CZ126699A3 - Polypeptide containing antigenic part of soluble antigen m. tuberculosis or variant of said antigen, dna molecule encoding such polypeptide, expression vector, host cell, diagnostic methods of m. tuberculosis infection and diagnostic kits - Google Patents

Abstract

Compounds and methods for diagnosing tuberculosis are disclosed. The compounds provided include polypeptides that contain at least one antigenic portion of one or more M. tuberculosis proteins, and DNA sequences encoding such polypeptides. Diagnostic kits containing such polypeptides or DNA sequences and a suitable detection reagent may be used for the detection of M. tuberculosis infection in patients and biological samples. Antibodies directed against such polypeptides are also provided.

Description

A polypeptide containing the antigenic part of the soluble antigens of M.

tuberculosis or a variant of said antigens, a DNA molecule encoding this polypeptide, an expression vector, a host cell, methods of diagnosing M. tuberculosis infection and diagnostic kits.

Field of technology

The invention describes the detection of infection with the microorganism Mycobacterium tuberculosis. In particular, the invention describes polypeptides containing Myobacterium tuberculosis antigen or a portion thereof or a variant thereof and the use of such a polypeptide for serum diagnosis of Mycobacterium tuberculosis infection.

Current state of the art

Tuberculosis is a chronic infectious disease that is generally caused by infection with the Mycobacterium tuberculosis microorganism. Tuberculosis is a major disease in developing countries and has become a growing problem in the developed countries of the world. 8 million new cases occur annually and 3 million people die. Although the infection may be asymptomatic for a period of time, the disease more commonly manifests as acute pneumonia, leading to fever and a nonproductive cough. If this disease is not treated, serious complications and death occur.

Although tuberculosis can be treated with extensive antibiotic treatment, such treatment is not sufficient to prevent the spread of the disease. However, infected individuals who remain symptom-free for a period of time are infectious. Additionally, although compliance with the treatment regimen is critical, patient behavior is difficult to monitor. Some patients do not adhere to the course of treatment, which can lead to the development of drug resistance.

Effective vaccination and accurate, early diagnosis of the disease are necessary to prevent the spread of tuberculosis. Currently

the most effective way of inducing protective immunity is vaccination with live bacteria. The most common Mycobacterium for these purposes is Bacillus Calmette-Guerin (BCG), a non-virulent strain of Mycobacterium bovis. In some countries, such as the United States, where the safety and effectiveness of BCG is disputed, they do not vaccinate the general public. Diagnosis is commonly made by a skin test that involves intradermal exposure to tuberculin PPD (purified protein derivative). Antigen-specific T cell responses are measurable by redness at the injection site 48 to 72 hours after injection, indicating exposure to mycobacterial antigens. However, the sensitivity and specificity of this test is a problem. This test cannot distinguish BCG-vaccinated individuals from infected individuals.

While macrophages have been shown to act as essential agents in immunity against M. tuberculosis, such immunity is predominantly induced by T-cells. The essential role of T-cells in protection against M. tuberculosis infection arises from the frequent presence of M. tuberculosis in AIDS patients, which is caused by CD4 T cell depletion, a condition associated with human immunodeficiency virus infection . Mycobacterium-reactive CD4 T-cells have been shown to be potent producers of gamma interferon (IFN-γ), which in turn triggers the anti-mycobacterial effects of macrophages in mice. While the role of IFN-γ in humans is less clear, studies show that 1,25-dihydroxy-vitamin D3, either alone or in combination with IFN-γ or tumor necrosis factor alpha, activates human macrophages to inhibit microorganism infection M. tuberculosis. IFN-γ is known to stimulate human macrophages to produce 1,25-dihydroxyvitamin D3. Similarly, IL-12 has been shown to play a role in the stimulation of tuberculosis. tuberculosis resistance to infection by the microorganism

M.

The problem of immunology of infection by the microorganism M. is described in the publication Chán and Kaufmann, • · • · · · ···· · ·· · • · ··· · · ·· ··· ··· ······· · · ···· ·· ·· ·· ·· ··

Tuberculosis: Pathogenesis, Protection and Control, Bloom (ed.), ASM Press, Washington, DC, 1994.

It is necessary to develop improved diagnostic methods for the detection of tuberculosis. The present invention fully fulfills this need and further provides other advantages.

The essence of the invention

The invention describes compositions and methods for diagnosing tuberculosis. Polypeptides are prepared that contain the antigenic part of the soluble antigen of the microorganism M.

i tuberculosis or variants of such an antigen that differ only in conservative substitutions and/or modifications. In one embodiment, the soluble antigen of the invention exhibits one of the following N-terminal sequences:

(a) Asp-Pro-Val-Asp-Ala-Val-Ile-Asn-Thr-Thr-Cys-Asn-Tyr-GlyGln-Val-Val-Ala-Ala-Leu (SEQ ID NO: 115);

(b) Ala-Val-Glu-Ser-Gly-Met-Leu-Ala-Leu-Gly-Thr-Pro-Ala-ProSer (SEQ ID NO: 116);

(c) Ala-Ala-Met-Lys-Pro-Arg-Thr-Gly-Asp-Gly-Pro-Leu-Glu-AlaAla-Lys-Glu-Gly-Arg (SEQ ID NO: 117);

(d) Tyr-Tyr-Trp-Cys-Por-Gly-Gln-Pro-Phe-Asp-Pro-Ala-Trp-GlyPro (SEQ ID NO: 118);

(e) Asp-Ile-Gly-Ser-Glu-Ser-Thr-Glu-Asp-Gln-Gln-Xaa-Ala-Val (SEQ ID NO:119);

(f) Ala-Glu-Glu-Ser-Ile-Ser-Thr-Xaa-Glu-Xaa-Ile-Val-Pro (SEQ

ID NO: 120);

(g) Asp-Pro-Glu-Pro-Ala-Por-Pro-Val-Pro-Thr-Thr-Ala-Ala-SerPro-Pro-Ser (SEQ ID NO: 121);

(h) Ala-Pro-Lys-Thr-Tyr-Xaa-Glu-Glu-Leu-Lys-Gly-Thr-Asp-ThrGly (SEQ ID NO: 122);

(i) Asp-Pro-Ala-Ser-Ala-Pro-Asp-Val-Pro-Thr-Ala-Ala-Gln-LeuThr-Ser-Leu-Leu-Asn-Ser-Leu-Ala-Asp-Pro-Asn -Val-Ser-PheAla-Asn (SEQ ID NO: 123);

(j) Xaa-Asp-Ser-Glu -Lys-Ser-Ala-Thr-Ile-Lys-Val-Thr-Asp-AlaSer (SEQ ID NO: 129);

(k) Ala-Gly-Asp-Thr-Xaa-Ile-Tyr-Ile-Val-Gly-Asn-Leu-Thr-AlaAsp (SEQ ID NO: 130) or (l) Ala-Pro-Glu-Ser-Gly -Ala-Gly-Leu-Gly-Gly-Thr-Val-Gln-AlaGly (SEQ ID NO:131), where Xaa can be any amino acid.

Furthermore, the invention describes polypeptides containing the immunogenic part of the antigen of the M. tuberculosis microorganism or a variant of such an antigen that differs only by conservative substitutions and/or modifications, wherein the antigen has one of the following N-terminal sequences:

(m) Xaa-Tyr-Ile-Ala-Tyr-Xaa-Thr-Thr-Ala-Gly-Ile-Val-Pro-GlyLys-Ile-Asn-Val-His-Leu-Val (SEQ ID NO: 132) or (n) Asp-Pro-Pro-Asp-Pro-His-Gln-Xaa-Asp-Met-Thr-Lys-Gly-TyrTyr-Por-Gly-Gly-Arg-Arg-Xaa-Phe (SEQ ID NO: 124 ) where Xaa can be any amino acid.

In another embodiment, the soluble M. tuberculosis antigen comprises an amino acid sequence encoded by a DNA sequence selected from the group consisting of sequences listed in SEQ ID NOS: 1,2,4-10, 13-25, 52, 94 and 96, complements of said sequences, and DNA sequences , which hybridize with the sequence shown in SEQ ID NO: 1,2, 4-10, 13-25, 52, 94 and 96 or their complements under stringent conditions.

The polypeptides comprise the antigenic region of the M. tuberculosis antigen or variants of such antigen that differ only by conservative substitutions and/or modifications, wherein the antigen comprises an amino acid sequence encoded by a DNA sequence selected from the group comprising the sequences listed in SEQ ID NO: 26-51, 133, 134, 158-178 and 196, complements of said sequence and DNA sequences that hybridize • · ··· ·· ·· ··· · · · • · φ φ φ · φ · · ••ΦΦ ·· ·· φφ ·· ·· the sequence shown in SEQ ID NO: 26-51, 133, 134, 158-178 and 196 or its complement under stringent conditions.

The invention further describes DNA sequences encoding the aforementioned polypeptides, recombinant expression vectors containing said DNA sequences, and host cells transformed or transfected with such expression vectors.

The invention describes fusion proteins containing a first and a second polypeptide according to the invention or, in another case, a polypeptide according to the invention and a known antigen of the microorganism M. tuberculosis.

Another aspect of the invention are methods and diagnostic tests for detecting tuberculosis in a patient. These methods include:

a) contact of the biological sample with at least one of the above mentioned polypeptides a

b) detecting the presence of antibodies in the sample, whereby the antibodies bind to the polypeptide or polypeptides, thereby detecting infection with the M. tuberculosis microorganism in the biological sample.

Suitable biological samples include blood, sputum, serum, plasma, saliva, cerebrospinal fluid and urine. Diagnostic kits contain one or more of the above-mentioned polypeptides in combination with a detection reagent.

The invention also describes methods of detecting M. tuberculosis infection including:

(a) obtaining a biological sample from the patient, (b) contacting the sample with at least one oligonucleotide primer in a polymerase chain reaction, wherein the oligonucleotide primer is specific for the DNA sequence encoding the polypeptides mentioned above, and (c) detecting the DNA sequence in the sample, which amplifies in the presence of the first and second oligonucleotide primers. In one embodiment of the invention, the oligonucleotide primer contains at least about 10 contiguous nucleotides of said sequence.

• ·

The invention further describes a method of microorganism M. tuberculosis in patients, which includes:

(a) obtaining a biological sample from the patient's body contact the sample with an oligonucleotide probe specific detection of infection (b) for the sequence

DNA encoding the above-mentioned polypeptides and detection of the DNA sequence in the sample, whereby

The DNA hybridizes with the oligonucleotide sequence V single probe.

embodiment of the invention, the oligonucleotide probe contains at least approximately 15 contiguous nucleotides of said DNA sequence.

Furthermore, the invention describes monoclonal and antibodies that bind to the polypeptides described above in the text as well as methods of their use in the detection of infection by the microorganism M. tuberculosis.

polyclonal

As stated above in the text, the invention generally relates to compositions and methods for the diagnosis of tuberculosis. Compositions according to the invention include polypeptides that contain at least one antigenic part of an antigen of the microorganism M. tuberculosis or a variant of such an antigen that differs only in conservative substitutions and/or modifications. Polypeptides of the invention include, but are not limited to, soluble antigens of the microorganism M. tuberculosis. The term "soluble antigen of the microorganism M. tuberculosis" ¹ ' is a protein originating from the microorganism M. tuberculosis, which is found in the filtrate of the culture of the microorganism M. tuberculosis. The term "polypeptide" means amino acid chains of any length that include full-length proteins (ie, antigens) where the amino acid residues are linked by covalent peptide bonds. A polypeptide comprising an antigenic portion of one of the above antigens may include the entire antigenic portion or may contain additional sequences. Said other sequences may come from the antigen of the natural microorganism M. tuberculosis • · ······· · · ···· · · * · · · ·· · · or it may be heterogeneous and then such sequences may (but may not) be antigenic.

The term "antigenic portion of an antigen (which may or may not be soluble) is a portion that is capable of reacting with serum obtained from individuals infected with M. tuberculosis (that is, generating an absorbance with serum obtained from infected individuals at least three standard deviations higher , than the absorbance obtained with serum from uninfected individuals, the absorbance being obtained by a representative ELISA test). The term "individual infected with M. tuberculosis" means a person who has been infected with M. tuberculosis (for example, shows a positive response to a PPD that is at least 0.5 cm in diameter). Infected individuals show symptoms of tuberculosis or are asymptomatic. Polypeptides showing at least an antigenic portion of one or more M. tuberculosis antigens described herein can generally be used for the detection of tuberculosis alone or in combination.

The compositions and methods of the invention also include variants of the above polypeptides. The term "variant A" means a polypeptide that differs from the native 'antigen only by conservative substitutions and/or modifications such that it has retained the antigenic properties of the polypeptide. Such variants can generally be identified by modifying one of the polypeptide sequences described above and evaluating the antigenic properties of the modified polypeptide using representative procedures described herein.

The term "conservative substitution" is that substitution where an amino acid is replaced by another amino acid that has similar properties such that one skilled in the field of peptide chemistry will assume that the secondary structure and hydropathic nature of the polypeptide will not be substantially changed. The following amino acids represent conservative changes: (1) ala, pro, gly, glu, asp, gin, asn, ser, thr • ·· • φφφ • · · · · · • ΦΦ φφφ «φ φφ

(2) Cys, cheese tyr, thr (3) wall, how many leu, met ala (4) fox, arg, his a (5) phew tire suffering

Variants can also be modified, for example by deletion or addition of amino acids, which have a minimal effect on the antigenic properties, secondary structure and hydropathic nature of the polypeptides. For example, the polypeptide may be linked to a signal (or leader) sequence at the N-terminal end of the protein that directs translational and post-translational transfer of the protein. A polypeptide can be linked to a linker or other sequence for easy synthesis, purification or identification of polypeptides (eg, poly-His) or to increase the ability of polypeptides to bind to a solid support. The polypeptide can bind to the Fc region of the immunoglobin.

