AU726886B2 - Human calcium sensor protein, fragments thereof and DNA encoding same - Google Patents

Description

WO 96/15801 PCT/US95/15203 HUMAN CALCIUM SENSOR PROTEIN.

FRAGMENTS THEREOF AND DNA ENCODING SAME This application is a continuation-in-part of 08/487,314 filed June 7,1995, which is a continuation-in-part of 08/344,836 filed November 23, 1994, which is a continuation-in-part of PCT/SE94/00483 filed May 24, 1994.

BACKGROUND OF THE INVENTION The present invention relates to a cDNA clone encoding a human calcium sensor protein of parathyroid, placental, and kidney tubule cells.

In WO 88/03271 there is described monoclonal antiparathyroid antibodies identifying a parathyroid cell membrane-bound calcium receptor or sensor, crucially involved in calcium regulation of the parathyroid hormone (PTH) release The receptor function is essential for maintenance of normal plasma calcium concentrations, and reduced receptor expression within proliferating parathyroid cells of patients with hyperparathyroidism (HPT) results in calcium insensitivity of the PTH secretion and variably severe hypercalcemia Reactivity with the antiparathyroid antibodies was also demonstrated for proximal kidney tubule cells and cytotrophoblast cells of the human placenta, and the cytotrophoblasts were demonstrated to exhibit an almost parathyroid-identical regulation of cytoplasmic calcium [Ca 2 i] The antibody-reactive structure was found to exert calcium sensing function also in the cytotrophoblasts, and as these cells constitute part of the syncytium, the calcium sensor was suggested to be actively involved in the calcium homeostasis of the fetus It was proposed that the antibody-reactive structure of the proximal kidney tubule cells exerts a similar calcium sensing function, and that the calcium sensor, thus, plays a more universal role in calcium regulation via different organ systems (1,7,9,10).

On HPT patients with hypercalcemia, surgery is performed to remove one or more of the parathyroid glands. It would be greatly desirable to have alternatives to this surgical procedure as HPT has proven to be a very common disorder and SUBSTITUTE SHEET (RULE WO 96/15801 PCT/US95/15203 surgery is a relatively costly procedure and sometimes even entails some risks for the patients.

The calcium sensor/receptor has been revealed as a 500 kDa single chain glycoprotein However, the amino acid sequence as well as the corresponding DNA sequences thereof are hitherto unknown.

SUMMARY OF THE INVENTION Therefore, an object of the present invention was to provide sufficient structural data of the calcium sensor/receptor to enable complete characterization thereof.

In one embodiment, the present invention provides complete amino acid sequence of the human calcium sensor protein of parathyroid, placental and kidney tubule cells.

In another embodiment the invention provides nucleic acid sequence encoding the human calcium sensor and nucleic acid probes for identifying other novel calcium sensor proteins.

Another object is to use said structural data to design novel treatment methods as well as compounds and compositions for treating calcium related disorders.

In other embodiments, the present invention provides identification of peptide regions within the calcium sensor protein cytoplasmic domain which are homologous to SH2 and SH3 binding motifs involved in signal transduction pathways.

Two important human diseases associated with perturbations of the calcium ion homeostasis are hyperthyroidism and osteoporosis. Thus, in one embodiment cells expressing the calcium sensor protein or a fragment thereof or comprising the cDNA encoding the calcium sensor protein of the present invention may be utilized in an assay to identify molecules which block or enhance the activity of the calcium sensor protein, including signal transduction pathways associated with the activity of the sensor. These molecules will be useful in the treatment of mammalian pathological conditions associated with perturbations in the levels of PTH, vitamins D3 production, WO 96/15801 PCT/US95/15203 estrogen, osteoclast activity or osteoblast activity (therefore, bone resorption and/or formation), calcium secretion and calcium ion homeostasis.

The present invention describes the isolation and characterization of cDNA clones encoding the calcium sensor/receptor in human placenta and Northern blots verifying the presence of the corresponding mRNA within the parathyroid and kidney. Close sequence similarity between the calcium sensor and a rat Heymann nephritis antigen, gp330 (11, 67), suggests that the common calcium sensor of the placenta, the parathyroid and kidney tubule is related to this antigen, represents the human homologue of gp330, and belongs to a family of large glycoproteins with receptor function and calcium binding ability. Therefore, a further object of this invention is to provide diagnostic assays and therapeutic methods based on human gp330.

BRIEF DESCRIPTION OF THE DRAWINGS Fig 1. Isolation by HPLC of peptides obtained after digestion of the calcium sensor protein with Lys-C endoprotease (solid line). Dashed line represents the chromatography of an identical reaction where the calcium-sensor was omitted. The flow rate was kept at 100 .l/min. Two peptide fractions which gave easily interpretable sequences are denoted by arrows.

Fig 2. Sequences of two Lys-C peptides (SEQ ID Nos. 1 and 2) isolated by HPLC of the calcium-sensor protein.

Fig 3. Partial nucleotide sequence (SEQ ID No. 3) and deduced amino acid sequence (SEQ ID No. 4) of the-cDNA clone, pCAS-2, encoding part of the calcium-sensor protein. Portions of the deduced amino acid sequence identical to the peptides 292 and 293 are underlined.

Fig 4. Alignment of the amino acid sequence of the calcium-sensor protein (SEQ ID No. 4) to corresponding portions of the Heymann antigen (HEYMANN, SEQ ID No. low density lipoprotein receptor (LDL-RC, SEQ ID No. and LDL related receptor protein (LDLRRP, SEQ ID No. Stars denote residues identical between the calcium sensor protein and any of -the WO 96/15801 PCT/US95/15203 other sequences. X denotes a position in the Heymann antigen sequence where identity has not been published.

Fig 5. Northern blot analysis of total RNA from parathyroid adenoma kidney liver placenta pancreas adrenal gland small gut Filters were hybridized with the 2.8 kb pCAS-2 insert probe, and reactions visualized by a phosphorimager. Locations of 28S and 18S ribosomal RNA are indicated.

Fig. 6. Complete nucleotide (SEQ ID No. 11) and amino acid (SEQ ID No. 12) sequence of the human calcium sensor 2.8 kb cDNA clone. The transmembrane domain of the sensor is shown in bold type. The three SH3 binding regions are underlined or overlined and the SH2 binding region is shown in strikethru.

Fig 7. Amino acid sequence of the calcium sensor cytoplasmic domain (SEQ ID No. 13) and comparison of the three calcium sensor SH3 binding regions (SEQ ID Nos. 14-16) to known SH3 binding motifs (SEQ ID Nos. 20-37).

Fig. 8. Comparison of relative binding strengths between a calcium sensor SH3 binding region and various GST fusion proteins comprising an SH3 domain.

Fig. 9. Comparison of the calcium sensor SH2 binding region (SEQ ID No. 19) with amino acid sequence requirements necessary for interaction with the SH2 region of the p85 regulatory subunit of PI3K (SEQ ID Nos. 38-78).

Fig. 10. Structure of human gp330, including the EGF repeat, growth factor repeats and YWTD spacer regions. N depicts the amino terminus of the protein and C the carboxyl-terminus. The arrow indicates the location of the transmembrane region.

Fig. 11. Strategy for extending CAS sequence from pCAS-2.

Fig.12. Comparison of the same region within different CAS cDNA sequences revealing amino acid sequence differences.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Unless indicated otherwise herein, the following terms have the indicated meanings.

WO 96/15801 PCT/US95/15203 The term "polypeptide" means a linear array of amino acids connected one to the other by peptide bonds between the a-amino and carboxy groups of adjacent amino acids.

"Substantially purified" is used herein to mean "substantially homogeneous", which is defined as a material which is substantially free of compounds normally associated with it in its natural state other proteins or peptides, carbohydrates, lipids). "Substantially purified" is not meantto exclude artificial or synthetic mixtures with other compounds.

The term is also not meant to exclude the presence of impurities which do not interfere with biological activity, and which may be present, for example, due to incomplete purification or compounding with a pharmaceutically acceptable preparation.

The term "biologically active polypeptide" means the naturally occurring polypeptide per se as well as biologically active analogues thereof, including synthetically produced polypeptides and analogues thereof, as well as natural and pharmaceutically acceptable salts and pharmaceutically acceptable derivatives thereof. The term "biologically active polypeptide" also encompasses biologically active fragments thereof, as well as "biologically active sequence analogues" thereof. Different forms of the peptide may exist. These variations may be characterized by difference in the nucleotide sequence of the structural gene coding for proteins of identical biological function.

The term "biologically active sequence analogue" includes nonnaturally occurring analogues having single or multiple amino acid substitutions, deletions, additions, or replacements. All such allelic variations, modifications, and analogues resulting in derivatives which retain one or more of the native biologically active properties are included within the scope of this invention.

In this application, nucleotides are indicated by their bases using the following standard one-letter abbreviations: Guanine G Adenine A Thymine T WO 96/15801 PCTUS9515203 Cytosine

C

Unknown

N

In this application, amino acid residues are indicated using the following standard one-letter abbreviations: Alanine

A

Cysteine

C

Aspartic Acid D Glutamic Acid E Phenylalanine

F

Glycine

G

Histidine

H

Isoleucine

I

Lysine

K

Leucine

L

Methionine

M

Asparagine

N

Proline

P

Glutamine Q Arginine

R

Serine S Threonine

T

Valine

V

Tryptophan

W

Tyrosine

Y

Unknown

X

The term "amino acid" as used herein is meant to denote the above recited natural amino acids and functional equivalents thereof.

This invention provides isolated nucleic acid molecules encoding a common calcium sensor protein of parathyroid, placental and kidney tubule cells and comprising a coding sequence selected from the group consisting of SEQ ID No. 3, SEQ ID No. 11, SEQ ID No. 83, SEQ ID No. 85, SEQ ID No. 87, and SEQ ID No. 89.

Furthermore, this invention provides a vector comprising an isolated nucleic acid molecule encoding the calcium sensor protein or a fragment thereof which encodes functional regions of the sensor.

WO 96/15801 PCT/US95/15203 7 Moreover, the invention provides a method of preparing calcium sensor protein which comprises inserting a nuleic acid encoding the calcium sensor or a fragment thereof in a suitable vector, inserting the resulting vector in a suitable host cell, recovering the calcium sensor protein produced by the resulting cell, and purifying the calcium sensor protein so recovered.

This method for preparing a calcium sensor protein or fragment thereof uses recombinant DNA technology methods which are well known in the art. Alternatively, the calcium sensor protein or a fragment thereof may be prepared using standard solid phase methodology of peptide synthesis.

The present invention also provides antisense nucleic acids which can be used to down regulate or block the expression of the calcium sensor protein either in vitro, ex vivo or in vivo.

The down regulation of gene expression can be made at both translational or transcriptional levels. Antisense nucleic acids of the invention are more preferentially RNA fragments capable of specifically hybridizing with all or part of the sequence selected from the group consisting of SEQ ID No. 3, SEQ ID No.

11, SEQ ID No. 83, SEQ ID No. 85, SEQ ID No. 87, and SEQ ID No.

89 or the corresponding messenger RNA. These antisense can be synthetic oligonucleotides prepared based on the sequence selected from the group consisting of SEQ ID No. 3, SEQ ID No.

11, SEQ ID No. 83, SEQ ID No. 85, SEQ ID No. 87, and SEQ ID No.

89, optionally modified to improve their stability of selectivity, as disclosed for instance in EP 92574. They can also be DNA sequences whose expression in the cell produces RNA complementary to all or part of the calcium sensor protein mRNA.

These antisenses can be prepared by expression of all or part of the sequence selected from the group consisting of SEQ ID No. 3, SEQ ID No. 11, SEQ ID No. 83, SEQ ID No. 85, SEQ ID No. 87, and SEQ ID No. 89 in the opposite orientation (EP 140 308) Material and Methods Tissue specimens. Samples of human parathyroid glands were obtained at surgery of patients with primary HPT. Other human tissue specimens (kidney, epididymis, liver, pancreas, adrenal gland, small gut, spleen, lung and striated muscle) were sampled WO 96/15801 PCTIUS95/15203 from organs removed at surgery. Human placental tissue was collected in conjunction with uncomplicated pregnancies at full term. All specimens were immediately quick-frozen in isopentane and stored at -70 0

C.

Isolation of the calcium sensor protein from human placenta. The 500 kDa calcium sensor protein was isolated and purified, from altogether 25 human placentas, by immunosorbent and ion exchange chromatographies, following a previously described protocol The procedure utilizes two different monoclonal antiparathyroid antibodies Ell and G1l, known to bind different epitopes of the calcium sensing protein; Ell has displayed no functional effect, while Gll efficiently blocks calcium regulation in both parathyroid and placental cells After purification, the calcium sensor protein preparation was subjected to gel chromatography on a Zorbax gel column (9.2 x 250 mm), prior to enzymatic digestion.

The biologically active calcium sensor protein of the present invention has been isolated as described. It can also be prepared by chemical synthesis in a recombinant DNA biosystem.

Biologically active fragments of the calcium sensor protein can also be prepared using synthetic or recombinant technologies which are known in the art.

Cleavage and sequence determination of isolated peptides. Cleavage of the 500 kDa protein with endoprotease Lys C from Achromobacter lyticus generated peptides, which were subjected to separation on a Brownlee microbore C4 column (2.2 x 30 mm), equilibrated in 5% acetonitrile in 0.02% trifluoroacetic acid. A linear gradient of 5 to 60% acetonitrile in 0.02% trifluoroacetic acid was employed for peptide elution, monitored at 214 nm using Waters 990 diod-array detector (Millipore Corporation, Millford, Mass). Amino terminal sequences of the peptides were determined in an ABI 470A gas-phase sequenator, equipped with an ABI 120A PTH-amino acid chromatograph (Applied Biosystems, Foster City, Ca., USA).

Oligonucleotide synthesis. Oligonucleotides were synthesized using an ABI 381 oligonucleotide synthesizer (Applied Biosys- WO 96/15801 PCT/US95/15203 tems). The following oligonucleotide mixture was utilized as a probe for screening of the placental cDNA library: CCA ATA IAG CTG ATC CTC AAA GAT ATC IAG IGA ATA IGG ATT CAT IGC G G G G G G (SEQ ID No. 8) The following two oligonucleotides were synthesized for use in PCR reactions: GCG GAATTC GTA ATG CAA CCA GAC GG C G C T G G T T (SEQ ID No. 9) ATA GGATCC TG ATC CTC AAA AAT ATC G T G G G

T

(SEQ ID No. The first nine nucleotides contain an EcoR I and a BamH I site, respectively, and the remaining nucleotides correspond to amino acid residues 1 to 6 of peptides 293 and to residues 8 to 13 of peptide 292.

Screening of a placental cDNA library with a mixed oligonucleotide probe. A placental 1 gt 11 cDNA library (Clontech, Ca., USA) was plated out to a density of approximately 2 x 105 plaques within a 20x25 cm agar plate.

Replicate filters (Hybond-N+, Amersham) of ten plates were prehybridized in 5 x SSPE (SSPE; 120 mM NaC1, 8 mM NaH2PO4, 0.8 mM EDTA, pH 5 x Denhart's solution 0.5% SDS, single stranded salmon sperm DNA (Sigma Chemical Co., S:t Louis, Ohio). The mixed oligonucleotide probe, endlabeled with y- [32p]-ATP and polynucleotide kinase (Amersham), was added to the hybridization mixture (30 x 106 cpm in 50 ml), and hybridization was carried out over night at 42 0 C. The filter was washed twice in 2 x SSPE and once in 0.1 x SSPE, exposed to an autoradiography screen and analysed by a phosphorimager (Molecular Dynamics, Image Count S.W, Sun Valley Ca).

PCR reaction.

Part of the X gt 11 cDNA clone CAS-1 was WO 96/15801 PCT/US95/15203 amplified by PCR using two degenerated probes corresponding to portions of peptides 292 and 293. The following conditions were used: 170 ng template DNA, 1 pmol of each oligonucleotide mixture as primers, dNTP 3mM, Taq-polymerase 0.75 u. The reaction was carried out in 20 pl. of lOmM Tris-HCl, pH 8.0, mM MgC12, 50mM KC1 in a Perkin-Elmer 9600 PCR-machine (Perkin-Elmer, Norwalk, USA). Two cycles of denaturation at 94 0

C

for 2 min. annealing at 47 0 C for 1 min and extension at 72 0 C for 1 min 30 sec were followed by 33 cycles of 94 0 C for 1 min. 54 0

C

for 45 sec. 72 0 C for 1 min and a final extension at 72 0 C for min.

Screening of a placental cDNA library with a PCR-fragment as probe. A placental X ZAP-II cDNA library, was screened with the PCR-fragment from the cDNA clone CAS-1 labeled by random priming as the probe. The screening was carried out as above. 2 x 106 plaques distributed on ten 20 x 25 cm agar plates were screened.

Nucleotide sequence determination. The insert of the phage clone CAS-2 was released from the phage vector in the Bluescript+ vector using a helper phage (Stratagene, La Jolla, Nucleotide sequence reactions were carried out according to the cycle sequencing procedure, utilizing a kit from Applied Biosystems. Sequences were analyzed in an ABI 373 A DNA sequenator using the Data Collection Program VIII software (Applied Biosystems). Completion of the CAS-2 2.8 kb cDNA sequence was accomplished by the dideoxynucleotide chaintermination method with Sequenase (United States Biochemical) and is shown in Figure 6(SEQ ID No. 11). Multiple sequencing analyses were performed on both strands of CAS-2 to confirm the sequence. Amino acid sequence deduced from the cDNA sequence was analyzed by a Macvector DNA/RNA software analysis package (Macintosh).

Reverse transcriptase PCR amplification and standard 32 p_ labeled probe screening of human lambda kidney cDNA libraries were used to complete the cloning of the CAS cDNA (SEQ ID No.

83).

Full-length human placental (SEQ ID No. 85), kidney (SEQ ID No. 87) and parathyroid (SEQ ID No. 89) CAS cDNA sequences were WO 96/15801 WO 9615801PCTIUS95/15203 obtained from PCR amp~lified human placental, kidney and parathyroid cDNA libraries as follows. Specifically primed first-strand cDNA was prepared using oligonucleotide primers designed off SEQ ID No. 83, total RNA PNAzol B method (Tel- Test), and a cDNA synthesis kit (Promega). The following primers with indicated sequence positions were used in the reactions: Fl s GCAGACCTAAAGGAGCG'I G7as CCCGACCATTGGAGAAGATA G2 Os GCCAGTACCAGTGCCATGA G2 9as CCTCATGACACTGATACTCTTI G2 6s GGCTGTGAGCAGGTCTGT Gi Gas CGACCACTAA'ITGAATCAAAATC Gl 6s CGGTGCTCGTGTGATACAG E2 as ATCCACATCCACATGCAG E4 s CCTCAAATGGCTGTAGCAACAA B9 as CTGCTGCTGCACGTGTGA s CCAGTCTGGATACACAAAATGT 23.5 GGCGCACTGCCAITC Gi 9s CTCAGATGGCTCTGATGAACT G3 6as GCGTTrTCTCTITC TITCC'FI G3 5s GAGAGTCATI'GCAAAGGAAGCA G3 las AATATATGTGCAAAAGTGTG TFI Four separate reverse trancriptase (RT) using the following primers: 1 1311 1054 2540 2109 4540 4338 6413 6157 8704 8570 10, 910 10,718 13, 026 12, 893 14,120

SEQ

SEQ

SEQ

SEQ

SEQ

SEQ

SEQ

SEQ

SEQ

SEQ

SEQ

SEQ

SEQ

SEQ

SEQ

SEQ

ID No. 91 ID No. 92 ID No. 93 ID No. 94 ID No. ID No. 96 ID No. 97 ID No. 98 ID No. 99 ID No. 100 ID No. 101 ID No. 102 ID No. 103 ID No. 104 ID No. 105 ID No. 106 reactions were performed RT reaction 1 (RT1) (RT2) (RT3) (RT4) primer G29as primer E2as primer 23.5 primer G3las The following primers were used for PCR with listed RT reaction: ur imer Fls/G7as G2Os/G29as G26s /Gl6as Gl6s /E2as E4s/B9as B5s/23 .5 Gl9s /G3 Gas G35s/G3las RT reaction RT1 RT1 RT2 RT2 RT3 RT3 RT4 RT4 PCR amplification of first-strand cDNA was performed in a Perkin-Elmer 9600 Thermal Cycler using the following program: 1 cycle of denaturation at 94 0 C for 2 min., followed by 40 cycles of denaturation at 9400 for 15 sec., annealing at 510C for WO 96/15801 PCTUS95/15203 sec., and extension at 72 0 C for 3 min., after which, the products of the reactions were separated by electrophoresis and gel purified (QIAGEN). PCR reagents were purchased from Perkin- Elmer and used according to manufacturer's suggestions.

PCR

fragments were then nucleotide sequenced using a dideoxynucleotide chain-termination method (Perkin-Elmer Prism Dye Deoxy Terminator Cycle Sequencing Kit), and an ABI 373 automated DNA sequencer (Applied Biosystems). PCR fragments from four separate reactions were sequenced on both strands to confirm sequence data. Computer generated DNA sequence analysis was performed using Auto-Assembler and Factura (Applied Biosystems), and MacVector and AssemblyLIGN (Eastman Kodak Company) software programs.

Database search. The EMBL-31 database in the Intelligenetics format (Intelligenetics Rel.5.

4 was searched for sequence similarities to the placental cDNA sequence using the FAST DB algorithm (13).

Immunostaining and Northern blot. Immunohistochemical studies were performed on acetone-fixed, 6 pun thick frozen sections, utilizing the monoclonal antiparathyroid antibodies Ell and Gll, at concentrations of 5 gg/ml, together with a mouse peroxidase antiperoxidase technique on human placental, parathyroid, kidney, and epididymis specimens as well as on the other human tissues see above Monoclonal antibodies to collagen-type II were used as negative controls (14).

Total RNA was extracted from tissue samples by the acid phenol/chloroform method. For Northern blot analysis approximately 10 ~g of total RNA was electrophoresed in a 1.5%/37% agarose/formaldehyde gel, blotted onto nylon membranes (Qiabrane, Diagen GmbH, Dusseldorf, Germany) and probed with the 2.3 kb clone (see results) labeled by the random priming method.

Hybridizations were performed at 42 0 C for 18-24 h in formamide, 4 x saline sodium citrate (SSC; 300 mM NaCl, 30 mM Na-citrate, pH 2 x Denhart's solution, 10% dextran sulfate (Kabi-Pharmacia, Uppsala, Sweden) and 100 pg/ml salmon sperm DNA. Filters were washed at a final stringency of 1 x SSC/O.1% WO 96/15801 PCT/US95/15203 '3 SDS for 30 sin at 42 0 C, and exposed within a phosphorimager as above.

CAS Peptide Binding Analysis: A peptide corresponding to one putative CAS SH3 binding region (ATPPPSPSLPAKPKPPSRR)

(SEQ

ID No. 18) was synthesized on an ABI model 430A synthesizer using FastMoc t m chemistry. The peptide was HPLC purified and analyzed by mass spectroscopy. 5 mg of the peptide was coupled to 500 ul of Amino Link (Pierce) agarose as described by the supplier. Efficiency of coupling was checked by RP-HPLC of peptide solution before and after coupling and spectrophotometrically at a wavelength of 220 nm. Both methods indicated a coupling efficiency of The coupled peptide was reacted with 5 ug aliquots of various GST-SH3 fusion proteins at room temperature for 1 hour before the resin was washed extensively with TTBS. The resin was boiled in SDS loading dye and electrophoresed on an SDS-PAGE gel. Binding ability of the various SH3 proteins for the peptide was judged by the relative intensity of the Coomassie blue-stainable bands on the SDS gel. GST protein alone was used alone as a control.

Expression and Purification of GST-SH3 fusion Proteins: Various GST-SH3-containing fusion clones were kind gifts from Dr. I.

Gout, Ludwig Inst. for Cancer Research, London, UK. The fusion proteins were all produced by inducing their expression in XLlblue E. coli using 1 mM IPTG. Cells containing the fusion proteins were sonicated in PBS containing 10 mM EDTA and 1% Triton-X 100. After pelleting cell debris, the cleared lysate was applied to a glutathione-Sepharose column (Pharmacia), and the bound fusion protein was eluted with 10 mM reduced glutathione in 50 mM Tris pH 8.0. These purified fusion proteins were then dialyzed extensively against PBS before being used in all subsequent experiments. Protein was quantified by measuring the absorbance at 280 nm followed by characterization by SDS polyacrylamide gel electrophoresis.

RESULTS

Isolation of the calcium sensor protein, peptide cleavage and sequence determination.

WO 96/15801 PCT/US95/15203 The calcium sensor protein was purified from placental tissue by means of Pectin chromatography, immunosorbent chromatography utilizing the immobilized monoclonal antiparathyroid antibodies, and finally ion exchange chromatography The same antibodies were used in a sandwich ELISA to monitor the purification In order to avoid contamination with low molecular peptides, the whole final preparation, consisting of 200 jig of the 500 kDa protein chain was made 6 M with regard to- guanidine-HCl and applied to a gel chromatography column, equilibrated with 2 M guanidine-HCl, 0.1 M Tris-Cl, pH 8.5. The column was eluted with the same buffer.

Virtually all protein material emerged close to the void volume at the expected position for a protein with a molecular mass of 500 kDa. Separate fractions containing this material were combined and endoproteinase Lys C (1 gg) was added. The digestion was allowed to proceed over night at 37 0 C. The fragmented protein was reduced by incubation with 0.1% 9mercaptoethanol at 37 0 C for 30 min and subsequently alkylated with 4-vinyl pyridine at room temperature for 2 h. The peptide mixture was then applied to a reversed phase C4 column equilibrated in 5% acetonitrile in 0.2% trifluoroacetic acid.

Peptides were eluted by a linear gradient of 5 acetonitrile in 0.02% trifluoracetic acid (Fig Due to the large number of peptides, the elution pattern was complex.

Several peptide fractions were sequenced in .a gas phase sequenator and easily interpretable sequences were obtained for two fractions (Fig 2, SEQ ID Nos. 1 and 2).

Isolation of a cDNA clone encoding the 500 kDa calcium sensor.

An oligonucleotide mixture (48 bp) was constructed to encode amino acid residues 2 to 17 of the sequenced peptide 292. To reduce the complexity of the oligonucleotide mixture, five inosine bases were inserted at degenerated positions where no guidance could be 'obtained from the codon usage in humans. At nine positions, where two bases were possible, one of the bases was suggested with a likelihood exceeding 70% from codon usage, and was therefore used in the oligonucleotide mixture.

The mixed oligonucleotide was radioactively labelled and WO 96/15801 PCT/US95/15203 used as a probe to screen a human placental X gt 11 cDNA library. Approximately 2 x 106 plaques were screened and a single positive clone, CAS-1, was found. The insert of this clone was estimated to 2.3 kb, by restriction mapping. To obtain a recognizable sequence of the clone in a rapid way, an attempt was made to PCR amplify part of the sequence using degenerated oliogonucleotides corresponding to part of peptides 292 and 293 as primers. A distinct DNA fragment of approximately 430 bp was obtained assuming that the peptide 292 is located carboxyterminal to peptide 293. The fragment was partially sequenced using the oligonucleotide mixture corresponding to peptide 293 as the primer. In one reading frame from the obtained sequence, the sequence VGRHI could be deduced, in excellent agreement with the carboxyterminal 5 amino residues of peptide 293. To obtain a clone with a larger insert a human placental X ZAP-II cDNA library reported to contain clones with large inserts was screened with the PCR fragment as the probe. From 2 x 106 plaques a single clone, CAS-2, was found. The insert of this clone, estimated to 2.8 kb, was released in the Bluescript vector, using a helper phage. Part of the insert of this clone, pCAS-2, was sequenced using synthetic oligonucleotides as primers (Fig 3, SEQ ID No. An open reading frame was found containing both peptide 292 and 293. There was perfect agreement between the peptide sequences and the predicted amino acid sequence (SEQ ID No. 4) from the cDNA clone. The complete sequence of the 2.8 kb CAS-2 is shown in Figure 6 (SEQ ID No.

11).

The CAS-2 sequence was extended using standard methodology.

Reverse transcriptase PCR amplification and standard 32 p-labeled probe screening of human lambda kidney cDNA libraries were used to complete the cloning of the CAS cDNA (SEQ ID No. 83). Probe fragments were designed off appropriate clones, starting with clone pCAS-2 (Figure 11), to allow isolation of overlapping but clones from these libraries. This cDNA walking procedure was used for the isolation of all cDNA clones except clones pMeg2, pHPlC8, pHPlBl, and pM4Bl. These clones were isolated from human kidney cDNA libraries using rat gp330 PCR amplified probe fragments (nts. 148-1249, 2892-3873, 4553-5693, and 5868-6968) obtained with rat -cDNA prepared from rat kidney WO 96/15801 PCTIUS95/15203 total RNA. Three small cloning gaps (aa 564-997, 1622-1836, and 2212-2312;) were completed by direct PCR amplification through these regions using specific human gp330 oligonucleotide primers and cDNA prepared from human kidney total RNA (CAS-1750, -1210, and -700).

An extended calcium sensor sequence is shown in SEQ ID No.

17. A complete human calcium sensor sequence in shown in SEQ ID Nos. 83 and 84. Based on the above cloning procedure amino acids 1-3711 of SEQ ID No. 84 were determined from human kidney cDNA whereas amino acids 3712-4655 were identified from the CAS- 2 placental cDNA clone (Figure 11).

Full-length human placental (SEQ ID Nos. 85 and 86), kidney (SEQ ID Nos. 87 and 88) and parathyroid (SEQ ID Nos. 89 and CAS cDNA and amino acid sequences have been determined by sequencing PCR fragments from specifically primed first-strand human placental, kidney and parathyroid cDNA, prepared using oligonucleotide primers designed off SEQ ID No. 83, total RNA RNAzol B method, and a cDNA synthesis kit as described in Material and Methods.

Comparison of all CAS sequences obtained so far reveals only four potential differences throughout the complete amino acid sequence: Ala 1287 to Ala/Pro, Ala 2 8 7 2 to Thr, Lys 4 0 9 4 to Lys/Glu, and Ile 42 10 to Ile/Leu (Figure 12). The ambiguous positions and the minor amino acid differences are most likely associated with normal ethnic and/or allelic variation differences being reflected in the cDNA sources used in constructing the cDNA libraries.

The 500 kDa placental calcium sensor belongs to the LDLreceptor superfamily.

A search in a database with the predicted amino acid sequence from Figure 3 (SEQ ID No 3) revealed that the placental 500 kDa protein is homologous to receptors belonging to the LDL-receptor superfamily. The highest similarity was found with the rat Heymann nephritis antigen (11, 67). Fig 4 shows an alignment of placental 500 kDa protein sequence to the sequence of the Heymann antigen (SEQ ID No. 5) as well as to two other members of the same protein superfamily, the LDL-receptor (SEQ ID No. 6) WO 96/15801 PCT/US95/15203 17 and the LDLreceptor-related protein (identical to the a 2macroglobulin receptor, (11,15,16), SEQ ID No. The sequence identity between the placental calcium-sensor and the Heymann antigen gp330 was estimated to be 82% in the region of comparison (236 amino acid residues). A complete sequence of the human calcium sensor protein is shown in SEQ ID No. 83.

Overall, the identity between rat gp330 and the human homolog is 77%. The structure of human gp330 is shown in Figure 10. The protein is 4655 amino acids in length and comprises an Nterminal signal peptide of 25 amino acids, a 4398 amino acid extracellular domain, a transmembrane region of 23 amino acids and a C-terminal domain of 209 amino acids. As shown in Figure the structure of human gp330 closely correlates with that of the rat homolog (Figure 3 of ref. 67).

Immunohistochemistry and Northern blot.

The close similarity between the placental 500 kDa calciumsensor protein and the rat Heymann nephritis antigen prompted the expanded immunohistochemical investigation of the present.

study. The antiparathyroid antibodies (Ell and Gil) were found to stain not only parathyroid, placental and proximal kidney tubule cells but also epididymal cells, as previously demonstrated for antibodies reactive with the Heymann antigen (17-20).

Northern blot analysis of total RNA (approximately 10 g/lane) from human kidney, placenta and parathyroid glands with the identified 2.8 kb clone as the probe, revealed one major hybridizing RNA species of approximately 15,000 bases in all these tissues (Fig Human liver, pancreas, adrenal gland, and small gut (Fig 5) as well as spleen, lung and striated muscle (not shown) lacked hybridizing species.

Identification of SH2 and SH3 binding regions in the cytoplasmic domain of the calcium sensor: Src-homology regions 2 and 3 (SH2 and SH3) are conserved sequence motifs consisting of approximately 100 and 60 amino acid residues, respectively, and are found in many eukaryotic proteins with diverse function (42-44). SH3 domains have been WO 96/15801 PCT/US95/15203

/F

identified in several cytoskeleton-associated proteins, such as p80/p85, myosinlb, spectrin, neutrophil NADPH oxidase-associated proteins p4 7 and p67, and in several yeast proteins important for morphogenesis Bemlp and ABP-1), mating (FUS1) or for regulation of ras activity (cdc25 and ste6 (for review see Mussachio et al. The observation that many SH3containing proteins are cytoskeleton-associated led to the suggestion that SH3 domains play a role in multimeric protein complex formation at or near cytoplasmic membranes. Some proteins that contain both SH2 and SH3 domains perform the function of adaptor molecules by joining activated receptor tyrosine kinases with p 2 1 ras guanine nucleotide-releasing protein (GNRP). For example, Grb2 and its homologues bind to phosphotyrosine on activated membrane-anchored receptor tyrosine kinases through their SH2 domain and to SOS through their aminoand carboxyterminal SH3 domains (46-50). These processes lead to translocation of SOS to the plasma membrane where ras proteins are interacted with and consequently activated. Thus, SH2/SH3-containing and SH2/SH3-binding proteins are involved in a highly conserved signal transduction pathways from activated receptors.

Complete nucleic acid sequencing and translation of the 2.8 kb human cDNA clone CAS-2 (Figure 6) (SEQ ID Nos. 11 and 12) demonstrate the existence of at least three potential SH3 binding regions denoted as CAS-PEP1 (SEQ ID No. 14), CAS-PEP2 (SEQ ID No. 15), and CAS-PEP3 (SEQ ID No. 16) (Figure All three of these CAS-2 cytoplasmic peptide regions have the required consensus sequence of a SH3-binding region, which is shown together with the CAS peptides in Figure 7 Further support that the cytoplasmic domain of CAS-2 binds SH3 regions is shown in the evidence in Figure 8. A region of the CAS-2 cytoplasmic domain (ATPPPSPSLPAKPKPPSRR) (SEQ ID No. 18) that included CAS-PEP1 (PSLPAKP, Figure 7) was synthesized. The peptide was incubated with various purified GST-SH3 fusion proteins and the relative binding strengths of the fusion proteins was assayed by SDS-PAGE (Figure The data clearly indicate that several of the SH3-region containing proteins had an affinity for the peptide containing CAS-PEP1, with the following relative order of decreasing affinities: LANE 6: SH3- WO 96/15801 PCT/US95/15203 PI3K (SH3 of p85 subunit of phosphoinositol- 3 kinase, (54,55)) LANE 7: SH3-PLC-gamma, (phospholipase-C gamma, LANE 2: SH3-FYN (src-family soluble tyrosine kinase, LANE 4: SH3-GRB2, (growth factor receptor binding protein N-terminal SH3) and LANE 5 (C-terminal SH3 of GRB2) (58,59).

Significantly, all of the positive reacting SH3-containing proteins shown in Figure 8 are intimately associated with signal transduction and stimulation of cell growth (54-59). PI3K contains two SH2 regions and one SH3 region. PI3K is relatively new to the family of signal transducing molecules, but appears to be involved with insulin signaling through the glucose transporter, and is believed to associate directly with the ras protein. PLC-gamma is a well known signaling molecule also containing two SH2 regions and one SH3 region, and is known to hydrolyze membrane lipids to other powerful downstream signaling molecules (eg. IP3 and diacylglycerol) when stimulated by ligand activated growth factor receptors. FYN is a highly characterized member of the src-family of soluble tyrosine kinases known to be intimately associated with cell growth and differentiation. FYN contains one SH2 and one SH3 region, is also known to be stimulated by ligand activated growth factor receptors. GRB2 contains two SH3 regions and one SH2 region, and is known as an adaptor molecule in that it has no known intrinsic enzymatic capabilities. GRB2 molecules are also stimulated by ligand activated growth factor receptors. It is also worth noting that SH3-GAP (GTP-ase activating protein, LANE 3, (60, and SH3-NCF (neutrophil cytotoxic factor-type 1, LANE 8, or -type 2, lane 9, (62, 63)) had little or no affinity for the peptide containing CAS-PEP1. This evidence supports the specificity of the interaction between the CAS-PEP1 and various SH3 domains. In addition, CAS-PEP1 does not bind a control GST fusion protein as shown in lane 1 of Fig. 8.

The cytoplasmic domain of CAS-2 also comprises a p85-SH2 binding region. Though different SH2 containing proteins all require phosphorylated tyrosine residues for an interaction, it is well established that the amino acid residues surrounding the tyrosine residue dictate the specificity and strength of the interaction Figure 9 defines those amino acid sequence requirements that are necessary for interaction with the SH2 WO 96/15801 PCTfUS95/15203 region of the p85 regulatory sbunit of PI3K. The evidence clearly shows that for a binding interaction to take place with the SH2 region of p85, the tyrosine residue must be included in the amino acid sequence motif YXXM (where can be any amino acid), and must have an acidic amino acid residue (D or E) approximately 3-5 residues in either direction of the YXXM motif. This exact amino acid sequence requirement exists in the .cytoplasmic domain of CAS-2 (FENPIYAQMENE) (SEQ ID No. 19), and is underlined in the CAS-2 cytoplasmic sequences at the top of Figure 9.

Altogether, the evidence demonstrates that the cytoplasmic domain of the calcium sensor protein of the invention contains three consensus SH3 binding regions and one potential SH2 recognition region of the type recognized by the SH2 region of p 85 and supports an involvment of SH2 and SH3 mediated signal transduction for biological activity of the calcium sensor protein, possibly through PI3K. The potential interaction of PI3K with the calcium sensor protein is even more interesting in light of recent evidence linking the CAS-2 protein to calcium sensing in human parathyroid tissue, given that calcium sensing appears to involve G-protein activation, PKC activation, and inositol phosphate generation, all of which are activities that can be associated with PI3K signal transduction cascades.

Therefore, these regions provide useful tools in assays for the identification of compounds that either stimulate or inhibit the signal transduction pathways used by the calcium sensor protein.

Using assay techniques known to those skilled in the art, agonists or antagonists which mimic or inhibit the activity of the calcium sensor protein SH2/SH3 regions will be useful for the treatment of diseases that are intimately associated with the sensor, such as primary hyperparathyroidism (HPT) (52) and osteoporosis.

The relation of the calcium sensor protein to the LDLreceptor superfamily of proteins was noted above. All of the members of the LDL-receptor superfamily are 'scavenger' proteins. None of these scavenger proteins have recognized signal transduction regions, and specifically, none of these scavenger proteins contain SH regions. Therefore it was WO 96/15801 PCT/US95/15203 .2/ entirely unexpected to identify SH2 and SH3 binding regions active in signal transduction in the calcium sensor protein.

The occurrence of these regions is a further indication that the calcium sensor protein is not a scavenger protein, even though it has regions of homology with the LDL-receptor superfamily of scavenger proteins.

Rat Heymann nephritis antigen, gp330, belongs to the LDL receptor superfamily -of large, multifunctional glycoproteins (68, 69, 70). Identification of the calcium sensor protein as the human homolog of rat gp330 enables new diagnostic and therapeutic agents for human disease.

Examples of diagnostic and therapeutic uses for gp330, or biologically active fragments thereof, are disclosed in EP 358,977, the entire contents of which are incorporated herein by reference. For example, human gp330, or fragment thereof, may be used in assays for detecting autoantibodies associated with human membranous glomerulonephritis. Examples of suitable assays include immunoassays, such as ELISA. Alternatively, synthetic peptides based on the human gp330 sequence may be used to localize immunodominent B- or T-lymphocyte recognition sites.

Therefore, the invention enables detection of gp330 specific autoantibodies and helper, cytotoxic or suppressor T-cells. The invention permits identification of patients who may develop idiopathic autoimmune membranous glomerulonephritis and patients susceptible to autoimmune membranous glomerulonephritis following a renal allograft.

Human gp330 is useful for treatment of human membranous glomerulonephritis according to a variety of methods, For example, gp330 may be coupled to a polyphenol followed by immunization of a patient according to U.S. Patent 4,702,907, the entire contents of which are incorporated herein by reference. Treatment in this manner results in selective immunosupression of antibodies specific for gp330. As an alternative method of treatment, it is also possible to selectively remove gp330-reactive autoantibodies from sera by immobilizing gp330, or fragment thereof, on a solid support and WO 96/15801 PCT/US95/15203 pass the sera over the support, thereby effectively removing autoantibodies characteristic of human membranous glomerulonephritis. Alternatively, human gp330, or a fragment thereof, can be directly administered to a patient in order to perturb formation of immune complexes. Synthetic peptides based on the sequence of human gp330 are also useful therapetically.

Administration of immunogenic peptides inhibits activation or function of gp330 specific helper and cytotoxic T-cells.

The structure of human gp330 includes 16 growth factor repeats separated by 8 YWTD spacer regions and 1 epidermal growth factor repeat in the immediate extracellular juxtamembrane region (Figure 11). Therefore, administration of gp330, or a fragment thereof having growth factor activity, is useful in the treatment of wounds, such as burns and abrasions.

Epidermal growth factor is also a potent inhibitor of gastric acid secretion. Therefore, gp330, or a fragment thereof having epidermal growth factor activity, is useful for treatment or prevention of gastric ulcers. Determination of effective amounts of therapeutic agent for administration is within the skill of the practitioner.

Discussion The important role of the parathyroid as key regulator of the calcium homeostasis has been related to its exquisite capacity to sense and respond to variation in the extracellular Ca 2 ion concentration. Essential for recognition of changes in external calcium is a cation receptor or sensor of the parathyroid cell membrane, the presence of which was implicated by a series of in vitro studies on parathyroid cell regulation 10, 21-24). The concept of a cell membrane receptor was further substantiated when monoclinal antiparathyroid antibodies were found to recognize and interfere with the calcium sensing of parathyroid cells Another crucial piece of evidence was obtained when cytotrophoblast cells of the human placenta, selected by their reactivity with the antiparathyroid antibodies, displayed parathyroid-like sensing of changes in external calcium, a function which also could be blocked by one of the anti-parathyroid antibodies The calcium sensor of WO 96/15801 PCT/US95/15203 ?13 the placenta was subsequently isolated by immunosorbent and ion exchange chromatographies and shown to consist of a large glycoprotein of approximately 500 kDa molecular size It was also demonstrated by immunoprecipitation that a protein of the same size reacted with the antiparathyroid antibodies within the parathyroid and kidney tubule cells (to be published, The parathyroid calcium sensor or receptor is known to have features in common with most other classical receptors for cellular activation, although it exhibits the unusual ability to bind and be activated by divalent cations. Cation binding triggers biphasic rise in [Ca 2 i] and concomittant activation of phospholipase C, possibly via a coupled G-protein, with a resulting accumulation of inositol phosphates An initial transient rise in [Ca 2 is due to inositoltrisphosphate (Ip3)induced mobilization of Ca 2 from intracellular sources, while an ensuing steady-state elevation in [Ca 2 is caused by calcium gating through plasma membrane channels, possibly mediated by increase in inositoltetraphosphate (Ip4) (9,10,23).

Sequence analysis of a partial cDNA clone and data-base comparison of the deduced amino acid sequence showed that the placental calcium sensor protein belongs to the LDL-receptor superfamily of proteins, and available sequences showed close similarity with the rat Heymann nephritis antigen (11,15,16).

This antigen was originally described in the rat as a 330 kDa glycoprotein (gp 330), present within the proximal kidney tubule brush border, and in placental and epididymal cells, but by special staining techniques also demonstrated to occur sparsely on rat kidney glomerular cells, as well as on pneumocytes II in the lung and sporadic cells of the liver and small intestine (17-19). It has later been proposed that the molecular size of the protein was underestimated and actually should be in the range of 500 kDa The Heymann antigen has been revealed as the dominating antigen causing membranous, autoimmune glomerulonephritis in the rat after immunization with a crude tubular protein fraction (17,19). Using anti-gp 330 antibodies a protein with an estimated molecular size larger than 400 kDa has been identified in man The sequence identity of 77% WO 96/15801 PCT/US95/15203 0?V between the human placental 500 kDa calcium sensor protein and the rat Heymann nephritis antigen indicates that they represent related forms of the calcium sensor protein in two different species. This view is supported by close similarities in tissue distribution of the two proteins, as revealed by the immunohistochemistry of the present study. The antibodies Ell and G1l, reacting with the calcium sensor protein, thus stain parathyroid cells, proximal kidney tubule cells, placental cytotrophoblasts and also epididymal cells. Furthermore, we have recently reported staining with one of the antiparathyroid antibodies preferentially within coated pits and the base of the proximal tubule microvilli, which equals that previously described with antibodies against the gp 330 protein (19,26). A recognized glycoprotein of similar size within the tubule brush border, renal maltase, has been located mainly to microvillar membranes and not within the coated invaginations (18).

Thus far recognized members of the LDL-receptor superfamily, the LDL-receptor, the LDL-receptor-related protein and the Heymann antigen, have been thought to function as receptors for proteins, but all exhibit functionally important Ca2+-binding ability (16,27,28). Thus, Ca 2 binding is necessary for the interaction of the LDL-receptor with apo-B The LDL-receptor related protein (a2-macroglobulin receptor) is also known to bind Ca 2 which induces conformational changes, and Ca 2 is necessary for binding of activated a2-macroglobulin to the receptor Recently, the rat Heymann antigen was shown by a blotting technique to interact with Ca 2 (28).

The Ca 2 binding motifs of the calcium sensor protein remain to be identified. The sensor protein (as well as the Heymann antigen) contains EGF-like modules, like other members of the LDL-receptor superfamily (11,16,27), which may represent putative Ca 2 binding sites. Thus, when present in the coagulation factors IX, X and protein C, each EGF-like module is known to bind one Ca 2 ion (29-34), and the EGF-like modules have also been demonstrated to mediate Ca 2 +dependent protein/protein interaction Kinetic data have suggested that the calcium sensor displays positive cooperativity in its interaction with Ca 2 a phenomenon which appears essential for WO 96/15801 PCT/US95/15203 the sigmoidal regulation of [Ca 2 and PTH release, with a steep relation within the physiological range of extracellular calcium The positive cooperativity should require multiple binding sites for Ca 2 possibly resulting from the repetitive EGF-like modules, generally present in molecules of the LDL-receptor superfamily (11,16,27). However, Ca 2 binding to EGF-like domains are known to induce only minor, localized pertubations of the three-dimensional structure and it is possible that the calcium sensor contains also other Ca 2 binding sites.

A 43 kDa membrane protein (a2-macroglobulin receptorassociated protein, or Heparin-binding protein) (28,36) is known to interact both with the LDL-receptor-related protein and with the rat Heymann antigen in a Ca2+dependent manner No physiological function has yet been assigned to this protein, but it appears also in tissues where the Heymann antigen and the LDL-receptorrelated proteins are not expressed An intriguing observation is the presence of a putative leucinezipper motif in the aminoterminal part of the 43 kDa protein considering that such motifs have been suggested to influence the opening and closure of membrane ion channels (37).

Since the 43 kDa protein interacts with the Heymann antigen, it can be assumed to form a complex also with the calcium sensor protein in a Ca 2 +-dependent manner. Interaction with the 43 kDa protein might be important for the transmission of Ca2+induced conformational changes within the extracellular portion of the molecule to the cell interior. It is also possible that additional proteins interact with the calcium sensor in a Ca2+dependent manner, and that such an interaction is important for the modulation of the sensor response. The mechanisms by which an activated calcium sensor triggers further signalling to the cell interior is unknown, although we have in preliminary experiments utilized immunoprecipitation to isolate a phosphorylated form of the sensor protein in dispersed parathyroid cells loaded with 3 2 p]-orthophosphate (unpublished observation).

The calcium sensor protein of the placenta may be involved WO 96/15801 PCT/US95/15203 .26 in maintenance of a feto-maternal Ca 2 gradient and placental Ca 2 transport, possibly by mediating calcium regulation of the parathyroid hormone related peptide (PTHrP) production and/or 1,25 (OH)2D3 metabolism Its presence already within the blastocyst (unpublished observation) may indicate a function also as adhesion molecule, or implicate involvement in .differentiation or 'growth regulation, as suggested for the Heymann antigen The function of a calcium sensor within the kidney tubule brush border is less well explored. However, it should be noted that the enzyme l-a-hydroxylase present in the placenta and proximal kidney tubule, is regulated by extracellular calcium, and the calcium sensor might accordingly regulate 1,25 (OH)2D3 metabolism, but it may possibly also influence Ca 2 reabsorption from the glomerular filtrate The significance of the presence of the calcium sensor protein on epididymal cells, as well as rat pneumocytes, liver and intestinal cells as implicated by the distribution of the Heymann antigen (18,19), yet remains unknown. It has, however, been proposed that several cell types may exhibit Ca 2 sensing ability for regulation of various functions, separate from the general calcium homeostasis, either during development or in the differentiated state The association with autoimmune nephritis substantiates that the Heymann antigen is an immunogen molecule. This may have implication also in parathyroid disorder, as we have recently reported the presence of circulating parathyroid autoantibodies and induction of class II transplantation antigen in the pathological parathyroid tissue of patients with primary HPT.

These findings suggested that autoimmune phenomena may be involved in HPT (39) and autoimmunity has also been implicated in the pathogenesis of rare idiopathic hypoparathyroidism The availability of cDNA clones for the calcium sensor should, enable extended studies on the pathophysiology in parathyroid disorder, and also in vestigation of a possible genetic abberration affecting the calcium sensing function of the parathyroid and kidney tubule in kindreds with familial hypocalciuric hypercalcemia (FHH) (40,41).

The skilled person within this art realizes that the information obtainable from the nucleotide sequences of SEQ ID No. 3, SEQ ID No. 11, SEQ ID No, 83, SEQ ID No. 85, SEQ ID No. 87, and SEQ ID No. 89 can be used for isolating the genomic sequence encoding the calcium sensor. Preferably, an analysis of overlapping cDNA clones in conjunction with PCR techniques is used. the genomic sequence can be obtained from the analysis of overlapping genomic cosmid and/or lambda phage clones.

The term "comprises/comprising" when used in this specification is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

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WO 96/15801 PCT/US95/15203 33 SEQUENCE LISTING GENERAL INFORMATION:

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STREET: 620 Christian Street, Apt. 1A WO 96/15801 PCT/US95/15203 CITY: Philadelphia STATE: Pennsylvania COUNTRY: USA POSTAL CODE: 19147 (ii) TITLE OF INVENTION: Human Calcium Sensor Protein, Fragments Thereof and DNA Encoding Same (iii) NUMBER OF SEQUENCES: 106 (iv) CORRESPONDENCE ADDRESS: ADDRESSEE: Rhone-Poulenc Rorer Inc.

STREET: 500 Arcola Rd., 3C43 CITY: Collegeville STATE: PA COUNTRY: USA ZIP: 19426-0107 COMPUTER READABLE FORM: MEDIUM TYPE: Floppy disk COMPUTER: Macintosh OPERATING SYSTEM: System 7.1 SOFTWARE: Word 5.1 (Patentin) (vi) CURRENT APPLICATION DATA: APPLICATION NUMBER: PCT FILING DATE:

CLASSIFICATION:

(vii) PRIOR APPLICATION DATA: APPLICATION NUMBER: US 08/344,836 FILING DATE: 23-NOV-1994 (vii) PRIOR APPLICATION DATA: APPLICATION NUMBER: US 08/487,314 FILING DATE: 07-JUNE-1995 (viii) ATTORNEY/AGENT INFORMATION: NAME: Savitzky, Martin REGISTRATION NUMBER: 29,699 REFERENCE/DOCKET NUMBER: A1355B-WO (ix) TELECOMMUNICATION INFORMATION: TELEPHONE: 610-454-3816 TELEFAX: 610-454-3808 INFORMATION FOR SEQ ID NO:1: SEQUENCE CHARACTERISTICS: LENGTH: 17 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: Xaa Ala Met Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gln Leu Tyr WO 96/15801 PCT/US95/15203 Trp INFORMATION FOR SEQ ID NO:2: SEQUENCE CHARACTERISTICS: LENGTH: 13 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Xaa Val Met Gin Pro Asp Gly Ile Ala Xaa Asp Trp Val INFORMATION FOR SEQ ID NO:3: SEQUENCE CHARACTERISTICS: LENGTH: 804 base pairs TYPE: nucleic acid STRANDEDNESS: double TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (ix) FEATURE: NAME/KEY: CDS LOCATION: 1..804 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:

AAA

Lys 1 TAC GTA ATG CAG CCA GAT GGA ATA GCA GTG GAC TGG GTT Tyr Val Met Gln Pro Asp Gly Ile Ala Val Asp Trp Val GGA AGG 48 Gly Arg CAT ATT TAC His Ile Tyr CTT GAT GGA Leu Asp Gly

TGG

Trp TCA GAT GTC AAG Ser Asp Val Lys

AAT

Asn 25 AAA CGC ATT GAG GTG GCT AAA Lys Arg Ile Glu Val Ala Lys AGG TAC AGA AAG Arg Tyr Arg Lys CTG ATT TCC ACT Leu Ile Ser Thr CTG GAC CAA 144 Leu Asp Gln CCA GCT GCT ATT Pro Ala Ala Ile GCT GTG AAT CCC AAA CTA GGG CTT Ala Val Asn Pro Lys Leu Gly Leu 55 ATG TTC TGG ACT Met Phe Trp Thr GAC TGG GGA AAG GAA CCT AAA ATC GAG TCT GCC TGG ATG AAT GGA GAG Asp Trp Gly Lys Glu Pro Lys Ile Glu Ser Ala Trp Met Asn Gly Glu 70 75 GAC CGC AAC ATC CTG GTT TTC GAG GAC CTT GGT TGG CCA ACT GGC CTT Asp Arg Asn Ile Leu Val Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu 288 WO 96/15801

TCT

Ser

GAG

Glu

ATT

Ile

ATC

Ile

GAC

Asp

GCA

Ala 130

GAT

Asp

GTT

Val 115

AAG

Lys

TAT

Tyr 100

ATT

Ile

GAA

Glu

TTG

Leu

GAA

Glu

GCA

Ala

AAC

Asn

ACC

Thr

ATG

GAC

Asp

AAA

Lys 120

CCT

ATC

Ile

GAT

Asp

AGC

TAC

Tyr

GGG

Gly

CTG

AGT GAC Ser Asp 110 GAT AGG Asp Arg 125 ATC TTT PCT/US95/15203 TTC AAG Phe Lys AGA GTC Arg Val GAA GAC 336 384 432 Met Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp 135 140 CAG TTA TAC TGG ATA TCT Gin Leu Tyr Trp Ile Ser AAG GAA AAG GGA Lys Glu Lys Gly 145

AAA

Lys

CTC

Leu

CCC

Pro

GGA

Gly

AGC

Ser 225

CCC

150

TTT

Phe

ACT

Thr

AAC

Asn

GGA

Gly 210

ACC

Thr

CCA

GGG

Gly

CAA

Gin

CTT

Leu 195

TAC

Tyr

ACT

Thr

TGC

CAA

Gin

GTT

Val 180

TGC

Cys

AGC

Ser

GAG

Glu

GGA

Gly 165

CGA

Arg

AAA

Lys

TGT

Cys

TGT

Cys

AAG

Lys

ATC

Ile

CAG

Gin

GCC

Ala

GAT

Asp 230

AAA

Lys

TTT

Phe

ATC

Ile

TGT

Cys 215

GCA

Ala

GAG

Glu

CAT

His

TGC

Cys 200

CCC

Pro

GCC

AAA

Lys

CAA

Gin 185

AGC

Ser

CAA

Gin

ATC

ACG

Thr 170

CTC

Leu

CAC

His

GGC

Gly

GAA

GAA GTA TGG AAA Glu Val Trp Lys 155 CTG GTA GTG AAC Leu Val Val Asn AGA TAC AAT AAG Arg Tyr Asn Lys 190 CTC TGC CTT CTG Leu Cys Leu Leu 205 TCC AGC TTT ATA Ser Ser Phe Ile 220 CTG CCT ATC AAC

CAA

Gin

CCT

Pro 175

TCA

Ser

AGA

Arg

GAG

Glu

CTG

AAT

Asn 160

TGG

Trp

GTG

Val

CCT

Pro

GGG

Gly

CCC

480 528 576 624 672 720 768 Ala Ile Glu Leu Pro Ile Asn Leu Pro 235 240 AGG TGC ATG CAC GGA Pro Pro Cys Arg Cys Met His Gly 245 GGA AAT TGC TAT TTT GAT GAG ACT Gly Asn Cys Tyr Phe Asp Glu Thr 250 255 GAC CTC CCC Asp Leu Pro

AAA

Lys 260 TGC AAG TGT CCT Cys Lys Cys Pro GGC TAC ACC 804 Gly Tyr Thr INFORMATION FOR SEQ ID NO:4: SEQUENCE

CHARACTERISTICS:

LENGTH: 268 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: Lys Tyr Val Met Gin Pro Asp Gly Ile Ala Val Asp Trp Val Gly Arg 1 5 0 His Ile Tyr Trp Ser Asp Val Lys Asn Lys Arg Ile Glu Val Ala Lys 25 WO 96/15801 Leu Asp Giy Arg Tyr Arg Lys' Trp Leu Ile Pro Ala Ala Ile Ala Val Asn Pro Lys Leu 50 Asp Trp Gly Lys Glu Pro Lys Ile Giu Ser Asp Arg Asn Ile Leu Vai Phe Giu Asp Leu 85 Ser Ile Asp Tyr Leu Asn Asn Asp Arg Ile 100 105 Giu Asp Vai Ile Giu Thr Ile Lys Tyr Asp 115 120 Ile Ala Lys Giu Ala Met Asn Pro Tyr Set 130 135 Gin Leu Tyr Trp Ile Ser Lys Giu Lys Gi 145 150 Lys Phe Gly Gin Giy Lys Lys Giu Lys Th~ 165 17( Leu Thr Gin Vai Arg Ilie Phe His Gin Lei 180 185 Pro Asn Leu Cys Lys Gin Ile Cys Ser H-i; 195 200 Gly Giy Tyr Ser Cys Aia Cys Pro Gin G1 210 215 Ser Thr Thr Giu Cys Asp Ala Ala Ile Gi 225 230 Pro Pro Cys Arg Cys Met His Giy Gly As 245 2 Asp Leu Pro Lys Cys Lys Cys Pro Ser G) 260 265 INFORMATION FOR SEQ ID SEQUENCE

CHARACTERISTICS:

LENGTH: 269 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: protein

G

A

G

0 y

U

ly la 75 liy 'yr iy eu Glu 155 Leu Ar Le.

Se: Le 23 Cy Thr A~ Leu M Trp M Trp P Trp S Thr I1 Asp 140 Val Vai Tyr ai Cys r Ser 220 u Pro 5 s Tyr 'r Thr et et 'ro ;er ~sp Ile I'rr Va Asi Lei 20 Ph Ii Ph~ Leu Phe Asn Thr Asp 110 Arg Phe Lys 1Asr n Lyc 19( u Lei e I e As ~e As PCT[US95/15203 Asp Gin Trp Thr Gly Giu Giy Leu Phe Lys Arg Val Giu Asp Gin Asn 160 1Pro Trp 175 Ser Val 1i Arg Pro e Giu Gly n Leu Pro 240 p Giu Thr 255; (xi) SEQUENCE DESCRIPTION: SEQ ID Xaa Xaa Xaa Xaa Xaa Pro Asp Giy Leu Ala Val Asp Trp Val Gly Arg 1 5 10 is His Ile Tyr Trp Ser Asp Ala Asn Ser Gin Arg Ile Glu Val Ala Thr 25 PCTIUS95/15203 WO 96/1580 1 Ile Leu Asp Gly Arg Tyr Arg Lys Trp Leu 40 Thr Thr Gin Leu Asp Gin Pro Asp His Ser Giu Ile Lys 145 Asn Trp Xaa Pro Giy 225 Pro Aia Gin Arg Ile Asp Ile 130 Leu Lys Leu Xaa G iy 210 Ser Pro Aia Gly Ser Asp Vali 115 Asn Phe Thr Xaa 195 Giy Thr Pro Ile Lys Val Tyr 100 Ile Giu Trp Giy Gin 180 Xaa Tyr Val1 Cys Leu Leu Giu Aia Vai Lys 165 Vali Cys Ser Gin Arg 245 la 1 Pro 70 Val 1Asn Ala Met Aia 150 Giu Arg Lys Cys Cys 230 Cys Asn 55 Lys Ser Asp Ile Lys 135 Xaa Asn Xaa Gin Ala 215 Xaa Met Pro Ile Glu Asp Lys 120 Pro Xaa Lys Xaa Val 200 CyE Xaa -Hii Lys Giu Asn Arg 105 Phe Xaa Giu Xaa 185 Cys Pro Xaa Gly s Ser 265 beu( Ser Leu 90 Val Asp Ser Xaa Lys 170 Xaa Ser Gin Xaa Gly 250 Ser ;iy kla 75 ily Tyr 3iy Leu Xaa 155 Val1 Xaa His Gly Xaa 235 As n G 1) Leu Trp Trp Trp Thr Asp 140 Xaa Leu Xaa Leu Ser 220 Xaa Cys Tyr Met Met Pro Ser Asp 125 Ile Xaa Val1 Xaa Cys 205 Asp Pro Tyr Ser Phe Asn Asn Asp 110 Arg Phe Xaa Val1 Xaa 190 Leu Phe Val1 Phe Trp Gly Giy Ser Arg Giu Arg Asn 175 Xaa Leu Val1 Thr Asp 255 rhr 3 iu Leu Lys Leu Asp Gin 160 Pro Xaa Arg Thr Met 240 Giu Asn Giu Leu Pro Lys Cys Lys Cy~ INFORMATION FOR SEQ ID NO:6: SEQUENCE CHARACTERISTICS: LENGTH: 280 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: iinear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: Arg Asp Ile Gin Ala Pro Asp Gly Leu Ala Val Asp Trp Ilie His Ser 1 5 10 Asn Ile Tyr Trp Thr Asp Ser Val Leu Gly Thr Val Ser Vai Ala Asp WO 96/15801 Thr Pro Asp Asp Thr His Leu Glu 145 Ala Leu Gly Tyr Thr 225 Cys Val Lys Arg Trp Ile Leu Ser Glu 130 Asp Asn Ser Val Leu 210 Cys Lei Arc 2 Gly Ala Gly Tyr Asp Ile 115 Asp Lys Arg Pro Asn 195 Cys Ala SThr g Leu !0 Val [le Thr Ser Leu 100 Ser Glu Val Leu Glu 180 Trp Leu Cys Glu Lys 26C ILys Arg Lys Thr 25 Leu Phe Arg Glu Asn PCT/US95/15203 Gly Ser Lys Val Pro 2 Leu Leu Ser Lys Phe Thr 165 Asp Cys Pro Pro iAla 245 Val Ala 70 Val Ser Ile Arg Trp 150 Gly Met Glu Ala Asp 230 Glu Asp 55 Lys Thr Gly Asp Leu 135 Thr Ser Val Arg Pro 215 Gly Ala ?ro Ile 3lu Arg Tyr 120 Ala Asp Asp Leu Thr 200 Gin Met Ala Val Lys Asn Leu 105 Asn His Ile Val Phe 185 Thr Ile Leu Val His Lys Ile 90 Tyr Gly Pro Ile Asn 170 His Leu SAsn Leu Ala 250 Gly Gly 75 Gln Trp Gly Phe Asn 155 Leu Asn Ser Pro Ala 235 Thr Phe Gly Trp Val Asn Ser 140 Glu Leu Leu Asn His 220 SArg Gin Thr 4et Leu Pro Asp Arg 125 Leu Ala Ala Thr Gly 205 Ser Asp Glu Gir Tyr Asn Asn( Ser 110 Lys Ala Ile Glu Gln 190 Gly Pro Met Thr His 270 Crp Gly Gly Lys Thr Val Phe Asn 175 Pro Cys Lys Arg Ser 255 Thr Thr Val Ile Leu Ile Phe Ser 160 Leu Arg Gin Phe Ser 240 Thr Thr

S

Val Ser Ser Thr Ala Val Arg 265 Thr Arg Pro Val Pro Asp Thr Ser 275 280 INFORMATION FOR SEQ ID NO:7: SEQUENCE CHARACTERISTICS: LENGTH: 281 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: WO 96/15801 pCTJUS95/15203 Val Giy Gly Thr Gly Leu Ser Asn Pro Asp Giy Leu Ala C 10 Val Asp Trp Asn Leu Pro Asp Ser Thr Asp Leu Leu Asn Arg Trp Arg Leu Ser 130 Tyr Gly Ala Gly Ser Asp Ile 115 Gin Trp Ala Leu Asp Val1 Tyr 100 Giu Asp Cys Val1 His Ile Val1 Phe Ile Asp Arg Val1 Ser 70 Val1 Thr Ala Pro Asp 150 Lys Gly Arg Thr Vai Leu Asp Val Gin 55 Leu Ile Gly Asp Thr Lys Giu Arg Ile 105 Ser Leu Asp 120 pHis Ile Phe 135 Trp Giu Thr Lvs Thr Leu Asp Thr Ile Giu Val Ser Lys Val Ser Ser Asn Giy Tyr Arg Ile GiyI 75 Ile Thr Trp 90 Tyr Trp Ala Gly Ser Asn Ala Leu Thr 140 Lys Ser Ile 155 Leu Ile Ser 170 Leu Arg Gin Gly Cys Ser Leu Pro Asp Arg 125 Leu Asn Thr Pro .As r 205 Leu Asp Asn Ala 110 His Phe Arg Leu Asp 190 Lei.

Arg Trp Gly Gly Arg Val1 Glu Ala His 175 Val Cys 'i PhE Giu Thr Ser Leu Giu Val1 Asp His 160 Arg Pro Leu Tyr Val Tyr Trp Thr 145 Lys Thr Thr Giy Thr 165 As Pro As n Met His Asp Pro 195 Leu 180 Cys His Lys Val1 Val1 Phe As n His Asn 200 Ala 185 Glj Leu Ser Pro Gly Giy Gly His 210 215 Lys Cys Ala Cys Pro Thr Ast SerGi Leu Gly Ser Asp Gly Arg Thr Cys Val Ser Asn 225 230 235 Phe Val Cys Lys Asn Asp Lys Cys Ile Pro Phe 245 250 Thr Glu Asp Asp Cys Gly Asp His Ser Asp Glu 260 265 Glu Phe Lys Cys Arg Pro Gly Gin Phe.

