AU8938601A - Lyme disease polynucleotides - Google Patents

Description

WO 98/59071 PCT/US98/12718 Lyme Disease Polynucleotides Field of the Invention The present invention relates to novel vaccines for the prevention or attenuation of Lyme disease. The invention further relates to isolated nucleic acid molecules encoding antigenic polypeptides ofBorrelia burgdorferi. Antigenic polypeptides are also provided, as are vectors, host cells and recombinant methods for producing the same. The invention additionally relates to diagnostic methods for detecting Borrelia gene expression.

Background of the Invention Lyme disease (Steere, Proc. Natl. Acad. Sci. USA 91:2378-2383 (1991)), or Lyme borreliosis, is presently the most common human disease in the United States transmitted by an arthropod vector (Center for Disease Control, Morbid Mortal. Weekly Rep. 46(23):531-535 20 (1997)). Further, infection of house-hold pets, such as dogs, is a considerable problem.

While initial symptoms often include a rash at the infection point, Lyme disease is a multisystemic disorder that may include arthritic, carditic, and neurological manifestations. While antibiotics are currently used to treat active cases of Lyme disease, B. burgdorferi persists even after prolonged antibiotic treatment Further, B. burgdorferi can persist for years in a mammalian 25 host in the presence of an active immune response (Straubinger, R. et aL, J. Clin. Microbiol.

35:111-116 (1997); Steere, N. EngL J. Med. 321:586-596 (1989)).

Lyme disease is caused by the related tick-borne spirochetes classified as Borrelia burgdorferi sensu lato (including B. burgdorferi sensu stricto, B. afzelii, B. garinii). Although substantial progress has been made in the biochemical, ultrastructural, and genetic characterization 30 of the organism, the spirochetal factors responsible for infectivity, immune evasion and disease pathogenesis remain largely obscure.

A number of antigenic B. burgdorferi cell surface proteins have been identified. These include the outer membrane surface proteins (Osp) OspA, OspB, OspC and OspD. OspA and OspB are encoded by tightly linked tandem genes which are transcribed as a single transcriptional unit (Brusca, J. et aL, J. BacterioL 173:8004-8008 (1991)). The most-studied B. burgdorferi membrane protein is OspA, a lipoprotein antigen expressed by borreliae in resting ticks and the most abundant protein expressed in vitro by most borrelial isolates (Barbour, et aL, Infection Immunity 41:795-804 (1983); Howe, et aL, Science 227:645 (1985)).

WO 98/59071 PCT/US98/12718 2 A number of different types of Lyme disease vaccines have been shown to induce immunological responses. Whole-cell B. burgdorferi vaccines, for example, have been shown to induce both immunological responses and protective immunity in several animal models (Reviewed in Wormser, Clin. Infect. Dis. 21:1267-1274 (1995)). Further, passive immunity has been demonstrated in both humans and other animals using B. burgdorferi specific antisera.

While whole-cell Lyme disease vaccines confer protective immunity in animal models, use of such vaccines presents the risk that responsive antibodies will produce an autoimmune response (Reviewed in Wormser, supra). This problem is at least partly the result of the production of B. burgdorferi specific antibodies which cross-react with hepatocytes and both muscle and nerve cells. B. burgdorferi heat shock proteins and the 41-kd flagellin subunit are believed to contain antigens which elicit production of these cross-reactive antibodies.

Single protein subunit vaccines for Lyme disease have also been tested. The cell surface proteins of B. burgdorferi are potential candidates for use in such vaccines and several have been shown to elicit protective immune responses in mammals (Probert, W. et al., Vaccine 15:15-19 (1997); Fikrig, E. et aL, Infect. Immun. 63:1658-1662 (1995); Langerman S. et al., Nature 372:552-556 (1994); Fikrig, E. et al., J. Immunol. 148:2256-2260 (1992)). Experimental OspA vaccines, for example, have demonstrated efficacy in several animal models (Fikrig, et al., Proc. Natl. Acad. Sci. USA 89:5418-5421 (1992); Johnson, et al., Vaccine 13:1086-1094 (1996); Fikrig, et al., Infect. Immun. 60:657-661 (1992); Chang, et al., Infection S 20 Immunity 63:3543-3549 (1995)), and OspA vaccines for human use are under clinical evaluation (Keller, et al, J. Am. Med. Assoc. 271:1764-1768 (1994); Van Hoecke, et al., Vaccine 14:1620-1626 (1996)). Passive immunity is also conferred by antisera containing antibodies Sspecific for the full-length OspA protein. Further, vaccination with plasmid DNA encoding OspA has been demonstrated to elicit protective immune responses in mice (Luke, C. et al., J. Infect.

25 Dis. 175:91-97 (1997); Zhong, W. et aL, Eur. J. Immunol. 26:2749-2757 (1996)).

Recent immunofluorescence assay observations indicate that during tick engorgement the expression of OspA by borreliae diminishes (deSilva, et al., J. Exp. Med. 183:271-275 (1996)) while expression of other proteins, exemplified by OspC, increases (Schwan, et Proc. Natl. Acad. Sci. USA 92:2909-2913 (1985)). By the time of transmission to hosts, 30 spirochetes in the tick salivary glands express little or no OspA. This down-modulation of OspA appears to explain the difficulties in demonstrating immune responses to this antigen early in infection following tick bites (Kalish, et al., Infect. Immun. 63:2228-2235 (1995); Gem, et al., J. Infect. Dis. 167:971-975 (1993); Schiable, et Immunol. Lett. 36:219-226 (1993)) or following challenge with limiting doses of cultured borreliae (Schiable, et al., Immunol. Lett. 36:219-226 (1993); Barthold, S.W. and Bockenstedt, Infeci. Immun.

61:4696-4702 (1993)).

Furthermore, OspA-specific antibodies are ineffective if administered after a borrelial challenge delivered by syringe (Schiable, et al., Proc. Natl. Acad. Sci. USA 87:3768-3772 (1990)) or tick bite (deSilva, et al., J. Exp. Med. 183:271-275 (1996)). To be efficacious, WO 98/59071 PCT/US98/12718 3 OspA vaccines must elicit protective levels of antibody which are maintained throughout periods of tick exposure in order to block borrelia transmission from the arthropod vector.

Vaccines in current use against other pathogens include in vivo-expressed antigens which could boost anamnestic responses upon infection, potentiate the action of immune effector cells and complement, and inhibit key virulence mechanisms. OspC is both expressed during infection (Montgomery, et aL, J. Exp. Med 183:261-269 (1996)) and a target for protective immunity (Gilmore, et aL, Infect. Immun. 64:2234-2239 (1996); Probert, W.S. and LeFebvre, Infect. Immun. 62:1920-1926 (1994); Preac-Mursic, et aL, Infection 20:342-349 (1992)), but mice immunized with this protein were only protected against challenge with the homologous borrelial isolate (Probert, et al, J. Infect. Dis. 175:400-405 (1997)).

Identification of in vivo-expressed, and broadly protective, antigens of B. burgdorferi has remained elusive.

Summary of the Invention The present invention provides isolated nucleic acid molecules comprising polynucleotides encoding the B. burgdorferi peptides having the amino acid sequences shown in Table 1. Thus, one aspect of the invention provides isolated nucleic acid molecules comprising polynucleotides having a nucleotide sequence selected from the group consisting of: a nucleotide sequence encoding any of the amino acid sequences of the full-length polypeptides shown in Table 1; a S 20 nucleotide sequence encoding any of the amino acid sequences of the full-length polypeptides shown in Table 1 but minus the N-terminal methionine residue, if present; a nucleotide sequence encoding any of the amino acid sequences of the truncated polypeptides shown in Table 1; and a nucleotide sequence complementary to any of the nucleotide sequences in or above.

Further embodiments of the invention include isolated nucleic acid molecules that comprise a polynucleotide having a nucleotide sequence at least 90% identical, and more preferably at least 95%, 96%, 97%, 98% or 99% identical, to any of the nucleotide sequences in or above, or a polynucleotide which hybridizes under stringent hybridization conditions to a polynucleotide in or above. This polynucleotide which hybridizes 30 does not hybridize under stringent hybridization conditions to a polynucleotide having a S nucleotide sequence consisting of only A residues or of only T residues. Additional nucleic acid embodiments of the invention relate to isolated nucleic acid molecules comprising polynucleotides which encode the amino acid sequences of epitope-bearing portions of a B. burgdorferi polypeptide having an amino acid sequence in or above.

The present invention also relates to recombinant vectors, which include the isolated nucleic acid molecules of the present invention, and to host cells containing the recombinant vectors, as well as to methods of making such vectors and host cells and for using these vectors for the production of B. burgdorferi polypeptides or peptides by recombinant techniques.

The invention further provides isolated B. burgdorferi polypeptides having an amino acid WO 98/59071 PCT/US98/12718 4 sequence selected from the group consisting of: an amino acid sequence of any of the fulllength polypeptides shown in Table 1; an amino acid sequence of any of the full-length polypeptides shown in Table 1 but minus the N-terminal methionine residue, if present; an amino acid sequence of any of the truncated polypeptides shown in Table 1; and an amino acid sequence of an epitope-bearing portion of any one of the polypeptides of or The polypeptides of the present invention also include polypeptides having an amino acid sequence with at least 70% similarity, and more preferably at least 75%, 80%, 85%, 90%, 96%, 97%, 98%, or 99% similarity to those described in or above, as well as polypeptides having an amino acid sequence at least 70% identical, more preferably at least identical, and still more preferably 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to those above; as well as isolated nucleic acid molecules encoding such polypeptides.

The present invention further provides a vaccine, preferably a multi-component vaccine comprising one or more of the B. burgdorferi polypeptides shown in Table 1, or fragments thereof, together with a pharmaceutically acceptable diluent, carrier, or excipient, wherein the B. burgdorferi polypeptide(s) are present in an amount effective to elicit an immune response to members of the Borrelia genus in an animal. The B. burgdorferi polypeptides of the present invention may further be combined with one or more immunogens of one or more other borrelial or non-borrelial organisms to produce a multi-component vaccine intended to elicit an :"immunological response against members of the Borrelia genus and, optionally, one or more nonborrelial organisms.

The vaccines of the present invention can be administered in a DNA form, "naked" DNA, wherein the DNA encodes one or more borrelial polypeptides and, optionally, one or more polypeptides of a non-borrelial organism. The DNA encoding one or more polypeptides may be constructed such that these polypeptides are expressed fusion proteins.

25 The vaccines of the present invention may also be administered as a component of a genetically engineered organism. Thus, a genetically engineered organism which expresses one or more B. burgdorferi polypeptides may be administered to an animal. For example, such a genetically engineered organism may contain one or more B. burgdorferi polypeptides of the present invention intracellularly, on its cell surface, or in its periplasmic space. Further, such a 30 genetically engineered organism may secrete one or more B. burgdorferi polypeptides.

The vaccines of the present invention may be co-administered to an animal with an immune system modulator CD86 and GM-CSF).

The invention also provides a method of inducing an immunological response in an animal to one or more members of the Borrelia genus, B. burgdorferi sensu stricto, B. afzelii, and B. garinii, comprising administering to the animal a vaccine as described above.

The invention further provides a method of inducing a protective immune response in an animal, sufficient to prevent or attenuate an infection by members of the Borrelia genus, comprising administering to the animal a composition comprising one or more of the polypeptides shown in Table 1, or fragments thereof. Further, these polypeptides, or fragments thereof, may WO 98/59071 PCT/US98/12718 be conjugated to another immunogen and/or administered in admixture with an adjuvant.

The invention further relates to antibodies elicited in an animal by the administration of one or more B. burgdorferi polypeptides of the present invention.

The invention also provides diagnostic methods for detecting the expression of genies of members of the Borrelia genus in an animal. One such method involves assaying for the expression of a gene encoding Borrelia peptides in a sample from an animal. This expression may be assayed either directly by assaying polypeptide levels using antibodies elicited in response to amino acid sequences shown in Table 1) or indirectly by assaying for antibodies having specificity for amino acid sequences shown in Table An example of such a method involves the use of the polymerase chain reaction (PCR) to amplify and detect Borrelia nucleic acid sequences.

The present invention also relates to nucleic acid probes having all or part of a nucleotide sequence shown in Table 1 which are capable of hybridizing under stringent conditions to Borrelia nucleic acids. The invention further relates to a method of detecting one or more Borrelia nucleic acids in a biological sample obtained from an animal, said one or more nucleic acids encoding Borrelia polypeptides, comprising: a) contacting the sample with one or more of the above-described nucleic acid probes, under conditions such that hybridization occurs, and b) detecting hybridization of said one or more probes to the Borrelia nucleic acid present in the biological sample.

Detailed Description The present invention relates to recombinant antigenic B. burgdorferi polypeptides and fragments thereof. The invention also relates to methods for using these polypeptides to produce 25 immunological responses and to confer immunological protection to disease caused by members of the genus Borrelia. The invention further relates to nucleic acid sequences which encode antigenic B. burgdorferi polypeptides and to methods for detecting Borrelia nucleic acids and polypeptides in biological samples. The invention also relates to Borrelia specific antibodies and methods for detecting such antibodies produced in a host animal.

S, Definitions The following definitions are provided to clarify the subject matter which the inventors consider to be the present invention.

As used herein, the phrase "pathogenic agent" means an agent which causes a disease state or affliction in an animal. Included within this definition, for examples, are bacteria, protozoans, fungi, viruses and metazoan parasites which either produce a disease state or render an animal infected with such an organism susceptible to a disease state a secondary infection).

Further included are species and strains of the genus Borrelia which produce disease states in animals.

WO 98/59071 PCT/US98/12718 6 As used herein, the term "organism" means any living biological system, including viruses, regardless of whether it is a pathogenic agent.

As used herein, the term "Borrelia" means any species or strain of bacteria which is members of the genus Borrelia. Included within this definition are Borrelia burgdorferi sensu lato (including B. burgdorferi sensu stricto, B. afzelii, B. garinii), B. andersonii, B. anserina, B.

japonica, B. coriaceae, and other members of the genus Borrelia regardless of whether they are known pathogenic agents.

As used herein, the phrase "one or more B. burgdorferi polypeptides of the present invention" means the amino acid sequence of one or more of the B. burgdorferi polypeptides disclosed in Table 1. These polypeptides may be expressed as fusion proteins wherein the B. burgdorferi polypeptides of the present invention are linked to additional amino acid sequences which may be of borrelial or non-borrelial origin. This phrase further includes fragments of the B. burgdorferi polypeptides of the present invention.

As used herein, the phrase "full-length amino acid sequence" and "full-length polypeptide" refer to an amino acid sequence or polypeptide encoded by a full-length open reading frame (ORF). An ORF may be defined as a nucleotide sequence bounded by stop codons which encodes a putative polypeptide. An ORF may also be defined as a nucleotide sequence within a stop codon bounded sequence which contains an initiation codon a methionine or valine codon) on the 5' end and a stop codon on the 3' end.

As used herein, the phrase "truncated amino acid sequence" and "truncated polypeptide" refer to a sub-sequence of a full-length amino acid sequence or polypeptide. Several criteria may also be used to define the truncated amino acid sequence or polypeptide. For example, a truncated polypeptide may be defined as a mature polypeptide a polypeptide which lacks a leader sequence). A truncated polypeptide may also be defined as an amino acid sequence which is a 25 portion of a longer sequence that has been selected for ease of expression in a heterologous system but retains regions which render the polypeptide useful for use in vaccines antigenic regions which are expected to elicit a protective immune response).

Additional definitions are provided throughout the specification.

Explanation of Table 1 30 Table 1 lists B. burgdorferi nucleotide and amino acid sequences of the present invention.

The nomenclature used therein is as follows: "nt" refers to nucleotide sequences; "aa" refers to amino acid sequences; refers to full-length nucleotide or amino acid sequences; and refers to truncated nucleotide or amino acid sequences.

Thus, for example, the designation "fl01.aa" refers to the full-length amino acid sequence of B. burgdorferi polypeptide number 101. Further, "flOl.nt" refers to the full-length nucleotide sequence encoding the full-length amino acid sequence of B. burgdorferi polypeptide number 101.

WO 98/59071 PCT/US98/12718 7 Explanation of Table 2 Table 2 lists accession numbers for the closest matching sequences between the polypeptides of the present invention and those available through GenBank and GeneSeq 3 databases. These reference numbers are the database entry numbers commonly used by those of skill in the art, who will be familar with their denominations. The descriptions of the numenclature for GenBank are available from the National Center for Biotechnology Information.

Column 1 lists the gene or ORF of the present invention. Column 2 lists the accession number of a "match" gene sequence in GenBank or GeneSeq databases. Column 3 lists the description of the "match" gene sequence. Columns 4 and 5 are the high score and smallest sum probability, respectively, calculated by BLAST. Polypeptides of the present invention that do not share significant identity/similarity with any polypeptide sequences of GenBank and GeneSeq are not represented in Table 2. Polypeptides of the present invention that share significant identity/similarity with more than one of the polypeptides of GenBank and GeneSeq are represented more than once.

Explanation of Table 3.

The B. burgdorferi polypeptides of the present invention may include one or more conservative amino acid substitutions from natural mutations or human manipulation as indicated in Table 3.

Changes are preferably of a minor nature, such as conservative amino acid substitutions that do not significantly affect the folding or activity of the protein. Residues from the following groups, as indicated in Table 3, may be substituted for one another: Aromatic, Hydrophobic, Polar, Basic, Acidic, and Small, 25 Explanation of Table 4 Table 4 lists residues comprising antigenic epitopes of antigenic epitope-bearing fragments present in each of the full length B. burgdorferi polypeptides described in Table 1 as predicted by the inventors using the algorithm of Jameson and Wolf, (1988) Comp. Appl. Biosci. 4:181-186.

The Jameson-Wolf antigenic analysis was performed using the computer program PROTEAN 30 (Version 3.11 for the Power Macintosh, DNASTAR, Inc., 1228 South Park Street Madison, WI). B. burgdorferi polypeptide shown in Table 1 may one or more antigenic epitopes comprising residues described in Table 4. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly. The residues and locations shown described in Table 4 correspond to the amino acid sequences for each full length gene sequence shown in Table 1 and in the Sequence Listing.

Polypeptides of the present invention that do not have antigenic epitopes recognized by the Jameson-Wolf algorithm are not represented in Table 2.

WO 98/59071 PCT/US98/12718 8 Selection of Nucleic Acid Sequences Encoding Antigenic B. burgdorferi Polypeptides The present invention provides a select number of ORFs from those presented in the fragments of the Borrelia burgdorferi genome which may prove useful for the generation of a protective immune response. The sequenced B. burgdorferi genomic DNA was obtained from a sub-cultured isolate of ATCC Deposit No. 35210. The sub-cultured isolate was deposited on August 8, 1997 at the American Type Culture Collection, 12301 Park Lawn Drive, Rockville, Maryland 20852, and given accession number 202012.

Some ORFs contained in the subset of fragments of the B. burgdorferi genome disclosed herein were derived through the use of a number of screening criteria detailed below. The ORFs are generally bounded at the amino terminus by a methionine residue and at the carboxy terminus by a stop codon.

Many of the selected sequences do not consist of complete ORFs. Although a polypeptide representing a complete ORF may be the closest approximation of a protein native to an organism, it is not always preferred to express a complete ORF in a heterologous system. It may be challenging to express and purify a highly hydrophobic protein by common laboratory methods.

Some of the polypeptide vaccine candidates described herein have been modified slightly to simplify the production of recombinant protein. For example, nucleotide sequences which encode highly hydrophobic domains, such as those found at the amino terminal signal sequence, have S 20 been excluded from some constructs used for in vitro expression of the polypeptides.

S* Furthermore, any highly hydrophobic amino acid sequences occurring at the carboxy terminus have also been excluded from the recombinant expression constructs. Thus, in one embodiment, a polypeptide which represents a truncated or modified ORF may be used as an antigen.

While numerous methods are known in the art for selecting potentially immunogenic S 25 polypeptides, many of the ORFs disclosed herein were selected on the basis of screening all theoretical Borrelia burgdorferi ORFs for several aspects of potential immunogenicity. One set of selection criteria are as follows: 1. Type I signal sequence: An amino terminal type I signal sequence generally directs a nascent protein across the plasma and outer membranes to the exterior of the bacterial cell.

30 Experimental evidence obtained from studies with Escherichia coli suggests that the typical type I signal sequence consists of the following biochemical and physical attributes (Izard, J. W. and Kendall, D. A. Mol. MicrobioL 13:765-773 (1994)). The length of the type I signal sequence is approximately 15 to 25 primarily hydrophobic amino acid residues with a net positive charge in the extreme amino terminus. In addition, the central region of the signal sequence adopts an alpha-helical conformation in a hydrophobic environment. Finally, the region surrounding the actual site of cleavage is ideally six residues long, with small side-chain amino acids in the -1 and -3 positions.

2. Type IV signal sequence: The type IV signal sequence is an example of the several types of functional signal sequences which exist in addition to the type I signal sequence detailed WO 98/59071 PCT/US98/12718 9 above. Although functionally related, the type IV signal sequence possesses a unique set of biochemical and physical attributes (Strom, M. S. and Lory, J. BacterioL 174:7345-7351 (1992)). These are typically six to eight amino acids with a net basic charge followed by an additional sixteen to thirty primarily hydrophobic residues. The cleavage site of a type IV signal sequence is typically after the initial six to eight amino acids at the extreme amino terminus. In addition, type IV signal sequences generally contain a phenylalanine residue at the +1 site relative to the cleavage site.

3. Lipoprotein: Studies of the cleavage sites of twenty-six bacterial lipoprotein precursors has allowed the definition of a consensus amino acid sequence for lipoprotein cleavage. Nearly three-fourths of the bacterial lipoprotein precursors examined contained the sequence at positions -3 to relative to the point of cleavage (Hayashi, S. and Wu, H. J.

Bioenerg. Biomembr. 22:451-471 (1990)).

4. LPXTG motif: It has been experimentally determined that most anchored proteins found on the surface of gram-positive bacteria possess a highly conserved carboxy terminal sequence. More than fifty such proteins from organisms such as S. pyogenes, S. mutans, B.

burgdorferi, S. pneumoniae, and others, have been identified based on their extracellular location and carboxy terminal amino acid sequence (Fischetti, V. ASM News 62:405-410 (1996)).

The conserved region consists of six charged amino acids at the extreme carboxy terminus coupled to 15-20 hydrophobic amino acids presumed to function as a transmembrane domain.

20 Immediately adjacent to the transmembrane domain is a six amino acid sequence conserved in nearly all proteins examined. The amino acid sequence of this region is L-P-X-T-G-X, where X is any amino acid.

An algorithm for selecting antigenic and immunogenic Borrelia burgdorferi polypeptides including the foregoing criteria was developed. The algorithm is similar to that described in U.S.

25 patent application 08/781,986, filed January 3, 1997, which is fully incorporated by reference herein. Use of the algorithm by the inventors to select immunologically useful Borrelia burgdorferi polypeptides resulted in the selection of a number of the disclosed ORFs.

Polypeptides comprising the polypeptides identified in this group may be produced by techniques standard in the art and as further described herein.

Nucleic Acid Molecules The present invention provides isolated nucleic acid molecules comprising polynucleotides encoding the B. burgdorferi polypeptides having the amino acid sequences shown in Table 1, which were determined by sequencing the genome of B. burgdorferi deposited as ATCC deposit no. 202012 and selected as putative immunogens.

Unless otherwise indicated, all nucleotide sequences determined by sequencing a DNA molecule herein were determined using an automated DNA sequencer (such as the Model 373 from Applied Biosystems, Inc.), and all amino acid sequences of polypeptides encoded by DNA molecules determined herein were predicted by translation of DNA sequences determined as WO 98/59071 PCT/US98/12718 above. Therefore, as is known in the art for any DNA sequence determined by this automated approach, any nucleotide sequence determined herein may contain some errors. Nucleotide sequences determined by automation are typically at least about 90% identical, more typically at least about 95% to at least about 99.9% identical to the actual nucleotide sequence of the sequenced DNA molecule. The actual sequence can be more precisely determined by other approaches including manual DNA sequencing methods well known in the art. As is also known in the art, a single insertion or deletion in a determined nucleotide sequence compared to the actual sequence will cause a frame shift in translation of the nucleotide sequence such that the predicted amino acid sequence encoded by a determined nucleotide sequence will be completely different from the amino acid sequence actually encoded by the sequenced DNA molecule, beginning at the point of such an insertion or deletion.

Unless otherwise indicated, each "nucleotide sequence" set forth herein is presented as a sequence of deoxyribonucleotides (abbreviated A, G, C and However, by "nucleotide sequence" of a nucleic acid molecule or polynucleotide is intended, for a DNA molecule or polynucleotide, a sequence of deoxyribonucleotides, and for an RNA molecule or polynucleotide, the corresponding sequence of ribonucleotides G, C and where each thymidine deoxyribonucleotide in the specified deoxyribonucleotide sequence is replaced by the ribonucleotide uridine For instance, reference to an RNA molecule having a sequence of Table 1 set forth using deoxyribonucleotide abbreviations is intended to indicate an RNA molecule 20 having a sequence in which each deoxyribonucleotide A, G or C of Table 1 has been replaced by the corresponding ribonucleotide A, G or C, and each deoxyribonucleotide T has been replaced by a ribonucleotide U.

Nucleic acid molecules of the present invention may be in the form of RNA, such as mRNA, or in the form of DNA, including, for instance, cDNA and genomic DNA obtained by 25 cloning or produced synthetically. The DNA may be double-stranded or single-stranded.

Single-stranded DNA or RNA may be the coding strand, also known as the sense strand, or it may be the non-coding strand, also referred to as the anti-sense strand.

By "isolated" nucleic acid molecule(s) is intended a nucleic acid molecule, DNA or RNA, which has been removed from its native environment For example, recombinant DNA molecules contained in a vector are considered isolated for the purposes of the present invention. Further examples of isolated DNA molecules include recombinant DNA molecules maintained in heterologous host cells or purified (partially or substantially) DNA molecules in solution. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the DNA molecules of the present invention. Isolated nucleic acid molecules according to the present invention further include such molecules produced synthetically.

In addition, isolated nucleic acid molecules of the invention include DNA molecules which comprise a sequence substantially different from those described above but which, due to the degeneracy of the genetic code, still encode a B. burgdorferi polypeptides and peptides of the present invention polypeptides of Table That is, all possible DNA sequences that encode WO 98/59071 PCT/US98/12718 11 the B. burgdorferi polypeptides of the present invention. This includes the genetic code and species-specific codon preferences known in the art. Thus, it would be routine for one skilled in the art to generate the degenerate variants described above, for instance, to optimize codon expression for a particular host change codons in the bacteria mRNA to those preferred by a mammalian or other bacterial host such as E. coli).

The invention further provides isolated nucleic acid molecules having the nucleotide sequence shown in Table 1 or a nucleic acid molecule having a sequence complementary to one of the above sequences. Such isolated molecules, particularly DNA molecules, are useful as probes for gene mapping and for identifying B. burgdorferi in a biological sample, for instance, by PCR, Southern blot, Northern blot, or other form of hybridization analysis.

The present invention is further directed to nucleic acid molecules encoding portions or fragments of the nucleotide sequences described herein. Fragments include portions of the nucleotide sequences of Table 1 at least 10 contiguous nucleotides in length selected from any two integers, one of which representing a 5' nucleotide position and a second of which representing a 3' nucleotide position, where the first nucleotide for each nucleotide sequence in Table 1 is position 1. That is, every combination of a 5' and 3' nucleotide position that a fragment at least contiguous nucleotides in length could occupy is included in the invention. "At least" means a fragment may be 10 contiguous nucleotide bases in length or any integer between 10 and the length of an entire nucleotide sequence of Table 1 minus 1. Therefore, included in the invention are contiguous fragments specified by any 5' and 3' nucleotide base positions of a nucleotide "6 sequences of Table 1 wherein the contiguous fragment is any integer between 10 and the length of an entire nucleotide sequence minus 1.

Further, the invention includes polynucleotides comprising fragments specified by size, in nucleotides, rather than by nucleotide positions. The invention includes any fragment size, in 5 contiguous nucleotides, selected from integers between 10 and the length of an entire nucleotide sequence minus 1. Preferred sizes of contiguous nucleotide fragments include 20 nucleotides, nucleotides, 40 nucleotides, 50 nucleotides. Other preferred sizes of contiguous nucleotide fragments, which may be useful as diagnostic probes and primers, include fragments 50-300 nucleotides in length which include, as discussed above, fragment sizes representing each integer 30 between 50-300. Larger fragments are also useful according to the present invention corresponding to most, if not all, of the nucleotide sequences shown in Table lor of the B.

burgdorferi nucleotide sequences of the plasimd clones listed in Table 1. The preferred sizes are, of course, meant to exemplify not limit the present invention as all size fragments, representing any integer between 10 and the length of an entire nucleotide sequence minus 1, are included in the invention. Additional preferred nucleic acid fragments of the present invention include nucleic acid molecules encoding epitope-bearing portions of B. burgdorferi polypeptides identified in Table 4.

The present invention also provides for the exclusion of any fragment, specified by 5' and 3' base positions or by size in nucleotide bases as described above for any nucleotide sequence of WO 98/59071 PCTIUS98/12718 12 Table 1 or the plasimd clones listed in Table 1. Any number of fragments of nucleotide sequences in Table 1 or the plasimd clones listed in Table 1, specified by 5' and 3' base positions or by size in nucleotides, as described above, may be excluded from the present invention.

Preferred nucleic acid fragments of the present invention also include nucleic acid molecules encoding epitope-bearing portions of the B. burgdorferi polypeptides shown in Table 1. Such nucleic acid fragments of the present invention include, for example, nucleic acid molecules encoding polypeptide fragments comprising from about the amino terminal residue to about the carboxy terminal residue of each fragment shown in Table 4. The above referred to polypeptide fragments are antigenic regions of particular B. burgdorferi polypeptides shown in Table 1. Methods for determining other such epitope-bearing portions for the remaining polypeptides described in Table 1 are well known in the art and are described in detail below.

In another aspect, the invention provides isolated nucleic acid molecules comprising polynucleotides which hybridize under stringent hybridization conditions to a portion of a polynucleotide in a nucleic acid molecule of the invention described above, for instance, a nucleic acid sequence shown in Table 1. By "stringent hybridization conditions" is intended overnight incubation at 42 C in a solution comprising: 50% formamide, 5x SSC (150 mM NaCI, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 5x Denhardt's solution, 10% dextran sulfate, and 20 g/ml denatured, sheared salmon sperm DNA, followed by washing the filters in 0.1x SSC at about 65 C.

20 By polynucleotides which hybridize to a "portion" of a polynucleotide is intended polynucleotides (either DNA or RNA) which hybridize to at least about 15 nucleotides and more preferably at least about 20 nt, still more preferably at least about 30 nt, and even more preferably about 30-70 nt of the reference polynucleotide. These are useful as diagnostic probes and primers as discussed above and in more detail below.

25 Of course, polynucleotides hybridizing to a larger portion of the reference polynucleotide, for instance, a portion 50-100 nt in length, or even to the entire length of the reference polynucleotide, are also useful as probes according to the present invention, as are polynucleotides corresponding to most, if not all, of a nucleotide sequence as shown in Table 1.

By a portion of a polynucleotide of "at least 20 nt in length," for example, is intended 20 or more contiguous nucleotides from the nucleotide sequence of the reference polynucleotide a nucleotide sequences as shown in Table As noted above, such portions are useful diagnostically either as probes according to conventional DNA hybridization techniques or as primers for amplification of a target sequence by PCR, as described, for instance, in Molecular Cloning. A Laboratory Manual, 2nd. edition, Sambrook, Fritsch, E. F. and Maniatis, T., eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989), the entire disclosure of which is hereby incorporated herein by reference.

Since nucleic acid sequences encoding the B. burgdorferi polypeptides of the present invention are provided in Table 1, generating polynucleotides which hybridize to portions of these sequences would be routine to the skilled artisan. For example, the hybridizing polynucleotides WO 98/59071 PCT/US98/12718 13 of the present invention could be generated synthetically according to known techniques.

As indicated, nucleic acid molecules of the present invention which encode B. burgdorferi polypeptides of the present invention may include, but are not limited to those encoding the amino acid sequences of the polypeptides by themselves; and additional coding sequences which code for additional amino acids, such as those which provide additional functionalities. Thus, the sequences encoding these polypeptides may be fused to a marker sequence, such as a sequence encoding a peptide which facilitates purification of the fused polypeptide. In certain preferred embodiments of this aspect of the invention, the marker amino acid sequence is a hexa-histidine peptide, such as the tag provided in a pQE vector (Qiagen, Inc.), among others, many of which are commercially available. As described in Gentz et aL, Proc. Natl. Acad Sci. USA 86:821-824 (1989), for instance, hexa-histidine provides for convenient purification of the resulting fusion protein.

Thus, the present invention also includes genetic fusions wherein the B. burgdorferi nucleic acid sequences coding sequences provided in Table 1 are linked to additional nucleic acid sequences to produce fusion proteins. These fusion proteins may include epitopes of borrelial or non-borrelial origin designed to produce proteins having enhanced immunogenicity. Further, the fusion proteins of the present invention may contain antigenic determinants known to provide helper T-cell stimulation, peptides encoding sites for post-translational modifications which enhance immunogenicity acylation), peptides which 20 facilitate purification histidine or amino acid sequences which target the fusion protein to a desired location a heterologous leader sequence). For instance, hexa-histidine provides for convenient purification of the fusion protein. See Gentz et al. (1989) Proc. Natl.

Acad. Sci. 86:821-24. The "HA" tag is another peptide useful for purification which corresponds to an epitope derived from the influenza hemagglutinin protein. See Wilson et al. (1984) Cell 25 37:767. As discussed below, other such fusion proteins include the B. burgdorferi polypeptides of the present invention fused to Fc at the N- or C-terminus.

Post-translational modification of the full-length B. burgdorferi OspA protein :expressed in E. coli is believed to increase the immunogenicity of this protein. Erdile, L. et aL, Infect. Immun. 61:81-90 (1993). B. burgdorferi OspA when expressed in E. coli, for example, 30 is post-translationally modified in at least two ways. First, a signal peptide is cleaved; second, lipid moieties are attached. The presence of these lipid moieties is believed to confer enhanced immunogenicity and results in the elicitation of a strong protective immunological response.

Variant and Mutant Polynucleotides The present invention thus includes nucleic acid molecules and sequences which encode fusion proteins comprising one or more B. burgdorferi polypeptides of the present invention fused to an amino acid sequence which allows for post-translational modification to enhance immunogenicity. This post-translational modification may occur either in vitro or when the fusion protein is expressed in vivo in a host cell. An example of such a modification is the introduction WO 98/59071 PCT/US98/12718 14 of an amino acid sequence which results in the attachment of a lipid moiety. Such a lipid moiety attachment site of OspA, which is lipidated upon expression in E. coli, has been identified.

Bouchon, B. et aL, AnaL Biochem. 246:52-61 (1997).

Thus, as indicated above, the present invention includes genetic fusions wherein a B. burgdorferi nucleic acid sequence provided in Table 1 is linked to a nucleotide sequence encoding another amino acid sequence. These other amino acid sequences may be of borrelial origin another sequence selected from Table 1) or non-borrelial origin. An example of such a fusion protein is reported in Fikrig, E. et aL, Science 250:553-556 (1990) where an OspAglutathione-S-transferase fusion protein was produced and shown to elicit protective immunity against Lyme disease in immune competent mice.

The present invention further relates to variants of the nucleic acid molecules of the present invention, which encode portions, analogs or derivatives of the B. burgdorferi polypeptides shown in Table 1. Variants may occur naturally, such as a natural allelic variant. By an "allelic variant" is intended one of several alternate forms of a gene occupying a given locus on a chromosome of an organism. Genes II, Lewin, ed., John Wiley Sons, New York (1985).

Non-naturally occurring variants may be produced using art-known mutagenesis techniques.

Such variants include those produced by nucleotide substitutions, deletions or additions.

The substitutions, deletions or additions may involve one or more nucleotides. These variants may be altered in coding regions, non-coding regions, or both. Alterations in the coding regions S* 20 may produce conservative or non-conservative amino acid substitutions, deletions or additions.

Especially preferred among these are silent substitutions, additions and deletions, which do not alter the properties and activities of the B. burgdorferi polypeptides disclosed herein or portions thereof. Also especially preferred in this regard are conservative substitutions.

The present application is further directed to nucleic acid molecules at least 90%, 25 96%, 97%, 98% or 99% identical to a nucleic acid sequence shown in Table 1. The above nucleic acid sequences are included irrespective of whether they encode a polypeptide having B.

burgdorferi activity. This is because even where a particular nucleic acid molecule does not encode a polypeptide having B. burgdorferi activity, one of skill in the art would still know how to use the nucleic acid molecule, for instance, as a hybridization probe. Uses of the nucleic acid molecules of the present invention that do not encode a polypeptide having B. burgdorferi activity include, inter alia, isolating an B. burgdorferi gene or allelic variants thereof from a DNA library, and detecting B. burgdorferi mRNA expression samples, environmental samples, suspected of containing B. burgdorferi by Northern Blot analysis.

Embodiments of the invention include isolated nucleic acid molecules comprising a polynucleotide having a nucleotide sequence at least 90% identical, and more preferably at least 96%, 97%, 98% or 99% identical to a nucleotide sequence encoding any of the amino acid sequences of the full-length polypeptides shown in Table 1; a nucleotide sequence encoding any of the amino acid sequences of the full-length polypeptides shown in Table 1 but minus the N-terminal methionine residue, if present; a nucleotide sequence encoding any of the WO 98/59071 PCT/US98/12718 amino acid sequences of the truncated polypeptides shown in Table 1; and a nucleotide sequence complementary to any of the nucleotide sequences in or above.

Preferred, are nucleic acid molecules having sequences at least 90%, 95%, 96%, 97%, 98% or 99% identical to the nucleic acid sequence shown in Table 1, which do, in fact, encode a polypeptide having B. burgdorferi protein activity By "a polypeptide having B. burgdorferi activity" is intended polypeptides exhibiting activity similar, but not necessarily identical, to an activity of the B. burgdorferi protein of the invention, as measured in a particular biological assay suitable for measuring activity of the specified protein.

Due to the degeneracy of the genetic code, one of ordinary skill in the art will immediately recognize that a large number of the nucleic acid molecules having a sequence at least 90%, 96%, 97%, 98%, or 99% identical to the nucleic acid sequences shown in Table 1 will encode a polypeptide having B. burgdorferi protein activity. In fact, since degenerate variants of these nucleotide sequences all encode the same polypeptide, this will be clear to the skilled artisan even without performing the above described comparison assay. It will be further recognized in the art that, for such nucleic acid molecules that are not degenerate variants, a reasonable number will also encode a polypeptide having B. burgdorferi protein activity. This is because the skilled artisan is fully aware of amino acid substitutions that are either less likely or not likely to significantly effect protein function replacing one aliphatic amino acid with a second aliphatic amino acid), as further described below.

The biological activity or function of the polypeptides of the present invention are expected to be similar or identical to polypeptides from other bacteria that share a high degree of structural identity/similarity. Tables 2 lists accession numbers and descriptions for the closest matching sequences of polypeptides available through Genbank and Derwent databases. It is therefore expected that the biological activity or function of the polypeptides of the present invention will be 25 similar or identical to those polypeptides from other bacterial genuses, species, or strains listed in Table 2.

By a polynucleotide having a nucleotide sequence at least, for example, 95% "identical" to a reference nucleotide sequence of the present invention, it is intended that the nucleotide sequence of the polynucleotide is identical to the reference sequence except that the polynucleotide sequence 30 may include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence encoding the B. burgdorferi polypeptide. In other words, to obtain a polynucleotide having a nucleotide sequence at least 95% identical to a reference nucleotide sequence, up to of 100) of the nucleotides in the reference sequence may be deleted, inserted, or substituted with another nucleotide. The query sequence may be an entire sequence shown in Table 1, the ORF (open reading frame), or any fragment specified as described herein.

As a practical matter, whether any particular nucleic acid molecule or polypeptide is at least 95%, 96%, 97%, 98% or 99% identical to a nucleotide sequence of the presence invention can be determined conventionally using known computer programs. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) WO 98/59071 PCT/US98/12718 16 and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al. See Brutlagetal.

(1990) Comp. App. Biosci. 6:237-245. In a sequence alignment the query and subject sequences are both DNA sequences. An RNA sequence can be compared by first converting U's to T's.

The result of said global sequence alignment is in percent identity. Preferred parameters used in a FASTDB alignment of DNA sequences to calculate percent identity are: Matrix=Unitary, ktuple=4, Mismatch Penalty=l, Joining Penalty=30, Randomization Group Length=0, Cutoff Score=l, Gap Penalty=5, Gap Size Penalty 0.05, Window Size=500 or the lenght of the subject nucleotide sequence, whichever is shorter.

If the subject sequence is shorter than the query sequence because of 5' or 3' deletions, not because of internal deletions, a manual correction must be made to the results. This is because the FASTDB program does not account for 5' and 3' truncations of the subject sequence when calculating percent identity. For subject sequences truncated at the 5' or 3' ends, relative to the query sequence, the percent identity is corrected by calculating the number of bases of the query sequence that are 5' and 3' of the subject sequence, which are not matched/aligned, as a percent of the total bases of the query sequence. Whether a nucleotide is matched/aligned is determined by results of the FASTDB sequence alignment This percentage is then subtracted from the percent Sidentity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This corrected score is what is used for the purposes of the present 20 invention. Only nucleotides outside the 5' and 3' nucleotides of the subject sequence, as displayed by the FASTDB alignment, which are not matched/aligned with the query sequence, are calculated for the purposes of manually adjusting the percent identity score.

For example, a 90 nucleotide subject sequence is aligned to a 100 nucleotide query sequence to determine percent identity. The deletions occur at the 5' end of the subject sequence S 25 and therefore, the FASTDB alignment does not show a matched/alignment of the first nucleotides at 5' end. The 10 unpaired nucleotides represent 10% of the sequence (number of nucleotides at the 5' and 3' ends not matched/total number of nucleotides in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 90 nucleotides were perfectly matched the final percent identity would be 90%. In another example, a 90 nucleotide subject sequence is compared with a 100 nucleotide query sequence. This time the deletions are internal deletions so that there are no nucleotides on the or 3' of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only nucleotides and 3' of the subject sequence which are not matched/aligned with the query sequence are manually corrected for. No other manual corrections are to made for the purposes of the present invention.

Vectors and Host Cells The present invention also relates to vectors which include the isolated DNA molecules of WO 98/59071 PCT/US98/12718 17 the present invention, host cells which are genetically engineered with the recombinant vectors, and the production of B. burgdorferi polypeptides or fragments thereof by recombinant techniques.

Recombinant constructs may be introduced into host cells using well known techniques such as infection, transduction, transfection, transvection, electroporation and transformation.

The vector may be, for example, a phage, plasmid, viral or retroviral vector. Retroviral vectors may be replication competent or replication defective. In the latter case, viral propagation generally will occur only in complementing host cells.

The polynucleotides may be joined to a vector containing a selectable marker for propagation in a host. Generally, a plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it may be packaged in vitro using an appropriate packaging cell line and then transduced into host cells.

Preferred are vectors comprising cis-acting control regions to the polynucleotide of interest Appropriate trans-acting factors may be supplied by the host, supplied by a complementing vector or supplied by the vector itself upon introduction into the host.

In certain preferred embodiments in this regard, the vectors provide for specific .expression, which may be inducible and/or cell type-specific. Particularly preferred among such vectors are those inducible by environmental factors that are easy to manipulate, such as temperature and nutrient additives.

20 Expression vectors useful in the present invention include chromosomal-, episomal- and virus-derived vectors, vectors derived from bacterial plasmids, bacteriophage, yeast episomes, yeast chromosomal elements, viruses such as baculoviruses, papova viruses, vaccinia viruses, adenoviruses, fowl pox viruses, pseudorabies viruses and retroviruses, and vectors derived from combinations thereof, such as cosmids and phagemids.

25 The DNA insert should be operatively linked to an appropriate promoter, such as the phage lambda PL promoter, the E coli lac, trp and tac promoters, the SV40 early and late promoters and promoters of retroviral LTRs, to name a few. Other suitable promoters will be known to the skilled artisan. The expression constructs will further contain sites for transcription initiation, termination and, in the transcribed region, a ribosome binding site for translation. The coding portion of the mature transcripts expressed by the constructs will preferably include a translation initiating site at the beginning and a termination codon (UAA, UGA or UAG) appropriately positioned at the end of the polypeptide to be translated.

As indicated, the expression vectors will preferably include at least one selectable marker.

Such markers include dihydrofolate reductase or neomycin resistance for eukaryotic cell culture and tetracycline or ampicillin resistance genes for culturing in E. coli and other bacteria.

Representative examples of appropriate hosts include, but are not limited to, bacterial cells, such as E. coli, Streptomyces and Salmonella typhimurium cells; fungal cells, such as yeast cells; insect cells such as Drosophila S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS and Bowes melanoma cells; and plant cells. Appropriate culture mediums and conditions for the WO 98/59071 PCT/US98/12718 18 above-described host cells are known in the art.

Among vectors preferred for use in bacteria include pQE70, pQE60 and pQE-9, available from Qiagen; pBS vectors, Phagescript vectors, Bluescript vectors, pNH8A, pNH6a, pNH18A, pNH46A available from Stratagene; pET series of vectors available from Novagen; and ptrc99a, pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia. Among preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG 44 pXTl and pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL available from Pharmacia. Other suitable vectors will be readily apparent to the skilled artisan.

Among known bacterial promoters suitable for use in the present invention include the E.

coli lac and lacZ promoters, the T3 and T7 promoters, the gpt promoter, the lambda PR and PL promoters and the trp promoter. Suitable eukaryotic promoters include the CMV immediate early promoter, the HSV thymidine kinase promoter, the early and late SV40 promoters, the promoters of retroviral LTRs, such as those of the Rous sarcoma virus (RSV), and metallothionein promoters, such as the mouse metallothionein-I promoter.

Introduction of the construct into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection or other methods. Such methods are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986).

Transcription of DNA encoding the polypeptides of the present invention by higher 20 eukaryotes may be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp that act to increase transcriptional activity of a promoter in a given host cell-type. Examples of enhancers include the enhancer, which is located on the late side of the replication origin at bp 100 to 270, the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication 25 origin, and adenovirus enhancers.

For secretion of the translated polypeptide into the lumen of the endoplasmic reticulum, into the periplasmic space or into the extracellular environment, appropriate secretion signals may be incorporated into the expressed polypeptide. The signals may be endogenous to the polypeptide or they may be heterologous signals.

The polypeptide may be expressed in a modified form, such as a fusion protein, and may include not only secretion signals, but also additional heterologous functional regions. For instance, a region of additional amino acids, particularly charged amino acids, may be added to the N-terminus of the polypeptide to improve stability and persistence in the host cell, during purification, or during subsequent handling and storage. Also, peptide moieties may be added to the polypeptide to facilitate purification. Such regions may be removed prior to final preparation of the polypeptide. The addition of peptide moieties to polypeptides to engender secretion or excretion, to improve stability and to facilitate purification, among others, are familiar and routine techniques in the art. A preferred fusion protein comprises a heterologous region from immunoglobulin that is useful to solubilize proteins. For example, EP-A-O 464 533 (Canadian WO 98/59071 PCT/US98/12718 19 counterpart 2045869) discloses fusion proteins comprising various portions of constant region of immunoglobin molecules together with another human protein or part thereof. In many cases, the Fc part in a fusion protein is thoroughly advantageous for use in therapy and diagnosis and thus results, for example, in improved pharmacokinetic properties (EP-A 0232 262). On the other hand, for some uses it would be desirable to be able to delete the Fc part after the fusion protein has been expressed, detected and purified in the advantageous manner described. This is the case when Fc portion proves to be a hindrance to use in therapy and diagnosis, for example when the fusion protein is to be used as antigen for immunizations. In drug discovery, for example, human proteins, such as, hIL5-receptor has been fused with Fc portions for the purpose of high-throughput screening assays to identify antagonists of hIL-5. See Bennett, D. et al., J.

Molec. Recogn. 8:52-58 (1995) and Johanson, K. et al., J. Biol. Chem. 270 (16):9459-9471 (1995).

The B. burgdorferi polypeptides can be recovered and purified from recombinant cell cultures by well-known methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography, lectin chromatography and high performance liquid chromatography ("HPLC") is employed for purification. Polypeptides of the present invention include naturally purified products, products of chemical synthetic procedures, and products produced by recombinant 20 techniques from a prokaryotic or eukaryotic host, including, for example, bacterial, yeast, higher plant, insect and mammalian cells.

Polypeptides and Fragments The invention further provides isolated polypeptides having the amino acid sequences in Table 1, and peptides or polypeptides comprising portions of the above polypeptides. The terms "peptide" and "oligopeptide" are considered synonymous (as is commonly recognized) and each term can be used interchangeably as the context requires to indicate a chain of at least to amino acids coupled by peptidyl linkages. The word "polypeptide" is used herein for chains containing more than ten amino acid residues. All oligopeptide and polypeptide formulas or sequences herein are written from left to right and in the direction from amino terminus to carboxy terminus.

As discussed in detail below, immunization using B. burgdorferi sensu stricto isolate B31 decorin-binding protein elicits the production of antiserum which confers passive immunity against Borrelia species and strains which express divergent forms of this protein. Cassatt, D. et Protection of Borrelia burgdorferi Infection by Antibodies to Decorin-binding Protein, in VACCINES97, Cold Spring Harbor Press (1997), pages 191-195. Thus, some amino acid sequences of the B. burgdorferi polypeptides shown in Table 1 can be varied without significantly effecting the antigenicity of the polypeptides. If such differences in sequence are contemplated, it should be remembered that there will be critical areas on the polypeptide which determine antigenicity. In general, it is possible to replace residues which do not form part of an WO 98/59071 PCT/US98/12718 antigenic epitope without significantly effecting the antigenicity of a polypeptide.

Variant and Mutant Polypeptides To improve or alter the characteristics of B. burgdorferi polypeptides of the present invention, protein engineering may be employed. Recombinant DNA technology known to those skilled in the art can be used to create novel mutant proteins or muteins including single or multiple amino acid substitutions, deletions, additions, or fusion proteins. Such modified polypeptides can show, enhanced activity or increased stability. In addition, they may be purified in higher yields and show better solubility than the corresponding natural polypeptide, at least under certain purification and storage conditions.

N-Terminal and C-Terminal Deletion Mutants It is known in the art that one or more amino acids may be deleted from the N-terminus or C-terminus without substantial loss of biological function. For instance, Ron et al. J. Biol.

Chem., 268:2984-2988 (1993), reported modified KGF proteins that had heparin binding activity even if 3, 8, or 27 N-terminal amino acid residues were missing. Accordingly, the present invention provides polypeptides having one or more residues deleted from the amino terminus of the amino acid sequence of the B. burgdorferi polypeptides shown in Table 1, and Spolynucleotides encoding such polypeptides.

0 Similarly, many examples of biologically functional C-terminal deletion muteins are known. For instance, Interferon gamma shows up to ten times higher activities by deleting 8-10 amino acid residues from the carboxy terminus of the protein See, Dobeli, et al. (1988) J.

Biotechnology 7:199-216. Accordingly, the present invention provides polypeptides having one or more residues from the carboxy terminus of the amino acid sequence of the B. burgdorferi polypeptides shown in Table 1. The invention also provides polypeptides having one or more amino acids deleted from both the amino and the carboxyl termini as described below.

The present invention is further directed to polynucleotide encoding portions or fragments" of the amino acid sequences described herein as well as to portions or fragments of the isolated amino acid sequences described herein. Fragments include portions of the amino acid sequences of Table 1, are at least 5 contiguous amino acid in length, are selected from any two integers, one of which representing a N-terminal position. The initiation codon of the polypeptides of the present inventions position 1. Every combination of a N-terminal and C-terminal position that a fragment at least 5 contiguous amino acid residues in length could occupy, on any given amino acid sequence of Table 1 is included in the invention. At least means a fragment may be contiguous amino acid residues in length or any integer between 5 and the number of residues in a full length amino acid sequence minus 1. Therefore, included in the invention are contiguous fragments specified by any N-terminal and C-terminal positions of amino acid sequence set forth in Table 1 wherein the contiguous fragment is any integer between 5 and the number of residues in a full length sequence minus 1.

Further, the invention includes polypeptides comprising fragments specified by size, in WO 98/59071 PCT/US98/12718 21 amino acid residues, rather than by N-terminal and C-terminal positions. The invention includes any fragment size, in contiguous amino acid residues, selected from integers between 5 and the number of residues in a full length sequence minus 1. Preferred sizes of contiguous polypeptide fragments include about 5 amino acid residues, about 10 amino acid residues, about 20 amino acid residues, about 30 amino acid residues, about 40 amino acid residues, about 50 amino acid residues, about 100 amino acid residues, about 200 amino acid residues, about 300 amino acid residues, and about 400 amino acid residues. The preferred sizes are, of course, meant to exemplify, not limit, the present invention as all size fragments representing any integer between and the number of residues in a full length sequence minus 1 are included in the invention. The present invention also provides for the exclusion of any fragments specified by N-terminal and Cterminal positions or by size in amino acid residues as described above. Any number of fragments specified by N-terminal and C-terminal positions or by size in amino acid residues as described above may be excluded.

The above fragments need not be active since they would be useful, for example, in immunoassays, in epitope mapping, epitope tagging, to generate antibodies to a particular portion of the protein, as vaccines, and as molecular weight markers.

Other Mutants In addition to N- and C-terminal deletion forms of the protein discussed above, it also will 20 be recognized by one of ordinary skill in the art that some amino acid sequences of the B.

burgdorferi polypeptide can be varied without significant effect of the structure or function of the protein. If such differences in sequence are contemplated, it should be remembered that there will be critical areas on the protein which determine activity.

Thus, the invention further includes variations of the B. burgdorferi polypeptides which 25 show substantial B. burgdorferi polypeptide activity or which include regions of B. burgdorferi e.i protein such as the protein portions discussed below. Such mutants include deletions, insertions, inversions, repeats, and type substitutions selected according to general rules known in the art so as to have little effect on activity. For example, guidance concerning how to make phenotypically silent amino acid substitutions is provided. There are two main approaches for studying the tolerance of an amino acid sequence to change. See, Bowie, J. U. et al. (1990), Science 247:1306-1310. The first method relies on the process of evolution, in which mutations are either accepted or rejected by natural selection. The second approach uses genetic engineering to introduce amino acid changes at specific positions of a cloned gene and selections or screens to identify sequences that maintain functionality.

These studies have revealed that proteins are surprisingly tolerant of amino acid substitutions. The studies indicate which amino acid changes are likely to be permissive at a certain position of the protein. For example, most buried amino acid residues require nonpolar side chains, whereas few features of surface side chains are generally conserved. Other such phenotypically silent substitutions are described by Bowie et al. (supra) and the references cited WO 98/59071 PCT/US98/12718 22 therein. Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic amino acids Ala, Val, Leu and Ile; interchange of the hydroxyl residues Ser and Thr, exchange of the acidic residues Asp and Glu, substitution between the amide residues Asn and Gin, exchange of the basic residues Lys and Arg and replacements among the aromatic residues Phe, Tyr.

Thus, the fragment, derivative, analog, or homolog of the polypeptide of Table 1, or that encoded by the plaimds listed in Table 1, may be: one in which one or more of the amino acid residues are substituted with a conserved or non-conserved amino acid residue (preferably a conserved amino acid residue) and such substituted amino acid residue may or may not be one encoded by the genetic code: or (ii) one in which one or more of the amino acid residues includes a substituent group: or (iii) one in which the B. burgdorferi polypeptide is fused with another compound, such as a compound to increase the half-life of the polypeptide (for example, polyethylene glycol): or (iv) one in which the additional amino acids are fused to the above form of the polypeptide, such as an IgG Fc fusion region peptide or leader or secretory sequence or a sequence which is employed for purification of the above form of the polypeptide or a proprotein sequence. Such fragments, derivatives and analogs are deemed to be within the scope of those skilled in the art from the teachings herein.

Thus, the B. burgdorferi polypeptides of the present invention may include one or more amino acid substitutions, deletions, or additions, either from natural mutations or human 20 manipulation. As indicated, changes are preferably of a minor nature, such as conservative amino acid substitutions that do not significantly affect the folding or activity of the protein (see Table 3).

Amino acids in the B. burgdorferi proteins of the present invention that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis. See, Cunningham et al. (1989) Science 244:1081-1085.

25 The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity using assays appropriate for measuring the function of the particular protein.

Of special interest are substitutions of charged amino acids with other charged or neutral **amino acids which may produce proteins with highly desirable improved characteristics, such as less aggregation. Aggregation may not only reduce activity but also be problematic when preparing pharmaceutical formulations, because aggregates can be immunogenic. See, e.g., Pinckard et al., (1967) Clin. Exp. Immunol. 2:331-340; Robbins, et al., (1987) Diabetes 36:838- 845; Cleland, et al., (1993) Crit. Rev. Therapeutic Drug Carrier Systems 10:307- 37 7 The polypeptides of the present invention are preferably provided in an isolated form, and preferably are substantially purified. A recombinantly produced version of the B. burgdorferi polypeptide can be substantially purified by the one-step method described by Smith et al. (1988) Gene 67:31-40. Polypeptides of the invention also can be purified from natural or recombinant sources using antibodies directed against the polypeptides of the invention in methods which are well known in the art of protein purification.

WO 98/59071 PCT/US98/12718 23 The invention further provides for isolated B. burgdorferi polypeptides comprising an amino acid sequence selected from the group consisting of: the amino acid sequence of a fulllength B. burgdorferi polypeptide having the complete amino acid sequence shown in Table 1; the amino acid sequence of a full-length B. burgdorferi polypeptide having the complete amino acid sequence shown in Table 1 excepting the N-terminal methionine; the complete amino acid sequence encoded by the plaimds listed in Table 1; and the complete amino acid sequence excepting the N-terminal methionine encoded by the plaimds listed in Table 1. The polypeptides of the present invention also include polypeptides having an amino acid sequence at least identical, more preferably at least 90% identical, and still more preferably 95%, 96%, 97%, 98% or 99% identical to those described in and above.

Further polypeptides of the present invention include polypeptides which have at least similarity, more preferably at least 95% similarity, and still more preferably at least 96%, 97%, 98% or 99% similarity to those described above.

A further embodiment of the invention relates to a polypeptide which comprises the amino acid sequence of a B. burgdorferi polypeptide having an amino acid sequence which contains at least one conservative amino acid substitution, but not more than 50 conservative amino acid *".substitutions, not more than 40 conservative amino acid substitutions, not more than conservative amino acid substitutions, and not more than 20 conservative amino acid substitutions. Also provided are polypeptides which comprise the amino acid sequence of a B.

burgdorferi polypeptide, having at least one, but not more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 conservative amino acid substitutions.

By a polypeptide having an amino acid sequence at least, for example, 95% "identical" to query amino acid sequence of the present invention, it is intended that the amino acid sequence of the subject polypeptide is identical to the query sequence except that the subject polypeptide S 25 sequence may include up to five amino acid alterations per each 100 amino acids of the query amino acid sequence. In other words, to obtain a polypeptide having an amino acid sequence at least 95% identical to a query amino acid sequence, up to 5% of the amino acid residues in the subject sequence may be inserted, deleted, (indels) or substituted with another amino acid. These alterations of the reference sequence may occur at the amino or carboxy terminal positions of the reference amino acid sequence or anywhere between those terminal positions, interspersed either individually among residues in the reference sequence or in one or more contiguous groups within the reference sequence.

As a practical matter, whether any particular polypeptide is at least 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, the amino acid sequences shown in Table 1 or to the amino acid sequence encoded by the plaimds listed in Table 1 can be determined conventionally using known computer programs. A preferred method for determining the best overall match between a query sequence (a sequence of the present invention) and a subject sequence, also referred to as a global sequence alignment, can be determined using the FASTDB computer program based on the algorithm of Brutlag et al., (1990) Comp. App. Biosci. 6:237-245. In a sequence alignment the WO 98/59071 PCT/US98/12718 24 query and subject sequences are both amino acid sequences. The result of said global sequence alignment is in percent identity. Preferred parameters used in a FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2, Mismatch Penalty=l, Joining Penalty=20, Randomization Group Length=0, Cutoff Score=l, Window Size=sequence length, Gap Penalty=5, Gap Size Penalty=0.05, Window Size=500 or the length of the subject amino acid sequence, whichever is shorter.

If the subject sequence is shorter than the query sequence due to N- or C-terminal deletions, not because of internal deletions, the results, in percent identity, must be manually corrected. This is because the FASTDB program does not account for N- and C-terminal truncations of the subject sequence when calculating global percent identity. For subject sequences truncated at the N- and C-termini, relative to the query sequence, the percent identity is corrected by calculating the number of residues of the query sequence that are N- and C-terminal of the subject sequence, which are not matched/aligned with acorresponding subject residue, as a, percent of the total bases of the query sequence. Whether a residue is matched/aligned is determined by results of the FASTDB sequence alignment. This percentage is then subtracted S. from the percent identity, calculated by the above FASTDB program using the specified parameters, to arrive at a final percent identity score. This final percent identity score is what is used for the purposes of the present invention. Only residues to the N- and C-termini of the subject sequence, which are not matched/aligned with the query sequence, are considered for the 20 purposes of manually adjusting the percent identity score. That is, only query amino acid residues outside the farthest N- and C-terminal residues of the subject sequence.

For example, a 90 amino acid residue subject sequence is aligned with a 100 residue query sequence to determine percent identity. The deletion occurs at the N-terminus of the subject sequence and therefore, the FASTDB alignment does not match/align with the first 10 residues at 25 the N-terminus. The 10 unpaired residues represent 10% of the sequence (number of residues at the N- and C- termini not matched/total number of residues in the query sequence) so 10% is subtracted from the percent identity score calculated by the FASTDB program. If the remaining 1 90 residues were perfectly matched the final percent identity would be 90%. In another example, a 90 residue subject sequence is compared with a 100 residue query sequence. This time the deletions are internal so there are no residues at the N- or C-termini of the subject sequence which are not matched/aligned with the query. In this case the percent identity calculated by FASTDB is not manually corrected. Once again, only residue positions outside the N- and C-terminal ends of the subject sequence, as displayed in the FASTDB alignment, which are not matched/aligned with the query sequence are manually corrected. No other manual corrections are to made for the purposes of the present invention.

The above polypeptide sequences are included irrespective of whether they have their normal biological activity. This is because even where a particular polypeptide molecule does not have biological activity, one of skill in the art would still know how to use the polypeptide, for instance, as a vaccine or to generate antibodies. Other uses of the polypeptides of the present WO 98/59071 PCTUS98/12718 invention that do not have B. burgdorferi activity include, inter alia, as epitope tags, in epitope mapping, and as molecular weight markers on SDS-PAGE gels or on molecular sieve gel filtration columns using methods known to those of skill in the art.

As described below, the polypeptides of the present invention can also be used to raise polyclonal and monoclonal antibodies, which are useful in assays for detecting B. burgdorferi protein expression or as agonists and antagonists capable of enhancing or inhibiting B.

burgdorferi protein function. Further, such polypeptides can be used in the yeast two-hybrid system to "capture" B. burgdorferi protein binding proteins which are also candidate agonists and antagonists according to the present invention. See, Fields et al. (1989) Nature 0o 340:245-246.

Epitope-Bearing Portions In another aspect, the invention provides peptides and polypeptides comprising epitope-bearing portions of the B. burgdorferi polypeptides of the present invention. These epitopes are immunogenic or antigenic epitopes of the polypeptides of the present invention. An "immunogenic epitope" is defined as a part of a protein that elicits an antibody response when the *whole protein or polypeptide is the immunogen. These immunogenic epitopes are believed to be confined to a few loci on the molecule. On the other hand, a region of a protein molecule to which an antibody can bind is defined as an "antigenic determinant" or "antigenic epitope." The 20 number of immunogenic epitopes of a protein generally is less than the number of antigenic epitopes. See, Geysen, et al. (1983) Proc. Natl. Acad. Sci. USA 81:3998- 4002.

Predicted antigenic epitopes are shown in Table 4, below. It is pointed out that Table 4 only lists amino acid residues comprising epitopes predicted to have the highest degree of antigenicity. The polypeptides not listed in Table 4 and portions of polypeptides not listed in Table 4 are not 25 considered non-antigenic. This is because they may still be antigenic in vivo but merely not recognized as such by the particular algorithm used. Thus, Table 4 lists the amino acid residues comprising preferred antigenic epitopes but not a complete list. Amino acid residues comprising other anigenic epitopes may be determined by algorithms similar to the Jameson-Wolf analysis or by in vivo testing for an antigenic response using the methods described herein or those known in the art.

As to the selection of peptides or polypeptides bearing an antigenic epitope that contain a region of a protein molecule to which an antibody can bind), it is well known in that art that relatively short synthetic peptides that mimic part of a protein sequence are routinely capable of eliciting an antiserum that reacts with the partially mimicked protein. See, Sutcliffe, et al., (1983) Science 219:660-666. Peptides capable of eliciting protein-reactive sera are frequently represented in the primary sequence of a protein, can be characterized by a set of simple chemical rules, and are confined neither to immunodominant regions of intact proteins immunogenic epitopes) nor to the amino or carboxyl terminals. Peptides that are extremely hydrophobic and those of six or fewer residues generally are ineffective at inducing antibodies that bind to the WO 98/59071 PCT/US98/12718 26 mimicked protein; longer, peptides, especially those containing proline residues, usually are effective. See, Sutcliffe, et al., supra, p. 661. For instance, 18 of 20 peptides designed according to these guidelines, containing 8-39 residues covering 75% of the sequence of the influenza virus hemagglutinin HA1 polypeptide chain, induced antibodies that reacted with the HA1 protein or intact virus; and 12/12 peptides from the MuLV polymerase and 18/18 from the rabies glycoprotein induced antibodies that precipitated the respective proteins.

Antigenic epitope-bearing peptides and polypeptides of the invention are therefore useful to raise antibodies, including monoclonal antibodies, that bind specifically to a polypeptide of the invention. Thus, a high proportion of hybridomas obtained by fusion of spleen cells from donors immunized with an antigen epitope-bearing peptide generally secrete antibody reactive with the native protein. See Sutcliffe, et al, supra, p. 663. The antibodies raised by antigenic epitope-bearing peptides or polypeptides are useful to detect the mimicked protein, and antibodies to different peptides may be used for tracking the fate of various regions of a protein precursor which undergoes post-translational processing. The peptides and anti-peptide antibodies may be used in a variety of qualitative or quantitative assays for the mimicked protein, for instance in competition assays since it has been shown that even short peptides about 9 amino acids) can bind and displace the larger peptides in immunoprecipitation assays. See, Wilson, et al., (1984) Cell 37:767-778. The anti-peptide antibodies of the invention also are useful for purification of the mimicked protein, for instance, by adsorption chromatography using methods 20 known in the art.

Antigenic epitope-bearing peptides and polypeptides of the invention designed according to the above guidelines preferably contain a sequence of at least seven, more preferably at least nine and most preferably between about 10 to about 50 amino acids any integer between 7 and 50) contained within the amino acid sequence of a polypeptide of the invention. However, 25 peptides or polypeptides comprising a larger portion of an amino acid sequence of a polypeptide of the invention, containing about 50 to about 100 amino acids, or any length up to and including the entire amino acid sequence of a polypeptide of the invention, also are considered epitope-bearing peptides or polypeptides of the invention and also are useful for inducing antibodies that react with the mimicked protein. Preferably, the amino acid sequence of the epitope-bearing peptide is selected to provide substantial solubility in aqueous solvents the sequence includes relatively hydrophilic residues and highly hydrophobic sequences are preferably avoided); and sequences containing proline residues are particularly preferred.

Non-limiting examples of antigenic polypeptides or peptides that can be used to generate an Borrelia-specific immune response or antibodies include portions of the amino acid sequences identified in Table 1. More specifically, Table 4 discloses a list of non-limiting residues that are involved in the antigenicity of the epitope-bearing fragments of the present invention. Therefore, the present inventions provides for isolatd and purified antigenic epitope-bearing fragements of the polypeptides of the present invention comprising a peptide sequences of Table 4. The antigenic epitope-bearing fragments comprising a peptide sequence of Table 4 preferably contain a WO 98/59071 PCT/US98/12718 27 sequence of at least seven, more preferably at least nine and most preferably between about 10 to about 50 amino acids any integer between 7 and 50) of a polypeptide of the present invention. That is, included in the present invention are antigenic polypeptides between the integers of 7 and 50 amino acid in length comprising one or more of the sequences of Table 4.

Therefore, in most cases, the polypeptides of Table 4 make up only a portion of the antigenic polypeptide. All combinations of sequences between the integers of 7 and 50 amino acid in length comprising one or more of the sequences of Table 4 are included. The antigenic epitope-bearing fragements may be specified by either the number of contiguous amino acid residues or by specific N-terminal and C-terminal positions as described above for the polypeptide fragements of the present invention, wherein the initiation codon is residue 1. Any number of the described antigenic epitope-bearing fragements of the present invention may also be excluded from the present invention in the same manner.

The epitope-bearing peptides and polypeptides of the invention may be produced by any conventional means for making peptides or polypeptides including recombinant means using nucleic acid molecules of the invention. For instance, an epitope-bearing amino acid sequence of the present invention may be fused to a larger polypeptide which acts as a carrier during recombinant production and purification, as well as during immunization to produce anti-peptide antibodies. Epitope-bearing peptides also may be synthesized using known methods of chemical synthesis. For instance, Houghten has described a simple method for synthesis of large numbers 20 of peptides, such as 10-20 mg of 248 different 13 residue peptides representing single amino acid variants of a segment of the HA1 polypeptide which were prepared and characterized (by ELISA-type binding studies) in less than four weeks (Houghten, R. A. Proc. Natl. Acad. Sci.

USA 82:5131-5135 (1985)). This "Simultaneous Multiple Peptide Synthesis (SMPS)" process is further described in U.S. Patent No. 4,631,211 to Houghten and coworkers (1986). In this 25 procedure the individual resins for the solid-phase synthesis of various peptides are contained in separate solvent-permeable packets, enabling the optimal use of the many identical repetitive steps involved in solid-phase methods. A completely manual procedure allows 500-1000 or more syntheses to be conducted simultaneously (Houghten et al. (1985) Proc. Natl. Acad. Sci.

82:5131-5135 at 5134.

Epitope-bearing peptides and polypeptides of the invention are used to induce antibodies according to methods well known in the art. See, Sutcliffe, et al., supra;; Wilson, et al., supra;; and Bittle, et al. (1985) J. Gen. Virol. 66:2347-2354. Generally, animals may be immunized with free peptide; however, anti-peptide antibody titer may be boosted by coupling of the peptide to a macromolecular carrier, such as keyhole limpet hemacyanin (KLH) or tetanus toxoid. For instance, peptides containing cysteine may be coupled to carrier using a linker such as m-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS), while other peptides may be coupled to carrier using a more general linking agent such as glutaraldehyde. Animals such as rabbits, rats and mice are immunized with either free or carrier-coupled peptides, for instance, by intraperitoneal and/or intradermal injection of emulsions containing about 100 .ig peptide or WO 98/59071 PCT/US98/12718 28 carrier protein and Freund's adjuvant. Several booster injections may be needed, for instance, at intervals of about two weeks, to provide a useful titer of anti-peptide antibody which can be detected, for example, by ELISA assay using free peptide adsorbed to a solid surface. The titer of anti-peptide antibodies in serum from an immunized animal may be increased by selection of anti-peptide antibodies, for instance, by adsorption to the peptide on a solid support and elution of the selected antibodies according to methods well known in the art.

Immunogenic epitope-bearing peptides of the invention, ie., those parts of a protein that elicit an antibody response when the whole protein is the immunogen, are identified according to methods known in the art. For instance, Geysen, et al, supra, discloses a procedure for rapid concurrent synthesis on solid supports of hundreds of peptides of sufficient purity to react in an ELISA. Interaction of synthesized peptides with antibodies is then easily detected without removing them from the support In this manner a peptide bearing an immunogenic epitope of a desired protein may be identified routinely by one of ordinary skill in the art. For instance, the immunologically important epitope in the coat protein of foot-and-mouth disease virus was located by Geysen et al supra with a resolution of seven amino acids by synthesis of an overlapping set of all 208 possible hexapeptides covering the entire 213 amino acid sequence of the protein.

Then, a complete replacement set of peptides in which all 20 amino acids were substituted in turn at every position within the epitope were synthesized, and the particular amino acids conferring specificity for the reaction with antibody were determined. Thus, peptide analogs of the 20 epitope-bearing peptides of the invention can be made routinely by this method. U.S. Patent No.

4,708,781 to Geysen (1987) further describes this method of identifying a peptide bearing an immunogenic epitope of a desired protein.

Further still, U.S. Patent No. 5,194,392, to Geysen (1990), describes a general method of detecting or determining the sequence of monomers (amino acids or other compounds) which 25 is a topological equivalent of the epitope a "mimotope") which is complementary to a particular paratope (antigen binding site) of an antibody of interest. More generally, U.S. Patent No. 4,433,092, also to Geysen (1989), describes a method of detecting or determining a sequence of monomers which is a topographical equivalent of a ligand which is complementary to the ligand binding site of a particular receptor of interest. Similarly, U.S. Patent No. 5,480,971 to Houghten, R. A. et al. (1996) discloses linear Ci-C 7 -alkyl peralkylated oligopeptides and sets and libraries of such peptides, as well as methods for using such oligopeptide sets and libraries for determining the sequence of a peralkylated oligopeptide that preferentially binds to an acceptor molecule of interest Thus, non-peptide analogs of the epitope-bearing peptides of the invention also can be made routinely by these methods. The entire disclosure of each document cited in this section on "Polypeptides and Fragments" is hereby incorporated herein by reference.

As one of skill in the art will appreciate, the polypeptides of the present invention and the epitope-bearing fragments thereof described above can be combined with parts of the constant domain of immunoglobulins (IgG), resulting in chimeric polypeptides. These fusion proteins facilitate purification and show an increased half-life in vivo. This has been shown, for WO 98/59071 PCT/US98/12718 29 chimeric proteins consisting of the first two domains of the human CD4-polypeptide and various domains of the constant regions of the heavy or light chains of mammalian immunoglobulins.

(EPA 0,394,827; Traunecker et al. (1988) Nature 331:84-86. Fusion proteins that have a disulfide-linked dimeric structure due to the IgG part can also be more efficient in binding and neutralizing other molecules than a monomeric B. burgdorferi polypeptide or fragment thereof alone. See Fountoulakis et al. (1995) J. Biochem. 270:3958-3964. Nucleic acids encoding the above epitopes of B. burgdorferi polypeptides can also be recombined with a gene of interest as an epitope tag to aid in detection and purification of the expressed polypeptide.

Antibodies B. burgdorferi protein-specific antibodies for use in the present invention can be raised against the intact B. burgdorferi protein or an antigenic polypeptide fragment thereof, which may be presented together with a carrier protein, such as an albumin, to an animal system (such as rabbit or mouse) or, if it is long enough (at least about 25 amino acids), without a carrier.

As used herein, the term "antibody" (Ab) or "monoclonal antibody" (Mab) is meant to include intact molecules, single chain whole antibodies, and antibody fragments. Antibody fragments of the present invention include Fab and F(ab')2 and other fragments including singlechain Fvs (scFv) and disulfide-linked Fvs (sdFv). Also included in the present invention are chimeric and humanized monoclonal antibodies and polyclonal antibodies specific for the S 20 polypeptides of the present invention. The antibodies of the present invention may be prepared by any of a variety of methods. For example, cells expressing a polypeptide of the present invention or an antigenic fragment thereof can be administered to an animal in order to induce the production of sera containing polyclonal antibodies. For example, a preparation of B. burgdorferi polypeptide or fragment thereof is prepared and purified to render it substantially free of natural 25 contaminants. Such a preparation is then introduced into an animal in order to produce polyclonal antisera of greater specific activity.

In a preferred method, the antibodies of the present invention are monoclonal antibodies or binding fragments thereof. Such monoclonal antibodies can be prepared using hybridoma technology. See, Harlow et al., ANTIBODIES: A LABORATORY MANUAL, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling, et al., in: MONOCLONAL ANTIBODIES AND T-CELL HYBRIDOMAS 563-681 (Elsevier, 1981). Fab and F(ab')2 fragments may be produced by proteolytic cleavage, using enzymes such as papain (to produce Fab fragments) or pepsin (to produce F(ab')2 fragments). Alternatively, B. burgdorferi polypeptide-binding fragments, chimeric, and humanized antibodies can be produced through the application of recombinant DNA technology or through synthetic chemistry using methods known in the art.

Alternatively, additional antibodies capable of binding to the polypeptide antigen of the present invention may be produced in a two-step procedure through the use of anti-idiotypic antibodies. Such a method makes use of the fact that antibodies are themselves antigens, and that, WO 98/59071 PCT/US98/12718 therefore, it is possible to obtain an antibody which binds to a second antibody. In accordance with this method, B. burgdorferi polypeptide-specific antibodies are used to immunize an animal, preferably a mouse. The splenocytes of such an animal are then used to produce hybridoma cells, and the hybridoma cells are screened to identify clones which produce an antibody whose ability to bind to the B. burgdorferi polypeptide-specific antibody can be blocked by the B. burgdorferi polypeptide antigen. Such antibodies comprise anti-idiotypic antibodies to the B. burgdorferi polypeptide-specific antibody and can be used to immunize an animal to induce formation of further B. burgdorferi polypeptide-specific antibodies.

Antibodies and fragements thereof of the present invention may be described by the portion of a polypeptide of the present invention recognized or specifically bound by the antibody.

Antibody binding fragements of a polypeptide of the present invention may be described or specified in the same manner as for polypeptide fragements discussed above., i.e, by N-terminal and C-terminal positions or by size in contiguous amino acid residues. Any number of antibody binding fragments, of a polypeptide of the present invention, specified by N-terminal and Cterminal positions or by size in amino acid residues, as described above, may also be excluded from the present invention. Therefore, the present invention includes antibodies the specifically bind a particuarlly discribed fragement of a polypeptide of the present invention and allows for the exclusion of the same.

Antibodies and fragements thereof of the present invention may also be described or 20 specified in terms of their cross-reactivity. Antibodies and fragements that do not bind polypeptides of any other species of Borrelia other than B. burgdorferi are included in the present invention. Likewise, antibodies and fragements that bind only species of Borrelia, i.e. antibodies and fragements that do not bind bacteria from any genus other than Borrelia, are included in the present invention.

Diagnostic Assays The present invention further relates to methods for assaying staphylococcal infection in !an animal by detecting the expression of genes encoding staphylococcal polypeptides of the present invention. The methods comprise analyzing tissue or body fluid from the animal for Borrelia-specific antibodies, nucleic acids, or proteins. Analysis of nucleic acid specific to Borrelia is assayed by PCR or hybridization techniques using nucleic acid sequences of the present invention as either hybridization probes or primers. See, Sambrook et al. Molecular cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 2nd ed., 1989, page 54 reference); Eremeeva et al. (1994) J. Clin. Microbiol. 32:803-810 (describing differentiation among spotted fever group Rickettsiae species by analysis of restriction fragment length polymorphism of PCR-amplified DNA) and Chen et al. 1994 J. Clin. Microbiol. 32:589-595 (detecting B. burgdorferi nucleic acids via PCR).

Where diagnosis of a disease state related to infection with Borrelia has already been made, the present invention is useful for monitoring progression or regression of the disease state WO 98/59071 PCT/US98/12718 31 whereby patients exhibiting enhanced Borrelia gene expression will experience a worse clinical outcome relative to patients expressing these gene(s) at a lower level.

By "biological sample" is intended any biological sample obtained from an animal, cell line, tissue culture, or other source which contains Borrelia polypeptide, mRNA, or DNA Biological samples include body fluids (such as saliva, blood, plasma, urine, mucus, synovial fluid, etc.) tissues (such as muscle, skin, and cartilage) and any other biological source suspected of containing Borrelia polypeptides or nucleic acids. Methods for obtaining biological samples such as tissue are well known in the art.

The present invention is useful for detecting diseases related to Borrelia infections in animals. Preferred animals include monkeys, apes, cats, dogs, birds, cows, pigs, mice, horses, rabbits and humans. Particularly preferred are humans.

Total RNA can be isolated from a biological sample using any suitable technique such as the single-step guanidinium-thiocyanate-phenol-chloroform method described in Chomczynski et al. (1987) Anal. Biochem. 162:156-159. mRNA encoding Borrelia polypeptides having sufficient homology to the nucleic acid sequences identified in Table 1 to allow for hybridization between complementary sequences are then assayed using any appropriate method. These include Northern blot analysis, S1 nuclease mapping, the polymerase chain reaction (PCR), reverse transcription in combination with the polymerase chain reaction (RT-PCR), and reverse transcription in combination with the ligase chain reaction (RT-LCR).

20 Northern blot analysis can be performed as described in Harada et al. (1990) Cell 63:303-312. Briefly, total RNA is prepared from a biological sample as described above. For the Northern blot, the RNA is denatured in an appropriate buffer (such as glyoxal/dimethyl *i sulfoxide/sodium phosphate buffer), subjected to agarose gel electrophoresis, and transferred onto a nitrocellulose filter. After the RNAs have been linked to the filter by a UV linker, the filter is prehybridized in a solution containing formamide, SSC, Denhardt's solution, denatured salmon *i sperm, SDS, and sodium phosphate buffer. A B. burgdorferi polynucleotide sequence shown in S" Table 1 labeled according to any appropriate method (such as the nP-multiprimed DNA labeling system (Amersham)) is used as probe. After hybridization overnight, the filter is washed and exposed to x-ray film. DNA for use as probe according to the present invention is described in 30 the sections above and will preferably at least 15 nucleotides in length.

S1 mapping can be performed as described in Fujita et al. (1987) Cell 49:357-367. To prepare probe DNA for use in S mapping, the sense strand of an above-described B. burgdorferi DNA sequence of the present invention is used as a template to synthesize labeled antisense DNA.

The antisense DNA can then be digested using an appropriate restriction endonuclease to generate further DNA probes of a desired length. Such antisense probes are useful for visualizing protected bands corresponding to the target mRNA mRNA encoding Borrelia polypeptides).

Levels of mRNA encoding Borrelia polypeptides are assayed, for using the RT-PCR method described in Makino et al. (1990) Technique 2:295-301. By this method, the radioactivities of the "amplicons" in the polyacrylamide gel bands are linearly related to the initial WO 98/59071 PCT/US98/12718 32 concentration of the target mRNA. Briefly, this method involves adding total RNA isolated from a biological sample in a reaction mixture containing a RT primer and appropriate buffer. After incubating for primer annealing, the mixture can be supplemented with a RT buffer, dNTPs, DTT, RNase inhibitor and reverse transcriptase. After incubation to achieve reverse transcription of the RNA, the RT products are then subject to PCR using labeled primers. Alternatively, rather than labeling the primers, a labeled dNTP can be included in the PCR reaction mixture. PCR amplification can be performed in a DNA thermal cycler according to conventional techniques.

After a suitable number of rounds to achieve amplification, the PCR reaction mixture is electrophoresed on a polyacrylamide gel. After drying the gel, the radioactivity of the appropriate bands (corresponding to the mRNA encoding the Borrelia polypeptides of the present invention) are quantified using an imaging analyzer. RT and PCR reaction ingredients and conditions, reagent and gel concentrations, and labeling methods are well known in the art. Variations on the RT-PCR method will be apparent to the skilled artisan. Other PCR methods that can detect the nucleic acid of the present invention can be found in PCR PRIMER: A LABORATORY MANUAL Dieffenbach et al. eds., Cold Spring Harbor Lab Press, 1995).

The polynucleotides of the present invention, including both DNA and RNA, may be used to detect polynucleotides of the present invention or Borrelia species including B. burgdorferi using bio chip technology. The present invention includes both high density chip arrays (>1000 oligonucleotides per cm 2 and low density chip arrays (<1000 oligonucleotides per cm 2 Bio 20 chips comprising arrays of polynucleotides of the present invention may be used to detect Borrelia species, including B. burgdorferi, in biological and environmental samples and to diagnose an animal, including humans, with an B. burgdorferi or other Borrelia infection. The bio chips of the present invention may comprise polynucleotide sequences of other pathogens including bacteria, viral, parasitic, and fungal polynucleotide sequences, in addition to the polynucleotide 25 sequences of the present invention, for use in rapid diffenertial pathogenic detection and diagnosis. The bio chips can also be used to monitor an B. burgdorferi or other Borrelia infections and to monitor the genetic changes (deletions, insertions, mismatches, etc.) in response to drug therapy in the clinic and drug development in the laboratory. The bio chip technology comprising arrays of polynucleotides of the present invention may also be used to simultaneously monitor the expression of a multiplicity of genes, including those of the present invention. The polynucleotides used to comprise a selected array may be specified in the same manner as for the fragements, i.e, by their 5' and 3' positions or length in contigious base pairs and include from.

Methods and particular uses of the polynucleotides of the present invention to detect Borrelia species, including B. burgdorferi, using bio chip technology include those known in the art and those of: U.S. Patent Nos. 5510270, 5545531, 5445934, 5677195, 5532128, 5556752, 5527681, 5451683, 5424186, 5607646, 5658732 and World Patent Nos. WO/9710365, WO/9511995, WO/9743447, WO/9535505, each incorporated herein in their entireties.

Biosensors using the polynucleotides of the present invention may also be used to detect, diagnose, and monitor B. burgdorferi or other Borrelia species and infections thereof.

WO 98/59071 PCT/US98/12718 33 Biosensors using the polynucleotides of the present invention may also be used to detect particular polynucleotides of the present invention. Biosensors using the polynucleotides of the present invention may also be used to monitor the genetic changes (deletions, insertions, mismatches, etc.) in response to drug therapy in the clinic and drug development in the laboratory. Methods and particular uses of the polynucleotides of the present invention to detect Borrelia species, including B. burgdorferi, using biosenors include those known in the art and those of: U.S.

Patent Nos 5721102, 5658732, 5631170, and World Patent Nos. W097/35011, WO/9720203, each incorporated herein in their entireties.

Thus, the present invention includes both bio chips and biosensors comprising polynucleotides of the present invention and methods of their use.

Assaying Borrelia polypeptide levels in a biological sample can occur using any art-known method, such as antibody-based techniques. For example, Borrelia polypeptide expression in tissues can be studied with classical immunohistological methods. In these, the specific recognition is provided by the primary antibody (polyclonal or monoclonal) but the secondary detection system can utilize fluorescent, enzyme, or other conjugated secondary antibodies. As a result, an immunohistological staining of tissue section for pathological examination is obtained.

Tissues can also be extracted, with urea and neutral detergent, for the liberation of Borrelia polypeptides for Western-blot or dot/slot assay. See, Jalkanen, M. et al. (1985) J. Cell.

Biol. 101:976-985; Jalkanen, M. et al. (1987) J. Cell. Biol. 105:3087-3096. In this technique, 20 which is based on the use of cationic solid phases, quantitation of a Borrelia polypeptide can be accomplished using an isolated Borrelia polypeptide as a standard. This technique can also be applied to body fluids.

Other antibody-based methods useful for detecting Borrelia polypeptide gene expression include immunoassays, such as the ELISA and the radioimmunoassay (RIA). For example, a I 25 Borrelia polypeptide-specific monoclonal antibodies can be used both as an immunoabsorbent and as an enzyme-labeled probe to detect and quantify a Borrelia polypeptide. The amount of a Borrelia polypeptide present in the sample can be calculated by reference to the amount present in "a standard preparation using a linear regression computer algorithm. Such an ELISA is described in Iacobelli et al. (1988) Breast Cancer Research and Treatment 11:19-30. In another ELISA assay, two distinct specific monoclonal antibodies can be used to detect Borrelia polypeptides in a body fluid. In this assay, one of the antibodies is used as the immunoabsorbent and the other as the enzyme-labeled probe.

The above techniques may be conducted essentially as a "one-step" or "two-step" assay.

The "one-step" assay involves contacting the Borrelia polypeptide with immobilized antibody and, without washing, contacting the mixture with the labeled antibody. The "two-step" assay involves washing before contacting the mixture with the labeled antibody. Other conventional methods may also be employed as suitable. It is usually desirable to immobilize one component of the assay system on a support, thereby allowing other components of the system to be brought into contact with the component and readily removed from the sample. Variations of the above WO 98/59071 PCT/US98/12718 34 and other immunological methods included in the present invention can also be found in Harlow et al., ANTIBODIES: A LABORATORY MANUAL, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988).

Suitable enzyme labels include, for example, those from the oxidase group, which catalyze the production of hydrogen peroxide by reacting with substrate. Glucose oxidase is particularly preferred as it has good stability and its substrate (glucose) is readily available.

Activity of an oxidase label may be assayed by measuring the concentration of hydrogen peroxide formed by the enzyme-labeled antibody/substrate reaction. Besides enzymes, other suitable labels include radioisotopes, such as iodine (12I, 121I), carbon (14C), sulphur 35 tritium indium and technetium and fluorescent labels, such as fluorescein and rhodamine, and biotin.

Further suitable labels for the Borrelia polypeptide-specific antibodies of the present invention are provided below. Examples of suitable enzyme labels include malate dehydrogenase Borrelia nuclease, delta-5-steroid isomerase, yeast-alcohol dehydrogenase, alpha-glycerol phosphate dehydrogenase, triose phosphate isomerase, peroxidase, alkaline phosphatase, asparaginase, glucose oxidase, beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphate dehydrogenase, glucoamylase, and acetylcholine esterase.

Examples of suitable radioisotopic labels include 3 H, 2'I, 1311 32 P, 35S, 4 C, 5t Cr, 57 To, 58 Co, 59 Fe, 7Se, 5 Eu, 90Y, 67 Cu, 217 Ci, 21 1 At, 2 12 Pb, 47 Sc, 09 Pd, etc. "'In is a preferred 20 isotope where in vivo imaging is used since its avoids the problem of dehalogenation of the "I or "'I-labeled monoclonal antibody by the liver. In addition, this radionucleotide has a more favorable gamma emission energy for imaging. See, Perkins et al. (1985) Eur. J. Nucl.

Med. 10:296-301; Carasquillo et al. (1987) J. Nucl. Med. 28:281-287. For example, '"In coupled to monoclonal antibodies with l-(P-isothiocyanatobenzyl)-DPTA has shown little uptake S* 25 in non-tumors tissues, particularly the liver, and therefore enhances specificity of tumor localization. See, Esteban et al. (1987) J.Nucl. Med. 28:861-870.

Examples of suitable non-radioactive isotopic labels include "Mn, 6' 2 Dy, 52 Tr, and 5 6 Fe.

Examples of suitable fluorescent labels include an '"Eu label, a fluorescein label, an isothiocyanate label, a rhodamine label, a phycoerythrin label, a phycocyanin label, an allophycocyanin label, an o-phthaldehyde label, and a fluorescamine label.

Examples of suitable toxin labels include, Pseudomonas toxin, diphtheria toxin, ricin, and cholera toxin.

Examples of chemiluminescent labels include a luminal label, an isoluminal label, an aromatic acridinium ester label, an imidazole label, an acridinium salt label, an oxalate ester label, a luciferin label, a luciferase label, and an aequorin label.

Examples of nuclear magnetic resonance contrasting agents include heavy metal nuclei such as Gd, Mn, and iron.

Typical techniques for binding the above-described labels to antibodies are provided by WO 98/59071 PCT/US98/12718 Kennedy et al. (1976) Clin. Chim. Acta 70:1-31, and Schurs et al. (1977) Clin. Chim. Acta 81:1-40. Coupling techniques mentioned in the latter are the glutaraldehyde method, the periodate method, the dimaleimide method, the m-maleimidobenzyl-N-hydroxy-succinimide ester method, all of which methods are incorporated by reference herein.

In a related aspect, the invention includes a diagnostic kit for use in screening serum containing antibodies specific against B. burgdorferi infection. Such a kit may include an isolated B. burgdorferi antigen comprising an epitope which is specifically immunoreactive with at least one anti-B. burgdorferi antibody. Such a kit also includes means for detecting the binding of said antibody to the antigen. In specific embodiments, the kit may include a recombinantly produced or chemically synthesized peptide or polypeptide antigen. The peptide or polypeptide antigen may be attached to a solid support.

In a more specific embodiment, the detecting means of the above-described kit includes a solid support to which said peptide or polypeptide antigen is attached. Such a kit may also include a non-attached reporter-labeled anti-human antibody. In this embodiment, binding of the antibody to the B. burgdorferi antigen can be detected by binding of the reporter labeled antibody to the anti-B. burgdorferi polypeptide antibody.

In a related aspect, the invention includes a method of detecting B. burgdorferi infection in a subject. This detection method includes reacting a body fluid, preferably serum, from the subject with an isolated B. burgdorferi antigen, and examining the antigen for the presence of S 20 bound antibody. In a specific embodiment, the method includes a polypeptide antigen attached to a solid support, and serum is reacted with the support. Subsequently, the support is reacted with a reporter-labeled anti-human antibody. The support is then examined for the presence of reporter-labeled antibody.

The solid surface reagent employed in the above assays and kits is prepared by known S 25 techniques for attaching protein material to solid support material, such as polymeric beads, dip sticks, 96-well plates or filter material. These attachment methods generally include non-specific adsorption of the protein to the support or covalent attachment of the protein, typically through a free amine group, to a chemically reactive group on the solid support, such as an activated carboxyl, hydroxyl, or aldehyde group. Alternatively, streptavidin coated plates can be used in conjunction with biotinylated antigen(s).

The polypeptides and antibodies of the present invention, including fragments thereof, may be used to detect Borrelia species including B. burgdorferi using bio chip and biosensor technology. Bio chip and biosensors of the present invention may comprise the polypeptides of the present invention to detect antibodies, which specifically recognize Borrelia species, including B. burgdorferi. Bio chip and biosensors of the present invention may also comprise antibodies which specifically recognize the polypeptides of the present invention to detect Borrelia species, including B. burgdorferi or specific polypeptides of the present invention. Bio chips or biosensors comprising polypeptides or antibodies of the present invention may be used to detect Borrelia species, including B. burgdorferi, in biological and environmental samples and to WO 98/59071 PCT/US98/12718 36 diagnose an animal, including humans, with an B. burgdorferi or other Borrelia infection. Thus, the present invention includes both bio chips and biosensors comprising polypeptides or antibodies of the present invention and methods of their use.

The bio chips of the present invention may further comprise polypeptide sequences of other pathogens including bacteria, viral, parasitic, and fungal polypeptide sequences, in addition to the polypeptide sequences of the present invention, for use in rapid diffenertial pathogenic detection and diagnosis. The bio chips of the present invention may further comprise antibodies or fragements thereof specific for other pathogens including bacteria, viral, parasitic, and fungal polypeptide sequences, in addition to the antibodies or fragements thereof of the present invention, for use in rapid diffenertial pathogenic detection and diagnosis. The bio chips and biosensors of the present invention may also be used to monitor an B. burgdorferi or other Borrelia infection and to monitor the genetic changes (amio acid deletions, insertions, substitutions, etc.) in response to drug therapy in the clinic and drug development in the laboratory. The bio chip and biosensors comprising polypeptides or antibodies of the present invention may also be used to simultaneously monitor the expression of a multiplicity of polypeptides, including those of the present invention. The polypeptides used to comprise a bio chip or biosensor of the present invention may be specified in the same manner as for the S. fragements, i.e, by their N-terminal and C-terminal positions or length in contigious amino acid residue. Methods and particular uses of the polypeptides and antibodies of the present invention 20 to detect Borrelia species, including B. burgdorferi, or specific polypeptides using bio chip and biosensor technology include those known in the art, those of the U.S. Patent Nos. and World Patent Nos. listed above for bio chips and biosensors using polynucleotides of the present invention, and those of: U.S. Patent Nos. 5658732, 5135852, 5567301, 5677196, 5690894 and World Patent Nos. W09729366, W09612957, each incorporated herein in their entireties.

Treatment: Agonists and Antagonists Assays and Molecules The invention also provides a method of screening compounds to identify those which enhance or block the biological activity of the B. burgdorferi polypeptides of the present invention. The present invention further provides where the compounds kill or slow the growth of B. burgdorferi. The ability of B. burgdorferi antagonists, including B. burgdorferi ligands, to prophylactically or therapeutically block antibiotic resistance may be easily tested by the skilled artisan. See, Straden et al. (1997) J Bacteriol. 179(1):9-16.

An agonist is a compound which increases the natural biological function or which functions in a manner similar to the polypeptides of the present invention, while antagonists decrease or eliminate such functions. Potential antagonists include small organic molecules, peptides, polypeptides, and antibodies that bind to a polypeptide of the invention and thereby inhibit or extinguish its activity.

The antagonists may be employed for instance to inhibit peptidoglycan cross bridge WO 98/59071 PCT/US98/12718 37 formation. Antibodies against B. burgdorferi may be employed to bind to and inhibit B.

burgdorferi activity to treat antibiotic resistance. Any of the above antagonists may be employed in a composition with a pharmaceutically acceptable carrier.

Vaccines The present invention also provides vaccines comprising one or more polypeptides of the present invention. Heterogeneity in the composition of a vaccine may be provided by combining B. burgdorferi polypeptides of the present invention. Multi-component vaccines of this type are desirable because they are likely to be more effective in eliciting protective immune responses against multiple species and strains of the Borrelia genus than single polypeptide vaccines. Thus, as discussed in detail below, a multi-component vaccine of the present invention may contain one or more, preferably 2 to about 20, more preferably 2 to about 15, and most preferably 3 to about 8, of the B. burgdorferi polypeptides shown in Table 1, or fragments thereof.

Multi-component vaccines are known in the art to elicit antibody production to numerous immunogenic components. Decker, M. and Edwards, J. Infect. Dis. 174:S270-275 (1996).

In addition, a hepatitis B, diphtheria, tetanus, pertussis tetravalent vaccine has recently been demonstrated to elicit protective levels of antibodies in human infants against all four pathogenic agents. Aristegui, J. et aL, Vaccine 15:7-9 (1997).

The present invention thus also includes multi-component vaccines. These vaccines 20 comprise more than one polypeptide, immunogen or antigen. An example of such a multicomponent vaccine would be a vaccine comprising more than one of the B. burgdorferi polypeptides shown in Table 1. A second example is a vaccine comprising one or more, for *example 2 to 10, of the B. burgdorferi polypeptides shown in Table 1 and one or more, for example 2 to 10, additional polypeptides of either borrelial or non-borrelial origin. Thus, a multicomponent vaccine which confers protective immunity to both a borrelial infection and infection by another pathogenic agent is also within the scope of the invention.

As indicated above, the vaccines of the present invention are expected to elicit a protective immune response against infections caused by species and strains of Borrelia other than B.

***burgdorferi sensu stricto isolate B31 (ATCC Accession No. 35210). Immunizations using decorin-binding protein and OspA derived from one strain ofB. burgdorferi has been shown to elicit the production of antiserum which confers passive immunity against other strains of B.

burgdorferi. Cassatt, D. et aL, Protection of Borrelia burgdorferi Infection by Antibodies to Decorin-binding Protein, in VACCINES97, Cold Spring Harbor Press (1997), pages 191-195.

Further, the inventors have found using an in vitro assay that antiserum produced in response to B. burgdorferi decorin-binding protein will kill several species of Borrelia. The amino acid sequences of decorin-binding protein expressed by different strains of B. burgdorferi are believed to diverge by as much as 25%. Thus, antisera elicited against decorin-binding proteins confers passive immunity against Borrelia expressing proteins having only 75% or less amino acid sequence similarity.

WO 98/59071 PCT/US98/12718 38 Further within the scope of the invention are whole cell and whole viral vaccines. Such vaccines may be produced recombinantly and involve the expression of one or more of the B. burgdorferi polypeptides shown in Table 1. For example, the B. burgdorferi polypeptides of the present invention may be either secreted or localized intracellular, on the cell surface, or in the periplasmic space. Further, when a recombinant virus is used, the B. burgdorferi polypeptides of the present invention may, for example, be localized in the viral envelope, on the surface of the capsid, or internally within the capsid. Whole cells vaccines which employ cells expressing heterologous proteins are known in the art. See, Robinson, K. et aL, Nature Biotech.

15:653-657 (1997); Sirard, J. et al., Infect. Immun. 65:2029-2033 (1997); Chabalgoity, J. et al., Infect. Immun. 65:2402-2412 (1997). These cells may be administered live or may be killed prior to administration. Chabalgoity, J. et aL, supra, for example, report the successful use in mice of a live attenuated Salmonella vaccine strain which expresses a portion of a platyhelminth fatty acid-binding protein as a fusion protein on its cells surface.

A multi-component vaccine can also be prepared using techniques known in the art by combining one or more B. burgdorferi polypeptides of the present invention, or fragments Sthereof, with additional non-borrelial components diphtheria toxin or tetanus toxin, and/or other compounds known to elicit an immune response). Such vaccines are useful for eliciting protective immune responses to both members of the Borrelia genus and non-borrelial pathogenic agents.

20 The vaccines of the present invention also include DNA vaccines. DNA vaccines are currently being developed for a number of infectious diseases. Boyer, J et al., Nat. Med. 3:526- 532 (1997); reviewed in Spier, Vaccine 14:1285-1288 (1996). Such DNA vaccines contain a nucleotide sequence encoding one or more B. burgdorferi polypeptides of the present invention oriented in a manner that allows for expression of the subject polypeptide. The direct 25 administration of plasmid DNA encoding OspA has been shown to elicit protective immunity in mice against borrelial challenge. Luke, C. et aL, J. Infect. Dis. 175:91-97 (1997).

The present invention also relates to the administration of a vaccine which is co-administered with a molecule capable of modulating immune responses. Kim, J. et aL, Nature Biotech. 15:641-646 (1997), for example, report the enhancement of immune responses produced by DNA immunizations when DNA sequences encoding molecules which stimulate the immune response are co-administered. In a similar fashion, the vaccines of the present invention may be co-administered with either nucleic acids encoding immune modulators or the immune modulators themselves. These immune modulators include granulocyte macrophage colony stimulating factor (GM-CSF) and CD86.

The vaccines of the present invention may be used to confer resistance to borrelial infection by either passive or active immunization. When the vaccines of the present invention are used to confer resistance to borrelial infection through active immunization, a vaccine of the present invention is administered to an animal to elicit a protective immune response which either prevents or attenuates a borrelial infection. When the vaccines of the present invention are;used to WO 98/59071 PCT/US98/12718 39 confer resistance to borrelial infection through passive immunization, the vaccine is provided to a host animal human, dog, or mouse), and the antisera elicited by this antisera is recovered and directly provided to a recipient suspected of having an infection caused by a member of the Borrelia genus.

The ability to label antibodies, or fragments of antibodies, with toxin molecules provides an additional method for treating borrelial infections when passive immunization is conducted. In this embodiment, antibodies, or fragments of antibodies, capable of recognizing the B. burgdorferi polypeptides disclosed herein, or fragments thereof, as well as other Borrelia proteins, are labeled with toxin molecules prior to their administration to the patient. When such toxin derivatized antibodies bind to Borrelia cells, toxin moieties will be localized to these cells and will cause their death.

The present invention thus concerns and provides a means for preventing or attenuating a borrelial infection resulting from organisms which have antigens that are recognized and bound by antisera produced in response to the polypeptides of the present invention. As used herein, a vaccine is said to prevent or attenuate a disease if its administration to an animal results either in the total or partial attenuation suppression) of a symptom or condition of the disease, or in the total or partial immunity of the animal to the disease.

The administration of the vaccine (or the antisera which it elicits) may be for either a 2 "prophylactic" or "therapeutic" purpose. When provided prophylactically, the compound(s) are provided in advance of any symptoms of borrelial infection. The prophylactic administration of the compound(s) serves to prevent or attenuate any subsequent infection. When provided therapeutically, the compound(s) is provided upon or after the detection of symptoms which indicate that an animal may be infected with a member of the Borrelia genus. The therapeutic administration of the compound(s) serves to attenuate any actual infection. Thus, the 25 B. burgdorferi polypeptides, and fragments thereof, of the present invention may be provided Seither prior to the onset of infection (so as to prevent or attenuate an anticipated infection) or after the initiation of an actual infection.

The polypeptides of the invention, whether encoding a portion of a native protein or a functional derivative thereof, may be administered in pure form or may be coupled to a macromolecular carrier. Example of such carriers are proteins and carbohydrates. Suitable proteins which may act as macromolecular carrier for enhancing the immunogenicity of the polypeptides of the present invention include keyhole limpet hemacyanin (K-LH) tetanus toxoid, pertussis toxin, bovine serum albumin, and ovalbumin. Methods for coupling the polypeptides of the present invention to such macromolecular carriers are disclosed in Harlow et aL, Antibodies: A Laboratory Manual, 2nd Ed.; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (1988), the entire disclosure of which is incorporated by reference herein.

A composition is said to be "pharmacologically acceptable" if its administration can be tolerated by a recipient animal and is otherwise suitable for administration to that animal. Such an agent is said to be administered in a "therapeutically effective amount" if the amount administered WO 98/59071 PCT/US98/12718 is physiologically significant. An agent is physiologically significant if its presence results in a detectable change in the physiology of a recipient patient.

While in all instances the vaccine of the present invention is administered as a pharmacologically acceptable compound, one skilled in the art would recognize that the composition of a pharmacologically acceptable compound varies with the animal to which it is administered. For example, a vaccine intended for human use will generally not be coadministered with Freund's adjuvant. Further, the level of purity of the B. burgdorferi polypeptides of the present invention will normally be higher when administered to a human than when administered to a non-human animal.

As would be understood by one of ordinary skill in the art, when the vaccine of the present invention is provided to an animal, it may be in a composition which may contain salts, buffers, adjuvants, or other substances which are desirable for improving the efficacy of the composition. Adjuvants are substances that can be used to specifically augment a specific immune response. These substances generally perform two functions: they protect the antigen(s) from being rapidly catabolized after administration and they nonspecifically stimulate immune responses.

Normally, the adjuvant and the composition are mixed prior to presentation to the immune system, or presented separately, but into the same site of the animal being immunized. Adjuvants S: 'can be loosely divided into several groups based upon their composition. These groups include 20 oil adjuvants (for example, Freund's complete and incomplete), mineral salts (for example, AlK(SO 4 AINa(SO4) 2 A1NH 4 silica, kaolin, and carbon), polynucleotides (for example, o poly IC and poly AU acids), and.certain natural substances (for example, wax D from Mycobacterium tuberculosis, as well as substances found in Corynebacterium parvum, or Bordetella pertussis, and members of the genus Brucella. Other substances useful as adjuvants S 25 are the saponins such as, for example, Quil A. (Superfos A/S, Denmark). Preferred adjuvants for use in the present invention include aluminum salts, such as AlK(SO,) 2 AINa(SO4), and

AINH

4 (SO4). Examples of materials suitable for use in vaccine compositions are provided in Remington's Pharmaceutical Sciences (Osol, A, Ed, Mack Publishing Co, Easton, PA, pp. 1324- 1341 (1980), which reference is incorporated herein by reference).

The therapeutic compositions of the present invention can be administered parenterally by injection, rapid infusion, nasopharyngeal absorption (intranasopharangeally), dermoabsorption, or orally. The compositions may alternatively be administered intramuscularly, or intravenously.

Compositions for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Carriers or occlusive dressings can be used to increase skin permeability and enhance antigen absorption. Liquid dosage forms for oral administration may generally comprise a liposome solution containing the liquid dosage form. Suitable forms.for suspending liposomes include emulsions, suspensions, solutions, syrups, and elixirs containing inert diluents WO 98/59071 PCT/US98/12718 41 commonly used in the art, such as purified water. Besides the inert diluents, such compositions can also include adjuvants, wetting agents, emulsifying and suspending agents, or sweetening, flavoring, or perfuming agents.

Therapeutic compositions of the present invention can also be administered in encapsulated form. For example, intranasal immunization of mice against Bordetella pertussis infection using vaccines encapsulated in biodegradable microsphere composed of poly(DL-lactideco-glycolide) has been shown to stimulate protective immune responses. Shahin, R. et aL, Infect Immun. 63:1195-1200 (1995). Similarly, orally administered encapsulated Salmonella typhimurium antigens have also been shown to elicit protective immunity in mice. Allaoui- Attarki, K. et al., Infect. Immun. 65:853-857 (1997). Encapsulated vaccines of the present invention can be administered by a variety of routes including those involving contacting the vaccine with mucous membranes intranasally, intracolonicly, intraduodenally).

Many different techniques exist for the timing of the immunizations when a multiple administration regimen is utilized. It is possible to use the compositions of the invention more than once to increase the levels and diversities of expression of the immunoglobulin repertoire expressed by the immunized animal. Typically, if multiple immunizations are given, they will be S' given one to two months apart.

According to the present invention; an "effective amount" of a therapeutic composition is S" one which is sufficient to achieve a desired biological effect. Generally, the dosage needed to provide an effective amount of the composition will vary depending upon such factors as the animal's or human's age, condition, sex, and extent of disease, if any, and other variables which can be adjusted by one of ordinary skill in the art.

The antigenic preparations of the invention can be administered by either single or multiple dosages of an effective amount Effective amounts of the compositions of the invention can vary S 25 from 0.01-1,000 gg/ml per dose, more preferably 0.1-500 tig/ml per dose, and most preferably 10-300 Lgg/ml per dose.

S. Having now generally described the invention, the same will be more readily understood through reference to the following example which is provided by way of illustration, and is not intended to be limiting of the present invention, unless specified.

Examples 1. Preparation of PCR Primers and Amplification of DNA Various fragments of the Borrelia burgdorferi genome, such as those of Table 1, can be used, in accordance with the present invention, to prepare PCR primers for a variety of uses. The PCR primers are preferably at least 15 bases, and more preferably at least 18 bases in length.

When selecting a primer sequence, it is preferred that the primer pairs have approximately the same G/C ratio, so that melting temperatures are approximately the same. The PCR primers and WO 98/59071 PCT/US98/12718 42 amplified DNA of this Example find use in the Examples that follow.

2. Isolation of a Selected DNA Clone From B. burgdorferi Three approaches are used to isolate a B. burgdorferi clone comprising a polynucleotide of the present invention from any B. burgdorferi genomic DNA library. The B. burgdorferi strain B3 IPU has been deposited as a convienent source for obtaining a B. burgdorferi strain although a wide varity of strains B. burgdorferi strains can be used which are known in the art B. burgdorferi genomic DNA is prepared using the following method. A 20ml overnight bacterial culture grown in a rich medium Trypticase Soy Broth, Brain Heart Infusion broth or Super broth), pelleted, ished two times with TES (30mM Tris-pH 8.0, 25mM EDTA, NaC), and resuspended in 5ml high salt TES (2.5M NaCI). Lysostaphin is added to final concentration of approx 50ug/ml and the mixture is rotated slowly 1 hour at 37C to make protoplast cells. The solution is then placed in incubator (or place in a shaking water bath) and warmed to 55C. Five hundred micro liter of 20% sarcosyl in TES (final concentration is then added to lyse the cells. Next, guanidine HC1 is added to a final concentration of 7M (3.69g in 5.5 ml). The mixture is swirled slowly at 55C for 60-90 min (solution should clear). A CsC1 gradient is then set up in SW41 ultra clear tubes using 2.0ml 5.7M CsCI and overlaying with 2.85M CsCI. The gradient is carefully overlayed with the DNA-containing GuHCI solution. The gradient is spun at 30,000 rpm, 20C for 24 hr and the lower DNA band is collected. The volume 20 is increased to 5 ml with TE buffer. The DNA is then treated with protease K (10 ug/ml) overnight at 37 C, and precipitated with ethanol. The precipitated DNA is resuspended in a desired buffer.

In the first method, a plasmid is directly isolated by screening a plasmid B. burgdorferi genomic DNA library using a polynucleotide probe corresponding to a polynucleotide of the present invention. Particularly, a specific polynucleotide with 30-40 nucleotides is synthesized using an Applied Biosystems DNA synthesizer according to the sequence reported. The oligonucleotide is labeled, for instance, with 32 P-y-ATP using T4 polynucleotide kinase and purified according to routine methods. (See, Maniatis et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, Cold Spring, NY (1982).) The library is transformed into a suitable host, as indicated above (such as XL-1 Blue (Stratagene)) using techniques known to those of skill in the art. See, Sambrook et al. MOLECULAR CLONING: A LABORATORY MANUAL (Cold Spring Harbor, N.Y. 2nd ed. 1989); Ausubel et al., CURRENT PROTOCALS IN MOLECULAR BIOLOGY (John Wiley and Sons, N.Y.

1989). The transformants are plated on 1.5% agar plates (containing the appropriate selection agent, ampicillin) to a density of about 150 transformants (colonies) per plate. These plates are screened using Nylon membranes according to routine methods for bacterial colony screening.

See, Sambrook et al. MOLECULAR CLONING: A LABORATORY MANUAL (Cold Spring Harbor, N.Y. 2nd ed. 1989); Ausubel et al., CURRENT PROTOCALS IN WO 98/59071 PCT/US98/12718 43 MOLECULAR BIOLOGY (John Wiley and Sons, N.Y. 1989) or other techniques known to those of skill in the art.

Alternatively, two primers of 15-25 nucleotides derived from the 5' and 3' ends of a polynucleotide of Table 1 are synthesized and used to amplify the desired DNA by PCR using a B. burgdorferi genomic DNA prep as a template. PCR is carried out under routine conditions, for instance, in 25 pl of reaction mixture with 0.5 ug of the above DNA template. A convenient reaction mixture is 1.5-5 mM MgC1, 0.01% gelatin, 20 pM each of dATP, dCTP, dGTP, dTTP, 25 pmol of each primer and 0.25 Unit of Taq polymerase. Thirty five cycles of PCR (denaturation at 94C for 1 min; annealing at 55°C for 1 min; elongation at 72 0 C for 1 min) are performed with a Perkin-Elmer Cetus automated thermal cycler. The amplified product is analyzed by agarose gel electrophoresis and the DNA band with expected molecular weight is excised and purified. The PCR product is verified to be the selected sequence by subcloning and sequencing the DNA product.

Finally, overlapping oligos of the DNA sequences of Table 1 can be chemically synthesized and used to generate a nucleotide sequence of desired length using PCR methods known in the art.

Expression and Purification Borrelia polypeptides in E. coli The bacterial expression vector pQE60 is used for bacterial expression of some of the 20 polypeptide fragements of the present invention. (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311). pQE60 encodes ampicillin antibiotic resistance ("Ampr") and contains i a bacterial origin of replication an IPTG inducible promoter, a ribosome binding site six codons encoding histidine residues that allow affinity purification using nickelnitrilo-tri-acetic acid ("Ni-NTA") affinity resin (QIAGEN, Inc., supra) and suitable single 25 restriction enzyme cleavage sites. These elements are arranged such that an inserted DNA fragment encoding a polypeptide expresses that polypeptide with the six His residues a "6 X His tag") covalently linked to the carboxyl terminus of that polypeptide.

The DNA sequence encoding the desired portion of a B. burgdorferi protein of the present invention is amplified from B. burgdorferi genomic DNA using PCR oligonucleotide primers which anneal to the 5' and 3' sequences coding for the portions of the B. burgdorferi polynucleotide shown in Table 1. Additional nucleotides containing restriction sites to facilitate cloning in the pQE60 vector are added to the 5' and 3' sequences, respectively.

For cloning the mature protein, the 5' primer has a sequence containing an appropriate restriction site followed by nucleotides of the amino terminal coding sequence of the desired B.

burgdorferi polynucleotide sequence in Table 1. One of ordinary skill in the art would appreciate that the point in the protein coding sequence where the 5' and 3' primers begin may be varied to amplify a DNA segment encoding any desired portion of the complete protein shorter or longer than the mature form. The 3' primer has a sequence containing an appropriate restriction site WO 98/59071 PCT/US98/12718 44 followed by nucleotides complementary to the 3' end of the polypeptide coding sequence of Table 1, excluding a stop codon, with the coding sequence aligned with the restriction site so as to maintain its reading frame with that of the six His codons in the pQE60 vector.

The amplified B. burgdorferi DNA fragment and the vector pQE60 are digested with restriction enzymes which recognize the sites in the primers and the digested DNAs are then ligated together. The B. burgdorferi DNA is inserted into the restricted pQE60 vector in a manner which places the B. burgdorferi protein coding region downstream from the IPTG-inducible promoter and in-frame with an initiating AUG and the six histidine codons.

The ligation mixture is transformed into competent E. coli cells using standard procedures such as those described by Sambrook et al., supra.. E. coli strain M15/rep4, containing multiple copies of the plasmid pREP4, which expresses the lac repressor and confers kanamycin resistance is used in carrying out the illustrative example described herein. This strain, which is only one of many that are suitable for expressing a B. burgdorferi polypeptide, is available commercially (QIAGEN, Inc., supra). Transformants are identified by their ability to grow on LB agar plates in the presence of ampicillin and kanamycin. Plasmid DNA is isolated from resistant colonies and the identity of the cloned DNA confirmed by restriction analysis, PCR and DNA sequencing.

Clones containing the desired constructs are grown overnight in liquid culture in LB media supplemented with both ampicillin (100 gg/ml) and kanamycin (25 lpg/ml). The O/N 20 culture is used to inoculate a large culture, at a dilution of approximately 1:25 to 1:250. The cells are grown to an optical density at 600 nm ("OD600") of between 0.4 and 0.6. Isopropyl-o-Dthiogalactopyranoside ("IPTG") is then added to a final concentration of 1 mM to induce transcription from the lac repressor sensitive promoter, by inactivating the lacI repressor. Cells subsequently are incubated further for 3 to 4 hours. Cells then are harvested by centrifugation.

25 The cells are then stirred for 3-4 hours at 4 0 C in 6M guanidine-HC1, pH 8. The cell debris is removed by centrifugation, and the supernatant containing the B. burgdorferi polypeptide is loaded onto a nickel-nitrilo-tri-acetic acid ("Ni-NTA") affinity resin column (QIAGEN, Inc., supra). Proteins with a 6 x His tag bind to the Ni-NTA resin with high affinity are purified in a simple one-step procedure (for details see: The QIAexpressionist, 1995, QIAGEN, Inc., supra). Briefly the supernatant is loaded onto the column in 6 M guanidine-HC1, pH 8, the column is first washed with 10 volumes of 6 M guanidine-HC1, pH 8, then washed with 10 volumes of 6 M guanidine-HCI pH 6, and finally the B. burgdorferi polypeptide is eluted with 6 M guanidine-HC1, pH The purified protein is then renatured by dialyzing it against phosphate-buffered saline (PBS) or 50 mM Na-acetate, pH 6 buffer plus 200 mM NaCI. Alternatively, the protein could be successfully refolded while immobilized on the Ni-NTA column. The recommended conditions are as follows: renature using a linear 6M-1M urea gradient in 500 mM NaC1, 20% glycerol, mM Tris/HCl pH 7.4, containing protease inhibitors. The renaturation should be performed over WO 98/59071 PCT/US98/12718 a period of 1.5 hours or more. After renaturation the proteins can be eluted by the addition of 250 mM immidazole. Immidazole is removed by a final dialyzing step against PBS or 50 mM sodium acetate pH 6 buffer plus 200 mM NaCI. The purified protein is stored at 4° C or frozen at -80" C.

The polypeptide of the present invention are also prepared using a non-denaturing protein purification method. For these polypeptides, the cell pellet from each liter of culture is resuspended in 25 mis of Lysis Buffer A at 4 0 C (Lysis Buffer A 50 mM Na-phosphate, 300 mM NaC1, 10 mM 2-mercaptoethanol, 10% Glycerol, pH 7.5 with 1 tablet of Complete EDTAfree protease inhibitor cocktail (Boehringer Mannheim #1873580) per 50 ml of buffer).

Absorbance at 550 nm is approximately 10-20 O.DJml. The suspension is then put through three freeze/thaw cycles from -70*C (using a ethanol-dry ice bath) up to room temperature. The cells are lysed via sonication in short 10 sec bursts over 3 minutes at approximately 80W while kept on ice. The sonicated sample is then centrifuged at 15,000 RPM for 30 minutes at 4*C. The supernatant is passed through a column containing 1.0 ml of CL-4B resin to pre-clear the sample of any proteins that may bind to agarose non-specifically, and the flow-through fraction is collected.

The pre-cleared flow-through is applied to a nickel-nitrilo-tri-acetic acid ("Ni-NTA") affinity resin column (Quiagen, Inc., supra). Proteins with a 6 X His tag bind to the Ni-NTA resin with high affinity and can be purified in a simple one-step procedure. Briefly, the supernatant is loaded onto the column in Lysis Buffer A at 4°C, the column is first washed with 20 10 volumes of Lysis Buffer A until the A280 of the eluate returns to the baseline. Then, the column is washed with 5 volumes of 40 mM Imidazole (92% Lysis Buffer A 8% Buffer B) (Buffer B 50 mM Na-Phosphate, 300 mM NaCl, 10% Glycerol, 10 mM 2-mercaptoethanol, 500 mM Imidazole, pH of the final buffer should be The protein is eluted off of the column with a series of increasing Imidazole solutions made by adjusting the ratios of Lysis Buffer A to 25 Buffer B. Three different concentrations are used: 3 volumes of 75 mM Imidazole, 3 volumes of 150 mM Imidazole, 5 volumes of 500 mM Imidazole. The fractions containing the purified protein are analyzed using 8 10 or 14% SDS-PAGE depending on the protein size. The purified protein is then dialyzed 2X against phosphate-buffered saline (PBS) in order to place it into an easily workable buffer. The purified protein is stored at 4 C or frozen at The following alternative method may be used to purify B. burgdorferi expressed in E coli when it is present in the form of inclusion bodies. Unless otherwise specified, all of the following steps are conducted at 4-10 0

C.

Upon completion of the production phase of the E. coli fermentation, the cell culture is cooled to 4-10"C and the cells are harvested by continuous centrifugation at 15,000 rpm (Heraeus Sepatech). On the basis of the expected yield of protein per unit weight of cell paste and the amount of purified protein required, an appropriate amount of cell paste, by weight, is suspended in a buffer solution containing 100 mM Tris, 50 mM EDTA, pH 7.4. The cells are dispersed to a homogeneous suspension using a high shear mixer.

WO 98/59071 PCTIUS98/12718 46 The cells are then lysed by passing the solution through a microfluidizer (Microfuidics, Corp. or APV Gaulin, Inc.) twice at 4000-6000 psi. The homogenate is then mixed with NaCI solution to a final concentration of 0.5 M NaC1, followed by centrifugation at 7000 x g for min. The resultant pellet is washed again using 0.5M NaC1, 100 mM Tris, 50 mM EDTA,'pH 7.4.

The resulting washed inclusion bodies are solubilized with 1.5 M guanidine hydrochloride (GuHCI) for 2-4 hours. After 7000 x g centrifugation for 15 min., the pellet is discarded and the B. burgdorferi polypeptide-containing supernatant is incubated at 4°C overnight to allow further GuHCI extraction.

Following high speed centrifugation (30,000 x g) to remove insoluble particles, the GuHCI solubilized protein is refolded by quickly mixing the GuHCI extract with 20 volumes of buffer containing 50 mM sodium, pH 4.5, 150 mM NaCI, 2 mM EDTA by vigorous stirring.

The refolded diluted protein solution is kept at 4 0 C without mixing for 12 hours prior to further purification steps.

To clarify the refolded B. burgdorferi polypeptide solution, a previously prepared tangential filtration unit equipped with 0.16 pm membrane filter with appropriate surface area Filtron), equilibrated with 40 mM sodium acetate, pH 6.0 is employed. The filtered sample is loaded onto a cation exchange resin Poros HS-50, Perseptive Biosystems). The column is washed with 40 mM sodium acetate, pH 6.0 and eluted with 250 mM, 500 mM, 1000 mM, and 1500 mM NaCI in the same buffer, in a stepwise manner. The absorbance at 280 mm of the effluent is continuously monitored. Fractions are collected and further analyzed by SDS-PAGE.

Fractions containing the B. burgdorferi polypeptide are then pooled and mixed with 4 volumes of water. The diluted sample is then loaded onto a previously prepared set of tandem columns of strong anion (Poros HQ-50, Perseptive Biosystems) and weak anion (Poros 25 Perseptive Biosystems) exchange resins. The columns are equilibrated with 40 mM sodium acetate, pH 6.0. Both columns are washed with 40 mM sodium acetate, pH 6.0, 200 mM NaC1.

The CM-20 column is then eluted using a 10 column volume linear gradient ranging from 0.2 M NaCi, 50 mM sodium acetate, pH 6.0 to 1.0 M NaCI, 50 mM sodium acetate, pH 6.5. Fractions are collected under constant A, monitoring of the effluent Fractions containing the B.

burgdorferi polypeptide (determined, for instance, by 16% SDS-PAGE) are then pooled.

The resultant B. burgdorferi polypeptide exhibits greater than 95% purity after the above refolding and purification steps. No major contaminant bands are observed from Commassie blue stained 16% SDS-PAGE gel when 5 p.g of purified protein is loaded. The purified protein is also tested for endotoxin/LPS contamination, and typically the LPS content is less than 0.1 ng/ml according to LAL assays.

Alternative Expression and Purification Borrelia polypeptides in E.

PCT/US98/12718 WO 98/59071 47 coli Tthe vector pQE1O is alternatively used to clone and express some of the polypeptides of the present invention for use in the soft tissue and systemic infection models discussed below.

The difference being such that an inserted DNA fragment encoding a polypeptide expresses that polypeptide with the six His residues a "6 X His tag") covalently linked to the amino terminus of that polypeptide. The bacterial expression vector pQE10 (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311) was used in this example. The components of the plasmid are arranged such that the inserted DNA sequence encoding a polypeptide of the present invention expresses the polypeptide with the six His residues a "6 X His tag")) covalently linked to the amino terminus.

The DNA sequences encoding the desired portions of a polypeptide of Table 1 were amplified using PCR oligonucleotide primers from genomic B. burgdorferi DNA. The PCR primers anneal to the nucleotide sequences encoding the desired amino acid sequence of a polypeptide of the present invention. Additional nucleotides containing restriction sites to facilitate cloning in the pQE10 vector were added to the 5' and 3' primer sequences, respectively.

For cloning a polypeptide of the present invention, the 5' and 3' primers were selected to amplify their respective nucleotide coding sequences. One of ordinary skill in the art would appreciate that the point in the protein coding sequence where the 5' and 3' primers begins may be varied to amplify a DNA segment encoding any desired portion of a polypeptide of the present 20 invention. The 5' primer was designed so the coding sequence of the 6 X His tag is aligned with the restriction site so as to maintain its reading frame with that of B. burgdorferi polypeptide. The 3' was designed to include an stop codon. The amplified DNA fragment was then cloned, and the protein expressed, as described above for the pQE60 plasmid.

The DNA sequences of Table 1 encoding amino acid sequences may also be cloned and 25 expressed as fusion proteins by a protocol similar to that described directly above, wherein the pET-32b(+) vector (Novagen, 601 Science Drive, Madison, WI 53711) is preferentially used in place of The above methods are not limited to the polypeptide fragements actually produced. The above method, like the methods below, can be used to produce either full length polypeptides or desired fragements therof.

Alternative Expression and Purification of Borrelia polypeptides in E. coli The bacterial expression vector pQE60 is used for bacterial expression in this example (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311). However, in this example, the polypeptide coding sequence is inserted such that translation of the six His codons is prevented and, therefore, the polypeptide is produced with no 6 X His tag.

The DNA sequence encoding the desired portion of the B. burgdorferi amino acid sequence is amplified from an B. burgdorferi genomic DNA prep the deposited DNA clones WO 98/59071 PCT/US98/12718 48 using PCR oligonucleotide primers which anneal to the 5' and 3' nucleotide sequences corresponding to the desired portion of the B. burgdorferi polypeptides. Additional nucleotides containing restriction sites to facilitate cloning in the pQE60 vector are added to the 5' and 3' primer sequences.

For cloning a B. burgdorferi polypeptides of the present invention, 5' and 3' primers are selected to amplify their respective nucleotide coding sequences. One of ordinary skill in the art would appreciate that the point in the protein coding sequence where the 5' and 3' primers begin may be varied to amplify a DNA segment encoding any desired portion of a polypeptide of the present invention. The 3' and 5' primers contain appropriate restriction sites followed by nucleotides complementary to the 5' and 3' ends of the coding sequence respectively. The 3' primer is additionally designed to include an in-frame stop codon.

The amplified B. burgdorferi DNA fragments and the vector pQE60 are digested with restriction enzymes recognizing the sites in the primers and the digested DNAs are then ligated together. Insertion of the B. burgdorferi DNA into the restricted pQE60 vector places the B.

burgdorferi protein coding region including its associated stop codon downstream from the IPTGinducible promoter and in-frame with an initiating AUG. The associated stop codon prevents translation of the six histidine codons downstream of the insertion point.

The ligation mixture is transformed into competent E. coli cells using standard procedures such as those described by Sambrook et al. E. coli strain M15/rep4, containing multiple copies of 20 the plasmid pREP4, which expresses the lac repressor and confers kanamycin resistance is used in carrying out the illustrative example described herein. This strain, which is only one of many that are suitable for expressing B. burgdorferi polypeptide, is available commercially (QIAGEN, Inc., supra). Transformants are identified by their ability to grow on LB plates in the presence of ampicillin and kanamycin. Plasmid DNA is isolated from resistant 25 colonies and the identity of the cloned DNA confirmed by restriction analysis, PCR and DNA sequencing.

Clones containing the desired constructs are grown overnight in liquid culture in LB media supplemented with both ampicillin (100 gg/ml) and kanamycin (25 g.g/ml). The O/N culture is used to inoculate a large culture, at a dilution of approximately 1:25 to 1:250. The cells 30 are grown to an optical density at 600 nm ("OD600") of between 0.4 and 0.6. isopropyl-b-Dthiogalactopyranoside ("IPTG") is then added to a final concentration of 1 mM to induce transcription from the lac repressor sensitive promoter, by inactivating the lacI repressor. Cells subsequently are incubated further for 3 to 4 hours. Cells then are harvested by centrifugation.

To purify the B. burgdorferi polypeptide, the cells are then stirred for 3-4 hours at 4 0 C in 6M guanidine-HC1, pH 8. The cell debris is removed by centrifugation, and the supernatant containing the B. burgdorferi polypeptide is dialyzed against 50 mM Na-acetate buffer pH 6, supplemented with 200 mM NaCl. Alternatively, the protein can be successfully refolded by dialyzing it against 500 mM NaCI, 20% glycerol, 25 mM Tris/HCl pH 7.4, containing protease WO 98/59071 PCT/US98/12718 49 inhibitors. After renaturation the protein can be purified by ion exchange, hydrophobic interaction and size exclusion chromatography. Alternatively, an affinity chromatography step such as an antibody column can be used to obtain pure B. burgdorferi polypeptide. The purified protein is stored at 4* C or frozen at -800 C.

The following alternative method may be used to purify B. burgdorferi polypeptides expressed in E coli when it is present in the form of inclusion bodies. Unless otherwise specified, all of the following steps are conducted at 4-10°C.

Upon completion of the production phase of the E. coli fermentation, the cell culture is cooled to 4-10*C and the cells are harvested by continuous centrifugation at 15,000 rpm (Heraeus Sepatech). On the basis of the expected yield of protein per unit weight of cell paste and the amount of purified protein required, an appropriate amount of cell paste, by weight, is suspended in a buffer solution containing 100 mM Tris, 50 mM EDTA, pH 7.4. The cells are dispersed to a homogeneous suspension using a high shear mixer.

The cells ware then lysed by passing the solution through a microfluidizer (Microfuidics, Corp. or APV Gaulin, Inc.) twice at 4000-6000 psi. The homogenate is then mixed with NaCI solution to a final concentration of 05 M NaCI, followed by centrifugation at 7000 x g for min. The resultant pellet is washed again using 0.5M NaCI, 100 mM Tris, 50 mM EDTA, pH 7.4.

The resulting washed inclusion bodies are solubilized with 1.5 M guanidine hydrochloride 20 (GuHCl) for 2-4 hours. After 7000 x g centrifugation for 15 min., the pellet is discarded and the B. burgdorferi polypeptide-containing supernatant is incubated at 4 0 C overnight to allow further GuHC1 extraction.

Following high speed centrifugation (30,000 x g) to remove insoluble particles, the GuHC1 solubilized protein is refolded by quickly mixing the GuHCl extract with 20 volumes of S 25 buffer containing 50 mM sodium, pH 4.5, 150 mM NaCI, 2 mM EDTA by vigorous stirring.

The refolded diluted protein solution is kept at 4°C without mixing for 12 hours prior to further purification steps.

To clarify the refolded B. burgdorferi polypeptide solution, a previously prepared tangential filtration unit equipped with 0.16 im membrane filter with appropriate surface area Filtron), equilibrated with 40 mM sodium acetate, pH 6.0 is employed. The filtered sample is loaded onto a cation exchange resin Poros HS-50, Perseptive Biosystems). The column is washed with 40 mM sodium acetate, pH 6.0 and eluted with 250 mM, 500 mM, 1000 mM, and 1500 mM NaI in the same buffer, in a stepwise manner. The absorbance at 280 mm of the effluent is continuously monitored. Fractions are collected and further analyzed by SDS-PAGE.

Fractions containing the B. burgdorferi polypeptide are then pooled and mixed with 4 volumes of water. The diluted sample is then loaded onto a previously prepared set of tandem columns of strong anion (Poros HQ-50, Perseptive Biosystems) and weak anion (Poros WO 98/59071 PCT/US98/12718 Perseptive Biosystems) exchange resins. The columns are equilibrated with 40 mM sodium acetate, pH 6.0. Both columns are washed with 40 mM sodium acetate, pH 6.0, 200 mM NaC1.

The CM-20 column is then eluted using a 10 column volume linear gradient ranging from 0.2 M NaCI, 50 mM sodium acetate, pH 6.0 to 1.0 M NaCI, 50 mM sodium acetate, pH 6.5. Fractions are collected under constant A~ monitoring of the effluent Fractions containing the B.

burgdorferi polypeptide (determined, for instance, by 16% SDS-PAGE) are then pooled.

The resultant B. burgdorferi polypeptide exhibits greater than 95% purity after the above refolding and purification steps. No major contaminant bands are observed from Commassie blue stained 16% SDS-PAGE gel when 5 gg of purified protein is loaded. The purified protein is also tested for endotoxin/LPS contamination, and typically the LPS content is less than 0.1 ng/ml according to LAL assays.

Cloning and Expression of B. burgdorferi in Other Bacteria B. burgdorferi polypeptides can also be produced in: B. burgdorferi using the methods of S. Skinner et al., (1988) Mol. Microbiol. 2:289-297 or J. I. Moreno (1996) Protein Expr. Purif.

8(3):332-340; Lactobacillus using the methods of C. Rush et al., 1997 Appl. Microbiol.

Biotechnol. 47(5):537-542; or in Bacillus subtilis using the methods Chang et al., U.S. Patent No. 4,952,508.

S 20 4. Cloning and Expression in COS Cells A B. burgdorferi expression plasmid is made by cloning a portion of the DNA encoding a B. burgdorferi polypeptide into the expression vector pDNAI/Amp or pDNAI (which can be obtained from Invitrogen, Inc.). The expression vector pDNAI/amp contains: an E. coli origin of replication effective for propagation in E. coli and other prokaryotic cells; an ampicillin resistance gene for selection of plasmid-containing prokaryotic cells; an SV40 origir of replication for propagation in eukaryotic cells; a CMV promoter, a polylinker, an intron; several codons encoding a hemagglutinin fragment an "HA" tag to facilitate purification) followed by a termination codon and polyadenylation signal arranged so that a DNA can be conveniently placed under expression control of the CMV promoter and operably linked to S 30 the SV40 intron and the polyadenylation signal by means of restriction sites in the polylinker.

The HA tag corresponds to an epitope derived from the influenza hemagglutinin protein described by Wilson et al. 1984 Cell 37:767. The fusion of the HA tag to the target protein allows easy detection and recovery of the recombinant protein with an antibody that recognizes the HA epitope. pDNAfl contains, in addition, the selectable neomycin marker.

A DNA fragment encoding a B. burgdorferi polypeptide is cloned into the polylinker region of the vector so that recombinant protein expression is directed by the CMV promoter. The plasmid construction strategy is as follows. The DNA from a B. burgdorferi genomic DNA prep is amplified using primers that contain convenient restriction sites, much as described above for WO 98/59071 PCT/US98/12718 51 construction of vectors for expression of B. burgdorferi in E. coli. The 5' primer contains a Kozak sequence, an AUG start codon, and nucleotides of the 5' coding region of the B.

burgdorferi polypeptide. The 3' primer, contains nucleotides complementary to the 3' coding sequence of the B. burgdorferi DNA, a stop codon, and a convenient restriction site.

The PCR amplified DNA fragment and the vector, pDNAI/Amp, are digested with appropriate restriction enzymes and then ligated. The ligation mixture is transformed into an appropriate E. coli strain such as SURE T (Stratagene Cloning Systems, La Jolla, CA 92037), and the transformed culture is plated on ampicillin media plates which then are incubated to allow growth of ampicillin resistant colonies. Plasmid DNA is isolated from resistant colonies and examined by restriction analysis or other means for the presence of the fragment enc6ding the B.

burgdorferi polypeptide For expression of a recombinant B. burgdorferi polypeptide, COS cells are transfected with an expression vector, as described above, using DEAE-dextran, as described, for instance, by Sambrook et al. (supra). Cells are incubated under conditions for expression of B.

burgdorferi by the vector.

Expression of the B. burgdorferi-HA fusion protein is detected by radiolabeling and immunoprecipitation, using methods described in, for example Harlow et al., supra.. To this end, two days after transfection, the cells are labeled by incubation in media containing 3

S-

cysteine for 8 hours. The cells and the media are collected, and the cells are washed and the lysed 20 with detergent-containing RIPA buffer: 150 mM NaC1, 1% NP-40, 0.1% SDS, 1% NP-40, DOC, 50 mM TRIS, pH 7.5, as described by Wilson et al. (supra). Proteins are precipitated from the cell lysate and from the culture media using an HA-specific monoclonal antibody. The precipitated proteins then are analyzed by SDS-PAGE and autoradiography. An expression product of the expected size is seen in the cell lysate, which is not seen in negative controls.

Cloning and Expression in CHO Cells The vector pC4 is used for the expression of B. burgdorferi polypeptide in this example.

Plasmid pC4 is a derivative of the plasmid pSV2-dhfr (ATCC Accession No. 37146). The plasmid contains the mouse DHFR gene under control of the SV40 early promoter. Chinese 30 hamster ovary cells or other cells lacking dihydrofolate activity that are transfected with these plasmids can be selected by growing the cells in a selective medium (alpha minus MEM, Life Technologies) supplemented with the chemotherapeutic agent methotrexate. The amplification of the DHFR genes in cells resistant to methotrexate (MTX) has been well documented. See, e.g., Alt et al., 1978, J.Biol. Chem. 253:1357-1370; Hamlin et al., 1990, Biochem. et Biophys.

Acta, 1097:107-143; Page et al., 1991, Biotechnology 9:64-68. Cells grown in increasing concentrations of MTX develop resistance to the drug by overproducing the target enzyme, DHFR, as a result of amplification of the DHFR gene. If a second gene is linked to the DHFR gene, it is usually co-amplified and over-expressed. It is known in the art that this approach may WO 98/59071 PCT/US98/12718 52 be used to develop cell lines carrying more than 1,000 copies of the amplified gene(s).

Subsequently, when the methotrexate is withdrawn, cell lines are obtained which contain the amplified gene integrated into one or more chromosome(s) of the host cell.

Plasmid pC4 contains the strong promoter of the long terminal repeat (LTR) of the Rouse Sarcoma Virus, for expressing a polypeptide of interest, Cullen, et al. (1985) Mol. Cell. Biol.

5:438-447; plus a fragment isolated from the enhancer of the immediate early gene of human cytomegalovirus (CMV), Boshart, et al., 1985, Cell 41:521-530. Downstream of the promoter are the following single restriction enzyme cleavage sites that allow the integration of the genes: Bam HI, Xba I, and Asp 718. Behind these cloning sites the plasmid contains the 3' intron and polyadenylation site of the rat preproinsulin gene. Other high efficiency promoters can also be used for the expression, the human B-actin promoter, the SV40 early or late promoters or the long terminal repeats from other retroviruses, HIV and HTLVI. Clontech's Tet-Off and Tet- On gene expression systems and similar systems can be used to express the B. burgdorferi polypeptide in a regulated way in mammalian cells (Gossen et al., 1992, Proc. Natl. Acad. Sci.

USA 89:5547-5551. For the polyadenylation of the mRNA other signals, from the human growth hormone or globin genes can be used as well. Stable cell lines carrying a gene of interest integrated into the chromosomes can also be selected upon co-transfection with a selectable marker such as gpt, G418 or hygromycin. It is advantageous to use more than one selectable marker in the beginning, G418 plus methotrexate.

The plasmid pC4 is digested with the restriction enzymes and then dephosphorylated using calf intestinal phosphates by procedures known in the art. The vector is then isolated from a 1% agarose gel. The DNA sequence encoding the B. burgdorferi polypeptide is amplified using PCR oligonucleotide primers corresponding to the 5' and 3' sequences of the desired portion of the gene. A 5' primer containing a restriction site, a Kozak sequence, an AUG start codon, and 25 nucleotides of the 5' coding region of the B. burgdorferi polypeptide is synthesized and used. A 3' primer, containing a restriction site, stop codon, and nucleotides complementary to the 3' coding sequence of the B. burgdorferi polypeptides is synthesized and used. The amplified fragment is digested with the restriction endonucleases and then purified again on a 1% agarose gel. The isolated fragment and the dephosphorylated vector are then ligated with T4 DNA ligase.

30 E. coli HB101 or XL-1 Blue cells are then transformed and bacteria are identified that contain the fragment inserted into plasmid pC4 using, for instance, restriction enzyme analysis.

Chinese hamster ovary cells lacking an active DHFR gene are used for transfection. Five gig of the expression plasmid pC4 is cotransfected with 0.5 gg of the plasmid pSVneo using a lipid-mediated transfection agent such as Lipofectin

T

or LipofectAMINE.

T M (LifeTechnologies Gaithersburg, MD). The plasmid pSV2-neo contains a dominant selectable marker, the neo gene from Tn5 encoding an enzyme that confers resistance to a group of antibiotics including G418.

The cells are seeded in alpha minus MEM supplemented with 1 mg/ml G418. After 2 days, the cells are trypsinized and seeded in hybridoma cloning plates (Greiner, Germany) in alpha minus WO 98/59071 PCT/US98/12718 53 MEM supplemented with 10, 25, or 50 ng/ml of methotrexate plus 1 mg/ml G418. After about 10-14 days single clones are trypsinized and then seeded in 6-well petri dishes or 10 ml flasks using different concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM).

Clones growing at the highest concentrations of methotrexate are then transferred to new 6-well plates containing even higher concentrations of methotrexate (1 pM, 2 pM, 5 pM, 10 mM, mM). The same procedure is repeated until clones are obtained which grow at a concentration of 100-200 pM. Expression of the desired gene product is analyzed, for instance, by SDS-PAGE and Western blot or by reversed phase HPLC analysis.

6. Immunization and Detection of Immune Responses B. burgdorferi propagation B. burgdorferi sensu stricto isolate B31 is propagated in tightly-closed containers at 34°C in modified Barbour-Stoenner-Kelly (BSKI) medium (Barbour, Yale J. Biol. Med.

57:521-525 (1984)) overlaid with a 5%O/5%CO/90%N 2 gas mixture. Cell densities of these cultures are determined by darkfield microscopy at 400X.

Immunization of Mice and Challenge with B. burgdorferi. For active immunizations BALB/cByJ mice (BALB, Jackson Laboratories) are injected intraperitoneally at week 0 with 20 g of recombinant borrelial protein, or phosphate-buffered saline (PBS), emulsified with complete Freund's adjuvant (CFA), given a similar booster immunization in incomplete Freund's adjuvant (IFA) at week 4, and challenged at week 6. For challenge B. burgdorferi are diluted in BSKII from exponentially-growing cultures and mice are injected subcutaneously at the base of the tail with 0.1 ml of these dilutions (typically 103-104 borreliae; approximately 10-100 times the median infectious dose). Borreliae used for challenge are passaged fewer than six times Sin vitro. To assess infection, mice are sacrificed at 14-17 days post-challenge, and specimens derived from ear, bladder, and tibiotarsal joints are placed in BSKII plus 1.4% gelatin, 13 g/ml amphotericin B, 1.5 g/ml phosphomycin, and 15 g/ml rifampicin, and borrelia outgrowth at two or three weeks is quantified by darkfield microscopy. Batches of BSKII are qualified for infection testing by confirming that they supported the growth of 1-5 cells of isolate B31. In some instances seroconversion for protein P39 reactivity is also used to confirm infections (see below). Others have previously shown that mice elicited antibodies to P39 when inoculated with live borreliae by syringe or tick bite, but not with killed borreliae (Simpson, et aL, J. Clin.

MicrobioL 29:236-243 (1991)).

Immunoassays Several immunoassay formats are used to quantify levels of borrelia-specific antibodies (ELISA and immunoblot), and to evaluate the functional properties of these antibodies (growth inhibition assay). The ELISA and immunoblot assays are also used to detect and quantify antibodies elicited in response to borrelial infection that react with specific borrelial antigens.

Where antibodies to certain borrelial antigens are elicited by infection this is taken as evidence that WO 98/59071 PCTIUS98/12718 54 the borrelial proteins in question are expressed in vivo. Absence of infection-derived antibodies (seroconversion) following borrelial challenge is evidence that infection is prevented or suppressed. The immunoblot assay is also used to ascertain whether antibodies raised against recombinant borrelial antigens recognize a protein of similar size in extracts of whole borreliae.

Where the natural protein is of similar, or identical, size in the immunoblot assay to the recombinant version of the same protein, this is taken as evidence that the recombinant protein is the product of a full-length clone of the respective gene.

Enzyme-Linked Immunosorbant Assay (ELISA). The ELISA is used to quantify levels of antibodies reactive with borrelial-antigens elicited in response to immunization with these borrelial antigens. Wells of 96 well microtiter plates (Immunlon 4, Dynatech, Chantilly, Virginia, or equivalent) are coated with antigen by incubating 50 1 of 1 g/ml protein antigen solution in a suitable buffer, typically 0.1 M sodium carbonate buffer at pH 9.6. After decanting unbound antigen, additional binding sites are blocked by incubating 100 1 of 3% nonfat milk in wash buffer (PBS, 0.2% Tween 20, pH After washing, duplicate serial two-fold dilutions of sera in PBS, Tween 20, 1% fetal bovine serum, are incubated for 1 hr, removed, wells are washed three times, and incubated with horseradish peroxidase-conjugated goat anti-mouse IgG. After three washes, bound antibodies are detected with H 2 0, and 2,2'-azino-di-(3-ethylbenzthiazoline sulfonate) (Schwan, et al, Proc. Natl. Acad Sci. USA 92:2909-2913 (1985)) (ABTS@, .Kirkegaard Perry Labs., Gaithersburg, MD) and A, is quantified with a Molecular Devices, 20 Corp. (Menlo Park, California) Vmax T plate reader. IgG levels twice the background level in serum from naive mice are assigned the minimum titer of 1:100.

In Vitro Growth Inhibition Assay Unlike other bacteria, borreliae can be killed by the binding of specific antibodies to their 25 surface antigens. The mechanism for this in vitro killing or growth-inhibitory effect is not known, but can occur in the absence of serum complement, or other immune effector functions.

Antibodies elicited in animals receiving immunizations with specific borrelial antigens that result in protection from borrelial challenge usually will directly kill borreliae in vitro. Thus, the in vitro growth inhibition assay also has a high predictive value for the protective potency of the borrelial S 30 antibodies, although exceptions, such as antibodies against OspC which are weak at in vitro growth inhibition, have been observed. Also, this assay can be used to evaluate the serologic conservation of epitope binding protective antibodies. A microwell antibody titration assay (Sadziene, et al., J. Infect. Dis. 167:165-172 (1993)) is used to evaluate the growth inhibition (GI) properties of antisera against recombinant borrelial antigens against the homologous B31 isolate, and against various strains of borrelia. Briefly, 105 borrelia in 100 1 BSKII are added to serial two-fold dilutions of sera in 100 1 BSKII in 96-well plates, and the plates are covered and incubated at 34 0 C in a 5%O/5%CO/90%N 2 gas mixture for 72 h prior to quantification of borrelia growth by darkfield microscopy.

WO 98/59071 I'CT/US98112718 Sodiumdodccylsulfate-lPolyacrylamide Gel Electrophoresis (SDS-PAGE) and Immunoblotting Using a single well format, total borrelial protein extracts, recombinant borrelial antigen, or recombinant P39 samples (2 g of purified protein, or more for total borrelial extracts) are boiled in SDS/2-ME sample buffer before electrophoresis through 3% acrylamide stacking gels, and resolving gels of higher acrylamide concentration, typically 10-15% acrylamide monomer.

Gels are electro-blotted to nitroccilulose membranes and lanes are probed with dilutions of antibody to be tested for reactivity with specific borrelial antigens, followed by the appropriate secondary antibody-enzyme (horseradish peroxidase) conjugate. When it is desirable to confirm to that the protein had transferred following electro-blotting, membranes are stained with Ponceau S.

Immunoblot signals from bound antibodies are detected on x-ray film as chemiluminescence using

ECL

T M reagents (Amersham Corp., Arlington Heights, Illinois).