The term "combined polypeptide" is a polypeptide that contains at least one of the above-mentioned antigenic properties and one or more other antigenic sequences of the M. tuberculosis microorganism, which are linked into a single amino acid chain by means of a peptide bond. The sequence can be linked directly (that is, without inserted amino acids) or they can be linked by a linker sequence (eg Gly-Cys-Gly) which does not substantially change the antigenic properties of the polypeptides.

In general, antigens of the microorganism M. tuberculosis DNA sequences encoding such antigens are prepared using various procedures. Soluble antigens can be isolated from culture filtrates of M. tuberculosis by techniques well known in the art, including reverse phase ion exchange chromatography. Purified antigens can then be evaluated for desired properties, such as the ability to react with serum obtained from an individual infected with M. tuberculosis. Such tests may be performed using the methods described herein. Antigens can then be partially sequenced · ···· ·· ·· ·· ·· aa for example using traditional Edman chemistry, which is described in Edman and Berg, EUR. J. Biochem. 80: 116-132,

1967.

Antigens can also be produced recombinantly using a DNA sequence that encodes an antigen that has been incorporated into an expression vector and expressed in a suitable host. DNA molecules encoding soluble antigens can be isolated by testing a suitable M. tuberculosis expression library using an antiserum (eg, rabbit) raised specifically against M. tuberculosis soluble antigens. DNA sequences encoding antigens that may or may not be soluble can be identified by testing an appropriate M. tuberculosis genome library or cDNA expression library with serum obtained from patients infected with M. tuberculosis. Such testing can be performed using methods well known in the art as described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, 1989.

DNA sequences encoding soluble antigens can also be obtained by testing for the presence of suitable M. tuberculosis cDNA or genomic DNA library DNA sequences that hybridize to degenerate oligonucleotides derived from partial amino acid sequences of isolated soluble antigens. Degenerate oligonucleotide sequences for use in such an assay can be designed and synthesized and the assay performed as described (for example) in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY (and in other publications listed here). In order to isolate probes from a cDNA library or from a genomic library, it is also possible to use polymerase chain reaction (PCR) using the above mentioned oligonucleotides. Library testing can be done using an isolated probe.

Regarding the method of preparation, the antigens described here are “antigenic. Antigens have the ability to be obtained from individuals infected with tuberculosis. Reactivity can be assessed, for example, using ELISA tests, where an absorbance with sera from infected individuals that is at least three standard deviations higher than absorbance obtained with sera from uninfected individuals is considered positive.

The antigenic properties of M. tuberculosis antigens can be prepared and identified using methods well known in the art, as described in Paul, Fundamental Immunology, 3d ed., Raven Press, 1993, pp. 243-247 and in other publications cited herein. Such methods include testing the properties of polypeptide moieties. It can react with the serum of the microorganism M.

of antigens is to use the representative ELISA test described here. The antigenic portion of the polypeptide is the portion that gives a signal in such a representative assay that is substantially the same as that generated by the full-length antigen. In other words, the antigenic portion of M. tuberculosis antigens generates at least approximately 20%, preferably 100%, of the signal induced by full-length antigens in the ELISA test model described here.

Parts and other variants of M. tuberculosis antigens can be generated synthetically or recombinantly. Synthetic polypeptides contain less than 100 amino acids, and generally less than about 50 amino acids, and can be made using methods well known in the art. For example, such polypeptides can be synthesized using any commercially available solid-phase procedure, such as Merrifield's solid-phase synthesis, where amino acids are sequentially attached to a growing amino acid chain (described in the Merrifield sequence,

J. Am. Chem. Soc. 85; automated synthesis

2149-2146, 1963). A facility for polypeptides is commonly available at • · • · · · ······· · 9

9999 99 99 99 99 99 suppliers such as Applies BioSystems, Inc., Foster City, CA and used as recommended by the manufacturer. Variants of the natural antigen can be prepared using standard mutagenesis methods, such as site-specific mutagenesis of oligonucleotides. A section of the DNA sequence can also be removed using standard methods to prepare truncated polypeptides.

Recombinant polypeptides containing portions and/or variants of a natural antigen can be readily prepared from the DNA sequence encoding the polypeptide using a number of methods. Supernatants from suitable host/vector systems that secrete recombinant protein into the culture medium must first be concentrated using commercially available filters. The concentrate can be applied to a suitable purification matrix, such as an affinity matrix or an ion exchange resin. For further purification of the recombinant protein, one or more reverse-phase HPLC runs can be used.

Any expression vector known in the art can be used to express the recombinant polypeptides described herein. Expression can be achieved in a suitable host cell that can be transformed or transfected with an expression vector that contains a DNA molecule that encodes a recombinant polypeptide. Suitable host cells include prokaryotic, yeast and higher eukaryotic cells. E. coli bacteria, yeast or a mammalian cell line such as COS or CHO are preferably used as host cells. DNA sequences expressed in this manner may encode naturally occurring antigens, portions of naturally occurring antigens, or other variants thereof.

Regardless of the method of preparation, the polypeptides obtained herein are substantially in pure form. It is preferred that the polypeptides have a purity of at least about 80%, preferably at least about 90%, and most preferably at least about 99%. Using the methods described herein, these substantially pure polypeptides can be combined.

In certain specific embodiments of the invention, polypeptides comprising at least an antigenic portion of a soluble antigen of the microorganism M. tuberculosis (or a variant of such an antigen) are described, wherein the antigen exhibits one of the following N-terminal sequences:

(a) Val-Pro-Val-Asp-Ala-Val-Ile-Asn-Thr-Thr-Cys-Asn-TyrGly-Gln-Val-Val-Ala-Ala-Leu (SEQ ID NO: 115) (b) Ala-Val-Glu-Ser-Gly-Met-Leu-Ala-Leu-Gly-Thr-Pro-AlaPro-Ser (SEQ ID NO: 116) (c) Ala-Ala-Met-Lys-Pro-Arg-Thr -Gly-Asp-Gly-Pro-Leu-GluAla-Ala-Lys-Glu-GlyArg (SEQ ID NO: 117) (d) Tyr-Tyr-Trp-Cys-Pro-Gly-Gln-Pro-Phe-Asp- Pro-Ala-TrpGly-Pro (SEQ ID NO: 118) (e) Asp-Ile-Gly-Ser-Thr-Glu-Asp-Gln-Gln-Xaa-Ala-Val (SEQ ID NO: 119) (f) Ala-Glu-Glu-Ser-Ile-Se-Thr-Xaa-Glu-Xaa-Ile-Val-Por (SEQ ID NO: 120) (g) Asp-Pro-Glu-Pro-Ala-Pro-Pro-Val -Pro-Thr-Thr-Ala-AlaSer-Pro-Pro-Ser (SEQ ID NO: 121) (h) Ala-Pro-Lys-Thr-Tyr-Xaa-Glu-Glu-Leu-Lys-Gly-Thr- AspThr-Gly (SEQ ID NO: 122) (i) Asp-Pro-Ala-Ser-Ala-Pro-Asp-Val-Pro-Thr-Ala-Ala-GlnGln-Thr-Ser-Leu-Leu-Asn-Ser -Leu-Ala-Asp-Pro-Asn-ValSer-Phe-Ala-Asn (SEQ ID NO: 123) (j) Xaa-Asp-Ser-Glu-Lys-Ser-Ala-Thr-Ile-Lys-Val- Thr-AspAla-Ser (SEQ ID NO: 129) (k) Ala-Gly-Asp-Thr-Xaa-Ile-Tyr-Ile-Val-Gly-Asn-Leu-ThrAla-Asp (SEQ ID NO: 130) ( l) Ala-Pro-Glu-Ser-Gly-Ala-Gly-Leu-Gly-Gly-Thr-Val-GlnAla-Gly (SEQ ID NO: 131) where Xaa can be any amino acid sequence, a cysteine residue is preferred. The DNA sequence encoding • · ······· · · ···· ·· ·· ·· ·· ·· the antigen designated above as (g) is described in SEQ ID NO: 52, the predicted amino acid sequence is described in SEQ ID NO: 53. The DNA sequence encoding the antigen designated above as (a) is shown in SEQ ID NO: 96; its deduced amino acid sequence is shown in SEQ ID NO: 97. The DNA sequence corresponding to antigen (d) is shown in SEQ ID NO: 24, The DNA sequence corresponding to antigen (c) is shown in SEQ ID NO: 25 and the DNA sequence corresponding to antigen ( 1) is described in SEQ ID NO: 94 and its deduced amino acid sequence is shown in SEQ ID NO: 95.

In another specific embodiment of the invention, polypeptides are described containing at least the immunogenic part of the antigen of the M. tuberculosis microorganism, which exhibits one of the following N-terminal sequences or their variants, which differ only by conservative substitutions and/or modifications:

(m) Xaa-Tyr-Ile-Ala-Tyr-Xaa-Thr-Thr-Ala-Gly-Ile-Val-ProGly-Lys-Ile-Asn-Val-His-Leu-Val (SEQ ID NO: 132) or (n) Asp-Pro-Pro-Asp-Pro-His-Gln-Xaa-Asp-Met-Thr-Lys-GlyTyr-Tyr-Pro-Gly-Gly-Arg-Arg-Xaa-Phe (SEQ ID NO: 124 ) where Xaa can be any amino acid, with a cysteine residue being preferred.

In another specific embodiment of the invention, polypeptides containing at least the antigenic part of the soluble antigen of the microorganism M. tuberculosis (or a variant of such an antigen) are described, which contain one or more amino acid sequences encoded by (a) DNA sequences listed in SEQ ID NO: 1, 2, 4- 10, 13-25, 52, 94 and 96 and (b) complementary to such DNA sequences or (c) DNA sequences substantially homologous to sequence (a) or (b).

In other specific embodiments of the invention, polypeptides containing at least the antigenic part of the antigen of the microorganism M. tuberculosis (or variants of such an antigen) are described, which may or may not be soluble and contain .

······· · · ···· ·· ·· ·· ·· ·· one or more amino acid sequences encoded by (a) the DNA sequences set forth in SEQ ID NOs: 26-51, 133, 134, 158178 and 196, (b) complements of such sequences, or (c) sequences

DNAs that are substantially homologous to the sequence shown in (a) or (b).

In a specific embodiment of the invention described above, M. tuberculosis antigens include variants that are encoded by DNA sequences that are substantially homologous to one or more of the DNA sequences listed herein. The term "substantially homologous" means DNA sequences that are able to hybridize under stringent conditions. Suitable stringency conditions include washing in 5XSSC, 0.5% SDS, 1.0 mM EDTA (pH 8.0); hybridization at a temperature of 50 °C to 65 °C, in a solution of 5XSSC, overnight or in case of homology between species hybridization takes place at a temperature of 45 °C in a solution of 0.5 X SSC; followed by two washes with each of the 2X, 0.5X and 0.2X solutions

SSC containing 0.1% SDS at 65 °C for 20 min. Such hybridizing DNA sequences are also encompassed by the invention. They are nucleotide sequences that encode an immunogenic polypeptide.

The invention also describes fusion proteins that comprise the first and second polypeptides of the invention or, alternatively, the polypeptide of the invention and a known M. tuberculosis antigen, such as the 38,000 molecular weight antigen described above, or ESAT-6 (SEQ ID NO : 98 and 99). The fusion proteins of the invention may also include a linker peptide between the first and second polypeptides.

The DNA sequence encoding the fusion protein of the invention was constructed using known recombinant techniques to incorporate the separate DNA sequences encoding the first and second polypeptides into a suitable expression vector. The 3' end of the DNA sequence encoding the first polypeptide was ligated with or without a peptide linker to the 5' end of the DNA sequence encoding the second polypeptide so that the reading frames of the sequences are in a phase that allows translation of the mRNA of the two DNA sequences into one fusion • · ·· ····· · · ···· ·· ·· ·· ·· ·· a protein that retains the biological activity of both the first and second polypeptides.

A peptide linker sequence can be used to separate the first and second polypeptides by a distance sufficient for each polypeptide to pack into its secondary and tertiary structure. Such a peptide linker sequence was incorporated into the fusion protein using standard methods well known in the art. Suitable peptide linker sequences can be selected based on the following factors (1) their ability to adopt a flexible extended conformation, (2) their inability to adopt a secondary structure that can interact with functional epitopes on the first and second polypeptides, and (3) the lack of hydrophobic or charged residues , which can react with the functional epitope of the polypeptide.

Preferred peptide linker sequences contain Gly, Asn and Ser residues. Other neutral amino acids such as Thr and Ala can also be used in the linker sequence. Amino acid sequences that can be used as linkers are described in Maratea et al., Gene 40: 39-46, 1985; Murphy et al., Proc. Nati. Acad. Sci. USA 83: 8258-8562, 1986; U.S.

Patent No. 4,935,233 and U.S. Pat. Patent No. 4,751, 180. Linker sequences can consist of one to 50 amino acids. Peptide linker sequences are not necessary if the first and second polypeptides have a non-essential N-terminal amino acid region that can be used to separate the functional domains and serve to prevent spherical hindrance.

The invention provides methods of using the polypeptides described above in the diagnosis of tuberculosis. The mentioned methods are used in the detection of infection by the microorganism M. tuberculosis in biological samples using one or more of the above-mentioned peptides, either alone or in combination. In embodiments of the invention where multiple polypeptides are used, the sample may contain polypeptides other than those described herein, such as the 38,000 molecular weight antigen described in Andersen and Hansen, Infect . Immun. 57: 2481-2488, 1989. The term "biological sample" is any antibody containing sample obtained from a patient. It is preferred that the sample be whole blood, sputum, serum, plasma, saliva, cerebrospinal fluid or urine. More preferably, the sample is blood, serum or plasma and the sample is obtained from the patient or from a blood bank. The polypeptide(s) are used in an assay as described above to determine the presence or absence of antibodies against the polypeptide(s) such antibodies are indicative of mycobacterial antigens, tuberculosis.