275 280 INFORMATION FOR SEQ ID NO:8: SEQUENCE

CHARACTERISTICS:

LENGTH: 48 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid Cys Trp Pro Thr Trp Pro Ala Lys Asp 270 Cys 255 Cys 240 Asp Pro WO 96/15801 PCT/US95/15203

L//

(iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE:

NO

(ix) FEATURE: NAME/KEY: modified_base LOCATION: 7 OTHER INFORMATION: /mod_base= i (ix) FEATURE: NAME/KEY: modified_base LOCATION: 28 OTHER INFORMATION: /mod_base= i (ix) FEATURE: NAME/KEY: modifiedbase LOCATION: 31 OTHER INFORMATION: /mod_base= i (ix) FEATURE: NAME/KEY: modifiedbase LOCATION: 37 OTHER INFORMATION: /mod_base= i (ix) FEATURE: NAME/KEY: modified_base LOCATION: 46 OTHER INFORMATION: /mod_base= i (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: CCARTANAGC TGRTCCTCRA AGATRTCNAG NGARTANGGR TTCATNGC 48 INFORMATION FOR SEQ ID NO:9: SEQUENCE

CHARACTERISTICS:

LENGTH: 26 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE:

NO

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: GCGGAATTCG TNATGCARCC NGAYGG 26 INFORMATION FOR SEQ ID SEQUENCE

CHARACTERISTICS:

LENGTH: 26 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid WO 96/15801 PCT/US95/15203 (iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID ATAGGATCCT GRTCYTCRAA DATRTC INFORMATION FOR SEQ ID NO:11: SEQUENCE CHARACTERISTICS: LENGTH: 2835 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (ix) FEATURE: NAME/KEY: CDS LOCATION: 1..2835 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:

CAA

Gln 1

AAA

Lys

GAC

Asp

ACA

Thr

TGG

Trp

GAC

Asp

GGA

Gly

GGC

Gly

ACT

Thr

TGT

Cys

GAG

Glu

ATC

Ile

TGT

Cys

CAT

His TGT GAG GAG AGG ACA TGC CAT CCT GTG GGG GAT Cys

CAC

His

GGA

Gly

AGC

Ser

TGT

Cys

GAG

Glu

TGT

Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp

CAC

His 20

GAT

Asp

GAG

Glu

GAC

Asp

ATG

Met

GTA

Val 100 5

TGC

Cys

AAC

Asn

TTT

Phe

CAT

His

AGG

Arg

CAC

His

ATC

Ile

TCA

Ser

CGA

Arg

TAC

Tyr 70

ACC

Thr

AGT

Ser

CCT

Pro

GAT

Asp

TGT

Cys 55

AAC

Asn

TGC

Cys

GAA

Glu

CTT

Leu

GAG

Glu 40

GTC

Val

GAC

Asp

CAT

His

CTG

Leu

CGT

Arg 25

GAA

Glu

AAT

Asn

TGT

Cys

CCT

Pro

AAA

Lys 105 10

TGG

Trp

AAC

Asn

CAG

Gln

GGG

Gly

GAA

Glu 90

TGC

Cys

CAG

Gln

TGT

Cys

CAG

Gln

GAC

Asp 75

TAT

Tyr

GAT

Asp

TGT

Cys

GCT

Ala

TGC

Cys

AAC

Asn

TTT

Phe

GGA

Gly

GAT

Asp

CCC

Pro

ATT

Ile

TCA

Ser

CAG

Gln

TCC

Ser

TTT

Phe 125 TTC CGC Phe Arg GGG CAA Gly Gln CGG GAG Arg Glu CCC TCG Pro Ser GAT GAA Asp Glu TGT ACA Cys Thr GCT GAC SAla Asp 110

TGT

Cys

AAT

Asn

TGC

Cys

CGA

Arg

CGG

Arg

AGT

Ser

TGT

Cys 26 48 96 144 192 240 288 336 384 TTG GAT GCG Leu Asp Ala 115 TCT GAT GAA GCT Ser Asp Glu Ala GAT TGT Asp Cys 120 CCC ACA CGC Pro Thr Arg

F

CCT GAT GGT Pro Asp Gly WO 96/15801 PCT/US95/15203 GAA TGC AAA GAA TGC AAA GCA TAC Ala Tyr 130 TGC CAG GCT Cys Gin Ala ACT ATG TTC Thr Met 135 Phe Glu Cys Lys

AAC

Asn 140 CAT GTT TGT ATC His Val Cys Ile

CCG

Pro 145 CCA TAT TGG AAA Pro Tyr Trp Lys

TGT

Cys 150 GAT GGC GAT GAT Asp Gly Asp Asp TGT GGC GAT GGT Cys Gly Asp Gly

TCA

Ser 160 GAT GAA GAA CTT Asp Glu Glu Leu

CAC

His 165 CTG TGC TTG GAT Leu Cys Leu Asp CCC TGT AAT TCA Pro Cys Asn Ser CCA AAC Pro Asn 175 528 CGT TTC CGG Arg Phe Arg AAT GGT GTG Asn Gly Val 195

TGT

Cys 180 GAC AAC AAT CGC Asp Asn Asn Arg

TGC

Cys 185 ATT TAT AGT CAT Ile Tyr Ser His GAG GTG TGC Glu Val Cys 190 GAG GAG CAC Glu Glu His GAT GAC TGT GGA Asp Asp Cys Gly

GAT

Asp 200 GGA ACT GAT GAG Gly Thr Asp Glu

ACA

Thr 205 TGT AGA Cys Arg 210 AAA CCG ACC CCT Lys Pro Thr Pro

AAA

Lys 215 CCT TGT ACA GAA Pro Cys Thr Glu

TAT

Tyr 220 GAA TAT AAG TGT Glu Tyr Lys Cys 672 720

GGC

Gly 225 AAT GGG CAT TGC Asn Gly His Cys

ATT

Ile 230 CCA CAT GAC AAT Pro His Asp Asn

GTG

Val 235 TGT GAT GAT GCC Cys Asp Asp Ala

GAT

Asp 240 GAC TGT GGT GAC Asp Cys Gly Asp

TGG

Trp 245 TCC GAT GAA CTG Ser Asp Glu Leu

GGT

Gly 250 TGC AAT AAA GGA Cys Asn Lys Gly AAA GAA Lys Glu 255 768 AGA ACA TGT Arg Thr Cys GAA GGA GGA Glu Gly Gly 275

GCT

Ala 260 GAA AAT ATA TGC Glu Asn Ile Cys CAA AAT TGT ACC Gin Asn Cys Thr CAA TTA AAT Gin Leu Asn 270 ACC AAT GTT Thr Asn Val TTT ATC TGC TCC Phe Ile Cys Ser ACA GCT GGG TTC Thr Ala Gly Phe

GAA

Glu 285 864 TTT GAC Phe Asp 290 AGA ACC TCC TGT Arg Thr Ser Cys GAT ATC AAT GAA Asp Ile Asn Glu GAA CAA TTT GGG Glu Gin Phe Gly

ACT

Thr 305 TGT CCC CAG CAC Cys Pro Gin His

TGC

Cys 310 AGA AAT ACC AAA Arg Asn Thr Lys

GGA

Gly 315 AGT TAT GAG TGT Ser Tyr Glu Cys

GTC

Val 320 TGT GCT GAT GGC Cys Ala Asp Gly

TTC

Phe 325 ACG TCT ATG AGT Thr Ser Met Ser

GAC

Asp 330 CGC CCT GGA AAA Arg Pro Gly Lys CGA TGT Arg Cys 335 GCA GCT GAG Ala Ala Glu

GGT

Gly 340 AGC TCT CCT TTG Ser Ser Pro Leu

TTG

Leu 345 CTA CTG CCT GAC Leu Leu Pro Asp AAT GTC CGA Asn Val Arg 350 TAT CTT CAA Tyr Leu Gin 1008 1056 1104 1152 ATT CGA AAA Ile Arg Lys 355 TAT AAT CTC TCA Tyr Asn Leu Ser

TCT

Ser 360 GAG AGG TTC TCA Glu Arg Phe Ser

GAG

Glu 365 GAT GAG Asp Glu 370 GAA TAT ATC CAA Glu Tyr Ile Gin

GCT

Ala 375 GTT GAT TAT GAT Val Asp Tyr Asp

TGG

Trp 380 GAT CCC AAG GAC Asp Pro Lys Asp WO 96/15801 PCTfUS95/15203

ATA

Ile 385 GGC CTC AGT GTT Gly Leu Ser Val

GTG

Va1 390 TAT TAC ACT Tyr Tyr Thr

GTG

Vai

CCC

Pro 410

CGA

Arg 395 GGG GAG GGC TCT Gly Giu Giy Ser 1200 TTT GGT GCT ATC Phe Gly Ala Ile

AAA

Lys 405 CGT GCC TAC ATC Arg Ala Tyr Ile AAC TTT GAA TCC Asn Phe Giu Ser GGC CGC Gly Arg 415 1248 AAT AAT CTT Asn Asn Leu CCA GAT GGA Pro Asp Gly 435

GTG

Val 420 CAG GAA GTT GAC Gin Giu Vai Asp

CTG

Leu 425 AAA CTG AAA TAC Lys Leu Lys Tyr GTA ATG CAG Vai Met Gin 430 TAC TGG TCA Tyr Trp Ser ATA GCA GTG GAC Ile Aia Vai Asp GTT OGA AGG CAT Val Giy Arg His GAT OTC Asp Val 450 AAO AAT AAA CGC Lys Asn Lys Arg

ATT

Ile 455 GAG GTG GCT AAA Glu Vai Ala Lys OAT OGA AGG TAC Asp Gly Arg Tyr 1296 1344 1392 1440 1488

AGA

Arg 465 AAO TGG CTG ATT Lys Trp Leu Ile

TCC

Ser 470 ACT GAC CTG GAC Thr Asp Leu Asp

CAA

Gin 475 CCA OCT OCT ATT Pro Ala Aia Ile

OCT

Ala 480 GTG AAT CCC AAA Val Asn Pro Lys

OTA

Leu 485 GGG CTT ATO TTC Gly Leu Met Phe

TGG

Trp 490 ACT GAC TOG OGA Thr Asp Trp Oly AAG GAA Lys Glu 495 CCT AAA ATC Pro Lys Ile OTT TTC GAO Val Phe Glu 515 GAO TCT 0CC TOG ATO AAT Glu Ser Ala Trp Met Asn 500 505 OGA GAG GAC CGC Gly Glu Asp Arg AAC ATC CTO Asn Ile Leu 510 GAT TAT TTG Asp Tyr Leu GAC CTT GGT TGG Asp Leu Oly Trp

CCA

Pro 520 ACT GGC CTT TCT Thr Gly Leu Ser AAC AAT Asn Asn 530 GAC CGA ATC TAO Asp Arg Ile Tyr

TGG

Trp 535 ACT GAC TTC AAO Ser Asp Phe Lys GAC OTT ATT GAA Asp Val Ile Glu 1536 1584 1632 1680 1728 1776

ACC

Thr 545 ATA AAA TAT GAT Ile Lys Tyr Asp

GGG

Oly 550 ACT OAT AOG AGA Thr Asp Arg Arg ATT OCA AAG GAA Ile Ala Lys Glu

OCA

Ala 560 ATO AAO CCT TAC Met Asn Pro Tyr CTG GAC ATC TTT Leu Asp Ile Phe

GAA

Glu 570 GAC CAO TTA TAC Asp Oin Leu Tyr TGG ATA Trp Ile 575 TOT AAG GAA Ser Lys Glu AAG AAA GAG Lys Lys Glu 595

AAO

Lys 580 GGA OAA OTA TGG Gly Glu Val Trp

AAA

Lys 585 CAA AAT AAA TTT Oin Asn Lys Phe GGG CAA OGA Gly Oin Gly 590 CAA OTT CGA Oin Val Arg AAA ACG CTG GTA GTG AAC CCT TGG CTO Lys Thr Leu Val Val Asn Pro Trp Leu 600 ATC TTT Ile Phe 610 CAT CAA CTC AGA TAC AAT AAG TCA GTG His Gin Leu Arg Tyr Asn Lys Ser Val 615 AAC OTT TGC AAA Asn Leu Cys Lys 1824 1872 1920

CAG

Gin 625 ATC TGC AGO CAC Ile Cys Ser His TGC CTT CTG AGA Cys Leu Leu Arg OCT OGA OGA TAO AGO TGT Pro Oly Oly Tyr Ser Cys 635 640 WO 96/15801 PCT/US95/15203 GCC TGT CCC CAA Ala Cys Pro Gin

GGC

Gly 645 TCC AGC TTT ATA Ser Ser Phe Ile

GAG

Glu 650 GGG AGC ACC ACT Gly Ser Thr Thr GAG TGT Glu Cys 655 1968 2016 GAT GCA GCC Asp Ala Ala GAA CTG CCT ATC AAC CTG CCC CCC CCA Glu Leu Pro Ile Asn Leu Pro Pro Pro 665 TGC AGG TGC Cys Arg Cys 670 CCC AAA TGC Pro Lys Cys ATG CAC GGA Met His. Gly 675 AAG TGT CCT Lys Cys Pro 690 AAA GGC ATC Lys Gly Ile 705 GGA AAT TGC TAT Gly Asn Cys Tyr

TTT

Phe 680 GAT GAG ACT GAC Asp Glu Thr Asp AGC GGC TAC Ser Gly Tyr

ACC

Thr 695 GGA AAA TAT TGT Gly Lys Tyr Cys

GAA

Glu 700 ATG GCG TTT TCA Met Ala Phe Ser TCT CCA Ser Pro

GGA

Gly 710 ACA ACC GCA GTA Thr Thr Ala Val

GCT

Ala 715 GTG CTG TTG ACA Val Leu Leu Thr 2064 2112 2160 2208 2256 CTC TTG ATC GTC Leu Leu Ile Val

GTA

Val 725 ATT GGA GCT CTG Ile Gly Ala Leu

GCA

Ala 730 ATT GCA GGA TTC Ile Ala Gly Phe TTC CAC Phe His 735 TAT AGA AGG Tyr Arg Arg

ACC

Thr 740 GGC TCC CTT TTG Gly Ser Leu Leu

CCT

Pro 745 GCT CTG CCC AAG Ala Leu Pro Lys CTG CCA AGC Leu Pro Ser 750 GTG ACC TTC Val Thr Phe TTA AGC AGT Leu Ser Ser 755 AGA TCA GGG Arg Ser Gly 770 CTC GTC AAG CCC Leu Val Lys Pro

TCT

Ser 760 GAA AAT GGG AAT Glu Asn Gly Asn

GGG

Gly 765 GCA GAT CTT Ala Asp Leu ATG GAT ATT GGA Met Asp Ile Gly

GTG

Val 780 TCT GGT TTT GGA Ser Gly Phe Gly 2304 2352 2400

CCT

Pro 785 GAG ACT GCT ATT Glu Thr Ala Ile AGG TCA ATG GCA Arg Ser Met Ala

ATG

Met 795 AGT GAA GAC TTT Ser Glu Asp Phe

GTC

Val 800 ATG GAA ATG GGG Met Glu Met Gly

AAG

Lys 805 CAG CCC ATA ATA Gin Pro Ile Ile

TTT

Phe 810 GAA AAC CCA ATG Glu Asn Pro Met TAC TCA Tyr Ser 815 GCC AGA GAC Ala Arg Asp

AGT

Ser 820 GCT GTC AAA GTG Ala Val Lys Val CAG CCA ATC CAG Gin Pro Ile Gin GTG ACT GTA Val Thr Val 830 AAC CCT TCT Asn Pro Ser 2448 2496 2544 TCT GAA AAT Ser Glu Asn 835 GTG GAT AAT AAG Val Asp Asn Lys

AAT

Asn 840 TAT GGA AGT CCC Tyr Gly Ser Pro GAG ATA Glu Ile 850 GTT CCA GAG ACA Val Pro Glu Thr

AAC

Asn 855 CCA ACT TCA CCA Pro Thr Ser Pro GCT GCT GAT GGA ACT Ala Ala Asp Gly Thr 860 TCT AAA CAA ACT ACC Ser Lys Gin Thr Thr

CAG

Gin 865 GTG ACA AAA TGG Val Thr Lys Trp

AAT

Asn 870 CTC TTC AAA CGA Leu Phe Lys Arg

AAA

Lys 875 2592 2640 2688 AAC TTT GAA AAT Asn Phe Glu Asn ATC TAT GCA CAG Ile Tyr Ala Gin ATG GAG Met Glu 890 AAC GAG CAA Asn Glu Gin AAG GAA Lys Glu 895 WO 96/15801 PCT/US95/15203 AGT GTT GCT GCG ACA CCA CCT CCA TCA CCT TCG CTC CCT GCT AAG CCT 2736 Ser Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro 900 905 910 AAG CCT CCT TCG AGA AGA GAC CCA ACT CCA ACC TAT TCT GCA ACA GAA 2784 Lys Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu 915 920 925 GAC ACT TTT AAA GAC ACC GCA AAT CTT GTT AAA GAA GAC TCT GAA GTA 2832 Asp Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val 930 935 940 TAG 2835 945 INFORMATION FOR SEQ ID NO:12: SEQUENCE CHARACTERISTICS: LENGTH: 945 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: Gin Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys 1 5 10 Lys Thr His His Cys Ile Pro Leu Arg Trp Gin Cys Asp Gly Gin Asn 25 Asp Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys 40 Thr Glu Ser Glu Phe Arg Cys Val Asn Gin Gin Cys Ile Pro Ser Arg 50 55 Trp Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg 70 75 Asp Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gin Cys Thr Ser 90 Gly His Cys Val His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys 100 105 110 Leu Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly 115 120 125 Ala Tyr Cys Gin Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile 130 135 140 Pro Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser 145 150 155 160 Asp Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn 165 170 175 Arg Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys 180 185 190 PCTJUS95115203 WO 96/1580 1 Gly Thr Asp Asn GJly Val Asp 195 Asp Cys Gly Asp 200 Glu Thr Giu Giu His 205 Cys Gly 225 Asp Arg Giu Phe Thr 305 Cys Ala Ile Asp krg 210 ks n :ys Thr Gly Asp 290 Cys Ala Ala Arg Glu 370 Lys Gly Gly Cys Gly 275 Arg Pro Asp Giu Lys 355 Giu Pro H~is Asp Ala 260 Phe Thr Gin Gly Gly 340 Tyr Tyr Thr Pro Lys 1 215 Cys Ile Pro 230 Trp Ser Asp 245 Giu Asn Ile Ile Cys Ser Ser Cys Leu 295 His Cys Arg 310 Phe Thr Ser 325 Ser Ser Pro Asn Leu Ser Ile Gin Ala 375 Vai Val Tyr 390 ~ro Cys Thr Giu 2) lis Asp ;iu Cys Cys 280 Asp As n Met Leu Ser 360 Val1 Leu Glu 265 Thr Ile Thr Ser Leu 345 Giu Asp *Thr Sle Asn ValC 235 Gly Cys 250 Gin Asn Ala Gly Asn Glu Lys Gly 315 Asp Arg 330 Leu Leu Arg Phe Tyr Asp Vai Arg 395 Pro Asn 410 .yr ~ys ksn Cys Phe Cys 300 Ser Pro Pro Ser Trp 380 G i) PhE Ly Asp Lys C Thr Giu 285 Glu Tyr Giy Asp Giu 365 Asp rGiu eGiu sTyr Yrl ~sp ;iy 1ln 270 rhr Gln Glu Lys Asn 350 Tyr Pro Giy Ser Val1 430 .Jys kla -lys 255 Lieu 1Asn Phe Cys Arg 335 Val1 Leu Ly~c Se~ Gl~ 41! Me Cys Asp 240 Giu Asn Val1 Giy Val1 320 Cys Arg Gin Asp Arg 400 {Arg t Gin Ile Gly Leu Ser Phe Gly Ala Ile Lys Arg Ala 405 Asn Asn Leu Val Gin Glu Val Asp 420 Leu Lys Leu 425 Giy Ile Ala Vai Asp Trp Vai Gly Arg His Ile Tyr Trp Ser Pro Asp 435 440 445 Asp Arg 465 Val Pro Val1 Val1 450 Lys As n Lys Phe Lys Trp Pro Ile Giu 515 Asn Leu Lys Glu 500 Asp Lys Ile Leu 485 Ser Leu Arg Ser 470 Gly Ala Gly Ile Giu 455 Thr Asp Leu Met Trp Met Trp Pro 520 Val Leu Phe As n 505 Thr Ala Asp Trp 490 Gly Gly Lys Leu 460 Gin Pro 475 Thr Asp Giu Asp Leu Ser Asp Ala Trp Arg Ile 525 Giy Ala Gly Asn 510 Asp Arg Ile Lys 495 Ile Tyr Tyr Ala 480 G iu Leu Leu PCTIUS95/15203 WO 96/15801 Ser Asp Phe Lys Asn A Thr I 545 Met A Ser L Lys L Ile F

E

Gin I 625 Ala C Asp I Met I Lys Lys 705 Leu Tyr Leu Arg Pro 785 Met Ala Ser Glu sn 30 le .sn ys lys 'he ;10 :le :ys la iis :ys 590 ly Leu Arg Asp Arg Ile Tyr Trp 535 Glu Asp Val Ile Glu 540 Lys Pro Glu Glu 595 His Cys Pro Ala Gly 675 Pro Ile Ile Arg ryr Tyr Lys 580 Lys Gin Ser Gin Ile 660 Gly Ser Ser Vai Thr 740 Asp Ser 565 Gly Thr Leu His Gly 645 Glu Asn Gly Pro Vai 725 Gly Val Gly 550 Leu Glu Leu Arg Leu 630 Ser Leu Cys Tyr Gly 710 Ile Ser Lyi Lei As 79 s Gi: a Va p As Thr A Asp I Vai T Vai V 6 Tyr A 615 Cys L Ser F Pro I Tyr I Thr 695 Thr Gly Leu Pro i Asn 775 p Arg 0 n Pro i Lys n Lys sp le *rp 'a1 00 sn jeu 'he le ?he 680 ly rhr Ala Leu Sei 76C Mel Se I1 Va As 84 Arg A Phe G 5 Lys G 585 Asn P Lys S Leu P Ile C

E

Asn I 665 Asp C Lys Aia l Leu Pro 745 Glu t Asp r Met e Ile i Val 825 n Tyr 0 rg lu 70 in 'ro er rg lu j50 ~eu lu Jal Alz 73( Ai1 As I1 Al Ph 81 Gi G1 Vai I 555 Asp G Asn L Trp L Val P 6 Pro G 635 Gly S Pro F Thr I Cys C Ala 715 SIle i Leu Gly e Gly a Met 795 e Glu 0 n Pro y Ser le in ys eu r o Ily ;er ro sp ;lu 700 Ja1 Ala Pro Asr Val 78C Se2 As I1 Pr Ala Leu Phe Thr 605 Asn Gly Thr Pro Leu 685 Met Leu Gly Lys Glj 76 Se2 I Pr e G1 o I 84 Lys G Tyr T 5 Gly G 590 Gln V Leu C Tyr S Thr C 6 Cys 1 670 Pro I Ala Leu Phe Leu 750 Val Gly Asp Met n Val 830 e Asn 1u rp in al lys ;er 1iu rg -ys Phe rhr Phe 735 Pro Thr PhE Phe Ty: 81' Th Pr G1 Ala 560 Ile Gly Arg Lys Cys 640 Cys Cys Cys Ser Ile 720 His Ser Phe Gly Val 800 r Ser r Val o Ser y Thr Ser Ser Leu 755 Ser 770 Glu Glu Arg Glu Gly Thr Met Asp Asn 835 Ala Ala Gly Ser 820 Val Asr 11~ Ly Al As Ile Val Pro Giu Thr Asn Pro Thr Ser Pro Ala Ala Asp 850 860 Gin Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gin Thr Thr WO 96/15801 865 870 Asn Phe Glu Asn Pro Ile Tyr Ala Gin Mi 885 8 Ser Val Ala Ala Thr Pro Pro Pro Ser P: 900 905 Lys Pro Pro Ser Arg Arg Asp Pro Thr P: 915 920 Asp Thr Phe Lys Asp Thr Ala Asn Leu V 930 935 945 INFORMATION FOR SEQ ID NO:13: SEQUENCE CHARACTERISTICS: LENGTH: 207 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: C-terminal

PC

Y9 875 et Glu Asn Glu Gin Lys 90 895 ro Ser Leu Pro Ala Lys 910 ro Thr Tyr Ser Ala Thr 925 al Lys Glu Asp Ser Glu 940 T/US95/15203 880 Glu Pro Glu Val (xi) Arg 1 Ser Ser Glu Glu Arg Glu Ile Val SEQUENCE DESCRIPTION: SEQ ID NO:13: Arg Thr Gly Ser Leu Leu Pro Ala Leu 5 10 Ser Leu Val Lys Pro Ser Glu Asn Gly 25 Gly Ala Asp Leu Asn Met Asp Ile Gly 40 Thr Ala Ile Asp Arg Ser Met Ala Met 55 Met Gly Lys Gin Pro Ile Ile Phe Glu 70 Asp Ser Ala Val Lys Val Val Gln Pro 90 Asn Val Asp Asn Lys Asn Tyr Gly Ser 100 105 Val Pro Glu Thr Asn Pro Thr Ser Pro 115 120 Thr Lys Trp Asn Leu Phe Lys Arg Lys 130 135 Pro Asn Val Ser Asn 75 Ile Pro Ala Ser Lys Gly Ser Glu Pro Gin Ile Ala Lys 140 Leu Val Gly Asp Met Val Asn Asp 125 Gin Pro Thr Phe Phe Tyr Thr Pro 110 Gly Thr Ser Leu Phe Arg Gly Pro Val Met Ser Ala Val Ser Ser Glu Thr Gin Thr Asn WO 96/15801 PCTIUS95/15203 Phe Glu Asn Pro Ile Tyr Ala Gin 145 150 Val Ala Ala Thr Pro Pro Pro Ser 165 Pro Pro Ser Arg Arg Asp Pro Thr 180 Thr Phe Lys Asp Thr Ala Asn Leu 195 200 INFORMATION FOR SEQ ID NO:14: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal Met Glu Asn Glu Gin Lys Glu Ser 155 160 Pro Ser Leu Pro Ala Lys Pro Lys 170 175 Pro Thr Tyr Ser Ala Thr Glu Asp 185 190 Val Lys Glu Asp Ser Glu Val 205 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: Pro Ser Leu Pro Ala Lys Pro 1 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) Ser 1 SEQUENCE DESCRIPTION: SEQ ID Leu Leu Pro Ala Leu Pro INFORMATION FOR SEQ ID NO:16: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear WO 96/15801 (ii) (iii) (v) PCTIUS95/15203 MOLECULE TYPE: peptide HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l6: Pro Ala Leu Pro Lys Leu Pro 1 INFORMATION FOR SEQ ID NO:17: SEQUENCE CHARACTERISTICS: LENGTH: 6412 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: GAATTCTGTC AATGAGCTGG CCTTCCTTAT AAAAGGATTT ACATTTTCTG CTTAAGAGGT

ATTATTTATA

TGTGCATTTT

TGCAAATTTT

TTATTAGAAA

GTTAATGGGC

AGTGCTATTG

GATTATCTTT

TATTTGGCCA

TCCTTCACCT

GACTGTGGGG

ACAGCCTTCA

AATGACTGTG

ACGGAGTTTA

GACAACTGCC

GTTTGAAATA

ATAAAGAACA

GCTGAGAAGA

TTGGTGATTG

AGAACTTCCA

TGGAGGGGTC

CTTCAGGTCC

ACAACAGGAA

GCTCCAATGG

ATGGCAGTGA

CCTGTGCCAA

GTGATGGCAG

TGTGCAATAA

ATGATAATAA

TTTCTGGTGA

ACAAATTCAC

GTCGTTGATA

CTCTTCTTGA

TGGCGCTTCT

AATGTGAACG

GGGTGGTGCC

GCACTGCATT

GCGCTGCATC

TGAGATGGAA

TGGGCGATGT

TGATGAGGCA

CAGAAGGTGC

CACTTCAGAT

TATTTGCGGG TGGGATCATA GGGAAGATGT GCCTTTTGAT

TTTCCTGTTG

TGGAAAAGTG

TAGGGAGCAT

GTGGCTGCAT

GAGTGCCAGT

GTGGACAATG

TCGGAAGAGT

AGTGTCTGTG

GTCCAATACT

GGGTGCCTGT

ATACCTCGTG

GAGAAAAATT

TTTAGAAGGA

ACTCAGAATA

TTAATGTAGA

CCATCTTTTA

GTCCACATGA

GTGAACGATG

GGAAGTGTGA

CACTTCACAC

CTTACCGCTG

TCAGGGACTG

AGTTTATCTG

GCCCTGATCG

TGTGCTTCAT

GTTGTTGCTT

ATCGGCACAT

TAGTTAAAAG

AGCTGTTGCA

CTTCTTCTGG

GGGCAACTGG

TGGTGCATCT

TAATGACAAC

CTGCTCACCG

TGATTACTAC

CAATGCCACC

CAATGGTGTA

CACTTGCCAG

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 TCTGGATACA CAAAATGTCA TAATTCAAAT ATTTGTATTC CTCGCGTTTA TTTGTGTGAC WO 96/15801 WO 9615801PCTJUS95/15203

GGAGACAATG

TGCAGCAGTG

CAAGAAACAG

ACTGTGGAGA

AGTTCCAATG

ATTGTTTGA

GAACATGCCT AGCTGATGAG TCTGTGACGG TGATAATGAC AGAATCAAAA CTGCTCGGAT GTGCATTCCC CAGTCTTGGC AATCAGAATT GCACCAGGAG TGTATCCCAA AGATATTCCG AGAGGGCTGC TTATACCTAG CATTAGTAAA ACCTTCGTCT GCTGATGCAC CTGTGCCACA GCGCTGCATC GAGATGATGA TGAGAAAGGC TGTGGCATTA CTGTATAGAC ACCTTAACCA TGACAAGCGG ACTTGTGTTG GAAGTGTGAG AATGTAATAG ACCAGATGGA AAGACCTGCC CCGTTACTAT 'FrGAGAAATT ACTGGACAAT GTTCTGGCAT TACACAGAGG CAAGTCATTG AAACCACAGA CTACCAGCTG CTGGTTCGAT GCCCGCCTGG CATGCTGCCC CAGCACTGTG ACTTGCCCTT CACCCTCAA'I CATTGGGAGA GTAGGCATGC TGGCCTAATG GCATCACCAI CTGGGTTACA TAGAGTACTC GCACTGCCTC ACCCTTTCGC AATACAAGGA CAGTGGAAJ AACACAACAC ACAGACCAT' TCCATATAGG CAGCCCATTC

TAACAGTGAT

CACATCTQGG

TGCCTCTCGA

TTCAAGTGTG

TGTGGGGATA

TCCGAGTTTC

TCTGTGATGG

AACTTGCTCT

AGGTGTGACC

ACTTGCCAAC

GTGATGCAGG

CCCCACGTGT

AACTCTGCAA

ATGAATGCCA

GTTrTCTATTG

ATATTGATGA

GCTCCTACAT

GGCAAAACAG

TAACTATAGA

TAGATTTGA

AGAGAATGT

CAGAAAGTCT

ATGGCCTCTT

TGGATGCCAA

ATGGGTACCT

ATGGAACCAA

TGATTACACC

TGATTTGGAG

TATTACCAT'I

SGGGAAACAAP

P TGACATCCA'I

'TGAGCAATCC

6.2Z

GAAAACCCTA

NGCTGTATTC

TGAACCTCC

ATGGTGGGAG

TGAGTGACGA

TCTGTGTAAA

CGATGTGGAT

GAAAATGAAT

GGCACAATGA

AGAATCAGTT

ATGAATCGAC

CCACCTCACG

CCACCTAGAT

TGACCCTTCA

TTCCTGTCGT

ATGCACAGAG

CTGTAAGTGT

TAACATCGAA

TGGCTATTTT

CCGAGTAGAG

TCTGAATAAG

GGCTGTAGAC

TGTCTCTGAC

CAACACCTTC

CTACTGGGCA

CAAGTCTGTG

AATGATCTAC

GGCCACCATC

TTTGAAGACA

TATGATGGA'I

GTGTACCATC

CTGTGGTACC

CTTATTGCAC

CTCAACATTG

TCCTTGTGGT

GTGCATCCCA

GGATAAAAGG

TGACAGACCT

TGTACTGACG

TCACCTGTGG

CTGTGGTGAC

TCCTGTCAGA

TGTGGAGACG

AGTGTCAAAT

GACTGTTTGG

ATCAGTGGCT

CCTGGTTACA

ATGCCTTTG

GCCCCAGGCT

CCCTATCTCA

TACTCCCTCA

AAGAGATTGT

ACAAACAAGG

TGGGTTTCCA

CTCAATGGTG

TGCTTTGATA

GACTGGGGTC

ATACTCCACC

TCTACTGGGC

GACACACGGT

CTATTTATTG

CAAATAGACA

CATATAGGCP

AACAATGGTC

CACTCACACA

GTATTGTGAT

CACTCTGAGC

AGCGAATGGA

CACCAGTGTC

CCGGACAGGA

GCTACATGAG

TTACGGAATG

TATAGCGACG

ACGGGCGCTG

GATCTGATGA

ATGACAATGG

ACAACAGCGA

GCGATCACAA

AGCTCATGTC

TCTGTAGCCA

ACCTCCGAGA

TTTTAGCAA

TCTTGGAAGG

ATTGGATTGA

AGACAATCAT

GAAAGCTCTA

GACACCGCCG

ATCCCAGAGG

ACCGCGCATA

AAGTTAGAGT

AGATGCCACC

GTATGATGGG

GACAGATTGG

GACACTGGTG

GCCCGTACCA

GCTGTTCTCA

1020 1080 1140 1200 1260 1320 1380 1440 1500 1560 1620 1680 1740 1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2520 2580 2640 2700 2760 2820 2 88 0 WO 96/15801 WO 9615801PCTIUS95/15203

TCTCTGCCTC

CACCCTTCAA

GTGCGCTAAC

CTCAGATGGC

CCAGTGCAGT

CCCTCGATGG

ATGGCAGTGC

CTGTGAGGAT

CCAGTTTCGG

TGATTGTGGA

TGACAACTTC

GTGCAATGGT

ATGCCATCCT

GTGTGATGGG

GTGCACAGAG

TGACCATTAC

CCATCCTGAA

TGGATCCGCT

TGGTGCATAC

TTGGAAATGT

CTTGGATGTT

TAGTCATGAG

GCACTGTAGP

GCATTGCATI

TGAACTGGGI

TTGTACCCA;

GTTTTTTGAC

CCAGCACTCC

TATGAGTGA(

GCCTGACAA'

TCAAGATGA(

CAGTGTTGT(

ATCAAGCCAG

CTGAGTGGCA G AATGAAAAGT C TCTGATGAAC IJ GACGGCAACT C TCTGATGAAG I QCCAACAAAC C AACTCAGATG1

TGTGCTAATGC

GACCACTCGG

ACAGAATTCA

GTAGATGACT

GTGGGGGATT

CAAAATGACT

AGCGAGTTTC

AACGACTGTG

TATTTTCAGT

GACTCTTGG.

TGCCAGGCTA

GATGGCGATG

CCCTGTAATT

GTGTGCAATG

AAACCGACCC

CCACATGACA

TGCAATAAAG

TTAAATGAGG

AGAACCTCCT

AGAAATACCA

CGCCCTGGAA

r GTCCGAATTC

GAATATATCC

3 TATTACAcTG AGGAAAAGG G ~CACCTACTG C CATTCCTAT C ~GGCCCTTG C ~CACCAGCCC G ~CCGTCTTCT T

;TTGCATCCC

AGACAGTTC C ;CCGCTGCAT C kTGAGCCCAT 9

WCTGCAAAAC

3CAGGGACAA C rCCGCTGTAA1

GTGGAGATAA

GATGTGTCAA

GGACAACTC

GTACAAGTGG

ATGCGTCTGA

CTATGTTCGA

ATGACTGTGG

CACCAAACCG

GTGTGGATGA

CTAAACCTTG

ATGTGTGTGA

GAAAAGAAAG

AGGATTTATC

GTCTAGATAT

AAGGAAGTTA

AACGATGTGC

GAAAATATAA

AAGCTCTTGA

TGCGAGGGGA

S73 TTCACTTGC G ATGCCCATG Ti TGGTGGAAA T CCGCAGCGC T ICAGACTTTA I TGTGAGAAT C LGAATCCTGG C

CACTGTGCC

CCGCAGGCC 9 rGAAGAATGC I LkATTACCGC

AGTGATGAG

ACTCACCAC

:TCAGATGAG

rcAGCAGTGC

%GATGAACGG

kCATTGTGTA

TGAAGCTGAT

ATGCAAAAAC

CGATGGTTCA

TTTCCGGTGT

CTGTGGAGAT

TACAGAATAT

TGATGCCGAT

AACATGTGCT

TGCTCCTGTA

CAATGAATGT

TGAGTGTGTC

AGCTGAGGGT

TCTCTCATCT

TTATGATTGG

GGGCTCTAGG

AGTGTCCAG P~ 'GCTCCAGCA C

'GTGATGGAC

'TCTGCCGACJ

'GCAATGCTC I ACCACTGTG I

AGTGTGACA

GCAGGACCTC

EGGAAGTGTG

.TGAGCTCTG

VGCATCCCAA

:AAGGCTGTG

EGCATCCCTC

;AAAACTGTG

kTTCCCTCGC

GACTGTGAGA

CACAGTGAAC

rGTCCCACAC

CATGTTGTA

GATGAAGAAC

GACAACAATC

GGAACTGATG

GAATATAAGT

GACTGTGGTG

GAAAATATAT

CAGCTGGGTT

GAACAATTTG

TGTGCTGATG

AGCTCTCCTT

GAGAGGTTCT

GATCCCAAGG

TTTGGTGCTA

LTGACTTCCG

CCAGTTCCT

GAAAGACTG

'GGGACAGTT

~CCAAAATTG

~CTCCAATGA

:ATTTAACGA

;CCGGCCGGG

%.TGTGGATAA

CCATCTCTG

k.GTGGGCCGT kGGAGAGGAC

TTCGTTGGCA

CTCCCCGGGA

GATGGATCTG

I'GAGGACCTG

TGAAATGCGA

GCTTTICCTGA

TCCCGCCATA

TTCACCTGTG

GCTGCATTTA

AGACAGAGGA

GTGGCAATGG

ACTGGTCCGA

GCGAGCAAAA

CGAAACCAAT

GGACTTGTCC

GCTTCACGTC

TGTTGCTACT

CAGAGTATCT

ACATAGGCCT

TCAAACGTGC

2940 3000 3060 3120 3180 3240 3 30 0 3360 3420 3480 3540 3600 3660 3720 3780 3840 3900 3960 4020 4080 4140 4200 4260 4320 4380 4440 4500 4560 4620 4680 4740 4800 WO 96/15801 WO 9615801PCTIUS95/15203

CTACATCCCC

GAAATACGTA

GTCAGATGTC

GCTGATTTCC

TATGTTCTGG

&GACCGCAAC

AACTTTGAAT

ATGCAGCCAG

AAGAATAAAC

ACTGACCTGG

ACTGACTGGG

ATCCTGGTTT

TTTGAACGAC CGAATCTACT TGATGGGACT GATAGGAGAG C TTT GAAGAC CAGTTATACT ATTTGGGCAA GGAAAGAAAG AATCTTTCAT CAACTCAGAT CCACCTCTGC CTTCTGAGAC TATAGAGGGG AGCACCACTG CCCATGCAGG TGCATGCACG CAAGTGTCCT AGCGGCTACA TCCAGGAACA ACCGCACTAG TCTGGCAATT GCAGGATTCT CAAGCTGCCA AGCTTAAGCA CAGATCAGGG GCAGATCTTA TATTGACAGG TCAATGGCAA AATA TTT GAA AACCCAATGT CCAGGTGACT GTATCTGAAA TGACATAGTT CCAGAGACAA ATGGA.ATCTC TTCAAACGMP ACAGATGGAG AACGAGCAMA CCCTGCTAAG CCTAAGCCTC CCGGCcGCAA

ATGGAATAGC

GCATTGAGGT

ACCAACCAGC

GAAAGGAACC

TCGAGGACCT

GGAGTGACTT

TCATTGCAAA

GGATATCTAA

AGAAAACGCT

ACAATAAGTC

CTGGAGGATA

AGTGTGATGC

GAGGAAATTG

CCGGAAAATA

CTGTGCTGT'I

TCCACTATAC

GTCTCGTCAM

ACATGGATA9

TGAGTGAAG]

ACTCAGCCAC

ATGTGGATA2

ACCCAACTT(

AATCTAAAC,

AGGAAAGTG'

CTTCGAGAA

TAATCTTGTG

AGTGGACTGG

GGCTAAACTT

TGCTATTGCT-

TAAAATCGAG

TGGTTGGCCA

CAAGGAGGAC

GGAAGCAATG

GGAAAAGGGA

GGTAGTGAAC

AGTGCCCAAC

CAGCTGTGCC

AGCCATCGAA

CTATTTTGAT

TTGTGAAATG

GACAATCCTC

AAGGACCGGC

GCCCTCTGAA

TGGAGTGTCT

CTTTGTCATG

AGACAGTGC7

~TAAGAATTAI

ACCAGCTGC1 k AACTACCAAC I TGCTGCGAC1

AGACCCAAC'

T TAAAGAAGA(

CAGGAAGTTG

GTTGGAAGGC

GATGGAAGGT

GTGAATCCCA

TCTGCCTGGA

ACTGGCCTTT

GTTATTGAAA

AACCCTTACA

GAAGTATGGA

CCTTGGCTCA

CTTTGCAAAC

TGTCCCCAAG

CTGCCTATCA

GAGACTGACC

GCGTTTTCAA.

TTGATCGTCG

TCCCTTTTGC

AATGGGAATG

GGTTTTGGAC

GAAATGGGGA

GTCAAAGTGC

GGAAGTCCCP

GATGGAACTC

TTTGAAAATC

CCACCTCCAJ

r' CCAACCTAT'

-TCTGA.AGTA.

ACCTGAAACT

ATATTTACTG

ACAGAAAGTG

AACTAGGGCT

TGAATGGAGA

CTATCGATTA

CCATAAAATA

GCCTGGACAT

AACAAAATAA

CTCAAGTTCG

AGATCTGCAG

GCTCCAGCTT

ACCTGCCCCC

TCCCCAAATG

AAGGCATCTC

TAATTGGAGC

CTGCTC!TGCC

GGGTGACCTT

CTGAGACTGC

*AGCAGCCCAT

TTCAGCCAAT

TAAACCCTTC

AGGTGACAAA

CAATCTATGC

PCACCTTCGCT

P' CTGCAACAGA Lr AG 4860 4920 4980 5040 5100 5160 5220 5280 5340 5400 5460 5520 5580 5640 5700 5760 5820 5880 5940 6000 6060 6120 6180 6240 6300 6360 6412 AGACACTTTT AAAGACACCG CAAATCTTG INFORMATION FOR SEQ ID NO:18: SEQUENCE CHARACTERISTICS: LENGTH: 19 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide WO 96/15801 PCT/US95/15203 (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: Ala Thr Pro Pro Pro. Ser Pro Ser Leu Pro Ala Lys Pro Lys Pro Pro 1 5 10 Ser Arg Arg INFORMATION FOR SEQ ID NO:19: SEQUENCE CHARACTERISTICS: LENGTH: 12 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: Phe Glu Asn Pro Ile Tyr Ala Gin Met Glu Asn Glu 1 5 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 9 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID Arg Xaa Leu Pro Pro Arg Pro Xaa Xaa 1 INFORMATION FOR SEQ ID NO:21: SEQUENCE

CHARACTERISTICS:

LENGTH: 9 amino acids WO 96/15801 PCT/US95/15203 TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Modified-site LOCATION: 9 OTHER INFORMATION: /label= hydrophobic (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: Arg Xaa Leu Pro Pro Leu Pro Arg Xaa 1 INFORMATION FOR SEQ ID NO:22: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: Pro Thr Met Pro Pro Pro Leu Pro Pro Val Pro 1 5 INFORMATION FOR SEQ ID NO:23: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: Pro Ala Tyr Pro Pro Pro Pro Val Pro Val Pro WO 96/15801 PCT/US95/15203 -5-7 1 5 1 INFORMATION FOR SEQ ID NO:24: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: Glu Val Pro Val Pro Pro Pro Val Pro Pro Arg 1 5 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID His Leu Asp Ser Pro Pro Ala Ile Pro Pro Arg 1 5 INFORMATION FOR SEQ ID NO:26: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: pCTfUS95/15203 WO 96/15801 His Ser Ile Ala Gly Pro Pro Val Pro Pro Arg 1 5 INFORMATION FOR SEQ ID NO:27: SEQUENCE

CHARACTERISTICS:

LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: Ala Pro Ala Val Pro Pro Ala Arg Pro Gly Ser 1 5 INFORMATION FOR SEQ ID NO:28: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: Gly Ala Pro Pro Val Pro Ser Arg Pro Gly Ala 1 5 INFORMATION FOR SEQ ID NO:29: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal pCTfUS9515203 WO 96/15801 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: Pro Pro Arg Pro Leu Pro Val Ala Pro Gly Ser 1 5 INFORMATION FOR SEQ ID SEQUENCE

CHARACTERISTICS:

LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID Pro Ala Pro Ala Leu Pro Pro Lys Pro Pro Lys 1 5 INFORMATION FOR SEQ ID NO:31: SEQUENCE

CHARACTERISTICS:

LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: Ala Pro Lys Pro Met Pro Pro Arg Pro Pro Leu 1 5 INFORMATION FOR SEQ ID NO:32: SEQUENCE

CHARACTERISTICS:

LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal WO 96/15801 PCT/US95/15203 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: Pro Pro Thr Pro Pro Pro Leu Pro Pro Pro Leu 1 5 INFORMATION FOR SEQ ID NO:33: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: Pro Ala Leu Pro Pro Pro Pro Arg Pro Val Pro 1 5 INFORMATION FOR SEQ ID NO:34: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: Arg Pro Arg Pro Leu Pro Pro Leu Pro Pro Thr 1 5 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

WO 96/15801 PCT/US95/15203 FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID Gly Val Arg Pro Leu Pro Pro Leu Pro Asp Pro 1 5 INFORMATION FOR SEQ ID NO:36: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36: Pro Pro Arg Pro Leu Pro Pro Arg Pro Pro Ala 1 5 INFORMATION FOR SEQ ID NO:37: SEQUENCE CHARACTERISTICS: LENGTH: 7 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (ix) FEATURE: NAME/KEY: Modified-site LOCATION: 3 OTHER INFORMATION: /label= hydrophobic (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: Xaa Pro Xaa Pro Pro Xaa Pro 1 INFORMATION FOR SEQ ID NO:38: SEQUENCE CHARACTERISTICS: LENGTH: 22 amino acids TYPE: amino acid

STRANDEDNESS:

WO 96/15801 PCT/US95/15203 TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: Glu Ser Asp Gly Gly Tyr Met Asp Met Ser Lys Asp Glu Ser Val Asp 1 5 10 Tyr Val Pro Met Leu Asp INFORMATION FOR SEQ ID NO:39: SEQUENCE CHARACTERISTICS: LENGTH: 18 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: Glu Glu Glu Glu Glu Tyr Met Pro Met Glu Asp Leu Tyr Leu Asp Ile 1 5 10 Leu Pro INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID Gln Gly Val Asp Thr Tyr Val Glu Met Arg Pro WO 96/15801 PCTIUS95/15203 INFORMATION FOR SEQ ID NO:41: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE-TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41: Asp Ser Thr Asn Glu Tyr Met Asp Met Lys Pro 1 5 INFORMATION FOR SEQ ID NO:42: SEQUENCE CHARACTERISTICS: LENGTH: 24 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) Gly 1 Gin SEQUENCE DESCRIPTION: SEQ ID NO:42: Pro Gly Gly Asp Tyr Ala Ala Met Gly Ala Cys Pro Ala Ser Glu 5 10 Gly Tyr Glu Glu Met Arg Ala INFORMATION FOR SEQ ID NO:43: SEQUENCE CHARACTERISTICS: LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY:.linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal WO 96/15801 PCT/US95/15203 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: Thr Pro Asp Glu Asp Tyr Glu Tyr Met Asn Arg Gin Arg Asp Gly Gly 1 5 10 Gly Pro Gly Gly Asp Tyr Ala Ala Met Gly Ala INFORMATION FOR SEQ ID NO:44: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: Cys Thr Ile Asp Val Tyr Met Val Met Val Lys 1 5 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) Ser SEQUENCE DESCRIPTION: SEQ ID Pro Ser Ser Gly Tyr Met Pro Met Asn Gin INFORMATION FOR SEQ ID NO:46: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide PCTUS95/15203 WO 96/15801 b6"- (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46: Asp Glu Asp Glu Glu Tyr Glu Tyr Met Asn Arg 1 5 INFORMATION FOR SEQ ID NO:47: SEQUENCE

CHARACTERISTICS:

LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47: Leu Glu Glu Leu Gly Tyr Glu Tyr Met Asp Val 1 5 INFORMATION FOR SEQ ID NO:48: SEQUENCE

CHARACTERISTICS:

LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: Glu Glu Leu Ser Asn Tyr Ile Cys Met Gly Gly 1 5 INFORMATION FOR SEQ ID NO:49: SEQUENCE

CHARACTERISTICS:

LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear PCTUS9/15203 WO 96/15801 (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: Val Ser Ile Glu Glu Tyr Thr Glu Met Met Pro 1 5 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID His Thr Asp Asp Gly Tyr Met Pro Met Ser Pro 1 5 INFORMATION FOR SEQ ID NO:51: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51: Lys Gly Asn Gly Asp Tyr Met Pro Met Ser Pro 1 5 INFORMATION FOR SEQ ID NO:52: SEQUENCE

CHARACTERISTICS:

LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

PCTIUS95/15203 WO 96/15801 67 TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal SEQUENCE DESCRIPTION: SEQ ID NO:52: Val Asp Pro Asn Gly Tyr Met Met Met Ser Pro 1 5 INFORMATION FOR SEQ ID NO:53: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: Pro Cys Thr Gly Asp Tyr Met Asn Met Ser Pro 1 5 INFORMATION FOR SEQ ID NO:54: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54: Thr Gly Ser Glu Glu Tyr Met Asn Met Asp Leu 1 5 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids WO 96/15801 PCT/US95/15203 TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID Asn Ser Arg Gly Asp Tyr Met Thr Met Gin Ile 1 5 INFORMATION FOR SEQ ID NO:56: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56: Val Ala Pro Val Ser Tyr Ala Asp Met Arg Thr 1 5 INFORMATION FOR SEQ ID NO:57: SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) Glu 1 SEQUENCE DESCRIPTION: SEQ ID NO:57: Arg Glu Asn Glu Tyr Met Pro Met Ala Pro Gin Ile His Leu Tyr 5 10 Ser Gin Ile Arg Glu WO 96/15801 PCT/US95/15203 INFORMATION FOR SEQ ID NO:58: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) Leu SEQUENCE DESCRIPTION: SEQ ID NO:58: Ser Asn Pro Thr Tyr Ser Val Met Arg Ser INFORMATION FOR SEQ ID NO:59: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59: Cys Pro Glu Lys Val Tyr Glu Leu Met Arg Ala 1 5 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID WO 96/15801 PCTIS95/15203 76 Asn Thr Thr Val Asp Tyr Val Tyr Met Ser His Gly Asp Asn Gly Asp 1 5 10 Tyr Val Tyr Met Asn INFORMATION FOR SEQ ID NO:61: SEQUENCE CHARACTERISTICS: LENGTH: 21 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61: Asn Cys Asn Asp Asp Tyr Val Thr Met His Tyr Thr Thr Asp Gly Asp 1 5 10 Tyr Ile Tyr Met Asn INFORMATION FOR SEQ ID NO:62: SEQUENCE CHARACTERISTICS: LENGTH: 27 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62: Tyr Val Asn Asp Ile Tyr Leu Tyr Met Arg His Leu Glu Arg Glu Phe 1 5 10 Lys Val Arg Thr Asp Tyr Met Ala Met Gln Glu 20 INFORMATION FOR SEQ ID NO:63: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear WO 96/15801 PCT/US95/15203 (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63: Asn Gin Glu Glu Ala Tyr Val Thr Met Ser Ser 1 5 INFORMATION FOR SEQ ID NO:64: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64: Phe Ile Ala Ser Lys Tyr Glu Asp Met Tyr Pro 1 5 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID Leu Gly Ser Gin Ser Tyr Glu Asp Met Arg Gly 1 5 INFORMATION FOR SEQ ID NO:66: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

WO 96/15801 PCT/US95/15203 TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66: Glu Asp Ala Asp Ser Tyr Glu Asn Met Asp Lys 1 5 INFORMATION FOR SEQ ID NO:67: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67: Glu Leu Gin Asp Asp Tyr Glu Asp Met Met Glu 1 5 INFORMATION FOR SEQ ID NO:68: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68: Ala Ala Cys Val Val Tyr Glu Asp Met Ser His 1 5 INFORMATION FOR SEQ ID NO:69: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids WO 96/15801 PCT/US95/15203 73 TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69: Ala Pro Pro Glu Glu Tyr Val Pro Met Val Lys 1 5 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID Ile Asp Ser Cys Thr Tyr Glu Ala Met Tyr Asn 1 5 INFORMATION FOR SEQ ID NO:71: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71: Val Ala Val Ala Glu Tyr Glu Ile Met Glu Gln 1 5 INFORMATION FOR SEQ ID NO:72: WO 96/15801 PCT/US95/15203 79 SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72: Met Ser Val Glu Ser Tyr Glu Glu Met Lys Met 1 5 INFORMATION FOR SEQ ID NO:73: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73: His Gln Thr Arg Glu Tyr Glu Ser Met Ile Glu 1 5 INFORMATION FOR SEQ ID NO:74: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74: Thr Leu Gin Asn Glu Tyr Glu Leu Met Arg Glu 1 5 PCTIUS95/15203 WO 96/15801 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID Gly Gly Glu Glu Ile Tyr Val Val Met Leu Gly 1 5 INFORMATION FOR SEQ ID NO:76: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76: Leu Glu Gly Glu His Tyr Ile Asn Met Ala Val 1 5 INFORMATION FOR SEQ ID NO:77: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL:

NO

FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77: Glu Ile Thr Glu Gin Tyr Ile Tyr Met Val Met WO 96/15801 1 5 INFORMATION FOR SEQ ID NO:78: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE:.peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78: Thr Glu Gln Tyr Ile Tyr Met Val Met Glu Cys 1 5 INFORMATION FOR SEQ ID NO:79: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79: Leu Pro Ala Lys Pro 1 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal PCTfUS95/15203 (xi) SEQUENCE DESCRIPTION: SEQ ID WO 96/15801 PCT/US95/15203 Leu Pro Ala Leu Pro INFORMATION FOR SEQ ID NO:81: SEQUENCE CHARACTERISTICS: LENGTH: 5 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81: Leu Pro Lys Leu Pro 1 INFORMATION FOR SEQ ID NO:82: SEQUENCE CHARACTERISTICS: LENGTH: 11 amino acids TYPE: amino acid

STRANDEDNESS:

TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (iii) HYPOTHETICAL: NO FRAGMENT TYPE: internal (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82: Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu 1 5 INFORMATION FOR SEQ ID NO:83: SEQUENCE CHARACTERISTICS: LENGTH: 14086 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: ORGANISM: Homo sapiens WO 96/15801 PCT/US95/15203 (ix) FEATURE: NAME/KEY: CDS LOCATION: 107..14074 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83: TTGCAGACCT AAAGGAGCGT TCGCTAGCAG AGGCGCTGCC GGTGCGGTGT GCTACGCGCG CCCACCTCCC GGGGAAGGAA CGGCGAGGCC GGGGACCGTC GCGGAG ATG GAT CGC 115 Met Asp Arg GGG CCG GCA GCA GTG GCG TGC ACG CTG CTC CTG GCT CTC GTC GCC TGC 163 Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu Ala Leu Val Ala Cys 950 955 960 CTA GCG CCG GCC AGT GGC CAA GAA TGT GAC AGT GCG CAT TTT CGC TGT 211 Leu Ala Pro Ala Ser Gly Gin Glu Cys Asp Ser Ala His Phe Arg Cys 965 970 975 980 GGA AGT GGG CAT TGC ATC CCT GCA GAC TGG AGG TGT GAT GGG ACC AAA 259 Gly Ser Gly His Cys Ile Pro Ala Asp Trp Arg Cys Asp Gly Thr Lys 985 990 995 GAC TGT TCA GAT GAC GCG GAT GAA ATT GGC TGC GCT GTT GTG ACC TGC 307 Asp Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys Ala Val Val Thr Cys 1000 1005 1010 CAG CAG GGC TAT TTC AAG TGC CAG AGT GAG GGA CAA TGC ATC CCC AGC 355 Gin Gin Gly Tyr Phe Lys Cys Gin Ser Glu Gly Gin Cys Ile Pro Ser 1015 1020 1025 TCC TGG GTG TGT GAC CAA GAT CAA GAC TGT GAT GAT GGC TCA GAT GAA 403 Ser Trp Val Cys Asp Gin Asp Gin Asp Cys Asp Asp Gly Ser Asp Glu 1030 1035 1040 CGT CAA GAT TGC TCA CAA AGT ACA TGC TCA AGT CAT CAG ATA ACA TGC 451 Arg Gin Asp Cys Ser Gin Ser Thr Cys Ser Ser His Gn Ile Thr Cys 1045 1050 1055 .1060 TCC AAT GGT CAG TGT ATC CCA AGT GAA TAC AGG TGC GAC CAC GTC AGA 499 Ser Asn Gly Gin Cys Ile Pro Ser Glu Tyr Arg Cys Asp His Val Arg 1065 1070 1075 GAC TGC CCC GAT GGA GCT GAT GAG AAT GAC TGC CAG TAC CCA ACA TGT 547 Asp Cys Pro Asp Gly Ala Asp Glu Asn Asp Cys Gin Tyr Pro Thr Cys 1080 1085 1090 GAG CAG CTT ACT TGT GAC AAT GGG GCC TGC TAT AAC ACC AGT CAG AAG 595 Glu Gin Leu Thr Cys Asp Asn Gly Ala Cys Tyr Asn Thr Ser Gin Lys 1095 1100 1105 TGT GAT TGG AAA GTT GAT TGC AGG GAC TCC TCA GAT GAA ATC AAC TGC 643 Cys Asp Trp Lys Val Asp Cys Arg Asp Ser Ser Asp Glu Ile Asn Cys 1110 1115 1120 ACT GAG ATA TGC TTG CAC AAT GAG TTT TCA TGT GGC AAT GGA GAG TGT 691 Thr Glu Ile Cys Leu His Asn Glu Phe Ser Cys Gly Asn Gly Glu Cys 1125 1130 1135 1140 ATC CCT CGT GCT TAT GTC TGT GAC CAT GAC AAT GAT TGC CAA GAC GGC 739 Ile Pro Arg Ala Tyr Val Cys Asp His Asp Asn Asp Cys Gin Asp Gly WO 96/15801 PCTIUS95/15203 1145 1150 1155 AGT GAT GAA CAT GCT TGC AAC TAT CCG ACC TGC GGT GGT TAC CAG TTC 787 Ser Asp Giu His Ala Cys Asn Tyr Pro Thr Cys Gly Gly Tyr Gin Phe 1160 1165 1170 ACT TGC CCC AGT GGC CGA TGC ATT TAT CAA AAC TGG GTT TGT GAT GGA 835 Thr Cys Pro Ser Gly Arg Cys Ile Tyr Gin Asn Trp Val Cys Asp Gly 1175 1180 1185 GAA GAT GAC TGT AAA GAT AAT GGA GAT GAA GAT GGA TGT GAA AGC GGT 883 *Glu Asp Asp Cys Lys Asp Asn Gly Asp Glu Asp Gly Cys Glu Ser Gly 1190 1195 1200 CCT CAT GAT GTT CAT AAA TGT TCC CCA AGA GAA TGG TCT TGC CCA GAG 931 Pro His Asp Val His Lys Cys Ser Pro Arg Glu Trp Ser Cys Pro Glu 1205 1210 1215 1220 TCG GGA CGA TGC ATC TCC ATT TAT AAA GTT TGT GAT GGG ATT TTA GAT 979 Ser Gly Arg Cys Ile Ser Ile Tyr Lys Val Cys Asp Gly Ile Leu Asp 1225 1230 1235 TGC CCA GGA AGA GAA GAT GAA AAC AAC ACT AGT ACC GGA AAA TAC TGT 1027 Cys Pro Gly Arg Glu Asp Glu Asn Asn Thr Ser Thr Gly Lys Tyr Cys 1240 1245 1250 AGT ATG ACT CTG TGC TCT GCC TTG AAC TGC CAG TAC CAG TGC CAT GAG 1075 Ser Met Thr Leu Cys Ser Ala Leu Asn Cys Gin Tyr Gin Cys His Glu 1255 1260 1265 ACG CCG TAT GGA GGA GCG TGT TTT TGT CCC CCA GGT TAT ATC ATC AAC 1123 Thr Pro Tyr Gly Gly Ala Cys Phe Cys Pro Pro Gly Tyr Ile Ile Asn 1270 1275 1280 CAC AAT GAC AGC CGT ACC TGT GTT GAG TTT GAT GAT TGC CAG ATA TGG 1171 His Asn Asp Ser Arg Thr Cys Val Glu Phe Asp Asp Cys Gin Ile Trp 1285 1290 1295 1300 GGA ATT TGT GAC CAG AAG TGT GAA AGC CGA CCT GGC CGT CAC CTG TGC 1219 Gly Ile Cys Asp Gin Lys Cys Glu Ser Arg Pro Gly Arg His Leu Cys 1305 1310 1315 CAC TGT GAA GAA GGG TAT ATC TTG GAG CGT GGA CAG TAT TGC AAA GCT 1267 His Cys Glu Glu Gly Tyr Ile Leu Glu Arg Gly Gin Tyr Cys Lys Ala 1320 1325 1330 AAT GAT TCC TTT GGC GAG GCC TCC ATT ATC TTC TCC AAT GGT CGG GAT 1315 Asn Asp Ser Phe Gly Glu Ala Ser Ile Ile Phe Ser Asn Gly Arg Asp 1335 1340 1345 TTG TTA ATT GGT GAT ATT CAT GGA AGG AGC TTC CGG ATC CTA GTG GAG 1363 Leu Leu Ile Gly Asp Ile His Gly Arg Ser Phe Arg Ile Leu Val Glu 1350 1355 1360 TCT CAG AAT CGT GGA GTG GCC GTG GGT GTG GCT TTC CAC TAT CAC CTG 1411 Ser Gin Asn Arg Gly Val Ala Val Gly Val Ala Phe His Tyr His Leu 1365 1370 1375 1380 CAA AGA GTT TTT TGG ACA GAC ACC GTG CAA AAT AAG GTT TTT TCA GTT 1459 Gin Arg Val Phe Trp Thr Asp Thr Val Gin Asn Lys Val Phe Ser Val 1385 1390 1395 GAC ATT AAT GGT TTA AAT ATC CAA GAG GTT CTC AAT GTT TCT GTT GAA 1507 Asp Ile Asn Gly Leu Asn Ile Gin Glu Val Leu Asn Val Ser Val Glu WO 96/15801 PCTfUS95/15203 1400 1405 1410 ACC CCA GAG AAC CTG GCT GTG GAC TGG GTT AAT AAT AAA ATC TAT CTA 1555 Thr Pro Glu Asn Leu Ala Val Asp Trp Val Asn Asn Lys Ile Tyr Leu 1415 1420 1425 GTG GAA ACC AAG GTC AAC CGC ATA GAT ATG GTA AAT TTG GAT GGA AGC 1603 Val Glu Thr Lys Val Asn Arg Ile Asp Met Val Asn Leu Asp Gly Ser 1430 1435 1440 TAT CGG GTT ACC CTT ATA ACT GAA AAC TTG GGG CAT CCT AGA GGA ATT 1651 Tyr Arg Val Thr Leu Ile Thr Glu Asn Leu Gly His Pro Arg Gly Ile 1445 1450 1455 1460 GCC GTG GAC CCA ACT GTT GGT TAT TTA TTT TTC TCA GAT TGG GAG AGC 1699 Ala Val Asp Pro Thr Val Gly Tyr Leu Phe Phe Ser Asp Trp Glu Ser 1465 1470 1475 CTT TCT GGG GAA CCT AAG CTG GAA AGG GCA TTC ATG GAT GGC AGC AAC 1747 Leu Ser Gly Glu Pro Lys Leu Glu Arg Ala Phe Met Asp Gly Ser Asn 1480 1485 1490 CGT AAA GAC TTG GTG AAA ACA AAG CTG GGA TGG CCT GCT GGG GTA ACT 1795 Arg Lys Asp Leu Val Lys Thr Lys Leu Gly Trp Pro Ala Gly Val Thr 1495 1500 1505 CTG GAT ATG ATA TCG AAG CGT GTT TAC TGG GTT GAC TCT CGG TTT GAT 1843 Leu Asp Met Ile Ser Lys Arg Val Tyr Trp Val Asp Ser Arg Phe Asp 1510 1515 1520 TAC ATT GAA ACT GTA ACT TAT GAT GGA ATT CAA AGG AAG ACT GTA GTT 1891 Tyr Ile Glu Thr Val Thr Tyr Asp Gly Ile Gin Arg Lys Thr Val Val 1525 1530 1535 1540 CAT GGA GGC TCC CTC ATT CCT CAT CCC TTT GGA GTA AGC TTA TTT GAA 1939 His Gly Gly Ser Leu Ile Pro His Pro Phe Gly Val Ser Leu Phe Glu 1545 1550 1555 GGT CAG GTG TTC TTT ACA GAT TGG ACA AAG ATG GCC GTG CTG AAG GCA 1987 Gly Gin Val Phe Phe Thr Asp Trp Thr Lys Met Ala Val Leu Lys Ala 1560 1565 1570 AAC AAG TTC ACA GAG ACC AAC CCA CAA GTG TAC TAC CAG GCT TCC CTG 2035 Asn Lys Phe Thr Glu Thr Asn Pro Gin Val Tyr Tyr Gin Ala Ser Leu 1575 1580 1585 AGG CCC TAT GGA GTG ACT GTT TAC CAT TCC CTC AGA CAG CCC TAT GCT 2083 Arg Pro Tyr Gly Val Thr Val Tyr His Ser Leu Arg Gn Pro Tyr Ala 1590 1595 1600 ACC AAT CCG TGT AAA GAT AAC AAT GGG GGC TOT GAG CAG GTC TGT GTT 2131 Thr Asn Pro Cys Lys Asp Asn Asn Gly Gly Cys Glu Gin Val Cys Val 1605 1610 1615 1620 CTC AGC CAC AGA ACA GAT AAT GAT GGT TTO GGT TTC CGT TGC AAG TGC 2179 Leu Ser His Arg Thr Asp Asn Asp Gly Leu Gly Phe Arg Cys Lys Cys 1625 1630 1635 ACA TTC GGC TTC CAA CTG GAT ACA GAT GAG CGC CAC TGC ATT GCT GTT 2227 Thr Phe Gly Phe Gn Leu Asp Thr Asp Glu Arg His Cys Ile Ala Val 1640 1645 1650 CAG AAT TTC CTC ATT TTT TCA TCC CAA GTT GCT ATT CGT GGG ATC CCG 2275 Gn Asn Phe Leu Ile Phe Ser Ser Gin Val Ala Ile Arg Gly Ile Pro WO 96/15801 PCTUS95/15203 1655 1660 1665 TTC ACC TTG TCT ACC CAG GAA GAT GTC ATG GTT CCA GTT TCG GGG AAT 2323 Phe Thr Leu Ser Thr Gin Glu Asp Val Met Val Pro Val Ser Gly Asn 1670 1675 1680 CCT TCT TTC TTT GTC GGG ATT GAT TTT GAC GCC CAG GAC AGC ACT ATC 2371 Pro Ser Phe Phe Val Gly Ile Asp Phe Asp Ala Gin Asp Ser Thr Ile 1685 1690 1695 1700 TTT TTT TCA GAT ATG TCA AAA CAC ATG ATT TTT AAG CAA AAG ATT GAT 2419 Phe Phe Ser Asp Met Ser Lys His Met Ile Phe Lys Gin Lys Ile Asp 1705 1710 1715 GGC ACA GGA AGA GAA ATT CTC GCA GCT AAC AGG GTG GAA AAT GTT GAA 2467 Gly Thr Gly Arg Glu Ile Leu Ala Ala Asn Arg Val Glu Asn Val Glu 1720 1725 1730 AGT TTG GCT TTT GAT TGG ATT TCA AAG AAT CTC TAT TGG ACA GAC TCT 2515 Ser Leu Ala Phe Asp Trp Ile Ser Lys Asn Leu Tyr Trp Thr Asp Ser 1735 1740 1745 CAT TAC AAG AGT ATC AGT GTC ATG AGG CTA GCT GAT AAA ACG AGA CGC 2563 His Tyr Lys Ser Ile Ser Val Met Arg Leu Ala Asp Lys Thr Arg Arg 1750 1755 1760 ACA GTA GTT CAG TAT TTA AAT AAC CCA CGG TCG GTG GTA GTT CAT CCT 2611 Thr Val Val Gin Tyr Leu Asn Asn Pro Arg Ser Val Val Val His Pro 1765 1770 1775 1780 TTT GCC GGG TAT CTA TTC TTC ACT GAT TGG TTC CGT CCT GCT AAA ATT 2659 Phe Ala Gly Tyr Leu Phe Phe Thr Asp Trp Phe Arg Pro Ala Lys Ile 1785 1790 1795 ATG AGA GCA TGG AGT GAC GGA TCT CAC CTC TTG CCT GTA ATA AAC ACT 2707 Met Arg Ala Trp Ser Asp Gly Ser His Leu Leu Pro Val Ile Asn Thr 1800 1805 1810 ACT CTT GGA TGG CCC AAT GGC TTG GCC ATC GAT TGG GCT GCT TCA CGA 2755 Thr Leu Gly Trp Pro Asn Gly Leu Ala Ile Asp Trp Ala Ala Ser Arg 1815 1820 1825 TTG TAC TGG GTA GAT GCC TAT TTT GAT AAA ATT GAG CAC AGC ACC TTT 2803 Leu Tyr Trp Val Asp Ala Tyr Phe Asp Lys Ile Glu His Ser Thr Phe 1830 1835 1840 GAT GGT TTA GAC AGA AGA AGA CTG GGC CAT ATA GAG CAG ATG ACA CAT 2851 Asp Gly Leu Asp Arg Arg Arg Leu Gly His Ile Glu Gin Met Thr His 1845 1850 1855 1860 CCC TTT GGA CTT GCC ATC TTT GGA GAG CAT TTA TTT TTT ACT GAC TGG 2899 Pro Phe Gly Leu Ala Ile Phe Gly Glu His Leu Phe Phe Thr Asp Trp 1865 1870 1875 AGA CTG GGT GCC ATT ATT CGA GTC AGG AAA GCA GAT GGT GGA GAA ATG 2947 Arg Leu Gly Ala Ile Ile Arg Val Arg Lys Ala Asp Gly Gly Glu Met 1880 1885 1890 ACA GTT ATC CGA AGT GGC ATT GCT TAC ATA CTG CAT TTG AAA TCG TAT 2995 Thr Val Ile Arg Ser Gly Ile Ala Tyr Ile Leu His Leu Lys Ser Tyr 1895 1900 1905 GAT GTC AAC ATC CAG ACT GGT TCT AAC GCC TGT AAT CAA CCC ACO CAT 3043 Asp Val Asn Ile Gin Thr Gly Ser Asn Ala Cys Asn Gin Pro Thr His WO 96/15801 PCTUS95/15203 r~z 1910 1915 1920 CCT AAC GGT GAC TGC AGC CAC TTC TGC TTC CCG GTG CCA AAT TTC CAG 3091 Pro Asn Gly Asp Cys Ser His Phe Cys Phe Pro Val Pro Asn Phe Gin 1925 1930 1935 1940 CGA GTG TGT GGG TGC CCT TAT GGA ATG AGG CTG GCT TCC AAT CAC TTG 3139 Arg Val Cys Gly Cys Pro Tyr Gly Met Arg Leu Ala Ser Asn His Leu 1945 1950 1955 ACA TGC GAG GGG GAC CCA ACC AAT GAA CCA CCC ACG GAG CAG TGT GGC 3187 Thr Cys Glu Gly Asp Pro Thr Asn Glu Pro Pro Thr Glu Gin Cys Gly 1960 1965 1970 TTA TTT TCC TTC CCC TGT AAA AAT GGC AGA TGT GTG CCC AAT TAC TAT 3235 Leu Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys Val Pro Asn Tyr Tyr 1975 1980 1985 CTC TGT GAT GGA GTC GAT GAT TGT CAT GAT AAC AGT GAT GAG CAA CTA 3283 Leu Cys Asp Gly Val Asp Asp Cys His Asp Asn Ser Asp Glu Gin Leu 1990 1995 2000 TGT GGC ACA CTT AAT AAT ACC TGT TCA TCT TCG GCG TTC ACC TGT GGC 3331 Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala Phe Thr Cys Gly 2005 2010 2015 2020 CAT GGG GAG TGC ATT CCT GCA CAC TGG CGC TGT GAC AAA CGC AAC GAC 3379 His Gly Glu Cys Ile Pro Ala His Trp Arg Cys Asp Lys Arg Asn Asp 2025 2030 2035 TGT GTG GAT GGC AGT GAT GAG CAC AAC TGC CCC ACC CAC GCA CCT GCT 3427 Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr His Ala Pro Ala 2040 2045 2050 TCC TGC CTT GAC ACC CAA TAC ACC TGT GAT AAT CAC CAG TGT ATC TCA 3475 Ser Cys Leu Asp Thr Gin Tyr Thr Cys Asp Asn His Gin Cys Ile Ser 2055 2060 2065 AAG AAC TGG GTC TGT GAC ACA GAC AAT GAT TGT GGG GAT GGA TCT GAT 3523 Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly Asp Gly Ser Asp 2070 2075 2080 GAA AAG AAC TGC AAT TCG ACA GAG ACA TGC CAA CCT AGT CAG TTT AAT 3571 Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gin Pro Ser Gin Phe Asn 2085 2090 2095 2100 TGC CCC AAT CAT CGA TGT ATT GAC CTA TCG TTT GTC TGT GAT GGT GAC 3619 Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val Cys Asp Gly Asp 2105 2110 2115 AAG GAT TGT GTT GAT GGA TCT GAT GAG GTT GGT TGT GTA TTA AAC TGT 3667 Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly Cys Val Leu Asn Cys 2120 2125 2130 ACT GCT TCT CAA TTC AAG TGT GCC AGT GGG GAT AAA TGT ATT GGC GTC 3715 Thr Ala Ser Gin Phe Lys Cys Ala Ser Gly Asp Lys Cys Ile Gly Val 2135 2140 2145 ACA AAT CGT TGT GAT GGT GTT TTT GAT TGC AGT GAC AAC TCG GAT GAA 3763 Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser Asp Asn Ser Asp Glu 2150 2155 2160 GCG GGC TGT CCA ACC AGG CCT CCT GGT ATG TGC CAC TCA GAT GAA TTT 3811 Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His Ser Asp Glu Phe WO 96/15801 PCT/US95/15203 2175 2175 2180 2165 2170

CAG

Gin TGC CAA GAA GAT GGT ATC TGC ATC CCG AAC TTC TGG GAA TGT GAT Cys Gin Glu Asp Gly 2185 Ile Cys Ile Pro Asn Phe Trp Glu Cys Asp 2190 2195 GGG CAT CCA GAC TGC CTC TAT GGA TCT GAT GAG CAC AAT GCC TGT GTC Gly His Pro Asp Cys Leu Tyr Gly Ser Asp Glu His Asn Ala Cys Val 2200 2205 2210 CCC AAG.ACT TGC CCT TCA TCA TAT TTC CAC TGT GAC AAC GGA AAC TGC *Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys Asp Asn Gly Asn Cys 2215 2220 2225 ATC CAC AGG GCA TGG CTC TGT GAT CGG GAC AAT GAC TGC GGG GAT ATG Ile His Arg Ala Trp Leu Cys Asp Arg Asp Asn Asp Cys Gly Asp Met 2230 2235 2240 AGT GAT GAG AAG GAC TGC CCT ACT CAG CCC TTT CGC TGT CCT AGT TGG Ser Asp Glu Lys Asp Cys Pro Thr Gin Pro Phe Arg Cys Pro Ser Trp 2245 2250 2255 2260 CAA TGG CAG TGT CTT GGC CAT AAC ATC TGT GTG AAT CTG AGT GTA GTG Gin Trp Gin Cys Leu Gly His Asn Ile Cys Val Asn Leu Ser Val Val 2265 2270 2275 TGT GAT GGC ATC TTT GAC TGC CCC AAT GGG ACA GAT GAG TCC CCA CTT Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp Glu Ser Pro Leu 2280 2285 2290 TGC AAT GGG AAC AGC TGC TCA GAT TTC AAT GGT GGT TGT ACT CAC GAG Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly Cys Thr His Glu 2295 2300 2305 TGT GTT CAA GAG CCC TTT GGG GCT AAA TGC CTA TGT CCA TTG GGA TTC Cys Val Gin Glu Pro Phe Gly Ala Lys Cys Leu Cys Pro Leu Gly Phe 2310 2315 2320 TTA CTT GCC AAT GAT TCT AAG ACC TGT GAA GAC ATA GAT GAA TGT GAT Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp Ile Asp Glu Cys Asp 2325 2330 2335 2340 ATT CTA GGC TCT TGT AGC CAG CAC TGT TAC AAT ATG AGA GGT TCT TTC 3859 3907 3955 4003 4051 4099 4147 4195 4243 4291 4339.