Detection of Borrelia mRNA expression Northern blot analysis is carried out using methods described by, among others, Sambrook et al., supra. to detect the expression of the B. burgdorferi nucleotide sequences of the present invention in animal tissues. A cDNA probe containing an entire nucleotide sequence shown in Table 1 is labeled with 3"P using the rcdiprime T M DNA labeling system (Amersham Life Science), according to manufacturer's instructions. After labeling, the probe is purified using a CHROMA SPIN-100 T M column (Clontech Laboratories, Inc.), according to manufacturer's protocol number PT1200-1. The puriflcd labeled probe is then used to detect the expression of Borrelia mRNA in an anim:l tissue sample.

Animal tissues, such as blood or spinal fluid, are examined with the labeled probe using ExpressHybTM hybridization solution (Clontech) according to manufacturer's protocol number 25 PT1190-1. Following hybridization and washing, the blots are mounted and exposed to film at S" 70 C overnight, and films developed according to standard procedures.

The disclosure of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited herein are hereby incorporated by reference in their entireties.

30 The present invention is not to be limited in scope by the specific embodiments described herein, which are intended as single illustrations of individual aspects of the invention.

Functionally equivalent methods and components are within the scope of the invention, in addition to those shown and described herein and will become apparant to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

Provisional Application Serial No. 60/057,483 filed 3 September 1997 is incorporated by reference herein in its entirety.

Throughout the specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Page(s)2 -21o are claims pages They appear after the table listings WO 98/59071 PCTIUS98/12718 56 TABLE 1. Nucleotide and Amino Acid Sequences flOl.aa bMSKIFLLFNAGFFFLKIILVFSYPEIKFSRQDPVFSDLKIKLKYN=QHIPLFFYSYKVKGDTFFKINKING -WQSGIATINLLDSPAVSVGQEILI PSKKGVVDSKDYRFNNLLLAT fLAKAEEKIKRVY-EFFDFVKNP DFGLFSGTELLFFLNANFIFPLKKFIVSSDFGFRNPFTGNSFHTGIDLAAPMNAEvyLLLLE tl~l. aa SYPEIKFSRQDPVFSlLKIKVLKKUQHIPLFFYSYKVKKGDTFFKIAKINGWQSGIATINtLDSPAVSVGQE ILI PSKKGVFVFDSKDYRFNNLLLATRDLAKAEKVKIKRNDRVYEFYFFDFV1UPDFGLFSGTELLFFLNANFIFP

LKKFIVSSDFGFRNDPFTGNKSFHTGIDLAAPA.EVYLLLLE

fl~l.nt

ATGAGTAAAATTTTTTTATTATTTAATGCAGGTTTCTTTTTTTTAAAAATAATTTATGTTTTTTCTTATCCAGAAA

TAAAAATTTCTCAAGG3CAAGATCCTGTTTTTTCTGATCTTAAAATTAAAGTTTTAAAATATAACAAAACAACA TATTCCTCTGTT TTTTACTCATATAAAGTTAAAAAAGGGGATACTTTTTTAAAATTGCCAATAAAATAAATGGA

TGGCAGTCCGGCATTGCTACTATTAATTTATTAGATTCTCCTGCTGTGAGTGTTGGGCAAGAGATTCTTATTCCCA

GTAAAAAAGGAGTTTTTGTTTTTGATAGTAAAGATTATAGATTTAATAATTTGC TTTAGCAACAAGGGATCTTGC

TAAAGCTGAAAAGGTAAAAATTAAAAGGAACGACAGAGTTTATGAATTTTATTTTTTTGATTTTGTTAAGAATCCA

GATTTTGGACTTTTTTCAGGCACAGAATTGCTTTTTTTCTTAAATGCCAATTTTATTTTTCCTTTAAAA.AAATTTA

TTGTTAGTTCTGATTTTGGATTTAGAAATGACCCTTTCACTGGC-AACAAAAGTTTCCATACAGGAATAGATCTTGC

AGCTCCAATGAATGCTGAAGTGTATCTTCTTCTTCTGGAATAG

tl~l.nt

TCTTATCCAGAAATAAAAATTTCTCAAGGCAAGATCCTGTTTTTTCTGATCTTAAAATTAAAGTTTTAAAATATA

ACAAAAAACAACATAT'TCCTCTGTT'TTTTTACTCATATAAAGTTAAAAAACGGGATACTTTTT'rTAAAATTGCCAA TAAAATAAATGGATGGCAGTCCGGCATTrGCTACTATTAAT'rTATTAGAPrCTCCTGCTGTGAGTGTTGGGCAAGAG ATTCTTATTCCCAQTAAAAAAGGAGTTTTTGTTTTTGATAGTAAAGATTATAGATTTAATAAWI-TGCTTrTAGCAA 9: CAAGGGATCT'rGCTAAAGCTGAAAAGGTAAAAATTAAAAGGAACGACAGAGTTTATGATTTTATTTTTGATTT TGTTAAGAATCCAGATTTTGGACTTTTTTCAGGrCACAGAATTGCTTTTI'TCTTAAATGCCAATTTTAT'PrTTCCT

TTAAAAAAATTTATTGTTAGTTCTGATTTTGGATTTAGAAATGACCCTTTCACTGGCAACAAAAGTTTCCATACAG

GAATAGATCTTIGCAGCTCCAATGAATGCTGAAGTGTATCTTCTTCTTCTGGAATAG

fll.aa VK KYIKTIFLISMVYFYCCTTIKINHDYETDFKVLESPSKYINIDVIKATNEYIYIQITNNSLDVVKIWQNTSLN NflKIVLKKDLTINETGYCYEFFIGPKTSFFKVYPLKIHSKKNSNNLSSTIKYPS IFKLNITKVGIEAKK TINVLITR'rrKINITNK tll.aa

CCTTIKINHYETFKVLESPSKYINIDVIKATNEYIYIQITNNSLDVVKINWQNTSLNNDKIVLKKEDLTINNET

GYIOYREFFIGPKTSFKFKVYPLKIHSKNKNSNNLSSTIKYPSIFKLNITKVGIEAKKTINVLITRTTKINITNK

fll.nt GTGGAAAAATTTCTTTTATTCCAGGAAATGAAAATATTrGCAGATCTTGGTTTTCATAAAACTAAGTAGAA.ATATTG TCAAATCTAACAATTCTGATTTCAATGGTTTATTTTTATTGTTGTACGACAATAAAAATAAACr-A

TGATTATGAAACTGATTTTAAAGTTCTAGAATCTCCCTCTAAATACATCAATATAGATGTAATTAAAGCTACAAAT

GAATATATTTATATTCAATTACAAACAATAGCTTAGACGTAGTAAAAATAAATTGGCAAAACACTAGTCTTAACA

ACGATAAGATCGTC-TTAAAAA AAGAAGATCTT CAAAATAAAGTATAAAAATAAATACAGAGAGTT WO 98/59071 PCTIUS98/12718 57 TABLE 1. Nucleotide and Amino Acid Sequences tll.nt AAAAGTAGGAA'ITGCA ATTATA AGACTCAAATAATTACTATA

TGA

fl2.aa

MRFYNFKFVLFTSAFQIDNKRFLLQSLEESDDKWLELED

SKRLLKGDEFKKLGGYIITDNEFYLKEIFGVIVDKNKNK

IDFKTKHFYTENFGGITFENLYSYDTIYPFDNRTKVEDFSEHSNINT.LFFPFRYLFKFKTELL

NKATLYSFDSDVKSLVNNSSIFLSDPETFYQSLTASLIYDYDYFTTELSGELSFEDIKSSELKLSLDF

GWKINLQKFTDNLRSALTLFKYTEFLEIYFSTLSINKTFKKGYMQIGLEPVNFFVLSKSFNFFNSQDJC

t12.aa

IFQIDNKRKTSKYRLLTELKAKGKTVKR-LKFIPLIGGA

SGYIITDLNTGTDSIERNLEDKNKNKDILKSKYINEIDD

N~KYYNFVFSNLKGLI<QNIHLFGVKINVIEAATKPPYI

ASKIWALPSGDFGFLNAIFYMGRVPVFYIPFFFRPGDSLF'NPSLGLNPPGFFTVYTLFSSSEDSSFLDF

*DFNNSGKKPYIRNGYLTYFFALAPSDYKIFDIYANFYSGIDFLGNTHKTLEGNFGLGFTR

NVYSYDGGYPFfNRTLKQSLFSFSNNKGDVFGFEVPFRYLTEFLLSDLFSVVLEYSDPYVNTflFRflRI

NDKSKQSSFDNSFKTNDSLYLNGLFLGELVKPEPDN

PTKFLRYPILFKLNQTPDKMMPINEKNIKVENKTETDYP

SFRGIPLNVFDYISPDNEKNLDK=IIAFNRIFNL

LNIYPNDKEKKSHINILLPIRPFRTKMTYFKYSVSVKS

IFSP=STSIDDFTLGLNFDKASLLLFYLEGGKYKKDMN

GIAQPEQPSYNESAYKERLYFFFVYPIRSLFLvDQLAKD EYYPKDSITTKVYLSYKLVT~rNLFLVVWILKTNLSLLFY EFLEIYFSTLSITKTKFKFGYQIGLEPFVDLSySQDPFNSLDRKSFISSGFKFNFYDKFVGE f 12.nt

ATCAATCTTCGATTTTAAACTTAATTTTATTTACTTCAT

CATTTCCGCAAAGTAATCAAAAGGTACACTAGCAATTAT

AAAACTACTCACAGGATAAAATGCTAAGGGTAAGACGTT

WO 98/59071 PCIUS98/12718 58 TABLE 1. Nucleotide and Amino Acid Sequences TCAAAAATACGAGAATGCTTAAAAAGTTGGAATAGATCCTGAGC=rTTATCAAAGGAAAGGGACTrGCCG GATC GTGTTAAATArAATCGTACTAAIrCACI'ATGGACTTACTAAAGATGA AAGTATTAT 'GAGAAr'AACTTGGTTGAAGATATAAAGAAAATAAAAGcAcAATATTAA.AGGc GACAGAATAGTCC'rTAATAAGAACTCTAAAAAACTTTATGCTATTGGAAATGTTGAATATATTCTTGATATGGATA

CCAGAACTATTAGCAGATCTGCATTATTAATTTATAAAG

TATTCTTCA AAA A AA AATGCAAAAAAATCAAATAGATCATATTCTTTCGTTTGGAGGAAAGGTTTrTAAAAAAGATA GACAATGATGTTACCAT'TT'rGGAACAAGCTTTTGCAACAACTAGTAAAATCCAGAGCCTTACTATTCAATCAAGG

CTTCTAAAATATGGGCATTGCCCTCGGGAGATTTTGGGTTTTTAAATGCCATATTTACATGGGAAGAGTTCCAGT

ATTTATATTC.. at- ~GCGGGTGrTTA CCATCTrwrAGGTCTAAATCCACGAAAA GGTTTTCTGTTTAATACCGTTATCTTTTTGGTAATAAATCTTCAAGTGAGATTCTTCTTnIT1rGGAT1.TG

ATTTCAATTCTGTTTATAATCGGGTAAAAAACCTTATATAAGAAATGGATATTTAACTTATTTTTTTGCAGAAAA

TTTAGCACCCAGTGTTAATAAAGATTATGTTAAGCTTATTTTTGACATTTATGCTAATCTGGGATTTTATTCTGGA

ATTGATTrTAATTTGGGCAATACT'GGGGCATTTTAAAACTTTGGAALGGAAATTTTGGATTGGGTPrTACCAGGA ATGTTTATAGTTACGATGGAGGATATTATCCTTrTTGATAATAGGACTTTAAAACAATCTCTTTTTAGTT=rCCAA TCTTAACAAAGGAGATGTATTTGGGTTGAAGTTCCTTTTrAGATATTTATTTAAATTTAAAACAGAATTTCTTTTIA

AGTGATGCACTTTTCTCGGTTGTTTTAGAGCACTATTCTGACCCGTATGTTAATATTGATTTTAGAGATAGGATAG

AAGTGCTACATTTTTTTCTCTTTTAAATTTAGATAAGATTCGGTTAAAGAGCAAACTAGCATTAGCACTTTTGA

T'rGGAATTTATCTTCTTTTTATAAGCGAACATT'rAATGACGGTTCGATTTAGATTATAAATTAATAATTTAGGT

TTATTAATTGGTTAATTTTTTATTCTAAAACAAAGTAGT

CTACAAGAAAATGGTTTTATTTGGAGAGAATTTATGCTCCATATATTGATTTGAATTTTCAAAAAGATCTTTACAA

TACATGCTTCGTAATAGATAATCCCGAATAATTGAAAAA

AATGATAAAAGAGTGTGA6AGGAGAAAAATACTAAAAAAACAACAGAATTAACCAAAGATT'rATATATTCC

TCCAG

AACCAATTACTTTAATATTGATCAATCCGATCTTTTTTATTAGGTTTGGCATrAATCCTTATTTAAGAAA

TAATGTTTTTTTGATATTATGGCATAACAAGTCCAAAGGACTTTAATTATGAAATAAAATTATTTATTTGAT

ATAAAAAATAAAACGGATATAAAAATTCATGCTGATTTTTACAATCGTTTAATTACTTTTGAAAATTTATTATATC

TTAATACTATTGAGTATAGTCCTTTAATAAAGATTTTAAAGTTAGTAGTAAAGGAGCACTCTAT

TATTAACCAATAAATTTAAACTTGCTTCCTTTTATTAGATATCCTTTATTTTCTAGAAGTACTTTAAAGTTTGAA

AATAAGGCTACTTTATATTCATTTAATAAAAAATATGATTCTGATGTAAAATCTTTGGTTAATAAGAATAGTAGTA

TTTTTTTATCTGATCCGGAAACTTTTTATCAAAGTTTAACAGCCTCTTTAATTTATGATTATGATTATTTTACTAC

TGAGCTTTCAGGTGAATTAAAAAATAGTTTTGAAGATATTAAAGCTTCTTCTGAGC'FrAAACTTTCTTTAGATTTT CCTTATTTGCTACAAGAAGCTGGGATTGGA6ATTAAATATTATAAAAAGTTTAAAGAAGATGCTATGAAAAACTCTG GAATTTCTGCTGT'rCAAAGTCCTTTIGGAGCCTCAAAAACCATCATCGCCTTATAAAAATTTAGAAATGTCTCCTGC

TTTGTATTATAAATTGAGCCGAGATATTGATATTTTAAATTAGTTTTTAGTCGCCTATGATCCTTTGATA

AATATAAT'rATGATCCTTTAAAAGGAGATTTTTCCAAGATTGGTACTACAA6CCAAACTT'GTTCCATATTCTTTAGA TTCTAGTDACAAAAAGGAATTGTACGTTTTAACTTTTTTITGACAATAAGCT'rTCTTTTAC CTTGGGGGTAGATGTT GGTTGGAAAATAAATTTrGCAGAAATTITACGGATAATGAACTTCGATCTGCATTGACTTTGAAGTTrTAAATATACAG AATT'1Tr'AGAAATTTACTTTTCTACTTTATCTATAATACTAAGACTTTTAAATATTTTAAAGGGTATATGGACCA AATTGGTCTAGAACCTGTTAATTTCTTTGT'rGATATCAAATCTTCAATTTCTTTAATCTCAAGACAGAAAA GATTCACTTTAATAA TA CAGGCTTTAAATTCAATTATGATTGGAAATTGTTGGAGAAT ATAATTTAGAACCAGATTTATTAGGGGATCTGATGGGATTATTCTCCTATTTGGAGAAA6TAATTTTACAATTTA TATTTCTGGAACTTTTTTGCTCCTATAAAGCG C'TGACAAAAAAATACGAGTTTATTATT t12 .nt ATTTTGCCCAGACTATAGATGATGAAAATTC AAAAGAAGTATTTAAGTCAAAAATCTTATTTA-A

GAGAACTTGAGCTTTCA.ACCGATGAGGATTTAAAAAAATGGGCCTTAAAAGAGGGTTTAAAAGAALACAGATGTTTC

AAAATACGAGAATTGC rTAAATTGATGTCTGAGCTWNTATCAAAGGAAAGGGACTTGCCGGA TCTGGTAGATATAAAATAATCATTGAAACTGCAGATAATCTTGAA6AATTTCACTTATGGACTTACTAAAGATGAAA

GTATATTTTGAAGGAAGAGTTAATATCTTGGTAGTTAAGAAAAACACAATATAAAGGCGA

CAGAATAGTCCTTAATAAGAACTCTAAAAAACTTTATGCTATTGGAAATGTTGAATATATTCTTGATATGGATACC

AATGAAAAGCTTTATTTTTATGGCAATGAATTTCTTGTCGATTTTGATTCTCAAAATTTTTTATTAAAAAATGGTA

TTCTTA A A AA A A AATCAAATAAAA TTCTCGTGAGAGTTAAAGT

CAATGATGTTACCATTTTGGAACAAGCTTTTGCAACAACTAGTAAAATTCCAGAGCCTTACTATTCAATCAAGGCT

TCTAAAATATGGGCATTGCCCTCGGGAGATTTTGGGTTTTTAAATGCCATATTTTACATGGGAAGAGTTCCAGTPAT

WO 98/59071 PCTIUS98/1271 8 59 TABLE 1. Nucleotide and Amino Acid Sequences

TTTATATTCCTTTTTTCAGACCGGGAGATAGTTTGTTTTTAATCCATCTTTAGGTCTAATCCACGAAAAGG

TTTTCTGTTTTAATACCGTTTT~rGGTAATAAATCTCAAGTGAAGATTCTCT'TTTGGATTTTGAT TTCAATTCTGT 'TATAA1"rCGGGTAAAAAACCTTATATAAGAAATGGATATTTAACTTATTT'TTTTGCAGAAAATT TAGCACCCAGTGTTAAAATAG'AGTTATTMrGACATTTATGCTAATCTGGGATTTTATTCTGGAAT

GTTATAGTACGATGGAGGATATTATCCTTTTGATAATAGGACTTTAAAACAATCTCTTTTTAGTTTTTCCAATC

TTAACAAAGGAGATGTATTTGGGTTTGAAGTCC TTTTATATAA'TAAA~~ CTTTTAAG

TGATGCACTTTCTCGTTITGACCATTGACCCGTATGTTAATATGATTTAGAGATAGGATAGAA

AGTGCTACATTTTTTCTCTTAAATTTAGATAAAGATTCGGTTAAAGAGCAAACTAGCATTAGCACTTTTGATT

GGAATTTATTCTTiIrATAAGCGAACATTTAATGACGGTTCGAT TTTATAAATATATAGTr AAG1TrTTAAATGTCGGGCTATGAAAATCTTTATGTTAAATCTCCTTTAGAGAACCAAAGATGTTAATGATCCT ACAGAAATGTTIrATTGGGAGAT'TAGCTCCATATATTGATTTGAATTTTCAAAAAGATCTTTACAATA

ACCAATGGACATTCCAGCTGATACTAAGAAATGATAATGCGCCCAGAAATTAAATCTAGAAGATAAAGATAA

TGATAAAAAGAGTGTGAAGGAGAAAATACTAAAAACAATrACAAAGATTTATATATTCCTCCAGAA CCAATTACTTTAAAAATATTGATCAATCCGATTCT1TTTTrATTAGGTTTGGCATTAATCCTrATTTAAGAAATA

ATGTTTT=TGATAATATGGCATAACAAGTCCAAAGGACTTTAATTATGAAATAAAAATTATTTATTTGATAT

AAAAAATAAAACGGATATAAAAATTCATGCTGATTTTTACAATCGTTTAATTACTTTTGAAATTTATTATATCTT

AATACTATTGAGTATAGTCCTTTAAATAAAGATTTTAAAGTTGAAGATAAAGATAAAA)AAAGTGAGCACTCTATTA

TTAACCAATAAATTAAACTTGCTTCCTTTTATTAGATATCCTTTATTTTCTAGAAGTACTTTAAGTTTGAAAA

TAAGGCTACTTTATATTCATTTAATAAAAAATATGATTCTGATGTAAAATCTTTGGTTAATAAGAATAGTAGTATT

TTT'rTATCTGATCCGGAAACTTTTATCAAAGTTTAACAGCCTCTTTAATTTATGATTATGATTATTTTACTACTG AGCTTTC-AGGTGAATTAAAAAATAGTTTTGAAGATATTAAAGCTTCTTCTGAGCTTAAACTTTCTTTAGATT'rTCC

TTATTTGCTACAAGAAGCTGGGATTGGAATTAAATATTATAAAAAGTTTAAAGAAGATGCTATGAAAAACTCTGGA

ATTTCTGCTGTTCAA6AGTCCTTTGGAGCCTCAAAAACCATCATCGCCTTATAAAAATTTAGAAATGTCTCCTGCTT TGTATTATAAAATTGAGCCGAGATATTTGGATTATTTTAAATTTAGT'TTTTTAGTCGCCTATGATCCTT'rGATAAA TAGAGTTTCTGAACTTTCTTrTAAGCTTAATGTTTTTGATTTTCAATTTTTGTTTGCTATGAAAGACGACTTTGAA TATAATTATGATCCTTTAAAAGGAGATTTITrCCAAGATTGGTACTACAACCAAACTTGTTCCATATTCTTTAGATT CTAGTTACAAAAAGGAATTGTACGTTTTAACTTTTTTTGACAATAAGCTTTCTTTrACCTTGGGGGTAGATGTTGG TTGGATATTGAAATAGGATAATGAACTTCGATCTGCATTGACTTGAAGTTrAAATATACAGAA

TTTAGAAATT~TACTCTACTTTATCTATTAATACTAAGACTTTTAAATATTTAAAGGGTATATGGACCAAA

TTGGTCTAGAACCTGTTAATTTCTT1TGTTGATTTATCAAAATCTTTCAATTTCTTTAATTCTCAAGACAGAAAAGA TTCAC TTAATAA~TCATCAGGCTTTAAATTCAATTTTATGATTGGAAATTTGTTGGAGAATAT AATTAGAACCAGATTATTAGGGATCTGATGGGATTTATTrCTCCTATTTGGAGAATAATTTACAATTTATA TTTCTT~GGAACTTTTTT~GCTCCTATAAAAGCGTCATTT AACAAAAAAATACGAGTTTATTATTAA

TAGAAAAACAAAAAAATAA

fl29.aa MTKKLFVRVLIFLISNNYAFAKDTIKDLFFIQDILIKKEKYSEVTJNNASLEGIIEIEHNGpYIKDHDSEVKLILKE NGYRRNFNFFNLLNTSNIIKSLSLFDSRPKNIKENEIILLETX4IKENPYKRYKDDDDFELKLSVTRKNNQIYLIL DFNFLFDQRKTFPSIYIKEEDVSTIIN SFMXLQDSSFLSPQAS tl29.aa

LSLFDSRPKNIKENIILLETMIKENPRYKDDDDFELKLSVTRKNQIYLILDFNFLFDQRKTFPSIYIKEED

VSTIINSFMKLQDSSFLSPQAS

fl29.nt

ATGACAAAAAAATTGTTTGTGAGGGTATTAATCTTTTTAATATCCAATAATTATGCTTTTGCAAAAGACACAATCA

AAGATTTGTTCTTATACAAGATATACTAATAAAAAAAGAGAAATATTCCGAGGTTCTAAATAATGCAAGCCTTGA

AGGCATTATTGAATTGAACATAACGGACCATACATAAAGATCACGATCAGAAGTTAAACTTATCCTAAAAGAA

AACGGATATAGAAGAAATTTCAACTT=rTAATCTTrTAAATACTAGTAATATAATCAAAAGTCTAAGCTTATTTG ACAGCAGACCAAAAAAc-ATTAAAGAAAATGAAATCATATTATTAGAGACAA).AATGATTAAAGAAAATCCCTATAA ACGATACAAAGACGATGATGATTTGAATTAAAACTAAGTGTAACTCGAAAAAATAATCAAATTTATT'rAATT.CTT WO 98/59071 PCTIUS98/12718 TABLE 1. Nucleotide and Amino Acid Sequences GAT'rTCAAT TTC CTATTTGATCAAAGAAAAACGTTTCCATCAATTTACATCAAAGAAGAAGATGTATCAACAATAA

TAAACAGCTTCATGAAACTACAAGATTCAAGCTTTTATCTCCTCAAGCTTCTTAA

t129 .nt

AAAGACACAATC.AAAGATTTGTTCTTTATACAAGATATACTAATAAAAAAAGAGAAATATTCCGAGGTTCTAAATA

ATGCAACCTGAAGGCATTATrGAAATTGAACATAACGGACCATACATTAAAGATCACGATTCAGAAGTTAAACT TATCCTAAAAGAAAACGGTTGAAA'1TACTTTACTTTTAAATACTAGTAATATAATCAAAAGT CTAAGCTTATT'TGACAGCAGACCAAAAAACATTAAAGAAAATGAAATCATATTATTAGAGAcAAAATGATTAAAG AAAATCCCTATAAACGATACAAAGACGATGATGATTT'rGAATTAAAACTAAGTGTAACTCGAAAAAATAATCAAAT TTATTTAATTCTTGATTTCAATTTCCTATIrGATCAAAG AAAAACGTTTCCATCAATTTACATCAAAGAAGAAGAT GTATCAACAATAATAAACAGCTTCATG7AAACTACAAGATTCAAGCTTTTTATCTCCTCAAGCTTCTTAA f142 .aa MDKISILYTLINI IIMLILISIWYLCKRK<NVSFTKRVFIALAIGIVFGMTIQYFYGTNSEITNETINWI SI LGDGY VRLLKNIIIPLIITSIISAI IKLTNSKDVGKMSLLVILTLVFTAGIAAIIGIFTALALGLTAEGLQAGTIEILQSE KLQKGLEILNQTTITKKITDLIPQNIFEflFAGLRKNSTIGVVIFSAIIGIAALKTSIKKPESIEFFKKIILTLQDI ILGVVTLILKLTPYAILALMTKITATSEIKSIIKLGEFVIASYIAIGLTFLMHMTrLIAINKLNPITFIKKIFPALS FAFISRSSAATI PINIEIQTKNLGVSEGIANLSSSFGTS IGQNGCAALHPAMLAIMIAPTQGINPTDI SFILTLIG LI IITSFGAAGAGGGATTASLMVLSAMNFPVGLVGLVISVEPI IDMGRTAVNVGGSMLAGVISAKQLKQFNHNIYN

QKELVNK

t142.aa .CKRKNVSFTKRVFIALAIGIVFGMT IQYFYGTNSEITNETINWI S I LCDGYVRLLKMI I I PLI ITS I I SAI I KLTN

SKDVGKMSLLVILTLVFTAGIAAIIGIFTALALGLTAEGLQAGTIEILQSE.KLQKGLEILNQTTITKKITDLIPQN

IFEDFAGLRKNSTIGWVIFSAIIGIAALKTS IKKPES IEFFKKI ILTLQDIILGVVTLILKLTPYAILALMTKITA TSEIKSIIKLGEFVIASYIAIGLTFLMHMTLIAINKLNPITFIKKIFPALSFAFISRSSAATI PINI EIQTKNLGV

SEGIANLSSSFGTSIGQNGCAALHPAMLAIMIAPTQGINPTDISFILTLIGLIIITSFGAAGAGGGATTASLMVLS

****AMFPVGLVGLVISVEPIIDMGRTAVNVGGSMAGVISAKQLKQFNHNIYNQKELVNK

f142.nt TAAGAGG ATAGAAATATTTAAAATAATCAATATTATAATAATGCTTAT'rCTAATAAGCA

TAGTTTATCTTTGTAAAAGAAAAAATGTTTCTTTTACAAAAAGAGTGTTTATAGCGTTAGCAATCGGAATAGTATT

TGGAATGACCATTCAATATTTTTATGGAACAAATTCAGAAATAACAAACGAAACTATAAATTGGATAAGTATTTTG

GGCGATGGATACGTAAGGCTCCTTAAAATGATTATAATCCCCTTAATAATAACATCAATAATCTCTGCAATAATAA

AACTAACCAATAGTAAAGATGTTGGGAAAATGAGCCTACTTGTAATATTAACACTAGTATTTAcAGCAGGTATTGC TGCCATAATTGGCATTTTCACTGCTrTAGCATTGGGATTAACAGCCGAAGGACTACAGCGGGAACCATCGAAATT

TTACAAAGTGAAAAAI'GCAAAAAGGCCTTGAAATATTAAATCAAACAACAATCACAAAAAAAATCACAGATCTTA

TTCCACAAAATATATTTGAAGATTTTGCAGGGCTAGAAAAAACTCAACCATCGGGGTCGTGATATTTI'CAGCTAT

CATAGGAATAGCCGCCCTTAAAACATCTATCAAAAAGCCAGAATCAATAGAAT'rTTTTAAAAAAATAATATTAACA CTCCAAGACATAATATTAGGTGTAGTAACTTTGATTTTAAAACTAACGCCTTATGcTATATTAGCTTTAATGACAA

AAATTACAGCAACCAGCGAAATCAAAAGCATAATAAAGCTTGGAGAATTTGTAATTGCTTCCTACATTGCCATAGG

TCTTACATTTCTTATGCATATGACATTAATTGCAATAAATAAATTAAACCCAATTACTTTTATAAAAAAAATATTC

CCAGCACTATCATT'rGCATTCATATCTAGGTCGAGTGCTGCAACr-ATACCCATAATATAGAAATTCAAACTAAAA ATCTGGGAGTAAGCGAAGGAATAGCAAATTTATCAAGCTCCTTTGGAACATCAATrGGGCAAAATGGTTGTGCAGC

ACTACACCCCGCTATGCTTGCAATAATGATAGCACCAACTCAGGGAATAAACCCCACAGATATTTCATTTATACTC

ACACTATGGATAATATATAATTICATTTGGAGCTGCTGGCGCTGGTGGAGGCGCAACAACAGCCTCACTAA

TGGTGCTCTCAGCAATGAACTTTCCAGTGGGATTGGTAGGACTTGTAATATCTGTTGAGCCTATAATTGACATGGG

AAGAACAGCTGTTAATGTAGGCGGCTCAATGCTTGCAGGCGTTATATCTGCTAAACAGCTCAAACAAT'rCAACCAT

AATATATACAACCAAAAAGAGCTTGTAAACAAATAA

t142 .nt WO 98159071 PCTIUS98/1 271 8 61 TABLE 1. Nucleotide and Amino Acid Sequences TGAkAA.ATT~=~A-.AATTTTGGTCCACCATGATCCATAC

TTATTTTTCAAATCGATAAAGACAAATGTATTTGGGTGT

CGAGCCTAATATTAC~TATAACTATATTTCAATAATACA

AGAAAGTGAATACTCTTAATACCATTTCGAGATCGCTAT

GCTTCCGTTGATGATAACGAGATCACGACACAATTCAGG

AAATcAAGcTGATTAACACACACCAAAACCGTTATCCAA

ATTTAGTTGAGCTGAAATACCTGGTGGTTTCGTTAAGAA

ccccTAAACACAAACAATA6AGATTTAAATAATAATCAAA

AAATGTTGACTGTTAACACC

ACACAATAAGAA6AACTGGATGATGTCTC6TCAAGCTC=

TTTCTT~ATATCAAAAATACCATATTAAAAATTCCGATT

ATTCTCTTTGTGGGTGACAACTAATTGAT

CCAAAAAGAGCTTGTAAACAAATAA

f147 .aa MKIIIIGGTSAGTSAAAKANRLNKKLDITIYEKTNIVSFGTCGLPYFVGGFFDNPNTMISRTQEEFEKTGI

SVKTN

*VIIGGGYIGIMVEAANRVRLIQLDKHILIDSFDEEIVTIMEELTKKGVLHTNEFKSLIGEKAGVVT

N1YQADAVILATGIKPDTEFLENQLKTNGAIIEYGETSIKNIFSAGDIVSNYIPATTN

ENTKIILAAGNAIIASAYKTKEGMFYPFRWINANA

*tl47.aa IKQTT~RTDLITGKIPINNEFTKNEG

KLDEINVIGGGYIGIEMVE

NGAVIR IHLSIAIY SKLTTKELGFSYSPPFSRTWDINIAGNA fl47.nt

ATGAAATAATAATTATTGGGGGAATCAGCAGGAACTAGTGCCGCAGCTAACCTTCAAAGC

TAAATCATTTAAACA* *TTTTTGACGGGCGCTCTTTGGGT

*ACCATCATACCAACCAAAATCAAACGAACCGTAATA

GTGATAATTGGTGGTGGATACATGGAATTGAAATGGTAGAAGCAGCAAAALAAAAAATTATAA

AAAGGGGGTAATCTTCATACAAATGAGTTTGTAAAAAGTTTAATAGGAGAAGGAAGTAGTAC

GCGTTCTCACGAAACTAATATTTG;AC

AGTAACATAATGGATATTATGGAGCAATGAAAATTTTCG

AGAATTCATTTTAAATATAAAAGAAAACTGCLCAACACA

C GGAcTrArATAAGAATGCCGTCAT AAAATTTTGACGAGAAGCTCGAAAGTCAAACcAAAATTAA

CAAAATTACAGCAAGACTAATATATTTA

GAAAACAAATCTGGAAGALAGAAATGGCTATAATCTCTATA

wo 98/59071 WO 9859071PCTIUS98/1271 S 62 TABLE 1. Nucleotidle and Amino Acid Sequences

TTGCAATCTATTCAAAACTTACAACAAAAGAGCTAGGGATGATGGATTTCTCATATTCCCCACCCTTCTCAAGAAC

TTGGGATATATTAA-ATATTGCTGGCAA6TGCTGCCAAATAG t147 .nt GCCGCAGCTAAAGCAAACCGCTTAAACAAAAAGCTAGACATTACTATCTATGAAAAAACAAATTGTATC"rTTG GAACCTGTGGCCTGCCTTACTTTGTGGGGGGATTC'rGACAACCCCAATACAATGATCTCAAGAACACAAGAAGA ATTCGAAAAAACTGGAATCTCTGTTAAAACTAACCACGA.AGTTATCAAAGAAG AACAAA~rTA

ATAAAAAATCAAAAAACAGGAACCATTTITTAACAATACTTACGATCAACTTATGATAGCAACTGGTGCAAAACCTA

TATTCCACCAATCAATAATATCAATCTAGAAAATTTTCATACTCTGAAAATTAGAAGACGGTCAAAAAATAAA

AAAATAAGGAAGAGAGAATTAAAAATATGAAATGGTGGTGGATACATTGGAATTrGAAATGGTAGAA

GCAGCAAAAAATAAAAGAAAAAATGTAAGATTAATTCAACTAGATAAGCACATACTCATAGATTCCTTTGACGAAG

AAATAGTCACAATAATGGAAGAAGAACTAACAAAAAAGGGGGTTAATCTTCATACAAATGAGTTTGTAAAAAGTTT

AATAGGAGAAAAAAAGGCAGAAGGAGTAGTAACAAACAAAAATACTTATCAAGCTGACGCTGTTATACTTGCTACC

GGAATAAAACCTGACACTGAATTTTTAGAAACCAGCTTAAAACTACTAAAAATGGAGCAATAATTGTAAATGAGT

ATGGCGAAACTAGCATAAAAAATATTTT'TTCTGCAGGAGATTGTGCAACTATTTATAATATAGTAAGTAAAAAAAA

TGAATACATACCCTTGGCAACAACAGCCAACAAACTTGGAAGAATAGTTGGTGAAAATTTAGCTGGGAATCATACA

GCATTTAAAGGCACATTGGGCTCAGCTTCAATTAAAATACTATCTTTAGAAGCTGCAAGAACAGGACTTACAGAAA

AAGATGCAAAAAAGCTCCAAATAAAATATAAAACGATTTTTGTAAAGGACAAAAATCATACAAATTATTATCCAGG

CCAAGAAGATCTTTATATTAAATTAATTTATGAGGAAAATACCAAAATAATCCTTGGGGCACAAGCAATAGGAAAA

AATGGAGCCGTAATAAGAATTCATGCTTTATCAATTGCAATCTATTCAAAACTTACAACAAAAGAGCTAGGGATGA

TGGATTTCTCATATTCCCCACCCTTCTCAA6GAACTTGGGATATATrAAATATTGCTGGCAATGCTGCCAAAkTAG fl52.aa

MIKFEFSDRFLLFSYFVLIMFIGSLLLMLPISWEGDGKLAYIDALFTAVSAVSITGLTTVKMEGFSTFGFILIMLL

IQLGGLGFISITTFYLLIPKKKKULTDARIIKQYSLSNIEYNPIRILKSILFITFSIEMIGLILILICFKLRGVNI

SFLEPALFTTISAFCNAGFSMHiSESIYAWRDVPEAIVVVS ILIIGGLGFMVYRDVNNTIKNKKKLSLHAKIVFSLS

FFLIIIGAILFFFTEMHKLKAGYSMSTLIFNSIFYSISTRTAGFNYLDNSLISGRTQIISLPFMFIGGAPGSTAGG

IKITTFFLIVLAVVKNQNGNGYIIGSYKVSIDSIRFALLFFARAIFILSFSFFMLLFFEGGSGNWKVIDLGYEVFS

0. AFGTVGLSVGVTQDLSFWGKVI II FTMFAGRIGLFSMAVFVSRKSRFEEFTRPRQDILVG t152.a WEGDGKLAYIDALFTAVSAVSITGLTTVFEGFSTFGFILIMLLIQLGGLGFISITTFYLLIPKKKMNLTDARI 1K

QYSLSNIEYNPIRILKSILFITFSIEMIGLILILICFLRGVNISFLEALFTTISAFCNAGFSMHSESIYAWRDVP

EAIVVVSILIICGGLGFMVYRDVNN'rIKNKKKLSLHAKIVFSLSFFLI IIGAILFFFTEMHKLKAGYSMSTLI FNS 0:...:IFYSISTRTAGFNYLDNSLISGRTQIISLPFMFIGGAPGSTAGGIKITTFFLIVLAVVKNQNGNGYIIGSYKVSID SIFALLFFARAIFILSFSFFMLLFFEGGSGNWKVIDLGYEVFSAFGTVGLSVGVTQDLSFWGKVI IIFTMFAGRI

GLFSMAVFVSRKSRFEEFTRPRQDILVG

f152.nt

ATGTTGAAATTTGAATTTAGCGACAGGTTTTTACTTTTTAGTTATTTTGTTTTAATTATGTTTATAGGCTCTCTTT

TGTTGATGTTGCCTATTTCCTGGGAAGGTGATGGcAAATTAGCATAcATTGATGCTCTTTTTACTGCTGT 1

TCTGC

TGTAAGTATTACGGGCCTTACAACGGTTAAAATGGAAGGCTTTCTACTTTTGGATTTATTTTGATAATGTTGCTA

ATCCAGCTTGGGGGACTrrGGA.TTTATAAGTATTACTACTTTTTATTTGCTTATACCTAAAAAGAAAATGAATTTAA

CAGATGCAAGAATAATAAAGCAGTATTCCCTTCAAATATAGAATATAATCCTATTAGAATTTTAAAAAGCATATT

GTTATAACTTTTrCAGAATGATAGGTTTAATATATACTTATTGTTTAAACTTAGGGGAGTGAATATT TCATTCTTAGAGGCT'rGTT-TACGACAATTTCTGCTTTTTGCAATGCAGGTTTTTCCATGCATTCTGAGAGTATTT ATGCATGGCGAGATGTTrCCTGAAGCTATAGTTGTGGTCTCTATTmAATAATTTGTGGTGGGCTTGGGTTI'ATGGT CTATAGAGATGTAAATAACACTATTAAAAACAAA AAh ACTATCGCT'rCATGCCAAGATAGTTTTTTCTTTAAGC

TTCTTTAATTATAATTGGTGCAATTTTATTTTTTTTACAGAGATGCATAAATAAAAGCTGGTTATTCAATGA

GCACTTTAATATTTAATTCAATTTTTTATTCGATTAGTACCAGAACAGCTGGTTTTAATTATCTTGATAATTCTTT

AATAAGCGGAAGAACTCAAATAATTTCTCTACCATTCATGTTTATTGGTGGTGCACCCGGATCAACTGCAGGAGGG

ATTAAGATTACAACATTTTTTTAATTGTATTGGCTGTTGT-AAAAATCAAAACGGCAATGGATATATTATTGGTT

WO 98/59071 PCT/US98/1271 8 63 TABLE 1. Nucleotide and Amino Acid Sequences CTTACAAGGTTCAAAATTATGATTATGCAAGACTATTTTArTTTAAGTT=TC -TcATCrcATrTrG nGGGGA~CTGGATTGGATTAAGGTT~rATGAAGGTTAT-AAGTATTCT GCTTTGGAACGGTTGGTCCA TGGAATAG ~TCATTTTGGGCCAAGTCATTATAATTITTA CTATGTTTGCAGGACGATGG mATGTGTTTTGTTTCAAAAAGTCCGTTTTGAAGAATTTAC AAGGCCAAGGCAAGATATTT1TGGTTGGTTGA t152 .nt TGGGAAGGTGATGGCAAT'AGCATACATTGATGCTCTT1TTACTGCTGTTTCTGCTGTAAGTATTACGGGCCTTA

CAACGGTTATGGAAGGCTTCTACTTTGGATATTTTGATAATGTTGCTAATCAGCTGGGGGACTTGG

CAGTATTCCCTTTCAAATATAGAATATAATCCTATGMTAAAGAATTTTATT1TTCAATTG AAATGATAGGTTwrAATATTAATACTTATTTGTTTAAACTTAGGGGAGTGAATATI'TCATTCTTAGAGGCTTITGTT TACGACAATTTCTGCTrTTTTGCAATGCAGGTTTTCCATGCATTCTGAGAGTATTTATGCATGGCGAGATGTTCCT GAAGCTATAGTTGTGGTCTCTAT'rrTAATAATTGTGGTGGGCTTGGGTTTATGGTCTATAGAGATGTAAATAACA CTATTAAAAACAA AA A ACTATCGCTTCATGCCAAGATAGTTTTTTCTTTAAGCTTCTTTTTAATTATAATTGG

TGCAATTTTAT?'TTTTTACAGAGATGCATAAATTAAAAGCTGGTTATTCAATGAGCACTTTAATATTTAATTCA

ATTTTTI'ATTCGATTAGTACCAGAACAGCTGGTTTAATTATCTTGATAATTCTTTAATAAGCGGAAGAACTCAAA

TAATTTCTCTACCATTCATGTTTATTGGTGGTGCACCCGGATCAACTGCAGGAGGGATTAAGATTACAACATTTTT

TTTAATTGTATTGGCTGTTGTTAAAAATCAAACGGCAPATGGATATATTIATTGGTTCTTACAAGGTTCAATAGAT

AGTATAAGATTTGCACTTTTATTTTTTGCAAGAGCTATTTTTATTTTAAGTTTTTCTTTTTTCATGCTTCTTTTTT

T'rGAGGGAGGATCTGGCAATTGGAAGGT'rAT'TGATTTAGGTTATGAAGTAT'rTTCTGCTTTTGGAACGGTTGGTCT

TTCAGTTGGAGTAACTCAGGATTTIGTCATTTTGGGGGAAAGTCATTATAATTTTTACTATGTTTGCAGGACGAATA

GGGCTTTTTTCAATGGCTGTTTTTGTTTCAAGAAAGTCGCGTTTTGAAGAATTTACAAGGCCAAGGCAAGATATTT

TGGTTGGTTGA

fl54.aa

TFILLFLFTKFSFVQAQANQILTEISPLSILSKNGKGSVYLKVSKSSDYILTLDKSSNSDFVFKIDISNK

KYITDKKRDFKIRLDKNSLYAIIYWGTENIKFSLTDLDFSILSSDSLKAKTSKIEKEDLFFTLKDLPLNT

AKLKKVLRIYKSNIYIAYQLENSDDIKVAEFIEDVGWFNLDSSVNNITNIVNFDFSINSKGNLYIAFVTKSA

FASELrIFNSRWIDISPGHIEFGSLLNISIDLDRLYLAYLREIRGEYKINLISNMGYGSINTVIAYSK

GDSNNSSNIGLISEPFLGIFNKSNNEIKSEFIVNNENAWNANIPSMANFIKGFFDSNFNQIIMSVSN

***PIVNICPLKSSRWINISPNVEEGLSAIGLYKNLFLAFEDNNNVRLYFKNKNWYFLNKLENFKSNVKSPQIGI

YGNQGLVISTLSSNSNELFFTLICQ

tl54.aa NQILTEI SPLSILSKNGKGSVLKVSKSSDYILTLDKSSNSDFVFKIYDISNKYITDKVRRDFKILDKSLYA

IIYVGTKNEIKFSLTDLDFSILSSDSLKAKTSKIEKELFFTLILPNLTAKLTYLRIYKSNIYAYQLEN

SDDIKVAEFIEDVGWFNLDSSVNRNITNIVNFDFSINSKGNLYIAFVTKSGADFASELIVKKFNSRXWIDISPGHI

**ENFGSLLNISIDLKDRLYLAYREIRGEYKINLISNMGYGSIWfDVIAYLSKGDSNVNSSNIGLISEPFIY

YKSNNEIYSEFIVNNENAWNANIPSVYMANFIKGFFSNFNQIIMSFVSENRPIVNICPLKSSRWIISPVEM

GLSADIGLYNMLFLAFDNVRLIYFINWFLNKLENFKSNVKSPQIGIYGNQGLVISTLSSNSNELFFTLI

CQ

fl54.nt

ATAATATAAATATTCATTATAAATTCTTTCACCACAACA

TATTAACAGAAATTAGTCCTTTAAGTATTTTAAGCAAAAATGGGAAGGAAGTGTTTACTTAAAAGTTAGCATC

TTCATTTTAccAAAGGTAATCGTTGTTAATTTAATCATA

AAATATATAACCGATAAAGTAAAAAGAAGAGATTTTAAAATAAGATTAGATAAAAATTCTCTTATGCAATAATAT

ATGTTGGTACTAAAAATGAAACATAAAGTTTTCGCTTACAGATTTAGATTTTTCAATTTfTAAGTAGCGATCCCT

GAACAACTTAATAAAAGTTTTTTCTAAGTTCTTTAATAC

WO 98/59071 PCT/US98/1271 8 64 TABLE 1. Nucleotide and Amino Acid Sequences GCCAAGCTTAAAAAATATGTATAGTTTAAGATTTT GTATCACTAGAAAATAGCGATG ATATTAAAGTTGCTGAATTTATTGAGGATGTTGGTTGGTTTAATCTTGATTCATCTGTTAATAGAAATAT'rACTAA TATAGTTAATTTTGATT'rTTCAATTAATTCTAAGGAATTTATATATTGCTTTTGTTACG.AATCAGGGGCTGAT

TI'TGCCACGAGCTTATAGI'AAAAAATTT'AATAGTAGAAAATGGATTGATATTAGTCCTGGTCACATAGAAAATT

?I'GGATCTrrTATTAAATATACTGTTAAGTGTTGTATTTAGCATATTTAAGGGAAATTAGGGGTGA ATATAAAATTAArAATCTCGAATATGGGTACGGAAGTATTTGGACCGATGTAATACATGCTTATTTAAGTAAA, GGTGATTCTAATGT'rAATTCATCAAACATTGGTTTAATATCTGAACCT'rTTTGGGCATTrTTTATAATTATAAGT CAAATAATGAGArI'AAATCTGAATTTATTGTAAACAATGAAAATGCTTGGGTAAATGCAAATA'FrCCTTCTGTTTA TATGGCCAATTTTATTAAAGGCTTTrGATTCTAATTTTAATCAATAATTATGAGTTrGTTCTGAAAATAGA

CCTATTGTAAACATTTGTCCTTTGAAAAGTAGTAGATGGATTAATATAAGTCCTAATGTTGAAATGGAAGGTTTAA

GTGCTGACATTGGGCTTTATAAAAATAATTTGTTTTAGCTTTTGAGGACAATAATAATGTGAGATDAATTTATTT

TAAGAATAAAAATTGGTATTTTTTAAATAAGCTTGAGAATTTTAAGAGTAATGTTAAAAGCCCTCAGATTGGAATT

TATGGCAATCAAGGGCTTGTAATCTCTACTTTAAGCTCTAATTCCAATGAATTATTTTTTACTTTGATTTGCCAAT

GA

t154 .nt

AATCAAATATTAACAGAAATTAGTCCTTTAAGTATTTTAAGCAAAAATGGGAAAGGAAGTGTTTACTTAAAAGTTA

GCAAATCTTCCGATTATATTTTAACCCTAGATAAGAGTTCAAATTCCGATTTTGTTTTTAAAATTTATGACATTTC

TAATAAAAAATATATAACCGATAAAGTAAAAAGAAGAGATTTTAAAATAAGATTAGATAAAAATTCTCTTTATGCA

ATAATATATGTTGGTACTAAAAATGAAAAr-ATAAAGTTTTCGCTTACAGATTTAGATTTTrTCAATTTAAGTAGCG

ATTCCCTGAAAGCTAAAACATCTAAGATTGAAAAAGAAGATTTATTTTTTACTTTAAAAGATTTGCCTGTTTTAAA

TTTCGCCAGCTTAAAAATATGTATTAAGGATTTATAAGCAATATTATATTGCTTATCAGCTAGAAAT

AGGTAATAGTGTATTTGAGTTGTGTTATTGT*TCGTATGAT

TTACTAATATAGTTAATTTTGATTTTTCAATTAATTCTAAAGGAAATTTATATATTGCTTTTGTTACGAAATCAGG

GGCTGATTTTGCCAGCGAGCTTATAGTTAAAAAATTTAATAGTAGAAAATGGATTGATATTAGTCCTGGTCACATA

GAAAATTTTGGATCTTTATTAAATATTAGCATTGATTTAAAAGATAGGTTGTATTTAGCATATTTAAGGGAAATTA

GGGGTGAATATAAAAT'TAATTTAATCTCGAATATGGGTTACGGAAGTATTTGGACCGATGTAATACATGCTTATTT

AAGTAAAGGTGATTCTAATGTTAATTCATCAAACATTGGTTTAATATCTGAACCTTTTTTGGGCATTTTTTATAAT

TATAAGTCAAATAATGAGATTAAATCTGAATTATTGTAAACAATGAAAATGCTTGGGTAAATGCAALATATTCCTT

CTGTTTATATGGCCATTTTATTAAAGGCTTTrrTTGATCTAATTTTAATCAAATAATTATGAGTTTTGTTTCTGA

AAATAGACCTATTGTAAACATTTGTCCTTGAAAAGTAGTAGATGGATTAATATAAGTCCTAATGTTGAAATGGAA

GGTTTAAGTGCTGACATTGGGCTTTATAAAAATAAT'TTGT'rTTTAGCTTTGAGGACAATAATAATGTGAGATTAA TTTATTTTAAGAATAAAAATTGGTATT=rTAAATAAGCTTGAGAATTTTAAGAGTAATGTTAAAAGCCCTCAGAT TGGAATTTATGGCAATCAAGGGCTTGTAATCTCTACTTTAAGCTCTALATTCCAATGAA.TTAT'rTTTTACTTTGATT

TGCCAATGA

f157.aa 5 MKIFLKVIGRGILGRLMVFRIQYDYLALISLLIVSFVGILLIYSSDYNISGSLTKNEYIKQTFWVIIGFFLIFIVG *0 KYDLKFVYSMVYPLYFLLILALIFTAFFGMTVNGARSWIGIWKLGGQPSEFGKVVIILTLSKFYTEKKGYNEFFTF ITAFLLIFPSVILILLQPDFGTAIVYLTIFIFISFFAGIDLHYVLAFALIGFFSFVFAILpVWyEYKVNMGNVFYL IFSNPFYFRVIMGVLLLILLISVLGFFISK.YGLSIKI IYFYFFASSILLVSIVFSKVLSKLMCTYQIKRFLVFLD

PAIDAKGAGWNLNQVKIAIGSGGLLGKGFLXKGPYTHANYVPSQSTDFIFSILAEEFGFLGVSTILILFFFLFFKFL

IINKSQDRYMALVISGILGLLFFTSFNVGMSLGVLPITGIPFPFLSYGGSSTITFFLAMSFYFNIESIVAMD

t157 .aa

PIMYYLALISLLIVSFVGILLIYSSDYNISGSLTKEYIKQTFWVIIGFFLIFIVGKYDLKFVYSMVYPLYFLLI

LALIFTAFFGMTVNGARSWIGIWKLGGQPSEFGKVVILTLSKFYTEKGYNEFFTFITAFLLIFPSVILILLQPD

FGTAIVYLTIFIFISFFAGIDLHYVLAFALIGFFSFVFAILPVWYEYKVNMGNVFYLIFSNPFYFRVIMGV=LIL

WO 98/59071 PCTJUS98/12718 TABLE 1. Nucleotide and Amino Acid Sequences LISVLGFFISKYGLS IKIIlYFY FFAS SILL VS IVF 5KVLSKLMTYQ I~.FLVF DpAIDAKGAGWNLNQVKIAI GSGLKFKPTA

PQTFFIAEGFGSIIFFFXLINSDYAVSI

GLLFFHTSFNVGSLGLPITGIPFPFLSYGGSSTITFFLMSFYFNIESIVAMD

fl57.nt

ATAGTTCTAGTAAGCTGAATAGAATAGTTTGAAATTATT

TGCTGTACTCTTGTCTTGCACATTAATGG

ATTTACAATATTTAAAACTTGGATATGTTTCATTTTGG~

GTTTTTTTCTTTTGTTTGCAATTTTACCGGTTTGGTATATATGGTTATTATGTATTTATCTT

TCTTGCCGAAGAGTTTGGGTTTTTGGGTGTTAGCACTATT

TATTATTTTCCTTTTTATTT

tl57.nt

*ATTATATGCTGTAGTATAATTCTMTGAATGTATATT

GCATTAATATGTTTA

CTTGGAT.TGATT

TCATTTTG

TAACCTAATTTATAT

TTGGCTTTrAATTTTTACTGCATT CrGAGCGTATGGAGTGGATTGGCATATGGAAACTTG

GAGCGCTTATTGAATGTTATTACCTCAATTCCGAAAGGT

TATATTTACTATCGATTATATTTCTGTATTAATTGACTA

TTGTCGATGAATACATTAATATCTMCGATGTTCCAGT

TACTTCTGTGGTTTCTTGACGTGTTATTAGGAA

CAAGTTCTATTTTATTAGTTcTATTTTTCAGTT

GAAGACATCAGATTAAACG

GGTTCTGGCGGTC'- i CC GATIAAGACCTTATACCCACGCTAATTATGTGCCATCTCAAAGCA

CAATTTTTCATTGCAGGTGGTTTGTTACCATTAATTTTT

c*TTTTATTTATAATATAA AAAAAAAGcTAGATTTGATT

GGCTTTTTCTCTTTATTGATGCTAGGTTCTTACGATCTT

CTTCCCTTGGTCTTCATCTTTTTGATTTTTTTATTGACA

AGTTGCTATGGATTGA

f17.aa

FLLKSIFRVLISASLPTKGSNFLAFASAVKFLTYFPISKCSFSSRISSSNSL

WO 98/59071 PCTIUS98/1271 8 0 0*@e 0e 0 0 9* 0@ 00 00 0 *0*0 0* 00 0 0 0 0* 66 TABLE 1. Nucleotide and Amino Acid Sequences t17. aa PLYFVPDTKFFETLSIRIVSCSLLLIFFCTMLflARPSTIAVFPTPGSPISIALFLFLLKS IFVRVLISASLPT1KGS

NFLAFASAVKFLTYFPISKCSFSSRISSSNSL

f17 .nt

ATGATTGTGTTTTTGTTTTTTTCAATATACTTAATTATATTATTTAAACGATCTTCAACTCGCCTCTATATTTTG

TTCCCGATACCAAGTTTGAAACCTTAAGCATTAGAATTGTTTTGTCTTGTAGTTTGCTACTTATDTTTTTTTGCAC

TATGCTTGATGCAAGGCCTTCAACTATTGCTGTTTrTrCCCACACCAGGTTCGCCTATTAGCATTGCACTATTTTTA TTTCTTrCTCAAGAGTATATTTGTAAGAG.rTTTTAATCTCTGCTTCTCTTCCAACCAAGGGGTCTAATTTTTTGGCTT TTGCAAGTGCTGTTAATTTTTGACATACTrTCCAATTTCAAAGTGCTCATTTTCAAGTCGTATTTCTTCATCAAA

TTCTTTGTAG

t17 .nt

CCTCTATATTTTGTTCCCGATACCAAGTTTGAAACCTTAAGCATTAGAATTGTTTTGTCTTGTAGTTTGCTACTTA

TTTTTTTTTGCACTATGCTTGATGCAAGGCCTTCAACTATTGCTGTTTTTCCCACACCAGGTTCGCCTATTAGCAT

TGCACTATTTTTATTTCTTCTCAGAGTATATTTGTAAGAGTTTTAATCTCTGCTTCTCTCC.ACCAAGGGGTCT

AATTTTTTGGCTTTTGCAGTGCTGTTAATTTTTGACATACTTTCCAATTTCAAAGTGCTCATTTTCAAGTCGTA

TTTCTTCATCAAATTCTTTGTAG

DEKAFI(VKNLRRFSNFIRILVIVEFLNSLLSLFVFLAGSYNIFVYNFQKFYLDLAIILSSVSFGLESTRLIFFYFLK

NKKIKYYLILIFSFIIFFIALVFKIFLSGNK

YNIFVYNFQKFYLDLAI ILSSVSFGLESTRLIFFYFLKNKKIKYYLILIFSFI IFFIALVFKIFLSGNK .nt ATGAAAGCTTTTAAAGTAAAAAATCTAAGACGTTTTTCAAATTTTATT'AGAATTTTGGTTATTGTATTGTTTrTAA ATTCTTTGTTAAGTTTGTTCGTGT'rTTTGGCTGGTTCTTACAATAT -rrrGTTTACAATTTCAGAAATTTTATCT

TGATCTTGCTATTATTTTAAGCTCTGTTTCTTTTGGACTTGAATCTACTAGACTGATATTTTTTTATTTTTTGAAA

AATAAAAAAATTAAGTATTIAT'rTAATTTTAATTTTTAGTTTTATAATTTTTTTTATTGCTCTTGTTTTTAAAATTT

TTCTTTCTGGTAATAA

ATAG

.nt WO 98/59071 67 TABLE 1. Nucleotide and Amino Acid Sequences PCT/US98/1 2718

S.

*0 0 esee Oe 0@ S

S.

00 SC S S

B

e.g.

S S 0O 0 55 0 S

OS

C

5.55..

S

OCOS

TACAATAT'DTAATTTT CAGATmATTTGATCTTGCTATTATTTTAAGCTCTGTTTCTrTTGGAC TTGAATCTACTAGACTGATATTTTTTTA TGAAAAAAATATATTATTTAATTTTAATTTTTAG ~TrATAATTTTTTTATTGCTCTTGTTTAAATTCTTTCTGGTAATAAATAG f186 .aa

MKXLIIIFI'LFLSQACNLSTMHXIDTKEDMXILYSEIAELRKKLNLNHLEIDDTLEKVAKEYAIKLGENRTITHTL

FGTTPMQRIHKYQSFNLTREILASGIELNRVVNAWLNSPSHKE-ALINTDTDKIGGYRLKTTDNIDIFVVLFGKRK

t186 .aa

TMHKIDTKEDMIILYSEIAELRKKLNLNHLEIDDTLEKVAICEYAIKLGENRTITHTLFGTTPMQRIHKYDQSFNLT

REILASGIELNRVVNAWLNSPSHErALINTDTDKIGGYRLKTTDNIDIFVVLFGKRKYKN~ f186.nt

ATGAAAAATGATTATAATTTTACACTGT=ATCTCAAGCATGCATTTAAGTACAATGCATAAAATAGATA

CAAAAGAAGATATGAAAATTCTATATTCAGAAATTGCTGATGGAAAATATTAA.ACCATCTAGAAAT

AGATGATACCCT'rGAAAAAGTTGCAAAAGAATATGCC-ATTAAACT GAAATGAATATCACACCCTT

TTTGGCACAACCCCATCAGAAAAAAGATCAATCCTTTAATTTAACAAGAGAAATACTGGCATCAG

GAATTGAACTTAACAGAGTAGTTAATGCATGGCTTAATAGTCCAAGCCACAAAGAAGCTCTTATTAATACAGATAC

CGATAAAATAGGTGGCTATAGATTAAAAACGACTGACAATATAGATATATTTGTAGTTCTTTTTGGAAAAAGAAAA

TATAAGAATTGA

t186 .nt

ACATGCTAAATAATAAAAGAAATAGAAATCTATATTCAGAAATTGCTGAATTGAGAAAAAAATTAA

ATCTAAA.cr-ATcTAGAAATAGATGATAcccTTGAAAAAGTTGCAAAAGAATATGccATTAA.AcTGGGAGAAAATAG AACAATAACTCACACCCTTTTTGGCACAACCC ATCAGAAAAAAGATCAATCCTTTAATTTAACA

AGAATACTGCATAGGATGAATTAACAGAGTAGTTAATGCATGGCTTAATAGTCCAAGCCACAAAGAAG

CTCTTATTAATArAGATACCGATAAAATGTGTTGTrAAAGCGCAAAAAATTGTAGT TATAGGTGGCTATAATTAAAAACGACTGTATTATAGATrTA f196..aa MWTWAMTT..ILIAFISILFFA1GM~ISK1VDQQFNLMINLIESIKSSFNLYISSMEKVRVSSMYFNSAEK FNEASKIKS1KIJSFISDQSEILIQTGSNMMVTDKEGKIVEfrTAVKDNSDFGKSIGDREYFTKJKESNSIVYNSFVM LAnPGSIEESLLWDISKIKKGQIPYILIGPLRDFETDNIFGYFMFLYSMDYIYRSFRGINFGILSSGRALAYD

TTGRLLVHHVVLPGDILTDISASYSNIIKKTSEDLLQKKEISTVYYYDPKSNKKYVGISQKVLLNLSNNKFILLM

RTSEDDFYYMSRATTIIAISFVFTLLLAIATLYLVKKLSSSLNKILEySERLASGNFTADINFGKWDTVELYSL

YEGLEQLRTNFSSVAKGIELDYLYEAIQIANASQNLSSGAVEQASTLEQMTANIEQISQGVSETENAATTEK

IAVNTNERTKEGHKSVVKAIEAMTVITEKIGIIDEITRQTNLLALNASIEAARVGEKGKGFEVVAAEVRKLAlQSK ESAREIIDIAN .SLTVASRAGENFEQ IVPGMEQTARLVI SNESYKQSVQIEQFKNAIEQ VSQLVQTTASS S EEL

SAMSEIMLESVKDLKESVDYFKIEK

OS

S. S 0 WO 98/59071 WO 9859071PCTIUS98/12718 68 TABLE 1. Nucleotide and Amino Acid Sequences tiSE .aa

MLINSKJVDQQFNLMINLIESIKSSFNLYISSMEEKVRVSSMYFNSAEKFNEKIKSRLSFISDQSEILIQTGS

NMMTKEGKIVFTTAVKDNSDFGKSIGREYFTKLKESNSVYNSFVDPGSIEESLLDISKIKtJJYQIPY ILIGMPLRDFETDNIFGYFMFLYSDYIYRSFRGFGILSSGALAYDTGRLLVrvVLPGDILTDI

SASYSNI

IKTSEDLLQKKEISTVYYYDPKSNKKYVGISQWVLLNLSNNKFILLMRTSEDDFYYMSRATTI

ILAISFVFTLL

MLAIATLYLVLSSSLNKILEYSERLASGNFTADINGKDVELYSLYEGLEQLRTNFSSVAKcGVIENLDYLYE NIQIANASQNLSSGAVEQASTLEQMTANIEQISQGVSETENAAT'EKIAVNTNERTKEGSVVKAErVIT EKIGIIDEITRQT NLLALNASIEAARVGEKGKGFEAXRLADQSKESAREIIIANRSLTVASRGENFEQI

VPGEQTARLVKNISNESYKQSVQIEQFKNAIEQVSQLVQTTASSSEELSAMSEKMLESVKDLKESVDYFKIEK

fl96 .nt

TTGGAATGCTTATTAATAGTAATTGGTGGATCAACAGTTAATCTTATGATATCTTATTGAGCATTAAG

TTCTTTTAATCTTTACATCTCTTCAATGGAAGAGAAAGTTAGGGTTAGTTCCATGTATTTCAACTCTGCTGAJA.AA

TTTAATGAGGCTAGTAAAATTAATCCAAAGGTTGAGCTTTATTTCAGATCAATCTGAATTCT~ATCAAACCG

GTAGTAATATGATGGTTACAGACAAAGAAGGTAA-TAGTGTTTACTACGGCGGTTAAGGATATAGTGATTTTGG

CAAATCTATTGGGGATAGAGAATATTTTACAAAACTTAAGGAGTCTAATAGTATTGTTTACAATTCCTTTGTCATG

TTGGCAGATCCCGGGTCTATTGAGGAGTCTTTACTTAAAGATATTTCCAAGATAATAAAAAAGGTCAGATTC

CTTACATATTAATAGGTATGCCATTAAGAGATTTTGAAACAGATAACATTTTTGGTTATTTTATGTTTCTTTATTC

AATGGATTATATATATAGGTCTTTTAGAGGGATTAATTTTGGAATACTCTCTAGCGGTCGTGCGCTAGCTTATGAT

ACTACGGGTAGATTGTTGGTTCATCATGTAGTATTGCCAGGTGATATTTTGACTGATATTAGTGCTTCTTATTCCA

ATATTATTAAGAAAACATCTGAAGATTTGTTGCAAAAGAATAAAGAAATTTCAACTGTTTATTATTATGATCCTAA

AAGCAATAAGAAATATGTGGGAATTAGTCAAAGGTGTTATTAAACTTGTCTAATAATAAATrTATTCTTTTAATG

AGAACTTCAGAGGACGATTTATTACATGTCACGAGCTACAACTATAATCTTAGCAATTAGTTTTGTATTTACAT

TACTTATGCTTGCTATTGCAACTCTTTATCTTGTGALAAAGTTAAGCTCTTCTTTGAATAAGATACTGGAATATTC

TGAGAGACTTGCTCTGGTAATTTTACTGCTGATATTAATTTTGGCAAATGGGATACTGTAGAGCTTTACAGTTTG

TACGAAGG~cTTGAGcAGTTGAGAACCAATTTTTCTTCAGTTGCAAAGGAGT'rAT'rGATCTAGATTATCTTT

ATGAAAATGCAATTCAATAGCAATGCAAGCCAGAATTTAAGTTCTGGCGCTGTTGAGCAGGCTTCTACTTTAGA

GCAAATGACAGCAAATATTGAGCAAATTTCACAAGGTGTTTCTGAGAATACTGAAAATGCAGCTACTACTGAAAAA

ATTGCTGTTAATACTAATGAAAGGACTAAAGAGGGGCATAAATCTGTTGTTAAGGCTATTGAGGCAATGACTGTAA

TTAC GAAATGATTrAGGTAAGCAAACCAATTTGCTTGCTTTAAATGCCTCGATTGAAGC

TGCACGAGTGGGAGAAAAGGGCAAGGGATTTGAAGTGGTAGCTGCTGAGGTTAGAAAGCTTGCAGATCAAAGCAA-A

GAATCAGCAAGAGAGATTATTGATATTGCAAACAGAAGTTTAACTGTTGCAAGTCGTGCTGGGGAAMATTTTGAAC

AAATAGTTCCTGGTATGGACAACAGCCAGACTTGTAAAAATATTTCTAATGAAAGTTATAAGCAAAGTGTTCA

AATAGAGCAATTTAAAAATGCAATAGAGC-AGGTTAGTCAGTTAGTCCAAACTAr-AGCCTCAAGCAGTGAAGAGCTT

TCTGCAATGTCTGAAAGATGTTAGAGAGTGTAAAGATTTAAAAGAATCTGTTGATTATTTAAGATCGAAAAGT

AA

t196.nt ATGCrITATT~AATAGTAAATTGGTGGATCAACAGTTTAATCTTATGATAAATCTTATTGAAAGCATTAAAAGTTCTT TTAATCTTAr-ATCTCTTCAATGGAAGAGAAAGTTAG3GGTTAGTTCCATGTATTCAACTCTGCTGAAAAATTTAA

TGAGGCTAGTAAAATTAAATCCAAAAGGTT-GAGCTTTATTTCAGATCAATCTGAAATTCTTATTCAAACCGGTAGT

AATATGATGGTTACAGACAAAGAAGGTAAAATAGTGTTTACTACGGCGGTTAAGGATAATAGTGATTTTGGCAAAT

C ATGGTGGAATTCAATTAAGGAGTCTAATAGTATTGTTTACAATTCCTTTGTCATGTTGGC AGATCCCGGGTCTATTGAGGAGTCTTTACTTAAAGATATTTCCAGT AAAAGTCAGATTCCTTAC

ATATTAATAGGTATGCCATTAAGAGATTTTGAAACAGATAACATTTTTGGTTATTTTATGTTTCTTTATTCAATGG

AT'rATATATATAGGTCTTTTrAGAGGGATTAATTTTGGAATACTCTCTAGCGGTCGTGCGCTAGCTTATGATACTAC GGGTAGAT'rGTTGGTTCATCATGTAGTATTGCCAGG'rGATATTLTTGACTGATATTAGTGCTTCTTATTCCAATATT WO 98/59071 PCTIUS98/1271 8 69 TABLE 1. Nucleotide and Amino Acid Sequences ATTAGACATTGAGATTGTGCAAAAATAAGAA'TICAACTG=TATATTATGATCCTAAAAdCA ATAAGAAATATGTGGGAATT~AGTCAAAGGTGTTATAAACTTGTCTAATAATAAATTTATTCTTTr'IAATGAGAAC

TTCAGAGGACGATTMTATTACATGTCACGAGCTACAACTATAALTCTTAGCAATTAGTTTGTATTT'ACATTACTT

ATGCTTGCTATTCcAACTCTATCTTGTGAAAAGTAAGCTCTCTTTGAATAAGATACTGGAATATTCTGAGA GACTTGCTCTGGTAATTTACTGCTGATAI'AATTTTGCA

ATGGGATACTGTAGAGCTTTACAGTTTGTACGA

AGGGCTGAGCAGTTGAGAACCAATTTITTCTCAG TCAAGGTTGAAcAATTTTTATGAA

TGACGCAATATGAGCAAT~CACAAGGTGTTTCTGAG-AATACTGAAATGCAGCTACTACTGAAAAAATTGC

TGTTAATACTAATGAAAGGACTAAAAGGGGCATAAATCTGTGTTAAGGCTATTGAGGCAATGACTGTAATTACT

GAAAA~rGGATTATGATAGAAACAGGAAACCAATTTGCTTGCTN'AAATGCCTCGATTGAAGCTGCAC GAGGGGAAGCAGATGAGT GGTAGCTGCTGAGGTTAGAAGCTTGCAGATCAAAGCAAAGAATC

AGCAGAAGATATGATTTGAAAAGAGTTAATGTTGCAAGTCGTGCTGGGGAAAATTTGAACAAATA

AG TTrAATCAAAGA~~ AGTCAGTTAGTCCAAACTACAGCCTCAAGCAGTGAAGAGCTTCTGC

AATGTCTGAAAAGATGTTAGAGAGTGTAAAGATTTAAAAGAATCTGTTGATTATTTTAAGATCGAGTA

f899.a MRFIIAFLMILNQGFSNLFSLPPEDI IFESSYEVAIKKAQKLNKNVLILVGRDIKENLIKDFLNSFTNGEI

IHKVS

RKSVFLVIDKDNEIFNKINLQKSPTIIFVDSKNEQIKAYVGAVLSSVQFDKDFLNYVMGAIKSTSVLKKQKDYEI

*NTAIDERTFFYKTLKGDWLKFNGKDRKLVLFDTDLKEFLVFKDINEKLYAPKSRIGNIYFSLLGNEE

LFGKI

V. K t899.aa f899 .nt TGAGATATTAAGAAATTTATAAA GATTT TCTTGTTAAATGATCGAGTAT AGAAAAAGTGTTTTTTTAGT1TATTGATAAGGATAATGAAATTTTTAATAAAATTAATCTACAAAAAAGTCCGACTA TTTTTTGAT.A .AGAAAAGAGTAGGGGCGTTACGTTCATG TAAGGATrTTAAACTATGTTATGGGAGCTATAAAATCAACAAGTGTTTTAAAAGCAAAAAGATGAAT

AAATCGTAAACTTTTCAAATAAGGTGCATAGTATGA-GC

GAACTTCTTGTCGTTAAAATTATTTAGTTATAACACTAG

**TATTCCTAAGTCTAGGATTGGTAATATTTATTTTTCATTATTGGGAAATGAAGAATGGAAGCTTTGATA

AAATAPL

t899 .nt

TTCTCTCCCAAATATAAT

TCTTAAATGGAA

TATACAGACAAAATTTTTGTTGTAGTAGATTTAAATATT

CAAAAAGTCCGACTATTTTTTrGTTGATTCTAGAGGCATAGCAGTGAGTGTTTGA

GCGGTTTTAGGGTTAACAAGGTTAAAC

AAAG~ATAA~rATCTCTGATGAGAGAACCTTTTTAAAACATTAAAAGGTGATTGATAAG

TTTAATGGTAAGACAGAAGCTTGTCTTTTTGATACAGATCTTAAGAATTTTTAGTTTTTAAAGATATTAATG

AAAAGTTTCATCAGCTGGATAGAGA

GCTTTTTGGAAAAATAAAATAA

WO 98/59071 TABLE 1. Nucleotide and Amino Acid Sequences f924.aa PCT/US9811 2718 *Q *t 0 MQDRFSFRKFLISVFLIFIVSGITYFYSTQLEKSQKCVEDNLAVKLVDMEDFYFDLNECLNDDFFI PRPD

FLNNUKLVVDGLIKNKFLDENFFKDLWIKENLFNVIEKENEKLIDKILEISK

t924.aa

TQMLEKSQKCVEDNLDAKKLVDMEDFYFDLNECLNMDDFFIPRPDFLNENLNKNLVVDGLIKNKFLDENFFKDLW

IKKIENLFNVDIEKENEKLIDKILEISK

f924 .nt

ATGCAAGATAGAAAGTTTAGTTTTAGAAAATATTTTTAATTTCAGTATTTTTGATTTTTATTGTTTCTGGTATTA

C'ITATTTCTATTCAACACA-AATGTTGGAAAAATCTCAAAAGTGTGTTGAAGACAATTTAGACGCTAAGGTTAAATT

AGTTGATATGGAAGATTTTTATTTTGATTTAAATGAATGTCTAAATATGGATGATTTTTTTATTCCAAGACCTGAT

TTTTTAAATGAAAATTTAAATAAGAATTTAGTTGTTGATGGATTGATTAAAAATAAATTTCTTGATGAGAATTTTT

TCAAGGATCTTTGGATAAAAAGGAAAAT'rTATTTAACGTTGATATTGAGAAGGAAATGAAAAATTAATAGATAA

GATTTTAGAAATTTCCAAATGA

t924 .nt

ACACAAATGTTGGA.AAAATCTCAAAAGTGTGTTGAAGACAATTTAGACGCTAAGGTTAAATTAGTTGATATGGAAG

ATTTTATTTGATTTAAATGAATGTCTAAATATGGATGATTTTTTTATTCCAAGACCTGATTTTTTAAATGAAAA

TTTAAATAAGAATTTAGTTGTTGATGGATTGATTAAAAATAAATTTCTTGATGAGAATTTTTTCAAGGATCTTTGG

ATTAAAAAGGAAAATTTATTTAACGTTGATATTGAGAAGGAGAATGAAAAATTAATAGATAAGATTTTAGAAATTT

CCAAATGA

f925.a

MIRKYLIYISLLFIVFEVYSKPAFISQDDSYELDFSSGEVDISVNTNSKFNLSFKDESWIYIKSIENE-AFIKLIGE

SYDNGAVFTFQTFKEGKIKLVFTYQNVKDSSEFNKIIILKITKNFEVAI pQGVGGGSSRDNNIETGNNLELGGGS

ISGATSKEIIVRALNLSYINDYKGAIDLLNK'FNDDKYILLKAEIHYKGDYLKSYENYLKLKSKYFQSIVFDLI

RLAIELNIKEEVLENARYLVEKNVDFSESIYLEIFEFLVTRGEHEFALNFSSLYFPKYINSSFSDKYSYLLGKLYE

SESKHKDFLKALHYYKLVIDNYPFSYYYEAKIRYLFLKIFF

t925.aa KPAFISQDDSYELD)FSSGEVDISVNTNSKFNLSFKDESWIYIKS IENEAFIKLIGEsyDNGAVFTFQTFKKEGKIK LVFTYQNVKDSSEFNKIIILKITKFEVAIpQGVGGGSSRlNNIETGNNLELGGGSISGATSKEIIVRALNLSYIN

DYKGAIDLLNKNF'NDDKYILLKAEIHKGDYLKSYENYLKLKSKYFQSIVFDLIRLAIELNIKEEVLEARYLV

EKVFSESIYLEIFEFLVTRGEHEFALNFSSLYFPKYINSSFSDKYSYLLGKLYESESKHKDFLKALHYYKLVID

NYPFSYY.YERAKIRYLFLKRFF

f925 .nt ATG~rAAAAATTGA~TATTAATTTGCTATTTATTGTTTTTGAAGTTTACTCTAAGCCAGCTTTTATAA

GTCAAGACGATTCGTATGAGCTTGATTTTAGTAGTGGAGAGGTAGATATTAGTGTAATACCAATTCAAATTAA

TCTTTCTTTAAAGATGAGTCTTGGATTTATATCAAAAGCATTGAAAATGAAGCTTTTATTAAGTTAATTGGAGAA

WO 98/59071 PCT/US98/12718 71 TABLE 1. Nucleotide and Amino Acid Sequences TCTTAACGGTTTTCTTAA

GTTCCTT

AAATGTTAAAGATCAAGTGAATTAATAAATAATTATCTTGAAATTACAAGAATTTGAAGTTGCAATTCC

ACAAGGCGTTGGTGGTGGCTCTAGCAGGGACAATAACATTGAAACTGGTAATAATCTTGAACTTGGGGGGGGGAGT

ATTAGCGGGGCAACTCTAAGAGATTATTGTTAGGGCTAAATTTGTCCTACATAATGATTACGAGCAA

TAGATTTGCTTAATAAGTATAATTCAATGAC AAAAArTTGAGGGAAATTCATTATAAAAAG AGTATAATTAGAATrATG

GTAGATATTTATTGAT~TTATT

AGGCTGCTAAGAATAAAT TTGAATTG=l'AGAAAACGGCAGAGATTAGTTGCAAA TTG

CTCTCTTTACTTCCTAAGTATATTAATTCAAGCTTTCAGACAAATATAGTTATGTTGGGAAAACTTTATGAG

TCCTTAT

ATTATTATr.AGAGAGCCAAGATAAGATATTATTTIAAAGCGGTTTTAG t925 .nt AAGCCAGCTTTTATAAGTCAAGACGATTCGTATGAGCTTGAT'rrAGTAGTGGAGAGGTAGATATTAGTGTAAATA CCAATTrCAAAATTTAATCTTTCTTTAAAGATGAGTCTG

''AACAACTGAAGACTTTTAT

TAGTATGGACTTAACGGTTTTATTCGCTTAAAAGCAATA

TTGGTTTTCACTTATCAAATGTTAAGATTCAAG

GATATATAACTTGAAAATTACAAAGAT

TTGAAGTTGCAATCCACAAGGCGTTGGTGGTGGCTCTAGCAGGGACATAA6CATTGAAACTGGTAATAATCTTGA

ACTTGGGGGGGGGAGTATTAGCGGGGCAACTTCTAAAGAGATTATTGTTAGGGCTTTAAATTTGTCCTACATAT

TG ATAGTATTTTATAGCGA T~CTTAAAGTATA A CTTATGAAAATTATTTGAAATTGAAGAGTAAATATTTCAGCAT

TGTTTTTGATCTAATTAGGCTTGCTATAGATAATAGGGTTTTAGAGCGCTAATATAGTT

TTTATTCGAACTTTCTAACTTATCTGTAAGGAGGAGG

TTGCTTTAAATTTTAGCTCTCTTTACTTTCCTAAGTATATTAATTCAAGCTTTTCAGACAAATATAGTTATTTGTT

ATTACCCTTTTAGTTATTATTATGAGAGAGCCAAGATAAGATATTTATTTTIAAGCGGTTTTTAG

f929.aa

IIDLKGYXLSVQQNNDFEQVLAQNFSNLNAYLFIIGFDPKIKAGTILFKTQIDIDPNSYMYEDITG

*DYDFNIVQGFLDKSVLYVFQKSVLNDVSSYRPIFFKGTLINKYARSSAYEENRSRESYPISLEYEKGE

DLIISKIEYEYSNVQGRYCLSSVSEVGKINNIyKTLLSKDEVKLHGVWYDVHDYNVKIDEVJFLS

FERQSSENLFRKNSQEVAKIEYISKPAYNINVSASLFSDLIVFIKIVDKNIEIKIDTSTNSYNSGFSG

TFRDNLVKSDY~SNVKKYFYPLYDNIYINFLNFLYIMSK

VESFFLEHSERIVQKQKFSTIILNPIKILKDDVSLVKGOKLKLERIEKI

t929 .aa

KDEIFKLLFFLASVKFVNDKTSINNNLVKEFGIDKYISQ

ENNDYEVLQFNNYFIFPIAGIFTIIPNYMLDTDDNVQFK

KSLYVFQKSVUDVSSYRPIFFDKVNGTVLINKYARSSAYEENRSRESYPISLEKYEKVGDLI

ISKIEKYEYSN

VQGRYCLSSVSEKVGKIDNNIYKTLLSKDEVKFLHGWYDVDYN nDWIDEVLFLSFQSSEFK SQEVAKIEYISPAYNTLNVSASLFSDLIVYNFWIK

KNIEIKIDTSTNSYDNSGFSGTFEVLVK

GSSDIYFIPSGNrDKIYDFSYPHLTYIDEKIYYGIFNIFPLFLEYEIDMGSYLVESFFLHSEIQ

KQKFSTIILNPIKILKDDVSLVKGQKLKLERITEKI

f 929 nt WO 98/59071 PCT/US98112713 72 TABLE 1. Nucleotide and Amino Acid Sequences ATGACAAAGGTTT'rGGTTGTTAGTGCGATTGCTCTTCTGAGTAAGGATAAAGAATTAATCCCATTTTATAAATTTT

TGTTATTTTTTCTATGTGTCAGAGAAATTTGTTACAAAG

AAGACTTrCTCCAGGATCGATAATCCAAATTCCAATGTTTTAGAAGTTAATAAAATGGAAGATTTTTTTGGAGAT A~ATGATTAAGTATAATCTTT ATCGAG.ATTATTAGATGTGTATrTTGAGCAGG

TGGTTTTAGCTCAAATTTTCAAATCTTAATGCATATT'TGTTTATATTGGTTTGATCCTAAAATTAAAGCTGG

AACGAT'rCTdTAAACTCAAATAGATATTGATCCAAAAAATTCTTATAACATGTATCTTGAAGATATTACAGGT

GATTTGATTA~ATATTATCAAGATT~AAAGAAAACTGTTTTGTATGTTTTTCAAAAATCTGTTT

TAAATGATGTGTCTTCTTATAGGCCTATATTTTTGACAAAGTTAATGAACTGTTCTTATTAATAAGTATGCAAG

ATCTTCAGCT'rATGAAGAAAACAGATCAAGAGAAAGCTATCCTATTTCTTAGAAAAATATAAAAAGTGGGGGAA GATTTAATAATTA AATAAAAGAATTAATGI'TCAGGGTAGATATTGTCTTTCTTCTGTGAGCG

AAAAAGTTGGTAAAATTGATAATAATATTTATAAAACTTTAAAGAATTTAAGCAAAGATGAAGTTTATAAATTTTT

GCATGGAGTTTGGTATGATGTTCATGACTATAATAAAATGCATGTCAAAGATATTGATGAAGTTTTATTCTTGTCT

TTTGAAAGGCAATCAAGCGAGATTAATCTTTTCAGGAAAAATTCTCAAGAAGT1TGCAAAGATGAATATATTTCAA

AACCTGCTTACAATACTCTTAATGTTAGTGCAAAGTCTCTTTTTTCAGATTTGATAGTTTATAACTTTTGGATCAA

AATTGTAGATAAAGAAAACATTGAAATCAAAATTGACACTAGCACAAATTCTTATGATAATAGTGGATTTTCGGGT

ACATTTAAGAGGTTTGATGAGAATGTCTTAAATGTTAAAAAAGGGAGTAGTGATATI'TATTTTATTCCTAGTGGAA

ATTACGTGTATAAGGATAAAATTTATGATTTTDCTTACCCCCATTTAACTTATATTGATGAGAATAAAATTTATTA

TGGCATTTTTAATATTTTTCCTTTAAAAAATAATTTTGTTCTTGAATATGAGATTGACATGGGTAGTTACAAGCTT

GTTGAATCTTTTTTCCTTGAGCATAGCGAAAGAATTGTTCAAAAGCAAAAATTTTCTACAATCATTTTAAATCCTA

TTAAAATTTTAAAAGATGATGTAAGCTTAGTTAAAGGGCAAAAWPTAAAGCTTGAGCGAATAGAAAAAATATGA

t929.nt

AAGGATAAAGAATTAATCCCATTTTATAAATTTTTGTTTTTATTCTTTTTTTTTACATTACTTGCTTGTTCCAAGG

TAAGCAAAGATTTTATTGTTTTTAACAAAGATGTAAAGACTTCTTCCAGGATCGATAATCCAAATTICCAATGTTTT

AGAAGTTAATAAAATGGAAGATTTTTTTGGAGATATTATAGATTTAAAAGGTTATAAAATTCTTTCAGTTCAGCAG

GAAATTTAAATTTAGATGTGTATTTTGAGCAGGTGGTTTTAGCTCAAAATTTTTCAAATCTTAATGCATATTGT

TTATTATTGGTTTTGATCCTAAATTAAAGCTGGAACGATTCTTTTTAAACTCAAATAGATATTGATCCAA~AA

TTCTTATAACATGTATCTTGAAGATATTACAGGTGATTATGATTTTAATATAGTTATTCAAGGATTTTTAAAAGAT

~AATCTGTTrrGTATGTTT'TTCAAAATCTGTTTTAAATGATGTGTCTTCTTATAGGCCTATATTTTrTGACAAG

TTAATGGAACTGTTCTTATTAATAAGTATGCAAGATCTTCAGCTTATGAAGAAAACAGATCAAGAGAAAGCTATCC

TATTTCTTTAGAAAAATATGAAAAAGT GGAGTrAATACAATGAAAAATATGAATATTCTAAT

GTTCAGGGTAGATATTGTCTTTCTTCTGTGAGCGAAAAAGTTGGTAAAATTGATAATAATATTTATAAAACTTTAA

AG7AATTTAAGCAAAGATGAAGTTTATAAATTTT'rGCATGGAGTTTGGTATGATGTTrCATGACTATAATAAAATGCA TGTCAAAGATATT1GATGAAGTTTTATTCTTGTCTTTTGAAGGCAATCAAGCGAGATTAATCTTTCAGGAAAAAT TCTCAAGAAGTTGCAAAGATTGAATATATTTCAAAACCTGrCTTACAATACTCTTAATGTTAGTGCAAAGTCTCT

TTTCAGATTTGATAGTTTATAACTTTGGATCAAAATTGTAGATAAAGAAAACATTGAAATCAAAATTGACACTAG

CA6CAAATTCTTrATGATAATAGTGGATTTTCGGGTACATTTAAGAGGTTTGATGAGAATGTCTTAAATGTTAAAA GGGAGTAGTGATATTTATTTTATTCCTAGTGGAAA6TTACGTGTATAAGGATAAAATTrTATGATTTTTCTTACCCCC ATTTAACTTATATTGATGAGAATAAATTTATTATGGCATTTTTAATATTTTTCCTTTAAAAAATAATTT'rGTTCT

AAGCAAAAATTTTCTACAATCATTTAATCCTATTAAAATTTTAAAAGATGATGTAAGCTTAGTTAAAGAA

AATTAAAGCTTGAGCGAATAGAAAAAATATGA

f933.aa

MNLLIFVLATFCVFSSFAQANDSKNGAFGMSAGEKLLVYETSKQDPIVPFLLNLFLGFGIGSFAQGI)ILGGSLIL

GFDAVGIGLILAGAYLDIKALDGITKKAAFQWTWGKGVMLAGVTMAVTRLTEIILPFTFANSYRKLKNSNVA

GGFEPSFDVAMGQSSALGFELSFKKSY

t933 .aa WO 98/59071 73 TABLE 1. Nucleotide and Amino Acid Sequences PCTIUS98/12718 0* ND)SKGAFG14SAGEKLLVYETSKQDPIVPFLLNLFLGFGIGSFAQGDILGGSLILGFDAVGIGLILAGAYLDIKAL

DGITKKAAFQWTWGKGVLAGVVTMAVTRLTEIILPFTFANSYNRKUKSLNVALGGFEPSFDVAMGQSSALGFEL

SFPKSY

f933 .nt ATGAATAAACT rr AATTTTGTTTGGCAACCTTTTGTGTTTTTCTAGCTTTGCTCAAGCTAATGATTCTAAAA

ATGGTGCGTTTGGGATGAGTGCTGGAGAAAAACTTI'GGTTTATGAAACTAGCAAGCAAGATCCTATTGTACCATT

TTATAC rwTGGTGATGCCTTGTAGAAATTGAGTTTATT

GGATTTGATGCGGTTGGTATAGGGCTTATACTTGCGGGGGCTTATTTGGATATCAAAGCGCTTGATGGTATTACTA

AAAAGCTGCTTTTcAATGGACTTGGGGTAAGGGAGTATGTAGCAGGTGTGGTTACTATGGCTGTGACAAGATT AACAGAAATTATTCTTCCATTTACATTTGCTAATAGTTAATGAG

AAAACCTTAATGTAGCTTTA

GGAGGATTTGAACCTAGTTTTGATGTTGCAATGGGCCAATCCAGTGCTCTTGGGTTTGAACTGTCTTTCAAAAAAA

GCTATTAA

t933 .nt

AATGATTCTAAAAATGGTGCGTTTGGGATGAGTGCTGGAGAAAAACTTTTGGTTITATGAAACTAGCAAGCAAGATC

CTATTGTACCATTTTTATTGAACCTTTTTTTAGGGTTTGGAATAGGCTCCTTTGCTCAAGGAGATATTCTTGGAGG

TTCTCTTATTrCTTGGATTTGATGCGGTTGGTATAGGGCTTATACTTGCGGGGGCTTATTTGGATATCAAAGCGCTT GATGGTATTAcTAAAAAAGCTGCTCAATGGACTTGGGGTAGGGAGTTATGTTAGCAGGTGTGGTTACTATGG C GGCAATAAAAT~CTTCCATTTACATTTGCTAATAGTTATAATAGGAAGCTAAAAAATAGCCT

TAATGTAGCTTTAGGAGGATTTGAACCTAGTTTTGATGTTGCAATGGGCCAATCCAGTGCTCTTGGGTTTGAACTG

TCT'ITCAAAAAAAGCTATTAA

f940.a

MPIYIFIILIAVLLIGVNIKKIAAAANIDRHTNSTLGIDLSVGIPIFYNDLSKAYPTNLYGGIGAIKYQILN

LAIGLELRYMNFDINHSFNILNPDSSVGKIFYSVPITFSINYIFDIGELFQIPVFTNIGFSLNTYGDNNITNL

RTFDALPTI SFGSGILwNYKwAFGATASWWMFEFGNSAKAHFALVSLSVTVNVNKL t940.aa

ANIRHTNSTLGIDLSVGIPIFNDLSKAYPLYPGGIGAIKYQYHINAIGLELRYNFDIHSNILPD

SSVGKI FYS P ITFSINYIFDIGELFQIPVFTNIGF SLNTYGDRNNNITNRTFDALPTIS FGSG ILWFYA-

GATASWWMMFEFGNSAKMAHFAILVSLSVTVNVNKL

f940 .nt

ATGAAAATATA~TTTAAACTAATTGCAGTCTTGCTAATTGGTGTAAACATAAAAAAAGCGCCGCAG

CCAATATTGATAGGCATACACTCCACTTTAGGAATAGATTTAAGTGTAGGAATCCCTATTTTTAACGACTT

ATCAAAAGCTTATCCTACCAATTTATATCCAGGAGGTATTGGGGCAATAAATACCAGTACCATATACAAT

TTGATGATGATAGAAGTACTTAATACTCTTAAATATCGT

CAAGTGTAGGTAATTTTTTATAGCGTGCCTATTACATTTTCAATAAATTATATATTTGATATAGGGTTATT

WO 98/59071 PCT/US98/1271 8 74 TABL:E 1. Nucleotidle and Amino Acid Sequences TCAAATTCCAGTCTTCACAAATATAG7GGTTTTCTCTTAATACATATGGAGATAGAAACAACAATATTACAAATTTA

AGAACTTGATGCACTCCCTACATCTCTTTTGGATCTGGATTTTATGGAACTTAACTATAAATGGGCTTTTG

GAGCAACAGCATCTTGGTGGATGATGTTTGAATTTGGAAATTCTGCTAAAATGGCACATTTTGCACTTGTATCATT

ATCAGTTACAGTATGTAAATAAAMTGTAG

t940.nt

GCCAATATTGATAGGCATACACTCCACTTTAGGATAGAT~TAAGTGTAGGAATCCCTATTTTTTACAACGACT

TATCAAGCTATCCTACCAATTTATATCCAGGAGGTATTGGGGCAATAAAATACCAGTACCATATTTTAAACAA

TTTAGCAATTGGACTTGAACTAAGGTATATGTTTAACTTTGATATTAACCATTCTTTTAATATATTAAATCCAGAT

TCAAGTGTAGGTAAAATTrTTTTATAGCGTGCCTATTACATTrTCAATAAATrATATATTTGATATAGGAGAATTAT TTCAATTCCAGTCTTCACAAATATAGGGTTTTCTCTAA AGAAAAAACAATATTACAAATTT AAGAACT'rrTGATGCACTCCCTACAATCTCTTTTGGATCTGGAATTTTATGGAACTTTAACTATAAATGGGCTTTT GGAGCAACAGCATCTTGGTGGATGATGTTTGAAT'rTGGAAATTCTGCTAAAATGGCACATTTTGCACTTGTATCAT

TATCAGTTACAGTGAATGTAAATAAATTGTAG

f943.a

MKNQFLNSYFQLITTIFLISSITIAAEEITSTLKVPNGFKVEIFLNNTIEKPRGITSDQDGNIFIGSGSTFAYFVT

KNRKIYTIAKTLQKPIGIDYWDNKILYISSVDKIYVVKNVKEEINKSIKSKDYTWKMQ IFALLPKNNSQM~HSGRYI KVDSKNNKLIVNIGSQHNVKIPPKKEAVILSINLKTKKEEIVAFGVRNSVGFDFHPISNEIYFSDNGQDGLGDNI P

PDEINVITEYKEHFGFPYVFGKNQKN~YGFYNKAPKNTKFIPSIYELPAHVAPLGIHFYRGNNFPKEYINKLFIA-H

GSWNRSSPVGYKITTLDIDSKTRTARNYiKTFLYGFLKHDKSKFGRPVDI ITYYDGSILFTDDFGNKIYRVYYEKI t943 .aa

EITSTLKVPNGFKVEIFLNNTIEKPRGITSIDQDGNIFIGSGSTFAYFVTKNKIYTIAKTLQKPIGIDYWDNKLYI

SSVDKIYVVKNVEENKSIKSHKDYTW~QIFALLPNSQMHSGRYIKDSKNNKLIVNIGSQHNVKI PPKKEA 99.: VILSINLKTKKE-EIVAFGVRNSVGFDFHPISNEIYFSDNGQDGLGDNI PPDEINVITEYK-HFGFPYVFGKNQKNY GFYNKAPKNTKFIPSIYELPAHVAPLGIHFYRGNNFPKEYINKLFIAEHGSWNRSJ PVGYKITTLDIDSKTRTARN 9 YKTFLYGFLKHDKSKFGRPVDI ITYYDGSILFTDDFGNKIYRVYYEI f943.nt ATGAAAATCAATTTrTTAAATAGCTATTTTCAATTAATTACAACTATTTTCTTAATCTCATCTATAACTATTrGCAG CAGAGAATA~AAG~cATAAAAGTTCCTAATGGATTTAAAGTCGAAATTTTTTTAAACAATACAATTGAA-AA ACCTAGAGGAATCACAA.GCGATCALAGATGGAAATATATTrATAGGATCTGGAAGCACTTTGCATACTTTGTAACA AAAAAcAGAAAAATT'rATAcC-ATA GCAAAAAcCCCTGCAAAAACCTATrGGTATTGATTATTGGGATAATAAACTCT ACATATCTTCTGTCGATAAAATATATGTAG TAATTAAAGATATAACATAAAATCACATAA

AGACTATACATGGAAGAA'TTGATTTTGCCAAAAAATAATICTCAAATGCACTCAGGACGTTACATT

AAAGTAGA'ITCTAAAA-ATAACAAATTA ATAGTAAATATAGGATCCCAGCACAATGTTAAATTCCCCCAAAAAAAG

AAGCAGTAATCCTTAGTATTATTAACAAAGAAAATAGCTTTTGGAGTGAGAAACTCAGTTGG

GTTITGATTTCACCCAATTAGCAATGAAATATATTTTAGCGACAATGGCCAAGACGGATTAGGAGACAACATTCCC

CCAGATGAAATAAACGTAATAACCGATTAGAATTrG. TCCTATGTGTTTGGAAAAAATCAAAAAA ATTACGGTTTTrATAACAA.AGCACCCAAAAACACTAAGTTTATCCCATCTATTTACGAACTTCCCGCACATGTAGC TCr-ACTTGGAATACACTT~TTACCGGGGAALATAAQTTTCCAAAAGAATACATAAATAAATTATTCATAGCAGAArCAC

GGCTCGTGGAACAGATCTTCTCCTGTTGGCTACAAAATAACAACACTAGACATTGATTCTAAAACCAGAACAGCAA

WO 98/59071 PCTIUS98/1271 8 TABLE 1. Nucleotide and Amino Acid Sequences GAATTACAAGAC rTrTTGArrAA CACGACAAATCTAAATGGACGCCCTGTTGATATAATCAC

ATATTATGACGGTTCAATCTTTTACAAGATDTGATATTCGTTTACTACGAAAAGATTTAA

t943.nt

GAAATAACAAGCACACTAAAGTTCCTAATGGATTAAAGTCGAAATTTTTTAAACAATACAATTGAAAAACCTA

GAGGAATCACAAGCGATCAAGATGGAATATATCATAGATCTGGAAGCACTTTTGCATACTTTGTAACAAAAAA

CAGAAAAATTTATACCATAGCAAAAACCCTGCAAAACCTATGGTATTGATTATTGGGATAATAA6AcTCTACATA TCTTrCTGTC AAATTTTGTAATTAAAGATATACATAAAATCACATAAAGACT ATACATGGAAAATGCAAATTTTTGCACTTTGCCAAAAAATAATTCTCAAATGCACTr-AGGACGI'rACATTAAAGT AGAT'rC AAAACA~ATGAAAAGTCCAGCACAATGTTAAAATCCCCCAAAAAAAGAAGCA GTAATCCTTGATA' AACAAAGAAAATGTTTTGGAGTGAGAAACTCAGTTGGGTTTG ATTTTCACCcATAcTAATTTrACGACAATGGCCAAGACGGATTAGGAGACA-ACATTCCCCCAGA TGAAATAAACGTAATAACCGATTAGAATrIGATCCCTATGTGTTTGGAAAAAATCAAAAAAATTAC

GGT

4 TATAACAAAGCACCCAAAAACACTAAGTTTATCCCATCTATTTACGAACTTccCGCACATGTAGCTCCAC

TTGGAATACACT'TTTACCGGGGAAATAACTTTCCAAAAGAATACATAA-ATAAATTATTCATAGCAGAACACGGCTC

GTGGAACAGATCTTCTCCTGTTGGCTACAAAATAACAACACTAGACATTGATTCTAAAACCAGAACAGCAAGAAAT

TACAAGACTTTTTTATATGGATTTTTAAAGCACGACAAATCTAAATTTGGACGCCCTGTTGATATAATCACATATT

ATGACGGTTCAATTCTTTTTACAGATGACTTTGGAAATAAAATATACAGAGTTTACTACGAAAAGATTTAA

f952.aa

****YAR'AVLIVLLFFYIWFFIILKRTNLFLLEKIQNGAILDIRSPKEYSKSHYLKSINIPFNNLFAKKDKLGD

FESPIIVYGKSFNKSYEAKKVLKSMGFKNVFVAGTLKDMPQAKKEVG

t952 .aa RM1TNLFLLEKIQNGAKILDIRSPKEYSKSHYLKSINIPFNNLFAKKDKLGDFESPI IVYGKSFNKSYEAKKVLK

SMGFKNVFVAGTLKDMPOAKKEVG

f952 .nt ATAA~rTGCAGATCAGTTTA TGTCTGC r~T~ATATTTGGTTTTTTATTATCCTTAGGATGA AAAGAACTAATC o~rTAGAAAAATCCAAAATGGAGCAAAAATTTGGATATTCGGTCTCCCAAAGAATA TAGCAAGTCT AT~GA~ATACTCCTTwTTAATAATTTATTTGCTAAAAAGGATAAATTAGGTGAT TTTGAGTCCCcATATTTAGTAATTTTAATAAGTCTTACGAGGCTAAAAAAGTTTTAAAAAGCATGG

GATTTAAGAATGTGTTTGTTGCTGGAACCTGAAAGACATGCCACAAGCAAAAAAAGAAGTTGGTTGA

t952.nt AGGATGAAAAGAACTAATcTGTTTTGTAAAAAAATCCAAAATGGAGCAAAATrTTGGATATTCGGTCTCCCA

AAGAATATAGCAAGTCTCATTATTTGAAGTCATTAACATTCCTTTATAATTATTTGCTAAAAAGGATAAATT

AGGTGATTIrGAGTCCCAATAATTGT'TrATGGTAAAAGTTTTAATAAGTCTTACGAGGCTAAAAAAGTTTAA AGCATGGGATTTAAGAATGTGTTrTGTTGCTGGAACCTTGAAAGACATGCcACAAGcAAAAAAAGAAGTTGGTTGA WO 98/59071 PCTIUS98/1271 8 76 TABLE 1. Nucleotide and Amino Acid Sequences f378 .aa MIKKFLLFAMLNIFLTNKAHSNEEIIEISTEIQKEKYIPFLISRGKTQL~FLVKTLEINPELDNYVNTVAKTyI

DESLIEGVNDIAYAQMLLETGALKFNGIVSKEQFSGIGATNLTKNSFSNITEGIAHIQHLKAYASKQNIK

SDMPRFYLVRGSAPTLTGKWAKDKLYDKKLXILTELLTEYNNANKS

t378.aa

NEEIIEISTEIQKKYIPFLISRGKTQLEDLVKYTLEINPELDKNYVNTVAKTYIDESLIEGVNYDIAYAQMLLET

GALKFNGIVSKEQHN.FSGIGATNNLTKGNSFSNITEGIKAHIQHLKAYASKQNIKSNMVDPRFYLVKRGSAPTIYD

LTGKWAKDKLYDKKLIKILLELLEYNNANKS

f378 .nt

ATGATAAAAAATTCTTGCTATTTGCAATGCTCAACATCTTTTTAACAAATAAAGCTCATAGTAATGAAGAGATAA

TCGAAATAAGTACT AAAAAGAAATTTCCCTTTTTAATAAGTAGAGGAAAAACTCAACTAGAAGA

GACGAATCTTTGATTGAAGGGGTTAATTATGACATTGCCTATGCTCAAATGTTACTAGAM\CAGGAGCTCTAAAAT

TCAATGGAATAGTTTCAAA.AGAACAACACAATTTTTCAGGAATAGGCGCTACTAATAATCTTACAAAAGGAAATTC

TCAAATATGGTTGATCCTAGATTTACCTTGTTAAAAGAGGATCTGCTCCAACAATATATGATTTGACTGGGAAAT

GGGCAAAAGACAAACTTTACGACAAAAAACTTAAAAAAATATTATTAGAACTATTAGAATATAATAATGCAAATAA

AAGCTAA

t378.nt AATGAAGAGATAATCGAAATAAGTACTGAAATACAAAAGGAAAAATATAI"1CCCTTTTTAATAAGTAGAGGAAAAA CTCAACTAGAAGACCT'rGTAAAATATACTCTAGAAATAAATCCAGAGCTTGACAAAAACTATGTAAATACTGTTGC

TAAACCTATATAGACGAATCTTGATTGAAGGGGTAATATGACATTGCCTATGCTCAAATGTTACTAGAAACA

GGAGCTCTAAAATTCAATGGAATAGTTTCAAAAGAACAACACAATTTTTCAGGAATA:GGCGCTACTAALTAATCTTA

CAAAAGGAAATTCTT'TTTCCAATATTACAGAAGGAATTAAAGCTCATATTCAACATTTAAAAGCTTATGCTTCAAA

ACAAALATATCAAATCAAATATGGT'rGATCCTAGATTTTACCTGTTAAAAGAGGATCTGcTCCAACAATATATGAT TTGACTGGGAAATGGGCAAAAGACAAACTTTACGACAAAAAACTTAAATTTTrGATATTAGAATATA

ATAATGCAAATAAAAGCTAA

f4 .aa MKLFRRN.VMI KMPSS FT IIFSL IVFVTILTYVI pAGK FDKEFKQMGDGSKREiIvAGTyQyvDRGSRGF LH PIMT I

LTAMSKGDMEAVEVIVFVLIVGGAYGIIMKTGAIDVGIYFLIKKLGHKDKLLIPLLMFIFSIGGTVTGMSEETLPF

YFVMIPLIVALGYDSLVGAAIIALGAGVGTMASTVNPFATGIASAIAS ISLQDGFYFRIVLYFVSVLAAITYVCVY

ASKIKDPSKSLVYSQKDEHYQYFVKKGLSTGDNAQNALEFTFAHKLVLLLFGFMILILIFSIVNLGWWMQEMTM

LYLGVAIISAFICKLGETEMWDAFVKGSESLLTAALVIGLARGVMIVCDDGLITDTMLNAATNFLYNLPRPLFI IL NEIIQIFIGFVVPSSSGHASLTMPIMAPLADFLS IPRASVVIAMQTASGLINLITPTSGVIMAVLGISRLSYGTWF

KFVLPLFMIEFFISILVIIANIYLSF

t4. aa WO 98/59071 PCTIUS98/12713 77 TABLE 1. Nucleotide and Amino Acid Sequences KFDKEFKQMGDGSKREI IVAGTYQYVDRSRGFLHPIMILTAMSKGEHAVEVIVFVLIVGGAYGIMTGAIDV GIYFLIKLG=~KLIJIPLLMFIFSIGGTVTGMSEETLPFYFVMIPLIVALGYDSLVGAI

IALGAGVGTMASTVN

PFATGIASAIASISLQDGFYFRIVLYFVSVLAAITYVCVYASIDPSKSLVYSQKEHYQYFVKDGLSTGDNA

QNALEFTFALVLLLFGFILILIFSIVNLGMQEMTMYLGVAIISAFICKLGETEMWDAyVKGSESLLTAL VILRVICDLTTLATNLNPPFINIQ

GVVSSHSTPMPAFSP

RASVVIAMQTASGLINLITPTSGVIAVLGISRLSYGTWFKFVLPLFMIEFFISILVIILITrLSF f4.nt

ATGAAATTATTAGGAGAAACGTTATGATCAAAATGCCAAGTAGTTACAATAATATTTTCTTTAATTGTATTTG

TTACCATTTTAACGTATGTGATTCCTGCCGGTAAGTTTGATAAAGAATTTAAGCAAATGGGTGATGGATCTAAAG

GGAAATAATTGTTGCTGGAA.CTTATCAATATGTAGATCGAGGCTCTAGGGGATTTTI'ACATCCTATTATGACTATT

TTAACCGCAATGTCAAAGGGGATGGAACATGCAGTTGAAGTTATTGTTTTTGTTTTAATTGT'rGGGGGTGCTTATG GGATTA'rTATGAAACTGGAGCAATAGATGTGGGAATTTATTTTTAATCAAGAAGTTGGGGCACAAAGATAAGTT GCT'rAICCTTGTTAATGTTTATTTTTCAATTGGTGGAACTGTAACCGGAATGAGTGAAGAGACCCTTCCTTTT TATTTGTATGATTCCCTTGATAGTAGCTTTGGGITATGATAG 1TCTTGTTGGAGCGGCTATTATTGCTTTAGGAG

CTGGAGTGGGAACTATGGCTTCTACTGTAAATCCATTGCGACAGGATTGCATCTGATAGCTTCTATTAGCTT

GCAGATGATTTTTTAGAATGTCTTTATTTTGTATCAGTATTGGCTGCTATAACCTATGTTTGTGTTTAT

GCGTCTAAATTAAAAAGGATCCCTCAAAATCGCTTGTGTATTCTCAAAAAGATGAACATTATCAATATTTTGTTA

AAAAGATGGACTTTCTACCGGAGATAATGCTCAGAATGCTCTTGAGTTTACTTTGCTCATAATTAGTTTACT

=ATGATAGTTGTTGTTTGATGTACTGTGGAGAGATAAT

TTGTATCTTGGAGTTGCTATTATATCGGCTTTTATTTGTAAATTAGGTGAA.CTGAAATGTGGGATGCGTTTGTGA

AAGGTTCTGAAAGTCTGCTAACCGCTGCTCTTGTTATTGGACTTGCTAGAGGTGTTATGATAGTATGTGATGATGG

GTTGATTACAGATACTATGTTAAATGCTGCTACTAATTTrTTTATACAATCTTCCAAGACCCCTTTTTATCATATTG AATGAAATTATTCAAATATTTATAGGATTTGTTGT'rCCATCTTCATCAGGACATGCTAGTCTCACTATGCCAATAA

TGGCTCCTCTTGCCGATTTTTTGTCAATTCCAAGAGCTTCAGTTGTTATTGCCATGCAGACTGCATCTGGGCTTAT

TAATTTGATAACACCTACCAGCGGAGTTATAATGGCTGTATTGGGGATATCCAGATTGAGTTATGGTACGTGGTTT

AAGTTTGTTTTACCATTTTATGGTrTTATCTCTATTT-TAGTTATTATAGCTAACATTTATTTAAGTT

TTTAG

t4.nt

AAGTTTATAAGAATTTAAGCAAATGGGTGATGGATCTAAAAGGGAAATAATTGTTGCTGGAACTTATCAATATG

TAGATCGAGGCTCTAGGGGATTTACATCCTATTATGACTATTAACCGCAATGTCAAAGGGGATGGAACATGC

AGTTGAGTTATTGTTTTGTTrAATTGTTGGGGGTGC TTGATTAGAATGGAGCAATAGATGTG GGATT~rTATCAGAATTGGGCAAAAGTAATTGCTATTCCTTrTGT'rAATGTTTAITTTrTTCAA TTGGTGGAACTGTAACCGGAATGAGTGAAGAGACCCTTCCTTTTTATTTTGTTATGATTCCCT'rGATAGTAGCTTT GGGTTATGATAGTCTTGTTGAGcGGcTATTATTGCTTAGGAGCTGGAGTGGGAACTATGGCTCTACTGTAAAT CCATTTGCGACAGGAATTGCATCTGCAATAGCTTCTATTAGC TcGTGTTA''TGATTTCTTT ATTTTGTATCA6GTATTGGCTGCTATAACCTATGTTTGTGTTATGCGTCTAAATTAAAAAGGATCCCTC~aAATC GCTTGTGTATCTCAAAAAGATGAACATTATCAA6TATTTGTTAAAAAAGATGGACTTrTCTACCGGAGATAATGCT CAAATGCTCTTGAGTTTACTTTGCTCATAATTAGrTT'rACTTTTATTGGATTTATGATATTGATTTTGATAT TTGATTATTGTGTGTCAAArAATTGACTGGTCATTTGCT

TATTGTAATTGGTAAATGAAATGTGGGATGCGTTTGTGAAAGGTTCTGAAAGTCTGCTAACCGCTGCTCTT

GTTATGGACTTGCTAGAGGTGTTATATAGTATGTGTGATGGGTTGATTACAGATACTATGTTAAATGCTGCTA

CTAA6TTrATACAATCTTCCAAGACCCTTTTATCATATTGAATGAAATTATTcAATATTATAGGATTTGT

TGTTCCATCTTCATCAGGACATGCTAGTCTCACTATGCCAATAATGGCTCCTCTTGCCGATT'TTTTGTCAATTCCA

AGAGCTTCAGTTGTTATTGCCATGCAGACTGCATCTGGGCTTATTAATTTGATAACACCTACCAGCGGAGTTATAA

TGGCTGTATTGGGGATATCCAGATTGAGTTATGGTACGTGGTTTAAGI-rTGTTTTACCATTATTTATGATrGAGTT

TTTTATCTCTATTTTAGTTATTATAGCTAACATTTATTTAAGTTTTTAG

WO 98/59071 PCTJUS98/1271 8 78 TABLE 1. Nucleotide and Amino Acid Sequences f 43. aa MKYFYFLFFLLIFNVYAQNVNSpALPSPPLJPEITENKPVERENSSKGENFSNVGLlGKYVNIDTILYGLDSQVTS

I

IKLKSSYFLKLKFALRIEFILYGIT=EYSRSAFLIYK

DKEKLTLIDILENEGNVVSIAAYYLGELNSLEYSNOVFEKYSGNDGARILIALGKSAVYQDRIYEI

SLDNYEGPS IKAAAIEALSYLASDKVTENAflLYLQSNNNNLNVKLAI IASLSKDPSLKSKEILQGFLRDSD)DNIRF KAINAIKGHRDSSAKDILIYKLKSDPSLKVREASAKALIDMDLGNIEIKN'IMFDFKIDNNFKSMySYLLnDSLK ALS IAT EIVNKENINRP SNVLRGVASMLAGKKGNFDNFYSKI IDSKNI DLRHLALKGAVYNKS SSLSDKLXKIKSE

TNSEYILU=Y

t43 .aa

LPSPPLLPEITENKPVERENSSKGENFSNVGLDGKYVNDTILYGLDSQVTSIIKALKKSSDSQYNFSLKKRLEKTF

NAELKREILELFISLYSGGIDTANYILENYSKRYSNALFGLAISYLKEFDDKEKLKKTLIDILENKEGNVSIA

AYYLGE-LNSLEYSKNUMMEVEKYSGNDGARREILIALGKMSAVDYQDRIYEISLDNYEGPSIKAAAIEALSYLASD

KTENADLYLQSNNNNLNVKLIIASISKDPSLKSKEILQGFLRDsrDDNIRFKAINAIKGHRDSSAKDILIYKLKS

DPSLKVREASAKALIDMDLGNIEIKIMFDFKIDNFKISMFSYLLDKDSLKSIALEIVNKENINRPSNVLRGV

ASMLAGKKGNFDNFYSKI IDSKNIDLRHLALKGAVYNKSSSLSDKLKKIKSETNSEYIKMLLKDY .0 f43.nt

ATGAAATACTTTTATTTTTTATTTTTTTTACTTATTTTAATGTGTATGCTCAAAATGTTAATTCTCCAGCTCTTC

CTAGTCCGCCTTTGTTGCCCGAAATTACAGAAAATAAGCCTGTTGAGAGAGAAAATTCTTCTAAGGGAGAGAATTT

TTCTAATGTTGGTTTAGATGGTAAGTATGTTAACGATACAATTCTTTATGGGCTTGATAGTCAAGTGACAAGCATT

ATAAAAGCTCTTAAAAAATCAAGCGATAGTCAATATAATTTTTCTCTTAAAAAAGACTTGAGAAAACTTTTAATG

CTGAGCTTAAAAGGGAA)ATACTTGAATTGTTTATTTCTCTTAAGTATTCGGGGGGCATTGATACAGCAAATTATAT

TCTTGAAAATTATGAGAGTAAAAGATATTCAAACGCTTTATTTGGCTTGGCAATTTCGTATCTTAAGGAGTTTGAT 7

GATAAAGAAAAATTAAAAAAAACTCTTATTGACATTCTTGAAAATAAAGAGGGCAATGTGGTATCTATTGCAGCTT

ATTATTTAGGAGAGCTTAATTCTCTTGAGTATCTAAAAACATGATGGAAGTTTTTGAAAAATATTCTGGAAATGA

TGGGGCTAGAAGAGAAATACTTATTGCTCTTGGAAAAATGTCCGCTGTTGATrATCAGGATAGAATTTATGAAATT

TCGCTAGATAATTACGAGGGCCCATCAATTAAGGCTGCTGCAATCGAAGCGTTGTCATATCTTGCTTCAGATAAAG

TAACTGAAATGCTGATTTGTATCTTCAGAGTAATAACAATAATTTAAATGTTAAATTAGCTATTATTGCTTCTTT

GTCCAAAGATCCT'rCTTTAAAGTCTAAAGAGATTrTTACAAGGAT'rTTTAAGAGATTCTGATGATAATATTAGGTTT AAAGCTATTAATGCAATCAAAGGACATAGGGACTCTTCTGCAGArTTTATAAGTTAAAAGCGATC

CATCTCTTAAAGTTAGGGAGGCTTCTGCTAAGGCCTTAATTGATATGGATCTTGGGAATATTGAGATAAAAAACAT

TATT~IrGA~r'AAGTTGCAAAATTTAAATTCAATGTTTAGTTACCTTTrAGATAAGGATTCTCTAAAA GCATTGTCAAT'rGCTTTAGAAATTGTTAAAAAAATAAACCTCAAATGTTTTAAGGGGCGTTGCTT CAATGTTGGCTGGTAAAAAGGGTAAT'rTTGATAATTTTTATTCTAAAATCATTGAcAGCAAAAATATTGATTTAAG

GCATTTAGCATTAAAAGGAGCTGTTTATAATAAATCTTCATCGCTTTCTGATAAGCTAAAAAAATTAAAAGTGAA

ACGAACTCCGAATATATTAAAATGCTTT'rAAAAGATTATTGA t43 .nt C'rrCCTAGTCCGCCTTTGTTGCCCGAAATTACAGAAAATAAGCCTGTTGAGAGAGAAAATTCTTCTAAGGGAGAGA

ATTTTCTAAGTTGGTTTAGATGGTAAGTATGTTAACGATACAATTCTTTATGGGCTTGATAGTCAAGTGACAA.G

CATTATAAAAGCTCTTAAAAAATCAAGCGATAGTCAATATAATTTTTCTCTTAAAAAAAGACT'rGAGAAAACTTTT

AATGCTGAGCTTAAAAGGGAAATACTTGAATTGTTTATTTCTCTTAAGTATTCGGGGGGCATTGATACAGCAAATT

ATATTCTTGAAAATTATGAGAGTAAAAGATATTCAAACGCTTTATTTGGCTTGGCAATTTCGTATCTTAAGGAGTT

WO 98159071 PCTIUS98/12718 79 TABLE 1. Nucleotide and Amino Acid Sequences TGAG~TAAGAAA~rAAAAAACCTTTTGCATCTTGAAAATAAAGAGGGCAATGTGGTATCTAT'rGCA GC rTATAGAACTATTCTTGAGTATTCAAAAGTGAGTTGAATTCTGGAA ATGATGGGG TGAAAAA~TGTCTTGGAAAAATGTCCGCTGTTGATGAAATTTA AATTCGCTAGATAATACGACGCCcATCAATTAAGGCTGCTGC.AATCGAAGCG?1'GTCATATCTTGCTI'CAGAT -AAGTAACTGAAAATGCTGATTTGTACTA TAACAATTATTAATGTATTATTGCTT GTTTAAAGCTATAGATAAG AAGATCTTCTGCAAAGGA.TATTTTGATTTATAAGCTTAAAAGC

GATCCPLTCTCTTAAAGTTAGGGAGGCTTCTGCTAAGGCCTTIAATTGATATGGATCGGATTAAAAA

ACATTATGT ~AGTGCATATTATrfCAATGTTAGTTACCrTTAGATAAGGATTCTCT

AAAGCATTGTCAATTGCTTTAGAATTGTAATAAAGAAATATAATAGACCCTCAAATGTTTAAGGGGCGTT

GCTT-CAATGTTGGCTGGTAAAAAGGGTAATTTTGATAATTr'rTATTCTAAAATCATTGA-CAGCAAAAATATTGATT

TAAGCATTACATAAAGGGCGTTTIATAATAAATCTTCATCGCTTCTGATAAGCTTAAAAAAATTAAAAG

TGAAACGAACTCCGAATATATTAAAATGCTTTTAAAAGATTATTGA

IfKFVLNNLFKGCLICFFLFFSCLTDRSIQDSHI SDIVEKKKEAVIIDDNNVVLGSNEGKFKRflYLIGLKDNESFF

LSDAFLKENNFYFKKARESYAKKNIGLTNYYLNKIVTNENQHSRELLAKANLFFGYVNYENGFYDLSEYNFDLFLK

DYKYSHASLLKYLVKEKSDAISAFKEINEFSISGYDREIYGFLSNKLGVSHLNLESLGFLDNSVFDTFVFN D

NVQVLLAVIKNGIFVGTLNSGLWFYDLKNKNIPLGSKISSLCFDSLKNLLLVGTVDKAIYSVNVDNLKKIEHLDF

*FSKNDNEKNINFIKEYKflSYFVGTYGGGLFELNLNKNSYKKHVIANNIDVNYFMDMEIKDKKLLFATFDHGLLIYD

CLTTDRSIQDSHISDIVEKKKEAVIIDDNNVVLGSNEGKFKRDYLIGLKDNESFFLSDAFLKENNFYFKKARESYA

KI=GLTNYYLNKIVTNENQHSRELLAKLFFGYVNYEGFYDLSEYNFDLFLKDYKYSHASLRLAELKYIVF

SDAISAFKEINEFSISGYDREIYGFLSNKLGVSHNESLGFLDNSVFDTFVFNDNIFVTNILGGLLRYN1KDC RVYLKCKSIFLNGIRGFADYNGTIYIGGVVYYIDDVDGDLKQINVPGNAlFSNVQVLLAVKNGIFVGTLNSGL

WFYDLKNWKNIPLGSNKISSLCFDSLKNLLLVGTVDKAIYSVNVI)NLKKIEHLDFFSKNDNEIKJNFIKEYKDSYF

VGTYGGGLFELNLNNSYKVIANNIDVNYFMMEIKDKLLFATFDHGLLIYDSENNWDYFGPNNGLLNLNLI

KVSRFENY-VILGTINNGLVFVDENIKKQL

ATGAAATTTTTGAATTTTAAG TTATATGTTTTTTCTTGTTTTTTTCCTGCCTTACTACAG ATAGATC ArAGTCCTTATAATTGGAAAAAGATATATTGATGATAATA TGTTGTTCTTGGGATAGTA rAGAGTT~AAGTAAAAATACTrn'r CTTAGTGATGCTT AAGAAA~rTATTA ACcAGGGAAAGTTATGCTAAAAAAAATATTG GCTTA AT~rGAAAATATAATGAGAATrAGCACAGCAGAGAATTGCTAGCTAAAGCA.

TTGTTGAAGAATTAATTTTT TATGATCTTTCCGAATATAATTGATCTATTTAA

GACTATAAATATTCTCATCTAGTTAAGATTAGCTGAATAAAATATCTTGTTAAAGAAAATCTGATGCAATTT'

C TTTTAGTTTAGATAC

TGATATATAATAATTTGATCTGCAACTTTAAATGCTATA

AAAATGACATTTGGGG

CACT

AGGATAAAAAAAGCATTTTTAAATGGCATrAGGGGTTTTGCGGATTATAATGGAACAATTTATATTGGTGGTAA

AAATGTTGTTTATTATATAGATGATGTTGATGGGGATTTAAAGCAAATAAATGTTCCCGGTAATGCTGATTTTAGC

AAGAAGTTCTCGTAATGAATTTGCCCAATTGTAGTTAGT

TAAAAATTGGAAAAATATACCGCTTGGATCTAATAAAATTTCTTCACTCTGCTTTGATAGTTTAAAAAATTTATT

WO 98/59071 PCTJUS98/127 18 TABLE 1. Nucleotide and Amino Acid Sequences

ATTAGTTGGAACAGTTCACAAGG-CTATTTATATGTTAATGTCGATAATTGAAAAAG-ATTGAACATTTGGATTTT

TTTGCAAAAGATATGAAAAATTTATTTATAAAAA.ATAAGAAGTATTTGTTGGAACATATG

GTGGGGGTCTTTTTGAATTAAATTTAAATAAAAATAGTTACAAAAAGCACGTTATTGCCAATAATATTGATGTTAA

TTATTTATGTTG TAAGTAAGTATTGTTTGCAACCTrTGATCATGGGTTrATTGATTTATGAT TCTGAAATGACAACTGGGATTATTTGGACCCAATAATGGGCTTCTTAA'rGAATTTAATAAAAGTTTCTAGAT

TTGAAAATTATGTCATACTGGGCACTATTAATAACGGTTTGGTTTTTGTAGATGAAAATATTAAAAAA.CAGTTATG

A

.nt

TGCCTTACTACAGATAGATCTATTCAAGATTCTCATATTAGTGATATTGTAGAGAAGAAAAAGAAGCAGTCATTA

TTGATGATAATAATGTTGTTCTTGGGAGTAATGAGGGTAAATrTAAAAGAGACTATTTGATAGGATTAAAAGATAA

TGAATCTTTTTTTCTTAGTGATGCTTTTTAAAAGAAAATAATTTTTATTTTAAAAAAGCCAGGGAAAGTTATGCT

AAA.AAAAATATTGGCTTGACAAATTIATTAT'ITGAATAAAATAGTAACTAATGAGAATCAGCACAGCAGAGAATTGC

TAGCTAAAGCGAATTTGTTTTTGGATATGTAAATTATGAGAATCGGTTTTTATGATCTTTCCGAATATAATTTTGA

TCTATTTTAAAAGACTATAA-ATATTCTCATGCTAGTTTAAGATTAGCTGAATTAAAATATCTTGTTAAAGAAAAA

TCTGATGCAATTTCTGCATTTAAAGAGATTAATGAATTTTCTATCTCAGGTTATGATAGAGAGATTTATGGCTTTT

TAAGTAATAAACTTGGAGTAAGTCATTTAAACTTAGAGTCTTTAGGATTTCTTGACAACAGCGTTTTTGATACATT

TGTCTTTAATGACAATATATTTGTAACTAATATATTGGGAGGGCTTTAAGATATAATATTAAAAAAAATGATTGT

AGAGTCTATCTTAAGGATAAAAAAAGCATTTTTTTAAATGGCATTAGGGGTTTTGCGGATTATAATGGAACAATTT

ATATTGGTGGTAAAAATGTTGTTTIATTATATAGATGATGTTGATGGGGATTTAAALGCAAATAAATGTTCCCGGTAA

TGCTGATTTTAGCAATGTACAAGTTTTGCTTGCTGTTAAAAATGGAATATTTGTTGGCACTCTAAATTCTGGATTA

TGGTTTTATGATTTAAAAAATTGGAAAAATATACCGCTTGGATCTAATAAAATTTCTTCACTCTGCTTITGATAGTT

TAAAAAATTTATTATTAGTTGGAACAGTTGACAAGGCTATTTATAGTGTTAATGTCGATAATTTGAAAAAGATTGA

ACATTTGGATTTTTTrAGCAAAAATGATAATGAAAAAAATATTAATTTTATAAWGAATATAAAGATAGTTATTTT GTTGGAACATATGGTGGGGGTCTTTrTGAATTAAATTTAAATAAAA.ATAGTTACAAAAAGCACGTTATTGCCAATA

ATATTGATGTTAATTATTTTATGTTGGTAAGTAAGTATTGTTTGCAACCTTTGATCATGGGTT

ATTGATTTATGATTCTGAAAATGACAACTGGGATTATTTTGGACCCAA6TAATGGGCTTCTTAATTTGAATTTAATA AAAGTTTCTAGATTTGAAAATtATGTCATACTGGGCACTATTAATAACGGTTTGGTTTTTGTAGATGAAAATATTA

AAAAACAGTTATGA

MHIFIWVPFQINLILFLLVSVAKINASSKFYYAEQJYVIFNSQMKKKPENYKKNIFFLQKALKYPFGNPKYSLTKI

ETKEQWEKYKLLFKMHVNLLLVRQNLHLGDLFDTRNLYFFKTPEKDGII SNLE.KSKKLYKLAINY-YSEALKYHKKL YTTVKLENDGITNWEDEYHKISLKELNYYI IKXELLRIDETKAFFEQGPNYY KINASSKFYAEQWYVIFNSQMKKPEKKIFFLQKALKYPFGNPKYSLTKIETKEQWEKYKLLFMHVrNLLLV

RQNJHLGDLFDTRNLYFFKTPEKGIISNLEKSKKLYKAINYSEALKYHKKLENYTTVKLENDGITNWEDEYHK

ISLKELNYYDIIKKELLRIDETKAFFEQGPNYY

.nt

ATGCATATTTTCAAAAATGTCCCCTTCCAAATAAATTTAATTTTATTTCTTTTAGTATCAGTTGCAAAGATAAATG

CATCGTCCAAATTTTATTACGCAGAACAATGGTATGTAATTTTTAATTCTCAAATGA A CCTGAAAACTA

TAAAAAAAATATATTTTTTCTTCAAAAAGCCTTAAAATACCCATTTGGAAATCCAAAATATTCTCTAACTAA-AATA

GAAACCAAAGAACAGTGGGAAAATATAAACTTCTTTCAAAATGCATGTAAACTTGCTTCTAGTTAGGCAAAAT

TACATTTAGGAGATTTATTCGACACAAGAAATTTATATrTTTTCAAAACTCCAGAAAAAGATGGAATTATTTCCAA TCTAGAAAA.ATCAAAAAAATTATATAAACTAGCTATTAArI'ACTACAGCGAAGCACTAAAATACCACAAAAAACTT GAAAATTAr-ACAACTGTTAAACTAGAAAACGATGGAATAACAAACTGGGAAGATGAATATCATAAAATTTCTCTTA WO 98/59071 PCT/US98/12718 81 TABLE 1. Nucleotide and Amino Acid Sequences AAGAGCTTAATTACTAGCTA AAAGATACTAAG AATTGACGAAACTAAACATTrTTTGAACAAGG

GCC-AACTATTATTAA

.nt -KINSSKFyyAEQwIFSQXKKPMWUIFFLQKALKYPFGNPKYSLTKIETKEQWEKYKLLFKIVNLLLV

RQNLHIGDLFDTRNLYFFKTPEKDGIISNLEKSKKYKLAINYYSEALKYHKLEYT'IVKLENDGITNWEDEYHK

ISLKELNYYlI IKKE-LLRIDETKAFFEQGPNYY f8.a MKNINL~ILLILTTHTLLFSCALIAlNKSKNLSTSEIILTQKTLLESSLIIPSNVEYRIPISSIQEILNNNNDSF

LIKKTAAKIKISPQKLEEIKNYNAYLNETEWIKFIDQSSVNGNLTIKIDTAFEKKTNFNHTNSI)NELTEL

IE-LQMHLEKEILNLIEQTFHDKNLGYIQLSHINSFFPQENINSITKEIDGKEYAPHIIANQLLKIKDKKYFEQF

MHFLICVENSKIKTI IEKQKISDLHELYYSKQSPPRRRKRSTAflSDNNNKYDIIPKIIDPNTGIEITPKNLRSILS NGDIILIKPKIDWTEFFYFWQHVGIFDEEKYE.ATKKIAFNGIDSFDIKSI ITSNQIKFDTASTQGSGYEKLSTYVQ SRILKIFSPITDIRTIQKA GRSRYIDNNFGY4VPLISSNLWTDSFNLEEIHNKTYCSLMVDRIYKIAGLNVSR

NYEISGIITPGEINAAYNFYMSYTIAGILPSVLPKRLIKPTLKEKFIGYNKEIVDAIELKKSKEKIFGRACNITN

LWCSGS

t8.aa CALIADNKSKNLSTSEIILTQKTLLESSLIKNIPSNVEYRI PISSIQEILNNNDSFLIKKTAAKIKISPQKLE-EIK

NLNAYKNYLNNETEWIKFIDQSSVNGNLTIKIDTAFEKKTNMNFINSDNENLTELIELQMHLEKEILNLIEQTFH

DKNLGYIQLSHINSFFPQENINSITKEIIDGKEYIAPHI IAQLLKIKDKKYFSQFMHFLKVENSKIKTI IEKQKI

SDLHNELYYSKQSPPRRRKRSTADSDNNNKYDIIPKIIDPNTGIEITPKNLRILSNGDIILIKPKIDWTEFFYFW

QHVGIFDEEKYEATKKIAFNGIDSFDIKSI ITSNQIKFDTASTQGSGYEK=STYVQSRILKIFSPITDIRTIQKAI

NFGRSRYIDNNFGYMVPLISSNLWTDSFNLEEIHNKTYCSLMVDRIYKITAGLNVSRNYEISGIITPGEINAAAYNF

YMSYTTIAGILPSVLPKRLIKPTLKEKFIGYNKEIVDAIELKKIFGACNITNLWCSGS

f8.nt ATAAGATATAATGATTATATATTATATAATACACACACTTTATTATTrCTCTTGTGCCTTAATTGCAG

*ATAATAAGTCAAAAAATTTAAGCACATCAGAAATCATATTAACACAAAAAACACTACTAGAAAGCTCTTTAATAAA

.**AAATCCTTCTAATGTAGAATATCGAATACCAATATCCAGTATC AGArrrACAACAGTCTTITT TTAATAAAAAAAACAGCAGCAAAAATCAAAATAAGCCCTCAAAAACTTrGAAGAAATAAAAAACTATCTAAATGCTr ATAAAAATTATCAAATAAAATGAAAT AAACAAAGTAGCGTCAATGGAAATTTAACAAT TAAAATTGATACTGCTTTTG(A A AACAAATTTTrAA.TCATACAAATTCAGATAATGAAAATTTAACAGAACTA ATAG-AACTrACAAATGCATCTGGAAAAAGAAATTTTrAAACTTATAcAcTTAGTAATTGA ATATACAATTAAGTCACATCAACTCATTCrTTCCTCAAGAAAATATAAACTCAATAACAAAAGAAATAATAGATGG AAAGAATATATTGCACCGCACATAATAGCAAAT CAATTATAAAAGTAATTTACAT

ATGCACTTTTTAAAAGTTAACGAATAAAAAATG.AAAAAATCAGATCTTCACAATG

AACTGTATATTCAAAACAATCCCCGCCCAGAAGAAGAAAAAGGTCAACTGCCGATTCCGATAATAACAATAAA-TA

CGATATAATACCAAAAATAATAGACCCAAATACAGGCATTGAAATAACTCCTAAAAATTTAAGATCTATTTITATCA

AATGGCGACATAATACT AATAACAAAATGTGAAGk TTA'TTTGGCAACATGTGGGAATAT TTGATGAAGAAAAATATGAAGCCACTAAAAAAATTGATATGA'rATGTITGATATAAAATCAATAAT T~cCCATCAATCAT'CGATACAGCATCTACTCAAGGT~CAGGATACGAAAAGCTTTCAACATACGTACAA

TCA~AATAAATA~TCACATAAAAAGACA'CAAGTATTAATTTTGGAAGAAGTA

GATACATTGACAATAACTTTGGATATATGGTTCCATTAATATCCTCTAATTTATGGACAGATTCATTCAATCTTGA

AGAAATTCACAACAAAACCTATTGCTCTTTAATGGTTAAATTTAATCAGCTTAATGTATcAAGA WO 98/59071 PCTr/US98/12718 82 TABLE 1. Nucleotide and Amino Acid Sequences

AATTACGATATCGGGAATAATTACTCCTGGAGAATAAATGCAGCAGCTTACAATTTTTACATGTCTTATACGA

TTGCAGGAATACTTCCAAGCGTGCTTICCAAAAAGGCTCATTAAACCAACATTAAAAGAAAAATTCATTGGTTACAA

TAAAGAAATAGTAGATGCAATAGAATTAAAAAAATCGAAAGAAAAAATTTTTGGGAGAGCTTGCAACATTrACAAAT

CTCTGGTGCTCAGGAAGTTAA

t8.nt

TGTGCCTTAATTGCAGATAATAAGTCAAAAAATTTAAGCACATCAGAAATCATATTAACACAAAAAACACTACTAG

AAAGCTCTTTAATAAAAA6ATCCTTCTAATGTAGAATATCGAATACCAATATCCAGTATCCAAGAAATTTTAAACAA TAACAATGAT'rCTTTTTATAAAACGACAATCAAAATAAGCCCTCAAAAACTTGAAGAAATAAAA

AACTATCTAAATGCTTATAAAAATTATCTAAATAATGAAACAGAATGGATAAAGTTTATAGATCAAAGTAGCGTCA

ATGGAAATTTAACAATTAAAATTGATACTGCTTTIGA AAA AA A AACAAATTTTAATCATACAAATTCAGATAATGA AAATTTAACAGAACTAA6TAGAACTACAAATGCATCTGGAAAAGAAATTTTAAACTTAATT1GAGCAAACATTTCAT

GATAAAAATTTAGGATATATACAATTAAGTCACATCAACTCATTCTTTCCTCAAGAAAATATAAACTCAATAACAA

AAGAAATAATAGATGGAAAAGAATATATTGCACCGCACATAATAGCAAATCAATTATTAAAAATAAAAGATAAAAA

ATATTTTGAACAATTTATGCACTTTTTAAAAGTTGAAAACAGCAAAATAAAAACAATAATTGAAAAACAAAAAATT

TCAGATCTTCACAATGAACTGTATTATTCAAAACAATCCCCGCCCAGAAGAAGAAAA.AGGTCAACTGCCGATTCCG

ATAATAACAATAAATACGATATAATACCAAAAATAATAGACCCAAATACAGGCATTGAAATAACTCCTAAAAATTT

AAGATCTATTTTIATCAA6ATGGCGACATAATACTAATAAAACCAAAAATAGATTGGACAGAATTTTTTTATTTTTGG

CAACATGTGGGAATATTTGATGAAGAAAAATATGAAGCCACTAAAAAAATTGCATTCAATGGAATTGATAGCTTTG

ATATAAAATCAATAATTACAAGCAATCAAATCAAATTCGATACAGCATCTACTCAAGGTTCAGGATACGAAAAGCT

TTCAACATACGTACAA6TCAAGA.ATATTAAAAATATTCTCACCAATAACAGACATAAGAACAATTCAAAAAGCTATT

AATTTTGGAAGAAGTAGATACATTGACAATAACTTTGGATATATGGTTCCATTAATATCCTCTAATTTATGGACAG

ATTCATTCAATCTTGAAGAAATTC-ACAAcAAAAccTATTGCTCTTTAATGGTTGATAGAATATATAAAATAGCAGG

ACTTAATGTATCAAGAAATTACGAAATTTCGGGAATAATTACTCCTGGAGAAATAAATGCAGCAGCTTACAATTTT

TAC-ATGTCTTATACGATTGCAGGAATACTTCCAAGCGTGCTTCCAAAAAGGCTCATTAAACCAACATTAAAAGAAA

AATTCATTGGTTACAATAAAGAAATAGTAGATGCAATAGAATTAAAAAAATCGAAA6GAAAAAATTTTTGGGAGAGC

TTGCAACATTACAAATCTCTGGTGCTCAGGAAGTTAA

f82 .aa MTRVFSKFFLFFCFSMLLFANSEDSNEKDIVSKDENPVFENEVLGYWVGYNDVSNIKMSI IYIYKYNGEVYGRILT IIKDGKKYDAKNIPSGDTVVGFENLAIEGLDFMWGLKYSSSSKKWDRGKI IDPKNGKIYNSEMRVDSKTGNLITKGK

VWIFGRSKIWTRAKDDEIPKLDLHMLVPA.PPVKK

t82.aa

EDSNEKDIVSKDENPVFENEVLGYVGYNDVSNIKNSIIYIYK!NGEVYGRILTIIKDGKKYDAKNPSGD)TWGFE

NLAIEGLDFMWGLKYSSSSKKWDRGKIIDPKNGKIYNSEMRVDSKTGNLITKGKVWIFGRSKIWTRAKDDEIPKLD

LHNLVPAPPVKK

f 82nt ATGACTAGAGT'rTTTTCAAAGTTTTTTCTTTTTTTTGTTTTTCAATGCTTTTATTTGCAAATTCAGAAGATTCAA ATGAAAAGGACATTGTTAGCAAGGATGAAAACCCTGTTTTTGAATGAAGT =TAGGATATTGGGTTGGTTATAA TGATGTAAGTAACATAAAGAATTCTATTATCTATATTTATAAATATAATGGGGAAGTTTATGGCCGAATTrTIAACT

ATAATAAAAGATGGCAAAAAGTATGATGCTAAAAATCCTTCAGGAGATACTGTAGTTGGGTTTGAAAATCTTGC-

TAGAGGGTCTTGATTTTATGTGGGGTCTTAAGTATTCTTCTTCTTCTAAAAAGTGGGATAGGGGCAAA6ATAATAGA WO 98/59071 PCTJUS98/I 2718 83 TABLE 1. Nucleotide and Amino Acid Sequences

TTGTTICCAGCGCCCCCTGTGAAAAAATAA

f82.nt

AAGTTAAATGAAAAAGATGTGCAAAGATGATAAAAGTTCTAATAAGTTTAGTATGGG

AATCTTGCAATAGAGGGTCTGATTATGTGGGGTCTTAAGTATTCTTCTTCAATGTATAGG~c

AATAAACTAACGAATTTATTGGTCTTGTGAACGAACTTA

CAAGGGGAAAGTTTGGATTTTTGGTAGAAGTAAAATGGACAAGAGCTAAAGATGATACAACTTAGAT

T1'GCATAATCT'rGTTCCAGCGCCCCCTGTGAAAAAATAA f 86.a IASGITQPNNKLKGSGYTIDSVI INENQNINHSYNIILKKGNYTLINRIHKILTSKKINNKIKSDSTIEIEAKNI

S

.EIIENKLDKNILSEAITTFI NNFLKNTI NMLEFLNNL

NIKELIQIIQAAQKINKLNGELILEEIDGNQN

t86.aa LKTDQSFNNSLSESKnEIADIYPTTNFLTGIGIVAGLAGGDSIKQKLIIKILEEMIINEIGSNNIESKNI ALVN-VSLQVKGNTIKGSKHKACVASILDSKDLTNGILLKTNLKNKEGEIIAIASGITQPNNKLKGSGYTIDSVI

IN

ENQNINHSYNIILKKGNYTLINRIHKILTSKKINNKIKSDSTIEIEAKNISLLEEIENIIETNPKILIDKKNGII

LASENAKIGTFTFSIEKDNQNIFLSNKTTIOVNSMNEFILKSNLSNKELIQIIQAAQKINKLNGELILEE

IDGNQN

f86.nt AATAAAATTTTAAAGGA~rGAATAGACGGGACTTGCTGGAAAGCCTATAAAACAAAAGAC C rTAT.-TGAATA.AAT

AGAATCAAAATATTAACCACAGTTATAATATAATTCTTAAAAAGGAAATTATACATTAATAAATAGAATTCATAA

AAATACCCGrGAATGATGACAAAAAG C ACCAT

TACATAATCAATGACTTC-TTCTGAAGCACAAATTTAGA

AATAAACAATCATACCAGATTATATTTTAkATCACACTG

AAAAATATCATATAGTCCAAATATATAAGGACTTTGAGA

TTGATGGAAACCAAAATTAA

t86.nt WO 98/59071 PCT/US9811271 8 84 TABLE 1. Nucleotide and Amino Acid Sequences CTA.AAAACAGATCAATrCATTTAACAATAGCCTATCTCGa-aAXCGTAAAATTAAAAGAAATTGCGGATATTTATCCCA

CAAATACAAATTTTTTAACAGGTATTGGAATAGTAGCGGGACTTGCTGGAAAAGGAGACTCTATAAAACAAAAAGA

CCTTAATA.AT TGAAACAAATATAAAGTCTAATAACATAGAAAGTAAAAATATT

GCACTAGTAAATGTCAGTCTCCAAGTAA.AGGTAATACAIATCAAAGGTTCAAAACATAAAGCTTGCGTTGCATCAA

TACTGGACTCAAAAGATTAACAAATGGAATACTTTTAAAAACAAATCTTAAAAATAAAGAGGGGGAAATAATAGC

-AATTGCATCAGGAAT'rAcAcAGCCCAATAATAA.M'TAAALAGGATCTGGATATACTATAGATAGTGTAATAATAAAT

GAGAATCAAAATATTAACCACAGTTATAATATAATTCTTAAAGATAACTATATGATCATA

AAATATTAACCTC AAAACAACAATATAAACCAAAAAAGAAAAAACATAAG ccTATGAAGTGAATAAATAGAAACCAACCCCAAGATATAATAGACAAAAAAAATGGTATTATT

TTAGCAAGTGAAAATGCAAAATAGGAACTTTTACAI'TTCATAAAAAACAAATTTTAAGTA

AAAATAACAAAACAACAATTCAAGTAAACTCAATGAAATTAAATGA.ATTTIATATTAAAAAATTCCAACAATCTTAG

CAATAAAGAATTAATTCAATAATTCAAGCTGCGCAAAAATTAATAAATTAA.PTGGGGAACTTATCTGGAGGAA

ATTGATGGAAACCAAAATTAA

MCPITFTIPFFLAIFFAFSSSFVTDSSVSLLSRNTSLFSTLTPISLP IISGTLPAIVTLSKKYLSISLSFSM4IFI

KSLFEVIKLPIWLFIIFASGYFLNAFSIFLCISSFLSFMFI

9 SSFVTDSSVSLLSRNTSLFSTLTPISLPIISGTLPAIVTLSKKYLSISLSFSKMIFIKSLFEVIKLPIWLFIIFAS

GYFLNAFSIFLCISSFLSFMFI

ATGTGTCCTATTACTTTTACCATTCCATTTTTTCTAGCAATATTTTTTGCTTTTTCAAGCTCCTTTGTTACGGACT

CTTCTGTGTCTTTGCTATCAAGAAATACGTCTCTTTT'rTCTACTTTAACTCCAATTTCTTTGCCTATTATTTCTGG TACGcTTCCTGCAATAGTTrACGCTGTCGAAAAAATATcTGTCAATCTcTTTAAGCTTTTCTAAAATGATTTTCATC

AATCTTTATTTGAGTGATTAAACTTCCCATATGGTTATTCATTATTTTTGCATCAGGATACTTTTTAAAGTT

TTTCGAT'TTrTTGTGTATTTCTTCTTTTTTATCTTTTATGTTTATATGA .nt

AGCTCCTTGTTACGGACTCTTCTGTGTCTTTGCTATCAAGAAATACGTCTCTTTTTTCTACTTTAATCCAATTT

CTTTGCCTATTATTTCTGGTACGCTTCCTGCAATAGTTACGCTGTCGAAAAATATCTGTCAATCTCTTAAGCTT

TTCTAAATGATTTTCATCAAATCTTTATTGAAGTGATTAA6ACTTCCCATATGGTTATTCATTATTTTGCATCA GGATAcTTTTTAAATGCTTTTTCGATTTTTTTGTGTATTTCTTCTTTTTTATCTTTTATGTTTATATGA f469.aa

MAVALSSGFISQKIFGIIIIMFLPTIIATPIINFLFKINSGLKELPIDQNTICVSFEYDNLILWF<

EIRKEGFFTQQIDSSQYINARNISFSIKREGSKITFECPLIIIQDLFRETILLEKITKETVSLRAK

KLDYSINDKILSNINLNKRIKXEIILELKSSNKADVIRELLSVINIEIDKERIFQDLEREKLITTAKEGFAI

PH KTNLJISKIHIAIGISHEGIDFNALDKNJSHVF IL ILC PAXDYVSYPRI LASWGKVDLYKKEI LNAICTDKEIY NlIVSZ t469.aa WO 98/59071 PCTIUS98/12718 TABLE 1. Nucleotide and Amino Acid Sequences P~ISFSIKEGSKITFECPNLIIIQDLFRETILNLEKITKEETVSLRpKLDYSINYDKILSNNNRIK KNI ILELKSSNKAVIRPTLSVINEIDERIFQDLMEREKLITTALKGFAIPHLKTNISIEAIGISHEGI DFNALDLSHVFILILCPAKDVSYPRIASVGKVDLYKXEILNAKTDKE=yNIVSZ f469 .nt

ATGCAATGA~CTTTCTCAGATTATACCAAAAAATATTGGAATCATAATAATAATGTGTT="GC

CAACAATCATTGCAACACCCATAATAAACTT TATAATATA~TGGACTTAAAAAAGAACTCCCAA.T AGATCAAAATACACACATATGCGTACT

CTAGTATAGCCATTCTTATATGGGACTAAAT

GAGTTAAGAAAAGAAGGATTTTTAAACArrAATATTTCACAATATATTAATGCAAGAAAAAACA

ATATATCCTTCTCAATAAAACGAGAAGGTAGCAAAATCACATTTGAATGCCCATAATCATT'TAATTATAATACA

AGATCTT1rGGAAATTAACTAGAAAAAATAACCAAAGAAGTTGAAACAGTCTCTTTAAGAGCAAAA AAACTAGATTACTCAATAAATTACGATAAAATCCTTAGTAATATCAACCTAAATAAAATAAAG