In embodiments of the invention where more than one polypeptide is used, it is preferred that the polypeptides are complementary (that is, one component of the polypeptide is used to detect infection in samples where infection cannot be detected by another component of the polypeptide). Complementary polypeptides can generally be identified by using individual polypeptides to evaluate sera samples obtained from a group of patients known to be infected with M. tuberculosis. By determining which samples test positive (as described later in the text) with each polypeptide, a combination of two or more polypeptides can be formed that are able to detect infection in most or all of the samples tested. Such polypeptides are complementary. Approximately 25 to 30% of serum samples from individuals infected with tuberculosis are negative for antibodies against any single protein, such as the 38,000 molecular weight antigen mentioned above. Therefore, complementary polypeptides can be used in combination with the 38,000 molecular weight antigen to increased the sensitivity of the diagnostic test.

The presence of sensitization to indicate

Harlow and Lané, Antibodies: Harbor Laboratory, 1988).

There are a number of assay formats that one skilled in the art can use to detect antibodies in a sample (described in A Laboratory Manual, Cold Spring A preferred embodiment of the invention involves the use of a polypeptide immobilized on a solid support. Antibodies will bind to it and thereby remove it from the sample. then they can detect using a detection reagent that contains a reporter group. Suitable detection reagents include antibodies that bind to the antibody/polypeptide complex and the free polypeptide is labeled with the reporter group (eg, a competitive assay). assay where the antibodies that bind to the polypeptide are labeled with a reporter group and allow the immobilized antigen to bind after incubation of the antigens with the sample.The extent to which the components of the sample inhibit binding of the labeled antibodies to the polypeptide indicates the reactivity of the sample with the immobilized polypeptide.

The solid support can be any solid material well known in the art to which the antigen can attach. The solid support can be the test well of a microtitre plate or a nitrocellulose or other suitable membrane. Alternatively, the solid support may be balls or discs, glass fibers, latex, or a plastic material such as polystyrene or polyvinyl chloride. The solid substrate can also be magnetic particles or a fiber optic sensor as described in U.S. Pat. Patent No. 5,359,681.

Polypeptides can be attached to a solid support using a number of methods known in the art, the use of which is described in the patent and scientific literature. In accordance with the invention, the term "bound" means a non-covalent connection such as adsorption and covalent connection (which may form a direct connection between the antigen and functional groups on a solid support or may be a cross-linking agent). Binding to the well surface of the microtitre plate or to ·

• · • ··

The polypeptide can be coated with a suitable hydroxyl group, for example, to bind to the membrane. In such cases, adsorption is achieved by contacting the polypeptide with a solid support in a suitable buffer for a suitable length of time. Contact time varies with temperature, but is typically between 1 hour and one day. In the general case, when the well of the plastic microtitre plate (polystyrene or polyvinyl chloride) is in contact with the polypeptide, its amount varies from approximately 10 ng to approximately 1 µg. An amount of about 100 ng is preferred, which is sufficient to bind a sufficient amount of antigen.

Covalent attachment of a polypeptide to a solid support can generally be achieved by first reacting the support with a bifunctional reagent that will react with both the support and the functional group on the polypeptide. This group is an amino group.

a support which by polymer coating using benzoquinone or by condensing an aldehyde group on the support with an amine or an active hydrogen present on the polypeptide (see, for example, Pierce Immunotechnology Catalog and Handbook, 1991, A12-A13).

In certain embodiments of the invention, the assay used is an ELISA. This test is performed by first contacting the polypeptide antigen immobilized on a solid support, usually the wells of microtitre plates, with the sample so that the antibodies against the polypeptide in the sample can react with the immobilized polypeptide. The unbound sample is then removed from the immobilized polypeptide and a detection reagent capable of binding to the immobilized antibody-polypeptide complex is added. The amount of detection reagent that remains bound to the solid support is then determined using a method suitable for the specific detection of the reagent.

When the polypeptide is immobilized on a support, as described above, the remaining binding site of the protein is blocked on the support. Any suitable blocking agent known in the art can be used for this purpose, such as bovine serum albumin or Tween 20™ (Sigma Chemical Co., St. Louis, MO). The immobilized polypeptide is then incubated with the sample and the antibodies are allowed to bind to the antigen. Before incubation, the sample can be diluted with a suitable diluent such as phosphate-buffered saline (PBS). A suitable contact time (that is, incubation time) is a period of time that is sufficient to detect the presence of antibodies in a sample infected with the M. tuberculosis microorganism. It is preferred that the contact time be sufficient to achieve a degree of binding that is at least 95% of the degree of binding at equilibrium between bound and unbound antibodies. It is easy for one skilled in the art to recognize that the time necessary to reach equilibrium can simply be determined by testing the degree of binding that occurs over a period of time. In general, 30 minutes at room temperature is sufficient incubation time.

Unbound sample can then be removed by washing the solid support with a suitable buffer such as PBS containing 0.1% Tween 20™. A detection reagent is then applied to the solid support. A suitable detection agent is any antibody-polypeptide complex and this is then detected by any method well known in the art. The detection reagent preferably contains a binding reagent (such as protein A, protein G, immunoglobin, lectin or free antigen) linked to the reporter group. Preferred reporting groups include enzymes (such as horseradish peroxidase), substrates, co-factors, inhibitors, dyes, radionuclides, luminescent moieties, fluorescent moieties and biotin. Conjugation of the binding agent to the reporter group can be achieved using standard methods. Common binding agents can also be coupled to various reporter groups, which come from many commercial sources (eg, Zymed Laboratories, San Francisco, CA and Pierce, Rockford, IL).

• · ······· · ·

9 9 9 99 99 99 99 99

The detection reagent is then incubated with the immobilized antibody-polypeptide complex for a time sufficient to detect bound antibodies. A suitable length of time can be determined according to the manufacturer's instructions or by testing the degree of bonding achieved over a period of time. Unbound detection reagent is removed and bound detection reagent is detected using a reporter group. The method used to detect a reporting group depends on the nature of the reporting group.

In the case of radioactive groups, a scintillation computer and autoradiographic methods are generally suitable. Spectroscopic methods can be used in the detection of dyes, luminescent groups and fluorescent groups. Biotin can be detected using avidin linked to various reporter groups (usually radioactive or fluorescent groups or enzymes). Enzyme reporter groups can be detected by addition of substrate (for a specific time) followed by spectroscopic or other analysis of the reaction products.

In order to determine the presence or absence of antibodies against M. tuberculosis in the sample, the signal detected from the reporter group, which remains bound to the solid support, is compared with the signal corresponding to a predetermined cut-off value. In one preferred embodiment of the invention, the predetermined value is the average signal obtained when the immobilized antigen is incubated with samples from an uninfected patient. A sample that generates a signal that is three standard deviations higher than the predetermined cut-off value is considered positive for the presence of tuberculosis.

In another preferred embodiment, the predetermined cut-off value is determined using a Receiver Operator Curve according to the method described in Sackett et al., Clinical Epidemiology: A Basic Science for Clinical Medicine, Little Brown and Co. , 1985, pp. 106-107.

In this embodiment of the invention, the cut-off value can be determined from a graph plotting the true positive range (that is, sensitivity) and the false positive range (that is, 100% specificity) that corresponds to each possible cut-off value of the diagnostic test result. The cutoff value on the graph that is closest to the upper left-hand corner (that is, the value that encloses the largest area) is the most accurate cutoff value, and a sample generating a signal that is higher than the cutoff value can be considered positive. Otherwise, the cut-off value can be shifted on the graph to the left to minimize the false positive range or to the right to minimize the false negative range. A sample generating a signal that is higher than the cut-off value determined here is considered positive for tuberculosis.

In a similar embodiment of the invention, the assay is performed in a fast flow or strip format assay where the antigen is immobilized on a membrane such as nitrocellulose. In a flow-through assay, antibodies in the sample bind to an immobilized polypeptide as the sample passes through the membrane. A detection reagent (eg, a protein A-colloidal gold complex) is then bound to the antibody-polypeptide complex, with the solution containing the detection reagent passing through the membrane. The detection of the bound detection reagent is then performed in the manner described above in the text. In a strip format assay, one end of the membrane to which the polypeptide is bound is immersed in a solution containing the sample. The sample migrates along the membrane from the region containing the detection reagent and into the region with the immobilized polypeptide. The concentration of the detection reagent on the polypeptides indicates the presence of antibodies against the microorganism M. tuberculosis in the sample. The concentration of the detection agent at the specified location generates a visible pattern such as a line. The absence of such a pattern indicates a negative result. The amount of polypeptide immobilized on the membrane, which is sufficient to form a visually recognizable pattern, in the event that the sample contains an amount of antibodies that is • · sufficient to generate a positive signal in the ELISA test, as described above in the text, is determined. It is preferred that the amount of polypeptide immobilized on the membrane is between about 25 ng and about 1 µg, more preferably between about 50 ng and about 500 ng. Such tests can typically be performed with a very small amount (for example, one drop) of the patient's serum or blood.

Of course, there are a number of other protocols that are suitable for using the polypeptides of the invention.

Furthermore, the invention describes antibodies against polypeptides according to the invention. Antibodies can be prepared by any of a number of methods known in the art. These methods are described in Harlow and Lané, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, 1988. In such a method, an immunogen comprising an antigenic polypeptide is introduced by injection into any of a number of mammals (eg, mouse, rat, rabbit, sheep, and goat). . In this step, the polypeptides of the invention can serve as an immunogen without being modified. In another case, particularly in the case of relatively short polypeptides, a strong immune response is achieved if the polypeptide is linked to a carrier protein such as bovine serum albumin or cone hemocyanin. The immunogen is introduced by injection into the animal host. It is preferable to establish a schedule in advance that includes one or more doses of immunization. Blood is taken from the animals at regular intervals. Polyclonal antibodies that are specific for the polypeptide can then be isolated from the antisera by, for example, affinity chromatography using the polypeptides coupled to a suitable solid support. Monoclonal antibodies that are specific for an antigenic polypeptide can be prepared, for example, using the method described in Kohler and Milstein, Eur. J. Immunol. 6: 511-519, 1976. These methods involve the preparation of cell lines capable of producing antibodies exhibiting the desired specificity (that is, reactivity with the polypeptide. Such cell lines are · ·· ·· ·· ·· ·· can produce, for example, spleen cells from animals that have been immunized as described above.The spleen cells are then immortalized, for example, by fusion with a myeloma cell fusion partner, preferably one that is syngeneic with the immunized animal. A number of fusion methods can be used. For example, spleen and myeloma cells can be combined for a few minutes with a nonionic detergent and then plated at a low density with selective medium that promotes the growth of hybrid cells but not myeloma cells .Preferred selection methods use HAT (hypoxanthine, thymidine) selection. After a sufficient time, usually about one to two weeks, hybrids are selected and their binding activity against the polypeptide is tested. Hybridomas with high reactivity and specificity are preferred.

Growing hybridoma colonies are isolated from the supernatants. Various methods can be used to increase the yield, such as introducing the hybridoma cell line by injection into the peritoneal cavity of a suitable vertebrate, such as a mouse. Monoclonal antibodies can then be harvested from ascites fluid or blood. Contaminants can be removed from antibodies using common methods such as chromatography, gel filtration, precipitation and extraction. The polypeptides of the invention can be used in a purification process such as affinity chromatography.

The antibodies can be used in diagnostic tests to detect the presence of M. tuberculosis antigens using tests similar to those described in more detail above and other methods known in the art, thereby providing methods for detecting infection of a patient with M. tuberculosis.

Diagnostic reagents according to the invention may also contain DNA sequences encoding one or more of the above-described polypeptides or one or more of their parts. During the test

Q Λ ···· ···

Z4 ··· · ···· ι«· · ·· based, on the polymerase chain reaction (PCR), at least two oligonucleotide primers can be used to amplify the cDNA of the M. tuberculosis microorganism obtained from a biological sample, with at least one of the oligonucleotide primers is specific for the DNA molecule encoding the polypeptide according to the invention. The presence of the amplified cDNA is then detected using methods well known in the art, such as gel electrophoresis. In a similar case, oligonucleotide probes that are specific for a DNA molecule encoding a polypeptide according to the invention can be used in hybridization in order to detect the presence of a polypeptide according to the invention in a biological sample.

The term "oligonucleotide primer/probe specific for a DNA molecule" means an oligonucleotide sequence that exhibits at least about 80%, preferably at least about 90%, and most preferably at least about 95% identity to the DNA molecule of interest. Oligonucleotide primers/or probes that can be used in the diagnostic methods of the invention preferably have at least about 10 to 40 nucleotides. In a preferred embodiment, the oligonucleotide primers contain at least about 10 consecutive nucleotides of a DNA molecule encoding one of the polypeptides described herein. It is preferred that the oligonucleotide probes used in the diagnostic methods of the invention contain at least approximately 15 consecutive oligonucleotides of a DNA molecule encoding one of the nucleotides described herein. Hybridization and PCR-based assay methods are well known in the art (eg, Mullis et al., Ibid; Ehrlich, Ibid.). Primers or probes can also be used to detect sequences specific for M. tuberculosis in a biological sample. DNA probes or primers that contain the oligonucleotide sequences described herein can be used alone, in combination with other sequences, or with previously antigen o toto·· » · * · · · · ··· to · ··« · to · to • • ••••to to to ···· ·· ·· · * to · ·· by defined sequences, such as molecular weight 38,000.

is listed here

Overview of images on the drawing

Figure 1A and B show proliferation stimulation of interferon-γ production in T cells obtained from first and second M. tuberculosis immune donors using antigens of molecular weight 14,000, 20,000 and 26,000 as described in Example 1.