4387 4435 4483 4531 4579 Ile Leu Gly Ser Cys Ser Gin His Cys 2345 Tyr Asn Met 2350 Arg

GAT

Gly Ser Phe 2355 GGG AGG ACT Gly Arg Thr 2370 CGG TGC TCG TGT GAT ACA GGC TAC ATG Arg Cys Ser Cys Asp Thr Gly Tyr Met 2360 2365 TTA GAA AGT Leu Glu Ser Asp TGC AAA GTT ACA Cys Lys Val Thr 2375 AAC AAA ATT ATT Asn Lys Ile Ile 2390 TCA TTG GTC GAG Ser Leu Val Glu 2405 ATT AGT GGT CGT Ile Ser Gly Arg

GCA

Ala

GCC

Ala

AAT

Asn

ATC

Ile TCT GAG AGT CTG Ser Glu Ser Leu 2380 GAC AGT GTC ACC Asp Ser Val Thr 2395 GGT TCT TAC ATT Gly Ser Tyr Ile 2410 TTT TGG TCT GAT Phe Trp Ser Asp CTG TTA CTT GTG GCA Leu Leu Leu Val Ala 2385 TCC CAG GTC CAC AAT Ser Gin Val His Asn 2400 GTA GCT GTT GAT TTT Val Ala Val Asp Phe 2415 GCA ACT CAG GGT AAA Ala Thr Gin Gly Lys AGT CAG Ser Gin ATC TAT Ile Tyr GAT TCA Asp Ser 2420 ACC TGG Thr Trp WO 96/15801 PCT/US95/15203 91/ 2425 2430 2435 AGT GCG TTT CAA AAT GGA ACG GAC AGA AGA GTG GTA TTT GAC AGT AGC 4627 Ser Ala Phe Gin Asn Gly Thr Asp Arg Arg Val Val Phe Asp Ser Ser 2440 2445 2450 ATC ATC TTG ACT GAA ACT ATT GCA ATA GAT TGG GTA GGT CGT AAT CTT 4675 Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val Gly Arg Asn Leu 2455 2460 2465 TAC TGG ACA GAC TAT GCT CTG GAA ACA ATT GAA GTC TCC AAA ATT GAT 4723 Tyr Trp Thr Asp Tyr Ala Leu Glu Thr Ile Glu Val Ser Lys Ile Asp .2470 2475 2480 GGG AGC CAC AGG ACT GTG CTG ATT AGT AAA AAC CTA ACA AAT CCA AGA 4771 Gly Ser His Arg Thr Val Leu Ile Ser Lys Asn Leu Thr Asn Pro Arg 2485 2490 2495 2500 GGA CTA GCA TTA GAT CCC AGA ATG AAT GAG CAT CTA CTG TTC TGG TCT 4819 Gly Leu Ala Leu Asp Pro Arg Met Asn Glu His Leu Leu Phe Trp Ser 2505 2510 2515 GAC TGG GGC CAC CAC CCT CGC ATC GAG CGA GCC AGC ATG GAC GGC AGC 4867 Asp Trp Gly His His Pro Arg Ile Glu Arg Ala Ser Met Asp Gly Ser 2520 2525 2530 ATG CGC ACT GTC ATT GTC CAG GAC AAG ATC TTC TGG CCC TGC GGC TTA 4915 Met Arg Thr Val Ile Val Gin Asp Lys Ile Phe Trp Pro Cys Gly Leu 2535 2540 2545 ACT ATT GAC TAC CCC AAC AGA CTG CTC TAC TTC ATG GAC TCC TAT CTT 4963 Thr Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe Met Asp Ser Tyr Leu 2550 2555 2560 GAT TAC ATG GAC TTT TGC GAT TAT AAT GGA CAC CAT CGG AGA CAG GTG 5011 Asp Tyr Met Asp Phe Cys Asp Tyr Asn Gly His His Arg Arg Gin Val 2565 2570 2575 2580 ATA GCC AGT GAT TTG ATT ATA CGG CAC CCC TAT GCC CTA ACT CTC TTT 5059 Ile Ala Ser Asp Leu Ile Ile Arg His Pro Tyr Ala Leu Thr Leu Phe 2585 2590 2595 GAA GAC TCT GTG TAC TGG ACT GAC CGT GCT ACT CGT CGG GTT ATG CGA 5107 Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg Arg Val Met Arg 2600 2605 2610 GCC AAC AAG TGG CAT GGA GGG AAC CAG TCA GTT GTA ATG TAT AAT ATT 5155 Ala Asn Lys Trp His Gly Gly Asn Gin Ser Val Val Met Tyr Asn Ile 2615 2620 2625 CAA TGG CCC CTT GGG ATT GTT GCG GTT CAT CCT TCG AAA CAA CCA AAT 5203 Gin Trp Pro Leu Gly Ile Val Ala Val His Pro Ser Lys Gin Pro Asn 2630 2635 2640 TCC GTG AAT CCA TGT GCC TTT TCC CGC TGC AGC CAT CTC TGC CTG CTT 5251 Ser Val Asn Pro Cys Ala -Phe Ser Arg Cys Ser His Leu Cys Leu Leu 2645 2650 2655 2660 TCC TCA CAG GGG CCT CAT TTT TAC TCC TGT GTT TGT CCT TCA GGA TGG 5299 Ser Ser Gin Gly Pro His Phe Tyr Ser Cys Val Cys Pro Ser Gly Trp 2665 2670 2675 AGT CTG TCT CCT GAT CTC CTG AAT TGC TTG AGA GAT GAT CAA CCT TTC 5347 Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp Asp Gin Pro Phe WO 96/15801 PCT/US95/15203 2680 2685 2690 TTA ATA ACT GTA AGG CAA CAT ATA ATT TTT GGA ATC TCC CTT AAT CCT 5395 Leu Ile Thr Val Arg Gin His Ile Ile Phe Gly Ile Ser Leu Asn Pro 2695 2700 2705 GAG GTG AAG AGC AAT GAT GCT ATG GTC CCC ATA GCA GGG ATA CAG AAT 5443 Glu Val Lys Ser Asn Asp Ala Met Val Pro Ile Ala Gly Ile Gin Asn 2710 2715 2720 GGT TTA GAT GTT GAA TTT GAT GAT GCT GAG CAA TAC ATC TAT TGG GTT 5491 Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gin Tyr Ile Tyr Trp Val 2725 2730 2735 2740 GAA AAT CCA GGT GAA ATT CAC AGA GTG AAG ACA GAT GGC ACC AAC AGG 5539 Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp Gly Thr Asn Arg 2745 2750 2755 ACA GTA TTT GCT TCT ATA TCT ATG GTG GGG CCT TCT ATG AAC CTG GCC 5587 Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser Met Asn Leu Ala 2760 2765 2770 TTA GAT TGG ATT TCA AGA AAC CTT TAT TCT ACC AAT CCT AGA ACT CAG 5635 Leu Asp Trp Ile Ser Arg Asn Leu Tyr Ser Thr Asn Pro Arg Thr Gin 2775 2780 2785 TCA ATC GAG GTT TTG ACA CTC CAC GGA GAT ATC AGA TAC AGA AAA ACA 5683 Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg Tyr Arg Lys Thr 2790 2795 2800 TTG ATT GCC AAT GAT GGG ACA GCT CTT GGA GTT GGC TTT CCA ATT GGC 5731 Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly Phe Pro Ile Gly 2805 2810 2815 2820 ATA ACT GTT GAT CCT GCT CGT GGG AAG CTG TAC TGG TCA GAC CAA GGA 5779 Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp Ser Asp Gin Gly 2825 2830 2835 ACT GAC AGT GGG GTT CCT GCC AAG ATC GCC AGT GCT AAC ATG GAT GGC 5827 Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala Asn Met Asp Gly 2840 2845 2850 ACA TCT GTG AAA ACT CTC TTT ACT GGG AAC CTC GAA CAC CTG GAG TGT 5875 Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu His Leu Glu Cys 2855 2860 2865 GTC ACT CTT GAC ATC GAA GAG CAG AAA CTC TAC TGG GCA GTC ACT GGA 5923 Val Thr Leu Asp Ile Glu Glu Gin Lys Leu Tyr Trp Ala Val Thr Gly 2870 2875 2880 AGA GGA GTG ATT GAA AGA GGA AAC GTG GAT GGA ACA GAT CGG ATG ATC 5971 Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr Asp Arg Met Ile 2885 2890 2895 2900 CTG GTA CAC CAG CTT TCC CAC CCC TGG GGA ATT GCA GTC CAT GAT TCT 6019 Leu Val His Gin Leu Ser His Pro Trp Gly Ile Ala Val His Asp Ser 2905 2910 2915 TTC CTT TAT TAT ACT GAT GAA CAG TAT GAG GTC ATT GAA AGA GTT GAT 6067 Phe Leu Tyr Tyr Thr Asp Glu Gin Tyr Glu Val Ile Glu Arg Val Asp 2920 2925 2930 AAG GCC ACT GGG GCC AAC AAA ATA GTC TTG AGA GAT AAT GTT CCA AAT 6115 Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp Asn Val Pro Asn WO 96/15801 PCTTUS95/15203 2935 2940 2945 CTG AGG GGT CTT CAA GTT TAT CAC AGA CGC AAT GCC GCC GAA TCC TCA 6163 Leu Arg Gly Leu Gin Val Tyr His Arg Arg Asn Ala Ala Glu Ser Ser 2950 2955 2960 AAT GGC TGT AGC AAC AAC ATG AAT GCC TGT CAG CAG ATT TGC CTG CCT 6211 Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gin Gin Ile Cys Leu Pro 2965 2970 2975 2980 GTA CCA GGA GGA TTG TTT TCC TGC GCC TGT GCC ACT GGA TTT AAA CTC 6259 Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr Gly Phe Lys Leu 2985 2990 2995 AAT CCT GAT AAT CGG TCC TGC TCT CCA TAT AAC TCT TTC ATT GTT GTT 6307 Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser Phe Ile Val Val 3000 3005 3010 TCA ATG CTG TCT GCA ATC AGA GGC TTT AGC TTG GAA TTG TCA GAT CAT 6355 Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu Leu Ser Asp His 3015 3020 3025 TCA GAA ACC ATG GTG CCG GTG GCA GGC CAA GGA CGA AAC GCA CTG CAT 6403 Ser Glu Thr Met Val Pro Val Ala Gly Gin Gly Arg Asn Ala Leu His 3030 3035 3040 GTG GAT GTG GAT GTG TCC TCT GGC TTT ATT TAT TGG TGT GAT TTT AGC 6451 Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp Cys Asp Phe Ser 3045 3050 3055 3060 AGC TCA GTG GCA TCT GAT AAT GCG ATC CGT AGA ATT AAA CCA GAT GGA 6499 Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile Lys Pro Asp Gly 3065 3070 3075 TCT TCT CTG ATG AAC ATT GTG ACA CAT GGA ATA GGA GAA AAT GGA GTC 6547 Ser Ser Leu Met Asn Ile Val Thr His Gly Ile Gly Glu Asn Gly Val 3080 3085 3090 CGG GGT ATT GCA GTG GAT TGG GTA GCA GGA AAT CTT TAT TTC ACC AAT 6595 Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu Tyr Phe Thr Asn 3095 3100 3105 GCC TTT GTT TCT GAA ACA CTG ATA GAA GTT CTG CGG ATC AAT ACT ACT 6643.

Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg Ile Asn Thr Thr 3110 3115 3120 TAC CGC CGT GTT CTT CTT AAA GTC ACA GTG GAC ATG CCT AGG CAT ATT 6691 Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp Met Pro Arg His Ile 3125 3130 3135 3140 GTT GTA GAT CCC AAG AAC AGA TAC CTC TTC TGG GCT GAC TAT GGG CAG 6739 Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala Asp Tyr Gly Gin 3145 3150 3155 AGA CCA AAG ATT GAG CGT TCT TTC CTT GAC TGT ACC AAT CGA ACA GTG 6787 Arg Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys Thr Asn Arg Thr Val 3160 3165 3170 CTT GTG TCA GAG GGC ATT GTC ACA CCA CGG GGC TTG GCA GTG GAC CGA 6835 Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu Ala Val Asp Arg 3175 3180 3185 AGT GAT GGC TAC GTT TAT TGG GTT GAT GAT TCT TTA GAT ATA ATT GCA 6883 Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser Leu Asp Ile Ile Ala WO 96/15801 PCTIUS95/15203 3190 3195 3200 AGG ATT CGT ATC AAT GGA GAG AAC TCT GAA GTG ATT CGT TAT GGC AGT 6931 Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile Arg Tyr Gly Ser 3205 3210 3215 3220 CGT TAC CCA ACT CCT TAT GGC ATC ACT GTT TTT GAA AAT TCT ATC ATA 6979 Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Giu Asn Ser Ile Ile 3225 3230 3235 TGG GTA GAT AGG AAT TTG AAA AAG ATC TTC CAA GCC AGC AAG GAA CCA 7027 Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gin Ala Ser Lys Glu Pro 3240 3245 3250 GAG AAC ACA GAG CCA CCC ACA GTG ATA AGA GAC AAT ATC AAC TGG CTA 7075 Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn Ile Asn Trp Leu 3255 3260 3265 AGA GAT GTG ACC ATC TTT GAC AAG CAA GTC CAG CCC CGG TCA CCA GCA 7123 Arg Asp Val Thr Ile Phe Asp Lys Gin Val Gin Pro Arg Ser Pro Ala 3270 3275 3280 GAG GTC AAC AAC AAC CCT TGC TTG GAA AAC AAT GGT GGG TGC TCT CAT 7171 Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn Gly Gly Cys Ser His 3285 3290 3295 3300 CTC TGC TTT GCT CTG CCT GGA TTG CAC ACC CCA AAA TGT GAC TGT GCC 7219 Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro Lys Cys Asp Cys Ala 3305 3310 3315 TTT GGG ACC CTG CAA AGT GAT GGC AAG AAT TGT GCC ATT TCA ACA GAA 7267 Phe Gly Thr Leu Gin Ser Asp Gly Lys Asn Cys Ala Ile Ser Thr Glu 3320 3325 3330 AAT TTC CTC ATC TTT GCC TTG TCT AAT TCC TTG AGA AGC TTA CAC TTG 7315 Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu Arg Ser Leu His Leu 3335 3340 3345 GAC CCT GAA AAC CAT AGC CCA CCT TTC CAA ACA ATA AAT GTG GAA AGA 7363 Asp Pro Glu Asn His Ser Pro Pro Phe Gin Thr Ile Asn Val Glu Arg 3350 3355 3360 ACT GTC ATG TCT CTA GAC TAT GAC ACT GTA AGT GAT AGA ATC TAC TTC 7411 Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp Arg Ile Tyr Phe 3365 3370 3375 3380 ACA CAA AAT TTA GCC TCT GGA GTT GGA CAG ATT TCC TAT GCC ACC CTG 7459 Thr Gin Asn Leu Ala Ser Gly Val Gly Gin Ile Ser Tyr Ala Thr Leu 3385 3390 3395 TCT TCA GGG ATC CAT ACT CCA ACT GTC ATT GCT TCA GGT ATA GGG ACT 7507 Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser Gly Ile Gly Thr 3400 3405 3410 GCT GAT GGC ATT GCC TTT GAC TGG ATT ACT AGA AGA ATT TAT TAC AGT 7555 Ala Asp Gly Ile Ala Phe'Asp Trp Ile Thr Arg Arg Ile Tyr Tyr Ser 3415 3420 3425 GAC TAC CTC AAC CAG ATG ATT AAT TCC ATG GCT GAA GAT GGG TCT AAC 7603 Asp Tyr Leu Asn Gin Met Ile Asn Ser Met Ala Glu Asp Gly Ser Asn 3430 3435 3440 CGC ACT GTG ATA GCC CGC GTT CCA AAA CCA AGA GCA ATT GTG TTA GAT 7651 Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg Ala Ile Val Leu Asp WO 96/15801 PCTllUS95/15203 3445 3450 3455 3460 CCC TGC CAA GGG TAC CTG TAC TGG GCT GAC TGG GAT ACA CAT GCC AAA 7699 Pro Cys Gin Gly Tyr Leu Tyr Trp Ala Asp Trp Asp Thr His Ala Lys 3465 3470 3475 ATC GAG AGA GCC ACA TTG GGA GGA AAC TTC CGG GTA CCC ATT GTG AAC 7747 Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg Val Pro Ile Val Asn 3480 3485 3490 AGC AGT CTG GTC ATG CCC AGT GGG CTG ACT CTG GAC TAT GAA GAG GAC 7795 Ser Ser Leu Val Met Pro Ser Gly Leu Thr Leu Asp Tyr Glu Glu Asp 3495 3500 3505 CTT CTC TAC TGG GTG GAT GCT'AGT CTG CAG AGG ATT GAA CGC AGC ACT 7843 Leu Leu Tyr Trp Val Asp Ala Ser Leu Gin Arg Ile Glu Arg Ser Thr 3510 3515 3520 CTG ACG GGC GTG GAT CGT GAA GTC ATT GTC AAT GCA GCC GTT CAT GCT 7891 Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala Ala Val His Ala 3525 3530 3535 3540 TTT GGC TTG ACT CTC TAT GGC CAG TAT ATT TAC TGG ACT GAC TTG TAC 7939 Phe Gly Leu Thr Leu Tyr Gly Gin Tyr Ile Tyr Trp Thr Asp Leu Tyr 3545 3550 3555 ACA CAA AGA ATT TAC CGA GCT AAC AAA TAT GAC GGG TCA GGT CAG ATT 7987 Thr Gin Arg Ile Tyr Arg Ala Asn Lys Tyr Asp Gly Ser Gly Gin Ile 3560 3565 3570 GCA ATG ACC ACA AAT TTG CTC TCC CAG CCC AGG GGA ATC AAC ACT GTT 8035 Ala Met Thr Thr Asn Leu Leu Ser Gin Pro Arg Gly Ile Asn Thr Val 3575 3580 3585 GTG AAG AAC CAG AAA CAA CAG TGT AAC AAT CCT TGT GAA CAG TTT AAT 8083 Val Lys Asn Gin Lys Gin Gin Cys Asn Asn Pro Cys Glu Gin Phe Asn 3590 3595 3600 GGG GGC TGC AGC CAT ATC TGT GCA CCA GGT CCA AAT GGT GCC GAG TGC 8131 Gly Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn Gly Ala Glu Cys 3605 3610 3615 3620 CAG TGT CCA CAT GAG GGC AAC TGG TAT TTG GCC AAC AAC AGG AAG CAC 8179 Gin Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn Asn Arg Lys His 3625 3630 3635 TGC ATT GTG GAC AAT GGT GAA CGA TGT GGT GCA TCT TCC TTC ACC TGC 8227 Cys Ile Val Asp Asn Gly Giu Arg Cys Gly Ala Ser Ser Phe Thr Cys 3640 3645 3650 TCC AAT GGG CGC TGC ATC TCG GAA GAG TGG AAG TGT GAT AAT GAC AAC 8275 Ser Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys Cys Asp Asn Asp Asn 3655 3660 3665 GAC TGT GGG GAT GGC AGT GAT GAG ATG GAA AGT GTC TGT GCA CTT CAC 8323 Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val Cys Ala Leu His 3670 3675 3680 ACC TGC TCA CCG ACA GCC TTC ACC TGT GCC AAT GGG CGA TGT GTC CAA 8371 Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly Arg Cys Val Gin 3685 3690 3695 3700 TAC TCT TAC CGC TGT GAT TAC TAC AAT GAC TGT GGT GAT GGC ACT GAT 8419 Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly Asp Gly Ser Asp WO 96/15801 PCT/US95/15203 3705 3710 3715 GAG GCA GGG TGC CTG TTC AGG GAC TGC AAT GCC ACC ACG GAG TTT ATG 8467 Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala Thr Thr Glu Phe Met 3720 3725 3730 TGC AAT AAC AGA AGG TGC ATA CCT CGT GAG TTT ATC TGC AAT GGT GTA 8515 Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile Cys Asn Gly Val 3735 3740 3745 GAC AAC TGC CAT GAT AAT AAC ACT TCA GAT GAG AAA AAT TGC CCT GAT 8563 Asp Asn Cys His Asp Asn Asn.Thr Ser Asp Glu Lys Asn Cys Pro Asp 3750 3755 3760 CGC ACT TGC CAG TCT GGA TAC ACA AAA TGT CAT AAT TCA AAT ATT TGT 8611 Arg Thr Cys Gin Ser Gly Tyr Thr Lys Cys His Asn Ser Asn Ile Cys 3765 3770 3775 3780 ATT CCT CGC GTT TAT TTG TGT GAC GGA GAC AAT GAC TGT GGA GAT AAC 8659 Ile Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn Asp Cys Gly Asp Asn 3785 3790 3795 AGT GAT GAA AAC CCT ACT TAT TGC ACC ACT CAC ACA TGC AGC AGC AGT 8707 Ser Asp Glu Asn Pro Thr Tyr Cys Thr Thr His Thr Cys Ser Ser Ser 3800 3805 3810 GAG TTC CAA TGC GCA TCT GGG CGC TGT ATT CCT CAA CAT TGG TAT TGT 8755 Glu Phe Gin Cys Ala Ser Gly Arg Cys Ile Pro Gin His Trp Tyr Cys 3815 3820 3825 GAT CAA GAA ACA GAT TGT TTT GAT GCC TCT GAT GAA CCT GCC TCT TGT 8803 Asp Gin Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu Pro Ala Ser Cys 3830 3835 3840 GGT CAC TCT GAG CGA ACA TGC CTA GCT GAT GAG TTC AAG TGT GAT GGT 8851 Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe Lys Cys Asp Gly 3845 3850 3855 3860 GGG AGG TGC ATC CCA AGC GAA TGG ATC TGT GAC GGT GAT AAT GAC TGT 8899 Gly Arg Cys Ile Pro Ser Glu Trp Ile Cys Asp Gly Asp Asn Asp Cys 3865 3870 3875 GGG GAT ATG AGT GAC GAG GAT AAA AGG CAC CAG TGT CAG AAT CAA AAC 8947 Gly Asp Met Ser Asp Glu Asp Lys Arg His Gin Cys Gin Asn Gin Asn 3880 3885 3890 TGC TCG GAT TCC GAG TTT CTC TGT GTA AAT GAC AGA CCT CCG GAC AGG 8995 Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg Pro Pro Asp Arg 3895 3900 3905 AGG TGC ATT CCC CAG TCT TGG GTC TGT GAT GGC GAT GTG GAT TGT ACT 9043 Arg Cys Ile Pro Gin Ser Trp Val Cys Asp Gly Asp Val Asp Cys Thr 3910 3915 3920 GAC GGC TAC GAT GAG AAT CAG AAT TGC ACC AGG AGA ACT TGC TCT GAA 9091 Asp Gly Tyr Asp Glu Asn Gin Asn Cys Thr Arg Arg Thr Cys Ser Glu 3925 3930 3935 3940 AAT GAA TTC ACC TGT GGT TAC GGA CTG TGT ATC CCA AAG ATA TTC AGG 9139 Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro Lys Ile Phe Arg 3945 3950 3955 TGT GAC CGG CAC AAT GAC TGT GGT GAC TAT AGC GAC GAG AGG GGC TGC 9187 Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp Glu Arg Gly Cys WO 96/15801 PCTIUS95/15203 3960 3965 3970 TTA TAC CAG ACT TGC CAA CAG AAT CAG TTT ACC TGT CAG AAC GGG CGC 9235 Leu Tyr Gin Thr Cys Gin Gin Asn Gin Phe Thr Cys Gin Asn Gly Arg 3975 3980 3985 TGC ATT AGT AAA ACC TTC GTC TGT GAT GAG GAT AAT GAC TGT GGA GAC .9283 Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn Asp Cys Gly Asp 3990 3995 4000 GGA TCT GAT GAG CTG ATG CAC CTG TGC CAC ACC CCA GAA CCC ACG TGT 9331 Gly Ser Asp Glu Leu Met His Leu Cys His Thr Pro Glu Pro Thr Cys 4005 4010 4015 4020 CCA CCT CAC GAG TTC AAG TGT GAC AAT GGG CGC TGC ATC GAG ATG ATG 9379 Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys Ile Glu Met Met 4025 4030 4035 AAA CTC TGC AAC CAC CTA GAT GAC TGT TTG GAC AAC AGC GAT GAG AAA 9427 Lys Leu Cys Asn His Leu Asp Asp Cys Leu Asp Asn Ser Asp Glu Lys 4040 4045 4050 GGC TGT GGC ATT AAT GAA TGC CAT GAC CCT TCA ATC AGT GGC TGC GAT 9475 Gly Cys Gly Ile Asn Glu Cys His Asp Pro Ser Ile Ser Gly Cys Asp 4055 4060 4065 CAC AAC TGC ACA GAC ACC TTA ACC AGT TTC TAT TGT TCC TGT CGT CCT 9523 His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr Cys Ser Cys Arg Pro 4070 4075 4080 GGT TAC AAG CTC ATG TCT GAC AAG CGG ACT TGT GTT GAT ATT GAT GAA 9571 Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys Val Asp Ile Asp Glu 4085 4090 4095 4100 TGC ACA GAG ATG CCT TTT GTC TGT AGC CAG AAG TGT GAG AAT GTA ATA 9619 Cys Thr Glu Met Pro Phe Val Cys Ser Gin Lys Cys Glu Asn Val Ile 4105 4110 4115 GGC TCC TAC ATC TGT AAG TGT GCC CCA GGC TAC CTC CGA GAA CCA GAT 9667 Gly Ser Tyr Ile Cys Lys Cys Ala Pro Gly Tyr Leu Arg Glu Pro Asp 4120 4125 4130 GGA AAG ACC TGC CGG CAA AAC AGT AAC ATC GAA CCC TAT CTC ATT TTT 9715 Gly Lys Thr Cys Arg Gin Asn Ser Asn Ile Glu Pro Tyr Leu Ile Phe 4135 4140 4145 AGC AAC CGT TAC TAT TTG AGA AAT TTA ACT ATA GAT GGC TAT TTT TAC 9763 Ser Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile Asp Gly Tyr Phe Tyr 4150 4155 4160 TCC CTC ATC TTG GAA GGA CTG GAC AAT GTT GTG GCA TTA GAT TTT GAC 9811 Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala Leu Asp Phe Asp 4165 4170 4175 4180 CGA GTA GAG AAG AGA TTG TAT TGG ATT GAT ACA CAG AGG CAA GTC ATT 9859 Arg Val Glu Lys Arg Leu' Tyr Trp Ile Asp Thr Gin Arg Gin Val Ile 4185 4190 4195 GAG AGA ATG TTT CTG AAT AAG ACA AAC AAG GAG ACA ATC ATA AAC CAC 9907 Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu Thr Ile Ile Asn His 4200 4205 4210 AGA CTA CCA GCT GCA GAA AGT CTG GCT GTA GAC TGG GTT TCC AGA AAG 9955 Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp Val Ser Arg Lys WO 96/15801 PCTfUS95/15203 Ci/ 4215 4220 4225 CTC TAC TGG TTG GAT GCC CGC CTG GAT GGC CTC TTT GTC TCT GAC CTC 10003 Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly Leu Phe Val Ser Asp Leu 4230 4235 4240 AAT GGT GGA CAC CGC CGC ATG CTG GCC CAG CAC TGT GTG GAT GCC AAC 10051 Asn Gly Gly His Arg Arg Met Leu Ala Gin His Cys Val Asp Ala Asn 4245 4250 4255 4260 AAC ACC TTC TGC TTT GAT AAT CCC AGA GGA CTT GCC CTT CAC CCT CAA 10099 Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu Ala Leu His Pro Gin 4265 4270 4275 TAT GGG TAC CTC TAC TGG GCA GAC TGG GGT CAC CGC GCA TAC ATT GGG 10147 Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg Ala Tyr Ile Gly 4280 4285 4290 AGA GTA GGC ATG GAT GGA ACC AAC AAG TCT GTG ATA ATC TCC ACC AAG 10195 Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile Ile Ser Thr Lys 4295 4300 4305 TTA GAG TGG CCT AAT GGC ATC ACC ATT GAT TAC ACC AAT GAT CTA CTC 10243 Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr Asn Asp Leu Leu 4310 4315 4320 TAC TGG GCA GAT GCC CAC CTG GGT TAC ATA GAG TAC TCT GAT TTG GAG 10291 Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr Ser Asp Leu Glu 4325 4330 4335 4340 GGC CAC CAT CGA CAC ACG GTG TAT GAT GGG GCA CTG CCT CAC CCT TTC 10339 Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu Pro His Pro Phe 4345 4350 4355 GCT ATT ACC ATT TTT GAA GAC ACT ATT TAT TGG ACA GAT TGG AAT ACA 10387 Ala Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp Thr Asp Trp Asn Thr 4360 4365 4370 AGG ACA GTG GAA AAG GGA AAC AAA TAT GAT GGA TCA AAT AGA CAG ACA 10435 Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser Asn Arg Gin Thr 4375 4380 4385 CTG GTG AAC ACA ACA CAC AGA CCA TTT GAC ATC CAT GTG TAC CAT CCA 10483 Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile His Val Tyr His Pro 4390 4395 4400 TAT AGG CAG CCC ATT GTG AGC AAT CCC TGT GGT ACC AAC AAT GGT GGC 10531 Tyr Arg Gin Pro Ile Val Ser Asn Pro Cys Gly Thr Asn Asn Gly Gly 4405 4410 4415 4420 TGT TCT CAT CTC TGC CTC ATC AAG CCA GGA GGA AAA GGG TTC ACT TGC 10579 Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly Lys Gly Phe Thr Cys 4425 4430 4435 GAG TGT CCA GAT GAC TTC CGC ACC CTT CAA CTG AGT GGC AGC ACC TAC 10627 Glu Cys Pro Asp Asp Phe Arg Thr Leu Gin Leu Ser Gly Ser Thr Tyr 4440 4445 4450 TGC ATG CCC ATG TGC TCC AGC ACC CAG TTC CTG TGC GCT AAC AAT GAA 10675 Cys Met Pro Met Cys Ser Ser Thr Gin Phe Leu Cys Ala Asn Asn Glu 4455 4460 4465 AAG TGC ATT CCT ATC TGG TGG AAA TGT GAT GGA CAG AAA GAC TGC TCA 10723 Lys Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly Gin Lys Asp Cys Ser WO 96/15801 PCTIUS95/15203 4470 4475 4480 GAT GGC TCT GAT GAA CTG GCC CTT TGC CCG CAG CGC TTC TGC CGA CTG 10771 Asp Gly Ser Asp Glu Leu Ala Leu Cys Pro Gin Arg Phe Cys Arg Leu 4485 4490 4495 4500 GGA CAG TTC CAG TGC AGT GAC GGC AAC TGC ACC AGC CCG CAG ACT TTA 10819 Gly Gin Phe Gin Cys Ser Asp Gly Asn Cys Thr Ser Pro Gin Thr Leu 4505 4510 4515 TGC AAT GCT CAC CAA AAT TGC CCT GAT GGG TCT GAT GAA GAC CGT CTT 10867 Cys Asn Ala His Gin Asn Cys Pro Asp Gly Ser Asp Giu Asp Arg Leu 4520 4525 4530 CTT TGT GAG AAT CAC CAC TGT GAC TCC AAT GAA TGG CAG TGC GCC AAC 10915 Leu Cys Glu Asn His His Cys Asp Ser Asn Glu Trp Gin Cys Ala Asn 4535 4540 4545 AAA CGT TGC ATC CCA GAA TCC TGG CAG TGT GAC ACA TTT AAC GAC TGT 10963 Lys Arg Cys Ile Pro Glu Ser Trp Gin Cys Asp Thr Phe Asn Asp Cys 4550 4555 4560 GAG GAT AAC TCA GAT GAA GAC AGT TCC CAC TGT GCC AGC AGG ACC TGC 11011 Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala Ser Arg Thr Cys 4565 4570 4575 4580 CGG CCG GGC CAG TTT CGG TGT GCT AAT GGC CGC TGC ATC CCG CAG GCC 11059 Arg Pro Gly Gin Phe Arg Cys Ala Asn Gly Arg Cys Ile Pro Gin Ala 4585 4590 4595 TGG AAG TGT GAT GTG GAT AAT GAT TGT GGA GAC CAC TCG GAT GAG CCC 11107 Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His Ser Asp Glu Pro 4600 4605 4610 ATT GAA GAA TGC ATG AGC TCT GCC CAT CTC TGT GAC AAC TTC ACA GAA 11155 Ile Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp Asn Phe Thr Glu 4615 4620 4625 TTC AGC TGC AAA ACA AAT TAC CGC TGC ATC CCA AAG TGG GCC GTG TGC 11203 Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys Trp Ala Val Cys 4630 4635 4640 AAT GGT GTA GAT GAC TGC AGG GAC AAC AGT GAT GAG CAA GGC TGT GAG 11251 Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu Gin Gly Cys Glu 4645 4650 4655 4660 GAG AGG ACA TGC CAT CCT GTG GGG GAT TTC CGC TGT AAA AAT CAC CAC 11299 Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys Lys Asn His His 4665 4670 4675 TGC ATC CCT CTT CGT TGG CAG TGT GAT GGG CAA AAT GAC TGT GGA GAT 11347 Cys Ile Pro Leu Arg Trp Gin Cys Asp Gly Gin Asn Asp Cys Gly Asp 4680 4685 4690 AAC TCA GAT GAG GAA AAC TGT GCT CCC CGG GAG TGC ACA GAG AGC GAG 11395 Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys Thr Glu Ser Glu 4695 4700 4705 TTT CGA TGT GTC AAT CAG CAG TGC ATT CCC TCG CGA TGG ATC TGT GAC 11443 Phe Arg Cys Val Asn Gin Gin Cys Ile Pro Ser Arg Trp Ile Cys Asp 4710 4715 4720 CAT TAC AAC GAC TGT GGG GAC AAC TCA GAT GAA CGG GAC TGT GAG ATG 11491 His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg Asp Cys Glu Met WO 96/15801 PCT/US95/15203 4725 4730 3 4735 4740 AGG ACC TGC CAT CCT GAA TAT TTT CAG TGT ACA AGT GGA CAT TGT GTA 11539 Arg Thr Cys His Pro Glu Tyr Phe Gin Cys Thr Ser Gly His Cys Val 4745 4750 4755 CAC AGT GAA CTG AAA TGC GAT GGA TCC GCT GAC TGT TTG GAT GCG TCT 11587 His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys Leu Asp Ala Ser 4760 4765 4770 GAT GAA GCT GAT TGT CCC ACA CGC TTT CCT GAT GGT GCA TAC TGC CAG 11635 Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly Ala Tyr Cys Gin 4775 4780 4785 GCT ACT ATG TTC GAA TGC AAA AAC CAT GTT TGT ATC CCG CCA TAT TGG 11683 Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile Pro Pro Tyr Trp 4790 4795 4800 AAA TGT GAT GGC GAT GAT GAC TGT GGC GAT GGT TCA GAT GAA GAA CTT 11731 Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser Asp Glu Glu Leu 4805 4810 4815 4820 CAC CTG TGC TTG GAT GTT CCC TGT AAT TCA CCA AAC CGT TTC CGG TGT 11779 His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn Arg Phe Arg Cys 4825 4830 4835 GAC AAC AAT CGC TGC ATT TAT AGT CAT GAG GTG TGC AAT GGT GTG GAT 11827 Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys Asn Gly Val Asp 4840 4845 4850 GAC TGT GGA GAT GGA ACT GAT GAG ACA GAG GAG CAC TGT AGA AAA CCG 11875 Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His Cys Arg Lys Pro 4855 4860 4865 ACC CCT AAA CCT TGT ACA GAA TAT GAA TAT AAG TGT GGC AAT GGG CAT 11923 Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys Gly Asn Gly His 4870 4875 4880 TGC ATT CCA CAT GAC AAT GTG TGT GAT GAT GCC GAT GAC TGT GGT GAC 11971 Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp Asp Cys Gly Asp 4885 4890 4895 4900 TGG TCC GAT GAA CTG GGT TGC AAT AAA GGA AAA GAA AGA ACA TGT GCT 12019 Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Giu Arg Thr Cys Ala 4905 4910 4915 GAA AAT ATA TGC GAG CAA AAT TGT ACC CAA TTA AAT GAA GGA GGA TTT 1206.7 Glu Asn Ile Cys Glu Gin Asn Cys Thr Gin Leu Asn Glu Gly Gly Phe 4920 4925 4930 ATC TGC TCC TGT ACA GCT GGG TTC GAA ACC AAT GTT TTT GAC AGA ACC 12115 Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val Phe Asp Arg Thr 4935 4940 4945 TCC TGT CTA GAT ATC AAT GAA TGT GAA CAA TTT GGG ACT TGT CCC CAG 12163 Ser Cys Leu Asp Ile Asn Glu Cys Glu Gin Phe Gly Thr Cys Pro Gin 4950 4955 4960 CAC TGC AGA AAT ACC AAA GGA AGT TAT GAG TGT GTC TGT GCT GAT GGC 12211 His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys Ala Asp Gly 4965 4970 4975 4980 TTC ACG TCT ATG AGT GAC CGC CCT GGA AAA CGA TGT GCA GCT GAG GGT 12259 Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys Ala Ala Glu Gly WO 96/15801 PCTJUS95/15203 4985 4990 4995 AGC TCT CCT TTG TTG CTA CTG CCT GAC AAT GTC CGA ATT CGA AAA TAT 12307 Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg Ile Arg Lys Tyr 5000 5005 5010 AAT CTC TCA TCT GAG AGG TTC TCA GAG TAT CTT CAA GAT GAG GAA TAT 12355 Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gin Asp Glu Glu Tyr 5015 5020 5025 ATC CAA GCT GTT GAT TAT GAT TGG GAT CCC AAG GAC ATA GGC CTC AGT 12403 Ile Gln Ala Val Asp Tyr Asp Trp Asp Pro Lys Asp Ile Gly Leu Ser 5030 5035 5040 GTT GTG TAT TAC ACT GTG CGA GGG GAG GGC TCT AGG TTT GGT GCT ATC 12451 Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg Phe Gly Ala Ile 5045 5050 5055 5060 AAA CGT GCC TAC ATC CCC AAC TTT GAA TCC GGC CGC AAT AAT CTT GTG 12499 Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg Asn Asn Leu Val 5065 5070 5075 CAG GAA GTT GAC CTG AAA CTG AAA TAC GTA ATG CAG CCA GAT GGA ATA 12547 Gin Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gin Pro Asp Gly Ile 5080 5085 5090 GCA GTG GAC TGG GTT GGA AGG CAT ATT TAC TGG TCA GAT GTC AAG AAT 12595 Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser Asp Val Lys Asn 5095 5100 5105 AAA CGC ATT GAG GTG GCT AAA CTT GAT GGA AGG TAC AGA AAG TGG CTG 12643 Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr Arg Lys Trp Leu 5110 5115 5120 ATT TCC ACT GAC CTG GAC CAA CCA GCT GCT ATT GCT GTG AAT CCC AAA 12691 Ile Ser Thr Asp Leu Asp Gin Pro Ala Ala Ile Ala Val Asn Pro Lys 5125 5130 5135 5140 CTA GGG CTT ATG TTC TGG ACT GAC TGG GGA AAG GAA CCT AAA ATC GAG 12739 Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu Pro Lys Ile Glu 5145 5150 5155 TCT GCC TGG ATG AAT GGA GAG GAC CGC AAC ATC CTG GTT TTC GAG GAC 12787 Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu Val Phe Glu Asp 5160 5165 5170 CTT GGT TGG CCA ACT GGC CTT TCT ATC GAT TAT TTG AAC AAT GAC CGA 12835 Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu Asn Asn Asp Arg 5175 5180 5185 ATC TAC TGG AGT GAC TTC AAG GAG GAC GTT ATT GAA ACC ATA AAA TAT 12883 Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu Thr Ile Lys Tyr 5190 5195 5200 GAT GGG ACT GAT AGG AGA GTC ATT GCA AAG GAA GCA ATG AAC CCT TAC 12931 Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala Met Asn Pro Tyr 5205 5210 5215 5220 AGC CTG GAC ATC TTT GAA GAC CAG TTA TAC TGG ATA TCT AAG GAA AAG 12979 Ser Leu Asp Ile Phe Giu Asp Gin Leu Tyr Trp Ile Ser Lys Glu Lys 5225 5230 5235 GGA GAA GTA TGG AAA CAA AAT AAA TTT GGG CAA GGA AAG AAA GAG AAA 13027 Gly Glu Val Trp Lys Gin Asn Lys Phe Gly Gin Gly Lys Lys Glu Lys WO 96/15801 PCTfUS95/15203 5240 5245 5250 ACG CTG GTA GTG AAC CCT TGG CTC ACT CAA GTT CGA ATC TTT CAT CAA 13075 Thr Leu Val Val Asn Pro Trp Leu Thr Gin Val Arg Ile Phe His Gin 5255 5260 5265 CTC AGA TAC AAT AAG TCA GTG CCC AAC CTT TGC AAA CAG ATC TGC AGC 13123 Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys Gin Ile Cys Ser 5270 5275 5280 CAC CTC TGC CTT CTG AGA CCT GGA GGA TAC AGC TGT GCC TGT CCC CAA 13171 His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys Ala Cys Pro Gin 5285 5290 5295 5300 GGC TCC AGC TTT ATA GAG GGG AGC ACC ACT GAG TGT GAT GCA GCC ATC 13219 Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys Asp Ala Ala Ile 5305 5310 5315 GAA CTG CCT ATC AAC CTG CCC CCC CCA TGC AGG TGC ATG CAC GGA GGA 13267 Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys Met His Gly Gly 5320 5325 5330 AAT TGC TAT TTT GAT GAG ACT GAC CTC CCC AAA TGC AAG TGT CCT AGC 13315 Asn Cys Tyr Phe Asp Glu Thr Asp Leu Pro Lys Cys Lys Cys Pro Ser 5335 5340 5345 GGC TAC ACC GGA AAA TAT TGT GAA ATG GCG TTT TCA AAA GGC ATC TCT 13363 Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser Lys Gly Ile Ser 5350 5355 5360 CCA GGA ACA ACC GCA GTA GCT GTG CTG TTG ACA ATC CTC TTG ATC GTC 13411 Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile Leu Leu Ile Val 5365 5370 5375 5380 GTA ATT GGA GCT CTG GCA ATT GCA GGA TTC TTC CAC TAT AGA AGG ACC 13459 Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His Tyr Arg Arg Thr 5385 5390 5395 GGC TCC CTT TTG CCT GCT CTG CCC AAG CTG CCA AGC TTA AGC AGT CTC 13507 Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu Ser Ser Leu 5400 5405 5410 GTC AAG CCC TCT GAA AAT GGG AAT GGG GTG ACC TTC AGA TCA GGG GCA 13555 Val Lys Pro Ser Giu Asn Gly Asn Gly Val Thr Phe Arg Ser Gly Ala 5415 5420 5425 GAT CTT AAC ATG GAT ATT GGA GTG TCT GGT TTT GGA CCT GAG ACT GCT 13603 Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro Glu Thr Ala 5430 5435 5440 ATT GAC AGG TCA ATG GCA ATG AGT GAA GAC TTT GTC ATG GAA ATG GGG 13651 Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met Glu Met Gly 5445 5450 5455 5460 AAG CAG CCC ATA ATA TTT GAA AAC CCA ATG TAC TCA GCC AGA GAC AGT 13699 Lys Gin Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser Ala Arg Asp Ser 5465 5470 5475 GCT GTC AAA GTG GTT CAG CCA ATC CAG GTG ACT GTA TCT GAA AAT GTG 13747 Ala Val Lys Val Val Gin Pro Ile Gin Val Thr Val Ser Glu Asn Val 5480 5485 5490 GAT AAT AAG AAT TAT GGA AGT CCC ATA AAC CCT TCT GAG ATA GTT CCA 13795 Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu Ile Val Pro WO 96/15801 PCT/US95/15203 5495 5500 5505 GAG ACA AAC CCA ACT TCA CCA GCT GCT GAT GGA ACT CAG GTG ACA AAA 13843 Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gin Val Thr Lys 5510 5515 5520 TGG AAT CTC TTC AAA CGA AAA TCT AAA CAA ACT ACC AAC TTT GAA AAT 13891 Trp Asn Leu Phe Lys Arg Lys Ser Lys Gin Thr Thr Asn Phe Glu Asn 5525 5530 5535 5540 CCA ATC TAT GCA CAG ATG GAG AAC GAG CAA AAG GAA AGT GTT GCT GCG 13939 Pro Ile Tyr Ala Gin Met Glu Asn Glu Gin Lys Glu Ser Val Ala Ala 5545 5550 5555 ACA CCA CCT CCA TCA CCT TCG CTC CCT GCT AAG CCT AAG CCT CCT TCG 13987 Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro Lys Pro Pro Ser 5560 5565 5570 AGA AGA GAC CCA ACT CCA ACC TAT TCT GCA ACA GAA GAC ACT TTT AAA 14035 Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp Thr Phe Lys 5575 5580 5585 GAC ACC GCA AAT CTT GTT AAA GAA GAC TCT GAA GTA TAG GATCAAGAAG 14084 Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val 5590 5595 5600 AA 14086 INFORMATION FOR SEQ ID NO:84: SEQUENCE CHARACTERISTICS: LENGTH: 4656 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84: Met Asp Arg Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu Ala Leu 1 5 10 Val Ala Cys Leu Ala Pro Ala Ser Gly Gin Glu Cys Asp Ser Ala His 20 25 Phe Arg Cys Gly Ser Gly His Cys Ile Pro Ala Asp Trp Arg Cys Asp 40 Gly Thr Lys Asp Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys Ala Val 55 Val Thr Cys Gin Gin Gly Tyr Phe Lys Cys Gin Ser Glu Gly Gin Cys 70 75 Ile Pro Ser Ser Trp Val Cys Asp Gin Asp Gin Asp Cys Asp Asp Gly 90 Ser Asp Glu Arg Gin Asp Cys Ser Gin Ser Thr Cys Ser Ser His Gin 100 105 110 Ile Thr Cys Ser Asn Gly Gin Cys Ile Pro Ser Glu Tyr Arg Cys Asp 115 120 125 WO 96/15801 PCT/US95/15203 3lu Asn Asp Cys Gin Tyr His Val 130 Pro Thr 145 Ser Gin Ile Asn Gly'Glu Gin Asp 210 Tyr Gin 225 Cys Asp Giu Ser Cys Pro Ile Leu 290 Lys Tyr 305 Cys His Ile Ile Gin Ile His Leu 370 Cys Lys 385 Gly Arg Leu Vai Tyr His Phe Ser 450 krg Cys Lys :ys Cys 195 Gly Phe Gly Gly Glu 275 Asp Cys Glu Asn Trp 355 Cys Ala Asp Glu Lei 43E Val Asp Cys Pro Asp Giy Ala Glu Cys Thr 180 Ile Ser Thr Glu Pro 260 Ser Cys Ser Thr His 340 Gly His Asn Leu Ser 420 1 Gin Asp GIn Asp 165 lu Pro Asp Cys Asp 245 His Gly Pro Met Pro 325 Asn Ile Cys Asp Leu 405 Glr Are Iil Leu 150 Trp Ile Arg.

Glu Pro 230 Asp Asp Arg Gly Thr 310 Tyr Asp Cys Glu Ser 390 Ile 1 Asn j Vai e Asn rhr Lys :ys Ala His 215 Ser Cys Val Cys Arg 295 Leu Gly Ser Asp Glu 375 PhE Gij Arc Ph G1 Cys I Val I Leu I Tyr~ 200 Ala Gly Lys His Ile 280 Glu Cys Gly Arg Gin 360 Gly Gly Asp Gly B Trp 440 r Leu ~sp ~sp lis 185 lal :ys krg Asp Lys 265 Ser Asp Ser Ala Thr 345 Lys

GT

Glu Ile Val 42 Thl As 97 Asp Asn Cys 170 Asn Cys Asn Cys Asn 250 Cys Ile Glu Ala Cys 330 Cys Cys Ile Ala His 410 Ala Asp n Ile Gly 155 Arg lu Asp Tyr Ile 235 Gly Ser Tyr Asn Leu 315 Phe Val Glu Leu Ser 395 Gly Va1 Thr Gin Ala Asp Phe His Pro 220 Tyr Asp Pro Lys Asn 300 Asn Cys Glu Ser Glu 380 Ile Arg Gly Vai Glu ys Ser Ser Asp 205 Thr Gin Glu Arg Va1 285 Thr Cys Pro Phe Arg 365 Arg Ile Ser Val Glr 44E Va Tyr I Ser Cys 190 Asn Cys Asn Asp Glu 270 Cys Ser Gin Pro Asp 350 Pro Giy Phe Phe Ala 430 1 Asn 1 Leu %sn ksp 175 ly Asp Gly Trp Gly 255 Trp Asp Thr Tyr Gly 335 Asp Gly Gin Ser Arg 415 Phe Lys Asr Thr 160 Glu Asn Cys Gly Va1 240 Cys Ser Gly Gly Gin 320 Tyr Cys Arg Tyr Asn 400 Ile His Val Val 455 460 Ser Val Giu Thr Pro Giu Asn Leu Ala Val Asp Trp Val Asn Asn Lys WO 96/15801 PCT/US95/15203 97 Ile Asp Arg Trp Gly 545 Gly Arg Thr Leu Leu 625 Ala Pro Val Cys Ile 705 Gly Ser Ser Lys Asn 785 Tyr Gly Gly 31u Glu 530 Ser Val Phe Val Phe 610 Lys Ser Tyr Cys Lys 690 Ala Ile Gly Thr Ile 770 Val Leu Ser Ile 515 Ser Asn Thr Asp Val 595 Glu Ala Leu Ala Val 675 Cys Val Pro Asn Ile 755 Asp Glu Val Tyr 500 Ala Leu Arg Leu Tyr 580 His Gly Asn Arg Thr 660 Leu Thr Gin Phe Pro 740 Phe Gly Ser Glu Thr Lys Val Asn Arg Ile Asp Met Val 1 485 Arg Val Ser Lys Asp 565 Ile Gly Gin Lys Pro 645 Asn Ser Phe Asn Thr 725 Ser Phe SThr SLeu Val Asp Gly Asp 550 Met Glu Gly Val Phe 630 Tyr Pro His Gly Phe 710 Leu Phe Ser Gly Ala 79( Thr Leu Pro Thr 520 Glu Pro 535 Leu Val Ile Ser Thr Val Ser Leu 600 Phe Phe 615 Thr Glu Gly Val Cys Lys Arg Thr 680 Phe Gin 695 Leu Ile Ser Thr Phe Val Asp Met 760 Arg Gli 775 Phe Asp 490 Ile Thr Glu 1 505 Val Gly Tyr I Lys Leu Glu Lys Thr Lys 555 Lys Arg Val 570 Thr Tyr Asp 585 Ile Pro His Thr Asp Trp Thr Asn Pro 635 Thr Val Tyr 650 Asp Asn Asn 665 Asp Asn Asp Leu Asp Thr Phe Ser Ser 715 Gin Glu Asp 730 Gly Ile Asp 745 Ser Lys His Ile Leu Ala Trp Ile Ser 795 Asn Leu Arg 540 Leu Tyr Gly Pro Thr 620 Gin His Gly Gly Asp 700 Gin Val Phe Met Ala 780 Leu Phe 525 Ala Gly Trp Ile Phe 605 Lys Val Ser Gly Leu 685 Glu Val Met Asp Ile 765 Asr Gly I 510 Phe Phe Trp Val Gin 590 Gly Met Tyr Leu Cys 670 Gly Arg Ala Val Ala 750 Phe 1 Arg Asn 195 iis Ser Met Pro Asp 575 Arg Val Ala Tyr Arg 655 Glu Phe His Ile Pro 735 Gin Lys Val Leu Pro Asp Asp Ala 560 Ser Lys Ser Val Gin 640 Gin Gin Arg Cys Arg 720 Val .Asp Gin SGlu Trp Lys Asn Leu Tyr Thr Asp Ser His Tyr Lys Ser Ile Ser Val Met Arg Leu Ala 805 810 Asp Lys 815 WO 96/15801 PCT/US95/15203 Thr Arg Arg Thr Val Val Gin Tyr Leu Asn Asn Pro Arg Ser Val Val 820 825 830 Val His Pro Phe Ala Gly Tyr Leu Phe Phe Thr Asp Trp Phe Arg Pro 835 840 845 Ala Lys Ile Met Arg Ala Trp Ser Asp Gly Ser His Leu Leu Pro Val 850 855 860 Ile Asn Thr Thr Leu Gly Trp Pro Asn Gly Leu Ala Ile Asp Trp Ala 865 870 875 880 Ala Ser Arg Leu Tyr Trp Val Asp Ala Tyr Phe Asp Lys Ile Glu His 885 890 895 Ser Thr Phe Asp Gly Leu Asp Arg Arg Arg Leu Gly His Ile Glu Gin 900 905 910 Met Thr His Pro Phe Gly Leu Ala Ile Phe Gly Glu His Leu Phe Phe 915 920 925 Thr Asp Trp Arg Leu Gly Ala Ile Ile Arg Val Arg Lys Ala Asp Gly 930 935 940 Gly Glu Met Thr Val Ile Arg Ser Gly Ile Ala Tyr Ile Leu His Leu 945 950 955 960 Lys Ser Tyr Asp Val Asn Ile Gin Thr Gly Ser Asn Ala Cys Asn Gin 965 970 975 Pro Thr His Pro Asn Gly Asp Cys Ser His Phe Cys Phe Pro Val Pro 980 985 990 Asn Phe Gin Arg Val Cys Gly Cys Pro Tyr Gly Met Arg Leu Ala Ser 995 1000 1005 Asn His Leu Thr Cys Glu Gly Asp Pro Thr Asn Glu Pro Pro Thr Glu 1010 1015 1020 Gin Cys Gly Leu Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys Val Pro 1025 1030 1035 1040 Asn Tyr Tyr Leu Cys Asp Gly Val Asp Asp Cys His Asp Asn Ser Asp 1045 1050 1055 Glu Gin Leu Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala Phe 1060 1065 1070 Thr Cys Gly His Gly Glu Cys Ile Pro Ala His Trp Arg Cys Asp Lys 1075 1080 1085 Arg Asn Asp Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr His 1090 1095 1100 Ala Pro Ala Ser Cys Leu Asp Thr Gin Tyr Thr Cys Asp Asn His Gin 1105 1110 1115 1120 Cys Ile Ser Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly Asp 1125 1130 1135 Gly Ser Asp Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gln Pro Ser 1140 1145 1150 WO 96/15801 PCT/US95/15203 100 Gin Phe Asn Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val Cys 1155 1160 1165 Asp Gly Asp Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly Cys Val 1170 1175 1180 Leu Asn Cys Thr Ala Ser Gin Phe Lys Cys Ala Ser Gly Asp Lys Cys 1185 1190 1195 1200 Ile Gly Val Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser Asp Asn 1205 1210 1215 Ser Asp Glu Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His Ser 1220 1225 1230 Asp Glu Phe Gin Cys Gin Glu Asp Gly Ile Cys Ile Pro Asn Phe Trp 1235 1240 1245 Glu Cys Asp Gly His Pro Asp Cys Leu Tyr.Gly Ser Asp Glu His Asn 1250 1255 1260 Ala Cys Val Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys Asp Asn 1265 1270 1275 1280 Gly Asn Cys Ile His Arg Ala Trp Leu Cys Asp Arg Asp Asn Asp Cys 1285 1290 1295 Gly Asp Met Ser Asp Glu Lys Asp Cys Pro Thr Gin Pro Phe Arg Cys 1300 1305 1310 Pro Ser Trp Gin Trp Gin Cys Leu Gly His Asn Ile Cys Val Asn Leu 1315 1320 1325 Ser Val Val Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp Glu 1330 1335 1340 Ser Pro Leu Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly Cys 1345 1350 1355 1360 Thr His Glu Cys Val Gin Glu Pro Phe Gly Ala Lys Cys Leu Cys Pro 1365 1370 1375 Leu Gly Phe Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp Ile Asp 1380 1385 1390 Glu Cys Asp Ile Leu Gly Ser Cys Ser Gin His Cys Tyr Asn Met Arg 1395 1400 1405 Gly Ser Phe Arg Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu Ser Asp 1410 1415 1420 Gly Arg Thr Cys Lys Val Thr Ala Ser Glu Ser Leu Leu Leu Leu Val 1425 1430 1435 1440 Ala Ser Gin Asn Lys Ile Ile Ala Asp Ser Val Thr Ser Gin Val His 1445 1450 1455 Asn Ile Tyr Ser Leu Val Glu Asn Gly Ser Tyr Ile Val Ala Val Asp 1460 1465 1470 Phe Asp Ser Ile Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr Gin Gly 1475 1480 1485 Lys Thr Trp Ser Ala Phe Gin Asn Gly Thr Asp Arg Arg Val Val Phe WO 96/15801 PCT/US95/15203 1490 1495 1500 Asp Ser Ser 1505 Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val Gly 1520 1510 1515 Arg Asn Leu Tyr Trp Thr 1525 Lys Ile Asp Gly Ser His 1540 Asn Pro Arg Gly Leu Ala 1555 Phe Trp Ser Asp Trp Gly 1570 Asp Gly Ser Met Arg Thr 1585 159 Cys Gly Leu Thr Ile Asp 1605 Ser Tyr Leu Asp Tyr Met 1620 Arg Gin Val Ile Ala Ser 1635 Asp Tyr Ala. Leu Glu Thr Ile Glu Val Ser 1530 1535 Arg Thr Val Leu Ile Ser Lys Asn Leu Thr 1545 1550 Leu Asp Pro Arg Met Asn Glu His Leu Leu 1560 1565 His His Pro Arg Ile Glu Arg Ala Ser Met 1575 1580 Val Ile Val Gin Asp Lys Ile Phe Trp Pro 0 1595 1600 Tyr Pro Asn Arg Leu Leu Tyr Phe Met Asp 1610 1615 Asp Phe Cys Asp Tyr Asn Gly His His Arg 1625 1630 Asp Leu Ile Ile Arg His Pro Tyr Ala Leu 1640 1645 Val Tyr Trp Thr Asp Arg Ala Thr Arg Arg 1655 1660 Trp His Gly Gly Asn Gin Ser Val Val Met '0 1675 1680 Thr Leu Phe Glu Asp Ser 1650 Val Met 1665 Arg Ala Asn Lys 167 Tyr Asn Ile Gin Trp Pro 1685 Leu Gly Ile Val Ala Val His Pro Ser Lys 1690 1695 Gin Pro Asn Ser Val Asn Pro Cys Ala Phe Ser Arg Cys Ser His Leu 1700 1705 1710 Cys Leu Leu Ser Ser Gin Gly Pro His Phe Tyr Ser Cys Val Cys Pro 1715 1720 1725 Ser Gly Trp Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp Asp 1730 1735 1740 Gin Pro Phe Leu Ile Thr Val Arg Gin His Ile Ile Phe Gly Ile Ser 1745 1750 1755 1760 Leu Asn Pro Glu Val Lys Ser Asn Asp Ala Met Val Pro Ile Ala Gly 1765 1770 1775 Ile Gin Asn Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gin Tyr Ile 1780 1785 1790 Tyr Trp Val Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp Gly 1795 1800 1805 Thr Asn Arg Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser Met 1810 1815 1820 Asn Leu Ala Leu Asp Trp Ile Ser Arg Asn Leu Tyr Ser Thr Asn Pro 1825 1830 1835 1840 WO 96/15801 PCT/US95/15203 )02- Arg Thr Gin Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg Tyr 1845 1850 1855 Arg Lys Thr Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly Phe 1860 1865 1870 Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp Ser 1875 1880 1885 Asp Gin Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala Asn 1890 1895 1900 Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu His 1905 1910 1915 1920 Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gin Lys Leu Tyr Trp Ala 1925 1930 1935 Val Thr Gly Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr Asp 1940 1945 1950 Arg Met Ile Leu Val His Gin Leu Ser His Pro Trp Gly Ile Ala Val 1955 1960 1965 His Asp Ser Phe Leu Tyr Tyr Thr Asp Glu Gin Tyr Glu Val Ile Glu 1970 1975 1980 Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp Asn 1985. 1990 1995 2000 Val Pro Asn Leu Arg Gly Leu Gin Val Tyr His Arg Arg Asn Ala Ala 2005 2010 2015 Glu Ser Ser Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gin Gin Ile 2020 2025 2030 Cys Leu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr Gly 2035 2040 2045 Phe Lys Leu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser Phe 2050 2055 2060 Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu Leu 2065 2070 2075 2080 Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gin Gly Arg Asn 2085 2090 2095 Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp Cys 2100 2105 2110 Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile Lys 2115 2120 2125 Pro Asp Gly Ser Ser Leu Met Asn Ile Val Thr His Gly Ile Gly Glu 2130 2135 2140 Asn Gly Val Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu Tyr 2145 2150 2155 2160 Phe Thr Asn Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg Ile 2165 2170 2175 WO 96/15801 PCTIUS95/15203 t03 Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp Met Pro 2180 2185 2190 Arg His Ile Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala Asp 2195 2200 2205 Tyr Gly Gin Arg Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys Thr Asn 2210 2215 2220 *Arg Thr Val Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu Ala 2225 2230 2235 2240 Val Asp Arg Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser Leu Asp 2245 2250 2255 Ile Ile Ala Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile Arg 2260 2265 2270 Tyr Gly Ser Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Glu Asn 2275 2280 2285 Ser Ile Ile Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gin Ala Ser 2290 2295 2300 Lys Glu Pro Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn Ile 2305 2310 2315 2320 Asn Trp Leu Arg Asp Val Thr Ile Phe Asp Lys Gin Val Gin Pro Arg 2325 2330 2335 Ser Pro Ala Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn Gly Gly 2340 2345 2350 Cys Ser His Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro Lys Cys 2355 2360 2365 Asp Cys Ala Phe Gly Thr Leu Gin Ser Asp Gly Lys Asn Cys Ala Ile 2370 2375 2380 Ser Thr Glu Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu Arg Ser 2385 2390 2395 2400 Leu His Leu Asp Pro Glu Asn His Ser Pro Pro Phe Gin Thr Ile Asn 2405 2410 2415 Val Glu Arg Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp Arg 2420 2425 2430 Ile Tyr Phe Thr Gin Asn Leu Ala Ser Gly Val Gly Gin Ile Ser Tyr 2435 2440 2445 Ala Thr Leu Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser Gly 2450 2455 2460 Ile Gly Thr Ala Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg Arg Ile 2465 2470 2475 2480 Tyr Tyr Ser Asp Tyr Leu Asn Gin Met Ile Asn Ser Met Ala Glu Asp 2485 2490 2495 Gly Ser Asn Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg Ala Ile 2500 2505 2510 Val Leu Asp Pro Cys Gin Gly Tyr Leu Tyr Trp Ala Asp Trp Asp Thr WO 96/15801 PCT/US95/15203 loq 2515 2520 2525 His Ala Lys Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg Val Pro 2530 253.5 2540 Ile Val Asn Ser Ser Leu Val Met Pro.Ser Gly Leu Thr Leu Asp Tyr 2545 2550 2555 2560 Glu Glu Asp Leu Leu Tyr Trp Val Asp Ala Ser Leu Gin Arg Ile Glu 2565 2570 2575 Arg Ser Thr Leu .Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala Ala 2580 2585 2590 Val His Ala Phe Gly Leu Thr Leu Tyr Gly Gin Tyr Ile Tyr Trp Thr 2595 2600 2605 Asp Leu Tyr Thr Gin Arg Ile Tyr Arg Ala Asn Lys Tyr Asp Gly Ser 2610 2615 2620 Gly Gin Ile Ala Met Thr Thr Asn Leu Leu Ser Gin Pro Arg Gly Ile 2625 2630 2635 2640 Asn Thr Val Val Lys Asn Gin Lys Gin Gin Cys Asn Asn Pro Cys Glu 2645 2650 2655 Gin Phe Asn Gly Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn Gly 2660 2665 2670 Ala Glu Cys Gin Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn Asn 2675 2680 2685 Arg Lys His Cys Ile Val Asp Asn Gly Glu Arg Cys Gly Ala Ser Ser 2690 2695 2700 Phe Thr Cys Ser Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys Cys Asp 2705 2710 2715 2720 Asn Asp Asn Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val Cys 2725 2730 2735 Ala Leu His Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly Arg 2740 2745 2750 Cys Val Gin Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly Asp 2755 2760 2765 Gly Ser Asp Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala Thr Thr 2770 2775 2780 Glu Phe Met Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile Cys 2785 2790 2795 2800 Asn Gly Val Asp Asn Cys His Asp Asn Asn Thr Ser Asp Glu Lys Asn 2805 2810 2815 Cys Pro Asp Arg Thr Cys Gin Ser Gly Tyr Thr Lys Cys His Asn Ser 2820 2825 2830 Asn Ile Cys Ile Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn Asp Cys 2835 2840 2845 Gly Asp Asn Ser Asp Glu Asn Pro Thr Tyr Cys Thr Thr His Thr Cys 2850 2855 2860 WO 96/15801 PCT/US95/15203 Ser Ser Ser Glu Phe Gin Cys Ala Ser Gly Arg Cys Ile Pro Gin His 2865 2870 2875 2880 Trp Tyr Cys Asp Gin Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu Pro 2885 2890 2895 Ala Ser Cys Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe Lys 2900 2905 2910 Cys Asp Gly Gly Arg Cys Ile Pro Ser Glu Trp Ile Cys Asp Gly Asp 2915 2920 2925 Asn Asp Cys Gly Asp Met Ser Asp Glu Asp Lys Arg His Gin Cys Gin 2930 2935 2940 Asn Gin Asn Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg Pro 2945 2950 2955 2960 Pro Asp Arg Arg Cys Ile Pro Gin Ser Trp Val Cys Asp Gly Asp Val 2965 2970 2975 Asp Cys Thr Asp Gly Tyr Asp Glu Asn Gin Asn Cys Thr Arg Arg Thr 2980 2985 2990 Cys Ser Glu Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro Lys 2995 3000 3005 Ile Phe Arg Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp Glu 3010 3015 3020 Arg Gly Cys Leu Tyr Gin Thr Cys Gin Gin Asn Gin Phe Thr Cys Gin 3025 3030 3035 3040 Asn Gly Arg Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn Asp 3045 3050 3055 Cys Gly Asp Gly Ser Asp Glu Leu Met His Leu Cys His Thr Pro Glu 3060 3065 3070 Pro Thr Cys Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys Ile 3075 3080 3085 Glu Met Met Lys Leu Cys Asn His Leu Asp Asp Cys Leu Asp Asn Ser 3090 3095 3100 Asp Glu Lys Gly Cys Gly Ile Asn Glu Cys His Asp Pro Ser Ile Ser 3105 3110 3115 3120 Gly Cys Asp His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr Cys Ser 3125 3130 3135 Cys Arg Pro Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys Val Asp 3140 3145 3150 Ile Asp Glu Cys Thr Glu Met Pro Phe Val Cys Ser Gin Lys Cys Glu 3155 3160 3165 Asn Val Ile Gly Ser Tyr Ile Cys Lys Cys Ala Pro Gly Tyr Leu Arg 3170 3175 3180 Glu Pro Asp Gly Lys Thr Cys Arg Gin Asn Ser Asn Ile Glu Pro Tyr 3185 3190 -3195 3200 WO 96/15801 Leu Ile Phe Ser Asn Arg Tyr Tyr 3205 Iob Leu Arg Asn Leu Thr 3210 PCT/US95/15203 Ile Asp Gly 3215 Tyr Phe Tyr Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala Leu 3220 3225 3230 Asp Phe Asp Arg Val Glu Lys Arg Leu Tyr Trp Ile Asp Thr Gin Arg 3235 3240 3245 Gin Val Ile Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu Thr Ile 3250 3255 3260 Ile Asn His Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp Val 3265. 3270 3275 3280 Ser Arg Lys Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly Leu Phe Val 3285 3290 3295 Ser Asp Leu Asn Gly Gly His Arg Arg Met Leu Ala Gin His Cys Val 3300 3305 3310 Asp Ala Asn Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu Ala Leu 3315 3320 3325 His Pro Gin Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg Ala 3330 3335 3340 Tyr Ile Gly Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile Ile 3345 3350 3355 3360 Ser Thr Lys Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr Asn 3365 3370 3375 Asp Leu Leu Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr Ser 3380 3385 3390 Asp Leu Glu Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu Pro 3395 3400 3405 His Pro Phe Ala Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp Thr Asp 3410 3415 3420 Trp Asn Thr Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser Asn 3425 3430 3435 3440 4 Arg Gin Thr Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile His Val 3445 3450 3455 Tyr His Pro Tyr Arg Gin Pro Ile Val Ser Asn Pro Cys Gly Thr Asn 3460 3465 3470 Asn Gly Gly Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly Lys Gly 3475 3480 3485 Phe Thr Cys Glu Cys Pro Asp Asp Phe Arg Thr Leu Gin Leu Ser Gly 3490 3495 3500 Ser Thr Tyr Cys Met Pro Met Cys Ser Ser Thr Gin Phe Leu Cys Ala 3505 3510 3515 3520 6 Asn Asn Glu Lys Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly Gln Lys 3525 3530 3535 Asp Cys Ser Asp Gly Ser Asp Glu Leu Ala Leu Cys Pro Gin Arg Phe WO 96/15801 PCT/US95/15203 3540 3545 3550 Cys Arg Leu Gly Gin Phe Gin Cys Ser Asp Gly Asn Cys Thr Ser Pro 3555 3560 3565 Gin Thr Leu Cys Asn Ala His Gin Asn Cys Pro Asp Gly Ser Asp Glu 3570 3575 3580 Asp Arg Leu Leu Cys Glu Asn His His Cys Asp Ser Asn Glu Trp Gin 3585 3590 3595 3600 Cys Ala Asn Lys Arg Cys Ile Pro Glu Ser Trp Gin Cys Asp Thr Phe 3605 3610 .361.5 Asn Asp Cys Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala Ser 3620 3625 3630 Arg Thr Cys Arg Pro Gly Gin Phe Arg Cys Ala Asn Gly Arg Cys Ile 3635 3640 3645 Pro Gin Ala Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His Ser 3650 3655 3660 Asp Glu Pro Ile Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp Asn 3665 3670 3675 3680 Phe Thr Glu Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys Trp 3685 3690 3695 Ala Val Cys Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu Gin 3700 3705 3710 Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys Lys 3715 3720 3725 Asn His His Cys Ile Pro Leu Arg Trp Gin Cys Asp Gly Gin Asn Asp 3730 3735 3740 Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys Thr 3745 3750 3755 3760 Glu Ser Glu Phe Arg Cys Val Asn Gin Gin Cys Ile Pro Ser Arg Trp 3765 3770 3775 Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg Asp 3780 3785 3790 Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gin Cys Thr Ser Gly 3795 3800 3805 His Cys Val His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys Leu 3810 3815 3820 Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly Ala 3825 3830 3835 3840 Tyr Cys Gin Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile Pro 3845 3850 3855 Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser Asp 3860 3865 3870 Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn Arg 3875 3880 3885 WO 96/15801 PCT/US95/15203 Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys Asn 3890 3895 3900 Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His Cys 3905 3910 3915 3920 Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys Gly 3925 3930 3935 Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp Asp 3940 3945 3950 Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu Arg 3955 3960 3965 Thr Cys Ala Glu Asn Ile Cys Glu Gin Asn Cys Thr Gin Leu Asn Glu 3970 3975 3980 Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val Phe 3985 3990 3995 4000 Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gin Phe Gly Thr 4005 4010 4015 Cys Pro Gin His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys 4020 4025 4030 Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys Ala 4035 4040 4045 Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg Ile 4050 4055 4060 Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gin Asp 4065 4070 4075 4080 Glu Glu Tyr Ile Gin Ala Val Asp Tyr Asp Trp Asp Pro Lys Asp Ile 4085 4090 4095 Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg Phe 4100 4105 4110 Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg Asn 4115 4120 4125 Asn Leu Val Gin Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gin Pro 4130 4135 4140 Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser Asp 4145 4150 4155 4160 Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr Arg 4165 4170 4175 Lys Trp Leu Ile Ser Thr Asp Leu Asp Gin Pro Ala Ala Ile Ala Val 4180 4185 4190 Asn Pro Lys Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu Pro 4195 4200 4205 Lys Ile Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu Val 4210 4215 4220 WO 96/15801 PCT/US95/15203 /O9 Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu Asn 4225 4230 4235 4240 Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu Thr 4245 4250 4255 Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala Met 4260 4265 4270 Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gin Leu Tyr Trp Ile Ser 4275 4280 4285 Lys Glu Lys Gly Glu Val Trp Lys Gin Asn Lys Phe Gly Gin Gly Lys 4290 4295 4300 Lys Glu Lys Thr Leu Val Val Asn Pro Trp Leu Thr Gin Val Arg Ile 4305 4310 4315 4320 Phe His Gin Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys Gin 4325 4330 4335 Ile Cys Ser His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys Ala 4340 4345 4350 Cys Pro Gin Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys Asp 4355 4360 4365 Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys Met 4370 4375 4380 His Gly Gly Asn Cys Tyr Phe Asp Glu Thr Asp Leu Pro Lys Cys Lys 4385 4390 4395 4400 Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser Lys 4405 4410 4415 Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile Leu 4420 4425 4430 Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His Tyr 4435 4440 4445 Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu 4450 4455 4460 Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe Arg 4465 4470 4475 4480 Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro 4485 4490 4495 Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met 4500 4505 4510 Glu Met Gly Lys Gin Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser Ala 4515 4520 4525 Arg Asp Ser Ala Val Lys Val Val Gin Pro Ile Gin Val Thr Val Ser 4530 4535 4540 Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu 4545 4550 4555 4560 Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gin PCT/US95/15203 WO 96/15801 //0 4570 4575 4565.

Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gin Thr Thr Asn 4580 4585 4590 Phe Glu Asn Pro Ile Tyr Ala Gln Met Glu Asn Glu Gin Lys Glu Ser 4595 4600 4605 Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu 4610 4615 Pro Ala Lys Pro Lys 4620 Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser 4625 4630 4635 Ala Thr Glu Asp 4640 Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val 4645 4650 4655 INFORMATION FOR SEQ ID SEQUENCE

CHARACTERISTICS:

LENGTH: 14042 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL:

NO

ANTI-SENSE:

NO

(vi) ORIGINAL

SOURCE:

ORGANISM: Homo sapiens TISSUE TYPE: Placenta (ix) FEATURE: NAME/KEY:

CDS

LOCATION: 68..14035 (xi) SEQUENCE DESCRIPTION: SEQ ID CGGTGCGGTG TGCTACGCGC GCCCACCTCC CGGGGAAGGA ACGGCGAGGC

CGGGGACCGT

CGCGGAG ATG GAT CGC GGG CCG GCA GCA GTG GCG TGC ACG CTG CTC CTG Met Asp Arg Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu

GCT

Ala CTC GTC GCC TGC Leu Val Ala Cys

CTA

Leu 20 GCC CCG GCC AGT Ala Pro Ala Ser CAA GAA TGT GAC Gin Glu Cys Asp

AGT

Ser GCG CAT TTT CGC Ala His Phe Arg GGA AGT GGG Gly Ser Gly CAT TGC His Cys 40 ATC CCT GCA GAC TGG AGG Ile Pro Ala Asp Trp Arg 205 TGT GAT GGG Cys Asp Gly GCT GTT GTG Ala Val Val AAA GAC TGT TCA Lys Asp Cys Ser

GAT

Asp 55 GAC GCG GAT GAA Asp Ala Asp Glu ATT GGC TGC Ile Gly Cys AGT GAG GGA Ser Glu Gly ACC TGC CAG CAG Thr Cys Gin Gin

GGC

Gly TAT TTC AAG TGC Tyr Phe Lys Cys WO 96/15801 PCT/US95/15203 CAA TGC Gin Cys ATC CCC AGC TCC Ile Pro Ser Ser

TGG

Trp 85

II

GTG TGT GAC Val Cys Asp CAA GAT Gin Asp CAA AGT Gin Ser 105 CAA GAC TGT GAT Gin Asp Cys Asp ACA TGC TCA AGT Thr Cys Ser Ser 110

GAT

Asp GGC TCA GAT GAA Gly Ser Asp Glu CAA GAT TGC TCA Gin Asp Cys Ser CAT CAG ATA ACA His Gin Ile Thr

TGC

Cys 115 TCC AAT GGT CAG TGT ATC CCA AGT GAA TAC AGG Ser Asn Gly Gin Cys Ile Pro Ser Glu Tyr Arg 120 125 349 397 445 493 541 589 TGC GAC CAC Cys Asp His CAG TAC CCA Gin Tyr Pro 145

GTC

Val 130 AGA GAC TGC CCC Arg Asp Cys Pro

GAT

Asp 135 GGA GCT GAT GAG Gly Ala Asp Glu AAT GAC TGC Asn Asp Cys 140 GCC TGC TAT Ala Cys Tyr ACA TGT GAG CAG Thr Cys Glu Gin

CTT

Leu 150 ACT TGT GAC AAT Thr Cys Asp Asn

GGG

Gly 155 AAC ACC Asn Thr 160 AGT CAG AAG TGT Ser Gin Lys Cys

GAT

Asp 165 TGG AAA GTT GAT Trp Lys Val Asp AGG GAC TCC TCA Arg Asp Ser Ser

GAT

Asp 175 GAA ATC AAC TGC Glu Ile Asn Cys GAG ATA TGC TTG Glu Ile Cys Leu

CAC

His 185 AAT GAG TTT TCA Asn Glu Phe Ser TGT 637 Cys 190 GGC AAT GGA GAG Gly Asn Gly Glu

TGT

Cys 195 ATC CCT CGT GCT Ile Pro Arg Ala GTC TGT GAC CAT Val Cys Asp His GAC AAT Asp Asn 205 GAT TGC CAA Asp Cys Gin GGT GGT TAC Gly Gly Tyr 225

GAC

Asp 210 GGC AGT GAY GAA Gly Ser Asp Glu

CAT

His 215 GCT TGC AAC TAT Ala Cys Asn Tyr CCG ACC TGC Pro Thr Cys 220 TAT CAA AAC Tyr Gin Asn 685 733 781 829 CAG TTC ACT TGC Gin Phe Thr Cys

CCC

Pro 230 AGT GGC CGA TGC Ser Gly Arg Cys

ATT

Ile 235 TGG GTT Trp Val 240 TGT GAT GGA GAA Cys Asp Gly Glu GAC TGT AAA GAT Asp Cys Lys Asp

AAT

Asn 250 GGA GAT GAA GAT Gly Asp Glu Asp

GGA

Gly 255 TGT GAA AGC GGT Cys Glu Ser Gly

CCT

Pro 260 CAT GAT GTT CAT His Asp Val His

AAA

Lys 265 TGT TCC CCA AGA Cys Ser Pro Arg

GAA

Glu 270 TGG TCT TGC CCA Trp Ser Cys Pro

GAG

Glu 275 TCG GGA CGA TGC Ser Gly Arg Cys

ATC

Ile 280 TCC ATT TAT AAA Ser Ile Tyr Lys GTT TGT Val Cys 285 GAT GGG Asp Gly ACC GGA Thr Gly TAC CAG Tyr Gin 320

ATT

Ile

TTA

Leu 290 GAT TGC CCA GGA Asp Cys Pro Gly

AGA

Arg 295 GAA GAT GAA AAC Glu Asp Glu Asn AAC ACT AGT Asn Thr Ser 300 AAC TGC CAG Asn Cys Gin AAA TAC TGT AGT ATG Lys Tyr Cys Ser Met 305 TGC CAT GAG ACG CCG Cys His Glu Thr Pro

ACT

Thr 310 CTG TGC TCT GCC Leu Cys Ser Ala

TTG

Leu 315 1021 1069 TAT GGA GGA GCG TGT Tyr Gly Gly Ala Cys 330 TTT TGT CCC CCA Phe Cys Pro Pro WO 96/15801 PCTIUS9/15203

GGT

Gly 335 TAT ATC ATC AAC Tyr Ile Ile Asn AAT GAC AGC CGT P Asn Asp Ser Arg I TGT OTT GAO TTT Cys Vai Giu Phe 1117 1165 GAT TOC CAG ATA Asp Cys Gin Ile GGC COT CAC CTO Gly Arg His Leu

TGG

Trp 355 OGA ATT TOT GAC Gly Ile Cys Asp

CAG

Gin 360 AAG TOT GAA AGC Lys Cys Giu Ser CGA CCT Arg Pro 365 TGC CAC TOT OAA Cys His Cys Glu OCT AAT OAT TCC

GAA

Glu 375 GGG TAT ATC TTO Gly Tyr Ile Leu GAG COT OGA Glu Arg Oly 380 ATT ATC TTC Ile Ile Phe 1213 1261 CAG TAT TGC AAA Gin Tyr Cys Lys 385 TTT GGC GAG GCC Phe Oly Giu Ala Ala Asn Asp Ser 390 TCC AAT Ser Asn 400 GGT COG OAT TTO Gly Arg Asp Leu

TTA

Leu 405 ATT GOT OAT ATT CAT OGA AGO AOC TTC Ile Oly Asp Ile His Gly Arg Ser Phe 410

CGG

Arg 415 ATC CTA GTG GAO Ile Leu Val Glu

TCT

Ser 420 CAG AAT COT OGA GTG GCC GTG GOT GTG Gin Asn Arg Gly Val Ala Val Gly Val

OCT

Ala 430 TTC CAC TAT CAC Phe His Tyr His CAA AGA OTT TTT TGG ACA GAC ACC OTG Gin Arg Val Phe Trp Thr Asp Thr Val 440 CAA AAT Gin Asn 445 1309 1357 1405 1453 1501 AAG GTT TTT Lys Vai Phe AAT OTT TCT Asn Val Ser 465

TCA

Ser 450 GTT OAC ATT AAT Val Asp Ile Asn

GGT

Oly 455 TTA AAT ATC CAA Leu Asn Ile Gin GAG GTT CTC Glu Val Leu 460 TGG OTT AAT Trp Val Asn OTT GAA ACC CCA Val Giu Thr Pro

GAG

Glu 470 AAC CTG GCT GTG Asn Leu Ala Val

GAC

Asp 475 AAT AAA Asn Lys 480 ATC TAT CTA GTG Ile Tyr Leu Val

OAA

Glu 485 ACC AAO GTC AAC Thr Lys Val Asn

CGC

Arg 490 ATA OAT ATG GTA Ile Asp Met Val

AAT

Asn 495 TTG GAT OGA AGC Leu Asp Gly Ser

TAT

Tyr 500 CGG GTT ACC CTT Arg Vai Thr Leu

ATA

Ile 505 ACT GAA AAC TTG Thr Glu Asn Leu 1549 1597 1645 CAT CCT AGA GGA His Pro Arg Oly

ATT

Ile 515 0CC GTG GAC CCA Ala Val Asp Pro OTT GOT TAT TTA Val Oly Tyr Leu TTT TTC Phe Phe 525 TCA OAT TGG Ser Asp Trp ATG GAT GGC Met Asp Oly 545

GAO

Glu 530 AGC CTT TCT GGG Ser Leu Ser Oly

OAA

Glu 535 CCT AAG CTO GAA Pro Lys Leu Glu AGG GCA TTC Arg Ala Phe 540 CTG GGA TGG Leu Gly Trp AGC AAC COT AAA Ser Asn Arg Lys

GAC

Asp 550 TTG GTG AAA ACA Leu Val Lys Thr

AAO

Lys 555 1693 1741 1789 1837 CCT OCT Pro Ala 560 GGG GTA ACT CTG Oly Val Thr Leu ATO ATA TCG AAG Met Ile Ser Lys

CGT

Arg 570 OTT TAC TOG OTT Val Tyr Trp Val

GAC

Asp 575 TCT COG TTT OAT TAC ATT GAA ACT OTA Ser Arg Phe Asp Tyr Ile Glu Thr Val

ACT

Thr 585 TAT OAT OGA ATT Tyr Asp Oly Ile

CAA

Oin 590 WO 96/15801 PCT/US95/15203 AGG AAG ACT GTA Arg Lys Thr Val

GTT

Val 595 CAT GGA GGC TCC His Gly Gly Ser

CTC

Leu 600 ATT CCT CAT CCC Ile Pro His Pro TTT GGA Phe Gly 605 GTA AGC TTA Val Ser Leu GCC GTG CTG Ala Val Leu 625 GAA GGT CAG GTG Glu Gly Gin Val

TTC

Phe 615 TTT ACA GAT TGG Phe Thr Asp Trp ACA AAG ATG Thr Lys Met 620 CAA GTG TAC Gin Val Tyr 1885 1933 1981 AAG GCA AAC AAG Lys Ala Asn Lys

TTC

Phe 630 ACA GAG ACC AAC Thr Glu Thr Asn TAC CAG Tyr Gin 640 GCT TCC CTG AGG Ala Ser Leu Arg TAT GGA GTG ACT Tyr Gly Val Thr

GTT

Val 650 TAC CAT TCC CTC Tyr His Ser Leu

AGA

Arg 655 CAG CCC TAT GCT Gin Pro Tyr Ala

ACC

Thr 660 AAT CCG TGT AAA Asn Pro Cys Lys

GAT

Asp 665 AAC AAT GGG GGC Asn Asn Gly Gly

TGT

Cys 670 GAG CAG GTC TGT Glu Gin Val Cys CTC AGC CAC AGA Leu Ser His Arg

ACA

Thr 680 GAT AAT GAT GGT Asp Asn Asp Gly TTG GGT Leu Gly 685 TTC CGT TGC Phe Arg Cys CAC TGC ATT His Cys Ile 705

AAG

Lys 690 TGC ACA TTC GGC TTC CAA CTG GAT ACA Cys Thr Phe Gly Phe Gin Leu Asp Thr 695 GAT GAG CGC Asp Glu Arg 700 CAA GTT GCT Gin Val Ala 2029 2077 2125 2173 2221 2269 2317 2365 GCT GTT CAG AAT Ala Val Gin Asn

TTC

Phe 710 CTC ATT TTT TCA Leu Ile Phe Ser ATT CGT Ile Arg 720 GGG ATC CCG TTC Gly Ile Pro Phe

ACC

Thr 725 TTG TCT ACC CAG Leu Ser Thr Gin

GAA

Glu 730 GAT GTC ATG GTT Asp Val Met Val

CCA

Pro 735 GTT TCG GGG AAT Val Ser Gly Asn

CCT

Pro 740 TCT TTC TTT GTC Ser Phe Phe Val ATT GAT TTT GAC Ile Asp Phe Asp

GCC

Ala 750 CAG GAC AGC ACT Gin Asp Ser Thr

ATC

Ile 755 TTT TTT TCA GAT Phe Phe Ser Asp

ATG

Met 760 TCA AAA CAC ATG Ser Lys His Met ATT TTT Ile Phe 765 AAG CAA AAG Lys Gin Lys GTG GAA AAT Val Glu Asn 785

ATT

Ile 770 GAT GGC ACA GGA Asp Gly Thr Gly

AGA

Arg 775 GAA ATT CTC GCA Glu Ile Leu Ala GCT AAC AGG Ala Asn Arg 780 AAG AAT CTC Lys Asn Leu 2413 2461 GTT GAA AGT TTG Val Glu Ser Leu

GCT

Ala 790 TTT GAC TGG ATT Phe Asp Trp Ile

TCA

Ser 795 TAT TGG Tyr Trp 800 GAT AAA Asp Lys 815 ACA GAC TCT CAT Thr Asp Ser His

TAC

Tyr 805 AAG AGT ATC AGT Lys Ser Ile Ser ATG AGG CTA GCT Met Arg Leu Ala ACG AGA CGC Thr Arg Arg

ACG

Thr 820 GTA GTT CAG TAT Val Val Gin Tyr AAT AAC CCA CGG Asn Asn Pro Arg

TCG

Ser 830 2509 2557 2605 GTG GTA GTT CAT Val Val Val His

CCT

Pro 835 TTT GCC GGG TAT CTA TTC TTC ACT GAT Phe Ala Gly Tyr Leu Phe Phe Thr Asp TGG TTC Trp Phe 845 WO 96/15801 PCT/US95/15203 CGT CCT GCT Arg Pro Ala

AAA

Lys 850 ATT ATG AGA GCA TGG Ile Met Arg Ala Trp 855 AGT GAC Ser Asp GGA TCT CAC CTC TTG Gly Ser His Leu Leu 860 2653 CCT GTA ATA Pro Val Ile 865 TGG GCT GCT Trp Ala Ala 880 AAC ACT ACT CTT Asn Thr Thr Leu

GGA

Gly 870 TGG CCC AAT GGC Trp Pro Asn Gly GCC ATC GAT Ala Ile Asp 2701 2749 TCA CGA TTG Ser Arg Leu

TAC

Tyr 885 TGG GTA GAT GCC Trp Val Asp Ala

TAT

Tyr 890 TTT GAT AAA ATT Phe Asp Lys Ile

GAG

Glu 895 CAC AGC ACC TTT His Ser Thr Phe

GAT

Asp 900 GGT TTA GAC AGA Gly Leu Asp Arg AGA CTG GGC CAT Arg Leu Gly His GAG CAG ATG ACA Glu Gin Met Thr CCG TTT GGA CTT Pro Phe Gly Leu

GCC

Ala 92.0 ATC TTT GGA GAG Ile Phe Gly Glu CAT TTA His Leu 925 TTT TTT ACT Phe Phe Thr

GAC

Asp 930 TGG AGA CTG GGT Trp Arg Leu Gly ATT ATT CGA GTC Ile Ile Arg Val AGG AAA GCA Arg Lys Ala 940 TAC ATA CTG Tyr Ile Leu 2797 2845 2893 2941 2989 3037 GAT GGT GGA Asp Gly Gly 945 CAT TTG AAA His Leu Lys 960 AAT CAA CCC Asn Gin Pro 975 GAA ATG ACA GTT Glu Met Thr Val CGA AGT GGC ATT Arg Ser Gly Ile

GCT

Ala 955 TCG TAT GAT Ser Tyr Asp

GTC

Val 965 AAC ATC CAG ACT Asn Ile Gin Thr TCT AAC GCC TGT Ser Asn Ala Cys ACG CAT Thr His AAC GGT GAC TGC Asn Gly Asp Cys

AGC

Ser 985 CAC TTC TGC TTC His Phe Cys Phe

CCG

Pro 990 GTG CCA AAT TTC Val Pro Asn Phe

CAG

Gin 995 CGA GTG TGT GGG Arg Val Cys Gly

TGC

Cys 1000 CCT TAT GGA Pro Tyr Gly GCT TCC AAT CAC TTG Ala Ser Asn His Leu 1010 ACG GAG CAG TGT GGC Thr Glu Gin Cys Gly 1025 ACA TGC GAG GGG GAC CCA ACA AAT Thr Cys Glu Gly Asp Pro Thr Asn 1015 ATG AGG CTG Met Arg Leu 1005 GAA CCA CCC Glu Pro Pro 1020 GGC AGA TGT Gly Arg Cys 3085 TTA TTT TCC TTC CCC TGT Leu Phe Ser Phe Pro Cys 1030 AAA AAT Lys Asn 1035 GTG CCC AAT TAC TAT CTC TGT GAT GGA Val Pro Asn Tyr Tyr Leu Cys Asp Gly GTC GAT GAT Val Asp Asp 1050 TGT CAT GAT AAC Cys His Asp Asn 1040 1045 3133 3181 3229 3277 3325 3373 AGT GAT GAG CAA CTA Ser Asp Glu Gin Leu 1055 TGT GGC Cys Gly 1060 ACA CTT AAT Thr Leu Asn AAT ACC Asn Thr 1065 TGT TCA TCT Cys Ser Ser

TCG

Ser 1070 GCG TTC ACC TGT Ala Phe Thr Cys

GGC

Gly 1075 CAT GGG GAG His Gly Glu TGC ATT CCT GCA CAC Cys Ile Pro Ala His 1080 GGC AGT GAT GAG CAC Gly Ser Asp Glu His 1095 TGG CGC TGT Trp Arg Cys 1085 AAC TGC CCC Asn Cys Pro 1100 GAC AAA CGC Asp Lys Arg AAC GAC TGT GTG GAT Asn Asp Cys Val Asp 1090 WO 96/15801 PCTIUS95/15203 ACC CAC GCA CCT GCT TCC TGC CTT GAC ACC CAA TAC ACC TGT GAT AAT 3421 Thr His Ala Pro Ala Ser Cys Leu Asp Thr Gin Tyr Thr Cys Asp Asn 1105 1110 1115 CAC CAG TGT ATC TCA AAG AAC TGG GTC TGT GAC ACA GAC AAT GAT TGT 3469 His Gin Cys Ile Ser Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys 1120 1125 1130 GGG GAT GGA TCT GAT GAA AAG AAC TGC AAT TCG ACA GAG ACA TGC CAA 3517 Gly Asp Gly Ser Asp Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gin 1135 1140 1145 1150 CCT AGT CAG TTT AAT TGC CCC AAT CAT CGA TGT ATT GAC CTA TCG TTT 3565 Pro Ser Gin Phe Asn Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe 1155 1160 1165 GTC TGT GAT GGT GAC AAG GAT TGT GTT GAT GGA TCT GAT GAG GTT GGT 3613 Val Cys Asp Gly Asp Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly 1170 1175 1180 TGT GTA TTA AAC TGT ACT GCT TCT CAA TTC AAG TGT GCC AGT GGG GAT 3661 Cys Val Leu Asn Cys Thr Ala Ser Gin Phe Lys Cys Ala Ser Gly Asp 1185 1190 1195 AAA TGT ATT GGC GTC ACA AAT CGT TGT GAT GGT GTT TTT GAT TGC AGT 3709 Lys Cys Ile Gly Val Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser 1200 1205 1210 GAC AAC TCG GAT GAA GCG GGC TGT CCA ACC AGG CCT CCT GGT ATG TGC 3757 Asp Asn Ser Asp Glu Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys 1215 1220 1225 1230 CAC TCA GAT GAA TTT CAG TGC CAA GAA GAT GGT ATC TGC ATC CCG AAC 3805 His Ser Asp Glu Phe Gin Cys Gin Glu Asp Gly Ile Cys Ile Pro Asn 1235 1240 1245 TTC TGG GAA TGT GAT GGG CAT CCA GAC TGC CTC TAT GGA TCT GAT GAG 3853 Phe Trp Glu Cys Asp Gly His Pro Asp Cys Leu Tyr Gly Ser Asp Glu 1250 1255 1260 CAC AAT GCC TGT GTC CCC AAG ACT TGC CCH TCA TCA TAT TTC CAC TGT 3901 His Asn Ala Cys Val Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys 1265 1270 1275 GAC AAC GGA AAC TGC ATC CAC AGG SCA TGG CTC TOT GAT CGG GAC AAT 3949 Asp Asn Gly Asn Cys Ile His Arg Xaa Trp Leu Cys Asp Arg Asp Asn 1280 1285 1290 GAC TGC GGG GAT ATG AGT GAT GAG AAG GAC TGC CCT ACT CAG CCC TTT 3997 Asp Cys Gly Asp Met Ser Asp Glu Lys Asp Cys Pro Thr Gin Pro Phe 1295 1300 1305 1310 CGC TGT CCT AGT TGG CAA TGG CAG TGT CTT GGC CAT AAC ATC TGT GTG 4045 Arg Cys Pro Ser Trp Gin Trp Gin Cys Leu Gly His Asn Ile Cys Val 1315 1320 1325 AAT CTG AGT GTA GTG TGT GAT GGC ATC TTT GAC TGC CCC AAT GGG ACA 4093 Asn Leu Ser Val Val Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr 1330 1335 1340 GAT GAG TCC CCA CTT TGC AAT GGG AAC AGC TGC TCA GAT TTC AAT GGT 4141 Asp Glu Ser Pro Leu Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly 1345 1350 1355 PCTIUS95/15203 WO 96/15801 GGT TGT ACT Gly Cys Thr 1360 CAC GAG TGT GTT CAA His Glu Cys Val Gin 1365 GAG CCC TTT GGG GCT Glu Pro Phe Gly Ala 1370 AAA TGC CTA Lys Cys Leu TGT CCA TTG GGA TTC Cys Pro Leu Gly Phe 1375 TTA CTT GCC AAT GAT TCT AAG Leu Leu Ala Asn Asp Ser Lys 1380 1385 ACC TGT GAA Thr Cys Glu

GAC

Asp 1390 4189 4237 4285 4333 ATA GAT GAA TGT Ile Asp Glu Cys GAT ATT Asp Ile 1395 CTA GGC TCT Leu Gly Ser TGT AGC Cys Ser 1400 CAG CAC TGT TAC AAT Gin His Cys Tyr Asn 1405 ATG AGA GGT Met Arg Gly TCT TTC Ser Phe 1410 CGG TGC TCG TGT GAT ACA GGC TAC Arg Cys Ser Cys Asp Thr Gly Tyr 1415 ATG TTA GAA Met Leu Glu 1420 AGT GAT GGG AGG Ser Asp Gly Arg 1425 ACT TGC AAA Thr Cys Lys GTT ACA GCA TCT GAG Val Thr Ala Ser Glu 1430 AGT CTG CTG TTA Ser Leu Leu Leu 1435 4381 4429 CTT GTG GCA AGT CAG AAC Leu Val Ala Ser Gin Asn 1440 AAA ATT ATT GCC GAC Lys Ile Ile Ala Asp 1445 AGT GTC Ser Val 1450 ACC TCC CAG Thr Ser Gin GTC CAC Val His 1455 AAT ATC TAT TCA TTG GTC GAG AAT Asn Ile Tyr Ser Leu Val Glu Asn 1460 GGT TCT Gly Ser 1465 TAC ATT GTA Tyr Ile Val

GCT

Ala 1470 GTT GAT TTT GAT Val Asp Phe Asp TCA ATT Ser Ile 1475 AGT GGT CGT ATC TTT TGG TCT GAT Ser Gly Arg Ile Phe Trp Ser Asp 1480 GCA ACT Ala Thr 1485 CAG GGT AAA Gin Gly Lys ACC TGG AGT GCG TTT CAA AAT GGA ACG GAC Thr Trp Ser Ala Phe Gin Asn Gly Thr Asp 1490 1495 AGA AGA GTG Arg Arg Val 1500 GTA TTT GAC AGT Val Phe Asp Ser 1505 AGC ATC ATC Ser Ile Ile TTG ACT GAA ACT ATT Leu Thr Glu Thr Ile 1510 GCA ATA GAT TGG Ala Ile Asp Trp 1515 4477 4525 4573 4621 4669 4717 4765 GTA GGT CGT Val Gly Arg 1520 GTC TCC AAA Val Ser Lys 1535 AAT CTT TAC Asn Leu Tyr ATT GAT GGG Ile Asp Gly 1540

TGG

rrp 1525 ACA GAC TAT GCT Thr Asp Tyr Ala 5 CTG GAA Leu Glu 1530 ACA ATT GAA Thr Ile Glu AGC CAC AGG ACT Ser His Arg Thr GTG CTG Val Leu 1545 ATT AGT AAA Ile Ser Lys

AAC

Asn 1550 CTA ACA AAT CCA Leu Thr Asn Pro AGA GGA Arg Gly 1555 CTA GCA TTA Leu Ala Leu GAT CCC Asp Pro 1560 AGA ATG AAT Arg Met Asn GAG CAT Glu His 1565 CTA CTG TTC Leu Leu Phe TGG TCT GAC TGG GGC Trp Ser Asp Trp Gly 1570 CAC CAC CCT His His Pro 1575 CGC ATC GAG CGA GCC Arg Ile Glu Arg Ala 1580 4813 AGC ATG GAC Ser Met Asp 1585 GGC AGC ATG CGC ACT GTC ATT GTC Gly Ser Met Arg Thr Val Ile Val

I

1590 CAG GAC AAG ATC TTC Gin Asp Lys Ile Phe 1595 AGA CTG CTC TAC TTC Arg Leu Leu Tyr Phe 1610 4861 4909 TGG CCC TGC GGC TTA ACT Trp Pro Cys Gly Leu Thr 1600 ATT GAC TAC CCC AAC Ile Asp Tyr Pro Asn 1605 WO 96/15801 PCT/US95/15203 ATG GAC Met Asp 1615 TCC TAT CTT GAT TAC Ser Tyr Leu Asp Tyr 1620 i/7 ATG GAC TTT TGC GAT Met Asp Phe Cys Asp 1625 TAT AAT GGA CAC Tyr Asn Gly His 1630 CAT CGG AGA CAG His Arg Arg Gin GTG ATA Val Ile 1635 GCC AGT GAT Ala Ser Asp TTG ATT Leu Ile 1640 ATA CGG CAC Ile Arg His CCC TAT Pro Tyr 1645 4957 5005 5053 510.1 GCC CTA ACT Ala Leu Thr CTC TTT Leu Phe 1650 GAA GAC TCT Glu Asp Ser GTG TAC Val Tyr 1655 TGG ACT GAC Trp Thr Asp CGT GCT ACT Arg Ala Thr 1660 CGT CGG GTT ATG Arg Arg Val Met 1665 CGA GCC AAC Arg Ala Asn AAG TGG Lys Trp 1670 CAT GGA GGG His Gly Gly AAC CAG TCA GTT Asn Gin Ser Val 1675 GTA ATG TAT AAT ATT CAA TGG CCC CTT GGG ATT GTT GCG GTT CAT CCT Val Met Tyr Asn Ile Gin Trp Pro Leu Gly Ile Val Ala Val His Pro 1680 1685 1690 TCG AAA Ser Lys 1695 CAA CCA AAT Gln Pro Asn TCT GTG Ser Val 1700 AAT CCA TGT Asn Pro Cys GCC TTT Ala Phe 1705 TCC CGC TGC Ser Arg Cys

AGC

Ser 1710 5149 5197 5245 CAT CTC TGC CTG His Leu Cys Leu CTT TCC Leu Ser 1715 TCA CAG GGG Ser Gin Gly CCT CAT Pro His 1720 TTT TAC TCC Phe Tyr Ser TGT GTT Cys Val 1725 TGT CCT TCA Cys Pro Ser GGA TGG Gly Trp 1730 AGT CTG TCT Ser Leu Ser CCT GAT Pro Asp 1735 CTC CTG AAT Leu Leu Asn TGC TTG AGA Cys Leu Arg 1740 5293 GAT GAT CAA CCT Asp Asp Gin Pro 1745 TTC TTA ATA Phe Leu Ile ACT GTA AGG Thr Val Arg 1750 CAA CAT ATA ATT TTT GGA Gin His Ile Ile Phe Gly 1755 ATC TCC CTT Ile Ser Leu 1760 AAT CCT GAG Asn Pro Glu GTG AAG Val Lys 1765 AGC AAT GAT Ser Asn Asp

GCT

Ala 1770 GCA GGG ATA Ala Gly Ile 1775 TAC ATC TAT Tyr Ile Tyr GAT GGC ACC Asp Gly Thr CAG AAT GGT TTA GAT Gin Asn Gly Leu Asp 1780 TGG GTT GAA AAT CCA Trp Val Glu Asn Pro 1795 AAC AGG ACA GTA TTT Asn Arg Thr Val Phe 1810 GTT GAA TTT GAT Val Glu Phe Asp 1785 GGT GAA ATT CAC Gly Glu Ile His 1800 GCT TCT ATA TCT Ala Ser Ile Ser 1815 ATG GTC CCC ATA Met Val Pro Ile GAT GCT GAG CAA Asp Ala Glu Gin 1790 AGA GTG AAG ACA Arg Val Lys Thr 1805 ATG GTG GGG CCT Met Val Gly Pro 1820 CTT TAT TCT ACC Leu Tyr Ser Thr 1835 5341 5389 5437 5485 5533 5581 5629 5677 TCT ATG AAC CTG GCC TTA GAT Ser Met Asn Leu Ala Leu Asp 1825 TGG ATT TCA AGA AAC Trp Ile Ser Arg Asn 1830 AAT CCT AGA ACT CAG TCA ATC GAG GTT TTG ACA CTC CAC GGA GAT ATC Asn Pro Arg Thr Gin Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile 1840 1845 1850 AGA TAC AGA AAA ACA TTG ATT GCC AAT GAT GGG ACA GCT CTT GGA GTT Arg Tyr Arg Lys Thr Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val 1855 186C 1865 1870 WO 96/15801 PCT/US95/15203 GGC TTT CCA ATT GGC ATA ACT GTT GAT CCT GCT CGT GGG AAG CTG TAC 5725 Gly Phe Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr 1875 1880 1885 TGG TCA GAC CAA GGA ACT GAC AGT GGG GTT CCT GCC AAG ATC GCC AGT 5773 Trp Ser Asp Gin Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser 1890 1895 1900 GCT AAC ATG GAT GGC ACA TCT GTG AAA ACT CTC TTT ACT GGG AAC CTC 5821 Ala Asn Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu 1905 1910 1915 GAA CAC CTG GAG TGT GTC ACT CTT GAC ATC GAA GAG CAG AAA .CTC TAC 5869 Glu His Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gin Lys Leu Tyr 1920 1925 1930 TGG GCA GTC ACT GGA AGA A GA GTG ATT GAA AGA GGA AAC GTG GAT GGA 5917 Trp Ala Val Thr Gly Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly 1935 1940 1945 1950 ACA GAT CGG ATG ATC CTG GTA CAC CAG CTT TCC CAC CCC TGG GGA ATT 5965 Thr Asp Arg Met Ile Leu Val His Gin Leu Ser His Pro Trp Gly Ile 1955 1960 1965 GCA GTC CAT GAT TCT TTC CTT TAT TAT ACT GAT GAA CAG TAT GAG GTC 6013 Ala Val His Asp Ser Phe Leu Tyr Tyr Thr Asp Glu Gin Tyr Glu Val 1970 1975 1980 ATT GAA AGA GTT GAT AAG GCC ACT GGG GCC AAC AAA ATA GTC TTG AGA 6061 Ile Glu Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg 1985 1990 1995 GAT AAT GTT CCA AAT CTG AGG GGT CTT CAA GTT TAT CAC AGA CGC AAT 6109 Asp Asn Val Pro Asn Leu Arg Gly Leu Gin Val Tyr His Arg Arg Asn 2000 2005 2010 GCC GCC GAA TCC TCA AAT GGC TGT AGC AAC AAC ATG AAT GCC TGT CAG 6157 Ala Ala Glu Ser Ser Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gin 2015 2020 2025 2030 CAG ATT TGC CTG CCT GTA CCA GGA GGA TTG TTT TCC TGC GCC TGT GCC 6205 Gn Ile Cys Leu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala 2035 2040 2045 ACT GGA TTT AAA CTC AAT CCT GAT AAT CGG TCC TGC TCT CCA TAT AAC 6253 Thr Gly Phe Lys Leu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn 2050 2055 2060 TCT TTC ATT GTT GTT TCA ATG CTG TCT GCA ATC AGA GGC TTT AGC TTG 6301 Ser Phe Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu 2065 2070 2075 GAA TTG TCA GAT CAT TCA GAA ACC ATG GTG CCG GTG GCA GGC CAA GGA 6349 Glu Leu Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gin Gly 2080 2085 2090 CGA AAC GCA CTG CAT GTG GAT GTG GAT GTG TCC TCT GGC TTT ATT TAT 6397 Arg Asn Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr 2095 2100 2105 2110 TGG TGT GAT TTT ACC AGC TCA GTG GCA TCT GAT AAT GCG ATC CGT AGA 6445 Trp Cys Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg 2115 2120 2125 WO 96/15801 PCT/US95/15203 fj ATT AAA CCA GAT GGA TCT TCT CTG ATG AAC ATT GTG ACA CAT GGA ATA 6493 Ile Lys Pro Asp Gly Ser Ser Leu Met Asn Ile Val Thr His Gly Ile 2130 2135 2140 GGA GAA AAT GGA GTC CGG GGT ATT GCA GTG GAT TGG GTA GCA GGA AAT 6541 Gly Glu Asn Gly Val Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn 2145 2150 2155 CTT TAT TTC ACC AAT GCC TTT GTT TCT GAA ACA CTG ATA GAA GTT CTG 6589 Leu Tyr Phe Thr Asn Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu 2160 2165 2170 CGG ATC AAT ACT ACT TAC CGC CGT GTT CTT CTT AAA GTC ACA GTG GAC 6637 Arg Ile Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp 2175 2180 2185 2190 ATG CCT AGG CAT ATT GTT GTA GAT CCC AAG AAC AGA TAC CTC TTC TGG 6685 Met Pro Arg His Ile Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp 2195 2200 2205 GCT GAC TAT GGG CAG AGA CCA AAG ATT GAG CGT TCT TTC CTT GAC TGT 6733 Ala Asp Tyr Gly Gin Arg Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys 2210 2215 2220 ACC AAT CGA ACA GTG CTT GTG TCA GAG GGC ATT GTC ACA CCA CGG GGC 6781 Thr Asn Arg Thr Val Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly 2225 2230 2235 TTG GCA GTG GAC CGA AGT GAT GGC TAC GTT TAT TGG GTT GAT GAT TCT 6829 Leu Ala Val Asp Arg Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser 2240 2245 2250 TTA GAT ATA ATT GCA AGG ATT CGT ATC AAT GGA GAG AAC TCT GAA GTG 6877 Leu Asp Ile Ile Ala Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val 2255 2260 2265 2270 ATT CGT TAT GGC AGT CGT TAC CCA ACT CCT TAT GGC ATC ACT GTT TTT 6925 Ile Arg Tyr Gly Ser Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe 2275 2280 2285 GAA AAT TCT ATC ATA TGG GTA GAT AGG AAT TTG AAA AAG ATC TTC CAA 6973 Glu Asn Ser Ile Ile Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gin 2290 2295 2300 GCC AGC AAG GAA CCA GAG AAC ACA GAG CCA CCC ACA GTG ATA AGA GAC 7021 Ala Ser Lys Glu Pro Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp 2305 2310 2315 AAT ATC AAC TGG CTA AGA GAT GTG ACC ATC TTT GAC AAG CAA GTC CAG 7069 Asn Ile Asn Trp Leu Arg Asp Val Thr Ile Phe Asp Lys.Gin Val Gin 2320 2325 2330 CCC CGG TCA CCA GCA GAG GTC AAC AAC AAC CCT TGC TTG GAA AAC AAT 7117 Pro Arg Ser Pro Ala Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn 2335 2340 2345 2350 GGT GGG TGC TCT CAT CTC TGC TTT GCT CTG CCT GGA TTG CAC ACC CCA 7165 Gly Gly Cys Ser His Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro 2355 2360 2365 AAA TGT GAC TGT GCC TTT GGG ACC CTG CAA AGT GAT GGC AAG AAT TGT 7213 Lys Cys Asp Cys Ala Phe Gly Thr Leu Gin Ser Asp Gly Lys Asn Cys 2370 2375 2380 WO 96/15801 PCTIUS95/15203 GCC ATT TCA ACA GAA AAT TTC CTC ATC TTT GCC TTG TCT AAT TCC TTG 7261 Ala Ile Ser Thr Glu Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu 2385 2390 2395 AGA AGC TTA CAC TTG GAC CCT GAA AAC CAT AGC CCA CCT TTC CAA ACA 7309 Arg Ser Leu His Leu Asp Pro Glu Asn His Ser Pro Pro Phe Gin Thr 2400 2405 2410 ATA AAT GTG GAA AGA ACT GTC ATG TCT CTA GAC TAT GAC AGT GTA AGT 7357 Ile Asn Val Glu Arg Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser 2415 2420 2425 2430 GAT AGA ATC TAC TTC ACA CAA AAT TTA GCC TCT GGA GTT GGA CAG ATT 7405 Asp Arg Ile Tyr Phe Thr Gin Asn Leu Ala Ser Gly Val Gly Gin Ile 2435 2440 2445 TCC TAT GCC ACC CTG TCT TCA GGG ATC CAT ACT CCA ACT GTC ATT GCT 7453 Ser Tyr Ala Thr Leu Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala 2450 2455 2460 TCA CGT ATA GGG ACT GCT GAT GGC ATT GCC TTT GAC TGG ATT ACT AGA 7501 Ser Gly Ile Gly Thr Ala Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg 2465 2470 2475 AGA ATT TAT TAC AGT GAC TAC CTC AAC CAG ATG ATT AAT TCC ATG GCT 7549 Arg Ile Tyr Tyr Ser Asp Tyr Leu Asn Gin Met Ile Asn Ser Met Ala 2480 2485 2490 GAA GAT GGG TCT AAC CGC ACT GTG ATA GCC CGC GTT CCA AAA CCA AGA 7597 Glu Asp Gly Ser Asn Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg 2495 2500 2505 2510 GCA ATT GTG TTA GAT CCC TGC CAA GGG TAC CTG TAC TGG GCT GAC TGG 7645 Ala Ile Val Leu Asp Pro Cys Gn Gly Tyr Leu Tyr Trp Ala Asp Trp 2515 2520 2525 GAT ACA CAT GCC AAA ATC GAG AGA GCC ACA TTG GGA GGA AAC TTC CGC 7693 Asp Thr His Ala Lys Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg 2530 2535 2540 GTA CCC ATT GTG AAC AGC AGT CTG GTC ATG CCC AGT GGG CTG ACT CTG 7741 Val Pro Ile Val Asn Ser Ser Leu Val Met Pro Ser Gly Leu Thr Leu 2545 2550 2555 GAC TAT GAA GAG GAC CTT CTC TAC TGG GTG GAT GCT AGT CTG CAG AGG 7789 Asp Tyr Glu Glu Asp Leu Leu Tyr Trp Val Asp Ala Ser Leu Gin Arg 2560 2565 2570 ATT GAA CGC AGC ACT CTG ACG GGC GTG GAT CGT GAA GTC ATT GTC AAT 7837 Ile Glu Arg Ser Thr Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn 2575 2580 2585 2590 GCA GCC GTT CAT GCT TTT GGC TTG ACT CTC TAT GGC CAG TAT ATT TAC 7885 Ala Ala Val His Ala Phe Gly Leu Thr Leu Tyr Gly Gin Tyr Ile Tyr 2595 2600 2605 TGG ACT GAC TTG TAC ACA CAA AGA ATT TAC CGA GCT AAC AAA TAT GAC 7933 Trp Thr Asp Leu Tyr Thr Gin Arg Ile Tyr Arg Ala Asn Lys Tyr Asp 2610 2615 2620 GGG TCA GGT CAG ATT GCA ATG ACC ACA AAT TTG CTC TCC CAG CCC AGG 7981 Gly Ser Gly Gin Ile Ala Met Thr Thr Asn Leu Leu Ser Gin Pro Arg 2625 2630 2635 WO 96/15801 GGA ATC AAC Gly Ile Asn 2640 PCTJUS9515203 ACT GTT GTG Thr Val Val AAG AAC Lys Asn 2645 /21 CAG AAA CAA CAG Gin Lys Gin Gin 2650 TGT AAC AAT CCT Cys Asn Asn Pro GCA CCA GGT CCA Ala Pro Gly Pro 2670 TGT GAA Cys Glu 2655 CAG TTT AAT Gin Phe Asn GGG GGC Gly Gly 2660 TGC AGC CAT ATC TGT Cys Ser .His Ile Cys 2665 AAT GGT GCC GAG Asn Gly Ala Glu TGC CAG Cys Gin 2675 TGT CCA CAT Cys Pro His GAG GGC Glu Gly 2680 AAC TGG TAT Asn Trp Tyr TTG GCC Leu Ala 2685 AAC AAC AGG Asn Asn Arg AAG CAC Lys His 2690 TGC ATT GTG Cys Ile Val GAC AAT Asp Asn 2695 GGT GAA CGA Gly Glu Arg TGT GGT GCA Cys Gly Ala 2700 TCT TCC TTC ACC Ser Ser Phe Thr 2705 TGC TCC AAT Cys Ser Asn GGG CGC Gly Arg 2710 TGC ATC TCG Cys Ile Ser GAA GAG TGG AAG Glu Glu Trp Lys 2715 TGT GAT AAT Cys Asp Asn 2720 GAC AAC GAC Asp Asn Asp TGT GGG Cys Gly 2725 GAT GGC AGT Asp Gly Ser GAT GAG Asp Glu 2730 ATG GAA AGT Met Glu Ser 8029 8077 8125 8173 8221 8269 8317 8365 8413 8461 8509 8557 GTC TGT Val Cys 2735 GCA CTT CAC Ala Leu His ACC TGC Thr Cys 2740 TCA CCG ACA Ser Pro Thr GCC TTC Ala Phe 2745 ACC TGT GCC Thr Cys Ala

AAT

Asn 2750 GGG CGA TGT GTC Gly Arg Cys Val CAA TAC Gin Tyr 2755 TCT TAC CGC Ser Tyr Arg TGT GAT Cys Asp 2760 TAC TAC AAT Tyr Tyr Asn GAC TGT Asp Cys 2765 GGT GAT GGC Gly Asp Gly AGT GAT Ser Asp 2770 GAG GCA GGG Glu Ala Gly TGC CTG Cys Leu 2775 TTC AGG GAC Phe Arg Asp TGC AAT GCC Cys Asn Ala 2780 ACC ACG GAG TTT Thr Thr Glu Phe 2785 ATG TGC AAT Met Cys Asn AAC AGA Asn Arg 2790 AGG TGC ATA Arg Cys Ile CCT CGT GAG TTT Pro Arg Glu Phe 2795 ATC TGC AAT Ile Cys Asn 2800 GGT GTA GAC Gly Val Asp AAC TGC Asn Cys 2805 CAT GAT AAT His Asp Asn AAC ACT Asn Thr 2810 TCA GAT GAG Ser Asp Glu AAA AAT Lys Asn 2815 TGC CCT GAT Cys Pro Asp CGC ACT Arg Thr 2820 TGC CAG TCT Cys Gin Ser GGA TAC Gly Tyr 2825 ACA AAA TGT Thr Lys Cys

CAT

His 2830 AAT TCA AAT ATT Asn Ser Asn Ile TGT ATT Cys Ile 2835 CCT CGC GTT Pro Arg Val TAT TTG TGT Tyr Leu Cys 2840 GAC GGA GAC AAT Asp Gly Asp Asn 2845 8605 8653 GAC TGT GGA Asp Cys Gly GAT AAC Asp Asn 2850 AGT GAT GAA Ser Asp Glu AAC CCT Asn Pro 2855 ACT TAT TGC Thr Tyr Cys ACC ACT CAC Thr Thr His 2860 ACG TGC AGC AGC AGT Thr Cys Ser Ser Ser 2865 CAA CAT TGG TAT TGT Gin His Trp Tyr Cys 2880 GAG TTC CAA TGC ACA Glu Phe Gin Cys Thr 2870 GAT CAA GAA ACA GAT Asp Gin Glu Thr Asp 2885 TCT GGG CGC TGT ATT CCT Ser Gly Arg Cys Ile Pro 2875 TGT TTT GAT GCC TCT GAT Cys Phe Asp Ala Ser Asp 2890 8701 8749 WO 96/15801 PCT/US95/15203 GAA CCT Glu Pro 2895 GCC TCT TGT GGT CAC Ala Ser Cys Gly His 2900 TCT GAG CGA ACA TGC Ser Glu Arg Thr Cys 2905 CTA GCT GAT GAG Leu Ala Asp Glu 2910 TTC AAG TGT GAT Phe Lys Cys Asp GGT GGG Gly Gly 2915 AGG TGC ATC Arg Cys Ile CCA AGC Pro Ser 2920 GAA TGG ATC Glu Trp Ile TGT GAC Cys Asp 2925 GGT GAT AAT Gly Asp Asn GAC TGT GGG GAT ATG Asp Cys Gly Asp Met 2930

AGT

Ser 2935 GAC GAG GAT Asp Glu Asp GAG TTT CTC Glu Phe Leu AAA AGG CAC CAG Lys Arg His Gin 2940 TGT GTA AAT GAC Cys Val Asn Asp 2955 TGT CAG AAT CAA Cys Gin Asn Gin 2945 AAC TGC TCG Asn Cys Ser GAT TCC Asp Ser 2950 AGA CCT Arg Pro 2960 GAT GTG Asp Val 2975 CCG GAC AGG AGG Pro Asp Arg Arg TGC ATT Cys Ile 2965 CCC CAG TCT Pro Gin Ser TGG GTC Trp Val 2970 TGT GAT GGC Cys Asp Gly 8797 8845 8893 8941 8989 9037 9085 9133 9181 GAT TGT ACT Asp Cys Thr GAC GGC Asp Gly 2980 TAC GAT GAG Tyr Asp Glu AAT CAG Asn Gin 2985 AAT TGC ACC Asn Cys Thr

AGG

Arg 2990 AGA ACT TGC TCT Arg Thr Cys Ser GAA AAT Glu Asn 2995 GAA TTC ACC Glu Phe Thr TGT GGT Cys Gly 3000 TAC GGA CTG Tyr Gly Leu TGT ATC Cys Ile 3005 CCA AAG ATA Pro Lys Ile TTC AGG Phe Arg 3010 TGT GAC CGG Cys Asp Arg CAC AAT His Asn 3015 GAC TGT GGT Asp Cys Gly GAC TAT AGC Asp Tyr Ser 3020 GAC GAG AGG GGC Asp Glu Arg Gly 3025 TGC TTA TAC Cys Leu Tyr CAG ACT Gin Thr 3030 TGC CAA CAG Cys Gin Gin AAT CAG TTT ACC Asn Gin Phe Thr 3035 TGT CAG Cys Gin 3040 AAT GAC Asn Asp 3055 AAC GGG CGC TGC Asn Gly Arg Cys ATT AGT Ile Ser 3045 AAA ACC TTC Lys Thr Phe GTC TGT Val Cys 3050 GAT GAG GAT Asp Glu Asp TGT GGA GAC Cys Gly Asp GGA TCT GAT GAG CTG Gly Ser Asp Glu Leu 3060 ATG CAC Met His 3065 CTG TGC CAC Leu Cys His

ACC

Thr 3070 9229 9277 9325 CCA GAA CCC ACG Pro Glu Pro Thr TGT CCA Cys Pro 3075 CCT CAC GAG Pro His Glu TTC AAG TGT GAC AAT Phe Lys Cys Asp Asn 3080 GGG CGC Gly Arg 3085 TGC ATC GAG Cys Ile Glu ATG ATG Met Met 3090 AAA CTC TGC Lys Leu Cys AAC CAC CTA GAT GAC Asn His Leu Asp Asp 3095 TGT TTG GAC Cys Leu Asp 3100 9373 AAC AGC GAT Asn Ser Asp 3105 GAG AAA GGC TGT Glu Lys Gly Cys GGC ATT AAT Gly Ile Asn 3110 GAA TGC CAT Glu Cys His 3115 GAC CCT TCA Asp Pro Ser ATC AGT GGC TGC GAT CAC AAC TGC ACA GAC ACC TTA ACC AGT TTC TAT Ile Ser Gly Cys Asp His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr 3120 3125 3130 TGT TCC TGT CGT CCT GGT TAC AAG CTC ATG TCT GAC AAG CGG ACT TGT Cys Ser Cys Arg Pro Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys 3135 3140 3145 3150 9421 9469 9517 WO 96/15801 PCT/US95/15203 GTT GAT ATT Val Asp Ile TGT GAG AAT Cys Glu Asn GAT GAA TGC Asp Glu Cys 3155 ACA GAG ATG CCT TTT Thr Glu Met Pro Phe 3160 GTC TGT AGC CAG AAG Val Cys Ser Gin Lys 3165 GTA ATA Val Ile 3170 GGC TCC TAC Gly Ser Tyr ATC TGT Ile Cys 3175 AAG TGT GCC Lys Cys Ala CCA GGC TAC Pro Gly Tyr 3180 CTC CGA GAA CCA Leu Arg Glu Pro 3185 GAT GGA AAG Asp Gly Lys ACC TGC Thr Cys 3190 CGG CAA AAC Arg Gin Asn AGT AAC ATC GAA Ser Asn Ile Glu 3195 9565 9613 9661 9709 9757 CCC TAT CTC Pro Tyr Leu 3200 ATT TTT AGC Ile Phe Ser AAC CGT Asn Arg 3205 TAC TAT TTG Tyr Tyr Leu AGA AAT Arg Asn 3210 TTA ACT ATA Leu Thr Ile GAT GGC Asp Gly 3215 TAT TTT TAC Tyr Phe Tyr TCC CTC ATC Ser Leu Ile 3220 TTG GAA GGA CTG Leu Glu Gly Leu 3225 GAC AAT GTT Asp Asn Val

GTG

Val 3230 GCA TTA GAT TTT Ala Leu Asp Phe GAC CGA Asp Arg 3235 GTA GAG AAG Val Glu Lys AGA TTG Arg Leu 3240 TAT TGG ATT Tyr Trp Ile GAT ACA Asp Thr 3245 9805 CAG AGG CAA Gin Arg Gin GTC ATT Val Ile 3250 GAG AGA ATG Glu Arg Met TTT CTG Phe Leu 3255 AAT AAG ACA Asn Lys Thr AAC AAG GAG Asn Lys Glu 3260 ACA ATC ATA AAC Thr Ile Ile Asn 3265 CAC AGA CTA His Arg Leu CCA GCT Pro Ala 3270 GCA GAA AGT Ala Glu Ser CTG GCT GTA GAC Leu Ala Val Asp 3275 9853 9901 9949 TGG GTT TCC Trp Val Ser 3280 AGA AAG CTC Arg Lys Leu TAC TGG Tyr Trp 3285 TTG GAT GCC Leu Asp Ala CGC CTG Arg Leu 3290 GAT GGC CTC Asp Gly Leu TTT GTC Phe Val 3295 TCT GAC CTC AAT GGT Ser Asp Leu Asn Gly 3300 GGA CAC CGC Gly His Arg CGC ATG Arg Met 3305 CTG GCC CAG CAC Leu Ala Gin His 3310 9997 TGT GTG GAT GCC Cys Val Asp Ala AAC AAC ACC Asn Asn Thr 3315 TTC TGC TTT GAT Phe Cys Phe Asp 3320 AAT CCC AGA Asn Pro Arg GGA CTT Gly Leu 3325 GCC CTT CAC Ala Leu His CCT CAA Pro Gin 3330 TAT GGG TAC Tyr Gly Tyr CTC TAC Leu Tyr 3335 TGG GCA GAC Trp Ala Asp TGG GGT CAC Trp Gly His 3340 CGC GCA TAC ATT Arg Ala Tyr Ile 3345 ATA ATC TCC ACC Ile Ile Ser Thr 3360 GGG AGA GTA Gly Arg Val GGC ATG GAT Gly Met Asp 3350 GGA ACC AAC AAG TCT GTG Gly Thr Asn Lys Ser Val 3355 10045 10093 10141 10189 10237 10285 AAG TTA GAG TGG Lys Leu Glu Trp 3365 CCT AAT GGC Pro Asn Gly ATC ACC Ile Thr 3370 ATT GAT TAC Ile Asp Tyr ACC AAT Thr Asn 3375 GAT CTA CTC Asp Leu Leu TAC TGG GCA Tyr Trp Ala 3380 GAT GCC CAC CTG GGT TAC ATA Asp Ala His Leu Gly Tyr Ile 3385

GAG

Glu 3390 TAC TCT GAT TTG Tyr Ser Asp Leu GAG GGC CAC CAT CGA Glu Gly His His Arg 3395 CAC ACG GTG TAT GAT His Thr Val Tyr Asp 3400- GGG GCA Gly Ala 3405 WO 96/15801 PCT/US95/15203 CTG CCT CAC CCT TTC Leu Pro His Pro Phe 3410 ACA GAT TGG AAT ACA Thr Asp Trp Asn Thr 3425 GCT ATT ACC ATT TTT GAA GAC ACT ATT TAT TGG Ala Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp 3415 3420 AGG ACA GTG GAA AAG GGA AAC AAA TAT GAT GGA Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly 3430 3435 10333 10381 TCA AAT AGA Ser Asn Arg 3440 CAG ACA CTG Gin Thr Leu GTG AAC Val Asn 3445 ACA ACA CAC Thr Thr His AGA CCA Arg Pro 3450 TTT GAC ATC Phe Asp Ile 10429 10477 CAT GTG His Val 3455 TAC CAT CCA Tyr His Pro TAT AGG Tyr Arg 3460 CAG CCC ATT Gin Pro Ile GTG AGC Val Ser 3465 AAT CCC TGT Asn Pro Cys

GGT

Gly 3470 ACC AAC AAT GGT Thr Asn Asn Gly

GGC

Gly 3475 TGT TCT CAT CTC TGC CTC ATC AAG CCA Cys Ser His Leu Cys Leu Ile Lys Pro GGA GGA Gly Gly 3485 3480 AAA GGG TTC Lys Gly Phe ACT TGC Thr Cys 3490 GAG TGT CCA Glu Cys Pro GAT GAC Asp Asp 3495 TTC CGC ACC Phe Arg Thr CTT CAG CTG Leu Gin Leu 3500 AGT GGC AGC ACC Ser Gly Ser Thr 3505 TAC TGC ATG Tyr Cys Met CCC ATG Pro Met 3510 TGC TCC AGC Cys Ser Ser ACC CAG TTC CTG Thr Gin Phe Leu 3515 10525 10573 10621 10669 10717 TGC GCT AAC Cys Ala Asn 3520 AAT GAA AAG Asn Glu Lys TGC ATT Cys Ile 3525 CCT ATC TGG Pro Ile Trp TGG AAA Trp Lys 3530 TGT GAT GGA Cys Asp Gly CAG AAA Gin Lys 3535 GAC TGC TCA Asp Cys Ser GAT GGC Asp Gly 3540 TCT GAT GAA Ser Asp Glu CTG GCC Leu Ala 3545 CTT TGC CCG Leu Cys Pro

CAG

Gin 3550 CGC TTC TGC CGA Arg Phe Cys Arg CTG GGA Leu Gly 3555 CAG TTC CAG Gin Phe Gin TGC AGT Cys Ser 3560 GAC GGC AAC Asp Gly Asn TGC ACC Cys Thr 3565 AGC CCG CAG Ser Pro Gin ACT TTA Thr Leu 3570 TGC AAT GCT Cys Asn Ala CAC CAA AAT His Gin Asn 3575 TGC CCT GAT GGG TCT Cys Pro Asp Gly Ser 3580 GAT GAA GAC CGT Asp Glu Asp Arg 3585 CTT CTT TGT Leu Leu Cys GAG AAT Glu Asn 3590 CAC CAC TGT His His Cys GAC TCC AAT GAA Asp Ser Asn Glu 3595 TGG CAG TGC Trp Gin Cys 3600 GCC AAC AAA Ala Asn Lys CGT TGC Arg Cys 3605 ATC CCA GAA Ile Pro Glu TCC TGG CAG TGT GAC Ser Trp Gin Cys Asp 3610 10765 10813 10861 10909 10957 11005 11053 ACA TTT Thr Phe 3615 AAC GAC TGT Asn Asp Cys GAG GAT Glu Asp 3620 AAC TCA GAT Asn Ser Asp GAA GAC Glu Asp 3625 AGT TCC CAC Ser Ser His

TGT

Cys 3630 GCC AGC AGG Ala Ser Arg TGC ATC CCG Cys Ile Pro ACC TGC CGG CCG GGC Thr Cys Arg Pro Gly 3635 CAG GCC TGG AAG TGT Gin Ala Trp Lys Cys 3650 CAG TTT CGG Gin Phe Arg 3640 TGT GCT AAT Cys Ala Asn GGC CGC Gly Arg 3645 GAT GTG GAT AAT GAT Asp Val Asp Asn Asp 3655 TGT GGA GAC Cys Gly Asp 3660 PCT/US95/15203 WO 96/15801 CAC TCG GAT GAG His Ser Asp Glu 3665 CCC ATT GAA GAA TGC Pro Ile Glu Glu Cys 3670 ATG AGC TCT GCC CAT CTC TGT Met Ser Ser Ala His Leu Cys 3675 GAC AAC Asp Asn 3680 TTC ACA GAA TTC Phe Thr Glu Phe AGC TGC Ser Cys 3685 AAA ACA AAT Lys Thr Asn TAC CGC TGC ATC CCA Tyr Arg Cys Ile Pro 3690 AAG TGG GCC GTG TGC Lys Trp Ala Val Cys 3695 AAT GGT GTA GAT GAC Asn Gly Val Asp Asp 3700 TGC AGG Cys Arg 3705 GAC AAC AGT Asp Asn Ser

GAT

Asp 3710 GAG CAA GGC TGT Glu Gin Gly Cys GAG GAG AGG ACA TGC Glu Glu Arg Thr Cys 3715 CAT CCT His Pro 3720 GTG GGG GAT Val Gly Asp TTC CGC Phe Arg 3725 TGT AAA AAT CAC CAC TGC ATC CCT Cys Lys Asn His His Cys Ile Pro 3730 CTT CGT Leu Arg 3735 TGG CAG TGT Trp Gin Cys GAT GGG CAA Asp Gly Gin 3740 CCC CGG GAG Pro Arg Glu AAT GAC TGT Asn Asp Cys 3745 GGA GAT AAC TCA Gly Asp Asn Ser GAT GAG Asp Glu 3750 GAA AAC TGT Glu Asn Cys