A

TTATTCTAGAATTA.ATCAAGCAATAAGGCTGATGTAATAAGAGAGCTTCTAAGA

ACTTAAATTGA

TAAAGAAAGAATATTICCAAGATT ATGAGGAATATACTACTGCACTAAAAGAAGGCTTTGCCATT

CCCCATTTAAAAACAAATTTAATATCAAAAATACATATTGCAATAGGAATAAGCCATGAGGGAATTGACTTTAATG

CTCTTGACAAGAACTTAAGTCATGT~ITTATATTAATACTGTGCCCAGCAA.AGATTACGTTAGCTACCCTAGAAT

TTTAGCATCTGTTGTGGGCAAAGTTGATCTGTACAAAAAAGAAATTTAjATGCAAACAGATAAAGAAATTTAT

AATATAATAGTGAGCTAA

t469.nt *TTTTTGCCAACAATCATTGCAACACCCATAATAACTTTTTATTTAATAAATAAAGTGGACTTAAAAA6GAAC

TCCCAATAGATCAAAATACACACATATGCGTATCATTTGATATGATAATTTAGCCAAAATTCTTATATGGGACTT

TAAAAATGAGTTAAGAAGAGATTTAAAATT AATATCTTCACAATATATTAATGCAAGA

AAAAACAATATATCCTTCTCAATAAAACGAGAAGGTAGCAAAATCACATTTGAATGCCCAAATAATCATTTAATTA

TATCAACTTAAA6CACTACTGAAATACAAAGTAAATTTTA

AGCAAAAAAACTAGATTACTCAATAAATTACGATAAAATCCTTAGTAATATCAACCTAAATAAAAGAATAAAAAAG

GAAAACATTATTCTAGAATTAAAA6TCAAGCAATAAGGCTGATGTAATAAGAGAGCTTCTAAGCGTAATAAACATTG TGCCATTCCCCA A.AArATTAAATCT~GAT~ATACCATGAGGGAATTGAC

TTAATGCTCTTGACAAGAACTTAAGTCATGTTTTATATAATACTGTGCCCAGCAAAGATTACGTTAGCTACC

CTAGAATITTTAGCATCTGTTGTGGGCAAAGTTGATCTGAAAAGAA'TAAGCAAAAACAGATAAAGA

AATATATATATAGGAGTAA

f477.a *MEKPQGVSIVGAISGAfrLAYGVPVLHTDHCAPLLWVEGLLEYGEKYYSQHKKPLFSSHMLDLSEEPI

KEIEISKKFL.MAIEMFLEIELGITGGEEDGVDNSDRALHLSTPDIYYGYSELLKVSPNFQIAAAFGNVH

GVYKPGNLTPKLKDGDYVISKTGVNMAKPVSYVFHGGSGSTIDEINEALSYGVVKMIDDTQWAAWEGVLN

YYKKESRLQGQLGDGKDIDIPNKK1FYDPRVWLREAEVSMDRVKAC4UNINR.NZ t477.aa NHVHsMEHYGVPVVLHTDCAKNLLPWVEGLLEYGECYYSQHKXpLFSSHMLDLSEEPIKENIEISKKFLERMAK IEMFLEIELGITGGEEGVDNSDRALHELFSTPEDIYYGYSELLKVSpNFQIAAAFGNVGVyXpGNVKLTPKVLK DGQDYVISKTGVNMAKPVSYVFHGGSGSTIDEINEALSYGVV~mIDTDTQWAAWEGVLNyyKKNESRLQGQLGD)G

KDIDIPNKKYDPRVWLREAEVSMDRVKIACGTLNNINBNZ

f477 .nt ATGGAAAAACCACAAGGAGTTTCAATAGT'rGGAGCTM'TTTCTGGTGCTATGCATGTTCATrTAATGGCAGAGCATT ATGGTGT'rCCTGTTGTCTTCATACTGATCACTGTGCTAAAATTTGCTTCCTTGGGTTGAAGGCCTTTTAGAATA TGGAGAGAAATACTATAGTCAGCACAAAAAACCATTATTTTC-TTCACATATGTTAGATTTATCAGA6AGAACCTATTI WO 98/59071 PCTIUS98/12713 86 TABLE 1. Nucleotide and Amino Acid Sequences

AAGAAATATGAATTTCTAAAAAATTCTTAGAAGAATCGGCAATTGAATGTTTTGGAATAGAGCTTG

GATAGGGGAGGAGATGCATAGTGGTTCTACATTTCCTAG

TATTTATTATGGATATTCAGAACTTTTAAAGTTAGCCCAAATTTTCAGATTGCAGAGCTGAATGTTCAT

GGGAAAACGGAGTACTCCAAATTAAGTGCAATTTAACAA

CAGGAGTAATATGGCTAAGCCAGTCTTATGTTTTCATGGAGGTCTGGATCTACAA TTGATAT AG

TAATAT'PAAGTAGAATTAAGAAGTAGTCAGAAACTTAGTGAGAAAC

t477 .nt ATGCATGTT ATATGAACTAGGTGTTCCTGTTGTTCTTCATACTGATCACTGTGCTAAAAATTTGC TTCCTTGGGTTGAAGGCCT ITGAATGGGATACTTAGTCAGCACAACCATTATTTTCTTCACA TATGTTAGATTTATCAGAAGAACCTATTAAAGAAAATATrGAAATTTCTAAATTCTTAAAGAATGGCAAA

ATGATTTTGATGGTGATAGGTGGAAGTGGTAATCGTGGT

TGCATGALACTATTTTCTACTCCTGAGGATATTTATATGGATATTCAGAACTTTTAAGTTAGCCCAA6TTTTCA GATTGCAGCAGCTTTTGGAATGTTCATGGGGTATATAACCGGGGAATGTTAAGCTTACTCAAGTTT'rAAA

GATGGTCAGATTATGTCATATCAAAAACAGGAGTAATATGGCTAAGCCAGTTTCTTATGTTTTTCATGGAGGGT

CTGGATCTACAATTGATGAGATTAATGAGGCGCTTTCTTATGGCGTTGTA.GATGATATGACACAGATACACA

GTGGGCTGCCTGGGAGGGTGTTTTAAATTATTACAAAAAAAATGAAAGTCGTTTGCAAGGTCATTAGGAGATGGC

AAGGATATTGATATTCCAAATAAGAAATTrTTATGATCCAAGGGTTTGGTTAAGAGAAGCTGAAGTTTCTATGAAAG 0* e ACCGTGTGAAGATTGCATGCAAAAATCTTAATAATATTAATAGAAATTAAL f488.aa 0* e* TGKGSVVIRARYHIEERAEDRNAIIVTEIPYTVKSALLMKVALLAKEEKLEGLLDIRDESDREGIRIVLEVKRGF DPHVIMLLYEYTEFKKHFSINNLALVNGIPKQLNLEELLFEFIEHRKNI IERRIEFDLRKAKEKAHVLEGLNIAL

NNIDEVIKIIKSSKLAKDARERLVSNFGLSEIQANSVLDMRLQKLTALEIFKLEEELNILLSLIKDYEDILLNPVR

IINI IREETINLGLKFGDERRTKIIYDEEVLKTSMSDLMQK-NIVVMLTKGFLKRLSQNEYKLQGTGGKGLSSFD LNDGDEIVIALCVNTHDYLFMISNEGKLYLINAYEIKDSSRASKGQNISELINLGDQEEILTIKNSKlLTDDAYLL LTTASGKIARPESTDFKAVKSRGvVIKLNDKDFVTSAEIVFWEKVICLsXXGSAFIFNSRDVRLTNRGTQGVCG MKL=GDLFVKVLSVKENPYLLIVSENGYGKRLNMSKISELKRGATGYTSYKKSDKKAGSVVDA-IAVSEDDE ILL V so. S'KRSKALRTVAGKVSEQGKDARGIQVLFLDNDSLVSVSKFIKZ t488.aa MATNMAPHNLREICDAIVYI4LDNENASIFDLLKIVKGPDFPTFGEIVYNDNLIKAYKTGKGSvvIRARYHIEERAE so DRNAIIVTEIPYTVNKSALLMVALLAKEEKLEGLLDIRDESDREGIRIVLEVKRGFDpHvIMLLYEYTEFKKHF SINNLALVNGIPKQLLEELLFEFIEHRKNI IERRIEFDLRXAKEKAHVLEGLNIALNNIDEVIKt IKSSKLAXDA RERLVSNFGLSEIQANSVLDMRIQKLTALEIFKLEEELNILLSLIKDYEDILLNPVRIINI IREETINLGLKFGDE RRTKIIYDEEVLKTSMSDLMQKENIVVMLTKKGFLKRILSQNEy= QGTGGKGLSSFDLNnGDEIVIALCVNTHDYL

FMISNEGKLYLINAYEIKDSSRASKGQNISELINLGDQEEILTIKNSKDLTDDAYLLLTTASGKIARFESTDFKAV

KSRGVIVIKLNDKDFVTSAEIVFKDEKVICLSKKGSAFIFNSRDVRLTNRGTQGVCGMKLKEGDLFVKVLSVKENP

YLLIVSENGYGIKRLNMSKISELKRGATGYTSYKKSDKAGSVVDAIAVSEDDEILLVSKRSKALRTVAGKVSEQGK

DARGIQVLFLDNDSLVSVSKFIKZ

f488.nt

ATGCCGTCATCATTTCCATTTCTTTTGGTAAATGGCTCTAGTGGAATTGCTGTTGGAATGGCTACTAATATGGCAC

CTCATAATTTAAGAGAAATTTGTGATGCCATTGTT1TACATGCTAGATAATGAGAATGCTTCTATATTTGATTTGCT TAAAATAGTTAAAGGGCCTGATTTCCCAACTTTTGGAGAGATrGTTTATAATGATAArTTTAATTAAAGrCATACAAA

ACTGGCAAGGGAAGTGTTGTTATTAGGGCAAGATATCATATTGAAGAAAGAGCAGAAGATAGAAATGCTATAATTG

TTACAGAAATACCTTATACGGTAAATAAATCTGCACTTCTTATGAAAGTTGCGCTTTTAGCAAAAGAAGAAAAGCT

AGAAGGACTTTTAGATATAAGAGATGAATCTGATCGAGAAGGTATTAGGATAGTTCTTGAAGTTAA6AAGAGGATTT WO 98/59071 PCTIUS98/12718 87 TABLE 1. Nucleotide and Amnino Acid Sequences GATCCTCATGTTATTATGAATTTGCTr'rATGAATATACTGAA?rTAAAAAGCAT-Tr'AGTATAAATAATTTAGCcC TTGT'rAATGGTATCCCAAACAGTTAAATTTAGAAGAATTGTTATTTIGAATTTATTGAGCATAGAAAAAATATTAT CGAAAGACGTATTGAAT?1'GACTGAGAAAGGCAAAAGAGAAAGCACATGTTCTTGAGGGATTAAATATTGCTTTA

AATATAAGAGAGTI'TTAGATTATAAACACTAAATTAGCAAAAGATGCAAGGGAGAGGCTTGTTTCGA

ATTTTGGTCTTCAGAGATTCAGGCCAATTCAGTT1CTTGATATGAGGTTAcAAAAACTTACAGCCCTTGAGATTT TAAGC TAGGACTAAATGTTAAGC TAAA~TAGAAATTCTTGAATCCAGTAAGG ATT~rATA~ATAGAAAGAATATTAATTTAGGTTGAAATTGGCGATGAACGTCGAACTAAAATAATTT

ATGTGAGAGTTTAAAACTGTAGTGGATTAATGCAAAAAGAAAATATTGTTGTTATGCTTACAAAGAA

AGGTTTCCITrAAAAGACTTTCACAAAATGAGTATAAATTGCAAGGTACGGGAGGAAAGGACTAAGTTCGTTTGAT CTAATGATGGAGATG.AGATTGTTATTGCTTTGTGTGTCAATAC CTATTTTTATCAAATGAAG GAAAGCTTTATTA6TCATGCTATGAAATAAAAGATTCTTCAAGAGCTCAAAAGGTCAGAATATTAGTGAGCT TATTAATTAGAA AAGATTACATAATGA~ATrATGATGATGCTTATTTATTG CTT ATCATGAGTGTAGATTCGAATCTAAATTAACGAATCACGAGGTGTTATTG TTATTAAACTGAATGATAAAGATTTTGTACAAGTGCAGAGATTGTTTAGAGAAATA

GTCTTTC

TAAAAAGGGTAGTG A~TTTTATAG GTTAGGCTTAcTAATAGAGGTACCCAAGGTGTTITGTGGA

ATGAAATTAAAGAAGGTGATTTGTTGTTAAGTTTTATCGGTTAAGAAATCCTTATCTT'TGATTGTTTCTG

AAAATGGGTATGGAAAAAGGTAAACATGTCTAAAATATCTGAGCTTAA.AGAGGAGCCACTGGTTATACTAGTTA

TAAAAAATCTGATAAAAAAGCGGGTAGTGTTGTTGATGCTATAGCAGTTTCAGAGGATGATGAAATCTTGCTTGTA

AGTAAACGTTCAAAAGCTTTAAGAACAGTAGCTGGAAA.AGTATCTGAACAAGGCAAAGATGCTAGAGGAATTCAAG

TATTATTTCTTGATAATGACAGCTTGGTTTCTGTTTCAAAATTTATTAAATAA

t488.nt ATGGCTACTAATATGCACCTCATAATTr'1AAGAGAAATTTGTGATGCCATTGTTTACATGCTAGATAATGAGAATG

CTTCTATATTTGATTTGCTTAAAATAGTTAAAGGGCCTGATTTCCCAACTTTTGGAGAGATTGTTTATAATGATAA

TTTATTAAGCTACAAATGGCAAGGGAAGTGTTGTTATTAGGGCAAGATATCATATTGAAGAAAGAGCAGA

GATAGAATGCTATAATTGTTACAGAATACCTTATACGGTAAATAATCTGCACTTCTTATGAAGTTIGCGCT

TAGCAAAAGAAGAAAAGCTAGAAGGACTTT1AGATATAAGAGATGAATCTGATCGAGAAGGTATTAGATAGTTCT TGAAGTTrAAAAGAGGATTTGATCCTCATGTTATTATGAATTTGCTTTATGAATATACTGAATTTAAAAAGCATTT

AGTATAAATAATTTAGCCCTTGTTAATGGTATTCCCAACAGTTAATTTAGAAGAATTGTTATTGATTTATTG

AGrATAGAAAAAATATTATCGAAAGACGTATTGAATTTGACTTGAGAAAGGcAAAAGAGAAAGCACTGTCTTA

GGATATTGTTATAAAAGGTATAGTATATACAATGAAGTC

CGTCGAACTAAAATAATTATGATGAGGAGGTTTTAAAACTAGTATGTCGGATTTAATGCAAA.AAATATTG

AGGACTAAGTTCGTTGATC AAGTGGTAATTATGCTTTGTGTGTCAATACTCATGATATTTA

TTTATGATTTCAAATGAAGGAAGCTTTATTTAATCAATGCTTATGAATAAAAGATCTTCAAGAGCCAAAG

S...TGATGATGCTTATTTATTGCTTACACTGCAAGTGGAAGATAGCTAGATTCGAATCTACAGAAGAGTA

AAGTCACGAGGTGTATTGTTATTAAC GAGTAGTGTCATGCAAGATTGTTAAGATG

AAAGATTTT~TAAGGATCTTAATATCAGAGTGCTCATGG

TACCCAAGGTGTTGTGGAATGAAATTAAGAAGGTGATTTGTTTGTTAAGTTTATCGGTTAAGAATCCT

TACTTATTTTAATGTTGAAGGTACTTTAAACGGTAAG~A

CCCGTAATGTTAAACGTAAACrGATTGTAGTTGATTAAG TGTAATTGTGAGAAGTAAGTTA6ACGACGAAGACGAAGCA

GAGTGGATCATTATCTAATGCGTGTTTTTAATTTAAA

f494.aa MPALIRKIFMIYFL CITLGFAMIFIDSKFTEQPNVKNQSINQHTIEPNLIFTSSIGGFLGGINYK

SNFYLNWGNLIILIYNIALIITVYSKSHS

t494.aa WO 98/59071 PCTIUS98/1271 8 88 TABLE 1. Nucleotide, and Amino Acid Sequences MIFIIDSKFTEQPNVKENQSKINQHTIEPNLfl4TSSIGGFLGVYVGIWIFNYIDKSNFYTNWGNLIILIYNIALIIT

VYSXSHS

f494 .nt

TTCTATAAAAATTTACATTTTCTATCTCCTTCAGTTT

TTGACAGCAAATTTACCGAACAGCCTAATGTTAAAGAAAATCAAGC ATTAATCAcATAACCA

AGCAATTTACCTAATGGGGAATTAATTATAAACTGCCTAATTATCACTGTATACTA

AATCACATAGTTAG

t494.nt

ATATTATAACATTCGAACTATTAAAATAACAATACAAAA

TTGA6ACCCAATTTAATCATGTTTACATCTTCTATAGGAGGATTTTTAGGTGTTTATGTTGGAATTTGGATCTTTAA

CTATGACAAAAGCAATTTTTACCTAAATTGGGGAAATTTAATAATATTAATATACAACATACCCTAATTATCACT

GTATACTCAAAATCACATAGTTAG

f516.aa MKKTPNTCIFLTLLI ISNLNALANEEGNTNEKNDQPKQISFFSPERGFIYSTGIGIGVGFFLNSNIKHLIFRPYY

TFSNNTFDFLIVAMILTRESLNIPKKMQYFKSYIGGGINWHIANLIKKTKYFSATIGIGGRFYLSTNFIEDIRFYE

KLPYVIEPYMFIEISSKKAI PLMGLDFKIDFLFLDTFNISFNFTIRYNFKDKEMET t516.aa :11: NEEGNTNEKNDQPKQISNFFSPERGFIYSTGIGIGVGFFLNSNIKHLIFRPYYTFSNNTFDFLIVAMILTRESLNI f516.nt

***ATGAAA)AACT'CCAAACTTGTATTTTCTAACATTGCTTATCATTTCCAATTTAATGCACTTGCAATGAAG

AAGGCAATACTAATGAAATGATCACCCAAACAAATCTCTAATTTTTAGCCCAGAAGAGGGTTCATATA

TTCAALCAGGAATTGGGATTGGAGTTGGATTTTTTCTAAATTCAAATATTAAACACCTTATCTTTAGACCTTATTAT

ACATTCTCTAATAATACTTTGATTTTTTAATCGTTGCTATGATATTAACAAGGGAAAGCCTTAATATCCCCAAAA

TTTTTCCGCCACCATTGGCATAGGTGGTCGTTTTTACCTATCTACAAACTTTATAGAAGACA'rTCGATTTTACGAA

AAATTGCCTTATGTAATAGAGCCTTATATGTTTATTGAAATTTCTTCTAAAAAGGCAATTCCTTTAATGGGGTTAG

ACTTTAAAATTGATT TA~TAAAATACATTTCTTTAATTTACTATAGATATAATTTTAAGGA

CAAAAACGAGATGGAAACATGA

tS16.nt

AATGAAGAAGGCAATACTAATGAAAAATGATCAACCCAAACAAA.TCTCTAATTTTTTAGCCAGAAAGAGGGT

CATTATCAAAGGATTGGATTGGAGTTGGATTTTTTCTAAA6TTCAALATATTAAACACCTTATCTTTAGACC TrrATTATACATTCTCTAATAATACTTTTGATTTTTAATCGTGCAGTTACAGAACCTrAATATC CCCAAAAAAATGCAATACTTTAAATCTTf GAGAGAAATGGCACATTGcAAACITAATTAAAAAAA CAAAATATTT'rTCCGCCACCATTGGCATAGGTGGTCGTTT'rTACCTATCTACAAACTTTATAGAAGACATTCGATT

TTACGAAAAATTGCCTTATGTAATAGAGCCTTATATGTTTATTGAAATTTCTTCTAAAAAGGCAATTCCTTTAATG

GGGTTAGACTTTAAATTGATTTTTATTTTAGATACATTTAACATTTCTTTTAATTTTACTATTAGATATA6ATT

TTAAGGACAAAAACGAGATGGAAACATGA

f 517. aa WO 98159071 PCr/US98/1271S 89 TABLE 1. Nucleotide and Amino Acid Sequences MIPVVASGGILIALSIAFVGIGPDGPNFAPFKQIADIGSIAFGMMLPVLAGFIAMIADKPGLTPGLVGGVI4S GNKAGFLGAIFAGFLAGYVAPFLARSVPEWLRPVMPIFVIPLI STIIVGFFMLYFGVYIGKFMGVLESGLKSLQ

SNSETFGVLGKIFLGLVLGSMITVDMGGPFNKVAFLFGVGLIPQVPEIMGMVAAAIPVPPMAMGLATFLAPKLFEN

EEKESGKIAFLISFIGISEGAIPFAASDPGRVIPSIVVGGAVSSIIAAFLGVANHAPHGGPIVPVIDNKFGFIIA

IAVGVAVATALVIFLKSLKLKESE

t517.aa

DKPGLTPGLVGGVMSGNVKAGFLGAIFAGFLAGYVARFLARRSVPEWLRPVMPIFVIPLISTIIVGFFMLYFGVYI

GKF!MGVLESGLKSLQSNSETFGVLGKIFLGLVLGSMITVDMGGPFNKVAFLFGVGLIPQVPEINGMVAAAIPVPPM

AMGLATFLAPKLFENEEKESGKIAFLISFIGISEGAIPFAASDPGRVIPSIVGGAVSSI IAAFLGVANHAPHGGP 1VLPVTIDNKFGFIIAIAVGVAVATALVIFLKSLKLKESE f5l7 .nt

ATGATTCCTGTTGTTGCAAGTGGAGGAATTTTAATTGCTCTTAGCATTGCTTTTGTTGGGATI'GGACCTGATGGGC

CTAATTTTGCTGAGCATCCATTTATAAGCAGATTGCAGATATTGGTTCTATAGCTTTTGGGATGATGTTGCCCGT

GCTTGCTGGTTTTATTGCAATGGCAATrrGCTGATAAGCCTGGTCTrACCCCCGGTCTTGTTGGTGGAGTAATGTCT

GGGAATGTAAAAGCAGGTTTCTTGGGCGCAATATTTGCGGGCTTTCTTGCAGGTTATGTTGCAAGGTTTTTAGCAA

GAAGATCTGTTCCTGAGTGGTTAGACCTGTAATGCCTATATTTGTAATTCCGCTAATAAGCACCATTATTGTCGG

CTTTTTTATGCTGTATTTTGGTGTTrATATTGGAAAATTTATGGGGGTGCTTGAGAGTGGGCT-TAAATCTI'TACAG

AGTAATTCGGAAACTTTTGGCGTGTTGGGTAAAATTTTCTTAGGCTTAGTACTAGGTTCAATGATTACTGTTGATA

TGGGCGGACCTTTTAATAAAGTGGCATTTCTTTTTGGTGTAGGGCTAATTCCTCAAGTGCCAGAAATAATGGGAAT

GGTAGCAGCAGCAATTCCTGT'rCC'rCCTATGGCTATGGGGCTTGCAACCTTTTTAGCACCTAAATTGTTTGAAAAT

GAAGAAAAAGAATCTGGTAAAATAGCCTTTTTAATTTCATTTATTGGTATTAGCGAAGGAGCTATTCCTTTTGCTG

CTAGTGATCCCGGACGGGTAATCCCTTCGATAGTGGTAGGGGGAGCTGTATCAAGCATTATTGCCGCTT~wT~IAGG

CGTTGCTAATCATGCTCC-ACACGGAGGACCAATAGTACTTCCTGTTATTGATAATAAATTTGGGTTTATTATTGCA

ATTGCTGTTGGAGTTGCGG'PrGCAACAGCTTTGGTAATTTTTTTGAAATCTTTAAAATTAAAGGAATCTGAATGA t517 .nt ATAAG7CCTGGTCTTACCCCCGGTCTTGTTGGTGGAGTAA6TGTCTGGGA.ATGTAAAAGCAGGTTTCTTGGGCGCAA

TATTGCGGGCTTCTTGCAGGTTATGTTGCAAGGTTTTTAGCAAGAAGATCTGTCCTGAGTGGTTAAGACCTGT

AATGCCTATATTTGTAATTCCGCTAATAAGCACCATTATTGTCGGCTTTTTTATGCTGTATT'I'GGTGTTTATATT

GGAAAATTTATGGGGGTGCTTGAGAGTGGGCTTAAATCTTTACAGAGTAATTCGGAAACTTTTGGCGTGTTGGGTA

.*AATTTCTTAGGcTAGTACTAGGTTCAATGATTACTGTTGATATGGGCGGACCTTTTAATAAAGTGGCATTTCT TTTGGTGTAGGGCTAATTCcTCAAGTGCCAG AATAATGGGAATGGTAGCAGCAGCAAT'rCCTGTTCCTCCTATG

GCTATGGGGCTTGCAACCTTTTTAGCACCTAAATTGTTTGAAATGAAGAAA.AGAATCTGGTAAAATAGCCT'TT

TAATrrTCATTTATTGGTATTAGCGAAGGAGCTATTrCCTTTTGCTGCTAGTGATCCCGGACGGGTAATCCCT'rCGAT

AGTGGTAGGGGGAGCTGTATCAAGCATTATTGCCGCTTTTTTAGGCGTTGCTAATCATGCTCCACACGGAGGACA

ATAGTACTITCCTGTTATTGATAATAAATTTGGGTTTATTATTGCAATTGCTGTTGGAGTTGCGGTTGCAACAGCTT

TGGTAATTTTTTrGAAATCTTTIAAAATTAAAGGAATCTGAATGA f5l9.aa

EMKIFIIYILTLVLGMAHLSFASDNYMVRCSKEEDSTTCIAXLKEIKEMKNYLFSMGIGIGDPIANIMITIPYI

NIDFGYGGFIGLSFNNGGIDVIFKQIGQYMIGGGIGIGAWSKTSLIPPNEEEETDyERIGVIRIPF

IMEYNFAKLSIGFKIYPAVGPTILLTKPSILFEGIKFNFFGFGFIYFAFN

t519.aa DNYMRCSKEEDSTTCIAKLKEIKEIKYDLFSMGIGIGDP IANIMITIPYINIFGYGGFIGLKSNNFENYLNGG IDVIFKKQIGQYMKIGGGIGIGADWSKTSLI PPNEEEETDYERIGAVIRIPFIMEYNFAKULSIGFKIYPAVGPTI

LLTKPSILFEGIKFNFFGFGFIKFAFN

WO 98/59071 PCT/US98/1271 8 TABLE 1. Nucleotide and Amino Acid Sequences f 519. nt

ATGATAAAAATTTTTAAAAAAATATACATTTTAACATTAGTATTAGGTATGGCACACCTTTCTTTTGCATCTGACA

ATTATATGGT AAGACAGAAGTCAACCACCTGTATCGCAAAGCTTAAGAAATAAAGAAAGAA AAATTATGACTTATTTTCAATGGGCATTGGAATAGGAGATCCTATT CATTrTATCATCTTATATA -AATATTGATrTTTGGATATGGAGGTTTrATrGGCCTATAAATTTAATACTAAATGGTGG-AATAG ACGTTATTTTTAAAAGAATGCATTTAA GGCGGCGGCATGGAATAGGTGCGGATTGGTCAAA AACATCtCCTTATACCCCCTAATGAAGAAGAAGAAACTGATTATGAGAGAATAGGCGCTGTTATAAGAATTCCTTTTr ATAATGGAATATA rrGAAA~TTCATAGGATTCAAAATTTATCCTGCAGTAGGGCCAACAATATTAC

TAACAAACCAAGCATTTATTTGAAGGAATTAAATTCAATTTTTTGGATTTGGATTCATAAAATTTGCATTTAA

TTAA

t5l9 .nt GACAATTATATGGTCA GACAGAAGTCAACCACCTGTATCGCAAAGCTTAAAGAAATAAA.AGAAA AGAAAAATTATGACTTATTTTCAATGGGCATTGGAATAGGAGATCCTATTGCAAATATTATGA'rTACAATTCCTTA

TATAAATATTGATTTTGGATATGGAGGTTTTATTGGCCTTAAGTCAAACAATTTTGAAAATTATCTAAATGGTGGA

ATAGACGTTATTTTTAAAAAGCAAATTGGACAATATATGAAAATTGGCGGCGGCATTGGAATAGGTGCGGATTGGT

CAAAAACATCCCTTATACCCCCTAATGAAGAAGAAGAAACTGATTATGAGAGAATAGGCGCTGTTATAAGAATTCC

TTTTATAATGGAATATAATTTTGCAAAAAATTTATCCATAGGATTCAAAA.TTTATCCTGCAGTAGGGCCAACAATA

TTACTAACAAAACCAAGCATTTTATTTGAAGGAATTAAATTCAATTTTTTTGGATTTGGATTCATAAAATTTGCAT

TTAATTAA

f520.aa

MRMLLATIILILTTGLLAAQSKSKSMTEDDFI)FDKLLAKEESVRRLFGIGFGVGYPLANITISVPYVDIDLGYGGF

VGLKPNNFLPYVVMGVDLLFKDEIHI~iTMI SGGIGiGADWSKGSPEKSNEKLEEEEENEAQQVASLQNRIEGWIRL

PLVIE-YSFLKNIVIGFKAVATIGTTMLLGSPMSFEGARFNFLGTGFIKIYI

t520.aa

:QSKSKSMTEDDFDFDKIJLAKEESVRRLFGIGFGVGYPLANITISVPYVDIDLGYGGFVGLKPNNFLPYVVMGVDLL

FKDEIHKN~TMISGGIGIGADWSKGSPEKSNEKLEEEEENE-AQQVASLQNRIGVVIRLPLVIEYSFLKNIVIGFKAV

ATIGTTMLLGSPMSFEGARFNFLGTGFIKIYI

f520.nt

ATGAGAATGCTATTAGCAACAATAATACTTATATTAACAACGGGTTTATTAGCTGCACAATCCAAAAGCAA-AAGTA

TGACTGAAGATGACTTTGATTTTGATAAACTTCTTGCAAAAGAAGAGTCTGTGCGCCGTTTATTTGGCATAGGTTT

TGGAGTTGGATATCCACTTGCAAACATTACAATATCTGTTCCATATGTAGACATAGACCTTGGGTACGGAGGATTC

GTAGGGCTTAAACCCAACAATTTCTrGCCCTATGTTGTGATGGGTGTAGATCTTCTATTTAAAGATGAAATACACA

AAAACACTATGATTTCTGGAGGCATTGGAATAGGTGCAGATTGGTCAAAA-GGAAGTCCTGAAAAATCAAATGAAAA

ACT GAAGGAGAAGACCAAAGTAGCTTCTCTTCAAAATAGAATAGGGGTTGTGATAAGATTG CCTTTGGTAATAGAGTACAGCTTrTCTTAAAAATATTGTGATTGATTTAAAGCTGTTGCTACTATTGGAACAACTA TGCTACTTGGCAGCCCAATGTCATTTGAAGGAGCTAGA.TTTAATTTcTTAGGrCACAGGcTTTATAAAAATATATAT

ATAG

t520 .nt CAATCCAAAAGCA.AAAGTATGACTGAAGATGACTTTGATT'rTGATAAACTTCTTGCAAAAGAAGAGTCTGTGCGCC

GTTTATTTGGCATAGGTTTTGGAGTTGGATATCCACTTGCAAACATTACAATATCTGTTCCATATGTAGACATAGA

CCTTGGGTAcGGAGGATTCGTAGGGCTTAAACCCAACAATTTcTTGCCCTATGTTGTGATGGGTGTAGATCTTCTA TTTAAAGATGAAATACACAAAAACACTATGATTTCTGGAGGCATTGGAATAGGTGrAGATTGGTCAAAAGGAAGTC

CTGAAAAATCAAATGAAAAACTTGAAGAAGAGGAAGAAAATGAAGCACAACAAGTAGCTTCTCTTCAAAATAGAAT

AGGGGTTGTGATAAGATTGCCTTTGGTAATAGAGTACAGCTTTCTTAAAAATATTGTGATTGGATTTAAAGCTGTT

WO 98/59071 PCTJUS98/1271 S 91 TABLE 1. Nucleotide and Amino Acid Sequences GCATTG7AACAGTCTCCGCATTATGAGGTGTTATCTGCrA

GCTTTATAAAAATATATATATAG

f523 .aa

MNKNFTPGFGFPGYSSAILYSIFISPGEIEKF~LGTYGL

NLGASIAILQIIETQTFEELLTFKIKFSNNLIMSIGSYA

QKRAEMSSLYAGINLIIFTNYALNKYNTSTFATILVLTS

RLTIKS1MIYKGIFVSFQNIIFSGLKSYSPYVILIEDINERINKKSI IINIPLINFVSXFGTIFVSVI SFFI ILKSYSSLPISIYEISYHSTLSFVFVFAFPHIPNSLIYI

ITMLCSTYTKGIELNVSNITPMPILISL-ATLLIDFAF

NIAIIHI INFKELKDQEKIN t523.a

IENIIENKNFKKLFGKTIYYGILTNIJSGVAVSIIAATIYLPQRIPILEKTIQNTCFFEKEALLETFFPKNIFKIFT

SSNPNLLSIYMISI IIGTSFYYAIQKGRIARELISASLHANGFIVILNIGIIFITANYANLKNFKYPNY TNSITFFLAWTII ILFVILPTISYRLTKSFMIYKGIFVSFQNIIFSGAKSYSPYVILIEnIKwERINIKxSII INIPLINFVSKFGTIFVSVISFFIILKSYSSLPISIYEI SYMSTLSFVFVFAFPHIPNSLIYI ITMLCSTYTKGIE LNVSNITPMLPILISLALLIDFAFNIAIIHI INFKELKDQEKIN f523 .nt ATGAATATAAAAATCAATTTTTTTTrCACTT'rGCCTATTGGAATCTr'rAGGATGI-TTTCCCTCTTGGAATTT

ATAGCTCCTTATCACATGC'ITTATAAGATTATCATACTTATCTC'ITATTCCCTTTTTAATATTTTCAATTCCATT

AGGAATrGAAATATTATTGAAAATAAAACTTTAAAAGCTTTTTGGTAAACAATATTATGGAATTTTAACT

AACCTATCTGGAGTTGCTGTATCAATAATAGCTGCAACAATATATCTTCCGCAAGAATTCCATACTAGAAA

CAATACAAAATACATGTTTTTTTGAAAAAGAAGCTTTACTAGAAACATTCTTTCCAAAATATTTTCAAAATATT

TAATTGCACCATCACA.CTTAAGAT

CAAAAGGCAGAATAGCTAGAGAACTGATGCTAAGCGATCCAATCTTTTTTACCATGCATGGGTTTATTGTAA

ACATATAAATTAGGG TTTTATAACAGCAAATTACGCTGCAACTTAAAAACTTCAAAGATTACCCAAA

TTTACAACACATACATCTTTTTGGCATGGACAATTATAATPTTTATTCGTAATATTGCCAACAATTAGTTAT

AGATTAACAAAAAGTTTTAAGTTTAGCTTTTTATCAAAATTTCAGGACTTG

CAAAAGATTCTTATTCCCC TTTAATAAAGTTACAA~~AAAAACCAT

AATAAAAACTTTTTGTCGATTATTTT

ATTTTAAAATCATATTCTAGCTTACCCATTTCTATTTATGAAATAAGCTATATGAGCAcT'rTATCATTTGTTTTTG TCTTTGCATTTCCTCATATACCAAATrATATTATCAGTTTGCTCTACATATACAAAAGGAAT

***AGAGCTAAATGTTCAAACATAACACCAATGCTGCCGATATTATCTCTTTGGCTTTACTAATCGACTTTGCTTTT

AACATTGCAATCATTCATATAATAAACTT J ATrAAGTAAAAATTAATTAA f523 .nt ATGA*ATTGAAAAATTAAG TTATAC TACGATG TCCAGATCATCAAAACA

ACAAAAGTTTGAAGACTATGACTCTCAAATTTCAAAT~-

TCTAGCAATCCAAATCTACTAGArAAGTCAATAA~AT~IITTAGAACA AAGGCAGAATAGcTAGAGAAcTGATGcTAAGcGcATcCAATcTTTTTrAccATGcAAATGGGTTTATTGTAAACAT

ATAAAAGACTTTTAACATAGCGAATAAACTAAATCCATA

ACACGAACTCCAATATAAA

TAACAAAAAG TT~AGTTTACCTTTT TCAcAAATAATATTTCAGGACTTGCAAA

AGATTLCTTATTCCCCTAGGTTATGAAATAACAAATATTAAACCATAATT

ATACTCTTAAATTTTTATT~-CATTGTCGATTATTTTAT

TAAAATCATATTCTAGCTTACCCATTCTATTTATGAATAAGCTATATGAGCACTTITATrCATTTGT'TTrTGTCTT TGCA6TrTCCTCATATACCAAATAGTTAATTTATATAATACAATGCTTTGCTCTACATATACAAAAGGAATAGAG

CTAAATGTTTCAACATAACACCAATGCTGCCGATATTAATCTCTTTGGCTTTACTAATCGACTTTGCTTTAACA

TTGCAATCATTCATATATAAACTTCAAAGAATTAAAGATCAAGAAATTATTrAA WO 98159071 PCTIUS98/12718 92 TABLE 1. Nucleotide and Amino Acid Sequences f526 .aa M= LQnUNZMS~ KLINKYKKTNFNIIDELSEIN

LFIISVFFNNK(GILIALNLGAEINFKYKISPISISIINEFEITKILIDYGISLNQIDDTGYSPIFWAIYTNNEK

IFE FLKESGALSFTLRKTPMQAAIETIKLIKSLEIYIDDNFmLmKLXEIVRILVK t526 .aa NSINTNTSTSIKELQKLYIFNSEYQKDKD'rLNEF INS ]NINDKEILQSLEKIKNELF I I SVFFNNKKGILIAL

NLGAEIFKYKISPISISIINNEFEITKILIDYGISLNQIDTGYSPIFWAIYTNNEKIFEFLKESGADLSFTLKN

RKTPMQAAIETENIKLIKSLEKIYIDDNFKXLIKcLNK~rRILVK f526 .nt ATGA.AAAAAGAATTCATTATGCTTT'rACTGTTATTGCAAACAATAATGAATTTAAACTCAATAAATACTAATACAA

GTACTTCAATAGTAAAAGAATTGCAAAAAAATTTATATATTTTCAATAGCAAAGAATATCAAAAAGATAAAGACAC

TTTAAATGA.ATTTATAAATTCAATAAATATAA-ATGACAA-AGAAATCTTACAAA6GTTTAGAAAA.AATCAAAAATGAG CTTTTTATAATATCTGTTTTTTrACATAAAGGTTTATGCACTAAATCTTGGAGCAGAAATAAACT

TTAAATATAAAATATCTCCAATTTCAATTTCATAATAAACAATGAATTTGAAATCACAAAATATTGATAGATTA

CGGAATAAGCCTTAATCAAATAGATGATACAGGTTATTCTCCAATATTTTGGGCAATATATACTAATAACGAAAAA

ATATTTGAATTTTAAAAGAAAGCGGAGCTGATTTAAGTTTCACACTTAAAAATAGAAAAA-CACCAATGCAAGCCG

CAATAGAAACAGAAAATATAAAACTAATTAAATCTCTGGAAAAGmAAAAAAATTTACATTGACGACAATTTCAAAAA AAAACTTAAAAAGCTTAAAA6ACAAAGAAATAGTTCGAATTTTAGTAAAATAG t526 .nt AACTCAATAAATACTAATACAAGTACTCAATAGTAAAAGAATT'C A A AA AAATTTATATATTTTCAATAGCAAAG

AATATCAAAAAGATAAAGACACTTTAAATGAATTTATAAATTCAATAAATATAAATGACAAAGAAATCTTACAAAG

TTAGAAAAAATCAAAAATGAGCTTTTTATAATATCTGTTTTTTTCAACAATAAAAAAGGGATTTTAATTGCACTA

AATCTTGGAGCAGAAATAAACTTTAAATATAAA6ATATCTCCAATTTCAATTTCAATAATAAACAATGAATTTGAAA

TCACAAAAATATTGATAGATTACGGAATAAGCCTTAATCAAATAGATGATACAGGTTATTCTCCAATATTTTGGGC

AATATATACTAATAACGAAAAAATATTTGAATTTTTAAAAGAA6AGCGGAGCTGATTTAAGTTTCACACTTAAAAAT AGAAAAACACCAATGCAAGCC cAAAAAAATTAATAATTAAATCTCTGGAAAAGAAAAAAATTT ACATTACGACAATTTCAA A AAA A AACTTAAAAAGCTTAAAACAAAGAAATAGTTCGAATTTTAGTAAAATAG f544.aa MTKRIILLVLMVSSTFTATI ISNYQNLMLSLVVLANFIPLLMDTSGMAGSQASALI IRELALGTVKVKDFFKVF

LKEICVSILVGAILASVNFLRIVFFVAPHHSDKLKIAFVVSSCLMVSLTVAKILGGLLPIVAKLLKLDPALMAGPL

ITTIADAITLIAYFNIAKWVLVSYAV*

t544.aa *:STFTATI ISNYQNIMLSLVLANFIPLLMDTSGNAGSQASALIIRELALGTVKVKDFFKVFLKEICvSlLVGAILA

SVNFLRIVFFVAPHHSDKLKIAFVVSSCLMVSLTVAKILGGLLPIVAKLLKLDPALMAGPLITTIADAITLIAYFN

****IAKAVLVSYAV

f544 .nt ATGAcAAAAAATAGAATAA.T'TGGcTTTTAGT'rcTTATGGTGTcTTcTAcTTTTAAGcTAcAATTATTTcAAATT ATCAAAATTTAATGTTGTCTTTAGTGGTTmAGCTAATTTTATTCCCCTTTrAATGGATACTTCAGGCAATGCCGG CTCTCAGGCATCTGCGCTAAkTAATTCGTGAGCTTGCTCTTGGTACTGTCAAGGTAAAGATTTTTTAAAGTGTTT TTAAAGGAAATATGTGTTAGCATTCTAGTGGGAGCAATTCTTGCTAGTGTTAATTTTTTAA.GAATTGTcTTTTTTG

TAGCTCCACACCATTCTGATAAGCTGAAAATAGCTTTTGTAGTTTCATCTTGCTTGATGGTAAGTTTGACAGTAGC

AAAGATATTGGGAGGTCTTTTACCCATTGTTGCTAAACTTTTAAAGTTGGATCCAGCACTTATGGCAGGCCCTTTA

WO 98/59071 PCTUS98/1271 8 93 TABLE 1. Nucleotide and Amino Acid Sequences ATcAcTAcAAT~GccAGATGTATTACTT=AATAGcTTATT'TAATATAGccAAAATGGTTTAGTTIAGCTATCC~tG

TTTAA

t544.nt TCTACTTTTACAGCTACAATTATTTCAAATT1ATCAAAATTTAATGTTGTCTTTAGTGGTTTTAGCTAATTTTATTC CCCTTTAATGGATACT~cAGGCAATGCCGGCTCTCAGGCATCTGCGCTAATAATTCGTGAGCTTGCTCTTGGTAC TGT A~TAAA~rAGGTTTTA6AGGAAATATGTGTTAGCATTCTAGTGGGAGCAATTCTTGCT AGTTTA'rT~rTAGATTTC~~rT'rGAGTCCACACCATTCTGATAAGCTGAAAATAGCTTTTGTAGTT CATCTTGCTTGATGGTAGGCGACA TTGGGTCTTTTACCCATTGTTGCTAAACTTTTAAA GTTGGATCCAGCACTTATGGCAGGCCCTTTAATcACTACAATTGCAGATGCTATTACTTTAATAGCTTATTTTAAT ATAGCAAAATGGGTTTTAGTTrAGCTATGcTGTTTAAf545 .aa MTKRIIWLLVLMVSSTFTATIISNYQNLMLSLVVLANFIpLLmTSGAGSQASALIIRELALGTVKVKDFFKVF

LKEICVSILVGA-ILASVNFLRVFFVAPHHSDKJKIAFVVSSCLMVSLTVAKILGGLLPIVAKLLKLDPALMAGPL

ITTIADAITLiAYFNIAKWVLVSYAV t545 .aa GSQASALI IRELA.LGTVKVKDFFKVFLKEICVSILvGA-ILAsvNFLRIVFFVAPHHSDKLKIAFVVSSCLMVSLTV

AKILGGLLPIVAKLLKLDPALMAGPLITTIADAITLIAYFNIAKWVLVSYAV

f545 .nt

ATGACAAAAAATAGAATAATTGGCTTTAGTTCTTATGGTGTCTC'ACTTTTACAGCTACAATTATTTCAAATT

ATCAAAATTTAATGTTGTCTTTAGTGGTTTTAGCTAATTTTATTCCCCTTTAATGGATACTTCAGGCAATGCCGG

CTCTCAGGCATCTGCGCTAATAATTCGTGAGCTTGCTCTTGGTACTGTCAAGGTAAAAGATTTTTTTAAAGTGTTT

TAGCTCCACACCATTCTGATAAGCTGAAAATAGCTTTTGTAGTTTCATCTTGCTTGATGGTAAGTTTGACAGTAGC

AAAGATATTGGGAGGTCTTrTrACCCATTGTTGCTAAACTTTTAAAGTTGGATCCAGCACTTATGGCAGGCCCTTTA ATCACTACAATTGCAGATGCTATTACT'rTAATAGCTTT'TAATGA.TGTTTTAGTTAGCTATGCTG

TTTAA

t545.nt GGCTCTCAGGCATCTGCGCTAATAATTCGTGAGCTTGCTCTTGGTACTGTCAAGGTAAAAGAT1TTTTTAAGTGT

TTTAAAGGAAATATGTGTTAGCATTCTAGTGGGAGCAATTCTTGCTAGTGTTAATTTTAAGAATTGTCTT.

9:...:TGTAGCTCCACACCATTCTGATAAGCTGAAATAGCTTTTGTAGTTTCATCTTGCTTGATGGTAAGT CAGTA GCAAAGATATTGGGAGGTCTTTACCCATTGTGcTAACTTTAAGTTGGATCCAGCACTTATGGCAGGCCCTT TAATCACTACAATTGCAGATGCTATTACTTTAATAGCTTATTTTAALTATAGCAAATGGGTTTrAGTrAGCTATGC

TGTTTAA

f577.aa TNIANHFSKIYNPDYPILKIFKQFKIIPLGFDPILIY =HHIiICYINTKYLEEYENFIKDGKFFISP yVELYIQ~VFFKKNNNI~4EFSLTQDQDF~~LLKLNKLI

GLSDITFNSLSEQEKSQIKFSYLIDNNEIVISNPNFIGILETSVLTKKFINWILYKKTQKTLIGFNNQSQNIC

FGFANGFTPYELNLKIKHSIDGISPFIIDETQINSHSYLSKTIEENLLNEWFFSKANNLKKNM

t577 .aa NKIVVLTD)NKTI pFyINQFNIENKANFIIKFRNNIDLQTIEKENAQIIISKIGNTNIANHFKSVKIN1NPDYPI LKHIFKQFNYKIIPLGFDIPILIYKNTHIKYINTKyLKEEFIKGKFFISPYVSENLFIsQiNVRSF WO 98/59071 PCT/US98112718 94 TABLE 1. Nucleotide and Amino Acid Sequences EKnQIkWKLEYFSSFLNQin LQKDFFNKGYLKLNKILLNKKSLLIAGLSDITFYNSLSEQEKSQIK FSYLINDNEIISNPNFIGILETSVLTNNIKK TQrLIGF NQSQSNICFIGFTPYKLNLKIKHS

IDGISPFIIDETQINSHSYVLSKKTIEKENLLINEWFFSKANNLRKN

f577.nt

ATGAAATAAAATTTATATAATAGCAATTTTATTAATTAGCCCTAGCTGTTCAACAAATAAGAACATCGTTG

TACTAACTGACAATAACAATACCATTTTTTAcATATTGATAcAArrTATA GTTTAGAAATAATATTGATCTGAAATGAAAAATCCATAATTATTrTCTAAAAACATTGGTAAC

ACAAATATI'GCTAACCATTTTAAATCTGTAAAAATCAATTATAATCCAGATTATCCTATCTTAAAGCATATTTTCA

AGCAATTTAACTACAAATATTCCATTGGGCTTTGACATTCCTATTTTAATCTATAAAATACACATCATATrAA AAAATACATAAACACTAAATATCTAAAAGAAGAATACGAAAATT'rATTAAAGATGGAAAA.TT'TTTTATATCGCCT TATGTTITCTGAAAATTrATTTATGTGATTCTCAAATAAATAATGTGAGATTTTCTTTTGAAAAAAATAA.ATTAA

ATTATAATGAGAATCAAATTTTAAAATGCTAGAATATTCTCATCATTTTTAAATACAAACAAATGGACTTGCA

AAAGATTTCTTTAATAAATACGGCTACCTAAAGTTAAATAAATATTGCTTAATAAAAAATCTCTTTTAATAGCA

GGATTGAGCGATATAACCTTCTACAATAGCTTAAGCGAACAAGAGAAGTCACAAATAAAATTrrTCCTATTTAATAA

ACGATAA.CAATGAAATTGTTATCTCAAACCCAAATTTTATTGGCATTTTAGAAACATCTGTTTTAACTAAAAAATT

TATCAACTGGATATTGTATAAAAAAACTCAAAAAACCCTAATTGGATTTAACAATCAATCCCAATCAAATATATGT

TTTGGATT'rGCCAATGGTTTACCCCTTACAAAGAATTAAATTTAAAAATAAACATTCAATTGATGGAATATCTC CT'rTTATTATTGACGAAACTCAAATCAATAGCCATTCCTATGTATTAAGCAAAACATTGAAAAAGAAAACTT

ACTAATAAATGAATGGTTTTTCTCTAAAGCTAATAATCTAAAAAAAAATAAAAATTAA

t577 .nt

AATAAGAACATCGTTGTACTAACTGACAATAAAACAATACCATTTTATATAAATCAATTTAATATAGAAAATAAAG

CAAATTTTATAATTAAGTTTAGAAATAATATTGATCTCACAAAAAGAAGCACAAATAATTATTTC

TGGACCATATCACATTAACGTAATATTTACAATACTT

TTAAAGCATATT'rTCAAGCAATTTAACTACAAAATTATTCCA'TTGGGCT'rTGACATT-CCTATTTTAATCTATAAAA ATACACATCATATTAAAAAATACATAAACACTAAATATCTAAAAGAAGAATACGAAAATTTCATrTAAAGATGGAAA

ATTTTTTATATCGCCTTATGTTTCTGAAAATTTATTTTATGTGATTTCTCAAATAA-ATAATGTGAGATTTTCTTTT

GAAAAAAATAAATTAAATTATAATGAGAATCAAATTTTAAAAATGCTAGAATAT'ITCTCATCATTTTAAATACAA

AACAAATGGACTTGCAAAAAGATTTCT'rTAATAAATACGGCTACCTAAAGTTAAATAAAATATTGCTTAATAAAAA

*ATCTCTTTAATAGCAGGATTGAGCGATATAACCTTCTACAATAGCTTAAGCGAACAAGAGAAGTCACAAATAAAA

TTTTCCTATTAATAAACGATAACAATGAALATTGTTATCTCAAACCCAAATTTTATTGGCATTTTAGAAACATCTG

TTTAACTAAAAAATTTATCAACTGGATATTGTATAAAAAAACTCAAAAAACCCTAATTGGATTTAACAATCAATC

CCAATCAAATATATGTTTTGGATTTGCCAATGGTTTTACCCCTTACAAAGAAT AATrAATAAA~CA ATTGATGGAATATCTCCTTTTATTATTGACGAAACTCAAATCAATAGCr-ATTCCTATGTATTAAGCAAAAAAACAA

TTGAAAAAGAAAACTTACTAATAAATGAATGGTTTTTCTCTAAAGCTAATAATCTAAAAAAAAATAAAAATTAA

f584.aa MIKTILLLVLYPVVVFSQISANQYFEGIYAKYQNIEDMQATINFTLKGLKQrGVLLYKFPDKFIINLDSNNQVFVS

DGEFLTVYVPSLGTSFNQQLLKGSSGGGLNKVLNSEYSVSYTNSPNLEDLDSSEPGKYIKLTFSRKLYKGAATINS

FIIAFAPDGIIRRITAPTSGGREIVIDLTAVKFNVGILDSKFKYDPPKSS~KVDNFLYDIKKN

t584.aa QISANQYFEGIYAKYQNIEDMQATINFTLKGLKQTGVLLYFPDKFIINLDSNNQVFVSlGEFLTVYfVPSLGTSFN QQLLKGSSGGGLMUCVLNSEYSVSYTNSPNLEDLDSSEPGKYIKLTFSRKLYKGAATINSFI IAFAPDGIIRPJTAF PTSGGREIDLTAVKNVGILDSKF~kYDPPKSSNCVDNFLYDIMcN f584.nt ATGATAAAAACAATACTTTTATTAGTTTTGTATCCTGTTGTTGTGTTTTCTCAAATATCTGcAAATCAATATTTTG

AAGGAATTTATGCTAATATCAAATATAGAGGACATGCAAGCAACAATTAATTTTACTTTAAAGGGGTTAA-AGCA

WO 98&59071 PCTIUS98/12718 TABLE 1. Nucleotide and Amino Acid Sequences AACAGGTGTTTGCTWATAAGTTC AAAGTAAcTr~~ CAATAATCAAGTTr=GTAACT TTCATCTGAGCCTGGAATATATTAAATTAACCTrCTAAAAGCTTTACAAGGGGGCTCTACTATTAATTCT TTTATTATTGCTTTTGCTCC GTGTATGAATATCTrCTACTAGTGGTGGGCATAG ATAAAGATTTTT AGAATATAAAAAATTGTGATTATTACTCAAATCT t584 .nt CAAATATCTGCAAAT ATTTGAGA~AGTAAATATCAAAATATAGAGGACATGCAGCAACAATTIA TTCAAATAATCAAGTTTTGAGGTGGA TTrAA'-TT CCATCTCTTGGGACTTCTTTTAAT

CAGCATTTTAAGGTAGA~TGGGAGGCTTTGAAGTTTAATATGATATAGCGTATCTTATACCA

ATTCTCCAAATTTAGAAGATCTCGATTCATCTGAGCCTGGAAATATATTAAATTAACCTTTCTAGAAAGCTTTrA

CAAGGGGGCTGCTACTATTAATTCTTATATGCTGCTCCGGATGGAATAATTAGAAGAATTACTGCTTTT

CCTACTAGTGGTGGGCGCGAAATAG'rrATTGATTTGACTGCTGTGAAGTTTAATGTTGGAATTCTTGATAGCAAAT TTAAATATGATCCTCCAAAATCrAAAGGAAATTrTTTAA

A~AATAA

f596.aa

RWCLYLLVFVALCVNNLFSDDYLIYDFDLSLNEFLEVSTRKDNLEPMVDSNRILLFYPPKKEIRKIFAA'DFDQ

YSKKYLFEHGVFFKNIPHGTSSIKYRLIVDGVWTNDEYNIUyv xiYLIPFSKIEIAKEKSSYISLRNPIQ SYDNNEIEIFYIGRPGQIVTAGSFNNFNPFLNRLIEKEDNKGIYTIKLKJLPKRIYYYFIDSGNKVIDNvNR

INLYFVEGIDNKIDFEVSYFDHK

t596.aa

DDYLIYDFDLSLNEFLEVSTKNLEPMVDSNRILLFYPPKEIRXIFADFDQYSKLFKKNEGVFFVKVI

PHGTSSIKYRLIVDGVWTNDYNKNVVxi'JLIPFSKIEIAKEKSSYISLRNPIQSYDNNEIEIFYIGRPGQIVTI a HK f596 .nt ATGAAAGAAAGGTGTTT TTTGTTTTGTTTATGTGTTrACAATCTTTTTTCAGATGATTATTAA TTTATGACTTTCATrA'TAAGATCAGATTACAAAGCACTTGAGCCTATGGTTGA TTCCAATCGTATATTATTGTTTACTCCTC ~GATGAAT TTGCTGCCTTTGACTTTGATCAG

TATTCTAAGAAATAT

1 TATTCAAATGAGCATGGAGTTTTTTTTGT'rAAAGTTAATATTCCTCATGGCACAA GCAGTATAAAATATAGGCTTATTGTAGACGGTGTTTGGACTAATGACGGAAT~GTG

ATTA

GGATTTAATCCCATTTTCTAAATGAGATCGCTAAAGAGAAG3TCCAGCTATATTTTTTGAGAAATCCAATACAA ATTAATTTATATTTTG G~TGTATAAA~'TGAAGTTCCTATTTGATCATAAGTAA t596.nt GATGATTATTTAATTTATGACTTGTTATTAAG rTAGAAGTTTCAACAAGAAAGACAATCTTG TACTTTGATCAGTATTCTAGATTT~' A A TG CTGGTrTTGTTAAAGTTAATATT

CCTCATGGCACAAGCAGTATAAMATATAGGCTTATTGTAGACGGTGTTGGACTAATGACGAGTATAATAAAAATG

AAATCCAATACAATCAAGTAATA GAA~TTCTGTGTCCTGGACAAATAGTTACAATA GCTGGTAGTTTTAACAATT'FrAATcCTTTTTTAATAGGCTATT

AAGGAATAGATTATACTA

TTACTAATTCCAGTGATTTATTTATATTGACAGATGTAA

WO 98/59071 WO 9859071PCTIUS98112718 TABLE 1. Nucleotide and Amino Acid Sequences

TAATGTTAATAGAATTAATTTATATTTTGTT~GAGGGAATTGATAATAAAATAGATTTCGAAGTTTCCTATTTTGAT

CATAAGTAA

f598 .aa MRQRVMIAMALSCHPSLLIADEPTTALDVTIQEQILLLIKNLSKKFNTSTIFITHlLAVVAEICDTVSvMYQGKIV

EEGTVEEIFNPKHPYTIGLLKSILTLEPNKKLYSTKENPKITKTSTEEF

t598.a

EPTTALDVTIQEQILLLIKNLSKKNTSTIFITHLAVVAEICDTVSVMYQGKI-VEEGIVEEIFNNPKHPYTIGLL

KSILTLEHflPNKKLYSTKENPMKITKTSTEEF f598 .nt

ATGAGACAAAGAGTTATGATTGCCATGGCTCTTAGCTGTCATCCATCCTTATTAATAGCAGATGAACCAACAACAG

CCCTTGATGTTACAATCCAAGAGCAAATATTATTATTAATCAAAAACCTATCTAAAAAATTCAATACTTCTACCAT

ATTTATAACTCATGATCTTGCGGTTGTTGCTGAAATTTGTGATACAGTATCTGTAATGTATCAAGGAAAA.ATTGTA

GAAGAAGGAACAGTAGAGGAAATATTTAACAATCCTAAGCATCCTTACACCATTGGGCTTTTAAAATCAATTCTTA

CGCTAGAACACGATCCAAATAAAAAGCTTTATTCAACAAAAGAAAACCCTATGAAGATCACAAAAACCAGCACCGA

GGAGTTTTAA

t598 .nt GAACCAACAACAGCCCTTGATGTTACAATCCAAGAGCAAATATTA'FrATTAATCAAAAACCTATCTAAAAAATTCA

ATACTTCTACCATATTTATAACTCATGATCTTGCGGTTGTTGCTGAAATTTGTGATACAGTATCTGTAATGTATCA

AGGAAAAAT'rGTAGAAGAAGGAACAGTAGAGGAAATATTTAACAATCCTAAGCATCCTTACACCATTGGGCTTTTA AAATCAATTCTTrACGCTAGAACACGATCCAAATAAAAAGCTTTATTCAACAAAAGAAAACCCTATGAAGATCACAA

AAACCAGCACCGAGGAGTTTTAA

f600.aa MAflMtERSI IGLFIALAFVSWLTVARVVRGQVQSLSSSEFIQAAKTLGATNQRIILKHLIPNSIGMIVIFTTIRVPS

FIMAEAFLSFLGLGISAPMTSWGELVQNGIATFVEYPWKVFIPAIVMTIFLLFMNFLGDGLRDAFDPKDSI

t600.aa

RVVRGQVQSLSSSEFIQAAKTLGATNQRIILIXHLIPNSIGMIVIFTTIRVPSFIMAEAFLSFLGLGISAPMTSWGE

LVQNGIATFEYPWFIPAIVTIFLLFMFLGDGLRDAFDPDSI

f600 .nt

ATGGATAGAAGATTACGGCTTATTCATAGCACTTGCATTTGTATCATGGTTAACAGTAGCTCGAG

TTGTACGAGGCCAAGTACAATCACTATCAAGTTCGGAATTATACAAGCAGCCAAAACCCTTGGTGCAACAAATCA

AAGAATAATCTTAAAACACTTGATCCCTAATAGCATTGGATGATAGTATATTCACAACAATAAGGGTTCCAAGC

TTTATTATGGCTGAAGCATTTTATCCTTTAGGACTGGAATTCAGCTCCAATGACAAGCTGGGGAGAATTAG

TGCAAATGGAATTGCTACATTTGTTGAATATCCATGGAAAGTTTTATTCCAGCTATAGTTATGACAATATTTCT

ATTATTTATGAACTTTTAGGTGATGGGCTAAGGGATGCT'TTGATCCAAAAGATAGCATCTAA

t600 .nt CGAGTTGTACGAGGCCAAGTACAATCACTATCAAGTTICGGAATTrATACAAGCAGCCAAAACCCTrGGTGCAACAA

ATCAAAGAATAATCTTAAAACACTTGATCCCTAATAGCATTGGAATGATAGTTATATTCACAACAATAAGGGTTCC

AAGCTTTATTATGGCTGAAGCATTTTATCCTTTTTAGGACTTGGAATTTCAGCTCcAATGACAAGCTGGGGAGA-A C

C

C

WO 98/59071 PCTIUS98112718 97 TABLIE 1. Nucleotide and Amino Acid Sequences TTAGTGCAAAATGGAATGCTACATTTGTTCGAATATCCATGGAAAGTT=rATrCCAGCTATAGTTATGACAATAT

TTICTATTATN'ATGAACTTTTAGGTGATGGGCTAAGGGATGCTITTGATCCAAAAGATACGCATCTAA

f 603. aa -MLKFTLXKILGIIPTLLVIIFLCFFVMA.PGSPFDSEPIDPQVALMEKYLKPFYIQAFYYITNALRGnLG

PSLKKMLTVSQYIKLGFPSLTLGVISLIISLSIGIPIGILA.A.IYKNTYVDYIITSIAILGISIPLFVIGPILQY

FFAIKWGLLYTSGWITERGGFSNLILPITLSPNAIFARIIRGSMLE IIQSI)FIRTARAKGLSFKIVIKEMR GAMLPVVSYIGPAFAA uSGSVVIEIFRIAGMGMFITESALNRflYPVLM!GGLLVYSIILL IS ILlSD IIYKI LDP

RV

t 603.a SPFDSEXPIDpQvKARI EEKyHLDKPFYIQAFYYITNALRGDLGPSLKKDLTVSQYIKLGFPKSLTLGVISLI IS LSIGIPIGILAAIYKTYVDYIITSIAILGISIPLFVIGPILQYFFAIKWGLLYTSGWITERGGFSNLILPI ITLS MPNVAIFARIIRGSMILEIIQSDFIRTAPAKGLSFKKIVIKHLRGAMLPVVSYIGPAFAAI ISGSVVIEKIFRIAG

MGMFITESALNRDYPVLMGGLLVYSIILLISILISDIIYKILDPRV

f603 .nt ATGTTAAAGTTTACTTTAAAATTTGATAACAACTTTACTGGTAATAATTTTTTTATGCT'rTTTTG

TAATGAGAATGGCTCCTGGAAGTCCATTTGATTCTGAAAAACCTATTGATCCTCAAGTAAAAGCAAGATTGATGGA

AAATATCACCTTGACAAGCCTTrATATTCAAGCT TATTACATTACAAACGCTCTCAGGGGAGATCTGGGA

CCTTCTTTGAAAAAGAAAGACCTTACAGTTAGTCATCTAATGATCCAAAATCACTTACACTAGGAG

TA1ATATCCCTTATTATATCACTATCAATAGGAATACCAATAGGTATATTAGCTGCCATTTATAAAAATACTTATGT GGATTATATAATAACAT AACAA'GGATCAACATTATTCGTAATAGGGCCAATTTTACAATAT

TTTTTTGCAATTAAATGGGGTTTGCTTTATACCTCTGGATGGATTACAGAAAGAGGAGGATTTTCAAATTTAATTC

TACCCATATAACTCTTAGCATGCCCAACGTAGCTATTTTCGAAGAATATCAAGGATCAATGCTAGAATAAT

ACAAGCGACTTTATAAGAACTGCGCGTGCAAAAGGGCTAAGCFTCAAAAAGATAGTTATAAAGCATATGTTAAGA

GGAGCAATGTTGCCTGTAGTAAGCTATATAGGTCCAGCATTTGCTGCTATAATATCTGGA6AGCGTGGTTATTGAAA

AAATATTTAGAATTGCTGATGATTTAACGACCGCACTAAACAGAGATTACCCAGTATTAATGGG

CGGATTGTTATTTCATAA T'TATTTCTATATTAATATCAGATATTATATATAAAATATTAGATCCA

AGAGTATAA

t603 .nt AGTccATTTGATTcTGAAAAAccTATTGATccTcAAGTAAAAGcAAGAvrGATGGAAAAATATcAccTTGACAAGC ***CTTTTTATATTCAGTrTTTCTAAAGCTCTCAGGGGAGATCTGGGACCTTCTTTGAAAAAGAAAGA CCTTACAGTTAGTCATCTAATGA ccAAAATcAcTTA-ACTAGGAGTAATATcccTTATTATATCA

CTATCAATAGGAATACCAATAGGTATATTAGCTGCCATTTATAAAAATACTTATGTGGATTATATAATAACATCAA

TAGCATATGGG~rTCATACATTATTCGTAATAGGGCCAATTTTACAATATTTTTTTGCAATTAAATGGGG TTTGCTTTATACCTC GAGAIAAAAAGGArTAMTATTACCCATAATAACTCTTAGC 4 ATGCCCACGTAGCTArTCCAAATAGG CA TAGAAATAATACAAAGCGACT'TATAAGAA CTGCGCGTG AAGGTAcTAAAAATAAACTTTTAAGAGGAGcAATGTTGCCTGTAGT 4: :AAGCTATATAGGTCCAGCATTTIGCTCTATAATATCTGGAAGCGTGTTGAAATTTAATGCTGGA

**ATGGGAGTTATAACAGATCCGCACTAAACAAGATTACCCAGTATTATGGGCGGATTGTTAGTATATCAA

TAATACTGCTTATTTATATTAATTDTTTAATTAACCAAGAGTATAA

f607.aa MKYIKIALLIIFSLIACISNKKEKIFRVSNLSEPSSLPQLSTDLYGS1IITNLFLGLAVKDSQTGKYKPGLA

KSWNISEDGIIYTFNJREDIVWSDGVAITAEEIKKSYLRILNKTAAMYANLIKSTIKNAQEYFDETVPESELGIK

AIDSKTILEITLTSPKPYFPDMLTHSAYIPVPMHfIVEKYGENWTNPENIWSGAYKLKERSInDKIVIEKEKYYNA INEIDEVIFYPTEGSVAYNMGELDFLQGAE4NLEEIKIRDDYYSGLKNGMAYIAFNTIKPLDNLKVRQAI SLAIDRETLTKVV1KGSSDPTNLTPDDYSYGThILFDPNAG(LLAEAGYPDGKGFPTLKYKISEGRPTTAE WO 98159071 PCTI/US98/1271 8 98 TABLE 1. Nucleotide and Amino Acid Sequences

FLQEQFKIILNINLEIEEEWTTFLGSRRTGNYQMSSVGWIGDYFDPLTFLDSLFTTENHFLGAYKYSNEYALI

KKSNFELDPIKQDILRQAEEIIAEKDFPMAPLYIPKSHYLFRNKWTGVPNIESYLYEDIKTKK

t607 .aa CISNAKEIVFRVSNLSEPSSLDPQLSTDLYGSNIITNLFLGLAVKSQTGKYKPGLAKSWNISEnGIIYTFNLR

EIVWSDGVAITAEEIKKCSYLRIILNAAMYANLIKSTIKNQEYFDETVPESELGIKAIDSKTLEITLTSPKPY

FPDMLTSAYIPVPEIVEKYGNWNPENIVSGAYEKERSINDKVIEEEKYYNAKVEIDEVIFYPTEGSV

AYMIGLFQAKNEIIDYSLNMAIFTIPINKRASADELKLG

SflPTRNLTPKFflDYSYGKNLILFDPENAIKLAEAGYPDGKGFPTLKYKISEGRPTTAEFLQEQFKILNINLEIE NEEWTTFLGSRRTGNYQMSSVGWIGDYFflPLTFLDSLFTTENHFLGAYKYSNICYDALIKXSNFELDPIKRQDILR

QAEEIIAEKDFPMAPLYIPKSH-YLFRNKWTGWVPNIAESYLYEDIKTKK

f607 .nt

ATGAAATATATAAAAATAGCCTTAATGCTAATAATTTTCTTTAATAGCATGTATTAGTAATGCTAAGA-

AATAGTTTCAGAGTATCAACTTAAGCGAGCCATCATCACTGTCCTCAACTCTCAACAGACCTrTACGGTAG

CAACATTATTACAAACCTATTCTTAGGCCTAGCGGTAAAGATTCTCAACTGGAATATAACAGACTTGCA

AAAAGTTGGAATATTTCTGAAGATGGAATTATTTACACATTTAACCTAAGAGAAGATATAGTTETGGAGCGATGG

TTGCCATTACTGCCGAGGAGATAAAAAATCATACCTAAGAATTTAAATAAAAAAACAGCTGCAATGTATGCTAA

TTTAATAAATCTACAATAAAAAATGCACAAGAATATTTCGATGAGACAGTGCCTGAATCTGAGCTTGGCATAAAG

GCTATTGACAGCAAAACCTTAGAGATAACATTAACATCTCCAAAGCCTTATTTTCCTGATATGCTAACACACTCAG

CATACATACCAGTTCCAATGCATATTGTTGAAAAATATGGAGAAAATTGGACAAATCCTGAAAATATAGTTGTTAG

TGGCGCATACAACTTAAAGAAAGATCAATTAACGATAAAATC

TAAAAAT~TATATGT

AAAATGTAGAAATTGATGAAGTAATATTTTACCCAACAGAAGGTAGCTGGCTTACAATATGTATC3TG

AACTCGATTTTCTACAAGGAGCAGAAAGAATAATTTAAGATTAAAGGATTATTATTCTTCGTT

TCCTTGCATGACAATAAATTTAAQTAACATATTTAGAAGATCGAAT AAGGAcACACT CA.*AAGAC GGCGATTATCACGATATATTTTTAACGTA

TCAAATGCAAAAGTATGATTATCTGA

ACCAAATATCGCAGAAAGCTATTTATATGAAGATATTAAAACTAAAAAATAA

t607.nt

TGATGATCAAAGAAAATTCGATTAATAGGGCTACCTACT

AACTCTCAACAGACCTTACGGTAGCAACATTATTACAACCTATTCTTAGGCCTAGCGGTA

ATCTC

:TGGAAAATATAAACCAGGACTTGCAAAAAGTTGGAATATTTCTGAAGATGGAATTATTTATACCTAG

GAAGATATAGTTGGAGCGATGGAGTTGCCATTACTGCCGAGGAGATAAAAAATCATACCTTTA6TA

CAAATCCTGAAATATAGTTGTTAGTGGCGCATACAACTTAAAGAAGTCAATTAACGATAAAATCGTATAGA

AAA-TAAAATTAGAAATTGATTAGATAATTCC6CGAGACT

GCTCAAGAAAAGTACCATTTAAGACGAAATATAAGATAA

TAGGTATTATTGTAAACGAGGAAAACTCAAACAAACATG

CACCCTCATAAAA6CTTATAGATTAAGAG

TCAGATCCAACAAGAAATCTAACTCCAAATTTGTGATTATTDCTTATGGAAAAAATTTAATACTAT'T'GATCCTG

AGAGAAAATTACGACGAACGATGAAGATCCLATAAAAATT

GGGGAAc~Ac~AATTTCAAcATAAAATcA6cTACTGA6CA

AAGAATGCAATCAGACGAACTGATACATTAGGGGTGTGA

ATTATTTTGATCCCTAACATTCTTAGACAGCTTATTTACAACAGAATcATTTTTTAGGCGTAAAAATTC WO 98/59071 PCTI/US98/12718 99 TABLE 1. Nucleotide and Amino Acid Sequences AAAcAAAGAGTATGATGc=DAATAAAAAATcTAATTTTG AAcTTGArccAATAAAAkAGAcAAGAcATTTTAA CAAGCTGAGGTAAGAAAAATTICCTATGGCACCTTTATATATACCCAAATCTCATTATCTTT'rCA

GAAATGATAAATGGACAGGTGGGTACCAAATATCGCAGAAAGCTATTTATATGAAGATATTAAAACTAAAAAATA

A

-f~ll.aa

MKKIFLFLFISFYLFGFESSLKIGIDVYVEAHEEGFLFIRKKPAIKSVLTESFEIPDKKKDVATYSFRTLSY

NKVNGEIRILNGRVI~iLLSLTSSTPVPNKGEAFHILIPICKKYGFPNFSTRSGDIDLEVLKSKEPFWFS IRSFEK-tnYLGRYQDNAYE.LLFKDQNQGKIEFNEL=FTFSDEVVIAGIIVDKINKILKTSEDSVYDL

DLVLVVDVDSMSNIEILEHLSIIEPQLQI'KSYRGLVFYKYLEFLTKAFDFNTIPYLNNILKYVNVGGG

GDYPEAVFEGIDAAVTQFDWRARFIIVIGDAPPHEYPRGSVYDVINSAKE DITIYGIIFQ t~ll.aa

FEDSSLKIGIDDVYVEAHEEGFHLFIRKKPAIKSVILTESFEIPDKKKDVATYSFRTLSYNKVNGDEIRILNGRVI

ELLSLTSSTPVPNKKFGEAFHILIPKKLKYGFPNFSTRSGDIDLEVLKSKKEPFWFSIRSFEKKYNDYLGRYQ

DNAYELLFKDQNQGKIEELt FTKFSDEVIANNGIDIVDKINKILSEDSVYDLDLVLVVDVTDSMKSNI

EILKEHLFSIIEPQLQKFKSYRIGLVFYKDYLEDFLTKAFDFNTPYLNNILKYVNVGGGGDYPE.AVFEGIDAAV'

QFDWRAERRFIIVIGDAPPH RGSIVYKDVINSAKEKDITIYGIIFQ f~ll .nt ATGAAGAAAATTTTATTTCTTTTTATTTT'rATTTGTTTGGATTTGAAGATAGTTCTTTGAAAATAGGTA TTGATGATGTTTATGTTGAGGcTCATGAAGAGGGATTTCATCTTTTTATTAGAAAAAAACCTGCAATCAAATCAGT

AATATTGACAGAGTCTT~TTGAAATTCCTGATAAGAAAAAGATGTGGCTACTTATICATTCGTACATTAAGTTAT

AATAAGGTTATGGAGPATGAArCGGATTTTAATGGAAGAGTTATTAAGATAAAGAACTTTTATCATTGACAT

*CTTCCACCCCTGTTCCTAATAAAGTTTGGAGAAGCTTTCATATATGATTCCAAA.TTAAATATGAT

**TCCAAATTrTTCAACAAGAAGTGGTGATATTGACTTAGAGTATTAAAAAGTAAAAAAGAGCCCTTTTGGTTTTECT

ATAAGATCTTTTGAGAAAAAATATAATGATTATTTGGGCAGATATCAAGACAATGCTTATGAATTGCTTTTCAAGG

ATGATCAAATCAGGGAAAAATTGAATTTAATGAATTAAAAGATACTTTTACAAAATTTTCAGATGAGGTTGTTAT

TGCTAATAATGGCATGATATTGTITGATAAAATAAACAAAATTTTAAAAAACTCAGAAGATTCAGTTTAGTTTA

*GATTTAGTGCTTGTTGTTGATGTTACTGATAGTATGAAAAGCAATATTGAGATTCTAAAGAGCATTTGTm'CA

TAATAGAACCTCAACTCAAAAGTTTAATCCTACAGAATAGGTCTTGTTTTTTATAAAGACTATCTTGAAGAT

TTTAACCAAAGC TT~rTTAATACTATTCCTTATTTAAATAATATTCTTAAGTATGTTAATGTTGGTGGCGGT GGGGATTATC CACGrGAGGTGTGCTGTGACCAA TGATTCGGCAGGAAGAGT

TTATTATTGTTATAGGAGATGCACCTCCTCATGAGTATCCAAGAGGGTCTATTGTTATAAAGATGTTATCATTC

TGCAAGAAAAGAATTCAATTAGGATAAATTCAGTAA

-ofoo: t6ll.nt

TTAGAAAAAAACCTGATAATATAATGCGGTTTGATCCATAAGAAAAAATGT~

TACTTATTCATTCGTACATTAAGTTATAATAAGGTTAATGGAGATGATTCGGATTAAATGGAGATT

AAGAATAAAGAACTTATCATTACATCTTCCACCCCTGCCTAATAA-AGTTGGAGAAGCTTTCTATAT

GAT TTTGTTTGC CTCAGAGATAAATCACAGAAGATTGAATATGATTAATATT .00. AAGAAAAAGrAGTGGGTTTTATTGAAT GGCATGATAT A CAA Trri7, ATAAAGACTATCTTGAAGATTTTTTAACCAAGCTT'TATTTTAATACTATTCCTTATTTATAATAT TCT AGAGTAGrGGGGTGGGGATTATCr-AGAAGCTGTTTGAGGGGATTGAGCGTGCC CTATTGTTTATAAAGATGTTATCAATTCTGCAAAGGAAAAAGATA ACAATTTATGGATAATATCGTAA WO 98/59071 PCT/US98/1271 8 100 TABLi 1 Nucleotide and Amino Acid Sequences f 617. aa MFFRNSFMALIFSSILSISYFFGDFFQFSYIISWR'ILFLIMATGIATCSNLGNQIyFGAFLyI

FSSFFGLTYFNFFLILLSSFFVGLLGLIPFFITFFFGLNKALTGLLISYGNQRLVDGFILNMLKTGSFSNQTRI

NSLFALDSSLIYLFLLGVSVWLFVFIHKTIYGLQLEILSN IDIFFN FK FAVFGSAFLNGLAGSMF

-VVFFRPYLVLGLTSGLGWSSLIVAVISGFNYV'VLFFSLLFSILIEFNNLNI=YFKYEFIGLCQIAIFISLFL

IKARKX

t617.a

AKSNSLNLGNGQIYFGAFLVYIFSSFFGLTYFFFLILLSSFFVGLLGLIPFFITFFFGLNKLTGLLIYGQ

RLDFLMKGFNTRNLADSILLLVVLYFHKIGQELNKIIFI

EFKYKFFAVFGSAFLNGLAGSM FFRPYLVLGLTSGLGWSSLIVAVSGFV

FFSLLFSILIENLN

NYDFKYEFIGLCQSIAIFISLFLIKARKK

f617 .nt

ATGATCTTTTTTAGAATAGCTTTAGGCATTAATTTTTCTTTCAATATTAAGTATTAGCTATTTTCGGTG

ATTTTATTCTTTAATAACTGCCTATTTTTATTGTCGGTG

TACTTGTGCCAAGAGTAATTCATTAATCTTGGGATGAAGGTCAGATTTATTI'GGGGCATTTTTAGTTTATATA

AAATCAAAGATTGGTGGATGGATTTATTTTAATATGTTAAAACAGGTAGTTTTTCTAATCAGACAAT

AATAGTTTGTTTGCTTTAreATTCATCACTTATTTACTTGTTTTTGCTTGGTGTATCAGTTTGGCTTTTTTATGTTT TTATTCACAAAAAAACTATTTATGGTCTTCAGCTTGAAATAT CGAAA~ ATGCTT=CA

TAAAGATAAAAGTTCCGATGGATCTTTATGCTCGTCAGT

GTAGTGTTTTTTAGACCATATTGGTAGGGCTAACTTCAGGACTTGGAGTAGTCTATGTTGTA

ATTAAAGCTAGGAAAAAGTAG

t6l7.nt **AGGATCTAACTGATAGTAGTTTTGGCTTtGTAAATTA i=GTACTTTTATTTTTTATCTTATCTTTTTGATTGGC CAAAAAAACTATTTATGGTCTTCAGCTTGAAATATTAAGCAATA AAAAAAGATAGACAT TTTAATT

GATTATTATTTGTTTTGATCTTTAAGTTGAGTTTTTTGG

TTTTAGACCATATTTGGTTAGGGCTAACTTCAGGACTTGGTTGGAGTAGTCTAAT

TTGCTGTTA

CTAGGAAAAAGTAG

f 631. aa PVLIITLFLIMATFLSPSISGARWIFFQGVSIQPSEIFKISFTIYLSAYLSKFD

GISKPLIFAIFW

VLIQDSAYALF

FSMFYFIVFLVAFMEYVRFFNYDSKYI

ASNLSGLKLMEKGLENDISLGEGLVFILFFy~FAHNRKF

AFSLILSMIIILPTILFSGSIVMLGINSMN

t631.aa WO 98159071 WO 9859071PCIUS98112718 101 TABLE 1. Nucleotide and Amino Acid Sequences

RISLNFLKKSIFPVLIITLFLIMATFLSPSISGAWIFFQGVSIQPSEIFKISFTIYLSAYLSKFDPRNNGISY

WIKPMLFAIWVLIILQNDYSTAIYFAILFFIVLFVSNMAFSYVFAIVVFLPVSAIFTMTEYRVSRI

FAFLNP

YDDPSGKGYQIIASLNALKSGGILGKGLGMGEVKLGKIPEANSDFIFSVLGEELGFLGVLFAISLFFLFFYFGYFI

AIHSNSRFKFFIAFISSLAIFLQSMILIAIGLLPPTGIMPFFSSGGSSIITALSGLISVSLSNN

f631.nt ATGT~GTAAGTAA1vCATTAGGACATGTTATTTGCTT GC~TATTGGTAGCCTATGGCCTTGTAG T M'ATACTTCTCCITTTTcTAACTTAGAATTGACAGGTAATCAATTrA rrccAATTAA CCTGTATTGATTATAACTCTTT1 AATTATGGCAACTTITT1ATCTCCAAGTATTCTGGAGCAAAGAGATGGA TATTCTTTCAAGGTGTTAGCATTCAACCTTCTGAGATTAAATATCTTr'rACTAT'ITATCm7rCAGCTTATTT GAGCAAGTTTGACCCAAGAAAAAACAATGGTAT'rTCATACTGGATAAAGCCAATGI'GATTTTTGCAATTTTTTGG

GTGTTAATAATTTGCAAACGATTATTCAACAGCTAATTTGCCATTCTTTTTTTATGTTTGTTTGTTT

CTAATATGGCATTTAGCTATGTTTGCTATTGTGGTTACTTTTTACC-AGTTCTGCTATATTCI'GATGCTTGA

ACCTTATAGGGTTCTAGAATTTTTGCCTTTCTCAATCCTTACGATGATCCTTCTGGCAAAGGTrACCAGATAATA GCATCTCTTAATGCTAAATGGGA T~GTAAAGGGCTGGGALTGGGAGAGGTAAAACTTGGAAAAT

TACCAGAGGCCAATTCGGATTTTATTTTCAGTTTTGGAGAAGAATTAGGATI'TTAGGGGTTTTGTTTGCTAT

AAGCTTGTTTTTTTTGT~rIACTrGGTTATTTTATAGCTATTCATTCTAATAGTAGGTTTAAATTTTTTATT

GCATTATTCAAGTCTTGCAATT~CTTCAAACATGATGAATATTTTAATTGCAATCGGTCTTTTGCCTCCTA

CAGGGATAAATTTACCATTT'TTTTCATCTGGGGGATCTTCTATTATTGTTACCATGGCATTGTCTGGCCTTATTTC

AAATGTTTCAAATAGATT'G

t631 .nt AGGATTTCTTTAAATTTTTrTAAAAAAATCAATATTTCCTGTATTGATTATAACTCTTTTTTTAATTATGGC.AACTT TTTTATCTCCAAGTATTrCTGGAGCAAALGAGATGGATATTCWI'TCAAGGTGTTAGCAT'ICAACCTTCTGAGATTTT

TAAAATATCTTTTACTATTATCTTCAGCTTATTGAGCAAGTTTGACCCAAGAAAAAACAATGGTATTTCATAC

TGGATAAAGCCAATGTTGATTTTTGCAATTTTTTGGGTGTTAATAATTTTGCAAAACGATTATTCAACAGCTATTT

ATTTTGCCATTCuTTTTTGTTTGTTTGTTTCTAATATGGCATTTAGCTATGTTTTGCTATTGTGGTTAC S T'rrTTACCAGTTCTGCTATATTCTTGATGCTTGAACCTATAGGGTTTCTAGAATTTTGCCTrTCTCAATCCT TACGATGATCCTTrCTGGCAAAGGT'rACCAGATAATAGCATCTCTTAATGC IAAATGGAT1TGTA .0 *AA~GCTGGAATGGAAGGTAAATTGGAAAATTACCAGAGGCCAATTCGGATTTTATTTTCAGTTCTTGG sO.AGAAA~AGGTTTTAGGGTTTGTTGCTATAAGCTTGTLmTTTTT'IACTTTGGTTATTTTATA GCTATTCATTCTAATAGTAGGTTAAATTTTATTGCATTATTTCAAGT ~GATTT~CAAAGCATGA :50:TGAATATTTTAATTGCAATCGGTCTTTGCCTCCTACAGGGATAA6ATTTACCATTTT1TTCATCTGGGGGATCTTC TATrATTGTTACCATGGCATTGTCTGGCCTTATTTCAAATGTTCAAAAAATTTAAGTAATAATTGA f647 .aa 0 6 Ifi FLSFFFRAFFLLFLIVILFFFLFFIDFIGKTKRYFPEFVRTKLGETSLVFDHNSNIILDEAR.LVF-

EAIDIQQIEKKDLKKEDSLNKLEFELKQKQKDLLQKIIDIINKYNDEEANILQTAVYLMNMPPE-DAVK

ELEDLNPELIAISYMRKIEELSKKEGRLS IVPYLSLMSKAALIRM4SVSSLE t647.aa 000IDFIGMYNTPEFPERVLLETSLVFDNSNIILDEARLVKEREAIDIKNQQIEKLEDLKLKESLKF-E

PYWLSLSKKAAILIRKMSVSSLE.

f647 .nt CGT TTTTATGTTTATTC TTGTTA GrATA TAT AAGATGT TAATAAGATATTTCCCCGATGTAAGAACCAAGT

GTTAGGAGAAACTTCTCTGGTCTTTGATCATAATTCTAATATAATTCTTGATGAAGCTAGACTTGTGAAGGAAG

GAAGC-TATTGATATTAAGAATcAGcAGATTGAAAAGcTTAAAGAAGATCTAAAGTTAAAAGAAGACAGTTTAAATA WO 98/590'71 PCTIUS98/1271 8 102 TABLE 1. Nucleotide and Amino Acid Sequences A~cTTGAATrTTGAGcTrAAGcAAAGAGAcAAGATTTAGATTTAAAAcAAAAAATAATAGATGAcATTATAAATAA ATATAATGATGAGGAAkGCAAATATTGccAAAcAGcTGTATATTAATGAATAGCACCACGAAGATGCTGTTAAG CGGCTTGAAGATTTAAATCccGAGCTTGCAATATCTTATATGCGGAAAATTG-AAGAGCTTTCCAAAAAGAAGGTC GTT'rATCAATTGTTCCTTATTGGTrATCTCTTATGGATTCTAAAAAAGCTGCTATATTGATTAGAAAAATGTCTGT TAGTTCATrGGAGTAG t647 .nt

ATTGATTTATTGGAATGTATAATACTAAAAGATATTTCCCCAATTTGTAAGAACCAAGTTGTTAGGAGAAACTT

CTCTrGGTCTTGATCATAATCTAATATAATTCTTGATGAAGCTAGACTGTGAAGAAAGAGAAGCTATTGATAT TAAGAATCAGCAGATTGAAAAGcTTAAAGAAGATCTAAAGTTAAAGAAGACAGTTTAAATAAGC'ITGAATTTGAG CTTAGCAAACAGAAGT~rAGA'FrAAAAAAAATATAATGCATrATAATAATTAAGATGAGG AAGCAAATATTT'rGCAAACAGCTGTATAT'rTAATGAATATGCCACCAGAAGATGCTGTTAAGCGGCTrGAAGATTT AAATCCCGAGCTTGcAATATcTTrATATGcGGAAAATTGAAGAGCTTTCCAAAAAAGAAGGTCGTTTATCATTGTT

CCTTATTGGTTATCTCTTATGGATTCTAAAAAAGCTGCTATATTGATTAGAAAAATGTCTGTTAGTTCATTGGAGT

AG

f653 .aa

MLTYGD)MVTLLLVFFVTIMFSLNDIIFQENVIRIMSASFTGAGFFKGGKTLDFSKLSYLSNSFMSLPSTVRNKQASQ

TAIXSMIEFIEKIQSKNIVVRQEERGIVISLAADAFFDSASAlVKLEENRDSIQKIASFIGFLSPRGYN1FKIEGH TDNIDTflVNGPWKSNWE-LSAARSVNLEHILNYLDQSDVKRIENNFEVSGFGGSRPIATDDTPEGRAYNE.RIDILI

TTDASLSFPKEIKQ

t653.a

*.*NDIIFQENVRIMSASFTGAGFFKGGKTLDFSKLSYLSNSFMSLPSTRNKQASQTAKSMIEFIEKIQSNIV

RQEERGIVISLAADAFFDSASADVKLEERDSIQKIASFIGFLSPRGYNFKIEGHTDNIDTDVNGPSWLSAA

RSVNMLEHILNYLDQSDVKRIENNFEVSGFGGSRPIATDDTPEGRAYNRRIDILITTDASLSFPKEIKQ

f653 .nt ATGTTGACTTATGGAGACATGGTTACTTTGCTGTGTGTTTTTTGTTA

GTCATTATGTATTATTT

TTCAAGAAAATGTGATAAGAATAATGTCTGCTTCTTTCACGGGTGCTGGATTCAGGGCGGTACTAGA

TTAGTAAATTATCTTATTTGAGTAATAGCTTTATGTCTTTGCCTTCTACTGTGCGCAATAAACAGCATCCG

ACTGCTAAAAATAAATCCATGATTGAATTTATGAGAAGATTCAGTCTAAAATATTGTAGTTAGGGAGA

GAGGTATTGTAATATCTCTGCAGCAGATGcATTTTGATTCTGCTAGTGCAGATGAAGCTTGAATAG

AGTCATAAATGACTTTGCTTTATCAAGTTATTAAAAGGA

ACAGATAATATTGATACTGATGTAAATGGACCTGGAAAAGCAATTGGGACTTTCGGCTGCTAGATCGTTAATA

*TGCTGGAACATATTTTGAACTATTTAGATcAATCTGATGTTAAAAGAATTGAAATAATTTTGGTATCTGTT

TGGTGGAAGTAGGCCTATGCAACAGACGATACCCCTGAGGGTAGGGCTTATAATAGAAGAATGATATAT

ACTACAGATGCATCTTTAAGTTTCrcCTAAGGAAA'ITAAGcAGTAA t653.nt.

GTAAACTTTAGATTTTAGTAAATTATcTTATTAGTAATAGCTTTATGTCTTTGCCTTCTACTGTGCAT6

ACAAGCATCTCAGACTGCTAAAATAAATCCATGATTGAATTTATGAGAAGATTCAGTCTAATATTAGTT

AGGCAAGAAGAGAGGTATTGTAATATCTCTTGCAGCATGCATTTTTTGATTCTGCTAGTA6GAA6Gc TTA6AATGGTCATAAA6ACTTTTTGCTTAGCTGGcAATTA AATAAAGGCAACAGTAAATTATATAAGAATGACCTTGGAAGcAATTGGGA .AGCTGT AG'ATCTGTTAATATGCTGGAACATATTTTGAACTATTTAGATCAATCTGATGTTAAAGAATAA6ATTTG AAGTATCTGGTTTGGTGGAAGTAGGCcTATTGCAACAGACGATACCCCTGAGGGTAGGGCTTATATAGAGAAT TGATATA'rrAATTACTACAGATGCATcTTTAAGTTTCCCTAAGGAAATTAAGCAGTAA f 664. aa WO 98/59071 PCTJUS98/1271 8 103 TABLE 1. Nucleotide and Amnino Acid Sequences MRMSVYGmFAYIRSMGYVLFFFASLAVNFFNIIQVGFFITF=EPRWDKISFNFSRWAKSFFSAGAFFNL

FKSLLKVIICLIYFIIENIGKISKLSEYTLQSGISTLVAYKICFSVMFLAIVGVFDYLFQRSQYIESLKM

LTIKIUAREPIKLL ARALYANVKVNEEIPREYWEIVSKILVRVYSITIFN t664.aa FVJNhIQVGFFITFYKSLEPRWKISFNFSRWA1NSFFSAGAFFNLFKSLLKVVIICLIYY-FI.ENNIGKISKLSEYT LQSGISIVVIAYKICFFSVMFLAVGVFDYLFQRSQYIESLIMTEEVQERKEMEGDPLLRSRIKER4RVTLST

NLRVAIPQADVVITNPEHFAVAIKDSETMLAPKLAKGQDEIALTIKIARNPMKLLAALYANKVNE

EIPREYWEIVSKILVRVYSITQ(FN

f 664. nt ATGCGTATGAGTGTTTATACTATGGG'IrTTGCATATATTAGATCTATCATGGGGTATGTCGTTTTGTT'TT'rTCG CATCTTTAGCTGTTAATrT'rTTGTAATATTATcAAGTAGGCTTTTTATTACTTTTAAATCTTTGGAGCCAAG GTGGGATAAAATTAGTTTTAATTTTTCCAGATGGGCA A AATTCTTTTTTTTCAGCAGGGGCTTTTTTCAATTTG TTTAAAAGTTTGTTAAAAGTTGTTATAATATGCT'rGATATATTATI'TATTATAGAAAACA.ATATAGGCAAAATTT

CTAAGCTTTCGGAGTATACACTTCAATCTGGAATTTCTATTGTGTTAGTGATTGCCTATAAGATATGTTTTTTTTC

AGTAATGTTTTTGGCAATTGTAGGGGTGTTTGATTATTTGTCAAAGATCTCAGTACATTGAGAGTTTGAAAATG

ACAAAGAGAGTAAGCGGAGAAGGAATGAAGTGACCTTTACTTCGATCTAGAATAAAAGAGAGAA

TGAGGGTTAT'DTAAGTACCAATTAAGAGTAGCTATTCCTCAAGCAGATGTAGTAATTACAAATCCAGAACATTT

TGCAGTTGCTATTAAATGGGATAGCGAAACAATGTTAGCTCCAAAGGTGCTTGCAAAAGGTCAAGATGAAATAGCT

CT AATAAAATCAAAATAGTTCCTTTAATGGAAAATAAGCTCCTTGCAAGAGCTCTTTATG

CTAATGTTAAGGTTAATGAAGAGATTCCAAGAGAATATTGGGAGATTGTTTCAAAAATTCTTGTGAGAGTATATTC

TATT~ACTAAAAAGTTAATTAG

t664.nt TTTGTTAATATTATTCAAGTAGGCTyTirATTACTTTTAAATCTGGAGCCAAGGTGGGATAAATTAGTTTA ATTTTrTCAG~O AAA TCTrTTCAGCAGGGGCTDTTTTCAATTGTTTAAAAGTTTGTTAAAAGT TGTTrATAATATGCTTGATATATTLATTTT TAAAACAAAGAA~TCTAAGCTTTCGGAGTATACA

CTTCAATCTGGAATTTCTATTGTGTTAGTGATTGCCTATAAGATATGTTTTTTTCAGTAATGTTTTTGGCAATTG

TAGGGGTGTTTGATTATGTCAAAGATCTCAGTACATGAGAGTTGAAAATGACAAAAGAAGAGGTAAAGCA

*.GGAAAGAATGAAGTACC=TACTTCGATCTAATAAAAGAGGGATTTAAGTACC

AATTTAA.GAGTAGCTATTCCTCAAGCAGATGTAGTAATTACAAATCCAGAACATTTTGCAGTTGCTATTAATGGG

ATAGCGAACAATGITAGCTCCAAAGGTGCT'GCAAAAGTCAAGATGAAATAGCTCTCACAATTAAAAAAA-TTGC

AAGAGAAAATAATGTTCCTTrTAATGGAAAATAAGCTCCTTGCAAGAGCTCTI'ATGCTAATGTTAAGGTTAATGAA GAAT -TTAATTTTCATCAA.GTAT

AG

f680.aa TLSFVLlFIITGILILLEFNFLKDFKGNILLAGIFMGLMQGLGALPGISRSGITIFSASVIGFNRSAFEI SFLSLIPIVFGAILLF.FDIFMLNFFEnLGALVAFVGIFSINFFFMLNNKKLYYFSILFLSI

IVCYF

VRI

t680.aa

ITGILILMEFNFLVDFKGNILLAGIFMGLMQGLGALPGISRSGITIFSASVIGFNSAFEISFLSLIPFG

ILL HEFYDIFMVLNFFEINLGALVAFVVG IFS INFFFKMLNNKKYYFS IYLFALSIIVCYFVRI f680 .nt WO 98/59071 PCT/US98/12718 104 TABLE 1. Nucleotide and Amino Acid Sequences ATGT=ACATTGTCTTTCGTTTTAATTATTTTATTATAACAGGGATTTTAATCTGATGCTAGAATTTAATTTTrT TAAAGTTGATTTTAAAGGTAATATrTTTGCAGATrTTGG GATWCAAGGCTTGGGTGCGCTTCC AGGAATCTCTCGTTCAGGAATTACGATCTTTTCGGCATCGGTATTGGATTTAATAGAAAAA6GTGCATTTGAAATT TCATTTrTATCTTTAATCCAATAGTTTTTGGAGCGATTTATAAAAA TrAGATATTTTTATGG TATTAGGAGCATTAGTrGCTTGTTGTTGGTATTTTCTCAATAAATTTCTTTTT -TAAAATGCTTAATAACaAAAAACTGTATTATTTTTICTATATATTTATTTGCACTTTCAATTATAGTTTGTTATTTT GTTlAGAATATGA t680.nt

ATAACAGGGATTTTAATCTTGATGCTAGAATTTAATTITTTAAAAGTTGATTTTAAAGGTAATATITTGTTAGCAG

GAATTTTTATGGGGCTGATGCAAGGCTTGGGTGCGCTTCCAGGAATCTCTCGTTCAGGAATTACGATCTTTTCGGC

ATCGGTTATTGGATTTAATAGAAAGTGCATTTGAAATTTCATTTTTATCTTTAATTCCAATAGTTTTTGGAGCG

ATTTTATTAA.AAC-ATAAAGAATTTrATGATATTTTrATGGTTTTAAATTTTTTGAAATAAACTTAGGAGCATTAG

TTGCTTTTGTTGTTGGTATTTTCTC.AATAAATTTCTTTTTTAAAATGCTTAATAACAAAAAACTGTATTATTTTTC

TATATATTTATTTGCACTTTCAATTATAGTTTGTTATTP1'GTTAGAATATGA f688.a MIVLLISIGCANAVHI INEIFKLIKKEQLSKES IKATIKKLKTPILLTSFTTAFGFLSLTTSS INAYKTMGIFMSI GVI ISMI ISLTVLPGIITLIPFAKKKSFEKEKENKLNKISFLERLAKLNTQITKSILKRKYTSSIMVLI ILGISFV

GLLKIEINFDEKDYFKESTSVKKTLNLMQKEMGGISIFKIEIEGRPGEFINAKAMQILDLITDKLDAFSAKTQSSS

INGILKFTNFKIKKESPLEYKLPENKI ILNKLINLIDKSDWTKDNKRMYINDDWSLISI IVRIEDNSTEGIKKFEK YAINTINEYMKNNKYHFSGVYDKVLIAKTMVKEQVINIITTLGSITLLLMFFFKSIKTGII IAI PVAWSVFLNFAV

MRLFGITLNPATATIASVSMGVGVDYSIHFFNTFILQYQINQIYKTALLESIPNVFNGIFANSISVGIGFLTLTFS

t688.aa

YKTMGIFMSIGVIISMIISLTVLPGIITLIPFAKKSFEKEKENKLNKISFLERLAKLNTQITKSILKRKYTSSIM

VLIILGISFVGLLKIEINFDEKDYFKESTSKTLNLMQKMGGISIFKIEIEGRPGEFNKARMQILDLITDKLD

AFSAKTQSSS INGILKFTNFKIKKESPLEYKJPENKIILNKLINLIDKSDWTKDNKRMYINDDWSLIS

IIVRIEDN

STEGIKFEKYAINTI~NEYMx UKSGVYDKVLIAKTMVKEQVINI ITTLGS ITLLLMFFFKSIKTGI IIAIPV AWSVFLNFAVMRLFGITLNPATATIASVSMGVGVYSIHFFNTFILQYQKNQIYKTALLESIPNVFNGIFNS

ISV

GIGFLTLTFSSYKIISTLGAIIAFTMLTTSLASLTLL.PLLIYLFKPRVKLASNNNFKKLKQZ-

f688 .nt P ATGATTGTTTTACTTATTTCAATCGGATGCGCC AATGCTGTAAAAAAAGAT T AATAAAAA

AAGAACAGCTCTCAAAAGAATCCATAAGCAACAATTAAAAAACTTAAAACACCCATCCTGCTAACATCTTTTAC

*AACTGCATTTGGATTTTTATCTCTTACAACCTCTTCAATTAATGCCTACAAACAATGGGTATTTTCATAA

GGAGTAATTATCTCAATGATAATCTCATTAACCGTTTACCTGGAATAATAACATTAATCCCATTTGAAAA

AGTCTTTTGAAAAAAGAAAATAAATAAAATATCCTTCCTTGAAAGACTTGCCAAACTAATACGCA

*AATAACAAAATCTATATTAAAAGAAATATACATCCTCTATAATGGTCCTCATCATACTGGGAATCTTTTA

TGCTAAAGCAATGcAAATATTAGACTTAATTACAGATAAGCTTGATGCATTCTGCAAAAACTCAATCTAGTTCT

ATATGATTAATAAATTAATAAAGACCATGGAAATCTAAT

AATAATACACATA6TGTGTAAACATGCAGAATAAATTCTA

CGTATGCTATTTTAATAATGAGCATACGAGAAAAATGAA

TAGTTACCATAGAAAGAATAAATTATCCGTTTTAAGTTA

TACAACAGTAAGAAGTTACTAACATTGACAACCATCTTT

TTTCTTAAATCTATAAAAACCGGAATAATTATTGCAATCCr-AGTAGCATGGTCAGTGTrTTTTAAACTTTGCTGTA

ATGAGATTATTTGGGATAACCTTAACCCCGCAACGGCCAATTGCATCTGTAGCATGGGAGTAGGTAGATT

ATTCAATTCATTTTTTcAATACATTTATTTTACAATACCAAAAAATCAAATcTACAAAACTGCACCTTATC

AATACCCAATGTATTTAATGGAATATTTGCATTCTATTTCTGTTGGAATAGGATTTTTAACTCTATTCG

WO 98/59071 PCTIUS98/1271 8 105 TABLE 1. Nucleotide and Amino Acid Sequences

TCTTATAAAATAATATCAACTCTTGGCAGCAATATGCTTTACAATGCTAACGACATCTCTTGCATCACTAACTC

TTTCCATATAr'A''AAA CTAGAGTAAAGCTAGCCTCAAACAACAATTTAAAAAATTAAAACA

ATAA

t688.nt TACAA~ATGGTArTTATGcATGGATAAA'CCAAGATATCCATrAACGTTrTACCTGGAA TAATAACAT'rAATCCCATTTGCAA AAAAGTC-TTTTGAAA GAAAAGA-AAATAAACTAAATAAAATATCCTT

CCTTGAAAGACTTGCCAAACTAAATACGCATAAATTTTTAAGAAAAACCTCTATAATG

GTCCTCATCATACTGGGAATTTCTTTGTAGGTCTTTTAAAATCGAAATCAATTTGATGAAAAAGATTACTTTA

AAGAAAGCACAAGTGTAAAAAAAACATTAAACCTAGAAAAATGGGA CGATTTTCAAAATAGA AATTGAAGGCAGGCCCGGTGAATTTJAAAATGCTAAAGCAATGCAAATATTAGACTTAATTrACAGATAAGCT'rGAT

GCATTTTCTGCAAAAACTCAATCTAGTCTATTAATGGAT'AA.T~~ATTAATAAAGA

CCCCACTAGAGTATAAA.CTGCCTGAAATAAAATTATACTAAACAAACTAATAAATTTGATAGA-TAAAAGCGATTG

GACTAAGGAcAATAAAAGAATGTACATTAACGATGACTGGTCATTAATATCTATCATAGTAAGAATTGAAGACAAC TCAACC AGATAAATTAAAAGCTATTAACACAATTAATGAATATATGAAAAATAA.TAAATATC

ATTTCTCAGGTGTTATGATAAGGTATTAATAGCTAAAACAATGGTAAAAGAACAGGTTATAAACATTATAACAAC

TCTTGGATCAATAACACTACTACTTATGTTTTTCTTTAAATCTATAAAAACCGGAATAATTATTGCAATCCCAGTA

GCATGGTCAGTGTTTTTAAACTTTGCTGATAATTTGAACCTTAAACCCCGCAACGGCAACAATTG

CATCTGTAAGCATGGGAGTAGGAGTAGATTATTCAATTCATTTTTTCAATACATTTATTTTACAATACCAAAAAAA

TCAAATCTACAAAACTGCACTTCTTGAATCAATACCCAATGTATTTAATGGAATATTTGCAAATTCTATTTCTGTT

GGAATAGGATTTTTAACTCTAACATTTTCGTCTTATAAAATAATATCAACTCTTGGAGCAATAATTGCTTTTACAA

TGCTAACGACATCTCTTGCATCACTAACTCTTCTTCCATTATAATTTATTTATTTAAACCTAGAGTAAAGCTAGC

CTCAAACAACAATTTTAAAAAATTAAAACAATAA

f704.aa HNYTKFQEFISEFLGTFILLALGTGSVAMTVLFSSSPEIPGEIIKGGYTNIVFGWGLGVTFGIYTAAR4SGAHLNP

AVSIGLASVGKPVSKLLHYIVAQILGAFTGALMTLVVFYPKWIEMYDPGLENTQGIMTFPAVPGFLPGFIDQIFG

PIGIGALAIYFLKNDTFLLMFLISVVGDFTHSDNPFIPFIVGVVLSIGISFGGNGYAINPARflLGPRILLLFAGFKNHGFNNLSIVI t704.a

*GEIIKGGYTNIVFGWGLGVTFGIYTAARMSGAHLNPAVSIGLASVGKFPVSKLLHYIVAQILGAFTGALMTLVV'Y

PKWIEMDPGLENTQGIMATFPAVPGFLPGFIDQIFGTFLLMFLISVVGDFTKKHSDNPFIPFIVGAVVLSIGISFG

GMNGYAINPARflLGPRILLLFAGF1NHGFNNLSIVIVPIIGPIIGAILGATIYEFTLKNNKD f704.nt ATGAATTATACAAAwACAGAATTTATAC GATTGGAA~ACCTATTGGCTCTAGGAACTGGT CTGTTGCAATGACAGTATTATTTTCCTCAAGTCCCGAAATACCGA ATTAGGATTCTT AGATGGTGGGTTGTGTAACGTTGG ATCCGAcGAGGGGAGCACACCTAACCCA

GCTGTTAGCATAGGATTAGCAAGTGTTGGAAAGTTCCCGTTCAAAACTTTTACATTACATTLGTAGCACAATAT

TAGGAGC rCGTcTATAATTGTCGTATTrATCCTAAATGGATAGAATGGATCCTGGCT'rAG AATC CGTTCTGTTTGCGATATACATTTG ACTGTCAA~cTTTCT

TTATTGTAGGAGCAGTGGTTATCATAGGGATAAGTTTCGGAGGAATGAACGGTTATCTATTAATCCTGCAAG

GGATCTGGGACCAAGAATTTACTCrTrATTTGCTGGATTTAAAAATCACGGATTTAACAATCTAAGTATAGTTATT

GTCATATGCATATGGATTGGGCAATTCATTCCAAAT-CAA

ACTAA

t704.nt

GGAGAATATAAAGAGGTATAAAAATATATI'GATGGGGATTGGGTGTAACGTTTGGTATTTACACAG

CAGCAAGAATGAGCGGAGcACACcTAAACCCAGCTGTTAGCATAGGATTAGCAAGTGTTGGAAAGTTTCCCGTTTC WO 98159071 PCTIUS98/1271 8 106 TABLE 1. Nucleotide and Amino Acid Sequences AAAACTTTTACA'rrACATTGTACACAAATATTAGGAGCTTTACAGGTGCATTAATGACACTTGTCGTATTTTAT CCTAAATGGATAGAAATGGATCCTGGCT'rAGAAAATACTCAAGGAATAATGGCAACTTTCCCTGCTGTTCCTGGAT

TTTT~GCCTGGATTTATTGATCAAATTTTTGGAACTTTGCTAATGTTTTTAATTTCTGTTGTTGGAGATTTAC

AAAACAGCGAAATCCATTTATTCCTTTGTAGGAGCAGTGGTTTTATCAATAGGGATAAGTTTCGGA

GGAATGAACGGTATGCTATTAATCCTGCAAGGGATCTGGGCCAAGAATTTTACTCT'rATTTGCTGGATTTAAAA

ATCACGGATTTAACATCTAAGTATAGTTATTGTACCAATAATGGCCCAATAATTGGAGCAATTTGGGAGCTAC

AATTTACGAATTTACACTAAAAAATAACAAAG

ACT1AA f707.a

MLFLLYILCSFVFLNLFAQGSSSYIDKQKELAIFYYEVGQRYINGKIKKGKLFQAALKIYPDLKKGDIKLA

VELDARIKDDNPKVVEDILEEIPGVHKIEINDFTNAPKIEYAQRERSKNQDKIIKFQFGKFARALISRN

FDLFD)SVIADKVNVMGQFESKNDFISTLSSASSKADADELEYLSVDDYYDLKSLKISKSNDTSFAVNVNAKKNDVT

KNFPFWKERQTLIFTTEDDNNWFLSSINZ

t707 .aa

MLFLLYILCSFFLLFAQGSSSYIDKQKELAIFYEVGQRYINVGKIKKGKLFQAKALKIYPDLKGFDIKA

VKELDARIDDNPKVMLEDIKLEEIPGIHEKIENDFTNAPKIEYIAQRESKQDKIIKFQFGKF~AALI

SIN

FDLFDSVIADKVNVMGQFESKND)FI STLS SASSKADADELEYLSVDDYYDLKSLKI SKSNflTSFAVNVNAKKNDVT

KNFPFWKERQTLIFT*IEDDNNWFLSSINZ

f707 .nt ATGAGAAGATTATTTCTTCTATATATTTATGTTCTTTTTTTTGAATTATTTGCTCAAGGTAG'rTCTTCTT

TTCATTTTAGGTGTAAAAAAAGTGAATA

AAGGAAAGCTTTTTCAAGCAAAAGCTTTAAAGATTTATCCAGATTTGAAAAGGGGTrTGATATCAAGCTTGCcA GTA*GGTGTCAG TAGTAATCC-GTGTTCTAGAATACTAGG

ATGTCCAAATAAACAGTTTCATCCCAATGAATTGTAA

AGGGACAATAGTAATTAGTCATTGAGTGAGGTTATCAGA

CCATAAATGA

t707 .nt

CAAGGTAGTTCTTCTTATATTGATAAGCAAAAGAGCTTGCTATTTTTTATTATGAGGTTGGTAGTATATAA

*ACGTTGGTAAAATTAAAAAAGGAAAGCTTTTTCAAGCAAAAGCTTTAAAGATTTATCCAGATGAAAGGTT

TGTTAGTGATAAGGTGTCAGTTAGTAATCAGGTTAGTGGA

ATAGTGGAAACGATGGA

ATCCTAAA

AAAATC

AGTAATATATTATTGAGTGAGG

TTTAATTTCTAGGAACTTATTTGTTTGATTCAGTTATTGCGGATAAAGTTAACGTTATCAGAA~TCA

AAAAATGATTTTATATCAACTTTATCAAGTGCTTCATCTAAGCCGATGCTGATGAGTAGAGTATTATCAGTTG

ATGATATTACGATTTAAAGTCTAAAATTCAAAATCCAACGATACTTCTTTTGTATTTAATGCCA

AAAATAGTCAAATTCTTGAAAAGCATTATTATCGGAGTA

AAT'rGGTT'TTTGTCTTCCATAAATTGA f709 .aa MLIFGFIGLFFLNIFSLRAQGIVTNDAQEEFKWALNSYNNGIYDDALLSFKKTLSFDPDYDThFVY"YLG

YVEEALMEWRNLKDQGYKVPYLHLISTIEQRRGIFSNYELNFKKLVKVASLDNSIYKRPHGYQITSDYGY

YAANFVGEILYFDVNNNVNALVDGFSYLKSPYDVIEALTLYSSDEIGVDKVLGVSIGKGTDE

LLAPQYMAIDKYIYVSEWGNKRVSKFGLEGDFILHFGSRTSG GLLGPTGVIY SLIEVDT WO 98159071 PCTIUS98/12718S 107 TABLE 1. Nucleotide and Amino Acid Sequences SGHYVTIGELSFGN SKGYY~KTTI KSI~IDNMvDN

AKSYSALDIIVRILGKYENSSSLVGKEFINNYVPVYIAK

IN-VFKSM* )IGNLESNNSF TVIDISTSRNSLPSDVTV

LKASLSSRAVFGINKFKSD:VYKNIFLLGDISLYVEGAI

FSS-YEGVSKVYDLILEQKTGTYLLEYYYPGPQEPNKYFNLSVEANINQQTGRGEFAYFIN

t709.aa QGVNDQEKANYNrDL~ SDNLYFTNYRGVELERLDGK

PYRLSIQRISYLFMKALNIKRHYISRDYGYA'VNIYDNN

NALVKDGFSYK]SPYDIEANNLLVTLYSSDEIGVYDKVLGVKRKSIGNKGTKELPQYMAIDYIYVzSE WGRVSKFGLEGDFILHGSRTSGYKGLLGPTGVTYIVADSLTIEVFDTSGHYSVhTSIEGIEGLS SflFVGINNVIrVSSKDGVKYSIAKTITKILKADOKNSKISSS

ILDANNQMIVSDFNNAKVSVYKSDASLYDSLNVD

VR~ILGKYENSKGPVLSNSSNNYVPVYVAKIIVFKSM

T

QIGQIfLMNSIASPINELNIRTSGYTAKDSKASLSSRAV

FSGGILNRKAFEKYSLDTIVSYYKNNIRFYLILFGNDPINSKLQYLVNETGGAVIPFSSYEGVSKVYDLILEQKT

GTYLLEYYYPGPQEPNKYFNLSVEANINQQTGRGEFAYFIN

f709.nt

ATTATTTGTTTGTTTTTTAATTTTGTGAGCAGATGTCAT

AAGATGCTCAAGAAGAGTTAATGGGCTCTTAATTCTTATAATAATGGAATTTACGATGATTCTTTATCTTT

TAAAAAAATTTTAAGCTTTGATCCTAATAATCTTGATTATCATTTTTGGACTGGCAATGTTTATTATAGACTGGGT

TATGTTGAAGAAGCTTTAATGGAATGGAGAATTTAAAGATCAAGGCTATAAGGTTCCCTATCTTAGACATTTrGA

TCTTGATAATTCTATTTATAAAAGGCCACATGGGTACCAGATACATCTTTAAGGGCTGATAGTACGGCGGATAT

TACGCTGCTAACTTTGTAGGCATGAAATATGTATTTTGATGTTAATAACATGTAATGCTTTAGTTAAAGATG

*~*GCTTTAGTTATTTAAAATCACCTTATGATGTTATTGALAGCTAATAATCTGCTTTATGTGACTCTTTATTCAAGTGA

TGAAATTGGTGTTTATGACAAGTCTTGGAGTTAAAAGGAAATCTATTGGGAATAAAGGCACAAAGATGGCGAA

.*GTAATTGGAC TAGTATTTTrCTTGTTCTAGAACTCAGGCTATAAGGGCCTTTAGGTCC CACAGGCGTTCDTTAGAAC rTTGAATTCTGAGAAATACC-ATTGAAGTrTTTTGATACT AGTGGTAATCATTTATATTCAGTTTTrACTTCTATTGAGGGAATAGAGGGGCTTACGTGATTTTGTAGGTAATA ATGTTATAGTATCCTCAAAAGATGGTGTTTATAATATATGCATGCTAGCATCA~rrAAG

AGATAAATGAATTCTAAAATTTCTTCATCTATTTGGATGCCAATAATCAGATGATTGTCTCAGATTTTAATAAT

TTCAAGGTCAGCTATAATTAAGTGTTAGAATATAG

*TTGGAGGGCCTAAATTTACGTTGAGCTTAATGTTAGCAGTAAACGGATACCAGTTGTTGGGCTTAAAAGTGA

AAATTTTTCAATTTCAAATGAAAATTATTACATTGTCAATCCCAAGGTGGCATATAATGTAAATGCTTCAAAAGAC

ATTAATATAGCAGTTGTTTTGATAAATCTTCTTTTAATTAAAGTAAtGAGTAATG CCCTAATGGAGTTGTCATCTA 1ATATJCATT CCCATTATAGATAATATTGA

AAGCTTAACAAATAGCATTAGAAATACAAGTTCTCTTGGTCCTTATAGTACAGATGCTGTAAAAACAGACGTI'AGT

TTAGTGAGTTGCTTTAAACGTTTA

ATGAACTTAAATCCTAAAATGAG

TT:'ACT

AAATTTGATACTTATGAGTCATTTGTAGACGCGGTTATC

TTTAC-GCCTATGTGA

A'ITATTATCCAGGCCCTCAAGAACCTATATTTATTTTGTGAAGCAAATATAAATCAACAGACAGG

AAGAGGGGAGTTTGCATATTTTATTAATTAG

t709 .nt CAGGATAGTTACTAATAAAGATGC CAAGGTAAGGTC 'rAATTCTTATAATAATGGAATTTACG ATGATGCTC TTT~AAAATrAGTTTGATCCAATAATCTTGATATCATTTTGGACTGGCAA- TGTTTATTATAGACTGGGTTATG'rTGAAGALAGCTTAATGGAATGGAGAAATTTAAAAGATCAAGGCTATAAGGTT CCCTATCTTAGACATTTGATTTCTACTATI'GAGCAAAGGAGAGGTATTTTrCAAATTATGAACTTAATTTTAAAA

AACTTGTAAAAGTTGCTTCTCTTGATAATTCTATTTATAAAAGGCCACATGGGTACCAGATTACATCTTTAAGGGC

TGATAAGTACGGCGGATATTACGCTGCTAACTTTGTAGGCAATGAAATATTGTATTTTGATGTTAATAACAATGTT

WO 98/59071 PCT/US98/12718 108 TABLE 1. Nucleotide and Amino Acid Sequences ATAAGGGCCTTTAGGTCCCACAGGCGTTACT rATTGAATGAACATTTATGTTGCTTCTCAATAC CATAG AATGGTACTTTTCGTTATCATAGATGGGCTG AGTGATT'rTGTAGGTAATAATGTTATAGTATCCTCAAAAGATGGTGTTTATAAATATAGATTGAAAGCAA TTACAA~rTAAAGCAGATAAAATGATTCTCTCATCTATTTTGGATGCCAATATCAATGAT

TGCCGTTATAGCAGTCGTAAGGGTCAGCTAGTGTAAGTA

GTTAGAAGAATAATTAGGCTTGGAGGGCCTAAAA'rrTACGTTGAGCTTAATGTTAGCAGTAAAAGCGGATTACCAG T'rGTTGGGCTTAAAGTGAAATTTTTCAATTTCAAATGAAAATTATTACATTGTCAATCCCAAGGTGGCATATAA

TGTAAATGCTTCAAAAGACATTAATATAGCAGTTGTTTTTGATAAATCTTCTTATATGAAAAAATATGATACAGAT

CAAATTGTAGGGTTAAATGCCCTAATGGAGTTGTCAAAAAATAAAACTTTAGTTTTATAAATGCAACAAGTGTGC

CCATTATAGATAATATTrGAAAGCTTAACAAATAGCATTAGAAATACAAGTTCTCTTGGTCCTTATAGTACAGATGC TGTAAAAACAGACGTTAGTTTGtAAGTT]GGCAGGTTCTGGGCTTATGTCAAAAGCTCAAGAAGAGCAGTAGTTTAT

TTTAGTGGTGGTATTTTAAATCGTAAAGCTTTTGAAAAGTACTCTTTAGATACAATAGTAAGCTATTATAAAAATA

ATAAAGTTATATCATGTATACCATAATACTATTTGTAGAA

AGGCGGTGCTGTAATTCCTTTTCATCTTATGAAGGTGTATCTAGTTTATGATAATTTTAGCAACG

GGCACTTATTGTTGGA6ATATTATTATCCAGGCCCTCAAGAACCTAATAAATATTTTATTTATCTGTTGAGCAA

ATATAAATCAACAGACAGGAAGAGGGGAGTTTGCATATTTTATAATTAG

f730 .aa

MIKSILDYLLTLHPVLLGLLGSTFTWFTTAFGAAVFFFRKVDNKIMDAMJGFSAGIMIAASFFSLIQPAIERAEE

LGYITWVPAVFGFLVGAFFIYIVDVFVPDLDKLTFIDEDLTKHGKKDFLLFTAV'rLHNFPEGLAVGVAFGALASNP 9: DIQTLVGAMLLTLGIGIQNIPEGAAISLPLRRGNVALAKCFNYGQMSGLVEIVGGLMGAYAVYSFTRILPFALAFS

AGAMIYVSIEQLIPEAKRKDIDNKVPSIFGVIGFTLMMFLDVSLGZ

t730.aa AVFFFRKVDNKIMDAMLGFSAGIMIAASFFSLIQPAIERAEELGYITWVPAVFGFLVGAFF IYIVDVFVPDLDKLT 4 4 FIDEDLTKMGKKDFLLFTAVTLHNFPEGLAVGVAFGALASNPDIQTLVGAMLLTLGIGIQNIPEGAAISLPLRRGN

VALAKCFNYGQMSGLVEIVGGLMGAYAVYSFTRILPFALAPSAGAMIYSIEQLIPEAKR.KDIDNKVPSIFGVIGF

TI MMFLDVSLGZ f730..nt

ATGA.TAAATCAATTTAGATATTTATTAACTTTGCATCCTGTATTATGGGACTTTAGGTTCTACTTTCACTT

GGTTTACTACAGCTTTTGGAGCAGCAGCAGTTTTTTCTTTAGAAGGTAGATAATAAAATAATGGACGCTATGCT

TGGTTTTTCAGCTGGCATTATGATAGCGGCCAGTLTTTTTTCGCTTATTCAGCCTGCTATAGAAAGAGCTGAAGAG

CTTGGATACATTACTTGGGTGCCGGCTGTTTTTGGATTTCTTGTGGGGCATTTTTTATATATATTGTAGATGTAT

TTGTTCCAGATCTGGATAAACTTACTTTTATTGATGAAGACTTAACTAAACATGGTAAAAAAGATTTTTACTCTT

~:.TACTGCTGTTACTTACATAATTTCCGAAGGATTGGCTGTTGGAGTTCTTTTGGAGCCTGGCGTCTAATCCA

GATATTCAAACTTTAGTTGGGGCTATGCTTCTTACGCTTGGTATTGGTATTCAAAATATTCCCAAGGAGCAGCTA

'ITTCTCTGCCTTAAGAAGAGGTAATGTTGCTrTGGCAAAATGCTTTAACTATGGCCAAATGTCAGGATTGGTAGA AA6TTGTGGGGGGGCTTATGGGTGCTTATGCGGTTTATTCTTTTACTCGAATTI'rACCTTTTGCTTTGGCTTTTTCT

GCAGGAGCTATGATTI'ATGTGTCALATTGAACAATTAATACCTAAGCTAAGAGAAAAGACATTGACAATAAAGTGC

CAA.GTATATTTGGTGTTATTGGTTTTACATTAATGATGTTTCTCGATGTTTCACTAGGTTAA

t730 .nt GCAGTTTTTTC TGAGTGTAAATAGAGCTATGCTTGGTTTTCAGCTGGCATTATGATAG

CGGCCAGTTTTTTTCGCTTATTCAGCCTGCTATAGAAAGAGCTGAAGAGCT'GGATACATTACTTGGGTGCCGGC

TGTTTTTGGATTTCTTGTTGG AT1'TAAAA~'TAGATGTATTTGTTCCAGATCTGGATAAACTTACT TTTATTGATGAAGACTTAACTAAACATGGTAAAAAAGAT'rTTTTACTCT'rTACTGCTGTTACTTTACATAATTTTC CAGAAGGATTGGCTGT'rGGAGTTGCTTTTGGAGCCTTGGCGTCTAATCCAGATATTCAAACTTTAGTTGGGGCTAT WO 98/59071 PCTIUS98/12718 109 TABLE 1. Nucleotide and Amino Acid Sequences GCTTTTACGCTTGGTATTGTATT1CAAAATATTCCCGAAG GACCAGCTA=rCTCTGCCTTrTAACGAAGAGGTAAT GTTGCTTGCAAGTTACTATGGC GGGGCTAGGGT ATGCGGTTTATTCTTI'TACTCGAA.TTTTAC~ i ZT?TTCTGCAGGAGCTATGATTTATGTGTCAAT TG-aACAATTAATACC GACAGGAAAATA2TATGCC;ACTATATTTGGTGTTATTGGTTTT ACATTAATGATGTTTCTCGATGTTT1CACTAGGTTAA f197 .aa

MLKLKYRFVGFLLLFLIFILLLFSTIFNFVLCGYLEDYYKQLTAQVRRAAFSLQSFLDTLHVIINGAASNILALE

TISEFAMSENRGKDFSESELIDLRKUPTr VDSKSKKYRQYLYNFMANLNDTLFEEFAFnFEGRVIVSTRHE

NNMDFGHSEANTNYFKKAVEDYRQNQLKFIGWYSNLSEGISAEVAIRSKQSEKKFAIIVPVYSPEDKLVCGYLAG

YLLNDIVAflSFDRF-FGFYKRGNFIYVDPNNIAVNPFEEYNTSRVSSFLNVLKDVFSKPPFPSNIASEVSVY'rI

DRILLSEMGEDCYYAMLPISSKLGEKSGVLIARLPYKDIYGVISSLRFQYILYSVLGIIALSIVSIRIDRIISFR

LNAIRVLVQDM4KGNLDKDYALfDDETLDELGMLSLQVV1KKAISVAISSVLRNISYVNKASLEVASSSQNLSS

SALQQASALEEMSANVEQIASGVNMSANNSYETEQIALKTNESQIGGRAVEESVIAMQDIVEKVSVIEEIARKTN

LLALNAIEAAGDEGKGFAVVASEIRKLAflLSKISALEIGELVEDNSKVATE.AGVIFKELPEIEETANLVKI SEGSSKQSDQIAQFKMALDQVGEVVQSSASSSEQLSSMSDKMLESKELRKSVLFFKIKDSKIENPENfDYDFRLI

DCPENSFKENQNLKSNGISTSNASGHNYSLDIESESSRTINKRDPKKAIDIAKLNFDDFSEF

t197.a

VLCGYLEDYYKQLTRAQVRRAAFSLQSFLDTLVIINGAASNALETISEFAMSENRGKDFSESELIDLRKUJPKFV

IDSVKVSRKQYLYNFMANaQ'mTLFEEFAFFDFEGRVIVSTRENNMDFGHSEANTNYFKKAVEDYRQNQLKFI

GWYSNLSEGISAEVAIRSKQSEKKAFAIIVPVYSPEDKLVCGYLAGYLLNDIVADSFDRFRFGFYKRGNFIYVDPN

IARLPYKDIYGVISSLRFQYILYSVLGIIALSIVLSIRIDRIISFRNAIRVLVQDMVKGNLDKDYALDDDENTLD

ELGMLSLQVVKAI=SVAISSVLNISYVNKASLEVASSSQNLSSSALQQASALEEMSANVEQIASGVNMSANNS

YETEQIALKTNENSQIGGRAVEESVIAMQDIVEKVSVIEIKTNLLALNAAIEAARAGDEGKGFAWVASEIRKL

ADLSKISALEIGELVEDNSKVATEAGVIFKEMLPEIEEANLVKCISEGSSKQSDQIAQFKMAIJDQVGEWVQSSAS

SSEQLSSMSDKMLEKSKELRKSLFFKIKDSKIENPENDDYDFRLIDCPENSFKDENQNLKSNGISTSNASGHNNY

***SLDIESESSVRTINKRVDPKKAIDIADKDLNFDDDFSEF

f197 .nt 4 ATGTTATrGALAGCTTAAATACAGGTTTGTTGGATTTTTATTATTGTTTTTAATTTTTATACTGCTACTTTTTTCCA CGATT~rTA~TrTTTAATTG T cGTTAGGTATTATGACA TTACAAGGGCGCAAGTAAGAAGAGC AGCTTTTCTTTGCAATCvrTTTAGACACCCTGCATGTCATAATCAATGGTGCAGCTTCTAATTGGCACTTGAA ACCATATCAGAATTTGCAATGTCTGAGAATAGAGGAAAAGATTTCTCTGAGTCGGAAT'rGATAGATTTAAGAAAAA

ATCCAAAATTTGTTATTGACTCTGTAAAGGTGAGCAAAAAATATCGACAATACTTATACAATTTATGGCCAATCT

TAA-AATGATACCCTTTTTGAAGAATTCGCT TTrG'rAGGGA GAfTAATGTTAGCACAAGACATGAG

AATATAGGATTTGTCTTTGAGGCTAATACCAATTATTTTAAAAAAGCTGTTGAGGATTATAGGCAAAACC

AATTAA.AATTTATAGGTTGGTATTCAAATCTTTCTGAAGGAATATCCGCAGAAGI'GCTATTAGGTCTAAACAAALG

CGAAAAAAAGGCTTTTGCAATAATTGTACCTGTATATTCCCCAGAAGATAAACTTGTTTGTGGGTATTTGGCCGGA

**TATTTGCTTAATGATATTGTGCGTGrIGTG TGTTCGGTTrATAAAAGALGGCAATTTTATTT

ATGTGGATCCCAACAATATAGCAGTTAATCCTTTTGAAGAATATAATGAAACCAGCAGGGTTAGTTCTAA-ATTTTT

GAATGTTCTTAAAGATGTTTTCTCTAAGCCCCCTTTCCATCAAACATGCCAGTGAAGTGTCGGTTTACACTATT

GATAAATATTTTGTCCGAAATGGGAGAAGATGTATTATGCAATGTTGCCCATAAGTAGTAAATGGGAGAALA

AGAGTGGAGTACTTATTGCTAGGCTTCCTTATAALGGATATTTACGGAGTAATATCTAGTCTAAGATTTCAGTATAT

TTATATTCAGTC TGCTAACTAGATTCTCAALTAGAATAGACAGGATTATTAGTTTTCGT TTAACGCATTAGAGTTCTAGTTCAGATATGGITAAGGGCATTTAGATAAAGATTATGCTCTGATrATGATG

AAAATACTCTTGATGAACTTGGCATGTTAAGTCTTCAGGTTGTTAAA.ATGAAAAAAGCTATTTCTGTAGCAATTTC

TAGTGTTTTGAGAAATATTAGCTATGTAAAGCAGTGATTGCCAGTTCAAGTCAAAAT1'TAAGCTCT

AGTGCATTGCAACAGGCATCTGCTCI'GAAGAAATGTCAGCTAATGTTGAGCAAATAGCCTCAGGTGTCAALCATGA

GCGCCAATAATTCTrATAAACAGAACAAATAGCTTTAAAGACGAATGAAAATrrCTCAGATAGGTGGTAGGGCCGT

TGAAGAATCTGTTATTGCTATGCAAGACATTGTGGAGAAAGTTAGTGTTATTGAAGAGATAGCTAGAAAAACCAAT

TTACTTGCTTTGAATGCGGCTATTGAAGCTGCAAGAGCAGGAGATGAGGGAAAGGGATTT1GCTGTTGTGGCCAGTG WO 98/59071 PCT/US98/12718 110 TABLE 1. Nucleotide and Amino Acid Sequences AGATTAGAAAGT'rGGCTGATTTGAGTAAAATTTCTGCTCTTGAGATTGGAGAGTTAGTTGAAGATAACTCTAAGGT AGCAACTGAAGCGGGAGTGATCTTTAAAGAAATGCTACCCGAAT'GAAGAAACGGC'rAATCT'rGTTAAGAAGATT TCAGAAGGTAGCTCTAAGCAAAGCGATCAGATTGCTCAATT'rAAAATGGCTTrAGATCAGGTTGGAGAAGTTrGTTC AATCTTkCAGCTTCAAGCAGTGAGCAGCTTTCTAGTATGTCCGATAAAATGTTAGAAAAGTCTAAGGAACTTAGAAA

ATCTGTATTATTTTTCAAAATTAAAGATTCTAA.AATTGAAAATCCAGAAAATGATGATTATGATTTCAGGTTAATA

GATTGTCCTGAAATTCTTTTAAAGATGAAAATCAAAATTTGAAAAGCAATGGAATTTCTACTTCAAATGCCAGTG

GGCATAATAATTATTC'TTrAGATATTGAGAGCGAATCTTCTGTAAGAACTATTAATAAGCGAGTTGATCCTAAAAA AGCTATCGA6TATTGCTGATAAGGATTTAAATTTTGATGATGATTTTTCAGAGTTTTAG t197 .nt GTTAGTTATAAGTTAT rTACGTTACAAGGGCGCAAGTAAGAAGAGCAGCTTTTTCTTTGC

AATCTTTTTTAGACACCCTGCATGTCATAATCAATGGTGCAGCTTCTAATTGGCACTTGAAACCATATCAGAATT

TGCAATGTCTGAGAATAGAGGAAAAGATTTCTCTGAGTCGGAATTGATAGATTTAAGAAAAAATCCAAAATTTGTT

ATTGACTCTGTAAAGGTGAGCAAAAAATATCGACAATACTTATACA6A'TTTATGGCCAATCTTAAAAATGATACCC

TTTGAAGAATTCGCTTTTTTTGATTTTGAAGGGAGAGTAATTGTTAGCACAAGACATGAGAATAATATGGATTT

TGGTCATTCTGAGGCTAATACCAATTATTTAAAAAAGCTGTTGAGGATTATAGGCAAAACCAATTAAAATTTATA

GGTTGGTATTCAAATCTTTCTGAAGGAATATCCGCAGAAGTTGCTATTAGGTCTAAACAAAGCGAAAAAAAGGCTT

TTGCAATAAT'rGTACCTGTATATTCCCCAGAAGATAAACTTGTTTGTGGGTATTTGGCCGGATATTTGCTTAATGA

TATTGTGGCAGATAGTTTTGATAGATTTAGATTCGGTTTTTATAAAAGAGGCAATTTTATTTATGTGGATCCCAAC

AATATAGCAGTTAATCCTTTTGAAGAATATAATGAAACCAGCAGGGTTAGTTCTAAATTTTTGAATGTTCTTAAAG

ATGTTTTCTCTAAGCCCCCTTTTCCATCAAACATTGCCAGTGAAGTGTCGGTTTACACTATTGATAGAATACTTTT

GTCCGAAATGGGAGAAGATTGTTATTATGCAATGTTGCCCATAAGTAGTAAATTGGGAGAAAAGAGTGGAGTACTT

ATTGCTAGGCTTCCTTATAAGGATATTTACGGAGTAATATCTAGTCTAAGATTTCAGTATATTTTATATTCAGTCT

TAGGCATTATAGCATTAAGTATTGTTCTTTCAATTAGAATAGACAGGATTATTAGTTTTCGTTTAAACGCAATTAG

AGTTCTAGTTCAAGATATGGTTAAGGGCAATTTAGATAAAGATTATGCTCTTGATGATGATGAAAATACTCTTGAT

GAACTTGGCATGTTAAGTCTTCAGGTTGTTAAAATGAAAAAAGCTATTTCTGTAGCAATTTCTAGTGTTTTGAGAA

ATATTAGCTATGTAAATAAGGCAAGTTTAGAAGTTGCCAGTTCAAGTCAAAATTTAAGCTCTAGTGCATTGCAACA

GGCATCTGCTCTTGAAGAAATGTCAGCTAATGTTGAGCAAATAGCCTCAGGTGTCAACATGAGCGCCAATAATTCT

TATGAAACAGAA.CAATAGCTTAAAGACGAATGAAAATTCTCAGATAGGTGGTAGGGCCGTTGAAGAATCTGTTA

TTGCTATGCAAGACATTGTGGAGAAAGTTAGTGTTATTGAAGAGATAGCTAGAAAAACCAATTTACTTGCT'GA

TGCGGCTATTGAAGCTGCAAGAGCAGGAGATGAGGGAAAGGGATTTGCTGTTGTGGCCAGTGAGATTAGAAAGTTG

GCTGATTTGALGTAAAATTTCTGCTCTTGAGATTGGAGAGTTAGTTGAAGATAACTCTAAGGTAGCAACTGAAGCGG

GAGTGATCTTTAAAGAAATGCTACCCGAATTGAAGAACGGCTAATCTTGTTAAGAAGATTCAGAAGGTAGCTC

TAAGCAAAGCGATCAGATTGCTCAATTTAAAATGGCTTTAGATCAGGTTGGAGAAGTTGTTCAATCTTCAGCTTA

.AGCAGTGAGCAGCTTTCTAGTATGTCCGATAAAATGTTAGAAAAGTCTAAGGAACTTAGAAAATCTGTATTATTTT

TCAAATTAAGATTCTAAATTGAAATCCAGAAATGATGATTATGATTCAGGTTAATAGATTGTCCTGAAAA

TTCTTTTAAGATGAAAATCAAAATTTGAAAAGCAATGGAATTTCTACTTCAAATGCCAGTGGGCATAATAAT'rAT 5.5: TCTTTAGATATTGAGAGCGAATCTTCTGTAAGAACTATTAATAAGCGAGTTGATCCTAAAAAAGCTATCGATATTG

CTGATAAGGATTTAAATTTGATGATGATTTTTCAGAGTTTTAG

f200 .aa MTISKVFSKFILKFLNSSAFVSVFALFVGFLIVGLVVMGLGHSPFRMYFIILEIIFSSpKHLGyvLSYSPLIFT

GLSIGISLKAGLFNIGEGQFILGSIVALIALLDLPPILHVITIFIITFLASGSLGILIGYLKAKFNISEVISG

IMFNWILFHLNNIILDFSFIKRflNSDFSKPIKESAYIDFLASWKLSPEGLAYRSSHPFVNELLKAPLHFGI ILGI I

FAILIFLKTIIGFKINTGSNIEASRCMGINAVLIFSMFLSAAVAGLAGAIQLMGVNKAIFKLSYQGIGF

NGIAASLMGNNS PIG IIFS SILFS ILLYGSSRVQS LMGLPS SIVSLMMGIIVLVI SASYFLNKI VLKG KVKYNN

ILD

t200 .aa LVVMGLGHSPFRMYFIILEIIFSSPKHLGYVLSYSAPLIFTGLSIGI

SLKAGLFNIGVEGQFILGSIVALIASVLL

DLPPILHVITIFIITFLASGSLGILIGYLKAKFNISEVISGm4FTWLFHLNNI

ILDFSFIKRDNSDFSKPIKESA

YIDFLASWKLSPEGLAYRSSHPFVNELLKAPLHFGIILGI IFAILIWFLLNKTI IGFKINATGSNIE-ASRCMIN WO 98/59071 PCTIUS98112718 TABLE 1. Nucleotide and Amino Acid Sequences KAVLIFSMFLSAAVAGLAGAIQLMGVNKAIFKLSYMQGIGFNGIAASLMGNNSPIGIIFSS

ILFSILLYGSSRVQS

LMGLPSSIVSLMMGIIVLVI:SASYFLNKIVLKGVKRKYNNILD

f200 .nt

ATGACAATTAGTAAACGTATTTAGTAAATTATZTTGAAATTTTTAAATTCTTCAGCATTTGTTIAGTGTAT=G

CTCTATTGTTGGATTTTTAATGTTGGGCTATGGTGATGGGGCTGGTCA-TTCTCCTTITTAGAATGTATITTTAT

AATA~AGAT~TTTTTT~cTcccAA~cATTTAGGTATGTTTAAGTTATTCAGCTCCTrTGATTTTACA GGTCTTrCTATGGTATTTCTTTrAAAGCGGTC'' ATTTGGTAGCCAGTTATACTAGGATCTA TTGTTGCTTTAATAGCATCAGACTTGATTGCCTCCAATTTACATGTAATACTATTTTTATTwATTrACTTT TTITAGCT'rCAGGCAGTTTAGGAATTTTAATCGGATATTTAAAAGCCAAATTCAATATTAGCGAAGTGATTTCAGGA

ATAATGTTATGAAIATCTTAAATTATTGTTATTTTATTAAAAGAGATAATAGTG

ATTTTTCAAACCCATTAAGAAAGCGCATATATTGATTTTTAGCTTCTGGAAGCTCTCACCAGAAGGTCTTGC

TTATAGATCTTCTCATCCTTTGTAATGAGCTTTTAAAAGCACCTCTTCATTTTGGAATAATTTAGGTATAATT

TTTGCTATTTTAATATGGTTTTTACTTAATAAAACTATTGATAATATCCACAGGAAGTAATATTG

AAGCTCAAGATGTATGGGTATTAATGTAAAAGCTGTGCTAAMTTTTTCAATGTTTCTCTCAGCAGCTGTTGCAGG

TCTTGCTGGTGCTATTCAACTTATGGGTGTTATAAAGCTATATTTAAGCTCTTATATGCAAGGAATTGGTTTT

AATGGGATAGCTGCTTCTCTTATGGGAAACAATTCGCCAATTGGCATAATATTTTCTAGCATTCTTTTT'rCTATAT

TGCTTTATGGAAGCAGTAGAGTTCAAAGT'TTAATGGGCCTTCCATCTTCAATTGTATCTTTGATGATGGGAATAAT

TGTTCTTGTAATTTCTGCTAGCTATTTTTTAAATAAAATTGTTTTAAAAGGTGTTAAGCGTGTCAAATATAATAAT

ATT~CTTGATTAG

t200 .nt

GGGCTAGTGGTGAGGGGCTTGGTCATTCTCCTTITTAGAATGTATTTTATAATATTAGAAATTATTTTTTCTTCTC

CCAAACATTAGGTATGTTTTAAGTTATTCAGCTCCTTTGATTTTTACAGGTCTTTCTATTGGTAT

T

TCTTAAA

S..AGCGGGTCTTTTTAATATTGGGGTTGAGGCCAGTTTATACTAGGATCTATTGTTGCTTTATAGCATAGTTTTA

CTGTTCTCATTCTTATCATTTTATCTTTGTCGCGTAGAT

TATGAATAAGCAATAT ACAGTATCGATAGTTATGTTATC AG TGTTTAACCATAGA **GCATATATTGATTTTTAGCTTCTrTGGAAGCTCTCACCAGAAGGTCTTGCTTATAGATCTTCTCATCCTTTTTA

ATGAGCTTTTAAAAGCACCTCTTCATTTTGGAATAATTTTAGGTATATTTGCTATTTTAATATGTTTTTACT

TAATAAACATTGATA.AAAA

CACAGGAAGTAATATTGAGCTTCAAGATGTATTTTAAT

GTAAGTTCATrTCAG

CCCGAGTTGAGCTCGTCATALTAG

GTTATAGTTTTAGTTTAAGAGGATGTTAGGTACGTCCTTG

AAcA~~cAT~AATTTcArA~TTTcAATCTAGAGATGGTA

AGTALGGCTCTTCATTT~TAGTGATATTCTTATCGTGTT

TTTTAAATAAAATTGTT=AAAAGGTGTTAAGCGTGTCAAATATAATAATATTCTTGATTAG

f208.aa MVSSFKIIFIELE...FPKRALFGLDIIFFyI..SQLIVNL

FDIIHCLIPLAFYSSYQLIIVAHETILNPIMLSLFKLFLRLLRFNDLIIEIYNSKELILIAFARTFSMSL

*LIPFTFFIIISSSKIVNSIPEKQEFNIIKNISIINEKAYIKYPFILIIKEDDIIYSKSDEIYSPSYRV

EKTwKFYIDKYLQRKSlSILGIFFTLFASFTIFLNFYKFFKASFLNPIILMTKILQDPLEYRKIQI

PFTLSEE

KVYEIAKSFNNLLLKEKLNS1RKSKIPLEIEKVKKIINKNQEIK t208.aa

IIIFSIFELLIEELSIILFLPYKIRFALIFLGFLFDTIFIFIFLYKITKAYLSQRLEIYVRNNLFFDIIHCLIPLA

FySSYQLKIIVAHETILNPIMLSLKLRFLRLLRFNLIIEIYYNSKENLILIAFARTFSMSLLIPFTFFIIIS SSKIVNSIPEKQEFNIIISIINEKAYIKEKYPFILIIKMKDDI

IYSKSDEIFVYYSPSEYRVIEMEKTKFYIDK

YLQRKSDSILGIFLFTLFASFTIFLM*FYKFFKASFLNPI

ILTKILQDPLEYRKIQIPFTLSEEKVYELAKSN

LLLKEKLNSKRKSKIPLEIEKVKKIINKNQEIK

f208 .nt WO 98/59071 PCTIUS98/12718 112 TABLE 1. Nucleotide and Amino Acid Sequences ATGGTAAAAAAATTTTC-AATTTTCTTAAACAATAATAAmTTICAATATTGAACTTTTAATCAAGAACTCT

CAATAATTCTTTTTTTACCATACAAMATACGATTTGCACTAATATTTCTTGGGTTTCTATTTGACACAATTTTTAT

TTTCATTerTTTATACAAAATAACCAAGGCCTACCTTTCCCAAGATTAGAAATCTACGTCAGAAACAATCTATTC

TTCGATATAATCCACTGCCTTATTCCI'TAGCGTTTTATAGCTCATAT-AGCTAAAAACATAATTGTCGCCCATG

AAACAATATTAAATCCAATAATGCTATCACTTTTCAAGTTAAGATTITTTAAGACTTCTTAGGTTTAATGACCTAAT

AATAGAAATATATTACAATCAAAA AGAACCTAATACTAATAGC-ATTTGCTAGGACATTTTCAATGAGCTTA TTAATACCAT TCTTTAATAACAAGCTCAAAAATTGTAAAMCAATACCAGAAAAACAAGAATTTA ATAT ATAATTTATAAAGAAGTTACATTAAAGAAAAATATCCCTTCATCTTAATAATCAA

GGAAAAGTGACTAAATATCAAAATCAGACGAAATATTTGTTTACTACAGTCCCAGTGAALTATAGAGTAATA

GAGAA AAAAATTAAAAAATTTCAAAAGGATCTATTCTTIGGAATT1'CTAT

TTACATTGTTTGCATCATTTACTATTTTTATGAATTTTTATAATTTTAAAGCAAGCTTTTAAATCCTAT

TATTTTAATGAcAAAAATTTTACAAGAcCCATTAGAATATCGAAAAATTCAAATTCCT'ITTTACTTTAAGCGAAGAA

AAAGTATATGAACTTGCAAAATCATTTAACAATCTCTTGCTAAAAGAAAAACTAAACTCAAAGCGAAAAAGCAAAA

TACCTTTA ATAAATAAAATATAATAAAAACCAGGAAATAAAATGA t208 .nt

ATAATAATTTTTTCAATATTTIGAACTTTTAATCGAAGAACTCTCAATAATTCTTTTTTTACCATACAAAATACGAT

TTGCACTAATATTTCTTGGGTTTCTATTTGACACAATTTTTATTTTCATTTTTTTATACAAAATAACCAAGGCCTA

CICTTTCCCAAAGATTAGAAATCTACGTCAGAAACAATCTATTCTTCGATATAATCCACTGCCTTATTCCTTTAGCG

TTTTATAGCTCATATCAGCTTAAAAACATAATTGTCGCCCATGAAACA-ATATTAAATCCAATAATGCTATCACTTT

TCAAGTTAAGATTTTTAAGAC'rTCTTAGGTTTAATGACCTAATGATAATCATCAAAAGAAAAGAA

CCTAATACTAATAGCATTTGCTAGGACATTTTCAATGAGCTTATTAATACCATTTACATTTTTTATAATAATATCA

AGCTCAAAAATTGTAAA.TTCAATACCAGAAAAACAAGAATTTAATATCATTAAAAATATATCAATAATAAATGAAA

:.AAGCTTACATTAAAGAAAAATATCCCTTCATCTTAATAA-TCAALGGAAAAAGATGACATAATATACTCAAAATCAGA

CGAAATATTTGTTTACTACAGTCCcAGTGAATATAGAGTAATAGAAATGGGAAAACAAAATTTTATATAGATAAA TATTTGCAAAGAAAAAGCGATTCTATTCTTGGAATTTTTCTAT~tTACATTGTTTGCATCATTTACTATTTTTTTAA