Figures 2A to D show the reactivity of antiserum against secretory proteins of M. tuberculosis , known M. tuberculosis 85b antigens and Tb38-1 and TbH-9 antigens with M. tuberculosis lysate (lane 2), with secretory proteins (lane 3), with recombinant Tb38-1 (lane 4), recombinant TbH-9 (lane 5) and recombinant 85b (lane 5).

Figure 3A shows stimulation of proliferation in TbH-9-specific T cell clones by M. tuberculosis secretory proteins, recombinant TbH-9 and control antigen TbRall.

Figure 3B shows stimulation of interferon-γ production in a TbH-9-specific T cell clone by M. tuberculosis secretory proteins, PPD, and recombinant TbH-9.

Figure 4 shows the reactivity of two representative polypeptides with serum from infected and uninfected individuals with M. tuberculosis compared to the reactivity of the bacterial lysate.

Figure 5 shows the reactivity of four representative polypeptides with serum from infected and uninfected individuals compared to the reactivity of antigens of molecular weight 38,000.

Figure 6 shows the reactivity of the 38,000 molecular weight natigen and TbRall antigens with serum from patients • ·

4 infected with the microorganism M. tuberculosis, donors positive for PPD and normal donors.

Figure 7 shows the reactivity of TbRa2A antigen with 38,000 molecular weight antigen negative serum.

Figure 8 shows the reactivity of SEQ ID NO: 60 antigen with serum from patients infected with M. tuberculosis and normal donors.

Figure 9 shows the reactivity of recombinant antigen TbH-29 (SEQ ID NO: 137) with serum from M. tuberculosis infected patients, PPD positive donors and normal donors as determined by indirect ELISA.

Figure No. 10 shows the reactivity of the recombinant antigen TbH-33 (SEQ ID NO: 140) with the serum of patients infected with the microorganism M. tuberculosis with the serum of infected patients determined by direct and indirect ELISA.

Figure 11 shows the reactivity of increasing concentrations of recombinant antigen TbH-33 (SEQ ID NO: 140) with serum from patients infected with M. tuberculosis and from normal donors, as determined by ELISA.

and from normal donors and with M. tuberculosis, as se

List of sequences: SEQ id NO: 1 Yippee sequence DNA TbRal SEQ id NO: 2 Yippee sequence DNA TbRalO. SEQ id NO: 3 Yippee sequence DNA TbRal1. SEQ id NO: 4 Yippee sequence DNA TbRal2. SEQ id NO: 5 Yippee sequence DNA TbRal3 SEQ id NO: 6 Yippee sequence DNA TbRal6 SEQ id NO: 7 Yippee sequence DNA TbRal7 SEQ id NO: 8 Yippee sequence DNA TbRal8 SEQ id NO: 9 Yippee sequence DNA TbRal9 SEQ id NO: 10 Yippee sequence TbRα24 DNA SEQ id NO: 11 Yippee sequence TbRα26 DNA SEQ id NO: 12 Yippee sequence TbRα28 DNA

• · • ·· • 9 • ··«

9 9 9 9 9 9 9 ·

Φ · · φ 9 9 99 9 9 9 9 9 9

SEQ id NO: 13 Yippee sequence DNA TbRa29 SEQ id NO: 14 Yippee sequence DNA TbRa2A SEQ id NO: 15 Yippee sequence DNA TbRa3 SEQ id NO: 16 Yippee sequence DNA TbRa32 SEQ id NO: 17 Yippee sequence DNA TbRa35 SEQ id NO: 18 Yippee sequence DNA TbRa36 SEQ id NO: 19 Yippee sequence DNA TbRa4 SEQ id NO: 20 Yippee sequence DNA TbRa9 SEQ id NO: 21 Yippee sequence DNA TbRaB SEQ id NO: 22 Yippee sequence DNA TbRaC SEQ id NO: 23 Yippee sequence DNA TbRaD SEQ id NO: 24 Yippee sequence DNA YYWCPG SEQ id NO: 25 Yippee sequence DNA AAMK SEQ id NO: 26 Yippee sequence DNA TbL-23 SEQ id NO: 27 Yippee sequence DNA TbL-24 SEQ id NO: 28 Yippee sequence DNA TbL-25 SEQ id NO: 29 Yippee sequence DNA TbL-28 SEQ id NO: 30 Yippee sequence DNA TbL-29 SEQ id NO: 31 Yippee sequence DNA TbH-5 SEQ id NO: 32 Yippee sequence DNA TbH-8 SEQ id NO: 33 Yippee sequence DNA TbH-9 SEQ id NO: 34 Yippee sequence DNA TbM-1 SEQ id NO: 35 Yippee sequence DNA TbM-3 SEQ id NO: 36 Yippee sequence DNA TbM-6 SEQ id NO: 37 Yippee sequence DNA TbM-7 SEQ id NO: 38 Yippee sequence DNA TbM-9 SEQ id NO: 39 Yippee sequence DNA TbM-12 SEQ id NO: 40 Yippee sequence DNA TbM-13 SEQ id NO: 41 Yippee sequence DNA TbM-14 SEQ id NO: 42 Yippee sequence DNA TbM-15 SEQ id NO: 43 Yippee sequence DNA TbH-4 SEQ id NO: 44 Yippee sequence DNA TbH-4-FWD. SEQ id NO: 45 Yippee sequence DNA TbH-12 SEQ id NO: 46 Yippee sequence DNA Tb38-1

28 9 9 9 9 9 99 9 9 9 9999 99 « 9 9 99999 9 9 4 9 99 99 • 9 • · · · and · ·· ·· SEQ ID NO: 47 is the DNA sequence of Tb38-4 SEQ ID NO: 48 is the DNA sequence of TbL-17 SEQ ID NO: 49 is the DNA sequence of TbL-20 SEQ ID NO: 50 is the DNA sequence of TbL-21 SEQ ID NO: 51 is the DNA sequence of TbH-16 SEQ ID NO: 52 is the DNA sequence of DPEP SEQ ID NO: 53 is the deduced amino acid sequence of DPEP SEQ ID NO: 54 is protein sequence DPV N-terminal antigens SEQ ID NO: 55 is protein sequence AVGS N-terminal antigens SEQ ID NO: 56 is protein sequence AAMK N-terminal antigens SEQ ID NO: 57 is protein sequence YYWC N-terminal antigens SEQ ID NO: 58 is protein sequence DIGS N-terminal antigens SEQ ID NO: 59 is protein sequence AEES N-terminal antigens SEQ ID NO: 60 is protein sequence DPEP N-terminal antigens SEQ ID NO: 61 is protein sequence APKT N-terminal antigens SEQ ID NO: 62 is protein sequence DPAS N-terminal

antigens

SEQ ID NO: 63 is the deduced amino acid sequence of the peptides

TbM-1

SEQ id NO: 64 Yippee deduced amino acid sequence TbRal SEQ id NO: 65 Yippee deduced amino acid sequence TbRalO SEQ id NO: 66 Yippee deduced amino acid sequence TbRall SEQ id NO: 67 Yippee deduced amino acid sequence TbRal2 SEQ id NO: 68 Yippee deduced amino acid sequence TbRal3 SEQ id NO: 69 Yippee deduced amino acid sequence TbRal6 SEQ id NO: 70 Yippee deduced amino acid sequence TbRal7

······· · · ···« ·· ·· ·· ·· ··

SEQ id NO: 71 Yippee deduced amino acid sequence TbRal8 SEQ id NO: 72 Yippee deduced amino acid sequence TbRal9 SEQ id NO: 73 Yippee deduced amino acid sequence TbRa24 SEQ id NO: 74 Yippee deduced amino acid sequence TbRa26 SEQ id NO: 75 Yippee deduced amino acid sequence TbRa28 SEQ id NO: 76 Yippee deduced amino acid sequence TbRa29 SEQ id NO: 77 Yippee deduced amino acid sequence TbRa2A SEQ id NO: 78 Yippee deduced amino acid sequence TbRa3 SEQ id NO: 79 Yippee deduced amino acid sequence TbRa32 SEQ id NO: 80 Yippee deduced amino acid sequence TbRa35 SEQ id NO: 81 Yippee deduced amino acid sequence TbRa36 SEQ id NO: 82 Yippee deduced amino acid sequence TbRa4 SEQ id NO: 83 Yippee deduced amino acid sequence TbRa9 SEQ id NO: 84 Yippee deduced amino acid sequence TbRaB SEQ id NO: 85 Yippee deduced amino acid sequence TbRaC SEQ id NO: 86 Yippee deduced amino acid sequence TbRaD SEQ id NO: 87 Yippee deduced amino acid sequence YYWCPG SEQ id NO: 88 Yippee deduced amino acid sequence TbAAMK SEQ id NO: 89 Yippee deduced amino acid sequence Tb38-1 SEQ id NO: 90 Yippee deduced amino acid sequence TbH-4 SEQ id NO: 91 Yippee deduced amino acid sequence TbH-8 SEQ id NO: 92 Yippee deduced amino acid sequence TbH-9 SEQ id NO: 93 Yippee deduced amino acid sequence TbH-12 SEQ id NO: 94 Yippee DPAS DNA sequence SEQ id NO: 95 Yippee deduced amino acid sequence DPAS SEQ id NO: 96 Yippee DPV DNA sequence SEQ id NO: 97 Yippee deduced amino acid sequence DPV SEQ id NO: 98 Yippee DNA sequence of ESAT-6 SEQ id NO: 99 Yippee deduced amino acid sequence EASAT-6 SEQ id NO: 100 is a sequence TbH-8-2 DNA SEQ id NO: 101 is a sequence TbH-9FL DNA SEQ id NO: 102 is the deduced amino acid sequence of TbH-9FL SEQ id NO: 103 is a sequence TbH-9-1 DNA SEQ id NO: 104 is the deduced amino acid sequence of TbH-9-1

• · · • · · · • · ···· ·· ·· ·· ·· ··

SEQ id NO: 105 is TbH-9-4 DNA sequence SEQ id NO: 106 is deduced amino acid sequence of TbH-9-4 SEQ id NO: 107 is Tb38-1F2IN DNA sequence SEQ id NO: 108 is TbH-lF2 RP DNA sequence SEQ id NO: 109 is deduced amino acid sequence of Tb37-FL SEQ id NO: 110 is deduced amino acid sequence of Tb38-IN SEQ id NO: 111 is Tb38-1F3 DNA sequence SEQ id NO: 112 is deduced amino acid sequence of Tb38-1F3 SEQ id NO: 113 is Tb38-1F5 DNA sequence SEQ id NO: 114 is Tb38-1F6 DNA sequence SEQ ID NO : 115 is the deduced N-terminal amino acid

DPV sequence

SEQ id NO: 116 Yippee deduced N-terminal amino acid sequence AVGS SEQ id NO: 117 Yippee deduced N-terminal amino acid sequence AAMK SEQ id NO: 118 Yippee deduced N-terminal amino acid sequence YYWC SEQ id NO: 119 Yippee deduced N-terminal amino acid sequence DIGS SEQ ID NO: 120 Yippee deduced N-terminal amino acid sequence AAES SEQ id NO: 121 Yippee deduced N-terminal amino acid sequence DPEP SEQ id NO: 122 Yippee deduced N-terminal amino acid sequence APKT SEQ id NO: 123 Yippee deduced N-terminal amino acid sequence DPAS SEQ ID NO: 124 Yippee protein DPPD sequence N-terminal

antigen

SEQ ID NO: 125-128 are the protein sequences of the four DPPD cyanogen bromide fragments

SEQ ID NO: 129 is the N-terminal protein sequence of the XDS antigen ···· ··· ···· • · · · ···· · ·· · ······ · ·

00·· 00 00 00 00 00

SEQ Appliances id NO: 130 is the N-terminal protein sequence of the antigen SEQ APE id NO: 131 is the N-terminal protein sequence of the antigen SEQ XYI id NO: 132 is the N-terminal protein sequence of the antigen SEQ id NO: 133 is the DNA sequence of the TbH-29 antigen SEQ id NO: 134 is the DNA sequence of the TbH-30 antigen SEQ id NO: 135 is the DNA sequence of the TbH-32 antigen SEQ id NO: 136 is the TbH-33 antigen DNA sequence SEQ 29 id NO: 137 is the predicted amino acid sequence of TbH- SEQ 30 id NO: 138 is the predicted amino acid sequence of TbH- SEQ 32 id NO: 139 is the predicted amino acid sequence of TbH- SEQ 33 id NO: 140 is the predicted amino acid sequence of TbH- SEQ id NO: 141-146 are the PCR primers used in the preparation

of a fusion protein containing TbRα3, a protein of molecular weight 38,000 and Tb38-1.