GCT

Ala 3755 TGC ACA Cys Thr 3760 GAG AGC GAG TTT Glu Ser Glu Phe CGA TGT GTC AAT CAG Arg Cys Val Asn Gin 3765 CAG TGC ATT CCC TCG Gin Cys Ile Pro Ser 3770 11101 11149 11197 11245 11293 11341 11389 11437 11485 11533 11581 11629 11677 CGA TGG ATC TGT GAC Arg Trp Ile Cys Asp 3775 CAT TAC AAC GAC TGT His Tyr Asn Asp Cys 3780 GGG GAC Gly Asp 3785 AAC TCA GAT Asn Ser Asp

GAA

Glu 3790 CGG GAC TGT GAG Arg Asp Cys Glu ATG AGG ACC TGC CAT Met Arg Thr Cys His 3795 CCT GAA Pro Glu 3800 TAT TTT CAG Tyr Phe Gin TGT ACA Cys Thr 3805 AGT GGA CAT Ser Gly His TGT GTA Cys Val 3810 CAC AGT GAA His Ser Glu CTG AAA Leu Lys 3815 TGC GAT GGA Cys Asp Gly TCC GCT GAC Ser Ala Asp 3820 TGT TTG GAT Cys Leu Asp 3825 3CG TCT GAT GAA Ala Ser Asp Glu GCT GAT Ala Asp 3830 TGT CCC ACA Cys Pro Thr CGC TTT CCT GAT Arg Phe Pro Asp 3835 GGT GCA Gly Ala 3840 TAC TGC CAG GCT Tyr Cys Gin Ala ACT ATG TTC GAA TGC Thr Met Phe Glu Cys 3845 AAA AAC Lys Asn 3850 CAT GTT TGT His Val Cys ATC CCG CCA TAT TGG Ile Pro Pro Tyr Trp 3855 AAA TGT Lys Cys 3860 GAT GGC GAT Asp Gly Asp GAT GAC Asp Asp 3865 TGT GGC GAT Cys Gly Asp

GGT

Gly 3870 TCA GAT GAA GAA Ser Asp Glu Glu CTT CAC Leu His 3875 CTG TGC TTG Leu Cys Leu GAT GTT Asp Val 3880 CCC TGT AAT Pro Cys Asn TCA CCA Ser Pro 3885 AAC CGT TTC Asn Arg Phe CGG TGT GAC AAC AAT Arg Cys Asp Asn Asn 3890 CGC TGC Arg Cys 3895 ATT TAT AGT Ile Tyr Ser CAT GAG GTG His Glu Val 3900 11725 11773 11821 TGC AAT GGT GTG GAT GAC TGT Cys Asn Gly Val Asp Asp Cys 3905 GGA GAT GGA ACT GAT Gly Asp Gly Thr Asp 3910 GAG ACA GAG GAG Glu Thr Glu Glu 3915 WO 96/15801 PCT/US95/15203 CAC TGT AGA His Cys Arg 392'0 AAA CCG ACC Lys Pro Thr CCT AAA Pro Lys 3925 CCT TGT ACA GAA TAT Pro Cys Thr Glu Tyr 3930 GAA TAT AAG Glu Tyr Lys TGT GGC AAT GGG CAT Cys Gly Asn Gly His 3935 TGC ATT CCA CAT GAC Cys Ile Pro His Asp 3940 AAT GTG Asn Val 3945 TGT GAT GAT Cys Asp Asp

GCC

Ala 3950 GAT GAC TGT Asp Asp Cys GGT GAC TGG Gly Asp Trp 3955 TCC GAT GAA Ser Asp Glu CTG GGT Leu Gly 3960 TGC AAT AAA Cys Asn Lys GGA AAA Gly Lys 3965 GAA AGA ACA Glu Arg Thr TGT GCT Cys Ala 3970 GAA AAT ATA Glu Asn Ile TGC GAG CAA AAT TGT Cys Glu Gin Asn Cys 3975 ACC CAA TTA Thr Gin Leu 3980 GAA ACC AAT Glu Thr Asn 11869 11917 11965 12013 12061 12109 12157 AAT GAA GGA GGA Asn Glu Gly Gly 3985 TTT ATC TGC Phe Ile Cys TCC TGT Ser Cys 3990 ACA GCT GGG Thr Ala Gly

TTC

Phe 3995 GTT TTT GAC AGA ACC TCC Val Phe Asp Arg Thr Ser 4000 TGT CTA GAT ATC AAT Cys Leu Asp Ile Asn 4005 TGC AGA AAT ACC AAA Cys Arg Asn Thr Lys GAA TGT GAA CAA TTT Glu Cys Glu Gin Phe 4010 GGG ACT Gly Thr 4015 TGT CCC CAG Cys Pro Gin

CAC

His 4020

GGA

Gly 5 AGT TAT GAG Ser Tyr Glu

TGT

Cys 4030 402! GTC TGT GCT GAT Val Cys Ala Asp GGC TTC Gly Phe 4035 ACG TCT ATG Thr Ser Met AGT GAC CGC CCT GGA Ser Asp Arg Pro Gly 4040 AAA CGA Lys Arg 4045 12205 TGT GCA GCT Cys Ala Ala GAG GGT AGC TCT CCT Glu Gly Ser Ser Pro 4050 TTG TTG Leu Leu 4055 CTA CTG CCT Leu Leu Pro GAC AAT GTC Asp Asn Val 4060 CGA ATT CGA AAA Arg Ile Arg Lys 4065 TAT AAT CTC Tyr Asn Leu TCA TCT Ser Ser 4070 GAG AGG TTC Glu Arg Phe TCA GAG TAT CTT Ser Glu Tyr Leu 4075 TGG GAT CCC RAG Trp Asp Pro Xaa CAA GAT GAG Gin Asp Glu 4080 GAA TAT ATC Glu Tyr Ile CAA GCT Gin Ala 4085 GTT GAT TAT Val Asp Tyr

GAT

Asp 4090 GAC ATA GGC CTC AGT Asp Ile Gly Leu Ser 4095 GTT GTG Val Val 4100 TAT TAC ACT Tyr Tyr Thr GTG CGA Val Arg 4105 GGG GAG GGC Gly Glu Gly

TCT

Ser 4110 12253 12301 12349 12397 12445 12493 12541 12589 AGG TTT GGT GCT Arg Phe Gly Ala ATC AAA Ile Lys 4115 CGT GCC TAC Arg Ala Tyr ATC CCC AAC TTT GAA Ile Pro Asn Phe Glu 4120 TCC GGC Ser Gly 4125 CGC AAT AAT CTT GTG CAG GAA GTT GAC CTG AAA CTG AAA TAC GTA ATG Arg Asn Asn Leu Val Gin Glu Val Asp Leu Lys Leu Lys Tyr Val Met 4130 4135 4140 CAG CCA GAT GGA ATA GCA GTG GAC TGG GTT GGA AGG Gin Pro Asp Gly Ile Ala Val Asp Trp Val Gly Arg 4145 4150 CAT ATT TAC TGG His Ile Tyr Trp 4155 CTT GAT GGA AGG Leu Asp Gly Arg TCA GAT GTC AAG AAT AAA Ser Asp Val Lys Asn Lys 4160

CGC

Arg 4165 ATT GAG GTG GCT AAA Ile Glu Val Ala Lys 417C WO 96/15801 PCT/US95/15203 TAC AGA Tyr Arg 4175 AAG TGG CTG ATT TCC Lys Trp Leu Ile Ser 4180 ACT GAC CTG GAC CAA Thr Asp Leu Asp Gin 4185 CCA GCT GCT ATT Pro Ala Ala Ile 4190 GCT GTG AAT CCC Ala Val Asn Pro AAA CTA Lys Leu 4195 GGG CTT ATG Gly Leu Met TTC TGG Phe Trp 4200 ACT GAC TGG Thr Asp Trp GGA AAG Gly Lys 4205 GAA CCT AAA Glu Pro Lys CTG GTT TTC Leu Val Phe 422E MTC GAG Xaa Glu 4210 TCT GCC TGG Ser Ala Trp ATG AAT Met Asn 4215 GGA GAG GAC Gly Glu Asp CGC AAC ATC Arg Asn Ile 4220 GAG GAC CTT GGT Glu Asp Leu Gly TGG CCA ACT GGC CTT Trp Pro Thr Gly Leu 4230 TTG AAC Leu Asn 4240 GAA ACC Glu Thr 4255 AAT GAC CGA ATC Asn Asp Arg Ile TAC TGG AGT GAC TTC Tyr Trp Ser Asp Phe 4245

AAG

Lys 4250 TCT ATC GAT TAT Ser Ile Asp Tyr 4235 GAG GAC GTT ATT Glu Asp Val Ile ATT GCA AAG GAA Ile Ala Lys Glu ATA AAA TAT Ile Lys Tyr GAT GGG ACT GAT AGG Asp Gly Thr Asp Arg 4260 AGA GTC Arg Val 4265 4270 12637 12685 12733 12781 12829 12877 12925 12973 13021 13069 13117 13165 GCA ATG AAC CCT Ala Met Asn Pro TAC AGC CTG GAC ATC Tyr Ser Leu Asp Ile 4275 TTT GAA Phe Glu 4280 GAC CAG TTA Asp Gin Leu TAC TGG Tyr Trp 4285 ATA TCT AAG Ile Ser Lys GAA AAG GGA GAA GTA Glu Lys Gly Glu Val 4290 TGG AAA Trp Lys 4295 CAA AAT AAA Gin Asn Lys TTT GGG CAA Phe Gly Gin 4300 GGA AAG AAA Gly Lys Lys 4305 GAG AAA ACG CTG GTA GTG AAC CCT TGG Glu Lys Thr Leu Val Val Asn Pro Trp 5 4310 CTC ACT CAA GTT Leu Thr Gin Val 4315 CCC AAC CTT TGC Pro Asn Leu Cys CGA ATC TTT CAT CAA CTC Arg Ile Phe His Gin Leu 4320 AGA TAC Arg Tyr 4325 AAT AAG TCA Asn Lys Ser

GTG

Val 4330 AAA CAG ATC TGC AGC CAC CTC TGC CTT CTG Lys Gin Ile Cys Ser His Leu Cys Leu Leu 4335 4340 AGA CCT Arg Pro 4345 GGA GGA TAC Gly Gly Tyr

AGC

Ser 4350 TGT GCC TGT CCC CAA GGC Cys Ala Cys Pro Gin Gly 4355 TCC AGC TTT Ser Ser Phe ATA GAG Ile Glu 4360 GGG AGC ACC Gly Ser Thr ACT GAG Thr Glu 4365 TGT GAT GCA Cys Asp Ala TGC ATG CAC Cys Met His 438E GCC ATY Ala Ile 4370 GAA CTG CCT Glu Leu Pro ATC AAC CTG CCC CCC Ile Asn Leu Pro Pro 4375 CCA TGC AGG Pro Cys Arg 4380 13213 13261 GGA GGA AAT TGC Gly Gly Asn Cys TAT TTT GAT Tyr Phe Asp 4390 GAG ACT GAC CTC CCC AAA Glu Thr Asp Leu Pro Lys 4395 TGC AAG Cys Lys 4400 TGT CCT AGC GGC TAC ACC GGA AAA TAT Cys Pro Ser Gly Tyr Thr Gly Lys Tyr 4405 TGT GAA ATG GCG TTT Cys Glu Met Ala Phe 4410 GCT GTG CTG TTG ACA Ala Val Leu Leu Thr 13309 13357

TCA

Ser 4415 AAA GGC ATC TCT CCA GGA ACA ACC GCA Lys Gly Ile Ser Pro Gly Thr Thr Ala

GTA

Val 442 4420 5 4430 WO 96/15801 PCT/US95/15203 ATC CTC TTG ATC GTC GTA Ile Leu Leu Ile Val Val 4435 ATT GGA GCT CTG GCA Ile Gly Ala Leu Ala 4440 ATT GCA GGA TTC TTC Ile Ala Gly Phe Phe 4445 CTG CCC AAG CTG CCA Leu Pro Lys Leu Pro 4460 CAC TAT AGA His Tyr Arg AGG ACC GGC TCC CTT Arg Thr Gly Ser Leu 4450 TTG CCT GCT Leu Pro Ala 4455 13405 13453 13501 AGC TTA AGC AGT CTC GTC AAG Ser Leu Ser Ser Leu Val Lys 4465 CCC TCT GAA AAT GGG Pro Ser Glu Asn Gly 4470 AAT GGG GTG ACC Asn Gly Val Thr 4475 TTC AGA TCA Phe Arg Ser 4480 GGG GCA GAT CTT AAC Gly Ala Asp Leu Asn 4485 ATG GAT ATT GGA GTG TCT GGT TTT Met Asp Ile Gly Val Ser Gly Phe 4490 13549 GGA CCT Gly Pro 4495 GAG ACT GCT ATT GAC AGG TCA ATG GCA ATG AGT GAA GAC Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp

TTT

Phe 4510 13597 4500 4505 GTC ATG GAA ATG Val Met Glu Met GGG AAG Gly Lys 4515 CAG CCC ATA Gin Pro Ile ATA TTT Ile Phe 4520 GAA AAC CCA Glu Asn Pro ATG TAC Met Tyr 4525 13645 TCA GCC AGA Ser Ala Arg GTA TCT GAA Val Ser Glu 4545 GAC AGT Asp Ser 4530 GCT GTC AAA Ala Val Lys GTG GTT CAG CCA ATC Val Val Gin Pro Ile 4535 CAG GTG ACT Gin Val Thr 4540 13693 AAT GTG GAT AAT Asn Val Asp Asn AAG AAT TAT GGA AGT CCC ATA AAC CCT Lys Asn Tyr Gly Ser Pro Ile Asn Pro 4550 4555 13741 TCT GAG Ser Glu 4560 ACT CAG Thr Gin 4575 ATA GTT CCA GAG Ile Val Pro Glu GTG ACA AAA TGG Val Thr Lys Trp ACA AAC Thr Asn 4565 CCA ACT TCA Pro Thr Ser CCA GCT Pro Ala 4570 GCT GAT GGA Ala Asp Gly AAT CTC TTC AAA Asn Leu Phe Lys 0 CGA AAA Arg Lys 4585 TCT AAA CAA ACT Ser Lys Gin Thr 4590 458 ACC AAC TTT GAA Thr Asn Phe Glu AAT CCA Asn Pro 4595 ATC TAT GCA Ile Tyr Ala CAG ATG Gin Met 4600 GAG AAC GAG Glu Asn Glu CAA AAG Gin Lys 4605 13789 13837 13885 13933 13981 GAA AGT GTT GCT GCG ACA Glu Ser Val Ala Ala Thr 4610 CCT AAG CCT CCT TCG AGA Pro Lys Pro Pro Ser Arg 4625 CCA CCT CCA TCA CCT TCG Pro Pro Pro Ser Pro Ser 4615 CTC CCT GCT AAG Leu Pro Ala Lys 4620 TAT TCT GCA ACA Tyr Ser Ala Thr 4635 AGA GAC CCA Arg Asp Pro 4630 ACT CCA ACC Thr Pro Thr GAA GAC ACT TTT Glu Asp Thr Phe 4640 AAA GAC ACC GCA AAT Lys Asp Thr Ala Asn 4645 CTT GTT AAA GAA GAC TCT GAA Leu Val Lys Glu Asp Ser Glu 4650 14029 GTA TAG CTATACC 14042 Val 4655 INFORMATION FOR SEQ ID NO:86: SEQUENCE CHARACTERISTICS: WO 96/15801 WO 96/580 1PCTfUS95115203 LENGTH: 4656 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 86: Met Asp Arg Gly 1 Val' Phe Gly Val Ile Ser Ile His Pro 145 Se r Ile Gly Gin Tyr 225 Cys Giu Cys Ala Arg Thr Thr Pro Asp Thr Vali 130 Thr Gin As n Giu Asp 210 Gin Asp Ser Pro Cys Cys Lys Cys Ser Giu Cys 115 Arg Cys Lys Cys Cys 195 Gly Phe Giy Giy Giu Leu Gly Asp Gin Ser Arg 100 Ser Asp Giu Cys Thr 180 Ile Ser Thr Giu Prc 260 Ser Pro2 5 Ala Ser Cys Gin Trp 85 Gin Asn Cys Gin Asp 165 Giu Pro Asp Cys *Asp 245 His *Giy kla Ala Val Ala Cys Thr Pro 31y Ser Gly 70 Val1 Asp Gly Pro Leu 150 Trp Ile Arg Giu Pro 230 Asp Asr Ar Ala His Asp 55 Tyr Cys Cys Gin Asp 135 Thr Lys Cys Ala His 215 Ser Cys Val Cys Ser Cys 40 Asp Phe Asp Ser Cys 120 Giy Cys Val1 Leu Tyr 200 Ala Gly Lys His Ile 280 ;iy 25 Ile Ala Ljys Gin Gin 105 Ile Ala Asp Asp His 185 Val1 Cys Arg Asp Lys 265 Ser Gin Pro Asp Cys Asp 90 Ser Pro Asp Asn Cys 170 Asn Cys Asn Cys As n 250 Cys Ile Giu Ala Giu Gin 75 Gin Thr Ser Giu Gly 155 Arg Giu Asp Tyr Ile 235 Gly Ser Tyr Leu Leu Cys Asp Asp Trp Ile Gly Ser Giu Asp Cys Cys Ser Giu Tyr 125 Asn Asp 140 Ala Cys Asp Ser Phe Ser His Asp 205 Pro Thr 220 Tyr Gin Asp Glu Pro Arg Lys Vai 285 eu Ser :ys Gly Asp Ser 110 Arg Cys Tyr Ser Cys 190 As n Cys Asn Asp Gil 270 Cys Ala Ala Cys Ala Gin Asp His Cys Gin Asn Asp 175 G ly Asp Gly Trp Gly 255 1Trp Asp Leu Asp Val1 Cys Gly Gin Asp Tyr Thr 160 Giu Asnr Cys Giy Val1 240 Cys Ser G ly 275 Ile Leu Asp Cys Pro Gly 290 Glu Asp Giu Asn Asn Thr Ser Thr Gly WO 96/15801 PCT/US95/15203 Lys Tyr Cys Ser Met Thr Leu Cys Ser 305 310 130 Ala Leu Asn Cys Gin Tyr 315 Gin 320

C

I

G

c 3 c C9 ys His Glu Thr Pro Tyr G 325 le Ile Asn His Asn Asp S 340 ;1n Ile Trp Gly Ile Cys A 355 is Leu Cys His Cys Glu C 370 :ys Lys Ala Asn Asp Ser I i85 390 ;ly Arg Asp Leu Leu Ile 405 Leu Val Glu Ser Gin Asn 420 Tyr His Leu Gin Arg Val 435 Phe Ser Val Asp Ile Asn S450 Ser Val Glu Thr Pro Glu 465 470 Ile Tyr Leu Val Glu Thr 485 Asp Gly Ser Tyr Arg Val 500 Arg Gly Ile Ala Val Asp 515 Trp Glu Ser Leu Ser Gly 530 Gly Ser Asn Arg Lys Asp 545 550 Gly Val Thr Leu Asp Met 565 Arg Phe Asp Tyr Ile Glu 580 Thr Val Val His Gly Gly 595 Leu Phe Glu Gly Gin Val ly Gly Ala C 3 ;er Arg Thr C 345 Lsp Gin Lys C 360 ;lu Gly Tyr I 375 ?he Gly Glu I ;ly Asp Ile 4 Arg Gly Val I 425 Phe Trp Thr 2 440 Gly Leu Asn 455 Asn Leu Ala Lys Val Asn Thr Leu Ile 505 Pro Thr Val 520 Glu Pro Lys 535 Leu Val Lys Ile Ser Lys Thr Val Thr 585 Ser Leu Ile 600 Phe Phe Thr ys I 30 ys *ys le la His 110 .la Asp Ile Val Arg 490 Thr Gly Leu Thr Arg 570 Phe Val Glu Leu Ser 395 Gly Val Thr Gin Asp 475 Ile Glu Tyr Glu Lys 555 Val Cys Glu Ser Glu 380 Ile Arg Gly Val Glu 460 Trp Asp Asn Leu Arg 540 Lei Tyl Pro I Phe I Arg 365 Arg Ile Ser Val Gin 445 Val Val Met I Leu Phe 525 Ala SGly r Trp y Ile o Phe 605 r Lys 0 Pro Asp 350 Pro Gly Phe Phe Ala 430 Asn Leu Asn Val Gly 510 Phe Phe Trp Va G1 Gly 335 Asp Gly Gin Ser Arg 415 Phe Lys Asn Asn Asn 495 His Ser Met SPro 1 Asp 575 n Arg [yr :ys Arg Tyr Asn 400 Ile His Val Val Lys 480 Leu Pro Asp Asp Ala 560 Ser Lys Tyr Asp Gl Pro His Pr Asp Trp Th 62 590 Gly Met Val Ala Ser Val Gin 640 610 615 Leu Lys Ala Asn Lys 625 Thr Glu Thr Asn Pro 635 Gin Val Tyr Tyr WO 96/15801 Ala Pro Va1 Cys Ile 705 Ser Tyr Cys Lys 690 Ala Leu Ala Va1 675 Cys Va1 Arg Thr 660 Leu Thr Gin

E

1 Gly Ile Pro Ser Gly Asn Ser Thr Ile 755 Lys Ile Asp 770 Asn Val Glu 785 Thr Asp Ser Thr Arg Arg Val His Pro 835 Ala Lys Ile 850 Phe Pro 740 Phe Gly Ser His Thr 820 Phe Met Sp

I

P

T

7

S

ro Tyr Giy Val T sn Pro Cys Lys er His Arg Thr 2 680 he Gly Phe Gin I 695 .sn Phe Leu Ile 710 'hr Leu Ser Thr 25 ;er Phe Phe Val 'he Ser Asp Met 760 [hr Gly Arg Glu 775 eu Ala Phe Asp 790 Tyr Lys Ser Ile 805 Val Val Gin Tyr Ala Giy Tyr Leu 840 Arg Ala Trp Ser 855 Leu Gly Trp Pro 'hr V 6 ~sp P )65 ~sp P jeu 1 Phe Gln Gly 745 Ser Ile Trp Ser Leu 825 Phe Asp Asn 13i 'a1 ;50 sn ~sn ~sp 'er lu 730 Ile.

Lys Leu Ile Val 810 Asr PhE G l Gl' Tyr Asn Asp Thr Ser 715 Asp Asp His Ala Ser 795 Met 1 AsI Th: Se y Le 87 His S Gly G Gly 1

E

Asp C 700 Gin I Val 1 Phe Met Ala 780 Lys Arg *i Pro r Asp r His 860 u Ala

S

er :ly jeu lu Ial 4et ksp Ile 765 Asn Asn Leu Arg Tr 841 Let I1 Leu 1 6 Cys C 670 Gly I Arg I Ala Va1 Ala 750 Phe Arg Leu Ala Ser 830 Phe i Leu e Asp PCTIUS95/1 5203 rg Gin ,iu Gin ?he Arg His Cys Ile Arg 720 Pro Vai 735 Gin Asp Lys Gin Val Glu Tyr Trp 800 Asp Lys 815 Val Val Arg Pro Pro Val Trp Ala 880 Ile Asn Thr Thr 870 Ala Ser Met Thr Gly 945 Lys Pro Ser Thr Thr Asp 930 Glu Ser Thr Arg Phe His 915 Trp Met Tyr His Leu Asp 900 Pro Arg Thr Asp Pro Tyr 885 Gly Phe Leu Val Val 965 Asn Trp Leu Cly Gly Ile 950 Asr Gly Val Asp Leu Ala 935 Arg Ile Asp Asp Arg Ala 920 Ile Ser Gin Cys Ala Arg 905 Ile Ile Gly Thr Ser Tyr 890 Arg Phe Arg Ile Gly 970 His Phe Leu Gly Va1 Ala 955 Ser Phe Asp Gly Glu Arg 940 Tyr Asn Cys Lys His His 925 Lys Ile Ala Phe Ile Glu 895 Ile Glu 910 Leu Phe Ala Asp Leu His Cys Asn 975 Pro Val His Gin Phe Gly Leu 960 Gin Pro Wb 96/15801 PCTfUS95/15203 132- 980 985 990 Asn Phe Gin Arg Val Cys Gly Cys Pro Tyr Gly Met Arg Leu Ala Ser 995 1000 1005 Asn His Leu Thr Cys Glu Gly Asp Pro. Thr Asn Glu Pro Pro Thr Glu 1010 1015 1020 Gin Cys Gly Leu Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys Val Pro 1025 1030 1035 1040 Asn Tyr Tyr Leu Cys Asp Gly Val Asp Asp Cys His Asp Asn Ser Asp 1045 1050 1055 Glu Gin Leu Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala Phe 1060 1065 1070 Thr Cys Gly His Gly Glu Cys Ile Pro Ala His Trp Arg Cys Asp Lys 1075 1080 1085 Arg Asn Asp Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr His 1090 1095 1100 Ala Pro Ala Ser Cys Leu Asp Thr Gin Tyr Thr Cys Asp Asn His Gin 1105 1110 1115 1120 Cys Ile Ser Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly Asp 1125 1130 1135 Gly Ser Asp Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gin Pro Ser 1140 1145 1150 Gin Phe Asn Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val Cys 1155 1160 1165 Asp Gly Asp Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly Cys Val 1170 1175 1180 Leu Asn Cys Thr Ala Ser Gin Phe Lys Cys Ala Ser Gly Asp Lys Cys 1185 1190 1195 1200 Ile Gly Val Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser Asp Asn 1205 1210 1215 Ser Asp Glu Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His Ser 1220 1225 1230 Asp Glu Phe Gin Cys Gin Glu Asp Gly Ile Cys Ile Pro Asn Phe Trp A C 1235 Glu Cys Asp C 1250 Ala Cys Val I 1265 Gly Asn Cys Gly Asp Met Pro Ser Trp 1315 Gly His Pro Asp 1255 Pro Lys Thr Cys 1270 Ile His Arg Xaa 1285 Ser Asp Glu Lys 1300 Gln Trp Gin Cys Cys Leu Tyr Gly Ser Asp Glu His Asn 1260 Pro Ser Ser Tyr Phe His Cys Asp Asn 1275 1280 Trp Leu Cys Asp Arg Asp Asn Asp Cys 1290 1295 Asp Cys Pro Thr Gin Pro Phe Arg Cys 1305 1310 Leu Gly His Asn Ile Cys Val Asn Leu 1320 1325 WO 96/15801 PCT/US95/15203 133 Ser Val Val Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp Glu 1330 1335 1340 Ser Pro Leu Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly Cys 1345 1350 1355 1360 Thr His Glu Cys Val Gin Glu Pro Phe Gly Ala Lys Cys Leu Cys Pro 1365 1370 1375 Leu Gly Phe Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp Ile Asp 1380 1385 1390 Glu Cys Asp Ile Leu Gly Ser Cys Ser Gin His Cys Tyr Asn Met Arg 1395 1400 1405 Gly Ser Phe Arg Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu Ser Asp 1410 1415 1420 Gly Arg Thr Cys Lys Val Thr Ala Ser Glu Ser Leu Leu Leu Leu Val 1425 1430 1435 1440 Ala Ser Gin Asn Lys Ile Ile Ala Asp Ser Val Thr Ser Gin Val His 1445 1450 1455 Asn Ile Tyr Ser Leu Val Glu Asn Gly Ser Tyr Ile Val Ala Val Asp 1460 1465 1470 Phe Asp Ser Ile Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr Gin Gly 1475 1480 1485 Lys Thr Trp Ser Ala Phe Gin Asn Gly Thr Asp Arg Arg Val Val Phe 1490 1495 1500 Asp Ser Ser Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val Gly 1505 1510 1515 1520 Arg Asn Leu Tyr Trp Thr Asp Tyr Ala Leu Glu Thr Ile Glu Val Ser 1525 1530 1535 Lys Ile Asp Gly Ser His Arg Thr Val Leu Ile Ser Lys Asn Leu Thr 1540 1545 1550 Asn Pro Arg Gly Leu Ala Leu Asp Pro Arg Met Asn Glu His Leu Leu 1555 1560 1565 Phe Trp Ser Asp Trp Gly His His Pro Arg Ile Glu Arg Ala Ser Met 1570 1575 1580 Asp Gly Ser Met Arg Thr Val Ile Val Gin Asp Lys Ile Phe Trp Pro 1585 1590 1595 1600 Cys Gly Leu Thr Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe Met Asp 1605 1610 1615 Ser Tyr Leu Asp Tyr Met Asp Phe Cys Asp Tyr Asn Gly His His Arg 1620 1625 1630 Arg Gin Val Ile Ala Ser Asp Leu Ile Iie Arg His Pro Tyr Ala Leu 1635 1640 1645 Thr Leu Phe Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg Arg 1650 1655 1660 WO 96/15801 PCT/US95/15203 Val Met Arg Ala Asn Lys Trp His Gly Gly Asn Gin Ser Val Val Met 1665 1670 1675 1680 Tyr Asn Ile Gin Trp Pro Leu Gly Ile Val Ala Val His Pro Ser Lys 1685 1690 1695 Gin Pro Asn Ser Val Asn Pro Cys Ala Phe Ser Arg Cys Ser His Leu 1700 1705 1710 Cys Leu Leu Ser Ser Gin Gly Pro His Phe Tyr Ser Cys Val Cys Pro 1715 1720 1725 Ser Gly Trp Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp Asp 17.30 1735 1740 Gin Pro Phe Leu Ile Thr Val Arg Gin His Ile Ile Phe Gly Ile Ser 1745 1750 1755 1760 Leu Asn Pro Glu Val Lys Ser Asn Asp Ala.Met Val Pro Ile Ala Gly 1765 1770 1775 Ile Gin Asn Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gin Tyr Ile 1780 1785 1790 Tyr Trp Val Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp Gly 1795 1800 1805 Thr Asn Arg Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser Met 1810 1815 1820 Asn Leu Ala Leu Asp Trp Ile Ser Arg Asn Leu Tyr Ser Thr Asn Pro 1825 1830 1835 1840 Arg Thr Gin Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg Tyr 1845 1850 1855 Arg Lys Thr Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly Phe 1860 1865 1870 Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp Ser 1875 1880 1885 Asp Gin Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala Asn 1890 1895 1900 Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu His 1905 1910 1915 1920 Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gin Lys Leu Tyr Trp Ala 1925 1930 1935 Val Thr Gly Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr Asp 1940 1945 1950 Arg Met Ile Leu Val His Gin Leu Ser His Pro Trp Gly Ile Ala Val 1955 1960 1965 His Asp Ser Phe Leu Tyr Tyr Thr Asp Glu Gin Tyr Glu Val Ile Glu 1970 1975 1980 Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp Asn 1985 1990 1995 2000 Val Pro Asn Leu Arg Gly Leu Gin Val Tyr His Arg Arg Asn Ala Ala WO 96/15801 PCT/US95/15203 2005 2010 2015 Glu Ser Ser Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gin Gin Ile 2020 2025 2030 Cys Leu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr Gly 2035 2040 2045 Phe Lys Leu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser Phe 2050 2055 2060 Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu Leu 2065 2070 2075 2080 Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gin Gly Arg Asn 2085 2090 2095 Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp Cys 2100 2105 2110 2 0 Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile Lys 2115 2120 2125 Pro Asp Gly Ser Ser Leu Met Asn Ile Val Thr His Gly Ile Gly Glu 2130 2135 2140 Asn Gly Val Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu Tyr 2145 2150 2155 2160 Phe Thr Asn Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg Ile 2165 2170 2175 Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp Met Pro 2180 2185 2190 3 Arg His Ile Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala Asp 2195 2200 2205 Tyr Gly Gin Arg Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys Thr Asn 2210 2215 2220 Arg Thr Val Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu Ala 2225 2230 2235 2240 Val Asp Arg Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser Leu Asp 2245 2250 2255 Ile Ile Ala Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile Arg 2260 2265 2270 Tyr Gly Ser Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Glu Asn 2275 2280 2285 Ser Ile Ile Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gin Ala Ser 2290 2295 2300 Lys Glu Pro Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn Ile 2305 2310 2315 2320 Asn Trp Leu Arg Asp Val Thr Ile Phe Asp Lys Gin Val Gin Pro Arg 2325 2330 2335 Ser Pro Ala Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn Gly Gly 2340 2345 2350 WO 96/15801 PCTIUS9515203 134 Cys Ser His Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro Lys Cys 2355 2360 2365 Asp Cys Ala Phe Gly Thr Leu Gln Ser Asp Gly Lys Asn Cys Ala Ile 2370 2375 2380 Ser Thr Glu Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu Arg Ser 2385 2390 2395 2400 Leu His Leu Asp Pro Glu Asn His Ser Pro Pro Phe Gln Thr Ile Asn 2405 2410 2415- Val Glu Arg Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp Arg 2420 2425 2430 Ile Tyr Phe Thr Gin Asn Leu Ala Ser Gly Val Gly Gin Ile Ser Tyr 2435 2440 2445 Ala Thr Leu Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser Gly 2450 2455 2460 Ile Gly Thr Ala Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg Arg Ile 2465 2470 2475 2480 Tyr Tyr Ser Asp Tyr Leu Asn Gin Met Ile Asn Ser Met Ala Glu Asp 2485 2490 2495 Gly Ser Asn Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg Ala Ile 2500 2505 2510 Val Leu Asp Pro Cys Gin Gly Tyr Leu Tyr Trp Ala Asp Trp Asp Thr 2515 2520 2525 His Ala Lys Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg Val Pro 2530 2535 2540 Ile Val Asn Ser Ser Leu Val Met Pro Ser Gly Leu Thr Leu Asp Tyr 2545 2550 2555 2560 Glu Glu Asp Leu Leu Tyr Trp Val Asp Ala Ser Leu Gin Arg Ile Glu 2565 2570 2575 Arg Ser Thr Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala Ala 2580 2585 2590 Val His Ala Phe Gly Leu Thr Leu Tyr Gly Gin Tyr Ile Tyr Trp Thr 2595 2600 2605 Asp Leu Tyr Thr Gin Arg Ile Tyr Arg Ala Asn Lys Tyr Asp Gly Ser 2610 2615 2620 Gly Gin Ile Ala Met Thr Thr Asn Leu Leu Ser Gin Pro Arg Gly Ile 2625 2630 2635 2640 Asn Thr Val Val Lys Asn Gin Lys Gin Gin Cys Asn Asn Pro Cys Glu 2645 2650 2655 Gin Phe Asn Gly Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn Gly 2660 2665 2670 Ala Glu Cys Gin Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn Asn 2675 2680 2685 WO 96/15801 PCT/US95/15203 /37 Arg Lys His Cys Ile Val Asp Asn Gly Glu Arg Cys Gly Ala Ser Ser 2690 2695 2700 Phe Thr Cys Ser Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys Cys Asp 2705 2710 2715 2720 Asn Asp Asn Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val Cys 2725 2730 2735 Ala Leu His Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly Arg 2740 2745 2750 Cys Val Gin Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly Asp 2755 2760 2765 Gly Ser Asp Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala Thr Thr 2770 2775 2780 Glu Phe Met Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile Cys 2785 2790 2795 2800 Asn Gly Val Asp Asn Cys His Asp Asn Asn Thr Ser Asp Glu Lys Asn 2805 2810 2815 Cys Pro Asp Arg Thr Cys Gin Ser Gly Tyr Thr Lys Cys His Asn Ser 2820 2825 2830 Asn Ile Cys Ile Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn Asp Cys 2835 2840 2845 Gly Asp Asn Ser Asp Glu Asn Pro Thr Tyr Cys Thr Thr His Thr Cys 2850 2855 2860 Ser Ser Ser Glu Phe Gin Cys Thr Ser Gly Arg Cys Ile Pro Gin His 2865 2870 2875 2880 Trp Tyr Cys Asp Gin Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu Pro 2885 2890 2895 Ala Ser Cys Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe Lys 2900 2905 2910 Cys Asp Gly Gly Arg Cys Ile Pro Ser Glu Trp Ile Cys Asp Gly Asp 2915 2920 2925 Asn Asp Cys Gly Asp Met Ser Asp Glu Asp Lys Arg His Gin Cys Gin 2930 2935 2940 Asn Gin Asn Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg Pro 2945 2950 2955 2960 Pro Asp Arg Arg Cys Ile Pro Gin Ser Trp Val Cys Asp Gly Asp Val 2965 2970 2975 Asp Cys Thr Asp Gly Tyr Asp Glu Asn Gin Asn Cys Thr Arg Arg Thr 2980 2985 2990 Cys Ser Glu Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro Lys 2995 3000 3005 Ile Phe Arg Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp Glu 3010 3015 3020 Arg Gly Cys Leu Tyr Gin Thr Cys Gin Gin Asn Gin Phe Thr Cys Gin WO 96/15801 PCT/US95/15203 )3( 3025 3030 3035 3040 Asn Gly Arg Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn Asp 3045 3050 3055 Cys Gly Asp Gly Ser Asp Glu Leu Met His Leu Cys His Thr Pro Glu 3060 3065 3070 Pro Thr Cys Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys Ile 3075 3080 3085 Glu Met Met Lys Leu Cys Asn His Leu Asp Asp Cys Leu Asp Asn Ser 3090 3095 3100 Asp Glu Lys Gly Cys Gly Ile Asn Glu Cys His Asp Pro Ser Ile Ser 3105 3110 3115 3120 Gly Cys Asp His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr Cys Ser 3125 3130 3135 Cys Arg Pro Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys Val Asp 3140 3145 3150 Ile Asp Glu Cys Thr Glu Met Pro Phe Val Cys Ser Gin Lys Cys Glu 3155 3160 3165 Asn Val Ile Gly Ser Tyr Ile Cys Lys Cys Ala Pro Gly Tyr Leu Arg 3170 3175 3180 Glu Pro Asp Gly Lys Thr Cys Arg Gin Asn Ser Asn Ile Glu Pro Tyr 3185 3190 3195 3200 Leu Ile Phe Ser Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile Asp Gly 3205 3210 3215 Tyr Phe Tyr Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala Leu 3220 3225 3230 Asp Phe Asp Arg Val Glu Lys Arg Leu Tyr Trp Ile Asp Thr Gin Arg 3235 3240 3245 Gin Val Ile Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu Thr Ile 3250 3255 3260 Ile Asn His Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp Val 3265 3270 3275 3280 Ser Arg Lys Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly Leu Phe Val 3285 3290 3295 Ser Asp Leu Asn Gly Gly His Arg Arg Met Leu Ala Gin His Cys Val 3300 3305 3310 Asp Ala Asn Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu Ala Leu 3315 3320 3325 His Pro Gin Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg Ala 3330 3335 3340 Tyr Ile Gly Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile Ile 3345 3350 3355 3360 Ser Thr Lys Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr Asn 3365 3370 3375 WO 96/15801 PCT/US95/15203 13q Asp Leu Leu Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr Ser 3380 3385 3390 Asp Leu Glu Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu Pro 3395 3400 3405 His Pro Phe Ala Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp Thr Asp 3410 3415 3420 Trp Asn Thr Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser Asn 3425 3430 3435 3440 Arg Gin Thr Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile His Val 3445 3450 3455 Tyr His Pro Tyr Arg Gin Pro Ile Val Ser Asn Pro Cys Gly Thr Asn 3460 3465 3470 Asn Gly Gly Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly Lys Gly 3475 3480 3485 Phe Thr Cys Glu Cys Pro Asp Asp Phe Arg Thr Leu Gin Leu Ser Gly 3490 3495 3500 Ser Thr Tyr Cys Met Pro Met Cys Ser Ser Thr Gin Phe Leu Cys Ala 3505 3510 3515 3520 Asn Asn Glu Lys Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly Gin Lys 3525 3530 3535 Asp Cys Ser Asp Gly Ser Asp Glu Leu Ala Leu Cys Pro Gin Arg Phe 3540 3545 3550 Cys Arg Leu Gly Gin Phe Gin Cys Ser Asp Gly Asn Cys Thr Ser Pro 3555 3560 3565 Gin Thr Leu Cys Asn Ala His Gin Asn Cys Pro Asp Gly Ser Asp Glu 3570 3575 3580 Asp Arg Leu Leu Cys Glu Asn His His Cys Asp Ser Asn Glu Trp Gin 3585 3590 3595 3600 Cys Ala Asn Lys Arg Cys Ile Pro Glu Ser Trp Gin Cys Asp Thr Phe 3605 3610 3615 Asn Asp Cys Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala Ser 3620 3625 3630 Arg Thr Cys Arg Pro Gly Gin Phe Arg Cys Ala Asn Gly Arg Cys Ile 3635 3640 3645 Pro Gin Ala Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His Ser 3650 3655 3660 Asp Glu Pro Ile Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp Asn 3665 3670 3675 3680 Phe Thr Glu Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys Trp 3685 3690 3695 Ala Val Cys Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu Gin 3700 3705 3710 WO 96/15801 PCTIUS95/15203 Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys Lys 3715 3720 3725 Asn His His Cys Ile Pro Leu Arg Trp Gin Cys Asp Gly Gin Asn Asp 3730 3735 3740 Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys Thr 3745 3750 3755 3760 Glu Ser Glu Phe Arg Cys Val Asn Gin Gin Cys Ile Pro Ser Arg Trp 3765 3770 3775 Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg Asp 3780 3785 3790 Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gin Cys Thr Ser Gly 3795 3800 3805 His Cys Val His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys Leu 3810 3815 3820 Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly Ala 3825 3830 3835 3840 Tyr Cys Gin Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile Pro 3845 3850 3855 Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser Asp 3860 3865 3870 Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn Arg 3875 3880 3885 Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys Asn 3890 3895 3900 Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His Cys 3905 3910 3915 3920 Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys Gly 3925 3930 3935 Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp Asp 3940 3945 3950 Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu Arg 3955 3960 3965 Thr Cys Ala Glu Asn Ile Cys Glu Gin Asn Cys Thr Gin Leu Asn Glu 3970 3975 3980 Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val Phe 3985 3990 3995 4000 Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gin Phe Gly Thr 4005 4010 4015 Cys Pro Gin His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys 4020 4025 4030 Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys Ala 4035 4040 4045 Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg Ile WO 96/15801 PCT/US95/15203 4050 4055 4060 Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gin Asp 4065 4070 4075 4080 Glu Glu Tyr Ile Gin Ala Val Asp Tyr Asp Trp Asp Pro Xaa Asp Ile 4085 4090 4095 Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg Phe 4100 4105 4110 Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg Asn 4115 4120 4125 Asn Leu Val Gin Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gin Pro 4130 4135 4140 Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser Asp 4145 4150 4155 4160 Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr Arg 4165 4170 4175 Lys Trp Leu Ile Ser Thr Asp Leu Asp Gin Pro Ala Ala Ile Ala Val 4180 4185 4190 Asn Pro Lys Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu Pro 4195 4200 4205 Lys Xaa Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu Val 4210 4215 4220 Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu Asn 4225 4230 4235 4240 Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu Thr 4245 4250 4255 Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala Met 4260 4265 4270 Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gin Leu Tyr Trp Ile Ser 4275 4280 4285 Lys Glu Lys Gly Glu Val Trp Lys Gin Asn Lys Phe Gly Gin Gly Lys 4290 4295 4300 Lys Glu Lys Thr Leu Val Val Asn Pro Trp Leu Thr Gin Val Arg Ile 4305 4310 4315 4320 Phe His Gin Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys Gin 4325 4330' 4335 Ile Cys Ser His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys Ala 4340 4345 4350 Cys Pro Gin Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys Asp 4355 4360 4365 Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys Met 4370 4375 4380 His Gly Gly Asn Cys Tyr Phe Asp Glu Thr.Asp Leu Pro Lys Cys Lys 4385 4390 4395 4400 WO 96/15801 PCT/US95/15203 Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser Lys 4405 4410 4415 Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile Leu 4420 4425 4430 Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His Tyr 4435 4440 4445 0 Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu 4450 4455 4460 Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe Arg 4465 4470 4475 4480 Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro 4485 4490 4495 Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met 4500 4505 4510 Glu Met Gly Lys Gin Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser Ala 4515 4520 4525 Arg Asp Ser Ala Val Lys Val Val Gin Pro Ile Gin Val Thr Val Ser 4530 4535 4540 Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu 4545 4550 4555 4560 Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gin 4565 4570 4575 Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gin Thr Thr Asn 4580 4585 4590 Phe Glu Asn Pro Ile Tyr Ala Gin Met Glu Asn Glu Gin Lys Glu Ser 4595 4600 4605 Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro Lys 4610 4615 4620 Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp 4625 4630 4635 4640 Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val 4645 4650 4655 INFORMATION FOR SEQ ID NO:87: SEQUENCE

CHARACTERISTICS:

LENGTH: 14080 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE:

NO

PCTJUS95/15203 WO 96/15801 f Y13 (vi) ORIGINAL

SOURCE:

ORGANISM: Homo sapiens TISSUE TYPE: Kidney (ix) FEATURE: NAME/KEY:

CDS

LOCATION: 105..14072 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87: GCAGACCTAA AGGAGCGTTC GCTAGCAGAG GCGCTGCCGG TGCGGTGTGC

TACGCGCGCC

CACCTCCCGG GGAAGGAACG GCGAGGCCGG GGACCGTCGC GGAG ATG GAT CGC GGG Met Asp Arg Gly 4660 CCG GCA GCA Pro Ala Ala GTG GCG TGC Val Ala Cys 4665 ACG CTG CTC CTG GCT Thr Leu Leu Leu Ala 4670 CTC GTC GCC Leu Val Ala TGC CTA Cys Leu 4675 164 GCG CCG GCC AGT GGC CAA GAA TGT Ala Pro Ala Ser Gly Gln Glu Cys 4680 GAC AGT Asp Ser 4685 GCG CAT TTT Ala His Phe CGC TGT GGA Arg Cys Gly 4690 AGT GGG CAT TGC Ser Gly His Cys 4695 TGT TCA GAT GAC Cys Ser Asp Asp 4710 ATC CCT GCA Ile Pro Ala GAC TGG Asp Trp 4700 AGG TGT GAT Arg Cys Asp GGG ACC AAA GAC Gly Thr Lys Asp 4705 260 308 GCG GAT Ala Asp GAA ATT Glu Ile 4715 GGC TGC GCT Gly Cys Ala GTT GTG Val Val 4720 ACC TGC CAG Thr Cys Gin CAG GGC Gin Gly 4725 TAT TTC AAG Tyr Phe Lys TGC CAG AGT Cys Gin Ser 4730 GAG GGA CAA TGC Glu Gly Gin Cys 4735 ATC CCC AGC Ile Pro Ser

TCC

Ser 4740 356 TGG GTG TGT GAC Trp Val Cys Asp CAA GAT CAA GAC TGT GAT GAT GGC TCA GAT Gin Asp Gin Asp Cys Asp Asp Gly Ser Asp 4745 4750 GAA CGT Glu Arg 4755 CAA GAT TGC TCA Gin Asp Cys Ser 4760 AAT GGT CAG TGT Asn Gly Gin Cys 4775 TGC CCC GAT GGA Cys Pro Asp Gly 4790 CAG CTT ACT TGT Gin Leu Thr Cys 4805 CAA AGT ACA TGC Gin Ser Thr Cys TCA AGT Ser Ser 4765 CAT CAG ATA His Gin Ile i ACA TGC TCC Thr Cys Ser 4770 GTC AGA GAC Val Arg Asp ATC CCA AGT Ile Pro Ser GCT GAT GAG Ala Asp Glu 479 GAA TAC Clu Tyr 4780 AAT GAC Asn Asp 5 AGG TGC GAC C Arg Cys Asp H 4 TGC CAG TAC Cys Gin Tyr 4800

AC

is L78E 'CA ACA TGT GAG ?ro Thr Cys Glu 548 596 GAC AAT GGG GCC TGC TAT AAC ACC AGT CAG AAG Asp Asn Gly Ala Cys Tyr Asn Thr Ser Gin Lys

TGT

Cys 4820 4810 4815 GAT TGG AAA GTT GAT TGC AGG GAC TCC TCA GAT GAA ATC AAC TGC ACT Asp Trp Lys Val Asp Cys Arg Asp Ser Ser Asp Clu Ile Asn Cys Thr 80As s 835 4825 toJv GAG ATA TGC TTG Glu Ile Cys Leu 4840 CAC AAT GAG TTT TCA TGT GGC AAT GGA His Asn Glu Phe Ser Cys Gly Asn Gly 4845 GAG TGT ATC Glu Cys Ile 4850 WO 96/15801 PCT/US95/15203 CCT CGT GCT TAT Pro Arg Ala Tyr 4855 GTC TGT GAC Val Cys Asp CAT GAC His Asp 4860 AAT GAT TGC CAA GAC GGC AGT Asn Asp Cys Gin Asp Gly Ser 4865 GAT GAA CAT Asp Glu His 4870 GCT TGC AAC Ala Cys Asn TAT CCG ACC TGC GGT Tyr Pro Thr Cys Gly 4875 GGT TAC Gly Tyr 4880 CAG TTC ACT Gin Phe Thr 740 788 836 TGC CCC Cys Pro 4885 AGT GGC CGA Ser Gly Arg TGC ATT TAT CAA AAC Cys Ile Tyr Gin Asn 4890 TGG GTT Trp Val 4895 TGT GAT GGA Cys Asp Gly

GAA

Glu 4900 GAT GAC TGT AAA Asp Asp Cys Lys GAT AAT Asp Asn 4905 GGA GAT GAA Gly Asp Glu GAT GGA Asp Gly 4910 TGT GAA AGC Cys Glu Ser GGT CCT Gly Pro 4915 884 CAT GAT GTT His Asp Val CAT AAA His Lys 4920 TGT TCC CCA Cys Ser Pro AGA GAA TGG Arg Glu Trp 4925 TCT TGC CCA GAG TCG Ser Cys Pro Glu Ser 4930 GGA CGA TGC ATC Gly Arg Cys Ile 4935 CCA GGA AGA GAA Pro Gly Arg Glu 4950 TCC ATT TAT Ser Ile Tyr GAT GAA AAC Asp Glu Asn 495!

AAA

Lys 4940

AAC

Asn 5 GTT TGT GAT GGG ATT TTA GAT TGC Val Cys Asp Gly Ile Leu Asp Cys 4945 ACT AGT ACC Thr Ser Thr GGA AAA Gly Lys 4960 TAC TGT AGT Tyr Cys Ser 980 1028 1076 ATG ACT CTG TGC TCT Met Thr Leu Cys Ser 4965 GCC TTG Ala Leu 4970 AAC TGC CAG Asn Cys Gin TAC CAG Tyr Gin 4975 TGC CAT GAG Cys His Glu

ACG

Thr 4980 CCG TAT GGA GGA GCG TGT TTT TGT CCC Pro Tyr Gly Gly Ala Cys Phe Cys Pro 4985 CCA GGT Pro Gly 4990 TAT ATC ATC Tyr Ile Ile AAC CAC Asn His 4995 1124 AAT GAC AGC Asn Asp Ser CGT ACC TGT GTT GAG Arg Thr Cys Val Glu 5000 TTT GAT GAT TGC CAG ATA TGG GGA Phe Asp Asp Cys Gin Ile Trp Gly 5005 5010 1172 ATT TGT GAC CAG Ile Cys Asp Gin 5015 AAG TGT GAA AGC CGA Lys Cys Glu Ser Arg 5020 CCT GGC CGT Pro Gly Arg CAC CTG TGC CAC His Leu Cys His 5025 TGT GAA GAA GGG TAT ATC Cys Glu Glu Gly Tyr Ile 5030 TTG GAG Leu Glu 5035 CGT GGA CAG Arg Gly Gin TAT TGC Tyr Cys 5040 AAA GCT AAT Lys Ala Asn GAT TCC Asp Ser 5045 TTT GGC GAG Phe Gly Glu GCC TCC Ala Ser 5050 ATT ATC TTC Ile Ile Phe TCC AAT GGT CGG GAT TTG Ser Asn Gly Arg Asp Leu 5055 5060 1220 1268 1316 1364 1412 TTA ATT GGT GAT Leu Ile Gly Asp ATT CAT GGA AGG AGC Ile His Gly Arg Ser 5065 TTC CGG ATC CTA GTG Phe Arg Ile Leu Val 5070 GAG TCT Glu Ser 5075 CAG AAT CGT GGA GTG GCC GTG GGT Gin Asn Arg Gly Val Ala Val Gly 5080 GTG GCT Val Ala 5085 TTC CAC TAT Phe His Tyr CAC CTG CAA His Leu Gin 5090 AGA GTT TTT Arg Val Phe 5095 TGG ACA GAC ACC rrp Thr Asp Thr

GTG

Val 5100 CAA AAT AAG GTT TTT TCA GTT GAC Gin Asn-Lys Val Phe Ser Val Asp 1460 5105 PCTUS95/15203 WO 96/15801 ATT AAT GGT Ile Asn Gly 5110 TTA AAT ATC Leu Asn Ile CAA GAG Gin Glu 5115 GTT CTC AAT GTT TCT Val Leu Asn Val Ser 5120 GTT GAA ACC Val Glu Thr CCA GAG AAC CTG GCT Pro Glu Asn Leu Ala 5125 GTG GAC Val Asp 5130 TGG GTT AAT Trp Val Asn AAT AAA Asn Lys 5135 ATC TAT CTA Ile Tyr Leu

GTG

Val 5140 GAA ACC AAG GTC Glu Thr Lys Val AAC CGC ATA GAT ATG Asn Arg Ile Asp Met 5145 GTA AAT Val Asn 5150 TTG GAT GGA Leu Asp Gly AGC TAT Ser Tyr 5155 CGG GTT ACC Arg Val Thr CTT ATA Leu Ile 5160 ACT GAA AAC Thr Glu Asn TTG GGG Leu Gly 5165 CAT CCT AGA His Pro Arg GGA ATT GCC Gly Ile Ala 5170 GTG GAC CCA ACT Val Asp Pro Thr 5175 GTT GGT TAT TTA TTT TTC TCA GAT Val Gly Tyr Leu Phe Phe Ser Asp 5180 TGG GAG AGC CTT Trp Glu Ser Leu 5185 TCT GGG GAA CCT AAG CTG Ser Gly Glu Pro Lys Leu 5190 GAA AGG GCA TTC ATG Glu Arg Ala Phe Met 5195 GAT GGC Asp Gly 5200 AGC AAC CGT Ser Asn Arg 1508 1556 1604 1652 1700 1748 1796 1844 1892 1940 1988 2036 AAA GAC TTG GTG AAA Lys Asp Leu Val Lys 5205 ACA AAG Thr Lys 5210 CTG GGA TGG Leu Gly Trp CCT GCT Pro Ala 5215 GGG GTA ACT Gly Val Thr

CTG

Leu 5220 GAT ATG ATA TCG Asp Met Ile Ser AAG CGT Lys Arg 5225 GTT TAC TGG Val Tyr Trp GTT GAC Val Asp 5230 TCT CGG TTT Ser Arg Phe GAT TAC Asp Tyr 5235 ATT GAA ACT Ile Glu Thr GTA ACT TAT Val Thr Tyr 5240 GAT GGA ATT CAA Asp Gly Ile Gin 5245 AGG AAG ACT Arg Lys Thr GTA GTT CAT Val Val His 5250 GGA GGC TCC CTC Gly Gly Ser Leu 5255 ATT CCT CAT Ile Pro His CCC TTT GGA GTA AGC Pro Phe Gly Val Ser 5260 TTA TTT GAA GGT Leu Phe Glu Gly 5265 CAG GTG TTC TTT ACA GAT Gin Val Phe Phe Thr Asp 5270 TGG ACA AAG Trp Thr Lys 5275 ATG GCC GTG CTG AAG GCA AAC Met Ala Val Leu Lys Ala Asn 5280 AAG TTC Lys Phe 5285 ACA GAG ACC Thr Glu Thr AAC CCA CAA GTG TAC TAC CAG GCT TCC CTG Asn Pro Gin Val Tyr Tyr Gin Ala Ser Leu 5290 5295

AGG

Arg 5300 CCC TAT GGA GTG Pro Tyr Gly Val ACT GTT TAC CAT TCC Thr Val Tyr His Ser 5305 CTC AGA Leu Arg 5310 CAG CCC TAT Gin Pro Tyr GCT ACC Ala Thr 5315 AAT CCG TGT Asn Pro Cys AAA GAT Lys Asp 5320 AAC AAT GGG Asn Asn Gly GGC TGT Gly Cys 5325 GAG CAG GTC Glu Gin Val TGT GTT CTC Cys Val Leu 5330 2084 2132 2180 2228 AGC CAC AGA Ser His Arg 5335 ACA GAT AAT GAT Thr Asp Asn Asp GGT TTG GGT Gly Leu Gly 5340 TTC CGT TGC Phe Arg Cys 5345 AAG TGC ACA Lys Cys Thr TTC GGC TTC CAA CTG GAT Phe Gly Phe Gin Leu Asp 5350 ACA GAT GAG CGC CAC Thr Asp Glu Arg His 5355 TGC ATT GCT GTT CAG Cys Ile Ala Val Gin 5360 PCT/US95/15203 WO 96/15801 AAT TTC Asn Phe 5365 CTC ATT TTT Leu Ile Phe TCA TCC Ser Ser 5370 CAA GTT GCT ATT CGT Gin Val Ala Ile Arg 5375 GGG ATC CCG TTC Gly Ile Pro Phe 5380 TCG GGG AAT CCT Ser Gly Asn Pro 5395 ACC TTG TCT ACC Thr Leu Ser Thr CAG GAA Gin Glu 5385 GAT GTC ATG Asp Val Met GTT.CCA

GTT

Val Pro Val 5390 TCT TTC TTT Ser Phe Phe GTC GGG Val Gly 5400 ATT GAT TTT Ile Asp Phe GAC GCC Asp Ala 5405 CAG GAC AGC Gin Asp Ser ACT ATC TTT Thr Ile Phe 5410 TTT TCA GAT ATG Phe Ser Asp Met 5415 TCA AAA CAC Ser Lys His ATG ATT Met Ile 5420 TTT AAG CAA Phe Lys Gin AAG ATT GAT GGC Lys Ile Asp Gly 5425 2276 2324 2372 2420 2468 2516 2564 ACA GGA AGA GAA ATT Thr Gly Arg Glu Ile 5430 CTC GCA GCT Leu Ala Ala 5435 AAC AGG GTG Asn Arg Val GAA AAT Glu Asn 5440 GTT GAA AGT Val Glu Ser TTG GCT Leu Ala 5445 TTT GAT TGG Phe Asp Trp ATT TCA Ile Ser 5450 AAG AAT CTC Lys Asn Leu TAT TGG Tyr Trp 5455 ACA GAC TCT Thr Asp Ser

CAT

His 5460 TAC AAG AGT ATC Tyr Lys Ser Ile AGT GTC ATG AGG CTA Ser Val Met Arg Leu 5465 GCT GAT AAA ACG AGA Ala Asp Lys Thr Arg 5470 CGC ACA Arg Thr 5475 GTA GTT CAG Val Val Gin TAT TTA Tyr Leu 5480 AAT AAC CCA Asn Asn Pro CGG TCG GTG Arg Ser Val 5485 GTA GTT CAT CCT TTT Val Val His Pro Phe 5490 2612 2660 GCC GGG TAT CTA Ala Gly Tyr Leu 5495 TTC TTC ACT Phe Phe Thr GAT TGG TTC Asp Trp Phe 5500 CGT CCT GCT AAA ATT ATG Arg Pro Ala Lys Ile Met 5505 CCT GTA ATA AAC ACT ACT Pro Val Ile Asn Thr Thr 5520 AGA GCA Arg Ala 5510 CTT GGA Leu Gly 5525 rGG AGT GAC GGA Trp Ser Asp Gly TCT CAC CTC TTG Ser His Leu Leu 5515 TGG CCC AAT Trp Pro Asn GGC TTG Gly Leu 5530 GCC ATC GAT Ala Ile Asp TGG GCT Trp Ala 5535 GCT TCA CGA Ala Ser Arg

TTG

Leu 5540 TAC TGG GTA GAT Tyr Trp Val Asp

GCC

Ala 5545 TAT TTT GAT AAA ATT GAG CAC AGC ACC Tyr Phe Asp Lys Ile Glu His Ser Thr TTT GAT Phe Asp 5555 5550 GGT TTA GAC Gly Leu Asp I TTT GGA CTT Phe Gly Leu 5575 CTG GGT GCC Leu Gly Ala 5590 HGA AGA Arg Arg 5560 AGA CTG GGC Arg Leu Gly CAT ATA His Ile 5565 GAG CAG ATG Glu Gin Met ACA CAT CCG Thr His Pro 5570 2708 2756 2804 2852 2900 2948 2996 GCC ATC TTT GGA Ala Ile Phe Gly ATT ATT CGA GTC Ile Ile Arg Val GAG CAT TTA TTT TTT Glu His Leu Phe Phe 5580 ACT GAC TGG AGA Thr Asp Trp Arg 5585 AGG AAA GCA Arg Lys Ala GAT GGT GGA GAA ATG ACA Asp Gly Gly Glu Met Thr 5600 5595 GTT ATC CGA AGT GGC Val Ile Arg Ser Gly 5605 ATT GCT TAC ATA Ile Ala Tyr Ile 5610 CTO CAT TTG AAA TCG TAT Leu His Leu Lys Ser Tyr 5615

GAT

Asp 5620 PCT/US95/15203 WO 96/15801 GTC AAC ATC CAG Val Asn Ile Gin ACT GGT Thr Gly 5625 TCT AAC GCC TGT AAT Ser Asn Ala Cys Asn 5630 CAA CCC ACG CAT CCT Gin Pro Thr His Pro 5635 CCA AAT TTC CAG CGA Pro Asn Phe Gin Arg 5650 3044 AAC GGT GAC Asn Gly Asp TGC AGC Cys Ser 5640 CAC TTC TGC His Phe Cys TTC CCG GTG Phe Pro Val 5645 GTG TGT Val Cys TGC GAG Cys Glu 567C GGG TGC Gly Cys 5655 CCT TAT GGA Pro Tyr Gly ATG AGG Met Arg 5660 CTG GCT TCC Leu Ala Ser AAT CAC TTG ACA Asn His Leu Thr 5665 GGG GAC CCA ACC Gly Asp Pro Thr AAT GAA Asn Glu 5675 CCA CCC ACG Pro Pro Thr GAG CAG TGT GGC TTA Glu Gin Cys Gly Leu 5680 TTT TCC TTC CCC TGT Phe Ser Phe Pro Cys 5685 AAA AAT GGC AGA TGT Lys Asn Gly Arg Cys 5690 GTG CCC Val Pro 5695 AAT TAC TAT Asn Tyr Tyr

CTC

Leu 5700 TGT GAT GGA GTC Cys Asp Gly Val GAT GAT Asp Asp 5705 TGT CAT GAT Cys His Asp AAC AGT Asn Ser 5710 GAT GAG CAA Asp Glu Gin CTA TGT Leu Cys 5715 GGC ACA CTT Gly Thr Leu AAT AAT Asn Asn 5720 ACC TGT TCA Thr Cys Ser TCT TCG Ser Ser 5725 GCG TTC ACC Ala Phe Thr TGT GGC CAT Cys Gly His 5730 GGG GAG TGC Gly Glu Cys 573E ATT CCT GCA CAC Ile Pro Ala His TGG CGC TGT GAC AAA Trp Arg Cys Asp Lys 5740 CGC AAC GAC TGT Arg Asn Asp Cys 5745 GCA CCT GCT TCC Ala Pro Ala Ser

AA

3092 3140 3188 3236 3284 3332 3380 3428 3476 3524 3572 3620 3668 3716 3764 GTG GAT Val Asp 5750 TGC CTT Cys Leu 5765 GGC AGT GAT GAG Gly Ser Asp Glu CAC AAC His Asn 5755 TGC CCC ACC Cys Pro Thr

CAC

His 5760 GAC ACC CAA Asp Thr Gin TAC ACC Tyr Thr 5770 TGT GAT AAT Cys Asp Asn CAC CAG His Gin 5775 TGT ATC TCA Cys Ile Ser

AAG

Lys 5780 AAC TGG GTC TGT Asn Trp Val Cys GAC ACA Asp Thr 5785 GAC AAT GAT Asp Asn Asp TGT GGG Cys Gly 5790 GAT GGA TCT Asp Gly Ser GAT GAA Asp Glu 5795 AAG AAC TGC Lys Asn Cys AAT TCG Asn Ser 5800 ACA GAG ACA Thr Glu Thr TGC CAA Cys Gin 5805 CCT AGT CAG Pro Ser Gin TTT AAT TGC Phe Asn Cys 5810 CCC AAT CAT CGA Pro Asn His Arg 5815 TGT ATT GAC Cys Ile Asp CTA TCG Leu Ser 5820 TTT GTC TGT Phe Val Cys GAT GGT GAC AAG Asp Gly Asp Lys 5825 GAT TGT Asp Cys 5830 GCT TCT Ala Ser 5845 GTT GAT GGA Val Asp Gly CAA TTC AAG Gin Phe Lys TCT GAT GAG GTT Ser Asp Glu Val 5835 TGT GCC AGT GGG Cys Ala Ser Gly 5850 GGT TGT GTA TTA AAC TGT ACT Gly Cys Val Leu Asn Cys Thr 5840 GAT AAA TGT ATT Asp Lys Cys Ile 5855 AGT GAC AAC TCG Ser Asp Asn Ser 5870 GGC GTC ACA Gly Val Thr 5860 GAT GAA GCG Asp Glu Ala 5875 AAT CGT TGT GAT GGT GTT TTT GAT TGC Asn Arg Cys Asp Gly Val Phe Asp Cys 5865 PCT/US95/15203 WO 96/15801 '/yb GGC TGT CCA Gly Cys Pro TGC CAA GAA Cys Gin Glu 5895 ACC AGG Thr Arg 5880 CCT CCT GGT ATG TGC Pro Pro Gly Met Cys 5885 CAC TCA GAT GAA TTT CAG His Ser Asp Glu Phe Gin 5890 GAT GGT ATC TGC Asp Gly Ile Cys ATC CCG Ile Pro 5900 AAC TTC TGG Asn Phe Trp GAA TGT GAT GGG Glu Cys Asp Gly 5905 3812 3860 3908 3956 CAT CCA GAC His Pro Asp 5910 TGC CTC TAT Cys Let Tyr GGA TCT Gly Ser 5915 GAT GAG CAC Asp Glu His AAT GCC Asn Ala 5920 TGT GTC CCC Cys Val Pro AAG ACT Lys Thr 5925 TGC CCT TCA Cys Pro Ser TCA TAT TTC CAC TGT GAC AAC Ser Tyr Phe His Cys Asp Asn 5930 5935 GGA AAC TGC Gly Asn Cys

ATC

Ile 5940 CAC AGG GCA TGG CTC TGT GAT CGG GAC His Arg Ala Trp Leu Cys Asp Arg Asp 5945 AAT GAC Asn Asp 5950 TGC GGG GAT Cys Gly Asp ATG AGT Met Ser 5955 4004 GAT GAG AAG Asp Glu Lys TGG CAG TGT Trp Gin Cys 5975 GAT GGC ATC Asp Gly Ile 5990 GAC TGC CCT ACT CAG Asp Cys Pro Thr Gin 5960

CCC

Pro 5965 TTT CGC TGT Phe Arg Cys GTG AAT CTG Val Asn Leu CCT AGT TGG CAA Pro Ser Trp Gin 5970 AGT GTA GTG TGT Ser Val Val Cys 5985 CTT GGC CAT AAC Leu Gly His Asn ATC TGT Ile Cys 5980 4052 4100 4148 4196 TTT GAC TGC Phe Asp Cys CCC AAT Pro Asn 5995 GGG ACA GAT Gly Thr Asp GAG TCC Glu Ser 6000 CCA CTT TGC Pro Leu Cys AAT GGG Asn Gly 6005 AAC AGC TGC Asn Ser Cys TCA GAT TTC AAT GGT Ser Asp Phe Asn Gly 6010 GGT TGT Gly Cys 6015 ACT CAC GAG Thr His Glu

TGT

Cys 6020 GTT CAA GAG CCC Val Gin Glu Pro TTT GGG GCT AAA TGC Phe Gly Ala Lys Cys 6025 CTA TGT Leu Cys 6030 CCA TTG GGA Pro Leu Gly TTC TTA Phe Leu 6035 CTT GCC AAT Leu Ala Asn

GAT

Asp 6040 TCT AAG ACC TGT GAA GAC ATA GAT GAA Ser Lys Thr Cys Glu Asp Ile Asp Glu TGT GAT ATT Cys Asp Ile 6050 6045 CTA GGC TCT TGT AGC CAG CAC Leu Gly Ser Cys Ser Gin His 6055 TGT TAC Cys Tyr 6060 AAT ATG AGA GGT TCT TTC CGG Asn Met Arg Gly Ser Phe Arg 6065 GAA AGT GAT GGG AGG ACT TGC Glu Ser Asp Gly Arg Thr Cys 6080 4244 4292 4340 4388 4436 TGC TCG Cys Ser 6070 TGT GAT ACA GGC Cys Asp Thr Gly TAC ATG TTA Tyr Met Leu 6075 AAA GTT Lys Val 6085 ACA GCA TCT GAG AGT CTG CTG TTA CTT GTG GCA AGT CAG Thr Ala Ser Glu Ser Leu Leu Leu Leu Val Ala Ser Gin