TGAATTTTTATAAATTTTTTAA.AGCAAGCTTTTTAAATCCTATTATTTTAATGACAAAAATTTTACAAGACCCATT

AGAATATCGAAAAATTCAAATTCCTTTTACTTTAAGCGAAGAAAAAGTATATGAACTTGCAAAATCATTTAACAAT

CTCTTGCTAAAAGAAAAACTAAACTCAAAGCGAAAAAGCAAAATACCTTTAGAAATTGAAAAGTAAATAA

TTAATAAAAACCAGGAAATAAAATGA

flIQIIIMLLALLDFPLNARLLDISIEKADEEIKKYSSNLLEKEYYTNFPSEIENIYKITEHFVKSILN

**TNYSLLNSNYKANLIQSELIDKKFLKKIFKIKNINGIFKSHSLIYTKKGFYKLELYIENNAEPLKIFNNT

YFLKNLDKISNEMIFFPREKREVNMIQKTTIAADSSSKPRGINYDTGIPFNVLIVDDSVFTVKQLTQIFTSEGFNI

*IDTAAflGEEAVIKIHYPNIDIVTLDITMPGITCLSNIMEFDKARVIMISALGKEQLVKDCLIKGAKTFIV

KPLDRAKVLQRVMSVFVK

t210.aa

*****RILDISIEKRADEEIKKYSSYNLILEKEYYTNFPTSEIENIYKLTEHFVKSIMLNKTNYSLLNSNAKYLQ

SEI* KKFIUNIKHSITKFKEYENELIFLIYLNDIN-IFR KREVNMIQKTTIAADSSSKPRGINYDTGIPFNVLIVDDSVFTVKQLTQIFTSEGFNIIDTAAlGEE-IKYNHP NIDIVTLDITMPKDGITCLSNIMFDKARVIMISALGKEQLVKICLIKGAKTFIVKPLflRAKVLQRMSVFV f210.nt

ATGAAAATTCAAATAATTATAATGCTGCTTGCATTGTTAGATTTTCCACTTAATGCCAGACTTTTCA

TTGAAAAGAGCAGATGAAGAAATAAAAAAATATTCGTCTTATAA-TTTAATTTTAGAAAAAGAATACTATACCAA

TTTTCCAAcAAGCGAAATAGAAAAAAATATTTATAAACTAACAGAACATTTTGTAAAAAGCATAATGCTCAATA

ACTAACTACAGCTTATTAATTCAAACTACAAAGAAGCAATAATATCTAATTCAAGCGAACTCATTGATAA

AATTTTTAAAATATAAAATATTTAAAATCAAAATATAAATGGAATTTTTAAAAGCCATTCACTAATATATAAA

WO 98159071 PCT/US98/1 2718 113 TABLE 1. Nucleotide and Amino Acid Sequences' AAAGGATrT=ACAAATTrACAACTTACATAGAAAATAATCGCAG

AACCTCAAAAATATTTAACCTTAACATTACT

TATTTTTAAAGAATTTAGATAA.AATAAGTAATGA.ATGATT

TTTTCCCAAGGGAATGA

t210 .nt

AGCTTGCTTATGAAAACGTA~AAAAAAATGCTTATATTA

AAAAAGAATACTATACCAATTrCCAACAAGCATGAAATT

AAATAACAGAACATITI'GTAAA

AAGCATAATGCTCAATAACTAACTACAGCTTATTAAATTCA-AC

AAGAC~AAACTAATCA

TGA

f22.aa MLKTLTKI ITISCL-VGCASLPYTPPKQNLNYLMELLPGANLYAHNLIINRSIYNSLSPKYKSVLGLISNLYFSY KKMNFALLIMGNFPKDIFWGIHKNRNTES IGNIFTNPKWKLKNSNIYI IPNKARTSIAITQKDITAKDNNI4LTT

KYIGEIEMFFWIQDPTLLLPNQIVSSKNLIPFSSGTLSINSLNQEEYIFKSLIKTNNPPILKILSKLIPTVL

TNMTNLTISSHIKTTIKDQNTVEIEFNIQKSSVESLIEKLASNIQT

t22 .aa

PYPKN"MLPALAVLKRINLPYSLLSLFYKNDALMNPDF

GIH2UMTESIGNIFTNPKWKLKNSNIYI

IPNKARTSIAITQKDITAKDNNMLTTKYIGEIEKMEMFFWIQDPTLL

LPNQIVSSKNLIPFSSGTLSINSLNQEEYIFKSLIKTNNPPILKILSKKLIPTVLTNMTNLTISSHIKTTIKDQNT

AGTTAAACATAAAAAATA~ACATTCATGCCTCATAGTGGATGCGCGCCCTACACTCCTC

**CAAAACAAAATCTAAATTACTTAATGGAACTTTTACCTGGCGCAAATTTATACGCCCATGTATAAA

C.GCATATATTTACCTATT.TCGTTGG rTACATATCTACA

AAAAAGAAATAACGATTTGCTCTACTAATAATGGGTAATTTCCCAAAAGATATTTTCTATCTAA

AAGATAAGATCATAGCAATATATTTACAAATCCAAATGGAACTTAAAAACATATATACATTAT

TCAAAACAACACTGATACAAAGTTACCAAAATAAGTAAC

AATATTTGGGAATGAAAATGAATTTTTTTGGATTCAAGATCCAACATTATCACCACAA

TATACGAAATATCCTACGGAATTTTTACGTAACAAGAAA

TTTTAAATCCTTAATCAAAACAAATAATCCACCAATACTAAAATATTGTCAAAAGTTAATTCCCGT

ACACTGCACC:CATTAGCAAAAGCAAAAA:CCAAACGTAATGA

TTAATATTCAAAAATCTAGTGTTGAAAGCCTTATAGAAAAACTAGCI'CAAATATTCAAACCTA

t22 .nt

CCTTACACTCCTCCAAAACAATCTAAATTACTTAATGGAACTTTTACCTGGCGCAAATATACCCTGTAA

ATAC TGTTAAAATAGATTTTGCTCTACTAATAATGGGTATCCCAAAGATATTCTGG GGATCAILTGGrAAAAAAA~AA~ATGcAAATAAA~AATTGAAACA ATATATACATTATCCAAACAAAGCTAGAACTAGCATTGCAATAACCC

AAGTATAACCGAGACATA

AAGAAGAATATATTrAAATCCTTAATCAAAACAAATAATCCACCAATACTAAAAATAAAAGTTGAAT TCCAACCGTCTTGACA ACATGACAAACCTCACAATATCAAGCCACATAAAGACCACAATAACA.TACG

GTTGAAATAGAATTTAATATTCAAAATCTAGTGTTGAAGCCTTATAGAAAACTAGCAATATCACCT

AA

f 221. aa WO 98/59071 PCT/US98/1271 8 114 TABLE 1. Nucleotide and Amino Acid Sequences

MGTFLSFSVGSDVEVKTFYVEVFYRQLFAT=VNDNMST

VFDKKLISQYAI[FIEVKKXFGE.ATLVTPLNYLWI)LGDSI IVLNKNILRITLKSYISNYNX t221.aa

SMDSVKEVLKSTIFDVEEVEFPYARQTLQFIAKTHLKYAVFNFDKNMFSYTFVFDKKLISQYAIFIEVKKK

FGEATLVTPLNYUMDLGDSIIVLNKNILRITLKSYISNYNK

f221.nt ATGGGTATTACAGrTTTTTATTTAT'rTTCTATTTTTGCATCTTTTGTTCTGGGTTCTAGCATGGATTCTGTTAAAG AGAATGTTCTCAAGAGCACTATTrTTTTATTATGATGTTGAAGAAGTTGA6ATTTCCTTATGCTAGGAAGCAGACTTT

ACAATTTATTGCTAAAACCCATTTAAAATATGCTGTTTTTAATTTTGACAAAAATAAAATGTTTTCGTACACTTTT

GTTTTTGATAAAAATAATATCTCAGTATGCAATTTTTATTGAGGTAAAGAAAAAGTTTGGCGAGGCTACACTAG

TAACGCCTTTGAATTATTTATGGGATCTTGGTGATTCTATTATTGTTWITAAATAAAAATATTTTAAGAATTACTTT

AAAATCTTATATTTCAAATTATAATAAATGA

t221.nt

AGCATGGATTCTGTTAAAGAGAATGTTCTCAAGAGCACTATTTTTTATTATGATGTTGAAGAAGTTGAATTTCCTT

ATGCTAGGAAGCAGACTTTACAATTTATTGCTAAAACCCATTTAAAATATGCTGTTTTTAATTTTGACAAAA ATAA AATGTTT1TCGTACACTTTTGTTTTTGATAAAAAATTAATATCTCAGTATGCAATTTTTATTGAGGTAAAGAAAAAG TTTGGCGAGGCTACACTAGTAACGCCTTTrGAATTATTTATGGGATCTTGGTGATTCTATTATTGTTTTAAATAAAA ATATTTTAAGAATTACTT'rAAAATCTTATATTTCAAATTATAATAAATGA f253.aa MYIEVRGQPNFFGLIPFFVFII IYLGTGIYLGVIGVEMAFYQLPASVAMFFASIVCFLVFKGKFSDKIHIFIK

GAAQYDIILMCLIFMLSGAFSSLCKEIGCVETVANLGIKYINPNWIVSGIFFVTCFLSFSAGTSVGSIVAIAPIAF

NIAVKSGINPNLIAASVMCGAMFGDNLSLISDTTIVSSRTQGSSILVFISSSFYAFPSAILTFFSFFFLSENLSN

ATNFLHESSIDLVKTVPYLMIIFFSLAGMNV.FIVLFLGILSICLISVLYGNLYFLDVMKINKGFLNMADLIFLSI

LTGGVSFAVIHNGGFKWLLIKLKSLIRGKSSAEFSIGAFVSIVDVFLAINNTIAILICGKVAIKIAFENNISVQRSA

SILD)MFSCIFQGI IPYGAQMI ILVNFSNGLVSPISILPFLVYFGFLLFFVILSILGLDIKKVFLFFLKK t253.aa

LVFKGKFSDKIHIFIKGAAQYDIILMCLIFMLSGAFSSLCKEIGCVETVANLGIKYINPNWIVSGIE'FVTCFLSFS

AGTSVGSIVAI-APIAFN-AVKSGINPNLIAASVMCGAMFGDNLSLISDTTIVSSRTQGSSILDVFISSSFYA.FPSA

ILTFFSFFFLSELSNATNFLHESSIDLVKTVPYLMI IFFSLAGMNVFIVLFLGILSICLISVLYGNLYFLDVMKN INKGFLNADLIFLSILTGGVSFAVIHNGGFKWLLIKLKSLIRGKSSAEFSIGAFSIVlVFLANNTIAILICGKV AXKIAFENISVQRSASILDMFSCIFQGI IPYGAQMIILVNFSNGLVSPISILPFLVYFGFLLFFVILSILGLflIK

KVFLFFLKK

f253.nt

ATGTATATGGAAAATATTAAGTAAGAGGGCAGCCAAATTTTTTTGGGCTTATTCCTTTTTTTGTTTTATATTA

TCTATTTAGGCACGGGGATTTATTITGGGAGTTATTGGTGTAGAAATGGCCTTTTATCAACTGCCGGCTAGTGTG

AATGTTTTTTGCTTCCATTGTTTGTTTTTTGTTTAGATTCCGACA.AAATTCACATATTTATTAAA

GGAGCAGCTCAGTACGATATTATACTAATGGTCTT1ATT1TTTATGCTTTCGGGAGCTTTCTCTTCTCTTTGTAAAG

AATAGGCTGCGTTGAACTGTAGCAAATTTGGGAATAATATATAATCCTAATTGGATTGTT'CTGGTATATT

TTTTACGTTTTTTTTCGCCTCGTGTTTGTCATCCTTGTT

AATATTGCTGTTAAAGcGGCATTAATCCGAATTTAATAGCAGCATCTGTAATGTGTGGAGCTATGTTTGGGATA ATCTTTCTTTAATATCAGATAcAACTATTGTTTCTAGTCGAACTCAAGGTAGTAGCATCTTAGATGTTTT"TATTAG TAGCAGTTTTTATGCTTTTCCATCCGCCATACTAACTTTTTTTTCTTTTTTCTTTCTTTCTGAAAATT'rGTCCAAT

GCCACAAACTTTTTACACGAAAGTTCAATAGATTTAGTGAAAACTGTGCC-TTATTTAATGATTATATTTTTCTCTT

WO 98/59071 PCT/US98/1271 8 115 TABLE 1. Nucleotide and Amino Acid Sequences

TAGCTGCGAATGAATGTTTTTATAGTTCTTT'TTTTAGGTATTCTTTCTATATGTCTTATTAGCGTTTGTATGGTAA

TTTATACTTTCTAGATG ATAAAATAAAGTTTTTAAATATGGCGGATI'GATTTTTCTTTCAATT

TTAACAGGGGGAGT'ITCTTTTGCCGTGATCATAATGGAGGCTTTAAATGGCTACTTATTAAATTAAAATCCTTGA

TTAGAGGAAAAAGTTCAGCGGAA1T'CTATTGGGGCTTTGTTTCAATAGTTGATGTTTTTCTTGCTAATAACAC AATTGCCATACTTATTTGC GAATGAAAGTGTTrGAAAATAACATCAGTGTTCAAAGAAGTGCT

TCTATTTAGATATGTCTCTTGTATTTCAAGCATTATCCTTATGGTGCGCAAATGATTATTTTAGTGAMT

TTTCAAATGGACTTGTGTCGCCAATTAGTATTGCCATTTT'rAGTTTATTTTGGATTTTTATTGTTTTTTGTTAT

TTTATCTATTTGGGCCTTGATATAAAAAAAGTTTTATTT'AA~AA

t253 .nt

TTGGTATTTAAAGGAAATTTTCCGACAAAATCACATATTTATTAAAGGAGCAGCTCAGTACGATATTATACTAA

TGTGTCTTATTTTTATGCTTTCGGGAGCTTCTCTTCTCTTTGTAAAGAAATAGGCTGCGTTGAAACTGTAGCAAA

TTTGGATAAAATATAACCTAATTGGATTGTTTCTGGTATATTTTTTGTAACCTGCTTTCTTTCTTTTTCT

GCCGGCACTTCTGTTGGATCTATCGTTGCAAT'rGCTCCTATTGCTTTAATATTGCTGTTAAAAGCGGCATTAATC

CGAATTTAATAGCAGCATCTGTAATGTGTGGAGCTATGTTTGGAGATAATCTTTCTTTAATATCAGATACAACTAT

TGTTTCTAGTCGAACTCAAGGTAGTAGCATCTTAGATGTTTTTATTAGTACC-AGTTTTTATGCTTTTCCATCCGCC

ATACTAACTTTTTTTTCTTTTTTCTTTCTTTCTGAAAATTTGTCCAATGCCACAALACTTTTTACACGAAAGTTCAA

TAGATTTAGTGAAACTGTGCCTTATTTAATGATTATATTTTTCTCTTTAGCTGGAATGAATGTTTTTATAGTCT

TTTTTTAGGTATTCTTTCTATATGTCTTATTAGCGTITTGTATGGTAATTTATACTTCTAGATGTAATGAAAAAC

ATTAATAAAGGGT'TTTAAATATGGCGGATTTGATTTTTCTTTCAATTTTAACAGGGGGAGTTTCTTTTGCCGTGA

TTCATAATGGAGGCTTTAAATGGCTACTTATTAAATTAAAATCCTTGATTAGAGGAAAAAGTTCAGCGGAATTTTC

TATTGGGGCTTTTGTTTCAATAGTTGATGTTTTTCTGCTAATAACACAATTGCCATACTTATTTGCGGCAAAGTA

GCAAAAAAGATAGCTTTTGAAAATAACATCAGTGTTCAAAGAAGTGCTTCTATTTTAGATATGTTCTCTTGTATTT

T'rCAAGGCATTATTCCTTATGGTGCGCAAATGATTATTTTAGTGAATTTTTCAAATGGACTTGTGTCGCCAATTAG

AAAGTTTTTTTATTTTTTTTAAAAAAATAA

f265.aa

KCFVSLSLLLIFFACSSNVEIELNDDISGIVSIFVNVNEFEKIRKELLTTLVGEEIANMPLFPVDEIKKYFKN

GEEKLGLKLLSIKTQGDSINLVKDNLIKILGDYKPDISVFKIEKDG1IIELNINLENATKNINENKEYIS

DALAALLPSDEIPMSAKEYVLVFLSDFTSKASELIDNSKLLVVKTSRNVQEQFGFKQINSNTLRFMDMKG

LSLETPIKLRLV

y t265.aa p SNVEIELNflDISGIVSIFVNVNREFEKIRKELLTTLVGEEIANMPLFPVDEIKKYFKNGEEKLGLXLLSIKTQGDS

INLVVKFDNLIKILGDYMKPDISVFKIEKKDGKNIIELNINLENATNINEISDALAALLPSDEIPMSK

YIflVLVYFLSDFTSKASELIDNSKLNLVVKTSRNVQEQFGFKQINSNTLRFEMDMVKGLSLETPIJRLVY f265.nt

ATAAATTTGTGCTATTTGTATTTTGTGACCA*GTAATATA

ATATTA~AAAT~TGGGATTATATGAAAAAACCGATATATCTGTGTTTAAGATAGAAAGTG

TAAAAATATTATTGAACTTAATATTAATGGAAACGCTACTAAGAATATTAATGAAAATAAAGAATATATTAGT

GATGCACTTGCTGCTCTrTGCCATCGGATGAGATCCCAATGTCTGCCAAGAATATAAAGATGTGGTAr'T

TTTATCGGATTTTACTTCCAAAGCAGTGAACTTATTGACAATTCCAAACTTAATCTTGTAGTTAAGACTTICTAG

AATTCAAAATTGTCACAATATCACCCGGTTAAGAAGTAAG

T'rAAGTCTTGAAACACCAATAAAACTTAGATTAGTTTATTGA t265 .nt WO 98/59071 PCT/US98/12718 116 TABLE 1. Nucleotide and Amino Acid Sequences

T=AGTATTAAATGATGATATTAGTGGTATTGTTTCAATATTTTAATGTTAATAGAGAATTTG

AAAAAATTAGAAAAGAACTCTTAACAACTTTGGTGGGAGAAGAAATTIGCAAATATGCCTCTT'ITTTCCTGTAGATGA

AATAAAAAAATACTTTAAAAATGGAGAGGAAAAGCTTGGGCTTAAGCTTTGAGTATTAAAACCCAAGGAGATT'CT

ATTAATTTAGTTGTTAAGTTTGATAAT'rrAATTAAMATTTTAGGCGATATATGAAAAAAcCCGATATATCTGTGT

TTAAGATAGAAAAAAAAGATGGTAAAAATATATTGAACTTAATATTAATT'GGAAAACGCTACTAAGAATAT.AA

TGAAAATAAAGAATATATTAGTGATGcAcTTGCTGCTCT''TGCCAT~CGGATGAGATCCCAATGTCTGCCAAAGAA

TAAAAGTTGTATTTTGATTCTC.ACATACTTGCATCACT

ATCTTGTAGTTAAGACTTCTAGAAATGTTCAAAACAATTTGGATTCAA.ACAAATTAACTCAAACACACTGCGGTT

TGAGATGGATATGGTTAAAGGATTAAGTCTTIGAAACACCAATAAAACTTAGATTAGTTTATTGA

f269 .aa

MIRLLFCIFFNISFLLFAGDYKGLDFKIKFFNQSIYRVNSNFIEVSLSNASESLTLEIGDINSFGFDFDVTJ

DTTNIKKRPIEYVKKRSKNVAIpVRNMSLRpNEKFSVVINLNQFflFSKDGVKGIFFPDISDPSKKSNII

TLFLNDGFDENPGSIDLVNLSENDIQDILKKKLSPDEIVKYLLKALQLGKKEKFFLYLDEGLLLNDKGKAYLY

KQKLSPI PNKN1EEYKEYLWNSNNSDIsKAPNKFSIIETTYSlTSGKVIADLYFDDGQFYISKRYTFFKYDYY

WIIYDYIVQNTGIKEK

t269.a

GDYKGLDFKIKFFNQSIYRVNSNVFIEVSLSNASESVLTLEIGDISFGFDFDVTDTTNIKVKRPIKKSN

Al PVRNMSLRPNEK.FSVVINLNQFVKFSKCDGVYFVKGIFFPDI SDPSKKKESNIITLFLNDGFDENPGS IDLVNLS ENNDIQDILKKKKLSPDEIVKYLLKALQLGKKEKFFLYLDIEGLLLNlKGKAYLYKQKLSPI

PNKNVVEEYKEYLW

NSNNSDI SKAPNKFSIIETTYSD)TSGKVIADLYFDD)GQFYI

SKRYTFFFKKYDYYWIIYDYIVQNTGIKEK

f269.nt ATATTAAATGTTTTTTTTTAGATT0TTCTTTTGGGGTAA0

TAGTAATGCGTCTGAGAGTGTTTTAACTTTAGATAGGCGATATTTTCTGCTTTGATTTGATGTTACT

GATACCACCAATATTAAAGTTAAAAGACCTATTGAATATGTTAAAAGATCTAAATTGATCCGTA

*00GAAAAAAGAAAAGTTCTTTTTATATCTTGATATGAAGGTTTGTTATTAA.ATGACAAGAGCTACCTAT

AAGCAAAAGTTATCACCTATCCCAATAAATGTAGTTGAAGAGTATAAAGAATATTTGTGGCTATATT

0:0..:TGGATAATTTATGATTACATGTTCAAAATACTGGCATTAAGGAAAAGTAA t269.nt

GGGTAAGGCTATTAATAGTTTATATTTTTGGTALAT.TTTT

00TCCTGTAGGCGGGTTTACTAA;AAGGTTAATTTGCTG 00 cGT~ccATATAGTAAGccATATAGTAAAAAcAAATT

GCATCGTGATTACTAACATAAATTCGATATATAACATGT

AGTATAGTGGTATTTAGGAMTcCGrATCGTCTTAAAAG

ATCAATTAGTTTTATAGTTGAGAACAGACTGCTGTATGC

GGCATACCTTTATAAGCAAAGTTATCACCTATTCCCAATAAAAATGTAGTTGAAGAGTATGATATGTGG

AATTCTAATAATTCGGATATTTCAAAGCACCAAATAATTTTCTATTATTGAALCTACTATTCTGATACTTCTG

GCAAGGTGATTGCTGATTTATATTTGACGATGGGCAATTTTATATTTCCAAAAGATATACTCTTCAAA

ATATGATTATTATTGGATAATTTATGATTACATTGTTC TACT AAAGTA WO 98/59071 PCTr/US98/12718 117 TABLE 1. Nucleotide and Amino Acid Sequences f29.aa

IILTNYPKSIYSYKIKRNE

t29.aa

NNKDIENLIKLHLYILTNNLSKELETINCIKNFDLEQHYLLITKYYLKIKYKEANDFLK(INQKINQKIKN

EISKRNDIE-IINENDKIQFLKKKLNINITYKISKKN

f29.nt

ATACGCACTTTTTTTATTTTATATTCTTGATCGGATAAA

AAAAAAATTAAACAAAGTTTATACATACGCA.GATGACA

t2 9.nt

TAAAGTTAGTTA*.TACGTAAGA

TGCTGAACTACGTATAAATTACAAA

AAAATTAGA*AAGTTTAAAA9.ACAAAGTAAATAAATAAA f290 .aa

HNIVGLLLLFPCNFVLENLEYKILDDKIYKPLFPSTITY

SGKVKCRIGFWQGLYKSFMNFSREY

t290 .aa

PPNSSLFLEKGQIVNFEEILKGLSVSSGNDSSIAIAEVVGNINSFVNLMNNLLLFMFFPSGYSSNY

NLVATAKGERRLVAVVKGINGFGEKSIAIqFEYFEGYSKFPLIVyGTFSKPF f290 .nt

ATATGACAGTTGGATGTTAATTTTTATTTCCTTGTTACT

TTCGTATACGG6TAALTACGGTTCAGCAATTATGTTGTCA

GCATCTATTAAGCATTGMCCCCTTTAAAATTAATTTC

GCTTAATTGAAGcTGAAAAGCGAAATATAAAATTrAAAAAGCATAGTTCCTATTAGCGATTCTGCTTCATATTATA ATGCACCCCCCAATTCTTCTTGATGTTTTTAGAAAAGGT

TTGTTAATTTATTAAG.GCT

WO 98/59071 PCT/US98/12718 118 TABLE 1. Nucleotide and Amino Acid Sequences

TTG=TCGATAMTTTCCATCTATTTGACATAAACTGTA

TTAATGAATATTAATGTTTTAATTAGGGCTTTTAATATGCATTTG~GAACCTTCTGGATATAGCAGCGAGA

ATAAGATTACAGCACTAGATATGGCTTTTI'GTGAAATCTTATATAGAAAAGTTITAAATTTATGCTTAATATTCA

TTCTTTAAAGTATTTTATTATCCAAAGAGTAGAAATTTAGGAACTGCTTTGTCATCAAAATTTTTAAACTTAAAA

GCTTAAATCTTGTTGCTACTGCTAAAAAGGGTGAGAGAGATTAATAGCAGTTGTATTGGGGGTTGAAAAAGGAAT

TAATGGATTTGGAGAGAAAATGAGATCTCGATTGAAATIATGAATGTTAAAA'CTAAA

TTTCCTTTAATAGTAA.AATTAAAAGAAAAAGTCTATAATGGTACAGTGGATACAGTTGCTCTTTTTTCTAAAGAGC

CTTTTTATATATTTAACAAAGATGTAA ATTATTATACTGTTGATAAATTGGTTGCTCC ACTTAGTGGGGATATGCCTGTTGGGAGGGCTATGAT TTTrGAAGAAAAGGTGTTGCTTTGTTT

AGTGGCAAGGTAAAAAGATTAGGGTTTGGCAAGGTCTTTATAAGAGTTTTATAAATCTTTTTTCAAGAGAGTATT

AA

t290 .nt GTTAATTTAGCTGAGATTAATAAATTATCAGAGTATGCAAAGTCAATAGTTTTAATAGATTT'rGATACTAAGCGAA

TACTTTATTCTAAGAAGCCCAATTTGGTTTTTCCTCCAGCATCTCTTACAAGATTGTACAATTTATACAGCTTT

AATTGAAGCTGAAAAGCGAAATATAAAATTAAAAAGCATAGTTCCTATTAGCGATTCTGCTTCATATTATAATGCA

CCCCCCAATTCTTCTTTGATGTrTTTTAGAAAAGGTCAATGTTAATTTTGAAGAGATTrTAAAAGGACTTTCAG

TTTCTTCGGGTAATGATTCTTCTATTGCAATTGCTGAGTTTGTAGTAGGCAATTTAAATAGCTTTGTTAATTTAAT

GAATATTAATGTTTTAAA.TTTAGGGCTTTTTAATATGCATTTTGTTGAACCTTCTGGATATAGCAGCGAGAATAAG

ATTACAGrCACTAGATATGGCTTTTTTTGTGAAATCTTATATAGAAAAGTTTAAATTTATGCTTAATATTCATTCTT

TAAAGTATTTTATTTATCCAAAGAGTAGAAATTTAGGAACTGCTTTGTCATCAAAATTTTTAAACTTAAAACAAG

AAATGCTAATTTATTAATATATGATTACCCTTATTCAGATGGCATTAAAACGGGATATATTAAGGAATCAGGCTTA

AATCTTGTTGCTACTGCTAAAAGGGTGAGAGAAGATTAATAGCAGTTGTATTGGGGGTTGAAAAAGGAATTAATG

GATTGAGAAATAGACTTCGATTGCAAAAAATTTATTTGAATATGGATTTAATAAATATTCTAATTCC

TTTAATAGTAAAATTAAAAGAAAAAGTCTATAATGGTACAGTGGATACAGTTGCTCTTTTTTCTAAAGAGCCTT

TATTATATTTTAACTAAAGATGAATTTGATAAATTAATATAAGTTATACTGTTGATAATTGGTTGCTCCA

GTGGGGATATGCCTGTGGGAGGGCTATGATTTTTT GAAGAAT GGTGCTTTCGTTAGTGG to 6CAGGTAAAAAGATTAGGGTTTTGGCAAGGTCTTTATAAGAGTTTTATAAATCTTTTTTCAAGAGAGTATTIAA to f291.aa

MSYDFITALVPIILIIIGLGIIKKPAYYVIPISLIATVAIVIFYKNLGIV]NTSLALEGALMGIWPIAVIIAAI

FTYKMSE-DQKDIETIKNILSNVSSDRRIIVLLVAWGFGNFLEGVAGYGTAVAIPVSILIAMGFEPFFACLICLIMN

***TSSTAYGSVGIPITSLAQATNLDVNIVSSEIAFQLILPTLTIPFVLVILTGGGIKGLKGVFLLTLLSGMSMAISQV

FISKTLGPELPAILGSILSMTITIVYARFFGNKETTERQSKNTISLSKGII-ACSPYILIVTFIVLVS

PLFNKIHEY

LKTFQSTISI. PEANPLHFKWISPGFLIILATTISYSIRGVPMLKQLKIFTLTLKKMALSSFIIICIVAISRLMT o H~SGMIRLANGISIITGKFGPLFSPLIGAIGTFLTGSDTVSLFGPLQrQMAENIGANPYWLAAGTGK

ISPQNITIATTTAGLIGQEGKLLSKTIIYALYYILATGLLVYLV

t291.aa too QKIETIILSNVSSDRRIIVLLVAWGFGNFLEGVAGYGTAVAIPVSILI VFPFALCI~SAG VGIPITSLAQATNLDVNIVSSEIAFQLILPTLTI

PFVLVTLTGGGIKGLKGVFLLTLLSGMSMAISQVFISKTLGP

ELALSLMIIYRFNETRSNILKI-CPIITILSLNJELTQT

SIYPEANPLHKWIISPGFLIILATISYSIRGVPMLKQLKIFTLTL

ALSSFIIICIVAISRHSMIRDL

ANGISI ITGKFGPLFSPLIGAGTFLGSDTVSNVLFGPLQTQMAENIGANPYWLAAATTGATGGMISPQNITI

ATTTAGLIGQEGKLLSKTIIYALYYILATGLLVYLV

f291.nt

ATGAATTCTTATGATTTTATAACAGCTTTGGTACCAATAATCCTAATAATTATTGGACTTGGCATTAAAGC

CACTCAGATCCTTATAACACGTCAATAATTTAACTGATG

AACCATTGATCTAGCCTATGGAAGCATGACGATATCGCT

WO 98/59071 PCTJUS98/12718 119 TABLE 1. Nucleotide and Amino Acid Sequences TTACATAcAAAATGTCAGAAGATCAAAAAGATATAAAACTATTAAAATATTTATCAAACGTATCTTCTGATA TTGTT CATCTGAGATTGcATccAACTAATACTCC AACCTTAACAATACCTTTTGTACTGGTAATTCTTACAGG

AGGGG~CATTAAAGGATTAAAAGGAGTATTCCTTCTTACCTTACTCTCAGGAATGTCAATGGCAATATCTCAAGTA

TACATACCTTGAAAAATGGcATTATcTTccTTATAATCATATGCATTGTTGCAATATCAAGATTAATGACA t291.nt

CAAAAAGATATAGAACTATTAAAAATATTTIATCAAACGTATCTTCTGATAGAAGAATTATAGTATTACTAGTTG

CATGGGGATTTGGAATTTTTTAGAAGGAGTTGCTGGATATGGACTGCTGTTGTCCTATATATTAT

AGATGATGACTTTGCGTATTGTATAGAACCTACGCAGAC

GTGATCTTAACTACCACATACTGTTACTGTCTTAATCTC

AATAATCACTAcAACTTTCGGATCTCGAGGCTAAGTAAG AGATCTTACTCCrAGAGCATGATTTA-TTTTTAAATTGTC

GACTCGATCTG...TTTCAGCAACA-ATTTCAGTT~GAAAA

AACATACCAACAAAAATTCT@9AAGATTGCGCCCCAATTA

TTATCTTTTCTTTTAAAATAGAACTAACTTCAGATT

AGATACAAGAACCTCCTAAGGTACCCGGTCTATTCTCAA

CATTcATATCGGGTCAGTAACGTAATTTCTACTGAAATG TCCTTACTGGCTTGCAGCAGCAATACAACAGGAGCAACTGGAGGGAArATTCCACATCACATAG 9 CAACAACAACTGCTGGATTAATTGGACAAG' f296.aa GTVGEQLNVNFIINSLNLSERGKSELyTIFHSAITKNNADKILYTLKF

YMFQWLFIATTINSRY

9 U LIEAEFISYVGVFLELESDGYEAYKWINIKIVNPYSVLGLTYSASDD)EVKKAYKSLIl'HPDANPRK

ANDKFIKIQDAYEKICKERNIR

t296 .aa IYF YSYSRSREFEFYKLSFLLMAKLLSILGTVTGEQLNYVNFI

INSLLSERGKSELYTIFHSKADK

ILTKGFHDFWFTK-NLRKLAKIYGFEEDYAKIlrNYVGT sAsDDEvflAYKsLviKYHPDKFADPVRQKANDKFIKIQDAYKICERIR f296 aft

ATCAGCATAATTTTTATTGTTTTTTTTTACCTTATGA-G

TTTATTTTCTTTTGTTATATTTAGGTTAATTCTAAAGAT

CTAATTGTTGGGTGATTTACTCTTTTATGTATGTTTTTT

WO 98/59071 PCTIUS98/12718 120 TABLE 1. Nucleotide and Amino Acid Sequences

GGAACTGTAACTGGGGAGCAGCTAAATTATGTCAATTTTATTATCAATTCTTTIGAATTTGTCTGAACGTGGTAAAT

CAGAATTGTATACCA'rTTTTCATTCTGCTATTACTAAAAATAA-TAATGCTGATAAAATTTTATATACCCTTAAGCT

TGGTTATTTTCAGCACAAAGATCTTTTITATATGGCTTTTTGCCACTCTTAAAGAAATTAACAGGCTTTCTAGGTAT

AAAAATTTAGAAGCTGAAAAATTTrATTTCTTATGTTGGTGTTTTTTTAGAACTTGAATCTGATGGTTATGAAGCTT

ATAAGATTTAAATTAAATGTAAATCCTTATAGTGTTTTGGGGTTAACATATAGTGCTAGCGATGATGAGGT

TAAAAAGGCGTATAAAAGCCTTIGTTATAAAATATCATCCTGATAAGTTTGCAAATGATCCTGTAA.GACAAAAAGAT

GCAATGTAATTTTAAAATCAAGATGCTTATGAAAAAATTGCAAGGAAAGAAATATAAGGTAA

t296.nt

ATATACTTTACAAGGGATTACTCATATTCTAGATCTAGAGAGTTTGAATTTTATAAACTTTCTTTTTTATTAATGG

CTAAATTGCTATCTATTTTAGGAACTGTAACTGGGGAGCAGCTAAATTIATGTCAATTTTATTATCAATTCTTTGAA

TTTGTCTGAACGTGGTAAATCAGAATTGTATACCATTTTTCATTCTGCTATACTAAAAATAATAATGCTGATAAA

ATTTTATATACCCTTAAGCTTGGTTATTTTCAGCACAAAGATCTTTTTATATGGCTTTTTGCCACTCTTAAAGAA-A

TTAACAGGCTTTICTAGGTATAAAAATTTAGAAGCTGAAAAATTATTTCTTATGTTGGTGTTTTTTTAGAACTTGA

ATCTGATGGTTATGAAGCTTAAAAATATTAATTGTAAATCCTTATAGTGTTTTGGGGTTAACATAT

AGTGCTAGCGATGATGAGGTTAAAAAGGCGTATAAAAGCCTTGTTATAAAATATCATCCTGATAAGTTTGCAAATG

ATCCTGTAAGACAAAAAGATGCAAATGATAAATTTATAAAAATTCAAGATGCTTATGAAAAAATTTGCAAGGAAAG

AAATATAAGGTAA

f3.aa MYKKNSIYMIMLI SLLSCNTSDPNELTRKKMQDKNVKI LGFLEKIQADNKEIVEKHIEKKEKQMVQAASVA.PINV ESNFPYYLQEEIEIKEEELVPNrDEEKKAEKAI SDGSLEFAKLVDDENKLKNESAQLESSFNNVYKEILELADLIQ AEVHVAGRINSYIKKRKTTKEKEYnCKREIKNKIEKQALIKLFNQLLEKRGDIENLHTQLNSGLSERASAKYFFEKA

KETLKAAITERLNNTKRKNRPWWARRTHSNLAIQAKNEAEDALNQLSTSSFRILEAMKIKEDVKQLLEEVKSFLDSS

KSKIFSSGDRJYDFLETSK

0 t3.aa :0e"g0 NELTRKKMQDKNVKILGFLEKIQADNKEIVEKHIEKKEKQMVQAASVAPINVESNFPYYLQEEIEIKEEELVPNTD

EEKKAEKAISDGSLEFAKLVDDENKLKNESAQLESSFNNVYKEILEILADLIQAEVHVAGRINSYIKKRKTTKEK.EY

KEIKKIEKQALIKLFNQLLEKRGDIENLHTQLNSGLSERASAKYFFEKAKETLKAAITENNKRKNRPWWAR

RTHSNLAIQAKNEAEDALNQLSTSSFRILEAMKIKEDVKQLLEEVKSFLDSSKSKIFSSGDRLYDFLETSK

0 ATGA AAAA A AATTTIATCAATTTACATGATAATGCTAATAAGTTTATTATcATGTAATACAAGTGACCCCAATG

AATTAACTCGTAAAAAAATGCAAGACAAGAACGTGAAAATTTTAGGATTTTTAGAGAAAATTCAAGCAGATAATAA

6 AGAAATTGTGAACTTGAAAAAAAAAGTGCAGGCTGCTTCTGTAGrCACCTATTAATGTA GAGAGTAATTTCCCATATATCTAGAAAAAATAAAGAA GTTCCAAATACTGATGAA-G AAAGAAGGCAGAGAAGGCArTAGCGATGGGAGTCTTGAATTTGCTAAATTAGTTGATGATGAAAATAAACTTAA *0:e AAATGAATCTGCGCJLATTAGAATCTAGTTTAATAATGTTATAAGAATCTTAGAACTGCAGATTTAATACAA~ GCAGAGGTGC-ATGTTGCAGGAAGGATAAATAGCTATATAAAAAAAAGAAAGAccAcTAAAGAAAAAGAATATAAGA 0 AGAGAGAAATTAGAAGTAAAAAGTCTAATTAAGTTGTTCAATCAGTTATTAGAAAAAAGAGGCGA 0000 TATTGAAATCTTCATACTCAATTAAATAGTGGACTTAGCGAGAGAGCATCTGCAAAATACTTTTTTGAGAAAGCC

AAAGAAACTITTAAAAGCTGCTATTACTGAAAGATTAAATAACAAACGTAAAAATCGGCCATGGTGGGCAAGAAGAA

CACATAGTAATTTAGCATCGCAAATAGAAGTCTTAAACCAATTAAGTACTTCTTCTTTTAG

GATACTTGAAGCAATGAAAATAAAGGAAGATGTAAAACAGCTTCTTGAAGAAGTAAAATCTTTTCTAGATTCTTCA

AAGAGCAAAATCTTTTCTAGTGGCGATAGATTATATGA6TTTTTTAGAGACGAGTAAATAA t3 .nt

AATGAATTAACTCGTAAAAAAATGCAAGACAAGAACGTGAAAATTTTAGGATTTTTAGAGAAAATTCAAGCAGATA

ATAAAGAAATTGTTGAAAAACATATAGAAAAAAAAGAAAAACAAATGGTGCAGGCTGCTTCTGTAGCACCTATTAA

TGTAGAGAGTAATTTCCCATATTATCTTCAAGAAGAAATAGAGATAAAAGAAGAAGAGTTGGTTCCAAATACTGAT

WO 98159071 PcTIUS98/12718 121 TABLE 1. Nucleotide and Amino Acid Sequences GAACAACAGGACACATTA CGATC GAGTCTTGAATTTGCTA-AATTAGTATGATGAAAATAAAC TTA-AGTTCCATGACATTATAGTAAAMTTA-tCTCGTTA

ACACGGTCTTGAGAGTATGTAAAAAAGAGCATAGAAGAA

TTCAAAGAGCAAATCTTTCTAGTGGCGATAGATTATATGATTTTTAGAGACGAGTAAATAA

MNKLLVISSVMSSTKKKIDFNNVVINDKTSPYKLN-FGT

SHFLISNNDIAINTSPYEKQNFFPKGLYIYNKQISKQEIIMI

ILNPKEDEIENCD)YGFSGFFV

LINKKNKTHRIGDMKLLTERGNSGSNADASGTANDGSTV

KSNNAPYKLNFTANIFGQERPVPFHLGIKLPN

t3 0.aa LSKSITKKSKYKIIRDYFINSNYVLVKIENKDLKFTI SKPIYDKKLNNYFFKGQTTSHFLI

SNNVDIAINTSPYEV

KQNMFFPKGLYIYNKKMISKQINNYGEIVIKHNKI ILNPKEflEIENCDYGFSGFFVLIKNGKYKKNFKETRHPRTI IGD0MFVIGGNSGSNADASGMNILGGSLVSNPKNTNFQ-

PVPFHLGIKILPN

TGTGATATTATTTACATCATCGCAACAC

CCAAACAAAAATATGGTATCAAAACATTTCGTAATGAAA

AGTTAATACTTAACTTTCAAAACAAATATCTA.GCAAAC

AGCTTTA*T ATTGAATCATAAAGCAACAATAAAACTTT TccAAGcA~AAAATAAAAGT~cA~AAAAACAGAAATTAA-

TAGGAATAAAACTTCCTAATTGA

nt AAACAAAACATGTTrTCCCAAAGGACTAAATTTATAAAAAATATATCG GAGAGATTGTAATAAGcACAACAAATTATATTAAATCCCAAGGAAGACGAAATATCATAAT CTGTCCrTTTTTAATAAAACTCCAATGATA

AA.TTAACC~A

f308 .aa

MQLNYFRLDFVAVLSFNNEWNDNFFIRFIFIFKTSDFVF

IPEFFWSLFKIIMVFIFLYLPSLYFNAFWISKFLTTFTA

WO 98/59071 PCTUS9811271 8 TABLE 1. Nucleotide and Amino Acid Sequences

EELFYRAFVITKFTQMGFPVVATAIELSSMFFAYGHILYYGILGFLVTFILGIFFAFTYLRYKVYYIFIHSFYNII

VSSLLLFLN

t3 08.aa

NSEFWNVDENHFYFWISRSFLIIFIIYFFKLTSSYDDFRVEFFIPKFKFIFLWDSVLIFIKTILIAMIVIFLIAFL

LEYLLPESVLVYYFQNNAGFNWKISSKKAFFLMTFTSFFTGAFEELFYRAFVITKFTQMGFPVVATAILSSMFFAY

GHLYYGILGFLVTFILGIFFAFTYLRYINVYYVIFIHSFNIIVSSLLLFLN

f308 .nt

ATGCAATTGTTAAAAAATAAATATCCATTCAAGCGGGCTTTGCTTGATCTTTTTTTGGTCTATGCTATTGTTTATT

TGGCATCTCCTTTTGTAAATG'ITAATTCAGAATTTTGGAATGTTGATGAAAATCATTTTTATTTT'GGATTTCAAG

ATCTTTTrTAATTATTTTTATAAI'TATTTTTTTAAACTTACCAGTTCTTATGATGATTTTAGAGTAGAGTI'T

ATTCCTAATTTAAATTTATTITTPCTTTIGGGATTCTGTTTTAATTTTTATTAAAACAATATTGATTGCAATGATAG

TCATTTTTTTAATAGCTTTTTTGCTTGAATATTTGTTGCCAGAATCGGTACTTGTCTATTATTTTCAAAACAATGC

TGGATTTAATTGGAAGmATTAGCAGTAAAAAAGCATTTTTTTTAATGACTTTTACCTCTTTTTTACAGGAGCTTTT

GAAGAACTTTTTTACAGGGCTTTTGTTATTACTAAGTTTACACAAATGGGATTTCCTGTTGTAGCTACCGCCATTC

TTAGTAGTATGTTTTTTGCTTATGGGCATTTATATTATGGAATTTTAGGATTTTTGGTTACATTTATATTAGGGAT

ATTTTTTGCTTTTACTTATTTAAGGTATAAAAATGTATATTATGTGATTTTTATACATAGTTTTTATAATATTIATT

GTTAGCAGCTTGTTGCTTTTTTTGAATTAA

t308 .nt

AATTCAGAATTTTGGAATGTTGATGAAAATCATTTTTATTTTTGGATTCAAGATCTTTTTTAATTATTTTTATA

TTTATTTTTTTAACTTACCAGTTCTTATGATGATTTTAGAGTAGAGTTTTTTATTCCTAATTT;LTTTATTTT

TCTTTGGGATTCTGTTTTrAATTTTTATTAAAACAATATTGATrTGCAATGATAGTCATTTTTTTAATAGCTTTTTTG

TGTTATTACTAAGTTTACACAAATGGATTTCCTGTTGTAGCTACCGCCATTCTTAGTAGTATGTTTGCTTAT

GGTATAAAAATGTATATTATGTGATTTTTATACATAGTTTT~IATAATATTATTGTTAGCAGCTTGTTGCTT

=T

GAATTrAA f3l.aa MKKYLFFILFLI SSNNLIVSYPLSFGGGFSYQFTNYTDKTGATKFAPNFTRADHGINLNLFFDANFELYF-A **FVVTBHIGRYFSLGLYGTYPMVFKEQVRMLFPLIGFKYAFDLSSNNFNLFFLSMGLAAflLFI

PDLDGLYIRPLFMLS

ISPFSNYFSGLTTEIMLGFNIGWRFFN

t31.aa

IVSYPLSFGGGFSYQFTNYDKTGATKFAPNFTRADHGINLNLFFDANYVLFEMSYKEAFVVTHNGRYFSIGLYGT

YPMVFKEQVMLFPLIGFKYAFDLSSNNLFFLSMGLAADLFIPDLDGLYIRPLFLSISPFSYKNSGLTTEI

NLGFNIGWRFFN

f31.nt AGcAGATCATGGGATTAATTTGAATTTATTTTTTGATGCAATTATGTACTTTTTGAAATGTCAGAGGCT

TTGTTATAATGAAATCCCTGCTAGACTTCAGTTCAAACG

TTAGAATGCTTTCCCATTAATTGGGTTTAATATGCTTTGATTTAAGCTCTAATAACTTCAATCTCTTTT

AGCATGGGGCTTGCTGCTGATCTTTATTCCCGATCTTGATGGTTTATATATTAGGCCTTGTTATGCTCT

ATTTCTTCATAAA.TTTTGTACATAATTCTGTTAACGTG

GATTTTTCAATTAG

WO 98/59071 PCTIUS98/12718 TABLE 1. Nucleotide and Amino Acid Sequences t31 .nt ATTGTTTCTTATcCACTTCTTTTGGTGGAGGTTTTTCTATCAATTTACTAATTATACTGATAAAACAGGCGCCA CTA~A'ITTGCTCCAAATTTAC AACGTAGGT'A~GATrTT'TGATGCAAATTATGTACT

TTTGAATGTCTTACAAAGAGGCTTTTGTTGTTACTCACAATGGGAGATATTTCTCGCTTGGGCTTTATGGAACA

TATCCAATGGTTCAACGGTAGTCCATTAATTGGGTTAAATATGCTTTGATTTAAGCT

CTAATAACTTCAATCTCTTTTTTTTAAGCATGGGGCTTGCTGCTGATCTTTTTATTCCCGATCTTGATGGTTTATA

TATTAGGcCT'rTGTTTATGCTTTCTATTTCTCCATTTCTAATTATAAAAATTTTTCTGGGTTAACAACTGAGATT

ATGCTTGGATTTAATATCGTGAT'ICATG

f939.aa

MKQKYENYFKKRLILNLLIFLLLACSSESIFSQLGNLQKIHEYILGSSSPRGSLVETLYIAAMHLFKK-NGK

IEKIDLSNSYEFTNDIVNI SGKTYLLAQNKEEELEVCELNGKDWTLKFKKPLKAYKFLKSVGRDGVKEAYILAIDK NNREKIFDLQGSDKTPPQATENDKFYQISNEENLITGNSLKIWQMNNNTYTNIDYQQAKEIMPI IKTSIRGSSEVL VM'rGGYNNLDTKFKVYSNTNNYTTPIFIQDEVGEFSSYFAREFNDAILIGSNNGFA.EFTKNKEGIFA.LRAPS(SVE PGAYNGSQLSKTGLNDII PVSNNTIYILTQGKGLWKLENPXKLTKE f939.aa CSSESIFSQLGNLQKIKHEYNILGSSSPRGISLVGETLYIAAMEHLFKKENGKIEKIDLSNSYEFINDIVNI SGKTY

LLAQNKEEELEVCELNGKDWTLKFKKPLKAYKFLXSVGRDGVKEAYILAIDKNNREKIFDLQGSDKTPPQATENDK

FyQISNEENLITGNSLKIWQMNNNTyTNIDyQQAKEIMpIIKTSIRGSSEVLVMTGGYNNLDTKFKVYSNTNNYTT PIFIQDEVGEFSSYFAREFNDAILIGSN~NGFAEFTKUKEGIFAJRAPSKSVEPGAYNGSQLSKTGLNDI IPVSNNT

IYILTQGKGLWKLENR

KLTKE

f939.nt ATGAAACAAAAATACGAACATTAAAAM'AFTACCTATTAATATTTI'TAcTACTAGCATGCT

CAAGCGAA.TCCATATTTTCACAATGAACGAAATAACTA.AATTTGGAGTTCAAG

TCCAAGAGGAATTTrCTCTAGTAGGAGAAACTCTCTAr-ATTGCAGCCATGCATTATTTAAAAAAGAAAACGGCAAG ATTGAAA~rGT1~GAGAM~CTTrATGAGTTTATAAACGALCATTGTAAATATATCTGGAAAAACCTATCT TAGC CAAAAAGAATAAGTGCGAGCTAAATGGAAAAGATTGGACATTAAAATTTAAAAAACC GCTAAAAGCATATAAATTC.IrAAAATCCGTAGGAAGAGATGGCGTAAAAGAAGCATATATTTTAGCTATAGATAAA

AATAATCGTGAGAAAATTTTGATCTACAAGGATCTGACAAAACACCACCACAAGCTACTGAAAATGACAAATTTT

ACAATTCAAGAGAAATTAATTACAGGAAATTCACT AATTGAAGAACAAATAC AAACATAGACTATCAACAGGCCAAAGAAATAATGCCTATCATAAAGCTAGGTcrrcTGAAGT'rTTA GTAATGACTGG GTAATATAAAAA~~AATTTACTCAAATACAAATAATTACACAACGCA TATTTATTcAAGAcGAAGTAGGcGAATTTAr-AGcTAcTTTGcAAGAGAATTAATGATGcGATATTAATCGG-

TAATATGATTGCAAATTACAAAATAAGAGGATTTTGCCCTACGGGCACCCTCAAAATCTGTAA

CCTGGAGCTTATAACGGALTCTCAGCTAAGCAAAACAGGCCTTAATGATATTZATTCCTGTATCAAACAACACGAr'rT ACATATTAACTCA3GGGCAAGGTTTGATGAACAATACAAATA t939.nt TGCTCAAGCGAATCCATATTTTCACAATTAGGAAAT± C TACTGTCAATrGCGTT CAAGTCCAAGAGGAATTTCTCTAGAGGAGAAAcTcTcTAcATTGcAGcr-ATGcATTATTTAAAAAGAAA~cGG CA~ATTAAAAATGA~TGACATTrCTTATGAGTTT~ATAAACGACATTGTAAATATATCTGGAAAAACCTAT

CTTTTAGCGCAAACAAAGAAGAAGAATTAGAAGTTTGCGAGCTAAATGGAAGATTGGACATTAAAATTTAA

AACCGCTrAAAAGCATATAAATTCTTAAAATCCGTAGGAAGAGATGGCGTAAAAGAAGCATATATTTTAGCTATAGA

TAAAAATAATCGTGAGAAATTTTTGATCTACAAGGATCTGACAAACACCACCACAAGCTACTGAAATGACAA

ITTTATCAATATCAAATGAAGAAAACTAATTACAGGAAATTCACTCAAAATATGGCAAATGA.ATAACAATACAT

WO 98159071 PCTIUS98/1271 8 124 TABLE 1. Nucleotide and Amino Acid Sequences

ACACAAACATAGACTATCAACAGGCCAAAGAAATAATGCCTATCATTAAACAAGCATTAGGGGCTCTTCTGAAGT

TTTAGTAATGACTGGTGGTTACAATAA.TTTAGATACAAAATTTAAAGTTTACTCAAATACAAATAATTACACAACG

CCATATTTATTCAAGACGAATAGGCGAATTTAGCAGCTACTTTGCAAGAGAATTTAATGATGCGATATTAATCG

GAAGTAATAATGGATTT CGATAAAATAGAGATTTTGCCCTACGGGCACCCTCAAAATCTGT

AGAACCTGGAGCTTATAACGGATCTCAGCTAAGCAAAACAGGCCTTAATGATATTATTCCTGTATCAAACAACACG

ATTTACATATTrAACTCAGGGCALAGGGTTTGT GATrGAAAAATACTAAAGAATAA f739.aa MQSGLKIKLILFFCCFACSCDINYPEIKLYKJN x F T.D4RDYSMSFDFAIKVISKDVFKLSIEN-KNNEFIQ VINNNYSSFFIDSSLGKDILYCKLRFNFFDKTFEDFTSCVRLFDKGMRVYNRELVISLGMS LDDVHNYVYKs KDMEMLNKLSNSKVFFVKTYKDKLHPVSSVVRIDSIDILEIDKAFDNYISFiYVEKNSNLFFKVG t739 .aa CCFACSCDINYPEIKELDYKINYYFTENRLDYSMSFDFAIKVINSKDVFKLSIENKNTME FIQVINNNYSSFFIDS

SLGKDILYCKDLRFNFFDKTFEDFTSCVRLFDKGMRVYNRELVISLGMSKYDLDDVHNYVYKSKDMEMLNKLSNSK

VFFVKTYKDKLHPVSSVVRIDSIDILEIDKAXFlNYI SFYYVEKNSNLFFKVG f739 .nt ATG4CAGAGCGGATTAAAAATTAA)ATTAATATTGTTTTTTTGTTGTTTTGCTTGTTCTTGCGACATAAATTATCCGG

AGATAAAAGAGCTTGATTATAAGATAAATTATTATTTTACTGAAAATCGCTTAGATTACTCTATGAGTTTTGATTT

TGCAATTAAAGTTATAAATTCAAAAGATGTTTTTAAATTATCAATAGAGAATAAGAACACTAATGAGTTTATTC.AA

GTGAT'rAATAATAATTATAGCTCTTTTTTTATTGATTCTAGCCTTGGAAAGGATATTCTATATTGTAAGGATTTGA

GGTTTAATTTTTTGATAAACTTTTGAAGATTTTACCTCATGTGTTCGTCTTTTTGATAAGGGCATGAGAGTATA

*:CAATAGAGAGCTTGTTATTTCTTTGGGTATGTCAAAATGATT TAGATGATGTTCACAA.TTATGTATATAAGTCT A*GTTGA *.ACATTACATCAATTTTGTAACTTAGAAATCT

CGGTCTCTTCAGTTGTTAGAATTGATTCA-ATAGATATTCTAGAGATTGAAAAGCATTTGATAATTACATAAGTTT

TTATTATGTCGAAAAAAATTCAAATCTTTTTTTTAAAGTTGGCTGA

t739.nt TGTTGTTT'rGCTTGTTCTTGCGACATAAATrATCCGGAGATAAAAGAGCTTGATTATAAGATAAATTATTATTTTA CTGAAAATCGCTTAGATTACTCTATGAGTTTrGATTTGAATTAAGT~ATAAATTCAAAAGATGTTTTTAAATT

ATCATAGAGATAAGACACTAATGAGTTTATTCAAGTGATTAATAATAATTATAGCTCTTTTTTATTGATTCT

9 AGCCTTGGAAAGGATATTCTATATTGTAAGGATTTGAGGTTTAATTTTTTTGATAAAACTTTTGAAGATTTTACCT

CATGGTTCGTCTTTTTGATAAGGGCATGAGAGTATACAATAGAG.GCTTGTTATTTCTTTGGGTATGTCAAAATA

TGATTTAGATGATGTTCACAATrATGTATATAAGTCTAAAGATATGGAAATGTrAAACAAGTTAAGCAATTCCAAA

GTATTTTTTGTTAAAACTTATAAAGACAAACTACATCCGGTCTCTTCAGTTGTTAGAATTGATTCAATAGATATTC

TAGAGATTGATAAAGCATTrT AIAAAGTTATTTCGAAAAAAATTCAAATCTTTTTT'ITAAAGT

TGGCTGA

f742 .aa 9**9 MHTNFSVLLLLIFLLILSFGGFGYYYQSLNDKREIMLNEVNSVIDRNYKKAYSVAKLLQDKYPQNEDIA MLTNTLAEIANSS PFESKDLQRDSANQILflKIKGQDNTKTVNENFDIAFNNRYIKDSTITENYSDRNDDVGI EDE DISEFKXSKI PEKIKPNTNPKEEDQIIQSPNPKLSNDQKLFNLEKLKKLSGKSNSENILNDSQKIENDKQNTN LSKEKNSENILKTPDNSKYSNNNNTTSLKKISSNSQKESELSP PSQ'rIIGKIYRPYSYLIKKELYEILDINTGRV

TLGKNLKEIKGLSNKFQKNELIENSKKEASNLLLTLIKIEPNLNIPKDPYKKEIFQLDKEDKKPQYLE

DLKSKVHSIKPIDLETKSRQQAIKDLNEFLKNNPNAQASKTLAQANKIQHLEDLKSKVHSIKPIDLENTKSRQQ

Al KDLNEFLKNPNDAQAS TLAQANKI QHLEDLKSKVHS IKP IDLENrKSRQQAIKDLNEFLICTNPNDAQASKTL AQANKIQHLEDLKSKVHS IKPIDLENTKSRQQAIKDLEFPNDAQASKTLAQANKIQHLEDLKSKVHSIPI

DLENTKSRQQAIKDLNEFXKNNPNDAQASKTLAQANKIQHLEDLKSKVHSIKPIDLENTKSRQQAIKDLNEFLKNN

PNDAQASKTLAQANKIQHLEDLKSKVHSIKPIDLENTKSRQQAIKDLNEFXKNNPNDAQASTLAQAYNNGDLLK

AENAYEKIIKLTNTQEDHYKLGIIRFKLKKYEHS IESFDQTIILDPKHKKALHNXGIALNMLNKNKKAIESFEXAI WO 98/59071 PCTr/US98112718 125 TABLE 1. Nucleotide and Amino Acid Sequences

QIDKYGTAYYQKGIAEE=GDMQQAFASFKAYLDIPNYALKAGVSNNLGNFKQSEEYLNFFNANAKKPNE-I

AILNLSIAKFEN~NcLEESLETINKAIEDLNPEKSEYLYLKAINLKKENYQNAISLYSLVIEEKNPETSAYINLAKA YEKSGNKSQAISTLEKIMnANLGILYEKYQKAIEIFEKAI INSflIEAKYNLATTLIEINI)NTRAD t742 .aa KLNfl1NREIMLNEVKNSVIIDRNYKKAYSVAKLLQDKYPQN~EDIAMLTNTLAEIANSSPFESKDLQRflSANQILDKI

KGQD

NKTNVNEFDIAFNNRYIKDSTITENYSDRNDDVGIEEDISEFKKSKIPEKIKPNTNPKEEIDQIIQSPNPKLSV

KESELSPPSQTIIGKI'RPYSYLIKELYEILDDGRVTLGKNRLKELIKKGLSNKFQKVNELIENSKNYEASN4

LLLTLIKDIEPLINIPKDPYKKEIFQLDKEDKKPQYLEDLKSKHSIKPIDLETKSRQQAIKDLNEFLINNPN

DAQASKTLAQAKIQHLEDLKSKHSIKPIDLENKSRQQAIKLNEFLKNPNAQASKTLAQANKIQHLEDLKS

KVHSIKPIDLETKSRQQAIKDLNEFLKNNPNAQASKTLAQANKIQHLEDLKSKVHSIKPIDLENTKSRQQAIKD

LNEFXPNDAQASKTLAQANKIQHLEDLKSKVSIKPIDLNTKSRQQAIKDLNEFXKNNPNDAQASKTLAQAN

KIQHLDLKSKHSIKPIDLENTKSRQQAIDLNEFLKNNPNDAQASKTLAQANKIQHLEDLKSKVHSIKPIDLEN

TKSRQQAIKDLNEFXKNNPNDAQASKTLAQAYENNGDLLKAENAYEKI IKLTNTQEDHYKLGIIRFKLKKYEHSIE SFIDQTIKLDPKA GAL1KA ESFEKAIQIDKNYGTAYYQKGIAEEUGDMQQAFASFKNAYNL

DKNPNYALKAGIVSNNLGNFKQSEEYLNFFNANAKKPNEIAIYNLSIAKFENNKLEESLETINKAIDLNPEKSEYL

YLXASINLKENYQNAISLYSLVIK"PENTSAYINLAKAYEKSGNKSQAISTLEKIINKNNKLALNNLGILYKKE

KNYQKAIEIFEKAIINSDIEAKYNLATTLIEINDNTRAKDLLREYTKLKPNNPEALHALGI IEYNENNNDQTLREL

IKKFPNYKINENIKKIIGI

f742 .nt GTTACTATATATATCAA ATAAGCAATGAGAAATAATGCTAAACGAAGTTAAAAP.TAGCGTAAT AGATCGAAACTATAAAAAAGCATAT1'CTGTTGCAAAACTTCTGCAAGACAAATACCCCCAAAATGAAGACATTGCA

ATGCTTACAAATACACTAGCAGAAATTGCCAA.CAGTAGTCCTTTTGAATCAAAAGACTTGCAAAGAGATTCTGCTA

ATCAAATCTTAGACAAGATCAAAGGTCAGCAAAAACATTAAACGAAAATTTTGATATAGCATTTAA

TAAAGAACATAAGACGCAAATACAAAATACTCTGACAGAAACGATGATGTTIGGCATTGAAGATGAA

GACATATCTGAAT'rTAAAAAAAGCAAAATCCCAGAAAAAATAAAACCAAATACAAACCCAAAAGAAGAAGACCAAA TAATACAA.TCTCCAAATCCGAAATTAAGTGTTAATGACCAAAAAAAT'rTATTTAATTTGGAAAAACTAAAAAAAAA TTTAAGTGGAAAATcAAATAAAA AAGATTCTCAAAAAAAGTACAAAACACAAAT

TTATCCAAAGAAAAAAATTCGGAGAATATTTI'AAAAACTCCGGACAACAGTAAATATTCAAACAATAACAATACTA

CATCTTTAAAAAATTCTTCAAATCCCAAAAAGAAAGTGAGCTrTrCTCCACCCAGTCAAACAATAATAGGGAA AATT'rATAGGCCATATAGCTACTTGATAAAAAAAGAGCTCTATGAAATATTAGACGATATTAATACCGGAAGAGTC AcL-TC~ A ACG~ITAAAAATrAATAAAAGGCTAAGCAACAAATTTCAAAAAGTAAATGAATTGA TTGAAAATTCAAAAAATAA AGAGCTTCAAATTTACTATT1AACCTTAAAAAGTTGACAAATCTCAT TAATATACCAAAAGATCCTAAAAGAT TCATAATAGAAAAACCTCAGTACCTAGAG C: GACCTTAAATCTAAAGTTCATTCAATAAAACCCATTGATCTTGAAAACACAAAATCACGCCACAAGCCATTAAPG

ATCTWACGAATTCTTGAAAACAATCCCAATGACGCTCAGGCCTCTAAACTTTAGCTCAAGCTAATAAAATAA

ACACCTAGAGGACCTTAATCTAAGGTCATTCAATAAACCCATTGATCTTGAAAACACAAAATCACGCCACA

CGCCATTAAGGATCTAACGAATTCTTGAAAAACAATCCCAATGACGCCAGGCCTCTAAAACTTAGTAGCTA

ATAAATACAACACCTrAGAGGACcTAAATCTAAGGTTCA.TTCAATAAACCCATTGATCTTGAAACAATC

ACGCCAACAAGCCATTAAGGATCTAAACGAATTCTTAAAAACAATCCCAATGACGCCCAGGCCTCTACTA

GCTCAAGCTAATAAATACAACACCTGGAGGACCTTAATCTAAGGTTATTCAATAAACCATTGATCAA

ACACAAAATCACGCCAACAAGCCATTAAGGATCTAAACGAATTCTTAAAACAATCCCAATGACGCCAGCTTA

AAACTTTAGCT AGTAAATCAACTGAGGACCTTAAATCTAAGGTTCATTCAATAAALACCCATTGAT

CTTGAAAACACAAAATCACGCCAACAAGCCATTAAGGATCTAAACGAATTCTTAAAAACA.ATCCCAATGCGCCAG

GCCTCTAAA6ACTT'TACTCAAGCTAATAAAATACAACACCTAGAGGACCTTAAATCTAAGGTTCATrCAATAAAAC

CCATTGATCTTGAAA-ACACAAAAT

CACGCCAACAAGCCATTAAGGATCTAAACGAATTCTAAAAAACAATCCCAATGACGCCCAGGCCTCTAAAACTTT

AGCTCAAGCTAATAAATACAACACCTGGAGGACCTTAA;TCTAAGGTTCATTCAATAAAACCCAT'GATCTGA

AACACAAAATCACGCCAACAAGCCATTAAGGATCTAAACGAATTCTTAAAAACAATCCCAATGACGCCCAGGCCTC

WO 98/59071 PCT/US98112718 126 TABLE 1. Nucleotide and Amino Acid Sequences

TAACTTT=AGCTCAAGCTTATAAAACAA'GGAGATTGCTAAAAGCAGAAAATGCATACGAAAAAATTATCAAA

CTCACAAATACCCAAGAAGATCACTATAAACTTGGAATCATTAGATTCAAGCTrAAAAAGTATGAACACTCAATAG

AATCATTTGATCAAACAATAAAACTCGACCCAAAACATAAAAAAGCACTTCATAACAAAGGAATAGCTTTAATGAT

GCTAAATAAAACAAAAAGCAATAGAATCTTTTGAGAAAGCAATACAAATTGATAAAAATTATGGCACCGCCTAC

TACCAAAGAAC AGAAATGGATATGCAACAAGCATTTGCAAGCrI'AAAAATGCCTACAATC TCGACAAAAACCC ATA~A'AAcAGAATATCAAATAACTTrGGGCAACTTCAAACAAAGTGAAGA GTATTrTAAATTTTTTTAATGCCAATGCAAAAAAACCTAACGAAATTGCTATTTACAACCTATCAATAGCAAAATT=

GAAAACAATAAACTTGAAGAATCTCTTGAAACAATAAACAAAGCCATAGATTAAATCCAGAAAAAAGTGAATATT

TATATTflAAAGCATCTATAAATCTTAAAAAAGAAAATACCAAAATGCTATATCACTTTACAGCTTAGTAATTGA

AAAAAACCCTGAAAATACTTCAGCCTATATAAACCTGGCAAAAGCATATGAAAAATCAGGAAATAAAAGTCAAGCA

ATCTCAACTCTTAAGTAAAAAATAAATGCTTAA.ACAATCTTGGGATACTTrACAAAAAAG AAAAAAATTATCAAAAAGCAA'FrGAAATTTTTGAAAAAGCAATAATCAATTCAGATATTGAAGCAAAATATAA.TCT

TGCAACCACTCTAATTGAAPATTAATGATAACACAAGAGCTAA-AGACCTTCTAAGAGAATATACAAAATTAAAACCA

AACAATCCAGAGGCCTTACATGCACTAGAATGAAATAATAAATGATCAAACACTAAGAGAAC

TTATAAAAAAATTTCCAAATACAAAAAAATATTAAAAATGATAA

t742 .nt

AAA.TTAAATGACAAAAATCGAGAAATAATGCTAAACGAAGTTAAAAATAGCGTAATAGATCGAAACTATAAAAAAG

CATATTCTGTTGCAAAACTTCTGCAAGACAAATACCCCCAAAATGAAGACATTGCAATGCTTACAAATACACTAGC

AGAAATTGCCAACAGTAGTCCTTTTGAATCAAAAGACTTGCAAAGAGATTCTGCTAATCAAATCTTAGACAAGATC

AAAGGTCAAGACAATACAAAAACAAATGTAAACGAAAATTTTGATATAGCATTTAATAATAGATACATTAAAGACA

GCACAATAACAGAAAACTACTCTGACAGAAACGATGATGTTGGCATTGALAGATGAAGACATATCTGAATTTAAAAA

AAGCAAAATCCCAGAAAAAATAAAACCAAATACAAACCCAAAAGAAGAAGACCAAATAATACAATCTCCAAATCCG

AAATTAAGTGTTAATGACCAAAAAAATTTATTTAATTTGGAAAAACTAAAAAAAAATTTAAGTGGAAAATCAAATA

GTGAAAATATTT'rAAACGATTCTCAAAAAATAGAAAATGATAAGCAAAACACAAATTTATCCAAAGAAAAAAATTC GGAGAATATT'rTAAAAACTCCGGACAACAGTAAATATTCAAACAATAACAATACTACATCTTTAAAAAAAATTTCT

TCAAATTCCCAAAAAGAAAGTGAGCTTTCTCC-ACCCAGTCAAACAATAATAGGGAAAATTTATAGGCCATATAGCT

AcTrATAAAAAAAGAGCTCTATGAAATATTAGACGATATTAATACCGGAAGAGTCACACTTGGAAAAAACAGATT AAAAGAATTAATTAAAAAAGGTCTAAkGCAACAAATTTCAAAAAGTAAATGAATTGATTGA.AAATTCAAAAAATAAA

GAAGCTTCAAATTTACTATTAACCTATAAAAAATACAAATCTCATTAATATACCAAAAGATCCTT

ACAAAAAAGAAATTTTTCAATTA AAAGCAAGCTCAGTACCTAGAGGACCTTAAATCTAAAGTTCA

TTCAATAAAACCCATTGATCTTGAAAACACAAAATCACGCCAACAAGCCATTAAGGATCTAAACGAATTCTTGAAA

AACAATCCCAATGACGCTCAGGCCTCTAAAACTTrTAGCTCAAGCTAATAAAATACAAC-ACCTAGAGGACCTTAAAT CTAAGGT'rCATTCAATAAAACCCATTGATCTTGAAAACACAAAATcAcGCCAACAAGCCATTAAGGATCTAAALCGA

ATTCTTGAAAAACAATCCCAATGACGCTCAGGCCTCTAAAACTTTAGCTCAAGCTAATAAAATACAACACCTAGAG

GACCTTAAATCTAAGGTTCATTCAATAAAACCCATTGATCTTGAAAACACAAAATCACGCCAACAAGCCATTAAGG

ATCTAAACGAATTCTTAAAAAACAATCCCAATGACGCCCAGGCCTCTAAAACTTTAGCTCAAGCTAATAAAATACA

ACACCTGGAGGACCTTAAATCTAAGGTTCATTCAATAAAACCCATTGATCTTGAAAACACAAAATCACGCCAAA

GCCATTAAGGATCTAAACGAATTCTTAAAAACAATCCCAATGACGCCAGGCCTCTAAAACTTTAGCTCAAGCTAAT

AAAATACAACACCTGAGGACCTTAAATCTAAGGTTCATTCAATAAACCCATTGATCTTGAAAACAcAAAATCACG

CCAACAAGCCATTAAGGATCTAAACGAATTCTAAAAACAATCCCAATGACGCCAGGCCTCTAAACTITAGCTA

AGCTAATAAAATACAACACCTAGAGGACCTTAAATCTAAGGTTCATTCAATAAAACCCATTGATCTTGAAAACA

AATrACGcCAACAAGccATTAAGGATCTAAACGAATCTTAAAAAACAATCCCAATGACGCCCAGGCCTCTAAA

CTTTAGCTCAAGCTAATAAAATAC-

AACACCTGGAGGACCTTAAATCTAAGGTTCATTCAATAAAACCCATTGATCTTGAAAACACAAAATCACGCCAC

AGccATTAAGGATCTAAACGAATTCTTAAAAACAATCCCAATGACGCCCAGGCCTCTAAAACTTTAGCTCAACTT

ATGAAAACAATGGAGATTTGCTAAAAGCAGAAAATGCATACGAAAAATTATCAAACTCACAAATACCCAGAGA

TCACTATAAACTTGGAAT ATGTCAC~AAGAGAATCAATAGAATCATTTGATCAACATA

AAACTCGACCCAAAACATAAAAAAGCACTTCATAACAAAGGAATAGCTTTAATGATGCTAATAAAAACAAAAAG

CAATAGAATCTT~TGAAG TCATGTAATAGGCACCGCCTACTACCAAAAAGGAATAGCAGA

AGAAAAAAATGGCGATATGCAACAAGCATTTGCAAGCTITAAAAATGCCTACAATCTCGACAAAAACCCATTAT

GrATTAAAGCAGGAATAGTATCAAATAACTGGGCAACTTCAAACAAAGTGAAGAGTATTTAAATTTTTTTAA.TG CCAATGCAAAAAAACCTAAcGAATTGCTATTTACAACCTATCAATAGCAAATGAACAATACTGAG

ATCTCTTGAAACAATAAACAAAGCCATAGATTTAAATCCAGAAAAAAGTGAATATTTATATTTAAAAGATCTATA

AACTAAAAATACAAGTT~-CTA-kCTGATGAAACCGAAAT WO 98/59071 PCT/US98/12718 127 TABLE 1. -Nucleotide and Amino Acid Sequences CAGCCTATATAAACrTGCAAAA~cTATGAAAAATCAGGAAATAAAGrCAGCA-ATCTCAACTCTTGAAAAGAT AAAAAAAATATACTA.CACTGAA

AAAC

ATTGAAATTTrTGAAAAAGCAATAATCAATCAGATATTGAAGAATATAATCTTGCAACCACTCTAAAA

TCAAGGAAATAAAAATAAAAAAATAACGAATATAAACCAGGATTAAATTCA

f743.a

MRYFNNKFLLLLSLYQLRGEMKKYQITS)IMYKQGYLIYE

NQLTEAEGAILLDGTAVGGEIDYILYYELGNILMFNRGEGYYPLAIK=SNSIKS.PNYDSALLNRANAYVQQGKITS

KE QADYMIDSFTRKEKSLISLNKNELKLGTHVAKDNIK

SFKDNLETNSLIELEKLNWQEELYIDE

t743.a

YSQRLIRIGKEEYYIQAIETLSDAIKYPKVQLGYYFLSIAYREQLTEAEGALLDG-TAVGGEIDYILY

LGNIMNRGEGYYPLAIKYYNSIKSRPNYDSALLNANAYVQQGKITSKEKEYQKAWDSYTMAIHDYSQFITLRS

KTEKKDSILLI ISYLRNEKINLEQLDKSLKGRTEHIVYAKEDKNQILYDSFKDNLETNSLILEKLNWQEELYIDE f743 .nt AMGATATATTAAAAATCAATT

ATTTTTTATTAATATCAA

TGGC

AACTAAC-AGAAGCAGAAGGAGCATTGCTCGATGGAATTGCAGTGGGGTGAAATCGACTACATACTATATATGA

*AAAAAGATACCAAAAGCTTGGGAcTCTTATACTATGGCTATCCACGACTACTCTCATTATTAcCCAGATC

TTTAAGTTTAAAGAAATACTACAT

GACAAAAGTTTGAAGGGGCGAACCGAGCATATTGTATACGCAAAGAAGATAAAAATCAAATACAAGATAGTT

CTAAAAATCTTATGGTGAAA

ATAA

t743.nt *'TATTCTCAAAGGCTAATTAG AATTGGCAAAGAAGAGATGAAAACAAATTACATTCAAGCATCGAACACTA GTA*TTAAATTCAAGAACCG kTCTTACAkCAAAAAATAC AAAGAATACCAAAAAGCTTGGGAcTcTTATACTATGGCTATCACGACTACTCTCAATTTAACCCTTAATC Aj AA&MAAACTTGTAATACATAGATAAATATTG~ACT ACAAAAGToAAGGGGCGAACCGAGCATATGTATACGCAAAAGAAGATAAAAATCAAATACTAGTAGT TAAAGACAACCTAGAAACAAATCTTAATTGAGCTAGAAACTTAATrGGCAAGAGGAGTTATAATAGATA

TAA

f748.aa MFIINLLLSTIKIITFTVIVCLTILSIFQPIYILXNEISITTRLGKIQRTLGLKKIPLIENVQIFPKI

IL

RW)EQITGEQIITAWI~NFTIKMRYPIAlpVGIKPLIRSD

IQRLSNGILTPQETKINGIYKITKGRKIIKEIIRIANTKDIGIEIVDVLIRTYDPSLIENRISF-QQ

IAERILEELSEELISAAAKKEDEAISAGUEYFQLSKVK

KRRIFSTDM~DFFQYLHKRN

WO 98/59071 PCT/US98/12718 128 TABLE 1. Nucleotide and Amino Acid Sequences t748 .aa

IFQPIYILKEEISITTRLGKIQRTELGLKYKIPLIEVQIFPKIILRGEPQRIPTGGEEKQLIWIDTTARW

KIADiNxFrriKTmsRAYVRIDAAIEPAVRGVIAKYPLLEIIRSSNDPIQRLSNGILTPQETKIN~GIYKITKGR{K f748 .nt

GATGGAAATTGCAGACATAAATAAATTTTACACAACAATAAAACAATGAGTAGAGCACGTAGTTGATGC

ACTAATAAGAAAGTTACTTATGACCCAAGCCTTATTGAATCTGTAAACAA

TGATCTCAAGACACA

ATGAAGAAAAACTGATGTAAA6CGATCTGACTGAAGAACG AATATTAAGTGAAGCAAAAGCCACTGCTGCAAAAATAAAAGCCGAAGGGGATAGAG GCCGC6ATTATTC AATrAAGCAATTGATTCATCGCGCTAAACAAACGATAAA

AAAAGAAAAATTTTCTCAACAGACATGGATTTCTTTCAATATCTTCACAAAAGAAATTGA

t748 .nt

ATTCACATTTTTGAGAAGATTCAACATGCTGAATCAGAT

AAATTTAGCTGGACTTAAATATAAATACCATTAATTGAAAATGTGCAATATTTCCCAATCATTCTAGATG

GGTGGACCAGACC~AGGGAGAAGATATTGTGTCATCAAG

AAATCGCAAAAATTAAACAAAACAGGAAGTAGTGATGTCGA

TTACTCGTAGGGTTTCAAACTTGTGATATAAGTAACACTTC

ACTTTTATGa.TACCCAAAAAATAAGTTTTAAACAAGC

G.

TTAAGTGAAGCAAAAGCCACTGCTGCAAAAATAAAAGCCGAAGGGGAT

AGCCGCATTATTCATG

r-TTGAAAATATTAAATTGAGATGAGTTAGATTAAGTAA

AAAATTTCTCAACAGACATGGATTTCTTTCAATATCTTCACAAAGAAA'I'GA

f764.aa MSGPKKLAIIALLVISIQGCKESSI IEKQFNYAIIFSDATEYFFEIQTTPFIKNEILFIND NEIIK KTTKX-

ILLTYSNEILEILKEKIFKISLKKSIDFLLEKSIDLQKTLLFRKSNEDEL~<GKEVI

TLINEKNISYIQTFITSQIKTI ILFSLRDNNIILKKILNSPFSKNKFVLIGNTRKDLKI

IKLKYIITLKBPDLIK

IAKVEKDFQYEFNIYKQ

f764.aa IKFSLKKSIDFLLEKSIDLQKTLLFRDKSLNNEDLEYLEEKNTLI=I SYIQTFITSQIKTI ILFS LRflNNIILKKILNSPFSKNIKFVLIGNTRKflLKI

IKLKYIITLKEPDLIKIAKDVEKDFQYEFNIYKQ

*f764.nt ATTTGCTAAATGTTAACCCTGTAT~ATc6rGTCAGATTCAT

TTGAAAAACAATTTAATTATGCAATAATTTTTTAGATGCAACTGAATATTTTTTTGATTCAACTCCATT

CAAAACAAATTTTATAAAATTGATAAAGCACTAAACA&A

WO 98/59071 PCTJUS98/112718 129 TAB3LE 1. Nucleotide and Amino Acid Sequences ATACTATTAACTCATAATCAAATAATGAAATCTAAATAACGAAATCTAAAAGAGAAATTTTATcTATcAA AAATAAAAT'TTTCTTAAAAAAATCTATTGACTr'rCTGCTTAACGAAAAATCAATAGATTTGCAAAAAACATTACT ATTAGAGACAAATCTCTAATAACGAAG-ACCTTGAATAC.LC A GCAGAAATTCAATATT ACTCTAATAAACGAAAAAAACATATCCTATA'ITICAAACATTCATTACT1'CTCAAATAAAAACAATAATA 'ATTCT CIrTAGAGTAAAATTTMtTAAAAGATCTAATTGCCTTTTTCTAAAAATATAAAATTTGTATTAAT TGGCAATACAAGuAAAGAC1TDAAAAPTTATTAAGCTAAAATATATAATCACCCTTAAAGAGCCTGATTTGATAAAA

ATAGCAAAAGATGTTGAAAAAGAT'TTCAATATGAATTAACATTTATAAACAATAA

t764.nt GAAACATTTATTTGCATAT'1TTCAGATGCAACTGAATATTTTTTTGAAATTCAAACAACTCCATTCA

TAAAAAACGAAJATACTATTTATAAATGA.CAAAAATTTAGAAATTATAAAAGACAAGCTTAAAACAACAAAAAAAAT

ACTATTAACTCATAAATCAAATAATGAATTCTAAATAACGAATTCTAAGAGAAATTTTTATCTATCAAAA

ATAAAATTTTCTCTAAAAAAATCTATI'GACTTTCTGCTTAACGAAAAATCAATAGATTTGCAAAAAALCATTACTAT

TTAGAGACAAATCTCTAATAACGAAGACCTGAATACTTLGA A A A A AAA CAGAAAAGCAT TCTAATAAAcGAAAAAAAcATATCCTATAT'IcAAACATTC-ATTAcTTcTrcAATAACAATT

TCTCT

TTAAGAGATAATAATATTATTTITAAAAAAGATACTAAATTCGCCTTTTTCTAAAAATATAAAATTTGTATTAATTG

GCAATACAAGAAAAGACTTAAAAATTATTAAGCTAAAATATATAATCACCCTTAAAGAGCCTGATTTGATAAAA-AT

AGCAAGTTTAAAATTCAATATGATTAATTTACAAA

f770.a

MINFSKSFFYPLPIGKIFVLSGMGSGKTSFLKGLALNLGISYFTSPTYNIVNVYDFINFKFYHIDLYRVSSLEEF

ELVGGLEILMDLDSIIAIEWPQIALSIVPKDRLFSLTFKIVGSGRVVELNG

t770.aa KTSFLXGLALNLGISYFTSPTYNIVNVYDFINFKFYHIDLYRVSSLEEFELVGGLEILMIlLDSI IAIEWPQIALS I

VPKDRIJFSLTFKIVGSGRVVELNG

f770.nt ATGATAAATI'TTCCAAATCTTTTTTTT~ ATCCTT'rGCCAATTGGTAAAATATTTGTTTAAGTGGTGACATG7GGAT

CTGGAAAACTAGTTTTTAAAGGGACTTGCCCTAACCTTIGGAATTTCTTATTTTACAAGTCCAACTTATAACAT

TGTTAATGTTATGATTATAAATTAATmATCATATTGATTTATATCGGGTGTCTTCTGAGAT GAGCTTGTTrGGGGGATGGAAATACTTATGGATCTTGACTCGATTATTGCTATTGAATGGCCACAAATTGCTTTGA

GCATTGTCCAAAAGATAGATTATTTCTTTAACTTTTAAAATAGTAGGTTCAGGCAGGGTTGTAGAACTTAATGG

?rAA t770 .nt 9 ATGTTAGTTAATTATTACTTGTTTAThTCGGGTGTCTTCTTTGGAAGTTGGCT

TGTTGGGGGATTGGAATACTTATGGATCTTGACTCGATTAGCTATTGAATGGCCACAATGCTAGAT

GTCAAGTGTATTTTA

TTTGATTAGTA

f790.aa MNTKATTPLILLLFLIQSLAFSSEIFE-FKYIKGSKFRJEGTDNQKIYFNGHYSSSNTNIQI

SSEIKDIKENFASIK

AFFRILKRENEPYLLNEEFEEIFSVNQGEYTIGANQKRPSRGIPRFPKTPIKEKWSYLAEYIASIDK

SlISYSYVNSYKDKYDEGTKSKIENN NQHFM3GNSLGRIVSIELPNDNLIETEEYIREKKIKAIEVEKNKGINLSFDIEFYPNSFQILQKYKIDLI

AKLLEKFKNNILIEGHTEQFGLEEEMHELSEM'ARAGNYLIKMKVKDDQILFKGWGSQKPKYPKSSPKAKN

RVEITILNN

t790.aa WO 98/59071 PCr/US98/1 2718 130 TABLE 1. Nucleotide and Amino Acid Sequences

SEIFEFKYTKGSKFRLEGT)NQKIYFNGHYNSSSNTNIQISSEIKDIKENASIKAFFRILKRENINPYLLNEEF

EEIFSVNKQGEYTIGANQKRPSVRGI PRFPKTPIKINEKWSYLAEEYIEASKIDKSIKDFVVKFNVNYEYKGKEEH

NGIHYIILSNYESQYNVKNISFYQKVDQKIYFDNEIGNTYKYSDKYIFEINQNNNQHFKMI:GNSLGRIVSIELPN

DNLIETEVENYIREKKIKAIEVENKGINLSFDIEFYPNSFQILQKEY=IDLIAKLEKFKNNILIEGHTEQF

-GLEEEMELSEKARAIGNYLIEKVDKDQILFKGWGSQKPKYPKSSPLKANRVEITILNN

f790 .nt

ATGAATACCAAGGCGACTACACCATGTTGTTATTIATTTI'TAATTCAAAGCTTAGCTTTTTCTTCTGAAATCTTTG

AATTTAAATACATTAAAGGTTCAAAGTTTG'TGAGCCGTACAAAAAATATATTTCAATGGCCATTA

TAATTCAAGCTCTAATACCAATATTCAATTTCAAGTAA AG.AAAGAATTTGCAAGCATTAAA GCTTTTTTAGAATC rAAGGAAATAGAACCTTACCTATTAAATGAAGAGTTTGAAGAAATCTTCA

GCGTAAATAACAGGAAACAAGGAACAAAAAAACCTTCTGTTAGAGGTATTCCAAGATTCCC

AAAAACACCAATCAAAATAAATGAAAAATGGTCATATCTTGCAGAAGAATATATAGAAGCGTCAAAAATAGACAAA

AGTATAAAAGATT'TCGTTGTAAAATTTAATGTTAACTAC ATTAGCAGAACACAATGGCAAGCATT ACCACATAATTCTTTCGAATTATGAATCACAATACAATGTAAAAAACATCTCTTTCTATCAAAA.AGTAGACCAAkA

AATTTATTTTGATAATGAAATTGGCAATACATATAAATACAGCGATAAATATATATTTGAAATAAATCAGAACAAC

AACCAACATTTTAAAATGATTGGAAACTCTCTTGGCAGAATAGTT'rCAATTGAGCTTCCAALATGATAATCTTATTG AAACTGAGGTTGAAAATTACATCCGAGAA AAAATAAAAGCTATTGAAGTTGAAAAAAACAATAAAGGTATTAA

TTTAAGCTTTGACATTGAATTTTATCCTAACTCATTTCAAATACTAAAAATTAAAATACTTATA

GCTAAACTTCTTGAAAAATTTAAAAAAAATAACATACTAATAGAAGGACATACTGAGCAATTTGGATTGGAAGAAG

AGATGCACGAGCTATCTGAAAAAAGAGCTCGTGCAATTGGAAATTATTTAATAAAAATGAAAGTAAAAGACAAAGA

CCAAATACTATTTAAAGGATGGGGATCTCAAAAACCAAAATATCCTAAGTCCTCCCCATTAAAGGCTAAAAATAGG

CGAGTAGAAATTACAATATTAAATAACTAA

t790 .nt

TCTGAAATCTTTGAATTTAAATACATTAAAGGTTCAAAGTTTAGATTAGAAGGCACAGATAATCAAAAAATATATT

TCAATGGCCATTATAATTCAAGCTCTAATACCAATATTCAAATTTCAAGTGAAATAAAAGACATAAAAGAAAACTT

GAAGAAATcTTCAGcGTAALATAAGcAAGGAGAATATACAATAGGAGCAAA.TCAAAAAAGACCTTCTGI'AGAGGTA TTCCAAGAT'rCCCAAAAACACCAATCAAAATAAATGAAAAATGGTCATATCTTGCAGAAGAATATATAGAAGCGTC AAAAATAGACAAAAGTATAAAAGAT'rTCGTTGTAA6AATTTAATGTTAACTACGAATATAAAGGCAAAGAAGAGCAC

AATGGCAAGCATTACCACATAATTCTTTCGAATTATGAATCACAATACAATGTAAAAACATCTCTTTCTATCAAA

AAGTAGACCAAAAAATTTATTTGATAATGAAATTGGCAATACATATAAATACAGCGATAAATATATATTTGAAAT

AAATCAGAACACACCAACATTTTAAAATGATT1GGAAACTCTCTTGGCAGAATAGTTTCAATTGAGCTT'CCAAAT GATAATCTTATTGAA6ACTGAGGTTGAAAATTACATCCGAGAAAAAAAAALTAAAALGCTATTGAAGTTGAAAAAAACA ATAAAGGTATTAATTTAAGC GACATTGAATTTTATCCTAACTCATTTCAAATACTACAAAAAGAATATAAAAA AATTGACCTTATAGCTAAACTTCTTGAATTAAAAT AATAATAGAAGGACATACTGAGCAATTT

GGATTGGAAGAAGAGATGCACGAGCTATCTGAAAAAAGAGCTCGTGCAATTGGAAATTATTTAATAAAAATGAAAG

STAAAGACAAGACCAAATACTATTTAAAGGATGGGGATCTCAAAAACCAAAATATCCTAAGTCCTCCCCATTAAA

GGCTAAAAATAGGCGAGTAAATCAATATATAA

f792.aa MKIFIYWVVIFFFSVFKVFSIYSLTDEEFFKKYSLFFVHKGFLSKNVNGKITKVQVNGINSRWVypFYKLPSRIT

SIYEDVYSSSSFLTTSNNLYVSYDYSKF*RKLVGIDKFNSGAYITSSAFSQGDYKRIAIGTAIHGIYLN-ASF

KNIJNRIIPQIYLGAGYYDIISAIEFSKEETNNLYFSSGVYGDIFL ISQKSGFIKKISFPFKkQI IRILDLSSKNVE KILVRTYDNHFYSYINGQWVFIGKLSLQDQDFFEKSQRMQLAKNKGS IYLTAYTLRNKKAVDERFKFIKDSGMNAV

VIDFKDDNGNLTYSSKLSLPNKLRSVKNFIDVPYILKKAKELGIYVIARCVFKDSKLYYDNFKHALWNKKTNKP

WAIIIKKDSSGLVKVQVEHWVDIFSPATWEYNISIAKEIQSFGVDEIQFDYIRFPSDGPVSLAISRKEQP

VDALESFLIMAREQLYVPISVDIYGYNGWFPTNSIGQNISMLSDYVDVISPMFYPSH =DDFLPSNFYYTKRAYRI YKEGSDRALAFSLDGVVIRPYVQAFLLGKERLVDDEIYLEYLXFQLKGIKESFGSGFSLwNAsNvYYMIKGSLKEY

LDSF

WO 98/59071 PCT/US98/12718 131 TABLE 1. Nucleotide and Amino Acid Sequences t792. aa IYSLTDEEFFKYSLFFVHnGFLSKNVNGKITKVQVNGINSRWVYPFYKVPSRITSIYEDVYSSSSFLTTSNNLY VSYDYS1Q*LVGIKNSGAYITSSAFSQGDYKRIAIGTAIHGIYLSVNGAISF~LNRIPQIYLGAGYYDII

SAI:EFSKEETNNYFSSGVYGDIFLISQKSGFIKISFPFKQIIRILDLSSNKLVRTYNHFYSYINGQWV

FIGKLSLQDQDFFEKSQRMQLAKNKGSIYLTAYTLNKAVDERFKFIKDSGI-AVVIDFKDDNGNLTYSSKLSLP

NKLRSVFIDVPYILKAELGIYVARCVVSKLYYDNFKHALWKKTNPWALIKKVDSSGLVKYVQVE

HWDIFSPATWEYNSIAKEIQSFGVDEIQFDYIRFPSDGPVSLAISRMKYEMQPVDALESFLIMAREQLYVPIS

VDIYGYNGWFPTNSIGQNISMLSDYVDVISPMFYPSHYTDDFLPSNFYYTKRAYRIYKEGSDRALAFSLDGVVIRP

YVQAFLLGKEERjVDDEIYtLEYLKFQLKGIKESFGSGFSLWNASNVYYMIKGSLXEYLDSF f792 .nt

ATGAAAATTTTTATCTATTGGGTAGTTATTTTCTTCTTTTCTGTTTTCAAGGTTTTTAGTATATATTCATTAACCG

ATGAGAA~rTTAAAATTAGrTTTTGTTCATAAAGGATTTTTAAGTAAAAATGTAATGGGAAAAT

AACCAA.AGTTCAAGTCAATGGGATAAATTCTAGGTGGGTTTACCCTTTTTATAAGCTTGTTCCTAGTCGAATTACT

TCTATTTATGAGGATGTTTATTCTTCAGTTICATTTTGACTACAAGTAACAATCTTTATGTTTCTTATGATTATT

CAAAAAT~rAAAATTATAGGAATTGATAAATTrTAA.TAGCGGTGC-ATATATTACATCTAGTGCCTTTTCTCA AGGAGATACAAGCGTATTGCTATTGGAACTGCGATTCATGGTATT'rATCTTAGTGTAATGGAGCTATTAGTTTT

AAAAATTTAAATCGTTTGATTCCGCAGATTTATTTAGGTGCAGGATATTACGATATTATTAGTGCTATTGAATTTT

CAAAGAAAGAAAATATTATAT~rCCTCTGGAGTTTATGGAGATATrTTTTTAATTAGTCAGAAAAGTGG

ATTTATTAAAAAAATATCTTTTCCTTTCAAAAAGCAAATAATACGTATTTTAGACTTATCTAGTAAGAATGTAGAA

AAAA'ITTTAGTCAGAACATATGACAATCATTTTTATTCTTATATTAATGGGCAATGGGTATTTATTGGAAAATTAT

CTTTGCAGGATCAGGATTTTTTTGAAAAATrCACAAAGGATGCAGCTTGCTAAAAATAAAGGGTCTATTTATTTAAC

AGCATATACATTGCGTAATAAGAAGGCAGTTGATGAAAGATTTAAATTTATTAAAGATTCAGGTATGA.ATGCTGTT

GTAATTGATTTTAAAGATGATAA.TGGTAATTTGACTTATTCTAGCAAGCTTTCTTTGCCCAATAAGTTGAGATCTG

TTAAAAACTTTATTGATGTTCCTrATATCTTAAAAAAGCAAAMGAGCTTGGAATTTATGTTATTGCTAGATGTGT

TGTATTAAAGATTCAAAATTGTATTATTATGATAATTTTAAACACGCCCTTTGGAATAAAAAAACCAATAAACCT

TGGGCTCATTTGATTAAAAAAGTTGATTCTAGTGGTCTTGTGAAAiTATGTACAAGTAGAGCATTGGGTAGATATTT

TTTCTCCTGCTACTTGGGAATATAATATTTCTATCGCAAAAGAAATTCAATCTTTTGGAGTTGACGAGATACAATT

TGATTATATTAGATTTCCATCAGATGGGCCTGTGTCTCTTGCAATCTCAAGAATGAATAATATGAGATGCAACCC

GTTATGCACTTGATCTTTTTGATATGGCAGAGAACAGCT'TATGTTCCTATTTCTGTTGATATTTATGGGT

ACAATGGCTGGTTTCCTACTAATAGTATTGCAAAATATTTCAATGTTATCAGATTATGTTGACGTCATATCTCC

TATGTTTATCCTTC CTTTCGTAT'TGCCAAGCAATTTTTATTACACAAAAAGAGCTTATAGGA.TT TATAAAGAGGGGAGTGATAGAGCACTGCI'TTTCTTTAGATGGGGTTGTTATTAGGCCT'rATGTTCA-AGCTTTTT

TATTGGAGAAATTGTGGTGAGAGATTTATTTGGAGTATTTAA.AGTTTCAGCTTAAGGAATTAAAGA

*.GTCAT1TTGGTAGTGGCTTTAGCCTTTGGAATGCATCTAATG rATTTATAAGATTTAAAAGAATAT

TTAGATTCTTTTA

t792.nt :'*:ATATATTCATTAACC AGAAT~AAATTGTA~TTTGTTC-ATAAAGGATTTTAAGTAA ATGTTAATGGGAAATAACCAATCA AAGGTATCTAGGTGGGTACCTTATAAGCTG

TCCTAGTCGAATTACTTCTATTTATGAGGATGTTTATTCTTCAAGTTCATTTGACTACAAGTAACAATCTAT

GTTTCTATTArAAATTAAATAGAGATAAATATGGGTGCATATATTACAT

CTAGTGCCTTTTCTCAGGAGATTACAGCGTATTGCTATTGGAACTGCGATTCATGGTATTTATCTTAGTGI

TGGAGC ATGTTTTATTACTTGATTCCGCAGATTTATTTAGGTGCAGGATATTACGATATA AGTGCTATTGAT~rAAGAAAAAATrTTTT CCTCTGGAGTTTATGGAGATATTTmTA FITAGTCAGAAAAGTGGATTATTAAA AAAATATCTTrTCCTTCAAAAAGCAAATAATACGTAT1'TTAGACTTATC TATATTAG AAAAvTAAGAcAATG CAc~~ ATTCTTATATTATGGGCAATGGGTA DATGGAAAATTATCTTTGCAGGATCAGGATT

TTAAATAAAGAGACGCTAAAAATAAAG

GGTCTATTTATTTAACAGCATATACATGCGTAATAAGAAGGCAGTGATGAAGAT'rTAAATTTA'rrAAAGATTC

AGGTATGAA.TGCTGTTGTAATTGATTTTAA-AGATGATAATGGTAATTTGACTTATTCTAGCAAGCTTTCTTTGCCC

AATAAGTTGAGATCTGTTAAAAACTTTATTGATGTTCCTTATATCTTAAAAAAGCAAAAGAGCTTGGAALTTTATG

TTATTGCTAGATGTGTTGTATTTAAAGATTCAAAATTGTATTAITATGATAATTTTAAACACGCCCTTTGGAATAA

AAAAACCAATAAACCTTGGGCTCATTTGATTAAAAAAGTTG7ATTCTAGTGGTCTTGTGAAATATGTACAAGTAGAG WO 98159071 PCTIUS98/1271 8 132 TABLE 1. Nucleotide and Amino Acid Sequences

GTTGATATTTATGGGTACAATGGCTGGTTTCCTACTAATAGTATTGGGCATATTTCAGTATCAGATTATG

TTAAAGGAATTAAAGAGTCATTGGTAGTGGCTTTAGCCTTTGGAATGCATCTAATGT

ATTATATAAG

TAGTTTAAAAGAATATTTAGATTCTTTrTTAA f797 .aa MSIKKFILTLI ILSLAKNSFSEN~EINIFENhNYIVKENIKTEIKKLKQSFLLASVDVAISQPYIELADLNGEP

IKE

LEGISYSFINVFSKIGSSAI ISFDLSNEASKKYKIIKLEFLSPDKGNFINQSSLTSGKQQSKKELAKDAYSFGTL RTESLSKTIAEYYKDNNWYYILAITVENNINKETEKYEIRINPKIYNDFQKKLRLHFKSNQIKFPI

PIIE

t797 .aa

KNSFSENEINIFEYIVKNIKTEIKKQSFLLASVDVAISQPYIELADLNGEPIKLEGISYSFINJ-FSKIG

SSAI ISFDLSNEASKKYKIIKLEFLSPDKGNFINQLSSLTSGKQQSKKELAcAYSFGTLRTESLSKTAEYYyjN

NWYYILAAITVENNINKETEKYEIRINPKIYNDFQKKLRLHFKSNQIKKFPIPIIE

f797.nt

ATGAGCATTAAAAAATTTATTTTAACCTTGATAATTCTTTCTCTAGCTAAAATAGCTTTTCTGAAACGATTA

ATTTCAACAATAATLATAAAATTT

ACTTCATCTGTTGATGTCGCCATTAGCCAACCCTACATAGAATTGGCAGATTTAAATGGAGAACCGATAAAAGAA

CTTGAAGGGATTAGTTATTCATTTATAAATGTATTTTCAAAAATTGGATCTTCTGCTATTATTTCATTTGACCTAT

CAAACGAAGCTTCCAAGAAATACAAAATCATAAAATTAGAATT1TTTAAGTCCAGATAAAGGCAATTTTATTAACCA

GCTAAGCAGCCTTACTAGTGGAAAACAGCAATCAAAAAAAGAGCTTGCAAAAGACGCTTACTCATTTGGTACATTA

AGAACTGAATCTCT'rTCAAAAACAAT GAA.ATCAGTAAACTGGTATTATATTTTAGCAGCAATAA

*CAGTAGAAATAATATAATAGAAACTGAAAATACGAAAAGAATTAACCCTAAAATATATAATGATTTTCA

AAAAAATGAG~rAATTTAAAAGCAACCAAATAAAAAAATTTCCAATACCCATTATAGAATAA t797 .nt

AAATTAAAAAACTAAP).CAAAGTT'TTTTACTTGCATCTGTTGATGTCGCCATTAGCCAACCCTACATAGAATTGGC

AGATTTAAATGGAGAACCGATAAAAGAACTTGAAGGGATTAGTTATTCAITTATAAATGTATTTTCAAAAATTGGA

AAAAGACGCTTACTCATTTGGTACATrAAGAACTGAATCTCTTTCAAAAACAATTGCAGAATATTACAAAGATAAC

AATACCCATTATAGAATAA

***.f799.aa MKKHIIIGIIFVAILLFFKILLI PRIQNKENNKNNIKMI ISYKQDKNRLSLKINIKTKKTTNLGKAKLDIYLDSKL IESNLLYISSKNFTTYANIIYQNESLLSI

ILKSNGNNNVFYSKRIKPRGKI

t799.aa HENNKNNIKMIISYKQDKNRLSLKINIKTKKTTNLGKAKLDIYLDSKLIESNLLYISSKNFTTYANI

IYQNESLLS

IILKSNGNNNVFYSKRIKPRGKI

WO 98159071 PCTIUS98/1 2718 133 TABLE 1. Nucleotide and Amino Acid Sequences f799 .nt ATGAAAAAA~CATATcA'rrATDGGGATAATCTTTGTTGCALTTCTTTTATTTTTAAAATTTTATTAATCCCA-AA TTCAAAATCACGAAAATAATAAAAATAATATCAAAATGTAATAAGCAAGAGCAA CGTACGCT AAAAAAAAACAAAATACCAACCTGGAAACAAATGAATTTT AATAAT ATTGAAGcAATTTGcTTTATATAAGCAGCAAAAACITTrACAACATATGCTAATATAATCTATCAAAATGAAAGTT

TATAGTTATATAGATAATGGCAATAATAATGTCDAATAAGAAACTAGAGGTAAAAT

ATGA

t799 .nt

CACGAAAATAATAAAAATAATATCAAAATGATAATAAGCTACAAGCAAGACAAAAACAGATTATCGCTAAAGATAA

ACATAAAAACAAAAAAACTACCAACCTGGGAAAAGCCAAACTAGATAT1'ATCTAGACAGTAAATTAATTGAAAG

CAATTTGCTTTATATAAGCAGCAAAAA.CTTTACAACATATGCTAATATAATCTATCAAAATGAAAGTTTATTAAGT

ATAATATTAAAGAGTAATGGcAATAATAATGTCTTTATAGTAAAAGAATAAAACCTAGAGGTAAAATATGA f800.a

MKHYKALILSLLFAIISCNTKTIJNELGEEQFKIPFGTLPGAIMPLNNKFTNSKFDIKTYNGLVYIAEIKTNKLMI

FNSYGKLIQTYQNGIFKTNPDLKIKKIDFEGIQAIYPLKDFI IVADKLNNKSKFNQKNIAYFMRILILNKNSSV EILGQEGLNGMPFPQIYDVNVDENGNIAI ISIYSEGYI IYSYNKEFSPLYKIYNKLLKTIDNQKKKYNISIDKV FFEVNKKTLYVKTTYYEIGDNENINDLGIKIKDQYIYKM4SLKKNKLEVINKIALPKNLLDDKQESFINIIKIQK DKI IATNNKNLSNNLIWKLDSKGSIKEQIALIEPPNLMFLSESLSKGILSILYGGKTGVSVYWWNLNALLKL t800.aa

KTLNELGEEQFKIPFGTLPGAIMPLNNKFTNSKFDIKTYNGLVYITAEIKTNKLMIFNSYGKLIQTYQNGIFKTNPD

LKIXKIDFEGIQAIYPLKDFI IVADK NNKKSKFNQKENIAYB'MRILILNKNJSSVEILGQEGLNGMPFPQIYDVNV

DEGNIAIISIYSEGYIIYSYNKEFSPLYKIYVNKLLKTIDNQKKKYNISIDKVFFEVNKTLYVKTTYYENIGD

NEIDLGIKIKDQYIYKSLKKELEVINKIALPKLLDDKQESFINI IKIQKDKIIASTNMKLSNNLIWKLD SKGSIEQIALIEPPNFLSESLSKDGILSILYGGKGVSVLWWDNr.JArL.T( f800.nt ATGAAAAAACACTATAAAGCTCTTATATTrAAGCTTGC'ITTTTGCAATTATATCATGTAATACTAAAACTTTAAACG

AATTAGGAGAAGAACAATTTAAAATACCATTTGGAACACTTCCTGGTGCA-ATAATGCCTCTGAATAACAAATTTAC

AAATTCAAAATTTGACATCAAAACGTATAACGGGCTAGTGTAAT GATAACATATAATGATT

TTCAACTCATACGGAAAACTAATACAAACATATCAATGAATTAAAACCCGATTTAAAAATAAAAA

AAATAGATTTTGAAGGAATTCAAGCAATATACCr-ACTAAGATTTATTATTGTCGCAGACAAACTAAATAATAA

AAATCAAAATTCAACCAAAAAGAGAATATTGCCTACTTCATGAGAATACTAATACTAAACAAACTCATCTGTA

GAAATTTTGGGTCAAGAAGGTTTAAACGGAATGCCATTTC

AAAIAGTTATTTGATGAAATGCA

ACATTGCAATAATATCAATATATAGCGAGGATATATAATATATTCTTACAATAAAGAATTTCCCCGCTT'rATA AATT~TACGTCAACAAAAACCTGTTAAAAACAATAACAcAGAAATCArCA T GTT TTTTTGAAGTCAACAAAAAAACTCTTTATGTAAAACTACTTACTATGAAAACATTrGGTGACAATGAAATATA .9AT A. CAGATGGTGAT

AAATAAAATTGC-TCTTCCTAAAACTTACTAGATGATAAACAAGAAAGCTTTATAAACATATAAAAATACAAA

GACAAAATAATAGCATCTACTAATATGAAAAATTTATC ACA~ATTGATAAACAAGGGCTCA

TTAAGAACAATAGCTTTAATTGAGCCTCCAA-ATTTAATGTTCTCTCTGAGAGTTTATCTAAAGATGGATACT

TAGTATACTTrTATGGCGGAAAAACTGGTGTTAGTGTTTACTGTGATAAGATTAATAA t800 .nt

AAAACTTTAAACGAATTAGGAGAAGAACAATTTAAAATACCATTTGGAACACTTCCTGGTGCAATAATGCCTCTGA

ATAACAAATTTACAAATTCAAAATTTGACATCAAACGTATAACGGGCTAGTGTACATTGCAGAAATAACAA

TAATTAATGATTTTCAACTCATACGGAAACTAATACAAACATACAAAATGGAATATTTAAAACAAACCCCGAT

TTAAAAATAAAAAAAATAGATTTTGAAGGAATTCAAGCAATA-TACCCACTAAAAGATTTTATT1ATTGTCGCAGAC WO 98/59071 PCTIUS9811271 8 134 TABLE 1. Nucleotide and Amino Acid Sequences CCCCGCTTTATAAAATTTACGTCAACAACTTAAA

AAATAAATCAAATCAC

AATGAATATAAACGATCTTGGAATTAAATTAAAG TATATATGT

.AA

AAAATTATAA

MYLLFIMLCEKSMSXGVWGTATMVFKGNEFVTIYYAGI

GTVSSWVPTADKFYELKTKFVDLGANYEGTIQGFVVPSYVPISSISELKGKGDKKIGIDAGAGTQIVTEQ

ALYGSEEVSEVLSDSKNWLPWKHAFRDKLDILMGEVTVLL

NDDFDAYFDHFYWSDDLILPLDKEPGKEYNAVEFVEKEIVVPKKTLFD

SSESVMLASLDSS IKRNEWILVPLWKPHWAFSRYDIKFLDDPDLIMGGIESVHTLVRLGLENDDFDAVDFY

SDDLILPLMDKNDKEPGKEYRNAVEFVEKNKEIVKTWVPEKYKTLFD

f810 .nt ATTTATATTATTTATTTTTT.9GCTTAGAAAAATCAGATA AACGAAATGAAGGATGG.GGAAGCGTCAAGAT 9TTTTTAA

AAGGTCAGAAAATTATATCTCAATTTATCTGACGAAAAA

@9TTTCTGTTCAACGTATTTTAGAACGAACAGTGTACT GTCATAGAGACTCAGTrTGGCACAGTC.TTCGATGGGTA

GGTAGTAAGTAAAAATATGATGTCGTCGACCATGTCGAA

99.9 TTTTGTAGAAGGAGGTATCTCATGGGGTTCTGAGTA

ATCTATAGGACATGTTATCTTGGAGCCTGGTTTTGTTAA

9 99CTAGTCGATATAGGGATTAACTCTCCTGTGCTGCTA AAAATGATAAAGAGCCAGGCAAGAATAC

CGCAATGCGGTTGAATTTGTTGAAGTGAGATAGAC

GTGGGTTCCAGAAAAATATAAGACCTTATTTGATTAA

TGGTAAAAGGTAAGATAATCGAA.TTGTTT99TGGGAGACGA

CTCATTTAAGTTTTAAATGCTCAGAAAATTATATCTTTA

GTTATCTGACGAAAAAGTCGTTTCTGTCTCGCAAATTTA

.9..TAACAGTTTGT~GTCATTTAGACATAGGTTTGGCAC

ATTCATTCGATGGGTAGGAAGTAAGTAAAAATATGAAAG

TGTCGA9TA

TTAAGAAGGTATATTGTTATAGGAGGTGTC

TCATAATTAGTGAGTAATCTAATAGGACATGTTATCTTTG

AGCCTGGTTTTGTTAATATTCTAGTCGTTATTGGGATAA

CGGAATTGTGCTGCTAATAGTTrAGAATTTTTACTTTTG

AGGTATATTGCTATGTAATATAGGCGCAGAACCAGGTGA

TTTGAAAAAAATTAGCTGTCAAAAAAGCTATGTA

f814.aa WO 98159071 WO 9859071PCT/US98/1271 8 135 TABLE 1. Nucleotide and Amino Acid Sequences

MLVKRIVGKPITMILILFSLLLMISLYTFSRLKVLLPGIDIPQISIHTVYPCGASPREVEESVSRVLESGLSSVKNL

K=ISVSSESSTVSLEHGTDLDLVLEIRALELVKSSLPSKSQTPRIFRYNLMPVMEVNSVRPVSELK

RYAflEIIKPGLERLDGVAIVTVNGGSKRVLIEVSQNRLESYGLSLSRISSIIASQNLELSAGNILENNLEYLVEV

SGKFKSIEEIGNVVIAYKIPDISSGINLSPIEIKZDIANIKTDFEDLSEYVEYNGLPSISLSVQKRSDSNSIAVS

NVVMNEIEKKLSMPKDMKLEIASDSTDFIKASISTVVNSAYFGAMLAIFVIFFFLRSFRATIIIGI SIP IAIVLT FCLMYFVNISLNIMSLAGLALGIGMVVDC SIVVIDNIYKYRQKGAKLISSSILGAQEI PITSSTFTSICVFGPF

LIFKSELGVYGDFFDFTFTIVSLGVSLLVAIFLVPVLSSVGLYTSFQKIKNAFIRKIDAFFASIYYFLEFL

YINLLNIVLNHLIFGLIVFFSFIGSLLLGLLLDTTFRGKSITINLNFPHKnLEAKFYSNRFLEIVKSE-A KGYKSIIATLRADRITFNVLFPLKEESRDNLTgSDYDSIKIflRIGNLYPEFIEPSISGALGGGDSIKIKI

SANDFEYIIYGKILVSMJKKEIPELVNPRLSISDFQLQIGVEIDRALVYNYGIDMNTILNELKANINGVVAGQYV

EKGLNYDIVLKLDRMDVNLKDLEKIFITNSSGVKIPFSSATFEKTNKAESIYRENQALTIYLNAGISPDDNLTQ

VTAKVDFNNKPHKEGITLKVEGEEFSNIMQFKIII~AIIVVFGIMASQFESFLKPFII IFTI PLTAIGV VLIHFLAGEKLSIFAAIGMLMILVGVVVNTGIVLVDYTGLLIKRGFGLREAIIESCRSRLRPILMSSLTSIIGLI

PM

AFSSGSGNELLKPIAFTFIGGMTASTFLTLFFIPMLFEIFPTCFKFQI

t8l4.a RLKVDLLPGIDI PQISIHTVYPGASPREVEESVSRVLESGLSSVKNLKNIYSVSSKESSTVSLEFYHGTDLDLVLN EIRDALELVKSSLPSKSQTPRIFRYNLUNIPVMEIVNSVRPVSELKRYADEI

IKPGLERLDGVAIVTVNGGSKKR

VIJIEVSQNqRLESYGLSLSRI SSIIASQNLELSAGNILENNLEYLVEVSGKFKS IEEIGNVVIAYKIPDI SSGINIJS

PIEIKLKIANIKTDFEDLSEYVEYNGLPSISLSVQKRSDSNSIAVSNVVMEIEKLKLSMPKDMXIJEIASDSTDF

IKASISTVVNSAYFGAMLAIFVIFFFLRSFRATI IIGISIPAIVLTFCLMYFVNISLNIMSLAGLALGIGMVVDC

SIVVIDNIYKYRQKGAKLISSSILGAQEMMLPITSSTFTSICVFGPFLIFKSELGVYGDF'FKDFTFTIVISLGVSL

LVAIFLVPVLSSE'1VGLYTSFQKNIKNAFIRXIDAFFASIYYFLEFLYINLLNIVLNHLIFGLIVFFSFIGSLLL

GLLLDVTTFTRGKENSITINLNFPHKTNLEYAKFYSNRFLEIVKSEAICGYKSIIATLRADRITFNVLFPLKEESRD

NLTQSVDYDSIK=IMRIGNLYPEFNIEPSISGALGGGDSIKIKISANDFEYIWYGKILVSMLKKEIPELVNP

*RLSISflFQLQIGVEIDRLVNYGIDMTILNLKANNGVVAGQYEKGLNYDWVLKLI)RMI)VKNLKDLKIFIT *SNSSGVKIPFSS-ATFEKTNKAESIYRNQA

TIYLNAGISPDDNLTQVTAKINVPHKFIHKEGTGN

S. FSNflMThQFKIIIMMAIIVVFGIMASQFESFLKPFI

IIFTIPLTAIGVVLIHFLAGEKLSIFAAIGMLMLVGVVVNT

GIVLVDYTGLLIKRGFGIJREAIIESCRSRLRPILMSSLTSI

IGLIPMAFSSGSGNELLKPIAFTFIGGMTASTFLT

LFFIPMLFEIFPTCFKFQI

f8l4.nt ATGTTGGTAAGAGAATAGTTGGcAAAcCAATAACAATGTTGATTTATTcATTGTTATTGATGATAAGTGT 5 ATACCTTTCAAGATTAAAGTAGATCTTTGCCGGGAATTGACATTCCCCAAATAAGTATTCACACTGTTTATCC 1* TGGCGCTTCTCCTAGAGAAGTTGAAGAGAGTGTTTCTAGAGTCCTTGAGAGTGGCTTGAGTTCGGTAAAGATTA AAAATATATATAGTGTATCTTCCAAGAAACAGCACCGT~rACTTGAATTTTATCATGGAACCGAT'I'IAGATT

TGTTAAGATCAAGTTGATGAAACTATCCGAACCGCCAGA

TCATTAAAACCTTAGAATGTTATCTTAGCGTTTACTA

AGTTcGTAAcTA~cG~TGAG~rGTGGTcATT~TTATGGA

GTAAAAGCGTGTTTAATTGAAGTTTCTCAAAACAGGCTGGAGTCTTATGGGCTTTCTTTGTCAAGATAT'I'C

AATTATAGCATCCCAAAATT TGGAACTTTCAGCTGGCAATATATTGGAGAACAACTTGGAATATT

TGT

TCTGAATrATCATAG TAGGTAATGTGGTCATAGCTTATAAGATACCCGACATTCTTCGGA

TAAATTTATCTCCTATTGAGATAAAACTCAGATATGCTAATATTAAAACCGATTTTGAAGATTTCGTA

TGTATTAGGTCTCATCTGCGTCAACTGGTCATCATCGTC

AAGTTAGAGATGAAATAATTTTC

TTTG

GTACTGATrATTAAAGCATCCATTCAACGGTTGTAATTCAGCCTATTGGGGCCATGCTTATATTGT

TATTTCTTAGACTAGCAATATTGATCATCAACATTTGC

T~GTTTAATGTATTTTGTAAATATTCTCTTAATATTATGAGTCTTGCGGGTCGCACTTATGGAGG

TGTTGACTGTTATG TAA~ATTT~ATTGCAAGAcACTTATTrrCGTCTTC' TATTCTCGGAGCTCAGGAGATGATGTTGCCTATTACATCTTC

CTTACTTCTATTTGTGTTCAT

CTTATTTTCAAATCAGAACTTGGGGTATATGGAGATTTTTTCAAAGACTTTACATTTACGATTGTTATTTCCTG

GTGTTTCTCTTTTAGTTGCAATTTTTGGTCCTGTTTTATCAAGCCACTATGTCGGTTATACAAGTTCC

AAGAATAATCTTTAGAACAGCTTT~TGATATTTTAATTT

WO 98/59071 PCT/US98/12718 136 TABLV 1. Nucleotide and Amino Acid Sequences TATATCAAT TTAAAATITAACACAAATTGATTTTGGGTGATTTTT'rTTTTAGTTTTATTGGCA

GCTTGCTTTTAGGATTATTGTTAGATGTGACAACTTTTACTAGAGGGAAGAGAACTCAATTACTATTAATTTAAA

TTTCCCCACAAAACTAATTTGGAATATCATTATTAGATTTTTAGAATTGTAAAGTGAGGCT

AAAGGATATAAAAGTATTATTGCTACTTTGCGTGCTGATAGAATAACTTCAACGTATTGTTTCCTCTCAAA.GAAG

AATCAAGAGCATAATTTAACCCAAAGCGTAGATTACGAT'TCTATTAAATATAAAATTATGAATCGTATTGGTAATCT

-TTATCCTGAATTAATATTGAGCCTTCCATTAGTGGCAATGCTT~AGGTGGTGGAGATTTATAAAA'rT'

TCGGCCAATGATTTTGAATATATAAAAGATTATGGAAAAATTTTAGTTTCCATGTTAAAAAGAAATTCCCGAAC

TTGTAATCCAAGGCTAGCATAAGTGATTTTCAGCTTCAAATTGGCGTTGAGATAGACAGAGCGCTAGTTTAT.

TTATGGTATTwGACATGAATAccATTAAATGAGTTGAAGGCCAATATTAATGGTGTTGTTGCTGGGCAA6TATGTG

GAGAAGGGACTTAATTATGATATTGTTCTTAAGCTTGATAGAATGGATGTAAAAATTTAAAAGATTTAGAAAAAA

TATTTATTACAAATTCATCTGGAGTTAAAATTCCTTTTTCATCAALTAGCCACCTTrTGAAAAACCAATAAGCCGA

ATCTATTTACAGAGAAATCAAGCTTTAACCATTTATCTTAATGCGGGTATTTCTC-AGATGATAATTTAACCCAA

GTAACCGCAAAGTTGTAGATTTATTAATATAGGTGCCCCATAAAGAAGGCATAACTCTTAAGGTTGAGGAG

AATATAATGAATTTTCAAATATCATGAATCAGTTTAAAATAATCA.TTATGATGGCTATTATTGTTGTGTTTGGTAT

TATGGCTTCTCAATTTGAATCTTTTTTAAAACCCTTTATTATTATI'TTTACAATTCCTTTAACGGCAATAGGGGTT

GTGCTTATACATTTTCTTGCAGGAGAAAAGCTTTCTATTTTGCTGCAATTGGTATGCTTATGCTTGTTGGTGTTG

TGGTAATACAGGATTGTTCTTGTAGACTATACTGGTTTATTGATCAAGAGGGGATTTGGCCTAAGAGAAGCAAT

TAT'rGAATCTGTCGTTCAGGCTTAGGCCAATTTTAATGTCTTCTTTGACCTCAATAATAGGGCTTATTCCAATG GCATTTTCTAGCGGAAGTGGAAATGAACTTCTAAAACCAATTGCATTTACTTTTAT'rGGCGGATGACAGCTAGCA CATTTCTTACTTTGTTrTTTATTCCCATGCTTTTTGAAATTTTTCCAACATGTTTCAAGTTTCAAATCTAG t814 .nt

AGATTAAAAGTAGATCTTTTGCCGGGAATTGACATTCCCCAAATAAGTATTCACACTGTTTATCCTGGCGCTTCTC

CTAGAGAAGTTGAAGAGAGTGTTTCTAGAGTCCTTGAGAGTGGCTTGAGTTCGGTAAAGAATTTAAAAAATATATA

TAGTGTATCTTCCAAAGCAAAGCAGCACCGTTTCACTTGAATTTTATCATGGAACCGATTTAGATTTGGTTTTAAAT

GAATGGTCCTAATGAATTCT*CCGAACCG.CCAATTTGTC

ATCTTAAAAACATCCCTGTAATGGAAATTGTTATTAAT'rCTGTAAGGCCAGTTTCTGAGCTTAAAAGATATGCCGA

TGAAATCATTAAACCTGGGCTTGAAAGGCTTGATGGAGTTGCAATTGTTACTGTTAATGGTGGAAGTAAAAAGCGT

GT'TTTAATTGAAGTTTCTCAAACAGGCTGGAGTCTTATGGGCTTTCTTTGTCAAGAATATCTTCAATTATAGCAT

CCCAAAATTTGGAACTTTCAGCTGGCAATATATTGGAGAACAACTTGGAATATTTGGTTGAAGTT'rCTGGAAAATT TAATC ATAGGTGTAGGTCATAGCTTATAAGATACCCGACATTTCTTCTGGCATAAATTTATCT

CCTATTGAGATAAAACTCAAAGATATTGCTAATATTAAAACCGATTTTGAAGATTTGTCTGAATATGTTGAATATA

ATGGGTTGCCTTCAATTTCTTTGTCGGTTCAAAAACGTAGTGATTCTAATTCTAT'rGCAGTTTCTAATGTTGTTAT

GAATGAAATAGAAAAATTGAA-ATTATCTATGCCTAAAGATATGAAATTGGAGATTGCTTCTGATAGTACTGATTTT

*ATTAAAGCATCCATTTCAACGGTTGTAAATTCAGCCTATTTTGGGGCCATGCTTGCAATATTTGTTAT.TTTTTTCT.

GTATTTTGTAAATATTTCTCTTAATATTATGAGTCTTGCGGGTCTTGCACTTGGGATTGGAATGGTTGTTGACTGT

TCAAT'rGTTGTAATAGACAATATATACAAATATAGGCAAAAAGGAGCAAAGCTTATTTCGTCT'rCTATTCTCGGAG CTCAGGAGATGATGTTGCCTATTACATC ETCAACTTTTACTTCTATTTGTGTTTTTGGTCCATTTCTTATTTTCAA6

ATCAGAACTTGGGGTATATGGAGATTTTTCAAAGACTTTACATTTACGATTGTTATTTCCTTGGGTGTTTCTCTT

TTAGTTGCAATTITTTTTGGTTCCTGTTTTATCAAGCCACTATGTCGGTTTATACACAAGTTTCCAAAAGAATATTA

AGAATGCTTTTATTAGGAAAATCGATGCCT'ITTTTGCTAGTATTTATTATTTrTr AGAGTTTTTGTATATCAATTT

ATTAAATATAGI'TTAAATCACAAATTGATTTTTGGGTTGATTGTTTTTTTAGTTTTATTGGCAGCTTGCTTA

GGATTATTGTTAGALTGTGACAACTTTTACTAGAGGGAAAGAGAACTCAATT ACTATTAATTTAAATTTTCCCCACA AAACTAT'rGAATATCArATTAAGATT'rTTAGAAATTGTAAAAAGTGAGGCTAAAGGATATAA AAGTATTATTGCTACTTTGCGTGCTGATAGAA6TAACTTTCAACGTATTGI'TCCTCTCAAAGAAGAATCAAGAGAT

AATTTAACCCAAAGCGTAGATTACGATTCTATTAAATATAAAATTATGAATCGTATTGGTAATCTTTATCCTGAAT

TTAATATTGAGCCTTCCATTAGTGGCAATGCTTTAGGTGGTGGAGATTCTATTAAAATTAAAATTTCGGCCAATGA

TTTGAATATATAAAAGATTATGGAAAAATTTTAGTTTCCATGTTAAAAAGGAA.ATTCCCGAACTTGTAA6ATCCA

AGGCTTIAGCATAAGTGATTTTCAGCTTCAAATTGGCGTTGAGATAGACAGAGCGCTAGTTTATAATTATGGTATTG

ACATGAATACCATTTTAAATGAGTTGAAGGCCAATATTAATGGTGTTGTGCTGGGCAATATGTGGAGAAGGGACT

TAATTATGATATTGTTCTTAAGCFrGATAGAATGGATGTTAAAAATTT AATAAAAAATATACA AAT'rCATCTGGAGTTAAAATTCCTTTTTCATCAATAGCCACCTTTGAAAAAACCAATAA6AGCCGAATCTATTTACA GAGAAAATCAAGCTTTAACCATTTATCTTAATGCGGGTATTTCTCCAGATGATAATTTAACccAAGTAACCGCAAA

AGTTGTAGATTTTATTAATAATAAGGTGCCCCATAAAGAAGGCATAACTCTTAAGGTTGAAGGAGAATATAATGA

WO 98/59071 PCTIUS98112713 137 TABLE 1. Nucleotide and Amino Acid Sequences TTCAATATCATAATCAG t TAAATCTAGTGTATTATM=?IGGTTTGGTAT'rATGGCTTCTrC AATTTGAATCTrrTTTAAACCCTTATTA 'AA~ CCTTTAACGGCAATAGGGGTTGTGCTTATACA

TTTTCTTCAGGAGAAAGCTTTCTATTTGCTGCAATTGGTATGCTTATGCTTGTTGGTGTTGTGGTAAATACA

GGAATTGTTCTGTAGACTATACGGTTATTGATCAAGAGGGGATTGGCCTAAGAGAAGCAATTATTGAATCTT

GTCGTTCAAGGCTTAGGccAATTmAATGTCTCTTTGACCTCAATAATAGGCTTATTCCAATGGCATTTTCTAG CGGAAGTGGAATGAACTTCTAAACcAATTGcATTAcTTATTGGCGGAATGACAGCTAGCACATTTCTTACT '.rrrATTCCCATGCTTAAAAATTITCCAACATGTTTCAAGTTCAAATCTAG f 818.aa ML~qHSKLIIQLKVVMThIyLKKmGNDmTFYNYRIEIVSNLSLELDVFECIEKIEQELGESIYYSKIGNVYGKGKK

GEKHGNGVWPEEFILIIYTSNQSIVERLKDIVI:DLNRSYPTEGINLFVLRNS

t818 .aa KKMGNDM'rKFYNYRIEIVSNLSLELDVFECIEKIEQELGES IYYSKIGNVYGKGKKGEKHGNGVWPEENFILI IYT

SNQSIVERLKDIVDDLNRSYPTEGINLFVLRNS

f818 .nt ATGTTGAAAAATCAT'rCAAAATTAATAAT1CAACTAAAAGTAGTTATGATGATTTATTTGAAGAAGATGGGGAATG

ATATGACTAAATTTTATAATTATAGGATTGAAATAGTTTCTAACTTATCTTTAGAGCTTGATGTTTTTGAATGTAT

AGAAAAAATAGAGCAAGAGTTAGGAGAGTCTATATATTATTCTAAGATAGGAAATGTTTATGGAAAAGGTAAGAAG

GGAGAAAAGrCATGGTAATGGCGTTTGGcCTGAAGAAAATTTTATTTTGATTATTTATACCTCCAATCAGTCTATTG

TTGAGCGATTAAAGGATATTGTGGATGATTTGAATCGTTCTTACCCTACAGAAGGGATTAATCTTTTTGTTTTGAG

AAAT'rTTAA ::t8l8.nt

*AAGAAGATGGGGATGATATGACTAATTTTATAATTATAGGATTGAATAGTTTCTAACTTATCTTAGAGCTTG

ATGTTTTTGAATGTAAAAATAACAATTAGGAGAGTCTATATATTATTCTAAGATAGGAAATGTTTA

TGAAAGTAAGAGGGGAAGATGTAATGGCGTTTGGCCTGAAGAAAATTTTATTTTGATTATTATACC

ATC'ITTTTGTTTTGLGAAATTCTTAA

f820.aa MLNNTYRIKTILTIFLAITLLTIYKYFTLMAFNNSPDNTISLKSNDImKGTIYDRNGKPIAFSSKSYSIGNQK

IEIVSTSETLGAILQINSRILKELSSNGFLYIKRIEESDLIKRIQAEGRLSNITLYPDYTRIYPRTTS

GVTNGEIFLNIGDTQFNEETNRTDDQGSIAKFENELTV

NSQNGEILSMVQFPQYDANFYSKYPEEIRXNLSSSLTYEPGSINKIFTVAIILESGKLNLEEKFLDNGIYQKQFPS

GEKITIKTLNPPYKHISTEILIYSSVGIAYITEKVSNYFYKKLLDFGFGEKVGVPFPGETKGLLNHYSKSGR

SKTGGEGSVIQAISNnf"IKKSDGNKFKERVSNAKL MV

NKGPLINDSKGSADYGYEDTSIAYTQKIYVRPYIGRA-M-

EIIEFIEHQQNTIAYKKIKMPSKIKIPKAETNYKNKTYLPNFINLSKAIDILKKTMKIKINGI)GFVYKQSI

SPNTKLEDITELELYLK

t820.aa

RISPDNTISLKSDIAKRGTIYDRNGKPIAFSSKSYSIGTNPQKINIVTSETLGAILQINSRILKEKLSSNKG

FLYIKRKIKREESDLIKRIQAEGRLSNITLYPDYTRIYPFRNTSNITGFVGTDNLGLEGIEFSNSILGKDKTKQ

QFLNEEPETNIHLTIDMDIQQGVSKIAKFKENPESLITLVMSQNGEILSMVQFPQYDANFYSKYPEIK

LSSSLTYEPGSINXIFTrVAIILESGKLNLEEKFLDNGIYQKQFPSGEKITIKTLNPPYKHIDSTEILIYSSNVGIA YITEKVSNEYx FYKrKLLFGFGEKVGVPFPGETKGLLNHYSKWSGRSKATIGFGQEIGVSAVQILQAASILSNNGIM LKPRIIKKISNDKGENIKEFDKEEIRKVISKNSAQKLKbN.ZEVNKGGIPNLKIKNLDI SAKSGTSQAIDRKTGK WO 98/59071 PCTIUS98/1271 8 138 TABLE 1. Nucleotide and Amino Acid Sequences

YSEYSIAYTQKIYVRPKIGRAPAEIFEQN~AKIMSIIKE

NKYLEPNFINLSEAIDILKYYITMIKINGDGFVYKQSISPNTKLEDITLELYLK

f820 .nt

AACATTTTGAAGAATGCAACAATAGCATTCTCTTCAAAATCCTACTCAATTGGTACAAATCCTCAAA

AGCTGAAGGCAGGCTTTCAAACATCACTTTATATCCTGATTACACAAGAATTTATCCCTTCAGGAATACCACAAGC

AATATTACTGGTTTTGTAGGAAcAGATAATCTTGGCCTAGGGCATTGAATTTTCCCTAAATAGCATATTAGGAA

AAGATAAAACCAGACATTTATAGGCAGAAACAAACAACATCCACTTAACAATAGACATGGATAT

ACAACAAGGTGTTAGCAAAATAGCTAAAAAATACTTTAAAGAAAATAATCCTGAAAGT'rTAATTrACCTTGGTAATG AACTcccAAAATGGAGAAATATTATCCATGGTTCAATTTCCTCAATATGATGCAAACTTTTATTCTAAATATCCTG

AAGAAATCCGAAAAAACCTTTCTTCATCTCTAACCTATGAGCCCGGAAGCATTAATAAAATTTTTACAGTTGCAAT

AATATTAGAAAGTGGAAAATTAAATTTAGAAGAAAAATTTTTAGACAATGGAATATATCAAAAACAATTTCCATCA

GGAGAAAAAATTACAATCAAkAACATTAAATCCCCCCTATAA.ACATATCGACTCTACAGAGATTTTAATTTATTCAT

CAAATGTTGGAATAGCTTACATTACTGAAAAAGTTAGCAATGAATACTTTTATAAAAAACTTTTAGATTTTGGCTT

TGGGGAAAAGTTGGAGTTCCATTTCCCGGAGAAACAAAAGGACTGCTAA)ATCATTATTCAAATGGTCAGGACGA

AGTAAGCTACAATTGGATTTGGACAAGAATAGGAGTGTCAGCGGTTCAAATATTACAGCTGAAGCATACTAA

GCAATAATGGAATAATGCTAAAACCTAGAATAATAAAAAAAATAAGCAACGATAAGGAGAAAATATTAAAGAATT

TGAAGAAATAAATAATATCCAAAAATTCAGCACAAAAGTTTTAAAAATGATGAGAGAAGTTGTA

AATAAAGGTGGAATTCCAAATCTTAAAATTAAAAATCTTGACATTTCTGCAAAAAGTGGAACATCTCAAGCTATTG

ATAGAAAAACGGGAAAATACTCAGAAGAAGACTATACATCTTCTATATTGGCAATATACCCCACAGAACAACCAAA

ATATATTATTTACATTGTATACAGATACCCAAAAATAATATACGGAACAAGAATAGCAGCCCCAATGGCAAAA

GAAATAATAGAATTTATTGAGCAC AC~AAATGAAAAAATAAAATGCCATCAAAAATCAAGA

TCCCTAAAGCTGAAACTAATTACAAAAACAAAACATACTTACCAAATTTTATCAACCTTTCTAAAAGAGAAGCAAT

AGACATACTAAAATACTATAAAAATACTATGAAAATAAAA-ATAAATGGCGATGGATTTGTTTACAAGCAA.AGTATA

t820..nt

TTCAATAACAGCCCAGACAACACAATATCTTTAAAGTCAAATGATATTGCCAAAAGAGGAACAATTTATGATAGAA

ATGGCAAACCAATAGCATTCTCTTCAAAATCCT.ACTCAATTGGTACAAATCCTCAAAAAATAGAAAATATTGTAAG

CACATCTGAAACTCTGGTGCAATACTTCAAATTAATTCAAGAATTTTAAGGAA

1

AGCTTTCCTCTAACAAAGGG

TTTTTTTT TAAGGAATCAGATTTAATAAAAAGAATTCAAGCTGAAGGCAGGCTTT

CAAACATCACTTTATATCCTGATTACACAAGAATTTATCCCTTCAGGAALTACCACAAGCAATATTACTGGTTTTGT

AGGAACAGATAATCTTGGCCTTGAGGGCAT TGAATTTTCCCTAAATAGCATATTAGGAAGATAAAACCAAGCAA CAATTTTTAAA.TGAGGAGCCAGAAACAAACAACATCCACTTAATGAAG AAACAAGGTGTTAGCA

AAATAGCTAAAAAATACTTTAAAGAAAATAATCCTGAAAGTTTAATTACCTTGGTAATGAACTCCCAAAATGGAGA

AATATTATCCATGGTTCAATTTCCTCAATATGATGCAACTTTTATTCTAAATATCCTGAAGAAATCCGAAAAAAC

CTTCTTCATCTCTAACCTATGAGCCCGGAAGCATTAATAAAATTTTACAGTTGCAATAATATTAGAA-AGTGGAA

AATTAAATT'AGAAGAAAAATTTTTAGACAATGGAATATATCAAAAACAATTTCCATCAGGAGAAAAAATTACAAT

CAAAACATTAAATCCCCCCTATAAACATATCGACTCTACAGAGAT'rTTAATTTATTCATCAAATGTTGGAATAGCT

TACATTACTGAAAAGTTAGCAATGAATACTTTATAAAAACTTTTAGATTTTGGCTTTGGGGAAAAAGTTGGAG

TTCCATTTCCCGGAGAAACAAAAGGACTGCTAAATCATTATTCAAAATGGTCAGGACGAAGTAAAGCTACAA.TTGG

ATTTGGACAAGAAATAGGAGTGTCAGCGGTTCAAATATTrACAAGCTGCAAGCATACTAAGCAATAATGGAATAATG

CTAAAACCTAATAAAAATACAGATAAAGGAGAAAATATTAAAGAATTTGATAAAGAAGAAATAA

GAA.AAGTAATATCCAAAAATTCAGCACAAAA.AGTTTTAAAAATGATGAGAGAAGTTGTAAATAAAGGTGGAATTCC

AAATCTTAAAATTAAAALATCTTGACA6TTTCTGCAAAAAGTGGAACrATCTCAAGCTATTGATAGAAAAACGGGAAAA

TACTCAGAAGAAGACTATACATCTTCTATATTGGCAATATACCCCACAGAACAACCAAAATATATTATTTACATTG

TATACAGATACCCAAAAAAAATAA-TATACGGAACAAGAATAGCAGCCCCAATGGCAAAAGAAATAATAGAATTTAT

TGAGCACCAACAAAATACAATAGCATATAAAAAAATTAAAATGCCATCAAAAATCAAGATCCCTAAAGCTGAAACT

AATTACAAAAACAAAACATACTTACCAAA.TTTTATCAACCTTTCTAAAAGAGAAGCAATAGACATACTAAAATACT

WO 98159071 PCT/US98/1271 8 139 TABLE 1. Nucleotide and Amino Acid Sequences

ATAAAAATACTAGAAAAAAAGCGATATTGTTACAACAAAGTATATCCCCCAATACAATT

AGAAGATATAACAGAGC'rrGAACTGTATTTAAAATAA f831.aa

-MAMTLLVFFIAIIFSIIVVFYNSLGDYVKSGGEIVENLEKDLNDYLKENDAKERZIFLRIRELISKEKI

KVRALLSKAILIEAVKEEIVPYLYIMANKLELQN

t831.aa YNSLGDYVKSGGEIVNLEKDLNDYLKENDAKEREKIFLRIRELISKEEISSYFI

SRFYLARAVYFQSQAQYDE

AflDLD KAKGIESEIAFLKAAVYEIMGLKEDALLVYEDLINSTSLDFLLLSKAILIEEKDKAKV EEl VKFPYENNLYINMAI.INKILELKQN f 831. nt AlrrCTTTAGGCAAGGATTATGTAAAGAGTGGCGGAGAAATAGTAGAAAATCTTGAAAAAGATTTAAATGATTATT

AAAGAAAATGATGCCAAAAAGAATTTCTTAGGATAAGGGAGCTTATTTCAAAGGAGATT

TCATCTTATTTATTTCAAGGTTCTATTTAGCCAGAGCTGTTTATTTCCAAAGTCAAGCACAGTATGATGAGGCTA

TTAAAGATTTAGATATTGTTATTAAGGCAAAGGTATGAAAGTGAAATTGCTTTC"IAATAAAGCTGCAGTTTA

T AAAGGT~AAGTCTTTGTTAGTTTATGAAGATCTTATC

TAGTACTAGATTA

AGGTAAGAGCTCTTTTGAGTAAGGCAATATTGTGGAAGTAACTTGCTGTGAAGTATACG

AGATTGTTAAGTTTCCGTATGAAATAATTTATATATAAATATGGCAAATAATAAATTTTAGAACTTAGCAA

TTAA

t831.nt

ATTTCATCTTATTTTATTCAAGGTTCTATTTAGCCAGAGCTGTTTACCAAGTCGCACAGTATGATGAG

GCTATAAGATTAGTATTTTATAAGCA AAGTGAAATGATTGCT TAGCTGCAG

AAAATTAA

f843.aa

DUKAIGNILLNMPLIFSIGISIGVAMGQGTAALGGLIGYLTFNITENYFIEAFSGLVEAETMSSVGRNFGVQT

LNTGIAGSLAVGLLVGYLHNKFYNMKLPKPFVFFSECHFVPIVI

ILPFCVFLAIFFCLIWSSFDDLIASLGLVR

*FEYFGSFLYGFLNRLLLPLGLHSILSFPFFTSLGGVEIGDRGLNIFYAQLLDPSLGFSSGFAISSGFY

LSMGPALVKIHDNVALSATFLGTPELITPLFHASFLLNF

VTGSSGLFMGLGSTWSLLAFFLYTSLRFFIVDPFGEKEL

IAHLLIQGLGGFDNITKLDVCSTRVDVTELVDNNLLKAVLKIGLVGKVQLFYGS'IKADYS

PK-

SLFEASVVAVDNVKKGFKTYIEMKEIKKLEKQGKSGKTYKLSELEIED

t843 .aa RMQTAGLGLFIMFEFGVATSVP

FVTNGASAGLGLNFN

KLPKPFVFFSECHFVPIVIILPFCVFLAIFFCLIWSSFDDLIASLGLFRFEYFGSFLYGFLLPLGIHSIL

SFPFEFTSLGGVEIVNGDTVRGL IFYAQLLDPSLGKFSSGF

ISSGFYLSIMFGLPGKIVEK

VALFGLALGTPELITPLFHAYGALAFNTGSSGLFMGLGS

TNWISVLPLGAFFALYFTFSWLYRYFDFQIFVTDDPFFEGQEGKLESLGIAHLLIQGGFDNITLVCSTRL

WO 98/59071 PCTIUS98/12718 140 TABLt 1. Nucleotide and Amino Acid Sequences HDVVTELVINNLLKEAGVKIGLVNGKVQLFYGSNYYID ITYSPSLFEASVVAVDNVKXGFKTYIEy,

EKKLEKQGKSGKTYKLSELEED

f843 .nt

-ATGAAGGCTATAGGCAATGCTATTCTTCTCAATATGCCTTTAATTTTTTCTATTGGAATTTC:TATTGGAGTTGCAA

GAATGGGGCAGGGAACAGCGGCTTGGGAGGCCT'ATTGGTTATTTAACATT'rAATATTACTGAAAATTATTTTAT

TGAGGCTTTTTCAGGGCTTGTTGAAGCAGAGACAATGTCTTCTGTTGGGCGTATAAAT'ITITTTGGTGTTCAAACT

TTAAATACGGGAATTGCAGGTTCTTTAGCGGTAGGCCTTTAGTTGGATATTTGCATAAcAA6ATTTATAATATGA

AGCTACCCAACCTTTTGTGTTTTTTCAGAGTGCCATTTTGTGCCTATAGTAATAATTTTACCCTTTTGTGTTTT

TTGGCTATATTTTTTGTTGATTTGGTCAAGTTTGACGATTTAATTGCATCTTTAGGTTTGTTTGTTTTTAGG

TTTGATAITTTGGCAGTTTCTTTATGGATTTTTAAATAGGCTTTTATTGCCTTTGGGGTTGCATTCTATTTTAT

CTTCCTTTTGAGTTACTTCTTTGGGAGGAGTGGAGATAGTTAATGGCGATACTGTTAGAGGTCTTAAGAATAT

ATTTTATGCTCAGCTATTAGACCCATCACTTGGTAAATTTrCATCAGGCTTTGCCAAAATTAGCAGTGGATTTTAT CTATCTATTATGTTrGGACTGCCCGGAGCA TrGGTTCAGTATTGTCATGAAGATAAAAATAAGG

TTGCAGCACTTCTTTTCTCTGGGGCCTTGACAGCTTTTTAACAGGAATAACTGAGCCTTTAGAATTTTTATTTAT

TTTCACAGCGCCTTTGCTTTATTTGTTCATGCCGCTTATTCGGGGTTTGCATTGTTGCTTGCTAATTTTTTTAAT

GTTACGATTGGCAATAGCTTTTCTACTGGATTTTTGGATTTTTTTATGTTTGGGATACTTCAAGGAAATTCTAAGA

CAAATTGGATTAGTGTATTACCTTTGGGGGCAATGTTTTTT1GCTCTTTATTATTTTACTTTTAGTTGGCTTTATAG

ATACTTTGATTTTCAGATATTTGTTACAGACGATCCAT'TTTTGAAGGCCAAGAAGGAAAGCTAGAGAGTCTCGGA

ATTGCGCATCTTTTAATTCAAGGTCTTGGTGGATT'rGATAATATTACAAAGCTTGATGTTTGTTCTACAAGATTGC

ATGTAGATGTTGTTAATACTGAGCTTGTTGATAATAATTTGCTTAAAGAGGCTGGAGTTCTTAAAATAGGGCTTGT

TAATGGCAAGGTTCAGCTTITTTTATGGATCTAATGTPrATTATATTAAAAATGCCATTGATACCTATTCTCCAAAG

AGTCTTITTTGAAGCTAGTGTTATGGTTGCAGTTGATAATGTAAAAAAAGGTTTTAAAACTTATATTGAAATGAAAG

AAGACAAAAAACTTGAAAAGCAAGGTAAATC-AGGAAAAACCTATAAGCTTAGCGAATTAGAAGAAGATTAG

t843.nt

AGAATGGGGCAGGGAACAGCGGCTTTGGGAGGCCTTATTGGTTATTITAACATTTAATATTACTGAAAATTATTTTA

TTGAGGCTTTTTCAGGGCTTGTTGAAGCAGAGACAATGTCTTCTGTTGGGCGTATAAATTTTTTTGGTGTTCAAAC

TTTAAATACGGGAATTGCAGGTTCTTTAGCGGTAGGCCT'rrTAGTTGGATATTTGCATAACAAATTTTATAATATG

AAGCTACCCAAACCTTTTGTGTTTTTTTCAGAGTGCCATTTTGTGCCTATAGTAATAATTTTACCCTTTTGTGTTT

TTTTGGCTATATTTTTTTGTTTGATTTGGTCAAGTTTTGACGATTTAATTGCATCTTTAGGTTTGTTTGTrnTAG GTTTGATATTTTGGCAG7rTTTTATGGATTTTTAAATAGGCTTTTATTGCCTTTGGGGTTGCATTCTATTTTA TCTTTCCTrTGAGTTTACTTCTTGGGAGGAGTGGAGATAGTTAATGGCGATACTGTTAGAGGTCTTAAGAATA TATTTTATGCTCAGCTATTAGACCCATCACTTGGTAA6ATTTTCATCAGGCTTGCCAAAATTAGCAGTGGATTTTA TCTATCTATTATGTTGGACTGCCCGGAGCAeCATTAGGGTTTACAAGGGTATGTTCATGAAGATAAAAATAAG GT'rGCAGCACTTCTTTCTCTGGGGCCTTGACAGCTTTTTTAACAGGAATAACTGAGccTTTAGAATTTTTATTTA

TTTTCACAGCGCCTTTGCTTTATTTTGTTCATGCCGCTTATTCGGGGTTTGCATTGTTGCTTGCTAATTTTTTTAA

TGTTACGATTGGCAATAGCTTrTCTACTGGATTTTTGGATTTTTTATGTTTGGGATACTTCAAGGAAAT'CTAAG

ACAAATTGGATTAGTGTATI'ACCTTTGGGGGCAATGTTTTTTGCTCTTTATTATTTTACTTTTAGTTGGCTTTATA

GATACTTTGAT'rTTCAGATATTTGTTACAGACGATCCATTTTTTGAAGGCCAAGAAGGAAAGCTAGAGAGTCTCGG AATTGCGCATCTTTTAATrCAAGGTCTTGG GATG.ATTAAACTTGATGTTTGTTCTACAAGATTG