SEQ ID NO: 147 is the DNA sequence of a fusion protein comprising

TbRα3, a protein with a molecular weight of 38,000 and Tb38-1

SEQ ID NO: 148 is the amino acid sequence of a fusion protein comprising TbRα3, a 38,000 protein, and Tb38-1

SEQ ID NO: 149 is the DNA sequence of the antigen of the microorganism M.

tuberculosis with a molecular weight of 38,000

SEQ ID NO: 150 is the amino acid sequence of the M. tuberculosis antigen with a molecular weight of 38,000

SEQ ID NO: 151 Yippee XP14 DNA sequence SEQ ID NO: 152 Yippee XP24 DNA sequence SEQ ID NO: 153 Yippee XP31 DNA sequence SEQ ID NO: 154 Yippee 5' DNA sequence of XP32 SEQ ID NO: 155 Yippee 3' DNA sequence of XP32

• · ·

SEQ ID NO: 156 is the predicted amino acid sequence of XP14 SEQ ID NO: 157 is the predicted amino acid sequence encoded by the reverse complement of XP14

SEQ ID NO: 158 is XP27 DNA sequence SEQ ID NO: 159 is XP36 DNA sequence SEQ ID NO: 160 is 5' DNA sequence of XP4 SEQ ID NO: 161 is 5' DNA sequence of XP5 SEQ ID NO: 162 is 5' DNA sequence of XP17 SEQ ID NO: 163 is 5' DNA sequence of XP30 SEQ ID NO: 164 is 5' DNA sequence of XP2 SEQ ID NO: 165 is 3' DNA sequence of XP2 SEQ ID NO: 166 is 5' DNA sequence of XP3 SEQ ID NO: 167 is 3' DNA sequence of XP3 SEQ ID NO: 168 is 5' DNA sequence of XP6 SEQ ID NO: 169 is 3' DNA sequence of XP6 SEQ ID NO: 170 is 5' DNA sequence of XP18 SEQ ID NO: 171 is 3' DNA sequence of XP18 SEQ ID NO: 172 is 5' DNA sequence of XP19 SEQ ID NO: 173 is 3' DNA sequence of XP19 SEQ ID NO: 174 is 5' DNA sequence of XP22 SEQ ID NO: 175 is 3' DNA sequence of XP22 SEQ ID NO: 176 is 5' DNA sequence of XP25 SEQ ID NO: 177 is 3' DNA sequence of XP25 SEQ ID NO: 178 is Full-length DNA sequence of TbH4-XP1 SEQ ID NO: 179 is predicted amino acid sequence of TbH4-

XP1

SEQ ID NO: 180 is the predicted amino acid sequence encoded by the TbH4-XP1 reverse complement

SEQ ID NO: 181 is the first predicted amino acid sequence encoded by XP36

SEQ ID NO: 182 is the second predicted amino acid sequence encoded by XP36

SEQ ID NO: 183 is the predicted amino acid sequence encoded by the XP36 reverse complement

O O · ·· · · ·· J J · · · · ···· • · · ♦ · · • · · · • · · · • · · SEQ id NO: 184 Yippee ···· · · · · ·· DNA sequence of RDIF2 • « · · SEQ id NO: 185 Yippee DNA sequence of RDIF5 SEQ id NO: 186 Yippee DNA sequence of RDIF8 SEQ id NO: 187 Yippee DNA sequence of RDIF10 SEQ id NO: 188 Yippee DNA sequence of RDIF11 SEQ id NO: 189 Yippee predicted amino acid sequence RDIF2 SEQ id NO: 190 Yippee predicted amino acid sequence RDIF5 SEQ id NO: 191 Yippee predicted amino acid sequence RDIF8

SEQ ID NO: 192 is the predicted amino acid sequence

RDIF10

SEQ ID NO: 193 is the predicted amino acid sequence

RDIF11

SEQ ID NO: 194 is the 5' DNA sequence of RDIF12

SEQ ID NO: 195 is the 3' DNA sequence of RDIF12

SEQ ID NO: 196 is the DNA sequence of RDIF7

SEQ ID NO: 197 is the predicted amino acid sequence of RDIF7 SEQ ID NO: 198 is the DNA sequence of DIF2-1

SEQ ID NO: 199 is the predicted amino acid sequence

RDIF2-1

SEQ ID NO: 200-207 are the PCR primers used in the preparation of a fusion protein containing TbRα3, a protein of molecular weight 38,000, Tb38-1 and DPEP (referred to here as TbF-2)

SEQ ID NO: 208 is the DNA sequence of the TbF-2 fusion protein

SEQ ID NO: 209 is the amino acid sequence of the TbF-2 fusion protein

Examples of embodiments of the invention

Example 1: Isolation of polypeptides from the culture filtrate of the microorganism M. tuberculosis and their characterization.

The example illustrates the preparation of soluble polypeptides of the microorganism M, tuberculosis from culture filtrate. Unless stated otherwise in the text, all percentage values are expressed as weight/volume percentages.

M. tuberculosis (either H37Ra, ATCC No. 25177 or H37Rv, ATCC No. 25618) was cultured in sterile GAS medium at 37°C for 14 days. The medium was then filtered through a 0.45 μ pore size filter by vacuum filtration (to capture the bulk of the cells) into a sterile 2.5 L container. The medium was then filtered through a 0.2 μ pore size filter into a sterile bottle with volume 4 1. Then NaN3 with a concentration of 0.04% was added to the culture filtrate. The bottles were then placed in a refrigerated room where the temperature is 4°C.

The culture filtrate was concentrated by placing it in a 12 L reservoir, autoclaving it, and loading it into a 400 ml Amicon stirred cell that had been washed with ethanol and which included a 10,000,000 MWCO membrane. The pressure was maintained at 0.42 MPa using nitrogen gas. This procedure reduces the volume from 12 L to approximately 50 mL.

The culture filtrate was then dialyzed into 0.1% ammonium bicarbonate using an 8,000,000 MWCO cellulose ester membrane, exchanging the ammonium bicarbonate solution twice. Protein concentration was then determined by a commercially available BCA assay (Pierce, Rockford, IL).

The dialyzed culture filtrate was then lyophilized and the polypeptides resuspended in distilled water. The polypeptides were then dialyzed against 0.01 mM 1,3-bis[tris(hydroxymethyl)methylamino]propane, pH 7.5 (Bis-Tris propane buffer), the starting conditions for ion exchange chromatography. Fractionation was performed using gel perfusion chromatography on a 4.6 mm x 100 mm POROS 146 II Q/M ion exchange column (Perseptive BioSystems, Framigham, MA) equilibrated with 0.01 mM Bis-Tris propane buffer pH 7.5 . Polypeptides were eluted with a linear gradient of 0 to 0.5 M NaCl in the above buffer system. The eluent was monitored at a wavelength of 220 nm.

• 9 • · • · ··«···· · « • · · · · *» 19 9 9 9 9 9 9

Polypeptides eluted from the ion exchange column were dialyzed against distilled water and lyophilized. The resulting material was dissolved in a solution of 0.1% trifluoroacetic acid (TFA) pH 1.9 in water, and the polypeptides were purified on a Delta-Pak C18 column (Waters, Milford, MA), 300 angstrom pore size, 5 micron particle size (3 .9 x 150mm). Polypeptides were eluted from the column with a linear gradient of 0 to 60% dilution buffer (0.1% TFA in acetonitrile). The flow rate was 0.75 mL/min and the HPLC eluent was monitored at a wavelength of 214 nm. Fractions containing eluted polypeptides were collected until the maximum purity of the individual samples was achieved. Approximately 200 purified polypeptides were obtained.

The isolated polypeptides were then tested for their ability to induce T-cell proliferation in the preparation of PBMC. PBMCs from donors known to have a positive PPD skin test and whose T cells proliferate in response to PPD and crude soluble proteins from MTB were cultured in medium containing RPMI 1640 supplemented with 10% pooled human serum and gentamicin o concentration of 50 µg/ml. The same isolated polypeptides at a concentration of 0.5 to 10 µg/ml were added to the two cultivation cultures. After six days of culture in 96-well round-bottom plates, 200 µl and 50 µl of medium were removed from each well for IFN-γ quantification as described below. Plates were then exposed to 1 µCi/well of tritiated thymidine for an additional 18 hours, cells were collected, and the degree of tritium uptake was determined using a gas scintillation counter. A fraction where the proliferations of both replicates are three times higher than the proliferation observed in cells cultured in medium alone is considered positive.

IFN-γ was measured using an ELISA assay. ELISA plates were coated with mouse monoclonal antibodies against human IFN-γ (Chemicon) in PBS for four hours at room temperature. The wells were then blocked with PBS containing 5% • · • ·

(weight/volume) of nonfat dry milk, for 1 hour at room temperature. Then the plates were washed six times with PBS solution with 0.2% TWEEN-20 and samples were diluted 1:2 with culture medium on the ELISA plates and incubated overnight at room temperature. Plates were washed again and polyclonal rabbit anti-human IFN-γ serum diluted 1:3,000 in PBS/10% normal goat serum was added to each well. Plates were then incubated for two hours at room temperature, washed, and horseradish peroxidase conjugated to anti-rabbit IgG (Jackson Labs.) was added at a 1:2,000 dilution in PBS/5% nonfat dry milk. After an additional two hours of incubation at room temperature, the plates were washed and TMB substrate was added. The reaction was stopped after 20 minutes with 1N sulfuric acid. The optical density was determined at a wavelength of 450 nm, with a wavelength of 570 nm used as a reference wavelength. Fractions that show twice the OD compared to the mean OD value from cells cultured in medium alone plus three standard deviations are considered positive.

For sequencing, polypeptides were individually dried on treated Biobrene™ glass fiber filters (Perkin Elmer/Applied BioSystems Division, Foster City, CA). Polypeptide filters were loaded onto a Perkin Elmer/Applied BioSystems Division Process 492 protein sequencer. Polypeptides were sequenced from the N-terminus using traditional Edman chemistry. By comparing the retention time of the PTH amino acid derivative with appropriate PTH derivative standards, the amino acid sequence for each polypeptide was determined.

Using the procedure described above, antigens were isolated that exhibit the following N-terminal sequences:

(a) Asp-Pro-Val-Asp-Ala-Val-Ile-Asn-Thr-Thr-Xaa-Asn-TyrGly-Gln-Val-Val-Ala-Ala-Leu (SEQ ID NO: 54) (b) Ala-Val-Glu-Ser-Gly-Met-Leu-Ala-Leu-Ala-Leu-Gly-Thr-ProAla-Pro-Ser (SEQ ID NO: 55) • · • · ·»····· · · • · · · ·· ·> · · · · ·· (c) Ala-Ala-Met-Lys-Pro-Arg-Thr-Gly-Asp-Gly-Pro-Leu-Giu-AlaAla-Lys-Glu- Gly-Arg (SEQ ID NO: 56) (d) Tyr-Tyr-Trp-Cys-Por-Gly-Gln-Pro-Phe-Asp-Pro-Ala-Trp-GlyPro (SEQ ID NO: 57) (e) Asp-Ile-Gly-Ser-Glu-Ser-Thr-Glu-Asp-Gln-Gln-Xaa-Ala-Val (SEQ ID NO: 58) (f) Ala-Glu-Glu-Ser-Ile-Ser-Thr -Xaa-Glu-Xaa-Ile-Val-Pro (SEQ ID NO: 59) (g) Asp-Pro-Glu-Pro-Ala-Pro-Pro-Val-Pro-Thr-Ala-Ala-Ala-AlaPro- Pro-Ala (SEQ ID NO: 60) and (h) Ala-Pro-Lys-Thr-Tyr-Xaa-Glu-Glu-Leu-Lys-Gly-Thr-Asp-ThrGly (SEQ ID NO: 61) where Xaa can be any amino acid.

Another antigen was isolated in addition to the method described above using a microbore HPLC isolation step. A 20 μl fraction containing the mixture of antigens from the chromatographic purification step described above was purified on an Aquapore C18 column (Perkin Elmer/Applied Biosystems Division, FosterCity, CA) with a pore size of 7 microns and a column size of 1 mm x 100 mm (Perkin Elmer/Applied Biosystems Biosystems Division Model 172. Fractions were eluted from the column with a linear gradient of 1%/min acetonitrile (containing 0.05% TFA) at a flow rate of 80 µl/min. The eluent was monitored at a wavelength of 250 nm. The original fraction was separated into four major folds plus other minor components, yielding a polypeptide with a molecular weight of 12,054 (as determined by mass spectrometry) and the following N-terminal sequence:

(i) Asp-Pro-Ala-Ser-Ala-Pro-Asp-Val-Pro-Thr-Ala-Ala-Gln-GlnThr-Ser-Leu-Leu-Asn-Asn-Leu-Ala-Asp-Pro-Asp -Val-Ser-PheAla-Asp (SEQ ID NO: 62)

This polypeptide is able to induce proliferation and IFN-γ production in PBMC preparation.

0 0 · ··· ···· • 00 · · · · · · ·· 0 * · · · 0 · · · · 000 000

000««·· 0 0

00 00 0 00 00

Other soluble antigens were isolated from the culture filtrate of M. tuberculosis as follows. The culture filtrate of the microorganism M. tuberculosis was prepared by the method described above in the text. Dialysis was performed against Bis-Tris propane buffer at pH 5.5. Fractionation was performed using anion exchange chromatography on a 4.6 x 100 mm Poros QE column (Perseptive Biosystems) equilibrated with Bis-Tris propane buffer pH 5.5. Polypeptides were eluted with a linear gradient of 0 to 1.5 M NaCl in the system described above at a flow rate of 10 mL/min. The column eluent was monitored at a wavelength of 214 nm.

Fractions eluted from the ion exchange column were collected and subjected to reverse phase chromatography using a 4.6 x 100 mm Poros R2 column (Perseptive Biosystems). Polypeptides were eluted from the column with a linear gradient of 0 to 100% acetonitrile (0.1% TFA) at a flow rate of 5 ml/min.

The eluent was monitored at a wavelength of 214 nm.

Fractions containing eluted polypeptides were lyophilized and resuspended in 80 μl of aqueous 0.1% TFA and subjected to reverse-phase chromatography on a 4.6 x 150 mm Vydac C4 column (Western Analytical, Temecula, CA) with by a linear gradient of 0 to 100% acetonitrile (0.1% TFA) at a flow rate of 2 mL/min. The eluent was monitored at a wavelength of 214 nm.

Fractions with biological activity separated into one major peak plus other minor components. Western blotting of this peak onto a PVDF membrane showed three major bands with molecular weights of 14,000, 20,000, and 26,000. These polypeptides were determined to have the following N-terminal sequences:

(j) Xaa-Asp-Ser-Glu-Lys-Ser-Ala-Thr-Ile-Lys-Val-Thr-Asp-AlaSer (SEQ ID NO: 129) (k) Ala-Gly-Asp-Thr-Xaa- Ile-Tyr-Ile-Val-Gly-Asn-Leu-Thr-AlaAsp (SEQ ID NO: 130) and « · · « : μ.

tuberculosis labeled with ³² P, (1) Ala-Por-Glu-Ser-Gly-Ala-Gly-Leu-Gly-Gly-Thr-Val-Gln-AlaGlu (SEQ ID NO: 131), where Xaa can be any amino acid.

