 100 Ma Gly Lys Pro He Thr Val Lys Cys Ser Val Ma Asp Val Tyr Pro 105 HO 115 120 Fhe Asp Arg Leu Glu He Asp Leu Leu Lys Gly Asp His Leu Met Lys 125 130 135 Ser Gin Glu Phe Leu Glu Asp Ma Asp Arg Lys Ser Lai Glu Thr Lys 140 145 150 Ser Leu Glu Val Thr Phe Thr Pro Val lie Glu Asp He Gly Lys Val 155 160 165 Leu Val Cys Arg Ma Lys Leu His He Asp Glu Met Asp Ser Val Pro 170 175 180 Thr Val Arg Gin Ma Val Lys Glu Leu Gin Val Tyr He Ser Pro Lys 185 190 195 200 Asn Thr Val He Ser Val Asn Pro Ser Thr Lys Leu Gin Glu Gly Gly 205 210 215 Ser Val Thr Met Thr cys Ser Ser Glu Gly Leu Pro Ma Pro Glu He 220 225 230 Phe Trp Ser Lys Lys Lai Asp Asn Gly Asn Leu Gin His Leu Ser Gly 235 240 245 Asn Ma Thr Leu Thr Leu He Ma Met Arg Met Glu Asp Ser Gly He 250 255 260 Tyr Val Cys Glu Gly Val Asn Leu He Gly Lys Asn Arg Lys Glu Val 265 270 275 280 Glu Leu He Val Gin Ma Phe Pro Arg Asp Pro Glu He Glu Met Ser 285 290 295 Gly Gly Leu Val Asn Gly Ser Ser Val Thr Val Ser Cys Lys Val Pro 300 305 310 Ser Val Tyr Pro Leu Asp Arg Leu Glu He Glu Leu Leu Lys Gly Glu 315 320 325 Thr He Leu Glu Asn He Glu Fhe Leu Glu Asp Thr Asp Met Lys Ser 330 335 340 Leu Glu Asn Lys Ser Leu Glu Met Thr Hie He Pro Thr He Glu Asp 345 350 355 360 Thr Gly Lys Ma Leu Val Cys Gin Ma Lys Leu His He Asp Asp Met 365 370 375 Glu He Glu Pro Lys Gin Arg Gin Ser Thr Gin Thr Leu Tyr Val Asn 380 385 390 Val Ala Pro Arg Asp Thr Thr Val Lai Val Ser Pro Ser Ser He Leu 395 400 405 Glu Glu Gly Ser Ser Val Asn Met Thr Cys Lai Ser Gin Gly Hie Pro 410 415 420 Ma Pro Lys He Lai Trp Ser Arg Gin Leu Pro Asn Gly Glu Leu Gin 425 430 435 440 Pro Leu Ser Glu Asn Ala Thr Leu Thr leu He Ser Thr Lys Met Glu 445 450 455 Asp Ser Gly Val Tyr Lai cys Glu Gly He Asn Gin Ma Gly Arg Ser 460 465 470 Arg Lys Glu Val Glu Leu lie lie Gin Val Thr Pro Lys Asp lie Lys 475 480 485 Leu Thr Ala Hie Pro Ser Glu Ser Val Lys Glu Gly Asp Thr Val He 490 495 500 lie Ser Cys Thr Cys Gly Asn Val Pro Glu Thr Trp lie lie Leu Lys 505 510 515 520 Lys Lys Ala Glu Thr Gly Asp Thr Val leu Lys Ser He Asp Gly Ma 525 530 535 Tyr Thr He Arg Lys Ala Gin Leu Lys Asp Ala Gly Val Tyr Glu Cys 540 545 550 Glu Ser Lys Asn Lys Val Gly Ser Gin Leu Arg Ser Leu Thr Leu Asp 555 560 565 Val Gin Gly Arg Glu Asn Asn Lys Asp Tyr Fhe Ser Pro Glu Leu Leu 570 575 580 Val Leu Tyr Phe Ma Ser Ser Leu He He Pro Ma He Gly Ifet He 585 590 595 600 He Tyr Fhe Ala Arg Lys Ma Asn Met Lys Gly Ser Tyr Ser Leu Val 605 610 615 Glu Ma Gin Lys Ser Lys Val 620

Claims: CLAIMS : 1. A monoclonal antibody recognizing an epitope dependent on the fourth immunoglobulin-like domain Of VCAM-7D. 2. A monoclonal antibody as defined in Claim 1, which blocks Ramos adhesion to VCAMl-expressing cells and which does not cross-block monoclonal antibody 4B9. 3. A monoclonal antibody as defined in Claim 1, selected from the group produced by hybridomas: (a) ED11.AG6 (ATCC HB 10962), (b) GE4.BG5 (ATCC HB 10961), and (c) GH12.AA12 (ATCC HB 10963). 4. A monoclonal antibody having the characteristics of EDll, Fab, Fab*' , F(ab) 2 , and F(v) fragments thereof, chimeric antibodies derived therefrom, heavy chain monomers or dimers formed therefrom, light chain monomers or dimers formed therefrom, or dimers consisting of one heavy chain and one light chain formed therefrom. 5. A monoclonal antibody having the characteristics of GE4, Fab, Fab", F(ab) 2 , and F(v) fragments thereof, chimeric antibodies derived therefrom, heavy chain monomers or dimers formed therefrom, light chain monomers or dimers formed therefrom, or dimers consisting of one heavy chain and one light chain formed therefrom. 