CATGTAGATGTTGTTAATACTGAGCTTGTTGATAATAATTGCTTAAAGAGGCTGGAGTTCTTAAAATAGGGCTTG

?AATGGCAAGGTTCAGCTTTTTTATGGATCTAATGTTTATTATATTAAAAATGCCATTGATACCTATTCTCCAAA

GAGTCTTT'rrGAAGCTAGTGTTATGGTTGCAGTTGATAATGTAAAAAAAGGTTTTAAAACTTATATTGAAATGAAA

GAAGACAAAAAACTTGAAAAGCAAGGTAAATCAGGAAAAACCTATAAGCTTAGCGAATTAGAAGAAGATTAG

f850.aa

MRFKIFLIIFIISNLKVYSYNYAIQYKNEGIDKYYFEILNDGFGFSLSFFDDLRSGSLIFTYVSKYNFIINLE-A

H1MLTYRGYKDSPKSLISRTDLIEIGFMYYFPILLLINGKNFGEIDLGIGVKNLLFGDWGGHLMQSI IHLILNQHRP IPSIKSYDSYNYRGFLSFALNYSYMNFLNLENYMDLSYFADYFKNSIGITLKNEN4IGFDIKLYSQIQN'QIKSLKT YSKTQEAETGIGINYQFYSNFFITNNLNIKNFSTKENFLSVGGFGII ITPEEYKKISESNNEFNVISNNFYFGFD

IMIPLKIRNSLFYKINENIHYFSISTNYYTNYNETNSFTNQLSSGIMYEFLPQKTFNPYLISGLFFAYQNNKDI

KSISRPIRIKNILQVGIENELGFLFKMLKYRNTEYIFKIYSKVINYI PIAYNLDEKKLEKHSINFNYLGIGIVVK WO 98/59071 PCT/US98/12718 141 TABLE 1. Nucleotide and Amino Acid Sequences t850. aa YSYNYAIQYNEGIlKYYFEILNDGFGFSLSDFFDDL GSLIFT VSK FIINLAJYRGYKSPKSLISR,

TDIIFYFILIGNGILIVNLGDGHMSILLQRISKYSNRFS

ALNYSYFLNLEMLSYFADYFI KUSIGITLNENIGFDIK YSQIQNQIKSLKTYSKTQEAETGIGINYQFY SKFFITNNLNIKNFSTKENFLSVGGFGII ITPEEYKISES1EFNVISNNFFGFIMIPLKIRSLpYKINEN nIHYFSIS vrM NNTNSFTNQLSSGIMYEFLPQKTFPYLISGLFFAYNQNNXDIKSIsRPIRIKNILQVGIE NELGFLFKMLKYRNTEYIFKIYSKVNYIPIAYNLlEKX~EKSINFNYLGIGIVVK f850 .nt ATGCGGTTTAAAAAAATTATAATTTA CTAATTTAAAGTTTATTCTTATAATTrATGCAATCC

AATAAAATGAGGTATGAATATAT~TGAATATAAATGATGGATTCGGATTTTCATTAAGCGATTT

T~rGAT~cTGAGAGTGT~TCTTATTTTTACCTATGTTTCAAAATACAATTTTATAATAAATTTAGAAGCA CACATGTTAACCTATAGGGGTTATAAAGACTCTCCGAAATCTTTAATTAGTAGAACAGACT'rAATTGAAATAGGCT TCATGTACTATTTTCCAATTTTATTGCTAATTAATGGAAAAAATTrTGGAGAAATAGACTTGGGAATTGGAGTTAA

AAACTTATTATTTGAATGGGGATTAGAACTATACTCATTTTAAATCAACACCGTCCA

ATTCCAAGTATAAAAAGCTACGACAGCTAATAA GTTTACTTTGCTCTAAATTACTCTTACATGA ATTTTTTAAATTTAGAAAATTATATGGACTTATCTATTTTGCAGATTATTTTATTA~AGTATTGGAATTAc

CTTAAAAAATGAAATATTGGATTTGATATAAAACTTATTCCCAAATTCAAATCAAATCAAAAGCCTCAAAACA

ATAATTAAATTAAAATTTCAACCAAAGAAAATTTCTTAAGCGTGGGGGATTTGGAATAATCATTACACC

TGAGAAAAAAACGACAAATAATGAATTTAATGTTATAAGTAATAATTTTTACTTTGGATTTGAT

ATTATGATCCCATTAAAATAAGAA TTCATTATTTTATAAAATAAATGAAAACATCAACCATTACTTTTCAATAT

CAACAAATTATTAC-ACTAATTATAATGAAACTAATAGCTTTACAAATCAATTATCATCAGGCATCATGTATGAATT

TTTACCACAAAAAACATTCAATCCTTACCTAATTTCGGGATTATTTTTTGCCTATAATCAAACAATAAAGATATC

AA.GACCAACAAGAAAACTCTAGTGATAATATAGTTTTC

AAATGCTAAAATACCGCAACACTGAGTATATTT1TCAAAATATATTCAAAAGTTAACTATATTCCTATAGCTTATAA CTTAGAT AAA~TAAACTCTATTAACTTTAATTATTTAGGAATGGAATAGTCGTTAAATAA t850.nt TATTCTTATAATTATGCAATCCAATATAAAAATGAAGGTAT.AAATA TGATACTAAATGATGGAT TCGGATTTTCATTAAGCGATTTTTTTGATGACTTGAGAAGTGGTTCTCTTAI-TT'rACCTATGTTTCAAAATACAA

TTTTATAATAATTTAGAGCACACATGTTAACCTATAGGGGTTATAAAGACTCTCCGAAATCTTTAATTAGTAGA

ACAGACTTAATTGATAGGCTTCATGTACTATrCCAATTTTATTGCTAATTAGAI-GAAA TAGACTTGGGAATGGAGTTrAAAAACTTATTATTGGAGACTGGGGAGGGCATTTAATGCAAAGCATAATTCACCT

CATTATACCGCATCAGAAAAGTCAACAATAAAGTTTACT

GCTCTAAATTACTCTTACATGAATTTTTAA6ATTTAGAAAATTATATGGACTTATCTTATTTTGCAGATTATTTTA AAACA~ATTGAA~rACTTAAAAATGAATATTGGATTGATATAAAACTTATTCCCAAATTCAAAA TCAAATCAAAAGC TAAAATAAAA Ah ~CGACG~GAAAATTATIrAC TCTAAAAATTTrTTTCATAAC ATA~AAATA.ATTCAACCAAAGAAAATTTCTTAAGCGTTGGGG GATTTGGAATAATCATrAACAATACA AACAGAATCAAATAATGAATTTAATGTTATAAGTAA TAATTTTTACTTTGGATTTGATATTATGATCC ATAT~AACTATTATAAAATAAATGAAAAC ATCAACCATTAC rAAATAAAATTA~IAATA TATGAAACTATAGCTTACAAATCAATTAT

CATCAGGCATCATGTATGAATTTTTACCACAAAAAACATTCAATCCTTACCTAATTTCGGGATATTTTTTGCCTA

TAATCAAACAATAAAGATATCAAAAGCATCTCAAGAC ATAATA~C TTcTAAGTTGGAATTGAA AATGAATTAGGATTTTTGTTCAAAATGCTAAAATACCGcAAcACTGAGTATATTcAAATATATTrCAAAAGTTA ACTATAI'CCTATAGCTTATAACrrGT .ATGAACTCTATTAACTTTAATTAT'rTAGGAAT

TGGAATAGTCGTTAAATAA

f853 .aa MKSFLFWVILGTVGTSSFAQNTPVAIINLYKEIITKTG FDSKVDIFKKTQGRLTDAEKKQVLQVLIADVLFSQE ASKQGIKISDDEVMQTIRTQFGLVNFTDEQIKQMIEKQGTNWGELLSSMKRSLSSQKLVLKQAQPKFSEIKTP

SEK

EIVEYYEANKTKFVNPDISRVSHIFFSTKDKKRSDVLDQAKNILSQIRSKKITFEEAVRKYSNDESSKAKNGDLGF

WO 98/59071 PCT/U598/12718 142 TABLE 1. Nucleotide and Ami~no Acid Sequences LSRGDQNAQNLLGADFVKEVFNFNGDISSPIASKErCFHIVKVTEKYAQRFLGLND)KVSPTADLIVKflAIRNNMIN

VQQQQIVVQVQQDMYGKLNKSANIQILDSSLK

t853 .aa

QNTPVAIINLYEIITKTGFDSKVDIFKTQGRLTDAEKKQVLQVLIADVLFSQEASKQGIKISDDEVMQTIRT

QFGLVNFTDEQIKQMIEKQGTNWGELLSSMdRSLSSQKLVLKQAQPKFSEIKTPSEKEIVEY'!EANKTKFVNPDIS

RVSHIFFSTKDFRSDVLDQAKILSQIRS'KKITFEEAVKYSNDESSKAKNGDLGFLSRGDQNAQNLLGADFVKE

VFNFNKGDISSPASKEGFIVKVEKYAQRFLGLNKVSPTALIVDAINNMINVQQQQIVVQVQQDMYGKLN

KSANIQIIJDSSLK

f853 .nt ATGAAGAGTTTTT'rATTTTGGGTAATATTGGGA.ACTGTAGGGATTAGCTCTTTTGCTCAAAATACTCCTGTTGCTA

TTATTAATTTATATAAGAATGAAATTATTACTAAAACTGGTTTTGATTCTAAGG'ITGATATATTAAAAAGACCCA

AGGTAGAGACTTAACTGATGCTGAGAAAAAGCAAGTTCTGCAAGTTTTAATAGCA-GATGTTCTTTTTAGTCAAGAG

GCTTCAAAGCAAGGAATTAAAATCTCAGATGATGAGGTTATGCAAACAATTAGAACTCAATTTGGGCTTGTGAATT

TTACTGATGAACAAATCAAGCAAATGATAGAAAAACAAGGTACAAATTGGGGCGAGCTTTTGTCTTCAATGAAAAG

ATCTCTGTCTTCTCAAAAGCTTGTrTTAAAGCAAGCTCAGCCTAAG TCTGAAATTAAAACTCCTAGTGAGAAA

GAAATTGTTGAGTATTATGAGGCTAATAAAACTAAGTTTGTAAATCCCGATATTTCAAGAGTTAGTCATATCTTT=

TTTCTACTAAAGATAAAAAAAGATCAGATGTTTTAGATCAAGCAAAAAATATTTTAAGCCAAATAAGATCAAAAAA

AATTACTTTGAAGAAGCTGTAAGAAAATATTCAAATGACGAATCTTCTAAGGCTAAAAATGGTGATCTTGGGTT

TTATCAAGAGGTGATCAAAATGCTCAAAATCTTCTTGGAGCCGATTTITGTGAAAGAGGTTTTTAATTTTAATAAGG

GTGATATATCTTCGCCTATTGCTTCAAAGGAAGGGTTTCATATTGTTAAAGTTACAGAAAAATATGCTCAGAGATT

TTTAGGTTTGAATGATAAAGTGTCTCCTACTGCAGATTTGATTGTCAAAGATGCAATAAGAAATAACATGATTAAT

GTTCAACAACAG4CAAATTGTTGTTCAAGTACAGCAAGATATGTATGGTAAGCTTAACAAGTCTGCAAATATACAAA

TCTTGGATTCTAGTCTAAAATAA

t853.nt CAAAATACTCCTGT'TGcTATTATTAATTTATATAAGAATGAAATTATTACTAAAACTGGTTT'rGATTCTAAGGTTG

ATATATTTAAAAGACCCAAGGTAGAGACTTAACTGATGCTGGAAAAAGCAAGTTCTGCAAGTTTAATAGCAGA

TGTTrCTTTTAGTCAAGAGGCTTCAAAGCAAGGAATTAAAATCTCAGATGATGAGGTTATGcAAACAATTAGAACT CAAT=TGGGCTTGTGAA =TTACTGATGAACAAATCAGA GTGAAAAG CAAATTGGGGCGAGC

TAAAACTCCTAGTGAGAAAGAAATTGTTGAGTATTATGAGGCTAATAALAACTAAGTTTGTAAATCCCGATATTICA

AGAGTTAGTCATATCTTTTTTTCTACTAAAGATAAAAAAAGATCAGATGTTTTAGATCAAGCAAAAAATATT'rTrA GCCAAATAAGATCAAAAAAAATTACT=rGAAGALAGCTGTAAGAAAATATTCAAATGACGAATCTCTAAGGCTA

AAATGGTGATCTTGGGTTT=TATCAAGAGGTGATCAAAATGCTCAAAATCTTCTTGGAGCCGATI'TTGTGAAAGAG

GTrTTTTAATTTTAATAAGGGTGATATATCTTCGCCTATTGCTTCAAAGGAGGGTTTCATATTGTTAA.AGTTrAG AAAATATGCTCAGAGAT TTGTTATAAATTCTCCTACTGCAGATTGATTGTCAAAGATGCAALT AAGAAATAAC-ATGATTAATGTTCAACAACAGCAAATTGTTGTrrCAAGTACAGCAAGATATGTATGGTAAGCTTAAC

AAGTCTGCAAATATACAAATCTTGGATTCTAGTCTAAAATAA

f859.aa KLpK~yKLILLFLFTTRLFSVKDEKSDNKLELF SN TETKIK NS DNSNSNSKKIK ES ILl fTNSEKNINSN

IYIQKSKKINPNRNLGNNQKTANDVFTKTSYYPNKDNFQEIAKFPAKTEKTIGPINL

II IILKTKGYTLIEYIElNN t859 .aa VKDEKSDNKLELFSNVETKiKKNsKNiYDSNSNSKKIKKES ILKRDTNSEKNINSNIYIQKSKKINYPNRNLGNNIN

QKTA

f859 .nt WO 98/59071 PCT/US98/1271 8 143 TABLE 1. Nucleotide and Amino Acid Sequences ?rCAAACAGCAAAGATCA AA AAATAT(AAGGTAAAACGAAATTAATC t859 .nt TATAATCCATTTCTCA AAAAA TTAATTACCCAACAGAATTAGGCAATATATAT TTCAAGAAATTAAAAATGcTAATAAATTTCCAGCTAAAACCGAACTCACATGCTTCGGCCCATATTA

AGTACAGAATATAAGTAACAGGTCCTATGAAAAAGC-TA

TAA

f86l. aa YKKYALRCLEALKFEVVNTGREIVFLGCTHYLHLKVMJEDFLKI

PVYENRE-LVVKNLIRSMNFSEHKGNYYKNDFD

FVDDEFYLTENKNLTFYQNFCKXYNLRFKGNIV

t861.aa

RIGGCQYVYVADNFPYGEKSPEYLLAVLFLIEKKCIYN±GLVANTISSYNYTNJFPVYTLPDVSS

S R.FKGMIV f861.nt AT A AA T CT TC T TT TA...T AA

GTGAAGGAGCAAGTAGTCGTATAATTCTAGAAAAGCTAT

TCTTGACGTT

AAGTAAAATTTAATGGATGTTGTG

AAAATTTTA

TTCATATTTCTGCGTTAT

CATTAACTTTAAAATCTTGAGAATGTAG

T*ATATTCTATATGTGA*ACGTGGGCTTATTGTGAA~-GGA

TAAAATTCCTA:GTAAGCTAATT

AGTTATCGTAAAATTTT

TTCGCTTTAAGGGAATGATAGTTTGA

t861.nt

AGATGGGTCATT=TTGCAATAATTCTAGAAAAGCTATT

TTTGACGTTTTTATAAGTAAAACAATTGTCTATTGCTT-

TAATTTTATTTCAAATATTGTTTCGATTTCTGCGTTATC

GTTAACTTTAAAATCTTATCAAAATCCTAACAATGTAGT

AAGTAATATACATATGATTTGATTGTAAGCTGCTGGAGAGCTATTGTTGATATGGGAGAATTA

CAAATTCCTGTTTGACTAATTGATGAAATGAAAAT

TT

GGTCCCTATGACTAGATAAAAATTTAATCT

TAATGGA

WO 98/59071 PCTIUS98/1271 8 144 TABLE 1. Nucleotide and Amino Acid Sequences TAGTGGTAAAAAATCTATTAGATCAATG7AATrTTTTCTGAACACAAAGGTAATTATTATAAGAATGATTT'GA=T TGTAGATGATGAGTTTATTTGACCGAAAATAAAAATTrGACTTTTTATCAAAATT=GCAAAAAATATAATCTT

CGCTTTAAGGGAATGATAGTTTGA

f363 .aa

MIRLKVLILCLFGIFVLNGFADTNFEFNFGGGVAFPVSPFSSFYNEALEINAKLKQNLPSDLSPIEKEEIVQNFSD

LANIAKAGIRYGTYAQFGAFDDFVSIGFELLFNTNLKAIKRSI)GTANENFSFIMAITPRFYTKLDFFVLALAFF

TGPKINIATSSADSVLAELGTMGWI)IGARLSFSFLILEGYYVWNIKNPKFSDFKFGIGFEFGIV

t363 .aa

DTNFEFNFGGGVAFPVSPFSSFYNEALEINAKLKQNLPSDLSPIEKEEIVQNFSDLANIAKAGIRYGTYAQFGAKF

DDFVSIGFELLFNINLLKAIKRSDGTANENFSFIMAITPRFYTKLDFFVLALAFFTGPKINIATSSADSVLAELGT

MGWDIGARLSFSFLILEG.YYVWNINPKFSDFKFGIGFEFGIV

f363 .nt ATGATTAGGCTTAAAGTTTTAATTTTGTrTTrATTTGGGATTTTTGTGTTAAATGGTTTTGCAGATACTAATTTTG AATTCAATTTTGGTGGTGGGGTTGCTT'rTCCTGTTAGTCCCTrTTCAAGCTTTTACAATGAGGCTTTAGAGATTAA

TGCAAAGCTTAAGCAAAATTTGCCTTCAGATTTATCCCCAATAGAAAAAGAAGAGATAGTCCAAAATTTTTCCGAT

TTAGCCAATATTGCTAAAGCTGGAATAAGATA'rGGAACTTACGCTCAATTTGGCGCTAAATTTGATGATTTTGTTT

CTATTGGATTTGAGCTTTTGTTTAACATTAATCTTCTTAAAGCAATAAAGCGTTCGGATGGAACTGCAAATGAAAA

TTCTCGTTTATTATGGCAATAACACCAAGATTTTATACAAAATTAGATTTTTTTGTTTTAGCTTTAGCGTTTTTC

ACAGGTCCTAAGATCAATATAGCGACTTCTTCTGCGGATTCTGTTTTAGCAGAACTGGGAACAATGGGCTGGGATA

T'rGGTGCTAGACTrrTCATTTTCTTTTTTAATTCTTGAAGGGTACTATGTTTGGAATATTAAAAACCCTAAATTTTC

TGATTTCAAGTTTGGAATAGGTTTTGAATTTG

GAATTGTGTAG

t363.nt GATACTAATTTTGAATTCAATTTrTGGTGGTGGGGTTGCTTTTCCTGTTAGTCCCTTTTCAAGCTTTTACAATGAGG

CTTTAGAGATTAATGCAAAGCTTAAGCAAAATTTGCCTTCAGATTTATCCCCAATAGAAAAAGAAGAGATAGTCCA

AAATTTTTCCGAT'rTAGCCAATATTGCTAAAGCTGGAATAAGATATGGAALCTTACGCTCAATTTGGCGCTAAA.TTT

GATGATTTTGTTTCTATTGGATTTGAGCTTTTGITTAACATTAATCTTCTTAAAGCAATAAAGCGTTCGGATGGAA

CTGCAAATGAAmTCTCGTTTATTATGGCAATAACACAGT AACAATGTTTTTTGTTTTAGC

TTTAGCGTTTTTCACAGGTCCTAAGATCAATATAGCGACTTCTTCTGCGGATTCTGTTTTAGCAGAACTGGGAACA

ATGGGCTGGGATATTGGTGCTAGACTTTCATTTTCTTTTTTAATTCTTGAAGGGTACTATGTrTGGAATATTAAAA

ACCCTAAATTTTCTGATTTCAAGTTTGGAATAGGTTTTGAATTTGGAATTGTGTAG

f368.aa

MIDLTQEKQEILIKNXFLAKVFGLMSIGLLISAVFAYATSENQTIKAIFSNSMSFMAMILIQFGLVYAISGALNK

ISSNTATALFLLYSALTGVTLSSIFMIYTQGSIVFTFGITAGTFLGMSVYGYTTTTDLTKMGSYLIMGLWGI I AS **LVNFFRSSGLNFLISILGVVIFTGLTAYDVQNISKKMLQDDTEIKRMAVVASLKLYLDFiNLFLYLLRFLGQ

**RRND

t368 .aa TSENQTIKAIIFSNSMSFAMILIQFGLVYAISGALNKISSNTATALFLLYSALTGVTLSS IFMIYTQGSIVFTFG ITAGTFLGMSVYGYTTTTDLTKMGSYLIMGLWGII IASLVNMFFRSSGLNFLISILGVVIFTGLTAYDVQNISKMD KM4LQDDTEI~RMAVVASLKLYLDFINLFLYLLRFLGQRRND f368 .nt WO 98/59071 PCTIUS98/1271 8 145 TABLE 1. Nucleotide and Amino Acid Sequences ATGATC ATACCAAAAAGAATAATAAAAAACAAGTTTAGCCA).AGTTTTCGGGCTTATGT CAATTGGACTTTTAATCTCGATT1'CTTCACTCAGAAAATCAAACAATCAAAGCAATAATAT'rCTC AATTAATGCATTTGGTATGATACTTATACAATTTGGA.CTTGTATATGCAATAAGTGGTGCTCTrAATAAA

ATATCAAGCAATACTGCAACAGCTCTTTTCTTGCTCTACTCAGCACTAACAGGAGTAACATTATCTTCTATATTTA

ATACACTACAACAACAGATCTAACAAAATGGGAAGCTADAAT CTTGGACATTATI'GC-ATCT CTTGTTAATATGTTTTTTAGAAGCTCAGGTCTrrAATTTCCTTATATCTATrirTGGGCGTAGTTATATTrTACAGGCT GGCGGTTGTAGCCTC-ACTTAAACT TA~AATTTA~'' t

TTATATCTTCTAAGATTTTGGGCCAA

AGAAGAAACGATTAA

t368 .nt

ACCTCAGAAAATCAAACAATCAAAGCAATAATATTCTCAAATTCAATGTCATTTATGGCTATGATACTTATACAAT

TTGGACT'TGTATATGcAATAAGTGGTGCTCTTAATAAAATATCAAGCAATACTGCAACAGCTCTTTTCTTGCTCTA CTCAGrcACTAACAGGAGTAACATTATCTTCTATATTTATGATTTACACACAAGGATCAATAGTATTCACATTCGGA

ATTACTGCTGGAACATTTCTTGGAATGTCTGTTTATGGATACACTACAACAACAGATCTAACAAAAATGGGAAGCT

ATTrAATAATGGGCTTATGGGGAATrCATTATTGCATCTCTTGTTAATATGTTTTTTAGAAGCTCAGGTCTTAATTT CCTTATATCTATTTTGGGCGTAGTTATATTTACAGGCTTAACAGCTTATGATGTTCAAAATATTrCTAAAATGGAC

AAAATGCTACAAGACGACACTGAAATAAAAAAC-AGAATGGCGGTTGTAGCCTCACTTAAACTTTATTTAGATTTTA

TAAATTTATTCTTATATCTTCTAAGATTTrTGGGCCAAAGAAGAAACGATTAA f371.aa

MKFFFLLQIALILLSNSSLLFGQSPPKEKEDSLLLYKEGKFKEAILNTLEEIRLNPSNLDARTILIWSLIAIGEYK

PAEKEAIIGLGIKKHDIRI IQALGEAYFFQKNYDNALKYFQEYISLDSKGARIIKVYNLIADSFYELKRYNEADFA

YEHALRFSPNNQNLLIKLARSRINANKILEELIKILTISPNNLEAKNLLEELKKSNNYP

t371.aa EDSLLLYKEGKFKEAILNTLEEIRLNPSNLDARTILIWSLIAIGEYKRAEKEAI IGLGIKKHDIRIIQALGEAYFF QKNyDNALKyFQEyISLDSKGARIIKVyNLIADSFYELKRYNEADFAYEHALRFSPNNQNLLIKLARSRINAKNKI

LAEEALIKILTISPNNLEAKNLLEELKKSNNKP

f371.nt ATGAAATTTTrmTTCTATTACAAATAGCT-rAATCTACTATCCAATTCAAGCTTGTTATTTGGACAATCACCGC CTAAAGAAAAAGAAGACTCTCTTCTrCTAAAAAGAAATAAA TATTTTAAACACGTTAGAAGA

AATTCGACTAAACCTAGTAACTAGATGCTAGGACAATATTGATATGGAGCTAATAGCCATAGGAGAATACAAG

AGAGCTGAAAAAGAGGCGATTATAGGACrGCTAAACTAAAATATAGATGAAG CrrrATTTCTTTC'A A A A AATTATGAcAATGCATTAAAATACTTTCAAGAATACATTAGCCTTGATTCTAAA-GGAGC AAGAATAATAAAAGTTTATAATTTAATGcAGATTcTTT rATGAGCTAAAAAGATATAATGAAGCCGAT'rTTGCA TACGAACATGCATTACGTTTTTCTCCTAATAACCAAAATCATAAATA AACAAGAA.TAALATGCAA

AAAATAAAATATTAGCAGAAGAAGCACTAAMTAAAATTCTTACAATCTCTCCTAATAATCTAGAGGCAAAAAATITT

ACTAGAAGAAT'AAAAAGCAACAACAAACCTTGA

t371 .nt GAAGAcTcTC-TTcTTCTATATAAAGAAGGAAAATITAAAGAAGCTATTTTAAACACGTTAGAAGAAATTCGACTAAL ATCCTAGTAACTTAGATGCTAGGACAATATTrGATATGGAGCTTAATAGCrATAGGAGAATACAAGAGAGCTGAAAA A.GAGGCGA'ITATAGCGACTTGGCATTAAAAAACATGArATAAGAA.TTATTCAAGCACTAGGAGAAGCTTATTTCTTT

CAAAAALAATTATGACAATGCATTAAAATACTTTCAAGAATACATTAGCCTTGATTCTAAAGGAGCAAGAATAATAA

AAGTTTATAATTTAATTGCAGATTCTrTTTTATGAGCTAAAAAGATATAATGAAGCCGATTTTGCATACGAACATGC ATTACGTTTmCTCCTAATAACCAAAATCTATTAATAAAATTAGCAArATCAAGAATAAATGCAAAAA6ATAAA6ATA

TTAGCAGAAGAAGCACTAATTAAAATTCTTACAATCTCTCCTAATAATCTAGAGGCAAAAAATTTACTAGAAGT

TAAAAAAGCACAAAAACTTGA

WO 98/59071 PCTIUS98112718 146 TABLPE 1. Nucleotide and Amino Acid Sequences f502 .aa MXKANFLSTNFLILLLVCFVNVNLFSDMIFKFKLVDQFFPFflKNKGEYEGLIFSILDKWAKNNAIMVEHIDN LNESEIEflEAIYLGLTYNVKLNDFFYFKSELARSISILFFNK ~STFLSNFNIGVIKNTIYEILRLKN VNTIFLAflNSQELVLALNDKDYIYGDCKTLYIAFLSEDLVIFTGDVFYSIKRVAISNA.PEIVwKNNLDL FSYLbMPEELVFSLSNAKGSFVDVGLYNDYPPLSFINSQGKLSGILVDLWNLLSRQHIFKPIFxGFSKEDIKx SLflGKSVGIFGGIISNflSVLENVNVVSKPIYPNFKFYSKDLSND)AGPINSQFIDFNFNNIQLwMwIVNNFID

IVNNSYGFIENSITTKYLLKLNGYNGRLKSYSIFNKNRFLVLAIDNRIYKVKYILNSIFDDISFESLLQIDKNW

LDKEEINSSRI-NSYKIMKFNIEEKIWLSIQKLNAVNWYPIDYVEANYKGINQFLLflKIRMFSGLRFNII KVHSSLDIdKKIKSGK.IDMLNTNATDSNLDNVFNIKLNSRI PLYIFSNKRVLPSRSLEKFAILDFLYSKNLASNI KSKLILVSSFNEALLLLYKGKVDGIISDEYTAAAVFEELNIDDVEKIPTFRflLAFDLSLAIYNQDYILKEI IQKVV

MRSNVDSQMYLNDWKDIY'!KSRSIRFKNFKFLVITFIIFYFTFLGFVIFMFRLSFEQKRRYSFVMNEKKIAEAA

NAAKTIFIANVSHDIRTPINGIMAATELLDTTILTDVQKDY'IRMrNYSSDSLLSLIDDILYLSKIDVNELYVESQE

IDLESEMEMVLKAFQSQCAKKNIDLFSYSKSIFNNYIKGDIVKIKQVLINLIGNAFKFTDDGVIVLNYEEVCRTRT

DGNRVLVTVEFKVIflTGKGIEKENFSKIFEIFKQEDDSSSRVHEGAGLGLSISELIRLMGGLGAVDSKVGEGTT FSFMLPFLLGSELKSKKLSNRFQSVNGDNKVLNVLLSQKSIKIFEHCSILLGCSSNVRYVASFEDAYKVF PS YNFVYINVNNDNIQEGIRLANNIE-RLNSDVQI IFLFYYLDNKALKNLKYGYVKKPLMGLGICSILYKKEFNPEMDF EflLWIDSALRIKEPINVLIAEDNQVNQKVLKDILVVIGINENFIDVVDDGVKALKSLKDKKYTISFIDIRMPRYD GFSVAKEIRKFEKAKNLKPCVLVAVTAHAI.QEYKDKCASGMNDYISKPIHI SSIKTILKKYLQFEVDDIGENENL NQLVKFPNLDVNRALKELNLSYVSYSELCRGLVDF ISINT IDLEKA-FDEEDLSLIKDISHSISGALSNMRS.ELYKD

FQKIETSKDSISELKKMYSFVKDDLFQLISDIKENILESEIVSENKLYFKNNDQFLNLLNKLLIGIKTRKPREYK

EILESINKYVLDDNIQVLFSDLRRNLRLYRFAESSKILEEIIEMLNNKRY

t502.a CFVNVNLFSKDIFKFKLVDQFFPFYYKNNKGEYEGLIFS ILnKWAKDNNADIMVEHIDNLNESEIEDEAIYLGLTY NVKIJNDFFYFKSELARS ISILFFKNSNKKYKNTHSTFLSNFNIGVIKNTIYEDILRLKNVNTIFLADNSQELVLAL

KNDKVDYIYGDCKTLHYIAN~NFLSEDLVIFTGDVFYSIKNRVAISRNAPEIVKNLNLDLFSYLMKMPEELVFSFLD

SNAKGSFVDVGLYNDYPPLSFINSQGKLSGILVDLWNLLSRQHIFKPIFKGFSKEDIKKSLnGKSVGIFGGI ISND

SVLENVVSKPIYPLNFKFYSKLSNDAGPINSQFIDFNFNNIQLNKKDIVNNFIDIVNNSYGFIENSITTKY

LLKLNGYNGRLKSYDSIFNNRFLVLAIDNRIYKVIKYILNSIFDDISFESLLQIDKNWLDKEEINSSRINSYKIM

NKVKFNIEEKIWLSKWNKNLAVKNWYPIDYVEANNYKGINQFLLDKIRMFSGLRFNIIKVHSSLDLKKLIKSGKI

DMLNTNATDSNLDNVFNIKLNSRIPLYIFSNKKRVLPSRSLEKFAILDFLYSKNLASNIKSKLILVSSFNEALLLL

.000.: YKGKVDGIISDEYTAAAVFEELNIDDVEKIPTFRDLAFDLSLAIYNQDYILKEIIQKVVMRSNVDSQMYLNDWKFD

**IYKSRSIFKNFKFLVITFIIFYFTFLGFVIIFMFLSFEQKRRYSFVNEKKIAEAANAAKTIFANVSHDIRT

PINGIMAATELLDTTILTDVQKDYVRMINYSSDSLLSLIDDILYLSKIDVNELYVESQEIDLESEMEMVLKAFQSQ

CAKKNIDLFSYSKSIFNNYIKGDIVKIKQVLINLIGNAFKFTDDGVIVLNyEEVCRTRTDGNRvLVTVE-FKVIDTG

KGIEKENFSKIFEIFKQEDDSSSRVHEGAGLGLSISRELIRLMGGLGIAVDSKVGEGTTIFSFMLPFLLGSELKSKK

LS nRFQSVNGDNKVLNVLLSQKSIKIFECSILLGCSSNVRyVASFDAyKVFKKypSyNFVYDJVNNDNIQEGI 0:0.0: RILAN.NIERLNSDVQIIFLFYYLlNKALKNLKYGYVKKPLMGLGICSILYKKEFNPE1MDFEDLVPIDSAILRIKEPIN

VLIAEDNQVNQKVLKDILVVIGINENFIDVVDDGVKALKSLKDKKYTISFIDIRMPRYDGFSVAKEIRKFEKAKNL

KPCVLVAVTAHALQEYKDKCLASGMNDYISKPIHISSIKTILKKYLQFEVDDIGENENLNQLVKFPNLDVNRALKE

LNLSYVSYSELCRGLVDFISINIIDLEKAFDEEDLSLIKDI SHSISGALSNMRSELYKDFQKIETSKDSISELKKM

.*YSFVKDDLFQLISDIKENILFESEIVSENLYFK.JNDQFLNLLNKLLIGIKTRKPREYKEILESINKYVLDDNIQV

*00. LFSDLRRNLRILYRFAESSKILEEIIEMLNNKRY f502 .nt ATGAAAAAAGCAAACTTrTTTAAGTACTAATTTTTTAATTTTACTTTTGGTTTGCTTTGTCAACGTCAATTTATTTT CTAAGGATATTTTCAAGTTTAAGCTTGTAGATCATTTTTTCCTTTrTACTACAAGAATAATAAAGGAGAATATGA AGGACTTATTTTTTCTAT TAAAAGGAAAAATAGCTGATATTATGGTTGAGCATATTGATAAT T'AAATGAAAGTGAAATTGAAGACGAAGCAATATATrTAGGATTAACT'rATAATGTAAAATTAAA.TGATTTTTTTT

ATTTTAAAGTAGCTGCTAGGAGTATTTCAATTTTATTTTTAAAAACTCTAATAAAAAATATAAAAATACCCA

TTCAAcATTTTTATCcAATTTTAATATAGGAGTTATTAAAAATACAATATATGAAGATATCTTAAGGTTAAAAAAC

GTTAACACCATT'I"TTTGGCTGATAATTCTCAAGAGTTAGTATTGGCCTTAAAAAACGATAAAGTTGATTATA.TAT

WO 98/59071 PCTIUS98/12718 147 TABLE 1. Nucleotide and Amino Acid Sequences ATGGTGAT~c~cAAGAcTT'ACATTATATTrCAAATAACTT t rTAAGTGAAGATCTrGTGATTTTACCCGGGCGATGT T-r rATAGTATCAAAAATAGAGTGGCTATTAGTAGAAATGCTCCTGAGATAGTAAAGAATTTGAAT'rTAGATTTG ATGTTGGTTrATATAATrGATTATCCTCCTTTAAGTTTTArATC.ACAGGAAAATTGTCTGGCATTTTAGTGGA TTTGTGGAATcTrcTCTCAAGACAACATATCTTAAACCTATITrTAAGGGATTTCCAAAGAGGATATTAAGAAA TCATAGTCGAATAGTGGTTTTTGGGGATTATAGAAT~TATGTGTTGGAAAATGT'rAATTATG TAGTAAGTAAGCCAATATATCCTCTTAAMTTAAA1'TTATTCTAAAACCTAAGCAATGATGCTGGTCCAATAAA TrCTAGTA~rAT~ATTTAATATATCATTAAAAGATAAGAATTTTAATAACTrTATAGAT A? GTAAAATCATTGG~rTTAGAAATCAAAACACAAATT~rrGTAAAATTAAATGGATATAACG

GTAGATTAAATCTTACGATTCGA~~ATAAAG~TAT~ACATAATGATAA

GGTTATTAAATATATTCTCAATTCTATATMGATGATATTCATTTGAATCTTGCTTCAAATAGATAAAAATTGG

TTGGTAAGAAAGATAAAGCTAAATAATGTTTAAA'rATGATAGGTTAAATTTAATATAGAAG AAAAAATTTGGT'rAT AAATAAATATTTGCTGTTAAAAAfrrGGTATCCAATAGATTATGTTGAGGC AAATATTTAAAGAAAAACAATTTT'rGCTTGATAAGATTAGAATGTTTTCAGGTTTGAGAT'rTAACATAATT

AAAGTACACAGCAGTTTAGATCTTAAAAAAI'AATCAAATCTGGAAAAATCGATATGCTAAATACTAATGCAACCG

ATrcAAATTTAGATAATGTrTTCAACATAAAATTAAATTCTCGAATTCCACTTTATATTTTTCAAATAAAAAAG

GGTGCTTCCATCTAGATC'TTTAGAAAAGTTTGCTATACTTGATTTTTTATATAGTAAAAATTTGGCTTCTAATATT

AATCAAAGCTTIATTCTGGTAAGCAGTTTAATGAAGCGTTGCTTCTTCTTATAAGGAAAGGTAGATGGGATTA

TTAGCGATGAGTATACAGCTGCTGCTGTTTTGAGGAATTAAATATTGAT-ATGTTGAAAAAATTCCTACTTTTAG

AGATTTrGGcTTTTGATT'rGAGTCTTGCTATTTATAATCAAGATTATATCTTGAAAGAAATTATTCAAAAAGTTGTT

ATGCGTTCAAATGTTGACAGTCAGATGTATTTAAATGATTGGAAATTTGATATTTA'ITATAAATCCAGAAGTATCA

GGTTTAAAAATTTCAAATTTTTAGTGATAACATTCATTATATTTTATTTTACTTTTTTAGGATTTGTAATTATATT

TATGTTCAGATATCATTGACGAAGAAATTTTTGTGATGAATGAAAAAA-AGATTGCGGAAGCCGCT

AATGCTGCTAAAACCATTT'TTATAGCCAATGTCAGTCATGATATTCGTACCCCTATTAACGGAATAATGGCGGCTA

CTGAGCTTTTGGATACAACTATTCTTACAGATGTTCAAAAAGATTATGTTAGGATGATAAATTATTCATCTGATTC

TTTGCTTCTTTAATTGATGATATATTGTATTTGTCTAAAATAGATGTCAATGAATTATATGTTGAGAGTCAAGAG

ATTGATTTAGAGA.GTGAAATGGAAATGGTTTTAAAAGCTC=AATCTCAATGTGCAAAGAAAAATATTGATTTAT

TCTCTTATCTAAATCTATN'TTAATAATTATATAAAGGGTGATATTGTAAAAATTAAACAAGTTTTAATTAATTT

AATAGGAAATGCTTTAAGTTTACAGATGATGGTGTTATTGTT"I'TAAATTATGAAGAAGTATGTAGAACAAGAACT

GATGGTAATAGGGTTTTG GTTACAGTTGAATTTAAGGTAATAGATACAGGCAAAGGGATTGAAAAAGAAAATTTTT CTAAGATA'ITTGAATATTTAAACAAGAGGATGAT~cTTCTTcAAGGGTTcATGAAGGTGcAGGAI'GGGATTGTC

AATATCTAGAAGCTTATAAGACTAATGGGTGGTCTTGGTATTGCTGTTGATAGCAAGGTGGGAGAGGGTACAACT

TTTTCATTTATGTrGCCCTTTTATTGGGTAGTGAGCTTAAAAGTAAAAAATTGTCAATCAATAGATTTCAATCAG

TAAATGGTGACAATAAGTATTAAATGTGCTTTTAAGTCAAAAATCTATTAAAATTTTTGAGCACTGTTCGATTITT

ATTGGGATGCTCTTCTAATGTGCGCTATGTAGCGTCTTmGAGGATGCTATAAAGTCT TCAAGAAATACCCTTCT TATAATTTGrTATATAAATGTAAATAACGATAATATTCAAGAGGGTATTCGACTTGCCAATAATATTGAAAGAC .4..TAAATTCTGATGTACAAATTATTr TTATTTTTGAATAAGTAAAAAATAAAATATGGTTA TGTTAAAAAGCCTrN'AATGGGGCTTGGTATATGCTCTATCTTTATAAA.AAGAGTTTAACCCAGAAATGGATTTT (GAGGATTTGGITrCCAATAGATAGTGCTTTAAGGATAAAAGAGCCCATTAATGTTTTAATAGCTGAAGATAATCAGG AACAAAGGTGAAGTATTTGTTG TTGCTATAATrTTGTTTGTAGATGATGG AGTAAAGGCTTTAAAATC'1rAAGTAAAAATATCTCTrTTATATATCGAATGCCAGATATGAT GGATTTTCGGTGGCTAGAATGATrAAAGAAATTA CTTGTGTT'ITGGTTGCTGTAA *.:.CAGCGCATGCTTTGCAArAGTATAAAGACAAGTGTCI'TGCAAGTGGTATGAATGATTATATCTCAAAACCAATACA CATAAGTTCAATAAAACTATATTAAAAAAATACTTACAG ~GA~iTAATGGGAGAATG i7. AATCAACTTGTTAAGTTrCTAA~AArAAC TTAAAAGAATTAAATCTTTCATATGTATCATATT CTGAATTATGTAGAGGGCTTGTTGATTTTATCTCTATAATT~L~~~ AGT'TTTGATGAGGAAGA TTTGTCTrTAArAAGGATATATCTCATTCAATATCTGGAGCTCTTTCTAATATGCGTAGCGAATTGTATAAAGAT TTTA AA AGA CAATAAGACAATTTCTGAGTTGA AA A A ATGTATTCTTTTGTAAAAGATG-ATTTAT TTCAACTAATAAGCGAAAAGAAA TTIGAGTCG TGTGGGAAGTATATTTTAA AAATAATGATCAATTTTTAAACCTTCTCAACAAACT1'TAA1'GGTATTAAGACTAGAAAGCCAAGAGAATACAAA GAAATCTAAC ATATTGTrGCAAT CAGGTATATTAGTGATCTTCGCAGAAATT

TAAGATTATATAGATTTGCTGGAGCTCTAGTCGAAGTATAAGTTAATAATAAGAGATATTLA

G

t502 .nt WO 98/59071 PCTIUS98/12718 .148 TABLE 1. Nucleotide and Amino Acid Sequences TGCT'rTGTCAACGTCAATTTATmCTAAGGATATTTCAGETTAAGCTGTAGATCAATTTTTTCCTTTTTACT

ACAATAAAGGAAGAGCTTTTTTTTAAAAGGAAGTAATCG

TATTATGGTTGAGCATATTGATAATTTrAAATGAAAGTGAAATTGAAGACGAAGCAATATATTTAGGATTAACTTrAT ATTATAATG T~~TTTAAAAGTGAGCTTGCTAGGAGTATTT~CAATTTATTTTTTAAAAACT CTAATAAAAATATAAATACCCATTCAACAT'rTTTATCCATTTTAATATAGGAGTTATTAAAAATACAATATA TGAAGATATCTTAAGG'rrAAAAAACGTTAACACCATTTTTTTGGCTGATAATCTCAAGAGTTAGTATTGGCCTrA

AAAAACGATAAAGTTGATTATATATATGGTGATTGCAAGACTTTACATTATATTGCAAATAACTTTTTAAGTGAAG

ATCTTGTGAT'rTTTACCGGGGATGTTT'rmATAGTATCAAAAATAGAGTGGCTATTAGTACAAATGCTCCTGAGAT AGTAAATTG AATGTTTCATATTTAATGAAATGCCTGAGGAACTTGTTTTTTCT'TT'rAGAT AGCATGCTAAGGGAAGTTTTGrGATGTTGGTTTATATAATGATTATCCTCCTTTAAGrTTATTAATCACAGG GAAAATTGTCTGGCATTTTAGTGGATTTGTGGAATCTTCTCTCAAGACAACATATCTTTAAACCTATTrr'rAAGGo ATT'rTCCAAAGAGGATATTAAGAAATCATTAGATGGAAAATCAGTAGGTATTTTTGGAGGAATTATTAGCAATGAT AGTGTGTTGGAAAATGTAATTATGTAGTAAGTAAGCCAATATATCCTCTTAAT'rTTAAATTTTATTCTAAAGACC TAAGCAATGATGCTGGTCCAATAAATTCTCAGTTAT'rGATTTTAATTTTAATAATATTCAATTAATAAGAATAA AGAAT'GTTATACTTATAATATGTAATATCATATGCGGTTTATAG AATTCAATAACAACAAAATAT

TGTTAAAATTAAATGGATATAACGGTAGATTAAAATCTTACGATTCGATTTTTAATAAAAATAGGTTTTAGTAT

TAGCCATTGATAATAGGATTTATAAGGTTATTAAATATAT'rCTCAATTCTATATTTGATGATATTTCATTTGAATC TTTGCTTCAAkATAGATAAAATTGGTTGGATAAAGAAGAGATTAATAGTCTAGAATAA -TAGTTATAAAATTATG

AATAAGGTTAAATTTAATATAGAAGAAAAAATTTGGTTATCAAAAAATAATAAATTAAATCTTGCTGTTAAAAATT

GGTATCCATAGATTATGTTGAGGCAATAATTATAAGGAATAATCATTTTGCTTGATAAGATTAGAATGTT

TTCAGGTTTGAGATTTAACATAATTAAAGTACACAGCAGTTTAGATCTTAAAATTAATCAATCT7GAAAAATC GATATGCTAAATACTAATGCAACCGATTCAATTTAGATAATGTTTTCACATAAATAAATrCTCGAATTCCAC TTTATATTTrTTCA.AATAAGAAAAGGGTGCTTCCATCTAGATCTTTACGAAAAGTTTGCTATACTTGATTTTTTATA

TAGTAAAAATTTGGCTTCTAATATTAAATCAAAGCTTATTCTGGTAAGCAGTTTTAATGAAGCGTTGCTTCTTCTT

TATAAGGGAAAGGTAGATGGGATTATTAGCGATGAGTATACAGCTGCTGCTGTTTTTGAGGAATTAAATATTGATG

GAAAGAAATTATTCAAAAAGTTGTTATGCGTTCAAATGTTGACAGTCAGATGTATTTAAATGATTGGAAATTTGAT

***ATTTATTATAA6TCCAGAAGTATCAGGTTTAAAAATTTCAAATTTTTAGTGATAACATTCATTATATTTTATTTTA

CTTTTTAGGATTTGTAATTATATTTATGTTCAGATTATCATTTGAGCAGAAAGAAGATATTCTTTTGTGATGAA

TGAAAAAAAGATTGCGGAAGCCGCTAATGCTGCTAAAACCATTTTT1ATAGCCAATGTCAGTCATGATATTCGTACC CCTATTAACGGAATAATGGcGGCTACTGAGCTTTTGGATACAACTATTCTTACAGATGTTCAAAAAGATTATGTTA GGATGATAAATTATTCATCTGATTCTTTGCTTTCTTAA?rGATGATATATTGTATTTGTCTAAAATAGATGTCAA

TGAATTATATGTTGAGAGTCAAGAGATTGATTTAGAGAGTGAAATGGAAATGGTTTTAAAAGCTTTTCAA-TCTCAA

TGTGCAAAGAAAAATATTGATTTATTCTCTTATTwCTAAATCTATTTTAATAATTATATAAAGGGTGATATTGTAA AATTAAACAAGT A~rATATGAAGTTrTAAGTTACAGATGATGGTGTTATTGTTTTAAATTA TGAAGAAGTATGTAGAACAAGAACTGATGGTAATAGGGTTTTGGTACAGTTGAATPrTAAGGTAATAGATACAGGC AAAGGGATTGAAAAAGAAAATT1TrC AGTTTAAATAAAGGAGTCTTCTTCAAGGGTTC

ATGAAGGTGCAGGATTGGGATTGTCAATATCTAGAGAGCTTATAAGACTAATGGGTGGTCTTGGTATTGCTGTTGA

TAGCAAGGTGGGAGAGGGTACAACTTTTTCATTTATGTTGCCCTTmTAT'rGGGTAGTGAGCTTAAAAGTAAAA6A TTGTCAATCAATAt;TTTCAATCAGTAAATGGTGACAATAAAGTATTAAATGTGCTTTTAAGTCAAAAATCTATTA

*AAATTTGAGCACTGTTCGATTTATTGGGATGCTCTTCTAATGTGCGCTATGTAGCGTCTTTGAGGATGCTTA

TAAAGTcTTCAAGAATAcccTTCTTATAArTTGTTTATATAAATGTAAATAACGATAATATTCAAGAGGGTATT CGACTTGCCAATAATATTGAAAGACTAAATTCTGTTCATTT' TATTTATTATTTAGATAATAAAG

CTCTAAAAAATTTAAAATATGGTTATGTTAAAAAGCCTTTAATGGGGCTTGGTATATGCTCTATTCTTTATAAAAA

.*AGAGTTr.AACCCAGAAATGGATTTTGAGGATTTGGTTCcAATAGATAGTGCTTTAAGGATAAAAGAGCCCATTAAT

GTTTTAATAGCTGAAGATAATCAGGTAAATCAAAAAGTGTTGAAAGATATCTTGTTGTTATAGGCATTAATGAAA

ATTTTATGATGTTGTAGATGATGGAGTAAAGGCTTAAAATC TAAGTAAAAATATCTCTTTTAT TGATATACGAATGccAAGATATGATGGATTTTCGGTGGCTAAGGAA6ATTAGAAAATTTGAAAAGGCAAAGAATTTA

AAGCCTTGTGTTTTGGTTGCTGTACAGCGCATGCTTTGCAAGAGTATAAAGACAAGTGTCTTGCAAGTGGTATGA

ATGATTATATCTCAAAACCAATACACATAAGTTCAATTAAAACTATATTAAAAAAATACTTACAGTTTGAAGTTGA

TGATATTGGGGAGAATGAAAATTTGAATCAACTGAAGTTCCTAATTAGATGTTAATAGGGCTTTAAAAGAA

TTAAATCTTTCATATGTATCATATTCTGAATATGTAGAGGGCTT-GTTGATTTTATCTCTATTrAATATTATGATT TGGAAAAAGCTTTTGATGAGGAAGATTTGTCTTTAATTAAGGATATATCTCATT CAATATCTGGAGCTCTTTCTAA

TATGCGTAGCGAATTGTATAAAGATTTCAAAAAATTGAAACAAGTAAAGATTCAATTTCTGAGTTGAAAAAAATG

TATTCTTTTGTAAAAGATGATTTATTTCAACTAATAAGCGACATAAAGGAAAATATTTTGTTTGAGTCTGAGATTG

TTAGTGAGAACAAGcTATATTTTAAAAATAATGATCAATTTTTAAACCTTCTCAACAAACTTTTAATTGGTATTA-A WO 98/59071 PCT/US98/1 2718 149 TAiBLE i. Nucleotide and Amino Acid Sequences

GACTAGAAAGCCAAGAGAATACAAAGAAATTCTTGAACTATATTTTTAGACGATAATATTCAGGTA

TTATTTAGTGATCTTC CGATTAATTTG~ TGCTGAGAGCTCTAAGATTCTTGAAGAGATTATTrG

AAATGCTATAAGCTTA

-f527.aa

MLLVKIAIFILILFLFTSCNQKQSEIQNLTHLLKSSNNRLDKFLIIDRVNIYIAQRYEDALEIVNNGIIDDE

SREYYPLYLYLMGNIYDSMGEDFVAFNIYKVDFDV SMTVKINNfSTflKIN7YFILNMGI SRGWDHIEWYFVFRIVYPKPE3NGWTWIGVYLGKK t527.m

CNQKQSEIQNLTHLLKSSNKNLDKFLIIDRVVNIYIANYEDALEIVNNGIIDDESREYYPLYLYLMGNIYDSM

GEDFVAFNIYKRVVDNFflDYVYEHSMKTRVAKIVNLNIflSIDKIYYKFILNMGIDNLNNEEKGNYFYNLALSL

EVQDYDESYFYYFLSIPRAHLKIDSRYFNVVTKINYFNNPEFVVRNGDLIQDVKMFVLSGNTSKLLNIRD

EFFIQSDQKGGKSNSINNSFLTTMIRLGGRRNGIQFAHEASSDDISYLESRGDHIHWYFVKRIVY

PKDPEINNGWTWIGVYLGK

f527 .nt

ATGAATCTATTGGTCAAAATTGCTAAATTTATT'ITGATTTTGTTTTTATTTACTTCTTGCAACCAAAAGCAAAGCG

AGATTCAAAATCTTACACATCTTTTAAATCTTCATAATGTAAAATCTTATTATTGATAGAGT

TGTTAACATATATATTGCATAATTTAGTCTTTAGAAATTGTAAAT

ATTGTAGAA

TCAAATTACTTTTTTTTAGGCAATAGTCAGGGAATTTGT

TTAATATTTACAAGCGTGTTGTTGATAATTTTGATGATTATGTTTATGAAACCATTCAATGAAAACAAGGGTTGC

TAAAAGATTGTCATTTAAATATTGATTCAATCGATAAATCAATTATTACAAATTTATATTAAATATGGGGATT

GATAATTTAAATAAT AGAGGATATTAATCTTGCGCTAAGTTTGGAAGATGTCAAGATTACG ATGAATCT ATTTAAAATTTTTCAATTCAGGAATTAATGTCTAGAGACTATTT

TAATGTTGTTACAAAATTAATACTTTAATAATCCAGAGTTTGTTGTTATAGAAATTTAGGAGATTTAATCCAG

GATGTTAAAATTTGTTCTTTCTGGTAATACTTCTAAATTGCTAAAGGAAGAATrTTTATTC *AAAGCTGGGATCAAGGGTGGAAAGAGTAATTCCA'rTAATACTAATAGCTTTTTAACCACTATGATTAGGCTTGG GGGGAGAAGAAAAAACGGAAATTGA CTTGAGGCAGATTCTAGTGACGATATATCTTATCTrGAG TCAAGGGGCTGGGAC AATAAGTTTGTTTTTAAAGAGTTTATCCTAAAGATCCAGAAATTA

ATAATGGC'TGGACTTGGATAGGCGTGTATTTAGGTAAAAAATAA

t527.nt C: TGCAACCAAGAACGGTCAACT'rACACATCTTTTAAAATCTTCTAATAAAAATAGATTAGATAAAT TTCT''TATAAA GTAAAATTGAAAA~IAGAAGTTTAGAAATTGTAAATAA TGAATMrGTGTOTTAGAGAATATTATCCTTTGTATC ITTTAGGATT'AGArrCCATG GGAGAAGATTTTGTAGCTTTTAATATTTACAAGCGTGTT GTAT'GTMrTTTTATGAAAACCATT :CAATGAAAACAAGGGTTGCCTAAGTGCATTAT?'ATA GATAAAATCAATTATTACAAATT GAAGATGTTCAAGATTACGATGAATCTTATTATAAAA TIr~TCAATrCCAAGGGCACATTTAAAAA

TAGATTCTAGAGACTATTTTAATGTTGTTACAAAAATTAA'ITACTTTAATAATCCAGAGTTTGTTGTTATAGAAA

TrTAGGAGATTAATCCAGATGTTAAAAATTTTGT'TTCTGGTAATACT~CTAAATTGCTTAATATAAGAGAT AAGAATAATTTTTTTATTC.AAAGCTGG CAAGTG A ATTCCATTAATACTAATAGCTr'ITTAA CCACTATGATTAGGCTTGGGcGGGAGAA.GAAAAAAC GA~A~rc~ CA~TTGAGGCAGATTCTAGTGA CGATATATCTTATCTTGAGTAGGGGCTGGGACCATATTCATOAATGGTATTGTrTTAAAAGAATTGTTTAT

CCTAAGATCCAGAATTAAAATGGCTGGACTTGGATAGGCGTGTATTTAGGTAAAAAATAA

f541.aa

MKILLLILLESIFLSCSGGSLGSEIPKVSLIIDGTFDDKSFNESALNGVKCVKEEFKIELVLKESSSNSYL.SD

LEGLKDAGSDLIWLIGyRFSDVAKVAALQNPDMKYAI IDPIYSNDPIpANLVGMTFRAQEGAFLTGYIAAKLSKTG WO 98/59071 PCT/US98/1271 8 150 TABLE? 1. Nucleotide and Amino Acid Sequences KIGFLGGIEGEIVDAFRYGYEAGAKYANKDIKISTQYIGSFADLEAGRSVATRMYSDEIDI IHH{AGLGGIGAIEV AKELGSGHYIIGVDEDQAYLAPDNVITSTTDVGRLNIFSNHLKTNTFEGGXLMhYGLKEGVVGFVRNPKMISF ELXEK IDNLSSKIINKEIIVPSNKESYECPLKEFI .t541.aa

CSGKGSLGSEIPKVSLIIDGTFDDKSFNESALNGVKKVKEEFKIELVLKESSSNSYLSDLEGLKDAGSDLIWLIGY

RFSDVAKVAALQNPDMKYA:IDPIYSN~DPIPANLVGMTFRAQEGAFLTGYIAAKLSKTGKIGFLGGIEGEIVAFR

YGYEAGAKYANDIKISTQYIGSFADLEAGRSVATRMYSDEIDIIHHAAGLGGIGAIEVAKELGSGHYI IGVDEDQ

AYLAPDNVITSTTKDVGRALNIFTSNHLKTNTFEGGKLINYGLKEGVVGFVRNPKMISFELEKEIDNLSSKIINKE

I IVPSNKESYEKFLKE Fl f541..nt ATGAATAAAATATTGTTGTTGATTTTGCTrGAGAGTATTGTTTTTTTATCTTGTAGTGGTAAAGGTAGTCrTGGGA

GCGAAATTCCTAAGGTATCTTTAATAATTGATGGACTTTTGATGATAATCTTTTAATGAGAGTGCTTTAAATGG

CGTAAAAAAGTTAAGAGAATTTAAATTGAGCTTGTTTTAAAAGAATCCTCATCAAATTCTTATTTATCTGAT

CTTGAAGGGCTTAAGGATGCGGGCTCAGATTTAAT'rTGGCTTATTGGGTATAGATTTAGCGATGTGGCCAAGGTTG

CGGCTCTTCAAAATCCCGATATGAAATATGCAATTATTGATCCTATTTATTCTAACGATCCTATTCCTGCAAATTT

GGTGGGCATGACCTTTAGAGCTCAAGAGGGTGCATTTTrTAACGGGTTATATTGCTGCAAAACTTTCTAAAACAGGT

AAAATTGGATTTTTAGGGGGAATAGAAGGCGAGATAGTAGATGCTTTTAGGTATGGGTATGAAGCTGGTGCTAAGT

ATGCTAATAAAGATATAAAGATATCTACTCAGTATATTGGTAGTTTTGCTGACCTTGAA6GCTGGTAGAAGCGTTGC

AACTAGGATGTATTCTGATGAGATAGACATTATTCATCATGCTGCAGGCCTTGGAGGAATTGGGGCTATTGAGGTT

GCAAAAGAACTTGGTTCTGGGCATTACATTATTGGAGTTGATGAAGATCAAGCATATCTTGCTCCTGACAATGTAA

TAACATCTACAACTAAAGATGTTGGTAGAGCTTTAAATATTTTTACATCTAACCATTTrAAAAACTAA6TACTTTCGA AGTGA*TATAATTGCTA *.ATGGGGTGAGATCTAAGTTCT

GAACTTGAAAAAGAAATTGACAATCTTTCTAGCAAAATAATCAACAAAGAAATTATTGTTCCATCTAATAAAGAAA

GTTIATAGAAGTTTCTTAAAGAATTTATTTAA

t541.nt

TGTAGTGGTAAAGGTAGTCTTGGGAGCGAAATTCCTAAGGTATCTTTAATAATTGATGGAACTTTTGATGATAAAT

CTTTTAATGAGAGTGCTTTAAATGGCGTAAAG'AAAAATTAATACTTGTI'TAAAAGAATC

CTCATCAAATTCTTATTTATCTGATCTTGAAGGGCTTAAGGATGCGGGCTCAGATTTAATT TGGCTTATTGGGTAT

AGATTTAGCGATGTGGCCAAGGTTGCGGCTCTTCAAAATCCCGATATGAAATATGCAATTATTGATCCTATTTATT

CTAACGATCCTATTCCTGCAAATTTGGTGGGCATGACCTTTAGAGCTCAAGAGGGTGCA'TTTTTAACGGGTTATAT

TGCTGCAAAACTTTCTAAAACAGGTAAAATTGGATTTTTAGGGGGAATAGAAGGCGAGATAGTAGATGCTTTTAGG

TATGGGTATGAAGCTGGTGCTAAGTATGCTATAGTTAGTTTACTCAGTATATTGGTAGTTTTGCTG

ACCTTGAAGCTGGTAGAAGCGTTGCAACTAGGATGTATTCTGATGAGATAGACATTATTCATCATGCTGCAGGCCT

TGGAGGAATTGGGGCTATTGAGGTTGCAAAAGAACTTGGTTCTGGGCATTACATTATTGGAGTTGATGAAGATCAA

GCATATCTT'GCTCCTGACAATGTAATAACATCTACAACTAAAGATGTTGGTAGAGCTTTAAATATTTTTACATCTA

ACCATTTAAAACTAATACTTTCGAAGGTGGCAAATTAATAATTATGGCCTTAAAGAAGGAGTTGTGGGGTTTGT

AAGAAATCCTAAAATGATTTCCTTTGAACTGAAAAAGAAATTGACAATCTTrCTAGCAAATAATCAACAAAGAA ATTATTGTT1CCATCTAATAAAGAAAGTTATGAGAAGTTTCTTAAAGAATTTATTTAA f561.aa

MYKNGFFKNYLSLFLIFLVIACTSKDSSNEYEEQEANSSKPDDSKIDETIGHHAMGVVHSKKDRKSLGKNI

KVFYFSEEDGHFQTIPSKENAKLIVYFYDNVYAEAPISISGKEAFIFVGITPDFKKIINSNLHGAKSDLIGTFKD

LNIKNSKLEITVDENSDAKTFLESVNYIIlGVEKISPMLTN t561.aa WO 98/59071 PCT/US98/12718 151 TABLE 1. Nucleotide and Amino Acid Sequences

FLESVNYIIDGVEKISPMLTN

f561.nt ATGTATAAAAATGGTTTTTTTAAAAACTATTTGTCATrrGTTTTTAATTTTTTTAGTAATTGCTTGTACTTCAAAG ATAG TATATTTGGACAAGGGAGAACTCTTCTAACCTGATGATTcT.AAATAGATA TACTATTrGGGCACG'rr'ITTCACGCTATGGGAGTAGTTCATrCAAAAAAGGATcGAAAAAGTT ±CCCCA A ATATA ATTTTATACAT~mTGCGGAAGGTCCAATTAGTATCTCTGGAAAAGAAGCCTTTATTTTTGTTGGGAT TACCCCTGAC TAAAATTATGATTACATGGCGCTAAAAGTGATCTTATTGGTACTTTTAAA.GAT CTTAATATTAAAAATTCAAAATTGGAAATTACAGTTGATGAGAATAATTCAGATGCCAAGACCT'rCCTTGAATCTG

TTAATTACATTATCGACGGCGTTGAAAAAATTTCACCTATGTTAACGAATTAA

t56l..nt TGTACTTCAAAAGATAGCTCAAATGAATATGTTGAGGAGCAAGAAGCGGAGAACTCTTCTAAGCCTGATGAT'rCTA

AATGTACTCATGCCTTTAGTAGGGATCTCAAAGTGAAGT

GGGGAAAAATATAAAGGTTTTTTA'FrT=TCTGAAGAAGATGGACATTTTCAAACAATACCCTCAAAAGAGAATGCA

AAGTTAATAGTTTATTTTATGACAATGTTTATGCAGGAGAGGCTCCAATTAGTATCTCTGGAAAAGAAGCCTTTA

TTTTTGTTGGGATACCCCTGACTTTAAAAAGATTATAAATAGCAATTTACATGGCGCTAAAAGTGATCTTATTGG

TACTTTAAAGATCTTAATATTAAAAATTCAAAATTGGAAATTACAGTTGATGAGAATAATTCAGATGCCAAGACC

TTCCTTGAATCTGTTAATACATTATCGACGGCGTTGAAAAAATTTCACCTATGTTAACGA6ATTAA f604.aa

MSFNKTKKIGKXIKIVTLLMLAVSLIACNNNSEKEKLAFKVYIGGAPSSLDPHLVDETIGARILEQIFSGLLTLNT

KTGYLKPGLAI~gEASKKTYQFYLNLFWSGVEITAEGIRKSFLRILNKETGSTNVDMLXSIIKNGQEYFlG 9 KVSDSELGIKAIDSKTLEITLTAPKPYFLELLLHYAFPVPIHVIEKYKGWTSPENMVTSGPFKLKKLPNEKI I FEKNERYYNAKEVEIJDELVYITSDNDLTVYNx N'IDAIFNSIPPDrIKLQKDYYQHKSNAIYLYSFNTKI

KPLDDARVREALTLAIDRETLTYKVLJNDGTVPTREITPDLKNYGKLALFDPEKSKLLADAGYPNGKGFPMLT

TLKYNTNETH£IIICCA IQNQWKILNINIMLTNENPVLTNSRTGNFEIIRVGRIGEYLDPHTYFTIFTRENSQLA SYGYSNLEFflKLIRESDLEKcDPIKKQLLRKAESIIIEKDFPAAPIYIYSGHLFRNDKWTGWNPNVSEVYYLSEL

KPIKNAKHN

9999 t604.aa

NNSEKEAFKYIGGAPSSLDPHLVDETIGARILEQIFSGLLTLNKTGKLKPGLANWEASKDKTQFYLR

DNLFWSDGVEITAEGIRxSFLRILNKETGSTNVDMLjKSIIKNGQEYFlGKVSDSELGIKAIDSKTLEITLTAPKPY ~FLELLLHYAFMPVPIHVIEYGNWTSPE2NMVTSGPFKLKKRLPNEKIIFEKNERYYNAKEVELDELVYITSDNflL IVYNMY~XKUNET~DAIFNSIPPDIVNEIK QKDYYQHKSNAIYLYSFNTKIKPLDDARVREALTLAIDRETLTYKVLN DGTVPTREITPDLYNYGKKALFDPEKSIKLLAlAGYPNGKGFPMLTKNTNETHKKIAAFIQNQWKKILNIN

MLTNENWPVLTNSRNTGNFEIIRVGRIGEYLDPHTYFTIFTRENSQLASYGYSNLEFDKLIRESDLEKDPIKRKQ

LLRKAESIIIEKDFPAAPIYIYSGHYLFRNDKWGWNPNVSEVYYLSELKPI1iAK1M f604 .nt ATGAGCTT'rAATAAAACTAAAAAATC GAAATATGACCATATGCTTGCTGTGTCTTTAA TTGCATGCATAATC AAGAAATGA~AATATACATAGGGGGAGCGCCCTCATCGCTTGA CCCTCATTTGGAA GCATGACAATTAACATTCTCAGGGCTTTTGACATTAAATACC

AAAACAGGAAAGCTAAAGCCCGGACTTGCTAAAAATTGGGAAGCCTCAGTAAACTTAT'AC

TAAGGGACAACCTTrGGAGCGATGGAGTTrGAAATTACCGCTGAAGGGATAAGAATCT'TT'rAAGAATTrT

AAATAAAGAAACAGGATCTACAAATGTTGACATGCTCAAATCATAAAATGAAGGATTTGACGGG

AAGTATCCGATCTGAACTTGGAATCAAGGCAATTGATAGTAAAACGCTGGAAATAACACTrACGGCCCCAAAGC

CATATTTTCTTGAACTGCTTCTACATTACGCATTCATGCCAGTACCTATTCATGTGATTGAAAAATATAAGGAAA

WO 98159071 PCT1US98/12718 152 TABLE 1. Nucleotide and Amino Acid Sequences TTGGACAAGCCCTGAAAACATGGTACTAGCGGTCCTTrA1rAAAAGTACTAATGAAAAAATTATC TA A AA AAACGAACG'IrTAATCAAGATGATTGATGAGCTTGTCTACATTrACGTCTGACAATG ATCTTACTGTGTACAATATGTACAAAAACAACGAAATTGATGCTATT'r=AACAGCATCCCCCCGACATTGTAAA

TGAAATAAAACTACAAAAAGACTATTACCAACACAAAAGTAATGCAATTTATTTATATTCATTTAATACAAAAATA

AACCCCTTGATGATGCTAGAGTTAGAGAGCTTAACCrACTATTGACAGAGAAACTTAAcTTACAAAGTGC TAAATGATGGCACAGT'rCCTACAAGAGAAATAACTCCTGATCTTAAAAATTACAATTACGGTAAAAAATTGGCT

AIT

1 1'GATCCTGAAAAATCTAAAAAGCT'TGCGTGAGTTCTAATGGGAAAGGATTCCCAATGCTAACA CTAAAATATAATACA;ACGAAACTCATAAAAAAATTIGCTGCATI'rATTCAAAACCAATGG~A A AA AAATTCTAA.ATA

TCATCTATGCTTACCAACGAAAA"IGGCCTGTTCTTACCAACAGCAGAAATACTGGCAATTTTGAAATAATAAG

AGTTGGACGCATTGGGGAATATTTAGATCCACACACATACTT'rACTATAT'CACAAGAGAAAATTcAcAAcrrrGCA

TCATACGGATATTCAAACCTAGAATTT'GACAAACTCATCAGAGAATCAGATCTTGAAAAAGATCCTATAAAAAGAA

AACAATTACTCAGAAAGCAGAATCATAATGAAAATTCTGCTGCACCAATATACATATATTCTGG

GCATTATCTTTTAGAAACGATAAATGGACTGGATGGAATCCTAATGTATCAGAGGTTTATTIATCTTTCTGAATTA

AAACCAATTAAAAATGCAAAACATAATTAA

t604.nt

TGCAATAATIAATTCAGAAAAAGAAAAATTAGCATTTAAAGTATACATAGGGGGAGCGCCCTCATCGCTTGACCCTC

ATTGTAGTAAATGACAATTTAGAACAAATATTCTCAGGGCTTTTGACATrAAATACCAAAAC

AGGAAAGCTAAAGCCCGGACTTGCTAAAAATTGGGAAGCCTCAAAAGATAAAAAAACATATCAATTTTATCTAAGG

GACAACCT'TTTTGGAGCGATGGAGTTGAAATTACCGCTGAAGGGATAAGAAAATCTTTTTTAAGAAT TAAATA

AAGAAACAGGATCTACAAATGTTGACATGCTCAALATCAATAATAAAAAATGGACAAGAGTATTTTGACGGGAAAGT

ATCCGATTCTGAACTTGGAATCAAGGCAATTGATAGTAAAACGCTGGAAATAACACTTACGGCCCCAAAGCCATAT

TTTCTTGAACTGCTTCTACATTACGCATTCATGCCAGTACCTATTCATGTGATTGAAAAATATAAGGGAAATTGGA

CAAGCCCTGAAAACATGGTTACTAGCGGTCCTTTTAAATTAAAAAAAAGATTACCTA.ATGAAAAAATTATCTTTGA

AAAAAACGAACGTTATTATAATGCAAAAGAAGTAGAACTTGATGAGCTTGTCTACATTACGTCTGACAATGATCTT

ACTGTGTACA.ATATGTACAAAAACAACGAAATTGATGCTATTTTTAACAGCATCCCGCCGGACATTGTAAATGAAA

TAAAACTACAAAAAGACTATT1ACCAACACAAAAGTAATGCAATT TATTTATATTCATTTAATACAAAAATAAAACC C GATGATGCTAGAGTTAGAGAAGCTTITAACCTTAGCTATIGACAGAGAAACTTTAACTTACAAAGTGCTAAAT GATGGCACAGTTCCTACAAGAGAAATAACTCCTGATCTTAAAAATTACAATTfACGGTAAAAAATTGGCTTTATTTG

ATCCTGAAAAATCTAAAAAGCTTTTGGCAGATGCAGGGTATCCTAATGGGAAAGGATTCCCAATGCTAACACTAAA

ATATAATACAAACGAAACTCATAAAAAAATTGCTGCATTTATTCAAAACCAALTGGAAAAAAATTCTAAATATCAAT

CTTATGCTTACCAACGAAAATTGGCCTGrTCTTACCAACAGCAGAAATACTGGCAATTTGAAATAATAAGAGTTG

GACGCATTGGGGAATATTTAGATCCACACACATACTTTACTATATTCACAAGAGAAAATTCACAACTTGCATCATA

CGGATATTCAAACCTAGAATTTGACAAACTCATCAGAGAATCAGATCTTAAAAAGATCCTATAAAAAGAAAACAA

TTACT AAAGAATATAA~GAAGT~CCTGCTGCACCAATATACATATATTCTGGGCATT ATCTTrTTAGAAACGATAAATGGACTGGATGGAATCCTAATGTATCAGAGGTTTATTATCTTTCTGAA6TTAAAACC

AATAAAAATGCAAAACATAATTAA

9 9 f736.aa CVI IL IFMLaSTSLLYNCKNQDNEKIVS IGGSTTVS PILDEMI LRYNKINNNTKVTYDAQGS SVGINGLFNKI YK IAISSRlLTYEEIEQGAKETVFAYDALIFITSPEIKITNITEENAKILNGEIQNWKQVGGPDAKINFINRDSSSG

SYSSIKDLLLNKIFKTHEEAQFRQDGIVVKSNGEVIEKTSLTPHSIGYIGLGYAKNSIEKGLNILSVNSTYPTKET

INSNKYTIKRNLIIvTNKYEDKSVTQFIDFMTSSTGQDIVEEQGFLGIKT t736.aa CKNQDNEKIVSIGGSTTVSPILDEMILRYNKINNNTKVTYDAQGSSVGflNGLFNKIYKIAI SSRDLTKEEIEQGAK

ETVFAYDALIFITSPEIKITITELAILNGEIQNKQVGGPDAKINFINRSSSGSYSSIKDLLLNKIFKTHE

EAQFRQDGIVKSNGEVIKTSLTPHSIGYIGLGYAKSIEKGLNILSVNSTYPTKETINSNKYTIIKRNLIIVTNN

KYEDKSVTQFIDFMTSSTGQDIVEEQGFLGIKT

f736.nt WO 98/59071 PCTUS98/1271 8 153 TABLE 1. Nucleotide and Amino Acid Sequences

ATAAAGTTACTATTAGTTACATTTAAACGAAATAGCAGA

AATGACATGLGTTCATTACCATCAAGATATTAAAATAAAA

CATAATAGACTCAGAAGAGATTGCTAAGGTTTAAATTTA

AAGACGATGTAGT

CTTATTATCACCGATAATAAATTAAAGAACACAATCAAG

AGA CAATGACATGAGCTAGTAATACTACACAATTCTTG

ATAA

t736 .nt

TGAAACAAATAA-ATTTATGAGTTCATTACCAATGCAAG

TTTAAAATAAA-CAATCAATACTCA~-CAGATGGTGAAAG

GCATACAAAAAATGATTACAGGTTAAAGAAATACAGGAA

GAATTTTCTTAGTTATTATCAGCTAAAAATCATTAAAGA

ATTGTAAATATGGATCAATGAAAGGGGTCGTCAATACTA

AAGGCTTITTTAGGGATAAAAACATAA

f752.aa MNKNVLcDDICKSD::G.:KVLRVFLGHFGDIIIKGNVCRV FYPVYKDFIKMNSIMPKL GTGIGSVyjLFKGKGITFDG GSINYQTETISLTVN.QALSSHLLTRIvyAVTIH~LFGIN t752.aa S FMSNFSNIFDEPSKKVIGVTGTDGKSSVCYYIY rFGKGFISVFDDSGSLIKPYQSTPESTEI HS T HG D E A L DV Y A V T IG E L F G IQ Y N K G FR V D A F

SDYS)KAKSFYLSKDFSIEYTSREYKVYANSLSNEVALL

0604 HESS IIYREVFWNEQEVVKNAILSAEXSEKEK -f752-.nt ATATAAATATGA

TTTGT

TAAAArAGGTCTTG~TATGTTGCAGTGG7TTCCTCGATC

TTTGGGTACAAGGA

TTTTTTATGATGAGCCTCAAA.TA.AGJATGA

-ATGATGCGAA-GTTGTGT

TTTTTTTCTTAAAAGGGTAGAGTTTTGrATTTTGTAGGG

GGACTATAATCTCGCACATCCATTCGATCTCTTTACCAG

WO 98/59071 PCTIUS98/12718 154 TABLE 1. Nucleotide and Amino Acid Sequences

TTAAAATGAAGCTCAATATGCATTCTTGAATCTACTTCTCATGGGCTTGACCTTGAAACAGCAAGGCTTATTGA

TGTTAATTATTTTGCAGTTGTTrI'ACCAATATGGACATGAGCATCTTGAAT'TCATGGCACAATTCAAAATTAT

TTGAATGTCAAGCTGGGTCTTTCGGTCTGTTAGTGATGATGCTGGTTTTGGGGTTATTAATCTT'GATGACCTTT

ATTCTTCTGATTTITAAGAATGCTGTTAAGAAATCTTTTACTTATAGCTAALAAAGCAGTAAAGCGGATTTTTTTGT

TAGTTTATGAGAGAAACGATTCTACTAGATTTGAATT'ITATCACAAGGGGGTTAAATATCTTGCTAATGTI'

AGCCTACTGGGGAGTTTTAATGTTGAGAATGTAATGGCTGCTCTTAT'ITTAGTTTCTCAAATTTTAAATATCGATA

'rrCAAGATATTGTTGATAAACTTAACTGCATAAAAGTCTTGATGGGCGTATGGATAGTATTAATTTGGGGCAAAA

TT'I'TCTGTAATAATTGATTATGCTCATACTCCTGGTGCTTTTCCAAGCTTTTCCTATTTTTAAAAGATTTGCT

ACCAATAGATTGATTTCTGTTTTTGGCTCTGCAGGAGAAAGAGATGTTGAAAAAAGATTTTTGCAAGGGCAAATCG

CAGATATTTATTCTGATTAATAATACTTTGCGATGAAGATCCAAGAGGCGAGAATAGTATGTGTATAATTAAAGA

CA'F~cAAGGATTTAATAAG'IGAAAATAAGGATTTATTTTTATTGCTGATAGAAAGCAGGCTATTGAA AAAGCAATAAGTCT'rGCAAAAGCAGGAGATTTGGTTGTTGCTTTGGGCAAAGGTCATGAAAGTTCAATAATTTATA

AAAATAGAGAAGTTTTTTGGAATGAACAAGAGGTAGTTAAAAATGCTATTTTAAGTTTAGAAAAATCAGAAAAGGA

GAAGTGA

t752 .nt TGTGTAA.AAGGT'rCTCTTGATTTAGAAATATCAGGAGTTACTTATAGTTCTAAATTGGTTrTTGCCCAGGTTTGTGT TT'rTTGCTCTTCCAGGAATTCATTTTGATGGGCATGATTTTATTGAATTGCAATTCAAAGGGTAGTAATGTTGT

TGTGTGTTCACGAGATGTGGATTTTTACAGTCCTAATGTTACTTATATTAAGGTAGATGACTTTAACATAAGAAAA

TT'rATGTCTAATTTTTCAAATATTTTTTATGATGAGCCTCAAAAAAATTAAAAGTTATTGGAGTCACTGGCACTG

ACGGGAAAAGTTCTGTTTGTTATTATATATATCTTCTTTTTAAAAAAAAGGGTGTTAAAGTAGGTTTTATATCGAC

AGTATTTTTTGATGATGGGAGTGGAAGCTTGATTAAAAATCCTTACAGACAATCAACTCCCGAGTCTACGGAAATA

CATTCATTTTTAAGCACCATGGTTAAAAATGAAGCTCA6ATATGCAATTCTTGAATCTACTTCTCATGGGCTTGACC

TTGAAACAGCAAGGCTTATTGATGTTAATTATTTTGCAGTTGTTTTTACCAATATTGGACATGAGCATCTTGAATT

TCATGGCACAATTCAAAATTATTTGAATGTCAAGCTGGGTCTTTTTCGGTCTGTrAGTGATGATGCTGGTTTTGGG GTTATTrAATCTTGATGACCTTTATTCTTCTGATTTTAAGAATGCTGTTAAGAAATCTTTTACTTATAGCTTAAAAA GCAGTAAAGCGGATTTTrGTTAGTTTTATTGATGAGAAAACCGATTCTACTAGATTTGAATTTTATCACAAGGG

GGTTAATATCTTGCTAATGTTAGCCTACTGGGGAGTTTTATGTTGAGAATGTAATGGCTGCTCTTATTTTAGTT

TCTCAAATTTTAAATATCGATATTCAAGATATTGTTGATAAACTTAACTGCATTAAAAGTCTTGATGGGCGTATGG

ATAGTATTAATTTGGGGCAAAATTTTTCTGTAATAATTGATTATGCTCATACTCCTGGTGCTTTTTCCAAGCTTTT

TCCTATTTTAAAAGATTTrGCTACCAATAGATTGATTTCTGTTTTTGGCTCTGCAGGAGAAAGAGATGTTGAAAAA ****AGAT'TTrTGCAAGGGCAAATCGCAGATATTTATTCTGATTTAATAATACTTTGCGATGAAGATCCAAGAGGCGAGA c. ATAGTAT TTTATAGCTGAAGGAATTGTAAATAAAGTTGAAAATAAGGATTATTTTTTATTGC TGATAGAAAGCAGCCTATTGAAAA6AGCAATAAGTCTTGCAAAAGCAGGAGATTTGGTTGTTGCTTTGGGCAAAGGT

CATGAAAGTTCAATAATTTATAAAPAATAGAGAAGTTTTTTGGAATGAACAAGAGGTAGTTAAAAATGCTATTTTAA

****GTTTAGAAAAATCAGAAAAGGAGAAGTGA

f798 .aa

MTFRTYKHIJELIMLPMLMLSCAFFKKPQSVHQDSNTGKPISDEKLHLISGKISNKKLPIINSNHDVTWIKTKAMTI

*.LGEDGKEIPEFKNKFGYSYIISPVKDGKYSYYASLLILFETTKNGDDEYEIEDVKFVTAGSTLLKNSLLAVENS

QEEG'iVTAYPFGILMSDEIKNAFKLTYKNGHWNYML-ADLTVKMKLTQETKIYKISLNSKLI IEFLKEVLKENSILK

DIAGDLFEDI

t798.aa CAFFKKPQSVHQDSNTGKPISDEKLHLISGKISNKKLP IINSNHflVTWIKTKAMTILGEDGKEIPEFKNKFGYSYI ISPVKMDGKYSYYASLLILFETTKNGDDEYEIEDVKFVTAGSTLELKNSLLAVENSQEEGyvTAYPFGILNSDEIK NA.FKcETYKNGWNYMLADLTVKNKLTQETKIYISLNSKLIIEFLKEVLKENSILKDIAGDLFEDI *f798.nt

ATGGTATTTAGAACATATAAACATTTGGAACTAATAATGCTGCCC-ATGTTAATGCTGAGTTGCGCTTTTTTTAAGA

AACCACAATCTGTACATCAAGACAGCAATACTGGCAAACCAATA-AGCGATGAAAAATTACATTTAATATCAGGCAA

AATTTCAATAAAAAATTGCCAATCATAAATAGTAATCATGACGTAACTTGATAAAAACAAAGGCAATGACAATC

WO 98159071 PCT1US98112718 155 TABLE 1. Nucleotide and Amino Acid Sequences

AATTGAAGATGTTAAATTGTAACAGCTGGCCACCCTAGAACAAAAACTCTTTAGCTGWAATTCA

GACATAGCTGAA*~ATGAAAAA

t798 .nt TGCGCT'rrTTTTAAGAAACCACAATCTGTACATCAACGACAGCAATACTGGCAAACCAATAAGCATAAAATTAC ATTTAATATCAGG AATTAAAAATGCCAATCATAAATAGTAATCATGACGTAACTTGATAAAAAC

AAAGGCAATGACAATCTTAGGCGAAGATGGAAAAGAAATACCAGAATTTAAAAACAAA.TTTGGATATTCTTATATA

ATATCTCCTGTAAAATGGATGGAAATATAGTTATTACGCGTCATTATTAATACTTTTTGCACTAA6TG GAGAGATAATTGArGAGATTTAAATT'rGTAACAGCTGGTTCCACCCTAGAACTTAAAATTCTCTT'TT

AGCTGTTGAAATTCACAAGAAGAAGGATATGTTACTGCATACCCATTTGAATATTGATGAGTGACGAGATTA

AAATTCTATATTAAAAGACATAGCTGGAGATTTATTTGAAGATATATA

f 805.a

MLRKIJKDISKIVLVTDGLTPNCQTCGKLIANGDEVYIAEDGLFHSVKSNTIAGSTLTMIQGLKNLIEFGFSLSDAV

QASSYNPTRILNIDKKGLICHGYDANLNVLDKDFNLKLTMIESKIIFNNL

t805.aa

CQTCGKLIANGDEVYIAEDGLFHSVKSNTIAGSTLTMIQGLKN~LIEFGFSLSDAVQASSYNPTRILNTDKXGLICH

GYDANLNVLDCDFNLKLTMIESKIIFNNL

f805.nt ATGCTTAGAAGC AGTTATAA TCCTTGTAACTGACGGACTTACTCCGATTGTCAAACTTGTG

GAAACTAATGCAACGGAGACGAAGTTTATATTGCAGAAGATGGATATTCCATAGCGTGAAAAGCAACACAAT

o.OACGACAATAATAAAGTTAAATTAAATTGTrACTACAGTT o ~CAAGcAAGcTCTTACAATCCAACAAGAATTCTCAATATGATAAAAAGGGCTTAATATGTCATGGATATGATGCAA o 0 o ACCTCAATGTCCTAGATAAAGATT'rTAATC AATACAGTGACTAAAATAATTTTTAACAATCTCTA

A

0: t805.nt AAAGCAACACAATAGCTGGATCACCCCATAA AGCTTAAAAATTTAATAGAATTTIGGT'rTCAGCTT o: o o: TTAACAATCTCTAA f635.aa

MKILWLIILVNLPLSCGESIKSNLGLRLRELEISGGGSSKIEVYKEFIIEKIKNILKIVNSIDKKARFFNLIG

Al SN P YDLDKQLEA YLNKLGDZ4GEDYFEFLMLRGANYYSLGD)LGNAI LFYDKASKKASTEEQKEGVSRIMSN

LK

t 635. aa WO 98159071 PCT/US98/l1fl 8 156 TABLE 1. Nucleotide and Amino Acid Sequences CGESKEKSNLGLRLRELEISGGGSESKIEVYKEFIEKDKILKIVNSIDAFFNLIGLEFFrJJGQYGPAIEY FAILEINpNNyLSHFyIGVASyNAKLRVKDEVEKYIIASFLKSLSIRDDFDSLFAISM4VYLKQLE AKN~yLNKLGDMGEDYFEFLMLRGANYYSLGDLGNALF'ZDKASKKASTEEQKEGVSRIMSNLK f 635.nt ATGAAAATT-rGTGGTTAATAATTCTTGTTAATTTATTTTATCTTGTGGCAATGAATCTAAAGAAAAATCAATC

TTGGTCTAATAAGATGATCAGGTGGTGGATCTGAATCTAAGATTGAAGTTTATAAGAATTTAT

TGAAAAGAGAAAGATATTTAAAGATAGTAATTCCATTGATAAGAAAGCCAGATTTmTAATTTAATTGGT

CTTGAATTT~TTTAAGCTTGGTCAGTACGGACCTGCTATTGAATATTTTGCTAAAAATTTAGAAATCAATCCCAATA

ATTATTTATCTCATTTTTATATAGGTGTTGCTTCTTATAATTTAGCTAAAAATTTAAGAGTAAAAGATGAAGTTGrA

AAAATACATAATTCTTGCTGAAAATTCTTTTTTAAAATCACTTTCAATTAGAGATGATTTTAAAGATTCTCTTTTT

GCCATTTCTAATATGTACGTATATGATCTTGATAAACAACTTGAAGCTAAAAATTATTTAAATAAACTTGGTGATA

TGGGTGAGGACTATTTTGAGTTTTATTAGAGGAATATTATTCGCTGGGCGATCTTGGTAATGCTAT

ATTGTTTTATGATAAAGcTAGTAAAAAGGCTTCAACTGAAGAGCAAAAAGAAGGTGTTTCTAGGATCATGAGTAAT

TTG-AAGTAA

t635 .nt

TGTGGCAATGAATCTAAAGAAAAATCAAATCTTGGTCTTAGATTAAGAGAATTGGAAATTTCAGGTGGTGGATCTG

AATCTAAGATTGAAGTTTATAAAGAATTTATTGAAAAAGAAGATAAGAATATTTTAAAGATAGTTAATTCCATTGA

TAAGAAAGCCAGATTTTTTAATTTAATTGGTCTTGAATTTTTTAAGCTTGGTCAGTACGGACCTGCTATTGAATAT

TTTGCTAAAATTTAGAAATCAATCCCAATAATTATTTATCTCATTTrTATATAGGTGTTGCTTCTTATAATTTAG

CTAAAAATTTAAGAGTAAAAGATGAAGTTGAAAAATACATAATTCTTGCTGAAAATTCTTTTTTAAAATCACTTTC

AATTAGAGATGATTTTAAAGATTCTCTT'rTTGCCATTTCTAATATGTACGTATATGATCTTGATAAACAACTTGAA

GCTAAAAAATTTAAATAAACTTGGTGATATGGGTGAGGACTATTTTGAGTTTTTAATGTTAAGAGGTGCAAATT

ATTATTCGCTGGGCGATCTTGGTAATGCTATATTGTTTTATGATAAAGCTAGTAAAAAGGCTTCAACTGAAGAGCA

AAAAGAAGGTGTTTCTAGGATCATGAGTAATTTGAAGTAA

f314.a .44 dNNCLIKFFIFLLVFSNSYVAFSKNVNVLIVTAMDSEFDQINKLMSNEEIVLKEYGLNKKILKGKLSNRNVMVI I

CGVGKVNAGVWTSYILSKYNISHVINSGVAGGVVSAKYKDIKVGDVVVSSEVAYHDVDLTKFGY'KVGQLTGGLPQK

FNANKNLIKNAIEAIKSKVGGSNAYSGLITVSGDQFIDPTYINKI IGNFKOVIAVEMEGAAIGHVSHMFNIPFIVIR

ISDIVNKEGNEVEYSKFSKIAAFNSAKVVQEILRKLZ

t314.aa KNNVLIV'rAMDSEFDQINKLMSNKEEIVLKEYGLNKKILKGKLSNRNVMVIICGVGKVNAGVWTSYILSKYfNISH 4: VINSGVAGGVVSAKYKDIKVGDVVVSSEVAYHDVDLTKFGYKVGQLTGGLpQKF'NANKLIKNAIEAIKSKVGGSN AYSGLIVSGDQFIDPTYINKI IGNFKDVIAVEMEGAAIGHVSHMFNIPFIVIRSISDIVNKEGNEVEYSKFSKIAA

FNSAKWVQEILRKLZ

f314.nt ATGAATAATTGTTTAATAAAGTTTrnATTTTTTTATTAGTTTTTTCAAACAGTTATGTTGCTTTCTAAAAATG

TCAATGTTTTAATAGTAACTGCTATGGACTCTGAGTITTGATCAGATAAATAAGCTTATGTCTAATAAGGAAGAAAT

AGTTCTTAAGGAGTATGGTCTTAATAAAAAGATTTTAAAGGGGAAGTTGTCTAATCGCAATGTTATGGTTIATTATT

TGTGGGGTTGGTAAGGTTAATGCTGGTGTGTGGACTAGCTACATTTTGTCAAAATACAACATAAGTCATGTCATTA

ATTCTGGCGTTGCTGGTGGCGTTGTTAGTGCTAAA AAATAGGGGAGATGTGGTGGTGTCTTCAGA

TTTAATGCCATAATTTATAATCCATAGAGGCCATTAAATCAAAGGTTGGAGGTTCTAATGCATATT

CAGGATTAATAGTTTCAGGAGATCAGTTTATTGATCCAACTTATATTAACAAAATTATAGGAAAC'ITTAAAGATGT

AATAGCTGTTGAGATGGAAGGTGCAGCAATAGGGCATGTTTCTCATATGTTTAATATACCTTTTATAGTTATTAGG

TCAATATCTGACATTGTAAATAAAGAAGGGAATGAGGTTGAAT.ATAGTAAATTTTCTAAAATAGCTGCTTTCAATT

CAGCCAAAGTTGTACAAGAAATTT'rAAGAAAACTTTAA WO 98/59071 PCT/US98/12718 157 TABLE 1. Nucleotide and Amino Acid Sequences t3 14. nt AAAATGTCAATGTTTTAATAGTAACTGCTATGGACTCTGAGT'rrGATCAGATAAATAAGcTTIATGTCTAATAAGG AAGAAATAGTTCTTAAGGAGTATGGTCTTAAAAAT AAGGATGTCTAATCGCATGTATGT TATrA~ITGGGGTTGTAAGTTATGTGGTGTGTGGACTAGCTACATTTTGTCAAAATAcAACATAAGTCAT GTCATTAATTCTGGCGTTGCTGGTGGCGTTG 1r~GTATcAGTTAATGGGAGATGTGGTGGTGT CTTCAGAGG TCTTAGTTGTGCAANGTCAGAGCGTAAGGATC TCAAAAATTAAGCAAATTAATGCATGCATAr-AGGCCATTAATCAAAGGTTGGAGGTCTAT GCAA'rCAGATTATATTTAGGGATAGITATGATCAACTTATATrAACAAAATTATAGGAALACTTTA AAGATGTAATAGCTGTTGAGATGGAAGGTGCAGCAATAGGGCATGTTTCTCATATGTTTAATATACCT'rrDATAGT TA'ITAGGTCATATCTGACATTG AAAAAGGAGGTTGAATATAGTAAAT'rTTCTAAAATAGCTGCT

TTCAATTCAGCCAAAGTTGTACAAGAAATTTTAAGAAAACTTTAA

f32.a MTKTLYLISLILLACNKNNKIPLIQKLDLPKSSILGFSNKMGII IKDYAFLSKSTKKNSELDYDYAILLRKDEVV

KIEKTLEKTERYGIEGNWILVNYKGTKRYIFSKDINIVNNLIIDHSKZ

t32.a CNKNNKIPLIQKLDLPKSSILGFSNKMGIIIKDYAFLSKSTKKNSELDYDYAILLRKDEVVKItxTLEKTE-RYGIE,

GNWILVNYKGTKRYIFSKDINIVNNLIIDHSKZ

f32 .nt

ATGAATACAAAAACATTATATTTAATATCCTTAATTCTTTTAGCTTGCAATAAAAATAACAAAATTCCTCTCATTC

AAAAATTAGATTTGCCCAAAAGCAGCATTCTTGGCTTAGCAATAAAATGGGCATAATAATAAAAGATTATGCTTT

TC'ITAGTAAAAGrCACTAAGAAAAATAGCGAATTGGATTATGATTACGCAATTCTACTCAGAAAAGACGAAGTCGTA

AAAATTGAAAAAACACTAGAAAAAACAGAGCGCTATGGAATTGAAGGAAATTGGATCCTAGTCAATTACAAGGGAA

CTAAAAGATACATCTTTAGCAAAGACATCAATATAGTCAACAATTTAATAATTGATCATTCTAAATAG

t32.nt V

TGCATAAATACAAA'ICCTCTCATTCAAAAATAGATTTGCCCAAAAGCAGCATTCTTGGCTTTAGCAATA

AAATGGGCATAATAATAAAAGATTATGCTTTTCTTAGTAAAAGCACTAAGAAAAATAGCGAATTGGATTATGATTA

CGCAATTCTACTCAGAAGACGAAGTCGTAAAAATTGAAAAACACTAGAAAAAACAGAGCGCTATGGAATTGAA

GGAAATTGGATCCTAGTCAATTACAAGGGAACTAAAAGATACATCTTTAGCAAAGACATcAATATAGTCAACAATT

TAATAATI'GATCATTCTAAATAG

f320.aa MKSIYALFLFINLSLLNISKKDLELKAQAECKIE EKNQFLKEIKpLvDAEKNNLLTLINKKI PI PENYKIPDLVNIDDFEDLKNLGAKTIKVRKILIEDLIRLIKDAmKGIEIKIKsAyTQEYQKFLFDYNVKTYGRK

VAETQSA.IPGHSQHHMGTAIDFINIDDNLLNTKEGKWLYENSLKYGFSVSYPKGYETDTGYKAEPWHYLYIGPKPC

FIQKKYFNNLQEH-TEFWNQNKTNLINLIEKYANZ

t320.aa

.NNISKPLEVLLKAQAMECKNFIEKPIQFLKEIKPLVDAEKNLLTLINKIIPIPENYKIPDLVNIDDFEDL

aLGAKTIKVKILIEDLIRLIKDAXKFGIEIKIKSAYRTQEYQKFLFDYNVKTYGRKVAETQSAIPGHSQHMGT AIDFINIlDNLLTKEGKWLYENSLKYGFSVSYPKGYETDTGYKAEPHYLYIGPKPCFIQKKYFNNLQHKLLEFW

NQNKTNLINLIEKYANZ

f320 .nt WO 98/59071 PCTIUS98/1271 8 158 TABLE 1. Nucleotide and Amino Acid Sequences ATGAAATcAA ATGcTTATTATTTCTAAT TTAA ATC rGTTGGCTAACAACATTTCAAAAAAAGATT TAGAAGTACTGCTAAAGATTGCCCAAGCAATGAA AGATCAATA'lAAAACCTATTCAGTT

CTTAAAAGAAATAAAACCCTTAGTAGATGCAGAAAAAAATAACCTCTTAACTCTAATAAATAAAAAAATACCAATT

CCTGAAAATTATAAAATACCTGATCTGGTAAATATTGATGATTTTGAAGATC?1'AAAAATCTGGAGCAAAGACTA

TTAAAGTAAGAAAAATATTAATCGAAGATTTAATTCGACTAATAAAAGATGCAAAAAAMTTGGGATTGAAATTAA

AATCAAATCTGcTTACAGAAcGCAAGATATCAAATTTTATTGATTACAATGTCAAAACTTATGGCAGAAAA

GTTGCAGAAACCCAATCAGCAATTCCAGGCCATTCTCAACATCAAGGAACATGTTAAAATAG

ATGATAATTTACTAAAAAGAGAATGTTTATGAAAACTCTCTAAAATACGGATTTITCCGTTTCATA

CCCAAAAGGATATGAAAcGGACACTGGATATAAAGCAG~AGCCTTGGCACTACTTATACATAGGACCTAAGCCATGC

TTAACCTATAAAAGAA'A

t320 .nt AACAACATTTcAAAAAAAGAT'rTAGAAGTACTGCTAAAGATTGCCCAAGCAATGAATAAGGAATGCAAAAATTTTA

TTGAAAAAAATCCTATTCAGTTCTTAAAAGAAATAAAACCCTTAGTAGATGCAGAAAAAAATAACCTCTTAACTCT

AATAAATAAAAAAATACCAATTCCTGAAAATTATAAAATACCTGATCTGGTAAATATTGATGATTTTGAAGATCTT

AAAAATCTTGGAGCAAAGACTATTAAAGTAAGAAAAATATTAATCGAAGATTTAATTCGACTAATAAAAGATGCAA

AAAAATTTGGGATTGAAATTAAAATCAAATCTGCTTACAGAACGCAAGAATATCAAAAATTTTTATTTGATTACAA

TGTCAAAACTTATGGCAGAAAAGTTGCAGAAACCCAATCAGCAATTCCAGGCCATTCTCAACATCATATGGGAACA

GCAATAGAT.ITTATAAATATAGATGATAATTTACTAAACACAAAAGAAGGAAAATGGCTTTATGAAA.ACTCTCTAA

AATACGGATTTTCCGTTTCATACCCAAAAGGATATGAAACGGACACTGGATATAAAGCAGAGCCTTGGCACTACTT

ATACATAGGACCTAAGCCATGCT'rTATTCAGAAAAAATATTTTAATAATTTACAACATAAGCTTCTTGAATTTTGG

AACCAGAACAAAACAAATCTTATTAACCTAATTGAAAAATATGCAAACTAA

f342 .aa MLYLGDNKAMRTKI IIMTIIILLAPI SGFSNSKESAP.GKFGAGI ILPLPIALQINIGNFDLDIGLYSGVNNLFSDW KTLFIADYIFYIYTFpGAANILFSVGAGGYGTIWFSRFGGSKSGSGPMSIGARLpLALNIAVFRKFDIFLRIA

PGLGMNVWSNGVGFRWEVFAGLGLRFWFTZ

t342.aa

~:LAPISGFSNSKESARGKFGAGIILPLPIALQINIGNFDLDIGLYSGVNNLFSDWKTLFIALDYIFYIYTFPGAANI

LDFSVGAGGYGTIWFSRGGSKSGSGPMSIGARLPLALNIAVFRFDIFLRIAPGLGVWSNGVGFREV'AGL

GLRFWFTZ

f342 .nt ATGCTATACTTGAAATAGCAGGAAATAATTATTATGACAATTATTATTTTATAG

CCCCAA

**TCTCAGGATTTTCTAATTCAAAAGAATCTGCAAGGGGTAAATTTGGAGAGGAATTATACTTCCATTACATTGC

TCTACAGATTAATATAGGAACTTTGATCTTGACATTGGTCTTACAGCGGAGTAAATAATTGTTTTAGACTGG

AAACATTATTTATAGC-ATTAGACTATATTTTCTACATATACACATTCCCGGGAGCTGCTAATATTTTGGATT

*CAGTTGCGCAGGGGrATATGGAAr-AATATGGTTTCAAGATTTGGAGGCAGTAAGTCAGGCTCAGACCALTG

*:CATTGGAGCAAGATTGCCTGGCCTTA-ATATTGCAGTATTTAGGAGAAATTCGACATATTTACATAGCA

**:CCCGGACTTGGAAT GAATGTTTGGAGTAATGGCGTTGGATTTAGATGGGAAGTATTCGCAGGATTGCTAGAT TCTGGT'rTACTTAA t342.nt

TTAGCCCCAATCTCAGGATTTTCTAATCAAAAGAATCTGCAAGGGGTAAATTGGAGCAGGAATTATACTTCCAT

TACATCCAAATAAAGACTGTCTAATGCTAACGGAAATTT

TTCAGACTGGAAAAC-ATTATTTATAGcATTAGAcTATATTTTCTACATATACACATTCCCGGGAGCCTTATT

TTGGATTTTTCAGTTGGCGCAGGGGGATATGGAACAATATGGTTTTCAAGATTTGGAGGC-AGTAAGTCAGCTCAG

GACCAATGAGCATTGGAGCAAGATTGCCTTTGGCCTTATATTGCAGTATTTAGGAAGAATTCGAATATTTTT

WO 98/59071 PCTIUS98/12713 159 TABLE Nucleotide and Amino Acid Sequences

ACAAACGA~XACAT=,ATACGGTATAAGGATTCCGAT

GGACTAAGATTCTGGTTTACTTAA

f352.aa EIK LNKKIKPKDYEXNIEIEETDDFENYEYNflEIEEQMRTITLLMKEZ t352 .aa

CISLFGANTISYSSIEIPLELSEEFKSSGNSDQNTSKHKIVSYEDPKKGKDLKLPENIRLKKLPQKRM

DEDKVEYNINELKKQTEEKISEUYITEKEVIKLUIPFD

NYEKINIENIEEETDDDFEDNYEYNDEIEEQMRTITLLMKEZ

f352.nt ATGAATAAAACAAAAAATCGAAGCCTTACGTATTTTATAATACTTTCATGTATATCATTATTrGGGGCTAATAATA

ATACAATAAGCTACTCTAGCATTGAATTCCTCTAGAAGACTTAAGTGAAGAATTTAAAAGTTCTGGGAATAAAAG

CGATCAAATAAATACCTCAAAACATTTAAACAAAAACATAGTTCTTATGAAGACCCAAAAAGGGTAAATCTA

AAATTGCCAGAAAATATAAGAGACAAAAAACTACCCCAAAAAAGAATGGACGAAAATGATCTAAAATCTGTAATTG

AAAATATAAAAAAATTAAAACTAGAAAGCTTTTAAAAACCAAAAATCAAAAAACATCGGAAAATGAAAA

TAAAAAAATAGAATCAATCGAAAACAAAAAGATTAACCAATAAATTAAAAAACGAAATAGTA

GAAATAAAAAAGCTCCTTAACAAAAAAATCAAGCCTAAACAAGATGAAATTACGAAAAAATAAATATTGAAAACA

TTGAAGAAGAAACTGATGATGATTTTGAAGACAATTATGAATATAATGATGATGAACAGGAAT

TACCCTTCTAATGAAGGAATAA

t352 .nt TGTATATCATTATTGGGGCTAATAATAATACAATAAGCTACTCTAGCATTrGAAATTCCTCTAGAAGACTTAAGTG AAGAATTTAAAAGTTCTGGGAATAAAAGCGATCAAATAAATACCTCAAATAACAAC

TTTCTTA

TGAAGACCCAAAAAAGGGTAAAGATCTAAAATTGCCAAATTAGGCAi TACCCCAAAAAAGAATG GACGAAAATGATC AATTTATAATAGATATAACTGAAC-TrAAAAACCA AAAA6TCAAAAAACATGAATAATAAATGACAATCGAAAAG AAAAGA T

AACCAATAAATTAAAAAATAGTAGAAATAAAAAAAAATCAAGCCTAAAGAAGATGAA

AATTAC ATATTGAAATAGAAATGATGATGATTTTAGCTATATTAG

ATGAATAGAAAGGAATACCTTCTAATGAAGGAATAA

MQIflGKIYSI ISFPVRDSVSTLGVIGILICFDESLDIIENQLYSSLFGSKYNFFMLDRNYMPIFSNLNNLQAKS FSTAYSENIFLSKVl-AYAKKDSSSSQYTFNYERDFYSLNFVKTflDFLTQGLILNVNSIpIMFKsNWVIFVAFLLLSF

AIIFYLCNTFVFSLINDFNRIVDYQKSKSDPFSLESPLEVKYSSSIISYISSKDNLSSKSNESFEKIKFYSEDLN

EYLEQIETAISN'rESIDSSILVYEQLRDTFSRESIDILKGFESIADPNDHKYISEISSNFEESVSFFYSID

LEIFNKVATINSTDIENIKSKFDLNIVFNVNKFALLSTSLQSVNKLLVSISAQTNMLAMAAIEAAKA

GDAGKSFAVVAEEIRKLAINSGKYSKTIKDELKTVDSIIAVINSEIDTIYKFIDIQDNVNNFSHEKVDLTLAK

.9 RXKEIGEFKRYLSHDTKIRDAKNMYKEIFNNHIFISGKFNNFSQDLKEFKVSMb4LDAVSSLQEYSSLVKSSKDK

ILKTKELIQKI[NDEIKDILFZ

t301.aa CFDESLDIrNQLYSSLKFGSKNFFMLRNYMPIFSNLNNLQAKSFSTAYSENFLSKVIAYAKKDSSSSQYTFN

YERDFYSLNFVKTDDFLTQGLILNTVNSIPIMFKSNWVIFVAFLLLSFAIIFYLCNTFVFSLINDFNRVYQKSKS

DPFSLESPLEVKYSSSIISYISSKLDNLSSKSNESFEKIKFYsEDLNEyLEQIETAISNTESIDSS ILVYEQLRDT FSRFEKSIVDILKGFESIADPINDH ISEISSNFEESVSFFYSIDKLEIFNKVATINSTDIENIKSKVFDLNI VFENVNKNFAnLLSQTNSLQSVKLLVSISAQTNMLA1AAIEAACAGDAGKSFAVVAEEIRKLAINSGKYSKTIK WO 98/59071 PCTIUS98/12718 160 TABLE 1. Nucleotide and Amino Acid Sequences

DEKVSIVNEDIKFDQNDNSHKVLLKFEGFEYSDKRDI~YE

FNNFISGKFFSQDLKEFKVSKMNLDAVSSLQEYSSLVKSSKDKILKTKELIQKTNEIKDILFZ

ATGCAAATAGATGGGAAATTrATTCTATAATAAGTTTTCCAGTTAGAGATTCTGT.ITCAACAT"rGGTGTGATAG

GGTTATTCTGTATGTGTTATGAACGTTTCTTTAATGTGA

AAATTATAATTTTTTATGCTTGACAGAAATTACATG7CCCATTTTTTCAAACCTTAATAATCTTCAGGCCAAATCT TTTTCTACAGCTTATAGTGAGAATTTTTrTGAGTAAAGTTATAGCTTATGCTAAAAAAGATTCTTCTAGCTCTCAGT ACACTTTAATATGAAAGAGATTTTATCTTAAACTTTGTAAAAACCGATGATTTrTGACTCAGGGGCTTAT TTTAATGTCAATTCCATTCCTATTATGTTTAAATCATTGGGTTATATTTGI'GCAT'PrTTATTATTGTCTTTT

GCAATTATTTTTATTTATGCAATACTTTTGTTTTTCATTAATTAATGATTTTAACAGAATTGTTGACTATCAAA

AATCAAAAAGCGATCCTTTTAGTCTTGAATCTCCCTTAGAGGTTAAGTATTCTTCATCTATTATTTCTrATATTAG TTCAAAGCTAGATAATCTGTCT~CTAAGAGTAATGAATC TTTGGAAGATAATTr TTCTAAGT GAATATTTGGAACAAATAGAAACTGCTATATCAAATACTGA6GAGTATAGATTCTAGCATTTTAGTTTACGAACAAC TAAGAGATACTTTTTCTAGATTTGAAAAATCAATTGT'rGATATTTTAAAAGGCTTTGAATCTATTGCTGATCCGAT TAATGATCACAATAAATATATATCAGAAATCTCTTCAAAT'TTTGAAGAGAGTGTTAGTTTTT'rCTATAGTATAGAT

AAATAAACTTTTAGTTTCAATTTCAGCTC-AGACCAATATGCTTGCTATGAATGCAGCATTGAAGCAGCAAAAGCA

GGTGATGCAGGTAAAGTTTTGCAGTTGTTGCTGAGGAGATTAGAAAGCTTGCTATTAATTCTGGAAAATATrCTA

AACCATTAAAGATGAACTTAAAACGGTCGACAGCATTATTGCAGTAA-TTAATTCAGAGATTGATACAATTTATAA

AAATTTrCATAGACATTCAAGATAATGTGGACAACAATTTTTCAAGACACGAGAAAGTAGATCTTACTCTTGCTAAG

CATTTTAAGAATTGGCGAGTTTAAAGAAAGGTATTTGTCTCACGATACTAAGATCAGAGATGCTAAGAATATGT

ATAAAGAATATTTAATAATCATTATTTTATTAGTGGCAAGTTTAACAACTTTAGTCAAGATTTAAAAGAGTTTAA

AGTTTCTAAGATGAATTTAGATGCGGTAGTTCTCTTCAGAATATTCATCTTTAGTAAAGTCTTCTAAGGATAAG

ATATTAAAGACAAAGGAATTGATTCAAAAGATTAATGATGAGATTAAAGATATTCTTTTTTAG

.nt TGCTTTGATGAGTCGTTAGATATTATTGAAAATCAG?1'GTATTCTTCTCTTAAATTTGGTAGTAAAAATTATAATT 0000 TTTTTATGCTTGACAGAAATTACATGCCCATTTTTTCAAACCTTAATAATCTTCAGGCCAAATCTT'r'TCTACAGC

TTATAGTGAGAATTTTTTGAGTAAAGTTATAGCTTATGCTAAAAAAGATTCTTCTAGCTCTCAGTACACTTTTAAT

TATGAAAGAGA'ITTTTATTCTTTAAACTTTGTAAAAACCGATGAI'TTTTGLCTCAGGGGCTTATTTTAAATGTCA

ATTCCATTCCTATTATGTTTAAATCAAAT'rGGGTTATATTTGTTGCATT'TTTATTATTGTCTTTTGCAATTATTTT 00 TTATTTATGCAATACTN'TGTTTTTTCATTAATTAATGATTTAACAGAATTGTTGACTATCAAAAATCAAAAAGC

GATCCTTTTAGTCTTGAATCTCCCTTAGAGGTTAAGTATTCTTCATCTATTATTTCTTATATTAGTTCAAAGCTAG

ATAATCTGTCTTCTAAGAGTAA-TGAATCTTTTGAGAAGATAAAATTTTATTCTGAAGATTGAATGAATATTTGGA

ACAAATAGAAACTGCTATATCAAATACTGAGAGTATAGATTCTAGCATTTTAGTTACGAACAACTAAGAGATACT

TTTTCTAGATTTGAAAAATCAATTGTTG;LTATTTTAAAAGGCTTT-AATCTATGCTGATCCGATrAATGATCACA ATAA6ATATATATCAGAAATCTCTTCAAATTTTGAAGAGAGTGTTAGTTTTTTCTATAGTATAGATAAAAATTTAGA

AATTTTTAATAAGGTTGCTACTATAAATTCTACTGTTGAAATAATAGITTTGATTTAAATATT

GTTTTTGAAAATGTGAATAAAAATTTTGCAGATC'ITTTGTCTCAAACAA6TAGTTTGCAA6AGTGTAAATAAACTTT

TAGTTTCAATTTCAGCTCAGACCAATATGCTTGCTATGAATGCGATGAGACAACAGGTGATGCAGG

0 TAAAAGTTTTGCAGTTGTTGCTGAGGAGATTAGAAAGCTTGCTATTAATTCTGGAAAATATTCTAAAACCATTAAA :GATGAACTTAAACGGTCGACAGCATTATTGCAGTAATTAATT AAATAAATTTAATTCATAG

ACATTCAGATAATGTGGACAACAATTTTTCAAGACACGAGAAAGTAGATCTTACTCTTGCTAAGCATTTTAAAGA

AATTGCGAGTTTAAGAAAGGTATTTGTCTCACGATACTAAGATrCAGAGATGCTAAGAATATGTATAAAGAAATA 00* TTTAATAATCAT'rATTTTATTAGTGGCAAGTTCAACTTAGTCAAGATTTAAAAGAGTTTAAAGTTTCTAAGA 0 0 TGAATTTAGATGCGGTAAGTTCTCTTCAAGAATATTCATCTrTAGTAAAGTCTTCTAAGGATAAGATATrAAAGAC

AAAGGAATTGATTCAAGATTAATGATGAGATTAAAGATATTCTTTTTTAG

f346.aa WO 98/59071 PCTIUS98/1271 8 161 TABLE 1. Nucleotide and Amino Acid Sequences MSIDKVPDEAFAEKIGDGIAILPTSNELLAPCDGKIGKIFKTHAFSLETKEGEIFVHFGINTLNLNGKGFrRV AE-EGINVKQGEVIIRLDLEYLKEHSESVITPVVIANSDEVSSIEYSFGRLDSEYILSSSTVLTEEIpRncISQTx

PVI:AGKLVLRVKKZ

t346.aa CDGKIGKIFKTNHAFSLETKGEIFVFGINTUNLNGKGFTRVAEEGVKQ

EVILLEYLESESVTPV

VIANSDEVSSIEYSFGRLENDSEYILSSSTVLTEEIRHKISQTKPVIAGKDLVLRVKKz f346 .nt

ATGTCAATTGATAAGGTTCCCGATGAAGCTTTTGCTGAAAAAATAGTTGGCGATGGAATTGCAATTCTTCCAACAA

GCAATGAGTTGTTGGCGCCTTGTGATGGGAA.ATAGGTAAAATTTTTALAACCAATCATGCCTTTAGCCTTGAAAC

TAAGAGGGCGTTGAATTTTGTCCATTTTGGAATAATACTCTTAATTTAAATGGTAAGGGTTTTACAAGAGTr

GCTGAAGAGGGCATAATGTTAACAAGGTGAAGTTATTATTAGGCTGATCTTGATATTTAAAGAGCATTCAG

AATCCGTTATTACTCCGGTTGTTA!ITGCAAATTCTGATGAAGTrTCAAGTATAGAATATTCTrTTGGAAGGCTrGA

AAATGATCTGATATATTTTATCATCTTCAACTGTCTTGACAGAAGATTAGGCATAATATCTCAACAAAG

CCTGTTIATAGCGGGCAAAGATTTGGTGTTGCGAGTTAAAAAGTAA

t346 .nt TG TAACATAGCTACTGACA.GGGGTAAT

TTGTCCATTTGGAATTAATACTCTTAATTTAAATGGTAAGGGTTTACAAGAGTTGCTGAAGAGGGCATTAATGT

TAACAGGTGAAGTTATTATTAGGCTTGATCTTGAATATTTAAAAGAGCATTCAATCCGTTATTACTCCGGTT

GTTATTGCAAATTCTGATGAAGTTTCAAGTATAGAATATTCTTTTGGAAGGCTTGAAAATGATTCTGAATATATTT

TATCATCTTCAACTGTCTTGACAGAAGAAATTAGGCATAAAATATCTCAAACAAAGCCTGTTATAGCGGGCAAAGA

TTTGGTGTTGCGAGTTAAAAAGTAA

f373 .aa 1MNYQRIKNYCKFTSVFLFFLFSCVSNELKLflQSLVKGKLVNGLRYYIYKNQTPKNAVNMGIVFNVGSLNEE-DNE.RG

**IAHYLEHMAFNGTKDYPGNSIVDVLKKFGMQFGADNAATSFDFTYYRIJDLSDGNNKDEIDESINILRNWASQISF

MKEEIDLERNIIIEKKGETYPGRIYEKMDKFLTSGSLYEPPSPIGLEEQILSFQPEDFKKFYRWYRPELASVI

WVGDIDPIEIEEKIKKQFVSWKPTKIKEVKVSLDVELKDKFLLLEDLEVGEPSLMFFKKEIINFVKTKlDLLNA IK1CSLLAALFENRFSELKTAGVKQFKNVSNKDFFSFKSDNNTIVAKSISLNFNPDHLNEGIQDFFYELERIRKFGF TQGELEKVRSQFYKSLELRKKNINKTNSWAIFQDLIETIA3rNGSNKFDMEYCLSFQYLEKIDLKTINNLVGREFD VKCAIFYSYGRAHPVLTLEDINLQKTALKRELKPYENSLIEGKFFKYSLDDKDI IRENEFENEISSFVLENGV

EVYFKYNDQKKGVIDFSATSWGGLINEDLKLIPVLSFAPGVVSGSGYGDYSALQIEKYLSDKAVSLRVGVGAQESY

ISGSSIKDLETLFQLIYFTFKEPKIDDVSLQNAINNIKALIKSNENSSDYHFHKAISKFLNNNDPRFEDTKDSDL

QYFTKENILSFYKKFTYANNFKFVLLETQIFRQZ

t373 .aa CVSNELfLQSLVKGKLVNGLRyYYQTPKAVNMGIVFVGSLNENERGIAHYLEHMAFNGTKDYPGNSIV DVLKKFGMQFGADINAATSFDFTYYRLDLSDGNNKEIDESINILRNWASQISFMKEEIDLE.RNI IIEEKKLGETrY PGRIYEDKFLTSGSLYEFRSPIGLEEQILSFQPEDFKKFYRKWYRPELASVIvvGDIDPIEIEEKIKKQFVSWK NPTDKIKEVKVSLDVELKDKFLLLEDLEVGEPSLMFFKKEI INFVKTKDDLLNAIKXSLLAALFENRFSELKTAGV .KQFKNVSNKDFFSFKSDNN'rIVAKSISLNFNPDHLNEGIQDFFYELERIRFGFTQGELEKVRSQFYKSLELRKKN INKNSWAIFQDLIEIAINGSNKFrDMEYCDLSFQYLEKIDLKTINNLVGREFDVKCAIFYSYHGRAHPVLTLED IDNLQKIALKRELKPYENSLIEGKFFKKSLDDKDIIRENEFNISSFvLENGvEVyFKYNDQKKGVIDFSATSWG

GLINEDLKLIPVLSFAPGVSGSGYGDYSALQIEKYLSDKAVSLRVGVGAQESYISGSSDKKDLETLFQLIYFTFK

EPKIDDVSLQNAINNIKALIKSNENSSDYHFHAISKFLNNNDPRFDTKDSDLQYFTKENILSFYKKRFTYANNF

KFVLLETQIFRQZ

f373 .nt WO 98/59071 PCT/US98/1271 8 162 TABLE 1. Nucleotide and Amino Acid Sequences ATGAATTATCAAAAATTAAATTATTGTAA=ACAAGCGTTTTTrCTATTTTrTTTGTTTCCTGTGTTTCTA ATGAGTAAATTAGATAAT GTAAGAAA GTCAATGGGCTAAGGTATTATATTTATAAAAATCA AACCCCAAGAATGCCGTTAATATGGGAATTGTTmTAATGTGGGCTCACTTAATGAAGAAGATAATGAGAGGGGA ATAGCGCATTATCTTGAACATATGGCT'rTTAATGGTACAAA-AGATTATCCAGGGAATTCTATAGTTGATGTTCTTA

AAAAATTTGGAATGCAATTTGGTGCTGACATTAATGCTGCTACTAGTTTTGATTTCACTTATTATAGACTTGATTT

GTCAAGTAATAAAGA''AGAATCTATAAATATTT'GAGAAACTGGGCTTCTCAAATCAGTTTC

ATGAAGAAGAAATAGATcTAGAGCGAATATTATTATGAGGAAAAAAAGCTTGGTGAGACTTATCCTGGAAGAA

TTTATGAGAAAATGGATAAGTTTTTGACAAGCGGAAGTCTTTATGAATTTAGAAGTCCTATTGGACTTGAAGAGCA

AATT N'ATCTTTTCAGCCAAGTrAAAA 'AAAATGGTATAGGCCAGAACTTGCAAGTGTTATT GTGGTAGGAGATATTGATCCTATAGAAATTGAAGAGA6AGATAAAGAAGCAATTTGTTTCTTGGAAAAATCCAACCG

ATAAAATTAAAGAAGTAAAAGTAAGTTTAGACGTAGAGCTTAAGGATAAATTTTTACTTTTAGAAGATTTGGAAGT

TGGAGAGCCTAGTI'TAATGTTCTTTAAAAAGGAAATTATTAACTTTGTAAAGACCAAAGATGACCTTr'rAAATGCT ATAAATTTTACGTTTTAATGTTCGATAGCGTGGA6GATT

AAAATGTTTCAAATAAAGATTTTTTCTCATTTAAATCAGATAACAATACCATTGTTGCAAAATCGATTTCTTTAAA

CTTITAATCCAGATCATTTGAACGAAGGAATACAAGACTTTTTTTATGAGCTTGAAGTAAAA rGTT

ACCCAAGGTGAGCTTGAAAAAGTTAGATCTCAATTTTACAAATCTAATAGAAAATTATAAAA

CAATTCATGGGCTATTTTTCAGGATTTAATAGAAATTGCTATTAATGGTTCTAATAAATTTGATATGAATGAATA

TTGCGATCTTTCTrTTTCAATATTTGGAAAAGATTGATAAAAAAAATTTGTAGGAAGAGAGTTTGAT

GTA.AAAAATTGTGCAATTTTTTATTCTTACCATGGAAGAGCACATCCTGTTTTAACTCTTGAAGATATTGACAATC

TTCAAAAGATAGCTTTAAAAAGAGAGTTAAAGCCTTATGAGAATTCTTTAATTGAAGGTAAATTTTTTAAGAAGTC

TTTAGATGATAAAGATATTATTAGAGAAAATGAGTTTGAAAATGAAArTTTCGTCATTTGTTCTrGAAAATGGGGTT GAAGTTTATTTTAAATATAATGATCAAAAAAAAGGTGTAATTGATTTTAGTGCAACTTCTTGGGGAGGTT TAATTA

ATGAAGATTTAA-AACTTATTCCTGTTTTATCTTTTGCTCCCGGAGTAGTATCTGGTTCGGGTTATGGTGATTATTC

TGCATTACAGATTGAAAAATATTTATCAGATAAAGCTGTTTCTTTAAGAGTTGGGGTTGGAGCTCAAGAATCATAT

ATTTCTGGAAGTTCAGATAAAAAAGATCTTGAAACTCTTTTTCZAGCTTATATATTTTACTTTTAAGGAACCCAAAA

TTGATGATGTTTCTTGCAAAATGCTATTAATAATATAAAAGCATTAATAAAGAGCAATGAAAATAGTTCTGATTA

TCATT'rTCATAAAGCCATTAGTAAATTTTTAAACAATAATGATCCTAGATTTGAAGATACAAAAGATAGTGATTTG

CAATATTTTACAAAAGAAAATATTTTGTCTTTTTATAAGAAAAGGT=TACTTATGCAAATAATTTTAAGTTTGTCT

TGCTGGAGACTCAGATATTCAGACAATAA

****t373.nt ::TGTGTTTCTAATGAGTTAAGTTAGATCAAAGTTTGGTAAAAGGAAA6ACTTGTCAATGGGCTAAGGTATTATATTT TGAGAGGGGAATAG7CGCATTATCTTGAACATATGGCTTTAGTCAAGTACCAGGGAATTCTATAGTT GATGTTCTTAAAAAATTTGGAATGCA6ATTTGGTGCTGACATTAATGCTGCTACTAGTTTTGATT1TCACTTATTATA

GACTTGATTTGTCAGATGGTAATAATAAAGATGAAATTGATGAATCTATAAATATTTTGAGAAACTGGGCTTCTCA

AATCAGTTCATGAAAGAAGAAATAGATCTAGAGCGAAATATTATTATTGAGA AA AA AAGCTTGGTGAGACTTAT CCT GAATTTAAATGTATTTTGACAAGCGGAAGTCTTTATGAATTTAGAAGTCCTATTGGAC

TIIGAAGAGCAAATTTTATCTTTCAGCCAGAAGATTTTAAAAAATTTTATAGAAAGTGGTATAGGCCAGAACTTGC

.*.AAGTGTTATTGTGGTAGGAGATATTGATCCTAAAATAGAAGTAGACAATTTGTTTCTTGGAAA

AATCCAACCGATAAAATTAAAGAAGTAAAAGTAAGTTTAGACGTAGAGCTTAAGGATAA6ATTTTrTACTTTTAGAAG ATTTGGAAGrrTGGAGAGCCTAGTTTAATGTTCTITTAAAAAGGAALATTATTAACTTTGTAAAGACCAA-AGATGACCT TTTAAA6TGCTATTAAAAAGTCTTTATTAGCCGCTCTTTTGAAAATAGATTTTCTGAATTAAAGACTGCTGGGGTA AAGCAATTTAAAAATGTTTCAAATAAAGATTTTTI'CTCArAACGAACAACATTGTTGCAAAATCGA

TTTCTTTAAACTTAATCCAGATCATTGAACGAAGGAATACAAGACTTTTTTATGAGCTTGAGAGGATAAGAAA

ATTTGGATTACCCAAGGTGAGCTTGAAAAAGTTAGATCTCAATTTTACAAATCTTTAGAATTAAGGAAAAAGA6AT ATAAATAAAACAAATTCATGGGCTATT'TTCAGGAT'rTAATAGAAATTGCTATTAATGGTTCTAATAA-ATTTGATA TGAATGAA.TATTGCGATCTTTCTTTTCATTT AAATATAAAAATAAA-CAATCTTGTAGGAAG AGAGTTGTGTAAATGTGAAT~rTATTTTACCATGGAAGAGCACATCCTGTTTAACTCTTGAAGAT

ATTGACAATCTTCAAAAGATAGCTTTAAAAAGAGAGTTAAA.GCCTTATGAGA.ATTCTTTAATTGAAGGTAAATTTT

T'rAAGAAGTCTTrGTAAAATTATGGAAGAGTTTGAAAATGAAATTTCGTCATTTGTTCTTGA

AAATGGGGTTGAAGTTTATTTTAAATATAATGATCAAAAAAAAGGTGTATTGATTTTAGTGCAACTTCTTGGGGA

GGTTTAATTAATGAAGATTTAAAACTTATTCCTGTTTTATCTTTTGCTCCCGGAGTAGTATCTGGTTCGGGTTATG

GTGATTATTCTGCATTACAGATTGAAAAATATTTATCAGATAAAGCTGTTTCTTTAAGAGTTGGGGTTGGAGCTCA

AGAATCATATATTTCTGGALAGTTCAGATAAAAAAGATCTTGAAACTCTTTTTCAGCTTATATATTTTACTTTTAAG

WO 98/59071 PCTIUS98/12713 163 TABLE 1. Nucleotide and Amino Acid Sequences GAACCCAATTGATGATGT=TTCCAAATGCTATTAATAATATAAAGCATTATAAGACrTA-AATA TAGTATTTCAATTTTTCAAAGAAAArTTTTATAAGAAAGGTTTACTTATGCAAATAATTTT

AAGTTTGTCTTGCTGGAGACTCAGATATTCAGACAATAA

f384.aa LISESTFIIDPIDGTSSFAAGLPSYGISLYASGGKIIEGAISLPLSGEFFITS1W yAIjMGYPLKryFN FIFDNSKCYNIHSLLAVSRSIIRLFNLDISSHHINGSCVYSFAKLFTGSAYFSFGLwDIACLAIGNKGMV GEFCG7KTLDILDSMYILEPNHIWSLKFFIYSDNKSTIIIRKAKKINK t384 .aa

CAXLILDFKSDGSIVTQVDKQIEQFLFKEIKKPGNFVLGEETISTYKEEYIKDALISESTFIIDPIDGTSSFAAGL

PSYGISLAYASGGKIIEGAI SLPLSGEFFITSKDNVFYAKKNIGSYPLKKDFNKFIFDNSKCYNIHSTJLAVSRSI

I

RLFNLDI SSEIHNGSCVYSFAKLFTGSYKAYFSFVGLWDIAACLAI-NKLGMVGEFYCGNKMTLDILDSMYILEP

NNHKRWSLKDFFIYSDNKSTIDIIRKDANKXINKZ

f384 .nt ATGGATTGGGATrTT AAATAATrTAAGACAACTAGGCTTGCATTAAGTGGTTGTGCTAAAT

TAATTTTAGATTTTAATCTGATGGGTCTATGTAACTCAGGTTGATAAGCAATTGAGCAATTCTTATTCAAAGA

GATCAAAAGCCTGGAAATTTTGTTCTTGGAGAAGAGACAATATCTACTTATAAAGAAGAGTATATCAAAGATGCT

TTAATATCAGAGAGTACTTTTATTATTGATCCTATTGATGGAACTTCTTCTTTTGCAGCAGGCCTTCCTTCATATG

GAATATCGCTAGCGTATGCTAGTGGCGGCAATTATTGAAGGAGCCATTTCTCT'CCTAAGCGGAGAGTTTTT

TATTACTTCTAAAGATAATGTATTTTATGCTAAAAAACATTGGTAGCTATCCTTTAAGGATTTTAATAAA

TTTATTTTTGATAATTCTAAATGTTACAATATTCATAGTTTANCTTGCAGTTTCAAGGTCTATTATAAGGTTATTTA

ATCTTGATATTTCTTCTCATATTCATATTAATGGTTCTTGTGTATATTCTTrI'GCTAAACTTTTTACAGGTTCTTA TAAGGCCTACTTTTCTTTTGTAGGACTTTGGGATATTGCAGCGTGTTrAGCTATTGGTAATAAATTGGGCATGGTT

GGCGAATTTTATTGTGGTAATAAAATGAC-ATTAGATATCTTAGATTCAATGTATATTTTAGAGCCTAATAATCATA

***AAAGATGGTCC TAAATTrATATCTGATAATAAATACAAAA''TAAAGTCA

TAAAAAAATCAAT.AAGTAA

t384.nt

AATTCTTATTCAAAGAGATCAAAAAGCCTGGAAATTTTGTTCTTGGAGAAGAGACAATATCTACTTATAAAGAAGA

GTATATCAAAGATGCTTrAATATCAGAGAGTACTTTTATTATTGATCCTATGATGGA.ACTTCTTCTTrTTGCAGCA

GGCCTTCCTTCATATGGAATATCGCTAGCGTATGCTAGTGGCGGCAAAATTATTGAAGGAGCCATTTCTCTTCCTT

TAAGCGGAGAGTTITrTATTACT'rCTAAAGATAATGTAT'TTATGCTAAAAAACATTGGTAGCTATCCTTTAAA AAGAT~AATAATTATrT~GATAATTCTAAATGTTACAATATTCATAGTTTACTGCAGTTTCAAGGTCT ATTATAAGGTTATTTAATCTTGATATTTCTTCTCATATrCATATTAATGGTTCT'rGTGTATAT'rCTTT'TGCTAAAC -:to:TTTrTACAGGTTCTTATAAGGCCTACTTTTCTTTTGTAGGACTTGGGATATTGCAGCGTGTIvTAGCTATTGGTAA

*GAGCCTAATAATCATAAAAGATGGTCCTTGAAGATTTTTTATTTATCTGATAATAAATCAACAATAGACATTA

TAAAAAGA~GCAATLAAAACAATAAGTAA

f860.aa MAFYKLNDNIAIAEDLLKYLLSSILECSQDDFLENYIEKGLIKKLENVINSNFEVITYTKAIEILENSIKcNFEI KPYWGIDLQTDHRYLTEETFKKPVIDYPKFKAFYMKANKDNKTVKGDILVPKIGEI IGGsEREDDLQKLEN~ RIKELNLNIEHLNMyLLRRFGSAPHSGFGLGLERLVQYSTGISNIRI)SIPFPRTPKNLYFZ t860.a WO 98/59071 PCTIUS98/12718 164 TABLE 1. Nucleotide and Amino Acid Sequences

GFGLGLERLVQYSTGISNIRDSIPFPRTPKNLYFZ

f86.0.nt AAATTCAAATTTTGAGGTTATTACCTATACTAAAGCAATTGAAATTCTTGAA~ACTA AA A ATTTTGAAATA TGGTCATTGATTATCCAAAAATTTCAAGCATTTT

ACATGAAGCAATAAGACAAT~

ATTCCCAAGGACTCCTM..AAATCTTTATTTTTAA

t860 .nt CAAATTTTGAGGTTATTACCTATACTAAAGCAATTGAAATTCTTGAAAACTCA AA AAA A AATTTGATAAACC

TTCGGATGTTCACGTAGAGTACACGAAATTAAACGTGGT

ATTGATTATCCAAAAAATTTCAAAGCATTTTACATGAAGCATAAGACAATAAACTGTTAA.GGAATGGACA

TACTTGTTCCAAAAATTGGAGAGATTATAGGGGGAAGCGAAAGAGAAGATGACCTTCAATTAGAAATAGAAT

AAAAGAATTAAACTTAAACATTGAACATCTAAACTGGTATCTTGATCTA6AGAAGATTTGGCTCGGCTCCTCATTCT

GGCTTTGGACTTGGACTTGAAAGATTGGTGCATACTCAACAGGAATATCTAATATAGAGATTCAATACCATTCC

CAAGGACTCCTAAAAATCTTTATTTTTAA

f446 .aa

MKILRLCLLFLFFACTFDYDEYSSRSDVAKKFPSIQILGIKYYDVVYNKE.QTVLNSLSFSYFNDYKIYKAENGRFL

YHSLDNEI SGKFNNLEGSYITKDLDMRDSVEFKIEDKNNYLLNSNRLLWKNKLKKLQSPPNELVLIRFNDSKING

KGFSYFLKSNVFYFDSGVEGIMNZ

t446.aa

CTFDYDEYSSRSDVAICKFPSIQILGIKYYDVVYNKEQTVLNSLSFSYFNIDYKIYKAENGRFLYHSLDNEISGKPNN

**LEGSYITKDLDMRDSVEFKIEDYLLNSNRLLWKDKKLQSPPNELVLIRFNDSKINGKGFSYFLKSNVFYF

DSGVEGIMZ

f446.nt *.*ATGAAAATACTrAGAcTTTGTTTGTTGTTTTTGTTTTTTGCTTGTACTrTTTGATTATGATGAGTATTCTAGTAGAT CTGATGTGGCCAAAAGTTrCCTTCAA.TACAAATATTAGGAATCAAGTATTATGATGTTGTATACAATAAAGAGCA AACCGTTTTAATTCTTrTAAGCTTTAGTTATTTCAATGAcTATAAAATT'rATAAGGCAGAGAATGGAAGGTTTTTA o ~TATCATTCCCTAGATAATGAAATTTCAGGGAAGTTTAATAATTTGGAA6GGTTCTTATATTACAAAGGATTTGGATA GAATAA6AGACAAGAAGTTGCAATCCCCCCCAAA6TGAGCTAGTATTAATTAGATTTAATGATAGCAAAATAAACGGA

AAAGGATTTTCTTATTTTTTAAAGAGCAATGTTTTTTATTTTGATTCTGGAGTTGAAGGAATCATGAATTGA

t446.nt TGTACTTTTGATTATGATGAGTA'ITCTAGTAGATCTGATGTGGCCAAAAAGTTTCCT'rCATACAA.ATATTAGGAA TAAAATTTATAAGGCAGAGAATGGAAGGTTTTTATATCAT'rCCCTAGATAATGAAATTTCAGGGAAGTTTAATAAT

TTGGAAGGTTCTTATATTACAAAGGATTTGGATATGAGAGATTCTGTAGAATTAATGAAAAAAT

ATTATTTGCTTAATTCAAATAGGCTTTATGGAAGATAAAGACAAGAAGTTGCAATCCCCCCCAAATGAGCTAGT

WO 98/59071 PCT/US98/12713 165 TABLE 1. Nucleotide and Amino Acid Sequences GCJ GArCTT7 AACACAGTTTTT GAT'rCTGGAGTTGAAGGAATCATGAATTGA f 457. aa FFLRYEIIGISKGFEF NIrMQNIEFNGLNIEGLKIEGMERLIFDNINEIGELDD FDYTEWVHFFRVVKSSSESYKIELLGD)VLNIQSRN1KLINDLFLVLSPGIZ t457 .aa CFLSCRSESRANLIEFFDSIKFQSSP EIFYLNIPSDDLKAKIRGLKSQADFIFYPLFNNLYEIIG

RKNISKGFEFEVVIKNINFQNGIEKFLAKLKIEGRSLNIKLEKEKIFDNLINEVIGELDDFDYTEVVHFFR

VVKSSSESYKIELLGDVLNIQSRNKLIILFLVLSPGIZ

f457 .nt

AAGTGATGATGATCTGAAGGCAAAATTCGTGGGTTGAAATCTAGGCAAGGATGATTCATTTTT'TATCCTTTG

TTTTAATTAAAGGTAAGAAAAAATCAGGTTATTAGTTAT

AAATATTAACTTTCAAAACGGTATAGAAATTTTTGGCTAAATTAAATAATTGAAGGC-AGATCTTTATAT

TAAAATTAGAAAA.AGACGTAAAAAAATATTTGACAATTTAATAAATGAAGTTATTGGAGAGTTIGGATGAT

TTTGATTACACTGAAGTTGTTCATTrTTTTAGAGTAGTTAAGAGTTCTTCTGAAAGTTATAAAATAGAGCTrTTAG

GAGATGTTTTAAATATACAGTCTAGAAATAAGCTTATTAA.TGATCTTTTTTTGGTTTTATCGCCTGGAITTTAA

t457 .nt TGT'TTTTTGTCTTGTAGATCTGAATCTAGATTGCC1YAA A TGTTI'TAATAGAGTTTTTTGATTCTATTAAAAATT TTCAAAGCAGTCCTGAAATATTTTTTAATTATrI'AAATATTCCAAGTGATGATGATCTGAAGGCAAAAA-TTCGTGG

GTTGAAATCTCAGGCAAAGGATGATTTCATTTTTTATCCTTTGTTTTTTAATAATCTAAGATATGAGATAATAGGT

**AGAAAAAATATTTCTAAGGGCTTTGAATTGAAGTTGTTATTAAAATATTAACTTTCAAAACGGTATAGAAAAAT

TTTTGGCTAATATAATAGGG T~AAATAATAAAAAGAGCGTAAAAAAAT ATTTGACAATT ATATAGTTGAATTGGATGATT'rTGATTACACTGAAGTI'GTTCATTTTTTTAGA

TTATTTATCTTTTTGGTTTTATCGCCTGGAATTTAA.

f542 .aa

MRIVIFIFGILLTSCFSRNGIESSSKIKISMVDGVLDDKSFNSSANEALLRLKFPENIEEVFSCAISGVYSS

VSDLDNLKRNGSflLIWLVGMLTDASLLVSSENPKISYGI IDPIYGDDVQIPENLIAVVFRVEPRCFFGWLYCSQ

KXLFWQNRFYRGNEGZ

t542.aa 0

CFSRNGIESSSCKIKISMIJVDGVLDDKSFNSSANEALLRLIKDFPENIEEVFSCAISGVYSSYVSDLDNLKRNGSD

LIWLVGYLTDASLLVSSENPKISYGIIflPIYGDDVQIPELIAVVFRVEPRCFFGWLYCSQKLFWQNRFYRGNE

GZ

f542.nt AT TTTTATCTCTTGAAATGAAAGTTGTA

AAAAAATTAAGATATCCATGTTGGTAGATGGTGTTCTTGACGACAAATCTTTTAATTCTAGTGCTAATGAGGCTTT

ATTACGCTTGAAAAAAGATTTTcCAGAAAATATTGAAGAAGTTTTTrTCTTGTGrCTArrrTCTGGAGTTTrATTCTAGT

TATGTTTCAGATCTTGATAATTTAAAAAGGAATGGCTCAGACTTGATTGGCTTGTAGGGTACATGCTTACGGACG

CATCTTTATTGGTTTrATCGGAGAATCCAAAAATTAGCTATGGAATAATAGATCCCATTTATGGTGATGATGTTCA WO 98/59071 PCT/US98/12718 166 TABLE 1. Nucleotide and Amino Acid Sequences

GATCGAATGT~-GTTTCGGAACAGTCTTTGTGTTTGACA

AAAAAGCT'TTTCTGGCAAAATAGGTTTTATAGGGGCGAATGAAGGGTAA

t542 .nt

GAATAATAGATCCCATTTATGGTGATGATGTTCAGATTCCTGAACTTGATTGCTGTTCAGGTAGAGCC

AAGGTT=GCGCAATCGCAAAACTTTGAATGTTAAGGATA

GGGTAA

f93.a

MKIAHISGTLIIVSFMVPVAVSSAKFIDTHEFNWENHDL

TGFLGSEKQQITIEKIIKLIKFEKIVIDPVFADDGEIYP

IFDNKIISGFRKIIKYANIITPNTELEMLSKSSKLN

NKD)DI IKAILNLDTKATVVVTSV'KRGNLLGNICYNPKNKEYSEFFLEGLEQNFSGTGDLFTSLLIGYJEKFETEQA LEKTTKAIHLI IKESIKENVSKKEGVRIENFLKNTFZ t-93.aa CIPVISSFNMQVCPFVTAVLSASTAYKFEVLTDHLEKFINIWKEQNEJ{FDILYTGFLGSEKQQITIEKI

IKLI

KFEKIVIDPVFADDGEIYPIFDNKI ISGFRKI IKYANI ITPNITELEMLSKSSKLNNDDI IKAILNLDTKATVVV TSVKRGNLLGNICYNPKKYSEFFLEGLEQNFSGTGDLFTSLLIGYLEKFETEQLEKTTKAIHLI

IKESIKENV

SKKEGVRIENFLKNTFZ

f93 .nt

ATAAGATTGATCTAATCACTGGAACTTTAATTCTCATAA

CTTCGTTTAATATGCAAGTTTGTCCTTTTGTGACAGCTGTCCTTTCTGCTTCCACAGCTTATAAAATTTGAAAT

foe* AGTGGATTTAACCGATCATTTAGAAATTATCAATATATGGAAGAACAAATGAGCACTTTGACATACTCTAT *ACCGGATTTCTGGGAAGCGAAAACATAATGGAAATA ATAATGAAAAATrG AACAAAGATGATATCATAAAAGCAATATTAAATCT'rGATACAAAAGCGACGGTAGTTGTTACAAGCGTTAA.AGGG 00 ~AAATTTCAGTGGAACAGGAGATTTATTTACCAGCTTACATAGGATATTGGATTGAACAGAGCAAGCC *0*00:TCCGAATTGAAAATTTCTTAAAAAATACATTTTGA t93.nt too#$:TGCATACCAGTAATATCTTCGTTTAATATGCAAGTTTGTCCTTTTGTGACAGCTGTCCTTTCTGCTTCCACAGCTT

AAATTTGAAAAAATTGTAATTGATCCTGTGTTTGCTGACGATGGAGATTTACCCTATATTGATAATAAATAA

AAGCTCAAAACTTAACAACAAGATG ATATCATAAGCAATATrATCTTGATAAAAGCGACGGTAGTTGTT

ACAAGCGTTAAAGGGGAATCTCTTGGGAAACATTTGCTACTCCTAACAAAGATACTCGGAGTTTTTTT

TAGAAGGATTAGAACAATTTrAGTGGAAr-AGGAGATTTATTTAcCAGCTTACTTATGATATTT'GGAAAAATT TGAAACAGAGCAAGCC AAAACAAAGTATTCACCTAATAATAGAGTATTAAGAAAATGTT TCAAAAAAAGAAGGGGTCCGAA'FrGAAAATTTCTTAAAAAATACATTTTGA flOS .aa WO 98/59071 PCTIUS98/12718 167 TABLE 1. Nucleotide and Amnino Acid Sequences

MGLYLKLRQSINLKSLFPLSVLFFSCNVDTDFSVLEFKVANFNLNDDFSQGLLSAYNILNRSFDLIIIIUL

EVDLIRVLFRAFKFYFDQGSGLSVSILSKINIKVLSVMQDSCDLKLGLLVDFKFENNHYGIVIYNLSK

DFIKSIANLQISEQILYLKAQDKMFILDESEFVIFDLLIlGFFSLIhNISNYTSLN-KIDFRVFSNFFARVSL YSFDM'VIAflYLHSNYVVENPQK-IVINZ t105.aa

CNVTFVEKAFLDFQLDANLRSDIINMILLMVFAKAFDG

GLSVSILSEKM KLSVMQDSCDLKLGLLVDFKFEHYGI MSKDFIKSIANLQISEQILYLKAQMKLM

FILDESFVIFDLLI'KGFFSLINDSNYTSLANKIDFRVFSFFARVSLYSFMVIADYLHSYVVENFPQKIVI

NZ

f105 .nt ATGGGCTTGTATTTGAAGTTG'ITGAGACAAAGTATCAACTTGAAGAGTTTATTTCCGCTTAGTGT'rTTAT'TTTTTT CCTGTAATGTTGTAGATACAGATI-rTAGTGTTTTGGAGTTTAAGGTTGCAAATTTTAATT'rAAATGATGATTTTTC

TQAAGGGTTACTTGATTCTGCTTATAATATTCTAATCGAAGTTTTGATTTAATAATTATTAGATCTTAGAAT

AAAATGTITCTTGATTTAATTAATAATAGAGTTTTATTTAGAGCTTI'AAGAATGCTTATTTTATTGATCAAGGTA

GTGGCCTTTCTGTTAGCATTCTTTCTAAGCGCAAAATAAATATTAAAGTTTTAAGTGTAATGCAGATTCTTGCGA

TTAATAGTGTGGATTATTAAAATATTGATTATAATTACA

GATTTTATTAAAAGTATTGCCATTGCAAATTAGTGAACAAATTTTATATTTAAAAGCCCATGGATAAATTGA

TGTTTATTTTAGATGAATCTGAATTTGTTATTTTTGATTTA TTAATC A)AAATGGATTTTTTAGCTTAATAAATGA TTCAAACTACACTTCAATGTTAGCAAATAAATTGATTTTAGAGTTTTTTCTAATTTTTT'rGCTAGGGTTTCTTTA

TATTCATTTATGTTTGTAATTGCAGATTATTTGCATAGCAATTATGTTGTTGAGAATTTTCCTCAAAAAATAGTTA

.9 TCAATTGA

TGTAATGTTGTAGATACAGATTTTAGTGTTTTGGAGTITAAGGTTGCAAATTTTAATTTAAATGATGATTTTTCTC

AAGGGTTACTTGATTCTGCTTATAATATTCTAAAITCGAAGTT rATATATTAGACTAAGAATAA ~AATGTTCT GTTATAATGGTTATTTAGAGCTTTAAGAATGCTTATTTTATTGATCAAGGTAGT

GGCCTTTCTGTTAGCATCTTTCTAAGCGCAAAATAAATATTAAAGTTTTAAGTGTAATGCAAGATTCTTGCGATT

TAAATTAGGATTGCTTGTGGATTTTAAATTTGAGAATAATCACTATGGTATTGTTATTTATAATTTAAGCAA.GGA

rTrAT rAAAAGTATTGCCAT CATATACATTTATATTTAAAAGCCCAAATGGATAA.ATTGATG rT AT'TrAGATGAATCT ~TGTT~rGTIATAATCAAAATGGATTTTTAGCTTAATAAATGATT CAAACTACACTTCATGTTAGAAA.TGTTTGG rTAATTTTTTGCTAGGGTTTCTTTATA

TTCATTTATGTTTGTAATTGCAGATTATTTGCATAGCAATTATGTTGTTGAGAATTTTCCTCAAAAATAGTTATC

AATTGA

.aa MKTFVIIGLSNLGIHLLEDLSRLDCQIII IDTSKELIEEYDVISTESFVVEQFTKNALKRI IpVDTDAVVIDFDDD

LGKSALVHYCNLGLKEICKTEDDAEILKTLGATKIIFPSKDAARRLTPLLVSPNLSTYNIIGYDIIVAETV

IPKMYVGKTLFEADLRRECGITVIAVRNLSNSRYEFVDGDYFFLKDDKIVCGKPDSIENFTNNKcDLIKDLISGSK

EDENIDAEKKSRFLGIFNMKIFQKDRIDNZ

CQIIIIDTSKELIEEYDVISTESFVVEQFTNLLKIIPVDTDAVVIDFDDDLGKSALv'rHYCNLLGLKEICVKTE NRflDAEILKTLGATKIIFPSKDAARRLTPLLVSPNLSTYNIIGYDIIVAETVIPKEYVGKTLFEADLRRECGITVI

AVRNIJSNSRYEFV)GDYFFLKDDKIVICGKPDSIENFTNNKDLIKDLISGSKEIENLNKDAEKKSRFLGIFNFMKI

FQKDRKDNZ

f150 .nt WO 98/59071 PCT/US98/1271 8 168 TAiUE 1. Nucleotide and Amino Acid Sequences ATGAAAACATTTGTTATTATTGGACTTAGTAATTTAGGCAT'rCACTTACTTGAAGATTTAAGCAGGCTTGATrGTC

AAATATTTTAAGAACACTAAAGAGCTTATTGAAGAATATGATGTGATATCTACAGAAAGCTTTGTTGTTGA

GCAATTCACTAAAAATGCTTTGAAAAGAATAATTCCAGTAGATACAGACGCTGTTG'TrATTGATTTTGATGATGAT

CTTGGCAAAAGTGCTCTTGTTACTCACTATGTAATCTTTTAGGTTGAAAGAAATATGCGTT'AAGACAGAAAATA

GAGATGATGCTGAAATCTTAAAAACTCTTGGGGCAACAAAAATTATATTTCCAAGTAAAGATGCTGCAAGAAGATT

AACTCCATTATTAGTATCTCCAATCTTTrCAACTTATAATATTATTGGGTATGATATTATTGTTGCTGAAACTGTT

ATTCCCAALAGAATATGTTGGTAAAACTCTTT'TTGAAGCCGATCTTAGAAGAGAATGTGGGATTACAGTTATTGCTG

TTAGAAATTTAAGTAATTCTAGGTATGAATTTGTTGATGGC Mr~TTTAAAAGTAATTAT TTGTGGTAAAC AAACTrAATTAAAATAGTTATAGTTAATTTCAGGCTCTAAA

GAGGATGAAAATTTAAATAAAGATGCTGAGAAAAAATCTAGATTTTTAGGGATTTTCAATTTTATGAAAATTTTTC

AAAAAGATCGTAAGGATAATTAG

.nt

TGTCAAATTATTATTATAGATACATCTAAAGAGCTTATTGAAGAATATGATGTGATATCTACAGAAAGCTTTGTTG

TTGAGCAATTrCACTAAAAATG7CTTTGAAAAGAATAATTCCAGTAGATACAGACGCTGTTGTTATTGA7r=rGATGA

TGATCTTGGCAAAAGTGCTCTTGTTACTCACTATTGTAATCTTTTAGGTTTGAAAGAAATATGCGTTAAGACAGAA.