Using the assays described herein, said polypeptides were shown to induce proliferation and IFN-γ production in PBMC preparations. Figure IA and B show the results of such assays using PBMC preparations from the first and second donors.

By testing the genomic library of the microorganism M.

using degenerate oligonucleotides that correspond to the N-terminal sequence and contain a codon deviation of the M. tuberculosis microorganism, DNA sequences were obtained that encode the antigens designated as (a), (c), (d) and (g). Testing was performed using the antigen-matching probe (a), identifying a clone exhibiting the sequence of SEQ ID NO: 96. The polypeptide encoded by the sequence of SEQ ID NO: 96 is contained in the sequence of SEQ ID NO: 97. Testing was performed using the antigen-matching probe (g), identifying a clone exhibiting the sequence SEQ ID NO: 52. The polypeptide encoded by the sequence SEQ ID NO: 52 is contained in the sequence SEQ ID NO: 53. Testing was performed using a probe corresponding to the antigens (d), identifying a clone showing the sequence of SEQ ID NO: 24 and further testing of the corresponding antigens (c) was carried out, showing the sequence of SEQ ID NO: 25.

The above amino acid sequences were compared to known amino acid sequences in the gene bank using the DNA STAR system. The database contains 173,000 proteins and is a combination of the Swiss and PIR protein sequence databases (antigen sequence versions (a) to (h) of substantial homology.

The amino acid sequence of the antigens (i) was found to be homologous to the sequence of the microorganism M. laprae. Sequences using the probe were identified by the clone together with the translated 87). No «··« · · · ···· ··· · ···· · ·· · ·· ··· ·· ·· ··· ··· ··· ··· ··· ··· ·········································································································································· ·*·· · · •··· ·· ·· «· ·· ·· microorganism M.laprae from genomic DNA using GENBANK. This sequence from the microorganism M library of the homologue of the microorganism M.

NO: 94).

amplified the full-length sequence obtained was then used in tuberculosis testing and a full-length copy of tuberculosis was obtained (SEQ ID

The amino acid sequence of the antigens (j) was found to be homologous to the known M. tuberculosis protein translated from the DNA sequence. To the best of the inventor's knowledge, this protein was not previously known to exhibit T-cell stimulatory activity. The amino acid sequence of the antigens (k) was found to be related to the sequence from the microorganism M. leprae.

The results of proliferation and IFN-γ assays for the three representative antigens listed above using three PPD positive donors are shown in Table 1:

Table No. 1: Results of PMBC proliferation and IFN-γ assays

Sequence proliferation IFN-γ (and) + - (C) +++ +++ (d) ++ + + (G) +++ +++ (h) + + + +++

The table indicates responses that give a stimulation index (SI) between 2 and 4 (compared to cells cultured in medium alone) as +, SI between 4 to 8, or 2 to 4 at a concentration of 1 µg or less are denoted as ++ and SI greater than 8 is denoted as +++. Antigen with sequence (i) was found to show high SI (+++) for one donor and lower SI (++ and +) for two other donors in proliferation and assays *

··· · * · Μ t · · • · · · · · · t · * ·

9 9 9 9 · < · · W · · · ·

9 9 9 9 9 9 9

9 99 9 9 · 9 9 9 9 9

IFN-γ. These results indicate that these antigens are capable of inducing proliferation and/or interferon γ production.

Example 2: Use of patient serum for isolation of M. tuberculosis antigens

This example illustrates the isolation of antigens from a lysate of M. tuberculosis by testing the serum of individuals infected with M. tuberculosis.

H37Ra labeled M. tuberculosis (Difco Laboratories) was added to a 2% NP40 solution. In another case, it was homogenized and sonicated three times. The resulting suspension was centrifuged at 13,000 rpm. in microcentrifuge tubes and the supernatant was passed through a 0.2 micron pore size syringe filter. The filtrate was bound to Macro Prep DEAE beads (BioRad, Hercules, CA). Beads were washed extensively with 20 mM Tris pH 7.5 and bound proteins were eluted with 1M NaCl. The NaCl eluate was dialyzed overnight against 10 mM Tris pH 7.5. The dialysate was treated with DNase and RNase at a concentration of 0.05 mg/ml for 30 minutes at room temperature and then with α-D-aminasidase at a concentration of 0.5 units/mg at pH 4.5 for 3 to 4 hours at room temperature. After the pH returned to 7.5, the material was fractionated via FPLC using a Bio Scale-Q-20 column (BioRad). Fractions were combined into nine pools, concentrated in a Centriprep 10 (Amicon, Beverly, MA) and assayed for serological activity by Western blotting using sera from patients infected with M. tuberculosis that was not immunoreactive with other antigens of the invention.

The most reactive fraction was subjected to SDS-PAGE and transferred to PVDF. A band of approximately 85,000 molecular weight excised, resulting in the sequence:

(m) Xaa-Tyr-Ile-Ala-Tyr-Xaa-Thr-Thr-Ala-Gly-Ile-Val-Pro-GlyLys-Ile-Asn-Val-His-Leu-Val (SEQ ID NO: 132) where Xaa can be any amino acid.

• φ · · · « ;·= Μ» of protein antigens in a total volume of 2 ml, which contains 100 μg of muramyl dipeptide (Calbiochem, La Jolla, CA) and 1 ml of incomplete Freund's adjuvant. Four weeks later, a dose of 100 µg antigens of incomplete Freund's adjuvant was again administered subcutaneously. Finally, the rabbit was immunized intravenously four weeks later with 50 µg of protein antigens. The antiserum was used to screen the expression library as described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, 1989. Bacteriophage plaques expressing immunoreactive antigens were isolated. Phagemid was obtained from plaques and nucleotide sequences of M. tuberculosis clones were derived.

32 clones were isolated. Of these, 25 represent sequences that have not previously been identified in the M. tuberculosis microorganism. Proteins are induced by IPTG and isolated by gel elution as described in Skeika et al., J. Exp. Copper. 181: 1527-1537, 1995. Representative partial sequences identified in this assay are set forth in SEQ ID NOs: 1 through 25. The corresponding amino acid sequences are shown in SEQ ID NO: 64-88.

By comparing these sequences with known sequences in the gene bank using the databases described above, it was found that clones such as TbRA2A, TbRA16, TbRA18 and TbRA29 (SEQ ID NO: 77, 69, 71, 76) show the same homology to sequences previously identified in Mycobacterium leprae, but not in M. tuberculosis. TbRAll, TbRA26, TbRA28 and TbDPEP (SEQ ID NO: 66, 74, 75, 53) were previously identified in the microorganism M. tuberculosis. No substantial homology was found with TbRA1, TbRA3, TbRA4, TbRA9, TbRA10, TbRA13, TbRA17, TbRA19, TbRA29, TbRA32, TbRA36 and overlapping clones TbRA35 and TbRA12 (SEQ ID NOS: 64, 78,

82, 83, 65, 68, 76, 72, 76, 81, 80, 67). Clone TbRa24 overlaps with clone TbRa29.

of DNA molecules assumed • » partial clone TbH-8 a- TbH-4 (SEQ ID NO: 43) and TbH-4-FWD (SEQ ID NO: 44) are sequences from the same clone that do not follow each other. The amino acid sequences of the antigens defined herein as Tb38-1, TbH-4, TbH-8, TbH-9 and TbH-12 are shown in SEQ ID NO: 89-93. Comparison of these sequences with known sequences in the gene bank using the above databases shows no substantial homology to TbH4, TbH-8, TbH-9 and TbM-3. Although little homology was found with TbH9. TbH-12 was found to be homologous to an antigenic protein of molecular weight 34,000 previously identified in the microorganism M. paratuberculosis (Acc. No. S28515). Tb38-1 was found to be located 34 base pairs upstream of the ESAT-6 antigen open reading frame previously identified in M. bovis (Acc. No. U34848) and M. tuberculosis (Sorensen et al., Infec .Immun.63: 1710-1717, 1995).

Probes derived from Tb38-1 and TbH-9, which were isolated from the H37Ra library, were used to identify clones in the H37Rv library. Tb38-1 hybridized with Tb38-1F2, Tb38-1F3, Tb38-1F5 and Tb38-1F6 (SEQ. ID NO: 107, 108, 111, 113 and 114). The sequences of SEQ ID NO: 107 and 108 are sequences from clone Tb38-1F2, but they are not contiguous. Two open reading frames were derived from the Tb38-IF2 clone; one corresponds to Tb37FL (SEQ ID NO: 109), the other may be a Tb38-1 homolog and is called Tb38-IN (SEQ ID NO: 110). The deduced amino acid sequence of Tb38-1F3 is shown in SEQ ID NO: 112. The TbH-9 probe identified three clones in the H37Rv library: TbH-9-FL (SEQ ID NO: 101), which may be a homologue of TbH-9 (R37Rα), TbH-9-1 (SEQ ID NO: 103) and TbH-8-2 (SEQ ID NO: 105), which is a partial clone of TbH-8. The deduced amino acid sequences of these three clones are shown in SEQ ID NO: 102, 104 and 106.

Further screening of the M. tuberculosis genomic DNA library, as described above, led to the discovery of additional reactive clones representing seven different

• · ' *. * * · · 1 · • · · Λ · ’

genes. One of these genes was identified as the above 38,000 molecular weight antigen. One was determined to be identical to the heat shock protein alpha-crystallin previously identified in M. tuberculosis. The third gene is identical to the TbH-8 antigen described above. The DNA sequences of the remaining five clones (referred to herein as TbH-29, TbH-30, TbH-32 and TbH-33) are shown in SEQ ID NO: 133136. The predicted amino acid sequences are shown in SEQ ID NO: 137-140. The DNA and amino acid sequences of these antigens were compared to gene bank sequences as described above. No homology to the 5' end of TbH-29 (which contains a reactive open reading frame) was found, although the 3' end of TbH-29 was found to be the same as cosmid Y227 of M. tuberculosis. TbH-32 and TbH-33 were found to be identical to the previously identified M. tuberculosis IS6110 insertion element and to the M. tuberculosis Y50 cosmid. No substantial homology to TbH-30 was found.

The positive phagemid was used to infect E. coli XL1 Blue MRF' as described in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY, 1989. Recombinant protein induction was performed by adding IPTG. The induced and uninduced lysates were subjected to SDS-PAGE in duplicate and transferred to nitrocellulose filters. Filters were reacted with human M. tuberculosis serum (1:200 dilution), which is reactive with TbH, and with rabbit serum (1:200 or 1:250 dilution), which is reactive with the N-terminal region of lacZ of molecular weight 4 000. The sera were incubated for two hours at room temperature. Bound antibodies were detected by addition of I-labeled protein A and subsequent exposure of the film for various times ranging from 16 hours to 11 days. The results of the immunoblots are shown in Table No. 2.

·

Table No. 2

antigen Human M. tb serum Anti-lacZ serum TbH-29 45,000 45,000 TbH-30 It is not reactive 29,000 TbH-32 12,000 12,000 TbH-33 16,000 16,000

A positive reaction of recombinant human M. tuberculosis antigens with human M. tuberculosis serum and anti-lacZ serum indicates that the reactivity of human M. tuberculosis serum is towards the fusion protein. Antigens reactive with anti-lacZ serum but not with human M. tuberculosis serum may be the result of human M. tuberculosis serum recognizing conformational epitopes or the kinetics of antigen-antibody binding may be such that a two-hour exposure of the serum to the immunoblot is insufficient.

Studies were performed to determine whether the TbH-9 and Tb38-1 antigens represent cellular proteins or are secreted into the culture medium of M. tuberculosis. In the first study, rabbit sera were raised against A) M. tuberculosis secretory proteins, B) known recombinant M. tuberculosis 85b secretory antigen, C) recombinant Tb-38-1, and D) recombinant TbH-9 using protocols that are essentially described in Example 3A. M. tuberculosis whole lysate, concentrated M. tuberculosis culture supernatant, and recombinant antigens 85b, TbH-9, and Tb38-1 were separated on a denaturing gel, immobilized on nitrocellulose membranes, and duplicate blots were probed using rabbit serum as described above in the text.

The results of said analysis using control serum (panel I) and antisera (panel II) against the secretory proteins, • · • · • · ···· recombinant Tb38-1 and recombinant TbH-9 are shown in Figures 2A to D, where the labels the tracks are as follows:

1) protein standards of molecular weights

2) 5 µg of lysate of the microorganism M. tuberculosis

3) 5 µg of secretory proteins

4) 50 ng recombinant Tb38-1 5) 50 ng recombinant TbH-9 a 6) 50 ng recombinant 85b.

Recombinant antigens have been manipulated with six terminal histidine residues and are therefore expected to have a mobility 1000 times greater than that of the native protein. Figure 2D shows the molecular weight of recombinant TbH-9, which is approximately 10,000 smaller than the molecular weight of the full-length antigen, which is 42,000. This leads to a substantial difference in the size of the immunoreactive native TbH-9 antigen in the lysate lane (indicated by the arrow ). These results indicate that Tb38-1 and TbH-9 are intracellular antigens and are not actively secreted by M. tuberculosis.