6. A monoclonal antibody having the characteristics of GH12, Fab, Fab', F(ab) 2 , and F(v) fragments thereof, chimeric antibodies derived therefrom, heavy chain monomers or dimers formed therefrom, light chain monomers or dimers formed therefrom, or dimers consisting of one heavy chain and one light chain formed therefrom. 7. A monoclonal antibody that binds to VCAM- 7D, does not bind to VCAM-6D, at least partially inhibits binding between VLA-4-expressing cells and VCAMl- expressing cells, and does not cross-block anti-VCAMl monoclonal antibody 4B9. 8. A monoclonal antibody according to Claim 7, selected from monoclonal antibodies EDll, GE4, or GH12. 9. A hybridoma selected from the group consisting of (a) ED11.AG6 (ATCC HB 10962) , (b) GE4.BG5 (ATCC HB 10961), and (C) GH12.AA12 (ATCC HB 10963). 10. A method for purifying VCAM-7D from a solution also containing VCAM-6D comprising contacting the solution with a substrate on which is immobilized a monoclonal antibody according to Claim 1. 11. A method for separating cells expressing VCAM-7D from cells expressing VCAM-6D comprising contacting a solution including cells expressing VCAM-7D with a substrate on which is immobilized an antibody according to Claim 1. 12. An in vitro or in vivo method for detecting the presence, in a biological sample or a mammal, of VCAM- 7D or cells expressing VCAM-7D, comprising contacting said biological sample with a detectably labeled antibody according to Claim 1. 13. A treatment for diseases in mammals characterized by cell-cell adhesion mediated by VCAM-7D comprising administering to a mammal suffering from such a disease an amount of a VCAMl domain 4 monoclonal antibody, or Fab, Fab', F(ab) 2 , or F(v) fragments thereof, chimeric antibodies derived therefrom, heavy chain monomers or dimers formed therefrom, light chain monomers or dimers formed therefrom, or dimers consisting of one heavy chain and one light chain formed therefrom, effective to at least partially inhibit in vivo said VCAM-7D-mediated cell-cell adhesion. 14. A therapeutic reagent comprising a monoclonal antibody selected from ED11.AG6 (ATCC HB 10962), GE4.BG5 (ATCC HB 10961), or GH12.AA12 (ATCC HB 10963), or Fab, Fab', F(ab) 2 , and F(v) fragments thereof, chimeric antibodies derived therefrom, heavy chain monomers or dimers formed therefrom, light chain monomers or dimers formed therefrom, or dimers consisting of one heavy chain and one light chain formed therefrom, in a pharmaceutically acceptable carrier. 15. A diagnostic kit comprising (1) as a reagent, a detectably labeled monoclonal antibody selected from EDll, GE4 or GH12; Fab, Fab', F(ab) 2 , or F(v) fragments thereof; chimeric antibodies derived therefrom; heavy chain monomers or dimers formed therefrom; light chain monomers or dimers formed therefrom; or dimers consisting of one heavy chain and one light chain formed therefrom; and (2) complete instructions for use of said reagent according to the method of claim 12.

Inventors: BENJAMIN CHRISTOPHER D, OSBORN LAURELEE, BENJAMIN, CHRISTOPHER, D., OSBORN, LAURELEE
Applicants: BIOGEN INC, BIOGEN, INC.
Application year: 1993
Main classification: C12P21
IPC codes: A61K38, A61K39, A61P29, C07K1, C07K14, C07K16, C12N5, C12N15, C12P21, C12R1, G01N33