AATAGAGATGATGCTGAAATCTTAAAAACTCTTGGGGCAACAAAAATTATATTTCCAAGTAAAGATGCTGCAAGAA

GATTAACTCCATTATTAGTATCTCCAAATCTTTCAACTTATAATATTATTGGGTATGATATTATTGTTGCTGAAAC

TGT'rATTCCCAAAGAATATGTTGGTAAAACTCTTTTTGAAGCCGATCTTAGAAGAGAATGTGGGATTACAGTTATT

GCTGTTAGAAATTTAAGTAATTCTAGGTATGAATTTGTTGATGGCGATTATTTTTTTTTAAAAGATGATAAAATTG

TAATTGTGGTAACCAGATAGCATTGAA.AATTTTACAATAATAAAGATTAATTAAAGATTTrAATTTCAGGCTC

TAAAGAGGATGAAAATTTAAATAAAGATGCTGAGAAAAAATCTAGATTTTTAGGGATTTTCAATTTTATGAAAATT

TTTCAAAAAGATCGTAAGGATAATTAG

***f2l9.aa M~LIARININTLFYGMII IIFALISCNHKNIQYDKRIKKFLDKNKIEYKIDSENDFIAFKDINNNEKEEVI IRSRL NSYKNSKIREIFGIVKVFDINTPKIKEI SDSLMSDSYNNVFGSuWEIIHNAERGINSLVYIVKAEEFANDTFLLDA

IDEISTISIFKKIITTNNENIDNNEENNNTNESNEQPTLKQEKTNSTKESNNELKEDQIEEELQEIKAQZ

t219.aa

CNHKNIQYDKRIKKFLDKNKIEYKIDSENDFIAFKDINNNEKEEVIIRSRLNSYKNSKIREIFGIVKVFDINTPKI

KEI SDSLMSDSYNNRVFGSWEIIHNAERGINSLVYIVKAEEFANDTFLLDAIDEIASTISIFKKIITTNNENIDNN

EENNNTNESNEQPTLKQEKTNSTKESNNELKEDQIEEELQEIKAQZ

f2l9.nt *ATGCTAATTGCAAGATAGAATAAATATTCTACGGCATGATCATTATCATTTTTGCACTrCATTTCTT

GCAATC-ATAAGAATATACAGTACGACAAGAGAATTAAAATTAATAACAATGAATATAAAATAGA

*:*CTCAGAAAATGACTTTATAGATAAAATACATAGAAAAAGAAGAAGTAATrATcAGATCAAGACTA AACTCATATAAAATCAAAGATAAGAGAAATATTTGGAATTGTTAAAGTATTTGATATAAArCACACCAAAAATAA

AAGAAATATCTGACTCGCTTATGAGCGATAGTTATAATAACAGAGTATTTGGATCGTGGGAGATTATTCATAATGC

AGAAAGAGGAATCAACTCTTTGGTATATATTGTAAAGCAGAAGAATTTGCAAATGATACATTGCTGTGCA

ATTGATGAGATTGCCTCAACAATAAGTATTTTCAAAA hTAATAACAACCAACAACGAAAACATTGATAATAATG AAAAATACATCAAGAATCAAATGAACAGCCCACCT AACAAAACATCAACAAAAGATC

TAATAACGAACTTAAAGAAGATCAAATAGAAGAAGAACTTCAAGAAATCAAAGCCCAATAA

t219 .nt

TGCAATCATAAGAATATAC-AGTACGACAAGAGAATTAAAAAATTTTTAGATAAAAACAAAATTGAATATAAAATAG

ACTCAGAAAATGACTTTATAG ATAAAAAAATAGAAAAAGAAGAAGTAATCATCAGATCAAGACT AAACTCATATAAAAATTCAAGTAAAATTTGATTTAAAGTATTrTGATATAAACACACCAAAAATA AAAGAAATATCTGACTCGCTTATGAGCGATAGTTATAATAACAGAGTATTTGGATCGTGGGAGATTIATTrATAATG

CAGAAAGAGGAATCAACTCTTTGGTATATATTGTAAAAGCAGAAGAATTTGCAAATGATACATTTTTGCTTGATGC

WO 98/59071 PC/US9811 2718 169 TABLE Nucleodde and Amino Acid Sequences f229 .aa

MVDLLPLVELSLYISFCCDFSIFILEELICHLILLGHPIIKTLYIDFCLSRQDKIFTSLSKYIN

VNMPLQKKSHLKRDLQRIAFIYAZ

t229.aa CKDFSIFNRILEELKCHLILLGHPIIKTLYIKHVDFCLSRQDNLKFIFTSLSKYINLELLEEFTLEI

IPGYVDFEK

PXLLDEFCITRINLNVQSFSLEFRKIVGI PEISYKKLNILINNIRKFPFDLNIDMTVNMPLQKSHLKRnLQRIAy

IYAZ

f229 .nt

ATGAGAGTAGATCTTTTACCTCTTGTCGAGTTAAGTCTTTATATTAATTTGTCATTTTGTTGTAAAGATTTTAGCA

TTTTTAATAGAATTTTAGAGGAATTAAATGTCATTTAATCTTGCTGGGTCATCCAATTATAAACACTTrACAT

TAAGCACGTAGATTTTTGTTTATCTAGGCAAGATAATTTAATTTATTTTCACTTCTTTGTCAGTATATTAT

TTGGAGTTATTAGAAGAATTTACT'rAGAAATTATTCCGGGTTATGTTGATTTTGAATTCAACTTTTGGATG

ATTTGTATTACTAGAATTAATCTTAATGTTCAAGTTTTTCTTTAGAGTTTAGAAGATTGTGGGGATACCCGA

9: AATTTCTTATAAAAAATTGAATAT rGTACATTAAATTTCCTTTTGATTTGAATATTGACATGACT t229.nt

TGTAAAGATTTTAGCATTTTTAAATTGAGATAAGTCATTTAATCTTGCTGGGTCATCCAATTA

TAACACTTTAATTAAGCACGTAGATTTTGTTTATCTAGGCAAGATAATTTAAA.TTTATTTTCACTTCTTT

GTCCAAGTATATTAATTTGGAGTTATTAGAAGAATTTACTTTAGAAATTATTCCGGGTTATGTTGATTTTGAAAAA

TTCAAACTTTTGGATGAATTT'rGTATTACTAGAATTAATCTTAATGTTCAA.AGTTTTTCTTTAGAGTTTAGAAAGA TTGTGGGGATACCCGAAATTTCTTATAAAAATTGAATATT TATAATTAAAT~CCTTTTGATTT ~GAATATTGACATGACTGTCAATATGCCTTTCA A A A AAATCTCATCTCAAGCGAGATTTGCAAAGAATTIGCTTTC

ATATATGCCTGA

f22 .aa MIJKTLTKIITISCLIVGCASLPYVrPPKQNLNYLMELLPGANLYAHVNLIKNRSIYNSLSPKYKSVLGLISNLYFSY

KYIGEIEIFFWIQDPTLLLPNQIVSSKNLIPFSSGTLSINSLNQEEYIF.SLIKTNNPPILKILSKLIPTVL

9* TNMTNLTISSHIKTTIKDQNTVEIEFNIQKSSVESLIEKLASNIQT t22.aa PTLLLPNQIVSSKNLIPFSSGTLSINSLNQEEYIFKSLIKTNNPPILKILSKrJLIPTVLTNMTNLTISSHIKTTIK

DQNTIVEIEFNIQKSSVE-SLIEKLASNIQT

f22 .nt ATGTTAAAAACATTAACAAAAATAATTACCATTTCATGCCTCATAGTGGGATGCGCAAGCCTGCcTTACACTCCTC

CAAACAAATCTAATTACTTAATGGAACTTTTACCTGGCGCAAATTTATACGCCCATGTAATTTAATTAAAAA

CAGGTCTATTTATAACTCTTTAAGCCCTAAATATAAATCAGTTCTTGGGCTTATAAGCAATTTATACTTTAGCTAT

AAAAAAGAAAATAACGATTTTGCTCTACTAATAATGGGTAATTTCCCAAAAGATATTTTCTGGGGAATTCATAAAA

WO 98/59071 PCT/tJS98/12718 170 TABLE 1. Nucleotide and Amino Acid Sequences ATGATCGACAACCAAATAAACAAT

TAAATAATTTCTA

TTAATATTCAAAAATCTAGTGTTGAAACCTTATAGAAACTAGCTTCAAATA'rrCAAACCTAA t22.nt TGCGCAAGCCTGCCTTACACTCCTCcAAAACAAAATCTAAATTACTTAATGGAACTTTTACCTGGCGCAAATT'rAT

ACGCCCATGTAAATTTAATTAAAAACAGGTCTATTTATAACTCTTAAGCCCTATATTCAGTTCTGGCT

GATATTTTCTGGGAATAAATGAATACAACAATAGGCAATATATTTACAATCCATGGAC

rpAAATAAAAAATTCAAAACAAATGATCAACCAAAAAACG AAAGACAATAATATGcTAAcAACAAAATATGGGGAAATAGAAATGAATGTTTTTTTGATTCAGAT CCAACATTATTGCTCCCAAACCAAATAGTAAGCAGCAAAATTTAATTCCCTTTAGCAGTGGAACTTT1GTCTATAA AcAGCTTAAATCAAGAAGAATATATTTTTAAATCCTTAATCAAAACAAATAATCCACCAATACTAAAAATATTGTC

AAAATATCACGCTAAAAGCAACCCAACACAAAAACCAAA

GACCAAAATACGGTTGAAATAGAATT'DAATATTCAAAAATCTAGTGTTGAAAGCCTTATAGAAAAACTAGCTTCAA

ATATTCAAACCTAA

f32.aa bTKTLYLISLILLACNKNKIPLIQKLDLPKSSILGFSNMGIIIKDYAFLSKSTKKNSELDYDYAILLRCDEW

KIEKTLEKTERYGIEGNWILVNYKGTKRYIFSKDINIVNNLIIDHSK

t32.aa CNKNNKIPLIQKLDLPKSSILGFSNMGI IIKDYAFLSKSTKKNSELDYDYAILLRKDEVVKIEKTLEKTE-RYGIE

GNWILVNYKGTKRYIFSKDINIVNNLIIDHSK

f32.nt ATGATAAAAATTTATTAATATCCTTAA6TTCTTTTAGCTTGCAATAAAATAACAAAATTCCTCTCATTC

AAAAATTAGATTTGCCCAAAAGCAGCATTCTTGGCTTTAGCAATAAAATGGGCATAATAATAAAAGATTATGC-TT

TCTTAGTAAAAGCACTAAGAAAA6ATAGCGAATTGGATTATGATTACGCAATTCTACTCAGAAAAGACGAAGTCGTA

AAAATTGAAAAAACACTAGAAAAAACAGAGCGCTATGGAATTGAAGGAAATTGGATCCTAGTCAATTACAAGGGAA

CTAAAGATACATCTTTAGCAAGACATCAATATAGTCAACATTTAA.TAATTGATCATTCTAATAG

t32 .nt

TGCAATAAAAATAACAAAATTCCTCTCATTCAAAAATTAGATTTGCCCAAAAGCAGCATTCTTGGCTTTAGCAATA

**.AAATGGGCATAATAATAAAAGATTATGCTTTTCTTAGTAAAAGCACTAAGAAAAATAGCGAATTGGATTATGATTA

CGCAATTCTACTCAGAAAAGACGAAGTCGTAAAAATTGAAAACACTAGAAAAAACAGAGCGCTATGGAATTGAA

GGAAATTGGATCCTAGTCAATTACAAGGGAACTAAAAGATACATCTTTAGCAAAGACATCAATATAGTCAACAATT

TA ATA6ATTGATCATTCTAAATAG f186.aa

MKLIIIFTLFLSQACNLSTMHKIDTKDMKILYSEIAELRKKLNLNHLEIDDTLEKVAKEYAIKLGENRTITHTL

FGTTPMQRIHICYDQSFNLTREILASGIELNRVVNAWLNSPSHKEALINTDTDKIGGYRLKTTDNIDIFVVLFGKRK

YKN

t186.aa WO 98/5907 1 PCTIUS98/12718 171 TABLE 1. Nucleotide and Amino Acid Sequences

CNSMKDYMIYEALIULHEIDLKAEATCGNTTTFT

PMQRImHDQSFNLTREILASGIELRVVAWLNSPSEEALINTDDKIGGYRLKTTDNIDIFVVLFGKRKY!M f 186 .nt ATGAAAATTGATATA~rTTACACTGTTTTrTATCTCAAGCATGCAATTTAAGTACAATGCATAAAATAGATA

CAAAAAGTATAAATCTTAWCAGAATGCTAATGAGAAAAATAAACTAAACCATCTAGAAAT

AGATGATACCCT'GAAG- CC AA CATTAAACTGGCAAAGAATATCACACCCTT TTTGGCACACCCATCAGAAAATCGATCAATCC TA'TACAAAAATGGCATCAG GGAATTAACAGnTGTATGAGGTAATAGTCCAAGCCACAAAGAAGCTCTTATTAATACAGATAC CGATAAAATAGGTGGCTATAGATTAAAACGAC GCAAAAAATGATCTTTTTGGCCA A GAA

TATAAGAATTGA

tl86 .nt

TGCAATTTAAGTACAATGCTAAAAAAAAAGTTAATCTATATTCAGAAATTGCTGAATTGA

GAAAAAAATTAAATCTAAACCATCTAGAAATAGATGATACCCTTGAAAA.AGTTGCAAAAGAATATGCCATTAAACT

GCGAAATAAACATAATCACACCCTTTTTGGCACAACCCCAATGCAAAGAATACATAAATACGATCAATCC

TTTAATTTAACAAGAGAAATACTGGCATCAGGAATTGAACTTAACAGAGTAGTTAATGCATGGCTTAATAGTCCAA

GCCACAAAGAAGCTCTTATTAATACAGATACCGATAAAATAGGTGGCTATAGATTAAAAACGACTGACAATATAGA

TATATTTGTAGTTCTTTTTAAGAATAAATA

f216.a

MIRVLLGSLAVSFLFSICMVFLNYDNLFSKKVFYFHSSKGFVANLRYLRDEQNLKDNLDLLVKDFLLGSNEGFSFG

FLLSDSRFLYSFLKNGVYYVNLSREFYDSFNNGDYNESNESFDVKVNLFAMSLIKTMRFNYPGKIKKIVILVECCI

LKEQS

t216.aa

CMVFLNYDNLFSKKVFYFHSSKGFVANLRYLRDEQNLKDNLDLLVKDFLLGSNEGFSFGFLLSDSRFLYSFLKNTGV

YYVNLSREFYSFNNGDYNESNESFDVKVNLFAMSLIKTMRFNYPGKIKKIVILVEGCILKEQS

f216.nt ATGATTAGGGTGCTTTTGGGGTCTTTGGCAGTAAGCTTTTGTTT'rCTATTTGTATGGTTTTTTTAAATTATGATA

ATCTTTTTCAAAAAGGTTTTTATTTTCATTCTAGCAAGGGATT'GTTGCTAATTTAAGATATTAAGAGATGA

AcAAATtTGAAG.TAI~rAGT~vTTAGTAAAAGATTTTCTTTAGGAAGCAATGAAGGGTTTTCTTTTGGG TTTITTATTAAGTGATTCAAGATTTTTATATTCTTTflTAAAGAATGGAGTTTATTATGTAAATCTTTCAAGAGAAT lTrTATGATTCTTTTAATAATGGTGATTATAATGAATCTAATGAATCTTTrGATGTTAAGGTCAATCT'ITTTTGCTAT GTCTTTAATAAAAACAATGCGCTTTAACTATCCTGGTAAGATAAAAAAGATrTGTTATTCTrGTTGAAGGGTGTATC

*TTAAAGGAGCAAAGTTGA

t2l6.nt TGTATGGTTTTrTTTAAATTATGATAATCTTTTTTAAACTTTTTTCTCTAGCAAGGGATTTGTTG C A~TAAATAGGTACAATrAG TATTGATCTAGTAAGAT1'TTCTTTTAGG AAGCAATGAACGTcTrGGGTT TTAGGTTC AAIrTTATATTCTTTTTTAAAGAATGrAGTT TATTATGTAATCTCAA~AGTT CTTTATAATAAGGTGATTATAATGAATCTAATGAATCTTTTG

ATGTTAAGGTCAATCTTTTTGCTATGTCTTT'AATAAAAACAATGCGCTTAACTATCCTGGTAAGATAAAAAAGAT

TGTTATTCTTGTTGAAGGGTGTATCTAAAGGAGCAAAGTTGA

f328 .aa MAIKYARENNIPFLGICLGLQLAVIEFARVCGILDADTEENLARKPLKSpVIHLLPEQKGIKDKGATMRLGGYP VILKNTIAFKLYGQDRI IERFRHRYEVNNflYIDLFAKNGLIVSGFSSDFKMAKLIEI PENKFFVACQFHPELITR

IENPAKLFLGLIKACI

WO 98/59071 PCTIUS98/12718 172 TABLE 1. Nucleotide and Amino Acid Sequences t328.aa RIIER RRYEVNDYIDLFAKNGLIVSGFSSDFAKLIEIPEFFVACQFHPELITINPAJJF

LGLIKACI

f328 .nt

ATGGCTATTAAATATGCTCGTGAGAATAATATTCCCTTCTTGGAATGTCTTGGTTTGCAGCTGCTGTAATAG

AATGTGATTTTGAATGTCGTCGGAATTGAGGCACCTAAA

TCCTGTTATCCATTTACTTCCTGAGCAAGGGAATTAAAGATAAGGGCGCTACAATGC

TGATATCCT

AATGCAAATAAAGAATCCTGAAATAAATTTTTCGTAGCTTGCCAGTTCATCCAG.CTTATTACAGA

ATAGAAAATCCAGCCAAGCTTTTTCTAGGATTAATTAAAGCTTGTATTTGA

t328 .nt

***CCAGTTTCATCCAGAACTTATTACAAGAATAGAAATCCAGCCAAGCTTTTTCTAGATAATTAAGCTTGTATT

TGA

f352.aa MNKTNRSLTYFI ILSCI SLFGANNNTISYSSIEIPLEDLSEFKSSGNKSDQINTSKHLNKNIVSYEDPKKGKDL KLPENIRDKKLPQKRMDENDLKSVIENYENKIKNIEKLLKTKNrQKTSENENKKIES

IEKKAKKYEILTNKLKNEIV

EIKLKIPEEYKNEIETDFDYENEETENPNGINKNNNKYI

EKKIDELEflRINENENTILDLQRELRNFKKKDNSDKNLEEIEENLSSIGRIINDLKRXISANEAINKENQKKIRTD KHK LKEL, KIKENEETILKLQKENFKEIYQKPLEETFTPSITSKDDLEENKLKKEYLKIEKESRDL EENTKSTPKTTMIKTADFQIYPDIYLNNYKFKEKGDQFAFKYYIEIDPTNNLNEALKNHEI

ISKYKFEKYFI

NPILEKEEFFRNLIEVKIHELGIYKNO-LKPEFKQIKIIK

t352.aa CISLFGANNTISYSSIEIPLEDLSEEFKSSGNKSDQINTSKHLNKS

SEDPKGKDLKLPENIRDKLPQKRM

DENDLKSVI~iYEKIKNIEKLLKTKNQKTSEM1KKIESIEXAEILTNKLKNEIVEIKKLTUI.KKIKPKEDE

NYEKINIENIEEETDDDFEDNYEYNDEIETEDNYPSNEGIINNLKNNEKYYAINEKIDELEDRIFNENED

TIDQERFKDSKLEENSIRnLRIAEIKNKITKKKLDIEE

TIKQEN"KKIQPNEFPISNDENKKELPEKSDENKTKTIT

DFIPILNKKKDFFKNYIIPNNNAKHISYF~TNIK

EFNI

VKNIHELGIMYRULKPEFKQII{IIK

f352 .rt

ATGAATAAACAAAAAATCGAAGCCTTACGTATTTTATAATACTTTCATGTATATCATTATTTGGGCTAATAATA

ATCAAGTCCACTGATCTTGAGCTATAGATAAGTTGATAA

CGATCAAATAAATACCTCAACTrAAAAAAATTTCTTATGAGACCAAAGGGTAAAGATCTA

A.AATTGCCAGAAAAGGCAAATACCCCAAAAAAGAATGGACGAAAATGATCTAAAATCTGTAATTG.

AAAATTATGAATAATAACTGAACTTTTAAAAACCAAAAATCAAAACATCGGAAAATGAAAA

TAAAAAAATAGAATCAATC GA-AATAAGCAAAAAAATATGAAATTTAA~'CGAAATAGTA

GAAATAAAAAAGCTCCTTAACAAAAAAATCAAGCCTAAAGAAGATGAAAATTAAAATATATTGAAAACA

WO 98/59071 PCIJUS98/1271 8 173 TABLE 1. Nucleotide and Amino Acid Sequences TTGAAGAAG~AACTGATGATGAT= GAAATAGATTAGTAA'GAAGAACAAATGAG7GACAAT TACCCTTcTAATGAACGGAATAATAAAcAATCTAAAAGAAATCTTAATGAAACGAAAAATATTATGCTATTAATG AAAAAAAAATCGATGAACTTGA.AGACAGAATCAACGAG AATGAAAACACTATITrTAGACTTGCAAAGAGAATrAAG GAATTI' A(.AAATCAGATAAAAACTT AAATGGAATTIATCTTCAATAGGAAGAATA -ATTAATGATCTAAAAGAAAAATCAGCGCAALTGAAGCAATAAACAAAGAATeA A AAA A AA ATAAGA.ACTGATA AACACAACT AAATAAGTAAAAGAAGAAATATTTAAAACTTCAAAAACAATTAAA CA~''rAAAAAAGA~rTCAA ccCTAAGAAAC C CCAAGCATACAAGTAAAAAT GACGATAAGAAAGA rAAAGAATrAGCCATAA AA A AA A AAAAGCCGAGATCTAG

AAGAAAATACTAAAAGCACCCCAAAAACAACTAGTAACACGT''CAAATCTACCCTGACATATATCT

TAAAATATAAATTAAGAAAGGAGTCATTTCATTAAAAAAAACACTATATATTGAAATAGAT

CCCACTAAcAATTTAAATGAGGcTTTAAAAAATCATGAAATAATCTCAAAATATAAATTTGAAAAATATTTCATTA ACCCTATCTAAAAAAT AGAAT'TTGACT.TGATCAAAAATATCCACGAACTAGGAATTAT

GTATAAAAATCTAAAGCCTGATAGAAAAAATAAA

t352 .nt TGTATATcATTATTTGGGGCTAATAATAATACAATAAGCTACTCTAGCATTGAAATTCCTCTAGAAGACTTAAGTG

AAGAAT'TTAAAAGTTCTGGGAATAAAAGCGATCAAATAAATACCTCAAAACATTTAAACAAAAACATAGTTTCTTA

TGAAGACCCAAAAAAGGGTAAAGATCTAAAATTGCCAGAAAAGGCAAATACCCCAAAAAAGAATG

GACGAAAATGATCTAAAATCTGTAATTGAAAATTATGAAAATAAAATTAAAAACATAGAAAAGCTTTTAAAALACCA

AAAATCAAAAAACATCGG AGAAAAAAAATAATCGAAAAAAAAGCAAAAAAATATGAAATTTT

AACCAATAAATTAAAAAACGAAATAGTAGAAATAAAAAAGCTCCTTAACAAAAAAATCAAGCCTAAAGAAGATGAA

AATTACGAAATATTGAAATAGAAATGATGATGATTTTGAAGACAATTATGAATATAATG

AGAATGAGACATGGGCAATTACCCTTCATAGATATACAcTAAAALGAAAATCTTAAT GAAAACGAAAAATATTATGCTATTAATGAA AA AA AAATCGATGAACTTGAAGACAGAATCAACGAGAATGAAAACA

CTATTTTAGACTTGCAAAGAGAATTAAGGAATTTTAAAAAAAAAGATAACTCAGATAAAAACTTAGAAGAAATTGA

GGAAAATTTATCTTCATGAGAAT AGTTAAAAAGAAAAATCAGCGCAAATGAAGCAATAAACAAA ***GAAAAT'A A A AAA A AATAAGAAACAAAAACACCAGAAAATAAGAAAGAAGAGA *CTATTTTAAAACTT AAAADTACArrAAAAG.ATACAAAAACCCTTAA-ATGAAGAAAC

TTTCACTCCAAGCATTACAAGTAAAAATGACGACTTAGAAGAAAATAAGAAATTAAAAAAGGAATATTTAAAGCCC

ATAGAAAAAAAAGAAAGCCGAGATCTAGAAGAAAATACTAAAAGCACCCCAAAAACAACTATGATAAAALCAGCAG

ATTTTCAAATCTACCCTGACATATATCTTAATAATTATAAATTTAAAGAAAAGGGAGATCAATTTGCATTTAAAAA

ACAAAACACATACTATATTGAAATAGATCCCACTAACAATTTAAATGAGGCTTTAAAAAATCATGAAATAATCTCA

AAATATAAATTTGAAAAATATTTCATTAACCCTATTC AAATAGAATTTAGAAACTTAATAGAAG

TCAAAAATATCCACGAACTAGGAATTATGTATAAAA-ATCTAAAGCCTGAATTTAAGC~AAATAAAAATAATTAAATA

A

f867.aa MNTKGKVVGVNGNLVTIEVEGSVSMEVLFVKTAGRNLKAEVRIRGNEvDAQVFE-LTKGISVGDLVEFTDKLLTV

LGPGLLTQVYDGLQNPLPELAQCGFFLERGLRPLNDKWFKKTSIVGDIVTIAGDFLGFVIEGTVHHQIMI

PFYKMfSYKIVEIVSDGflYSIDEQIAVIEDDSGMRHNITMSFHWPVKVPITNYKERLIPSEPMLTQTRIIDTFFPV AKGGTFCIPGPFGAGKTVLQQV'rSRNADVDVVI rAACGERAGEVVETLKEFPELMrDPKTGKSLMDRTCI ICNTSSM

PVAESYATGYRMLILASSWQARKGLEPEAPYEVAFEAIV

NGDIGSVTVGGSVSPAGGNFEEPVTQATLKVGAFHGLTRRSDARFUPAISPLESWSKYKGIDQFTYASF

LVKGNEINQMThflVVGEEGISNDDFLIYLKSELLDSCYLQQSFDSIDAAVSSERQNYMFDIVYNILKTNFEFSDKL QARflFINELRQNLLDNLSSFKHFNCLEHALGELnIFKKVI t867 .aa GRNLKAEVIRIRGNEDAQVFELTKGISVGDLVEFTflKLLTVELGPGLLTQVYflGLQNPLPELAIQCGFFLF'V

LRPLNKKWNFKKTSKVG)IVIADFLGFVIEGTVHHQIMIPFYKRDSYKIVEIVSDGDYIDEQIAVIEDDSGM

RHNITMSFHWPVKVPITNYKELIPSEPMLTQTRITDTFFPVAKGGTFCIPGPFGAGKTVLQQVTSRNAI)DVII

AACGERAGEVVETLKEFPELMDPKTGKSLMflRTCIICNTSSMPVAAREASVYTAITIGFYYRQMGLDILLLADSTS

RWAQARMSGRLEEIPGEEAFPAYLESIASFYERAGILNNGDIGSVTVGGSVSPAGGNFEEPVI'QATLKVG

AFHGLTRERSDARKFPAISPLESWSKYKGVIDQKKTEYARSFLVKGNEINQMMKVVGEEGI

SNDDFLIYLKSELLD

WO 98/59071 PCT/US98/1271 8 174 TABLE 1. Nucleotide and Amino Acid Sequences

ELINKKVI

f867.nt ATGAAGTTTTATTTGTAAAGACTGCTGGTAGGAA TTAAGCAGAAGTAATTCGTATTAG TG GA TGCCGT TATTAAGGTTTGTTGGAGACCTAGTGAATTTACAGACCTTTACAGTT

CTGTAATTGAAGATGATTCTGGTATGAGGCATAATATTACATGTCTTTTCATTGGCCGTTAGTTCCTATTAC

TAATTATAAGGAACGCCTTATTCCTAGTGAACCTATGTTGACTCAAACTAGAATTATAGATACAT'rr'CCCAGTT GCAAGGAC TGATCGTCTTGGCGAAAGTCTACGTAAGCA TGGCGAGGAGGCTTTTCCGGCATATCTTGAGTCTGTTATrCCTTTTAAGCAGGTATGTAG.TTCTT

TTTATTAAAATCCGAGCTACTTGATTCGTGCTATTTGCAGCAAAATTCATTTGATTCTATTGATGCTGCTGTTAG

TTCAGAGCGTCAAAATTATATGTTTGATATAGTTTATAACATTCTTAAAACTAACTTTGAGTTTTCTGATAAACTT

CAAGCAGAGATTTTATAAATGAGTTAAGGCAAAATCTTTTAGACATGAATCTTTCTTCTTTTAAGGATCATAAGT

TTAATAA ATTGGAGCATGCTTTGGGTGAATTGATAAATTTTAAAAAGGTAATTTAG t867.nt

GGTAGGAATTTAAAAGCAGAAGTAATTCGTATTAGGGGCAATGAAGTTGATGCACAGGTTTTTGAATTGACAAAAG

OGAT

ATCTGTTGGAGACCTAGTTGAATTTACAGACAAACTTTTAACAGTTGAACTCGGACCAGGGCTTTAACTCAAGTA

TATGATGGGCTTCAAAATCCTTTGCCTGAATTGGCTATTCAATGTGGATTTTTTTTAGAGGGGAGTATATTTAA

GGCCCTTGAATAAAGATAAAAAGTGGAATTTTAAAAAAACCTCCAAAGTTGGAGATATCGTTATTGCAGGAGATTT

TTTAGGTTTTGTAATTGAGGGAACTGTTCACCATCATAATGATTCCATTTTATAAAGGGATTCTTATAAAATT

GTGGAGATTGTAAGTGATGGCGACTATTCGATTGATGAGCAATTGCTGTTGAGATGTTCTGGTATGAGGC

ATAATATTACAATGTCTTTTCATTGGCCTGTTAAGTTCCTATTACTAATTATAAGAACGCCTTATTCCTAGTGA

ACCTATGTTGACTCAAACTAGAATTATAGATACATTTTTCCCAGTTGCAAGGTGGAACTTTmGCATTCCGGGT

CCTTGGAGAACGTCTACGTAAATGATCGTTGAGATATTGA

GGGAGAAGGTAAATTAAGATCCGATATGTCAAACGA

AT*AGAAGCTGATTTT AACTCAGCGTCGCAAAGTCG A

ACGTTATTGTATTAAGAAGGCTGTTCTTTGCGTCATCAA

GGGCTCAAGCAATGAGAGAATGTCTGGACGCCTTAGGAA CCTCGGCTTTCCGGCATATCTTGA

GTCTGTTATTGCTTCCTTTTATGAAAGGGCAGGTATTGTAGTTCTTAATAATGGGGATAGATCTGTAACAGTT

GGTGGCTCTGTAAGTCCTGCTGGTGGTAATTTTGAAGAGCCAGTTACTCAAGCACTT'AAAGTTGTAGGAGCAT

TTCACGGGCTTACAAGAGAAAGGTCTGATGCTAGGAATTTCCAGCTATTAGTCCTCTTGATCTTGGAGTAAATA

TAAAGGCGTTATTGATCAAAAAAAGACTGAATATGCAAGATCTTTTTTGGTGAAGGTAATGATTAATCAAATG

ATGAAAGTTGTTGGAGAAGAAGGCATAAGTAACGATGATTTrTAATTTATTTAAATCCGAGCTACTTGATTCGT

GCTATTTGCAGCAAAATTCATTTGATTCTATTGATGCTGCTGTTAGTTCAGAGCGTCAAAATTATATGTTTGATAT

AGTTTATAACATTCTTAAACTAACTTTGAGTTTTCTGATAA.ACTTCAAGCAAGAGATTTTATAATGAGTTAAGG

CAAAATCTTTAGACATGAATCTTCTTCTTTTAAGGATCATAAGTTTAATAATTGGAGr-ATGCTTTGGGTGAAT

TGATAAATTTTAAAGGTATTTAG

WO 98/59071 PCTIUS98/1 2718 175 TABLE 1. Nucleotide and Amino Acid Sequences f868 .aa

MKVYSKIESAGNVTTVTAQGIKYGELAIVKAKDTSSLAEVIKLREKVSLQVYGGTRGVSTSDEIKFLGHSMQV

SFSDNLLGRIFDGSGNPRGGPSLDDNLIEIGGPSANPTKRIVPRNMhIRTGLPMIDVFNTLVESQKLPIFSVSGEP YNELLIRIALQAEDMLIILGMGLDYLTFSLEKGGALSRAIFFVHTAN1fSVVESLTVPDISLSVAEKFALK GKLVLLTDMTFAAMISITMEQVPSNRGYPGDLYSQLAYRYEKAIDFEGAGSITILAVTMPGDDVTHPp DNrGITEGQYYLKGGRIEPFGSLSLKQMVNSRTRI)ID1RTIMSMKLYASSKESVIA1GFNMTKWDEKLLxY S~ffESKMDLSIPLEEALDLGWSILASCFSPKETGIKTDLIEKYWPGKETY t868.aa

QGIKYGELAIVKAKD)TSSLAEVIKLDRBKVSLQVYGGTRGVSTSDEIKFLGHSMQVSFSDNLLGRIFI)GSGNPRDG

GPSLnDNLIEIGGPSANPTKRIVPRNMIRTGLPMIDVFNTLVESQKLPIFSVSGEPYNE-LLIRIALQAEVDLI ILG

GMGLDDYLTFSLEKGGALSRAIFVHTADSVESLTVPDISLSVAEKFALKGKVLVLLTDMNAAMKE

ISITMEQVPS-NRGYPGDLYSQLAYRYEKAIDFEGAGSITILAVTTMPGDDVTHPVPDNTGYITEGQYYLKGGRIEP

FGSLSRLKQMVNSRTRnDHRTIMDSMIYKLYASSXESVKKAMGFNMTKWDEKLLKYSNMFESKMDLSVNIPLEEA

LDLGWSILASCFSPKETGIKTDLIEKYWPKKETY

fBGB .nt

ATGAAAAGAGTCTATAGTAAAATAGAGTCTATAGCAGGCAATGTAATAACTGTTACAGCTCAAGGTATTAAGTATG

GTGAGCT'rGCTATTGTAAA.AGCAAAAGATACAAGTTCTCTAGCCGAAGTAATTAAACTTGATCGAGAAAAAGTTTC

TCTTCAGGTTTATGGTGGTACAAGAGGTGTTTCCACGTCAGACGAGATAAAGTTTTTAGGGCATTCAATGCAGGTT

TCATTTTCTGACAATTTGTrCGGCAGAATTTTTGATGGTTCTGGGAATCCTAGAGATGGGGGCCCTTCTCTTGATG

ATAATTTGATTGAAATTGGTGGGCCTTCTGCAAATCCTACAAAACGCATTGTTCCTAGAAATATGATAAGGACAGG

GCTTCCAATGATAGATGTTrTTTAATACTCTTGTTGAATCTCAAAAATTGCCAATrTTTTTCTGTTTCTGGTGAGCCT

*TATAATGAGCTTCTTATAAGAGCACTTCAAGCAAAGTTGATTTAATAATTCTTGGCGGAATGGGACTTAAGC

ATGATGATTATTTAACTTTTAAAGATTCTTTAGAAAAGGGAGGTGCTTTAAGTAGAGCAATTTTTTTTGTTCATAC

TGCTAATGATTCTGTTGTTGAATCTTTAACTGTTCCTGATATTTCACTTCTGTTGCTGAAAAGTTTGCTCTAAAG

GGCAAAAAAGTTTTGGTGCTCTCACAGACATGACAAATTTGCTGATGCAATGAAAGAAATATCTATTACAATGG

AACAAGTGCCTTCTATAGAGGTTATCCCGGGGATTTGTATTCTCAGCTTGCATATCGTTATGAGAAGGCTATTGA

CTTTGAAGGCGCAGGATCATAATCTCATAACAGCGGGTGACGATGTTACTCATCCTGTTCCT

GACAATACTGGATACATTACAGAAGGTCATACTATTrTAAAAGGTGGCAGAATAGAGCCr'r'rTGGGTCTCTTTCAA GACTTAAG7CAAATGGTAAATAGTAGAACTAGAGACGATCACAGGACTATAATGGATTCAATGATCAAGCTTTATGC

ATCTTCAAAAGAGTCTGTAGAAAAAAAGGCTATGGGATTTAATATGACTAAGTGGGATGAAAAATTGCTCAAGTAT

AGCAATATGTTTGAAAGTAAGATGATGGATTGTCTGTTAATATCCTTAGAAGAGGCTTTAGATTTAGGTTGGA

GCATTCTrGCTAGTTGTrTAGCCCAAAAGAAACGGGAATAAAAACAGATCTTrATTGAAAATATTGGCCTAAAAA

AGAGACTTATTGA

t868.aft

CAAGGTATTAAGTATGGTGAGCTTGCTATTAACAAGTCATTCTCTAGCCGAAGTAATTAAA.CTTG

ATCGAGAAAAAGT~TCTCTCAGGTTATGTGGTACAA-AGGTGTTrCCACGTCAGACGAGATAAAGTTTTTAGG

GCATTCAATGCAGGTCATTTCTGACAATTGTTGGGCAGAATTTGATGGTTCTGGGAATCCTAGAGATGGG'

GGCCCTTCTCTT GTATGTGATGTGGGCCTTCTGCAAATCCTACAAAACGCATTGTTCCTAGAA ATATGATAAGGACAGGGCTTCCAATGATAGATGTTrAATACTCTGTTGAATCTCAAAAAT1'GCCAATTTTTTC TGTTcTGGTGAGccTATAATAG~cTATAAGAATGcAcTCAAGCAGAAGTTGATTTAATAATCTTGGC GGAATGGGAC TACTAGTATAC~TAG TTCTTAGAAAAGGGAGGTGCTTTAAGTAGAGCAA TTrrTTGTTCATACTGCTAATGATTCTGTTGTTGAATCTTAACTGTTCCTGATATTTCACTrTCTGTTGCTGA

AAAGTTTGCTCTAAAGGGCAAAAAAGTTTTGGTGCTTCTCACAGACATGACAAATT-TTGCTGATGCAATGAAAGAA

ATATCTA~TTACAATGGAACAAGTGCCTTCTAATAGAGGTTATCCCGGGGATTTGTATTCTCAGCTTGCATATCGTT

ATGAGAA.GGCTATTGACTTTGAAGGCGCAGGATCAATTACAATACTTGCAGTTACAACAATGCCGGGTGACGATGT

TACTCATCCTGTTCCTGACAATACTGGATACATTACAGAAGGTCAATACTAmTAAAAGGTGGCAGAATAGAGCCT

TT'TGGGTCTCTTTCAAGACTTAAGCAAATGGTAAATAGTAGAACTAGAGACGATCACAGGACTATAA.TGGATTCAA

TGATcAAGC-TTTATGCATCTTCAAAAGAGTCTGTAGAAAAAAAGGCTATGGGATTTAATATGACTAAGTGGGATGA

AAAATTGCTCAAGTATAGCAATATGTTTGAAAGTAAGATGATGGATTTGTCTGTTAATATTCCTTAGAAGAGGCT

WO098/59071 PCTIUS98/1271 8 176 TABSLE 1. Nucleotide and Amino Acid Sequences

TTAGATTTAGGTTGGAGCATTCTTGCTAGTTGTTTAGCCCAAAGAAACGGAATAAAAACAGATCTTATTGAA.A

AATATTGGCCTAAAAAAGAGACTTATTGA

f872.a MSAVLFFFALPFSISLYSSSNKFPYWLLEKGRQFLYSKSEFSKSNLTHAINYLQEALLpRxGVYPEASYYLSVA

YGMSGNAILEKLNLYKSFEDRYYLLDESFEILFSLAKMAELENNTIDYLNDILNFSTI=YYSYHDYSQG

ENSMSNNELNASFYLTSYLKQVRGAFGID)FTFNLYRFIQTYNVIDTHQLLSKVYLHLKAYELSITHGLIAAVGILTR

MYDYVCYYEPVYQFLPSFVQKINKYKAIKNAFESTDFWEIVYNVAAATYAYSNGNYKRAIDTWKLVVDLAPRF

SPYIAKSRSQIKNSVYLXKN

t872.a SNINFPYWILLEKGRQFLYSKSEFSKSNLTHANLQEALLRKGVPASYYLSVAYGMSGNMILEKLNLYKSFE1)

RYYLLDESFEKICILFSLAKMAELENNYVDTIDYLNDILNKFSTKKDYYSYHDYSQGENSMS-NNELNASFYLTSYLK

QVRGAFGIDFTFNLYRFKNYNVIDTHQLLSKVYLHLKAYELS ITHGLIAAVGILTMYDYVCYYEPVYQFKNLRSF

VQKINKKAIKNAFESTDFWEIVYNVAAATYAYSNGNYKFRAIDTWKLVVDLAPRFSPYIAKSRSQIKNSVYLKKN

f872 .nt ATGAGAAGTGCGGTTTTATTTTTTTTTGCT'FrGCCTT CTATTTCTTTGTATTCTTCAAGTAATAAAAATTTTC

CGTATTGGAT=TTACTTGAAAAAGGCAGGCAATTTCTTTATTCTAAATCTGAATTTAGTAAGTCTAATCTTACACA

TGCTATTAATTATTTGCAGGAAGCTTTGCTTAGAAAAGGCGTTTATCCTGAGGCTAGTTATTATTTGTCAGTAGCT

*TATGGTATGTCTGGCAATGCTATTCTTGAAAAATTAAACCTTTATAAGTCTTTTGAAGACAGATATTATTTGCTAG

ATATTTGAAAA ATTTCTACAAAGCGATGGATATTTGT*A

*.TGATTATTTGALATGACATATTAAATAAGTTTTCAACTAAAAAAGATTATTATAGTTATCATGATTATTCTCAAGGC

GAAAACAGTATGTCAAATAATGAACTTAATGCTTCATTTATTT AACTTCTTATAAAACAAGTAAGAGGAGCTT TTGGTATTGATTTTACTTTTAATCTTTACAGATTTAAAACTACAATGTTrATTGATACTCATCAATTATTGTCAAA AGTTTATTTGrCACTTAAAAGCTTATGAGCTTTCAATTACTCATGGACTTATAGCTGCAGTAGGAATTTTAACAAGA

ATGTATGATTATGTTTGTTATTATGAACCTGTGTATCAGTTAAAAAT=TAAGGTCTTTTGTTCAAAAAATTAATA

o.0. AGTATAAGGCAATAAAAAATGCTr'=rGAATCTACAGATT=TTGGGAAATAGT'=TATAATGTTGCTGCTGCTACTTA

TGCATATTCTAATGGCAATATAAATTTAGAGCAATAGATACTTGGAAATTAGTAGTAGATCTTGCGCCAAGGTTT

TCTCCTTATATTGCTAAATCAAGAAGTCAA.ATTAAAAATTCTGTATATAAAAAAAAATTAA

0 *t872.nt o: AGTAATAAAAAT CCGTATTGGATTTTACTTGAAAAAGGCAGGCAATTTCT'=TATTCTAAATCTGAATTTAGTA 0 AGTCTAATCTTACACATGCTATTAATTATTTGCAGGAAGCTTTGCTTAGAAAAGGCGTTTATCCTGAGGCTAGTTA

TTATTTGTCAGTAGCTTATGGTATGTCTGGCAATGCTATTCTTGAAAAATTAAACCTTTATAALGTCTTTTGAAGAC

AGATATTATTTGCTAGATGAATCTTTaAA A AA TACTTITTTTT AGCTAAAATGGCTGAACTTGAGAATA ATTATGTTGATACTATTGATTA ATACTTAATATTCAACTAAAAAAGATTATTATAGTTATCA

TGPLTTATTCTCAAGGCGAAAACAGTATGTCAAATAATGAACT'IAATGCTTCATTTATTTAACTTCTTATAAAA

CAAGTAAGAGGAGCTTTTGGTATTGATTTTACTTTTAATCTTTACAGATrTAAAAACTACAATGTTATTGATACTC ATCAATTATTGTCAAAAGT=TAT=TGCACTTAAAAGCTTATGAGCT'rTCAATTACTCATGGACT'rATAGCTGCAGT AGGAATTTTAACAAGAATGTATGATTATGTTTGTTATTATGAACCTGTGTATCAG AAAAATTITAAGGTCTTTT

GTTAAATATATAAGC.TAAATCTGAATCTACAGATTTTGGGAAATAGTTTATAATG

TTGCTGCTGCTACTTATGCATATTCTAATGGATAAATTGGATG TTrGGAALATTAGTAGTAGA

TCTTGCGCCAAGGTTTCTCCTTATATTGCTAAATCAAGAAGTCAAATAAAAATITCTGTATATTTAAAAAAAAAT

TAA

f874 .aa MLKSNKVVLIGAGGVGSSFAYALTIDNSLVHELVI IDVNENKAKGEVMDLNHGQMFLKKNINVLFGTYKDCANAflI VVITAGLNQKPGETRLDLVDKNSKIFKDIITNVVSSGFDGIFVASNPVDIMTYVTM2KYSKFPIHKVIGTGTILDT

SRIJRYFLSDHFNVNTQNIHSYIMGEHXSSFATWDETKIAMKPLSEYLAEGKITELELDEIHKKVVNAAYEVIKLK

WO 98/59071 PCTiUS98/1271 8 177 TABLE 1. Nucleotide and Amino Acid Sequences GATYYAIGLGIIKJIVNAI IGDQNVILPI SSYINGQYGGLIKDIYIGAPAIVCKEGVEVLNFKISPKELDKFN~SSA NQLKSYIflKMEF t874 .aa ALTIDNSLVHELVIIDVNNAKGEVMLNHGQFLK~N~iVLFGTYCANADIVVITAGLNQKPGETLLVDK NSKIFKDIITNVSSGFDGIFVVASNPVDIMTYVTMKYSFPIHKVIGTGTILD'rSRLRYFLSDHFNVNTQNIHsy

IMGEHXD)SSFATWDETKIAMKPLSEYLAEGKITELELD-EIHKKVVNAAYEVIKLKGATYYAIGLGIKNIVNMIIGD

QNVILPISSYINGQYGGLIlIYIGAPAIVCKEGVKEVLNFKISPKELDKFNSSANQLKSyIKMEF f874 .nt ATGCTTAAGTCTAATAAAGTTGTTCTTATTGGAGCTGGTGGGGPrGGTTCAAGCTTTCGTATGCTTTAACAATAG ACAATTCACTTGTACATGAACT'rGTAATTATTGATGTTAATGAAAATAAAGCAAAAGGGGAGGTCATGGACCTTAA

TCATGGCCAAATGTTTTTAAGAGAATATTATGTATGTTTGGGACTTACAAAGATTGTGCTATGCAGATATT

GTTGTAATTACAGCAGGACTTAATCAAAAGCCTGGTGAGACAAGACTTGATTTGGTTGATAAAATTCTAAAATTT

TTAAAGATATTATAACTAATGTTGTATCTAGCGGTTTTGATGGTATTTTTGTTGTTGCAAGCAATCCTGTAGACAT

TATGACTTATGTTAC-AATGAAATATTCCAAATTTCCTATTCATAAGGTTATTGGTACTGGGACTATTCTTGATACT

TCAAGACTTAGATATTTTTTAAGTGATCATTTTAATGTGAACACTCAAAATATACATTCATATATrATGGGTGAGC

ACGTGACAGTTCTTTTGCTACGTGGGATGAAACAAAAATAGCAATGAAGCCTTTGTCAGAATATCTTGCTGAAGGC

AAAATAACTGAGTTGGAGCTTGATGAAATTCATAAAAAGGTTGTGAATGCTGCTTATGAAGTTATTAAGTTAAAGG

GGGCAACCTATTATGCTATTGGAC'ITGGTATTAAGAATATTGTAAATGCAATAATTGGAGATCAGAATGTTATTCT

GCCAATATCTTCTTATATTAATGGCCAGTATGCGGGGATTGA'ITAAAGATATTTATATTGGAGCGCCTGCTATAGTT

TGTAAGGAAGGAGTCAAAGAAGTTTTAA)ACTTTAAGATAAGCCCTAAAGAGCTTGATAAGTTTAATAGTTCTGCTA

ATCAGCTTAAAAGCTATATTGATAAAATGGAATTTTAG

t874'.nt

GCTTTAACAATAGACAATTCACTTGTACATGAACTTGTAATTATTGATGTTAATGAAAATAAAGCAAAAGGGGAGG

***TCATGGACCTTAATCATGGCCAAGTrTAAAGAATAGTATTGTTTGGGACTTACAAAGATTGTGC

TAATGCAGATATTGTTGTAATTACAGCAGGACTTAATCAAAAGCCTGGTGAGACAAGACTTGATTTGGTTGATAAA

AATTCTAAATTTTTAAAGATATTATAACTAATGTTGTATCTAGCGGTTTGATGGTATTTTTGTTGTTGCAAGCA

ATCCTGTAGACATTATGACTTATGTrACAATGAAATATTCCAAATTTCCTATTCATAAGGTTATTGGTACTGGGAC ****TATTCTTGATACTTCAAGACTTAGATATTTTTAAGTGATCATTTAATGTGAACACTCAAAA6TATACATTCATAT

ATTATGGGTGAGCACGTGACAGTTCTTTTGCTACGTGGGATGAAACAAATAGCAATGAAGCCTTTGTCAGAATA

TCTTGCTGAAGGCAAAATAACTGAGTTGGAGCTTGATGAAATTrATAAAAAGGTTGTGAATGCTGCTTATGAAGTT ATTAAGTTAAAGGGGGCAACCTATTATGCTATT'GGACTTGGTATTAAGAATATTGTAA6ATGCAATAATTGGAGATC

AGAATGTTATTCTGCCAATATCTTCTTATATTAATGGCCAGTATGGGGGATTGATTAAAGATATTTATATTGGAGC

GCCTGCTATAGTTTGTAAGGAAGGAGTCAAAGAAGTTTTAAACTTTAAGATAAGCCCTAAAGAGCTTGATAAGTTT

AATAG'PTCTGCTAATCAGCTTAAAAGCTATATTrGATAAAATGGAATTTTAG f886.aa

MKKKQLILLLFMPQIIYAKSYFASDVFFNKYQKLNEKPKTGFYIEYYSVDDTEKLYLYKENNLIKYKTIQIIENTK

KITCYflTKDTIKUxEEzYDNuNNxIQEIEYDSKGKTLETANVYNELISLKTNQKPKIYYSKDDNGKLLKI

TGSNFQIWNYGINGDIKSTYFDIKKATTKVIKYDDKRNSNSTIINKIKSKEKNQYLDEEKIVNTFEEENTKII

STYXAINNLIKEETYKNNELIKVDFQYNESDMIIFQNTK KDQyTNKIEYEYNKDNQLKSKKIYENDI IYLKT

EYNNEYEEEIYYNPALRVKHKGKVTEEKPIGTN

t886.aa

SYFASDVFFNKYQKLNEKPKTGFYIEYSVDDTEKLYLYKENNLIKKIQIIENTKKITCYDTYKDTKRKEEIDN

LNNXIQEIEYDSKGKTLETANYVYENENLISKNLTINQKPKLIYYSKDDNGKLLKITGSNFQIWNYGINGDIKST

YFDIKKATTKVIKYDDKXRN~SNSTI IVNNKIKSKEKNQYLDEEKIVNTFEEEN'rKI ISTYKANNLIKEETYKNNEL IKVNDFQYNESDMIIFQNTKEKDKDQYTNTKIEYEYNKDNQLKSKKIyENDI IYLKTEYHNDNEYEEEIYYNKCKPA

LRVKHKNGKVTEEKPIGTN

WO 98/59071 PCTIUS9812718 178 TABLE 1. Nucleotide and Amino Acid Sequences f 886. ant AGA A AA A ACAATTAATACT'rCTTCTATTTATGCCACAAATTATTTATGCAAAAAGCTATTTTGCATCTGATG TATTTTTCAATAAATACCAAAAATTAAATGAAAAACCAAAAACGGGGI'TTATATTGAGTATTATTCTGTrGATGA TACTGAAAAACTCTACCTATACAAAGAAAATAACTTAAATCAACA CATAAGAAAACACAAAA

AAATTGAATATGATAGCAAAGGAAAAACTCTTGAAACAGCAAATTACGTTTATGAAAACGAAAACTTAATATCTAA

AAATTTAAACAATAAACCAAAAACCAAAATTAATATATTATTCTAAAGACGACAATGGTAAATTACTAAAATA

ACAGGATCAAATTTCCAAATTTGGAACTATGGAATTAATGGCGACATAAAATCTACATATTTT-GACATCAAAAAG

CAACAACAAAAGTTATAAAATATGATGATAA.AAAAAGAAATTCAAACAGTACAATAATTGTTAATAATAAAATAAA

ATCCAAAGAAAAAAACCAATATTTAGATGAAGAAAATAGTAAATACCTTGAGAAGAGAATACAAAAATCATA

TCTACCTACAAGGCAAACAACCTATAAAGACTTAATAGAACTTATAAAAGTAAATGATTTTC

AATACAACGAATCTGATATGATAATTTTTCAAACACTAAAGAAAAGGATAAGACCAATACACCAATACTAAAT

TGAATACGAATATAACAAAGACAATCAATTAAAAAGCAAAAAAATTTATGAGAACGATATAATTTATCTAAAAACT

GAATACCACAATGACAATGAATATGAAGAAGAAATATACTACAATAAAAAACCTGCTCTTAGGGTAAAACACAAGA

ACGGAAAAGTCACCGAAGAAAAACCAATAGGAACAAAT'rAA t886.nt

AGCTATT'TTGCATCTGATGTATTTTTCAATAAATACCAAAAATTAAATGAAAAACCAAAAALCGGGGTTTTATATTG

AGTATTATTCTGTTGATGATACTGAAAACTCTACCTATACAAAGAAAATAACTTAATAAAATACAAAA CAATTCA AAT AAAACCAAAATCTTTATGATACAAAAGATACAAGA GAAA'TCGATAAT

TTAAATAACAAAATACAAGAAATTGAATATGATAGCAAAGGAAAAACTCTTGAAACAGCAAATTACGTTTATGAAA

ACGAAAACTTAATATCTAAAAATTTAAAAACAATAAACCAAAAACCAAAATTAATATATTATTCTAAAGACGACAA

9. TGGTAAATTACTAAAAATAACAGGATCAAATTTCCAAATTTGGAACTATGGAATTAATGGCGACATAAAATCTACA

TATTTTGACATCAAAAAGCAACAACAAAAGTTATAAATATGATGATAAAAAAAGAAATTCAAACAGTACAATAA

TTGTTAATAATAAAATAAAATCCAAAGAAAAAAACCAATATTTAGATGAAGAAAAAATAGTAAATACCTTTGAAGA

AGAGAATACAAAAATCATATCTACCTACAAGGCAAACAACCTAATTAAAGAAGAAACATATAAAAATAATGAACTT

***ATAAAAGTAAATGATTTTCAATACAACGAATCTGATATGATAATTTTTCAAAACACTAAAGAAAAGGATAAAGACC

AATACACCAATACTAAAATTGAATACGAATATAACAAAGACAATCAATTAAAAAGCAAAAAAATTTATGAGAACGA

TATAATTTATCTAAAAACTGAATACCACAATGACAATGAATATGAAGAAGAAATATACTACAALTAAAAAACCTGCT

9:...:CTTAGGGTAAAACACAAGAACGGAAAAGTCACCGAAGAAAAACCAATAGGAACAAATTAA f888.aa

NQDIIKTELEISKLKKEDKKLQNIITAEKHNTKTKIDELKKNIQNINNKQKKFAEYFNLKLKVKYKKIEEQ

9:...:TNISLNCEFFIREELFFINYIDLKKIENYYLLEISNITPEKIETKKAVFKTSSSVNEIADHITKYSLKEILGREF LKININVNNSDAKIYIEKFVSKGIYHDNIFDISKLPNKEIEIQITSANFENYSIKRTVKNADSI ILDIDLKRTI

SKKVSIKSNVQSKVFKKGIFMGETPIEIEKPENQDIILLKSKGYKDKFKLNKEEDQVEIEMIKTNKNP-LIDTRDK

FYVNLAVFTL ST IGAI FAGTLLNNSEVLYKITGNHF rNKRLTAEDVYMAKAEQMTATFLFGVGITLT IGSF IS LIT

HLVEYIKEANMGE

t888.aa SNIEYNFSYI INTKKEIDLKKGIEKQLDKIYDKITEHINNDDKSIIEDIYINQDIIKTELEISKLKKEMDKYKL

QNIITAKEKHNTKTKIDELKKNIQNINNKQKKFAEYFNNLKKLKVKYKKIEQTNISNLNKEFFIREELFFINYID

LKKIEN'IYLLEISNITPEKIETKKAVFKTSSSVNEIADHITKYSLKEILGREFLKININVKNNSDAKIYINEKFVS

KGIYHDNIFDISKLPNKEIEIQITSANFENYSIKRTVKNADSIILDIDLXRTISKKVS IKSNVQSKVFKKGIFMGE

TPIEIEKPENQDIILLKSKGYKKFKLINKEEDQVEIEMIKTNKNRIDTRDKFYVNLAVFTLSTIGAIFAGTLLN

NSEVLYKITGNHFINxRLTAEDVYMAKAEQMTATFLFGVGITLTIGSISLITHLVEYIKEANMGE f 888. nt WO 98/59071 PCT/US98/1 2718 179 TABLE 1. Nucleotide and Amino Acid Sequences ATGGAAAAGCT'rAAACTAAAGCTAGCAATACCATTGC ATT1AATTCAAAATTCAAAGTATA TTGAATACAATTTTTCC AACTATCAAAGAAATACTAAAAAAGGGTATTGAAAAACAATT GGACAAAATCTAGTAAACGAAAATAC TAGACAAGAGCATCATTGAAGACAT ITATATA

AATAAGTATATAAAAAGACTTAAAI'ACAATTAAAAAGAATGATAAAAAAATTCAAAACA

TAATAACCGCAAAAGAAAAGCATAACACCAAAACCAAAATTGATGAGCTAAAAATCATTACA

TAACAAAAAATTGAGATATTTACAATTAAAAACTAAATAAATAAAAAAACGAAGAGCAA

ACAAATATAT ATTATAATTTTATAAGAGAAGAATTATTTTTTATTAACATATTGATCTrAAAA AAATGAATTATATTrGCT~AATTACAACATCACTCCTGAGAAAATTGGACTAAAAAAGCGGTATTTAA

AACATCATCTTCTGTTAATGAAATTGCAGATCACATAACAAAATACAGCCTCAAAGAAATAFTGGGCAGAGAATTT

TTAAAATCAACATTAACGTCAAAAATAACTCGGATGCAAA.ATCCATG AAT1GTCAAGA

TCTATCACGATAATAT'TTGACATTCTAAACTCCAAAAAATTAAAAACACAAGTGCAAATTT

CGAAAACTATTCTATTAAAAGAACGGTAAAAAATGCAGACTC ATTAAATATTAAAAAGAACAATC TCTAAAAAAGTATCAATTAAAAGCAATGTACAATCTAAAGT?'TAAGATM TGAAACCCAA TTGAAAT'rGAAAAACCAGAAAATCAAGATATCATCTTGCTTAAATCTAAAGGATATAAAGATAA-ATTCAAGTTAAT AAATAAAGAAGAAGATCAAGTAGAAATAGAAAT AAAATAAAAAATTATCGACACAAGAGATAAA

TTTTATGTCATCTGGCCGTCT"IACATTAAGCACAATAGGAGCCATTTTTGCAGGAACATTGCTTAACAATTCAG

AGA TTAAACGCACACTTTATTAACAAAAGATTAACAGCAGAAGATGTTTATATGGCAAAAGC

GGAACAAATGACTGCAACATTTCTATTTGGAGTAGGAATCACTTTAACTATTGGAAGCTTTATCTCATTAATAACT

CATTTGAATTT AGACAAATATGGGAGAATAG t888 .nt

AGTAATATTGAATACAATTTTTCCTATATCATATCAAAAAATTGACCTAAAAAAGGGTATTGAAA

AACAATTGGACAAAATCTATGATAAAATAACAGAACATATAGTAAACAATGATGACAAGAGCATCATTGAAGACAT

TTATATAAATCAGTTAAAACGATTGAAATTA ATAAAAAAGGATAAAAAAAAACTT

CAAAACATAATAACCGCAAAAGAAAAGCATAACACCAAAACCAAAATTGATGAGCTTAAAAAAAATATTCAAAATA

*AGAGCAAACAAATATATCAATTTAAATAAGAATTTTTATAAGAGAAGAATTATTTTTTAT'AACTATATTGAT

CT AAAATGAArTATTGCTAGAAATTAGCAACATCACTCCTGAGAAAATTGAGACTAAAAAAGCGG TATTTAAAACATCATCTrCTGTTAATGAAATTGCAGATCACATAACAAAATACAGCCTCAAAGAAATATTGG7GCAG

AGAATTTTTAAAAATCAACATTAACGTCAAAAATAACTCGGATGCAAAATCTACATAAATGAAAAATTTGTTTCA

AAAGGAATCTATCACGATAATATTTTTGACATTTCTAAACTCCCAAACAAAGAAATTGAAATACAAATCACAAGTG

a: CAAATTTCGAAAACTATTCTATTAAAAGAACGGTAAAAAATGCAGACTCAATAATATTAGATATTGACTTAAAAAG AACAATCTCTAAAAAAGTTATrAGATTCACAGT1TAAAGAATAGGGA *.*ACCCCAATTGAAATTGAAAAACCAGAAAATCAAGATATCATCT'rGCTTAAATCTAAAGGATATAA6AGATAAATTCA AGTT AAAAAGAACAAGTAGAAATAGAAATGATAAAAACTAACAAAAATAGACTTATCGACACAAG CACCAAA AATGCTCACATCTATTTGGAGTAGGAATCACTTTAACTATTGGAAGCTTTATCTCA'TT

AATAACTCATATGAAATAAAGAAAGGGAGAATAG

f893.aa

MVRFLGFLYLITTIPLIKSCDAAQFGDYKPLYFENEDLKTANEYINSLGYKTISEYTTKIDILDFPENXEITINE

INlLDLRSFLKLSNLFNIEKKLLYVERFKSINFKNLKKELNINAflIHSLDYKTKNFISSIIFLIIII LLIFLDPTNSIFTLIFLLISSLAFMISKEIMYFPFI9LSYLLFLIISNFNKIYLKEINFLTLMTKIKLLF

LFTFTALYFITITTFFTTNIDPTFIAFVAIPTLCIFLIFSWIKTESNFKTFLFPIEIEKKIEGKKAJKSKIAIH

LLLFTLSLIPFAYSSYLNSYENINYLYSKKLNYFDYLNPNNIYIMLGYNKDMPNIIGYLSHILYQNEJKYNITAK

YGIKIEYEKDIIPTYVKFDIKDALLNUI~K~_NNDKYIF

FSLPFFVLLFLFKAIRFTILLNIN

EKTYKKYIQG

t893.a CDAAQFGDYKPLYFENENflLKTANYINSLGYKTISEYTTKIDILDFPENKEITINEINKLNNLDLRKSIFLKKLS NLFNIEHKKLLYVENRFKSINFKNLKKELNINADIHSLDYKTKINFISSIIFLII

IILLIFLDPTNSIFTLIIFLLI

WO 98/59071 PCT/US98/12718 180 TABLE 1. Nucleotide and Amino Acid Sequences SSLAFMISKEIMYFYPFTVLSYJLFLIISINKIYLKENLTLMKIKLLFLFTFTALYFITITTFFTrTN IDP'rFIAFVAIPTLCIFLIFSWIKTESNFKDTFLFPIEIKEKKIEGKKALKSKIAILLLFTLSLIPFAYSSYMLN SYMInLYSKKLNYFDYLNPIYIMGYKDMPNIIGYLSHILYQNELKYNITAKyGKI PKIKYFE-I=K IEIHPKTVYEVDKSFIDEILKDLASLFUKPILIYKNNINTDKIUYIcLFFFSLPFFVLLFLFKAIRFTI

LLNINECTYKKYIQG

f8.93 .nt ATGGTGCGTTTTTTAGGT ~rAATATAACAACACTTATCAAATCCTGTGATGCAGCTCAATTTG

GAGACTACAAACCTTTATACTTTGAAATGAAAATGATCTAAAAACTGCCAATGAATATATAAATTCACTAGGATA

CAAACAATCTCAGAATACACAACAAAAATTGACATTTTAGACTTTCCCGAAAATAAAGAAATCACAATAAATGAG

ATAAACAAACTTAACAATCTTGACCTGAGAAAAAGCATATTTTITAAAAAAGCTCTCCAATCTTTTCAACATAGAGC

ACAAA.AAACTTCTTTATGTTGAAAACAGGTTTAAGAAATTAAACTAAAAAAAGAACTCAATATTAA

TGCCGACATACATTCTCTTGACTACAAAACAAAAATTAATTTTATTTCAAGCATAATATTTCTAATCATAATAATT

TTATTAATTTTTTTAGACCCAACAAACTCTATATTTACTTTAATTTTTCATTAATTTCATCTCTTGCTTTTATGA

TAAGCAAGAAATAATGTATTTTTATCCATTTACAGTTCTCTCTTATTTGTTATTTpTAATAATCAGTAATTTAA

CAAAAATTACAATAAAATATATTTAAAAGAAATAAATTTTTTAACACTAATGACAAAAATAAACACTTACTATTT

TTATTTACATTCACAGCTCTATATTTCATTACAATCACAACCTTTTTTACTACAATATTGATCCCACTTTTATTG

CATTTGTCGCAATACCAACCCTT'rGCATTTTCTTAATTTTCAGCTGGATAAACAGAAAGCAATTTTAAAGACAC TTTCTTrATTCCCAATCGAATAAAATGAG)AGTTTAAATCAAAAAxrAGCAATACAT

CTACTACTATTTACACTCTCATTAATTCCTTTCGCTTATTCAAGCTATATGCTAAATTCTTATGAAAACAT.TAACT

ACCTTTACAGTAAAAAATTAAATTACTTTGATTATTTAAATCCTAATAACATTTATATAATGCTGGGATACAACAA

AGACATGCCCAATATTATAGGGTACCTATCCCACATTCTTTATCAA.AACGAACTAAAATACAA.TATTACCGCTAAG

TATGGAAAAATTCCTAAAGATATAAAAGAAAATTACTTTGAAATCAAAAACGACAAAATAGAAATTCATCCTAAAA

9.9 CTGTTTACGAAGTAGACAAATCATT'rATTGATGAAATTCTTAAAAAAGATCTTGC.AAGTCTGTTTTTAAAAAATAA 0AAATCCAATCCTATTTAGAACAATAACAACACAGATAAAAAAAATTACAAAATACTTTTCTTT :000*, TTCTCTTTGCCCTTCTTTGTATTACTATTCCTATTTAAGCATAAGATTTACAATTCTTTTAAACATAAATGAAA

AAACCTATAAAAAATATATTCAAGGATAA

t893.nt

TGTGATGCAGCTCAATTTGGAGACTACAAACCTTTATACTTTGAAAATGAAAATGATCTAAAAACTGCCAATGA-AT

ATATAAATTCACTAGGATACAAAACAATCTCAGAATACACAACAAAAAT'rGACATrTAGACTTTCCCGAAAATAA 0 AGAAATCACAATAAATGAGATAAACAAACTTAACAATCTTGACCTGAGAAAAAGC-ATATTTTTAAAAAAGCTCTCC 9; 0, AATCTTTTCAACATAGAGCACAAAAAACTTCTTTATGTTGAAAACAGGTDTAAAAGTATAAATTTTAAAAACCTAA AAAAAGAACTCAATATTAATGCCG7ACATACATTCTCTTGACTACAAAACAAAAATTAATTTTATT.TCAAGCATAAT ATTTCTAATCATAATAATTrATTAATTTTTAGACCCAACAACTCTATATTACTTTAATTTTCTATTAATT TCATCTCTTGCTTTTATGATAAGCAAAGAAATAATGTATTTTTATCCATTTACAGTTCTCTCTTATTTGTTATTTr TAATAATCAGTAATTTT AAAATCAAA.AATTAAAAGAAkATAAATTTTTTAACACTAATGACAAA

AATAAAACACTTACTATT'TTTATTTACATTCACAGCTCTATATTTCATTACAATCACAACCTTTTTTACTACAAAT

ATTGATCCCACTTTTrATTGCATTTGTCGCAATACCAACCCTTTGCAT"TTrCTAATTCAGCTGGATAAAAACAG AAAGCAATTTITAAAGACACTTTCTTATTCCCAATCAATAGGAAAAAAGAAAACTTTAA6A -*soATCAAAAATAGCAATACATCTACTACTATTTACACTCTCATTAATTCCT''rCGCTTATTCAAGCTATATGCTAAAT TCTTATGAAAAC-ATTAAcTACCTTTAcAGTAAAAAATTAAATTAcTTTGATTATTTAAATCCTAATAACATT'rATA

TAATGCTGGGATACAACAAAGACATGCCCAATATTATAGGGTACCTATCCCACATTCTTTATCAAAACGAACTAAA

ATACAATATTACCGCTAAGTATGGAAAAATTCCTAAAGATATAAAAGAAAATTACTTTGAAATCAAAAACGACAAA

ATAGAAATTCATCCTAAAACTGTTTACGAAGTAGACAAATCATTTGTAATCTAAAACTGCAA

GTCTGTTTTTAAAAAAAAAATCCAATCCTTAAAAACGATTTACCGTAAAA

TTACAAAATACTTTTCTTTTTCTCTTTGCCC?1'CTTTGTATTACTATTCCTATTTAAGCAA.TAAGATTTACAATT

CTTTAAACATAAATGAAAAAACCTATAAAAAATATATTCAAGGATAA,

f895.aa

MIRALLTND)LFLSCLVSGISAQVIKYGIQTVKTRKLKLTPVHLLKKIFLETGGMPSSHSSTVTALSTSIALTEGID

TNFIIALAFALITIRDSFGVRYMSGVQAEYLNALSEKLKKEIKIDTTKKVVKGHKKKEVLTGI IIGIVSAYIVCY WO 98/59071 PCTIUS98fl27I8 181 TABLE 1. Nucleotide and Amino Acid Sequences t895 .aa AQVIKYGIQTVKTRKLKLTPVHLLKKIFLETGGMPSSHSSTVTALSTSIALTEGID)TNFIIALAFALUTRISFGv RYMSGVQAELNALSEKKEIKIDTT'KIKvKGCKKKETGII IGIVSAYIVCYF f895 .nt ATGATAAGGGCATTGCTTACCAATGATCTTTTTTTGTCT'rGTCTTGTATCAGGAATT'rCTGCTCAAGTGATTAAAT ATGGTATCCAAACTGTACAAA? AATAACTCCAGTACATCTTTTAAAAAAAATTTTTCTAGAAAC

AGGAGGCATGCCAAGTAGTCATTCATCAACGGTCACCGCTCTTTCAACCTCAATCGCACTAACTGAAGGAATAGAT

ACAATTTTATAATAGCTCTTGCATTGCCCTATTACAATAAGAGATTCTTTCGGCGTAAGATATATGTCTGGAG

TTCAAGCAGAATATTTAAGATTAAAATAAAAAAAGAATAATGCCAAAAAAAAGT

GGTCAAGGGGCACAAAAAGAAAGAGGTT1CTAACGGGCATAATAATAGGAATAGTCTCTGCGTATATTGTGTGCTAT T'rTTAG t895 .nt

GCTCAAGTGATTAAATATGGTATCCAAACTGTAAAACAAGAAAGTTAAAACTAACTCCAGTACATCTTTTAAAAA

AAATTTTTCTAGAAACAGGAGGCATGCCAAGTAGTCATTCATCAACGGTCACCGCTCTTTCAACCTCAATCGCACT

AACTGAAGGAATAGATACAAATTTTATAATAGCTCTTGCATTTGCCCTTATTACAATAAGAGATTCTTTCGGCGTA

AGATATATGTCTGGAGTTCAAGCAGAATATTTAAATGCATTATCAGAAAATTAAAAAAAGAkA.TAAAAATTGACA

CAACAAAAATAAAAGTGGTCAAGGGGCACAAAAAGAAAGAGGTTCTAACGGGCATAATAA.TAGGAATAGTCTCTGC

GTATATTGTGTGCTATTTTTAG

f605.aa 0@ Se MYIGAAGKSFSI IIDSAFLSNCFLFIGSFSRSDSLMSLSNSRFEYPYDASCEFSLVNIVKYVCGSKYSPMRPTLII

SKLPVFLLLVRTGQFSLVSIRLIFRIFFHWFZ

t605.aa CFLFIGSFSRSDSLMSLSNSRFEY PYDASCEFSLVNIVKYVCGSKYSPMRPTLI ISKLPVFLLLVRTGQFSLVSIR OSSO *LIFR.IFFHWFZ .f605.nt ATGTATATTG GTGCAGCAGGAATCTTTTTCAA'rrATTATGATTCTGCTTTCTGAGTAATTGTTTTCTTTTTA

TAGGATCTTTTTCAAGATCTGATTCTCTGATGAGTTTGTCAAATTCTAGGTTTGAATATCCGTATGATGCAAGTTG

0:906:TGATrTTTCTCTGTGAATATAGTAAAGTATGTGTGTGGATCTAAATATCCCCAATGCGTCCAACTCTTATTATT

TCAAAATTGCCAGTATTTCTGCTGTTGGTAAGAACAGGCCAATTTTCGTTGGTAAGCATAAGATTGATATTTAGAA

.5.59 TTTTTTTC1"CATTGGTTTTGA to t605.nt *TGTTi-cTTTTTATAGGATcTTTCAAGATCTGATTCTCTGATGAGTTGTCAAATTCTAGGTTTGAATATCCGT

ATGATGCAAGTTGTGAATTTTCTCTGTGAATATAGTAAAGTATGTGTGTGGATCTAAATATTCCCCAATGCGTCC

AACTCTTATTATTTCAAAATTGCCAGTATTrCTGCTGTGGTAAGAACAGGCCAATTTTCGTTGGTAAGCATAAGA TTGATATTTAGAATTrTCCATTGGTT1'TGA f6O6.aa MKLQRSLFLIIFFLTFLCCNNERKEGVSFKISLGAEPSSLDPQLAEDNVASKMIDTmFRGIVTGDPNTGGNKPGL AKGWDISSDGTVYTFNLREKITWSDGVAITAEGIRKSYLRILNKE-TGSKYVEMVKSVIKGQKYFlGQVTDSELGI RAIDEKTLEITLESPKPYFIDMLVHQSFIPVPVHVEKYGQNWTSPENMvTSGPFKLKERI PNEKYVFEKNNKYYD SNEVELEEITFYTrTNDSsTAYKMYENEELDAIFGSIPPDLIKNLKLRsDYYSSAVNAIYFYAFNTHIKPLDNVKIR

KALTLAIDRETLTYKVLDNGTTPTRRATPNFSSYSYAKSLELFNPEIAKTLLAEAGYPNGNGFPILKLKYNTNAN

WO 98/59071 PCTIUS98/12718 182 TABLE 1. Nucleotide and Amino Acid Sequences

KKICEFIQNQWKKNLNIDVELENEEWTTYLNTKANGNYEIARAGWIGDYAPLTFLSIFTQGYTQFSSHNYSNPEY

NELIKKSDLELDPIKRQDLRQAEEIII=FPIAPIYIYGNSYLFRDKWTGWNTNILERFI)LSQLxiLcNKZ t606.a

CCNMKGSKSGESLPLENAKIDMRITDNGNPLKWISGVTN

REKITWSDGVAITAEGIRSYLRLNKETGSKVKSVKGQKYFGQVTDSELGIRAIDEKTLEITLESPKP

YFIDMLVHQSFI PVPVHTEKYGQNWTSPENMTSGPFKLKERIPNVFEKNYYDSNEVELEETFY'r'pDS STAYNMYENET.AIFGSIPPDLINiLKLRSDYYSSAVNAIYFYAFNTHIKPLDNVKIRKALTLAIDRETLTYKVL DNGTTrPTRRATPNFSSYSYAKSLELFNPEIAKTLLAEAGYPNGNGFP

ILKLKYNNEANKICEFIQNQWI<,JLNI

DVELEEEWTTYILNTKANGNYEIARAGWIGDYAPLTFLSIFTQGYTQFSSHNYSNPEYNELIKKSDLELDPIKRQ

DILRQAEEII IEKDFPIAPIYIYGNSYLFRNDK~'rGWNTNILERFDLSQLKLKNKZ f606 .nt

ATGAATTACAAGGTCATTATTTTTAATAATATTTTTTCAACTTTTCTTTGTTGTAATAACAAGGAAAGAAA.AG

AAGGAGTATCATTTAAAATAAGCTTGGGAGCAGAGCCAAGCAGTCTTGACCCTCAATTAGCAGAGGATAATGTCGC

ATCAAAATGATTGACACAATGTTTAGAGGGATTGTTACAGGAGATCCTAATACAGGGGGATACCGGGACTT

GCAAAAGGGTGGGATATTTCTTCTGATGGAACAGTTTACACATTTAACCTAAGAGAAAAAATCACTTGGAGTGACG

GAGTTGCAATCACTGCAGAAGGAATTAGAAAATCTTATCTTAGAATTTTAATAAAGAAACTGGCTCAAAGTACGT

TGATGTATGTATAATGCAATATTAGAAGGCGCCGATGAT

AGAGCGATTGATGAAAAAACATTAGAAATAACACTGGAATCACCAAAACCTTATTTTATTGATATGTTAGTACACC

AATCATTTATTCCAGTACCAGTTCATGTTACCGAAGTATGGACAACTGGACAGCCCCGAACATGGTGAC

AAGTGGTCCTTTTAAATTAAAAGAAAGAATTCCTAACGAAAAPATATGTCTTTGAAAAAAATAACAAATACTACGAC

TCAAATGA.AGTAGAATTAGAAGAGATTACATTTTACACAACAAATGACAGCTCAACAGCGTATAAAATGTATGAAA

*ATGAAGAGCTAGATGCAATTTTTGGTTCCATACCCCCAGATCTAATCATCTAATTAGAGCGACTATTA

CTCATCAGCTGTTAATGCCATATACTTTTACGCGTTCAATACACACATCAAACCACTTGACAACGTTAAAATTAGA

AAAGCCTTAACTCTTGCTATTGACAGAGAAACGCTTACATATAAAGTTCTTGACAACGGGACTACCCCTACAAGAA

::TCTAGCTGAAGCTGGATATCCTAATGGCAATGGATTTCCAATTTTAAAATTAAAATACAATAI;AAACGAAGCAAAT

AAAAAAATTTGTGAATTTATTCAAACCAATGGAAAAAAAATTTAAATATTGATGTGGAACTTGAAAACGAAGAAT

GGACAACATACTTAAACACTAAGGC.AAATGGAAATTAG) ACAACGAGGATAGGCGATTATGCTGA TCCTTTGACATTTTTAAGCATATrCACACAAGGATACACACAATTCTCATCTCATAATTACTCAAACCCAGAATAC

AACGAACTTATAAAGAAATCCGACCTTGAGCTTGATCCAATAAAAAGACAAGACATTTTAAGACAAGCAGAAGAGA

TAATTATTGAAAAAGATTTTCCAATAGCACCAATATACATATATGGGAACAGTTACCTTTTCAGAAATGACAAATG

GACAGGGTGGAACACCAATATTTTAGAAAGATTTGATTTATCTCAGCTAAATTAAAAAATAAATAA

t606 .nt TGTTGTAATAACAAGGAAAGAAAAGAAGGAGTATCATTTAAAATAAGC'rTGGGAGCAGAGCCAAGCAGTCTTGACC

CTATACGGAATTGACAATATGCCAGTAAGATTAAGGTCA

*:TACAGGGGGAAATAAACCGGGACTTGCAAAAGGGTGGGATTTTCTTCTGATGGAACAGTTTACACATTTAACCTA

AGAGAAAAAATCACTTGGAGTGACGGAGTTGCAATCACTGCAGAAGGAATTAGAAATCTTATCTTAGAATTTTAA

ATAAAGAAACTGGCTCAAAGTACGTTGAAATGGTTAAATCGGTAATTAAATGGTCAAAAATATTTTGATGGACA

AGTGACTGACTCTGAACTTGGAATTAGAGCGATGTAAACTTGATAATGCAATCACCAAAACCT

TAT'rTTATTGATATGTTAGTACACCAATCATTTATTCCAGTACCAGTCATGTTACCGAAAAGTATGGACAAACT

GGACAAGCCCCGAAAACATGGTGACAAGTGGTCCTTTTAAATTAAAAGAAAGAATTCCTAACGAAAAATATGTCTT

TGAAAAAAATAACAAATACTACGACTCAAATGAAGTAGAATTAAGGTAATTrCCAAAG C

TCAACAGCGTATAAATGTATGAAAATGAAGAGCTAGATGCAAT'N'TTGGTTCCATACCCCCAGATCTAATCAAAA

ATCTAAAATTAAGAAGCGACTATTACTCATCAGCTGTTAATGCr-ATATACTI'TTACGCGTTCAATACACACATCAA

ACCACTTGACAACGTTAAAATTAGAAALAGCCTTAACTCTTGCTATTGACAGAGAAACGCTTACATATAAAGTTCTT

GACAACGGGAC

T

rACCCCTACAAGAAGAGCAACTCCCAACTTTAGTTCATATTCTTATGCAAAGTTTAGAATTAT

TTAATCCTGAAATTGCAAAAACCCTTCTAGCTGAAGCTGGATATCCTAATGGCAATGGATTTCCAATTTTAAAATT

AAAATACAATACAAACGAAGCAAATAAAAAAATTTGTGAATTTATTCAAAACCAATGGAAAAAATTTAAATATT

GATGTGGAACTTGAAAACGAAGAATGGACAACATACTTAAACACTAAGGCAAATGGAAATTATGAAATAGCAAGAG

CAGGATGGATAGGCGATTATGCTGATCCTTTGACATTTTTAA.GCATALTTCACACAAGGATACACACAATTCTC-ATC

WO 98/59071 PCTJUS98/12718 183 TABLE 1. Nucleotide and Amino Acid Sequences TCATAAT'rACTCAAACCCAGAATACAACGAACTTATAAAGAAA TCCGACCTTGAGCTTGATCCAATAAAAAGACAA

GACTTTAAGCAACAGAGAATATTATGAAAAAGATTTTCCAATAGCACCAATATACATATATGGGAACA

GTTACC TTAAAGC~AGAAGTGGAACACCAATATTTTAGAAAGATTTGATTTATCTCAGCTAAA

ATTAAAAAATAAATAA

f679.aa M'NSSCVLQN7LFLFLFLSLVSCFAIISGNNFIKAHSKEFDLNNLNWLWNFYTKKNFKHFNIDPSSYIVA YLFKKIGFEEI±IEYM KATAGDSIASQFAGIKLIEYFNSAKYASELIGEKLYKKYENNKFIILGYFKSLYWQ KDKALSLLNKJDK4KFSDYQENEILLKAVLYLNLSNVSESKIYNLFENLPANYUWRAYDYFI IENKSRYF GANFLLVFKyANGNNGAINILNGLNYYDNNSDVYKAFISSGKVSNALTFFSKIKSKYNYYLGIL NLRElaNLGLLLLKEYLEGLDLNNEINRLDLLNTAFSNLIFTKSARDYFAESLPKFYTEGIDKKNSTBIKILEEYIL

ESIQLEDYGLYKLYSNAQKISNLSKLAFINARIYHKLIKPNVSGEYKSLLHSAVNYDKWSYSSFMSRYLLD

QNIDEFFTGGSDIKYEQSDYEIFLEGFLKFNLCNYVRGFISEDFRNGYKFSLDFYK ELLKSN ATLVIN YLVNQDESALMNDYKLYPYLYGSLIEYWAKRRGLEASVVFSLIKAESSFEKAVSKPGAVGLMQVMPSTANDI S

KELKYFNYDLKIPKD)NIIIGTYLKKRISTTGSLYJAYGGIGNVRKWEXSYGHLSKELFIEAIPFSQTRNYI

KKILVYSVFYDALYEKKGIDSV =KIMGEFPKNZ t679.aa

CFAKEISGNNFIKAHSKEFDLNNLNLWNFDYTKKNF'DIKHNIDPSSYIYVAYLFKKIGFEEKFVEYMKKAIANG

DSIASQFAGIKLIEYFNSAKEYFASELIGEKLYKKYENNKFI ILGYFKSLYWQKKNDKALSLLNKLDKI4KFSDYQE NENILLKAVLYLNLSNVSESKIYFNELFENLPANYLHVRAYDYFI IENKSRYFGANFLNLVRFKYEVANGNFNGAI NILNKGLNDYYDNIVLSDVYKAFISSGKVSNALTFFSKIKSKYNYYLGILNLREI NLGLLLLKEYLEGLDLN 00* NSVLSKLAFINARLIYHKLIKPNVSGEYSLLHSAVNYDKWSYSSFMSRYLLDQNIDEFFTGGSDIKYEQSDYEIF LEGFLKFNLCN'iVRGFISEDFRNGYKFSLDFYRKVYDELLKSENYEDATLVINYLVNQDESALMENDYKRLYPYLY GSLIIYWAKRRGLEASVVFSLIKAESSFEKIAVSKPGAVGLMQVMP STANDISKELKYFNYDLKIPKDNII IGTY-Y

LKRISTTGSLYKALASYNGGIGNVRKWEKSYGLSKELFIEAIPFSQTRNYIKILVYSVFYDALYEIGIDV

VKIMGEFPKNZ

f679 .nt ATGTTTAATAGAAGTTCTGTGTATACAAAATTTTCTT'rTTCTTTTTTTATTTTAAGTTTAGTTTCTTGCTTTG CAAAAAAAGAA.ATCTCAGGcAATAATTTTATTAAGGCGCA1rCAAAAGAGTTTGATTTAAATAATTTAAAT'rGGTT ATGGATTTTGATTC A TGTA TrTAACATAGATCCAAGTTCTTACATATATGTTGCT

TATTATTAAAAAAAGGTGAAGAGAAATTTGTAGAGTATATGAAAAAGGCCATAGCTAATGGAGATAGCA

0 TTGCATCCCAGTTTrGCTGGGATTAAGCTTATTGAATATTTTAACTCAGCAAAAGAGTATTTTGCATCTGAATTGAT

TGGAGAGAAGCTTTATAAAAATACGAATAAATTTAATGGGGTACTTAAAGTCTTTATTGCA

AAGAAAAACGATAAGGCACTTAGTCTTTTAAATAAGCTTGATAAGATGAAATTTTCTGATTATCAGGA~AATGAA

ATATTTTATTAAAAGCAGTTCTTACCTTAATCTTCTAATGTAAGTGAGTCAAAATTTATTTTAATG 'TT TGAGAACTTACCTGCAAATAACATGTAAGAGCTATGATTATTTATTATTGAAAATAAGTCTAGGTATrT (GGTGCAAATTTTTTAAATCTTGTTAGATTAAGTATGAAGTGGCAAATrGGCAATTTAATGGTGCAATAAATATAT TAAAAAAATGGTTAATATT~rATACAAAACA~GTATAAT ATAAGTTATcTIATTC TGGCAAAGTTTCAAATGC LACTTTTGAATAACATATAAAATTATTATTTAGGTATrTCTA AACC TTGAAAATTAGCCTTCTTAAAGAATATCTTGAAGGTTTAGATCTTAACA-TGAGA TTAAGTGLTGTATCG

TAGGGAGGTATTCG

AAGTTTACCCAAGTTTATACCGAGGGCGATAAAAAAAATTCTACTTTTATTAAGATTTTrAGAAGAGTATATTTTG GAA~AATcAG~rGAGATATGGCAATCTTTATAAGCTrTTATTCTAATGCTcAAAAAGTTATTTCTATCTG TTTGTCTAAGCTTrGCTTTTATTAATGCAAGGCTTATATATCATAAATTAATTAAACCTAACGTAAGCGGAGAATA CAAGAGTCTTTTGCATTCTGC GrATTAAAGTTTATTCTTCATTTATGAGTAGGTACTTATTAGAT

CAAAATTATGATTTTTAAGGGGGCTGATATTAAGTATGAGCAATCCGATTATGAGATTTT'ITGGAG

GGTTTTTAAAATT~CAATCTTTGTAATTATGTTAGAGGGTTTATTTCTGAGrATTDTTAGGAATGGATATAAATTTTC ACTTGATTTTTATcGAAAAGTATACGATGAACTTTTAAAGAGTGAAAATTATTACGATGCAACTCTTGTGATTAAT

TATCTTGTAAATCAAGATGAATCTGCTTTAATGGAGAATGACTATAAAAGACTTTATCCTTATTTGTATGGATCTT

TGATAGAATATTGGGCTAAAAGGAGAGGGCTTGAAGCTAGTGTTGTATTTTCTTTAATAAAAGCAGAGAGTAGCTT

WO 98/59071 WO 9859071PCTIUS98112713 TABLE 1. Nucleotide and Amino Acid Sequences

TCAAAAGTTTAAACGTCGTGCTAGAGTTCACAACATAATC

AAGATAGATTATTATAAATCAAGTAAATATG~AATTTAA

AAGAACAACGCGCTAAGCCTGGCTTAGGGATGATTAAAT

GGGAATAGAATGCAAACTTATGGCATCTTGCACAGATTT

AAAATTATTTCGATTTAGTTGAGAAAGGAAATATAATAA

TTATGGGCGAATTCCCCAAAAATTAA

t679 .nt TTTG ±rCA AA A AA AACCGCAATTTTAGCCTCAAAGTGTTATAT

ATGTAGATTGTAAAAAAATTGTACTTACTGTCATCTCTT

TGTCTTTTTAAATGATGAAAATTTGGAAGAAGCAACATG

GATAGCATTGCATCCCAGTTTGCTGGGATTAAGCTTATTGAATATTAACTCAGCAGGTATTCTCTG

AATTGATTGGAGAGAAGCTTTATAAAAATACGAAATAATAAATTTATATACTGGGGTACTTTAAGTCTTTA

TTGGCAAAGAAAAACGATAAGGCACTTAGTCT'TTAAATAAGCTTGATAAGATGAAATTTTCTGATTATCAGA

AATGAAAATATTTTATTAAAAGCAGTTCTTTACCTAATCTTCTAATGTAGTGAGTAATTTATTTTAATG

AGTTTAACTCTCATATAAGAGGTAGTATTTATAAAAGCA

GTTTGTCATTTAACTTAATAATTAGGCATGATTATGGAT

AATATATTAAATAAAAATGGTTTAAATGATTATTATGACAATAACATTGTATTAGTGATGTTATGCTrTA TTGTTGAATTAAGTTACTTTATAA

TTG

TATTCTAAACCTTAGAGAGAAAATAATTTAGGACTTCTTCTTTTAAGAATATCT'GAGTTTAGATCTTAAC

AATGAGATTAACAGGCTTGATTTGCTTAATACTGCTTTTAGATTAATTTTTACTAGAGCGA-GGGTTATT

TTGCCGAAAGTTTACCCAAGTTTTATACCGAGGGCGATAAAAAAAATTCTACTTTTATTAAGATTTTAGAAGAGTA

TATTTTGGAATCAATTCAGCTTGAAGACTATGGCATCTTTATAAGCTrTATTCTTGCTAAGTTATTTCT

AATTCTGTTTTGTCTAAGCTTGCTTTTATTAATGCAAGGCTTATATATCATAAATTAATTAAACCTAACGTAAGCG

GAGAATACAAGAGTCTTTTGCATTCTGCTGTTAATTATGATAAATGGTCTTATTCTTCATTTATGAGTAGGTACTT

ATTAGATCAAAATATTGATGAATTTTTTACAGGTGGGTCTGATATTAAGTATGAGCAATCCGATTATGAGATTTTT

TTIGGAAGGGTTTTTAAAATTCAATCTTTGTAATTATGTTAGAGGGTTTATTTCTGAGGATTTrAGGAATGGATATA

AATTTTCACTTGATTTTTATCGAAAAGTATACGATGAACTTTTAAAGAGTGAA)AATATTACGATGCAACTCTTGT

GATTAATTATCTTGTAAATCAAGATGAATCTGCTTTAATGGAGAATGACTATAAAAGACTTTATCCTTATTTGTAT

GGATCTTTGATAGAATATTIGGGCTAAAGGAGAGGGCTTGAAGCTAGTGTTGTATTTTCTTTAATAAAGCAGAGA

GTAGCTTTGAAAATGCTGTCTCAAAACCGGGTGCTGTTGGCCTATGCAGTATGCCATCAACAGCAAATGA

TATTTCTAAGAACTTAAGTATTTTAACTATGATTTAAGATTCCGA AATATGACTATAT

TTAAAAAAAAGAATATCTACAACTGGCAGTCTTTATAAGGCTCTTGCGTCTTATAAGGGGTATTGGTAATGTTA

GAAAGTGGGAGAAAAGTTATGGACATTTGTCAAAAGAGCTTTTTATTGAGGCAATTCCCTTTAGTCAAACTAGGAA

TTATATTAAAAAATATTAGTTTATTCGGTATTTTATGATGCTTTGTATGAAAGAAGGGATAGATTCAGTAATA

GTTAAAATTATGGGCGAATTCCCCAAAA)ATTAA

fll-12 .nt p p.

C

TAAAAGGAGA

TTGATGTCTT

AATGTAAAAG

CAAGAAAAGC

AATCCTATAG

ATTTCAATTG

AATGAAGAAA

TCTAAATTTT

AAAGCTGATT

AATCCTAAGA

AAGATAGATA

AGCTCTGCGG

AGATTAGAGA

GACGCAAGAA

GTGAGAAAGG

AATAAAAAAT

ATATTTTTAT GAGAAAAAGT GTAATCTAGA TTCCAAATTA AAGTTTCGGA TAGTGTTCAA AAAAAAGCTT TACTAAAAAT AGCCTATAAT ACCTTCAGAA CGCATACTGA AAAAAAAGAG AGGAAGCTGA TGCAGCAAWI' CTGAATTAAT TAGAGAAGTA TGTATGATGT AATTGGAAAG

ACAATAGAGA.TAAGATAAAT

GTGAACTTGA GCAGCTTATA

C

1 TTTCTTTTT TGACAACGCT GTAAAAATAA TAGATCTTAT GTGCTTTAAG TAATTTAGAA AAGAAATAAA AGAGCTTATT

AA

TTGTTTTTAT ATGCATTATT .AATGGGAGGA TCTAGTAACA AAGAACAAAA AAATAACAAT GAAGATGGTC T'rAATGATTT ATATAATAAT TTTGGAGAAC .GGAAATATGA GGATTTAATT TCACCAAAGA ATAAGGCTAA TATACCAAAT ACAAAAAAGG AGAATTTAAT CCCTTCTACT AAATATTTAG AAGAAAATAT TCTTAAAAAC CGTGTAATTA AAGATGAATA TGCTTTAATA ATTAACAATA AAAAAACATC ATTAATGGAG AAATTAACAC AATTGTTGCA AAATAATTITA AATATGATTG ATATGGCAGA AAATGAAATA CAGAAAAGGT TAAAALGAAAG CATTATTAAA GCATTAAAAT TGTCTAGACA GGCTTTAAGT TCTTTTGCCT CTAAAAGAAT TGAACCAATG AAACATGCAA AAACTGTTTT AGAAAGTCTC WO 98159071 WO 9859071PCTIUS98/12718 185 TABLE 1. Nucleotide and Amino Acid Sequences tll-12 .nt TTrGTAATCTAGATTrCCAAATTATCTAG ACAGAAAAAACAATTAAA.AGAAGTTTCGGATAGT GTTCAAGAAGATGGTCT'rAATGATTAAATACA AGAAAGTTTACTAAAAA'rT'GGAGAAC GGAAATGGGA~rTArAACCTATAAGCCTATAATACCTTCAGAATCACCAAAGAATAAGGCTAATATACC

AAATATTITCAATTGCGCATACTGAAAAAAAAGAGACAAAAAAGGAGAATTTAATCCCTTCTACTAATGAAGAAAAG

GAAGCTGATG ACATATTTGAAATTCTTAAAAACTCTAAATTTT1CTGAATTAATrAGAGAAG

TACGTGTAATTAAAGATGAATATGCTTL'AATAAAAGCTGTITTTAGATGAAATAATAA

AACATCATTAATGGAGAATCCTAAGAACAATAGAAAAAAAATACCATTGCAAAATAATTTA

AAGATAGATAGTGA6ACTTGAGCAGCTTATAAATATGATTGATATGGCAGAAAATGAAATAAGCTCTGCGGCTTTCT

TTTTITGACAACGCTCAGAAAAGGTTAAAAGAAAGCATTATAAATAAATAATAATAGATCTTATGC

ATTAAA6ATTGTcTAGAcAGGCTTTAAGTGACGCAAGAAGTGCTTTAAGTAATI"1AGAATCTTTTGCCTCTAAAAGA

ATTGAACCAATGGTGGAGAGAAAAGGTTATTAAACATGCAAAAACTGTTTTAGAAAGTCTCAATA

AAAAA

fll-12.a

KENIFMRKSL

EKQKSFTKNF

EE2KEADAAIK

PKNNRDKINK

LESIKNNRSYA

KK

FLYALLMGGL

GERKYEDLIN

YLEENILKNS

LTQLLQNNLK

LKLSRQALSD

MSCNLDSKLS

PIEPIIPSES

KFSELIREVR

IDSELEQLIN

ARSALSNLES

SNKEQKNNNN VKEVSDSVQE PRKANIPNI SIAHTEKKT

VIKDEYALIK

MIDMAENEIS

FASKRIEPMV

ADLYDVIGKI

SAAFFFDNAQ

RKEEIKELIK

DGLNDLYNNQ

KKENLIPSTN

NNKKTSLMEN

KRLKESIIKR

HAKTVLESLN

tll-12 .aa CNDSKLSSNKEQ~NNNNVKEVSDSVQEDGLNDLYNNQEKQSFTKNFGERKYEDLINPIEPI IPSESPKNKANI P

NISIAHTEKKETKKENLIPSTNEEKEADAAIKYLEENILKSKFSELIREVRVIKDEYALIKADLYDVIGKINNKK

TSLMPKNNRDKINKLTQLLQNNLKIDSELEQLnMUIDMAENEISSAAFFDNAQKRLKESIIKRLESKNNRSYA

LKLSRQALSDARSALSNLESFASKRIEPMVRKE-EIKELIKHAKTVLESLNKK

f11-4.nt

TAAAGGAGTT

TGTAAATGGT

ACATCTATTG

ATCACAAAAT

GAAAAATCCA

GTAAAGGATA

GTTTTTCAAA

AAGAATGGAC

AATGGTGATA

GCTGAAAATT

AAATGTATTC

CTTAAAAACA

TACAAATGAG

ATGTAGACAA

ATCAAGTAT'r

TAACTCCGGA

A.AAAAGAAAT

CTCCTCGCTT

CACTAATTAA

TAAAGATGGT

AAAGTACCCA

CGGTAAGCGT

AAACTCTTAT

AAAATGATGG

TAAACTAATA

TACCATTGAT

AGATGAGATA

AGAGCTAGAA

TGAAGATCAA

AATCAAATTG

TATAGGT'rAT

GAAATTACTG

AAAATACAAT

TTWCTTTTAAA

GAAAATGTA

TGAGTACGAA

TTGGCAATAT

GAAGCAACTG

AGTGAAGCCA

AATTTAGCAA

AAAAATACCA

ATAAAGAATT

AATGCTACCT

GATGAGTTGC

GAACTTAAAA

GAACATTCAA

GAAACATACT

AAAACATTGA

CTATACTGCT

TAGAAAGTAA

CAGGCCTAAG

AGGAAGCTCA

AGGAAAGTAA

CATCAGAAAA

ATGCAGCCAA

TAAAAATATC

CCGTTGTAAA

ACAGTAAAAT

TTGAAGGTGT

CAACTTTAAG

APATAATTTCA

ATCAGCACTA

TTCGGAAAAA

AGATGACTCT

AAACATAGAA

AATTGATTCG

AAGTAATTTG

GGTAAGTAGC

TAAGTT'rAAT

TGAAACTAAA

ATGCAGCGAA

CTAA

tll-4 .nt

ATGTAAATGGTATGTAGACAATACCATTGATGAAGCAACTGTAGAGTAAATCAGCACTAACATCTATGATCAA

GTATGTAATATAGCACAGGCCTAAGTTCGGAAAAAATCACAAAATTAACTCCGGAAGAGCTAGAAA

ATTTIAGCAAAGGAAGCTCAAGATGACTCTGAAAAATCCAAAAAAGAAATTGAAGATCAAAAAAATACCAAGGAAAG

TAAAAACATAGAAGTAAAGGATACTCCTCGCTTAATCAAATTrGATAAAGAATTCATCAGAAAAA.ATTGATTCGGTT

TTTCAAACACTAATTAATATAGGTTATAATGCTACCTATGCAGCCAAAAGTAATTTGAAGAATGGACTAAAGATGG

TGAAATTACTGGATGAGTTGCTAAAAATATCGGTAAGTAGCAATGGTATAAAAGTACCCAAAAATACAATGAACT

TAAAACCGTrrGTAAATAAGTTTAATGCTGAAAATTCGGTAAGCGTTTCTTTTAAAGAACATrCAAACAGTAAAATT WO 98/59071 WO 9859071PCT[US98/12718 186 TABLE 1. Nucleotide and Amino Acid Sequences GAAACTAAAAAATGTATTCAAACTCTrrATGAAAAATGTAGAAACATACTTTGAAGGTGTATGCAGCGAACTTAAAA

AC.AAAAATGATGGTGAGTACGAAAAA

fll-4.aa

RSLQMSKLIL

TKLTPEELEN

FQTLINIGYN

ENSVSVSFKE

AISILLIISC

LAKEAQDDSE

ATYAAKSNLK

HSNSKIEETKK

KWYVDNT IDE

KSXKEIEDQK

NGLKMVKJLD

CIQTLMKNVE

ATVESKSALT

N'rKESINIEV

ELLKISVSSN

TYFEGVCSEL

SIDQIVLDEIS

KTPRLIKLI

GDKSTQKYNE

KNKNDGEYEK

EATGLSSEKI

KNSSEKIflSV LKTVV1NKFNA

TLTTLS

tll-4.a

CKWYVDNTIDEATVESKSALTSIDQVLDEISEATGLSSEKITKLTPEELENLAKEAQDDSEKSKKEIEDQKNTKES

KNIEVKDTPRLIKLIKNSSEKIDSVFQTLINIGYNATYAASNLKNGLK1VKLLDELLKISVSSNGDKSTQKYNEL KTVVNKFNAENSVSVSFKEHSNSKIETKKCIQTLMKNVETYFEGVCSELNKNlGEYEK f 112-1 .nt TGAATCTCTA AAGATTTTAG CAGGGGAGAA AATATGAAAA AAAGTTTTTT ATCAATATAC ATGTTAATTT CAATAAGTTT ATTATCATGT GATGT'rAGTA GATTAAATCA GAGAAATATT AATGAGCTTA AAATTTTTGT TGAAAAGGCC AAGTATTATT CTATAAAATT AGACGCTATT TATAACGAAT GTACAGGAGC ATATAATGAT ATTATGACTT ATTCGGAAGG TACATTTTCT

GATCAAAGTA

AAGTTTAAGG

ATTGATGATT

AGGTTAATCA

AGCTTGAAAA

TTGCGGGATC

AGCTATATCT ATATTTAAAA AAGACAATAA AATTGTTAAT GATTATAGAA GAATACAAAC CTATGTTTTT AAGTAAATTA

CGTT

C.

C

CV.

t112-1 .nt ATGTGALTGTTAGTAGATTAAATCAGAGAAATATTAATGAGCTTAAAA6TTTTTGTTGAAAAGGCCAAGTATTATTCT

ATAAAATTAGACGCTATTTATAACGAATGTACAGGAGCATATAATGATATTATGACTTATTCGGAALGGTACATTTT

CTGATCAAAGTAAGGTTAATCAAGCTATATCTAATAAAAAATAATGTTAATAAGTTTAAGGAGCT

TGAAAGATATGAAGATAAAACTATGTTTTTAAGTAAATTAATTGATGATTTT

f 112-1 .aa ISKDFSRGEN MKIKSFLSIYM LISISLLSCD VSRIJNQRNIN ELKIFVEKAK. YYSIKLDAIY NECTGAYNDI MTYSEGTFSD QSKVNQAISI FKKDNKIVNK FKELEKIIEE YKPMFLSKLI

DDFAGSV

t112-l1a CDVSRLNQRNINELKIFVEKAKY-YSIKLDAIYNECTGAYNDIMTYSEGTFSDQSKVNQAIS IFKKD)NKIVNKFKEL

EKIIEEYKPMFLSKLIDDF

f 14-8 .nt

C

V

TAAATACAGA.

TTGCTTTTGA

TCTGATAAAG

AAAAAAATAA

CATAAAGAALA

GCTTCCAGG

AAATTTAGAA

CTTTCAGAGA

TTCGGAGGCA

GGACTAGAAA

GCCAT'rCAAG

ATGCTTGCAA

AGAAATCAAA

AAAATACACT

AATATGAAAA

AATTAGACTT

AAAACACCTA

TTATAAGAAA

TTTTTGACGA

TTTTGGATTT

GAGAGTATTT

TTCAGATTTT

ATCCAACATG

GCTTAATGAT

AAGAATGCAA

GTCCGTTGGA

TTCTCCCTTA

TTCGGGCCAA

CTCACTTAAT

AGATAAACTA

ATGAAATACT

AGCACTAATC

GAAGCAAGCT

TTAATAAAT'r

GAAGAACCTT

AAAATATCTG

AGCGCTATTG

ATACAAGGTT

CACGTATATT

AAAAATTCGT

ATATATGTGT

AAGAAGATAT

CTAAAGAAGA

TGATAGAAAT

CAGATCAATA

AAGACACCCC

ATGTCAATAA

TATTTAATAT

CTAAAAAAGA

TTGAAAAATT

GTGTGTTT'1

TAAATATCCA

AGATCCAAA6T

AGCTAATGAG

CGGAATATTG

GCAATCTAA

ATTAAAAGAT

TTTCAACAGA

TATCCTAGGG

ACTATCTATA

WO 98/59071 187 TABLE 1. Nucleotide and Amino Acid Sequences PCT/US98/1271 8 AAAGAAACTT TCTCAAAAAT GCTAAATCAA CTTTTATTAG AT'rATAAA-3A TGATAAAGAT CATATACGAA CAGAGACAAA TAAACI'AAA TCTCATACAA CTGCACTT CGAACAACTTI GATAAAAAAG AAGACGAAGC ATATGAACCT AAAAATCAGA TATTTTCAAT AAGTAACCTT

TAA

t14-8 .nt

TTGCAATTCAGATTTAGCACTAATICAAGAAGATATTAAATATCCATCTGATAAAGAGAAATCAAAATCCAACATG

GAAGCAAGCTCTAAAGAAGAAGATCCAAATAAAA.AAATAAAAAATACACTGCTTAATGATT1TAATAAATTTGATAG AAA.TAGCTAT CTAGAATTAA.AATCAAGACTTCAGATCAATACGGAATATTGGC TTTCCAGGAATTAGACTTrGTCCGTTGGA.AAAATATCTGAAGACACCCCGCAATCTAAATT A AC TATTCTCCCTTAAGCGCTATTGATGTCAATAAATTAAAAGATCTTrTCAGAGATTATAAGAAATTCGGGCCAAATAC

AAGGTTTATTTAATATTTCAACAGATCGGAGGCATTTTTGACGACTCACTTATCACGTATATTCTAAGA

TACTGGGCTAAATGTGAATATTTTAAA

ACTTTCTCAAAAATGCTAAATCAACTTTTATTAGATTATAAAAATGATAAAGATCATATACGAACAGAGACA-TA

AACTTAAATCTCATACAACTGCACTTTTCGAACAACTTGATAAAAAGAAGACGAGCATATGAACCTAATCA

G

f14-8.aa

IQSHSRRVFM

KIKNTLLNDL

FRKNTYSPLS

LEILDLDKLK

KXEDEAYEPK

=YYICVCVFL LLNACNSflFS TNQEDIKYPS DKEKSKSNME ASSKEEDPNK INLIEIANEH KEKYEKRMQE EPSDQYGILA FQELDLSVGK ISEDTPQSKK AIDVNKLKDL SEIIRNSGQI QGLFNIFNRF GGIFDDSLNH VYSKKDILGG NSFEKLLSIK ETFSKHLNQL LLDYKNDKDH IRTETNKLKS HTTALFEQLD

NQIFSISNL

tl4-8 .aa CNDSNEIYSKKKNESKEPKINLNLjLEAEKKERQESQGL

FQLLVKSDPSKRNYPSIVKKDSIRSQQLNFRGIDSNVSK

ILGELLKKSELSKTSMNLLYKDDITTKKHTLELKEEYPN

f17-6 .nt

TAAAGGAGGG

GCTTGCAGGC

TCAAGGCCCA

CTTAAGAAAA

AAAAAACAAC

AGAAAACAAC

TACAATTTTA

ATGACGTCTT

GAAAGATCTA

GAATTAAAGG

ATATTTrAATTr

TTCAAAAAAG

TTTGAACAAA

GATTATAAAA

AATGGAATTA

TATTTATGAA

CGG7ATTTTAA

AAACTGAAAG

AACAACAAGA

AAGAAGAAGA

AACTAAAAAA

AAGAA.AAATA

TTAGGGGATT

TAAGATATAG

AATTCGCAAA

CTTI-rAGCGC

ACAATCTAGA

TATTATATAT

ATCTAAAAAC

AGCAACAAGC

ATACCACATA

TATCGATCAA

CTCTAAGCAA

AGAAGAGCTT1

GCTTAAGAAA

TACGCTATCT

TGTAAAAAGT

GAATTGGGGG

AAGACACACT

.TATTATTCAA

TATTGGAGGA

CAAACTAGAT

AAAAGGAAGT

AGATATTAAT

ATTACAACTA

AAAGACATTA

AAAGAATCAA

AAGAAAAAAC

AAACAACAAG

AATGATTTAA

ATGGAAAAAG

CCAGGGACTG

TATACTGTTT

GATATAAATA

GCTCTTGACA

ATTGCAGATT

GTTGCAGGAA

AAGCTTAAAT

TAI'TGTTTT TCTGTTTTTA AATACCCGCC TACTGAAAAA AGCCTAAAAC AGAAGAAGAG AACAAGAAGA AGAGCTTAAG AAGAAGAGAA GGAAGAACTA AAAAGCAAAT AGAATCGGCC AACCTGAAGA CCATTACGGG AAGATATATC TGACAATACC TAAGCCCCCT GGATCCTCAT AACTAGCATC AGTAGCAAGT TAGTAAGTGA TCACCTATAT TAGAAATACT TAAAAATTCA AAGCAAAAAA ACTTTTATTA CTTATTCAAA TGAACTGGTT AAGAGCTTAT AGTGTCAAAA TCTAG-AAGCA GAA.AATCTAG TATAAACTTT AA tl7-6 .nt TTGCAGGCCGGATTTTAATATcr.ATcAAAAAGACATTAAATAcCCGCCTACTGAAAAATCAAGGCCCAAAACTGAA

AGCTCTAAGCAAAAAGAATCAAAGCCTAAAACAGAAGAAGAGCTTAAGAAAAAACAACAAGAAGAAGAGCTTAAGA

wo 98159071 WO 9859071PCT/US98/12718 TAB LE 1. Nucleotide and Amino Acid Sequences

AAAAACAACAAG.AAGAAGAGCTTAAAACAAGAAGGTAGAAAACAAGAAA

WGAAGAACTAAGAAAACAACAACTAAAAAATACGCTATCTAATGATTTAAAAAAGCAAATAGAATCGGCCTACAAT

TTTAAAGAAAAATATGTAAAAAGTATGGAAAAAGAACCTGAAGACCATTACGGGATGACGTCTT'rTAGGGGATTGA

ATTGGGGGCCAGGGACTGAAGATATATCTGACAATACCGAAAGATCTTAAAAGAAAATTATACTGT

TTTAAGCCCCCTGGA6TCCTCATGAATTAAAGGAATTCGCAAA6TATTATTCAAGATATAAATAAACTAGrCATCAGTA GCAATATTTTAT~c~rTGCcTATTGGAGGAGCTCTGACATAGTAGTGATCACCTATATTTCAAAAAAG

ACAATCTAGACAAACTAAATCGATAAAATTAAMTTCATTTGAACAAATATTATATATAAAAGG

AAGTG TCGAACAAAATTTT-IATTAGATTATAAAAATCTAAAAACAGATATTAATAAGCTTAAATCT TAT'rCAAATGAACTGGTTAA6TGGAATTAAGCAACAAGCTCTAGAAGCAGAAAATCTAGAAGAGCTTATAGTGTCAA

AATATAAACTT

f 17-6 .aa RRVFMKYHII TTIFVFLFLA CRPDFNIDQK DIKYPPTEKS RPKTESSKQK ESKPKTEEEL KKKQQEEELK KKQQEEELK KQQEEELKKK QQEEEKEELR KQQLKNTLSN DLKKQIESAY NFKEYKSM EKEPEDHYGM TSFRGLNWGP GTEDISDNTE RSIRYRRETY TVLSPLDPHE LKEFANIIQD INKLASVASI FNSFSAIGGA LDIVSDI{LYF =KDNLDKLDI ADLEILKNSF EQILYIKGSV AGKAKKLLLD YKNLKTDINK LKSYSNELVN GIKQQALEAE NLEELIVSKY

KL

t17-6.a

CRPDFNIDQKDIKYPPTEKSRPKTESSKQKESKPKTEELKKKQQEEELKKKQQEEELKKQQEEELKKKQQEEEK

EELRQQLKNTLSNDLKKQIESAYNFKEK1VKSME-KEPElHYGMTSFRGLNWGPGTEDISDNTERSIRYRRHTYTV LSPLDPHELKEFANI IQDINKLASVASIFNSFSAIGGALDIVSDHLYFKKDNLDKLDIADLEILKNSFEQILYIKG SVAGKAKKLLLDYK =KTDINKLKSYSNELVNGIKQQALEAENLEELIVSKYKL f 19-2 .nt

TAAAGAAAGA

ATATTTGTTT

AAACCTAAAA

AAAGAACAAA

AATGATTTAA

TTAAAAGAAG

GATGGAACAA

GCTTATAGCA

ATGGCATCAG

GAAAAGATAG

GTTTTAAAAA

GAAATGATGC

AAAAATGAAC

GAAGCACTAA

tl9-2 .nt

TTAAATCATA

TTCTATTTTT

CAGAAACAAG

AAGAAGCAAA

GAAATTT~AAT

AATCCTCAAG

ATGAACAATT

TCTTAAATAC

GACAAACACA

TTAATTGTTT

AGCTTAAAGA

ACAAGCTCTT

TTAAGTCTTA

AGCTAAAAAA

TTCAAGGAGA GTATTTATGA AACACTATAT AATTGTGCAT AAATGCTTGT TATCCAGTTG CATCTAATAA AATAGAATTA CTTAAATCAA GAAGAAGTCC CAAATCAAGA AGCAAACTAC AGAAGAAGGC ATTPIATAAAA AA6ACAGAAAA CACGCTGCTT AGAAACAGCT AAAAAAGATA ATGATAAATA TACACAAAAG CCAATACGGA ATACTGGCTT TCAAAGATTT GTTCTGGCTA GTCCGCAAAT. ACCGAAAGAT CTAAAGCCTA TAGAAAACGA TATTAATGAC GCTTCCTTAA AGAATTTTTC AGAAATTGTA GGGCATATTT AATACCCTTA ACTCACTTGG GGGTAAT'TTT GTATCCCAAA AAAGACAATT TGGAAAAATT AGAGACTTCA TTCTTTGGAA AATTTTTTAG AGATAAAAAA AATCGCCTCA ATTAGACTAT CAAAATAATA CAAATCGTAT ACAMACAGAT TGCAGACACA CTTTTCAATC AAATGACAAA AAAACCCGAA TACCATATGC TCAATAGAGG ACCTTTAA

TTGITATCCAGTTGCATCTAATAAAATAGAATTAAAACCTAAAACAGAAACAAGCTTAALATCAAGAAGAAGTCCCA

AATCAAGAAGCAAACTAcAAAGAAGAAAAAGAAGCAAAAGAAGAAGGCATT~AATAAAAAAACAGAAAACACGCTGC

TTAATGATTTAAGAATTTAATAAAACAGCAAAGTATAAAAACACAAAAGTTAAAAGAAGAATC

CTCAAGCCAATACGGAATACTGGCTTTCAAAGATTTGTTCTGGCTAGATGGAACAAATGAACAATTGTCCGCAAAT

ACCGAAAGATCTAAAGCCTATAGAAAACGAGCTTATAGCATCTTAAATACTATTAATGACGCTTCC'rAAAGAATT TTTCAGAAATTGTAATGGcATCAGGACAAACACAGGGCATATTTAATAccCTTAACTCACTTGGGGGTAATTTTGA

AAAGATAGTTAATTGTTTGTATCCCAAAGCATTGAATAAGACTTCAGTTTTAAAAAAGCTTAAA

GATTCTTTGGAAAATTTTTTAGAGATAAAAAAAATCGCCTCAGAAATGATGCACAAGCTCTTATTAGACTATCAAA

ATAATACAAATCGTA-TACAAACAGATAAAAATGAACTTAA GTCTTATGCAGACACACTTTTCAATCAAATGACAAA

AAAACCCGAAGAAGCACTAAAG

WO 98/59071 WO 9359071PCTIUS98/12713 189 TABLE 1. Nucleotide and Amino Acid Sequences f 19-2. aa

RKIKSYSRRV

EEEAKEEGI

GTNEQLSANT

KIVNCLYPKK

N=LSYADTL

FMKHYIIVHI

NKKTENTLLN

ERSKA.YRRA

DNLEK=ESV

FNQMMKPEE

FVFLFLNACY

DLRNLIETAK

YSILNTINDA

LIJKSLEN

ALKL1NTICS

PVASNKIELK

RDNDKY'rQKL

SLKUFSEIVM

FLEIKCIASE

IEDL

PKTETSLNQE

KEESSSQYGI

ASGQTQGIFN

MMKLLLDYQ

EVPNQEANYK

LAFKDLFWLD

TLNSLGGNFE

NNTNRIQ'rnK t19-2.aa

CYPVASNKIELKPKTETSLNQEEVPNQEANYKEEKEAKEEGINKKTENTLLNDLR.NLIETAKDNDKYTQKLKEES

SSQYGILAFKDLFWLDGTNEQLSATERSKAYRKRAYSILNT INDASLKFSEIVMASGQTQGIFNTLNSLGGNFE

KIVNCLYPKKDNLEKLETSVLKKLKDSLENFLEIKKIASEMMHKLLLDYQNNTNRIQTDKNELKYADTLFNQMTK

KPEEALK

f19-4 .nt 9* a a,

TAATCTATAC

GTTTTTTTAC

CATGTTGATA

AAAGAA.ATCA

GATGATACAA

AGTTTTTTAA

AAATCACCCG

ATTAATCACC

AAGATCAAAA

AAAAGGGTCT

TCAGGAACCT

AATCTGAAAA

TAATTGAGGA

TTTAAATAG

AAACAAAAAA,

TCGAAAAACG

ACAATAAGAA

CAGATGATGA

GAAAAGTATT

TAGACTCAAA

ATTCCCTTGA

TATTAGATCA

AT'rCGATAC

GAATATTTTT

CTGCACCGCT

CGAATATATT

AAAATTGCTA

AGTTITTCGAG

ATTTAATAAA

AAATAGCATA

AAATGAGACC

ACAGCTGTTC

TCAAAACAAT

GATATACGAT

AACCATGAAG

AATGAAATAA

CAAGCTAAAC

ATAGATAA~A

TTTGTAACAA

GCAATTCTAG

TTAAATAAAG

TCTATAAGGA-

GAAAATTCtA

CAGTTTAATG

CTGAAGCGAA

AAAATTTAAT

CAGTAGATCA

GAGCTTTCGA

TATTTCATAA

AGCTAAACAT

CAAGCTCTTT

ATTTTTTTTC

TAAAACCAGA

AAAAAA.ATAA

ATGAAAAACA ACATAATTTT ATGCATGTGT

AATAAAAAAA

AGCAACAACC

AAACCCCGTA

TTTTATAAAT

ACCAACACTA

AGAGCAGGTA

AGATTTGGAA

AACAATCATA

TGATTCTAAA

AGAGGTTAGA

AAACCATATT ATCACTGCCG AATTAA tl9-4 .nt CTGCACCGCTAACCATGAAGCTAAGCGAAAATAAAAAAACATGTTGATAAAACAAAAAACGAATATATrAATGAA

ATAAAAAATTTAATAGCAACAACCAAAGAAATCATCGAAAAACGAAAATTGCTACAAGCTAAACCAGTAGATCAAA

ACCCCGTAGAT AAAAATAAGTTGAGATAGATAAGAGCTTTCGATTTTATAATAGTTTT'IT AACAGATGATGAATTTAATAAATrTGTAACAATATTTCATAAACCAACACTAAAATCACCCGGAAAAGTATTAAAT

AGCATAGCAATTCTAGAGCTAAACATAGAGCAGGTAATTAATCACCTAGACTCAAAAAATGAGACCTTAAATAG

CAAGCTCTTA GAAGTAACCCTGAACAGCTGTTCTCTATAAGGAATTTTTTTCAACAAT CATAAAAGGGTCTTAACTAAAATA TCTATAAACCAGATGATTCTAAATCAGGAACCTAT

TTCGATACGATATACGATCATATGAAAAAGGGTAGAAATCTGAAAAAA

f19-4.aa SILIEENIFH KNNIILCMCV FLLLNSCTAN HEAEAKIKKH VDKTKNEYIN EIKLIATTK EIIEKRKLLQ AKPVDQNPVD DTNNKKCVFEI DKRAFDF INS FLTDDEFNKF VTIFHKPTLK SPGKVtANSIA ILELNIEQVI NHLDSKNETL I4KASSLDLEK IIK4SLEQLFS IRNFFSTIIK RVLLDHQNNE NSIKPDDSKS GTYFDTIYDQ FNEXNKEVRN LKKTILSLPN t19-4.aa CTANHEAEAKIKDrKTKNEYINEIINLIATTKEI IEKRKLLQAKPVDQNPVDD'rNNKKVFEIDKRAFDFINSFL

TDDEFNKFVTIFHXPTLKSPGKVLNSIAILELNIEQVINHLDSKNETLNKASSLDLEKIKNSLEQLFSIRNFFSTI

IKRVLLDHQNNENSIKPDDSKSGTYFDTIYDQFNEKNKEVRNLKK

f 19-6 .nt WO 98/59071 WO 9859071PCT/US98/12718 TABLE 1. Nucleotide and Amino Acid Sequences

TAAAGGAGAG

GCTTGCAGTA

TCAAAGCCCA

CTAAAGAAAA

ACAGCTAATA

TACGGGGTAC

AACACCGAAA

CTTCATGAAT

GTAGATATGT

TT1ATATCCCA TATTAATGAA ATGCCATATA AW1'GCAACTA CAGATTTTAA TACTGATCAA AAAGGCAT.TA

AAACTGAAGA

AACAACAACT

AGCATAAAGA

AGGCTTTCAA

GATCTATAAG

TAAAGGAATT

TTAATTTCTT

AAAAGACAAT

CTCTAAGCAA AAAGAATTAA

AAAAAATAAA

AAAGTATAAA

AGGATCGAAT

ATTTAGAAGA

CTCAAATATT

TAGCTCTATT

CTGGACAAAC

CTACTTAATG

AAAAGAATGA

TGGGGGCCGG

CATACTTATA

GTTACAAATG

GGGACAGCTC

CAGATCTGTC

TATTTGTTTT

AATACCCGCC

AGCCTAAAAC

ATTTAAAAAA

AAGAAGAACC

GGACTGAAGA

CTATTTTAAG

AAAATAALACT

TTGATATAAC

GGATTTAG

TCTATTTTTA

TACCGAAAAA

AGAAAAAGAA

TTCAATAGAA

CGAAGATCAA

TGTATCTGCC

CACGCTGAGT

GGTGCCAGTA

AACCGATAGC

t19-6 .nt .9 9* 9*

TTGCAGTACAGATTTTIAATACTGATCAAAAAGGCATTAAATACCCGCCTACCGAAAAATCAAAGCCCAAAACTGAA

GACTCTAAGCAAAAAGAATTAAAGCCTAAAACAGAAAAAGAACTAAAGAAAAACAACAACTAAAAAATAAACTAC

TTAATGATTTAAAAAATTCAATAGAAACAGCTAATAAGCATAAAGAAAAGTATAAAAAAGAATGAAAGAAGAACC

CGAAGATCAATACGGGGTACAGGCTTTCAAAGGATCGAATTGGGGGCCGGGGACTGAGATGTATCTGCCAACACC

GAAAGATCTATAAGATTTAGAAGACATACTTATACTATTTTAAGCACGCTGAGTCTTC-ATGAATTAAAGGAATTCT

CAA)6TATTGTTACAATGAAAATAAACTGGTGCCAGTAGTAGATATGTTTAATTTCTTTAGCTCTATTGGGACAGC

TCTTGATATAACAACCGATAGCTTATATCCCAAAAAGACAA-TCTGGACAAACCAGATCTGTCGG

f19-6.aa RRVLMKCHII ATIFVFLFLA CSTDFNTDQK GIKYPPTEKS KPKTEDSKQK ELKPKTEKEL KKKQQLKNKL LNDLKNS lET ANKHKEKYKK PMKEEPEDQY GVQAFXGSNW GPGTEDVSAN TERSIRFRRH TYTILSTLSL HELKEFSNIV TNEKLVPVV. DMFNFFSSIG TALDITTDSL YPKKTIWTNQ ICRI t19-6.aa CSTDFNTDQKGIKYPPTEKSKPKTEDSKQKELKPKTEKELKKKQQLKLLDLKNSIETANKHKEKYKKRMiKEEP

EDQYGVQAFKGSNWGPGTEDVSANTERSIRFRRHTYTILSTLSLHELYKEFSNIVTNENKLVPVVDMFNFFSSIGTA

LDITTDSLYPKKTIWTNQICR

f21-4 .nt 9.9.9.

9**9*9 9

TAGGAGACAA

CTGATAAGTT

TTAGAAAGTT

GGATTTTTAG

AAACAAATTC

GAAACATATT

GGACTTGAAG

AAAAAAGCTT

GCAACTGGAG

TGGCAGTGTG

ATGACCAATG

GGAGAAACTG

TCTTTATGAA

CTTGTAAGAA

CAGAACAAAA

AAATTTTAGA

AAGAATTAA.A

CTGGGTATGA

ATAAATTAAA

TACAAGAGGC

TAACGCATGG

CTAATAGTTT

AAGTTATAAC

TAGAAGGTAA

TAAAAAAATA AAAATGTTTA TTATTTGTGC TGATGTAACT AGTAAAGATT TAGAAGGGGC

TGTAAAAAAA

GACAAAAGAT

GAATAAGATA

AGAA.AAAATA

TGAACTTTCA

TAAAAAGAAA

TTCTCAAGTC

GGGGT'rTAAA

TAATTCGCTT

AAAAGAATAA

ACAGAACAAG

TTAAACACAT

GAAAAATTAG

AACA.AAATAA

GAGAGCTTAA

TTTGAAGAGT

CAAAGACAAG

AATATGACTA

AAAAAGATTG

AGATAAAAAA

TAGATACAAA

ACTCTAAAAA

AAGAA.AAATT

AAAAGAAAAA

ATAAAAACCA

GTGGTGTTGG

GTGGTAATAA

AAGAAGAACT

TATTTTTATG

GGTGAAAGAT

ACAAGTTGAA

AGAAATTGAA

AACTTCTATT

AAACGGAAAA

AGAGGAGAGA

AGCTGAATCT

ATTACAAGCT

TACTAGCGAT

TAAAAATATT

t21-4 .nt

TTGTAAGAATGATGTAACTAGTAAAGATTTAGAAGGGGCGGTGAAAGATTTAGAAAGTTCAGAACAAAATGTAAAA

AAAACAGAACAAGAGATAAAAAAACAAGTTGAAGGATTTTTAGAAATrflTAGAGAcAAAAGATTTAAACACATTAG

ATACAAAAGAAATTGAAAAACAAATTCAAGAATTAAAGAATAAGATAGAAAAATTAGACTCTAAAAAAACTTCTAT

TGAAACATATTCTGGGTATAGAAAAAAAAAAGAATAAACGGAAAAGGACTTGAAGAtAAA WO 98159071 WO 9859071PCTIUS98/12718 191 TABLE 1. Nucleotide and Amino Acid Sequences TTAAATCGAACTTTCAGACAGCT AAAGAAAGGAAAAAAGT=ACAAGAC7GCTAAAAAGAAAT

TTGAAGAGTATAAAAACCAAGCTGAATCTGCAACTGGAGTAACGCATGGTTCTCAAGTCCAAAGACAAGGTGGTGT

TGATACACTrGCATTGCTATGTGGG1TAATTGACTAGTGGTAATAATACTAGCGATATG ACCAATGAAGTTATAACTAATTCGC TTAATIGAGAACAAAAATATTGGAGAAACTGTAGAAGGTA

AAAAI.GAA

f2l-.aa

ETIFMNYKIK

FLEILETKDL

LEDKLNELSE

QCANSLGFKN

MIFIICAIPML

NTLDTKEIEK

SLKKKKEERK

MTSGNNTSDM

ISSCKNDVTS KDLEGAVKDL ESSEQNVKKT EQEIKKQVEG QIQELKNKIE KLDSKKTSIE TYSGYEEKIN KIKEKLNGKG KALQEAKKKF EEYKNQAESA TGVTHGSQVQ RQGGVGLQAW TNEVITNSLK KIEEELKNIG ETVEGKKE t21-4.aa CKNDVTSLEGAVKDLESSEQNKKTEQEIKKQVEGFLEILETKDLNTLDTKEIEKQIQELKNKIEKLDSKKTS

I

ETYSGYEEKINKIKEKLNGKGLEDLN'ELSESLKKKKEERKKALQEAKKKFEEYKNQAESATGVTHGSQVQRQGGV

GLQAWQCANSLGFKN~MTSGNNTSDMTNEVITNSLKKIEEELKNIGETVEGKKE

f24-l.nt S. 5555*S 5.55 S S S. S 55S5

S

TAAGCTGGTA

GAAGTTGTGG

GGGATAAAGG

AAAGAGGGCA

GACAGTGAGG

TTAAGTGCGA

GCTACAAATC

GGGATGAAGA

GGAAAGTTTG

GCTGCAATTG

GTGAAGGGGA

CTGAAA.GCTG

GTTGATG7GTG

GTTAGTGGGG

GGAGAGAAGC

GATGGTGCGG

GCTTTrGAGGG

AAGGCTGAGG

AAGACAGCTG

GCNAAGGNTG

GAAGCTGCTN

GAGGCAGGGA

AGCAAGGCGG

AAGGCTGCGG

CCGATTGCTG

ATGAAGAAGG

AAGTTTGCTG

GAGTTGTTGG

GCTGCAATTG

GGGATTGCTA

GT1'GCTGCTG

GCTAATGCTC

AGTGGGGAAC

GAGGGAAAGA

GGGGATGCGG

ACACTGTAAA

ATA1ATGATGC

AGATTGTTGA

ATGAAAAGGC

CTGCTAGCAA

?I'GTTAAGGC

CGATTGCTGC

AGGATGATCA

CTGTGAAGAA

GAGAAGTTGT

TTGCTAAGGG

CTGCTGCTGA

CTGCTGGGGA

AGCAGATAT'r

CTGAGGATGC

AGTTTGATCA

GGATGGCTAA

GGGCTATTAA

AGGGGGCTTC

CTGATAAGGC

GGGGGAGTGA

AGTTGTTTGG

CTGGTGCTGT

CTGCTGGTGC

CTGCTATI'GG

ATGATCAGAT

TGAAGAAGGA

ATMAGCTGGT

GAGAAGTTGT

AGGGGATAAA

CTAAAGGGGA

ATGGGGACAG

AGATATTAAG

AGCCTGAGGA

AGTTTAATCA

GACAGCTGAG

TAAGGTTGCT

AGCTGCTAGG

AGGGAAGTTG

GGCGGCTGGT

TGCGGATGCG

TGCTATTGGG

GATTGCTGCT

TGATGAGAAA

GGATAATGCT

GATAAAGGAG

AGGGGAGAAT

CAGTGAGGCT

AAGTGCGATT

TAAAAATCCG

GGATGAGATG

GGATGGAAAG

AGAAGTTAGC

AA.GTGGTACT

GAGTGTGACG

AAAGCTGAAA

GAAGGCTGGT

TAGTGCTGTT

GGCTGATCAG

GAAGGGTAAT

TGCTGCTGCT

TGAGAAAGGG

AAAAGCTGTA

GGATAATGCT

GGAGATTGTT

GAATAATAAA

TGAGGCTGCT

TGCGATTGTT

GGCTAAAAAT

GGATGGGATG

GGGGCTTCA6A

GATAAGGCGA

GGGAGTGAAA

TTTGGGAAGG

GCTGTTAGTG

GCTGAGCAGG,

AATAAAGATG

GCTATTGCTT

GGGAAGGCTG

GGTGCTGCGA6

ATTGTTGAAG

AATAAAAAGG

GCTAGCAAGG

GT1'AAGGCTG

ATTGCTGCTG

AAGAAGGATG

TTrTGCTGTGA

GAGTTGTTGG.

GATGCAATTG

GGGATTGCTA

GTTGCTGCTG

GCTGATGCTA

AGTGGGGAGC

GATGGAGAGA

GCGGATGATG

ATTGCTTTGA

AAGGCTGAGG

AAGACAGCTG

GCGAAGGCTG

GAAGCTGCAG

GGGGCAGGGA

AGCAAGGCGG

AAGGCTGCTG

CCGATTGCTG

AAGAAGGATG

GTGGTACTGA

GTGTGACGGG

AGCTGAAAGT

CTGGTGCTAA

CTGTTAGTGG

ATGGAAAGAA

AGGATGCGGA

TGAGGGGGAT

AGGGGGCTAT

AGGCTGCTGA

CTGCTGGGGG

CAGGGAAGTT

CGGCTGGTGC TGTTAGTGCT CTGGTGAGGC TGAGCAGGAT CTATTGGGAA GGGTAATGGG ATCAGATTGC TGCTGCTATT AGGGTAATAA TGAGAAAGAG ATAAGCTGGT AACAGCTGTA GAGAAGT'rGT GGATAATGNT AGGGGATAAA GGAGATTGTT CTANAGNGGN NAATAATAAA ATGGGGACAG TGAGGCTGCT AGATATTAAG TGCGATTGTT AGCCTGGGGA TGCTAAA6AAT GTGCGGATTD TGGTGATGGG GGGGGATGGC TAAGGATGGA GGGCTATTAA GGGAGCTAGC AGGGGGCTTC AAGTGGTACT CTGATAAGGA TAGTGTGACG GGGGGAGTGA AAAGCTGAAA AGTTGTTTGG GAAGGCTGGT CTGGTGCTGT TAGTGCTGTT GTGAGGCTGC TGGTGATCAG CTGCTATTGG GGATAA6AGAT ATCAGATTGC TGCTGCTATT

TGCAATTGGA

GATTGCTAAG

TGCTG4CTGCT

TGCTCATGGG

GGAGCAGATA

GCCTGCAGAT

TTTTGGTGAT

GGCTAAGGAT

TAAGGGAGCT

TAAPGATAGT

GAGTGAAAAG

GTTGGGAAA

WO 98/59071 WO 9859071PCTIUS98/I 2718 TABL 1. Nucleotide and Amino Acid Sequences

GCTTTGAGGG

AAGGCTGAGG

AAGACAGCTG

GCTAAGGTTG

GAAGCTGCTG

GGGGAGCAGA

GGAGAGA.AGC

GATGCGGAWI'

TTGAGGGGGA

GAGGGGGCTA

AAGGCTGCTG

GCTGCTGGGG

GCAGGGAAGT

GCGGCTGGTG

GCGGATGCGG

GCTATTGGGA

ATTGCTGCTG

AATAATGAGA

GTGGATAATG

AAGGAGATTG

AGGGAGAATA

GACAGTGAGG

TTAAGTGCGA

GCTACAAATC

AAGGATGAGA

AAGGATGGAA

ATTAAGGAAG

GCTTCAAGCG

GCTGATAAGG

GGGGGGAGTA

AAGTTGTTTG

AAGGCGGCTG

GGATGGCTAA

GGGCTATTAA

AGGGGGCTTC

CTGATAAGGC

GGGACAGTGA

TATTAAGTGC

CTGCAGAGGC

TTGGTGAGGA

TGGCTAAGGA

TTAAGGGAGC

ATAAGGATAG

GGAGTGAAAA

TGTT~TGGGAA

CTGTTAGTGC

CTGAGCAGGA

ATAAAGATGA

CTATTGCTTT

AAGGGAAGGC

ATGCGAAGGC

TTGAAGCTGC

ATAAAGAGGC

CTGCTAGCAA

TTGTTACGGC

CGATTGCTGC

TGAAGAAGGA

AGTTTGCTGT

TTAGCGAGTT

GTACTGATGC

CGAGTGTGAC

AAAAGCTGAA

GGAAGGCTGG

GTGCTGTTAG

GGATGGAAAG

AGGAGTTAGC

AAGTGGTACT

GAGTGTGACG

GGCTGCTAGC

GATTGTTAAG

TAAAAATCCG

TGGGATGAAG

TGGAAAGTTT

TGCTGCATT

TGTGAAGGGG

GCTGAAAGCT

AGTTGATGGT

TGTTAGTGGG

TGGAAAGAAG

GGATGCGGAT

GAGGGGGATG

TGAGGGGGCT

TGCTGATAAG

TGGGGGGAGT

AGGGAAGTTG

GGCGGCTGGT

TGCGGCTGCT

TGCTATTGGG

TGATCAGATT

GAAGAGTAAT

GTTGGATAAG

AATTGGAGAA

GGGGATTGCT

AGCTGCTGCT

TGCTGGTGCT

TGCTGGTTAG

TTTGCTGTGA

GAGTTGTTGG

GCTGCAATTG

GGGATTGCTA

AAGGCAGCTG

GCTGCGGCTG

ATTGCTGCTG

AAGGATGATC

GCTGTGAAGA

GGAGAAGTTG

ATTGCTAAGG

GCTGCTGCTG

GCTGCTGGGG

GAGCAGATAT

CCTGCAGATG

TTTGGTGATG

GCTAAGGATG

TCAAGTGGTA

G7CGAGTGTGA

GAAAAGCTGA

TTTGGGAAAG

GCTGTTAGTG

GGTGAGCAGG

AAGGGTAATG

GCTGCTGCTA

GATGGTGAGA

CTGGTAAA.AG

GTTGTGGCTA

AAGGGGATAA

GCTGAAGGGG

GGTGCTAATG

AGGATGGTGG

ATAAGCTGGT

GAGAAGTTGT

AGGGGATAAA

GTGCTGTTAG

CTGGTGCGGC

CTATTGGGA

AGATTGCTGC

ATGATGAGAA

TGGATAATGC

GGATAAAGGA

AAGGGGAGAA

ACAGTGAGGC

TAAGTGCGAT

CTACAAATCC

GGATGAAGAA

GAAAGTTTGC

CTGATGCAAT

CGGGGATTGC

AAGCTGTTGC

TTGATGATGC

CTGTTAGTGG

ATGGAGAGAA

AGGATGGTGC

TTGCTTTGAG

AAGGGAAGGC

CTGTAAAGAC

ATGCTGGTGC

AGGAGATTGT

AGAATAATAA

GGGACAGTGA

TGAGAAAGAG

AAAAGCTGTA

GGCI'GATGC-T

GGAGATTGTT

TGCTGTTAGT

TGAGCAGGAT

GGGTGATGGG

TGCTATTGCT

AGGGAAGGCT

TGGTGCTGCG

GATTGTTGAA

TAATAAAAAG

TGCTAGCAAG

TGTTAAGGCT

GATTGCTGCT

GGATGATCAG

TGTGAAGGGT

TGGAGAAGTT

TAAGGGGATA

TGCTGCTACA

TCATGCTGGG

GGAGCAGATA

GCCTGCAGAG

GGATTTTGGT

GGGGATGGCT

TGAGGGGGCT

AGCTGAGGGG

TGCGAAGGCT

TGAAGCTGCT

AAAGGCAGGG

GGCTGCTAGC

a. a a. a a a a.

t24-1 .nt 0 a

TGGTGAGGCTGAGCAGGATGGAGAGAAGCCTGAGGATGCTAAAAATCCGATTGCTGCTGCTATTGGGAAGGGTAAT

GGGGATGGTGCGGAGTTTGATCAGGALTGAGATGAAGALAGGATGATCAGATTGCTGCTGCTATTGCTTTGAGGGGGA

TGGCTAAGGATGGAAAGTrTGCTGTGAAGGGTAATAATGAGAAAGAGAAGGCTGAGGGGGCTATTAAAGAAGTTAG CGAGTTGTTGGATAAGCTGGTAACAGCTGTAAAGACAGCTGAGGGGGCTrCAAGTGGTACTGATGCAATTGGAGAA

GTTGTGGATAATGNTGCNAAGGNTGCTGATAAGGCGAGTGTGACGGGGATTGCTAAGGGGATAAAGGAGATTGTTG

AAGCTGCTNGGGGGAGTGAAAAGCTGAAAGTTGCTGCTGCA NGNAATAGGCAGGGAAGTTIGTT

TGGGAAGGCTGGTGCTGATGCTAATGGGGACAGTGAGGCTGCTAGCAAG

f24-1.aa AGNTVKTAEG ASSGTDAIGE WVDNDAKVAD KASVTGIAKG

EGNEKAGKLF

TNPIAAAIGN

AIGEVVDNAG

DGAAGDSEAA

GAEFDQDEMK

TA.EGASSGTD

AGKLFGKAGA

IAAAIGKGNA

LLDKLVKAVK

AAAYKGENNKG

GKAGANAHGD

KDEDADFGDG

AAKAADKDSV

SKAAGAVSAV

KDDQIAAAIA

AIGEVVDNXA

DANGDSEAAS

DDGADFGDGM

TAEGASSGTA

AGKLFGKAGA

SEAASKAAGA

MKKDDQIAAA

KGIAKGIKEI

SGEQILSAIV

LRGMAKDGKF

KXADKASVTG

KAAGAVSAVS

KKDDQIAAAI

AIGEVVDNAA

VSAVSGEQIL

IALRGMAKDG

VEAAGGSEKL

KAAGEAEQDG

AVKGNNEKEK

IA.KGIKEIV'E

GEQILSAIVK

ALRGMAXDGK

KAADKDSVTG

IKEIVEAARG

SAIVKAADAA6

KFAVKNDEKG

KAAAAEGENN

EKPEDAKbUPI

AEGAIKEVSE

AAXGSEKLKV

AAAAGAAflQD

FAVKKDEKGK

IA.KGIKEIVE

GEQILSAMV

SEKLKVAAAK,

EQDGKKPADA

KAEGAIKGAA

KKAGKLFGKV

AAAIGKGNGD

LLDKLVTIAVK,

AAAXXXNNKE

GEKPGDAKNP

AEGAICGASE

AAGGSEKLKV

AAGEAAGDQE NAHGDSEAAS -KAAGAVSAVS wo 98159071 WO 9859071PCT/US98/12718 TABLE 1. Nucleotide and Amino Acid Sequences

GKKPEEAKNP

AEGAII(KGVSE

AAGDSEAASK

ADFGEDGMKK

AADKDSVKGI

AGAVSAVSGE

AAAIALRGMA

EIVEAAGGSE

SAIVTAAAAG

DGKFAVKSND

DKASVTGIAK

AAGAVSAG

t24-l..aa IAAAIGflKDG

LLDKLVICAVK,

AAGAVSAVSG

DDQIAAAIAL

AKGIKEIVEA

QILSArV-KAA

KDGKFAVKGN

KLKAVAAATR

EQDGEKPAEA

GEKGKAEGA.I

GIK.EIVEAAG

DAEFNQDGMX

TAEGASSGTA

EQILSAIVKA

RG1AIGKA

AGGSEKLKAA

DAAEQDGKFP

NECGKAEGAS

TNPIAAAIGK

KEVSELLDKEJL

GSKKLKAAAA

KDQIAAAIrA AIGEVVAlAA

AAAGAAEQDG

V=DEXGKAE

AAEGENVXKA

ADATNPIAAA

SGTDAIGEVV

GKVDARAGD

GNEDGADFGK

VKAVKTAEGA

EGENNKKAGK

LRGMAKDGKF

KVAI)KASVTG

EKPAEANPI

GA.IKGAAAIG

GKLFGKVDGA

IGNKEDADF

DNDAKAADKA

SEAA.SKAAGA

DEMKKDDQIA

SSGTDAIGEV

LFGKAGAGAG

AVKDGGEKE

IAKGIKEIV

AAAIGKGDGD

EVVDNAGAAK

AGDSEAASKA

GDGM=DDQI

SVTGIA.KGIK

VSAVSGEQIL

AAIALRGMAK

VANAGAAKAA

ANGDSEAASK

GE-AEQDGEKPEDAMNPIAAAIGKGNGDGAEFDQDEMKKDDQIAAAIALRGMAXflGKFAVKGNNEKEKAEGAIKEVS ELLDKLV'rAVKTAEGASSGTDAIGEVVDNXAKXADKASVTGIAKGIK-IVEAAXGSEKLKVAAAXXNNKEAGKLF

GKAGADANGDSEAASK

f28-2 .nt S.