AAC

Asn 6100 6090 6095 AAA ATT ATT GCC Lys Ile Ile Ala GAC AGT GTC Asp Ser Val 6105 ACC TCC CAG GTC CAC AAT ATC Thr Ser Gin Val His Asn Ile 6110 TAT TCA Tyr Ser 6115 4484 TTG GTC GAG Leu Val Glu AAT GGT TCT TAC ATT Asn Gly Ser Tyr Ile 6120 GTA GCT GTT GAT TTT Val Ala Val Asp Phe 6125 GAT TCA ATT Asp Ser Ile 6130 4532 PCT/US95/15203 WO 96/15801 AGT GGT CGT ATC Ser Gly Arg Ile 6135 TTT TGG TCT Phe Trp Ser GAT GCA Asp Ala 6140 /19 ACT CAG GGT AAA ACC TGG AGT Thr Gin Gly Lys Thr Trp Ser 6145 GCG TTT CAA Ala Phe Gin 6150 AAT GGA ACG Asn Gly Thr GAC AGA AGA GTG GTA Asp Arg Arg Val Val 6155 TTT GAC Phe Asp 6160 AGT AGC ATC Ser Ser Ile 4580 4628 4676 ATC TTG ACT GAA ACT Ile Leu Thr Glu Thr 6165 ATT GCA ATA GAT TGG Ile Ala Ile Asp Trp 6170 GTA GGT Val Gly 6175 CGT AAT CTT Arg Asn Leu

TAC

Tyr 6180 TGG ACA GAC TAT Trp Thr Asp Tyr GCT CTG Ala Leu 6185 GAA ACA ATT Glu Thr Ile GAA GTC Glu Val 6190 TCC AAA ATT Ser Lys Ile GAT GGG Asp Gly 6195 4724 AGC CAC AGG 1 Ser His Arg CTA GCA TTA Leu Ala Leu 6215

ACT

Thr 620C GTG CTG ATT AGT Val Leu Ile Ser AAA AAC Lys Asn 6205 CTA ACA AAT Leu Thr Asn CCA AGA GGA Pro Arg Gly 6210 GAT CCC AGA ATG Asp Pro Arg Met AAT GAG Asn Glu 6220 CAT CTA CTG His Leu Leu TTC TGG TCT GAC Phe Trp Ser Asp 6225 4772 4820 4868 TGG GGC CAC CAC CCT CGC Trp Gly His His Pro Arg 6230 ATC GAG Ile Glu 6235 CGA GCC AGC Arg Ala Ser ATG GAC Met Asp 6240 GGC AGC ATG Gly Ser Met CGC ACT Arg Thr 6245 GTC ATT GTC Val Ile Val CAG GAC Gin Asp 6250 AAG ATC TTC Lys Ile Phe TGG CCC Trp Pro 6255 TGC GGC TTA Cys Gly Leu

ACT

Thr 6260 4916 ATT GAC TAC CCC Ile Asp Tyr Pro AAC AGA Asn Arg 6265 CTG CTC TAC Leu Leu Tyr TTC ATG GAC TCC TAT Phe Met Asp Ser Tyr 6270 CTT GAT Leu Asp 6275 4964 TAC ATG GAC T Tyr Met Asp I GCC AGT GAT Ala Ser Asp 6295 TTT TGC Phe Cys 6280 GAT TAT AAT Asp Tyr Asn GGA CAC Gly His 6285 CAT CGG AGA His Arg Arg TTG ATT ATA CGG Leu Ile Ile Arg CAC CCC TAT GCC CTA His Pro Tyr Ala Leu 6300

ACT

Thr 630 CAG GTG ATA Gin Val Ile 6290 CTC TTT GAA Leu Phe Glu ATG CGA GCC Met Arg Ala GAC TCT GTG Asp Ser Val 6310 AAC AAG TGG Asn Lys Trp 6325 TGG CCC CTT Trp Pro Leu GTG AAT CCA Val Asn Pro TAC TGG ACT GAC Tyr Trp Thr Asp 6315 CAT GGA GGG AAC His Gly Gly Asn 6330 GGG ATT GTT GCG Gly Ile Val Ala 6345 TGT GCC TTT TCC Cys Ala Phe Ser 6360 CGT GCT ACT CGT Arg Ala Thr Arg CGG GTT Arg Val 6320 5 5012 5060 5108 5156 5204 5252 CAG TCA GTT Gin Ser Val GTA ATG Val Met 6335 TAT AAT ATT Tyr Asn Ile

CAA

Gin 6340 GTT CAT CCT TCG Val His Pro Ser 6350 AAA CAA CCA Lys Gin Pro AAT TCC Asn Ser 6355 CGC TGC AGC CAT CTC Arg Cys Ser His Leu 6365 TGC CTG CTT TCC Cys Leu Leu Ser 6370 TCA GGA TGG AGT Ser Gly Trp Ser 6385 5300 TCA CAG GGG Ser Gin Gly 6375 CCT CAT TTT TAC TCC TGT GTT TGT CCT Pro His Phe Tyr Ser Cys Val Cys Pro 6380 PCT/US95/15203 WO 96/15801 CTG TCT CCT Leu Ser Pro 6390 GAT CTC CTG Asp Leu Leu AAT TGC Asn Cys 6395 TTG AGA GAT GAT CAA Leu Arg Asp Asp Gin 6400 CCT TTC TTA Pro Phe Leu 5348 ATA ACT Ile Thr 6405 GTA AGG CAA Val Arg Gin CAT ATA ATT TTT GGA His Ile Ile Phe Gly 6410 ATC TCC Ile Ser 6415 CTT AAT CCT Leu Asn Pro

GAG

Glu 6420 5396 GTG AAG AGC AAT GAT GCT ATG GTC CCC ATA GCA GGG ATA CAG Val Lys Ser Asn Asp Ala Met Val Pro Ile Ala Gly Ile Gin 6425 6430 AAT GGT Asn Gly 6435 5444 TTA GAT GTT GAA TTT GAT GAT GCT Leu Asp Val Glu Phe Asp Asp Ala 6440 GAG CAA Glu Gin 6445 TAC ATC TAT Tyr Ile Tyr TGG GTT GAA Trp Val Glu 6450 5492 AAT CCA GGT Asn Pro Gly 6455 GAA ATT CAC AGA Glu Ile His Arg GTG AAG ACA GAT GGC Val Lys Thr Asp Gly 6460 ACC AAC AGG ACA Thr Asn Arg Thr 6465 GTA TTT GCT TCT ATA TCT Val Phe Ala Ser Ile Ser 6470 ATG GTG Met Val 6475 GGG CCT TCT Gly Pro Ser ATG AAC CTG GCC Met Asn Leu Ala 6480

TTA

Leu

TCA

Ser 6500 GAT TGG ATT TCA AGA Asp Trp Ile Ser Arg 6485 AAC CTT TAT TCT ACC Asn Leu Tyr Ser Thr 6490 AAT CCT Asn Pro 6495 AGA ACT CAG Arg Thr Gin ATC GAG GTT TTG Ile Glu Val Leu ACA CTC Thr Leu 6505 CAC GGA GAT His Gly Asp ATC AGA TAC AGA AAA Ile Arg Tyr Arg Lys 6510 ACA TTG Thr Leu 6515 ATT GCC AAT GAT Ile Ala Asn Asp 652C ACT GTT GAT CCT Thr Val Asp Pro 6535 GAC AGT GGG GTT Asp Ser Gly Val 6550 GGG ACA GCT CTT Gly Thr Ala Leu GGA GTT Gly Val 6525 GGC TTT CCA Gly Phe Pro ATT GGC ATA Ile Gly Ile 6530 5540 5588 5636 5684 5732 5780 5828 5876 5924 3 GCT CGT GGG Ala Arg Gly AAG CTG TAC Lys Leu Tyr 6540 TGG TCA GAC CAA GGA ACT Trp Ser Asp Gin Gly Thr 6545 CCT GCC AAG ATC Pro Ala Lys Ile 6555 GCC AGT GCT Ala Ser Ala AAC ATG Asn Met 6560 GAT GGC ACA Asp Gly Thr TCT GTG AAA ACT CTC Ser Val Lys Thr Leu 6565 TTT ACT Phe Thr 6570 GGG AAC CTC Gly Asn Leu GAA CAC Glu His 6575 CTG GAG TGT Leu Glu Cys

GTC

Val 6580 ACT CTT GAC ATC Thr Leu Asp Ile GAA GAG Glu Glu 6585 CAG AAA CTC Gin Lys Leu TAC TGG GCA GTC ACT Tyr Trp Ala Val Thr 6590 GGA AGA Gly Arg 6595 GGA GTG ATT Gly Val Ile GAA AGA GGA AAC GTG Glu Arg Gly Asn Val 6600 GAT GGA ACA Asp Gly Thr 6605 GAT CGG ATG ATC CTG Asp Arg Met Ile Leu 6610 GTC CAT GAT TCT TTC Val His Asp Ser Phe 6625 5972 6020 6068 GTA CAC CAG CTT TCC CAC CCC TGG GGA ATT GCA Val His Gin Leu Ser His Pro Trp Gly Ile Ala 6615 662U CTT TAT TAT ACT GAT GAA Leu Tyr Tyr Thr Asp Glu 6630 CAG TAT GAG GTC Gin Tyr Glu Val 6635 ATT GAA AGA GTT GAT AAG Ile Glu Arg Val Asp Lys 6640 PCT/US95/15203 WO 96/15801 GCC ACT Ala Thr 6645 GGG GCC AAC Gly Ala Asn AAA ATA Lys Ile 6650 GTC TTG AGA GAT AAT Val Leu Arg Asp Asn 6655 GTT CCA AAT CTG Val Pro Asn Leu 6660 AGG GGT CTT CAA Arg Gly Leu Gin GTT TAT Val Tyr 6665 CAC AGA CGC His Arg Arg AAT GCC Asn Ala 6670 GCC GAA TCC Ala Glu Ser TCA AAT Ser Asn 6675 GGC TGT AGC Gly Cys Ser AAC AAC Asn Asn 6680 ATG AAT GCC Met Asn Ala TGT CAG Cys Gin 6685 CAG ATT TGC Gin Ile Cys CTG CCT GTA Leu Pro Val 6690 CCA GGA GGA TTG Pro Gly Gly Leu 6695 TTT TCC TGC Phe Ser Cys GCC TGT Ala Cys 6700 GCC ACT GGA Ala Thr Gly TTT AAA CTC AAT Phe Lys Leu Asn 6705 CCT GAT Pro Asp 6710 ATG CTG Met Leu 6725 AAT CGG TCC Asn Arg Ser TCT GCA ATC Ser Ala Ile TGC TCT CCA TAT Cys Ser Pro Tyr 6715 AGA GGC TTT AGC Arg Gly Phe Ser 6730 GTG GCA GGC CAA Val Ala Gly Gin 5 AAC TCT TTC Asn Ser Phe 6720 TTG GAA TTG Leu Glu Leu 6735 ATT GTT GTT TCA Ile Val Val Ser

TC

TCA GAT CAT Ser Asp His

TCA

Ser 6740 GAA ACC ATG GTG Glu Thr Met Val

CCG

Pro 674! GGA CGA Gly Arg 6750 AAC GCA CTG Asn Ala Leu CAT GTG His Val 6755 GAT GTG GAT Asp Val Asp GTG TCC Val Ser 6760 TCT GGC TTT Ser Gly Phe ATT TAT Ile Tyr 6765 TGG TGT GAT Trp Cys Asp TTT AGC AGC Phe Ser Ser 6770 6116 6164 6212 6260 6308 6356 6404 6452 6500 6548 6596 6644 6692 6740 6788 6836 TCA GTG GCA TCT Ser Val Ala Ser 6775 GAT AAT GCG Asp Asn Ala ATC CGT Ile Arg 6780 AGA ATT AAA C Arg Ile Lys ATA GGA GAA Ile Gly Glu 6800 CA GAT GGA TCT Pro Asp Gly Ser 6785 AAT GGA GTC CGG Asn Gly Val Arg TCT CTG ATG Ser Leu Met 6790 AAC ATT GTG Asn Ile Val ACA CAT GGA Thr His Gly 6795 GGT ATT GCA GTG GAT Gly Ile Ala Val Asp 6805 TGG GTA GCA Trp Val Ala 6810 GGA AAT CTT TAT TTC ACC AAT Gly Asn Leu Tyr Phe Thr Asn 6815

GCC

Ala 6820 TTT GTT TCT GAA Phe Val Ser Glu ACA CTG Thr Leu 6825 ATA GAA GTT Ile Glu Val CTG CGG ATC Leu Arg Ile 6830 AAT ACT ACT TAC Asn Thr Thr Tyr 6835 AGG CAT ATT GTT Arg His Ile Val 6850 CGC CGT GTT Arg Arg Val GTA GAT CCC Val Asp Pro 685! CTT CTT Leu Leu 6840 AAA GTC ACA GTG GAC ATG CCT Lys Val Thr Val Asp Met Pro 6845 AAG AAC AGA TAC Lys Asn Arg Tyr CTC TTC Leu Phe 6860 TGG GCT GAC TAT GGG CAG AGA Trp Ala Asp Tyr Gly Gin Arg 6865 CCA AAG ATT Pro Lys Ile 6870 GTG TCA GAG Val Ser Glu 6885 GAG CGT TCT 1 Glu Arg Ser

P

E

GGC ATT GTC Gly Ile Val 6890 'TC CTT 'he Leu ;875 GAC TGT ACC Asp Cys Thr AAT CGA ACA GTG CTT Asn Arg Thr Val Leu 6880 GCA GTG GAC CGA AGT Ala Val Asp Arg Ser 5 6900 ACA CCA CGG GGC Thr Pro Arg Gly

TTG

Leu 689 PCT/US95/15203 WO 96/15801 GAT GGC TAC GTT Asp Gly Tyr Val TAT TGG Tyr Trp 6905 GTT GAT GAT TCT TTA Val Asp Asp Ser Leu 6910 GAT ATA ATT Asp Ile Ile GCA AGG Ala Arg 6915 6884 6932 ATT CGT ATC Ile Arg Ile AAT GGA Asn Gly 6920 GAG AAC TCT Glu Asn Ser GAA GTG Glu Val 6925 ATT CGT TAT Ile Arg Tyr GGC AGT CGT Gly Ser Arg 6930 TAC CCA ACT CCT Tyr Pro Thr Pro 6935 TAT GGC ATC Tyr Gly Ile ACT GTT Thr Val 6940 TTT GAA AAT Phe Glu Asn TCT ATC Ser Ile 6945 ATA TGG Ile Trp 6980 GTA GAT AGG Val Asp Arg 6950 AAT TTG AAA Asn Leu Lys AAG ATC TTC CAA GCC Lys Ile Phe Gin Ala 6955 AGC AAG Ser Lys 6960 GAA CCA GAG Glu Pro Glu 7028 7076 AAC ACA Asn Thr 6965 GAG CCA CCC Glu Pro Pro ACA GTG Thr Val 6970 ATA AGA GAC Ile Arg Asp AAT ATC Asn Ile 6975 AAC TGG CTA Asn Trp Leu

AGA

Arg 6980 GAT GTG ACC ATC Asp Val Thr Ile TTT GAC AAG CAA Phe Asp Lys Gin 6985 CCT TGC TTG GAA Pro Cys Leu Glu GTC CAG CCC CGG TCA CCA Val Gin Pro Arg Ser Pro 6990 GCA GAG Ala Glu 6995 GTC AAC AAC Val Asn Asn

AAC

Asn 700C AAC AAT GGT GGG TGC Asn Asn Gly Gly Cys 7005 TCT CAT CTC Ser His Leu 7010 TGT GCC TTT Cys Ala Phe TGC TTT GCT Cys Phe Ala 701E CTG CCT GGA TTG Leu Pro Gly Leu CAC ACC CCA AAA TGT His Thr Pro Lys Cys 7020

GAC

Asp 7025 7124 7172 7220 7268 7316 GGG ACC Gly Thr 7030 TTC CTC Phe Leu 7045 TG CAA AGT GAT .eu Gin Ser Asp GGC AAG AAT TGT GCC Gly Lys Asn Cys Ala 7035 ATT TCA ACA GAA AAT Ile Ser Thr Glu Asn 7040 ATC TTT GCC Ile Phe Ala TTG TCT AAT TCC TTG Leu Ser Asn Ser Leu 7050 AGA AGC Arg Ser 7055 TTA CAC TTG Leu His Leu

GAC

Asp 7060 CCT GAA AAC CAT Pro Glu Asn His AGC CCA Ser Pro 7065 CCT TTC CAA Pro Phe Gin ACA ATA Thr Ile 7070 AAT GTG GAA Asn Val Glu AGA ACT Arg Thr 7075 GTC ATG TCT Val Met Ser CTA GAC TAT GAC AGT Leu Asp Tyr Asp Ser 7080 GTA AGT Val Ser 7085 GAT AGA ATC Asp Arg Ile TAC TTC ACA Tyr Phe Thr 7090 CAA AAT TTA Gin Asn Leu 709E GCC TCT GGA GTT Ala Ser Gly Val GGA CAG Gly Gin 7100 ATT TCC TAT Ile Ser Tyr GCC ACC CTG TCT Ala Thr Leu Ser 7105 7364 7412 7460 7508 7556 TCA GGG Ser Gly 7110 ATC CAT ACT CCA Ile His Thr Pro ACT GTC Thr Val 7115 ATT GCT TCA Ile Ala Ser GGT ATA Gly Ile 7120 GGG ACT GCT Gly Thr Ala GAT GGC ATT GCC TTT Asp Gly Ile Ala Phe 7125 GAC TGG ATT ACT AGA Asp Trp Ile Thr Arg 7130 AGA ATT Arg Ile 7135 TAT TAC AGT Tyr Tyr Ser

GAC

Asp 7140 TAC CTC AAC CAG Tyr Leu Asn Gin ATG ATT AAT TCC ATG Met Ile Asn Ser Met 7145 GCT GAA GAT GGG TCT Ala Glu Asp Gly Ser 7150 AAC CGC Asn Arg 7155 7604 PcT[US95/1 5203 WO 96/1580 1 ACT GTG ATA GCC CGC GTT CCA Thr Val Ile Ala Arg Val Pro 7160 I$-3 AAA CCA AGA GCA ATT Lys Pro Arg Ala Ile 7165 TGC CAA GGG TAC Cys Gin Cly Tyr 7175 CTG TAC TGG Leu Tyr Trp GCT CAC Ala Asp 7180 TGG GAT ACA Trp Asp Thr GTG ITA GAT CCC Val Leu Asp Pro 7170 CAT GCC AAA ATC His Ala Lys Ile 7185 ATT GTC AAC AGC Ile Val Asn Ser 0 GAG ACA CC Giu Arg Ala 7190 ACA'TTG CCA Thr Leu Ciy GCA AAC Gly Asn 7195 TTC CCC CTA Phe Arg Val

CCC

Pro 720 ACT CTC Ser Leu 7205 GTC ATC CCC Val Met Pro ACT CCC Ser Cly 7210 CTC ACT CTC Leu Thr Leu CAC TAT CAA Asp Tyr Ciu 7215 GAG CAC Clu Asp Leu 7220 CTC TAC TCC CTG Leu Tyr Trp Val CAT CCT ACT CTC CAC Asp Ala Ser Leu Gin 7225 ACC ATT CAA CCC AC Arg Ile Giu Arg Ser 7230 ACT CTC Thr Leu 7235 ACG CCC CTG Thr Cly Val CAT CCT CAA Asp Arg Giu 7240 GTC ATT GTC Val Ile Val 7245 AAT CCA CC Asn Ala Ala GTT CAT CCT TTT Val His Ala Phe 7250 CAC TTC TAC ACA Asp Leu Tyr Thr 7265 CCC TTC ACT CTC Cly Leu Thr Leu 7255 TAT CCC CAG Tyr Cly Gin TAT ATT TAC TGG ACT Tyr Ile Tyr Trp Thr 7260 CAA ACA ATT Gin Arg Ile 7270 TAC CCA CCT Tyr Arg Ala AAC AAA Asn Lys 7275 TAT CAC CCC Tyr Asp Cly TCA CGT Ser Cly 7280 CAC ATT CCA Gin Ile Ala 7652 7700 7748 7796 7844 7892 7940 7988 8036 8084 8132 8180 8228 8276 8324 8372 ATG ACC ACA AAT TTG Met Thr Thr Asn Leu 7285 CTC TCC CAC CCC ACC Leu Ser Gin Pro Arg 7290 CCA ATC Ciy Ile 7295 AAC ACT GTT CTC Asn Thr Val Val 7300 AAC AAC CAC AAA Lys Asn Gin Lys CAA CAC Gin Gin 7305 TGT AAC AAT Cys Asn Asn CCA CCA CCT Ala Pro Cly 732E

CCT

Pro 7310 TCT CAA CAC TTT Cys Ciu Gin Phe AAT CCC Asn Cly 7315 CCC TCC AC Cly Cys Ser CAT ATC TGT His Ilie Cys 7320 CCA AAT GGT Pro Asn Gly CCC AAC AAC Ala Asn Asn TGT CCA CAT GAG Cys Pro His Giu 7335 CCC AAC TCC Cly Asn Trp TAT TTC Tyr Leu 7340 CCC GAG TGC CAG Ala Clu Cys Gin 7330 ACC AAG CAC TC Arg Lys His Cys 7345 TTC. ACC TGC TCC Phe Thr Cys Ser AAT CAC AAC GAC Asn Asp Asn Asp 738 ATT CTC Ilie Val 7350 AAT CCC Asn Cly 7365 3AC AAT GGT GAA ksp Asn Cly Ciu CCA TGT Arg Cys 7355 CGT CCA TCT Cly Ala Ser

TCC

Ser 7360 CCC TCC ATC Arg Cys Ilie TCC GAA GAG TGG AAG Ser Glu Glu Trp Lys 7370 TGT CAT Cys Asp 7375 ~0 TGT CCC CAT GC Cys Cly Asp Cly ACT CAT GAG ATG CAA Ser Asp Clu Met Ciu 7385 ACT CTC TGT CCA CTT Ser Val Cys Ala Leu 7390 CAC ACC His Thr 7395 TCC TCA CCC Cys Ser Pro ACA CCC TTC ACC TGT Thr Ala Phe Thr Cys 7400 CCC AAT Ala Asn 7405 CCC CCA TCT Gly Arg Cys CTC CAA TAC Val Gin Tyr 7410 PCT/US95/15203 WO 96/15801 TCT TAC CGC Ser Tyr Arg 7415 TGT GAT TAC TAC Cys Asp Tyr Tyr AAT GAC Asn Asp 7420 TGT GGT GAT GGC AGT GAT GAG Cys Gly Asp Gly Ser Asp Glu 7425 8420 GCA GGG TGC Ala Gly Cys 7430 CTG TTC AGG Leu Phe Arg GAC TGC Asp Cys 7435 AAT GCC ACC Asn Ala Thr ACG GAG Thr Glu 7440 TTT ATG TGC Phe Met Cys AAT AAC Asn Asn 7445 AGA AGG TGC Arg Arg Cys ATA CCT Ile Pro 7450 CGT GAG TTT Arg Glu Phe ATC TGC Ile Cys 7455 AAT GGT GTA Asn Gly Val

GAC

Asp 7460 AAC TGC CAT GAT AAT AAC ACT TCA GAT Asn Cys His Asp Asn Asn Thr Ser Asp 7465 GAG AAA AAT TGC CCT Glu Lys Asn Cys Pro 7470 GAT CGC Asp Arg 7475 ACT TGC CAG Thr Cys Gin CCT CGC GTT Pro Arg Val 7495 GAT GAA AAC Asp Glu Asn 7510 TCT GGA Ser Gly 7480 TAC ACA AAA Tyr Thr Lys TGT CAT Cys His 7485 AAT TCA AAT Asn Ser Asn TAT TTG TGT GAC Tyr Leu Cys Asp GGA GAC AAT GAC TGT Gly Asp Asn Asp Cys 7500

GGA

Gly 7505 ATT TGT ATT Ile Cys Ile 7490 GAT AAC AGT Asp Asn Ser AGC AGT GAG Ser Ser Glu 8468 8516 8564 8612 8660 8708 8756 8804 8852 8900 CCT ACT TAT Pro Thr Tyr TGC ACC Cys Thr 7515 ACT CAC ACA Thr His Thr TGC AGC Cys Ser 7520 TTC CAA Phe Gin 7525 TGC GCA TCT Cys Ala Ser GGG CGC Gly Arg 7530 TGT ATT CCT Cys Ile Pro CAA CAT Gin His 7535 TGG TAT TGT Trp Tyr Cys

GAT

Asp 7540 CAA GAA ACA GAT Gin Glu Thr Asp TGT TTT Cys Phe 7545 GAT GCC TCT Asp Ala Ser GAT GAA CCT GCC TCT Asp Glu Pro Ala Ser 7550 TGT GGT Cys Gly 7555 CAC TCT GAG His Ser Glu CGA ACA TGC CTA GCT Arg Thr Cys Leu Ala 7560 GAT GAG TTC Asp Glu Phe 7565 AAG TGT GAT GGT GGG Lys Cys Asp Gly Gly 7570 AGG TGC ATC CCA Arg Cys Ile Pro 7575 AGC GAA TGG Ser Glu Trp ATC TGT Ile Cys 7580 GAC GGT GAT Asp Gly Asp AAT GAC TGT GGG Asn Asp Cys Gly 7585 GAT ATG AGT Asp Met Ser 7590 GAC GAG GAT Asp Glu Asp AAA AGG Lys Arg 7595 CAC CAG TGT His Gin Cys CAG AAT CAA AAC TGC Gin Asn Gin Asn Cys 7600 TCG GAT TCC Ser Asp Ser 7605 TGC ATT CCC Cys Ile Pro GAG TTT CTC TGT GTA Glu Phe Leu Cys Val 7610 AAT GAC AGA CCT CCG Asn Asp Arg Pro Pro 7615 GAC AGG AGG Asp Arg*Arg 7620 TCT TGG GTC TGT GAT Ser Trp Val Cys Asp 7625 GGC GAT Gly Asp 7630 GTG GAT TGT Val Asp Cys ACT GAC Thr Asp 7635 8948 8996 9044 9092 9140 GGC TAC GAT Gly Tyr Asp

GAG

Glu 7640 AAT CAG AAT TGC ACC AGG AGA ACT TGC Asn Gin Asn Cys Thr Arg Arg Thr Cys TCT GAA AAT Ser Glu Asn 7650

I

7645 GAA TTC ACC TGT GGT TAC Glu Phe Thr Cys Gly Tyr 7655 GGA CTG TGT ATC CCA AAG ATA TTC AGG TGT Gly Leu Cys Ile Pro Lys Ile Phe Arg Cys 7660 7665 PCTUS95/1520 3 WO 96/15801 GAC CGG CAC Asp Arg His 7670 AAT GAC TGT Asn Asp Cys GGT GAC Gly Asp 7675 TAT AGC GAC GAG AGG Tyr Ser Asp Glu Arg 7680 GGC TGC TTA Gly Cys Leu TAC CAG Tyr Gin 7685 ACT TGC CAA Thr Cys Gin

CAG

Gin 769( AAT CAG TTT ACC TGT CAG AAC GGG CGC Asn Gin Phe Thr Cys Gin Asn Gly Arg

TGC

Cys 7700 0 7b5 ATT AGT AAA ACC Ile Ser Lys Thr TTC GTC Phe Val 7705 TGT GAT GAG Cys Asp Glu GAT AAT Asp Asn 7710 GAC TGT GGA Asp Cys Gly GAC GGA Asp Gly 7715 TCT GAT GAG Ser Asp Glu CCT CAC GAG Pro His Glu on 773! CTG ATG Leu Met 7720 CAC CTG TGC His Leu Cys CAC ACC His Thr 7725 CCA GAA CCC Pro Glu Pro ACG TGT CCA Thr Cys Pro 7730 TTC AAG TGT GAC Phe Lys Cys Asp AAT GGG CGC Asn Gly Arg 7740 TGC ATC GAG ATG ATG AAA Cys Ile Glu Met Met Lys 7745 CTC TGC AAC CAC CTA GAT Leu Cys Asn His Leu Asp 7750 GAC TGT Asp Cys 7755 TTG GAC AAC Leu Asp Asn AGC G Ser 7760 TGT GGC ATT AAT GAA Cys Gly Ile Asn Glu 7765 TGC CAT Cys His 7770 GAC CCT TCA Asp Pro Ser ATC AGT Ile Ser 7775 GAT GAG AAA GGC Asp Glu Lys Gly GGC TGC GAT CAC Gly Cys Asp His 7780 TGT CGT CCT GGT Cys Arg Pro Gly 7795 AAC TGC ACA GAC Asn Cys Thr Asp ACC TTA ACC AGT TTC Thr Leu Thr Ser Phe 7785 TAT TGT TCC Tyr Cys Ser 7790 9188 9236 9284 9332 9380 9428 9476 9524 9572 9620 9668 9716 9764 9812 9860 9908 TAC AAG CTC Tyr Lys Leu

ATG

Met 7800 TCT GAC AAG CGG Ser Asp Lys Arg TTT GTC TGT AGC Phe Val Cys.Ser 782( ACT TGT Thr Cys 7805 GTT GAT ATT Val Asp Ile GAT GAA TGC Asp Glu Cys 7810 ACA GAG ATG CCT Thr Glu Met Pro 7815 CAG AAG TGT GAG Gin Lys Cys Glu AAT GTA ATA GGC Asn Val Ile Gly 7825 TCC TAC ATC Ser Tyr Ile 7830 TGT AAG TGT Cys Lys Cys GCC CCA GGC TAC CTC Ala Pro Gly Tyr Leu 7835 CGA GAA Arg Glu 7840 CCA GAT GGA Pro Asp Gly AAG ACC TGC CGG CAA Lys Thr Cys Arg Gin 7845 AAC AGT AAC ATC GAA Asn Ser Asn Ile Glu 7850 CCC TAT Pro Tyr 7855 CTC ATT TTT Leu Ile Phe

AGC

Ser 7860 AAC CGT TAC TAT Asn Arg Tyr Tyr TTG AGA Leu Arg 7865 AAT TTA ACT Asn Leu Thr ATA GAT Ile Asp 7870 GGC TAT TTT Gly Tyr Phe TAC TCC Tyr Ser 7875 CTC ATC Leu Ile GTA GAG Val Glu

TTG

Leu GAA GGA CTG Glu Gly Leu 7880 GAC AAT GTT GTG GCA Asp Asn Val Val Ala 7885 TTA GAT TTT GAC CGA Leu Asp Phe Asp Arg 7890 AAG AGA TTG TAT TGG ATT GAT ACA CAG AGG CAA GTC ATT

GAG

Lys Arg Leu Tyr Trp Ile Asp Thr Gln Arg Gln Val Ile Glu 7895 Arg Leu7900 7905 7895 TTT CTG AAT AAG ACA AAC AAG GAG ACA ATC ATA AAC CAC AGA Phe Leu Asn Lys Thr Asn Lys Glu Thr Ile Ile Asn His Arg 7915 7920 0 AGA ATG Arg Met 791 PCTIUS95/15203 WO 96/15801 CTA CCA Leu Pro 7925 GCT GCA GAA Ala Ala Glu AGT CTG Ser Leu 7930 /s q GCT GTA GAC TGG C Ala Val Asp Trp 7935 GAT GGC CTC TTT Asp Gly Leu Phe 7950 ;TT TCC Val Ser GTC TCT Val Ser TAC TGG TTG GAT Tyr Trp Leu Asp GCC CGC CTG Ala Arg Leu 7945 CGC ATG CTG Arg Met'Leu 3

GCC

Ala GGT GGA CAC Gly Gly His ACC TTC TGC Thr Phe Cys 797!

CGC

Arg 796( CAG CAC Gln His 7965 TGT GTG GAT Cys Val Asp AGA AAG CTC Arg Lys Leu 7940 GAC CTC AAT Asp Leu Asn 7955 GCC AAC AAC Ala Asn Asn 7970 CCT CAA TAT Pro Gin Tyr ATT GGG AGA Ile Gly Arg TTT GAT AAT CCC Phe Asp Asn Pro AGA GGA Arg Gly 7980 CTT GCC CTT Leu Ala Leu

CAC

His 798E 9956 10004 10052 10100 10148 10196 10244 10292 GGG TAC CTC TAC TGG GCA Gly Tyr Leu Tyr Trp Ala 7990 GAC TGG GGT Asp Trp Gly 7995 CAC CGC GCA TAC His Arg Ala Tyr 8000 GTA GGC ATG GAT Val Gly Met Asp 8005 GAG TGG CCT AAT Glu Trp Pro Asn GGA ACC AAC AAG TCT GTG Gly Thr Asn Lys Ser Val 8010 ATA ATC Ile Ile 8015 TCC ACC AAG Ser Thr Lys

TTA

Leu 8020 GGC ATC ACC ATT GAT Gly Ile Thr Ile Asp 8025 TAC ACC AAT GAT CTA Tyr Thr Asn Asp Leu 8030 CTC TAC Leu Tyr 8035 TGG GCA GAT Trp Ala Asp GCC CAC CTG GGT TAC Ala His Leu Gly Tyr 8040 ATA GAG Ile Glu 8045 TAC TCT GAT TTG GAG GGC Tyr Ser Asp Leu Glu Gly 8050 CAC CAT CGA His His Arg 805E CAC ACG GTG TAT His Thr Val Tyr GAT GGG GCA CTG CCT Asp Gly Ala Leu Pro 8060 CAC CCT TTC GCT His Pro Phe Ala 8065 ATT ACC ATT TTT GAA GAC Ile Thr Ile Phe Glu Asp 8070 ACT ATT TAT Thr Ile Tyr 8075 TGG ACA GAT TGG AAT ACA AGG Trp Thr Asp Trp Asn Thr Arg 8080 ACA GTG GAA AAG GGA Thr Val Glu Lys Gly 8085 AAC AAA TAT Asn Lys Tyr 8090 GAT GGA TCA AAT Asp Gly Ser Asn 8095 AGA CAG ACA Arg Gin Thr

CTG

Leu 8100 GTG AAC ACA ACA Val Asn Thr Thr CAC AGA His Arg 8105 CCA TTT GAC ATC CAT GTG Pro Phe Asp Ile His Val 8110 TAC CAT CCA TAT Tyr His Pro Tyr 8115 10340 10388 10436 10484 10532 10580 10628 10676 AGG CAG CCC SArg Gn Pro TCT CAT CTC Ser His Leu 8131 ATT GTG Ile Val 8120 AGC AAT CCC Ser Asn Pro TGT GGT Cys Gly 8125 ACC AAC AAT Thr Asn Asn GGT GGC TGT Gly Gly Cys 8130 TGC CTC ATC AAG Cys Leu Ile Lys CCA GGA Pro Gly 8140 GGA AAA GGG Gly Lys Gly TTC ACT TGC GAG Phe Thr Cys Glu 8145 TGT CCA GAT GAC TTC CGC Cys Pro Asp Asp Phe Arg 8150 ACC CTT CAA Thr Leu Gin 8155 CTG AGT GGC AGC ACC TAC TGC Leu Ser Gly Ser Thr Tyr Cys 8160

ATG

Met 8165 CCC ATG TGC TCC AGC ACC CAG TTC CTG Pro Met Cys Ser Ser Thr Gin Phe Leu TGC GCT AAC AAT Cys Ala Asn Asn 8175 GAA AAG Glu Lys 8180

I

8170 PCTUS95/15203 WO 96/15801 TGC ATT CCT Cys Ile Pro GGC TCT GAT Gly Ser Asp ATC TGG TGG Ile Trp Trp 8185 AAA TGT GAT GGA CAG Lys Cys Asp Gly Gin 8190 AAA GAC TGC TCA GAT Lys Asp Cys Ser Asp 8195 CAA CTG Glu Leu 8200 GCC CTT TGC Ala Leu Cys CCG CAG Pro Gin 8205 CGC TTC TGC Arg Phe Cys CGA CTC GGA Arg Leu Gly 8210 CAG TTC CAG TGC Gin Phe Gin Cys 8215 AGT GAC GGC Ser Asp Gly AAC TGC Asn Cys 8220 ACC AGC CCG Thr Ser Pro CAG ACT TTA TGC Gin Thr Leu Cys 8225 CAC CCT CTT CTT Asp Arg Leu Leu 10724 10772 10820 10868 10916 AAT CCT CAC Asn Ala His 8230 CAA AAT TGC Gin Asn Cys CCT CAT Pro Asp 8235 GGG TCT CAT Gly Ser Asp

GAA

Glu 8240 TGT GAG AAT CAC CAC Cys Glu Asn His His 8245 TGT CAC TCC AAT CAA Cys Asp Ser Asn Glu 8250 TGG CAC Trp Gin 8255 TGC CCC AAC Cys Aia Asn

AAA

Lys 8260 CGT TCC ATC CCA Arg Cys Ile Pro GAA TCC Glu Ser 8265 TGG CAC TGT Trp Gin Cys GAC ACA Asp Thr 8270 TTT AAC CAC Phe Asn Asp TGT GAG Cys Glu 8275 CAT AAC TCA Asp Asn Ser CAT CAA CAC ACT TCC Asp Glu Asp Ser Ser 8280

CAC

His 828E TGT CCC AGC Cys Aia Ser 5 AGG ACC TGC CGG Arg Thr Cys Arg 8290 CCC CAG CCC TGG Pro Gin Ala Trp 8305 CCC GGC CAC Pro Giy Gin 8295 TTT CGG TCT CCT Phe Arg Cys Ala AAT GGC CCC TGC ATC Asn Gly Arg Cys Ile 8300 10964 11012 11060 11108 11156 AAG TGT Lys Cys 8310 GAA CAA Glu Glu 8325 SAT GTG GAT AAT Asp Val Asp Asn CAT TGT Asp Cys 8315 GGA CAC CAC Cly Asp His TCG CAT Ser Asp 8320 GAG CCC ATT Glu Pro Ile TGC ATC AGC Cys Met Ser TCT GCC Ser Ala 8330 CAT CTC TGT His Leu Cys CAC AAC Asp Asn 8335 TTC ACA GAA Phe Thr Glu

TTC

Phe 8340 AGC TGC AAA ACA Ser Cys Lys Thr AAT TAC Asn Tyr 8345 CGC TCC ATC Arg Cys Ile CCA AAC Pro Lys 8350 TGG CCC CTG Trp Ala Val TGC AAT Cys Asn 8355 11204 11252 GGT CTA CAT Cly Val Asp CAC TGC Asp Cys 8360 AGC GAC AAC AGT Arg Asp Asn Ser 8365 CAT GAG CAA GGC Asp Glu Gin Gly TGT GAG GAG Cys Glu Glu 8370 ACG ACA TCC CAT Arg Thr Cys His 8375 CCT GTG GGG Pro Val Cly CAT TTC Asp Phe 8380 CGC TGT AAA Arg Cys Lys AAT CAC CAC TGC Asn His His Cys 8385 TGT GGA CAT AAC Cys Cly Asp Asn ATC CCT CTT Ile Pro Leu 8390 CGT TGG CAG Arg Trp Gin TGT CAT GGG CAA AAT Cys Asp Cly Gin Asn 8395

CAC

Asp 8400 11300 11348 11396 11444

TCA

Ser 8405 CAT GAG GAA AAC TCT CCT CCC CGG GAG Asp Giu Giu Asn Cys Ala Pro Arg Glu TGC ACA GAG Cys Thr Clu 8415 AGC GAG TTT Ser Glu Phe 8420 j 8410 CGA TCT GTC AAT Ara Cys Val Asn CAG CAG TGC ATT CCC Gin Gin Cys Ile Pro 8425 TCG CGA TGG ATC TGT Ser Arg Trp Ile Cys 8430 GAC CAT Asp His 8435 PCTIUS95/15203 WO 96/15801 TAC AAC GAC Tyr Asn Asp TGT GGG Cys Gly 8440 GAC AAC TCA Asp Asn Ser ACC TGC CAT CCT Thr Cys His Pro 8455 GAA TAT TTT Glu Tyr Phe

CAG

Gin 8461 /S7 GAT GAA CGG GAC Asp Glu Arg Asp 8445 TGT ACA AGT GGA Cys Thr Ser Gly

D

GCT GAC TGT TTG Ala Asp Cys Leu TGT GAG ATG AGG Cys Glu Met Arg 8450 CAT TGT GTA CAC His Cys Val His 8465 AGT GAA CTG Ser Glu Leu 8470 AAA TGC GAT Lys Cys Asp GGA TCC Gly Ser 8475 GAT GCG Asp Ala 0 TCT GAT Ser Asp 848 GAA GCT Glu Ala 8485 GAT TGT CCC Asp Cys Pro ACA CGC TTT CCT GAT Thr Arg Phe Pro Asp 8490 GGT GCA Gly Ala 8495 TAC TGC CAG Tyr Cys Gin

GCT

Ala 8500 ACT ATG TTC GAA Thr Met Phe Glu TGC AAA AAC CAT GTT Cys Lys Asn His Val 8505 TGT ATC Cys Ile 8510 CCG CCA TAT Pro Pro Tyr TGG AAA Trp Lys 8515 TGT GAT GGC C Cys Asp Gly I CTG TGC TTG Leu Cys Leu i 8535

AT

Asp 3520 GAT GAC TGT GGC Asp Asp Cys Gly GAT GGT Asp Gly 8525 TCA GAT GAA Ser Asp Glu GAA CTT CAC Glu Leu His 8530 GAT GTT CCC TGT Asp Val Pro Cys AAT TCA CCA AAC CGT Asn Ser Pro Asn Arg 8540 TTC CGG TGT GAC Phe Arg Cys Asp 8545 AAC AAT Asn Asn 8550 TGT GGA Cys Gly 8565 :GC TGC ATT TAT Arg Cys Ile Tyr AGT CAT Ser His 8555 GAG GTG TGC Glu Val Cys AAT GGT Asn Gly 8560 GTG GAT GAC Val Asp Asp 11492 11540 11588 11636 11684 11732 11780 11828 11876 11924 11972 12020 12068 12116 12164 12212 GAT GGA ACT Asp Gly Thr GAT GAG Asp Glu 8570 ACA GAG GAG Thr Glu Glu CAC TGT His Cys 8575 AGA AAA CCG Arg Lys Pro

ACC

Thr 8580 CCT AAA CCT Pro Lys Pro ATT CCA CAT Ile Pro His TCC GAT GAA Ser Asp Glu 8611 TGT ACA GAA TAT Cys Thr Glu Tyr 8585 GAC AAT GTG TGT Asp Asn Val Cys 8600 CTG GGT TGC AAT Leu Gly Cys Asn 5 GAG CAA AAT TGT Glu Gin Asn Cys GAA TAT Glu Tyr AAG TGT Lys Cys 8590 GGC AAT GGG Gly Asn Gly CAT TGC His Cys 8595 GAT GAT GCC GAT GAC Asp Asp Ala Asp Asp 8605 AAA GGA AAA GAA AGA Lys Gly Lys Glu Arg 8620 TGT GGT GAC TGG Cys Gly Asp Trp 8610 ACA TGT GCT GAA Thr Cys Ala Glu 8625 AAT ATA TGC Asn Ile Cys 8630 ACC CAA TTA AAT GAA GGA GGA TTT ATC Thr Gin Leu Asn Glu Gly Gly Phe Ile 8640 8635 TGC TCC TGT ACA GCT Cys Ser Cys Thr Ala 8645

GGG

Gly 865C TTC GAA ACC AAT GTT TTT GAC AGA ACC Phe Glu Thr Asn Val Phe Asp Arg Thr

TCC

Ser 8660 8655 TGT CTA GAT ATC Cys Leu Asp Ile AAT GAA Asn Glu 8665 TGT GAA CAA TTT GGG ACT TGT CCC Cys Glu Gin Phe Gly Thr Cys Pro 8670 CAG CAC Gin His 8675 TGC AGA AAT ACC AAA GGA AGT TAT Cys Arg Asn Thr Lys Gly Ser Tyr 8680 GAG TGT GTC TGT Glu Cys Val Cys 8685 GCT GAT GGC TTC Ala Asp Gly Phe 8690 PCTUS95/15203 WO 96/15801 ACG TCT ATG AGT Thr Ser Met Ser 8695 GAC CGC CCT GGA AAA Asp Arg Pro Gly Lys 8700 CGA TGT GCA GCT GAG GGT AGC Arg Cys Ala Ala Glu Gly Ser 8705 TCT CCT TTG Ser Pro Leu 8710 TTG CTA CTG Leu Leu Leu CCT GAC Pro Asp 8715 AAT GTC CGA Asn Val Arg ATT CGA Ile Arg 8720 AAA TAT AAT Lys Tyr Asn CTC TCA Leu Ser 8725 TCT GAG AGG Ser Glu Arg TTC TCA GAG TAT CTT Phe Ser Glu Tyr Leu 8730 CAA GAT Gin Asp 8735 GAG GAA TAT Glu Glu Tyr

ATC

Ile 8740 CAA GCT GTT GAT Gin Ala Val Asp TAT GAT TGG GAT CCC Tyr Asp Trp Asp Pro 8745 GAG GAC Glu Asp 8750 ATA GGC CTC Ile Gly Leu AGT GTT Ser Val 8755 GTG TAT TAC Val Tyr Tyr ACT GTG Thr Val 8760 CGA GGG GAG Arg Gly Glu GGC TCT Gly Ser 8765 AGG TTT GGT Arg Phe Gly GCT ATC AAA Ala Ile Lys 8770 CGT GCC TAC ATC Arg Ala Tyr Ile 8775 CCC AAC TTT Pro Asn Phe GAA TCC Glu Ser 8780 GGC CGC AAT 1 Gly Arg Asn ATG CAG CCA Met Gin Pro 8800 AAT CTT GTG CAG Asn Leu Val Gin 3785 GAT GGA ATA GCA Asp Gly Ile Ala 12260 12308 12356 12404 12452 12500 12548 12596 12644 12692 12740 12788 12836 GAA GTT GAC CTG AAA CTG Glu Val Asp Leu Lys Leu 8790 AAA TAC GTA Lys Tyr Val 8795 GTG GAC TGG GTT GGA Val Asp Trp Val Gly 8805 AGG CAT ATT TAC TGG Arg His Ile Tyr Trp 8810 TCA GAT Ser Asp 8815 GTC AAG AAT Val Lys Asn

AAA

Lys 8820 CGC ATT GAG GTG Arg Ile Glu Val GCT AAA CTT GAT GGA Ala Lys Leu Asp Gly 8825 AGG TAC Arg Tyr 8830 AGA AAG TGG Arg Lys Trp CTG ATT Leu Ile 8835 TCC ACT Ser Thr GGG CTT Gly Leu GCC TGG Ala Trp 8870 GAC C Asp I

:TG

Leu 3840 GAC CAA CCA GCT GCT ATT Asp Gin Pro Ala Ala Ile 8845 GCT GTG AAT Ala Val Asn CCC AAA CTA Pro Lys Leu 8850 ATG TTC TGG ACT GAC Met Phe Trp Thr Asp 8855 ATG AAT GGA GAG GAC Met Asn Gly Glu Asp TGG GGA Trp Gly 8860 AAG GAA CCT Lys Glu Pro AAA MTC GAG TCT Lys Xaa Glu Ser 8865 GGT TGG CCA ACT GGC Gly Trp Pro Thr Gly 8885

CTT

Leu 8894 887!

TCT

Ser

D

CGC AAC ATC Arg Asn Ile 5 ATC GAT TAT Ile Asp Tyr TTG AAC Leu Asn *8895 AAT GAC CGA Asn Asp Arg CTG GTT TTC GAG GAC CTT Leu Val Phe Glu Asp Leu 8880

ATC

Ile 8900 TAC TGG AGT GAC TTC AAG GAG GAC GTT Tyr Trp Ser Asp Phe Lys Glu Asp Val 8905 ATT GAA ACC ATA Ile Glu Thr Ile 8910 AAA TAT GAT Lys Tyr Asp 8915 CCT TAC AGC Pro Tyr Ser 8930 GGG ACT GAT Gly Thr Asp

AGG

Arg 8920 AGA GTC ATT GCA AAG GAA GCA ATG AAC Arg Val Ile Ala Lys Glu Ala Met Asn 12884 12932 12980 8925 CTG GAC ATC Leu Asp Ile 8935 TTT GAA GAC CAG Phe Glu Asp Gin TTA TAC TGG ATA TCT AAG GAA AAG GGA Leu Tyr Trp Ile Ser Lys Glu Lys Gly 8940 8945 PCTIUS95/15203 WO 96/15801 GAA GTA

TGG

Glu Val Trp 8950 AAA CAA AAT Lys Gin Asn AAA TTT Lys Phe 8955 GGG CAA GGA AAG AAA GAG AAA ACG Gly Gin Gly Lys Lys Glu Lys Thr 8960 CTG GTA Leu Val 8965 GTG AAC CCT Val Asn Pro TGG CTC Trp Leu 8970 ACT CAA.GTT Thr Gin Val CGA ATC Arg Ile 8975 TTT CAT CAA Phe His Gin

CTC

Leu 8980 AGA TAC AAT AAG Arg Tyr Asn Lys TCA GTG Ser Val 8985 CCC AAC CTT TGC Pro Asn Leu Cys 899C AAA CAG ATC TGC Lys Gin Ile Cys AGC CAC Ser His 8995 CTC TGC CTT Leu Cys Leu CTG AGA Leu Arg 9000 CCT GGA GGA Pro Gly Gly TAC AGC Tyr Ser 9005 TGT GCC TGT Cys Ala Cys CCC CAA GGC Pro Gin Gly 9010 13028 13076 13124 13172 13220 13268 13316 13364 TCC AGC TTT ATA GAG Ser Ser Phe Ile Glu 9015 GGG AGC ACC ACT Gly Ser Thr Thr 9020 GAG TGT GAT Glu Cys Asp GCA GCC ATC GAA Ala Ala Ile Glu 9025 CTG CCT ATC AAC CTG CCC Leu Pro Ile Asn Leu Pro 9030 CCC CCA TGC AGG TGC Pro Pro Cys Arg Cys 9035 ATG CAC GGA GGA AAT Met His Gly Gly Asn 9040 TGC TAT TTT GAT GAG Cys Tyr Phe Asp Glu 9045 ACT GAC Thr Asp 9050 CTC CCC AAA Leu Pro Lys TGC AAG Cys Lys 9055 TGT CCT AGC Cys Pro Ser

GGC

Gly 9060 TAC ACC GGA AAA Tyr Thr Gly Lys TAT TGT Tyr Cys 9065 GAA ATG GCG Glu Met Ala TTT TCA AAA GGC ATC Phe Ser Lys Gly Ile 9070 TCT CCA Ser Pro 9075 GGA ACA ACC Gly Thr Thr GCA GTA Ala Val 9080 GCT GTG CTG Ala Val Leu TTG ACA Leu Thr 9085 ATC CTC TTG lie Leu Leu ATC GTC GTA Ile Val Val 9090 ATT GGA GCT CTG Ile Gly Ala Leu 9095 GCA ATT GCA Ala Ile Ala GGA TTC TTC Gly Phe Phe 9100 CAC TAT AGA AGG ACC GGC His Tyr Arg Arg Thr Gly 9105 TCC CTT Ser Leu 911C TTG CCT GCT Leu Pro Ala 0 CTG CCC AAG Leu Pro Lys 9115 GGG AAT GGG Gly Asn Gly 9130 CTG CCA AGC TTA Leu Pro Ser Leu 9120 GTG ACC TTC AGA Val Thr Phe Arg 9135 AGC AGT CTC GTC Ser Ser Leu Val AAG CCC TCT GAA AAT Lys Pro Ser Glu Asn 9125 TCA GGG GCA Ser Gly Ala

GAT

Asp 9140 13412 13460 13508 13556 13604 13652 13700 13748 CTT AAC ATG GAT ATT GGA GTG TCT GGT Leu Asn Met Asp Ile Gly Val Ser Gly 9145 TTT GGA Phe Gly 9150 CCT GAG ACT Pro Glu Thr GCT ATT Ala Ile 9155 GAC AGG TCA Asp Arg Ser ATG GCA Met Ala 9160 ATG AGT GAA Met Ser Glu GAC TTT GTC Asp Phe Val 9165 ATG GAA ATG GGG AAG Met Glu Met Gly Lys 9170 GCC AGA GAC AGT GCT Ala Arg Asp Ser Ala 9185 CAG CCC ATA ATA TTT Gin Pro Ile Ile Phe 9175 GAA AAC CCA ATG TAC TCA Glu Asn Pro Met Tyr Ser 9180 GTC AAA GTG GTT CAG CCA ATC CAG GTG ACT GTA TCT GAA AT GTG GAT Val Lys Val Val Gin Pro ie Gin Val Thr Val Ser Glu Asn Val Asp 9190 995 92 prT/nIqS95/152 03 WO 96/15801 AAT AAG AAT TAT GGA AGT CCC ATA AAC CCT TCT GAG ATA GTT CCA GAG Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu Ile Val Pro Glu 9205 9210 9215 9220 ACA AAC CCA ACT TCA CCA GCT GCT GAT GGA ACT CAG GTG ACA AAA TGG Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gln Val Thr Lys Trp 9225 9230 9235 AAT CTC TTC AAA CGA AAA TCT AAA CAA ACT ACC AAC TTT GAA AAT CCA Asn Leu Phe Lys Arg Lys Ser Lys Gin Thr Thr Asn Phe Glu Asn Pro 9240 9245 9250 ATC TAT GCA CAG ATG GAG AAC GAG CAA AAG GAA AGT GTT GCT GCG ACA Ile Tyr Ala Gin Met Glu Asn Glu Gin Lys Glu Ser Val Ala Ala Thr 9255 9260 9265 CCA CCT CCA TCA CCT TCG CTC CCT GCT AAG CCT AAG CCT CCT TCG AGA Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro Lys Pro Pro Ser Arg 9270 9275 9280 AGA GAC CCA ACT CCA ACC TAT TCT GCA ACA GAA GAC ACT TTT AAA GAC Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp Thr Phe Lys Asp 9285 9290 9295 9300 ACC GCA AAT CTT GTT AAA GAA GAC TCT GAA GTA TAG CTATACCA Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val 9305 9310 INFORMATION FOR SEQ ID NO:88: SEQUENCE

CHARACTERISTICS:

LENGTH: 4656 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88: Met Asp Arg Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu Ala Leu 1 5 10 Val Ala Cys Leu Ala Pro Ala Ser Gly Gin Glu Cys Asp Ser Ala His 25 Phe Arg Cys Gly Ser Gly His Cys Ile Pro Ala Asp Trp Arg Cys Asp 40 Gly Thr Lys Asp Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys Ala Val 55 Val Thr Cys Gin Gin Gly Tyr Phe Lys Cys Gin Ser Glu Gly Gin Cys 65 70 75 Ile Pro Ser Ser Trp Val Cys Asp Gin Asp Gin Asp Cys Asp Asp Gly 90 95 Ser Asp Glu Arg Gin Asp Cys Ser Gin Ser Thr Cys Ser Ser His Gir 100 105 110 Ile Thr Cys Ser Asn Gly Gin Cys Ile Pro Ser Glu Tyr Arg Cys Asj 115 120 125 v 13796 13844 13892 13940 13988 14036 14080 p 1 PCT/US95/15203 WO 96/15801 His Val 13( Pro Th: 145 Ser G1 Ile As Gly G1 Gin As 21 Tyr G] 225 Cys As Glu Si Cys P Ile L 2 Lys T 305 Cys H Ile Gin His Cys 385 Gly Leu Tyr Phe

L

0 r n n u p .0 in sp er r e 91 Ii Il

L

3.

L'

A

V

H

Arg Asp Cys Prc Cys Glu Gin Lei 15( Lys Cys Asp Tr] 165 Cys Thr Glu'Ii 180 Cys Ile Pro Ar 195 Gly Ser Asp Gl Phe Thr Cys Pr 23 SGly Glu Asp As 245 Gly Pro His A 260 o Glu Ser Gly A: 275 u Asp Cys Pro G 0 r Cys Ser Met T 3 s Glu Thr Pro T 325 e Asn His Asn 1 340 e Trp Gly Ile 355 eu Cys His Cys 70 ys Ala Asn Asp rg Asp Leu Leu 405 al Glu Ser Gin 420 [is Leu Gin Arg 435 er Val Asp Ile 150 o1 p e g u To 10 sp sp rg 1 hY 1 As Cy

G

S

3

I

A

V

I

Asp Gly 135 Thr Cys Lys Val Cys Leu Ala Tyr 200 His Ala 215 Ser Gly Cys Lys SVal His SCys Ile 28( y Arg Gli 295 r Leu Cy 0 r Gly Gl p Ser Ar rs Asp G1 3 Lu Glu G: 375 er Phe G 90 le Gly A sn Arg G 'al Phe 4 sn Gly 455 Ala Asp Glu Asn Asp 140 Asp Asn Gly Ala Cys 155 Asp Cys Arg Asp Se 170 His Asn Glu Phe Se: 185 Val Cys Asp His As 20 Cys Asn Tyr Pro Th 220 SArg Cys Ile Tyr G1 235 Asp Asn Gly Asp Gl 250 SLys Cys Ser Pro Ai 265 e Ser Ile Tyr Lys V 0 2 u Asp Glu Asn Asn T] 300 s Ser Ala Leu Asn C 315 y Ala Cys Phe Cys P 330 g Thr Cys Val Glu P 345 Ln Lys Cys Glu Ser I 0 ly Tyr Ile Leu Glu 380 ly Glu Ala Ser Ile 395 sp Ile His Gly Arg 410 ly Val Ala Val Gly 425 rrp Thr Asp Thr Val 140 Leu Asn Ile Gin Glu 460 r r

P

r .n u rg a] h: y r hI .r 3(

A

I

S

V

C

G\

Cys Tyr Ser Cys 190 Asn Cys SAsn i Asp Glu 27( 1 Cy r Se s Gl1 o Pr ne As 35 g Pr rg G le PI er P 'al A 4 1n P 145 Jal I Gin Tyr Asn Thr 160 Asp Glu 175 Gly Asn Asp Cys Gly Gly Trp Val 240 SGly Cys 255 i Trp Ser s Asp Gly r Thr Gly n Tyr Gin 320 o Gly Tyr 335 p Asp Cys 10 :o Gly Arg Ly Gin Tyr he Ser Asn 400 he Arg Ile 415 .la Phe His Lsn Lys Val Leu Asn Val WO 96/15801 A63 Val Asp PCTIUS95/15203 .sn Lys 480 Ser Val Giu Thr Pro Giu Asn Leu Ala 465 470 Trp Val Asn A 475 Ile 'F Asp G Arg G Trp G Gly S 545 Gly V Arg P Thr\ Leu E Leu I 625 Ala Pro Val Cys Ile 705 Gly Ser Ser Lys Asn 785 Thr yr ly ly lu 30 er ral 'he ra1 ?he 'ys 3er Tyr Cys Lys 690 Al IlE Gl Th: Il 77 Va As Leu Val G 4 Ser Tyr A 500 Ile Ala V 515 Ser Leu S Asn Arg L Thr Leu P Asp Tyr I 580 Vai His C 595 Glu Gly C Ala Asn I Leu Arg Ala Thr 660 Val Leu 675 Cys Thr Val Gin a Pro Phe ,r Asn Pro 740 r lie Phe 755 e Asp Gly 0 1 Giu Ser p Ser His lu 85 rg al er ys sp ,65 le ly ;ln -ys Pro 645 Asn Ser PhE As Th 72' Thr L Val '9 Asp I Gly Asp 550 Met Glu Gly Val Phe 630 Tyr Pro His Gly i Phe 710 r Leu 5 ys V Thr ?ro ;lu 1 535 Leu Ile Thr Ser Phe 615 Thr Gly Cys Arg Phe 695 Leu Ser al 3 eu 'hr 20 !ro la1 3er Ja1 Leu 600 Phe Glu Va1 Lys Thr 680 Glr IlE Th: Asn Ile 505 Val Lys Lys Lys Thr 585 Ile Thr Thr Thr Asp 665 AsF i Leu 4 PhE r Gli Arg 490 Thr Gly Leu Thr Arg 570 Tyr Pro Asp Asn Va1 650 Asr Asr As! Sei I Gii 73 Ile E Glu Tyr I Glu Lys i 555 Val Asp His Trp Pro 635 Tyr Asn' Asp Thr Ser 715 Asp 0 e Asp sp ~sn eu krg 540 Leu yr Gly Pro Thr 620 Gin His Gl Gl As! Gli Va Ph Met V Leu G