The finding that TbH-9 is an intracellular antigen was confirmed by determining the reactivity of TbH-9-specific T cell clones with recombinant TbH-9, M. tuberculosis secretory proteins, and PPD. A TbH-9-specific T-cell clone (designated 131TbH-9) was generated from PMBCs of healthy PPD-positive donors. The proliferative response of 131TbH-9 to secretory proteins, recombinant TbH-9, and the M. tuberculosis control antigen, TbRall, was determined by measuring tritiated thymidine uptake as described in Example 1. As shown in Figure 3A, clone 131TbH-9 specifically responds to TbH -9, indicating that TbH-9 is not an essential component of the secretory proteins of M. tuberculosis. Panel #3B shows production of IFN-γ by a second TbH-9-specific T-cell clone (designated PPD 800-10) prepared from PBMCs from a healthy PPD-positive donor, followed by stimulation of the T-cell clone with secretory proteins, PPD, or • · • · recombinant TbH-9. These results further confirm that TbH-9 is not secreted by M. tuberculosis.

C. Use of serum from patients exhibiting extrapulmonary tuberculosis to identify DNA sequences encoding M. tuberculosis antigens.

Genomic DNA was isolated from M. tuberculosis strain Erdman, randomly digested, and an expression library constructed using the Lambda ZAP expression system (Stratagene, La Jolla, CA). The resulting library was screened using pools of sera obtained from individuals with extrapulmonary tuberculosis as described above in Example 3B, using goat anti-human IgG+A+M(H+L) conjugated to alkaline phosphatase as secondary antibodies.

18 clones were isolated. Four of these (referred to here as XP14, XP24, XP31 and XP32) were found to bear some similarity to known sequences. The determined DNA sequences of XP14, XP24 and XP31 are set forth in SEQ ID NO: 151 to 153, with the 5' and 3' DNA sequences of XP32 set forth in SEQ ID NO: 154 and 155. The predicted amino acid sequence of XP14 is set forth in SEQ ID NO: 156. Reverse complement XP14 was found to encode the amino acid sequence shown in SEQ ID NO: 157.

By comparing the sequences of the remaining 14 clones (referred to here as XP1-XP6, XP17-XP19, XP22, XP25, XP27, XP30 and

XP36) with sequences in the genebank as described above in the text shows no homology except for the 3' ends of XP2 and XP6, which bear homology to the known cosmid of M. tuberculosis. The DNA sequences of XP27 and XP36 are set forth in SEQ ID NOs: 158 and 159, with the 5' sequences of XP4, XP5, XP17, and XP30 set forth in SEQ ID NOs 160 to 163 and the 5' and 3' sequences of XP2, XP3, XP6, XP18 , XP19, XP22, and XP25 are set forth in SEQ ID NOs: 164 and 165, 166 and 167, 168 and 169, 170 and 171, 172 and 173, 174 and 175, and 176 and 177. XP1 was found to overlap with sequences TbH4 DNA as described above. Full length sequence • · ······· · · ···· ·· ·· ·· ·· ··

TbH4-XP1 DNA is shown in SEQ ID NO: 178. This DNA sequence was found to contain an open reading frame encoding the amino acid sequence shown in SEQ ID NO: 179. The reverse complement of TbH4-XP1 was found to contain an open reading frame encoding the amino acid the sequence set forth in SEQ ID NO: 180. The DNA sequence of XP36 was found to contain two open reading frames encoding the amino acid sequence set forth in SEQ ID NO: 181 and 182, with the reverse component comprising the open reading frame encoding the amino acid sequence set forth in SEQ ID NO: 183.

Recombinant XP1 protein was prepared as described in Example 3B, using a metal ion affinity chromatography column for its purification. Recombinant XP1 was found to stimulate cell proliferation and IFN-γ production in T-cells isolated from donors immune to M. tuberculosis.

C. Preparation of soluble antigens of M. tuberculosis using rabbit anti-serum against split proteins of M. tuberculosis

A lysate of M. tuberculosis was prepared as described above in Example 2. The resulting material was fractionated by HPLC and the serological activity of the fractions was tested by western blotting using serum from patients infected with M. tuberculosis showing weak or no immunoreactivity with other antigens according to the invention. Rabbit antiserum was raised against the most strongly reacting fraction using the method described in Example 3A. The anti-serum was used to test a genomic DNA expression library of M. tuberculosis strain Erdman, which was prepared as described above. Bacteriophage plaques expressing immunoreactive antigen were isolated. Phagemid was obtained from plaques and nucleotide sequences of M. tuberculosis clones were determined.

• · · · • · ······· · · ···· ·· ·· ·· ·· *·

He isolated ten distinct clones. One of them was found to be TbRα35 mentioned above, and another one was the previously identified M. tuberculosis antigen HSP60. Furthermore, of the remaining eight clones, six (referred to here as RDIF2, RDIF5, RDIF8, RDIF10, RDIF11 and RDIF12) were found to bear similarity to previously determined sequences of M. tuberculosis. The determined DNA sequences of RDIF2, RDIF5, RDIF8, RDIF10 and RDIF11 are set forth in SEQ ID NO: 184188, with the corresponding predicted sequences set forth in SEQ ID NO: 189-193. The 5' and 3' DNA sequences of RDIF12 are shown in SEQ ID NO: 194 and 195. No substantial homology to the RDIF-7 antigen was found. The determined DNA sequence and predicted amino acid sequence of RDIF7 are set forth in SEQ ID NO: 196 and 197. Another clone, designated herein as RDIF6, was isolated, but was found to be identical to RDIF5.

Recombinant RDIF6, RDIF8, RDIF10 and RDIF11 were prepared as described above. These antigens were found to stimulate cell proliferation and IFN-γ production in T-cells isolated from donors immune to M. tuberculosis.

Example 4: Purification and characterization of a polypeptide from an isolated protein derivative of tuberculin.

The M. tuberculosis polypeptide was isolated from the isolated tuberculin protein derivative (PPD) as follows:

PPD was prepared according to a published procedure with some modifications (described in Seibert et al., Tuberculin purified protein derivative. Preparation and analyzes of large quantity for standard. The American Review of Tuberculosis 44:9-25, 1941). The Rv strain of M. tuberculosis was cultured for 6 weeks in synthetic medium in stirred vessels at 37°C. The containers containing the bacterial culture were then heated to a temperature of 100 °C in • · ······· · · ···· ·· ·· ·· ·· φ·

Tb01B93 1-2 ++++ 1, 853 0.634 0.998 1,022 1,030 1,314 Tb01B93 1-19 ++++ 2, 657 2,322 0, 608 0.837 1.857 2,335 Tb01B93 1-8 +++ 2, 703 0.527 0.492 0.281 0.501 2, 002 Tb01B93 1-10 +++ 1, 665 1,301 0.685 0.216 0, 448 0, 458 Tb01B93 1-11 +++ 2, 817 0.697 0.509 0, 301 0.173 2, 608 Tb01B93 1-15 ++ + 1.28 0.283 0.808 0.218 1,537 0.811 Tb01B93 1-16 +++ 2, 908 >3 0.899 0.441 0.593 1,080 Tb01B93 1-25 +++ 0.395 0, 131 0.335 0.211 0.107 0.948 Tb01B93 1-87 +++ 2, 653 2,432 2,282 0.977 1,221 0.857 Tb01B93 1-89 +++ 1,912 2,370 2,436 0.876 0.520 0.952 Tb01B94 1-108 +++ 1, 639 0, 341 0, 797 0, 368 0.654 0.798 Tb01B94 1-201 +++ 1,721 0.419 0, 661 0, 137 0.064 0, 692 Tb01B93 1-88 ++ 1,939 1,269 2,519 1,381 0, 214 0.530 Tb01B93 1-92 ++ 2,355 2,329 2, 78 0.685 0.997 2,527 Tb01B94 1-109 ++ 0.933 0, 620 0.574 0, 441 0.5 2, 558 Tb01B94 1-210 ++ 2, 777 >3 0.393 0, 367 1.004 1,315 Tb01B94 ++ 2,913 0, 476 0.251 1,297 1,990 0.256

• * « A • · • ·· ······· · · ···· ·« ·· ·· 9· ··

1-224 Tb01B93 1-9 + 2, 694 0.278 0.210 0.140 0, 181 1,586 Tb01B93 1-14 + >3 1,538 0, 282 0.291 0.549 2, 880 Tb01B93 1-21 + 2.645 0.739 2,499 0.783 0.536 1, 770 Tb01B93 1-22 + 0.714 0, 451 2, 082 0.285 0.269 1, 159 Tb01B93 1-31 + 0.956 0.490 1,019 0.812 0.176 1,293 Tb01B93 1-32 2,261 0.786 0.668 0.273 0.535 0, 405 Tb01B93 1-52 0.658 0, 114 0.434 0.330 0.273 1,140 Tb01B93 1-99 2,118 0.584 1, 62 0, 119 0.977 0.729 Tb01B94 1-130 1,349 0.224 0.86 0.282 0, 383 2.146 Tb01B94 1-131 0.685 0, 324 1.173 0.059 0.118 1,431 AT4- 0070 normal 0.072 0.043 0.092 0.071 0.040 0.039 AT4- 0105 normal 0.397 0.121 0.118 0.103 0.078 0, 390 3/15/94 -1 normal 0.227 0.064 0.098 0.026 0.001 0.228 4/15/93 -2 normal 0.114 0.240 0.071 0.034 0.041 0.264 5/26/94 -4 normal 0.089 0.259 0.096 0.046 0.008 0.053 5/26/94 -3 normal 0.139 0.093 0.085 0.019 0.067 0.01

β 4 • 4 • · • *4 4 • 44

5Ί »4*4 44 » 4 4 « • 4 44

44

Based on the cutoff values obtained from the receiver operator curves, the TbRa3 antigen detected 23 positive sera out of 27, TbH4 detected 18 positive sera out of 27, and TbH12 detected 15 positive sera out of 27. When these antigens are used in combination, these four antigens achieve a theoretical sensitivity of 27 positive sera from 27, which indicates that these antigens complement each other in the serological detection of infection with the microorganism M. tuberculosis. Additionally, several recombinant antigens detected positive sera that were not detected even using the 38,000 molecular weight antigen, indicating that these antigens may be complementary to the 38,000 molecular weight antigen.

The reactivity of recombinant TbRall antigen with sera from patients with M. tuberculosis shows that it is negative for the 38,000 molecular weight antigen, as well as for sera from PPD-positive and normal donors, as determined by ELISA as described above in the text. The results are shown in Figure 6 and indicate that the TbRall antigen, while negative with sera obtained from PPD positive and normal donors, was detected by s=rum which was negative with an antigen of molecular weight 38,000. Of the thirteen negative sera tested of the 38,000 molecular weight antigen, nine were positive with the TbRall antigen, indicating that this antigen can react with a subset of sera that are negative when reacting with the 38,000 molecular weight antigen. Conversely, the reaction of the TbRall antigen with a group of sera that are positive with the 38,000 molecular weight antigen, the mean OD 450 value for the TbRall antigen was lower than that obtained when reacting with the 38,000 molecular weight antigen. The data indicate an inverse relationship between the presence of TbRall antigen activity and 38,000 molecular weight antigen positivity.

The TbRa2A antigen was tested in an indirect ELISA. At the beginning, 50 ul of serum was used at a dilution of 1:100 and incubated

• · • · • · it ·· it · • ··· • ·· · · t <

• to»· ·· «to ·· ·· ·» at room temperature for 30 min, followed by washing with PBS and Tween solution, followed by incubation with protein A (Zymed, San Francisco, CA) at a dilution of 1 : 10,000 labeled biotin. This is followed by washing and 50 µl of streptavidin-horseradish peroxidase complex (Zymed) at a dilution of 1:10,000 is added and the mixture is incubated for 30 minutes. After washing, the assay was developed in the presence of TBM substrate as described above. The reactivity of TbRa2A with serum obtained from patients positive for the M. tuberculosis microorganism and with serum from normal donors is shown in Table No. 4. The average value for the reactivity of TbRa2A antigens with serum obtained from patients positive for the M. tuberculosis microorganism was 0.444 with a standard deviation 0.309. The mean serum reactivity value for normal donors was 0.109 with a standard deviation of 0.029. Testing of sera that show a negative reaction with the 38,000 molecular weight antigen (Figure #7) also indicates that the Tbra2A antigen is capable of detecting sera of this group.

Table No. 4: Reactivity of TbRa2A antigens with serum from patients positive for the M. tuberculosis microorganism and with serum from normal donors.

Serum ID status FROM 450 Tb85 TB 0, 680 Tb86 TB 0.450 Tb87 TB 0.263 Rb8 8 TB 0.275 Tb89 TB 0.403 Tb91 TB 0.393 Tb92 TB 0.401 Tb93 TB 0.232 Tb94 TB 0, 333 Tb95 TB 0.435 Tb96 TB 0.284

·· *· ·· · ·· ·· ···· ··· ···· • ·· · · ··· · · · · ·· ··· ·· ·· ··· ··· · ······ · · ···· ·· ·· ·· ·· ··

Tb97 TB 0, 320 Tb99 TB 0, 328 TblOO TB 0.817 TblOl TB 0, 607 Tbl02 TB 0.191 Tbl03 TB 0, 228 Tbl07 TB 0, 324 Tbl09 TB 1,572 Tbll2 TB 0, 338 DL4-0176 normal 0.036 AT4-0043 normal 0, 126 AT4-0044 normal 0.130 AT4-0052 normal 0, 135 AT4-0053 normal 0, 133 AT4-0062 normal 0, 128 AT4-0070 normal 0.088 AT4-0091 normal 0, 108 AT4-0100 normal 0.106 AT4-0105 normal 0.108 AT4-0109 normal 0, 105

Reactivity of recombinant antigens (g) (SEQ ID NO: 60) with sera obtained from M. tuberculosis positive patients and with sera from normal donors was determined by ELISA as described above. Figure 8 shows the results of titration of antigens (g) with four sera obtained from patients who are positive for the microorganism M. tuberculosis, all of which show a positive reaction with the antigen of molecular weight 38,000, and with four sera of normal donors. All four positive sera react with antigen (g).