SS

S

TAAAAAGGAA

TTAGTATTTA

ATAGAACAGT

TCAGTAGATA

AAAACTTATG

GCTAATAATA

GCTCAAAATA

GAACAAAGTA

GAAGAAGAAA

CTTTCAGAAA

AACAATACAC

AATTTAGACG

ATGCGTCTT

GAGGCTAAGG

CGGTTCGGTG

GCTATAGACT

CAGGGAAATT

ATATAAATAT

GTTCTCTTT

T'rGCATTAGC

AAAATAGTAA

ATCCAATCTT

AAGAATCCCT

ATGTAAAGAT

ATTTTAAAAA

TTAAAGCTAA

TTAAAAATGC

TCCTTGAGTT

CATCTCCTTT

TTATGGAGCA

ATAAACTAGC

GCAGTrTTTAA TTGCT'rCTGC

CTTIGCAAAAA

TATGCGATTA

TTTATTTGAA

ATTAAAAGAT

GGAAATTGAA

ACAAGTAGGT

ACCAAATTCA

GGAAGAAAAT

TAGCCTTACT

CTTAGATGAA

CACGCAAATT

TGAAAAAGAT

GAATAGAAAA

AGCAACTAAT

AGAATCTATT

CGGACGTGAT

ATGCATTGAA

AGAAATAGAA

TGTTTAATAA

AGT'rGTTCTG

CATCAAGAAA

TCTCCTAAAG

TCTAATCAAC

AGTCC-AGCAA

AAATCAGCTA

ACAACAAGTA

TTTGCACAAG

GTTAATCATG

TATGAAACTT

ATAAAGACTA

TC'rTGGGTAT

TATAAAAGAC

ATGCAACATG

TATACACAA?,

AATATATTCA

AAATTrTTTAT

GTTTTCTATC

ATAAAAATAC

ACGTTACATC

ATATGTCAGA

TAATACAA.AA

CTCCACAACA

AAACTCCTGC

AAGAGTATGA

CTAATCCTGA

TATCAAACTT

TTATGCCTAA

CTGCTAAAGG

TATACAATGG

CAAAAAATTT

AAGCTATTGA

AGCTTTAA

TATACCTAAT

TAAAAAATCT

TACTAATACT

ATCAAATAAA

TGATCCTGGT

TGACTCGCAT

TGATCCAATT

TATTCCTTCA

GCAAACATCT

AAACAAATTA

GTTATTCTCT

ATT1ACAAGAA

CATGCTAGAT

CAATTCALTAC

AGCATACAGA

TTATCTTCAA

t28-2 .nt

S*

S. S

S

AAAAGATCATCAAGAAAATAAAAATACTACTAATACTTCAGTAGATAAAAATAGTAAGGAAATTTTCCTA

GAGTCTACATAAACTTACATCTCATGTCATACTTTAAGT

CTGGTGCTAATAATAAAGAATCCCTACCAAACAAGTCCAGCAATAATACAAATGACTC

TGCTCATA

TGTAAATGAAAAATAATATACTCACAACATGATCCAATTGAACAAAGTAATTAATAGCCTT

ACAACATAATCGTTCTCGAAAGATAGTATAAGATGAAGA

AGTATGAGCAACATCTCTTCAGATTAAATGCCACGCAAATTGTTAATCATGcTAATCCT

AAT

AAACAATACACTCCTTGAGTGAAAAGATTATGAAACTTTATCAAACTTGTATTCTCTATAACGATCT

ccTTAGCA.TAAGATCTCTTTGGAGACAT

CTTGGGTATCTGCTAAAGGCATGCTAGATGAGGCTAAGGATAACTAGCAGAATCTATTTATAAAGACTATACA

TGGCAATTCATACCGGTTCGGTGGCAGTTTTAACGGACGTAAG

CTCAATAT~T

ATGCTGTCGAGATATTCCAAGTTGTACTACGGAATTGAA

AAGAAATAGAAAATATATTCAG

f28-2 .aa PCTIUS98I112718 WO 98/59071 194 TABLE 1. Nucleotide and Amino Acid Sequences

KGNINIMRLC

VDKNSKEIES

QNNVKMEENK

SEIKNATQIV

RSFMEQATNS

IDFASACIEY

LIKIFIIPNL

P1DVTSSNKK

SATPQHDPIE

NHANPENKLN

WVSAXGMLDE

TQKAIDYLQQ

VFSSLFLFES CSGFLSKKSI TYDPILQVGS NQHMSDDPGA QSNFKQNSLTT TSKTPAIPSE NtLLEFE=fY ETLSNLLFSN AKDKLjAESIY KRLYNGNSYR GNSCMKIEN IFKL

EQFALALKDH

NNKESLPNSS

EEIKANLDEF

LD)ASPLNP.KI

FGGSFNGRDM

QENKNTrTNTS

PAIIQNDSHA

AQEEYEQTSL.

KTIMPKLQEM

QHAKNLAYPA

t28-2 .aa KDHQEMM-NTSVDKNSKEIESPKDVTSSNKKYPILQVGSNQHMSDDPGANNKESLPNSSPAI

IQNDSHAQNN

VKMKSATPQDPIEQSNFKNSLTTTSKTPAIPSEEEIKANLDEFAQEYQTSLSEIKNATQIVNHANPENKL

NTLLEFKYETLSNLLFSLDASPLNKIKTIMPKLQMRSFMEQATNSWVSAKGMLDEAKDKLESYKRLYN

GNSYRFGGSFNGRDMQHAKNLAYRAIDFASACIEYTQKAIDYLQQGNSCKKEIENIFK

f28-3 .nt

TAGATGAATT

CTCTCTTGTA

GACAACAACA

AGAAGTACAA

GATATGCAAA

AAAGCTAATG

TAATTGCTAA

ACCTATATGA

AGTCTTTTAA

ATAATGCTTA

ATGATAATAG

AAGATAGTAA

ATTATTTATT

TAATCTTGCA

TACTTTAGGA

TATGAAACAA

TAGCAGCAGT

TATTATGAAG

AACTATAAAA

AGAGAACGCT

GCACCAAGCT

TGCATTTAAT

TGAGGCATAA

TTATCCACTT

GACAACGCTG

AGCAGCAATG

AACATAGACA

CTTCCCCAAC

GAAATTGAAT

CAAATACTTG

AGAAAAGCAC

ATTGCTAAGG

TCCCTGGGAA

TAGTTTCAAT

AGCAGGTTAC

AGAGTAGAAG

AAAATCATTT

AAGTTAATAG

CTTCTACAGA

ATAATATAGA

CTAAATCTAA

TTAAGAGTAG

TAGCTGATAC

TCCAAATATC

AGACATACTA

TCGCAGGCCT

AGTTGTTGCA

TGAATCCAGT

AGAGTGCGCT

AAGCTTGCTT

TCAAGATAAT

TCATACTTCT

TGCCTTTAAA

96 6 S 6666..

S

9 AGACTAAGAA AAGATTTAGA AATACAGCTA ATTCTTATTT CAAACCTTAT TGCTTAGCCT TTTATCATTT GTTATAATGA GATGCAAAGA GAAAGGCAGT t28-3 .nt

TTTACAAGTACTCGCAGTACAGTCGCTCAAACAAGCTTA

ACTTTAGGAAGCAGCAATGAGAGTAGAAGTCGCAGGCCTAGAAGTACA

TGCTTATATGAACAACATAG

AcAA~ATATGTcGTTcAAGTATGACGATTCCACATATGG ATccAGTAAAGCTAATGAAGATAGTAATATTATGAAGGAAATTGAATCTTCTACAGAAGAGTGCGCTAGACTAAGA

AAGATTTAGAAACTATAAACAAATACTTGATAATATAGAAAGCTTGCTTAATACAGCTAATTCTTATTAGAGA

ACCAAAGACAACATAGTACAACTTGTACTCCAGTTGTAG

TAGGATAATCTTTATGTTAGAGATATCCGGAACGTCGCT

AAAGATGCAAAGAGAAAGGCAGTTGAGGCA

f28-3.a MNLIAKLFIL STLVSIPNIL SCNLYDNLAD NAEQVTDILD NNKSFNTLGS SNESRSRRPR STNNAYMKQN IDKNHLVVAD MQNDNSSSSL PQQVNSESSK ANEDSNIMKE IESSTEECAR LRKDLETIKQ ILDNIESLLN TANSYLENAR KAPKSNQDNQ TLLLSLHQAI AKVKSSHTSF IICYNDAFNS LGIADTAFKD AKRKAVEA t28-3 .aa CLYDNLDNAEQVTDILDNS LGSSNESRSRRPRSTNNAYiIQNIDKNLVVAMQ~rNSSSSLPQQVNSE

SSKANEDSNIMCIESSTEECARIRDLETIKQILDNIESLLNTANSYLEARKAPKSNQDNQTLLLSLQAK

KSSHTSFIICYNDAFNSLGIAlTAFKDAKRKAVEA f31-2 .nt TAAAAAAATA AGGAGGTATT AATGAAAAGG AAAAGCAATA TATGTATTTC ACTTCTAGTC ACAATATTAT TTGTGTCTTG CAAGTTTTTT GGAAATAAAA GCGCAAGTAA AGAAAAAGAA *666 9* 66 6656 6 wo 98159071 WO 9859071PCT/US98/12718 195 TABLE 1. Nucleotide and Amino Acid Sequences GAAACTTCTTl

GACAAACAAG

CCTTrACATGC

CAAGAAAATA

ACAACTA-AAA

AATACCATTG

CCT1'CTGAAA

TACACTCAGC

GA.TGATTCTA

ATAGAZACAG

AATATAGATA

AAAGCCAGCC

G7AATTTAAGC

AAAGGAGACA

TTAAAGATG

GACAAGATGA

TI'TCTGATAC

AAAAAAATAC

TTGCTGATGC

AAGATAAATT

CATATCAATC

ATACCTATGG

AACGTAAACA

T'rAGCACAAT

TTGCACAGTA

TAAAAGACTA

ATWTAAAA AT

GATCTTATGC

AAGCTG'N'AA

ATGCTGTCAA

AGTTTGCAAG

TAAGAGCTAT

TGCTAGCAAG

AAGTGATGTT

CCI'ATT.GTT

AAATGAAGAA

TAGCCTAGAT

CAGCTGTGAT

AGCTCTTGCT

GTTAAAGAGT

TAAGGAAGCC

TGCAACAGCT

AGTTAGAGAT

TGATGCTTTT

AC7AGTTTAAT

TGTTATTGTA

AGCAAAAATG

CGACAAGCTG

ATTAGTAAGT

ACAGGTGACG

AGTGATACTA

GATAAAAAAA

TCCATTVTATA

ACGTATCGCA

GATCTAGAGA

GCTGTGCCTA

ATAAAGCAGG

CAAAGTGCTG

GTTCTTCTTA

GCTATTGCAA

GATGCTGCTA

GGCACTAT'T

TTTGCTCGTA

TGTGATGTTI'

CGGGAACAGC

CCAAAAAGCA

CTAATAGAGA

AGCTTAATGC

ACAAATATAC

TT~GAGTGT

AGTAAAA6CT

GTTATTACAA

CTATTGAAGC

CCGATGACGA

TTATI'AAAAA

CATCTAGCTT

AACAATATGC

CTAGTATGCC

ATTATAGAGG

ATAAAAAAGT

TGCTTCTTCA

TACTAGTAGC

TAGAGATAAG

TTTTTTTAGC

AGGCTATTAT

TAGTGTAGGA

AGACGAAAAG

AAAAAATTTA

TGAAAGTAAA

AAAGAAAAGA

AACTATTGAG

ATCTTGTAGC

TAATGGAAAT

TTATGTCAAA

AGACGAGGTA

TGCGCTTTAG

t31-2 .nt 4* *9 4* TTGCAAGTTrTTTGGAAATAAAAGCGCATAGAAAAGACTTCTTTTTCTGATACTGCTAGCAAGATT AGTAAGTCGGGAACAGCTGCTTCrrAAAAAGAAAA A~ TGATGTTACAGGTGACGCCAAAAAGC

ATACTAGTAGCCCTTACATGCTTGCTGATGCCCTTATT~GTTAGTGATACTACTAATAGAGATAGAGATAAGCAAGA

AAATAAGTAATTAATGAGAAATAAAAAAGTTAATGCTTTTTTTAGCACAACTAAAACATATCAATCT

AGCCTAGATT~CCATTTATAACAAATATACAGGCTATTATAATACCATT GATACCTATGGCAGCTGTGATACGTATC

GCATTGAGTGTTTTAGTGTAGGACCTTCTGAAAAACGTAAACAAGCTCTTGCTGATCTAGAGAAGTTAAAACTAGA

CGAAAAGTACACTCAGCTTAGCACAATGTTAAAGAGTGCTGTGCCTATATCAAAATA

GATTCT

ATTGCACAGTATAAGCGAAGCCATAAAGCAGGCTATTGAAGCTGAAAGTAAAATAGAGACAGTAAAAGACTATGA

CAGCTCAAAGTGCTGCCGATGACGAAGAAAATTGTATAAAAATAGTTAGAGATGTTCTTCTTAT

TATTAAAAAAACTATTGAGAAAGCCAGCCGATCTTATGCTGATGCTTTTGCTATTGCAACATCTAGCTTATCTTGT

AGCGAATTTAAGCAAGCTGTTAAGAGTTTAATGATGCTGC AcAA~TAGAAAAGG~ G

CTGTCAATGTTATTGTAGGCACTATTTCTAGTATGCCTTATGTCAAATTTAAAGATGAGTTTGCAAGAGCAAAAT

GTTTGCTCGTAATTATAGAGGAGACGAGAAAGATAAGGTATCGACAAG

f 31-2. aa

ICNKEVLMKRK

KQEKN'rSDVT

TKTYQSSLDS

TQEJSTMLKSA

IDNLKIVRDV

GDNAVNVIVG

SNICISLLVT

GDAKKHTSSP

IYNKYTGYYN

VPSYYK1L

LLIIKKTIEK

TISSMPYVKF

ILFVSCKFFG

YML.ADALIVS

TIDTYGSCDT

DSIAQYKEAI

ASRSYAflAFA PDEFARA1K4F

NKSASKEKE

DTTNRDRDKQ

YRIECFSVGP

KQAIEAESKI

IATSSLSCSE

ARNYRGDEVD

TSFSDTASKI

ENKDKLNEED

SEKRKQALAD

ETVKDYATAQ

FKQAVKEFND

KMIRAIDKIJC

SKSGTAASSD

ICUILIAFFST

LEKLKLDEKY

SAADDEICKRN

AAKQYANGNI(

DVYXKVAL

t31--2.

CKFFGNKSASKEKEETSFSDTASKISKSGTAASSDKQEKNTSDVTGDAKHSSpyMLAfALIVSDTTRDRDKQE NKIINMUZ FTKYSLSYKTYNITGCTREFVPERQLDELL

EKYTQLSTMLKSAVPSYYKLDSIAQYKEAIKQAIEAESKIETVDYATAQSAADDEKRNIDNLKIRDVLI

IKKTIEASRSYAlAFAIATSSLSCSEFKQAVKEFNflAAKQYANGNKGDNAVVIVGTISSMPYVKFDEFAAKM

FARNYRGDEVDKMIRAIDK

f32-4 .nt TAAGGAAATA TGAGGAATAT TAGCAATTGT ATCAAATATA TTATATTAAC AATGCTTATT GGATI'ATTAA TTTTTTGTTG TGCAACCTTT GTTTGGTTGA *TTGGAATTTT TTATTCAAAT AACTTTAAAG AAGAGCGGAA TTATTCAATA AGCCCAATAG ATAGTGTTAT TATGCGTAAA TGTTATITA AAGAATTTAA GTCTGGACTT ATTAAAAGCG TATTCTTTAA GAAATTAGAT WO 98/590~71 196 TABLE 1. Nucleotide and Amino Acid Sequences PCrfUS98/1271 8

GTAAATGTTA

AATTCWI'ATC

TTTAAAAATG

GTTTACGGAG

GTTAAATTAA

AACATTAATG

ATTTCCCATA

TTTCAAACAC

ACTCTAAAAA

CATCTTATCA

TTAT'rTTTAA

GATTI'AGA.TA

ATAAAATGAA

ATGCTTTATT

ATAATAAAGA

CAGAAAAGGA

TTTTAAGGAG

TATGGAGTTT

TGGTATAGAT

CTCAAAAGAG

ACAATATACT

TAACTCGTTA

GTATATTTTA

GAATAGTTCT

CTAAATAAGG

GTCGTAGTG

GATGCTAAAT

GCTTIATI'CC

CCAGCAA'rrG

TT~AAAGCAAA

CAAACTAATA

TACTAA

TAGATAAACA

ATAATGGATT

TATACGATCA

AAATTATTGG

TAGTAAATGT

AAACTTTAAA

ATTTCTTATC

AAATCTGCTA

TTTAATGAAT

ACGTGATATG

CAATTATGAT

TTTCAAAATT

AGTTACTTTG

AAAGTATAAT

t32-4 .nt

AAATAACTTTAAAGAAGAGCGGATTATTCAATAAGCCCAATAGATAGTGTTATTATGCGTAAATGTTATTTTAAA

GAATTTAAGTCTGGACTTATTAAAAGCGTATTCTTTAAGAAATTAGATGTAAATGTTAACTCTAAAATTTTAAGG

AGCTAAATAAGGTAGATAAACAAAATCTGCTAAATTCTTATCCATCTTATCATATGGAGTTTGTCGTAGTTGATAA

TGGATTTTTAATGAATTTTAAAAATGTTATTTTTAATGGTATAGATGATGCTAAATTATACGATCAACGTGATATG

GTTTACGGAGGATTTAGATACTCAAAAGAGGCTTATTCCAAATTATTGGCAATTATGATGTTAAATTAAATAAAA

TGAAACAATATACTCCAGCAATTGTAGTAAATGTTTTCAAAATTAACATTAATGATGCTTTATTTAACTCGTTATT

AAAGCAAAA.ACTTTAAAAGTTACTTTGATTTCCCATAATAATAAAGAGTATATTTTACAAACTAATAATTTCTTA

TCAAAGTATAATTTTCAAACACCAGAAAAGGAGAATAGTTCTTAC

f32-4.aa

GNMPRNISNCI

YFKEFKSGLI

KCNVIFNGIDD

INDALFNSLL

KYIILTM.LIG

KSVFFKKLDV

AKLYDQRDMV

KQKTLKVTLI

LLIFCCATFV WMIGIFYSNN FKEERNYSIS PIDSVIMRKC NVNSKNFKEL NKVDKQNLLN SYPSYHMEFV VVDNGFI !NF YGGFRYSKEA YFQIIGNYDV KLNKMKQYTP AIVVNVFKIN SHNNKEYILQ TNNFLSKYNF QTPEKENSSY t32-4.aa NNFKEERNYSI SPIDSVIMRKCYFKEFKSGLIKSVFFKKLDVNVNSKFKELNKVDKQNLLNSYPSYFVmN

GFLFIFNGIDDAKLYDQRDMYGGFRYSKEAYFQIIGNDKKQYTPAIVFKININALFSLL

KQKTLKVTLISHNNKEILQTNNFLSKYNFQTPEKENSSY

f4-15 .nt

TAAATGAGCA

TCTATAAATA

CAAAATATTG

ACGGTATCAA

AAGTACTACA

GAAAAGGAAT

TTGAGCATCT

TCAACTTTAA

TTATTATTTG

AATCCCCCAA

ATTIAAAAAGG

AAAAAAGATT

TTGGACCTAC

GACACAATAA

AAAAAGTAAT

AAGAACAAAA

AAAAACAAGA

TTCAAACGGT

AGCAAGCTTA

TTCTAAAACC

TAPATAAATAA

AAAATTTCAA

TCTTAACCCT

ACGACATCCA

GTACTGGTGA

ATCATTCAAT

TGCCTCACGA

CAGACTTAAA

TTTAATATTA

AACCAAAGAA

GCCTGAAAAA

AGAAATAAGG

TCCGATTCAA

AGAAGATAAA

AAAATTGTTA

AGAAATI'AAA

TAAAGATAAA

AAAACCCAAA

GAAA.TACTTA

AGATTACAAC

ACAAGTCTTT

TAATCTAAAA

CTAGAAATT

AAAACATCTG

CAGAAACAAA

GAATCAAATC

ACATTCACTC

ATCTTGCCCA

GACTTTAAAG

AATATTGAGA

AATAACAACA

GATTATATTT

AATCCTATCT

AAAGTGACTA

CAAATGAATA

TTAGTAATTC

TGATCTTGTC

AAAAGCAAGA

ATGCAGCAAA

AAATTCCAAA

TTGATTTTAG

CACAGGGGAA

CCCCAGAAAA

ATT'rCTTCCA

ACACTATTAA

TAAAAGACCT

ATAGATTTCA

TAGCGAAAA

AAAAT'rTCAC

AAAAAGAATT

TTGTGATTTA

ATCTGAAAAA

AATAATCCCT

AAGCATTGAG

CATCACAAGA

AGTGGAGTCT

TCCAAAAAGC

AAATCAAGAC

CATCATGCTC

tAAAGACACA

AATAAAAAAC

AACAATAGAA

TAAAATTTTA

AGTGTAA

t4-15 .nt

TTGTGATTTATCTATAAATAAAGAACAAAAACCAAAGAAAAACATCTGAAAAGCAAGAATCTGCAAT

ATTGAAAAACAAGAGCCTGAAAAACAGAAACAAMTGCAGCAAA.ATAATCCCTACGGTATCAAAACGGTAG

AAATAAGGGAATCAAATCAAATTCCAAAAAGCATTGAGAAGTACTACAAGCAAGCTTATCCGATAACTTCAC

TCTATTGACCAAAAGATTTAACGAAAATTGC!CCGGAAT

WO 98159071 PCT/US98/12718 197 TABLE 1. Nucleotide and Amino Acid Sequences GAGTCTTTGAGCATCTTAATAAATrTA TTTAAAGCCCCAGAAATCCAAAAAGCTCAACTTTrAA

AATTAAAAATAAAATA~GAGAT~CTTCCAAATCAAGACTTA

T

ITfATTTGTCTTAACCCTTAAGA

TAAAAATAACAACAACACTATTIAACATCATGCTCAATCCCCCAAACGACATCCAAAAACCCAAAGATTATATTTTA

AAAGACC TAGCCATAAGGATGGTGAGAA.ATACTTAAATCCTATCTATAGATTTCAAATAAAAA

ACAAAAAGATATCATTCAATAGATACAACAAAGTGACTATTAGCGAAAAAACAATAGAATTGGACCTACTGCC

TCACGAACAAGTCTTTCAATGAATA.AAAATTTCACTAAA

.aa

MSIKCVILILL

VSIQ'rVEIRE

SILINKKLLD

PPNflIQKPKD

DLLPHEQVFQ

EILILSCDLS

SNQIPKSIEK

FKAPENPKSS

YILKDLKDTI

NNIQ*=ILD

INKEQKTKEI(

YYYKQAYPIQT

TLKFKEIKN

KKGTGEKYLN

TITDLNNLKL

TSEKQESEKQ

FTLDFSITRE

IENFFQNQDL

PIYRFQIKNK

VIQKELV

NIEKQEPEKQ

KE=LPEDKI

LFVLTLKDKN

KDYHS IDYNK

KQNAAKIIPT

LPTQGKVESL

NNNTINIMLN

VTISEKTIEL

t4-15 .aa CDLSINKQKTKEKTSEKQESEKQNIEKQEPEKQKQNAAKII PTVS IQTVEIRESNQIPKS IEKYYKQAYPIQTFT

LDFSITREKEFLKPEDKILPTQGKESLSILINKKLLDFKAPENPKSSTLKNFKEIKIENFFQNQDLLFVLTLKD

KITINILPPNDIQKPKDYILKDLKDTIKKGTGEKYLNPIYRFQIKN =DYHSIDYNKVTISEKTIELDLLP

HEQVFQMNKNFTK

f4-50 .nt

TAGAAGGAGG

AAACTATTGG

TCCTCTAAGG

GTACTTTTTG

GCCTTAAGAG

GAAGAAGAAG

GACTTAATGC

CGTGTTTTAG

AAAGCTCAAA

GGAGAGAAAA

AAAAAATGAA

TCGCATGTAG

AT'rTAAAAAA

AAGCTTTTAC

AAGCAAAAGT

CTTTAAAGCT

TTGAGGTTGT

AGGAA.TCTAA

TAGAAAATCA

AAAATAATAA

AATTGGAAPAG CTAAATTCAA TAGTTATAGC TATTGGATTA GTAGAAAGAA CAAATGCAGC CAAAATT'rTA AAAATAAAAA .AAGAAGCCAC AGGTCTTAAA ACCGGTTCCA-AGGTAACAAG ACAAGCCATT GTTGAAACA G GAAAGTTCCT TAAAGAAACT GGAAACAGTG GTCAATTCTT AGAATCGCTA GAAGACGTTG GAATAATAGG AAATAATCCT ATAAACACAG CTGAAAGATT ACTTAAAGTG GTTAAGGAAA AACAAAATAT AAGCAAAAA-A AAGAPLATAA

CTTGTTTTTT

TCTTGAATCG

GGGAAAAGGT

TGGTGGACTA

TAAGATAATA

GGCTATGTTT

CTTAAAAGCC

GCTTGCGGCT

TGAAAATGGT

t4-50 .nt

ATGTAGTATTGGATTAGTAGAAAGAACAAATGCAGCTCTTGAATCGTCCTCTAAGGATTTAAAAAACAAAATTTTA

AAAATAAAAAAGcACCGGGAAAAGGTGTACTTTTTGAAGCTTTTACAGGTCTTAAAACCGGTTCCAAGGTAA

CAAGTGGTGGACTAGCCTTAAGAGAAGCAAAAGTACAAGCCATTGTTGAAACAGGAAAGTTCCTTAAGATAATAGA

AGAAGAAGCTTTAAAGCTTAAAGAAACTGGAAACAGTGGTCAATTCTTGGCTATGTTT.GACTTAATGCTTGAGGTT

GTAGAATCGCTAGAAGACGTTGGAATAATAGGCTTAAAAGCCCGTGTTTTAGAGGAATCTAAAAATAATCCTATAA

ACACAGCTGAAAGATTGCTTGCGCTAAAGCTCAAATAGAAAATCAACTTAAAGTGGTTAAGGAAAAACAAAATAT

f4-50.aa KEEKMIKIGKL NSIVIALFFK LLVACSIGLV ERTNAALESS SKDLKNK ILK IKKEATGKGV LFEAFTGLKT GSKVTSGGLA LREAKVQAIV ETGKFLKIIE EEALKLKETG NSGQFLAMFD LIILEVVESLE DVGIIGLKAR VLEES(NPI NEAERLLAAK AQIEQLKVV KEKQNIENGG EKKNNKSKKK K t4-50 .aa WO 9859071PCTIUS98/12718 WO 98159071 198 TABLE 1. Nucleotide and Amino Acid Sequences CSIGLVRTNALESSSLKKILKIKKEATGKGVLFEAFTGLKTGSKVTSGGLLREAKVQAIVETGKFLKI IE EEALKLKETGNSGQFLAMFDLMLEVVESLEDVGI IGLKARVLEESKNPNAELLAAKAQIENQLKVVKEKQNI

ENGGEKKNKSKKKK

f4-66 .nt

TAATTITTTAA

ATTTTATTAT

AGGAGAAGGC

ATTTCTTI'G

GTAGTTCTTG

GTAAAAGAAA

GCTCTTGAGA

GAAAAAACTT

GCTTGTA.ATC

AATTTAAATA

TTGTTATTTr

CTTCAAAGGT

TAGATTCTTT

ATAGCAATCC

TGCTTGTTAC

GCTCAAATGT

ACATAGATAA

T'rGTAAAAA TTrTACATAAT

ATTATTCTTT

TTTAAATGCT

AAATGATGAT

CGACAAGTTr TGT'rGTTAAG

TGCAAATGTT

TTTGCGACAA

TTATGATGCA

AGTAATGTGT

TCTTGTAAAG

TCTAATGGTG

CAAAAAGAAG

AATCAA.ATTT

TGTI!TAAAGG

GCCAATGCTA

TCTTTTATGA

TCTGCTTCGT

GTGGGAGACG

AATTTAATTA

CATCAAALTAA

CTTTGTTTTT

TTAATTTAAA

CCAAAAGAAA

AACAGCAATT

CTACTAAAAA

TTTAA

TATGAAAAAT

TTCTGATCTT

AGAACTTAAA

TCTTGAACAG

TGAAGAGAAG

GGCTAAAATG

GCTACAGGTT

CATTGAAGAG

t4-66 .nt

C

S

C

55S5

TTGTAAGAATTTAATATCTGATCTTAGGAGAAGGCCTTCAAAGGTTTTAAATGCTTCTAATGGTGCATCAAAT

AAAGmAACTTAAAATTTCTTTTGTAGATTCTTTAAATGATGATCAAAAAGAAGCTTTGTTTTTTCTTGAACAGGTAG

TTCTTGATAGCAATCCCGACAAGTTTAATCAATTTTTATTAAATGAAGAGAAGGTAAAAGAAATGCTTGTTAC

TGTTGTTAAGTGTTTAAAGGCCAAA.AGAAAGGCTAAAATGGCTCTTGAGAGCTCAAATGTTGCAAATGTTGCCAAT

GCTAAACAGCAATTGCTACAGGTTGAA.AAAACTTACATAGATAATTTGCGACAATCTTTTATGACTACTAAAAACA

TTGAAGAGGCTTGTAATCTTGTAAAAAATTATGATGCATCTGCTTCGTTT

f4-66.aa FLKFKYLHNS NVCGRRMKNI LLFVILLFFS CKEFNYSDLR RRPSKVLNAS NGASNKELKI SFVDSLNDDQ KEALFFLEQV VLDSNPDKFN QIFNLNEEKV KF.MLVTVVKC LKAIKRKAKMA LESSNVANVA NAKQQLLQVE KTYIDNILRQS FMTTKNIEEA CNLVKNYDAS ASF t4-66 .aa CKEFNYSDLRRRPSKVLNA.SNGASNKELKISFVDSLNUDQKEALFFLEQVVLDSNPDKFNQ

IFNLNEEKVKEMLVT

VVKCLKAIXRKAKMALESSNVANVANAKQQLLQVEKTYIDNLRQSFMTTKNIEEACNLVKNYDASASF

f42-1.nt

TAATTATTAA

TCTACAATAT

AACAAAATGG

TGTTTAAGTA

ACTAGAAGTC

TATTCATATT

AATCTAAGGA

TAGCCTTCTT

ATGATATTTT

AAAATGAGGC

GTTCTTATTC

GCAAAAGCAA

GAAGAGATTT

GTTAGTATTA

TAATTTAGAA

TATAGTTAAA

TTCTAGAGAG

CTGA

ATGAACAAAA

GGTTGTGATT

AAGAAATACA

AATTCTAAAA

ACTAATGTTT

AATTTTCTAT

TGTCAAGCAA

TGGATAATC

TTAAATTAGG

CGGATTCCTA

TTCATTATTA

TAATGCTGAA

AAATTATAAA

TGTAAATAAT

TAATAAAACC

t42-1.nt

TTGTGATTTGTCAAGCAATAATGCTGAACAAAATGGATGATATTTTTAATTTAGAAAGAATACAGTAAT

TCAAATTATAAATGTTAAGTAAATGAGGCTATAGTTAAAAATTCTAAAATTAAATTAGGTGTATAATACTA

GAAGTCGTTCTTATTCTTCTAGAGAGCTAATGTTTCGGATTCCTATAATAAAACCTATTCATATTGAAGA

C

f42-1.aa LLKSKEKRFM NKXFSISLLS TILAFLLVLG CDLSSNNAEN KMIDDIFNLEK KYMDNSNYKC LSKNEAIVKN SKIKLGVNNT RSRSYSSRET NVSDSYNKTY SYCKSN WO 98159071 WO 9859071PCTIUS98/1 2718 199 TABLE 1. Nucleotide and Amino Acid Sequences t42-l.aa CnLSS1NDDIFDINLEEYMDNSNYKCLSIEAV SKIKLGINNTRSRSYSSRETNVSDSYNKTYSYCKSN f43-3 .nt

TGAATATTAA

TITI'TACTAA

AGACAAAAAC

GACCTGCTTA

GCTTTAACTG

GGTGCACTTA

CAAAAAAGCA

TAATAAAA

TGCTAAACAG

GTGATTTAAC

GAGAAAAGCT

GTGCTGGAGA

ATCATATAAA

CCTTCAAAGA

AGGAATAANA

CTGTAAMTCT

CCAAAAAGAA

ATCTGAAGAC

ATTTGATAAA

GALGTGAACTT

GGTGGTTAAG

ATGAAAATTA

AATGATACTA

GCAACACAAG

CAAAAAACAC

TTTTTAGGAT

GATAAGTGTA

GGGGCTCTTG

TCAACATATT

ATACTAGCCA

AAAAACCAAA

ATCTTGACTG

ATGACGAAGA

CTG7GGGATAA

GTGGCGGTAT

ATTTTIGTTTA

AACAAAAAGT

ATCTAAAGAA

GTTAAAAACC

CAAAATAAAA

TTCTGAACAA

AGATAGTTTT

S S 5~ S S

S.

5*

S

S*

S. 5* S S

S.

GCAACTAGTG CAAGTAGTAC CTGCCAAGCT CAGCAATAA t43-3 .nt

CTGTAATTCTAATGATACTAATACTAGCCAAACAAAAAGTAGACAAAAACGTGATTTAACCCAAAAAGAAGCAACA

CAAGAAAAACCAAAATCTAAAGAAGACCTGCTTAGAGAAAAGCTATCTGAAGACCAAAAAACACATCTTGACTGGT

TAAAAACCGCTTTAACTGGTGCTGGAGAATTTGATAAATTTTAGGATATGACGAAGACAAAATAAAAGGTGCACT

TAATCATATAAAGAGTGAACTTGATAAGTGTACTGGGGATAATTCTGAACAACAAAAAAGCACCTTCAAAGAGGTG

GTTAAGGGGGCTCTTGGTGGCGGTATAGATAGTTTTGCAACTAGTGCAAGTAGTACCTGCCAAGCTCAGCAA

f43-3 .aa ILIIKKGIXM KIINILFCLF LLMLNSCNSN DTN'rSQTKSR QKRDLTQKEA TQEKPKSKED LLREKLSE-DQ KTHLDWLKTA LTGAGEFDKF LGYDEDKIKG ALNHIKSELD KCTGDNSEQQ KSTFKEVVKG ALGGGIDSFA TSASSTCQAQ Q t43-3 .aa

CNSNDTNTSQTKSRQKRDLTQKEATQEKPKSKEDLLREKLSED)QKTHLDWLKTALTGAGEFDKFLGYDEDKIKGAL

NHIKSELDKCTGDNSEQQKSTFKEVVKGALGGGIDSFATSASSTCQAQQ

f45-2.nt

S

S..

S5 S. S

S

TAGGAGAGAA

ATTTCTTGCA

AAAGGATTTG

AAAGTAGATG

GA.TGATCCTA

AATGCATTAG

GAAGCTGAAG

AAAGAAAAAG

GAACAACAAA

AAAGAAAAAA

AAAAGGCAAG

AATATTGATG

ACTGGGCCTG

GGG'rrAGAAG

GCTAGGGACG

GPLGCCTAAGT

AAATCAAAAT

AAAGGATACA

TAATTATGAA TAAAAAAACA AGAATI'TTGC AACTGGTAAA TAAATAAGAT TTTAGATCCA AAGTAGCAAA AAAATTACAL ATGGCAGTGG AATAAATCCG TATTAAAAGC AATAGAACAA TTGATTATTT GTGCTGTT'TT GATATAAAAC AAAATTCAGA CTAAAGT'rGA

AAATAALTAGA

AAGAACAAAA

GAGAAAGAGA

TTGATAACCA

TTATAAAATG

TGTATGATGA

AGGAATCAGA

CGCTAAGAAC

TAAAAGAAAG

TAGAAGAAGT

TCAGTGACAG

AGAAAATAAA

CGAACAAAAC

AAGACATCAA

AGAGGCAGAA

AATTAAAACA

GCAAACGACT

TTTTACCAAT

AGACGAAGGA

TAAATTAAAT

TGTAAATGTT

TAAAAAATAT

TCAGTAA

GTAAAGGATA

GAAGAAGAAA

CCACCAGTAT

AGTGATGGTC

GAAAMACAAG

AAACAAGAAT

GAAGAGCAAC

CAACAAAAAC

CTTATAGCTA

GTAGGCCCAC

GGCAATAAT'r

TTAGGAAAAT

GAAGGCAATA

AAAT'rGCTTC

AAGAAGAATT

TGCCGGAAAA

AACAAGAAAA

AGAATACAGA

TAGCTAAAGC

AAAGAAAAGC

GACAACAAGA

AAATAGATGA

AAGGCGTTAT

CTATACGCGA

TATTGAAAGA

AACCATATAC

TGCGCTGATA

AGGGAAAATT

AAGTGGTACA

AATGCAGGGC

TATTCACAAT

AAAAGTAGAA

AGAAAACATT

TAAAGAAGAA

TAAAGCAGAA

AGAGGAAGAA

GATCAATGAA

AGATAGAATT

AACTTGGGAG

ATTGAGTGAT

TGGT1'ACGAA

AGAAAAATTA

TGAAGAAATT

AGCGAAATTA AAGAA.GATTr CTTAAAGATA GTTCTAAATT t45-2 .nt WO 98/59071 PCT/US98/12718 200 TABLE 1. Nucleotide and Amino Acid Sequences

TTGCAAGAATTTTGCAACTGGTAAAGATATAAAACAAATTCAGAAC-GGAAATTAGGATTTGTATAGATT

TTAGATCCAGTAAAGGATAAAATTGCTTCAAGTGGTACAAAAGTAGATGAAGTAGCAAATTACAAGAGAAG

AAAAAAGAATTAATGCAGGGCGATGATCCTAATGGCAGTGGAATAAATCCGCCACCAGTATTGCCGGAAATAT

TCACAATAATGCATTAGTATAACAAGAAATAGGTCAACAAGAAAAGTAGAGAAGCTGAA

GCTAAAGTrAGAAAAAAACAAATCAAGAAATAAAGATAAACGAAC

AAAACAAACAAGAATTAGCTAAAGCTAAAGAACAAAAACAAAAATCAAGAAGAGCAACA

AAGAAAAGCTAACGAAAAAAAAAGGAA AAACAAAAACGAAACAAGAAGAGGAA

GAAAAAGGCAAGTTGATAACCAATTAAACACTTATAGCTAAAATAGATGAGATCAATGAAATATTGATGTTA

TAAATGGCAAACGACTGTAGGCCCACAAGGCGTTATAGATAGAATTACTGGGCCTGTGTATGATGATTTTACCAA

TGGCAATAATTCTATACGCGAACTTGGGAGGGG rGAAGACAGAAGACGAAGGATTAGGAAAATTATTG

AAGAATTGAGTGATGCTAGGGACGCGCTAAGAACTAAA.TTAAATGAAGGCAATAAACCATATACTGGTTACGAAG

AGCCTAAGTTAAAAGAALAGTGTAAATGTTAGCGAAFAAAAATAAATAAAATCAAAATTAGAAGA

AGT'rAAAAAATATCTrAAAGATAGTTCTAAATTTGAAGAAATTAAAGGATACATCAGTGACAGTCAG f45-2.a ERIIMNKKTL I ICAVFALI I SCKNFATGKD IKQNSEGKIK GFVNKILDPV KDKIASSGTK VDEVAKKLQE EEKEELMQGD DPNGSGINPP PVLPEIHNN ALVLKAIEQS DGQQEKKVEE AEAKVEENKE KQENTEENIK EKEIIDEQNK QELAKAKEEE QQKEQKRHQE EQQRKAKAEK EKREREEAEQ QKRQQEEEEK RQVDNQIKTL IAKIDEINN IDVIKWQTTV GPQGVIDRIT GPVYDDFTNG NNS IRETWEG LEEESE-DEGL GKLLKELSDA RDALRTKLNE GNKPYTGYEE PKLKESVNVS EIKEDLEKLK SKLEEVKKYL KDSSKFEEIK GYISDSQ t45-2.aa

CKNFATGKDIKQNSEGKIKGFVNKILDPVKDKIASSGTKVDEVAKKLQEEEKEELMQGDDPNGSGINPPPVLPENI

*HNNALVLKAIEQSDGQQEKKVEEAEAKVEENKEKQENTEENI KEKEI IDEQNKQELAKAKEEEQQKEQKRHQEEQQ

RKAKAEKEKREREEAEQQKRQQEEEEKRQVDNQIKTLIAKIDEINENIDVIKWQTTVGPQGVIDRITGPVYDDFTN

GNNSIRETWEGLEEESEDEGLGKLLKELSDARflALRTKLNEGNKPYTGYEEPKLKESVNVSEIKEDLEKLKSKLEE

.*.VKKYLKDSSKFEEIKGYISDSQ

f47-2 .nt S 500TGAATATTAA TAATAAAAAA AGGAGTAACA ATGAAAATCA TCAACATATT ATTTTGTATA see* TCTTTGCTAC TACTAAATAG CTGTAATTCC AATGATAATG.ACACTTTAAA AAACAATGCC CAACAAACAA AAAGCAGGAA AAAACGTGAT TTAAGCCAAG AAGAACTGCC ACAACAAGAA &see.:AAAATCACTT TAACATCCGA CGAAGAAAAA ATGTTTACTT CATTAATCAA TGTGTTTAAA 0 TACACAATTG AAAAATTAAA CAATGAAATA CAAGGGTGCA TGAATGGAAA CAAAAGTAAA *:*0.:TGTAATGACT TCTTTGATTG GCTTTCTGAA GATATTCAAA AACAAAAAGA ATTAGCTGGT GCTTTTACCA AGGTTTACAA CTTCTTAAAA TCAAMhGCAC AAAATGAAAC TTTTGATACT TATATTAAAG GAGCTATTGA TTGTAAAAAA, AACACTCCAC AAGATTGTAA TAAAAATAAT GAAATATGGG GAGGTGGACA ACTTANTAGN GCAATATTTT AG t47-2 .nt CTGTAATTCCAATGATAATGACACTTTAAAAAACAATGCccAACAAACAAAAAGc AGGAAAAAACGTGATTTAAGC CAAGAAGAACTGCCACAACAAGAAAAATCACTT'rAACATCCGACGAAGAAAAAATGTTTACTTCATTAATCAATG TGTTTAAA ATGAATAAATAAAAAGGGTGCATGAATGGAAACAAAAGTAAATGTAATGA

CTTCTTTGATTGGCTTTCTGAAGATATT

CAAAAACAAAAAGAATTAGCTGGTGCTTTTACCAAGGTTTACAACTTCTTAAAATcAAAAGCACAAAATGAAACTT TTGATACTTATATTAAAGGAGCTATTGATTGTAAAAAAAACACTCCACAAGATrGTAATAAAAATAATGAA f47-2 .aa ILIIKKGVTM KIINILFCIS LLLLNSCNSN DNDTLKNNAQ QTKSRKKRDL SQEELPQQEK WO 98/59071 WO 9859071PCT/UJS98/12718 201 TABLE 1. Nucleotidle and Amino Acid Sequences ITLTSDEEXM FTSLINVFKY TIEKLNNEIQ GCMNGNKSKC NflFFflWLSED IQKQKELAGA FTKVYNFLKS KAQNETFDTY IKGAIDCXXN TPQDCNKNNE IWGGGQLXXA IF t47-2.aa

CNNNTKRQTSKRLQEPQKTTSEX=SIVKTELNIGMGKKN

FFDWLSEDIQKQKELAGAFVNFLKSKAQNETFDTYIXGAIDCITPQDcNMNE f49-2 .nt TAAATGTTICA AAACAATCAT TTAACAACTT TCTTTGTTTT @6 0@ S 0e S 0 @0 @0 S S 0

OSOS

S S 00 S 0@ 0 0 55 0 SC 55 05 0

C

0e05

S

@600.5

C

0S0 CO.

0 05CC C S 0@ S

CC..

0 eggs

ACGGGGATTG

AAAGTTGCTG

GGTGCTGGTA

GTTAGTGGGG

GGAGAGAAGC

GATGGTGCGG

TTGAGGGGGA

GAGGGGGCTA

GCTGAGGGGG

GCGAAGGTTG

GAAGCTGCTG

GCAGGGAAGT

AAGGCGGCTG

GCTGCTGGTG

ATTGCTGCTG

ATGAAGAAGG

AAGTTTGCTG

GCTGCTGAGT

GGTACTGATG

GCGAGTGTGA

GAAAAGCTGA

GGGAAGGCTG

GCTGTTAGTG

GCTGATCAGG

AAGGGTNATG

CTAAGGGAAT

CTGCTGAAGG

ATGCTGGGGA

AGCAGATATT

CTGGGGAGGC

AGTTTAAGGA

TGGCTAAGGA

TTAAGGGAGC

CTTCAAGTGG

CTGATAAGGC

GGGGGAGTAA

TGTTT~GGGAA

GTGCTGTTAG

CGGCTGCTGG

CTATTGGGAA

ATGATCAGAT

TGAAGAGTGG

TGTTGGATAA

CAATTGGAGA

CGGGGA'FrGC AAGTT1GCTGC

GTGCTGGTGC

CTGT TAGTGG

AGGGAAAGAA

NGGAGAATGG

TAAACAAAAA

TATTAATTGT

AAAGGAGATT

GGAGAATAAT

CAGTGAGGCT

AAGTGCGATT

TAAAAATCCG

TGAGATGAAG

TG7GAAAGTTT

TGGCGAGTTG

TACTGCTGCA

GAGTGTGAAG

AAAGCTGAAA

AGTTGATGCT

TGCTGTTAGT

TGATCAGGAG

GGGTGATGCG

TGCTGCTGCT

TGGTGGTGAG

GCTGGTAAAA

AGTTIGTGGCT

TAAGGGGATA

TGCTACAGGG

TAATGCTGGG

GGAGCAGATA

G7CCTGGGGAT

TGCGGAGTTT

AATATGAAAA.

AAAAGCCAAG

GTGAAGCTG

GAAAAGGCAG

GCTAGCAAGG

GTTAAGGCTG

ATTGCTGCTG

AAGGATGATC

GCTGTGAAGA,

TGGATAAGC'

ATTGGAGAAG

GGGATTGCTA

GTTGCTGCTG

GCTCATGCTG

GGGGAGCAGA

GGAAAGAAGC

GAGAATGGTG

ATTGCTTTGA

AAAGGGAAGG

GCTGTAAAGA

AATGCTGGTG

AAGGAGATTG

GAGAGTAATA

GACAGTGAGG

TTAAGTGCGA

GCTANAAATC

AANNATGANG

AAATT'rCAAG

TTGCTGATAA

CTGGGGGGAG

GGAAGTTGTT

CGGCTGGTGC

CTGGTGAGGC

CTATTGGGAA

AGATTGCTGC

ATGATGAGAA

TGGTAAAAGC

TTGTGGCTGA

AGGGGATAAA

CTAALAGAGGG

GGGACAGTGA

TATTAAiGTGC

CTGGGGATGC

CGGAGTTTAA

GGGGGATGGC

CTGAGGGGGC

CAGCTGAGGG

CTGCAAAGGT

TTGAAGCTGC

AAGGGGCAGG

CTGCTAGCAA

TTGTTAAGGC

CGATTGCTGC

GATGA

TGCAAT'rTTA

GGCGAGTGTG

TGAAAAGCTG

TGGGAAGGCT

TGTT AGTGCT

TGCGCAGGAT

GGGTAATGAG

TGCTATTGCT

AGGGAAGGCT

TGTAAAGACA

TGATAATGCT

GGAGATTGTT

CAATGAAAAG

GGCTGCTAGC

GATTGTTAAG

TAAAAATCCG

TCATGATGGG

TAAGGATGGA

TATTAAGGGA

GGCTTCAAGT

TGCTGATAAG

TGGGGGGAGT

GAAGTTGI'T

GGCGGCTGGT

TGCTGATGCG

TGCTATTGGG

t49-2 .nt

TTGTAAAAGCCAAGTTGCTGATAAGGCGAGTGTGACGGGGATTGCTAGATAGAATTTGAAGCTGCT

GGGGGGAGTGAAAAGCTGAAAGTTGCTGCTGCTGAGGGAATAAAGAGAGTTTTGGGAAGG

CTGGTGCTGGTAATGCTGGGGACAGTGAGGCTGCTAGCAAGGCGGCTGGTGCTGTTAGTGCTGTTAGTGGGGAGCA

GATATrrAAGTGCGATTGTTnGGCTGCTGGTGAGGCTGCGCAGGATGGAGAGAAGCCTGGGGAGGCTAAAAATCCG ATTGCTGCTGCTATTGGGAAGGGTAATGAGGATGGTGCGGG AGAGAAGAAGAGATCAGATTG CTGCTGCTATTGCTTTGAGGGGGATGGCTAAGGATGGAAAG T1GTTAGAGTAAGGAGTGA

GGGGGCTATTAAG

f49-2 .aa MFKTIIKQ KN

VAAAEGENNE

EXPGEAKNPI

GAIKGAGELL

AAG7GSKKLKV

AGAAAGDQEG

MKKISSAILL

KAGKLFGKAG

AAAIGKGNED

DKLVKAVKTA

AAAKEGNEKA

KKPGDAXNPI

T'rFFVFINCK

AGNAGDSEAA

GAEFKDEMKK

EGASSGTAAI

GKLFGKVDAA

AAAIGKGDAE

SQVADKASVT

SKAAGAVSAV

DDQIAAAIAL

GEVVAflDNAA

RAGDSEAASK

NGAEFNHDGM

GIAKGIKEIV

SGEQILSAIV

RGMAKWGKFA

KVADKASVKG

AAGAVSAVSG

KKDDQIAAAI

EAAGGSEKIJK

KAAGEAAQDG

VINDEKGYKAE

IARGIKEIVE

EQILSAIVKA

ALRGMAKDGK

WO 98/59071 WO 98/907 1PCT/US98/12718 202 TABLE 1. Nucleotide and Amino Acid Sequences FAVKSGGGE-K GKAEGAIKGA AELLDKLVKA VKTAEGASSG TDAIGEVVAN AGAAKVADKA SVTGIAKGIK EIVEAAGGSE KLKVAAATGE, SNKGAGKLFG KAGAGANAGD SEAASKAAGA VSAVSGEQIL SAIVKAAflAA DQEGKKPGDA XNIPIAAAIGK GXXENGAEFX XXG t49-2 .aa

CKSQVADKASVTGIAKGIKEIVEAAGGSEKLIVAAAEGENNEKAGKLFGKAGAGNAGDSEAASKAAGAVSAVSGEQ

ILSAIVKAAGEAAQDGEKPGEAKNPIAAAIGKGNEDGAEFKDEKKDDQIAAAIALRGMAKIGKFAVKNDEKGYAE

GAIK

f 5-14 .nt

TAGAAATTCA

GCTGTTTTTG

AATGCAAAAG

ATTACTTICAA

GATAATGAAT

TTGCCGGAAA

GGTGGTCAAC

GAAGTTGTAG

AGTCAAAAGC

GCAAAAGCTA

CAACAGGAAG

AAACAAGAAG

GAAATAAATA

ATAGATAAAA

AAAACTTGGG

TTGAGTGATA

GTTCTAGAAA

TTAGAAAAAT

TTTGAAGAAA

AAACAAAGGA

CACTTATAAT

GGAAAATTAA

GTAGTTCAAA

TAATGCAGGG

ATAGTCATGA

AAGAAGACCA

AGGAGAAAAA

AAAAAGAAGA

GAGCAGATAG

AAGCTAGGGT

AAGAAAAGAA

AGGATATTGA

TTACGGGGCC

GAGATTTAGA

CTAGACATAA

AGGAGCCTAA

TAAAATCAGG

TTAAAGGATA

GAAAACAAAA

TTrCTTGTAAA AGGATTTTT1A

AGTAGATGAA

CGATGATCCT

CAATCCACCA

AAAAGCAAAA

AGAAGAACAA

AGAGAGAAAC

AGAAAGAGAA

TAAAGCAGAA

AGTTAAATAT

TGGTATAAAT

TGTATATGAT

GGATGAAGAA

TTTAAGAACC

TTTAAAAGAA

ATTAGAAGAA

CATTGAGGAT

AGTATGAATA

AATTATGCAA

GATAAGGTTT

TTAGCAAAAA

AATAACAGAG

GTACCAAAAG

GAATCTAAAG

GATAGTAAAA

TCTAAAGAAG

GAACGACTAA

AAAGAAAAAC

AAAATTAAAA

GGTAAAACAA

GATTTTACTG

GGCGAAGAAT

AAATTAAATG

AATGTAAATG

GTTAAAAAAT

AAAA.AATATT

CTGGTAAAGA

TAGATCCAGC

AATTACAAGA

CAATAGCACT

TAAAAGCAGC

ATAAAGTTGA

AAGAAAAAGT

AACAACAAAA

AACAACAAGA

AAGAAAGAGA

CACTTACAGA

TTGTAGGAGC

ATGGGAATAA

TAGGAAAATT

AGGGTAATAA

TTAGTGATAT

GATTATTTTT

TATAAAACAA

AAAAGATAAA

AGAAGATGAA

GTTACCAGTA

AGCACAAAGT

GGAAGAAAAA

GGAGAAGCAA

ACAAGAAGAA

ACAAAAAAGA

GGAACAACAA

CAAAATAGAT

AGAAGAAGTT

AGCTATATAC

ATTGAAAGAA

AGCATATATT

TCAATCAGAT

too.

o* ATTTTGAAAA TGAAGATAAT AGTAATTCAT ATTGA -14. nt

TTGTAAAAATTATGCAACTGGTAAAGATATAAAACAAAATGCAAAAGGGAAAATTAAAGGATTTTTAGATAAGGTT

TTAGATCCAGCAAAAGATAAAATTACTCAAGTAGTTCAAAAGTAGATGAATTAGCAAAAAAATTACAAGAAGAAG

ATGAAGATAATGAATTAATGCAGGGCGATGATCCTAATAACAGAGCAATAGCACTGTTACCAGTATTGCCGGAAAA

TAGTCATGACAATCCACCAGTACcAAAAGTAAAAGCAGCAGCACA.AGTGGTGGTCAACAAGAAGACCAAAAAGCA

*AAAGAATCTAAAGATAAAGTTGAGGAAGAAAAAGAAGTTGTAAGGAAAAGAAAGATAGTAAAAA.AG.

AA.AAAGTGGAGAAGCAAAGTCAAACAAGAGAAAAATCTAA.AGAAGAACAACAAAAACAAGAAGA

AGCAAAAGCTAGAG AAAAAAAAGAGAC AACAAGAAAAGCAAGGAAGAAGCT AGGGTTAAAG AAAAAAAAGAGGGACAAAAAGAAGAAAATTAAATATA AAATTAAAACACTTACAGACAAAATAGAT AAAAAGAATAGGTATAAATGGTAAAACAATTGTAGG AGCAGAAGAAGTTIATAGATAAAATTrACGGGGCCTGTATATGATGATTTTACTGATGGGAATAAAGCTATATACAAA

ACTTGGGGAGATTTAGAGGATGAAGAAGGCGAAGAATTAGGAAAATATTGAAGAATT~GAGTGATACTAGAATA

ATTTAAGAACCAAATTAAATGAGGGTAATAAAGCATATATTGTTCTAGAAAGGAGCCTAATTTAAAAGAATGT

AAATGTTAGTGATATTCAATCAGATTTAGAAAAATTAAAATCAGGATTAGAAGAAGTTAAAAAATATTT'rGAAAAT

GAAGATAATTTTGAGATAAGTCTGAGGATAGTAATTCATAT

f 5-14 .aa

KFKTKEKTKS

TSSSSKVDEL

GQQEDQKAKE

KARAD REREE

INKDIDGING

MNKKILI IFA

AKKLQEEDED

SKDKVEEEKE

RLKQQEQKRQ

KTIVGAEEVI

VFALIISCKU

NELMQGDDPN

VVEEKKEEQD

QEEARVKAEK

DKITGPVYID

YATGKDflCQN

NRAIALLPVL

SKKEKVEKQS

EKQEREEQQK

FTDGNKAIYK

AKGKIKGFLD

PENSHDNPPV

QKQKEEERNS

QEEEKKVKYK

TWGDLEDEEG

KVLDPAK.DKI

PKVKAAAQSG

KEEQQKQEEA

IKTLTDKIDE

EELGKLLKEL

WO 98/59071 WO 9859071PCTIUS98112718 203 TABLE 1. Nucleotide and Amino Acid Sequences SDTRHLRTK LNEGNKAYI LEKEPNLKEN VNVSflIQSDL EKLKSGLEEV KKYFENEDNF EEIKGYIEDS NSY t5-14 .aa CKNYATGKDIKQNAKGKIKGFLflKVLPADKITSSSSKVDELAKKQEEDEDNELMQGDDPNNRAIALLPVLPEN SHD)NPPVPKVKAAAQSGGQQEDQKAKESKE; EKEVVEE=CEQDSKKEKVEKQSQKQKEERNSxEQQKQEE AKARAflREREERLKQQEQRQQEEARVKAEKKQEREEQQKQEEEIXVXYKIKTLTDKIDEInKIDGINGKTIvG AEEVIDKITGPVYDDFTDlGAIYKTWGDLEDEEGEELGT.KELSflTPRLRTKLNEGNKAyTVLEKpNLKENv

NVSDIQSDLEKLSGLEEVKKYFENE-DNFEEIKGYIEDSNSY

f5-15 .nt TAACTTATGA ATAAGAAAAT GAAAATGTTT ATTATI'TGTG CTGTTTTTGC AI'GATGATT TCTTGCAAGA ATTATGCAAG TGGTGA.AAAT CTAAAAAATT CAGAACAAAA TCTAGAAAGT TCAGAACAAA ATGTAAAAA AACAGAACAA GAGATAAAAA AACAAGTTGA AGGATTTITTA GAAATTCTAG AGACAAAAGA TTTATCTAAA TTAGATGAAA AAGATACAAA AGAAATTGAA AA.ACAAATTC AAGAATTAAA GAATAAAATA GAAAAAT'rAG ATTCTAAAAA AACTTCTATT GAAACATATT CTGAGTATGA AGAAAAAATA AACAAAATAA AAGAAAAATT GAAAGGAAAA GGACTTGAAG ATAAATTTAA GGAGCTTGAA GAGAGTTTAG CAAAGAAAAA GGGGGAGAGA AAAAAAGCTT TACAAGAGGC CAAACAGAAA TTTGAAGAAT ATAAAAAACA AGTAGATACT TCAACTGGGA AAACTCAAGG CGACAGGTCT AAAAACCGAG GTGGTGTTGG AGT4GCAAGCT *TGGCAGTGTG CCAATGAATT AGGTTTGGGT GTAAGTTATT CTAATGGCGG CGGCA AGCATACG ATAATAGCAAACAAAGTT ATAGATGATT CTCTTAAAAA GAT'rGAAGAA GAACTTAAGG GAATAGAAGA AGATAAAAAA GAATAA t5-15.nt TGCAAGAA6TTATGCAAGTGGTGAAAATCTAAAAA-ATTCAGAACAAAATCTAGAAAGTTCAGAACAAAATGTAAAA

AAACAAACAGAATAAAAACAATTGAGGTTTTAGAXICTAGAGACAAAAGATTTATCTAAATTAG

ATAAAGAAAAAAATGAAAAACAAATTCAAATAAATAATGAATA TCTAAAAA AACTTCTATTGAAACATATTCTGAGTATGAAGAAAAAATAAACAAA6ATAAAAAATAAGAAGATT GAAGATAAATT1TAAGGAGCTT AGGGIrACAGAAGGGGGAAAGTTTACAAGAGGCCA

ACAGAAT~GAAGATATAAAACAAGTAGATACTTCAACTGGGAAAACTCAAGGCGACAGGTCTAAAAACCG

AGGTGGTGTTGGAGTGCAAGCTTGGCAGTGTGCCAATGAATTAGGTTTGGGTGTAAGTTATTCTAATGGCGGCAGT

GACAACAGCAATACTGATGAATTAGCAAACAAAGTTATAGATGATTCTCTTAAAAAGATTGAAGAAGAACTTAAGG

f 5-15 .aa- LMNKKHKMFI ICAVFALMIS CKUYASGENL KNSEQNLESS EQNVKKTEQE IKKQVEGFLE ILETKDLSKL DEKDTKEIEK QIQELKNKIE KLDSKKTSIE TYSEYEEKIN KIKEKLKGKG LZDKFKELEE SLAKKKGERK KALQEAKQKF EEYKKQVDTS TGKTQGDRSK NRGGVGVQAW QCANELGLGV SYSNGGSDNS NTDELANKVI DDSLKKIEEE LKGIEEDKKE t5-15.aa

CKNYASGENLKNSEQNLESSEQNVKKTEQEIKXQVEGFLEILETKDLSKLDEKDTKEIEKQIQELKNKIEKLDSKK

TS IETYSEYEEKINKIKEKLKGKGLEKFKELEESLAKKKGERKKALQEAKQKFEEYKKQVDTSTGKTQGDRSKNR

GGVGVQAWQCANELGLGVSYSNGGSDNSNTDELANKVIDDSLKKIEEELKGIEEDKKE

f51-2 .nt TAATTGTTTG GGGT'rGTGGT AAACTTAAGG CTTATGGAGT GGATTATGAA TAAAAAAATG AAAATATTTA TTATTTGTGC TGTATTrTGTG CTGATAAGTT CTTGCAAGAT TGATGCAACT GGTAAAGATG CAACTGGTAA AGATGCAACT GGTAA.AGATG CAACTGGTAA AGATGCAACT GGTAAAAATG CAGAACAAAA TATAAAAGGG AAAGTTCAAG GATTTTTAGA AAAGATTTTA wo 98/59071 WO 9859071PCT/US98/1271 8 TABLE 1. Nucleotide and Amino Acid Sequences

GATCCAGTAA

'rTACAAGAAG

GGAGAAGAAT

AATGCGGAAG

GAGACTGAAG

GCACAAGAAA

GAAAAGAAAC

AAACTTGCGG

AGTGTAAAAC

GATGACAACA

GGATTGGGAA

AATAAAGATA

GATGTCAGCG

GmAATATCTTA

TAA

AGGATAAAAT

AAGAAAAGGT

CAAAAGAGGA

AGGATAAGAA

AAGATGAAGA

GAAAACAACG

GAAAACGACA

ATAAAATAGA

CGAAAGCAGT

AAAAAGCTAT

AATTATTGAA

ATAAAAAATA

AAATTAAAGA

AAGACAAT'rC

TGCTTCAAAT

AAATAACGGG

TGAAGAAGAA

AGTTGTTAAT

TAAAGAAGAA

ACAAGAAGAA

AGAACAAAGA

TGAGATAAGT

TATAGATAAA

ATATAAAACA

AGAATTGAGT

TTATGCCCAT

AGATTTAGAA

TAAATTTGAA

GGTCCAATAG

GAAGAAGAAA

AATGAGCAAG

TTAGAAGAGA

ATAGAGAAAC

AAGAAACGAA

AAAGAAAGGA

TGGAATATTG

ATTACGGGGC

TGGGGAGATT

GATACTAGAG

GAAAATGAGC

AAAGTAAAAT

GAAATTAAAG

CAGATGAATT

ATGATAA-AGC

CTGTAATTT

AAGAATTAGA

AAAAACAAGA

AAAAACAAGA

GAGCTAAAAA

ATGGTATAGA

CTGTATATGA

TAGAAGATGA

ATGAGTTAAG

CTCCTCTAAA

CAGGATTAGA

GATACATCAG

GGCAAAAAAA

TGTCTTTTTA

AGAAGAAAAA

AGTTAAAAAA

AGTGGAAAAA

ACAGCAAGAA

CAAAATTAAA

AAGTCAAACA

TTATTTTACC

AGAAGGCGAA

AACCAAATTA

AGAAAATGTA

AAAGGTTAAA

TTACAGTCAG

t5l-2 .nt 00.

TTGCAGATTGATGCAACTGGTAAAGATGCAACTGGTAAAGATGCAACTGGTAAAGATGCAACTGGTAAAGATGCA

ACTGGTAAAAATGCAG AATTAAG~ATTCAAGGATTTTTAGAAAAGATT'rTAGATCCAGTAAAGG ATAAAATTGCTTCAAATGGTCCAATAGCAGATGAATTCCCA AA AA AATTACAAGAAGAAGAAAAGGTAAATAACGG

GGAAGAAGAAAATGATAAAGCTGTCTTTTTAGGAGAAGAATCAAAAGAGGATGAAGAAGAAAATGAGCAAGCTGTT

AATTTAGAAGAAAAAAATGCGGAAGAGGATAAGAAAGTTGTTAATTTAGA-AGAGAAAGAATTAGAAGTTAAAAAAG

AGACTGAAGAAGATGAAGATAAGAAAAAAA AAAAGAAGTGGAAAAAGCACAAGAAAGAAAACA

ACGACAAGAAGAAAAGAAACGAAAAAAACAAGAACAGCAAGAAGAAAAGAAACGAAAACGACAAGAACAAAGAAAA

GAAAGGAGAGCTAAAAACAAAATTAAAAAACTTGCGGATAAAATAGATGAGATAAGTTGGAATATTGATGGTATAG

AAAGTCAAACAAGTGTAAAACCGAAAGCAGTTATAGATAAA-ATTACGGGGCCTGTATATGATTATTTTACCGATGA

CAACAAAAAAGCTATATATAAAACATGGGGAGATTTAGAAGATGAAGAAGGCGAAGGATTGGGAAAATTATTGAAA

GAATTGAGTGATACTAGAGATGAGTTAAGAACCAAATTATAGTATAAAATATGCCCATGAAAATG

AGCCTCCTCTAAAAGAAAATGTAGATGTCAGCGAAALTTAAAGAAGATTTAGAAAAAGTAAAATCAGGATTAGAAAA

GGTTAAAGAATATCTTAAAGACAATTCTAAATTTGAAGAAATTAAAGGATACATCAGTTACAGTCAG

f~l-2 .aa 66.66.

.6 6

LFGVVVNILRL

KNAEQNIKGK

EESKEDEEEN

QERKQRQE-EK

VKPKAVIDKI

KDNKKYYAHE

MEWIDXOTK

VQGFLEKILD

EQAVNLEEKN

KRKKQEQQEE

TGPVYDYFTD

NEPPLKENVD

IFIICAVFVL

PVKDKIASNG

AEEDKKVVNL

KKRKRQEQRK

DNKKAIYKTW

VSEIKEDLEX

ISSCKIDATG

PIADELAKKL

EEKELEVKKE

ERRAKNKIKK

GDLEDEEGEG

VKSGLEWVK

KDATGKDATG

QEEEKVNNGE

TEEDEDKEEI

LADKIDEISW

LGKLLKELSD

YLKDNSKFEE

KDATGK2DATG EENflKAVFLG

EKQKQEVEKA

NIDGIESQTS

TRDELRTKLN

IKGYISYSQ

t5l-2.a

CICIDATGKDATGKDATGKDATGKDATGKAEQNIKGKVQGFLEKILDPVKDKIASNGPIADELAKKQEEEKVNNG

EEEDKAVFLGEESKEDEEENEQAVNLEEKAEE-DKKVNLEKELVKKETEEDEDKEEIEKQKQEVEKAQERKQ

RQEEKKRKQEQQEEKRRQEQRCEAIKKLADKIDEISWNIDGIESQTISVKPKAVIDKITGPVYDFTDD

NAY~IYKTWGDLEDEEGEGLGKLLKELSDTfELRTLNDNKYYAHEEPPLKENVDVSEIYKEDLEKVKSGLEK

VKEYLKDNSKFEEIKGYISYSQ

f6-21 .nt TAGGCAAAAT TTAAATTTAT AAAAACTTGT AAGGATGCTT GTATGAAAAT ATTGATAAAA AAGTTAAAAG TTGTATTATT TCTCAATTTA ATTTTACTTA TTTCTTGTGT TAATGAAAGT AATAGAAACA AATTGGTTTT TAAGCTAAAT ATTGGAAGTG AGCCTGCTAC TTTAGATGCT CAATTAATAA ACGATACGGT TGGATCAGGG ATTGTAAGCC AAATGTTTCT TGGCATTTTA GATGGAGATC CCAGGACTGG AGGATACAGA CCGGGACTTG CTAAAAGTTG GGATATTTCT WO 98/59071 WO 9859071PCTIUS98/1 2713 205 TABLE 1. Nucleotide and Amino Acid Sequences GATGACGGAG TAG=~ATAC GTTTCATTTA AGAGATAATC TGTTTGGAG TGATGGAGT'r TCCATTACTG CCGAAGAATA A tG-21.nt TrCTTTAAGAAATAATGAAAAAATTTTAAGCTAAATATTGGAAGTGAGCCTGCTACTT'rAGATGCT CAATTATAACGATACGGTTGATCGGGATTGTAAGCCAAATGT'rTCTTGGCATTTAGATGGAGATCCCAGGA

CTGGAGGATACAGACCGGGACTTGCTAAAAGTTGGGATATTTCTGATGACGGAGTAGTTTATACGTTTCATTTAAG

AGATAATCTTGTTTGGAGTGATGGAGTTTCCATTACTGCCGAAGAA

fG-2l.aa AKFKFIKTCK DACMKILIKK LKVVLFLNLI LLISCVNESN RNKLVFKLNI GSEPATLDAQ LINDTVGSGI VSQMFLGILD GDPRTGGYRP GLAKSWDISD DGVVYTFHLR DNLVWSDGVS

ITAEE

t6-2l.aa

CVNESNRNKLVFKLNIGSEPATLDAQLINDTVGSGIVSQMFLGILDGDPRTGGYRPGLAKSWDISDDGVVYTFHLR

DNLVWSDGVSITAEE

fS-27.nt *Se.

TAAAGAAAAG

ATAATTATTG

ATGAAATACC

AATGGTAATT

GACTCGATAA

TTAACAGAAA

GATCCTGAAA

CTCAAAGTAA

GATCTATTAA

GACAATTGGA

ACAGATTTTG

AGAAAAATTG

TACATCTACA

TACGAAACAT

AATTTAAGCT

AGAAAATTAA

ACATTAAATA

GATA'TACTC

AAACCACTTIC

AGTAGGCATA

CTTGCATAAA AAGTATAACA CACTAAAATT AAA'ITTATAC

TTAAAAACAT

TCAATCTACA

TAAGCAGAAA

AAGAAAATTT

ATATTTTGAT

AATCTAGCTT

CCTACATTTA

ACGTATCGCA

ATAAAGAAAT

AAATTGAAAA

GTATGAAAAT

TTGTTATAGC

TATACTCTGA

AAATGGAGCC

TAGTATTAAG

TAAAATTAAA

TTTTAAAATT

AATTTTAA

TTCCTTATT

CGATACAAAC

TTATGATAAT

TAAAGTCAAT

AAATGAAGAA

TAATAAAAGC

CGATAAAAGC

CAGTATAAAA

TAAAATATCT

AACAGAGCTT

TCCAAAATTA

AAAI'rAT'AC

TAAATTACGC

TCCTGTGAGA

TCCTCAAAAA

AATTCTTTAA

AGTTATATAG

TTGTTAATTT

CATAAATTAG

AAAATATCCAk

ATTTTCATCA

AAAATTAATT

ATTATCAGTA

ACAGGGAAAT

TTTAATAAGG

AAAAATATTT

AAAACAGAAT

TTTGAAAAAT

CCCTGTGAAA

TTTCTAAACT

GCCTTAAAGA

ATAATAGAGC

TAATTAAAAT

AATCACTTAA

TAGGTTGCAA

GAAA.ACTAAA

TTGTGGGAGT

AAAAAAAAGG

ATTCAAAATA

TTITCACTAAC

ACATTAACAT

AGTATATTTT

TGCAAAAACG

ATAATGAAAT

CAGACGCTCC

ATTTAAATAT

CTATTTATGA

ATTCAAAAAC

TAGCAAAAAA

CAAAAAGAZAT

GGAACAAAAA

ATCCATCCCA

ATTTCAAGAA

ATACAACCCT

ATT~ACAAATA

TAAAGCAGAA

TAATTCAAGA

TGACTTTAAG

AGCATATATA

TATTGATAAT

AGAGGATTAT

CTCTGAAACT

ACTGTTTTTG

TGAGAATGAT

AATAAAAGAA

CATTGAAAAA

ATCTTACGGA GAAAAGGGAG AATTCALCATT TGAAATATAT CTTAAAAGAA GTAGATCATT GCATAAAAAA TTTGCAATCA t6-27 .rit

TTGCAATCCATCCCAAATGGTAATTCAATCTACACGATACAAACCATAAATTAGGAAAACTAAAATTTCAAGAA

GACTCGATAATAAGCAGAAATTATGATAATAAAATATCCATTGTGGGAGTATACAACCCTrAACAGAAAA.AGAAA ATTTTAAAGTCAATATTTTCATCAAA A A AAGGATTACAAATAGATCCTGAAAATATTTTGATAAATGAAGAAAA AATAA.TATCAAATTAAGCAAATCAAAGTAAAATCTAGCTrrTAATAAAAGCATTATCAGTATTTCACTA

ACTAATTCAAGAGATCTATTAACCTACATTTACAAAGAAGGATCTTAACATTGACTTTAAGGACA

AT'TGGAACGTATCG AATTAATATAGGAATTTAGCATATATAACAGATTTTGATAA-AGAAAT TAAAATATCTAAAAATATTTrGCAAAAACGTATTGATAATAGAAAAATTGAAATTGAAAAAACAGAGCTTAA-AACA

GAA.TATAATGAAATAGAGGATTATTACATCTAC-AGTATGAAAATTCCAAAATTATTTGAAAAALTCAGACGCTCCCT

CTGAAACTTACGAAACATTTGTTATAGCAAATTATTACCCCTGTGAAAATTTAAATATACTGTTTTTG)ATTTAAG

CT'rATACTCTGATAAATTACGCTTTCTAAACTCTATTTATGATGAGAATGATAGAAAATTAAAAATGGAGCCTCCT wo 98159071 WO 9859071PCTIUS98/1271 8 TABLE 1. Nucleotide and Amino Acid Sequences GTGAGua.GCCTTAGATAAAATAAGACTAAAAT'TATCCTCAAAAAATAATAGA.GC TAGCAAAAAACATTGAAAAAGATATTACTCTAAAATTAAAATCTTACGGAGAAAAGGGAGAAT'rCACATTTGAAAT ATATAAACCACT'rCTTTTAAATTCTTAAAAGAAGTAGATCATTGCATAAAAATTTGCAATCAAGTAGGCATAAA f6-27.aa

RKACIKSITN

GqFNLHDTNH

PENILINEEK

NWNVSHSIXF

IYSMXI PKLF SLIIKIKM~ IIALKLNLYS KLGKLKFQED SIISRNYDNK

INYSKYKAEL

NKEYILAYIT

EKSDAPSETY

KVKSSFNKSI

DFDKEIKISK

ETFVTANYYP

YIESLKEQKM!

ISIVGVYNPL

ISISLTNSRD

NILQKRIDNR

CELNILFLN

IELAKNIEKD

KYLKNISLFL

TEKENFKVNI

LLTYIYDKST

KIEIEKTELK

LSLYSDKLRF

ITLKLKSYGE

LILGCKSIPN

FIKKKGLQID

GKYINIDFKD

TEYNEIEflYY

LNSIYDENDR

KGEFTFEIYK KKEPPVRA LKNSKTIKET LNIVLSPQKI PLLLKFLKEV DHCIKNLQSS RHKF t6-27 .aa

CKSIPNGNFNLHDNHKLGKLKFQEDSIISRNYDNKISIVGVYNPLTEKENFKVNIFIKKKGLQIDPENILINEEK

INYSKYKAELKVYKSSFNKSIISISLTNSDLLTYIYDKSTGKYINIDFKDNWNVSHSIKFNKEYILAYITDFDKEI

KIS=ILQKRIDNRKIEIKTELKTEYNEIEDYYIYSMKI PKLFEKSDAPSETYETFVIANYYPCENLNILFLNLS

LYSDKLRFLNSIYDENDRKLKMEPPVRALKNSKTIKETLNIVLSPQKIIELAKNIEKDITLKLKSYGEKGEFTFEI

YKPLLLKFLKEVDHCIKNLQSSRHKF

f 6-5 .nt

TAAATGAAGA

TCTTTGGTAA

AA.TTATCCTG

TCATCTGATT

TCTAGTTTCA

TATAGAATAC

TCTTATCTTG

GCTAAAAAAT

CTTGTTAAGA

AAGTTTrTTAA AGTTTTTAAT ATCCGTTTAT

AAATACCAGA

ATTTGAAGAT

TTGAAAGCTT

ATAATAATAT

TTATTGCTTA

AAAAACAAAA

TTATGGATAA

GTAAAAATTA

CTTGA

AAAAGATAAA

TTCAAATTTT

GAGTGATACT

TAATTTTATT

TAGCTTGACC

AATTATGAAA

TAAGTATTGG

TT~TAGTCTTG

TTTTTATTGT

ATAAATTTAA

AAAATAAAAG

AAAAATAGTG

AAAGATCTTT

CAAGGTGCAT

AATTTTTCAT

ATTGTAATTG

GCGAATGTAA

TTTATGGTTG TTCAACTATA CTGTTTTATC ATCTTTAATG

ACTACGAACA

CTTATATTTA

TTATTTATAA

CTTTTAAGGC

TGAAAATAAA

CAAAAAACCA

AGATGGAATA

TTTGCATTAT

CGTTGATGAA

TAAGAAATTA

AGAAGTTTTA

TTTTCCAACT

TI'TAGATTCT

TATACTCAAA

1:6-5 .nt TTGTCAACTATATCTTTGGTAAAAATAC AAAAAAATATTAACTGTTTTATCATCTTTAATGAAT TATCCTGATTGAA-GATTTCAAATTTAAAATAAAAGACTACGAACATT'rGCATTATTCATCTGATTTTGAAAGCT

TGAGTGATACTAAAAATAGTGCTTATATTTACGTTGATGAATCTAGTTTCAATAATAATATTAATTTTATTAAAGA

TCTTTATAA.AGAATTTGAATTATTGCTTATAGCTTGACCCAAGGTGCATCTTTTAAGGCA

GAAGTrTTTATCTTATCTT AAAAAATAGAATTTTcATTGAAAATAAATTT'rCCAACTGCTAAAA

AATTTATGGATAATAAGTATTGGATTGTAATTGCAAAAAACCATTTAGATCTCTTGTTAAGAGTAAAAAT

MKKFLISVYF LLFYGCSTIS LVKIPEKDKI NLTVLSSLN YPDLKISNFK IKDYEHLHYS SDFESLSDTC NSAYIYVDES SFNNNINFIK DLFIYNKKJY RILIAYSLTQ GASFKAEVLS YLEXQKIMKN FSLKINFPTA KKJFDNKYWI VIAKNHLDSL V TJNYVL NVKMEYILKK

FLT

aa

CSTISLVKIPEKDKINLTVLSSLMNYPDLKISNFKIKDYEHLHYSSDFESLSDTIKNSAYIYVDESSFNNNINFIKD

LFIYKLYRILIAYSLTQGASFKAEVLSYLEQKIMFSLKINFPTAKKFMDNKYWIVIAKNHLDSLVKSKN

PCTIUS98/12713 WO 98/59071 PTU9/21 0 TABLE I. Nucleotide and Amino Acid Sequences f7-30 .nt

TAGAGACGAA

ATAATGAAAA

-T'TCTTCT'r GATAT'rGAAA

GTTTGGCT'T

GTGTI"TGAAA

CTAAAAAATC

GTCACAAGCA

ATPTAAAGAC

GCGAATCAAT

ATTTAATGCT

TGACTGTAAA

ATTTTGATCC

GAATTAC!CTA

AAATGTTAAA

AAAAATTAAT

ACCATCACTT

CGATGAAGCA

ATCTTATGTG

CGTGTTT'GGC

CTACAATCGA

AGATTTACAA

TTTTTAGGGA

CCCCAAAAAC

GAACTTTTTA

ATCAAATACT

GATGAAAATG

TACATAGAAA

AATCAAGTTC AAGGGGGCAA TATTTTGGCT ACTGTTACTA CAACCCTAAC AAACAAAGAA GATACTCAAC CGCACTAAAT ATCCTAATGA CAAATTTCCT GAACTAAAGA AACAAATATA AAACCGAACC GATTGTATTT GTGTTACA AAAAATACAG CAGAAGATAA t7-30 .nt TTGCGAATCAATACCATrACTTCCCCAAAAACCAACCCTAACAAACAAAGAAGATATTGAAAATTTAATGCTCGAT

GAAGCAGAACTTTTTAGATACTCAACCGCACTAAATGTTTGGCTTTTGACTGTAAAATCTTATGTGATCAAATACT

ATCCTAATGACAATTCCTGTGTTTGAAATTTTGATCCCGTGTTTGGCGATGAAAATGGAACTAAAGAAACAAA

TATACTAAAAAATCGAATTACCTACTACAATCGATACATAGAAAAA-ACCGAACCGATTGTATTTGGGTGTTACAAA

AAATACAGCAGAAGA

f7-30.a RRSHKQNVKR FTKSSSRGQI M~KNLKTKINF LGIFWLLLLF LSCESIPSLP QKPTLTNKED IENLMLDEAE LFRYSTALNV WLLTVKSYVI KYYPNDKFPV FENFDPVFGD ENGTKE.TNIL FRITV1NY IEKTEPIVFG CYKKYSRR t7-30.a

CESIPSLPQKPTLTNKEDIELMLDEAELFRYSTALNVWLLTVKYVKYYPNDKFPVFENFDPVFGDENGTKETN

ILKRITYYNRYIEKTEPIVFGCYKKYSRR

f76-1 .nt TGAATATTAA TAATAAAAAA TTTTTACTAA TGCTAAACGG AGACAAAAGC GTGATTTAAC AAAGAAGACC TGCTTAGAGA AAAACCGCTT TAACTGGTGT ATTAAATCAG CACTrGAACA GGAAAAAACA CCTTCAAAAC TTTGCAGATC AAGCAACTGC AGGAGTAACA ATGAAAATTA CTGTAATTCT AATGATACAA CCAAAAAGAA GCAACACAAG AAAGCTATCT GATGATCAAA TGGAAAATTT GATAAATTCT TATAAAGACT GAACTTGATA TACCGTTCAA GGGTTTTTTA TACCTGCAAT TAA

TCAACATATT

ATACCAAGCA

AAAAACCTAA

AAACACAACT.

TAGAAAATGA

AATGTAATGG

GCGGCGGCAA

ATTTTGTTTG

GACAAAAAGC

ATCTAAATCT

TGACTGGTTA

TGAAGGCAAA

AAATGATGAA..

TATAGATAAT

t76-1 .nt CTGTAATTCTAATGATACAAATAC AGAAAAGAAAAGGTGATTTAACCCAAAMAGAAGCAACA

CAAGAAAAACCTAAATCTAAATCTAAAGAAGACCTGCTAGAAAAAGCTATCTGATGATCAAAAAACACAACTTG

ACTGGTTAAAAACCGCTTTAACTGGTGTGGAAAATTTGATAAATTCTTAGAAAATGATGAAGGCAAAATTATC

AGCACTTrGAAcATATAAAGACTGAACTTGATAAA GATGATAGAGAAAACCTTCAAAACTACC GTTCAAGGGTTTTTTAGCGGCGGcAATATAGATAATTTTGCAGATCAAGCAACTGCTACCTGCAAT f76-1.aa ILIIKKGVTM KIINILFCLF LLMIJNGCNSN DTNTKQTKSR QKRflLTQKEA TQEKPKSKSK EDLLREXLSD DQKTQLDWLK TALTGVGKFD KFLENDEGKI KSALEHIKTE LDKCNGNDEG KNTFKTTVQG FFSGGNIDNF ADQATATCN t76-1.aa WO 98/59071 WO 9859071PCT/US98/112718 TABLE 1. Nucleotide and Amino Acid Sequences

CNNTTQKRKDTKAQKKKKDLRKSDKQDLTLGGDF=GJK

ALEHIKTELDKCNGNDEGKNTFKTTVQGFFSGGNIDNFADQATATCN

f8-10 .nt

TAAGTAAGGA

TTAACTGCTT

ATTTCAAATC

ATAAATTT1AA GAACCT'cGG

CCACGGGAAT

TATAGTATTT

ATACTGTCAA

GATGATGTGG

AATTTAAAAA

AAGATGTCAA

AACGCCAAGC

GAAGCAGAAA

GAATATTTAT

GCAATCCAGA

AAGATGCAGA

TAGAAAAAGC

ATCAATATGG

TAATATCTGA

TATTAAATGC

TAAAAGTACT

TTGTTCACTT

GACTTAAAAA

AACGTCTTIW

TTGGATCTTA

GGCTGAAAAG

GAAATATAAT

T'rTTAACACA

TTCTGATAAA

GAATGCAGAT

AATGTTGGCT

TACAGGTAGT

TATTGAAACT

AGAA.ATATTT

ATATTCCAAA

TTTGTTWTGAA.

ATTGGATTAT

TGTGGTTGCA

CGAGATAATT

ACGATTATAA

AATAAGAAAA

ATAATAAAAA

AGAGAAAAAT

GTTTTTGGAG

GAGAGATCTA

AATGAATTAA

AGCCTATTTA

AAAGATACTC

AAATTATTAT

CAAAATAATG

CTTTCCAATC

TTAATATATA

GCATATTTGT

GAACTCTAAG

ATAAATTACT

ATGTAAAAAA

GTATGTAT'rG

TTAGGTATAG

AGAAATTTTC

ATCTATTTGG

TAGGTAAACT

CTATAAAAAC

AAAATTTTAT

AAATTCAAGA

CCCTTAA

TTGT'rTGTTT

TAAGGGGATA

TGATGATTTA

AATGGAAGAA

GGCAGAATCA

AAGGCGTGTT

AGAAATTIAGA

AAGTACTCTT

AGATATTTCA

AATCGTTTfCA

AAAAACAGAT

AAAATATAAT

t8-1Q .nt

TTGCAATCCAGATTTTAACACAAATAAGAAAGAACTCTAAGTAAGGGGATAATTTCAAATCAAGATGCAGATTCT

GATAATATA~A~TAATACTTGATGATTTAATAAATTTAATAGAAAAGCGAATGCAGATAGAGAAAAAT

ATGTAAAAATGGAAGAAGAACCTTCGGATCAATATGGAATGTTGGCTGTTTTTGGAGGTATGTATTGGGCAGA

ATCACCACGGGAATTAATATCTGATACAGGTAGTGAGAGATCTATTAGGTATAGAAGGCGTGTTTATAGTATTTTA,

TTAAATGCTATTGAAACTAATGAATTAAAGAAATTTTCAGAAATTAGAATACTGTCAATAAAAGTACTAGAAATAT

TTAGCCTATTTAATCTATTrGGAAGTACTCTTGATGATGTGGTTGTTCACTTATATTCCAAAAAAGATACTCTAGG TAAACTAGATATTTCAAATTTAAAAAGACTTAAAAATTTGTTTGAAAAATTAT.TATCTATAAAAACAATCGTTtCA

AAGATGTCAAAACGTCTTTTATTGGATTATCAAAATAATGAAAATTTTATAAAAACAGATAACGCCAAGCTTGGAT

CT PATGTGGTTGCACTTTCCAATCtAAATTCAAGAAAAATATAATGAAGCAGAAALGGCTGAAA f 8-10 .aa VRRIFMKYNT IISIFVCLFL TACNPDFNTN KKRTLSKGII SNQDADSDKI IKKLLDDLI NLIEKANADR EKYVKKMEEE PSDQYGMLAV FGGMYWAESP R.ELISDTGSE RSIRYRRRVY SILLNAIETN E-LKKFSEIRI LSIKVLEIFS LFNLFGSTLD DVVVHLYSKK D'rLGKLDISN LKRIIKNLFEK LLSIKTIVSK MSKRLLLDYQ NNENFIKTDN AKLGSYVVAL SNQIQEKYNE AERLKSEIIL IYTL t8-10a

CNPDFNTNKKRTLSKGIISNQDADSDKIIKNKLLDDLINLIEKANADREKYVKKMEEEPSDQYGMLAVFGGMYWAE

SPRELISDrGSERSIRYRRRVYSILLNAIETNELGCFSEIRILSIKVLEIFSLFNLFGSTLDDVvVHJYSKKDTLG KLDISNLMUiLFEKLLSIKTIVSKSKLLLDYQNNENFIKTDNAKLGSYVVALSNQIQEKYNEAERLK f 8-14 .nt

TAATATATAT

TATACATTGT

AAAGAGGAAC

GCTATTAPATA

AAATTGAAAG

TCCGTAGAAT

TCAATTGAGC

GAAGAAAAGC

TCTTGATTAA

TAACGATAGG

AAAAAAATAA

ATTTATATGG

ACAAGGGTTT

CTGCGGTGTC

ATAATCAAAA

AAGCGGATAA

GGGAAAGGAG

ATTGATGTCT

CAATGATATA

AAATAAAAAA

AGACGTGACC

TTTAGGAGAA

AAAAGAGATA

AGCAATTAAA

AGTATT'rTTA

TGTAATCTAA

AAAGAAGCTT

GAAAAAAAAG

ACCCTCCCCT

TCTAATAATA

AAAGAAGAGG

GATATAGAGA

TGAAAAAAAA

ATTCTAAATT

TAAATGGCGT

ATTTTATTAA

TAGAACCTGT

GGATTGGTAT

ATTTTTITCCC

ATCTTATTGG

AATGTTTTTA

ATCTGGTAAT

TCAAGAAAAT

AAATTCGGAA

AGTGGCGCCC

ACCAACCATT

TTCTACTGAG

AGAATCTGGA

WO 98/59071 PCT/US98/12713 4 209 TABLE 1. Nucleotide and Amino Acid Sequences TTTCCCGAGT TAATTGAGAA TGTGTGCTCA CT'rAAACATG AATATACTTT AATAAGAAGT GATTTTTATG ATGTGATAAC TAAGA'FTCAG AATAAAAAAA TATCACTAAT GAAAAATTCT CATAATAATA GAAATAAAAT AAGGGAACTA GTACAATTGC AAAATAATTT AAAGATAGGA GACGAACTI'G ATAAAAITAT GGGTTIGCATT GATACTGCAG AACAAGAGAT AAGATCTGCC GCTTTCTTTT TTGATGAAGC TAAGGAAAGC T'rAA-AAGAAG GTATTATTAA AAGATTGGAA -AAAAGTAAAA ATAGGGCAGC ATCACAATI'A TCTAAAAAGG CTTTAAATAG AGCAGAGGAT GCTTTAAGGT GCTTAGAAAA TTATTCTTCT AAAAAAGGTG AGGCAATAGG AAGAAGAAGC TTTATAAAAG AAGTTGITGA ACAGGCAAAA AATGCTTTAA GTAAGTCTTA A t8-14 .nt

TTGTAATCTAAATTCTAAATI'ATCTGGTAATAAAGAGGAACAAAAAAATAACAATGATATAAAAGAAGCTTTAAAT

GGCGTTCAAGAAAATGCTATAATAATTTATAGAAAAAGAAAAGT

TAAAICGGAAA

AATTGAAAGACAAGGGTTTAGACGTGACCACCCTCCCCTTAGAACCTGTAGTGGCGCCCTCCGTAGAATCTGCGGT

GTCTTTAGGAGAATCTAATAATAGGATTGGTATACCAACCATTTCATGAATAAAAGGTAA

GAAGAGGATTTTTTCCCTTCTACTGAGGAAGAAAAGCAAGCGGATAAAGCAATTAAAGATATAGAGAATCTTATTG

GAGAATCTGGATTTCCCGAGTTAATTGAGAATGTGTGCTCACTTAAACATGAATATACTTTAATAAGAAGTGATTT

TTATGATGTGATAACTAAA CGAAAAAACACTAATGAAAAATTCTCATAATAATAGAAATAAAATA AGGGAACTAGTACATGAATATAAAAGGCGAACTTGATAAAATTATGGG

ETGCATTGATACTG

CAGAACAAGAGATAAGATCTGCCGCTTTCTTTTTTGATGAAGCTAAGGAAAGCT'rAAAAGAAGGTATTATTAAAAG

ATTGGAAAAAAGTAAAAATAGGGCAGCATCACAATTATCTAAAAAGGCTTTAAATAGAGCAGAGGATGCTTTAAGG

TGCTTAGAAATTATCTTCTAAAAAAGGTGAGGCAATAGGAAGAAGAAGCTTTATAAAAGAAGTTGTTGAACAGG

CAAAAAATGCTTTAAGTAAGTCT

f8-14.aa YIFLIKGKES IFMKKKMFLY TLLTIGLMSC NLNSKLSGNK EEQKNN'NDIK EALNGVQENA *INNLYGNKKE KKDFIIKiSEK, LKDKGLDVTT LPLEPVVAPS VESAVSLGES NNRIGIPTIS IEHNQKKEIK EEDFFPSTEE EKQADKAIKD IENLIGESGF PELIENVCSL KHEYTLIRSD FYDVZtTKIQN KKISLMKNSH NNRbIKIRELV QLQNNLKIGD ELDKIMGCID TAEQEIRSAA FFFDEAXESL KEGIIKRLEY( SIMRAASQLS KKALNRAEDA LRCLENYSSK KGEAIGRRSF IKEVVEQAKN ALSKS t8-14.aa

CNLSKLSGNKEEQKNNDIKALNGVQEINNLYGNEIFKFIKNSEKLKDKGLDVTTLPLEPVVAPSVSAV

SLGESNNRIGIPTISIEHNQKKEIKEDFFPSTEEEKQADKAIDIENLIGESGFPELIENVCSLHEYTLIRSDF

YDVITKIQNKISLMNSHNKIRELVQLQNNJKIGDELDKIMGCIDTAEQEIRSAAFFFfEAKESLEGIIK

LEKSKNRAASQLSKKALREDALRCLENYSSKKGEAIGRRSFIKEVVEQAKNALSKS

*fOlA.nt BBOOI TGATATTTTTTAGG TCGTT~rAAAAAATGA.TAAAACTGTTTTAACT~ TACTGTTCTCATGCTC ~ATTATACAAAAGGATAAGTGAATTAcAATCAAGCCCTA- ACTTGGAAAMAAAGCAAAAAG AATTAAGCACCCAAAATCTrCAAAACTTACAACAAAGC CAGTTCTTAAAGAAGAAATArAAAGACAAGAATTTGATGAGAATGATGATA

ATAAAATAGGTCCAAATATCGAAATGTGCTCAAACAATAAACACGGATATTCAAAAAATCCCTAATGATCA

ATTTGGAATAAATAAAACTTATAAAAAAAAATAATGACTTTATGTTAAAAGAATCGACTT

AGAAGATTATTTTACTCATCTTTAAATTATGATGAATAAAATCAAAAAATTAGCCACAATACTCGACAT

CAAGCTCAAACG.ACTACCATTACACACTTATTGGTTAATTTTTGGACAGGATTTAAATCCAAGAAGCATTTC-A

AAGCGCTGTTAATATTTTAACTAAGACGAGCAAAGCGCC TAATATTAGAA .CATGAG

ATTCAGGAAAATTTTGAAAAACTAATGCAAGAGAGAAATTCATGGATAAAAATCGTCGATAACATTAT'GAT

ATGACAAAAATACGGGAGGATGCAAAGCTGATGGAAAAATTCTCGGAGAAGTAATAAGGGTTGGATACGAGCATGA

ACTCGACTCAAATAAAGTATGCAAATTTAAACAATATTGAAACACCGCTAAAAACCTGTTGTGACCACATAC-AC

TACTAA

WO 98/59071 PCTfUS98/12718 210 TABLE 1. Nucleotide and Amino Acid Sequences tOlA.nt BBOO1

TGCTCTTTTATTCTAAATCAAACAACACAGAAGCGATAAGTGAATTACAATCAAGCCCTATTAAACTTGGAAAAA

TTAAAGTTTACAAAAAACAGAAAAGATTGTAAGCACCCAAAATCTTCAAAACTTACAACAAAGccAGT'rCTTTAA

AAATAAAAAAATAATAAAAAA~GCACAAGAATTGATGAGAATGAAAAATTGATTAATAAAATAGGT

-CCAAATATCGAAATGTTTGCTCAACAATAAACACGGATATTCAAAAAATCGAACCTAATGATCAATT'rGGAATA ATAAAACTTTAT~TcAAAAAAA ATA TGACTTTATGTTAAAAGAcAATCGACTTAGAAGATTATT

TTACTCATCTTTAAATTATGATGAAAATAAAATCAAAAAATTAGCCACAATACTCGCGCAAACATCA.AGCTCAAAC

GACTACCATTACACACTTAr t rGGTTAATTTTTTGGACAGGATrAAAATCCAAGAAGCATTTGAAAGCGCTGTTA

ATATTTTAACTAAAGACGAGCAAAAGCGCCTAATTTTATTAAAAAAATAAAAGAGATTCAGGAAAA

TTTTGAAAAACTAATGCAAGAGAGAAATTCATGGATAAAAATCGTCGATAACATTATTGGCGAATATGACAAAAAT

ACGGGAGGATGCAAAGCTGATGGuAAAAATTCTCGGAGAAGTAATAAGGGTTGGATACGAGCATGAACTCGACTCAA ATAAAAGTATGCAAATT'rTAAACAATAT'rGAAACACCGCTAAAAACCTGTTGTGACCACATACACTAC fOlA.aa BB001

LIFFKDYVLKRNKIWKTLKLFQITLLFSCSFYSKSNNTE-AISELQSSPIKLGKIKVLQKTEKIVSTQNLQNLQQSQ

FFKNEK=KI IKKIAQEFDF.NEILINKIGPNIEMFAQTINTDIQKIEPNDQFGINKTLFTEKKDNNIDFMLKDNRLR

RLFYSSLNYDEKIKKLATILAQTSSSNDYHYTLIGLIFWTGFKIQEAFESAVNILTKDEQKRLIFNFRTKTVKEI

QENFEKLMQERNSWIKIVDNIIGEYDKNTGGCKADGKILGEVIRVGYEHELDSNKSMQILNNIETPLKTCCDHIHY

tOlA.aa BB001 CSFYSKSNNTEAI SELQSSPIKLGKIKVLQKTEKIVSTQNLQNLQQSQFFKNEKEKIIKKIAQEFDENEKLINKIG

PNIEMFAQTINTDIQKIEPNDQFGINTLFTEKKDNNIDFMELKDNRLRRLFYSSLNYDENKIKKLATILAQTSSSN

DYHYTLIGLIFWTGFKIQE-AFESAVNILTKDEQKRLIFNFRTKTVKEIQEFEKLMQERNSWIKIVDNIIGEYDKN

TGGCKAflGKILGEVIRVGYEHELSNKSMQILNNIETPLKTCCDHIHY f02A.nt BB002

TAATTAATACTGGTTTTAATTTATAAGGAGAGTATTTTAAAAAGCCAAACTAAATATAATCAAGATTAATATTA

TTACAATGATATTAACTTTAATTTGCATCTCATGTGCACCTTTTAACAAAATCAATCCCAAGGCAAATGAAAACAC

CAAGCTTAAAAAAAACACCAGACTGAAAAAACCCGCCAATCCAGGGGAAAACATCCAAAATTTTAAAGATAAATCT

GGAGACCTTGGCGCTTCTGATGAAAAATTTATGGGAACTACCGCTTCAGAGCTAAAAGCAATTGGTAAGGAGCTAG

***AAGATCGAAAAATCAATACGATATACAAATAGCCAAAATTACTAATGAAGAATCTAACCTATTAGATACTTATAT

.**TCGGGCTTATGAACTAGCTAACGAAAATGAAAAAATGCTTTTAAAAAGATTTCTTCTTTCATCTTTAGATTATAAA

AAAGAAAACATAGAGACATTAAAAGAAATTCTTGAAAAACTCATAAATAATTACGAAAACGACCCCAAAATTGCTG

CAAATTTCCTTTATCGCATAGCGCTGGATATTCAATTAAAACTGGAAAAGCACTTAAAATCAATAAATGAAAAACT

GGACACTCTAAGCAAG ATCAAGAATTAGAGGCGTTGCTAGAACAAGTAAAATCTGCCTTACAGCTA

CAAGAAAAGTTTAAAAAAACCCTAAACAAAACTCTTGAAGATTACCGTAAAAATACTAACAACATTCAAGAAALATA

AAGTACTAGCAGAACACTTTAATAAATATTACAAAGACTCTGATTCTTTACAATCTGCCTTTTATTAA

tO2A-nt BB002 TGTGCACCTTTTAACAAAATCAATCCCAAGGCAAATGAAAACACCAAGCTTAAAAAAAACACCAGACTGAkAAAAAC

CCGCCAATCCAGGGGAAAACATCCAAAATTTTAAAGATAAATCTGGAGACCTTGGCGCTTCTGATGAAAAATTTAT

GGGAACTACCGCTTCAGAGCTAAAAGCAATTGGTAAGGAGCTAGAAGATCGAAAAAATCAATACGATATACAAATA

GCCAAAATTACTAATGAAGAATCTAACCTATTAGATACTTATATTCGGGCTTATGAACTAGCTAACGAAAATGAAA

AAATGCTTTTAAAAAGATTTCTCTTCATCTAA AAAAGAACTGGcTAAGATCT

TGAAAAACTCATAAATAATTACGAAAACGACCCCAAAATTGCTGCAAATTTCCTTTATCGCATAGCGCTGGATATT

CAATTAAAACTGGAAAAGCACTTAAAATCAATAAATGAAAAACTGGACACTCTAAGCAAAGAAAATTCAAAAGAAG

ATTTAGAGGCGTTGCTAGAACAAGTAAAATCTGCCTTACAGC AGAATTAAAACCTAAACAAA-AC

TCTTGAAGATTACCGTAAAAATACTAACAACATTCAAGAAAATAAAGTACTAGCAGAACACTTTAATAAATATTAC

AAAGACTCTGATTCTTTACAATCTGCCTTTTAT

f02A.aa BB002 WO 98159071 PCTIUS98/1271 8 211 TABLE 1. Nucleotide and Amino Acid Sequences LILVLIYKESILXCAkLNIKINIITMILTLICISCAPFNKINPKNTKL1TRaPANPGENIrQNFKn<SG EIETLKEILEKLINY=PKIAANFLYRILIQLKLEIHLKSlEKLDTLSKENSKEDLEATLLEQVKSLQLQ

EKFKCTLNKTLEDYRETNNIQENKVAEHFNKYYKDSDSLQSAFY

-tO2A.aa BBO02 AKITNEEsNLLDrylRAYELANEKLLKFLLSSLDYKENIETLKEILFEKLINNYENDPKIAANFLYRmrDI QLKLELMsINEKLDTLSKENSKELEALLEQVKSALQLQEKFKKTLNKTLEDYRNTNIQIKVLAEHNKYY

KDSDSLQSAFY

fO3A.nt BB006

TGATTTAATGTAAATTTTAATTACCGCCTAAAAAAGGCTTTAAATGGTATAAGGAAGAGATCTAATGGTATTTA

G AACATATAAACATTTGGAACTAATAATGCTGCCCATGTTAATGCTGAGTTGCGCTTTTTTTAAGAAACCACAATC

TGTACATCAAGACAGCAATACTGGCAAACCAATAAGCGATGAAAAATTACATTTAATATCAGGCAAAATTTCAAAT

AAAAAATTGCCAATCATAAATAGTAATCATGACGTAACTTGGATAAAAACAAAGGCAATGACAATCTTAGGCGAAG

ATGGAAAAGAAATACCAGAATTTAAAAACAAATTTGGATA'ITCTTATATAATATCTCCTGTAAAAATGGATGGAAA

ATATAGTTATTACGCGTCATTATATACTTTTTGAAACAACTAAAAATGGAGATGATGAATATGAAATTGAAGAT

GTTAAATTTGTAACAGCTGGTTCCACCCTAGAACTTAAAAATTCTCT'PrTAGCTGTGArCCGAAG GATATGTTACTGCATACCCATrTGGAATATTGATGAGTGACGAGATTAAAAATGCTTTTrAAATTAACATATAAAAA

TGGTCATTGGAATTATATGCTTGCAGATTTAACTGTCAAAAATAAACTTACTCAAGAAACTAAAATTTATAAAATT

*.TCTCTTAATTCAAATTAATATTGAATTTTAAAGAAGTGCTAAAAGAAAATTCTATATTAAAAGACATAGCTG

GAGATTTATTTGAAGATATATAA

*tO3A.nt BB006

TGCGCTTTTTTTAAGAAACCACAATCTGTACATCAAGACAGCAATACTGGCAAACCAATAAGCGATGAAAAATTAC

ATTTAATATCAGGcAAAATTTCAAATAAAAAATTIGCCAATCATAAATAGTAATCATGACGTAACTTGGATAAAAAC AAAGGcAATGACAATCTTAGGcGAAGATGGAAAAGAAATACCAGAATTTAAAAACAAATTTGGATATTCTTATATA ATATCTCCTG AATGTGAAAATTATTACGCGTCATTATTAATACrTTTTGAAACAACTAAAAATG

GAGATGATGAATATGAAATTGAAGATGTTAAATTTGTAACAGCTGGTTCCACCCTAGAACTTAAAAATTCTCTTTT

AGCTGTTGAAAA6TTcACAAGAAGAAGGATATGTTACTGCATACCCATTTGGAATATTGATGAGTGACGAGATTAAA AATGCT'-TATAAAAAA GGTCA6TTGGAATTATATGCTGCAGATTTAACTGTCAAAAATAAACTTA CTCAAGAAACTAAAA'I-rTATAAAATTTCTCT ATCATATArATrrAAGATGCTAAAAGA SfO3A.aa BB006

FNVFNYRLKALNGIKEDLMVFRTYHLEL!LPILSCAFFKKPQSVHQDSNTGKPISDEKJHLISGKISNX

*.KLPIINSNHDVTWIKTKTILGEDGKEIPEFKNFGYSYIISPVKDGKYSYYASLLILFETTGDDEYEIEDV

KTAGSTLELKSLLAVENSQEEGYTAYPFGILMSDEIKAFKLTYKGHWNYMLALTVKNKLTQETKIYKIS

LNSKLIIEFLKEVLKENSILKDIAGDLFEDI

tO3A.aa BB006

CAFFKKPQSVHQDSN~TGKPISDEKLHLISGKISNKKLPIINSNHDVTWIKTKAMTILGEDGKEIPEFKNKFGYSYI

ISPVKDGKYSYYASLLILFETKNGDDEYEIEDVKFVTAGSTLELKcNSLLAVENSQEEG'iVTAYPFGILMSDEIK

NAFX.LTYKNGHWNYMLADLTVKNKLTQETKIYKISLNSKLIIEFLKEVLKENSILKDIAGDLFEDI

f04A.nt BBO11 TAATTACCAAAGATAAGTAAAcTTGCAAATAAAACTACACGTATTGAAAGTAGATTTGAAA.TTTCCATTATATT'rA

TATATAATGGCACTAAATATCTGAAAATGAAGGAGAAGCGGGTGGGCAATAAAATTTTTTATATTTCAGTGGTTTT

AATTTAATAGTTGGTTGCGACTGGGGAACTATTAAJLGATAAAAGTACAGAAATrTCCAAGCTATTAAGAACGGAC WO 98/59071 PCTIUS98/12718 212 TABILE 1. Nucleotide and Amino Acid Sequences AAAGATAAGACTAAAAATCAAGATAG AATAGAATTGGGTGAAGATAATTTrTGTATCTAAAAATAATATGTCTACTA CTGATACGGGCATTACTAGTTTAGGAAGTCTAAACAACTTGGATTTAATTAATCGTrCACAGCGGGTCAGTGAACC ACCTATAATCTCAATGAGAAAGCCATAGCTACTAGAATGTTATACAA'A TTACTATA

ATAAACCCAAAACCAGCTCAAAATTITGGGAAATTCTTTAAACAATACTACTACTGAAGATAGTGTGAAGTTTTTAT

CAATTGAAAACCAAGAGTGGCTTATTAGTAAAAAGATrTTTGCCCAGTAAGTTGGAAAATTrrAGAAAGCTTTCTAAA

-AACACAACACGAAAAAGAAGCTTTTAAGACGGCTAAAACTATACAAAGTCTCATTAGTAATTCCAATATGGGTAAA

GAAATATTAAG TAGAGAATCACITAATrGTTTGAAGGCATACAACAAAAATTCCATAGTC AAAGGAATTCATrTAAAATAA ±CC TG.AAATCTTATATTTAAATCCTTT'rC

ATCTAAAAGA'AAGTTATAAG'GNGTGAAATCCAAAGTAATTTCAAALTTGCAGATGTT

AGCTGGAATAATGCAAACTCTCTTTrAAAAGAATCTATAGAAA.ATAATCAGGCAATTGAAAAAAGGTATGACA

ATGAGAGTAGAAAGCAAGGTCAAATTGGTGGACCTGCTAATAGATGGGATAAAAATCAAGCTGACAATTTTGCTAA

GGA.TGCAAAGTATAAGGCAGAACATTCAGCAAATGATTTGGAAAATGCAGCCAACTATTTTAGATATAGTTGTTCA

*AATGAAAAAGAAGCTAAAAAGCTATGAAATAAAGTTTGTACGAATTGGTATTAGCCTATAA

tO4A.nt BBO11

TGCGACTGGGGAACTATTAGTATCAAATICCAAGCTATTAAGAACGGACAAAGATAAGACTAAAA

ATCAAGATAGAATAGAATTGGGTGAAGATAATTTTGTATCTAAAAATAATATGTCTACTACTGATACGGGCATTAC

TAGTTTAGGAAGTCTAAACAACTTGGATTTAATTAATCGTTCACAGCGGGTCAGTGAACCACCTATAATCTCAAAT

GAGAAAGCCATAGCTACTCAAGCAAAAGTAGATTTAATGAACAACATTAATGTTACTATAATAAACCCAAAACCAG

CTCAAAATTTGGGAAATTCTTTAAACAATACTACTACTGAAGATAGTGTGAAGTTTATCAATTGAAAACCAAGA

GTGGCTTATTAGTAAAAAGATTTTGCCCAGTAAGTTGGAAAATTTAGAAAGCTTTCTAAAAACACAACACCAA.AAA

GAAGCTTTTAAGACGGCTAAAACTATACAAAGTCTCATTAGTAATTCCAATATGGGTAAAGAAATTATTAAGTTTA

AGGAAGAATATTACAAACTTTATAArI1T1GTTTGAAGGCATACAACAAAAATTCCATAGTCAAAGGAATTCATTTAT

*AA.AGATACTAAATTTGGGAAAAA.AAAGATAATTTAAATCCTTTTCATCTATAGAGAAAGAA

ATTAGAGATTTGAATTATAAGTTGNGTGAAATCCAAAGTAATTTTCAAATTGCAGATGTTAGCTGGAATAATGCAA

ACTCTCTTTTAAAGAATCTATAGAAATTAATTCAGGCAATTGAAAAAAGGTATGACAATGAGAGTAGAAAGCA

AGGTCAAATTGGTGGACCTGCTAATAGATGGGATAAAAATCAAGCTGACAATTTTGCTAAGGATGCAAAGTATAAG

GCAGAACATTCAGCAAATGATTTGGAAAATGCAGCCAACTATTTTAGATATAGTTGTTCAAATGAAAAAGAAGCTA

AAAAGCTATTAAGATAAAAGTTTACGAATITGGTATTAGCCTA

fO4A-aa BBO11 LPKISKLANKTTRIESRFEISIIFIYNGTKYL4EKRVGNKIFYISVVLILVGCDWGTIKDKSTEISKJLRTDK DKTKNQDRIELGEDNFVSKNMSTTDTGITSLGSLNNLDLINRSQRVSEPPIISNEKAIATQAKVDLMNNINVTI I

NPKPAQNLGNSLNN'TTEFDSVKFLSIENQEWLISKKILPSKLENLESFLKTQHEKEAFKTAKTIQSLISNSNMGKE

IIKFKEEYYKLYNLFEGIQQKFHSQRNSFIKDTKFGENRQKN~AVIFKSFSSIEKEIRDnLNYKLXEIQSNFQIADVS

WNNANSLLKESIEKJIQAIEKRYDNESRKQGQIGGPANRWDKQADNFAKDAKYKAEHSANDLENAANYFRYSCSN

EKEAKKLLEEIKKRFVRIGISL

*tO4A.aa BBO11

CDWGTIKDKSTEISKLLRTDKKTNQDRIELGDNFVSKNMSTTDTGITSLGSLNNLDLIRSQRVSEPPIISN

EKIATOTAKVDLMNINVTIINPKPAQNLGNSLNNTTTEDSVKFLSIENQEWLISKKILPSKLENLESFLKTQHE-K

EAFKTAKTIQSLISNSNMGKEI IKFKEEYYKLYNLFEGIQQKFHSQRNSFIKDTKFGENRQKNAVIFKSFSSIEKE IRDNYrKLXEIQSNFQIAVSWANSLLKESIEKLIQAIEKRYDNESRKQGQIGGpANRWDQADNFAKDAKYK

AEHSANDLENAANYFRYSCSNEKEAKKIJLEEIKKCRFSJRIGISL

*BB009 TAAATAAATTGTA TAATAAAAAAGAAAACTATTTTAAAAAAAGATTAATTTTAAACCTATTAA

TATTTTTACTACTAGCATGCTCAAGCGAATCCATATTTTCACAATTAGGAAATCTGCAAAAAATAAAACATGAATA

CAATATTTTGGGCAGTTCAAGTCCAAGAGGAATTTCTCTAGTAGGAGAAACTCTCTACATTGCAGCCATGCATTTA

TTTAAAAAGAAAACGGCAAGATTGAAAAAATTGATTTGAGCAATTCTTATGAGTTrATAAACGACATTGTAAATA TATCTGGAAAAACCTATCTTTTAGCG AACAGAAGATGATTTGCGAGCTAAATGGAAAAGATTG GACATTAAAAT'rTAAAAAACCGCTAAAAGCATATAAATTCTTAAAATCCGTAGAAGAGATGGCGTAA WO 98/59071 PCT/US98/12713 213 TABLE 1. Nucleotide and Amino Acid Sequences BB009 TGCTCAAGCGAATCCATATTTTCACAATTAGGAAATcC AATA~AGA~AT rGGGCA6GTT

-CAAGTCCAAGAGGAATTTCTCTAGTAGGAGAAACTCTCTACATTGCAGCCATGCATTATTTAAAAAAGAAAACGG

cAAGATTGAAAAAATTGATTGAGCAATTvCTTATGAGTTTvATAAACGACATTGTAAATATATCTGGAAAAACCTAT CTT TTAGCGCAAACAAAGAAGAAGAATT1AGAAGTTTGCGAGCTAAGAAGTGAATAATAA AACCGCTAAAAGCATATAAATT1CTTAAAATCCGTACGAAGAGATGGCG BB009

INCRIKKYENYFGKRLILNLLIFLLLACSSESIFSQLGNLQKIHKYNLGSSSPRGISLVGETLYIAAMHLF

IKKENGKIEKIDLSNSYEFINDIVNISGKTYLLAQNKEEE-LEVCELNGKDNTLKFKKPLKAYKFLKSVEEMA

BB009 CSSES IFSQLGNLQKIKHEYNILGSSSPRGISLVGETLYIAAMHLFKKEGKIEKIDLSNSYEFINDIVNISGKTY

LLAQNKEEELEVCE-LNGKDWTLKFKPLKAYKFLKSVEEMA

fO6A.nt BB014

TAAGAGCTATAGAGATTTGGTTGGCGTTTGTATAATAGCATTGGCTTTATTGGGTTGTTATTTGCCTGATA

ATCAGGAACAAGCTGTTrCAAACTTTTITTTGAGAATTCGGAAAGTAGTGATATGGGTTCCGATGAGATTGTTACTGA

.~.AGGCATATTTTCTAGTTTAAAATTATATGCGTCTGAACATCGTTTATTGGTTGAGATAAA.AAAGACTTTAATTAGT

*.TTAAAAGATCCTAATTATCNNGNTGTAGTACNCCCAGTGAGTGACTATAATGAGGAGTATTTTAATAAATTCTTTC

TAGATTTAGGGTCTGAGCAATCTAAAGACCTGATTAAGTTGTTTATTATGAAATACGAATAA

ATTTATGCGTATAGTTCGTTGGCTGTATTCATGTATAGAGGAGTTATATTCTCTAGATATTAAGTATTCTGGCGAG

GGACAGGTTACTAATCTGCCCTCTTACA

TTAATAAAGAGT

*ATAATAGCCCAGTTTCTATTTTACCTACATAA

tO6A.nt BB014 TGTTATTTGCCTGATAATCAGGAACAAGCTG~cAAACTTTTTTTGAGATTCGGAAAGTAGTGATATGGGTTCCG

ATGAGATTGTACTGAAGGCATATTTCTAGTTAAATTATATGCGTCTGAACATCGTTTATTIGGTTGAGATA

AAAGACTTTAATTAGTTTAAAAGATCCTAATTrATCNNGNTGTAGTACNCCCAGTGAGTGACTATAATGAGGAGTAT

TTTAATAATTCTTTCTAGATTTAGGGTCTGAGCAATCTAAAGACCTGATTAAGTTGTTTATTATGGTAAAT

AGCAGAACAATAATAAATTTATGCGTATAGTTCGTTGGCTGTATTCATGTATAGAGGAGTTATATTCTCTAGATAT

TAAGTATTCTGGCGAGGGGAGCCATGAGTATAATCGTAATATGCCTAGACCCACTGCTTATGAACAATAT'rAA fO6A.aa BB014 GAYMRILVGVCIIALALLGCYLPDNQEQAVQTFFENSESSMGSEIVTEGIFSSLKLYASEHLLVEIKTLI

SL

KDPNYVXPVSYNEEYFNFFLDLGSEQSKDLIKLFIMVKNEQNNNFRIVRWLYSCIEELYSLDIKSGEG

SHEYNRNMPRPTAYEQYLKVKRYDYNSPVSILPT

*tO6A.aa BB014 CYLPDNQEQAVQTFFENSESSDMGSDEIEGIFSSLLYASEHLLVEIKKTLISLKD

PNYVXPVSDYEE

FNKFLDLGSEQSKDLIKLFIMVEQNKFMRIVRWLYSCIEELYSLDIKYSGEGSHEyNNMpRpTAYEQYLK

VKRYDYN

fO7A.nt BB023

TAAAGTATTTTATTTTTTTATTATCCACTGTTCTTTTTGCTCAAGAGACTGATGGATTAGCAGAGGGTTCTAAA

GGGCAGAGCCTGGAGATTrAGTTTTAGATTTTGCCGAGCTTGCAAGAGATCCAAGTTCAACTAGACTTGA.TCTAC WO 98/59071 WO 9859071PCTIUS98/12718 214 TABI:E 1. Nucleotide and Amino Acid Sequences AATTATGTGArATGTATATTCGGGCGCI'CTGGTATTGTTAAGCCGGAAGATATGGTGTAGATCTrGGGATA

AATAATTGGAGCGTTTTACTTACTCCTTCTGCAAGGTTGCAGGCTTACGTTAAAAATTCAGTTGTTGCGCCCGCTG

TTGTTAAGAGTGAGTCAAAAACGTACGCAGGTGATACTATTTTAGGGGTAAGAGTTTTGTTTCCAAGCTATTCTCA

ATCATCTGCTATGATTrATGCCA.CCATTTAAAATTCCTrrTTATTCAGGGGAAAGTGGCAATCAATTTAGGCAAA

GGTCTTATTGATAACATTAAAACCATGAAAGAAATTAAGGTATCTGTTTATAGTTTAGGGTATGAGATAGATCTTG

-AGGTTTTATTrGAAATATGAATGNCATGGAATATGCTTNTCTATGGGTACTAA TAGGGGTGA TTTAATTGGTcAAATcCTAA~cTATATrccTAATATATCATCCAAATTATTAAAGACGATGTTCCAAATTATCCT CTTGCT'rCAAGTAAAATGAGATTTAAGGCTTTTAGAGTTTCAAAGTCACACAGTTCAAAAGAGCAAAATTTCATCT

TTTAGTTAAGATTAGAGTCTTTATGATAAGTTGAGTQTTTCAATAGATTCTGATATTGACAGTGAGTCTGT

ATTTAAGTTrATGAGACTAGCGGAACTGAATCCCTTCGTAAATTAAAGGCACACGNAACNTTTAAAAGNGTTTTA

AAGCTTAGAGAAAAAATTTCTATGCCTGAAGGCTCTTITCCAAAACTTTGTAGAAAAGATTGAGAGTGAAAAACCTG

AAGAATCATCTCCGAAAALATTAG

tO7A.nt BB023

GAGGGTTCTAAAAGGGCAGAGCCTGGAGAATTAGTTTTAGATTTTGCCGAGCTTGCAAGAGATCCAAGTTCAACTA

GACTTGATCTTACAAATTATGTTGATTATGTATATTCGGGCGCTTCTGGTATTGTTAAGCCGGAAGATATGGTTGT

AGATCTTGGGATAAATAATTGGAGCGTTTTACTTACTCCTTCTGCAZGGTTGCAGGCTTACGTTAAAAATTCAGTT

GTTGCGCCCGCTGTTGTTAAGAGTGAGTCAAAAAGGTACGCAGGTGATACTATTTTAGGGGTAAGAGTTTTGTTTC

CAAGCTATTCTCAATCATCTGCTATGATTATGCCACCATTTAAAATTCCTTTTTATTCAGGGGAAAGTGGCAATCA

ATTTTTAGGCAAAGGTCTTATTGATAACATTAAAACCATGAAAGAAATTAAGGTATCTGTTTATAGTTTAGGGTAT

GAGATAGATCTTGAGGTT'rTATTTGAAGATATGA.ATGNCATGGAATATGCTTNNTCTATGGGTACTTTAAAGTTTA

AAGGGTGGGCTGATTTAATTTGGTCAAATCCTAACTATATTCCTAATATATCATCCAGAATTATTAAAGACGATGT

TCCAAATTATCCTCTTGCTTrCAAGTAAA.ATGAGATTTAAGGCTTTTAGAGTTTCAAAGTCACACAGTTCAAAAGAG

CAAAATTTCATCTTTTATGTTAAAGATTITAAGAGTTCTTTATGATAAGTTGAGTGTTTCAATAGATTCTGATATTG

999 AC-AGTGAGTCTGTATTTAAAGTTTATGAGACTGCGGAACTGAATCCCTTCGTAAATTAAAGGCACACGNAACNTT TAAAAGNGTTTAAAGCTTAGAGAAAAAATrTCTATGCCTGAAGGCTCTTTCCAAAACTTTGTAGAAAAGATTGAG 9 AGTGAAAAACCTGAAGAATCATCTCCGAAAA-AT 9. fO7A.aa BB023 SILFFLLSTVLFAQETDGLAEGSKRAEPGELVLDFAELAlDPSSTRLDLTNYVDYVYSGASGIVKPEDMVVDLGIN NWSVLLTPSqARLQAyVKNSWvApAVVKSESKRYAGDTILGVRVLFPSYSQSSAMIMPPFKIPFYSGESGNQFLGKG LIDNIKTMKEIKVSVYSLGYEIDLEVLFElMNXMEYAXSMGTLKFKGWAfLIWSNPNYIPNISSRI

IKDDVPNYPL

ASSKMRFKAFRVSKSHSSKEQNFIFYVKDLRVLYDKLSVSIDSDIDSESVFKVYETSGTESLRKLKAHXTFKXVLK

LREKISMPEGSFQNFVEKIESEKPEESSPKN

tO7A.aa BB023 EGSKRAEPGELVLDFAELARDPSSTRLDLTNYVDYVYSGASGIVPDMVVDLGINNWSVLLTPsARLQAYVKNSV VAPAVVKSESKRYAGDTILGVRVLFPSYSQS SAMIMPPFKIPF-YSGESGNQFLGKGLIDNIKTMXEIKVSVYSLGY 9: EIDLEVLFEDXMMEYAXSMGTLKFKGWADLIWSNPNYIPNISSRIIKDDVPNypLAssKmRFKAFRVSKSHSSXE QNFIFYVKLRVLYDKLSVSIDSDIDSESVFKVYETSGTESLRLKAHCTFXVKLEXISmpEGSFQNFVEKIE

SEKPEESSPKN

fO8A.nt BB024

TGATTATAAAAAGATAAATGAAAATATCAACATATTATTTTGTTTATTTTTACTAATGCTAA

ACGGCTGTAATTCTAATGATAATGACACTTTAAAAACAATGCCcAACAAACAAAAAGAcGGGGAAAGCGTGATTT AACC AAAAAACCAAAACAAAATCTAAAGAAGAACTACTTAGAGAAAAGCTATCTGACGATCAA

AAAACACATCTTGACTGGTTAAAACCCGCTTTAACTGGTGCTGGAGAATTTGACAAATTCTTAGAAAATGATGATG

ATAAAATAAAATcAGC-ACTTGATCATATAAAAACTCAACTTGATAGTTGTAATGGTGATCAAGCAGAACAACAAAA AACCACTTrTCAAAACTGTGGTTACAGAATTCTTTAAAAATGGTGATATAGATAATTTTGCAACTGGAGCGGTTAGT

AACTGCAATAATGGTGGCTAA

tO8A.nt BO2 BB024 WO 98/59071 PCTIUS98/1271 8 215 TABLE 1. Nucleotide and Amino Acid Sequences TGTAATTCTAATGATAATGACACTTTAAAAAACAATGCC ACACAAGCGGAGGTGATTTAACCC

AAAAGAACACACAGAAAACAAA.ATCTAAAGAAGAACTACTTAGAGAAAAGCTATCTGACGATCAAAAAAC

ACATCTTGACTGGTTAAAACCCGCTTTAACTGGTGCTGGAGAATITTGACAAATTCTTAGAAAATGATGATGATAAA

ATAAAATCAGCACTTGATCATATAAAAACTCAACTGATAGT'GTAATGGTGATCAAGCAGAACAACAAAAAACCA

-CTTTCAAAACTGTGGTCGATTIAAAGGGTTGTATTCATGGAGCGGTTAGTAACTG

CAATAATGGTGGC

fO8A.aa BB024 ILIIKKGVnTEKIINLFCLFLLmLNGcNSNIDNDTLKNNAQQTKRRGKRflLTQKETTQEKPKSKEELLREKSDDQK

THLDWLKPALTGAGEFDKFLENDDDKIKSALDHIKTQLDSCNGDQAEQQKTTFKTVVTEFFXNGDIDNFATGAVSN

CNNGG

tO8A.aa BB024 1TQKETTQEKPKSKEE-LLREKLSDDQKTHLDWLKPALTGAGEFDKFLENDD

DKIKSALDHIKTQLDSCNGDQAEQQKTTFKTVTEFFKGDIDNFATGAVSNCNGG

fO9A.nt BB025

TGATTATAAAAAGATAATAATACAACATATTATTOTTATT=TTACTAATGCTAA

ACGGCTGTAATTCTAATGATACTAATAATAGCCAAACAAAAAGTAGACAAAAACGTGATTTAACCCAAAAAGAAGC

AACACAAGAAAAACCTAAATCTAAAGAAGAACTTCTTAGAGAAAAGCTAAATGATAATCAAAAAACACACCTTGAC

TGGTTAAAAGAAGCTCTGGGCAATGATGGAGAATTTAATAAATTTTTAGGATATGATGAAAGCAAAATAAAATCTG

CACTTGATCATATAAAGAGTGAACTTGACAGTTGTACTGGAGATAAGGTTGAAAATAAAAATACCTICAAGCAGGT

CGTTCAGGAGGCCCT'rAAAGGGGGCATAGACGGCTTTGAAAATACTGCAAGTAGTACGTGCAAAAATTCATAA Soso tO9A.nt BB025

TGTAATTCTAATGATACTAATAATAGCCAAACAAAAAGTAGACAAAAACGTGATTTAACCCAAAAAGAAGCAACAC

AAGAAAAACCTAAATCTAAAGAAGAACTTCTTAGAGAAAAGCTAAATGATAATCAAAAAACACACCTTGACTGGTT

AAAAGAAGCTCTGGGCATAGAATTAAA TAGAAGTA.GAATAACTGCACTT *GATCATATAAAGAGTGAACTrGACAGTTGTACTGGAGATAAGGTTGAAAATAAAAATACCTTCAAGCAGGTCGTTC

AGGAGGCCCTTAAAGGGGGCATAGACGGCTTTGAAAATACTGCAAGTAGTACGTGCAAAAATTCA

fO9A.aa BB025 S ILIIKKGIIMKIINILFCLFLMNGCNSNDTNNSQTKSRQKRDLTQKEATQEKPKSKEELLRELNDNQKTHLDW

LKEALGDGEFNKFLGYDESKIKSALDHIKSELDSCTGDKVEKNTFKQVQEALKGGIDGFENTASSTCKNS

tO9A.aa BB025 Goes 1TQEKpKSKEELREKLNDNQKTHLDWLKEALGNDGEFNICFLGYDESKIKS

ALDRIKSELDSCTGDKVENKNTFKQVVQEALKGGIDGFENTASSTCKNS

0 000 00 000 0.0.

0 00 00 0 *0 00 00 0 0 0 00.

0'0 00 O 0 0 00 *00r8 0.0.

0 0 0 0 @0 0 0.0..

0 0 0000w 00 0 0 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

Query GenSeq GenSeq Gene Description ScoreS P-VAlue AccessScr -au fOlA.aa gi26 9 0 2 56 (AE000790) antigen, P35, putative [Borrelia burgdorferi] 1523 5.90E-209 gOAaa~ 1269026 AE0790) B. burgdorferi predicted coding region BBA69 [Borrelia .1320 2. 1OE- 174 TOXAaa giW 290285 (AE000790) B. burgdorferi predicted coding region BBA68 [Borrelia 27 -7.50E-7 1 fO2A.aa 2i126901 05 (AE00789 B. burgdorferi predicted coding region BB138 (Borrelia 1531 8.40E-54 fO2A.aa i169009 (AEOOO7 89) antigen, P35, putative [Borrelia burgdorferi] 151 2.70E-48 fO2Aaa gi1690 8 (AE000787) antigen, P35, putative [Bor-elia burgdorferil 155 4.20E-22 fO2A.aa gi2900- (AE000789) B. burgdorferi predicted coding region BB139 [Borrelia -154 1.30E-21 fOA.aa gi1268805 1 (AEOl 127) -antigen, S2, putative [Borrelia burgdorfril 1223 7.60E- 164 fO3A.aa gil1063419 S2 gene product [Borrelia burgdorferi] 1161 3.OOE-22 fO3A.aa gl2690~227 (AE000790) antigen, S2 [Borrelia burgdorferi] >pir1D70207ID70207 116 9.70E-22 fO3A.aa 22i690128 (AE000788) protein p23 [Borrelia burgdorferi] >pirlC70257IC70257 110 5.70E- 19 f03A.aa gil2689956 0007 85) protein p23 [Borrelia burgdorferi] >pirfD70225ID70225 104 7.90E-15 fO4A.aa IgI607 (AE000784) B. burgdorferi predicted coding region BBH 18 [Borrelia 1873 5.60E-250 fO4A.aa ~1 09 A008)B ugofr rdce oigrgo B1 Brei ~14E1 gi2687919 (AE001 117) B. burgdorferi predicted coding region BB0028 [Borrelia _696 47.20E-92 fO6A.aa gi126901 29 (AE000788) outer membrane protein [Borrelia burgdorferi] 884 4.80E- 124 fO6 _a gil2690i89 (AE000789) conserved hypothetical protein [Borrelia burgdorferi] 731 2.20E- 118 f06A.aa gi1520 7 83 unknown [B3orrelia burgdorferi] >gil55 1742 unknown [Borrelia 337 4.30E-59 fO7A.aa gi2880 (AEOO1 168) flagellar filament outer layer pfotein (flaA) [Borrelia 166 2.50E-224' f07A.aa M575447 FlaA protein [Borrelia burgdorferi] >gi11019754 orf [Borrelia 1645 3.60E-221 fO7A.aa g1152896 flagellar filament surface antigen [Spirochaeta aurantial 144 1.70E-38 fOA.aa giii0 endoflagela sheath protein [reponemna pallidum]. 139 3.80E-29 f7A aa 1433524 flagellin FlaA1 [Serulina hyodysenteriae] >giI904393 endoflagellar 119 3.OOE-26 fO 7A.a p. A2 flagellar filament surface antigen 116ohata au40E-11 f_7Aaa_ A32814 1_11 __940EI_ fO8A.aa giI1209837 lipoprotein [Borrelia bgrgdorferi] 08 2. 1OE-78 fO8A.aa gi121212 80 (AF000270) lipoprotein [Borrelia urgdorferi] >gi13095 109 547 4.OOE-70 fO8A.aa gi1 1209873_ lipoprotein [Borrelia burgdorferi] 303I 3.70E-5A 0 '.0 00 '.0 -4 0~ 00 4' a.

o a.

a a a a a a a. TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f08A.aa gi 109 8 43 lipoprotein [Borrelia burgdorferil 395 2.0E4 fO8A.aa gi109849 lipoprotein [Borrelia burgdorferi] 219 2.60E-27 f08A.aa gi391 (AF046998) 2.9-8 lipoprotein [Borrelia burgdorferi] 234 4.30E-27 fO8A-.aa gil1209831 lipoprotein [Borrelia burgdorfeni 209 11E2 fO8A.aa gi13095107T (AF046999) 2.9-9 lipoprotein [Borrelia burgdorferil' 200 1.80E3-22 fO8A.aa gi112095857 1ipoprotein [Borrelia burgdorferi] 20 2.50E3-21 ?~f08. gnI1iPIDIe26 surface-exposed lipoprotein [Borrelia afzelii] 14~2 1.80E-1 8244 fO9A.aa Ri11209843 lipoprotein [Borrelia burgdorferil 453 8.0E6 fO9A.aa gi2121280 (AF000270) lipoprotein [Borrelia burgdorferil 7gi113095 109 379 1.001-56 fO9A.aa gi 297 ipoprotein [Borrelia burgdorferi] 282 1. 1OE-45 fO9A.aa gi 983 porotein [Borrelia burg orferi] 77 _7 TO--44 fO9A.aa gi094 lipoprotein [Borrelia burgdorferi] 143 1.60E-13 fO9A.aa gnI1IDe26 surface-exposed lipoprotein [Borrelia afzelii] III 3.60E- 13 FO9A.aa gil3095 105 (AF046998) 2.9-8 lipoprotein [Borrelia burgdorferi] 142 5.40E- 13 flOl.aa gil2688708 (AE0O1 176) conserved hypothetic al protein [Borrelia burgdorferi] 1099 4.50E-152 f0o 5.a a gil26869 (AEOQ1 175) B. burgdo fri predicted coding region BB0758 [Borrelia 1262.20E- 177 fI I- 12.aa gi12690139 (AE000788) B. burgdorferi predicted coding region BBKO1 [Borrelia 1434.70E3-193 fi ITI-12aa gi290030 (A100078) B. burgdorferi predicted coding region BBGOI [Borrelia 1066 1.40E3-13 8 f I I-12.aa gi (AE000784) B. burgdorer predicted coding region BBH37 [Borrelia 6.20E3-93 Tfl- 12. aa gi290 (AE000787) B. burgdorferi predicted coding region BBJ08 [Borrelia 192 2.70E-75 ?fW~ ag-160159j (AE000788) B. burgdo fri predicted coding region BBK12 [Borrelia 1144 2.70E3-147 T I-.aa gi291 (AE000788) B. burgdorferi predicte coding region BBKO7 [Borrelia 5.70E- 127 fT11-4. aa g12690095 (AE000789) B. burgdorferi predicted coding region BBIO [Borrelia ___153 1.30E-34 flIl-4.aa gji9097i (AE000787) B. burgdorfieri predicted coding region BBJ31 [Borrelia 115 1.40E- 2 f IT-4aa gil2690219 (AE000787) B. burgdorferi predicted coding region BBJ45 [Borrelia 115 1.40E- 12 fi 12-1.aa gi12690054 (AE000784) B. burgdorferi predicted coding region BBHO6 [Borrelia 573 7.OOE-75 f 12.aa '1688 (AEOO1 182) B. burgdorferi predicted coding region BB0838 [Borrelia 6008 0 f 2.a g1688 (AE001 174) B. burgdorferi predicted coding region BB03 Borrelia 987-6.20E3-133 f 1-.ag1695 (AE00O785) antigen, P35, putative [Borrelia burgdorferi] 385r 2.70E3-75 0 00 *o e. TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f 14-8.aa giI2690120 (AE000789) B. burgdorferpredicted3 coding region BB134 [Borrelia 30~i 2.60E-6 f 14-8.aa i2690UO32 (AE000784) antigen, P35, putative [Borrelia burgdorferi] 287 4.OOE-64 f 14-8.aa gi12690100 (AE000789) B. burgdorferi predicted coding region BI6Borrelia 12 1. I0E-38 flW" 148aag12690115 (A2E000789) B. burgdorferi predicted coding region BB128 [Borrel-a -173 I-T.70E-28 f 14-8.aa 1i12690116 (AE000789) B. burgdorferi predicted coding region BB129 [Borrefia 163, 8.20E-24 f 14T8aa gi12690207 (AE000787) B. burgdorferi predicted coding region BBJ02 [Borrelia 22 1 .90E-23 fl4-8.aa -g29009 (AE000789) B. burgdorferi predicted coding region BBI15 [Borrelia 140 3.0EL-12 f14-8.aa gi26901 5 (AE000788) antigen, P35, putative [Borrelia burgdorferi] II1 1.OOE- 11' f 142.aa gi26865 (AEO0L 172) glutamate transporter (gltP) [Borrelia burgdorferi] 2233 7.19999999 999982e- 311 T 4 2.a a gnlIle23 hypothetical protein [Bacillus subtilis] >gnlIPIDlel 182902 727 2.60E-156 3874 fT142.aa gnl1IlDIlO Proton/sodium-glutamate symport protein (Glutamate-aspartate 762 9.0-4 ___16231 f I42 .aa gl 174711 roton glutamnate symport protein (gltP) [I-aemopHilus influenzae] 0 2.1OE-131' f142.aa gi298758 (AE000735) proton/sodium-glutamate symport protein [Aguifex 111 8.0 3 f 142.aa g1143000 proton glutamnate symport protein [Bacillus stearothermophilus] 125 1 .20E-30 f 142.aa gi143002I proton glutamnate symport protein [Bacil-lus caldo5tenax] 12 1.90E-28 f 12.- gn1lDiiI IT proton/sodium-glutamnate symport protein [Bacillus subtilis] 122 22E2 _____83024 fi 42. aa gailPiDid 10 glutamate transporter [Caenorhabditis eleis] 121 1.80E-22 f 142.aa gi11255318 coded for by C. elegans cDNA cmO8h9; coded for by C. ele-gans cDNA 121 2. 1OE-22 f 142.aa _gil38712 (AF017 105) amino acid transporter [Chlamydia psittaci] 135 3.60-22 f 142.aa gi12655021 (AFO 18259) glutamnate transporter 5A [Ambystoma tigrinum] 125 7.70E-22 f 142.aa gnlIPIDel4 gluT-R gene product [Clostridium perfringens] 199 4.60E-21 f 142.aa gi1396412 g1tP [Escherichia coli] >gil 471 6 0 proton-glutamate [Escherichia 1091 7.90E-21 f 17.aa gi268856 (AEOl 172) NADH oxidase, water-forming (nox) [Borrelia burgdorferi] 2245 7.20E-3031 f 147.aa g1142030 NADH oxidase [Serpulina hyodysenteriae] 318 9.20E-105 f147.a ~iF502W(AE001077) NADH oxidase (noxA-2) [Archaeoglobus fliul33 29E9 0 00 -4

I-

00 ft ft ft.

ft *4 ft ft C ft S ft *ft ft ft ft.

ft S. ft ft ft* ft ft ft. ft TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f 147.aa g 27 2 90 (AF04 1467) coenzyme A disulfide reductase [Staphylococcus aureus] 194 2.60E-90 f1-4"7.aa g126503 (AE001088) NADH oxidase (noxA-1) [Archaeoglobus fulgidus] 286 3.30E3-88 f-47.aa nIIDPID~lJIO H20-formning NADH Oxidase [Streptococcus mutans] 3C 4.30E3-85 f 147.aa Igi 4902 NADH peroxidase [Enterococcus faecalis] >pirlST 83321S 18332 NADH 638 3.20E3-83 f 1 47.aa gi 59136 NADH- oxidase (nox) [Methanococcus jannaschii] >pirlA6438 1 IA648- 1 35 4T.8013-g3 f 147.aa giili622461 (AE00898) NADH oxidase [Methanobacterium thermoautotrophicum] -303 8.40E3-72 f 17. aa gi147045 'NADH oxidase [Enterococcus faecalis] >pirIS26965l52695 NADH 3T7 8.80E3-71 I oxidase f 147.aa IgiI2650233 (AB001077) NADH oxidase (noxA-3) [Archaeoglobus fulgidusi 312 2.0013-63 f 147.aa IgiII 6 7 4 132 (AiEOOOO44) Mycoplasma pneumoniae, NADH oxidase; similar to 175 7.OOE-61 f 147.aa Igil 145969 NADH oxidase [Mycoplasma genitallum] >pirID64230ID64230 NADHf I4 4.LO-0E-513 147.aa gi689 (AE000975) NADH oxidase (noxA-5) [Archaeoglobus fulgidus] 143 2.00E-40 f7 aa 1i2983379 (AE000709) NTDH oxidase [Aquifex aeolicus] T62 -3.50E3 a gi2885 (AEOOT1172) conserved hypothetical protein [Borrelia burgdorferil T F9 -2.701-OE17-9 f 150.aa gi (A0 43) hypotheticl protein [Auifex aeolicus] 238 1.0-2 f 150.aa 1 1519 (AFOO 1974) putative TrkA [Thermoanaerobacter ethanolicus] 175 5.80E-23 li177829 unknown [Bacillus subtilis] >gntlPIDldlOG7628 orf4 [Bacillus 212 1.50E-21 fi 50.aa gnllPIDlel 1 simrilar to hypothetica proteins [Bacillus subtilis] 181 6.O T-7 f 150.aa gnllPIDIdlO hypothetical protein (Synechocystis sp.) >pirIS75999IS75999 T12 3.70E3-11 ___11497_ f 15-2.aa 'gi12688660 (A-EOl 172) K+ transport protein (ntpJ) [Borrelia burgdorferi) 2200 2.40000000 0012 13ef152.aa gi12983882 (AE000743) K+ transport protein homolog [Aguifex aeolicus] 239 3.60E3-106 f 152.aa gnllPIDlel 1 similar to Na+-transporting ATP synthase [Bacillus subtilis] 158' 6.60E-64 f 152.aa gnlIP1D~el I1 similar to Na+-transporting ATP synthase [Bacillus subtilis] -T3-1 3.40E3-62 fl152.aa gnlIPIDIdl10 Na+ -ATPase subunit J [Synechocystis sp.] >pirl575455lS75455 141 -1.70E3-551 1_ 18749_ 0 00 *Doi Eon

A

a.

a S. At* A *a a A A A

A..

S A A A A A.

A A *AA A. A TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBanik and Derwent databases.

f 152.a gnlIPIiDIdlO Na+ -ATPase subunit J [Enterococcus hirael 209 4.OOE-45 04799 f 152.aa 1iI258~51795 (AF001974) putative TrkG [Thermoanaerobacter ethanolicus] 149 2.20E-29 f152. aa gi 646 (A-0-0-003)Mycoplasma pneumoniae, translocating ATPase 104 4.00E-28 f152aa giII046024 Na+ ATPase subunit J [Mycoplasma genitalium] >pir1F64235IF64235 114 2.80E-27 fi 52.aa gi1567062 i-KT1 [Triticum aestivum] >pir1S47582IS47582 high-affinity potassium 137 2-!.OOE-17 2j 8 (AEOO1 172) B. burgdorferi predicted coding region BB0722 [Borrelia -2456 0 f 157.aa gi2688641 (AEOO 171) rod shape-determining protein (mreB-2) [Borrelia f 157.aa gif 143 65 7 endospore forming protein [Bacillus subtilis] 24 -2760E-61 f 157.aa gi1580938 internal open reading frame (AA 1-290) [Bacillus subtilis] 224i 2.60E-61 f 157.aa gi12982781 (AE000670) rod shape determining protein RodA [Aquifex aeolicus] 333 5.40E3-61 f 157.aa gil8937 spoVE gene product (AA 1-366) [Bacillus subtilis] >gnlIDIeI 185111 224 7.70E-59 fi 57.aa gil 14795 rod-shape-determining protein [Escherichia coli] :>gil 1778551 34 6. 1OE-58 f 157.aa gnlIPlDIe32 sfr [Streptomyces coelicolor] 32 T 6.0E5 f 157.aa gi11572976 rod shape-determining protein (mreB) [Haemophilus influenzae] 307 4.OOE-56 f 157.aa gnlIPiDlel 1 similar to cell-division protein [Bacillus subtilis] 203 2.60E-45 __85075 7. aa gi14 6 978 4 putative cell division protein ftsW [Enterococcus hirael 231___ 6.90E-43_ f 157.aa gil 0 621 strong sequence similarity to FtsW, RodA, and SpoV-E [Cyanophora 206 3.O0E-41 f 157.aa gnliii 5 D~ldll rod-shape-determining protein [Synechocystis sp.] 184 1.60E-38 19002 f157.aa giI 146039 cell division protein [Escherichia coli] >gi140857 FtsW protein 104 8.30E-35 f157.aa gi1154 6 92 cell division protein (ftsW) [Haemophilus influenzae] Il4 3.30E-33 f 157.aa gi 165286 FtsW [Borrelia burgdorfeR) >gi12688164 (AEOO1 137) cell division 170 '6.201E-32 f 17-6.aa gi12690100 (A00()789) B. burgdorferi predicted _coding region BB116 [Borrelia 1250 I .70E-16'I f 17-6.aa gi12690 120 k(AE000789) B. burgdorferi predicted coding region BB134 [Borrelia 142 3.40E-59 f17-6.aa gi1260115 (AE000789) B. burgdorferi predicted coding region BB128 [Borrelia 447 t6.701EE-56 f 17 6 aa g2905 J(AE000784) antigen, P35, putative [Borrelia burgdorferil 182 1.1I0E_34 f1g.a il2689955_ (AE000785) antigen, P35, putative [Borrelia burgdorferi] 196 0E34 9 9.

9 9 9 9.

9 9 9.