S

Phe P 525 Ala F Gly 'I Trp Ile C Phe 605 Lys I Vai Ser Gly r Leu 685 Glu I Vai 1 Met e Asp t Ile al ly 'he 'he 'rp Tal ;in 590 "ly 4et T'yr Leu Cys 670 Gly Arg Ala Val Al 75( Ph Asn L 495 His P Ser P Met P Pro I Asp 5 575 Arg I Vai Ala Tyr Arg 655 Glu Phe His Ile Pro 735 i Gin 0 e Lys eu 'ro isp sp la 360 jer ys Ser aVal 3Gl 640 Gin Gin Arg Cys Arg 720 Va1 Asp Gin Ser Phe Phe Val C> 745 Phe Ser Asp Met Ser Lys His Me 760 765 Thr Leu Tyr Gly Ala 790 Lys Arg 775 Phe Ser Glu Asp Ile Ile Trp Ser Leu Ile Va1 Ala Ser 795 Met Ala 780 Lys Arg Asn Asn Leu Arg Leu Ala Val Tyr Asp Glu Trp 800 Lys WO 96/15801 805 810 Asn Asn PCT/US95/15203 815 Val Val Thr Arg Arg Val His Pro 835 Ala Lys Ile 850 Ile Asn Thr 865 Ala Ser Arg Ser Thr Phe Met Thr His 915 Thr Asp Trp 930 Gly Glu Met 945 Lys Ser Tyr Pro Thr His Asn Phe Gin 995 Asn His Leu 1010 Gin Cys GlI 1025 Thr Val Val 820 Phe Ala Gly Met Arg Ala Thr Leu Gly 870 Leu Tyr Trp 885 Asp Gly Leu 900 Pro Phe Gly Arg Leu Gly Thr Val Ile 950 Asp Val Asn 965 Pro Asn Gly 980 Arg Val Cys i Thr Cys Gli SLeu Phe Se: 10: Gin Tyr Leu 825 Pro Arg Ser Tyr Leu Phe 840 Trp Ser Asp 855 Trp Pro Asn Val Asp Ala Asp Arg Arg 905 Leu Ala Ile 920 Ala Ile Ile 935 Arg Ser Gly Ile Gin Thr Asp Cys Ser 985 Gly Cys Pro 1000 u Gly Asp Pro 1015 Phe Thr i Gly Gly Tyr 890 Arg Phe Arg Ile Gly 970 His Tyr Thr Ser Leu 875 Phe Leu Gly Val Ala 955 Ser Phe Gly Asp His 860 Ala Asp Gly Glu Arg 940 Tyr Asn Cys Met 830 Trp Phe Arg Pro 845 Leu Leu Pro Val Ile Asp Trp Ala 880 Lys Ile Glu His 895 His Ile Glu Gin 910 His Leu Phe Phe 925 Lys Ala Asp Gly Ile Leu His Leu 960 Ala Cys Asn Gin 975 Phe Pro Val Pro 990 Arg Leu Ala Ser 1005 Asn Glu Pro Pro Thr Glu 1020 r Phe Pro Cys Lys Asn Gly Arg 30 1035 Cys Val Pro 1040 Asn Tyr Tyr Leu Cys Asp Gly Val Asp 1045 Asp Cys His Asp Asn Ser Asp 1050 1055 Glu Gin Leu Thr Cys Gly 1075 Arg Asn Asp 1090 Ala Pro Ala 1105 Cys Ile Ser Gly Ser Asp Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala Phe 1060 1065 1070 His Gly Glu Cys Ile Pro Ala His Trp Arg Cys Asp Lys 1080 1085 Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr His 1095 1100 Ser Cys Leu Asp Thr Gin Tyr Thr Cys Asp Asn His Gin 1110 1115 1120 Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly Asp 1125 1130 1135 Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gin Pro Ser 1140 1145 1150 WO 96/15801 PCT/US95/15203 Gin Phe Asn Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val Cys 1155 1160 1165 Asp Gly Asp Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly Cys Val 1170 1175 1180 Leu Asn Cys Thr Ala Ser Gin Phe Lys Cys Ala Ser Gly Asp Lys Cys 1185 1190 1195 1200 0 Ile Gly Val Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser Asp Asn 1205 1210 1215 Ser Asp Glu Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His Ser 1220 1225 1230 Asp Glu Phe Gin Cys Gin Glu Asp Gly Ile Cys Ile Pro Asn Phe Trp 1235 1240 1245 Glu Cys Asp Gly His Pro Asp Cys Leu Tyr Gly Ser Asp Glu His Asn 1250 1255 1260 Ala Cys Val Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys Asp Asn 1265 1270 1275 1280 Gly Asn Cys Ile His Arg Ala Trp Leu Cys Asp Arg Asp Asn Asp Cys 1285 1290 1295 Gly Asp Met Ser Asp Glu Lys Asp Cys Pro Thr Gin Pro Phe Arg Cys 1300 1305 1310 Pro Ser Trp Gin Trp Gin Cys Leu Gly His Asn Ile Cys Val Asn Leu 1315 1320 1325 Ser Val Val Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp Glu 1330 1335 1340 Ser Pro Leu Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly Cys 1345 1350 1355 1360 4 Thr His Glu Cys Val Gin Glu Pro Phe Gly Ala Lys Cys Leu Cys Pro 1365 1370 1375 Leu Gly Phe Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp Ile Asp 1380 1385 1390 Glu Cys Asp Ile Leu Gly Ser Cys Ser Gin His Cys Tyr Asn Met Arg 1395 1400 1405 Gly Ser Phe Arg Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu Ser Asp 1410 1415 1420 Gly Arg Thr Cys Lys Val Thr Ala Ser Glu Ser Leu Leu Leu Leu Val 1425 1430 1435 1440 Ala Ser Gin Asn Lys Ile Ile Ala Asp Ser Val Thr Ser Gin Val His 1445 1450 1455 Asn Ile Tyr Ser Leu Val Glu Asn Gly Ser Tyr Ile Val Ala Val Asp 1460 1465 1470 Phe Asp Ser Ile Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr Gin Gly 1475 1480 1485 WO 96/15801 PCT/US95/15203 Lys Thr Trp Ser Ala Phe Gin Asn Gly Thr Asp Arg Arg Val Val Phe 1490 1495 1500 Asp Ser Ser Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val Gly 1505 1510 1515 1520 Arg Asn Leu Tyr Trp Thr Asp Tyr Ala Leu Glu Thr Ile Glu Val Ser 1525 1530 1535 Lys Ile Asp Gly Ser His Arg Thr Val Leu Ile Ser Lys Asn Leu Thr 1540 1545 1550 Asn Pro Arg Gly Leu Ala Leu Asp Pro Arg Met Asn Glu His Leu Leu 1555 1560 1565 Phe Trp Ser Asp Trp Gly His His Pro Arg Ile Glu Arg Ala Ser Met 1570 1575 1580 Asp Gly Ser Met Arg Thr Val Ile Val Gin Asp Lys Ile Phe Trp Pro 1585 1590 1595 1600 Cys Gly Leu Thr Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe Met Asp 1605 1610 1615 Ser Tyr Leu Asp Tyr Met Asp Phe Cys Asp Tyr Asn Gly His His Arg 1620 1625 1630 Arg Gin Val Ile Ala Ser Asp Leu Ile Ile Arg His Pro Tyr Ala Leu 1635 1640 1645 Thr Leu Phe Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg Arg 1650 1655 1660 Val Met Arg Ala Asn Lys Trp His Gly Gly Asn Gin Ser Val Val Met 1665 1670 1675 1680 Tyr Asn Ile Gin Trp Pro Leu Gly Ile Val Ala Val His Pro Ser Lys 1685 1690 1695 Gin Pro Asn Ser Val Asn Pro Cys Ala Phe Ser Arg Cys Ser His Leu 1700 1705 1710 Cys Leu Leu Ser Ser Gin Gly Pro His Phe Tyr Ser Cys Val Cys Pro 1715 1720 1725 Ser Gly Trp Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp Asp 1730 1735 1740 Gin Pro Phe Leu Ile Thr Val Arg Gin His Ile Ile Phe Gly lie Ser 1745 1750 1755 1760 Leu Asn Pro Glu Val Lys Ser Asn Asp Ala Met Val Pro Ile Ala Gly 1765 1770 1775 Ile Gin Asn Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gin Tyr Ile 1780 1785 1790 Tyr Trp Val Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp Gly 1795 1800 1805 Thr Asn Arg Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser Met 1810 1815 1820 Asn Leu Ala Leu Asp Trp Ile Ser Arg Asn Leu Tyr Ser Thr Asn Pro WO 96/15801 PCT/US95/15203 16 7 1825 1830 1835 1840 Arg Thr Gin Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg Tyr 1845 1850 1855 Arg Lys Thr Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly Phe 1860 1865 1870 Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp Ser 1875 1880 1885 Asp Gin Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala Asn 1890 1895 1900 Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu His 1905 1910 1915 1920 Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gin Lys Leu Tyr Trp Ala 1925 1930 1935 Val Thr Gly Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr Asp 1940 1945 1950 Arg Met Ile Leu Val His Gin Leu Ser His Pro Trp Gly Ile Ala Val 1955 1960 1965 His Asp Ser Phe Leu Tyr Tyr Thr Asp Glu Gin Tyr Glu Val Ile Glu 1970 1975 1980 Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp Asn 1985 1990 1995 2000 Val Pro Asn Leu Arg Gly Leu Gin Val Tyr His Arg Arg Asn Ala Ala 2005 2010 2015 Glu Ser Ser Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gin Gin Ile 2020 2025 2030 Cys Leu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr Gly 2035 2040 2045 Phe Lys Leu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser Phe 2050 2055 2060 Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu Leu 2065 2070 2075 2080 Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gin Gly Arg Asn 2085 2090 2095 Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp Cys 2100 2105 2110 Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile Lys 2115 2120 2125 Pro Asp Gly Ser Ser Leu Met Asn Ile Val Thr His Gly Ile Gly Glu 2130 2135 2140 Asn Gly Val Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu Tyr 2145 2150 2155 2160 Phe Thr Asn Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg Ile 2165 2170 2175 WO 96/15801 PCT/US95/15203 Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp Met Pro 2180 2185 2190 Arg His Ile Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala Asp 2195 2200 2205 Tyr Gly Gin Arg Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys Thr Asn 2210 2215 2220 Arg Thr Val Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu Ala 2225- 2230 2235 2240 Val Asp Arg Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser Leu Asp 2245 2250 2255 Ile Ile Ala Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile Arg 2260 2265 2270 Tyr Gly Ser Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Glu Asn 2275 2280 2285 Ser Ile Ile Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gin Ala Ser 2290 2295 2300 Lys Glu Pro Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn Ile 2305 2310 2315 2320 Asn Trp Leu Arg Asp Val Thr Ile Phe Asp Lys Gin Val Gin Pro Arg 2325 2330 2335 Ser Pro Ala Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn Gly Gly 2340 2345 2350 Cys Ser His Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro Lys Cys 2355 2360 2365 Asp Cys Ala Phe Gly Thr Leu Gin Ser Asp Gly Lys Asn Cys Ala Ile 2370 2375 2380 Ser Thr Glu Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu Arg Ser 2385 2390 2395 2400 Leu His Leu Asp Pro Glu Asn His Ser Pro Pro Phe Gin Thr Ile Asn 2405 2410 2415 Val Glu Arg Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp Arg 2420 2425 2430 Ile Tyr Phe Thr Gin Asn Leu Ala Ser Gly Val Gly Gin Ile Ser Tyr 2435 2440 2445 Ala Thr Leu Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser Gly 2450 2455 2460 Ile Gly Thr Ala Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg Arg Ile 2465 2470 2475 2480 Tyr Tyr Ser Asp Tyr Leu Asn Gin Met Ile Asn Ser Met Ala Glu Asp 2485 2490 2495 Gly Ser Asn Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg Ala Ile 2500 2505 2510 WO 96/15801 PCT/US95/15203 Val Leu Asp Pro Cys Gin Gly Tyr Leu Tyr Trp Ala Asp Trp Asp Thr 2515 2520 2525 His Ala Lys Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe Arg Val Pro 2530 2535 2540 Ile Val Asn Ser Ser Leu Val Met Pro Ser Gly Leu Thr Leu Asp Tyr 2545 2550 2555 2560 Glu Glu Asp Leu Leu Tyr Trp Val Asp Ala Ser Leu Gin Arg Ile Glu 2565 2570 2575 Arg Ser Thr Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala Ala 2580 2585 2590 Val His Ala Phe Gly Leu Thr Leu Tyr Gly Gin Tyr Ile Tyr Trp Thr 2595 2600 2605 Asp Leu Tyr Thr Gin Arg Ile Tyr Arg Ala Asn Lys Tyr Asp Gly Ser 2610 2615 2620 Gly Gin Ile Ala Met Thr Thr Asn Leu Leu Ser Gin Pro Arg Gly Ile 2625 2630 2635 2640 Asn Thr Val Val Lys Asn Gin Lys Gin Gin Cys Asn Asn Pro Cys Glu 2645 2650 2655 Gin Phe Asn Gly Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn Gly 2660 2665 2670 Ala Glu Cys Gin Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn Asn 2675 2680 2685 Arg Lys His Cys Ile Val Asp Asn Gly Glu Arg Cys Gly Ala Ser Ser 2690 2695 2700 Phe Thr Cys Ser Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys Cys Asp 2705 2710 2715 2720 Asn Asp Asn Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val Cys 2725 2730 2735 Ala Leu His Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly Arg 2740 2745 2750 Cys Val Gin Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly Asp 2755 2760 2765 Gly Ser Asp Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala Thr Thr 2770 2775 2780 Glu Phe Met Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile Cys 2785 2790 2795 2800 Asn Gly Val Asp Asn Cys His Asp Asn Asn Thr Ser Asp Glu Lys Asn 2805 2810 2815 Cys Pro Asp Arg Thr Cys Gin Ser Gly Tyr Thr Lys Cys His Asn Ser 2820 2825 2830 Asn Ile Cys Ile Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn Asp Cys 2835 2840 2845 Gly Asp Asn Ser Asp Glu Asn Pro Thr Tyr Cys Thr Thr His Thr Cys PCT/US95/15203 WO 96/15801 2850 Ser Ser 2865 Trp Tyr Ala Ser Cys Asp Asn Asp 293( 2855 2860 Ser Glu Phe Gin Cys Ala Ser Gly Arg Cys Ile Pro Gin His 2870 2875 2880 Cys Asp Gin Glu Thr Asp Cys. Phe Asp Ala Ser Asp Glu Pro 2885 2890 2895 Cys Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe Lys 2900 2905 2910 Gly Gly Arg Cys Ile Pro Ser Glu Trp Ile Cys Asp Gly Asp 2915 2920 2925 Cys Gly Asp Met Ser Asp Glu Asp Lys Arg His Gin Cys Gin 0 2935 2940 Asn Gin Asn Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg Pro 2945 2950 2955 2960 Pro Asp Arg Arg Cys Ile Pro Gin Ser Trp Val Cys Asp Gly Asp Val 2965 2970 2975 Asp Cys Thr Asp Gly Tyr Asp Glu Asn Gin Asn Cys Thr Arg Arg Thr 2980 2985 2990 Cys Ser Glu Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro Lys 2995 3000 3005 Ile Phe Arg Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp Glu 3010 3015 3020 Arg Gly Cys Leu Tyr Gin Thr Cys Gin Gin Asn Gin Phe Thr Cys Gin 3025 3030 3035 3040 Asn Gly Arg Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn Asp 3045 3050 3055 Cys Gly Asp Gly Ser Asp Glu Leu Met His Leu Cys His Thr Pro Glu 3060 3065 3070 Pro Thr Cys Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys Ile 3075 3080 3085 Glu Met Met Lys Leu 3090 Asp Glu Lys Gly Cys 3105 Gly Cys Asp His Asn 312 Cys Arg Pro Gly Tyr 3140 Ile Asp Glu Cys Thr 3155 Asn Val Ile Gly Ser 3170 Glu Pro Asp Gly Lys 3185 Cys Asn His Leu Asp Asp Cys Leu Asp 3095 3100 Gly Ile Asn Glu Cys His Asp Pro Ser 3110 3115 Cys Thr Asp Thr Leu Thr Ser Phe Tyr 5 3130' Lys Leu Met Ser Asp Lys Arg Thr Cys 3145 3150 Glu Met Pro Phe Val Cys Ser Gin Lys 3160 3165 Tyr Ile Cys Lys Cys Ala Pro Gly Tyr 3175 3180 Thr Cys Arg Gin Asn Ser Asn Ile Glu 3190 3195 Asn Ile Cys 313 Val Cys Leu Prc Ser Ser 3120 Ser Asp Glu Arg Tyr 3200 WO 96/15801 PCT/US95/15203 /7/ Leu Ile Phe Ser Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile Asp Gly 3205 3210 3215 Tyr Phe Tyr Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala Leu 3220 3225 3230 Asp Phe Asp Arg Val Glu Lys Arg Leu Tyr Trp Ile Asp Thr Gin Arg 3235 3240 3245 1 0 Gin Val Ile Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu Thr Ile 3250 3255 3260 Ile Asn His Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp Val 3265 3270 3275 3280 Ser Arg Lys Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly Leu Phe Val 3285 3290 3295 Ser Asp Leu Asn Gly Gly His Arg Arg Met Leu Ala Gin His Cys Val 3300 3305 3310 Asp Ala Asn Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu Ala Leu 3315 3320 3325 His Pro Gin Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg Ala 3330 3335 3340 Tyr Ile Gly Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile Ile 3345 3350 3355 3360 Ser Thr Lys Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr Asn 3365 3370 3375 Asp Leu Leu Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr Ser 3380 3385 3390 Asp Leu Glu Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu Pro 3395 3400 3405 His Pro Phe Ala Ile Thr e Phe Glu Asp Thr Ile Tyr Trp Thr Asp 3410 3415 3420 Trp Asn Thr Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser Asn 3425 3430 3435 3440 Arg Gin Thr Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile His Val 3445 3450 3455 Tyr His Pro Tyr Arg Gin Pro Ile Val Ser Asn Pro Cys Gly Thr Asn 3460 3465 3470 Asn Gly Gly Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly Lys Gly 3475 3480 3485 Phe Thr Cys Glu Cys Pro Asp Asp Phe Arg Thr Leu Gin Leu Ser Gly 3490 3495 3500 Ser Thr Tyr Cys Met Pro Met Cys Ser Ser Thr Gin Phe Leu Cys Ala 3505 3510 3515 3520 Asn Asn Glu Lys Cys Iie Pro Ile Trp Trp Lys Cys Asp Gly Gin Lys 3525 3530 3535 WO 96/15801 PCTUS95/15203 /7-2- Asp Cys Ser Asp Gly Ser Asp Glu Leu Ala Leu Cys Pro Gin Arg Phe 3540 3545 3550 Cys Arg Leu Gly Gin Phe Gin Cys Ser Asp Gly Asn Cys Thr Ser Pro 3555 3560 3565 Gin Thr Leu Cys Asn Ala His Gin Asn Cys Pro Asp Gly Ser Asp Glu 3570 3575 3580 Asp Arg Leu Leu Cys Glu Asn His His Cys Asp Ser Asn Glu Trp Gin 3585 3590 3595 3600 Cys Ala Asn Lys Arg Cys Ile Pro Glu Ser Trp Gin Cys Asp Thr Phe 3605 3610 3615 Asn Asp Cys Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala Ser 3620 3625 3630 Arg Thr Cys Arg Pro Gly Gin Phe Arg Cys Ala Asn Gly Arg Cys Ile 3635 3640 3645 Pro Gin Ala Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His Ser 3650 3655 3660 Asp Glu Pro Ile Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp Asn 3665 3670 3675 3680 Phe Thr Glu Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys Trp 3685 3690 3695 Ala Val Cys Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu Gin 3700 3705 3710 Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys Lys 3715 3720 3725 Asn His His Cys Ile Pro Leu Arg Trp Gin Cys Asp Gly Gin Asn Asp 3730 3735 3740 Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys Thr 3745 3750 3755 3760 Glu Ser Glu Phe Arg Cys Val Asn Gin Gin Cys Ile Pro Ser Arg Trp 3765 3770 3775 Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg Asp 3780 3785 3790 Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gin Cys Thr Ser Gly 3795 3800 3805 His Cys Val His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys Leu 3810 3815 3820 Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly Ala 3825 3830 3835 3840 Tyr Cys Gin Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile Pro 3845 3850 3855 Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser Asp 3860 3865 3870 Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn Arg WO 96/15801 PCT[US9515203 123 3875 3880 3885 Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys Asn 3890 3895 3900 Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His Cys 3905 3910 3915 3920 Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys Gly 3925 3930 3935 Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp Asp 3940 3945 3950 Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu Arg 3955 3960 3965 Thr Cys Ala Glu Asn Ile Cys Glu Gin Asn Cys Thr Gin Leu Asn Glu 3970 3975 3980 Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val Phe 3985 3990 3995 4000 Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gin Phe Gly Thr 4005 4010 4015 Cys Pro Gin His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys 4020 4025 4030 Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys Ala 4035 4040 4045 Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg Ile 4050 4055 4060 Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gin Asp 4065 4070 4075 4080 Glu Glu Tyr Ile Gin Ala Val Asp Tyr Asp Trp Asp Pro Glu Asp Ile 4085 4090 4095 Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg Phe 4100 4105 4110 Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg Asn 4115 4120 4125 Asn Leu Val Gin Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gin Pro 4130 4135 4140 Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser Asp 4145 4150 4155 4160 Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr Arg 4165 4170 4175 Lys Trp Leu Ile Ser Thr Asp Leu Asp Gin Pro Ala Ala Ile Ala Val 4180 4185 4190 Asn Pro Lys Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu Pro 4195 4200 4205 Lys Xaa Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu Val 4210 4215 4220 WO 96/15801 PCTIJS95/15203 Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu Asn 4225 4230 4235 4240 Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu Thr 4245 4250 4255 Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala Met 4260 4265 4270 Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gin Leu Tyr Trp Ile Ser 4275 4280 4285 Lys Glu Lys Gly Glu Val Trp Lys Gin Asn Lys Phe Gly Gln Gly Lys 4290 4295 .4300 Lys Glu Lys Thr Leu Val Val Asn Pro Trp Leu Thr Gin Val Arg Ile 4305 4310 4315 4320 Phe His Gin Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys Gin 4325 4330 4335 Ile Cys Ser His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys Ala 4340 4345 4350 Cys Pro Gin Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys Asp 4355 4360 4365 Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys Met 4370 4375 4380 His Gly Gly Asn Cys Tyr Phe Asp Glu Thr Asp Leu Pro Lys Cys Lys 4385 4390 4395 4400 Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser Lys 4405 4410 4415 Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile Leu 4420 4425 4430 Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His Tyr 4435 4440 4445 Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu 4450 4455 4460 Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe Arg 4465 4470 4475 4480 Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro 4485 4490 4495 Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met 4500 4505 4510 Glu Met Gly Lys Gin Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser Ala 4515 4520 4525 Arg Asp Ser Ala Val Lys Val Val Gin Pro Ile Gin Val Thr Val Ser 4530 4535 4540 Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu 4545 4550 4555 4560 WO 96/15801 PCTIUS95/15203 Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gin 4565 4570 4575 Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gin Thr Thr Asn 4580 4585 4590 Phe Glu Asn Pro Ile Tyr Ala Gin Met Glu Asn Glu Gin Lys Glu Ser 4595 4600 4605 Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala 4610 4615 4620 Lys Pro Lys Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp 4625 4630 4635 4640 Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu 4645 4650 INFORMATION FOR SEQ ID NO:89: SEQUENCE CHARACTERISTICS: LENGTH: 14044 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear Asp Ser Glu Val 4655 (ii) MOLECULE TYPE: cDNA (iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE: NO (vi) ORIGINAL SOURCE: ORGANISM: Homo sapiens TISSUE TYPE: Parathyroid (ix) FEATURE: NAME/KEY: CDS LOCATION: 65..14032 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89: TGCGGTGTGC TACGCGCGCC CACCTCCCGG GGAAGGAACG GCGAGGCCGG GGACCGTCGC GGAG ATG GAT CGC GGG CCG GCA GCA GTG GCG TGC ACG CTG Met Asp Arg Gly Pro Ala Ala Val Ala Cys Thr Leu 4660 4665 CTC CTG GCT Leu Leu Ala 4670 109 CTC GTC GCC TGC CTA GCC CCG Leu Val Ala Cys Leu Ala Pro 4675 GCC AGT GGC CAA Ala Ser Gly Gin 4680 GAA TGT GAC AGT GCG Glu Cys Asp Ser Ala 4685 CAT TTT CGC TGT GGA AGT GGG CAT TGC ATC CCT His Phe Arg Cys Gly Ser Gly His Cys Ile Pro 4690 4695 GCA GAC TGG AGG TGT 205 Ala Asp Trp Arg Cys 4700 GAA ATT GGC TGC GCT 253 Glu Ile Gly Cys Ala 4715 GAT GGG ACC AAA GAC TGT TCA GAT GAC GCG GAT Asp Gly Thr Lys Asp Cys Ser Asp Asp Ala Asp 4705 4710 GTT GTG ACC TGC CAG CAG GGC TAT TTC AAG TGC CAG AGT GAG GGA CAA -301 Val Val Thr Cys Gin Gin Gly Tyr Phe Lys Cys Gin Ser Glu Gly Gin WO 96/15801 PCT/US95/15203 /76 4730 4720 TGC ATC CCC AGC Cys Ile Pro Ser 4725 4735 TCC TGG Ser Trp 4740 GTG TGT GAC CAA GAT Val Cys Asp Gin Asp 4745 CAA GAC TGT GAT GAT Gin Asp Cys Asp Asp 4750 GGC TCA GAT Gly Ser Asp GAA CGT CAA GAT TGC Glu Arg Gin Asp Cys 4755 TCA CAA Ser Gin 4760 AGT ACA TGC Ser Thr Cys TCA AGT CAT Ser Ser His 4765 TAC AGG TGC Tyr Arg Cys CAG ATA ACA TGC Gin Ile Thr Cys 4770 TCC AAT GGT Ser Asn Gly CAG TGT Gin Cys 4775 ATC CCA AGT Ile Pro Ser

GAA

Glu 4780 397 445 493 541 GAC CAC Asp His 4785 TAC CCA Tyr Pro 4800 3TC AGA GAC TGC Val Arg Asp Cys CCC GAT GGA GCT GAT Pro Asp Gly Ala Asp 4790 GAG AAT GAC TGC CAG Glu Asn Asp Cys Gin 4795 ACA TGT GAG Thr Cys Glu CAG CTT ACT TGT GAC Gin Leu Thr Cys Asp 4805 AAT GGG Asn Gly 4810 GCC TGC TAT Ala Cys Tyr

AAC

Asn 4815 ACC AGT CAG AAG Thr Ser Gin Lys TGT GAT Cys Asp 4820 TGG AAA GTT Trp Lys Val GAT TGC AGG GAC TCC Asp Cys Arg Asp Ser 4825 TCA GAT 589 Ser Asp 4830 GAA ATC AAC Glu Ile Asn TGC ACT GAG ATA TGC Cys Thr Glu Ile Cys 4835 TTG CAC Leu His 4840 AAT GAG TTT Asn Glu Phe TCA TGT GGC Ser Cys Gly 4845 GAC AAT GAT Asp Asn Asp AAT GGA GAG TGT ATC Asn Gly Glu Cys Ile 4850 CCT CGT GCT TAT Pro Arg Ala Tyr 4855 GTC TGT GAC Val Cys Asp

CAT

His 486C 685 TGC CAA Cys Gin 4865 GAC GGC AGT GAC Asp Gly Ser Asp GAA CAT Glu His 4870 GCT TGC AAC Ala Cys Asn TAT CCG ACC TGC GGT Tyr Pro Thr Cys Gly 4875 GGT TAC CAG TTC ACT Gly Tyr Gin Phe Thr 4880 TGC CCC AGT GGC CGA Cys Pro Ser Gly Arg 4885 TGC ATT Cys Ile 4890 TAT CAA AAC Tyr Gin Asn

TGG

Trp 4895 GTT TGT GAT Val Cys Asp TGT GAA AGC Cys Glu Ser GGA GAA GAT GAC Gly Glu Asp Asp 4900 TGT AAA GAT AAT Cys Lys Asp Asn 4905 GGA GAT GAA GAT GGA Gly Asp Glu Asp Gly 4910 GGT CCT Gly Pro 4915 CAT GAT GTT His Asp Val CAT AAA His Lys 4920 TGT TCC CCA AGA GAA TGG Cys Ser Pro Arg Glu Trp 4925 TCT TGC CCA GAG TCG GGA CGA TGC ATC TCC ATT TAT AAA GTT TGT GAT Ser Cys Pro Glu Ser Gly Arg Cys Ile Ser Ile Tyr Lys Val Cys Asp 4930 4935 4940 GGG ATT TTA GAT TGC CCA GGA AGA Gly Ile Leu Asp Cys Pro Gly Arg 4945 4950 GAA GAT GAA AAC AAC Glu Asp Glu Asn Asn 4955 ACT AGT ACC 973 Thr Ser Thr GGA AAA TAC TGT AGT Gly Lys Tyr Cys Ser 4960 ATG ACT CTG TGC TCT Met Thr Leu Cys Ser 4965 GCC TTG AAC Ala Leu Asn 4970 TGC CAG TAC Cys Gin Tyr 4975 1021 1069 CAG TGC CAT GAG ACG CCG TAT GGA GGA GCG.TGT TTT TGT CCC CCA GGT Gin Cys His Glu Thr Pro Tyr Gly Gly Ala Cys Phe Cys Pro Pro Gly WO 96/15801 PCT/US95/15203 (77 4985 4980 4990 TAT ATC ATC Tyr Ile Ile AAC CAC Asn His 4995 AAT GAC AGC CGT ACC Asn Asp Ser Arg Thr 5000 TGT GTT GAG Cys Val Glu TTT GAT GAT Phe Asp Asp 5005 CGA CCT GGC Arg Pro Gly TGC CAG ATA TGG Cys Gin Ile Trp 5010 GGA ATT TGT Gly Ile.Cys GAC CAG Asp Gin 5015 AAG TGT GAA Lys Cys Glu

AGC

Ser 5020 1117 1165 1213 1261 CGT CAC CTG Arg His Leu 5025 TGC CAC TGT Cys His Cys GAA GAA Glu Glu 5030 GGG TAT ATC Gly Tyr Ile TTG GAG CGT GGA CAG Leu Glu Arg Gly Gin 5035 TAT TGC AAA GCT AAT Tyr Cys Lys Ala Asn 5040 GAT TCC Asp Ser 5045 TTT GGC GAG Phe Gly Glu GCC TCC Ala Ser 5050 ATT ATC TTC Ile Ile Phe

TCC

Ser 5055 AAT GGT CGG GAT Asn Gly Arg Asp TTG TTA ATT GGT GAT Leu Leu Ile Gly Asp 5060 ATT CAT Ile His 5065 GGA AGG AGC Gly Arg Ser TTC CGG Phe Arg 5070 1309 ATC CTA GTG Ile Leu Val CAC TAT CAC His Tyr His 5090

GAG

Glu 5075 TCT CAG AAT CGT Ser Gin Asn Arg GGA GTG Gly Val 5080 GCC GTG GGT Ala Val Gly CTG CAA AGA GTT Leu Gin Arg Val TTT TGG ACA GAC ACC Phe Trp Thr Asp Thr 5095

GTG

Val 5100 GTG GCT TTC Val Ala Phe 5085 CAA AAT AAG Gin Asn Lys GTT CTC AAT Val Leu Asn 1357 1405 1453 GTT TTT TCA GTT GAC ATT Val Phe Ser Val Asp Ile 5105 AAT GGT Asn Gly 5110 TTA AAT ATC Leu Asn Ile CAA GAG Gin Glu 5115 GTT TCT Val Ser 5120 GTT GAA ACC Val Glu Thr CCA GAG AAC Pro Glu Asn 5125 CTG GCT GTG Leu Ala Val 5130 GAC TGG GTT AAT Asp Trp Val Asn

AAT

Asn 5135 1501 AAA ATC TAT CTA Lys Ile Tyr Leu GTG GAA Val Glu 5140 ACC AAG GTC AAC CGC ATA GAT ATG Thr Lys Val Asn Arg Ile Asp Met 5145 GTA AAT Val Asn 5150 1549 TTG GAT GGA Leu Asp Gly AGC TAT Ser Tyr 5155 CGG GTT ACC Arg Val Thr CTT ATA Leu Ile 5160 ACT GAA AAC Thr Glu Asn TTG GGG CAT Leu Gly His 5165 TTT TTC TCA Phe Phe Ser CCT AGA GGA ATT Pro Arg Gly Ile 5170 GCC GTG GAC Ala Val Asp CCA ACT Pro Thr 5175 GTT GGT TAT Val Gly Tyr

TTA

Leu 5180 1597 1645 1693 1741 GAT TGG GAG Asp Trp Glu 5185 AGC CTT TCT Ser Leu Ser GGG GAA CCT AAG CTG Gly Glu Pro Lys Leu 5190 GAA AGG GCA TTC ATG Glu Arg Ala Phe Met 5195 GAT GGC AGC AAC CGT Asp Gly Ser Asn Arg 5200 AAA GAC TTG GTG AAA Lys Asp Leu Val Lys 5205 ACA AAG Thr Lys 5210 CTG GGA TGG Leu Gly Trp

CCT

Pro 5215 GCT GGG GTA ACT Ala Gly Val Thr CTG GAT ATG ATA TCG Leu Asp Met Ile Ser 5220 AAG CGT GTT TAC TGG Lys Arg Val Tyr Trp 5225 GTT GAC Val Asp 5230 1789 TCT CGG TTT GAT TAC ATT GAA ACT GTA ACT TAT GAT GGA ATT CAA AGG Ser Arg Phe Asp Tyr Ile Glu Thr Val Thr Tyr Asp Gly Ile Gin Arg 1837 WO 96/15801 PCT/US95/15203 5235 AAG ACT GTA Lys Thr Val 5250 AGC TTA TTT Ser Leu Phe 5265 GTG CTG AAG Val Leu Lys 5280 GTT CAT GGA GGC Val His Gly Gly 5240 TCC CTC ATT CCT Ser Leu Ile Pro 5255 TTC TTT ACA GAT Phe Phe Thr Asp CAT CCC TTT GGA GTA His Pro Phe Gly Val 5260 5245 GAA GGT CAG Glu Gly Gin

GTG

Val 527C TGG ACA Trp Thr 5275 AAG ATG GCC Lys Met Ala GCA AAC Ala Asn AAG TTC Lys Phe 5285 ACA GAG ACC Thr Glu Thr AAC CCA CAA GTG TAC Asn Pro Gin Val Tyr 5290

TAC

Tyr 5295 CAG GCT TCC CTG Gin Ala Ser Leu AGG CCC Arg Pro 5300 TAT GGA GTG Tyr Gly Val ACT GTT Thr Val 5305 TAC CAT TCC Tyr His Ser CTC AGA Leu Arg 5310 CAG CCC TAT Gin Pro Tyr CAG GTC TGT Gin Val Cys 533C GCT ACC Ala Thr 5315 AAT CCG TGT Asn Pro Cys AAA GAT AAC AAT GGG Lys Asp Asn Asn Gly 5320 GGC TGT GAG Gly Cys Glu 5325 GTY CTC AGC CAC Val Leu Ser His AGA ACA GAT Arg Thr Asp 5335 AAT GAT GGT TTG GGT TTC Asn Asp Gly Leu Gly Phe 5340 1885 1933 1981 2029 2077 2125 2173 2221 2269 2317 2365 CGT TGC AAG TGC ACA TTC Arg Cys Lys Cys Thr Phe 5345 GGC TTC CAA CTG GAT Gly Phe Gin Leu Asp 5350 ACA GAT Thr Asp 5355 GAG CGC CAC Glu Arg His TGC ATT GCT GTT CAG Cys Ile Ala Val Gin 5360 AAT TTC Asn Phe 5365 CTC ATT TTT Leu Ile Phe TCA TCC Ser Ser 5370 CAA GTT GCT Gin Val Ala

ATT

Ile 5375 CGT GGG ATC CCG Arg Gly Ile Pro TTC ACC Phe Thr 5380 TTG TCT ACC Leu Ser Thr CAG GAA Gin Glu 5385 GAT GTC ATG Asp Val Met GTT CCA Val Pro 5390 GTT TCG GGG Val Ser Gly GAC AGC ACT Asp Ser Thr 541C AAT CCT TCT TTC TTT Asn Pro Ser Phe Phe 5395 GTC GGG Val Gly 5400 ATT GAT TTT Ile Asp Phe ATC TTT TTT TCA Ile Phe Phe Ser GAT ATG Asp Met 5415 TCA AAA CAC Ser Lys His

ATG

Met 542C GAC GCC CAG Asp Ala Gin 5405 ATT TTT AAG Ile Phe Lys AAC AGG GTG Asn Arg Val CAA AAG 1 Gin Lys 5425 GAA AAT Glu Asn 5440 ATT GAT GGC ACA Ile Asp Gly Thr GGA AGA GAA ATT CTC GCA GCT Gly Arg Glu Ile Leu Ala Ala 5430 5435 GTT GAA AGT Val Glu Ser TTG GCT Leu Ala 5445 TTT GAT TGG Phe Asp Trp ATT TCA Ile Ser 5450 AAG AAT CTC Lys Asn Leu

TAT

Tyr 5455 TGG ACA GAC TCT Trp Thr Asp Ser CAT TAC His Tyr 5460 AAG AGT ATC Lys Ser Ile AGT GTC ATG AGG CTA Ser Val Met Arg Leu 5465 GCT GAT Ala Asp 5470 2413 2461 2509 2557 2605 AAA ACG AGA Lys Thr Arg CGC ACG GTA GTT CAG Arg Thr Val Val Gin 5475 TAT TTA Tyr Leu 5480 AAT AAC CCA Asn Asn Pro CGG TCG GTG Arg Ser Val 5485 GTA GTT CAT CCT TTT GCC GGG TAT CTA TTC TTC ACT GAT TGG TTC CGT Val Val His Pro Phe Ala Gly Tyr Leu Phe Phe Thr Asp Trp Phe Arg WO 96/15801 PCT/US95/15203 /7q 5490 CCT GCT AAA Pro Ala Lys 5505 ATT ATG AGA Ile Met Arg 5495 GCA TGG Ala Trp 5510 AGT GAC GGA TCT CAC Ser Asp Gly Ser His 5515 CTC TTG CCT Leu Leu Pro 5500 GTA ATA AAC ACT ACT Val Ile Asn Thr Thr 5520 CTT GGA TGG CCC AAT Leu Gly Trp Pro Asn 5525 GGC TTG Gly Leu 5530 GCC ATC GAT Ala Ile Asp

TGG

Trp 5535 2653 2701 2749 GCT GCT TCA CGA Ala Ala Ser Arg TTG TAC TGG GTA GAT Leu Tyr Trp Val Asp 5540 GCC TAT Ala Tyr 5545 TTT GAT AAA Phe Asp Lys ATT GAG Ile Glu 5550 CAC AGC ACC His Ser Thr CAG ATG ACA Gin Met Thr 557C TTT ACT GAC Phe Thr Asp 5585 TTT GAT Phe Asp 5555 GGT TTA GAC Gly Leu Asp

AGA

Arg 5560 AGA AGA CTG Arg Arg Leu ATC TTT GGA Ile Phe Gly GGC CAT ATA GAG Gly His Ile Glu 5565 GAG CAT TTA TTT Glu His Leu Phe 5580 CAT CCG TTT GGA His Pro Phe Gly CTT GCC Leu Ala 5575 TGG AGA CTG Trp Arg Leu GGT GCC Gly Ala 5590 ATT ATT CGA Ile Ile Arg GTC AGG Val Arg 5595 AAA GCA GAT Lys Ala Asp 2797 2845 2893 2941 2989 GGT GGA Gly Gly 5600 GAA ATG ACA Glu Met Thr GTT ATC Val Ile 5605 CGA AGT GGC Arg Ser Gly ATT GCT Ile Ala 5610 TAC ATA CTG Tyr Ile Leu

CAT

His 5615 TTG AAA TCG TAT Leu Lys Ser Tyr GAT GTC Asp Val 5620 AAC ATC CAG Asn Ile Gin ACT GGT Thr Gly 5625 TCT AAC GCC Ser Asn Ala TGT AAT Cys Asn 5630 CAA CCC ACG Gin Pro Thr CCA AAT TTC Pro Asn Phe 5650

CAT

His 5635 CCT AAC GGT GAC Pro Asn Gly Asp TGC AGC Cys Ser 5640 CAC TTC TGC His Phe Cys CAG CGA GTG TGT Gin Arg Val Cys GGG TGC Gly Cys 5655 CCT TAT GGA Pro Tyr Gly

ATG

Met 5660 TTC CCG GTG Phe Pro Val 5645 AGG CTG GCT Arg Leu Ala CCA CCC ACG Pro Pro Thr 3037 3085 TCC AAT Ser Asn 5665 GAG CAG Glu Gin 5680 CAC TTG ACA TGC His Leu Thr Cys GAG GGG Glu Gly 5670 GAC CCA ACM Asp Pro Thr AAT GAA Asn Glu 5675 TGT GGC TTA Cys Gly Leu TTT TCC Phe Ser 5685 TTC CCC TGT Phe Pro Cys AAA AAT Lys Asn 5690 GGC AGA TGT Gly Arg Cys

GTG

Val 5695 CCC AAT TAC TAT Pro Asn Tyr Tyr CTC TGT GAT GGA GTC Leu Cys Asp Gly Val 5700 GAT GAT Asp Asp 5705 TGT CAT GAT Cys His Asp AAC' AGT Asn Ser 5710 3133 3181 3229 3277 3325 3373 GAT GAG CAA Asp Glu Gin TTC ACC TGT Phe Thr Cys 573C CTA TGT GGC ACA Leu Cys Gly Thr 5715 GGC CAT GGG GAG Gly His Gly Glu CTT AAT AAT ACC TGT TCA Leu Asn Asn Thr Cys Ser 5720 TCT TCG GCG Ser Ser Ala 5725 TGC ATT CCT GCA CAC Cys Ile Pro Ala His 5735 TGG CGC TGT GAC Trp Arg Cys Asp 5740 AAA CGC AAC GAC TGT GTG GAT GGC AGT GAT GAG CAC AAC TGC CCC ACC Lys Arg Asn Asp Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr WO 96/15801 PCT/US95/15203 5745 5750 /ao GAC ACC CAA Asp Thr Gin 5755 CAC GCA His Ala 5760 CCT GCT TCC TGC CTT Pro Ala Ser Cys Leu 5765 TAC ACC Tyr Thr 5770 TGT GAT AAT Cys Asp Asn

CAC

His 5775 3421 CAG TGT ATC TCA Gin Cys Ile Ser AAG AAC Lys Asn 5780 TGG GTC TGT GAC ACA Trp Val Cys Asp Thr 5785 GAC AAT GAT Asp Asn Asp TGT GGG Cys Gly 5790 3469 3517 GAT GGA TCT Asp Gly Ser GAT GAA AAG Asp Glu Lys 5795 AAC TGC AAT TCG Asn Cys Asn Ser 5800 ACA GAG ACA Thr Glu Thr TGC CAA CCT Cys Gin Pro 5805 AGT CAG TTT AAT Ser Gin Phe Asn 5810 TGC CCC AAT Cys Pro Asn CAT CGA His Arg 5815 TGT ATT GAC Cys Ile Asp CTA TCG TTT GTC Leu Ser Phe Val 5820 TGT GAT GGT Cys Asp Gly 5825 GAC AAG GAT Asp Lys Asp TGT GTT Cys Val 5830 GAT GGA TCT Asp Gly Ser GAT GAG Asp Glu 5835 GTT GGT TGT Val Gly Cys 3565 3613 3661 GTA TTA Val Leu 5840 AAC TGT ACT Asn Cys Thr GCT TCT Ala Ser 5845 CAA TTC AAG Gin Phe Lys TGT GCC Cys Ala 5850 AGT GGG GAT Ser Gly Asp

AAA

Lys 5855 TGT ATT GGC GTC Cys Ile Gly Val ACA AAT Thr Asn 5860 CGT TGT GAT Arg Cys Asp GGT GTT Gly Val 5865 TTT GAT TGC Phe Asp Cys AGT GAC Ser Asp 5870 AAC TCG GAT Asn Ser Asp GAA GCG Glu Ala 5875 GGC TGT CCA Gly Cys Pro ACC AGG Thr Arg 5880 CCT CCT GGT Pro Pro Gly ATG TGC CAC Met Cys His 5885 TCA GAT GAA TTT Ser Asp Glu Phe 5890 CAG TGC CAA Gin Cys Gin GAA GAT GGT Glu Asp Gly 5895 ATC TGC ATC CCG AAC TTC Ile Cys Ile Pro Asn Phe 5900 3709 3757 3805 3853 3901 TGG GAA TGT Trp Glu Cys 5905 GAT GGG CAT Asp Gly His CCA GAC TGC Pro Asp Cys 5910 CTC TAT GGA TCT Leu Tyr Gly Ser 5915 GAT GAG CAC Asp Glu His AAT GCC Asn Ala 5920 TGT GTC CCC Cys Val Pro AAG ACT TGC Lys Thr Cys 5925 CCT TCA TCA TAT Pro Ser Ser Tyr 5930 TTC CAC TGT Phe His Cys

GAC

Asp 5935 AAC GGA AAC TGC Asn Gly Asn Cys ATC CAC Ile His 5940 AGG GCA TGG Arg Ala Trp CTC TGT Leu Cys 5945 GAT CGG GAC Asp Arg Asp AAT GAC Asn Asp 5950 TGC GGG GAT Cys Gly Asp ATG AGT Met Ser 5955 GAT GAG AAG Asp Glu Lys GAC TGC Asp Cys 5960 CCT ACT CAG Pro Thr Gin CCC TTT CGC Pro Phe Arg 5965 3949 3997 4045 TGT CCT AGT TGG Cys Pro Ser Trp 5970 CTG AGT GTA GTG Leu Ser Val Val 5985 CAA TGG CAG Gin Trp Gin TGT CTT GGC Cys Leu Gly 5975 CAT AAC ATC TGT GTG AAT His Asn Ile Cys Val Asn 5980 TGC CCC AAT GGG ACA GAT Cys Pro Asn Gly Thr Asp 5995 TGT GAT GGC ATC TTT GAC Cys Asp Gly Ile Phe Asp 5990 4093 4141 GAG TCC CCA CTT TGC AAT GGG AAC AGC TGC TCA GAT TTC AAT GGT GGT Glu Ser Pro Leu Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly WO 96/15801 PCT/US95/15203 6000 TGT ACT CAC GAG Cys Thr His Glu 6005 6010 6015 TGT GTT Cys Val 6020 CAA GAG CCC Gin Glu Pro TTT GGG Phe Gly 6025 GCT AAA TGC CTA TGT Ala Lys Cys Leu Cys 6030 CCA TTG GGA Pro Leu Gly TTC TTA Phe Leu 6035 CTT GCC AAT Leu Ala Asn GAT TCT Asp Ser 6040 AAG ACC TGT Lys Thr Cys GAA GAC ATA Glu Asp Ile 6045 GAT GAA TGT GAT ATT CTA GGC TCT TGT AGC CAG CAC Asp Glu Cys Asp Ile Leu Gly Ser Cys Ser Gin His 6050 6055 TGT TAC AAT ATG Cys Tyr Asn Met 6060 AGA GGT TCT Arg Gly Ser 6065 TTC CGG TGC Phe Arg Cys TCG TGT Ser Cys 6070 GAT ACA GGC TAC ATG Asp Thr Gly Tyr Met 6075 TTA GAA AGT Leu Glu Ser 4189 .4237 4285 4333 4381 4429 4477 4525 GAT GGG Asp Gly 6080 AGG ACT TGC Arg Thr Cys AAA GTT Lys Val 6085 ACA GCA TCT Thr Ala Ser GAG AGT Glu Ser 6090 CTG CTG TTA Leu Leu Leu

CTT

Leu 6095 GTG GCA AGT CAG Val Ala Ser Gin AAC AAA Asn Lys 6100 ATT ATT GCC Ile Ile Ala GAC AGT Asp Ser 6105 GTC ACC TCC Val Thr Ser CAG GTC Gin Val 6110 CAC AAT ATC His Asn Ile TAT TCA Tyr Ser 6115 TTG GTC GAG Leu Val Glu AAT GGT Asn Gly 6120 TCT TAC ATT Ser Tyr Ile GTA GCT GTT Val Ala Val 6125 GAT TTT GAT TCA Asp Phe Asp Ser 6130 ATT AGT GGT Ile Ser Gly CGT ATC Arg Ile 6135 TTT TGG TCT Phe Trp Ser GAT GCA ACT CAG Asp Ala Thr Gin 6140 GGT AAA ACC Gly Lys Thr 6145 TGG AGT GCG Trp Ser Ala TTT CAA AAT Phe Gin Asn 6150 GGA ACG GAC AGA Gly Thr Asp Arg 6155 AGA GTG GTA Arg Val Val 4573 4621 TTT GAC Phe Asp 6160 AGT AGC ATC Ser Ser Ile ATC TTG ACT Ile Leu Thr 6165 GAA ACT ATT GCA Glu Thr Ile Ala 6170 ATA GAT TGG Ile Asp Trp

GTA

Val 6175 GGT CGT AAT CTT Gly Arg Asn Leu TAC TGG ACA Tyr Trp Thr 6180 GAC TAT GCT CTG GAA Asp Tyr Ala Leu Glu 6185 ACA ATT GAA GTC Thr Ile Glu Val 6190 4669 TCC AAA ATT Ser Lys Ile GAT GGG Asp Gly 6195 AGC CAC AGG Ser His Arg ACT GTG Thr Val 6200 CTG ATT AGT AAA AAC CTA Leu Ile Ser Lys Asn Leu 6205 ACA AAT CCA AGA Thr Asn Pro Arg 6210 GGA CTA GCA Gly Leu Ala TTA GAT Leu Asp 6215 CCC AGA ATG Pro Arg Met AAT GAG CAT CTA Asn Glu His Leu 6220 CTG TTC TGG Leu Phe Trp 6225 ATG GAC GGC Met Asp Gly 6240 TCT GAC TGG Ser Asp Trp GGC CAC Gly His 6230 CAC CCT CGC His Pro Arg ATC GAG Ile Glu 6235 CGA GCC AGC Arg Ala Ser ATC TTC TGG Ile Phe Trp 6255 4717 4765 4813 4861 4909 AGC ATG CGC ACT GTC Ser Met Arg Thr Val 6245 ATT GTC CAG GAC AAG Ile Val Gin Asp Lys 6250 CCC TGC GGC TTA ACT ATT GAC TAC CCC AAC AGA CTG CTC TAC TTC ATG Pro Cys Gly Leu Thr Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe Met WO 96/15801 PCTIUS95/15203 6260 6265 6270 GAC TCC TAT CTT GAT TAC ATG GAC TTT TGT GAT TAT AAT GGA CAC CAT 4957 Asp Ser Tyr Leu Asp Tyr MetAsp Phe Cys Asp Tyr Asn Gly His His 6275 6280 6285 CGG AGA CAG GTG ATA GCC AGT GAT TTG ATT ATA CGG CAC CCC TAT GCC 5005 Arg Arg Gin Val Ile Ala Ser Asp Leu Ile Ile Arg His Pro Tyr Ala 6290 6295 6300 CTA ACT CTC TTT GAA GAC TCT GTG TAC TGG ACT GAC CGT GCT ACT CGT 5053 Leu Thr Leu Phe Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg 6305 6310 6315 CGG GTT ATG CGA GCC AAC AAG TGG CAT GGA GGG AAC CAG TCA GTT GTA 5101 Arg Val Met Arg Ala Asn Lys Trp His Gly Gly Asn Gin Ser Val Val 6320 6325 6330 6335 ATG TAT AAT ATT CAA TGG CCC CTT GGG ATT GTT GCG GTT CAT CCT TCG 5149 Met Tyr Asn Ile Gin Trp Pro Leu Gly Ile Val Ala Val His Pro Ser 6340 6345 6350 AAA CAA CCA AAT TCC GTG AAT CCA TGT GCC TTT TCC CGC TGC AGC CAT 5197 Lys Gin Pro Asn Ser Val Asn Pro Cys Ala Phe Ser Arg Cys Ser His 6355 6360 6365 CTC TGC CTG CTT TCC TCA CAG GGG CCT CAT TTT TAC TCC TGT GTT TGT 5245 Leu Cys Leu Leu Ser Ser Gin Gly Pro His Phe Tyr Ser Cys Val Cys 6370 6375 6380 CCT TCA GGA TGG AGT CTG TCT CCT GAT CTC CTG AAT TGC TTG AGA GAT 5293 Pro Ser Gly Trp Ser Leu Ser Pro Asp Leu Leu Asn Cys Leu Arg Asp 6385 6390 6395 GAT CAA CCT TTC TTA ATA ACT GTA AGG CAA CAT ATA ATT TTT GGA ATC 5341 Asp Gin Pro Phe Leu Ile Thr Val Arg Gin His Ile Ile Phe Gly Ile 6400 6405 6410 6415 TCC CTT AAT CCT GAG GTG AAG AGC AAT GAT GCT ATG GTC CCC ATA GCA 5389 Ser Leu Asn Pro Glu Val Lys Ser Asn Asp Ala Met Val Pro Ile Ala 6420 6425 6430 GGG ATA CAG AAT GGT TTA GAT GTT GAA TTT GAT GAT GCT GAG CAA TAC 5437 Gly Ile Gin Asn Gly Leu Asp Val Glu Phe Asp Asp Ala Glu Gin Tyr 6435 6440 6445 ATC TAT TGG GTT GAA AAT CCA GGT GAA ATT CAC AGA GTG AAG ACA GAT 5485 Ile Tyr Trp Val Glu Asn Pro Gly Glu Ile His Arg Val Lys Thr Asp 6450 6455 6460 GGC ACC AAC AGG ACA GTA TTT GCT TCT ATA TCT ATG GTG GGG CCT TCT 5533 Gly Thr Asn Arg Thr Val Phe Ala Ser Ile Ser Met Val Gly Pro Ser 6465 6470 6475 ATG AAC CTG GCC TTA GAT TGG ATT TCA AGA AAC CTT TAT TCT ACC AAT 5581 Met Asn Leu Ala Leu Asp Trp Ile Ser Arg Asn Leu Tyr Ser Thr Asn 6480 6485 6490 6495 CCT AGA ACT CAG TCA ATC GAG GTT TTG ACA CTC CAC GGA GAT ATC AGA 5629 Pro Arg Thr Gin Ser Ile Glu Val Leu Thr Leu His Gly Asp Ile Arg 6500 6505 6510 TAC AGA AAA ACA TTG ATT GCC AAT GAT GGG ACA GCT CTT GGA GTT GGC 5677 Tyr Arg Lys Thr Leu Ile Ala Asn Asp Gly Thr Ala Leu Gly Val Gly WO 96/15801 PCTIS95/15203 1i3 6515 6520 6525 TTT CCA ATT GGC ATA ACT GTT GAT CCT GCT CGT GGG AAG CTG TAC TGG 5725 Phe Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp 6530 6535 6540 TCA GAC CAA GGA ACT GAC AGT GGG GTT CCT GCC AAG ATC GCC AGT GCT 5773 Ser Asp Gin Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala 6545 6550 6555 AAC ATG GAT GGC ACA TCT GTG AAA ACT CTC TTT ACT GGG AAC CTC GAA 5821 Asn Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu 6560 6565 6570 6575 CAC CTG GAG TGT GTC ACT CTT GAC ATC GAA GAG CAG AAA CTC TAC TGG 5869 His Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gin Lys Leu Tyr Trp 6580 6585 6590 GCA GTC ACT GGA AGA GGA GTG ATT GAA AGA GGA AAC GTG GAT GGA ACA 5917 Ala Val Thr Gly Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr 6595 6600 6605 GAT CGA ATG ATC CTG GTA CAC CAG CTT TCC CAC CCC TGG GGA ATT GCA 5965 Asp Arg Met Ile Leu Val His Gin Leu Ser His Pro Trp Gly Ile Ala 6610 6615 6620 GTC CAT GAT TCT TTC CTT TAT TAT ACT GAT GAA CAG TAT GAG GTC ATT 6013 Val His Asp Ser Phe Leu Tyr Tyr Thr Asp Glu Gin Tyr Glu Val Ile 6625 6630 6635 GAA AGA GTT GAT AAG GCC ACT GGG GCC AAC AAA ATA GTC TTG AGA GAT 6061 Glu Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp 6640 6645 6650 6655 AAT GTT CCA AAT CTG AGG GGT CTT CAA GTT TAT CAC AGA CGC AAT GCC 6109 Asn Val Pro Asn Leu Arg Gly Leu Gin Val Tyr His Arg Arg Asn Ala 6660 6665 6670 GCC GAA TCC TCA AAT GGC TGT AGC AAC AAC ATG AAT GCC TGT CAG CAG 6157 Ala Glu Ser Ser Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gin Gin 6675 6680 6685 ATT TGC CTG CCT GTA CCA GGA GGA TTG TTT TCC TGC GCC TGT GCC ACT 6205 Ile Cys Leu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr 6690 6695 6700 GGA TTT AAA CTC AAT CCT GAT AAT CGG TCC TGC TCT CCA TAT AAC TCT 6253 Gly Phe Lys Leu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser 6705 6710 6715 TTC ATT GTT GTT TCA ATG CTG TCT GCA ATC AGA GGC TTT AGC TTG GAA 6301 Phe Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu 6720 6725 6730 6735 TTG TCA GAT CAT TCA GAA ACC ATG GTG CCG GTG GCA GGC CAA GGA CGA 6349 Leu Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gin Gly Arg 6740 6745 6750 AAC GCA CTG CAT GTG GAT GTG GAT GTG TCC TCT GGC TTT ATT TAT TGG 6397 Asn Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp 6755 6760 6765 TGT GAT TTT AGC AGC TCA GTG GCA TCT GAT AAT GCG ATC CGT AGA ATT 6445 Cys Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile WO 96/15801 PCT/US95/15203 6770 6775 6780 AAA CCA GAT Lys Pro Asp 6785 GGA TCT TCT CTG ATG Gly Ser Ser Leu Met 6790 AAC ATT GTG ACA CAT Asn Ile Val Thr His 6795 GGA ATA GGA Gly Ile Gly GGA AAT CTT Gly Asn Leu 6815 6493 GAA AAT GGA GTC Glu Asn Gly Val 6800 STAT TTC ACC AAT Tyr Phe Thr Asn CGG GGT ATT Arg Gly Ile 6805 GCA GTG GAT Ala Val Asp TGG GTA GCA Trp Val Ala 6810 6541 6589 GCC TTT Ala Phe 6820 GTT TCT GAA Val Ser Glu ACA CTG Thr Leu 6825 ATA GAA GTT Ile Glu Val CTG CGG Leu Arg 6830 ATC AAT ACT ACT TAC CGC CGT GTT CTT CTT AAA GTC ACA Ile Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr GTG GAC ATG Val Asp Met 6845 6637 6835 6840 CCT AGG CAT ATT Pro Arg His Ile 6850 GTT GTA GAT Val Val Asp CCC AAG Pro Lys 6855 AAC AGA TAC Asn Arg Tyr CTC TTC TGG GCT Leu Phe Trp Ala 6860 6685 6733 GAC TAT GGG Asp Tyr Gly 6865 CAG AGA CCA Gin Arg Pro AAG ATT Lys Ile 6870 GAG CGT TCT Glu Arg Ser TTC CTT Phe Leu 6875 GAC TGT ACC Asp Cys Thr AAT CGA Asn Arg 6880 ACA GTG CTT Thr Val Leu GTG TCA Val Ser 6885 GAG GGC ATT Glu Gly Ile GTC ACA Val Thr 6890 CCA CGG GGC Pro Arg Gly

TTG

Leu 6895 6781 6829 GCA GTG GAC CGA Ala Val Asp Arg AGT GAT Ser Asp 6900 GGC TAC GTT Gly Tyr Val TAT TGG GTT Tyr Trp Val 6905 GAT GAT TCT TTA Asp Asp Ser Leu 6910 GAT ATA ATT Asp Ile Ile GCA AGG ATT Ala Arg Ile 6915 CGT ATC AAT GGA Arg Ile Asn Gly 6920 GAG AAC TCT Glu Asn Ser GAA GTG ATT Glu Val Ile 6925 6877 CGT TAT GGC AGT Arg Tyr Gly Ser 6930 CGT TAC CCA Arg Tyr Pro ACT CCT Thr Pro 6935 TAT GGC ATC Tyr Gly Ile ACT GTT TTT GAA Thr Val Phe Glu 6940 AAT TCT ATC Asn Ser Ile 6945 ATA TGG GTA Ile Trp Val GAT AGG Asp Arg 6950 AAT TTG AAA Asn Leu Lys AAG ATC Lys Ile 6955 TTC CAA GCC Phe Gin Ala 6925 6973 7021 7069 AGC AAG Ser Lys 6960 GAA CCA GAG Glu Pro Glu AAC ACA GAG Asn Thr Glu 6965 CCA CCC ACA GTG Pro Pro Thr Val 6970 ATA AGA GAC Ile Arg Asp

AAT

Asn 6975 ATC AAC TGG CTA Ile Asn Trp Leu AGA GAT Arg Asp 6980 GTG ACC ATC Val Thr Ile TTT GAC Phe Asp 6985 AAG CAA GTC Lys Gin Val CAG CCC Gin Pro 6990 CGG TCA CCA Arg Ser Pro GCA GAG GTC Ala Glu Val 6995 AAC AAC AAC CCT TGC Asn Asn Asn Pro Cys 7000 TTG GAA AAC AAT GGT Leu Glu Asn Asn Gly 7005 TTG CAC ACC CCA AAA Leu His Thr Pro Lys 7020 7117 7165 GGG TGC TCT CAT Gly Cys Ser His 7010 CTC TGC TTT Leu Cys Phe GCT CTG CCT GGA Ala Leu Pro Gly 7015 TGT GAC TGT GCC TTT GGG ACC CTG CAA AGT GAT GGC AAG AAT TGT GCC Cys Asp Cys Ala Phe Gly Thr Leu Gin Ser Asp Gly Lys Asn Cys Ala 7213 WO 96/15801 PCT/US95/15203 I s6 7025 7030 7035 ATT TCA Ile Ser 7040 ACA GAA AAT TTC CTC Thr Glu Asn Phe Leu 7045 ATC TTT GCC TTG Ile Phe Ala Leu 7050 AAC CAT AGC CCA Asn His Ser Pro 7065 TCT AAT TCC TTG AGA Ser Asn Ser Leu Arg 7055 CCT TTC CAA ACA ATA Pro Phe Gin Thr Ile 7070 AGC TTA CAC Ser Leu His AAT GTG GAA Asn Val Glu TTG GAC CCT Leu Asp Pro 7060 AGA ACT Arg Thr 7075 GTC ATG TCT Val Met Ser CTA GAC Leu Asp 7080 TAT GAC AGT Tyr Asp Ser GTA AGT GAT Val Ser Asp 7085 7261 7309 7357 7405 7453 7501 AGA ATC.TAC TTC Arg Ile Tyr Phe 7090 ACA CAA AAT Thr Gin Asn TTA GCC Leu Ala 7095 TCT GGA GTT Ser Gly Val GGA CAG ATT TCC Gly Gin Ile Ser 7100 TAT GCC ACC Tyr Ala Thr 7105 CTG TCT TCA Leu Ser Ser GGG ATC Gly Ile 7110 CAT ACT CCA His Thr Pro ACT GTC Thr Val 7115 ATT GCT TCA Ile Ala Ser GGT ATA Gly Ile 7120 GGG ACT GCT Gly Thr Ala GAT GGC Asp Gly 7125 ATT GCC TTT Ile Ala Phe GAC TGG Asp Trp 7130 ATT ACT AGA Ile Thr Arg

AGA

Arg 7135 ATT TAT TAC AGT Ile Tyr Tyr Ser GAC TAC Asp Tyr 7140 CTC AAC CAG Leu Asn Gin ATG ATT Met Ile 7145 AAT TCC ATG Asn Ser Met GCT GAA Ala Glu 7150 GAT GGG TCT Asp Gly Ser AAC CGC Asn Arg 7155 ACT GTG ATA Thr Val Ile GCC CGC Ala Arg 7160 GTT CCA AAA Val Pro Lys CCA AGA GCA Pro Arg Ala 7165 ATT GTG TTA GAT Ile Val Leu Asp 7170 CCC TGC CAA Pro Cys Gin GGG TAC Gly Tyr 7175 CTG TAC TGG Leu Tyr Trp GCT GAC TGG GAT Ala Asp Trp Asp 7180 7549 7597 7645 7693 7741 ACA CAT GCC Thr His Ala 7185 AAA ATC GAG Lys Ile Glu AGA GCC Arg Ala 7190 ACA TTG GGA Thr Leu Gly GGA AAC Gly Asn 7195 TTC CGC GTA Phe Arg Val ACT CTG GAC Thr Leu Asp 7215 CCC ATT Pro Ile 7200 GTG AAC AGC Val Asn Ser AGT CTG GTC Ser Leu Val 7205 ATG CCC AGT GGG CTG Met Pro Ser Gly Leu 7210 TAT GAA GAG GAC Tyr Glu Glu Asp CTT CTC Leu Leu 7220 TAC TGG GTG Tyr Trp Val GAT GCT Asp Ala 7225 AGT CTG CAG Ser Leu Gin AGG ATT Arg Ile 7230 7789 7837 GAA CGC AGC Glu Arg Ser ACT CTG Thr Leu 7235 ACG GGC GTG Thr Gly Val GAT CGT Asp Arg 7240 GAA GTC ATT Glu Val Ile GTC AAT GCA Val Asn Ala 7245 GCC GTT CAT GCT Ala Val His Ala 7250 TTT GGC TTG Phe Gly Leu ACT CTC TAT Thr Leu Tyr 7255 GGC CAG TAT ATT TAC TGG Gly Gin Tyr Ile Tyr Trp 7260 GCT AAC AAA TAT GAC GGG Ala Asn Lys Tyr Asp Gly 7275 7885 ACT GAC TTG TAC ACA Thr Asp Leu Tyr Thr 7265 CAA AGA ATT TAC CGA Gin Arg Ile Tyr Arg 7270 7933 7981 TCA GGT CAG ATT GCA ATG ACC ACA AAT TTG CTC TCC CAG CCC AGG GGA Ser Gly Gin Ile Ala Met Thr Thr Asn Leu Leu Ser Gin Pro Arg Gly WO 96/15801 PCT/US95/15203 7280 ATC AAC ACT GTT Ile Asn Thr Val 7285 GTG AAG Val Lys 7300 7290 AAC CAG AAA CAA CAG TGT AAC Asn Gin Lys Gin Gin Cys Asn 7305 GAA CAG TTT Glu Gin Phe AAT GGG Asn Gly 7315 GGC TGC AGC Gly Cys Ser CAT ATC His Ile 7320 TGT GCA CCA Cys Ala Pro 7295 AAT CCT TGT Asn Pro Cys 7310 GGT CCA AAT Gly Pro Asn 7325 TTG GCC AAC Leu Ala Asn 8029 8077 8125 GGT GCC GAG TGC Gly Ala Glu Cys 7330 CAG TGT CCA Gin Cys Pro CAT GAG GGC AAC TGG His Glu Gly Asn Trp 7335

TAT

Tyr 734C AAC AGG AAG Asn Arg Lys 7345 CAC TGC ATT His Cys Ile GTG GAC Val Asp 7350 AAT GGT GAA Asn Gly Glu CGA TGT GGT GCA TCT Arg Cys Gly Ala Ser 7355 TCC TTC ACC TGC TCC Ser Phe Thr Cys Ser 7360 AAT GGG Asn Gly 7365 CGC TGC ATC Arg Cys Ile TCG GAA Ser Glu 7370 GAG TGG AAG Glu Trp Lys

TGT

Cys 7375 8173 8221 8269 GAT AAT GAC AAC Asp Asn Asp Asn GAC TGT GGG GAT GGC Asp Cys Gly Asp Gly 7380 AGT GAT Ser Asp 7385 GAG ATG GAA Glu Met Glu AGT GTC Ser Val 7390 TGT GCA CTT Cys Ala Leu CAC ACC His Thr 7395 TGC TCA CCG Cys Ser Pro ACA GCC Thr Ala 7400 TTC ACC TGT Phe Thr Cys GCC AAT GGG Ala Asn Gly 7405 CGA TGT GTC CAA Arg Cys Val Gin 7410 TAC TCT TAC Tyr Ser Tyr CGC TGT Arg Cys 7415 GAT TAC TAC Asp Tyr Tyr AAT GAC TGT GGT Asn Asp Cys Gly 7420 GAT GGC AGT Asp Gly Ser 7425 GAT GAG GCA Asp Glu Ala GGG TGC Gly Cys 7430 CTG TTC AGG Leu Phe Arg GAC TGC Asp Cys 7435 AAT GCC ACC Asn Ala Thr ACG GAG TTT ATG Thr Glu Phe Met 7440 TGC AAT AAC Cys Asn Asn 7445 AGA AGG TGC Arg Arg Cys ATA CCT Ile Pro 7450 CGT GAG TTT Arg Glu Phe

ATC

Ile 7455 8317 8365 8413 8461 8509 8557 8605 TGC AAT GGT GTA Cys Asn Gly Val GAC AAC Asp Asn 7460 TGC CAT GAT Cys His Asp AAT AAC Asn Asn 7465 ACT TCA GAT Thr Ser Asp GAG AAA Glu Lys 7470 AAT TGC CCT Asn Cys Pro GAT CGC ACT TGC CAG Asp Arg Thr Cys Gin 7475 TCT GGA Ser Gly 7480 TAC ACA AAA Tyr Thr Lys TGT CAT AAT Cys His Asn 7485 TCA AAT ATT TGT ATT Ser Asn Ile Cys Ile 7490 CCT CGC GTT TAT TTG TGT Pro Arg Val Tyr Leu Cys 7495 GAC GGA GAC AAT GAC Asp Gly Asp Asn Asp 7500 TGT GGA GAT AAC AGT GAT GAA AAC Cys Gly Asp Asn Ser Asp Glu Asn 7505 7510 CCT ACT TAT Pro Thr Tyr TGC ACC Cys Thr 7515 ACT CAC ACG Thr His Thr ATT CCT CAA Ile Pro Gin 7535 8653 TGC AGC AGC AGT GAG Cys Ser Ser Ser Glu 7520 TTC CAA TGC Phe Gin Cys 7525 GCA TCT GGG CGC TGT Ala Ser Gly Arg Cys 7530 8701 CAT TGG TAT TGT GAT CAA GAA ACA GAT TGT TTT GAT GCC TCT GAT GAA His Trp Tyr Cys Asp Gin Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu 8749 WO 96/15801 PCTIUS95/15203 7540 7545 CGA ACA Arg Thr 7560 7550 CCT GCC TCT Pro Ala Ser TGT GGT Cys Gly 7555 CAC TCT GAG His Ser Glu TGC CTA GCT GAT GAG TTC Cys Leu Ala Asp Glu Phe 7565 8797 8845 AAG TGT GAT Lys Cys Asp 7570 GGT GGG AGG TGC Gly Gly Arg Cys ATC CCA Ile Pro 7575 AGC GAA TGG Ser Glu Trp ATC TGT GAC GGT Ile Cys Asp Gly 7580 GAT AAT GAC TGT GGG GAT Asp Asn Asp Cys Gly Asp 7585 ATG AGT Met Ser 7590 GAC GAG GAT Asp Glu Asp AAA AGG Lys Arg 7595 CAC CAG TGT His Gin Cys 8893 8941 CAG AAT Gin Asn 7600 CAA AAC TGC Gin Asn Cys TCG GAT Ser Asp 7605 TCC GAG TTT Ser Glu Phe CTC TGT GTA AAT GAC Leu Cys Val Asn Asp 7610

AGA

Arg 7615 CCT CCG GAC AGG Pro Pro Asp Arg AGG TGC Arg Cys 7620 ATT CCC CAG Ile Pro Gin TCT TGG GTC TGT GAT Ser Trp Val Cys Asp 7625 GGC GAT Gly Asp 7630 8989 GTG GAT TGT Val Asp Cys ACT GAC GGC TAC GAT Thr Asp Gly Tyr Asp 7635 GAG AAT Glu Asn 7640 CAG AAT TGC Gin Asn Cys ACC AGG AGA Thr Arg Arg 7645 TGT ATC CCA Cys Ile Pro ACT TGC TCT GAA Thr Cys Ser Glu 7650 AAT GAA TTC Asn Glu Phe ACC TGT Thr Cys 7655 GGT TAC GGA Gly Tyr Gly

CTG

Leu 7660 AAG ATA TTC Lys Ile Phe 7665 AGG TGT GAC Arg Cys Asp CGG CAC AAT GAC TGT Arg His Asn Asp Cys 7670 GGT GAC TAT AGC GAC Gly Asp Tyr Ser Asp 7675 9037 9085 9133 9181 9229 GAG AGG GGC TGC TTA Glu Arg Gly Cys Leu 7680 TAC CAG ACT TGC CAA Tyr Gin Thr Cys Gin 7685 CAG AAT Gin Asn 7690 CAG TTT ACC Gin Phe Thr

TGT

Cys 7695 CAG AAC GGG CGC Gin Asn Gly Arg TGC ATT AGT AAA ACC Cys Ile Ser Lys Thr 7700 TTC GTC Phe Val 7705 TGT GAT GAG Cys Asp Glu GAT AAT Asp Asn 7710 GAC TGT GGA Asp Cys Gly GAC GGA TCT GAT GAG Asp Gly Ser Asp Glu 7715 CTG ATG Leu Met 7720 CAC CTG TGC His Leu Cys CAC ACC CCA His Thr Pro 7725 GAA CCC ACG TGT Glu Pro Thr Cys 7730 CCA CCT CAC Pro Pro His GAG TTC Glu Phe 7735 AAG TGT GAC Lys Cys Asp AAT GGG CGC TGC Asn Gly Arg Cys 7740 TGT TTG GAC AAC Cys Leu Asp Asn 9277 9325 9373 ATC GAG ATG ATG AAA CTC Ile Glu Met Met Lys Leu 7745 TGC AAC CAC CTA GAT Cys Asn His Leu Asp 7750

GAC

Asp 7755 AGC GAT GAG AAA GGC Ser Asp Glu Lys Gly 7760 TGT GGC Cys Gly 7765 ATT AAT GAA Ile Asn Glu TGC CAT Cys His 7770 GAC CCT TCA Asp Pro Ser

ATC

Ile 7775 9421 AGT GGC TGC GAT Ser Gly Cys Asp CAC AAC TGC ACA GAC His Asn Cys Thr Asp 7780 ACC TTA ACC Thr Leu Thr 7785 AGT TTC TAT TGT Ser Phe Tyr Cys 7790 9469 9517 TCC TGT CGT CCT GGT TAC AAG CTC ATG TCT GAC AAG CGG ACT TGT GTT Ser Cys Arg Pro Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys Val WO 96/15801 PCT/US95/15203 7795 7800 7805 'GAT ATT GAT GAA Asp Ile Asp Glu 7810 TGC ACA GAG ATG CCT Cys Thr Glu Met Pro 7815 TTT GTC TGT AGC CAG AAG TGT Phe Val Cys Ser Gin Lys Cys 7820 9565 GAG AAT GTA Glu Asn Val 7825 ATA GGC TCC Ile Gly Ser TAC ATC Tyr Ile 7830 TGT AAG TGT Cys Lys Cys GCC CCA Ala Pro 7835 GGC TAC CTC Gly Tyr Leu 9613 9661 CGA GAA Arg Glu 7840 CCA GAT GGA Pro Asp Gly AAG ACC Lys Thr 7845 TGC CGG CAA Cys Arg Gin AAC AGT Asn Ser 7850 AAC ATC GAA Asn Ile Glu

CCC

Pro 7855 TAT CTC ATT TTT AGC AAC CGT TAC TAT Tyr Leu Ile Phe Ser Asn Arg Tyr Tyr 7860 TTG AGA Leu Arg 7865 AAT TTA ACT Asn Leu Thr ATA GAT Ile Asp 7870 9709 GGC TAT TTT Gly Tyr Phe TAC TCC Tyr Ser 7875 CTC ATC TTG Leu Ile Leu GAA GGA Glu Gly 7880 CTG GAC AAT Leu Asp Asn GTT GTG GCA Val Val Ala 7885 TTA GAT TTT GAC Leu Asp Phe Asp 7890 CGA GTA GAG Arg Val Glu AAG AGA Lys Arg 7895 TTG TAT TGG Leu Tyr Trp ATT GAT ACA CAG Ile Asp Thr Gin 7900 AGG CAA GTC Arg Gin Val 7905 ATC ATA AAC Ile Ile Asn 7920 ATT GAG AGA Ile Glu Arg ATG TTT Met Phe 7910 CTG AAT AAG Leu Asn Lys ACA AAC Thr Asn 7915 AAG GAG ACA Lys Glu Thr 9757 9805 9853 9901 9949 CAC AGA His Arg CTA CCA Leu Pro 7925 GCT GCA GAA Ala Ala Glu AGT CTG Ser Leu 7930 GCT GTA GAC Ala Val Asp

TGG

Trp 7935 GTT TCC AGA AAG Val Ser Arg Lys CTC TAC Leu Tyr 7940 TGG TTG GAT Trp Leu Asp GCC CGC Ala Arg 7945 CTG GAT GGC Leu Asp Gly CTC TTT Leu Phe 7950 GTC TCT GAC Val Ser Asp CTC AAT Leu Asn 7955 GGT GGA CAC Gly Gly His CGC CGC Arg Arg 7960 ATG CTG GCC Met Leu Ala CAG CAC TGT Gin His Cys 7965 GTG GAT GCC AAC Val Asp Ala Asn 7970 AAC ACC TTC Asn Thr Phe TGC TTT Cys Phe 7975 GAT AAT CCC Asp Asn Pro AGA GGA CTT GCC Arg Gly Leu Ala 7980 9997 10045 10093 10141 CTT CAC CCT Leu His Pro 7985 CAA TAT GGG Gin Tyr Gly TAC CTC TAC Tyr Leu Tyr 7990 TGG GCA GAC TGG Trp Ala Asp Trp 7995 GGT CAC CGC Gly His Arg GCA TAC Ala Tyr 8000 ATT GGG AGA Ile Gly Arg GTA GGC Val Gly 8005 ATG GAT GGA Met Asp Gly ACC AAC Thr Asn 8010 AAG TCT GTG Lys Ser Val

ATA

Ile 8015 ATC TCC ACC AAG TTA GAG TGG CCT AAT Ile Ser Thr Lys Leu Glu Trp Pro Asn 8020 GGC ATC Gly Ile 8025 ACC ATT GAT Thr Ile Asp TAC ACC Tyr Thr 8030 10189 AAT GAT CTA Asn Asp Leu CTC TAC TGG GCA Leu Tyr Trp Ala 8035 GAT GCC CAC CTG Asp Ala His Leu 8040 GGT TAC ATA GAG TAC Gly Tyr Ile Glu Tyr 8045 10237 TCT GAT TTG GAG GGC CAC CAT CGA CAC ACG GTG TAT GAT GGG GCA CTG Ser Asp Leu Glu Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu 10285 PCT/US95/15203 WO 96/15801 Si 8050 CCT CAC CCT Pro His Pro 8065 TTC GCT ATT Phe Ala Ile 8055 ACC ATT Thr Ile 8070 TTT GAA GAC ACT ATT Phe Glu Asp Thr Ile 8075 TAT TGG ACA Tyr Trp Thr 8060

GAT

Asp 8080 TGG AAT ACA AGG ACA GTG GAA AAG Trp Asn Thr Arg Thr Val Glu Lys 8U^b GGA AAC AAA Gly Asn Lys 8090 TAT GAT GGA Tyr Asp Gly

TCA

Ser 8095 10333 10381 10429 8085 AAT AGA CAG ACA Asn Arg Gin Thr CTG GTG Leu Val 8100 AAC ACA ACA Asn Thr Thr CAC AGA His Arg 8105 CCA TTT GAC Pro Phe Asp ATC CAT Ile His 8110 GTG TAC CAT Val Tyr His CCA TAT AGG CAG CCC Pro Tyr Arg Gin Pro 8115

ATT

Ile 8120 GTG AGC AAT Val Ser Asn CCC TGT GGT ACC Pro Cys Gly Thr 8125 CCA GGA GGA AAA Pro Gly Gly Lys 8140 AAC AAT GGT GGC Asn Asn Gly Gly 8130 TGT TCT CAT Cys Ser His CTC TGC CTC ATC AAG Leu Cys Leu Ile Lys 8135 GGG TTC ACT Gly Phe Thr 8145 TGC GAG TGT CCA GAT Cys Glu Cys Pro Asp 8150 GAC TTC CGC ACC CTT CAA CTG AGT Asp Phe Arg Thr Leu Gin Leu Ser 8155 GGC AGC ACC TAC TGC Gly Ser Thr Tyr Cys 8160 ATG CCC Met Pro 8165 ATG TGC TCC Met Cys Ser AGC ACC Ser Thr 8170 CAG TTC CTG Gin Phe Leu

TGC

Cys 8175 10477 10525 10573 10621 10669 10717 10765 10813 GCT AAC AAT GAA Ala Asn Asn Glu AAG TGC Lys Cys 8180 ATT CCT ATC Ile Pro Ile TGG TGG AAA Trp Trp Lys 8185 CTG GCC CTT Leu Ala Leu 0 TGT GAT GGA CAG Cys Asp Gly Gin 8190 TGC CCG CAG CGC Cys Pro Gin Arg 8205 AAA GAC TGC Lys Asp Cys TCA GAT Ser Asp 8195 GGC TCT GAT Gly Ser Asp

GAA

Glu 820( TTC TGC CGA Phe Cys Arg 821C CTG GGA CAG TTC Leu Gly Gin Phe CAG TGC AGT GAC GGC AAC TGC ACC AGC Gin Cys Ser Asp Gly Asn Cys Thr Ser 8215 8220 CCG CAG ACT Pro Gin Thr 8225 TTA TGC AAT Leu Cys Asn GCT CAC Ala His 8230 CAA AAT TGC Gin Asn Cys CCT GAT GGG TCT GAT Pro Asp Gly Ser Asp 8235 GAA GAC CGT CTT CTT Glu Asp Arg Leu Leu 8240 TGT GAG Cys Glu 8245 AAT CAC CAC Asn His His TGT GAC Cys Asp 8250 TCC AAT GAA Ser Asn Glu

TGG

Trp 8255 CAG TGC GCC AAC Gin Cys Ala Asn AAA CGT Lys Arg 8260 TGC ATC CCA Cys Ile Pro GAA TCC Glu Ser 8265 TGG CAG TGT Trp Gin Cys GAC ACA Asp Thr 8270 TTT AAC GAC Phe Asn Asp AGC AGG ACC Ser Arg Thr 829( TGT GAG Cys Glu 8275 GAT.AAC TCA Asp Asn Ser GAT GAA GAC AGT TCC Asp Glu Asp Ser Ser 8280 CAC TGT GCC His Cys Ala 3285 GGC CGC TGC Gly Arg Cys 10861 10909 10957 11005 11053 TGC CGG CCG GGC Cys Arg Pro Gly CAG TTT CGG TGT GCT AAT Gin Phe Arg Cys Ala Asn 8295 8300 ATC CCG CAG GCC TGG AAG TGT GAT GTG GAT AAT GAT TOT GGA GAC CAC Ile Pro Gin Ala Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His PCTfUS95/15203 WO 96/15801 8305 8310 8315 TCG GAT Ser Asp 8320 GAG CCC ATT Glu Pro Ile GAA GAA Glu Glu 8325 TGC ATG AGC TCT GCC Cys Met Ser Ser Ala 8330 CAT CTC TGT His Leu Cys

GAC

Asp 8335 AAC TTC ACA GAA Asn Phe Thr Glu TTC AGC TGC Phe Ser Cys 8340 AAA ACA AAT TAC Lys Thr Asn Tyr 8345 CGC TGC ATC Arg Cys Ile CCA AAG Pro Lys 8350 TGG GCC GTG Trp Ala Val TGC AAT Cys Asn 8355 GGT GTA GAT Gly Val Asp GAC TGC Asp Cys 8360 AGG GAC AAC Arg Asp Asn AGT GAT GAG Ser Asp Glu 8365 CAA GGC TGT GAG Gin Gly Cys Glu 8370 GAG AGG ACA Glu Arg Thr TGC CAT Cys His 8375 CCT GTG GGG Pro Val Gly GAT TTC CGC TGT Asp Phe Arg Cys 8380 AAA AAT CAC Lys Asn His 8385 CAC TGC ATC His Cys Ile CCT CTT CGT TGG.CAG Pro Leu Arg Trp Gin 8390 TGT GAT Cys Asp 8395 GGG CAA AAT Gly Gin Asn GAC TGT Asp Cys 8400 GGA GAT AAC Gly Asp Asn TCA GAT Ser Asp 8405 GAG GAA AAC Glu Glu Asn TGT GCT Cys Ala 8410 CCC CGG GAG Pro Arg Glu

TGC

Cys 8415 ACA GAG AGC Thr Glu Ser TGG ATC TGT Trp Ile Cys GAG TTT CGA TGT GTC Glu Phe Arg Cys Val 8420 GAC CAT TAC AAC GAC Asp His Tyr Asn Asp 8435 AAT CAG CAG Asn Gin Gin 8425 TGT GGG GAC Cys Gly Asp 8440 TGC ATT CCC Cys Ile Pro TCG CGA Ser Arg 8430 11101 11149 11197 11245 11293 11341 11389 11437 11485 11533 11581 11629 11677 AAC TCA GAT GAA CGG Asn Ser Asp Glu Arg 8445 GAC TGT GAG ATG Asp Cys Glu Met 8450 AGG ACC TGC Arg Thr Cys CAT CCT His Pro 8455 GAA TAT TTT Glu Tyr Phe CAG TGT ACA AGT Gin Cys Thr Ser 8460 GGA CAT TGT Gly His Cys 8465 GTA CAC AGT Val His Ser GAA CTG Glu Leu 8470 AAA TGC GAT Lys Cys Asp GGA TCC GCT GAC TGT Gly Ser Ala Asp Cys 8475 TTG GAT GCG TCT GAT Leu Asp Ala Ser Asp 8480 GAA GCT Glu Ala 8485 GAT TGT CCC Asp Cys Pro ACA CGC Thr Arg 8490 TTT CCT GAT Phe Pro Asp

GGT

Gly 8495 GCA TAC TGC CAG Ala Tyr Cys Gin GCT ACT Ala Thr 8500 ATG TTC GAA Met Phe Glu TGC AAA Cys Lys 8505 AAC CAT GTT Asn His Val TGT ATC Cys Ile 8510 CCG CCA TAT Pro Pro Tyr TGG AAA TGT GAT GGC Trp Lys Cys Asp Gly 8515 GAT GAT GAC TGT GGC Asp Asp Asp Cys Gly 8520 GAT GGT TCA Asp Gly Ser 8525 GAT GAA GAA Asp Glu Glu 853C CTT CAC CTG TGC Leu His Leu Cys TTG GAT Leu Asp 8535 GTT CCC TGT AAT TCA CCA AAC Val Pro Cys Asn Ser Pro Asn 8540 CGT TTC Arg Phe 8545 CGG TGT GAC AAC Arg Cys Asp Asn AAT CGC TGC ATT TAT Asn Arg Cys Ile Tyr 8550 AGT CAT GAG GTG TGC Ser His Glu Val Cys 8555 11725 11773 11821 AAT GGT GTG GAT GAC TGT GGA GAT GGA ACT GAT GAG ACA GAG GAG CAC Asn Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His WO 96/15801 PCT/US95/15203 8q/ 8570 8560 TGT AGA AAA CCG Cys Arg Lys Pro 8565 8575 ACC CCT Thr Pro 8580 AAA CCT TGT Lys Pro Cys ACA GAA TAT Thr Glu Tyr 8585 AAT GTG TGT Asn Val Cys 0 GGC AAT GGG Gly Asn Gly CAT TGC ATT CCA CAT His Cys Ile Pro His 8595

GAC

Asp 860C GAA TAT AAG TGT Glu Tyr Lys Cys 8590 GAT GAT GCC GAT Asp Asp Ala Asp 8605 AAA GGA AAA GAA Lys Gly Lys Glu 8620 ACC CAA TTA AAT Thr Gin Leu Asn GAC TGT GGT GAC Asp Cys Gly Asp 8610 TGG TCC GAT Trp Ser Asp GAA CTG GGT TGC AAT Glu Leu Gly Cys Asn 8615 11869 11917 11965 12013 12061 AGA ACA TGT Arg Thr Cys 8625 GCT GAA AAT Ala Glu Asn ATA TGC GAG CAA AAT Ile Cys Glu Gin Asn 8630

TGT

Cys 8635 GAA GGA GGA TTT ATC Glu Gly Gly Phe Ile 8640 TGC TCC Cys Ser 8645 TGT ACA GCT Cys Thr Ala GGG TTC Gly Phe 8650 GAA ACC AAT Glu Thr Asn

GTT

Val 8655 TTT GAC AGA ACC Phe Asp Arg Thr TCC TGT CTA GAT ATC Ser Cys Leu Asp Ile 8660 AAT GAA TGT GAA CAA Asn Glu Cys Glu Gin 8665 TTT GGG Phe Gly 8670 12109 ACT TGT CCC Thr Cys Pro TGT GCT GAT Cys Ala Asp 8690

CAG

Gln 8675 CAC TGC AGA AAT His Cys Arg Asn ACC AAA Thr Lys 8680 GGA AGT TAT Gly Ser Tyr GGC TTC ACG TCT Gly Phe Thr Ser ATG AGT Met Ser 8695 GAC CGC CCT Asp Arg Pro

GGA

Gly 8700 GAG TGT GTC Glu Cys Val 8685 AAA CGA TGT Lys Arg Cys AAT GTC CGA Asn Val Arg 12157 12205 GCA GCT GAG Ala Ala Glu 8705 GGT AGC TCT Gly Ser Ser CCT TTG TTG CTA Pro Leu Leu Leu 8710 CTG CCT GAC Leu Pro Asp 8715 12253 ATT CGA AAA TAT AAT Ile Arg Lys Tyr Asn 8720 CTC TCA TCT GAG AGG Leu Ser Ser Glu Arg 8725 TTC TCA GAG TAT CTT Phe Ser Glu Tyr Leu 8730

CAA

Gin 8735 12301 GAT GAG GAA TAT ATC CAA GCT GTT Asp Glu Glu Tyr Ile Gin Ala Val 8740 GAT TAT GAT TGG GAT CCC Asp Tyr Asp Trp Asp Pro 8745 GAG GAC Glu Asp 8750 12349 ATA GGC CTC Ile Gly Leu .TTT GGT GCT Phe Gly Ala 8770 AGT GTT Ser Val 8755 GTG TAT TAC Val Tyr Tyr ACT GTG Thr Val 8760 CGA GGG GAG Arg Gly Glu ATC AAA CGT GCC Ile Lys Arg Ala TAC ATC Tyr Ile 8775 CCC AAC TTT Pro Asn Phe

GAA

Glu 8780 GGC TCT AGG Gly Ser Arg 8765 TCC GGC CGC Ser Gly Arg GTA ATG CAG Val Met Gin AAT AAT Asn Asn 8785 CTT GTG CAG GAA Leu Val Gin Glu GTT GAC CTG AAA CTG Val Asp Leu Lys Leu 8790 AAA TAC Lys Tyr 8795 12397 12445 12493 12541 12589 CCA GAT GGA ATA Pro Asp Gly Ile 8800 GCA GTG GAC TGG GTT GGA Ala Val Asp Trp Val Gly 8805 AGG CAT ATT TAC TGG Arg His Ile Tyr Trp 8810

TCA

Ser 8815 GAT GTC AAG AAT AAA CGC ATT GAG GTG GCT AAA CTT GAT GGA AGG TAC Asp Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr WO 96/15801 PCT/US95/15203 /988 8825 8820 8830 AGA AAG TGG Arg Lys Trp GTG AAT CCC Val Asn Pro 885C CCT AAA CTC Pro Lys Leu 8865 CTG ATT Leu Ile 8835 TCC ACT GAC CTG GAC Ser Thr Asp Leu Asp 8840 CAA CCA GCT GCT ATT GCT Gin Pro Ala Ala Ile Ala 8845 AAA CTA GGG CTT Lys Leu Gly Leu ATG TTC Met Phe 8855 TGG ACT GAC Trp Thr Asp TGG GGA AAG GAA Trp Gly Lys Glu 8860 CGC AAC ATC CTG Arg Asn Ile Leu GAG TCT GCC Glu Ser Ala TGG ATG AAT GGA GAG Trp Met Asn Gly Glu 8870

GAC

Asp 8875 GTT TTC Val Phe 8880 GAG GAC CTT Glu Asp Leu GGT TGG Gly Trp 8885 CCA ACT GGC Pro Thr Gly CTT TCT ATC GAT TAT Leu Ser Ile Asp Tyr 8890

TTG

Leu 8895 AAC AAT GAC CGA Asn Asn Asp Arg

ATC

Ile 8900 ACC ATA AAA Thr Ile Lys TAT GAT Tyr Asp 8915 TAC TGG AGT GAC Tyr Trp Ser Asp GGG ACT GAT AGG Gly Thr Asp Arg 892( CTG GAC ATC TTT Leu Asp Ile Phe 8935 AGA GTC ATT Arg Val Ile 0 GAA GAC CAG Glu Asp Gin GCA AAG GAA GCA Ala Lys Glu Ala 8925 TTA TAC TGG ATA Leu Tyr Trp Ile 8940 TTC AAG GAG GAC Phe Lys Glu Asp 8905 GTT ATT GAA Val Ile Glu 8910 ATG AAC CCT TAC AGC Met Asn Pro Tyr Ser 8930 TCT AAG GAA AAG GGA GAA Ser Lys Glu Lys Gly Glu 8945 GTA TGG AAA CAA AAT Val Trp Lys Gin Asn 8950 AAA TTT GGG CAA GGA Lys Phe Gly Gin Gly 8955 12637 12685 12733 12781 12829 12877 12925 12973 13021 13069.

13117 13165 13213 13261 13309 13357 AAG AAA GAG AAA ACG Lys Lys Glu Lys Thr 8960 CTG GTA GTG AAC CCT Leu Val Val Asn Pro 8965 TGG CTC Trp Leu 8970 ACT CAA GTT Thr Gin Val

CGA

Arg 8975 ATC TTT CAT CAA Ile Phe His Gin CTC AGA Leu Arg 8980 TAC AAT AAG Tyr Asn Lys TCA GTG Ser Val 8985 CCC AAC CTT Pro Asn Leu TGC AAA Cys Lys 8990 CAG ATC TGC AGC Gin Ile Cys Ser 8995 GCC TGT CCC CAA Ala Cys Pro Gin 9010 CAC CTC TGC CTT CTG AGA His Leu Cys Leu Leu Arg 5 9000 CCT GGA GGA Pro Gly Gly TAC AGC TGT Tyr Ser Cys 9005 GGC TCC AGC Gly Ser Ser TTT ATA GAG GGG AGC Phe Ile Glu Gly Ser 9015 ACC ACT GAG TGT Thr Thr Glu Cys 9020 CCA TGC AGG TGC Pro Cys Arg Cys GAT GCA GCC Asp Ala Ala 9025 ATT GAA CTG Ile Glu Leu CCT ATC AAC CTG CCC Pro Ile Asn Leu Pro 9030

CCC

Pro 9035 ATG CAC GGA GGA AAT Met His Gly Gly Asn 9040 TGC TAT TTT GAT GAG Cys Tyr Phe Asp Glu 9045 ACT GAC Thr Asp 9050 CTC CCC AAA Leu Pro Lys

TGC

Cys 9055 AAG TGT CCT AGC Lys Cys Pro Ser GGC TAC Gly Tyr 9060 ACC GGA AAA Thr Gly Lys TAT TGT GAA Tyr Cys Glu 9065 ATG GCG TTT TCA Met Ala Phe Ser 9070 AAA GGC ATC TCT CCA GGA A A ACC GCA GTA GCT GTG CTG TTG ACA ATC Lys Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile PCT/US95/15203 WO 96/15801 1q3 9080 9085 9075 CTC TTG ATC GTC Leu Leu Ile Val 9090 GTA ATT GGA Val Ile Gly GCT CTG Ala Leu 9095 GCA ATT GCA GGA TTC TTC CAC Ala Ile Ala Gly Phe Phe His 9100 TAT AGA AGG Tyr Arg Arg 9105 ACC GGC TCC Thr Gly Ser CTT TTG CCT GCT CTG CCC AAG CTG CCA AGC Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser 9110 9115 TTA AGC Leu Ser 9120 AGT CTC GTC Ser Leu Val AAG CCC Lys Pro 9125 TCT GAA AAT Ser Glu Asn GGG AAT Gly Asn 9130 GGG GTG ACC Gly Val Thr

TTC

Phe 9135 AGA TCA GGG GCA GAT CTT AAC ATG GAT ATT GGA GTG TCT GGT Arg Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly TTT GGA Phe Gly 9150 13405 13453 13501 13549 13597 13645 13693 13741 9140 9145 CCT GAG ACT Pro Glu Thr ATG GAA ATG Met Glu Met 9170 GCC AGA GAC Ala Arg Asp 9185 TCT GAA AAT Ser Glu Asn 9200 GCT ATT GAC AGG TCA Ala Ile Asp Arg Ser 9155 ATG GCA ATG AGT GAA Met Ala Met Ser Glu 9160 GGG AAG CAG CCC Gly Lys Gin Pro ATA ATA Ile Ile 9175 TTT GAA AAC Phe Glu Asn

CCA

Pro 9180 GAC TTT GTC Asp Phe Val 9165 ATG TAC TCA Met Tyr Ser GTG ACT GTA Val Thr Val AAC CCT TCT Asn Pro Ser 9215 AGT GCT GTC Ser Ala Val AAA GTG GTT CAG CCA Lys Val Val Gin Pro 9190 ATC CAG Ile Gin 9195 GTG GAT AAT AAG Val Asp Asn Lys 9205 AAT TAT GGA Asn Tyr Gly AGT CCC ATA Ser Pro Ile 9210 GAG ATA GTT CCA Glu Ile Val Pro GAG ACA Glu Thr 9220 AAC CCA ACT Asn Pro Thr TCA CCA Ser Pro 9225 GCT GCT GAT GGA ACT Ala Ala Asp Gly Thr 9230 CAG GTG ACA Gin Val Thr AAC TTT GAA Asn Phe Glu 925C AAA TGG Lys Trp 9235 AAT CTC TTC Asn Leu Phe

AAA

Lys 9240 CGA AAA TCT Arg Lys Ser AAA CAA ACT ACC Lys Gin Thr Thr 9245 GAG CAA AAG GAA Glu Gin Lys Glu 9260 13789 13837 13885 AAT CCA ATC TAT Asn Pro Ile Tyr GCA CAG ATG GAG AAC Ala Gin Met Glu Asn 9255 AGT GTT GCT GCG ACA CCA Ser Val Ala Ala Thr Pro 9265 CCT CCA TCA CCT TCG Pro Pro Ser Pro Ser 9270 CTC CCT Leu Pro 9275 GCT AAG CCT Ala Lys Pro GCA ACA GAA Ala Thr Glu 9295 AAG CCT CCT TCG AGA Lys Pro Pro Ser Arg 9280 AGA GAC Arg Asp 9285 CCA ACT CCA Pro Thr Pro ACC TAT TCT Thr Tyr Ser 9290 13933 13981 14029 14044 GAC ACT TTT AAA Asp Thr Phe Lys GAC ACC GCA Asp Thr Ala 9300 AAT CTT GTT AAA GAA GAC TCT Asn Leu Val Lys Glu Asp Ser 9305 GAA GTA Glu Val 9310 TAG CTATACCAGC TA INFORMATION FOR SEQ ID WO 96/15801 PCT/US95/15203 lq/ SEQUENCE CHARACTERISTICS: LENGTH: 4656 amino acids TYPE: amino acid TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID Met Asp Arg Gly Pro Ala Ala Val Ala Cys Thr Leu Leu Leu Ala Leu 1 .5 10 Val Ala Cys Leu Ala Pro Ala Ser Gly Gin Glu Cys Asp Ser Ala His 20 25 Phe Arg Cys Gly Ser Gly His Cys Ile Pro Ala Asp Trp Arg Cys Asp 40 Gly Thr Lys Asp Cys Ser Asp Asp Ala Asp Glu Ile Gly Cys Ala Val 55 Val Thr Cys Gin Gin Gly Tyr Phe Lys Cys Gin Ser Glu Gly Gin Cys 70 75 Ile Pro Ser Ser Trp Val Cys Asp Gin Asp Gin Asp Cys Asp Asp Gly 90 Ser Asp Glu Arg Gin Asp Cys Ser Gin Ser Thr Cys Ser Ser His Gin 100 105 110 Ile Thr Cys Ser Asn Gly Gin Cys Ile Pro Ser Glu Tyr Arg Cys Asp 115 120 125 His Val Arg Asp Cys Pro Asp Gly Ala Asp Glu Asn Asp Cys Gin Tyr 130 135 140 Pro Thr Cys Glu Gin Leu Thr Cys Asp Asn Gly Ala Cys Tyr Asn Thr 145 150 155 160 Ser Gin Lys Cys Asp Trp Lys Val Asp Cys Arg Asp Ser Ser Asp Glu 165 170 175 Ile Asn Cys Thr Glu Ile Cys Leu His Asn Glu Phe Ser Cys Gly Asn 180 185 190 Gly Glu Cys Ile Pro Arg Ala Tyr Val Cys Asp His Asp Asn Asp Cys 195 200 205 Gin Asp Gly Ser Asp Glu His Ala Cys Asn Tyr Pro Thr Cys Gly Gly 210 215 220 Tyr Gin Phe Thr Cys Pro Ser Gly Arg Cys Ile Tyr Gin Asn Trp Val 225 230 235 240 Cys Asp Gly Glu Asp Asp Cys Lys Asp Asn Gly Asp Glu Asp Gly Cys 245 250 255 Glu Ser Gly Pro His Asp Val His Lys Cys Ser Pro Arg Glu Trp Ser 260 265 270 Cys Pro Glu Ser Gly Arg Cys Ile Ser Ile Tyr Lys Val Cys Asp Gly 275 280 285 WO 96/15801 PCTUS95/15203 Thr Gly lie Leu Asp Cys Pro Giy Arg Giu Asp Glu 290 295 Asn Asn Thr Ser 300 Lys 305 Cys I Ile I Gin His Cys 385 Gly Leu Tyr Phe Ser 465 Ile Asp Arg Trp Gly 545 'Yr is [le Ile eu 370 Lys Arg Vai His Ser 450 Val Tyr Glj Gi Gii 534 Cys E Glu Asn I Trp 355 Cys Ala Asp Glu Leu 435 Vai Glu Leu Ser Ile 515 j Ser 0 er I Chr iis 340 ly His Asn Leu Ser 420 Gin Asp Thr Vai Tyr 500 le t Pro 325 Asn Ile Cys Asp Leu 405 Gin Arg Ile Pro Gl 48~ ArC Thr I 310 Tyr Asp Cys Glu Ser 390 Ile Asn Vai Asn Glu 470 Thr I Vai jeu 3 iy Ser Asp lu 375 Phe Gly Arg Phe Gly 455 Asn Lys Thr Cys Ser Aia 1 3 Gly Aia Cys 1 330 Arg Thr Cys 1 345 Gin Lys Cys 360 Gly Tyr Ile Gly Giu Ala Asp Ile His 410 Gly Vai Ala 425 Trp Thr Asp 440 Leu Asn Ile Leu Aia Vai Vai Asn Arg 490 Leu Ile Thr 505 Thr Vai Gly 520 ~eu 115 ?he Ial lu Leu Ser 395 ly Vai Thr Gin Asp 475 Ile Glu Tyr Asn C Cys I Glu I Ser Glu 380 Ile Arg Gly Vai Glu 460 Trp Asp Asn Leu -ys Sro ?he krg 365 Arg Ile Ser Val Gin 445 Val Va Met Let Phe 52 Gin *J Pro C Asp 350 Pro Gly Phe Phe Ala 430 Asn Leu Asn Vai i Gly 510 e Phe a Phe [Pyr .ly 335 ksp ly ln Ser Arg 415 Phe Lys Asn Asn Asn 495 His Ser Met Gin 320 Tyr Cys Arg Tyr Asn 400 Ile His Vai Vai Lys 480 Leu Pro Asp Asp Ala Vai Asp Prc Leu Ser Giy Giu Pro Lys Leu Giu Arg Al 535 540 Ser Asn Arg Lys Asp Leu Vai Lys Thr Lys Leu Giy Trp Pro Ala 550 555 560 Gly Vai Arg Phe Thr Val Leu Phe 610 Leu Lys Thr Asp Val 595 Glu Ala Leu Tyr 580 His Gly Asn Asp 565 Ile Gly Gin Lys Met Glu Gly Val Phe Ile Thr Ser Phe 615 Thr Ser Vai Leu 600 Phe Glu Lys Thr 585 Ile Thr Thr Arg 570 Tyr Pro Asp Asn Val Tyr Asp Gly His Pro Trp Thr 620 Pro Gin Trp Ile Phe 605 Lys Val Val Asp 575 Gin Arg 590 Gly Vai Met Ala Tyr Tyr Ser Lys Ser Val Gin WO 96/15801 625 Ala Pro Ser Tyr Leu Ala Arg Thr Pro 645 Asn 630 Pro Gly Cys Val1 Lys Val1 650 Asn 635 Tyr Asn PCTfUS95/15203 640 Arg Gin 655 Giu Gin His Gly Leu Cys 670 660 Val1 Cys Ile 705 Giy Ser Ser Lys Asn 785 Cys Val Leu Ser His Arg Lys 690 Ala Ile Gly Thr Ile 770 Val1 675 Cys Val Pro Asn Ile 755 Asp Giu Thr Gin Phe Pro 740 Phe Gly Ser Phe Asn Thr 725 Ser Phe Thr Leu Tyr Gly Phe 710 Leu Phe Ser Giy Aia 790 Lys Phe 695 Leu Ser Phe Asp Arg 775 Phe Ser Thr 680 Gin Ile Thr Vali Met 760 Giu Asp Ile ksp ELeu Phe Gin Giy 745 Ser Ile Trp Ser Asn Asp Ser Giu 730 Ile Lys Leu Ile Val1 810 Asp Thr Ser 715 Asp Asp His Aia Ser 795 Met Gly Asp 700 Gin Val1 Phe Met Aia 780 Lys Arg Leu 685 Giu Val1 Met Asp Ile 765 Asn Asn Leu Giy Arg Aia Vali Aia 750 Phe Arg Leu Ala Phe His Ile Pro 735 Gin Lys Vali Tyr Asp 815 Arg Cys Arg 720 Val1 Asp Gin Giu Trp 800 Lys Thr Asp Ser His 805; Thr Arg Arg Thr Vai Val Gin Tyr 820 Leu Asn Asn Pro Arg Ser Val Vai 825 830 Val Ala Ile 865 Ala Ser Met Thr Gly Hjis Lys 850 As n Ser Thr Thr Asp 930 Glu Pro 835 Ile Thr Arg Phe His 915 Trp Met Phe Met Thr Leu Asp 900 Pro Arg Thr Ala Arg Leu Tyr 885 Gly Phe Leu Val Gly Ala Gly 870 Trp Leu Gly Giy Ile Tyr Trp 855 Trp Val1 Asp Leu Ala 935 Arg Leu 840 Ser Pro Asp Arg Ala 920 Ile Ser Phe Asp Asn Ala Arg 905 Ile Ile Gly Phe Gly C ly Tyr 890 Arg Phe Arg Ile Thr Ser Leu 875 Phe Leu Gly Val Ala 955 ksp Hlis 860 Ala Asp G ly Giu Arg 940 Tyr Trp 845 Leu Ile Lys His His 925 Lys Ile Phe Leu Asp Ile Ile 910 Leu Ala Lei.

Arg Pro, Trp Giu 895 Giu Phe Asp aHis Pro Val1 Ala 880 His Gin Phe Gly Leu 960 950 Lys Ser Tyr Asp Val1 965 Asn Ile Gin Thr Gly Ser 970 Asn Ala Cys Asn Gin 975 WO 96/15801 PCTIUS95/15203 Pro Thr His Pro Asn Gly Asp Cys Ser His Phe Cys Phe Pro Val Pro 980 985 990 Asn Phe Gin Arg Val Cys Gly Cys Pro Tyr Gly Met Arg Leu Ala Ser 995 1000 1005 Asn His Leu Thr Cys Glu Gly Asp Pro Thr Asn Glu Pro Pro Thr Glu 1010 1015 1020 Gin Cys Gly Leu Phe Ser Phe Pro Cys Lys Asn Gly Arg Cys Val Pro 1025 1030 1035 1040 Asn Tyr Tyr Leu Cys Asp Gly Val Asp Asp Cys His Asp Asn Ser Asp 1045 1050 1055 Glu Gin Leu Cys Gly Thr Leu Asn Asn Thr Cys Ser Ser Ser Ala Phe 1060 1065 1070 Thr Cys Gly His Gly Glu Cys Ile Pro Ala His Trp Arg Cys Asp Lys 1075 1080 1085 Arg Asn Asp Cys Val Asp Gly Ser Asp Glu His Asn Cys Pro Thr His 1090 1095 1100 Ala Pro Ala Ser Cys Leu Asp Thr Gin Tyr Thr Cys Asp Asn His Gin 1105 1110 1115 1120 Cys Ile Ser Lys Asn Trp Val Cys Asp Thr Asp Asn Asp Cys Gly Asp 1125 1130 1135 Gly Ser Asp Glu Lys Asn Cys Asn Ser Thr Glu Thr Cys Gin Pro Ser 1140 1145 1150 Gin Phe Asn Cys Pro Asn His Arg Cys Ile Asp Leu Ser Phe Val Cys 1155 1160 1165 Asp Gly Asp Lys Asp Cys Val Asp Gly Ser Asp Glu Val Gly Cys Val 1170 1175 1180 Leu Asn Cys Thr Ala Ser Gin Phe Lys Cys Ala Ser Gly Asp Lys Cys 1185 1190 1195 1200 Ile Gly Val Thr Asn Arg Cys Asp Gly Val Phe Asp Cys Ser Asp Asn 1205 1210 1215 Ser Asp Glu Ala Gly Cys Pro Thr Arg Pro Pro Gly Met Cys His Ser 1220 1225 1230 Asp Glu Phe Gin Cys Gin Glu Asp Gly Ile Cys Ile Pro Asn Phe Trp 1235 1240 1245 Glu Cys Asp Gly His Pro Asp Cys Leu Tyr Gly Ser Asp Glu His Asn 1250 1255 1260 Ala Cys Val Pro Lys Thr Cys Pro Ser Ser Tyr Phe His Cys Asp Asn 1265 1270 1275 1280 Gly Asn Cys Ile His Arg Ala Trp Leu Cys Asp Arg Asp Asn Asp Cys 1285 1290 1295 Gly Asp Met Ser Asp Glu Lys Asp Cys Pro Thr Gin Pro Phe Arg Cys 1300 1305 1310 WO 96/15801 PCTJUS95/ Pro Ser Trp Gin Trp Gin Cys Leu Gly His Asn Ile Cys Val Asn Leu 1315 1320 1325 Ser Val Val Cys Asp Gly Ile Phe Asp Cys Pro Asn Gly Thr Asp Glu 1330 1335 1340 Ser Pro Leu Cys Asn Gly Asn Ser Cys Ser Asp Phe Asn Gly Gly Cys 1345 1350 1355 1360 Thr His Glu Cys Val Gin Glu Pro Phe Gly Ala Lys Cys Leu Cys Pro 1365 1370 1375 Leu Gly Phe Leu Leu Ala Asn Asp Ser Lys Thr Cys Glu Asp Ile Asp 1380 1385 1390 Glu Cys Asp Ile Leu Gly Ser Cys Ser Gin His Cys Tyr Asn Met Arg 1395 1400 1405 Gly Ser Phe Arg Cys Ser Cys Asp Thr Gly Tyr Met Leu Glu Ser Asp 1410 1415 1420 Gly Arg Thr Cys Lys Val Thr Ala Ser Glu Ser Leu Leu Leu Leu Val 1425 1430 1435 1440 Ala Ser Gin Asn Lys Ile Ile Ala Asp Ser Val Thr Ser Gin Val His 1445 1450 1455 Asn Ile Tyr Ser Leu Val Glu Asn Gly Ser Tyr Ile Val Ala Val Asp 1460 1465 1470 Phe Asp Ser Ile Ser Gly Arg Ile Phe Trp Ser Asp Ala Thr Gin Gly 1475 1480 1485 Tl.. m, m Ala Phe Gln Asn Giv Thr Asp Arg Arg Val Val Phe /15203 1490 1495 1500 Asp Ser Ser Ile Ile Leu Thr Glu Thr Ile Ala Ile Asp Trp Val Gly 1505 1510 1515 1520 Arg Asn Leu Tyr Trp Thr Asp Tyr Ala Leu Glu Thr Ile Glu Val Ser 1525 1530 1535 Lys Ile Asp Gly Ser His Arg Thr Val Leu Ile Ser Lys Asn Leu Thr 1540 1545 1550 Asn Pro Arg Gly Leu Ala Leu Asp Pro Arg Met Asn Glu His Leu Leu 1555 1560 1565 Phe Trp Ser Asp Trp Gly His His Pro Arg Ile Glu Arg Ala Ser Met 1570 1575 1580 Asp Gly Ser Met Arg Thr Val Ile Val Gin Asp Lys Ile Phe Trp Pro 1585 1590 1595 1600 Cys Gly Leu Thr Ile Asp Tyr Pro Asn Arg Leu Leu Tyr Phe Met Asp 1605 1610 1615 Ser Tyr Leu Asp Tyr Met Asp Phe Cys Asp Tyr Asn Gly His His Arg 1620 1625 1630 6 Arg Gin Val Ile Ala Ser Asp Leu Ile Ile Arg His Pro Tyr Ala Leu 1635 1640 1645 Thr Leu Phe Glu Asp Ser Val Tyr Trp Thr Asp Arg Ala Thr Arg Arg PCTfUS95/15203 WO 96/15801 1650 Val Met Arg Ala 1665 Tyr Asn Ile Gin Gin Pro Asn Ser 1700 Cys Leu Leu Ser 1715 Ser Gly Trp Ser 1730 Gin Pro Phe Leu 1745 Leu Asn Pro Glu Ile Gin Asn Gly 1780 Tyr Trp Val Glu 1795 Thr Asn Arg Thr 1810 Asn Leu Ala Leu 1825 Arg Thr Gin Ser Arg Lys Thr Leu 186 1655 sn Lys Trp 1670 crp Pro Leu 1685 Jal Asn Pro Ser Gin Gly 966 i660 His Gly Cys Pro 1720

I

Leu Ser Pro Asp 1735 Ile Thr Val Arg 1750 Val Lys Ser Asn 1765 Leu Asp Val Glu Asn Pro Gly Glu 1800 Val Phe Ala Ser 1815 Asp Trp Ile Ser 1830 Ile Glu Val Leu 1845 Ile Ala Asn Asp 0 ly Gly Asn Gin S 1675 le.Val Ala Val H 1690 Ala Phe Ser Arg L705 His Phe Tyr Ser Leu Leu Asn Cys 1740 Gln His Ile Ile 1755 Asp Ala Met Val 1770 Phe Asp Asp Ala 1785 Ile His Arg Val Ile Ser Met Val 1820 Arg Asn Leu Tyr 1835 Thr Leu His Gly 1850 Gly Thr Ala Leu 1865 er Val Val Met 1680 is Pro Ser Lys 1695 :ys Ser His Leu 1710 Cys Val Cys Pro 1725 Leu Arg Asp Asp Phe Gly Ile Ser 1760 Pro Ile Ala Gly 1775 Glu Gin Tyr Ile 1790 Lys Thr Asp Gly 1805 Gly Pro Ser Met Ser Thr Asn Pro 1840 Asp Ile Arg Tyr 1855 Gly Val Gly Phe 1870 Pro Ile Gly Ile Thr Val Asp Pro Ala Arg Gly Lys Leu Tyr Trp Ser 1875 1880 1885 Asp Gin Gly Thr Asp Ser Gly Val Pro Ala Lys Ile Ala Ser Ala Asn 1890 1895 1900 Met Asp Gly Thr Ser Val Lys Thr Leu Phe Thr Gly Asn Leu Glu His 1905 1910 1915 1920 Leu Glu Cys Val Thr Leu Asp Ile Glu Glu Gin Lys Leu Tyr Trp Ala 1925 1930 1935 Val Thr Gly Arg Gly Val Ile Glu Arg Gly Asn Val Asp Gly Thr Asp 1940 1945 1950 Arg Met Ile Leu Val His Gin Leu Ser His Pro Trp Gly Ile Ala Val 1955 1960 1965 His Asp Ser Phe Leu Tyr Tyr Thr Asp Glu Gin Tyr Glu Val Ile Glu 1970 1975 1980 Arg Val Asp Lys Ala Thr Gly Ala Asn Lys Ile Val Leu Arg Asp Asn 1985 1990 1995 2000 WO 96/15801 PCTIUS95/15203 66 Val Pro Asn Leu Arg Gly Leu Gin Val Tyr His Arg Arg Asn Ala Ala 2005 2010 2015 Glu Ser Ser Asn Gly Cys Ser Asn Asn Met Asn Ala Cys Gin Gin Ile 2020 2025 2030 Cys Leu Pro Val Pro Gly Gly Leu Phe Ser Cys Ala Cys Ala Thr Gly 2035 2040 2045 0 Phe Lys Leu Asn Pro Asp Asn Arg Ser Cys Ser Pro Tyr Asn Ser Phe 2050 2055 2060 Ile Val Val Ser Met Leu Ser Ala Ile Arg Gly Phe Ser Leu Glu Leu 2065 2070 2075 2080 Ser Asp His Ser Glu Thr Met Val Pro Val Ala Gly Gin Gly Arg Asn 2085 2090 2095 Ala Leu His Val Asp Val Asp Val Ser Ser Gly Phe Ile Tyr Trp Cys 2100 2105 2110 Asp Phe Ser Ser Ser Val Ala Ser Asp Asn Ala Ile Arg Arg Ile Lys 2115 2120 2125 Pro Asp Gly Ser Ser Leu Met Asn Ile Val Thr His Gly Ile Gly Glu 2130 2135 2140 Asn Gly Val Arg Gly Ile Ala Val Asp Trp Val Ala Gly Asn Leu Tyr 2145 2150 2155 2160 Phe Thr Asn Ala Phe Val Ser Glu Thr Leu Ile Glu Val Leu Arg Ile 2165 2170 2175 Asn Thr Thr Tyr Arg Arg Val Leu Leu Lys Val Thr Val Asp Met Pro 2180 2185 2190 Arg His Ile Val Val Asp Pro Lys Asn Arg Tyr Leu Phe Trp Ala Asp 2195 2200 2205 4 Tyr Gly Gin Arg Pro Lys Ile Glu Arg Ser Phe Leu Asp Cys Thr Asn 2210 2215 2220 Arg Thr Val Leu Val Ser Glu Gly Ile Val Thr Pro Arg Gly Leu Ala 2225 2230 2235 2240 Val Asp Arg Ser Asp Gly Tyr Val Tyr Trp Val Asp Asp Ser Leu Asp 2245 2250 2255 Ile Ile Ala Arg Ile Arg Ile Asn Gly Glu Asn Ser Glu Val Ile Arg 2260 2265 2270 Tyr Gly Ser Arg Tyr Pro Thr Pro Tyr Gly Ile Thr Val Phe Glu Asn 2275 2280 2285 Ser Ile Ile Trp Val Asp Arg Asn Leu Lys Lys Ile Phe Gin Ala Ser 2290 2295 2300 Lys Glu Pro Glu Asn Thr Glu Pro Pro Thr Val Ile Arg Asp Asn Ile 2305 2310 2315 2320 Asn Trp Leu Arg Asp Val Thr Ile Phe Asp Lys Gin Val Gin Pro Arg 2325 2330 2335 WO 96/15801 PCT/US95/15203 Ser Pro Ala Glu Val Asn Asn Asn Pro Cys Leu Glu Asn Asn Gly Gly 2340 2345 2350 Cys Ser His Leu Cys Phe Ala Leu Pro Gly Leu His Thr Pro Lys Cys 2355 2360 2365 Asp Cys Ala Phe Gly Thr Leu Gln Ser Asp Gly Lys Asn Cys Ala Ile 2370 2375 2380 Ser Thr Glu Asn Phe Leu Ile Phe Ala Leu Ser Asn Ser Leu Arg Ser 2385 2390- 2395 2400 Leu His Leu Asp Pro Glu Asn His Ser Pro Pro Phe Gln Thr Ile Asn 2405 2410 2415 Val Glu Arg Thr Val Met Ser Leu Asp Tyr Asp Ser Val Ser Asp Arg 2420 2425 2430 Ile Tyr Phe Thr Gln Asn Leu Ala Ser Gly Val Gly Gin Ile Ser Tyr 2435 2440 2445 Ala Thr Leu Ser Ser Gly Ile His Thr Pro Thr Val Ile Ala Ser Gly 2450 2455 2460 Ile Gly Thr Ala Asp Gly Ile Ala Phe Asp Trp Ile Thr Arg Arg Ile 2465 2470 2475 2480 Tyr Tyr Ser Asp Tyr Leu Asn Gin Met Ile Asn Ser Met Ala Glu Asp 2485 2490 2495 Gly Ser Asn Arg Thr Val Ile Ala Arg Val Pro Lys Pro Arg Ala Ile 2500 2505 2510 Val Leu Asp Pro Cys Gin Gly Tyr Leu Tyr Trp Ala Asp Trp Asp Thr 2515 2520 2525 His Ala Lys Ile Glu Arg Ala Thr Leu Gly Gly Asn Phe ArgVal Pro 2530 2535 2540 Ile Val Asn Ser Ser Leu Val Met Pro Ser Gly Leu Thr Leu Asp Tyr 2545 2550 2555 2560 Glu Glu Asp Leu Leu Tyr Trp Val Asp Ala Ser Leu Gin Arg Ile Glu 2565 2570 2575 Arg Ser Thr Leu Thr Gly Val Asp Arg Glu Val Ile Val Asn Ala Ala 2580 2585 2590 Val His Ala Phe Gly Leu Thr Leu Tyr Gly Gin Tyr Ile Tyr Trp Thr 2595 2600 2605 Asp Leu Tyr Thr Gin Arg Ile Tyr Arg Ala Asn Lys Tyr Asp Gly Ser 2610 2615 2620 Gly Gin Ile Ala Met Thr Thr Asn Leu Leu Ser Gin Pro Arg Gly Ile 2625 2630 2635 2640 Asn Thr Val Val Lys Asn Gin Lys Gin Gin Cys Asn Asn Pro Cys Glu 2645 2650 2655 Gin Phe Asn Gly Gly Cys Ser His Ile Cys Ala Pro Gly Pro Asn Gly 2660 2665 2670 Ala Glu Cys Gin Cys Pro His Glu Gly Asn Trp Tyr Leu Ala Asn Asn iUrSen /LI2ni WO 96/15801 J, 2675 2680 2685 Arg Lys His Cys Ile Val Asp Asn Gly Glu Arg Cys Gly Ala Ser Ser 2690 2695 2700 Phe Thr Cys Ser Asn Gly Arg Cys Ile Ser Glu Glu Trp Lys Cys Asp 2705 2710 2715 2720 Asn Asp Asn Asp Cys Gly Asp Gly Ser Asp Glu Met Glu Ser Val Cys 2725 2730 2735 Ala Leu His Thr Cys Ser Pro Thr Ala Phe Thr Cys Ala Asn Gly Arg 2740 2745 2750 Cys Val Gin Tyr Ser Tyr Arg Cys Asp Tyr Tyr Asn Asp Cys Gly Asp 2755 2760 2765 Gly Ser Asp Glu Ala Gly Cys Leu Phe Arg Asp Cys Asn Ala Thr Thr 2770 2775 2780 Glu Phe Met Cys Asn Asn Arg Arg Cys Ile Pro Arg Glu Phe Ile Cys 2785 2790 2795 2800 Asn Gly Val Asp Asn Cys His Asp Asn Asn Thr Ser Asp Glu Lys Asn 2805 2810 2815 Cys Pro Asp Arg Thr Cys Gin Ser Gly Tyr Thr Lys Cys His Asn Ser 2820 2825 2830 Asn Ile Cys Ile Pro Arg Val Tyr Leu Cys Asp Gly Asp Asn Asp Cys 2835 2840 2845 Gly Asp Asn Ser Asp Glu Asn Pro Thr Tyr Cys Thr Thr His Thr Cys 2850 2855 2860 Ser Ser Ser Glu Phe Gin Cys Ala Ser Gly Arg Cys Ile Pro Gin His 2865 2870 2875 2880 Trp Tyr Cys Asp Gin Glu Thr Asp Cys Phe Asp Ala Ser Asp Glu Pro 2885 2890 2895 Ala Ser Cys Gly His Ser Glu Arg Thr Cys Leu Ala Asp Glu Phe'Lys 2900 2905 2910 Cys Asp Gly Gly Arg Cys Ile Pro Ser Glu Trp Ile Cys Asp Gly Asp 2915 2920 2925 Asn Asp Cys Gly Asp Met Ser Asp Glu Asp Lys Arg His Gin Cys Gin 2930 2935 2940 Asn Gin Asn Cys Ser Asp Ser Glu Phe Leu Cys Val Asn Asp Arg Pro 2945 2950 2955 2960 Pro Asp Arg Arg Cys Ile Pro Gin Ser Trp Val Cys Asp Gly Asp Val 2965 2970 2975 Asp Cys Thr Asp Gly Tyr Asp Glu Asn Gin Asn Cys Thr Arg Arg Thr 2980 2985 2990 Cys Ser Glu Asn Glu Phe Thr Cys Gly Tyr Gly Leu Cys Ile Pro Lys 2995 3000 3005 Ile Phe Arg Cys Asp Arg His Asn Asp Cys Gly Asp Tyr Ser Asp Glu 3010 3015 3020 L*J. U J WO 96/15801 PCT/US95/15203 Arg Gly Cys Leu Tyr Gin Thr Cys Gin Gin Asn Gin Phe Thr Cys Gin 3025 3030 3035 3040 Asn Gly Arg Cys Ile Ser Lys Thr Phe Val Cys Asp Glu Asp Asn Asp 3045 3050 3055 Cys Gly Asp Gly Ser Asp Glu Leu Met His Leu Cys His Thr Pro Glu 3060 3065 3070 Pro Thr Cys Pro Pro His Glu Phe Lys Cys Asp Asn Gly Arg Cys Ile 3075 3080 3085 Glu Met Met Lys Leu Cys Asn His Leu Asp Asp Cys Leu Asp Asn Ser 3090 3095 3100 Asp Glu Lys Gly Cys Gly Ile Asn Glu Cys His Asp Pro Ser Ile Ser 3105 3110 3115 3120 Gly Cys Asp His Asn Cys Thr Asp Thr Leu Thr Ser Phe Tyr Cys Ser 3125 3130 3135 Cys Arg Pro Gly Tyr Lys Leu Met Ser Asp Lys Arg Thr Cys Val Asp 3140 3145 3150 Ile Asp Glu Cys Thr Glu Met Pro Phe Val Cys Ser Gin Lys Cys Glu 3155 3160 3165 Asn Val Ile Gly Ser Tyr Ile Cys Lys Cys Ala Pro Gly Tyr Leu Arg 3170 3175 3180 Glu Pro Asp Gly Lys Thr Cys Arg Gin Asn Ser Asn Ile Glu Pro Tyr 3185 3190 3195 3200 Leu Ile Phe Ser Asn Arg Tyr Tyr Leu Arg Asn Leu Thr Ile Asp Gly 3205 3210 3215 Tyr Phe Tyr Ser Leu Ile Leu Glu Gly Leu Asp Asn Val Val Ala Leu 3220 3225 3230 Asp Phe Asp Arg Val Glu Lys Arg Leu Tyr Trp Ile Asp Thr Gin Arg 3235 3240 3245 Gin Val Ile Glu Arg Met Phe Leu Asn Lys Thr Asn Lys Glu Thr Ile 3250 3255 3260 Ile Asn His Arg Leu Pro Ala Ala Glu Ser Leu Ala Val Asp Trp Val 3265 3270 3275 3280 Ser Arg Lys Leu Tyr Trp Leu Asp Ala Arg Leu Asp Gly.Leu Phe Val 3285 3290 3295 Ser Asp Leu Asn Gly Gly His Arg Arg Met Leu Ala Gin His Cys Val 3300 3305 3310 Asp Ala Asn Asn Thr Phe Cys Phe Asp Asn Pro Arg Gly Leu Ala Leu 3315 3320 3325 His Pro Gin Tyr Gly Tyr Leu Tyr Trp Ala Asp Trp Gly His Arg Ala 3330 3335 3340 Tyr Ile Gly Arg Val Gly Met Asp Gly Thr Asn Lys Ser Val Ile Ile 3345 3350 3355 3360 WO 96/15801 PCTfS95/15203 Ser Thr Lys Leu Glu Trp Pro Asn Gly Ile Thr Ile Asp Tyr Thr Asn 3365 3370 3375 Asp Leu Leu Tyr Trp Ala Asp Ala His Leu Gly Tyr Ile Glu Tyr Ser 3380 3385 3390 Asp Leu Glu Gly His His Arg His Thr Val Tyr Asp Gly Ala Leu Pro 3395 3400 3405 His Pro Phe Ala Ile Thr Ile Phe Glu Asp Thr Ile Tyr Trp Thr Asp 3410 3415 3420 Trp Asn Thr Arg Thr Val Glu Lys Gly Asn Lys Tyr Asp Gly Ser Asn 3425 3430 3435 3440 Arg Gin Thr Leu Val Asn Thr Thr His Arg Pro Phe Asp Ile His Val 3445 3450 3455 Tyr His Pro Tyr Arg Gin Pro Ile Val Ser Asn Pro Cys Gly Thr Asn 3460 3465 3470 Asn Gly Gly Cys Ser His Leu Cys Leu Ile Lys Pro Gly Gly Lys Gly 3475 3480 3485 Phe Thr Cys Glu Cys Pro Asp Asp Phe Arg Thr Leu Gin Leu Ser Gly 3490 3495 3500 Ser Thr Tyr Cys Met Pro Met Cys Ser Ser Thr Gin Phe Leu Cys Ala 3505 3510 3515 3520 Asn Asn Glu Lys Cys Ile Pro Ile Trp Trp Lys Cys Asp Gly Gin Lys 3525 3530 3535 Asp Cys Ser Asp Gly Ser Asp Glu Leu Ala Leu Cys Pro Gin Arg Phe 3540 3545 3550 Cys Arg Leu Gly Gin Phe Gin Cys Ser Asp Gly Asn Cys Thr Ser Pro 3555 3560 3565 Gin Thr Leu Cys Asn Ala His Gin Asn Cys Pro Asp Gly Ser Asp Glu 3570 3575 3580 Asp Arg Leu Leu Cys Glu Asn His His Cys Asp Ser Asn Glu Trp Gin 3585 3590 3595 3600 Cys Ala Asn Lys Arg Cys Ile Pro Glu Ser Trp Gin Cys Asp Thr Phe 3605 3610 3615 Asn Asp Cys Glu Asp Asn Ser Asp Glu Asp Ser Ser His Cys Ala Ser 3620 3625 3630 Arg Thr Cys Arg Pro Gly Gin Phe Arg Cys Ala Asn Gly Arg Cys Ile 3635 3640 3645 Pro Gin Ala Trp Lys Cys Asp Val Asp Asn Asp Cys Gly Asp His Ser 3650 3655 3660 Asp Glu Pro Ile Glu Glu Cys Met Ser Ser Ala His Leu Cys Asp Asn 3665 3670 3675 3680 Phe Thr Glu Phe Ser Cys Lys Thr Asn Tyr Arg Cys Ile Pro Lys Trp 3685 3690 3695 Ala Val Cys Asn Gly Val Asp Asp Cys Arg Asp Asn Ser Asp Glu Gin WO 96/15801 PCT/US95/15203 3700 3705 3710 Gly Cys Glu Glu Arg Thr Cys His Pro Val Gly Asp Phe Arg Cys Lys 3715 3720 3725 Asn His His Cys Ile Pro Leu Arg Trp Gin Cys Asp Gly Gin Asn Asp 3730 3735 3740 Cys Gly Asp Asn Ser Asp Glu Glu Asn Cys Ala Pro Arg Glu Cys Thr 3745 3750 3755 3760 Glu Ser Glu Phe Arg Cys Val Asn Gin Gin Cys Ile Pro Ser Arg Trp 3765 3770 3775 Ile Cys Asp His Tyr Asn Asp Cys Gly Asp Asn Ser Asp Glu Arg Asp 3780 3785 3790 Cys Glu Met Arg Thr Cys His Pro Glu Tyr Phe Gin Cys Thr Ser Gly 3795 3800 3805 His Cys Val His Ser Glu Leu Lys Cys Asp Gly Ser Ala Asp Cys Leu 3810 3815 3820 Asp Ala Ser Asp Glu Ala Asp Cys Pro Thr Arg Phe Pro Asp Gly Ala 3825 3830 3835 3840 Tyr Cys Gin Ala Thr Met Phe Glu Cys Lys Asn His Val Cys Ile Pro 3845 3850 3855 Pro Tyr Trp Lys Cys Asp Gly Asp Asp Asp Cys Gly Asp Gly Ser Asp 3860 3865 3870 Glu Glu Leu His Leu Cys Leu Asp Val Pro Cys Asn Ser Pro Asn Arg 3875 3880 3885 Phe Arg Cys Asp Asn Asn Arg Cys Ile Tyr Ser His Glu Val Cys Asn 3890 3895 3900 Gly Val Asp Asp Cys Gly Asp Gly Thr Asp Glu Thr Glu Glu His Cys 3905 3910 3915 3920 Arg Lys Pro Thr Pro Lys Pro Cys Thr Glu Tyr Glu Tyr Lys Cys Gly 3925 3930 3935 Asn Gly His Cys Ile Pro His Asp Asn Val Cys Asp Asp Ala Asp Asp 3940 3945 3950 Cys Gly Asp Trp Ser Asp Glu Leu Gly Cys Asn Lys Gly Lys Glu Arg 3955 3960 3965 Thr Cys Ala Glu Asn Ile Cys Glu Gin Asn Cys Thr Gin Leu Asn Glu 3970 3975 3980 Gly Gly Phe Ile Cys Ser Cys Thr Ala Gly Phe Glu Thr Asn Val Phe 3985 3990 3995 4000 Asp Arg Thr Ser Cys Leu Asp Ile Asn Glu Cys Glu Gin Phe Gly Thr 4005 4010 4015 Cys Pro Gin His Cys Arg Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys 4020 4025 4030 Ala Asp Gly Phe Thr Ser Met Ser Asp Arg Pro Gly Lys Arg Cys Ala 4035 4040 4045 WO 96/15801 PCT/US95/15203 Ala Glu Gly Ser Ser Pro Leu Leu Leu Leu Pro Asp Asn Val Arg Ile 4050 4055 4060 Arg Lys Tyr Asn Leu Ser Ser Glu Arg Phe Ser Glu Tyr Leu Gin Asp 4065 4070 4075 4080 Glu Glu Tyr Ile Gln Ala Val Asp Tyr Asp Trp Asp Pro Glu Asp Ile 4085 4090 4095 0 Gly Leu Ser Val Val Tyr Tyr Thr Val Arg Gly Glu Gly Ser Arg Phe 4100 4105 4110 Gly Ala Ile Lys Arg Ala Tyr Ile Pro Asn Phe Glu Ser Gly Arg Asn .4115 4120 4125 Asn Leu Val Gin Glu Val Asp Leu Lys Leu Lys Tyr Val Met Gin Pro 4130 4135 4140 Asp Gly Ile Ala Val Asp Trp Val Gly Arg His Ile Tyr Trp Ser Asp 4145 4150 4155 4160 Val Lys Asn Lys Arg Ile Glu Val Ala Lys Leu Asp Gly Arg Tyr Arg 4165 4170 4175 2 Lys Trp Leu Ile Ser Thr Asp Leu Asp Gin Pro Ala Ala Ile Ala Val 4180 4185 4190 Asn Pro Lys Leu Gly Leu Met Phe Trp Thr Asp Trp Gly Lys Glu Pro 4195 4200 4205 Lys Leu Glu Ser Ala Trp Met Asn Gly Glu Asp Arg Asn Ile Leu Val 4210 4215 4220 Phe Glu Asp Leu Gly Trp Pro Thr Gly Leu Ser Ile Asp Tyr Leu Asn 4225 4230 4235 4240 Asn Asp Arg Ile Tyr Trp Ser Asp Phe Lys Glu Asp Val Ile Glu Thr 4245 4250 4255 4 Ile Lys Tyr Asp Gly Thr Asp Arg Arg Val Ile Ala Lys Glu Ala Met 4260 4265 4270 Asn Pro Tyr Ser Leu Asp Ile Phe Glu Asp Gin Leu Tyr Trp Ile Ser 4275 4280 4285 Lys Glu Lys Gly Glu Val Trp Lys Gin Asn Lys Phe Gly Gin Gly Lys 4290 4295 4300 Lys Glu Lys Thr Leu Val Val Asn Pro Trp Leu Thr Gln Val Arg Ile 4305 4310 4315 4320 Phe His Gln Leu Arg Tyr Asn Lys Ser Val Pro Asn Leu Cys Lys Gin 4325 4330 4335 Ile Cys Ser His Leu Cys Leu Leu Arg Pro Gly Gly Tyr Ser Cys Ala 4340 4345 4350 Cys Pro Gln Gly Ser Ser Phe Ile Glu Gly Ser Thr Thr Glu Cys Asp 4355 4360 4365 Ala Ala Ile Glu Leu Pro Ile Asn Leu Pro Pro Pro Cys Arg Cys Met 4370 4375 4380 WO 96/15801 PCT/US95/15203 Pro Lys Cys Lys 4400 His Gly Gly Asn Cys Tyr Phe Asp Glu 4385 4390 So7 Thr Asp Leu 4395 Cys Pro Ser Gly Tyr Thr Gly Lys Tyr Cys Glu Met Ala Phe Ser Lys 4405 4410 4415 Gly Ile Ser Pro Gly Thr Thr Ala Val Ala Val Leu Leu Thr Ile Leu 4420 4425 4430 Leu Ile Val Val Ile Gly Ala Leu Ala Ile Ala Gly Phe Phe His Tyr 4435 4440 4445 Arg Arg Thr Gly Ser Leu Leu Pro Ala Leu Pro Lys Leu Pro Ser Leu 4450. 4455 4460 Ser Ser Leu Val Lys Pro Ser Glu Asn Gly Asn Gly Val Thr Phe Arg 4465 4470 4475 4480 Ser Gly Ala Asp Leu Asn Met Asp Ile Gly Val Ser Gly Phe Gly Pro 4485 4490 4495 Glu Thr Ala Ile Asp Arg Ser Met Ala Met Ser Glu Asp Phe Val Met 4500 4505 4510 Glu Met Gly Lys Gin Pro Ile Ile Phe Glu Asn Pro Met Tyr Ser Ala 4515 4520 4525 Arg Asp Ser Ala Val Lys Val Val Gin Pro Ile Gin Val Thr Val Ser 4530 4535 4540 Glu Asn Val Asp Asn Lys Asn Tyr Gly Ser Pro Ile Asn Pro Ser Glu 4545 4550 4555 4560 Ile Val Pro Glu Thr Asn Pro Thr Ser Pro Ala Ala Asp Gly Thr Gin 4565 4570 4575 Val Thr Lys Trp Asn Leu Phe Lys Arg Lys Ser Lys Gin Thr Thr Asn 4580 4585 4590 Phe Glu Asn Pro Ile Tyr Ala Gin Met Glu Asn Glu Gin Lys Glu Ser 4595 4600 4605 Val Ala Ala Thr Pro Pro Pro Ser Pro Ser Leu Pro Ala Lys Pro Lys 4610 4615 4620 Pro Pro Ser Arg Arg Asp Pro Thr Pro Thr Tyr Ser Ala Thr Glu Asp 4625 4630 4635 4640 Thr Phe Lys Asp Thr Ala Asn Leu Val Lys Glu Asp Ser Glu Val 4645 4650 4655 INFORMATION FOR SEQ ID NO:91: SEQUENCE CHARACTERISTICS: LENGTH: 19 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE:

NO

WO 96/15801 PCT/US95/15203 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91: GCAGACCTAA AGGAGCGTT 19 INFORMATION FOR SEQ ID NO:92: SEQUENCE CHARACTERISTICS: LENGTH: 20 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92: CCCGACCATT GGAGAAGATA INFORMATION FOR SEQ ID NO:93: SEQUENCE CHARACTERISTICS: LENGTH: 19 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93: GCCAGTACCA GTGCCATGA 19 INFORMATION FOR SEQ ID NO:94: SEQUENCE CHARACTERISTICS: LENGTH: 21 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE: NO WO 96/15801 PCTfUS95/15203 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94: CCTCATGACA CTGATACTCT T 21 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 18 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: 'linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE:

NO

(xi) SEQUENCE DESCRIPTION: SEQ ID GGCTGTGAGC AGGTCTGT 18 INFORMATION FOR SEQ ID NO:96: SEQUENCE CHARACTERISTICS: LENGTH: 23 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96: CGACCACTAA TTGAATCAAA ATC 23 INFORMATION FOR SEQ ID NO:97: SEQUENCE CHARACTERISTICS: LENGTH: 19 base pairs TYPE: nucleic acid STRANDEDNESS: single; TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE:

NO

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:97: CGGTGCTCGT

GTGATACAG

WO 96/15801 PCT/US95/15203 INFORMATION FOR SEQ ID NO:98: SEQUENCE CHARACTERISTICS: LENGTH: 18 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL:

NO

(iv) ANTI-SENSE:

NO

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:98: ATCCACATCC ACATGCAG 18 INFORMATION FOR SEQ ID NO:99: SEQUENCE CHARACTERISTICS: LENGTH: 22 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99: CCTCAAATGG CTGTAGCAAC AA 22 INFORMATION FOR SEQ ID NO:100: SEQUENCE CHARACTERISTICS: LENGTH: 18 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100: CTGCTGCTGC ACGTGTGA 18 INFORMATION FOR SEQ ID NO:101: SEQUENCE CHARACTERISTICS: WO 96/15801 PCT/US95/15203 LENGTH: 22 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101: CCAGTCTGGA TACACAAAAT GT 22 INFORMATION FOR SEQ ID NO:102: SEQUENCE CHARACTERISTICS: LENGTH: 15 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL: NO ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102: GGCGCACTGC CATTC INFORMATION FOR SEQ ID NO:103: SEQUENCE CHARACTERISTICS: LENGTH: 21 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103: CTCAGATGGC TCTGATGAAC T 21 INFORMATION FOR SEQ ID NO:104: SEQUENCE CHARACTERISTICS: LENGTH: 21 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear WO 96/15801 PCT/US95/15203 (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104: GCGTTTTCTC TTTCTTTCCT T 21 INFORMATION FOR SEQ ID NO:105: SEQUENCE CHARACTERISTICS: LENGTH: 22 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105: GAGAGTCATT GCAAAGGAAG CA 22 INFORMATION FOR SEQ ID NO:106: SEQUENCE CHARACTERISTICS: LENGTH: 23 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: other nucleic acid (iii) HYPOTHETICAL: NO (iv) ANTI-SENSE: NO (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106: AATATATGTG CAAAAGTGTG TTT 23

Claims (21)

1. 2. The cDNA according to claim 1, comprising all or part of a nucleotide sequence selected from the group consisting of SEQ ID No. 3, SEQ ID No. 11, SEQ ID No, 83, SEQ ID No. 85, SEQ ID No. 87, and SEQ ID No. 89, 9
2. 3. A vector comprising a cDNA according to claim 1.
3. 4. A host cell expressing the cDNA according to claim 1, S: 5. A host cell according to claim 4, wherein said cell is useful in an assay to identify molecules which block or enhance the activity of said calcium sensor protein,
4. 6. An isolated and purified human calcium sensor protein, wherein the protein includes an amino acid sequence selected from SEQ ID No. 4, SEQ ID No. 12, SEQ ID No.84, SEQ ID No. 86, SEQ ID No. 88, and SEQ ID No. 90 or allelic variants thereof.
5. 7. An isolated and purified human calcium sensor protein according to claim 6 comprising an amino acid sequence selected from the group consisting of SEQ ID No. 4, SEQ ID No. 12, SEQ ID No.84, SEQ ID No. 86, SEQ ID No. 88, and SEQ ID No.
6. 8. A fragment of the human calcium sensor protein wherein said fragment has the activity of any one of the proteins according to claim 6. 15/09 '00 FRI 11:36 [TX/RX NO 5908] 214
7. 9. A fragment according to claim 8, wherein said fragment is immunogenic. A fragment according to claim 9, wherein said fragment binds antibodies against human calcium sensor protein.
8. 11. A fragment according to claim 8 comprising the cytoplasmic domain of human calcium sensor protein or a fragment thereof.
9. 12. A fragment according to claim 11, wherein said fragment binds SH2 and/or SH3 domains.
10. 13. A peptide comprising 4 to 12 amino acids from the sequence of the human calcium sensor protein wherein the peptide includes an amino acid sequence selected from SEQ ID No. 4, SEQ ID No. 12, SEQ ID No.84, SEQ ID No. 86, SEQ ID No. 88, and SEQ ID No. 90 or allelic variants thereof, wherein said peptide binds SH2 or SH3 domains.
11. 14. The peptide of claims 13 comprising an amino acid sequence selected from the group consisting of LPAKP, LPALP and LPKLP. The peptide of claim 13 comprising an amino acid sequence selected from the group consisting of ENPIYAQMENE.
12. 16. The fragment of claim 12 having about 20 amino acids, wherein said amino acids include all or a part of the sequence ATPPPSPSLPAKPKPPSRR.
13. 17. A fragment according to claim 8, wherein said fragment has growth factor activity.
14. 18. A method of identifying agonists and/or antagonists of human calcium sensor protein activity comprising contacting potential agonists or antagonists with said calcium sensor ,protein and determining the ability of said potential 215 agonists or antagonists to block or enhance the activity of said calcium sensor protein wherein the protein includes an amino acid sequence selected from SEQ ID No. 4, SEQ ID No. 12, SEQ ID No.84, SEQ ID No. 86, SEQ ID No. 88, and SEQ ID No. 90 or allelic variants thereof.
15. 19. An antisense nucleic acid capable of down regulating or blocking expression of a human calcium sensor protein. The antisense nucleic acid according to claim 19 wherein said antisense nucleic acid is an RNA capable of specifically hybridizing with all or part of the sequence of SEQ ID No. 3, SEQ ID No. 11, SEQ ID No. 83, SEQ ID No. SEQ ID No. 87, and SEQ ID No. 89, or the corresponding messenger RNA.
16. 21. A method of down regulating or blocking expression of calcium sensor protein comprising administration of an antisense nucleic acid according to claim 19 in an amount effective to down regulate or block expression of calcium sensor protein.
17. 22. A method of identifying agonists and/or antagonists of human calcium sensor protein activity comprising: a) expressing a cDNA according to claim 1 in a host cell; b) contacting potential agonists or antagonists with said host cell; and c) determining the ability of said agonists or antagonists to block or enhance the activity of said calcium sensor protein or fragment thereof.
18. 23. A pharmaceutical composition comprising the human calcium sensor protein according to claim 6.
19. 24. A pharmaceutical composition comprising the fragment of the human calcium sensor protein according to Claim 8. 216 A method of treating human membranous glomerulonephritis comprising administration of an effective amount of the pharmaceutical composition according to claim 23.
20. 26. A method of treating human membranous glomerulonephritis comprising immobilization of the human calcium sensor protein according to claim 6 on a solid support; passing patient sera comprising autoantibodies against human gp330 over said solid support; and returning the sera to the patient.
21. 27. The use of the fragment of the human calcium sensor protein according to claim 8 for the manufacture of a pharmaceutical for the treatment of human membranous glomerulonephritis. DATED this 17th day of August 2000. AVENTIS PHARMACEUTICALS, AND GORAN AKERSTROM, CLAES JUHLIN, LARS RASK AND GORAN HJALM WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P7372AU00 LCG:KMH:JL