9* 9* 9** 9 .9 9* 9 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f7 6.aa gi290114 (A13000789) BB urgdorferi predicted coding region lB3127 (Borrelia 176 1.003- 16 f 17-6Wa gniliPDIO'gene required for phosphoylation of oligosaccharides/ has 178 2.80E3-15 fl.7-6.aa gi1269020.7 (AE000787) B. burgdorfri predicted coding region BBJ02 [Borrelia, I1 3.50E-3 f 17-6-.aa gnlIPIDIe32 (AJ00496) cyclic nucleotide-gated channel beta subunit 152 1.T ~IOE f 170.aa g 28852 (AEO 171) B. burgdorfei predicted coding region BB0708 [Borrelia 524 2F6-0E-73 f 86.Aa 1i2688622 (A13001 169) B. burgdorferi predicted coding region BB0689 [Borrfelia 792 1.90E-105 f 186.'aa gi2882 (AE00-169) B. burgdorferi predicted coding region BB0689 [Borrelia 792 1.801E-105 f 19-2.aa gi 290120 (AE000789) B. burgdorferi predicted coding region BB134 [Borrelia 1341 2.ToE-f77 f 19-2.aa g12689955 (A00085) antigen, P35, putative [Borrelia burgdorferi] 347 7.0013-53 19-2aa gi 2690052 (AE000784) antigen, P35, putative [Borrelia burgdorferi] 254 7.70E-53 f 19-2.aa 1i2690100 (XAEO007 89) B. burgdorferi predicted coding region BBI16 [Borrelia, 14i2 6.60E-50 f 19-2.aa gil2 90115 (AE000789) B. burgd orfer predicted coding region B18[orreli 144 7.60E-34 ?T i g 90116 .(AE000789) B. burgdoferi predicted coding region BBI29 [Borrelia -2.20E-21 f19-2.aa gi2690207 (Ai1000787) B. burgdorferi predicted coding region BBJ02 [Borrelia 171 2.OOE- 16 f 19-2.aa gi609 (AE000-O789) B. burgdorferi predicted coding region BBII15 [Borrelia 6~6 1.20E3-1.5 f 19-2.aa gil2690125 (AE000788) antigen, P35, putative [Borrelia burgdorferi] 122 5.70E3-14 f 19-4.aa IgiI2690116 (AN3000789) B. burgdorferi predicted coding region BB129 [Borrelia 1129 DO3E-150 f 19-4.aa gi12690099 (AiE000789) B. burgdorferi predicted coding region BBI15 [Borrelia 260_ 3.0013-30 f 19-4.aa gi12689955 (A13000785) antigen, P35, putative [Borrelia, burgdorferi] 180, 1.80E-'23 f19-4.aa gi2690120 (AE000789) B. burgdorferi predicted coding region BB134 [Borre-lia 18 1.50E-21 f 19-4.aa giI2690052~ (AE000784) antigen, P35, putative [Borrelia burgdorferi] 192 1.2O1-9 fl-9-4.aa giI2i69027 (A1E W787) B. burgdorferi predicted coding region BBJ02 [Borrelia 14T9 8.90E3-14 f19-4.aa, gi 2900 8 (AE000789) B. burgdorferi predicted coding region BB114 [Borrelia 138 8.OOE- 12 f 1T6.a ii 12690115 (AEOOO7 89) B. burgdorferi predicted coding region BB128 [Borrelia 995 1.2013-131' f 19-6.aa gi12690100 (AE000789) B. burgdorferi predicted coding region BBI 16 [Borrelia f1 9-6.aa gi12689955 (AE000785) antigen, P35, putative [Borrelia burgdorferi] 219 2.0013-36 f 19-6.aa gil2690120 (A13000789) B. burgdorferi predicted coding regionBB134 [Borrelia 144 3.5013-34 f 19-6.aa gi12690052 i(AE000784) antigen, P35, putative [Borrelia burgdorferi] 130, 6.3013-12 f 196.-aa gi12688620 j(ABOOl 169) methyl-accepting chemnotaxis protein (mcp-5) [Borrelia 30931 0 0 00 9*O a. a a..

a.

a a a a a *a a a. a a a a S TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GeniBank and Derwent databases.

f 196.aa gi2861(AE001 169) methyl-accepting chemnotaxis protein (mcp-4) [Borrelia 6153 -1.90E3-83 f 196.aa i498 tlpC gene product [Bacillus subtilis] >pir11404961140496 methylation 180 6.90E-28 f 193.a gnlIPl1DldlO methyl-accepting chemnotaxi-s protein TlpC [Bacillus subtilis] ~~4.90E-27 07002 fl99.a gnlIPIDIelIl methyl-accepting chemnotaxis protein [Bacillus subtilis] 162 5. 10OE-25 73493 f 196.a gi882594 ORF-f506 [E-scherichia coll >gil 1789453 (AE000389) aerotaxis 204'-1 .70E-24 f 196.aa gil148350j tas [Enterobacter aerogenes] >pirID32302ID32302 probable aspartate .179 1.80E3-24 if3.a i1h6R5Futativ-e[Rhodobacter capsulatus] >pirIJC4735IJC4735 207 1 .80E-24 f 196.aa gi 154381 chemoreceptor [Salmonella typhimurium] >pidA47l78!A47178 230 2.OOEi f 196.aa, gi1459690 transmembrane receptor [Bacillus subtilis] >gnlIPlIDlel 185997 212 1.40E-23 fi 96.aa gi180501 MCPA protein [Rhodobacter sphaeroides] >pirl570094IS54262 237 2. 10OE-23 fT 19.a g102 mcpA gene product [Caulobacter crescentus] >pirIS23064IS23064 mcpA 238 7.30E3-23 f 196.aa gi 441 sensory transducer protein [Clostridium thermocellum] 227 8.90E-23 f 9.ia gi1016 Trg sensory transducer protein [Escherichia coli] 2Ti 2.F4013-20 f 19.a gnllPIDIdl10 Methyl-accepting chemnotaxis protein III (MCP-III) (Ribose and 211 2.50E3-20 15762 f 197.aa gi2688 6 21 (AEOO 1169) methyl-accepting chemotaxis protein (mcp-4) [Borrelia 3724 0 f 197.aa g12688620 (AE001 1695 methyl-accepting chemnotaxis protein (mcp-5) [Borrelia 615 8.40E83 f 197.aa giII066850 putative [Rhodobacter capsulatus] >pir1JC4735IJC4735 .227 9.8013-27 f 197.aa giI8-8594 ORF f506 [Escherichia coli] >gil 1789453 (AE-000389) aerotaxis 217 1.001-26 fi 97 .aa g154381 chemoreceptor [Salmonella typhimurium] >pirIA471I781A47 178 239 2.8013-25 fi L97.aa Igi49484i tlpC gene product [Bacillus subtilis] >pir11404961140496 methylation 202 5. 1 f 197.aa g D MiP-1 DT 10 methyl-accepting chemnotaxis protein TIpC (Bacillus subtilis] 202 5. 1 OE-2 1i97.aa g112564665 (AF022807) putative methyl accepting chemnotaxis protein [Rhizobium 212 7.2013-24 f197 aa gil459691 transmembrane receptor [Bacillus subtilis] >gnllPIDIe 1185996 215 1. 1013-23 f197.aa gi143218 serine chemoreceptor [Escherichia coli] >bbs1127562 serine 236 2.8013-23 f197.aa gi1537 197 CG Site No. 63; alternate gene name cheD [Escherichia coli] 236 2.9013-23 f 197.aa gi1 148077 methyl-accepting chemnotaxis protein I [Escherichia coli] >gil2367378 2361 2.9013-23 f 197.aa gnllPIDId10 transducer [Pseudomonas aeruginosa] 1 1781 4.2013-23 00 9.*9 9** 9* .9 9 4 9 9 9* 0 **0 4 94 .9 9900 9 4 9 9* 0 9* 090 9* 9 9 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent datatbases.

f 197.aa gil148349 tse [Enterobacter aerogenes] >pirIC323021C32302 serine transducer 234I 5.50E-23 T -1262835 chemotactic transducer [Pseudomonas aeruginosa] 5.70E-23 9,12~688600 (ABOll 18) ribose/galactose ABC transporter, permease protein 1887 5.10E3-266 f200.aa gnlIPIDe31 unknown [Bacillus subtilis] >gnlIPlIlel 184234 similar to 283 1.50E3-63 .1453__ f200.aa Igi12649711 (AE001042) ribose ABC transporter, permease protein (rbsC-1) 202 FI-6E-7 f200.aa 12 I230609 (AF00038) putative polytopic protein [Mycoplasma fermentans] 2.0E27 f200.aa gnllPBIle3l unknown [Bacillus subtilis] >gnlIP1D~el184235 similar to 112 1.1013-18 11493 f200.aa I i950073 membrane forming protein [Mycoplasma_7_ carc l]>pirIS77 901S77796J TM1 5.60E-16 f200.aa 101268899 (AOOl 168) ribose/galactose ABC transporter, permease protein 108 2.OOE- 1' f208.aa 191681 (AIEQO 1168) B. burgdorferi predicted coding region BB0674 [Borrelia 1726 6.70E-244 f2 1-4.aa 9i 1733 Bbk2. 11 [Borrelia burgdorferi] >pirlS .053 1 IS7053 1 bbk2. 11 prtin474 3.OOE-70 f21-4.aa gi 26272 6 7 ErpL [Borrelia burgdorferi] 477 6.0-9 f21-4.aa gi17~07281 putative outer membrane protein.[B3orrelia burgdorfer1 _73~ 660T-6-6 f21-4.aa 18 2 spF [Borrelia. brgdorferi] >pirlS70532lS70532 outer surface protein 503 6.0E6 f21-4,aa i 1i707287 putative outer membrane protein [Borrelia burgdorferi] 3.OO0E-60 f2 1-4.aa gil 1707290 putative outer surface protein [Borrelia burgdorferi] 342 3.20E3-49 f2l-4.aa gi.633 ErpK [Borre ia burgdorfri] 2 6 f21-4.aa I i46482~ outer surface protein F [Borrelia burgdorferi] >pirII402871140287 321 3.80E-38 f21-4.aa 10963 BbK2. 10 precursor [Borrelia burgdorferi] >pirIS705341570534 bbK2. 10 121 -3.90E-3:1 f21-4.aa R89040 BbK2.10 precursor [orre ia bUrgdorferi] >pirlS70533IS70533 bbK2.10 118 2.30E3-33 f2 -4.a 051120 outer surface protein G [Borrelia burgdorferi] >gil 1373118 ErpG 107 3.0E3 f21-4.aa gi2442 (AF020657) ErpX protein [Borrelia burgdorferi] 118 6.OOE- 14 f2l1 .aa gi268603 (AEOOl 168) conserved hypothetical protein [Borrelia burgdorferi] 867 2.60E- I116 f210.aa Igi289604 (AEQ0_ 1698_) chemotaxis response rgulator (cheY-3) [Borrelia 733 1 .40E-97 f2 10.aa I i1408274i CheY [B orrelia burgdorferi] 720 9.OOE-96 f210.aa.gi 1J765976~ chemotaxis-protein CheY [Treponema pallidum] 405 61. o-E 52 f210.aa Igill 2682 chemnotactic response protein [Bacillus subtilis] >gnllPIDlel 185224 184 8.OOE-30 Q210. aa Igil940 149 ICheY [Thermotoga maritima] 171 1.50E3-27_ 00 a a a S a a a a *a.

a.

a a. a a S.

a *a S a. a S a a a a S a. a. a TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in Genflank and Derwent databases.

f210.aa gil2~649557 (A.1300103 1) chemotaxis response regulator (cheY) [Archaeoglobus 168 L.5013-26 f210.aa gii620085~ cheY gene product [Listeria monocytogenes] 183 5.0013-26 f210.aa gnllPLDle24 YneI [Bacillus subtilis] >gil870926 response regulator E-24 f210.aa gi1 149620 ORF2 [Leptospira, borgpetersenii] >spIP24086IYLB3_LEPIN 121 4.70E-22

______HYPOTHETICAL

f210.aa gil 1408275 orfX; putative OrfX protein [Borrelia burgdorferil 208 -9-.20E-22 f2lO.aa gi[994802 cheY gene jeroduct [Halobacterium salinarium] >pir1S58645lS5865 CheY -139 8T.90E- 18 f210.aa gi1143598 spoOF [Bacillus subtilisi >gil 143601 SpoOF protein [Bacillus 113 4.7013- 11 f2l6.aa gi126858 6 (AEO 167) conserved hypothetical protein [Borrelia burgdorferi] 804 1.01- 09 f216T i 1554 orfA [Borrelia burgdorferi] 472 1.1013-91 f219.aa gi268594_ (ABO0l 167) B. burgdorfri predicted coding region BB0664 [Borrelia 1122 3.1013-148 f22.aa gjl268779 (AEOQ 118 1) B. burgdorferi predicted coding region BB0832 [Borrelia 1400 4.90E-188 f22.aa gi2688779 (AE001 18 1) B. burgdorferi predicted coding region BB0832 [Borrelia 1400~ 4.90E-188 f22 1.aa gi689 (AEOl 167) B. burgdorferi predicted coding region BB62[Borrelia -692 2.60WE-93 f229.aa gi1268591 '(AEOOI 167) oxygen-independen coproporphyrinogen III oxidase, 8 7.80E3-120 f 24 -g a a gi2399 putative vis recombination cassette, Vls6 [Borrelia burgdorferi] 924 1.80E3-114 I laa gi12039284_ putative vAs recombination cassette Vls5 [Borrelia burgdorferi] 86 6.30E- 107 f24- 1.aa gi203~79287 putative vAs recombination cassette Vis8 [Borrelia burgdorferil 824 1.5013- 104 f 2- 1 aa gi203289 putative Ais recombination cassette VislO [Borrelia burgdorferi] 829 750E-N0 f24- I.aa gi12039320 vmp-like sequence protein VlsE [Borrelia burgdorferi] 644 1. 1 OE-9 8 f24-1.aa gi12039288 putative vis recombination cassette Vls9 [Borrelia burgdorferil 783 8.20E-96 f'24-1.aa gi12039330 vmp-like sequence protein VIsE [Borrelia burgdorferil 742 -6.30E-95 f24-Tai120933 vmp-like sequence protein VlsE [Borrelia burgdorferi] 509 1.50E-92 f24- 1. aa gi12039286 putative vis recombination cassette Vls7 [Borrelia burgdorferi] 754 6.60E-92 f24- 1. aa gil203932 4 vmp-like sequence protein VlsE [Borrelia burgdorferi] 48 8.1013-86 f24- 1 aa g12039316 vmp-like sequence protein VlsE [Borrelia burgdorferi] 531 1.7013-85 f24-1.aa gi12039312 vmp-like sequence protein VlsE [Borrelia burgdorferi] 531 1.2013-83 f24-l1.aa gi12039326 vmp-like sequence protein VlsE [Borrelia burgdorferi] 476 2.0013-82 f24- 1.aa 'gi12039332 jvmp-like sequence protein VisE [Borrelia burgdorferi] 4741 5.1013-82 f24-1.aa gi12039328 jvmp-like sequence protein VNsE [Borrelia burgdorferi] 4201 3.5013-59

C',

00 I-s -4 I-s 00 0 9 U 4 a.

U

4 S 4

U..

U U U US U *U U U U S S. TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f253.aa gi268567 '(AEQO 1165) Na+/H+ antiporter (nhaC- 1) [Borrelia burgdorferi] 2241 0 f253.aa gi286 i(AEOOlI 165) antiporter (nhaC-2) [Borrelia burgdorferil '609 6.40E-155 f253.aa i5 8 Na+/H+ antiporter [Bacillus firmus] >pirIA415941A4 1594 _T5_8 9.40TE-5 f'25'3.aa gi 174661 Na+IH+ antiporter (nhaC) [Haemophilus influenzae] 143 4.2-0-14 f253.aa giii1iI11 similar to Na+IH+ antiporter [Bacillus subtilisl 3 .2E1 85625 137__ 1.20E__ II f253.aa gnl!PID~e32 hypothetical protein [Bacillus subtilis] >gnlIPID~el 1182969 133 2.OOE- II ___4972_ g26688a 5 (AEO 1TU conserved hypothetica protein orre la burgdorferi] T) 9.90E- 161 f269.aa gi268850 (AEQ001164) B. burgdorferi predicted coding region BB0624 [IBorrelia. 1654 5.50E-226 _28a AE000788) B. burgdorferi predicted coding rein683 [orei 2.80E-222 f28-2.aa, gi160161 '(AE000788) B. burgdorferi predicted coding region BBK49 [Borrelia 1068 2.20,- 163 f28-3.aa gi2690138 (AE000788) immunogenic protein P37, putative [Borrelia burgdorferi] 281 6.00-48 f28-3.aa gi290127 (AiE007 88) immunogenic protein P37 [Borrelia burgdorferi] 209 3.20E3-28 f28-3.aa gi2590 immunogenic protein P37 [Borrelia burgdorferi] 208 4.50E-28 f28-3.aa gi603 (AEOOO7 88) immunogenic protein P7, putative [Borrelia burgdorferij 172 5.50E3-17 f29.aa gi28764 (AEQ0l 180) B. burgdo eri predicted coding region BB0826 [IBorrelia W -8.20E- 116 f290.aa gi2883 (AE0Tf 62) serine-type D-Ala-D-Ala carboxypeptidase (dacA) 2046 1.50E3-281 f290.aa gjll43439 DD-carboxypeptidase [Bacillus sutls] >pirlB427081B42708 T1 Y .0f290.aa giiIDll1 D-alanyl-D-alanine carboxypeptidase (penicilin binding 161 6.60P--36 gid!PID~dlO Probable penicillin-binding protein. [Escherichia coli] 131 3.30E-28 16562 f290.aa spIP376041 PENICILLIN-BINDING PROTEIN 6B PRECURSOR 13 9. 1OE-29 f290.aa giII72 9 374 penicillin-binding protein 5 (dacA) [Haemnophilus influenzae] 145 3.0013-27 f290.aa 101580849i D-alanine carboxypeptidase [Bacillus stearothermophilus] 170 4. 1 OE-27 f290.aa igiTI78549 penicillin-binding protein 5 IlEscherichia -coli] >0i141212 precursor 1 3.20E3-26 f290.aa 9il142820 penicillin-binding protein 5 [Bacillus subtilis] 137 4.0-6 f9.a gi1410134 penicillin-binding protein [Bacillus subtilis] >gn11PIDell185588 1371 4.60E26 f290.aa 61l41218 prcro Ece Ich oi] 136 1.30E-251 It a a. a 9. a a a a. a a a.

a a a a a a..

a a at a a a 9 9 a a a. a a a a 9* a. TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.,: f290.aa gnlIPIDldlO Penicillin-binding protein 6 precursor (D-alanyl-D-alanine 136 1 .30E-25 f290.aa gil 1864022 pencillin binding protein 4 [Staphylococcus aureus] 155 5. 1OE-22 f290.aa gnlIPIDel5 penicillin binding protein 4 [Staphylococcus aureus] 155 5.IlOE-22 f290.aa gnIIPLDIe26 penicillin-binding protein 4 (Staphylococcus aureus] 155 5. 1 OE-22 4682 f29 1 aa gi1.26888538 A00 162) L-lactate permease (lctP) [Borrelia burgdorferi] 2473 0 f29 1.aa gnII1DIie27 lactate premease [Streptococcus iniae] 56EE3 T9F.aa gi1882504 ORF f560 [Escherichia coli] >gil 1789347 (AE000380) -f560; This 560 aa 3 3.60E3-95 f29 1.aa gi123 13225 (AE000535) L-Iactate permfease (lctP) [Helicobacter pylon]l 359 1. 10OE-94 f291.aa gi123 13224 (A13000535) L-lactate permease (lctP) [Helicobacter pylori] 34 2.90E-93 f29 Laa gi1404693 L-lactate permease [Escherichia coli] >gi1466741 aug is 3rd start 331 7.20E-82 f291 .aa gnllPiDlIe3l hypothetical protein [Bacillus subtilis] >gnlIPIDleI 186107 330 9.0013-80 3006 f291.aa gnlIPIldlO lactate permease [Bacillus subtilisi. T- l.70E-61 f291.aa gnllPI:)lelIl L-lactate permease [Bacillus subtilis] >pirIF69649IF69649 300 1.1OE6 f29 I. .aa gnlIPIIDIdlO homologue of L-lactate permease of E. coli [Bacillus 265 6.40E3-56 f291.aa gi1249804 (AE001049) Llatteprmease (lctP) [Archaeoglobus fulgidus] 170 .1.50E-47 f29 1.aa gnIPIDle2 L-lactate permease [Sulfolobus solfatanicus] 163 2.60E-44 ___3914_ f'291. aa gi154148 L-lactate permease (lctP) [Haemophilus influenzae] 1I73 6.001-35 f296.aa gi26951 I(AEQ0l 161) chaperonin, putative [Borrelia burgdorferi] 1276 4.40E- 177 f296.aa gi1840643 mucZ gene product [Coxiella burnetii] >pir11408521140852 mucZ ___101 7.90E- 12 f3.aa gil2 8 797 (AEOO 183) B. burgdorferi predicted coding region BB0844 [Borrelia 160-4 _1.4013E-211l gi12688765 (AEOl 180) B. burgdorferi predicted coding region BB0825 [Borrelia 1343 2.0013-181 f301.aa Igit2688521 (AEO 161) methyl-accepting chemnotaxis protein (mcp-3) [Borrelia 1 27561 0 f301 .Laa IgiI 1805311 methyl-accepting chemnotaxis protein B [Treponema denticola] 2111 7.0013-72 0 00 00 4 99..

4..

9 *O 9 4.

4 a. 6 9 6 9 4 69 9. 4 9. 4 644 6*9 4 09 469 4 0 4 4. 6 4 *4 4 9 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

1301 aa g 5822 (AEQOl 161) methyl-accepting chemnotaxis protein (mcp-2) [Borreli .a 89 2.80E- 18 £301 .aa g137665~ (AF016689) Mcp-2 [Treponema pallidum] 189 3.50E- 171 f0 1.aa gi 2352917 (AF012922) methyl-accepting chemotaxis protein [Treponema 187 5.70E-1 f301.aa i[T3776 MCP- 1 [Treponema pallidum]i 59E7 gi692 097F027868) YoaH [Bacillus subtilis] >gnlIPlDIeI 185333 similar to 184 2.80E- 161 f301.aa gi1542 transducer HtB protein [Halobacteriuim salinarum] -177~ -2.20E-15 f301.aa gi415694 chemoreceptor [Desulfovibrio vulgaris] >p-R1G3 69431G36943 163 -3.50E-1f301.aa giI459691 Ktransmembrane receptor [Bacillus subtilis] >gnlIPIDle 185996 163 4.90E-15 f301.aa giI214730 OIRF2 [Desulfurococcus SR. SY] 13 58E1 f301.aa giI2914132 methyl accepting chemotaxis homolog [Treponema denticolal 170 1.i OE 1 f301.aa gi49689 transmemnbrane receptor [Bacillus subtilis] >gnlIPIDIel 1185998 164 1-l.30OE-14 f301 .aa gi4648 Tlp eepoduct [Bacillus subtilis] >pir11404961140496 methylation 170 80E- 14 f301.aa 1i231316 (AE000530) methyl-accepting chemotaxis transducer (tlpC) -170 -TOEf308.aa gi268527i (ABO0l 161) B. burgdorferi predicted coding region BB0592 [Borrelia 1227 1.70E-176 f31-2.aa gi12602027 (AE000787) B. burgdorferi predicted coding region BBJ36 [Borrelia 1771 7.20E-235 fiI-2.aa 0 (AE000787) B. burgdorferi predicted coding region BBJ34 [Borre ia 423~ 4.60E-88 f3 aa 012688766 -(AEQOI 180) B. burgdorferi predicted coding region BB0824 [Borrelia 957 7.80E- 133 f314.aa gi2884 j (AEOOl 160) pfs protein (pfs-2) [Borrelia burgdorferi] 1329 7.40E- 180 1M.a iI690087 (AE000789) pfs protein (pfs) [Borrelia burgdorferi] 335 1.0E7 f3 14.aa gi12688288 (AEOOl 143) pfs protein (pfs-l1) [Borrelia burgdorferil 26 1.OOE-65 f3 14.aa gi12738591 (AF01288 6) Pfs [Buchnera aphidicola] 115 1 .70E-52 f~4a gi11552737 similar to purine nucleoside phosphorylase (deoD)) [Escherichia 133 6.90E-52 £3 14.aa giiilIl~e11 similar to purine nucleoside phosphorylase [Bacillus 137' 1 .20E-49 f314.aa gi11475 pfs [Escherichicoi >i457 107 ORF [Escherichia coli] SUB 9-219) 133 2.50E-2 £3 14.aa Igill574146 pfs protein (pfs) [Haemophilus influenzae] >pirIC64169IC64169-pfs- 110T 2.70E-37 ?faa gi122716 (AFOO9 177) pfs protein homolog [Helicobacter pylori] 118 3.30E-23 f~l4.aa gi12313168 (AE000530) pfs protein (pfs) [Helicobacter pylon] 115 -L OOE-22 f~l4.aa Igill11777939 Pfs [Treponema pallidum] 102 -1.90E_2 f3 14.aa 8970~ (AE000785) burgdorferi predicted coding region BBE07 [Borrelia 191 1.50E- 191 f314.aa gnIIPIDIe24 unknown [Mycobacterium tuberculosis] >sptQl108891Y05A MYCTU 105 7.6-1 002 00 a a a.

a a.

a. .a a a a.

a a a a a..

a a a.

a a. a. a a a a a a S.

a a. a a a a a a a a a a. a TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f32-4.aa gi12690221 (AE000787) B. burgdorferi predicted *coding region BJ7[orrelia 119 2 -4-.0013-3 f32-4.aa gi12689979 (A1E000785) B. burgdorferi predicted coding region B l6 [Borrelia 103 4. ~IOE f32.aa gi2688767 (AEOl 180) B. burgdorferi predicted coding region BB0823 [Borrelia .6 1.80E-81 f32.aa gi2688767 (AEOOI 180) B. burgdorferi predicted coding region BB0823 [Borrelia 62 1.80E-81 f320.aa Igil2688497 (AEQ0l 159) carboxypeptidase, putative [Borrelia burgdorferil 1373 6.40E-186 f320.aa Hi2529473 (AF006665) YokZ [Bacillus subtilis] 136 9.80E3-28 f320.aa gi12415396 (AFO 15775) carboxypeptidase [Bacillus subtilis] >gnlIlD~e 1185433 136 1.90E3-27 f320,aa gi11209528 D,D-carboxypeptidase [Enterococcus faecalis] 148 3.30OE- 16 ______>spIQ477461VANY ENTFA f320.aa Igil 155044 vanY [Transposon Tn 1546] >gi1149F126 D,D-carboxypeptidase [Plasmnid 142 1.60E3-13 f328.aa g268802 (AEOO 159) CTP synthase (pyrG) [Borrelia burgdorferi] 869 6.TIE- 19 f328.aa 11591801 CTP syinthase (pyrG) [Methanococcus jannaschii] >pir11364446l364446 325 6.20E3-59 f328.aa gi26503 (A13001088) CTP synthase (pyrG) [Archaeoglobus fulgidus] 304 4.2013-54 f328.aa gi11399854 CTP synthetase [Synechococcus PCC7942] >spIQ547751PYRGSYNP7 313 3.30E3-52 __CTP_ f328.aa g nIIP IDldl1O CTP synthetase [Synechocystis sp.] >pirl5758401575840 CTP -295 1.80E-50 19032 f328.aa gij439 CTP synthetase [Bacillus subtilis] gil853762 CTP synthase [Bacillus 27 .60E-49 f328.aa gi2983754 (AE000735) CTP synthetase [Aguifex aeolicus] 271 -1.503-4 f328.aa gi11574630 CTP synthetase (pyrG) [Haemophilus influenzae] >pirIF6418 1 F64 P tue6181 2371 90E-44 f38aa gi413755 CTP synhtase [Spiroplasma citri] >spIP522001PYRG SPICI CTP 231 3.0013-44 f328.aa 2T (A13000826) CTP synthase [Methanobacterium thermoautotrophicumn] 257 2.80E3-40 Wf328.aa gi1950067 CTP synthase [Mycoplasma capricolum] >pirIS77767IS77767 CTP 220 4.10E3-39 synthase f328.aa IgiI90 4 007 cytidine triphosphate synthetase precursor [Giardia intestinalis] 219 2.OE3 f328.aa Igi14'47~478. CTP synthetase (EC 6.3.4.2) [Escherichia coli] 217 2.90E3-38 f328.aa Igil882674I CP synthetase [Escherichia coli] 5>gi11789 142 (AE000361) CTP 214 7.70E-38 f328.aa 1i38 88 CT synthase [Azospirillum brasilense] >pir[1394961S25101FCTP 132 3.20E-37 f342.aa gi2889 (ABO0l 158) B. burgdorferi predicted coding region BB0563 [Borrelia, 944 5.3013-1305 f346 aa gifT272356 phosphotransferase enzyme 11 [Borrelia burgdorferi] >gi12688474 828 1.101-108

C,,

00

N

-a 00 0@ 9 9 *9 9 0 9 9@ 0 9 9 9 0 0 o 9 00* 6. 0. %09* TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in Genflank and Derwent databases.

M P.a g 463ITS enzyme HII gic [Escherichia coli] >gii 145605 PTS enzyme HI1 gic T3 8.80E-5 f?6.a i 1314675 glucose-specific component HIA of the PTS system [Escherichia coli] 385 9.30E-53 f?6.a i ~J47658~ LI(Glc) (crr) (AA 1 169) [Salmonella typhimurium] -382 2.30E-51 f346.aa gil.574566 glucose phosphotransferase enzyme HI-glc (crr) [Haemophilus 397 8.70E-50 f346.aa gil43819 nagE gene product [Kiebsiella pneumoniae] >irS18607lS18607 349 2.80E-41 MT46.aa gi 46913 N-acetylglucosamine transport protein [Escherichia coli] 33 3.20E-39 f346.aa gi 1072418 gIcA [Staphylococcus carnosus] >pir1S46952lS46952 '317 7.20E-37 0 6.a gil 1072419 glcB (Staphylococcus carnosus] >pirlS63606lS46953 315 1 .40E-36 f?46.a gill 46177 phosphotransferase system glucose-specific enzyme II [Bacillus 295 7.30E-36 f36a il5200 PTS glucose-specific permease [Bacillus stearothermophilus] 294 8.80OE 36 f346.aa gnlUPBDleII alternate gene name: yzfA; simnilar to phosphotransferase 293 1 .40E-33 18 8187 f346.aa gil580912 enzyme Ifi-glucose [Bacillus subtilis] 257 1 .20E-30 f346.aa gi 60268 1 lphosphocarrier protein (enzyme 11A) [Mycoplasma capricolum] 24 1 _05E-28 f346.aa gi 1432153 cellobiose-specific PTS permease [Klebsiella oxytoca] 25~7 1 .20E-28 f352.aa gil 2688482 (AEQO 157) B. burgdorferi predicted coding region BB0553 [Borrelia 254 0 f352.aa gi2888 (AEOO 1157) B. burgdorferi predicted coding re gion BB0553 [Borrelia 1.30E-132 f363.aa gi2886 (AEOl 156) B. burgdoiferi predicted coding region BB0543 [Borrelia 1109 5.40E- 153 f368.aa gi2885 (AE0O1 155) conserved hypothetical integral membrane protein 1133 4.1 OE- 157' f?8.a i lJ787047 (AE0001 81) o234; This 2.34 aa ORF is- 26 pct identical (15 gaps) to T7 1.40E-67 f368.aa gJIDT405_ (AE000601) conserved hypoteical integral membrane protein 129 3.50E- 16 f368.aa gniiiieI2 SIR [Cowpox virus] T3 -18E1 f368.aa gnllPID~dlO 24K membrane protein [Ps-eudomonas aeruginosa] 10 9.OOE-13 f38a gi 18 put. 23.5-kd protein [Escherichia, coli] >gil 1787275 (AE000 199) 101 L00E-1 1 f37 Laa gi288452 (AEOl 155) conserved hyp-otheiaprotein [Borrelia burgdorferi] -6 3-60E- 143 f371.aa gi1l.99W 0rf256 [Treponema palldum] T5 L1.OE-15 f373.aa gi128853 (AEQ0l 155) zinc protease, putative [Borrelia burgdorferi] 3663,__ 01 f373.aa gill.574200 hypothetical [Haemophilus influenzae] >pirlE64171I1E6.4171 2951 2.70E-67 f373.aa igi11787770 i(AE000246) f93 1; residues 5-650 are 99 pet identical to YDDC _ECOLI 2891 1.OE-571

W,

'.0

I

I

*1O

I

p i p *1 0 p p p

I

p..

0 *Op pp p pp I p 0.

pp *ep*.

p p I P I P p TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases., f373.aa gi535004 cds 106 gene product [Escherichia coli] 289 3.0E5 f373.aa gi1799369 Imetalloendopeptidase [Pisum sativum] 148 7.10E3-28 f373.aa gi12827039 (AF008444) chioroplast processing enzyme [Arabidopsis thaliana] 150' 1 .70E-26' f373.aa g12983709 (AE000732) processing protease [Aguifex aeolicus] _F 4.30E-OP 27 f373.aa i214155 (AE000609) protease (pqgE) [Helicobacter pylonl >pirID64646ID64646 115 530E-23 f378.aa. 1i28458 (AEQ0l 155) B. burgdorferi predicte coding region BB0531'[Borrelia 10TO30 1-30E-136 fb84.aa I (AEOO 154) inositol monophosphatase [Borrelia burgdorferi] 3.80E-20 f4-15.aa ~i2~28(AE000790) surface lipoprotein P27 [Borrelia burgdorferi] 1400 1.5E- f4-15.aa gi 144008 P27 [Borrelia burgdorferif >pir1S349951S34995 surface lipoprotein 46 2.40E-96 f-S0.aa gil2690243 (AB000790) Idecorin binding protein B (dbpB) [Borrelia burgdorferi] 900 6.30E- 117 f4-50.aa IgiI206238 1 decorin binding protein B [Borrelia burgdorferi] 897 1.60E- 116 f4-50.aa g2809217 (AF042796) putative decorin-binding protein precursor [Borrelia 887 3 60E3-115 f1-50.aa 1i2809218 (AF042796) decorin-binding protein precursor [Borrelia burgdorfri] 172 2.0013-33 f4-50.aa gi2690249 (AE000790) decorin binding protein A (dbpA) [Borrelia burgdorferi] -176 95E3 f4_ 0.aa gi12062379 decorin binding protein A[orrelia burgdorferi] T--177 T7-IE32 f4_6. aa gi12690229 (AE000790) chpAl potein, putative [Borrelia burgd-orfer] -807 1-f.603- 107 f4.aa gil268~78787 (AEOO 183) cosre hyoheia integral membrane protein 2408 0 f4.aa gi2697115 (AF008219) unknown [Borrelia afzelii] 1138 1.90E3-305 f4.aa gi11573583 H. influenzae predicted coding region HI0594 [Haemophilus 337 -2.1OE-1 09 f4.aa gi1788636 (AE000319) o513; This 513 an ORF is 31 pct identical (30 gaps) to 327 9.10E-80 f4.aa gnIWiDId 10 homologue of hypothetical protein H1I10594 of H. influenzae 357 5.40E-69 09571 1 1 f42- 1 aa giI28993 (AE000794).conserved hypothetical protein [Borrelia burgdorferil 49 2.70E3-62 f42- 1 aa IgI693 (AE000793) conserved hypothetical protein [Borrelia burgdorferi]' 312 1.001-37 f43-3.aa gi12210__370 lipopro tein [Borrelia burgdorferi] 5g[0519--462 1.5013-69 rf43-3 .aa IgiI2 121803 (A020ipoprotein [Borrelia burgdorferi 54639 19 T 1.80E3-55 f43-_3 aa gi1 1209837 lipoprotein [Borrelia burgdorferi] 365, 3. 10E-55 ff43-3 ;aa gi11209873 lipoprotein [Borrelia burgdorferil 269 5.30E3-32 f43-3.aa 11089lipoprotein [Borrelia burgdorferi] 141 1.70E- 13 f43-3.aa gi39105 (AF046998) 2.9-8 lipoprotein [Borrelia burgdorferi] 9.60E- 13 f3-3.aa Igil395107 (AF046999) 2.9-9 lipoprotein [Borrelia burgdorferi] .03f 00 I 9 999 .9.

9 99 9 9 .9 a* 9 9 9 99 9 9 9 9 9 999 999 9 99 999. 9999 9 9 9 9 9 99 9 99 99999 *9 9 999** 99 99 9 9 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.' f43.aa gi12688752 (AEQ0l 179) B. burgdorferi predicted coding region BB081 1 [Borrelia 233 6.60000000 084856e- 315 f446.aa g2 8383 (ABO0 151) B. burgdorferi predicted coding region BB0464 [Borrel~a_ 9 20 7.2 65E-72-4 f45-2.aa gi169017 ErpB2 [Borrelia burgdoiferi] >gil 1373 133 E!2B [Borrelia 364 7.50E-78 f45-2.aa gi12627270 ErpJ [Borrelia burgdorferi] 2.50E77 f45-2.aa gi12627268 ErpM [Borrelia burgdorferil 45 9.70E-65 f45-2.aa gi11373 144 ErpD [Borrolia burgdorferi] 31 19 60RE -5 8 f45-2.aa g 1244442 (AF020657) ErpX protein [Borrelia burdrei 380 2.80E-553 f45-2.aa 0DT1051120 outer surface protein G [Borrelia burgdorferi] >gil 1373 118 ErpG 213 7.10E-35 f45-2.aa gi1633 ErpK [Borrelia burgdorferi] 152 1.60E-21 f45-2.aa gn1lPDe2 (AJ00496) cyclic nucleotide-gated channel beta subunit I198 2.80H- 16 19895 f45-2.aa gi14482 outer surface protein F [Borrelia burgdorf-eri] >pir1140287II40287 III 5.70E- 14 f?5-2.aa '1246532 ORF 73, contains large -complex repeat CR 73 [Kaposi's 174 5.9 0-I f4 2aa~I6O~ glutamnic acid-rich protein [Plasmodium falciparum] 6__19 OE-1 f45-2.aa gi1170728 putative outer membrane protein [Borrelia burgdorferi] _101 2.20E- 13 f45-2.aa gi11633572 Herpesvirus saimiri ORF73 homolog [Kaposi's sarcoma-associated 175 4.1E-3 f45-2.aa giiIP~IIo 1 gene required for phosphoylation of oligosaccharides/ha-s 166 5.60E- 13 12343 f45-2.aa gl12690100 (AE000789) B. burgdorferi predicted coding region BBI16 [Borrelia 161 2.70E- 12 f457.aa gil2688369 (AEOO1 150) B. burgdorferi predicted coding region BB0456 [Borrelia 1021 6.20E- 139 f469aa gi2886 (AEOO1 150) Na+JH+ antiporter (napA) [Borrelia burgdorferi] 541.O-1 f4-.agi11209849 lipoprotein [Borrelia burgdorferi] 742 2.30E-97 f47-2.aa gi1 1209857 lipoprotein [Borrelia burgdorferi] 407 7.80E-86 f7aa gil 1209831 lipoprotein [Borrelia burgdorferi] 393 5.OOE82 f47-2.aa gnIIPlDIe26 surface-exposed lipoprotein [Borrelia burgdorferi] 321 2.60E-73 18245 Lf47-2. aa gi1120987 4 lipoprotein [Borrelia burgdorferi] 348 1. 1OE-64 f47-2.aa gniPDiIeI6 surface-exposed lipoprotein [Borrelia gariniil 333 1.40E-57 8239__ ff47-2 aa ~nI1~2 ufc-xoe iortin [Borrelia afzelii] 9 .6E4

-W

00 i o 0* 0 0 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f47-2.aa ?i39 0 AF046999) 2.9-9 lipoprotein [Borrelia burgdorferi] 328 3.80E-40 f47-2.aa nIPIIe26 surface-exposed lipoprotein [Borrelia garin ii] 320 1.'70E3-39 f47-2.aa Igi11209837 lipoprotein [Borrelia burgdorferi] 210 4.80E-29 f47-2.aa IgiI212128 0 (AF000270) lipoprotein [Borrelia burgdorferi] >gM1095 109 205 1. 1OE-27 f47-2.aa Igi~ 3 09510 (AF046998) 2.9-8 lipoprotein [Borrelia burgdorferi] 217 6.30E3-25 f47-2.aa Igil1209873 liooprotein [Borrelia burgdorferi] 113 '2.40E-1I1 f477.aa gil268830 I(AEQ0l 149) fructose-bisphosphate aldolase (fba) [Borrelia 1506 3.6013-202, f477.aa gi825 fructose 1,6-bisphosphate aldolase [Escherichia coli] >0i141423 -T5- 1.1OE-131 f477.aa gi[2708661 PAF037440) fructose 1,6-bisphosphate aldolase [Edwardsiella 593 -1.0E124 f477.aa gil11573507 fructose-bisphos-phate aldolase (Tha) [Haemophius influenzae] 560 8.50E- 120 f477.aa gi1671841 fructose 1,6-bisphosphate aldolase [Campylobacterjejuni] 856 3.8ET 13 T4 7 7.a a IgnllPIDld 10 fructose 1,6-bisphosphate aldolase.[Schizosaccha.b~romyces 749 1.70E-99 S~04756__ f477.aa jj143337 'east fructose-bisphate-aldolase [Saccharomyces cerevisiae] >gi13696 459 1.20E3-92 f477.aa gniIiPIiiIe9 fructose- 1,6-bisphosphate aldolase [Euglena gracilis] 701 6.30E-92 S~0134__ f477.a iff fructose 1,6 bisphosphate-aldolase [Neurospora crassa] 64 1.50E3-84 f477.aa gi140495 fructose-bisphosphate aldolase [Corynebacterium glutarnicum] 204 6.80E-37 f477.aa gnllPIDle3 1 Fba [MYcobacterium tuberculosis] 207 1 .50E-35 S~5480 f477.aa gil 1045692 fr-uctose-bisphosphate aldolase [Mycoplasma genitalium] 108 2.1OE-23 f477.aa gnllPIDldlO hypothetical protein [Bacillus subtilis] >gnlIPID~el 184692 102 2.70E- S03809 3220 f488.aa gi12688338 (AEQ0l 148) DNA &Xrase, subunit A (gyrA) [Borrlia burgdoRferi]320 f488.aa gil 1790876 DNA gyrase subunit A [Clostridium acetobutylicum] 822 1 L-OE- 171 f488.aa Igil2650163 (A1E001072) DNA gyrase, subunit A (gyrA) [Archaeoglobus fulgidus] 483 1LIOE-162 f488.aa IgI01 ORF 821 (aa 1-821) [Bacillus subtilis] >gnItPlDldlOO5785 A subunit of .836 6. 1OE-159 f?88.a gi1 4 59929 gyrase A-subunit [Pseudomonas aeruginosa] >spIP48372IGYRAPSEAE 418 7.003- 155 T4 88. aa gi114420 DNA gyrase A [Campylobacterjejuni] >pirlA48902lA48902 DNA grase 508, 7.50E3-154 It 00 S S 4*e 5 @5 S S *5

S

S.

S

**S

5 5 9 9 -4 6% .0 0 0 g*S:0 0. *0 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f488.aa gi1466275 gyrase A [Mycobacterium tuberculosis] >spIQ077O2GYRAMYCTU 395 35E-152 M 8.aa 'gnIPlDe2 GyrA [Mycobacterium tuberculosis] 395 2 OOE- 151 6924 f488.aa gi4348-5 DNA gyrase A subunit [Haloferax] >pirIS3057 I S30571 DNA 275 6.1OE-151 _________topoisomerase f488.aa gnlIPIDIdlO (ABOlOO8i) ATsbunit of DNA gyrase (Bacillus sp.] -549 -T.20E- 150 25098 f488.aa gnlIPID~e2I DNA gyrase subunit A [Mycobacterium smegmatis] 388 5.90E- 150 4031.

f488.aa g171385 DNA gyrase [Serratia marcescens] 378 6.OOE-148 f48a gnIIDe1 DNA topoisomerase (ATP-hydrolysing) [Mycobacterium smegmatis] -388 7.30E- 147 f488.aa i4163 gyrA gene product (AA 1-875) [Escherichia coli] >gi141636 DNA gyrase 38.3 2.409714Z f488.aa gi497i6i DNA gyrase subunit A [Mycoplasma genitalium] 514 5.2E-14 f49-2.aa gi120398 putative vIs recombination cassette VIs3 [Borrelia b-urgdorferi] 943- 2.30E-120 f49-2.aa g12547241 vmp-like sequence protein VIsE [IBorrelia burgdofferi] 43 4.108-106 f49-2.aa g123934i vmp-like sequence erotein VIsE [Borrelia burgdorferi] 458 3.OE 04 ff49_2.aa i T uttvvsrembntocasteVs[oreibudoer]731.E-0 f49-2.aa gi12039281 putative Ais recombination cassette Vls4 [Borrelia burgdorferi] '793 .0E-920 f49-2.aa gi12039283 putative vAs recombination cassette Vls9 [Borrelia burgdorferi 329 1.80E-88 f49-2.aa gi12039308 vmp-Iike sequence protein VIsE [Borrelia burgdorferi] 65 1.40E-88 f49-2.aa gi12039288 ptaive sqecembprotion Vassett [Borr elia burgdorferi] 367 1.0E8 f49-2.aa 412039332 vmp-like sequence protein VIsE [Borrelia burgdorferi] 45049 1.40E-88 f49-2. aa g10~398vp eqec ti VisE [Borrelia burgdorferi 62 1.50E-83 f49-2.aa 0i20393 vmp-like sequence protein VIsE [Borrelia burgdorferi] 47 25E6 f49-2.aa gi2392 vmptatie vseq reo ntin cassett [Borrelia burgdorferi] 44 1.80E-77 f44. g i12688346 (AEQOI 148) B. burgdorfri predicted coding regio'n BB0428 [Borre-lia 547 8.208-7-4 f5-1.aa il2627268 ErpM [Borrelia burgdorferi] 13 .0-3

CIO

00

C

C* C C. S S 0.

5 0 *5 0 a

C

C

0*C CCC

S

S CC a S. *9 C 0*C C C CC CS S S C C C 00 Se eGO C S CesSo 0* CC C S TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in Genflank and Derwent databases.

f5314.aa gil 1373 14ErpD [Borrelia burgdorferi] 53~ 4.40E-87 f5:14.aa "gil227270 ErpJ [Borrelia burgdorferi] 503 4.30E3-83 f5:14.aa gi1199017 ErpB2 [Borrelia burgdorferi] >gil 1373 133 ErpB [Borrelia. 503 2.60E-82 f5-14.aa gi2442 (AF020657) ErpX protein [Borrelia burgdorferi] 399 9.30E-57 f5I14.aa gIII 5ie32 (7UJ000496) cyclic nucleotide-gated channel beta subunit 228 1.50E3-20 f 57 4 7a gnl11IlDIdl.0 gene required for phosphoylation. of oligosaccharides/ has 203 8.70E- 8 12343 ?3TF4_. gi2246532 ORE 73, contains large complex repeat CR 73 [Kaposi's 97 3.301-1 f5-14.aa gi637 Herpesvirus saimiri ORF73 homolog [Kaposi's sarcoma-associated ___192 1.20E3-161 f5-14.aa gi13068583 (AF000580) Ree-ie [Dictyostelium discoideum] 197 3.6-6 f5-14.aa gi12690100 (AE000789) B. burgdorferi predicted coding region BBI16 [Borrfelia 2.90E-15 f5-14.aa 1118257 3 9 No defintition line found [Caenorhabditis elegans] 168 1.60- 1 f5-14.Aa gi10418 (7UF05693) mature parasite-infected erythrocyte surface antigen ~i20E1 f14.aa gnIIPiDIe34 EO2A1O.2 [Caenorhabditis e egans] I f5-14.aa gijO511 2 0 outer surface protein G [Borrelia burgdorferi] >gil13731 18 ErpG 157 '3.3OE- 12 f5-15.aa gi2627267 ErpL [Borrelia burgdorferi] T_1152 4.40E3-147 f5-15.aa giI[197833 Bbk2.1 1 [Borrelia, burgdorferi] >pirIS7053 I S70531 bbk2.l1 protein 8 9773F 10 8 15.aa gi864 OspF [B orrelia burgdorferi] >pirIS705321S70532 outer surface protein 325 1 .00E-72 15. aa gi 1707281 putative outer membrane protein [Borrelia burgdorferi] 32 1.80E3-72 135.aa'giI 1707287 putative outer membrane protein [orrelia burgdorferi] 322 6.60E-'70 g3T i i466482 outer surface protein F [Borrelia burgdorferi] >pir I402871140287 448 6.80-68 f5-15.aa gi11707290 putative outer surface protein [Borrelia. burgdorferi] 290 1.90E3-52 f5-15.aa gi163633 Erp2K [Borrelia burgdorferi] 17~2 8.70E3-43 f5-15.aa gi863 BbK2.10 precursor [Borrelia burgdorferi] >pirIS705341S70534 bbK2.10 153 1. 10OE-42 f5315.aa gi864 BbK2. 10 precursor [Borrelia burgdorferi] >piIS70533IS70533 bbK2. 10 124 4.30E3-39 f5-15.aa 1i1051120 outer surface protein G [Borrelia burgdorferi] >gil 13731 18 ErpG 105 35109-2-3 f5-15.aa gilT73144 ErpD [Borrelia. burgdorferi] 103 1. 10E- 14 gi2885 (AEOOl 179)'B. burgdorferi predicted coding region BB0806 [Borrelia 2651 0 f502.aa ITj T AO-l146) sensory transduction histidine kinase, putative 7575__

(I)

'~0 .4 cc 0 0000 0 Se S 0 00

B

S0 90

S

0 0 eeg e.g 0 C *0 C S S S 5 S *50 0 505 S S.

**eS e.Se 0 C 0 0 00 0* 60600 00 0 005.0 0S 55 0 0 TAB3LE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.0 f502.aa gnllPlDIdlO (A]3006363) homologue of histidine kinase [Candida albicans] 29 .8E5 f502.aa gi11354473 0s-i1p -[Neurospora crassa] 275 3.30E-57 g52. i11679757 two-component histidine kinase CHK-1I [Glomrerella cingulata) 382 4-.-20E-57 f502.aa gi11262208 Nik- 1 [Neurospora crassa] >gil 12W2210 Nik-1I [Neurospora crassa] 27 6.30E-57 f502.aa gil2460283 (AF024654) hybrid histidine kinase DHKB [Dictyostelium discoideum] _77 _3.9_0_E-53 f502.aa gnllPJDldlO sensory transduction histidine kinase [Synechocystis sp. -288 _7SUR f502.aa gi12623815 (AE030352) two comnponent sensor [Pseudomonas aeruginosa] 25 f302.aa 1i1939724 putative sensor kiase regulatory protein for production of f502.aa gt1532~9 regulatory protein [Pseudomonas syringae] >spIP480271LEMA_-PSESY -248 17.20oE-49 f502.a t prB483 two-component regulatory protein lem A Pseudomonas syringae 248 1 .30E-49 ______B41863 f502.aa gnllPIDldlO sensory transduction histidine kinase [Synechocystis sp.] 252 2. 1OE-49 502.aa gnIJPIDtdIO sensor-regulator protein [Escherichhia coli] >gil 1789 149 26 .02185_ f502.aa 9i1463 195 pectate lyase [Pseudomonas viridiflava] 24 7.50E-49 f502.aa igftlPDkIl0 sensory transduction histidine kinase [Synechocystis sp.] 24 1.002-48 1 1-2.aa gi2442 (AF020657) ErpX protein [Borrelia burgdorferi]T7 B 1-2.aa Igll2627268 ErpM (Borrelia burgdorferi] 399 3.20E-57 1-2.aa Igi1 1373 144 ErpD [Borrelia burgdorferi] 282 2.20E-50 1-2.aa Ig1677 ErpJ (Borrelia burgdorferi] 271 6.002-34' f3T-2.a Igill 99017 ErpB2 [Borrelia burgdorferi] >gil 1373 133 ErpB [Borrelia 271 -2-.50E-33 f51-2.aa IgiI1051120 outer surface protein G [Borrelia burgdorferi] >gi113731 18 ErPG 109 3.70E-22 1-2.aa gnIiiPlItikO gene required for phosphoylation of oligosaccharides/ has 203 5.40E-189 112343 B -TaaI gil 1707281 putative outer membrane protein [Borrelia burgdorferi] Ill 7.018' l-2.aa giI896042 OspF [Borrelia burgdorferi] >pirlS70532l570532 outer surface protein 11l 2.1TOE- 17 1-2.aa gi1 1707281 putative outer membrane protein [Borrelia burgdorferi] 1111 7.50E- 7 f51-.a nlIPIDle32 J(AJ000496) cyclic nucleotide-gated channel beta subunit 1981 1 .60E- 16 -4 00 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

__9895 f51-2.aa gi124653 2 -ORE 73, contains large cornplex repeat CR 73 [Kaposi's 176 2.30OE- 14 1-2.aa jnIPIiiiIe34 EO2AlO.2 [C7aenorhabditis elegans] 170 2.l1OE- 13 f51-2.aa g11160299 glutamic acid-rch protein [Plasmodium falc-iparum]l 157 7.30E- 12 f 5 f6 aa g128836 (AEOO1 146) B. burgdorferi predicted coding region BB0409 [Borrelia 1096 2OOE- 150 17.aa gi12688320 (AEOl 146) PTS system, fructose-specific IIABC component 1637-1 2_.3013-228 f517.aa gnlIPIDD' el 1 similar to fructose phosphotransferase system enzyme HI 256 4T.E88 83221 f517.aa gi1396296 similar to phosphotransferase system enzyme HI [Escherichia coli] 305 9.10E-86 f517.aa 'i1405893- fructose-specific IIBC component [Escherichia colil >gil450372 -224 -7 -0E-4 T517.aa ~J513.fructose enzyme 11 [Rhodobacter capsulatus] >gil46021 fructose 222 4.70E3-79 fS 1 7.aa 115lS73422 fructose-permease ILBC component (fruA) [Haemophilus influenzae] 225 6.90E3-69 f517.aa 912688554 (AEQ0l 164) PTS system, fructose-specific ULABC component (fruA-2) 2 36 8.2 0E-60 17.aa ignllPIDlel 1 phosphotransferase system (PTS) fructose-specific enzyme IIBC 195 2.80E3-65 85030 f517.aa gi1155369 PITS enzyme-Il fructose [Xanthomonas campestris] >pirIB40944IB40944 187 81E-6P2 f517.aa g11~ 3 503 similar to fructose-specific phosphotransferase enzyme HI 145 1.9013-3 f517.aa glJIPiiiIJIU HrsA [Escherichia coli] >gil 1786951 (AEOOO 176) 148~ 2.80E-39 111544 17.aa gi[1813488 phosphotransferase enzy.me II [Bacillus firmus] 226 3.90E3-39 17.aa gil757734 fruA gene product [Bacillus amyloliguefaciens] >pirlS59965l559965 177 _2.50E-3 f517.aa gnlIPIDIdlO PTS SYSTEM, FRUCTOSE-SPECIFIC UIBC COMPONENT (EilBC- 173 1. 1OE-34 16984 FRU) 17.aa gi 16737 31 (AEOOOO1O) Mycoplasma pneumoniae, fructose-permease IIBC 143 9.0013-33 19.aa gi168327§ (AEQ0l 146) B. burgdorferi predicted coding region BB30406 [Borrelia 106 _5.7_0&145 f519,aa gi2882 (AEOO1 146) B. burgdorfert predicte coding region BO45 [Borrelia 261 1'.20E-47 f520.aa gi2882 (AEOO1I 146) B. burgdorferi predicted coding region BB0405 [Borrelia -70-2 3T9_09719 f520.aa gil28327 (AEOl 146) B. burgdorferi predicted coding region BB0406 [Borrelia 261 4.0013-47 f523.aa 1-i2680 (AE001 145) glutamate transporter, Putative [Borrelia burgdorferi]- 20071 9.90E-284I f526.aa Igi26830 I(AEQ0l 145) B. burgdorferi predicted coding region BB0399 [Borrelia 1 10871 1.60E-145] .2 00 S S S S S. TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f527.aa gil2688310 (AEQ0l 145) B. burgdo-feri peicted coding regionT3B0398 [Borrelia 1814 7.60E-29 f54 1.aa 1158421 antigen P39 [Borrelia burgdorferi] >gi12688281 (AEOO1 143) basic 706 5S.401-230O £541I.aa gi1175325 BmpA protein [Borrelia burgdorferi] "-TZ7- 9.8-0E-229 f341 .aa gnlIPIDIel 1 bmpA(p39,ORFI) [Borrelia burgdorferij 1695 1.70E-229 L aa gnlIPlDIe 11 membrane protein A [Borrelia burgdorferi] >giIS 16592 membrane 164 3.40E-22 1 f341.aa gnIIPLDIe 11 membrane protein A [Borrelia burgdorferi] 163 1 .20E-226 f541.aa gnlIPIDIe 11 bmpA(p39,ORFI) [Borrelia burgdorferi] 1551 LOE-0 £54T1.-aa gnlIPlDIe I1F membrane protein A [Borr-elia afzelii] 150~2 5.66E-202 41. .aa gnlIPIDIel 1 membrane protein A [Borrelia afzel 149 1.0-0 £54 1.aa gnlIPIDIe 11 membrane protein A [Borrelia garinii] 149 3.70E-201 f541.aa gnIIPIDIel 1 membrane protein A [Borrelia afzelii] 1493 9.60E-201 f 54I .Faa gnIIPIDIe I1I membrane protein A [Borrelia gariniji 148 4.60E3-200 f541.aa gnIIlPDe23 membrane protein A [Borrelia garinii] 1216 1.20E3-162 ___7214_ f541I.aa gnlIPIDIe23 membrane protein A [lBorrelia garinii] 1211 5.90E3-162 f541I.aa gnlIPLDIe23 membrane protein A [Borrelia garinfi] 1098 2.003- 146 f54 1.aa 1i26882282 (AE001143) basic membrane protein B (bmpB3) [Borrela b-urgorferi] 519 1.2013-123 f542.aa gi5 422 [Borrelia burgdorferi iminunodominant antigen P39 gene, complete 711 1.70E3-95 f542.aa 9 8 (AEOO 143) basic membrane protein B (bmpB) [Borrelia burgdorferi] 711 1.70E-95 f542.aa g~i1744i membrane lipoprotein IBorrelia butgdorferi] 708 8.60E-9 f542.aa nIPIiDe1 I bmpB(p39,ORF2) [Borrelia burgdorferil 6-9-8. WE_____97 0 '.0

(A

C

-4

-J

'.0 00 k'J -4 00 e TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f542.aa gnllPL)lel 1 bmpB(p39,ORF2) [Borrelia afzelii] 63 1 OOE-84 f54T2. aa gnliPIDIel I'bmpB(p39,ORF2) [Borrelia garinii] 61 9.2013-8 f542.aa gnllPIDle23 membrane protein A [Borrelia garinii] 153 1.70E3-32 7209 f542.aa gnlIPIDIe 1 F mpA(p39,ORF 1) [Borrelia burgdorferi] l 3.80E3-32 ___72828__ f542.aa gnllPIDle23 membrane protein A [Borr-elia garinii] 153 2.OE3 fS42-.aa gil 1753225 BmpA protein [Borrelia burgdorferi] 155 2.80E-31 f 542. aa gnllPIDIel 1 bmpA(p39,ORF1) [Borrelia burgdorferi] 155 2.80E3-31 542 .aa giI5841 antigen P39 [Borrelia burgorferi] >gil2688281 (AEOO1 143) basic 155 2.80E3-3.1 f542.aa gnl T~ Imembrane protein A [Borrelia garinli] 15 1OOE-30 f542.aa gnlIPIDlel 1 membrane protein A [Borrelia afzelii] 144 1.9013-30 ______172829 f542.aa gnlIPLDlel 1 membrane protein A [Borrelia afzeliji -~2.70E-30 ______172830 f544.aa Igi12 6 8 8 2 8 4 (A.E001 143) Mg2+ transport protein (mgtE) [Borrelia burgorferi] 860 4.20E3-119 f544.aa g111753228 MgtE Borrelia burgdorferil 855 2.20E3-1 18 f544. aa gI 9724 MgtE [Bacillus firmus] >pir1140201114 02 0 l mgtE protein Bacillu-s I-7 3.70E-37 f34a gil78028 extended ORF of mgtE gene; transcription from this start point Is -18 2 170-73 f544.aa gnllPIDle3l unknown [Mycobacterium tuberculosis] 183 4.50E-31 5479 544.aa gnllPlDl)dlO Mg2+ transporter [Synechocystis sp.] >pirlS77552lS77552 Mg2+ 165 4.60E3-3 1 f544.aa glIIPIDlel I (AJ00257 1) YkoK [Bacillus subtilis] >gnllPIDlel 1183350 similar 14I .3E3 ___81529__ f544.aa IgiI2621701 (AE000843) Mg2+ transporter [Methanobacterium thermoautotrophicuml 1421 3.20E3-2 1 00 S

*S

a

S.

S

*S*

S.

S

S

S

*5* S S S. S S S. 55 5 5 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

C545.a ~i268824 (AOOIn43) M g2+ transport protein (mgtE) [Borrelia b-urgdo6rferil f545.aa gi11753 228 MgtE[Borrelia burgdorferi] i--Bclu f545.a 724 t [Bacillus 1ims >iI420111 4 2 lmt rten-Bclu 4S.aa gi178022 extended 0R of mgtE gene; transcription from tIs satpiti aa iiiilPi~le3 1unknown [Mycobacterium tuberculosis] f545.aa gnllPlDl)dlO Mg2+ transporter [Synechocystis spi ]>-pir1S775521S77552 Mg2+ f545.aa guliPIDle11 (AJ00257 1) YkoKT[Bacillus subtilis] >gnIIPIDIell18 33 50 similar 1529 f545.aa gil2 6 2 1 7 01 (E0843) M 2+ transport-R ethanubacterium thermauotopicumlf561.aa -i4245~ lipoprotein [Borrelia burgdorferil >gi 26 882 71 (AEOl 4)lportI f561 .aa gi49 5738 P22 [Borrelia burgdorferil f577.aa gi1268 826 1 (AEQO 141) B. burgdorfri pr-edi1cted coding region BEs0-352 itBofrelia f584.aa gi12 6 8 8246 (AOO 140) B. bugofrredicted coding region BB0346[Brea f56a 9121~4 92 Q~ 1140) P261[B-orreliabur dorferil >pirG7Ol4ll-7Ol 4 l P26 73596. aa ~I~i6 A006)P26 _[Borrela bugdorferil >gi1228 1465 (AiF000366) P26 f'9 8 .aa g1228 2?AF 0366) olgopeptide ermease homolog D [Borrelia burgdorferil TS-98.a M43607 sporulation r-otein Bacillus sutilis)jl 5-98. aa gn IH~ll ofigopeptide ABC transporter (ATP-binding protein) [Bacillus 83166 1 9 8.aa M537676 oligopeptide transport ATP-binding protein (oppD) L.haopiu f598.aa A pD [Bacillus subtilisj >gnllPIDlell 3 15 1gopeptide

B

9 8a a -61i787051 (AEOOOl) 18 2 4 c identical (33 gaps) to 25 residues from f598.aa '8i147 3 46 A rotein [Streptococcus pneumoniae) >pir S I15S 11152 ariE f598-.aa i' 47805 0 D( l-335) [Salmonella typhimurium] >spIP425OPPD

SALTY

f598.aa pA04131 oligopeptide transport protein oppi) Salmonella typhimuriumn f598.aa H1787499 (AE000223) oho e t tasport ATP-bincln rtei 0 P 98.aa i 495177 ATP inding roen[atccu lcii> PO IOPPDLACTLC 86, .Ts-1 816 3 .71- 18 182 183 1 .30E-34 4.50E3-31 1654.60-3 142

TOOO

3.20E3-21 DOE1- 132 19-30 4.0013-264 1094 TI-T47 1322 1.20E3-180 1010 5.90E137 372 -372 1.F20E-4q5 UM-14-4 3441 8.0013-42 3461 2.50E3-4 1 .332 -332 332 5.70E3-405 5.70E240 8 .40OE-40 (~3 -4

GO

0 0* *0* TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f598.aa gnI1PIDIl oligopeptidepermease [Streptococcus pyogenes] 331 1.1OE-39 7587 f 5 98.a a gi1308850 ATP binding protein [Lactococcus lactis] >pirIA532901AS3290 329 1.6013-39 f598.aa gi123 13399 '(AE000548) dipeptide AB3C transporter, ATP-binding protein (dppD) 322 2.30E-39 f6-2 Laa gi281468 (AF000948) OppAIV [Borrelia burgdorferi] >gil2 6 8 9 89 1 (AE000792) 565 -4.30E3-73 M-2 Laa gi2532S6 (AF005657) plasminogen binding protein [Borrelia burgdorferil 315 1.20E3-37 f62~a i1 82 (AEOO 1139) oligopeptide. ABC transporter, periplasmic 31 1F6-TW3f6-2 1.aa i128O544 (AF04307 1) oligopeptide permease periplasinic binding protein 314 E-3 f6-2.aa. gii22T17 (AF000366) oligopeptide permease homolog Al [lBorrelia burgdorferil 314 1.60E3-37 f6-21.aa gi126882 2 7 (AEQ0l 139) oligopeptide ABC transporter, periplasmict 290 3.90E-34 f-1.agi228458 (AF000366) oligopeptide permease homolog All [Borrelia burgdorferi] 290 3.90E3-34 fZ-2l.aa gil228 1455 (AF000365) oligopeptide permease homolog AV [Borrelia burgdorferi] 279 9.9013-34 7f-2l.aa gi126 902 6 1 (AE000790) oligopeptide ABC transporter, periplasmaic 282 5.30E3-33 f6- 1 aa i11616644 P30 [Borrelia burgdorferi] 271 6.70E-32 f6-i~a gi2882 (AEQ0l 139) oligopeptide ABC transporter, periplasmnc 268 5.001-31 f6-21.aa gi122 8 14 5 9 (AF000366) oligopeptide permease homolog A11I [Borrelia 26 5.OOE-3 I f6--I.aa gil-8O-9S5 46- (AF04307 1) oligopeptide permease periplasmic binding protein 268 5.00-31 M 2 a a bbs16 1785 60 kda antigen [Borrelia coriaceae, C053, ATCC 4338, Peptide, 514 255 2.90E-36 f -21.aa Wi29839 34 (AE000740) transporter (extracellular solueni n rotein family 154 3.50E3-14 f6-27.aa i289911 AE000792) B. burgdorferi predicted coding region BB3B09 [Borrelia 177 7.30E3-240 gi2689905 (AE000792) B. burgdorferi predicted coding region BBB27 [Borrelia 932 7.50E-126 f 00.aa gil2-2-846h (AF000366) oligopeptide permease homolog C [Borrelia burgdorferi]r1 731 1.40E- 100 f600.aa gi2884 (AE001 140) oligopeptide AB3C transporter, permease protein (oppC-1) -731 1.40E-100 f600.aa gi1143 6 0 6 sporulation protein [Bacillus subtilis] >pir1C38447IC38447 32 5.003-481 f600.aa 01I400 0 7 OppC gene produict [Bacillus subtilis] >gnlPIDlel 183 165' oIgopeptide 372 5.0013-481 f600.aa gill 74 7 oligopeptide transport system permease protein (oppC)C [Haemophilus 372 '7.30E3-48 f600.aa g 90-S4- O6p C (AAI-301) [Salmonella typhimurium] >pirC29333I1QREBOC 36- 4.20E3-47 f600.aa guliPIDId 10 Oligopeptide transport system permease protein OppC. -3-66 4.T201-4 7 15493 f 0.a gnIN~Dlel 1 (AJ00257 1) DppC [Bacillus subtilis] >gnlIP1DI 83314 2671 1T70EW2' q.

cj~ '.0 00 k~J 00 *9 9 9@ 9 9 *9* 9* 9 9 9 9 9 .9 9 9* TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f 00.aa ema gi11732 315 transport system permease omolog [Listera monocytogenesl 33 5.30E-42 f600.aa gi5805Y dciAC [Bacillus subtilis] >spIP269O4IDPPCBACSU DIPEPTIDE 258 1.SO0E-40

______TRANSPORT

f O.aa gnl1PIIDldl0 'oligopeptide transport system permease protein [Synechocystis 24 2.01- ___11164_ 0. aa gi 6 7 94 7 AppC [acillus subtiis] >gn LPIle II831 6 0 olioetd ABC 2 2.80E-37 f600.aa 1147dptide transporter protein dppC [Bacillus fru]21 12E3 f600.aa sRJQ10 3 PUTATIE PEPTIDE TRANSIPORT PERMEASE PROTEIN -290 71501E-35 iYO2L-MYC CY373.O1C.

TU T6 00. aa gil 15 3 2 2 0 1 1~K [Srpomcscelicolor] 29T 1T6--5 f603.aa 2281460 TAF000366) oligopeptide permease homolog B [orrlabgfe ri 1 15 22 -3.8 0E-2 11 f603.aa gil 1574678- dipeptide transport system permease protein (dp) [Flaemophilus -392 1.30E-100 f603.aa 1gnltPJD~el 1 ohigopeptide ABC transporter (permease) [Bacillus s-ubtilisl 74 SWK9- 83164 f 3.aa 0i1580897 OppB gene product [Bacillus subtilis] >prl51523-1lB38447 373 6.6E-9 760 3 aa g I7803 OPP B A-3) [Sloel1yhmru]>iI2333IQREBOB 371 701-96 f03aa gi1879 (AE00223) oligopeptide transport system permease protein OppB 3 -3.5013T-9-5 f603.aa gnIIDkIiO Oligopeptide transport system permease protein OppB. 357 3.5013-94 15492 i15808 5 0 -dciAB [Bacillus subtilis] >gnllPIDlel 181494 (AJ002571) -DppB 350 9.10E-9 f603aa ~3317~6~spoulaton roten [acilus ubtilis] >gil 143605 sporulation 34 24E8 f603.aa i~92~ tansmemnbrane protein [Esch1erichiiacoli] >gil46 66 8 2 dppB29 960-9 f603.aa il797 053 (AEOOO 185) o30O6; This 306 aa ORF is 46 pet identicl (32 gaps) to 284 3.8013-77 3 aa gil97 2 89 5 DppB [Haemophitus influenzae] >gi 15741 14 dipeptide transport system -301 -2.50E3-76 f603.aa 1ii2182646 (AE000098) Y4tP [Rhizobium sp.NGR2341 >sp1Q53 l91IY4TPRHISN 294 9. 1013-74 f603.aa g!12993 140 (AE000692) transporter (Opplic family) [Auifex aeolicus] 169) 2.3013-73 g63a i677946 AppB [Baclussbtls >gnllP10ell183159 oligopeptide ABC 218 8.7013-73 f 0 .a a i 2 5 A0066) oligopeptide permease homolog AIII [Borrelia 21 f604.aa gi12805 (A037)oioetd emes eilsi idn rotein 2818 0 f604.aa gi 2688226 (AE001 139) oligopeptide ABC transporter, periplasmic 2823 0 f604aa i1V12688227 I(AE001 139) oligopeptide ABC transporter. periplasmic 1738 141-3 00

GO

S

9 Se S 9.

S. 55

C

C

C

9C* *C* 9 *59 C *C S S C S S C C S SC C 55 C C C C

S

C. C TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases. f604.aa gi122 8 1 4 5 8 (AF000366) oligopeptide pernease homolog All [Borrelia burgdorferi] 1731 1.30-E-233 f604.aa gi1228 1468 (AF000948) OppAIV [Borrelia burgdorferi] >gi12689 8 9 1 (AE000792) 1675 3.60E3-229 TO04aa gil2688228 (AEQ0l 139) oligopeptide ABC transporter, periplasmi~c 718 1.60E-204 If 604. aa i1894 (AF04307 1) oligopeptide permease periplasmic binding protein 718 3.OOE-204 f604aa gi122538 (AF005657) plasminogen bidn prti Brei urgdorferi] 71..O-0 ROO 4. aa g121457 (A000366) oligopeptide permease homolog Al [Borrelia burgdorferi] 714 2.0013-203 4. aa bbs116178 60 kda antigen [Borrelia coriaceae, C053, ATCC 4338, Peptidle,514 704i 1.20E3-190 f604.aa gi21455 (AF000365) oligopeptide permease hbmologA [Borrelia burgdorferil 14 02 -18 E- 18 8 f604.aa g29026 (AE000790) oligopeptide ABC transporter, periplasrnic 1400 3.40E-189 f604,aa gi11616644 P30 [Borrelia burgdorferil 858 74-01TI7 f604.aa gi47802 Opp A (AA1-542) [Salmonella yphimuium]m >gi14780 precursor 296 9.0013-114 f6D6.aa gil228 1458 (AF000366) oligopeptid6 permease homolog All [Borrelia burgdorferil 2762 0 f606.aa gil2688227 (ABO0l 139) oligopeptide ABC transporter, periplasmic 2774 0 f606.aa gi122814 6 8 (AF000948) OppAlVU [B4ei ugofr]>i2689891 (AE000792) 1817 651-4 M6a gi180946~ (AF04307 1) oligopeptide permease pEriplasmic bindin protein 1739 .01-3 f606.aa g112~ (AEO 139) oigopeptide AC transporter, periplasmic 1738 4.20E3-234 f606.aa gi1228 1459 -(AF000366) oligopeptide permease hOMo1LAuI [Borrelia 1733 2.0013-233 06T a a bbs1161785 60 kda antigen [Borrelia c-oiaceae, C053, ATCC 4338, Peptide, 514 762 1.70E-201 f60-6.aa gil228 1455 (AF000365) oigopeptide ermease liomolog AV [Borrelia burgdorferi] -1456 1.80E3-1951 f606.aa ~i2690261- (AE000790) oiopeptid& ABC transporter, periplasnuic 1f4 54 3.30E3-195 f606.aa g1223286 (AE005657) p asminogen bidn rti Bria burgdorferil 751 2.OOE-192 f606.aa g!2829(A13001 139) oligopeptide ABC transporter, periplasmic 751 2.7013-192 f606..aa gi1280 9 544 (AF04307 1) o-ligopeptide permease perip lasmic binigpoein 751 6.90E3-192 f606.aa gil228i435V (AF000366) oligopeptide permease homolog- AlI [Borrelia burgdorferi] 748 2.40E--191 f606.aa gi1164 P30 [Borrelia burgdorferi] 1 20 7.30E-163 f606.aa gi4780 2 Opp A (AAI1-542) [Salmonella typhimurium] >gil478. 8 precursor 285 '7.80E3-106 f607.aa gi1228 1457 I(AF000366) oligopeptide permease homolog Al [Borrelia burg dorferi] 2694 0 f607.aa 12 38 AOS5) smoenbdi rotein [Borrelia bur dorferi] 0 f607.aa gi 285 4 (A-07)o igopept e perrnease periplasmic binding protein 2708 0 f607aa ig88 K(E001139) oligopeptideABC transporter, periplasmic 27141 01 f 7aa lb s1161785 160 kda antigen [Borrelia coriaceae, C053. ATCC 4338, Peptide, 514 1 12721 3.80E3-242 No Cj kej -0 9 99 9 9 9 0* .9 *9 9 9 *9 9 9

S..

9 99. 999.

9 9 9 9* 94 9 9* 9 9 TA.BLE 2. Closest maitching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f607.aa gi 2809546 (AF04307 1) oligopeptide perm -ease periplasmice binding protein '718 1.~4024 f7.aa gil2688226 (AEO0l 139) oligopeptide ABC transporter, periplasmnic 71-8 3.0E-204 f7.aa gi1229T439- (AF000366) oligopeptide permease homnolog AII [Borrelia 713~ 1.70E3-201 TO 7. aa gi28827 (AE001 139) oligopeptide ABC transporter,_periplasmiuc 73T12T4-2 f607.aa g281458 (AF000366) oligopeptide permease homolog ALL [Borrelia burgofrl75 .039 f607.aa gTi8468 (AF000948) OppAV Borrelia burgdorfe.i >gi1269891I (AB000792) _O W~ 8.0- 9 f07.aa gi60261 (AE00790) oligopeptide ABC transporter, periplasmic 0 1.20E3-144 f607.aa gi128145 (AF000365) oligopeptide permease homolog AV [Borreli burgdorferi] 600 7-6-T144 f607.aa gl16 P-30[B orrelia burgdorferil 709 5.40E- 103 f607.aa gil47802 Opp A (AA1-542) [Salmonella typhimuriuml >gi147808 precursor 261 8.50E-65 f61 Laa g112688231 (AE001 139) 13. burdreipredicted coding region BB0325 [Borrelia 1907 1LOE-261 f6-17.aa 0i12689213 (AEQOl 138) conserved hypothetical integral membrane protein 1574 2.70E3-226 f617.aa i126471 (AEQO 1042) rioe ABC transporter, permease protein (rbsC- 1) 109 7.0013-12 f631aa gd1165286 FtsW [Bofrelia burgdorferi] >gil26881 6 4 (AEOOI 137) cell division 1820 4.00-259 f63 I. .aa iilI2 membrane protein [Bofrelia burgdorferi] >gnl1P1D~e228289 ftsW 1815 2.10E3-259 9592__ T63 1. .aa 603 cell division protein [seherichia coli] >gi140857 FtsW rotein 362 1.30E-60 f63 I aa gi80938 internal open reading framne (AA 1-290) [Bacillus subtilis] 4071 4.90E3-53 T nIIfPDIe3T FtsW [Mycobacterium tuberculosis] >spIOO6223IFTWHMYCTtJ 412 5.40E-3 5953 f63 La gi1580937 spoVE gene product (AA 1-366) [Bacillus subtilisl >gnlIPlDIel 185111 410 2.0E5 f63 1 aa gil143657 endospore forming protein [Bacillus subtilis] 40-5 -1.20E3-52 733 1. a a giiiPIdkO rod-shape-determining protein [Synechocystis sp.] 358 MOET13 ,19002__ f63 1 aa gnlIPIDlel2 (AL022602) cell divisin protein FtsW [Mycobacterium leprae] 396 6.70E3-51 187793 1 7031.aa IgiI162 1 3 Istrong sequence similarity to FtsW, RodA, and SpoV-E [Cyanophora 34 1.001-50 f63l.aa 1011574 6 92 cell division protein (ftsW) [Haemophilus influenzae] 304 4.2013-50 f63 I aa gnllPIDIel I similar to cell-division protein [Bacillus subtilis] 281 1.80F,-46 850751 f63 1.aa i11I469784_ putative cell division protein ftsW [EnterOCOCCus hirae] 2471 1.60E3-3

(A

'~0 4 -4 Co 0O**

S

*5

S

S* *S

S

S

*5

S

S

*5* S S S S S S S S S S* S 55 S 55* S S S S S S S *5 55 5 5 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases. 0 f63I. aa gi1527 rod shape-determnng prtin (reB) [Hamohilus influenzae] 196 1.20E-37 f631.aa gl17 6 9 5 rod-shape-determnIning protein [Escherichia coli] >gil 1778551 194 5.OOE-35 f635.aa ~i 115282 or7; Method: conceptual translation supplied by author (Borrelia 1166 1.02- 156 f635.aa gil1448949 0RFf 224; The predicted gen roduct showed weak homology with the 62 2.80E-12 f647.aa gil268R 180 (AEOOI 137) faelrprotein (flbB) IlBorrelia burgdorferil 1032 1.OOE- 140 f 7.a gi 119632 3 putative [Borei bugo r __01 1.50B-140 f47.aa gi 1165270 orf 19; Method: conceptual translation supplied by author [Borrelia 1019 7. 1OE- 139 47a gi121 08242 22.5K protein [Teoeapliu]200 4.70E-241 gi12688737 (ABOOl 178).B. burgdorferi predicted coding ro-B0792 [Borrelia 1095 _T.102- 14 8 f653.aa g1165265 MIotB [Borrelia burgdorferi] >gill 185054 flagellar motor apparatus 1220 1.70E-164 f653.aa gi1139928 6 MotB [Treponema phagedenisl 5.80E-5 f653.aa gi219696 MotB [Treponema palliduml 179 1.30E-49 f664.aa giI1185062 flagellar export protein [Borrelia burgdorf-eri] T4 306 1 .9-0 E-199 f664.aa gi11165257 FlhB [Borrelia burgdorferi] >gi12688194 (AEOO1 137) flagellar 1430 1.90E- 199 tf664.aaj911168 FlhB' [Treponernaallidurn] >pirIPC4I15IPC4115 flagellar protein 272 5.0E6 f 664. aa gi395390 flgla isynthetic protein [Bacillus subtilis] -433 1.30E-61 .a gnlIPIDe eII flagella-associated protein [Bacillus subtilis] 433 1.30E-61 f664.aa g111147737 third gene in fliQ operon; membrane protein homolog [Caulobacter 353 1.702-4 f6 aa g1339 AE000589) flagellar bisnhetic protein (flhiB) [Helicobacter 203 1.20-44 f664.aa, gi129842 5 0 (AE000768) flagellar biosynthetic protein FlhB, [Aguifex aeolicus] _3F _3.002E-44 f664.aa gi1245970 2 .Fh [Agrobacterium tumefaciens] 34 6.2013-44 f664.aa gi1793892 fl [Yersinia enterocolitica] >pir1S54213IS54213 flhB protein 3301 1.T30E39 f664.aa gnlIPIDIdlO Flagelar biosynthetic protein FlhB. [Escherichia coli] 325 2.20E-39 f664.aa IgiI475 126 yscU [Yersinia pseudotuberculosis] >gil2996233 (AF053946) Yop 309 9.802-38 f664a 101497216 YscU [Yersiniua enterocolitical 308 1.402-37 f664.aa gnlIPTDIdlO flagellar protein FlhB [Salmonella typhimurium] 312 2.102-37 107477 f664.aa gnlIPlDle28 Isecretion system apparatus, SsaU [Salmonella typhimuriumn] 312 8.20E-37 L 3684 1_ 1 -4 bI-.

00 00 9 9 .9 9 99 9 9 9* 9. 9 9 9 9 60:.0..

0 9 9'0 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases. -79.aa gil2 88 158 (ABO0l 136) B. burgdo fri predicted congrin BB0259 [Borrelia 37141 0 f 679. aa gnliPIDldlO soluble lytic transglycosylase [Synechocystis sp.] 8)Tf~ 11473 f679.aa' gnllPIDle 11 iilar to lytic transglycosylase [Bacillus subtilis] T09 2.10E2-21 f67 9.a a gil298 4090 00756) hypo etica erotein [Auifex aeohicus III 9.30E2-17 f8 0. aa AR5 AE00 136) bacitracin resistance protein (bacA) 113orrelia 769 3.90E- 109 N680 aa ginll:Ie II similar to bacitracin resistance protein (undecaprenol 174 7.30P-- 18 85988 -3 f 68TO.aa gI2622 (A12000905) Witain. resistance protein [Mth nctrum 152- 30CE-16 012.a it984378 (AE000777) undecaprenol kinase [Aguifex aeolicus] 12 39E f680.aa gi827 CG Site No. 29739 [Escherichia col >gi117 89437 (AE000387) 139 g f688.aa g2881 4 00 15 conserved- hypotheticl integra membrane protein 24970 f688.aa -i~43 AEOO1O19) conserved hypothetical poen[rhegou ugds 1 .021 f 88.aa ill51T86 M. Jannaschii predicted coding region MJ1562 [Methanococcus 17 T~~ f7-30.aa gi126900 (AE00786) conserved hypothetical protein [orrelia burgdo-rferij 681 .9E f_ 04.aa gi12688137 01 134 glycerol uptake facilitator (glpF) [Borrelia f04.aa gi1142997 glycerol upake facilitator [Bacillus ubtfis] gPel 1891501T3T 7 i aIi152 1003 CO 106.1 [Caenorhabditis eegansil T3'AATM A tr142 8 012- f'704.aa Igil529582 water cnlannei protein L~tu ,iuivC~ri'-Uaj f704.aa dbjiA OW(AB005.07) aquaporin -7 [Rattus norvegicus] T133 F-T.OE4 rTO-.ia 'pirA57 1191 aquaporin 3 -human 14 T -2T aA57 119 6_1116_'930_4 f704.a gill 109920 coded for by C. eeascNA cmlbl1 strong similarity to MW iT .3E-p f704.aa gnllIPIDldlO (ABO1325) aquaporin 3 [Homo sapiens] >sp1Q924821AQP3..HUMAN 148 5.30E-43 f'704+.aa gn ID dlO (A12008775) aquaporin 9 [Homo sapiens] 14 141-7 25786____ f704.aa i146 188 1 cerol diffusion facilitator [Escherichia coli] >gi1305030 CG Site 146 1.364( f704.aa gi11065485 stro sIlrt to the MIP family of transmembrane channel 179 O.4E-39 04.a s1P 1101GLYCEROL UPTAKE 4FACILITATOR PROTEIN.14 30E3 0 0 .0 0 0** 0@ 0 0 *0 0* 0 0 0 0 0 0

SO**

0 0 0 *0 0 0 0S 0 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.' I GLPF-SHI I L11 f704.aa giI2587035 (AF026270) PduF [Salmonella typhimurium] >spIP3745lIIPDUF SALTY 168 7.30E3-39 f 704.aa gi11399489 lycerol dfiffusion facilitator [Pseudomonas aeruginosa] 154 7.90E-59 74.aa gi1264144 (AE00 1005) glycerol uptake facilitator, MIPcanl(l 5 1.3E-38 f07a i~~A (AQO 14B.bgrferi predicted coding region BB0238 [Borreia10 .E-6 f709.aaE g11268_T3_ (AEOl 133) B. burgdorferi predictedI codling region BB0236 [Borrelia 3437 0 f730aa i-68 11 (AEQ0 132) gufA protein [Borrelia burgdorferi] >pir1C701271C7l2 T _7 3.01319 f730.aa gi 17757 coded for by C. elegans cDNA CEESS55F; coded for by C. elegans 235 2.80E3-83 f730.aa i12621 54 2 (AE00083 1) conserved protein [Methanobacterium thermoautotrophicurm] 259 1. 10OE-74 f730.aa gnl!PIDiel18 gufA gene product [Myxococcus xanthus] >gil49253 orfX gene 7 175 2.30E-35 f730.aa g28109 (AE000757)'hypothetical prtein [Auiex aeolicus] 171 7.00E-28 f 76.a 0168115 (AEQOI 132)_phosphate ABC transporter, periplasmidc phosphate-binding ITO-3 2.101-186 fj6.aa gi 6258 (00929) phosphate-binding protein PstS [Methanobacterium T1 4.40H-30 f f736.aa iil(AE0009929) hosphate-binding protein PstS homolog [Methanobacterium T135 -2.80E3-24 I36.a giii hID~d 10 0R18[aillus subtilis] >gnlIPIDIel 185766 alternate gene T .031 10224_____ 739.aa g126881 19 (AEQ0l 132) B. burgdorferi predicted coding region BB0213 [Borrelia 1139. 1.10E-156 f'742.aa gi28100 (AE50l1131) surface-located membrane protein 1 (imp I) [Borrelia 5654 0 f-42a i11120~ (AE000799) 0-linked GlcNAc transferase Methanobacterium 200 9.30E3-22 f742.aa iT22106- (AE000798) 0-linked GcN -c transferase [Methanobacterium T_18 5.80OE-17 f742.aa pirIE69l9O1 conserved hypothetical protein MTH68 Methanobacterium 154 1.60E3-14 E69190 f7-42-.aa M591608 Itransformation sensitive protein [Methanococcus jannaschii] 109 9 .90E- 14 f742.aa giII59778 ISPINDLY [Arabidopsis thaliana]' 101 1.40H3-13 f742.aa gi12984175 _(AE000762) hypothetical protein [Aguifex aeolicus) 132 7.30E-13 f742.aa i3317(AF056 198) HsP 7-Isp 90 org ain oen h olog [Drosophila 10 5.40E-1 1 f7 3.aa igi2688104' (AEO 131) B. burgdorfei redicte coding region 9929[or a ~171-7 f748.aa IiI2688089 ABOOl 1 30) Lambda CIsali-oern rotein (hflC) [Borrelia 1T 15. 51OE-220

(I,

'0 -4 -4 00 0 0 0 OjO 0 @0 0 0 0 0 0* *0 0 9 0 @00 0 0 90 0 **0 000 0000 0 0 0 0 @0 0 00 0* @00 0 *0 000 00 0 9 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases. f78a gl31H putative integrl membrane protease required for high frequency TF9 T fl 8.aa g 115731 0 7 Lambda CHI stablffity-governing protein (hflC) [Haemophilus 13 -6 E2 f8.aa g1735Y [IC [Vibrio parahaemolyticus] >spIP4O606HFLC2/MPA HFLC -T~6 ____PROTEIN 0_ fI53.aa i12 6 8 9 0 92 (AEOO1130) 2585__ f752.aa g-i1284050 (A130075) UDP-MurNacrieid synthetase [Auie eoIcsl 202 9. OE-74 f 72.a gi4 06 urE gene prodc [BaciHus subtilis] >gnlIPID1_el185108 17 04 -7 g~i1ID~t1d10 IUDP-MurNac-tripeptide synthetase [Synechocystis sp.] 6 52E5 11466 f?52.a gnIID~OT iJD-MurNAc--tripeptide synthetase [Rickettsia prowazekii] -108 -2.3011-51 f752.aa gii1574688 UDP-MurNac-tripeptide synhea (nrE) [Haemophilus influenzaeI T66 1.2011-50 f-52.aa gn~ 1Del2 (AL022602) udp-n-acetylmurainoylaianyl-dglutamate T ~3.20E3-50 f752. .aa gn11PlDDe3 1 MurE [Mycobacterium tuberculosis] 181 4.0E4 6022f752.a gi158 1032 UDP-MurNac-trp eptide synthetase.(MurE) [Escherichia coi] 1T75 1.3014 f752.aa gi12177 0 98 UDP-MurN c-ptie meo-iainpielte 1igase [Escherichia 12 37E4 f752.aa g123 14673 (AE099648)IJDPMur ac-tripepflide synthetase (inurE) [Hel icobac ter 137 9.80E-41 f752.aa gi140843 UJDP-NacetylmuramoylaayI-D- utamate- 2,6,daioinlt las1T35 1.709-20' f 76-1 .aa 11ll209837 ipoprotein [Borrelia burgdorferi] 3 2.80E-49 f77~ a i1209873 lipoprotein [Borrelia burgdo feri] 25 _3i 7 _.00E3-37 7C- I Fa -Ri11209843 lipop rotein [B3ofrelia, burgdorferil 26 T.3011-32 f-76- -aa gi12122807() lipoprotein [Borrelia burgofri MgI39510 9 258 1.20F,15 f76- 1.aa. gnllPID~e26 surfface-exposed lipoprotein [Borrelia afzelii] 116 2.40E- 18 80-.aIH0515IA0 9)2.-8 lpoprotein [Borrelia burgdorferi] 148 5.8013-14 f76-1.aa ig 13095107 KAF06999) 2.9-9 lipoprotein [Borrelia burgdorferil 127 7.20E-1 1 f'76.aa1 Ri126 09 (EOO01129 3. burgdorferi predicted coding region. BB0193 [Borrelia 12 -18, 1.20E- 16 f770.aa 1i2688077 (A001 129) conserved hyothetical protein [Borrelia burgdorferi] _46 7.6011-87 ff7 90. aa g112688065 (AO 18) outer membrane protein (tpn50) [orrelia burgdorferil 2 .013 .6-271

CA

CA)

00 0 000 0 00 000 000 0 00 00 S 0@ 00 *0 0 0 0 *00 0 0 0 0 00 0 *0.

0000 0000 0 0 0 0 00 00 00 000.0 *0 0 *00*~ 0* 0 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f790.aa gi145815. TpN50 precursr[rpnm aldm 13 4.~30E3 f790.aa 83 9 T OUTER MEMBAN PROTEIN TPN5O PRECURSOR. -134 43E3

A__

i13 65 atien[ repna pallid] pir156 61967 antigen tpp57 73T 4309 f792.aa 12688052 (AEO0l 127) B. burgdorferi predicted coding region 30 165 [Borrelia 3185 0 f'797.aa giI2688056 (AiEO01 127) B. burgdorferi predicted coding region BB0159 [Borrelia 1116 5.30E1-48 f798.aa gi28851 (AE001 127) antigen, S2, putative [Borrelia burgdorferi] T7-3 9.70E-164 f798.aa tg06 4 1-9 S2 gene product [Borrelia burgdorferi] 116 -4.70E3-23 f798.aa gi2927(E070 antigen, S2 [Borrelia burgdorferi] >pir1D70207ID70207 116 1 .50E-22 f798.aa gi1269 0 1 2 8 (AE00O07 88) protein p23 [Borrelia bur dorferi] >pirIC70257IC70257 110 1740E- 19 f798.aa gi26956 (A000785) protein p23 B-orrelia burgdorferi] >pir D702517225 104 2.70E3-15 f799.aa gi12 68 8 04 3 (AE00 1126) B. b rgdorferi predicted coding region BBOI156 [Borrelia 632 1.4013-83 f8-10.aa gi1269052 AE0007 84) antigen, P35, putative [Borrelia burgdorferil 1241 10E-1 iF268955 (AE000785) antigen, P35, putative [Borrelia burgdorferi] 298 1.70E-7 f8-10 go 1i2690120 (TAE000789) B. burgdorr predicted coding region B3B134 [Borreli 254 3.80-4 f8-10.aa gi 12 P9OlO1O (AE000789) B. burgdorferi predicted coding region BBI116 [Borrelia 182 2.90E3-31f f8-10.aa i1600 (AE000787) B. burgdorferi predicted coding region BBJ02 [Borrelia 196 1.502 f8-10.aa- gif 069 (AE000789) B. burgdorferi predicted coding region BB129 [Borrelia 192 -5.5013-20 f8-10.aa i2690125 (A13000788) antigen, P35, putative [Borrelia burgdorferi] 129 5.80E3-14 f8-10.aa giI2 6 9O 2

O

6 (AE000787) B. burgdorfe-ri predicted- coding region BJO Borrelia 103 1.1013-13 T8 -l10. aa gi1269 00 9 9 (AE000789) B. burgdorferi predicted coding reion BB15 [Borrelia 14 8.01-2 i2690115 gI1iYA 0007 8 9 B. burg orferi predicted coding region BB128 [Borrelia 130 3.0E- 2 f8-1 .aa i1O7 (AE000784) B. burgdorferi prdce coing regionB-17BoriaT 26320 f8-14.aa gi12690188 (AE0007 8 7 B. burgdorferi predicted coding region BBJOS [Borrelia 599 3.50E3-123 f81 1-903 (AE00078 B. burgdorferi predicted coding regionBGO [orei.37401-0 f1 4. aa H2690139 8) B. burgdorferi predicted coding region IBKO1 [Borrelia 173 8.OEi9 k8. a a g612 6 887 83 I(AEOOI 182) B. burgdorfer peicted coding region BB0840 [Borrelia -295 0 fg.aa _Ii 297 1 (AF0082 19) unknown [Borrelia aftehl 149 2.80E-205 00.a i 684 AOI 2)B brgoei peicted coig rin BB0155 [Borrelia 193 .01-6 f805.aa ii2688039 I(AEQ0l 126) Naeyguoain--hst dacetylase (nagA) 6411 6.3013-851 00 0 0 @0 000.

0 @0 0 0 @0 0 00 00 0 0 0 000 000 0 0 00 @0 0 @0 0 0 0 0*0 0 @00 0 00 *000 0000 0 0 0 0 00 00 @0 @0000 0 @000 0 00 0 0 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases. '0 f8 I0.aa gi126880 2 4 (AFO0l 125) glycine betaine, L-proline ABC transporter, 1527 4.0-0 f8198a~ 4805 g Ycine betaine-binding protein precursor [Bacillus subtilis] 179 6.80-2 f8 10.aa gi11850605 ProX [Streptococcus mutans] -18 2.30E- 18 8 14.aa prD70l171 acri flavine resistance protein (acrB) -homolog Lyme disease 5165 ______ID70117 f8 14.aa igil268 27 (ABO001125) acriflavine resistance protein (acrB) [Borrelia -5-1T1 0 f8 14.aa Igit28334 AE00707) cation efflux (AcrB/AcrD/AcrF family) [Aguiffex aeolicus] 325 4.80-119 f8 14.aa 123126 (AE000574) acriflavine resistance protein (acrB) [Helicobacter 327 4.50E3-111 f8. aa 11306786 AF059041) RND pump protein [Helicobacter pyloril 297 1.70E3-116 f8 I4.aa gn IPID e1 similar to acriflavin resistance protein [Bacillus subtilis] 257 8.U9_0B -10 0 82651 fW1l4.a gi1157391 4 acriflavine resistance protein (acrB) [Haemophilus influenzae] 29 2.T1 OE-9 f8 14.aa gnIiPDe mexF [Pseudomonas aeruginosa] 30 2.OOE-98 6815 f8 14.aa gnlIPIDIdlO cation efflux system prot-ein CzcA [Synechocystis sp.] 198 1 .30E-87' 119295 fg14.aa gnlIPIDIe28 membrane-bound cation-proton-antiporter [Ralstonia eutropha] 28 2.20E-87 5274 7814.aa gi438854 envD homologue; ORFB [Pseudomonas aeruginosal >pirtS3963015S39630 290 6.TO T7 f8 14.aa gnIlPIDIdlO CzcA [Alcaligenes sp.] >pirlXC47001JC4700 cadmium, zinc, -275 8.2013-87 11721 f~4a i214107 (AE0065 cation efflux system protein (czcA) [H-elicobacter 26 2.30E386 f8.14.aa piIA38301 cation efflux system membrane protein czcA Alcaligenes 275 3.10E3-86 _______A33830 814.aa~ gnlIPIDldlO envD gene prodfuct homolog [Eschenichia coli] >gi1 1788814 283 8.3013-86 17073 ThTlg~a gi126 8 0 32 J(AEO 125) 13. burgdorferi predicted coding region BB0 139 [Borrelia 64 I3.OOE-87 f82.aa g-1268729 I(AE001 177) B. burgdorferi predicted coding region BB0776 [Borrelia -991 2.23 f820.aa gi1268029 (AE001125) 2entrcillin-bi ndin protein (pbp-1) [Borrelia -3171 0 f 920. aa gi 580936 SoVD [Bacillus subtilis] >gnlIPIDIell185 107 penicillin-binding 149 3.0013-49 f820.aa II50283 penicillin-bindin protein 2 [Neisseria meningitidis] 1541 6.00E-431 f820.aa__jnIIPID el2 (AL022602) penicillin binding protein 2 [Mycobacterium 1821 4.20E-421 -4 -s -4 00 6 9.

a 99 99 .9 9 9 999 999 9 9 99 99 9 9. 9.

9 9 999 9e 06. 9e 'go 9999 99 V TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases., 0 f820.aa gi 509 190 penicillin-binding protein 2 [Neisseria meningitidis] 158 1.70E_4_ f820.aa giI509 118 penicillin-binding protein 2 [Neisseria meningitidis] 151_ 7.10E_41 f8_20. aa gi840842 penicillin-binding protein 3 [Pseudomonas aeruginosal 177 1.2013-40 i1509065 penicillin-binding protein 2 [Neisseria meningitidis] 1521 1.40E-40 f820.aa giS09043 penicillin-binding protein 2 [Neisseria meningitidis] 1501 2.70E3-40 f820.aa gi 509 159 penicillin-binding protein 2 [Neisseria meningitidis] 1 2.80E-40 f820.aa g50120 penicillin-binding protein 2. [Neisseria meningitidis] 155~ 1.60E-39 f820.aa i 0157 penicillin-bindIng protein 2 [esseria meningitidis] 155 f820.aa 1i50912 penicillin-binding protein 2 [Neisseria me-ning tdis] 158 L7_OE-39 f820.aa gi 4578 penicli-idng protein 2 (AA 1 58 1) [Nisramnniii]___155 2-1.30E-38 f820.aa gil 150279 penicillin binding protein 2 [Neisseria gonorrhoeael 154 8.70E-38 f831.aa g~i1818(AE00 124) B. burgdorferi predicted coding region BBO 29 [Borrelia 994 1.2013-33 f843.aa gi16_88014 (AEOO 124) PTS system, maltose and glucose-specific IIAB3C component 2590 0 f843.aa gi269579 (AE001 166) PTS system, glucose-specific 1I13C component (ptsG) 594 1.80E-129 f84.a 07248 glA [Staphylococcus carnosusi >pif[ 469521S46952 28 1.001-72 f843.aa 1111}Q/ 441 9 glcB [Staphylococcus carnosus] >pir S63606IS4 6 9 5 3 248 1.0013-66 f843.ad djIID86417 YflF [Bacillus subtilis] >gnltPLDIeI 182760 similar to 215 7.90 f843.aa jgi12971 0 4 (AF003742) MalX homolog [Eschercha coli] -182 8f.9013_-64 f843.aa gi143819 _nagE gene product [Klebsiella pneumoniae] ErS867S80 264 8.5013-63 T8 4 3.aa Hi14 913 N-acetylglucosamie transport protein [Esheirhia160 18607 256 1. 10F,-62 -f843.aa gil!99 5 6 IlGIc [Bacillus subtilis] >gn]IPIDlel 184979 phosphotransferase system -315 5.0-6 f843.aa dbilIDWY78i0 NagE [Vibrio cholerae non-Oil >pirIJC5651IJC565I 26 .8E6 f843.aa IgiI289888 (AE000792) PTS system, maltose and glucose-specific IIABC component 198 1.1013-60 f843.aa Igil!97- 3 6 enzyme Il-glcC [Salmonella typhimurium] >pirIS36620IS36620 1.2013-58 f843.aa iII47393 L1.cose-specific enzyme 11 of phosphotransferase system [Escherichi-a 226 3.90E-57 f843.aa gn IPDIeI 1 alternate gene name: yzfA; similar to phosphiotransferase. 180 9.001-56 f83A 1 732194 JP75 ermease or lucose [Vibrio furnissii] 349,43E5 -4 -4 00 S 6

S

6@O *e4.

0*

S

S 55 0% 5*

S

S

S

C..

S S S S *S S *S S *S 6e*** S S SC *S 5 9 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f850.aa gi 268799 9 I(AEQ0l 123) B. burgdorferi predicted coding region BBOI 10 [Borrelia 2374 0 f853.aa gi 268799 (AE001 123) basic membrane protein [Borrelia burgdorferi] Th-7 2.20E-2241 f853.,aa gi 155055 basic membrane protein precursor [Trepo nema pallidumn] 13 3T0E24 f859.aa giI2-6802( AIEQ0123) B. burgdorferi predicted coding region BB0102 [Borrelia T 8 -TO fI f86.aa gil2688725 (AEQOl 177) flagellar P-ring protein (flgI) [Borrelia burgdorferil 164 1.50E-217 f86.aa gi1292002 AF19213) FlgI Vibrn cholerael 13 gi40550 flagellar P-ring protein [Pseudomonas putida spQ52082IFLGI- PSEPU -102 -T7-OEW13 f86.aa g1144 flagellin [Caulobacter crescentus] >pirIA418911A4l891 basal body 116 -770E,-13 f860'.aa gi2979 H123) asparaginyl-tRNA synthetase (asnS) [Borrelia 1110) 2.40E-149 f860.aa gjV1574761 asparaginyl-tRNA synthetase (asnS) lHaemnophi us influenzae] 63 .6-3 f860.aa gi173 as aginyl-tRNA synthetase (asnS) [Escherichia colij >gi14 1000 622 CI WE-2 f96iia gniIPIDIe12 (J224 4) aaraginy-tRNA synthetase [Arabidopsis thaliana] 40 2.40E-80 f860.aa gnliPIIDIdlO asparaginyl-tRNA synthetase [Synechocystis sp.] 61 4.50E3-80 ______11495 f860.aa gi1530408 Asn-tRNA synthetase [Mycoplasma capricolum) >pirIS778421577 842 T3 f860.aa 111045792 asparag inyl-tRNA synthetasd (My coplasma genitaliuni] 36 2. 201-6 2 786.aa i11674281 (AE000057) Mycoplasma pneumontae, asparaginyl-tRNA synthetase; 338 3.10H3-61: f860.aa g~nIiiii1I2 (AJ222645) asparaginyl-tRNA synthetase [Arabidopsis thaliana] 364 3.901E-59 102700 f860.aa gnlIPlDIe26 YCR024c, len:492 [Saccharomyces cerevisiae] >pirlS 194351S.19435 53?0 3.90E3-47 ______14488 f860.aa gnlIPIDIe25 asparaginyl-tRNA synthetase [Salmonella typhi] 370 1.70E3-46 4305 -f9TT-a- gnIIPIDIel8 asparagine--UZNA ligase [Lactobacillus delbrueckii] -22 -rj.T6--r74 f960.aa pirIS7 10721 asparagine--tRNA ligase (EC 6.1.1.22) asnS Lactobacillus 4---E4 IS71072_____ f86O.aa gn PID elS asparagine--tRNA ligase [Lactobacillu dIbrueckli] 22 2.40E3-44 8572__ -f860.aa giII146247 asparaginyl-tRNA synthetase [Bacillus subtilis] >gn IP 1 1l18368 2341~TWI f86 Laa gi12687975 (AQI122) glutamate racemase (murl) [Borrelia burgdorferi] 1 13541 2.90E-1861 0 00 00 0 0060 S OS 5 0 *5 0 55 5*

S

0 *55 @55

S

S SO S S S S 0 0 5@O 0 *SS SO 0000 0000 0 0 00 OS 00606 S 0 SOSSe 0@ 0 TABLE 2. Closest matching sequences between the polypeptides of thepresent invention and sequences in GenBank and Derwent databases.. 0 f86 Laa gil39631 4 glutam te synthase [Escherichia coli] >gil29042 8 glutamnate synthase 168~ 1.20E3-16 f861.aa gniiIDiell glutamnate racemase [Bacillus subtilis] >gnllPIDlell84O88 120 1.80E-13 f861.aa "pirlJ-C55857T 'glutamnate racemase (EC 5.1.1. 3) Bacillus pumilus 122 T.8093-3 IC5587 f86.aa sp1P529731 PROBABLE GLUTAMATE RACEMASI3 (EC 114 8.10E3-13

MURIHA

IEIN f8_67.aa L'12687979 (ABO0l 122) V-type ATPase, subunit A (atpA) [Borrelia burgdorferil 2826 0 f867.aa pir!JC5532 1J vacuolar-type ATPase (EC A chain Desulfurococcus 594 2.20E3-162 ______C5532 f8 7aa g~i126 0 567 VATPase ah subunit [D-eufrococcus sp.) SY]2 T 0E- 16 f867.aa gi21476T ATPase Alh subunit [Tefrococcus sp. SY 592 3.10E-162 f867.aa gnIlPED~I10 Na+ -ATPase alpha subunit [Enterococcus hirae] -601 1.0E13 _87a 9i115909 5 5 H-+-transporting ATP syntse subunit A (atpA) [Methanococcus 585 6.OOE-147 f867 .aa 1i496904 mnembrane ATPase [Haloferax volcanil] >ir S55995S45 144 728 6.O- 4 f867.aa gil 12927 ATPase alpha subunit [Suffolobus acidocaldarius] >pirlA28652lA28652 54 5.00E3-163 f867.aa gil2649416 (AEOO 1023) H+-transporting ATP synthase, subu-nit A (atpA) 748 2.OET14 f867.aa gil2622 05 2 (AE000869) ATP synthase, subunit A [Methanobacterium 607 9.40E3-146f867.aa ill 6926 vacuolar ATPase vma-1I [Neuro-spora crassa] >pirIA30799IPXNCV7 302 9.OOE- 145 f867.aa 1i149820 ATPase alpha subunit [Methanosarcina barkerd >pirIA34283IA34283 743 1.40E3-143 f87aa gill6 0 7 3 6 vacuolar ATPase [Plasmodium falciparum] >pirIA485821A48582 vacuolar 305 9.40E3-140 f86 7aa iiiI0 denosine triphosphatase A subunit [Acetabularia acetabulum]30 9OE-7 109732_____ f867.aa IgA190 4 8 ATPase alpha-subunit [Thermnus aguaticus thermophilus] 68 4.80E3-136 f868.aa igi126879 80 -(ABO0l 122) V-type ATPase, subunit B (atpB) [Borrelia burgdorferil '2205 1.80E3-298 f868.aa I i1159094 1-+-transporting ATP synthase, subunit B (atpB) [Methanococcus 156 2.003-F14 f868.aa giI265628 ATPase beta subunit [Thermococcus sp.] 151 3.3013-108 f868.aa gi2042 V-ATPase B subunit [Desulfurococcus sp. SY] 15I .030 f868.aa gil43641 A TP synthase subunit [Halobacterium salinarium] >pirlS 147331S 14733 1501 1.80E3-107 fSl .a gil 49821 JATPase beta subunit [Methanosarcinabarkeri] >pirB34283IB34283 1721 1hOOE-1051 LA0 %0

CI

En 00 a TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f868.aa gnllPIDldlO Na+ -ATPase bea subunit [Enterococcus hirae] 151 1.4013- 105 f868.aa- gii 64945 (A13001023) H+-transportn ATP synthase, subunit B (atpB) 151 f86 .aa gi990 membrane ATPase [Haloferax volcanij >pirIS5589-61-S45 14515 5.0-6 f868aa gill 963 AIAO H+ ATPase, subunit B [Methanosarcina mazeij 173 2.20E3-102~ f868.aa ~~051(AE00869) T ytase, subunit B [MethanobacteriumT3 .E-0 aa,~ giillPID~dl 0 adenosine triphosphatase B subunit [Acetabularia acetabulum] 159 1.30E3-101 09734 f868.aa 0i1864 Similar to vacuo ar ATP synthase (strong). [Caenorhabditis elegans] 163 1.3T-10 f868:*aa- 1459198 vacuolar H+ -ATPase subunit B [Gossypiu hirstu f868.aa giIl 6 7lOS vacuolar ATPase B subunit [Hordeumn vulgare]16 460-0f >sPIQ400781VATILHORVU f872.aa g'II26798 (AEOOI 122) B. burgdorferi predicted coding region BB0099 [Borrelia 1684 1.60E230 f874.aa 687965 (AE01121) L-lactate dehydrogenase (ldh) [Borrelia burgdorferi] 1603 2.80E3-217 M7aaIgO i37 L_ lactate dehydrogenase [Bacillus psychrosaccharolyticus] 52 3.109-109 ?T74.aa p 081831 L-lactate dehydrogenase (E3C 1.1.1.27) X Bacillus 43E 0 S09 T874. aa pirIA258OSI L-Iactate dehydrogenase (EC 1. 1. 1.27) Bacillus subtilis -520 1Y.0-OE 107 f874,aa gi4136 L-lactate dehydrogenase [ailsegateriumi irISOOI331DEBSLM 4-3 5. 201-10 7 084.aa gi 433 lactate dehydrogenase (EC, 1. 1. 1.27) [Bacillus sterthropius] 514 6.6:0-0 f 87 4.a-a gnlIDIdlO L-lactate dehydrogenase [Bacillus subtilis] >gnIIlPDte1182257 512 8.90E3-107 09574 T874.a gil 1431i34 lactate dehydrogenase (E .1.1.27) [Bacillus caldotenax] 516 1.70E3-106 f87ia 1143132 actate ehydrogenase (AC 1. 1.27) [Bacillus caldolyticus] 56 -2.30E3-106 f874.aa- gi142392 AD-dependent dehydrogenase unidentified] 508 4.40E-106 f874.aa g111431~30 L lactate dehydrogenase [Bacillus caldotenax] >eirSOOfl91SOOO 19 510 1.101-105 f874.aaIi ~4225 L-lactate dehydrogenase [Pediococcus acidilactici] 3--C 1.70E3-91 Jf874.aa gi1l847956 IL-lactate dehydrogenase [Lactobacillus sake] >spIP5 93 lLDH LACSK -381 -2.3013-91 f874.aa gIF~~ L- lactate eydogenase actobacillus plantarum] >pirA369571A36957 547 2.3013-9 1 f874.aa gIi 9575 IL(+)-lactate dehydro~enase [Lactobacillus casei] _386 3.2013-91 f88.aa il2687958 I(AEQOI 120) B. burgdorferi predicted coding region BB0077 [Borrelia 179 951-2371

::P

0 '4D 00

W~

S. TABLE 2. Closest matching sequences between the polypeptides; of the present invention and sequences in Genflank and Derwent databases.

f888.aa gi12 6 879 59 (ABO0l 120) B. burgdorferi predicted Coding region BB0075 [Borrelia 2351.59994 318 f893.aa gi12687962 (AEOOl 120) B. burgdorferi predicted coding region BB0071 fiBorrelia 2514 0 f895.aa gi2W'87953fT (AO 120) conserved hypothetical protein [Borrelia burgdorferil 747 3.60E-100 f895.aa gnIPID~1F similar to hypothetical proteins [Bacillus subtilis] 103 2.50E3-35 f899.aa gi126879 4 6 (AEQOl 119) B. burgdorferi predicted coding region BB0066 [Borrelia 1T6 1 -4.3-0E-158 f924.aa i12-68 34(AEO01 1 18)-B. burgdorferi predicted coding region BB0044 [Borrefi-a 69 3.90E-93 f925'.a4. gi268793.5 (ABOOlI 118) B. burgdorferi predicted coding region BB0043 [Borrelia 1771 7.50E-241! f929.aa gi268716(AE0O117) B. burgdorferi predicted coding region BB0038 [iBorrelia 2589 0 f93.aa gi 2688703 (AEOOl176 pyrid oxal knase (pdxK) [Borrelia burgdorferi] 1334 60E-181 f933.aa gi2687917 00O~ 1117)B. burgdorferi predicted coding region BB0034 [Borrefia 902 1.901E-122 f933.aa gi269091 (AE000789) conserved hypothetical protein jiBorrelia burgdorferil 13 3._1 7 f933.aa gi12690 2 2 5 (AE000790). conserved hypothetical protein [Borrelia burgdorferi] 149~ f.5-0E-37 f93.a i269045 (AE000784) conserved hypothetical protein [Borrelia burgdorferi] T--F2 5.7013-28 f933.aa gi 2239281 No definitionline found [Borrelia -burgdorfer!] -148 -2.4013-14 f939aa i12 8 7 99 (BO~l117 B.burdoreripredcte coingregon B002 [Brreia 796T~6 f940.aa gi12 6 87 9 19 (ABOOI 117) B3. burgdorferi predicted coding region BB0028 [Borrelia 1799 7.50E3-21 f943-.aa il1 687905 01 116) B. burgdorferi predicted coding region BB0024 [Borrelia 2001501-7 f943.aa 11592 L-sorbosone dehydrogenase [unidentified] 175 2.30E3-15 f943.aa gnIPIDiiIdiO L-sorbosone dehydrogenase [Acetobacter liquefaciens] 173 4.40E3-15 ___06418_ f952.aa gi12687880 (ABO0l 115) gipE protein (glpE) [Borrelia burgdorferi]l 62 2.90E-84 Query GenSeq GenSeq Gene Description 13LAST BLAWST Access Score P-Value N o. I_ I I fO7A.aa R33279 43 kD endoflagellum sheath protein. 1 1201 6.10E3-25 f 142.aa R95044 Apoetosis partici pating protein. 1 1031 4.70131 f147.aa W18209 IStaphlococcus aureus Coenzyme A disulphide reductase (CoADR). I _1941 4.8013-9 11 0 Un

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'.0 14 -4 00 a. a a a a..

a a .a a. a a a .a a a a TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.. 0 f 147.a W642 Water-forming NADH oxidase. ~369 8OE-8 f 147.aa R.32089 Benzene dioxygenase polypeptide V. 104 4770R3-11 fl47aa R697-33 Ar-omatic dihydrodiol/catechol deoxygenase 105 9.OOWTIT fT i 152.a -R81- -High affinity potassium uptake transporter HKTI. 137 3.7018 f 157.aa 1W15 192 Staphylococcus aureus cell surface protein. 239 3.40E3-37 7 T-6a IW763 Mannose-I-phosht rnsferase protein MNN4. T78 -T2 0 E- 16 77a 1W362 Human follicle stimulating hormone GPR N-ternminal sequence. 1453 1.30E3-11I f 17-6.aa 1W2 Human thyrotropin GPR N-termiinal sequence. 144 1.90E3-1I1 I 7-.a W21591 Anitibiotic potentiating petide 4__1f 5.10E- 11 f 61 W05196 Helicobacter pyloni 50 ka protective antigen G3.8. 183 270-8 f 96.aa IW20Tf H9. pyloni inner membrane protein 14p 12015orf 12. 1803.ZOEWT7 f196.aa IW20287 H. pyloni inner membrane protein', 24132293.aa. -T9 6.5013-15 f 96.aa- W20769 H. pylon inner membrane protein, 07ee20513orf2g. 69 1.0-1 f 96.aa W20767 H. pylori cytoplasmic protein, 07ee25l3orf 1. 140 6.103- 4, f F9 7 aa W20769 H. pylori inner membrane protein, 07ee205 13orf28. 15T .30E- 19 TJ 97IiW W228 H. pylori inner membrane protein, 24132293.aa. 190 2.OOE- 19 f 197.aa 1WO5 196 Helicobacter pylori 50 kDa protective anifgen G3.8. 17 4.003- 16 f 197a W2091 H. pylorn inner membrane protein 14gpl120l5orf 12. 182 ~6.-1 f 197.a W20767 H. pylori cy toplasmic protein, 07ee2O513orf 1. T 15 IMf-T ~f~liia R9629 B burgdorferi Osp operon. 321 7.001-39 ~2TW. a T- B. burgdorferi OspG lipoprotein. T107 6.10E-4 f24 W267 Borrelia variable major protein-(VMP)-Ik~e -prot-ein VIsE. 4 2 T TO E.60-7 2 f29 a W20152 H. pylont transporter protein, 1464715.aa. 336 1.70E-41 f29 aa W2468 Helicobacter pylori transporter protein 4882763.aa. 234 8.20E-27 f 9 La W20528 H. pylori cell envelope transporter protein 4882763.aa. -234 t291 aa W20592 H. pylon transporter protein, OlceII513orf21. 16 r 7.-1 f301.aa W20287 H. pylon inner membrane protein, 24132293.aa. 15 8 1 WO E- 13 W20916 H. pylori inner membrane protein l1,gpl2O I orf 12. E~191-13 f301.aa W20769 H. Pylori inner membrane protein, 07ee20513orf2S. F5-8 2.40E- 13 f301.aa W05 196 Helicobacter pylori 50 kDa protective antigen G3.8. 157 2.80E- 13 MI0. aa W20767 pylori cytoplasn-ic protein, 7ee2O5l3orfl1. 138 4. O-I Ii 00 *5

S

S

S

S

S S S S S S 55 S S S S S. 5 TABLE 2. Closest matching -sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.' f320.aa R24300 Glycopeptide resistance protein VanY from E.faecium. 1-72 .9E-1 f3 2 8.a a R1 5642 CTP synthetase. 274 3.OE-50 f328.aa W 20778 H. pylori cytoplasn-ic protin, 07ge2O4I5orf6. 122 1.9013-34 3 5 2.aa W0362-6 Human thyrotropin GPR N-terminal sequence. 153 4-.-703- 12 rf352.aa IW21591 Antibiotic otentiatin peptide 152_T 6.60E- 12 f352.aa W03627 Human follicl siuating hormone GPR N-term-inal sequence. T4_5 _5.301E-iM f4-50.aa W07 187 B. garinii IP90 decorin binding protein. 305 1.014 a W07 186 B. afzelii strain pGau decoi bning protein. _7T1-61 1.60E3-34 f4T-50.aa W-7 185 B. burgdorferi HB-19 decorin bindingprotein. 173 2.80E-3i f4-50.aa W07 183 B. burgdorferi B31 decorin binding protein. 176 1.803 f4-50.aa W07 190 B. burgdorferi JD1 Idecorin binding protein. 177 1.80E3-33 f4-50.aa W07 182 B. burgdorferi 297 decorin binding protei n. F1013-32 W07 189 B. burgdorferi LP7 decorifi binding protein. 177 1.IOE-32 f4-50.aa W07 188 B. burgdorferi LP decorin binding protein. 177i 3.9013-31 f450aaW07 184 B. burg orferi Sh.2.82 decorin binding prten 17 __0E f45-2.aa R8-9476 B. burgdorferi OspG lipoprotein. 213i 1.3012-35 f45-2.aa R70491 Leucocytozoan protozoa structural protein epitope. 206 2. 10OE-20 f4-5-2.aa W03626 Human thyrotropin GPR N-terminal sequence. 2H .1 13-20 f4-5-2.aa W03627 Human follicle stimulating hormone GPR N-terminal sequence. 202 8. 906E3-19 f15-2.aa 069629 B. burgdorferi Os pF operon. 111 iI~IE14 T45-2.aa W30763 Mannose- I-phosphate transferase protein MNN4. 16 L OOE-13 45-2.aa IR76 Chicken leucocytozoan immunogenic protein for use in vaccines. 154 7. 10E- 12 f488.aa 1W15078 M. leprae, gyrA precursor. 390 2.7013- 143 f488.aa JR88733 S.aureus mutant grIA protein. 69 6.70E3-122 f488.aa RZ88731 S.aureus topoisomerase IV grIA subun it. 69 6.70E3-122 f4-2aaW22676 Borrelia variable major protein (VMP)-like protein VsE 49 2.70E3-75 f5-14aa W2 Human thyrotropin GPR N-termi~nal sequence. 234 6.60E3-23 14.aa W03627 Human follicle stimulating hrmone GPR N-terminal sequence. 231 1.40E3-22 .f5-14.aa R70491 Leucocytozoan protozoa structural protein epitope. 221 .0013-20 f5-14.aa W 30763 Mannose- I-phosphate transferase protein MNN4. 203 1.60E3-18' f5-14.aa JR76 Chicken leucocytozoan immunogenic protein for use in vaccines. 187 2. 1013-151

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5-4 k-a -a 00 0 0 0

S

S

S S 5 0 5 5 50 e so S S S S S S *5 S S TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBankc and Derwent databases.

f5-1 T a W21591 Antibiotic potentiating peptide 176 4.60E3-15 f5-14.aa_ JR69629 B9. burgdorferi 0OspF operon. 106 3.50E3-13 f5-14.aa R89476 B.bu-rgdorferi ospo lipoprotein. 157 6.20E-T3 f5-14.aa W32 53 6 Trypanosoma. cruzi antigen. 141 3-5.16T f -15.aa R-696 29 B. burgdorferi OspF operon. 48 1.30E-68 5.aai- R89476 B. burgdorferi OspG lipoprotein.. 105 5.80E3-24 f 0 2.a a R69852 Ethylene response (T)mutant protein etri-3. T91 t.90E-35 f502.aa R69849 Ethylene response (ETR) gene product. 191 2.-70E-35 f 02.aa R69853 Ethylene response (ETR) mutant protein etrl-4. 1911 2.70E-35 f502.aa IZ685 Ethylene response (ERTR) mutant protein etrl-1. 91 3.6013-35 f502.aa IR69851 Ethylene response (ETR) mutant protein etrl-2. 91 3.60E-35 f502.aa JR74632 QETR ethylene response (ETR) protein from Arabidopsis thaliana. 1901 5.2013f-2-6 f502.aa JR74629 Tomato et ylene response (TETR) protein. 171 6.50E-23 f502.aa I743 Nr (never ripe) tomato ethylene response (ETR) protein. 171I 6750E-23 f502.aa R74630 Tomato TGETR I ethylene response protein. 123 1.20E3-19' f5l-2.aa W03 62 HmatyrroiGP N-terminal sequence. 235 2.90E-23 12 aa R89476 B. burgdorferi OspG lipoprotein. 109 6.90E23 fS l-2.aa W03627 Human follicle stimulating hormone GPR N-term-inal sequence. 228 2.20E-22 l-2.aa W30763 Mannose- I-phosphate_ transferase proteinM NN4. 203 1.003- 1 -2.aa R7491 Leucocytozoan protozoa structural protein epitope. 191 7.50E-I8 fS 1-2.aa R97866 Chicken leucocytozoan immunogenic protein for use in vaccines. 183 4.80E3-16 ~-2.aa W2159 Antibiotic potentiating peptide __159 6.201-13 f31-2.aa R68838 Plasmodium falciparum ABRA gene protein. 142 1.10-12 f91-2.aa R27530 Plasniodium falciparum, bloodand liver stage ABRA antigen. T 42 2.-80E3-12 P31-2.aa W31186 Hu m an p 16 0 po Iy peptide 31 e6-0.2. -14 8 2.730E-11 f51-2.aa W31185 Human p 160 polypeptide 160.1. 148~ 2.4-I IT f517.aa IW24296 Staphylococcus aureus Gene #1 polypeptide sequence 2. 237 6.80E3-30 f54I.aa JR31013 P39-alpha. 123 3.80E-229 fP541.aa R33280 P39-beta. 504 1. 90E3-117 f542.aa R33280 IP39-beta. 711 3.20E3-96 f 2.a R31013 IP39-alpha._ 101 7.9013-16

CA,

-4 4 .4 4 4 TABLE 2. Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases., f561a JR69631 B. burgdorferi T5 protein. 982 6.90E3-131 f598.aa IW20289 H. -pylori transporter protein, 242 18968.'aa. 264 9.90E3-33 f598.aa IW20640 H. pylori transporter protein, _02ce1I 1022orf8. 26 1.001-30 f598.aa IW20101 H. pylori transporter protein I11 132-77g.aa. -233 8.50E3-27 f598.aa IW20861 H. pylori cell envelope transporter protein, 12gelIO3O5orf 16. 233 9.60E3-27 f598.aa IW34202 Streptomyces effux pump poen(frenolicin gene D product). 196 2.80E-21 f598.aa _R71091 C. jejuni PEBlIA antigen from ORF3. f600.aa W25527 Staphylococcu aureus Giene #20 polypeptide sequence 2. 209 3.40E3-26 f600.aa W34201 Streptomyces efflux pump protein (frenolicin_ gene C product). 169 6.50E-9 f600.aa W20639 H. pylori transporter protein, O2celI 1022orf7. 127 1.1013-14 f603.aa W34200 stetmcsefflux pump protein (frenolcngn rdc) 155 7.40OE-32 f606.aa ROT-3 Hyaluronic acid synthase of Streptococcus equisimiflis. 11 2.20E3-25 f36.aa R48035 H-yaluronic acid synthase of Streptococcus equisimilis. ~116 1-.501-26 7f37.aa R480192 Hyaluronic acid synthase of Streptococcus equisinulis. 141 .0E2 f3Ia W112 Staphylococcus aureus cell surface protein. 160 T6 6 4.a a _W20105 H. pyloni flagella-associated -protein, 1 171928.aa. 202 3.20E-46 0 f664 .aa W20688 H. pylori flagella-associated protein 04ge I 1713orf5. 202 2.60E3-45 f664.aa R97245 Virulence gene cluster polypeptide product. 158 393 -1OEM3 f 7 O aa _0 0 15 3 Nematode-inducible transmembrane pore protein. 104 2.50E3-18' NO04. a a R33913 Sequence encoded by TobRB7-5A which encodes a membrane channel 104 2.5013-18 f7F-a- R77082 Tobacco root specific promoter RB7 from clone lambda5A (ToblZB7-5A).- 2.50E3-18 f742.aa W46499 Amidno acid sequence of the spindly (SPY) protein of Arabidopsis. 101_I 2.50E3-14 7752.aa W20733 H. pylori cell envelope protein, 06cp I 1722orf 15. 141 3.01-37 f752.aa W20358 H. pylori cell envelope protein 263663 12.aa. 1F0 4.20E3-18 f814.aa W20753 H. pyloni transporter protein, 06gp1I 1202orf7. 178 7.90E-3 f814.aa W02 H.-pylori cell envelope transporter protein 33399142.aa. 160 2.013-21 8T3. .aa RI 4 319 Human T-cell immunosuppressive factor. 167h~ 1.2013-19 f860.aa W21894 Asparaginyl-tRNA synthetase from Staphylococcus aureus. 245 2.30E3-38 f360.aa W33903 Streptococcus pneumoniae asparaginyl tRNA synthetase. 177 1. 10OE-22 f 86 7. aa W34261 jAn alpha subunit of a thermostable ATPase. 592 1.30B 16 f 8 7. aa 1R10098 JAlpha subunit of ATP-synthase. 741[ 4.9013-144.

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4-'

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4-' 00 9 9 9 .9 .9 *9 9 9 9 9.9 9* 9 9 9 9*9 9 9e 9*c* 9 9 99 9 99999 9 99 9 2 TABLE Closest matching sequences between the polypeptides of the present invention and sequences in GenBank and Derwent databases.

f867.aa R31522 Carrot reverse transcriptase. 311~f 4.60E-130 f867.aa R10099 Beta subunit of ATP-synthase. 121 7.90E3-14 f867.aa W"34-0 A-beta subunit of a thermostable ATIPase. 116 1.OOE- 12 f 868. aa WVNT2 A beta subunit of a thermostable ATPase. 151 -6.To-9 f868.aa R10099 Beta subunit of ATP-synihase. 172 1.90E3-106 f998.aa W34261 An alpha subunit of a thermostable ATPase. TF7 3.1T01-19 f869.aa, R 10098 Alpha subunit of ATP-synthase. 113 2.OOE- 19 F 868. aa R31522 Carrot reverse transcriptase. TT61 1OE-15 f874.aa R10591 L-Iactic acid dehyrogenase. 538 7.20E-109 ?874.a R08355 Recombinant thermo philic NAD-depenan deydognae.S3 9.80-99 f874.aa R0929 Recombinant thermophii NDdpnatehdrogenase. 455 9.80E-99 f874.aa R15736 L-lactic 'acid dehydrogenase.- 426 1 6 0TI f874.aa P91948 Pig H4 isoenzyme. 393 2.0013-82 f874.aa IW33 108 Chicken lactic acid dehydrogenase type B subunit. 390 2.20E3-80 f874.aa IW33 107 Cicken lactic acid dehydrogenase type B subunit. ~35 1 1 OE79i' f874.aa IP89 Tes-specific lactate dehydrogenase sub-unit LDH-C4. 33 5.50E3-74 f874.aa, R94013 Heat resistant maleate, dehydrogenase.' 255 1.30E3-55 OM74.aa RT11TT Recombinant L-2-hydroxyisocaproic acid dehydrogenase. 2 27.0E-49 f874. aa FR62605EP. falciparum lactate dehydrogenase.251 .OE4 f874.aa W1476 Eimeria lactate dehydrogenase. .2031 1.1013-25 f9-43.aa -P9 12 23 Coenzyme-Independent L-sorbosone dehydrogenase from Gluconobacter 1751 4.30E3-16

CA,

PCTIUJS98112718 WO 98/59071 260 TABLE 3. Conservative Amino Acid Substitutions.

Aromatic Phenylalanine Tryptophan Tyrosine Hydrophobic Leucine Isoleucine Valine, Polar Glutarnine Asparagine Basic Arginine Lysine Histidine Acidic Aspartic Acid Glutamic Acid Small Alanine Serine Threonine, Metbionine Glycine

S

WO 9859071PCT/US9811271 8 WO 98/59071 261 TABLE 4. Residues Comprising Epito-Bearing Fragments Query Residues Comprising Epito-Bearing Fragments fi 01.aa from about Lys-62 to about Gly-.64, from about Ser- 111 to about Asp-113, from about Arg-136 to about Arg-139, from about Pro- 189 to about Asn-193.

fl 1.aa from about Pro-38 to about Lys-40, from about Glu-92 to about Lys-96.

fl2.aa from about Pro-288 to about Asp-290, from about Asn-336 to about Gly-338, from about Tyr-410 to about Gly-413, from about Asp-418 to about Arg-420, from about Pro-552 to about Val-555, from about Gln-643 to about Asp-645, from about Gln- 1061 to about from about Asn-I 130 to about Lys- 1132.

f 129.aa frm about Glu-7 6 to about Arg-8 1, from about Lys- 144 to about fl47.aa from about Gln-94 to about Tbr-96.

'fl52.aa from about Gly-35 to about Gly-37, from about (iln-321 to about ___Gly-323.

f154.aa from about Asn-39 to about Lys-4l, from about Ser-74 to about Lys-77, from about Ser-213 to about Gly-215, from about Ser-303 about Asp-306, from about Asp-422 to about Asn-424.

f 157.aa from about Lys-21 to about Asp-24, from about Ser-45 to about Tyr-47.

f17.aa from about Arg-17 to about Asn-20, from about Thr-94 to about Gly-96.

fl186.aa from about Lys-305 to about Tyr-308.

f 196.aa from about Lys-121 to about Asn-123, from about Pro-278 to about from about Glu-576 to about Tyr-578.

f899.aa from about Asn- 174 to about Asp- 177.

f925 .aa fro m about Lys-20 1 to about Asp-204, from about Phe-29 1. to Ils-294.

f929.aa from about Pro- 139 to about Asn- 14 1, from about Arg-2 Io about Glu-2 14, from about Tbr-370-to about Asn-375.

f933.aa from about Ser- 139 to about Lys-143.

f940.aa from about Gly- 143 to about Asn- 148.

f943.aa from about Asp-58 to about Asp-60, from about Lys-157 to about Asn-159, from about Asp-217 to about Asp-221, from about LYS- 250 to about Asn-254, from about Pro-262 to about Asn-264, from Gly-305 to about Trp-30'7.

f952.aa from about Ser-52. to about Ser-54.

f4.aa from about Ar-64 to about Arg-67.

f43.aa from about Ser-84 to about Gin-87, from about Asp-23 I to about from about Ar-296 to about Ap300. 13t from about Glu-136 to about Gly-138, from about As- 5 3 to about Lys-155, from about Asp-289 to about Asp-29 1, from about to about Asn-461.

from about Glu- 120 to about Asp- 122, from about Pro-2O 4 to abou T o26.

f8.aa from about Pro-263 to about Arg-265, from about Asp- 2 7 4 to about Lys-27.7= f82.aa from aout Iyr-bo to aoOUt Uly-00, irUM dIXUL .0i- Lys- 119, from about Asp- 121 to about Gly- 123, from about Pro- 128 to about Gly 13 1.

I

WO 9859011PCT/US98/12718S wo 98/59071 262 TABLE 4. Residues Comprising Epito-Bearing Fragments 9* f86.aa from about Asn- 179 to about Asn- 18 1, from about Lys- 192 to about Asn-194, from about Lys-270 to about Asn-272, from about Lys-9 to about Lys-282, from about Asp-331 to about Asn-333.

f477.aa from about Pro-250 to about Lys-253.

f488.aa from about Lys-76 to about Lys-79, from about Asn-486 to about Asp-489, from about Lys-508 to about Gly-5 10, from about Asnto about Gly-562.

f494.aa from about Ls-76 to about Asn-78.

16.aa from about Lys-32 to about Asp-34.

f523.aa from about Pro-202 to about Asn-206, from about Lys-255 to about f526.aa from about Asn-85 to about Lys-88, from about Asp- 136 to about Gly-138.

f577.aa from about Cys-iS8 to about Lys-22, from about Asn-297 to about f584.aa from about Pro- 131 ito about Lys- 13 3, from about Pro-200 to about ____Ser-202.

f596.aa from about Arg-42 to about Asp-44, from about Asp-i 17 to about DEr-I 19, from about Pro-205 to about Asp-207.

f600.aa from about Pro- 143 to about Asp- 145.

f603.aa from about Ptie-35) to about Ser-37.

f607.aa, from about Gln-67 to about Lys-70, from about Asp-273 to about Tyr-275, from about Asp-333 to about Gly-338, from about Proto about Lys-362, from about Arg-409 to about Gly-41 1.

f611.aa from about Arg-l33to about Gly-135.

f631.aa from about Pro-132 to about Asn-136, from about Asn-159 to about Tyr- 16 1, from about Pro-216 to about Asp-218, from about to about Lys-223.

f688.aa from about Lys-266 to about Asp-268, from about Lys-27 1 to about Asn-273, from about Lys-315 to about Lys-3 18.

f704.aa from about Lys-250U to about Lys-253.

f707.aa from about Lys-131 to about Asp-134, from about Asp-246 to about Asn-249.

f709.aa from about Tyr-39 to about Gly-42, from about Lys-148 to about Gly-i150, from about Arg-269 to about Gly-272, from about S erto about Tyr-468, from about Asn-489 to about Asn-49 1, from about Lys-575 to about Asp-578, from about Pro-642 to about Lys- 644.

f197.aa from about Pro-217 to about Asp-21.9, from about Glu-675 to about Asp-678, from about Pro-687 to about Asn-689, from about Gluto about Gln-696.

f200.aa from about Arg- 1 4 to about Phe- 1.79.

f208.aa from about Arg-326 to about Ser-328.

f210.aa from about Pro-]191 to about Ile- 194.

f221.aa from about Asn-133 to about Asn-135.

f253.aa from about Arg-191 to about Gly-194.

f269.aa from about Ser-271 to about Thr-273, from about Asp-284 to about 2 8 6 f29.aa from about Pro-159 to about Ser-161.

f290.aa from about Pro-240 to about 01 -244.

f29 1.aa. -fro mabout Gln-267 to about Lys-269.

WO S/5071PCT/IJS98/12718 wo 98159071 263 TABLE 4. Residues Comprising Epito-Bearing Fragments 9* f296.aa from about Glu-98 to about f3.aa from about Asn-241 to about Lys-245.

from about Asn-156 to about Tyr-159, from about Asn- 178 to about Lys- 180.

f939.aa from about Ser-245 to about Asn-249.

f739.aa from about Asn-80 to about Tyr-82, from about Lys-208 to about Ser-2 f742.aa from about Ser- 141 to about Asp- 145, from about Asn-222 to about Gln-225, from about Asp-243 to about Tyr-247, from about Asnto about Asn-25 I.' f743.aa from about Arg- 11 to about Gly-ll1 4 from about Pro- 131 to about f790.aa from about Thr-40 to about Asn-42-, from about Ser-53 to about from about Lys-215 to about Asp-218, from about Asn-274 about Gly-277.

f792-aa from about Val-82 to about Ser-84, from about Ser-102 to about Asn- 104, from about Gln- 127 to about Tyr- 130, from about Lys- 309 to about Asn-3 14, from about Lys-375 to about Thr-377, from about Pro-S 11 to about His-S 13, from about Tbr-5 15 to about Asp- 517.

f797.aa from about Pro- 119 to about Gly- 122, from about Lys- 166 to about Asn-169. l f799.aa from about Asn-31 to about Asn-34, from about G~-44 to about Asn-47, from about Pro-123 to about Gly-125.

f8l4.aa from about Ser-120 to about.Ser-122, from about Arg-636 to about from about Cys-967 to about Ser-969.

f820.aa from about Thr-563 to about Tyr-565.

f850.aa from about Tyr-159 to about Tyr-164, from about Gln-375 to about A sp-379.

f853.aa from about Thr- 180 to about Lys- 184, from about Arg-23 Ito about Asp-233, from about Asn-252 to about Gly-254.

f859.aa from about Lys-46 to about Ser-52, from about Pro-88 to about Asn-9 1, from about Asn- 117 to about As-120.

ff86 1.aa from about Asp-3 6 to about Lys-40,. from about Lys-219 to about f368.aa from about Gln-228 to about Asn-23 1.

f37 1.aa from about Tyr- 109 to about Asn-1 111, from about Asn- 16 2 to Gln-164.

f502.aa from about Asn- 118 to about Lys- 122, from about Ser-269 to about Gly-271, from about Lys-370 to about Asp-373, from about Asnto about Lys-5i 1, from about Lys-705 to about Ar -707, from abo-ut Thr-912 to about Gly-9 14, from about Pro-12l3 to about Asp 1216, from about Asn-1491 to about Arg-1493.

ff527 .aa from about Cys-20 to about Gin-22, from about Asn-38 to about, from. about Phe- 12 to about Asp- 14, from about Lys- 1 6 0 to about Asn-162, from about Ser-199 to about Asp-201, from ____about GEn-2-58 to about Gly- 2 6 l, from about Arg-282 to about Asn-284, from about Ser-297 to about Asp-299.

f541.aa. from a-bout Ser-68 to about Asn-7 1.

f604.aa from about Lys-77 to about Gly-79, from about Lys-201 to about from about Asp-252 to about Asp-254, from about Tyr-.

WO 98/59071 PCT/tJS98/12718 264 TABLE 4. Residues Comprising Epito-Bearing Fragments 347 to about Gly-350, from about Asp-514 to about Trp-5 16.

0 0 0 f736.aa from about Lys-20 to about Asn-24, from about Arg-147 to about from about Ser-23 1 to about Lys-233.

f752.aa from about Tbr- 119 To about Lys- 122, from about Pro-420 to about' Gl-422.

f798.aa from about Asp-33 to about Tbr-36, from about Lys- 180 to about His- 183.

f635.aa from about Pro- 100 to about Asn- 102, from about Asp- 145 to about Phe- 147.

f32.aa froim about Lys- 18 to about f320.aa from about Asn- 193 to about Leu- 195, from about Gin-248 to Lys-250.

f352.aa from about Ser-4b to about Asn-49.

f301.aa from about Lys- 178 to about Lys-180, from. about Ser-401 to about ____Tyr4 f373.aa from about Gly-88 to about Lys-90, from about Asn-539 to about from about Glu-654 to about Ser-657.

f384.aa from about Pro-250 to about Asn-252, from about Asp-266 to about Lys-268.

f446.aa from about Asp-20 to about Ser-26, from about Asn-146 to about Lys-149.

f542.aa from about Arg-86 to about Gly-88, from about Arg-163 to about f93.aa from about Asn-152 to about Asp-155.

f 105.aa from about Asp-48 to about f 150.aa. from about Tbr-214 to about Asp-2 18, from about Asp-256 to Asp-259.

f219.aa from about Asn-77 to about Asn-8 1, from about Asp-ill1 to about Asn- f229.aa from about Gln-6 1 to about Asn-63.

f32.aa from about Lys- 18 to about fl86.aa -from about Lys-305 to about Tyr-308.

f216.aa. from abou t -Ser-L105 to about Asn- 107.

f328.aa from about Asn-105 to about Asp-107.

f352.aa frm about Ser-46 to about Asn-49.

f867.aa from about Thr-3 to about Gly-5, from about Lys- 156 to about Serf868.aa from about Arg-94 to about Gly-96, from about Pro-2 5 7 to about Gly-26 1, from about Pro-295 to about Asp-297, from about Alg 340 to about Asp-342.

f872.aa from about Ser- 19 to about Lys-23, from about Thr- 13 9 to about Asp- 142, from about Ser-282 to about Tyr-286, from about Ser-3 11 to about Ser-3 13.

f886.aa from about Tbr-83 to about Asp-85, from about A 1-0 6 to about Lys- 108, from about Lys- 143 to about Gly- 147, from about Asp)to about Asn-191.

f888.aa from about Asn-.65 to about Asp-67.

f893.aa Tfm about Asn-203 to about Asn-207, from about Tbr-4465.to Asn-450.

f605.aa from about Arg-31 to about -sp33.

f606.aa from about Asn-68 to about GI -71, from about Asn-136 to about wo 98/59071 WO 9559071PC-rfUS98/12713 265 TABLE 4. Residues Comprising Epito-B earing Fragments Lys-139, from about Asn-223 to about Tyr-22 6, from about Serto about Tyr-279, from about Pro-362 to about Asn-365, from about Arg-503 to about Trp-507.

f679.aa from about Lys- 154 to about Asp- 156, from about Lys-224 to about Arg-226, from about Asn-260 to about Asp-264, from about Glu-363 to about Lys-366, from about Asp-387 to about Gly-389, from about Tyr-441 to about Lys-443, from about Arg-501 to about Tyr- 504.

fll-12.aa from about Pro-91 to about Asn-93, from about Pro- 18 1 to about 86, from about Lys-244 to about Ser-248.

ifl 1-4.aa from about Asn- 160 to about Lys- 163.

if 4-8.aa from about Pro-92 to about Gha-95, from about Lys-123 to about from about Lys-215 to about Asp.-219.

if 17-6.aa from about Pro-36 to about Glu-38.

f19-2.aa from about Ser- 104 to about Ser- 106, from about Gln-230 to about if 19-4. aa from about Val-79 to about Thr-82, from about Pro- 195 to about ____Gly-201.

fl9-6.aa from about Asp-24 to about Lys-30, from about Pro-36 to about f2l14.aa from about Cys-24 to about Asn-26.

f28-2.aa from about Ser-77 to about Lys-80, from about Tyr-274 to about An-277.

f28-3.aa from about Glu-53 to about .Arg-57, from about Gln-82 to about Asn-85, from about Gln- 157 to about Asn- 159.

0f 1 -2.aa from about Arg-95 to about Arg-97, from about Asn-297 to about Asn-299.

f4-15.aa from about Pro- 182 to about Asp--184, from about Lys-220 to about Asp-222.

f4-50.aa from about Thr- 109 to about Asn- 111.

f42-l.aa from about Asn-55 to about Asn-57, from about Arg-81I to about Ser-84, from about Asp-94 to about Asn-97.

f45-2.aa from about Asn-83 to about Gly-86: f47-2.aa from about Ser-29 to about Asp-33, from about Asn-94 to about Lys-99, frm about Pro- 152 to about Lys- 157.

if49-2.aa from about Asn-452 to about Gly-454.

f5-14.aa from about Glu-102 to about Asp-106, from about b-272 to abou Asn-275, from about Glu-3 13 to about Asn-3 15, from about Serto about Ser-372.

f5-15.aa from about Lys- 170 to about Gly- 173, from about Asn- 194 to Gly-196.

ifS -2.aa from about Asp-302 to about Lys-304.

f6-21.aa from about Glu-38 to about Asn-42, from about Arg-84 to about if6-27.aa from abut Asp-67 to about Asn-69, from about Arg-85 to about Asn-89, from about Lys- 168 to about Gly- 17 1, from about Lys- 179 to about Asn-181, from about Ser-380 to about His-382.

from about Ser-67 to about Asn-7 1.

f7-30.aa from about Pro-94 to about Asp-96, from about Lys-144 to about ____Arg-1I ,f76-1.aa from about Asn-30 to about Lys-35, from about Lys- 113 to about- WO 98159071 WO 9859071PCTIUS98112718 TABLE 4. Residues Comprising Epito-Bearing Fragments Gly- 16. from about (Mu- 119 to about Lys- 12 1.

f8-10.aa from about Pro-25 to about Lys-'32, from about Ser-168 to about 172.

fOl1aaa,._bbOO 1 from about Pro- 123 to about Asp- 125, from about Ser- 179 to about 1, from about Lys-Z55 to about Gly-259.

_bbO~l 1 from about Ala8 about Mrg 17, from about Tyr3 I to about Gly4O, from about Ser65 to about Lys78, from about Va193 to about Asp 102, from about Serl2O to about 11e129, from about Pro 156 to about Glul170, from about Lys 187 to- about Asn 196, from about His205 to about Lys2l4, from about Gly226 to about Glu235, fro about Gln253 to about Asn266, from about Glu283 to about Glu293, from about Leu.3 11 to about fle320, from about Arg-326 to Gly335, from about Pro340 to about Ala349 fD2a.aa-bb0O2 from about Tyr- 169 to about Asn- 17 1, from about Tyr-242 to about from about Lys-264 to about Asp-267.

_bb9 from about Met7 to about Lys 16, from about Lys47 to about Ser57, from about AsnSO to about Ser89, from about Gly 103 to about Glu 113, from about Lysl25 to about Pro 133, from about Lysl38 about Ala147 fO3a.aa-bbOO6 from about Asp-54 to about Tbr-57, from about Lys-201 to about His-204.

_bbOl14 from about Pro23 to about Gln3 1, from about Ser37 to about from about Leu76 to about Asn84, from about Leu76 to about Va184, from about Ser89 to about Asn97, from about to about Lysil 13, from about Asnl2O to about Metl28, from about to about Giy 167, from about Ly 173 to about B all181 _bb023 from about Aspl17 to about' Gly27, from about Argr4O to about Asp48, from about Va164 to about Asp72, from about Glu 105 to about Thrl 13, from about Serl4l to about Gly 150, from about Aspl155 to about H1e163, from about Asnl184 to about Lysl198, from about 11e219 to about Pro227, from about Ser230 to about Phe238, from about Ser24l to about Asn.250, from about Asp27O to about Va]278, from about Ser285 to about Leu293, from about Glyu3O7 about Ser3 15, from about Lys327 to about Asn.335 f08a..aa-bb024 from about Asn-30 to about. Asp-33, from about Ser-1 16 to about Asi- 18, from about Asn- 154 to about Gly- 156.

f09a.aa-bb025 from about Asn-30 to about Ser-35, from about Tbr- 145 to about Asn- 148.

S *5

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PCT/US98112718 WO 98/59071 267 Applzcanr's or agents Bi B7P7 Ineatol hc zN. Unssgned INDICATIONS REATING TO A DEPOSITED MICROORGANISM PCT Rule Mibx) A. The indficatins made below relate to thte mirora ism re tn in the dcziption on pop 8 ,line B. MIENTFICATION OF DEPOSrT Furtherdcposi am idcotiied an an additional sie Name of depositry instituon American Type Culture Collection Address of deposiury insatution (uscludi-gpostal code and country) 10801 University Boulevard Manassas, Virginia 20110-2209 United States of America Date of deposit August 8, 1998 Accession Num~ber 202012 C. ADDITONAL INDICATIONS (aav blmki tfnas appicable) This infarmation is continued on an additional sheci D. DESIGNATED STATES FOR WHICH INDICATIONS ARE MADE a7f ted w are mat for alldatipned m) E. SEPARATE FURNISHING OF INDICATIONS 17a- bkmk ifat a~picahA,) The indications listed below will be submitted to the Intnationnal Bureau Later (jpe45~ the generwal rr? ofw ihmaiZ Number of Drpaalt-

C.

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For receiving Office use only El1Ths shw was received with t kmnternati o la tion AuzhariZd affi=r ?m CTJR 34 (July 1992) For International Bureau use only Thu shectwa jecd by fte ln~naz00" B- oan-a AvItduofflcc

Claims (17)

1. An isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence selected from the group consisting of: a nucleotide sequence encoding any one of the amino acid sequences of the polypeptides shown in Table 1; or a nucleotide sequence complementary to any one of the nucleotide sequences in a nucleotide sequence at least 95% identical to any one of the nucleotide sequences shown in Table 1; or, a nucleotide sequence at least 95% identical to a nucleotide sequence complementary t. any one of the nucleotide sequences shown in Table 1.

2. An isolated nucleic acid molecule of claim 1 comprising a polynucleotide which hybridizes under stringent hybridization conditions to a polynucleotide having a nucleotide sequence identical Sto a nucleotide sequence in or of claim 1.

3. An isolated nucleic acid molecule of claim 1 comprising a polynucleotide which encodes an epitope-bearing portion of a polypeptide in of claim 1.

4. The isolated nucleic acid molecule of claim 3, wherein said epitope-bearing portion of a polypeptide comprises an amino acid sequence listed in Table 4. 0 A method for making a recombinant vector comprising inserting an isolated nucleic acid Smolecule of claim 1 into a vector.

6. A recombinant vector produced by the method of claim

7. A host cell comprising the vector of claim 6.

8. A method of producing a polypeptide comprising: growing the host cell of claim 7 such that the protein is expressed by the cell; and recovering the expressed polypeptide.

9. An isolated polypeptide comprising a polypeptide selected from the group consisting of: WO 98/59071 PCT/US98/12718 269 a polypeptide consisting of one of the complete amino acid sequences of Table 1; a polypeptide consisting of one the complete amino acid sequences of Table 1 except the N-terminal residue; a fragment of the polypeptide of having biological activity; and a fragment of the polypeptide of which binds to an antibody specific for the polypeptide of An isolated antibody specific for the polypeptide of claim 9.

11. A polypeptide produced according to the method of claim 8.

12. An isolated polypeptide comprising an amino acid sequence at least 95% identical to a sequence selected from the group consisting of an amino acid sequence of any one of the polypeptides in Table 1.

13. An isolated polypeptide antigen comprising an amino acid sequence of an B. burgdorferi epitope shown in Table 4.

14. An isolated nucleic acid molecule comprising a polynucleotide with a nucleotide sequence Sencoding a polypeptide of claim 9. A hybridoma which produces an antibody of claim

16. A vaccine, comprising: one or more B. burgdorferi polypeptides selected from the group consisting of a polypeptide of claim 9; and a pharmaceutically acceptable diluent, carrier, or excipient; wherein said polypeptide is present, in an amount effective to elicit protective antibodies in an animal to a member of the Borrelia genus.

17. A method of preventing or attenuating an infection caused by a member of the Borrelia genus in an animal, comprising administering to said animal a polypeptide of claim 9, wherein said polypeptide is administered in an amount effective to prevent or attenuate said infection.

18. A method of detecting Borrelia nucleic acids in a biological sample comprising: contacting the sample with one or more nucleic acids of claim 1, under conditions such that hybridization occurs, and detecting hybridization of said nucleic acids to the one or more Borrelia nucleic acid WO 98/59071 PCT/US98/12718 270 sequences present in the biological sample.

19. A method of detecting Borrelia nucleic acids in a biological sample obtained from an animal, comprising: amplifying one or more Borrelia nucleic acid sequences in said sample using polymerase chain reaction, and detecting said amplified Borrelia nucleic acid. A kit for detecting Borrelia antibodies in a biological sample obtained from an animal, comprising a polypeptide of claim 9 attached to a solid support; and detecting means.

21. A method of detecting Borrelia antibodies in a biological sample obtained from an animal, comprising contacting the sample with a polypeptide of claim 9; and detecting antibody-antigen complexes.