The reactivity of recombinant TbH-29 antigens (SEQ ID NO: 137) with sera obtained from M. tuberculosis positive patients, PPD positive donors and normal donors was determined by indirect ELISA as described above. The results are shown in Figure 9. The TbH-29 antigen detected 30 out of 60 M. tuberculosis sera and 2 out of 27 normal sera.

Figure No. 10 shows the results of ELISA tests (direct and indirect) of TbH-33 antigen (SEQ ID NO: 140) with sera obtained from patients who are positive for the microorganism M. tuberculosis and with sera from normal donors and with pooled sera obtained from patients who are positive for the microorganism M. tuberculosis. The mean OD 450 was shown to be higher in sera obtained from M. tuberculosis -positive patients than in sera from normal donors, with the OD 450 significantly higher in the indirect ELISA than in the direct ELISA. Figure 11 shows a titration curve of the reactivity of recombinant TbH-33 with sera obtained from patients and from normal donors, showing that the OD 450 value increases with increasing antigen concentration.

The reactivity of recombinant antigens RDIF6, RDIF8 and RDIF10 (SEQ ID NO: 184-187) with sera obtained from M. tuberculosis positive patients and from normal donors was determined by ELISA as described above. RDIF6 antigen detected 6 positive sera of 32 and none of 15 normal sera; RDIF8 antigen detected 14 positive sera of 32 and none of 15 normal sera; and RDIF10 antigen detected 4 positive sera out of 27 and 1 sera Z out of 15 normal sera. In addition, the RDIF10 antigen was found not to detect any of the 5 sera obtained from donors positive for PPD.

Example 7: Preparation and characterization of fusion proteins of the microorganism M. tuberculosis.

A fusion protein containing the TbRA3 antigen, the 38,000 molecular weight antigen, and the Tb38-1 antigen was prepared as follows:

• · ··· · · ·· ··· »· ······· · · ····*· ·· ·· ·· ··

Each of the TbRα3, 38kD and Tb38-1 DNA constructs was modified by PCR to fuse them and subsequently express the TbRα3-38kD-Tb38-1 fusion protein. The DNA of TbRα3, 38kD and Tb38-1 antigens was used to perform PCR using primers PDM-64 and PDM-65 (SEQ ID NO: 141 and 142), PDM-57 and PDM58 (SEQ ID NO: 143 and 144) and PDM- 69 and PDM-60 (SEQ ID NO: 145146). In each case, DNA amplification was performed using 10 µl of 10x concentrated Pfu buffer, 2 µl of 10 mM dNTP, 2 µl of each of the PCR primers at a concentration of 10 µM, 81.5 µl of water, 1.5 µl of Pfu DNA polymerase (Stratagene, La Jolla, CA) and 1 µl of DNA at a concentration of 70 ng/µl (for the TbRα3 antigen) or 50 ng/µl (for the 38,000 and Tb38-1 antigens). For the TbRα3 antigen, denaturation was performed at 94°C for 2 min, followed by 40 cycles at 96°C for 15 s and 72°C for 1 min, and a final cycle at 72°C for for 4 minutes. For the 38,000 molecular weight antigen, denaturation was performed at 94°C for 2 minutes, followed by 40 cycles of 96°C for 30 seconds and 68°C for 15 seconds and 72°C for 3 minutes and the last cycle is at 72°C for 4 minutes. For the Tb38-1 antigen, denaturation was performed at 94°C for 2 minutes, followed by 10 cycles of 96°C for 15 seconds and 68°C for 15 seconds and 72°C for 1.5 minutes, 30 cycles of 96°C for 15 seconds, 64°C for 15 seconds, and 72°C for 1.5 minutes, and a final cycle of 72°C for 4 minutes.

The TbRa3 antigen PCR fragment was digested with NdeI and EcoRl restriction endonucleases and cloned directly into the PT7aL2IL1 vector using the NdeI and EcoRl restriction sites. The 38,000 molecular weight PCR fragment was digested with Sse8387I restriction enzymes, treated with T4 DNA polymerase to blunt ends, and then digested with EcoRl for direct cloning into ······· · · ···· ·· ·· ·· ·· · · vector pT7AL2Rα3-1, which was digested with the restriction enzymes StuI and EcoRI. The Tb38-1 antigen PCR fragment was digested with Eco47III and EcoRI restriction enzymes and directly sub-cloned into pT7AL2Rα3/38kD-17, which was digested with the same enzymes. The entire fusion was then transferred into pET28b using the NdeI and EcoRI restriction sites. The fusion construct was confirmed by DNA sequencing.

The expression construct was transformed into BLR pLys S E.coli (Novagen, Madison, WI) and cultured overnight in LB medium with kanamycin (30 µg/ml) and chloramphenicol (34 µg/ml). This culture (12 ml) was used to inoculate 500 ml of 2XYT with the same antibiotics and the culture was induced with IPTG at an OD 560 of 0.44, with a final IPTG concentration of 1.2 mM. Four hours after induction, bacteria were harvested and sonicated in 20 mM Tris (pH8.0), 100 mM NaCl, 0.1% DOC, 20 µg/ml leupeptidin, 20 mM PMSF, followed by centrifugation at 26,000xg. The resulting pellet was resuspended in 8 M urea, 20 mM Tris (pH 8.0), 100 mM NaCl and bound to Perlinked Nickel resin (Invitrogen, Carlsbad, CA). The column was washed several times with the above buffer and eluted with an imidazole gradient (50 mM, 100 mM, 500 mM imidazole, 20 mM Tris(pH8.0), 100 mM NaCl was added to 8 M urea). The eluate containing said protein was then dialyzed against 10 mM Tris (pH 8.0).

The DNA and amino acid sequences of the resulting fusion protein (designated here as TbRa3-38 kD-Tb38-1) are set forth in SEQ ID NOs: 147 and 148.

A fusion protein containing the two antigens TbH-9 and Tb38-1 (designated here as TbH9-Tb38-1) was prepared using a similar procedure to that described above. The DNA sequence of the TbH9-Tb38-1 fusion protein is set forth in SEQ ID NO: 151.

A fusion protein containing the antigens TbRa3, 38,000 molecular weight antigen, Tb38-1 and DPEP was prepared as follows.

• · · · • ·

Each of the TbRα3, 38 kD, and Tb38-1 DNA constructs was modified by PCR and cloned into vectors in essentially the same manner as described above. The primers PDM-69 (SEQ ID NO: 145) and PDM-83 (SEQ ID NO: 200) were used to amplify the Tb38-1A fragment. Tb38-1A differs from Tb38-1 in the presence of a Dral restriction site at the 3' end of the coding region, which keeps the terminal amino acid intact while forming a blunt, in-frame restriction site. The TbRα3/38kD/Tb38-1A fusion was then transferred into pET28b using the NdeI and EcoRI restriction sites.

DPEP DNA was used to perform PCR using primers PDM-84 and PDM-85 (SEQ ID NO: 201 and 202) and 1 µl of DNA at a concentration of 50 ng/µl. Denaturation was at 94°C for 2 minutes, followed by 10 cycles of 96°C for 15 seconds, 68°C for 15 seconds, and 72°C for 1.5 minutes; followed by 30 cycles at 96°C for 15 seconds, 64°C for 15 seconds and 72°C for 1.5 minutes, and the last cycle at 72°C for 4 minutes. The DPEP PCR fragment was digested with restriction EcoRI and Eco72I enzymes and cloned directly into the pET28Rα3/38kD/38-1A construct, which was digested with Dral and EcoRI restriction enzymes. The correctness of the fusion construct was confirmed by DNA sequencing. The recombinant protein was prepared according to the procedure described above. The DNA and amino acid sequences of the resulting fusion protein (referred to herein as TbF-2) are set forth in SEQ ID NOs: 203 and 204.

Example 8: Use of fusion proteins of the microorganism M.

tuberculosis in the serological diagnosis of tuberculosis. The effectiveness of the fusion protein TbRa3-38kD-Tb38-1, which was prepared according to the procedure described above in the text, in the serological diagnosis of tuberculosis was determined by the ELISA test.

The ELISA assay was carried out according to the protocol described in Example 6, in which the wells of the plates were coated with the fusion • · • · • ··· protein at 200 ng/well. A panel of sera was selected from a group of patients positive for tuberculosis, previously demonstrated by either ELISA or western blot, to react with each of the three antigens individually or in combination. Such a panel will allow a detailed determination of the serological reactivity of the fusion protein, which will allow to determine whether all three epitopes react with the fusion protein. As Table 5 shows, all four sera that react with the TbRα3 antigen are detectable only by the fusion protein. It is also possible to detect three sera that react only with the Tb38-1 antigen, as well as two sera that react only with the 38,000 molecular weight antigen. The remaining 15 sera are positive when reacting with the fusion protein, which was determined to be based on the cutoff value of the test corresponding to the mean of the values of negative results plus three standard deviations. These data show that all three epitopes in the fusion protein are active.

Table 5: Reactivity of the three-peptide fusion protein with sera from patients positive for M. tuberculosis.

Serum ID Status ELISA and/or western transmission Reactivity of individual proteins Fusion recombin ant Fusion recombin ant 38,000 Tb38-1 TbRa3 FROM 450 Status 01B93I-40 TB - - + 0, 413 + 01B93I-41 TB - + + 0, 392 + 01B93I-29 TB + - + 2, 217 + 01B93I- 109 TB + +/- + 0.522 + 01B93I- 132 TB + + + 0.937 + 5004 TB +/- + +/- 1,098 + 15004 TB + + + 2,077 +

• · • ··· ······· · · ···· · · ·* ·· · · ··

39004 TB + + + 1, 675 + 68004 TB + + + 2,388 + 99004 TB - + +/- 0, 607 + 107004 TB - + +/- 0.667 + 92004 TB + +/- +/- 1,070 + 97004 TB + - +/- 1,152 + 118004 TB + - +/- 2, 694 + 173004 TB + + + 3,258 + 175004 TB + — + 2,514 + 274004 TB - - + 3,220 + 276004 TB - + - 2,991 + 282004 TB + - - 0.824 + 289004 TB - - + 0.848 + 308004 TB - + - 3, 338 + 314004 TB - + - 1,362 + 317004 TB + - - 0.763 + 312004 TB - - + 1,079 + D176 PPD - - - 0.145 D162 PPD - - - 0.073 - D161 PPD - - - 0.097 - D27 PPD — - - 0.082 - A6-124 Normal - - - 0.053 - A6-125 Normal - - - 0.087 - A6-126 Normal - - - 0, 346 +/- A6-127 Normal — — - 0.064 - A6-128 Normal - - 0.034 - A6-129 Normal - - 0.037 - A6-130 Normal — — - 0.057 - A6-131 Normal — - 0.054 - A6-132 Normal — — 0.022 - A6-133 Normal - - 0.147 - A6-134 Normal - - - 0.101 - A6-135 Normal — — 0.066 -

• ·

A6-136 Normal - - 0.054 - A6-137 Normal - - - 0.065 — A6-138 Normal - - - 0.041 — A6-139 Normal - - - 0, 103 — A6-140 Normal - - - 0.212 - A6-141 Normal - - - 0.056 — A6-142 Normal - - - 0.051 —

The reactivity of the TbF-2 fusion protein with serum from patients positive for M. tuberculosis was tested by ELISA according to the protocol described above. The results of the above studies (Table 6) show that all antigens function independently of the fusion protein.

• · · ·

Table 6: Reactivity of TbF-2 fusion protein with TB serum and with normal serum

Serum ID Status TBF OD450 Status TbF-2 OD450 Status ELISA Reafctivitq 38 kD TbRa3 Tb38-1 DPEP B931-40 TB 0.57 + 0.321 + - + - + B931-41 TB 0.601 + 0.396 + + + + - B931-109 TB 0.494 + 0.404 + + + ± - B931-132 TB 1.502 + 1.292 + + + + + 5004 TB 1,806 + 1,666 + ± ± + - 15004 TB 2,862 + 2.468 + + + + - 39004 TB 2.443 + 1.722 + + + + - 68004 TB 2.871 + 2,575 + + + + - 99004 TB 0.691 + 0.971 + - ± + - 107004 TB 0.875 + 0.732 + - + + - 92004 TB 1.632 + 1,394 + + + + - 97004 TB 1.491 + 1,979 + + + - + 118004 TB 3.182 + 3.045 + + ± - - 173004 TB 3.644 + 3.578 + 4- + + - 175004 TB 3.332 + 2.916 + + + - - 274004 TB 3,696 + 3.716 + - + - + 276004 TB 3.243 + 2.56. + - - + - 282004 TB 1,249 + 1.234 + + - - - 289004 TB 1,373 + 1.17 -I-' - + - - 308004 TB 3.708 + 3.355 + - - + - 314004 TB 1,663 + 1,399 + - - + - 317004 TB 1.163 + 0.92 + + - - - 312004 TB 1.709 + 1,453 + - + - - 380004 TB 0.238 0.461 + - + - + 451004 TB 0.18 - 0.2 - - - - ± 478004 TB 0.188 - 0.469 + - - - and 410004 TB 0.384 + 2.392 + + - - + 411004 TB 0.306 + 0.874 + - + - + 421004 TB 0.357 + 1,456 + - + - + 528004 TB 0.047 - 0.196 - - - - + A6-87 Normal 0.094 - 0.063 - - - - - A6-88 Normal 0.214 - 0.19 - - - - - A6-89 Normal 0.248 - 0.125 - - - - - A6-90 Normal 0.179 - 0.206 - - - - - A6-91 Normal 0.135 - 0.151 - - - - - A6-92 Normal 0.064 - 0.097 - - - - - A6-93 Normal 0.072 - 0.098 '·: - - - - A6-94 Normal 0.072 - 0.064 - - - - - A6-95 Normal 0.125 - 0.159 - - - - - A6-96 Normal 0.121 - 0.12 - - - - - Cut-off 0.284 0.266

It will be of interest to those skilled in the art if the order of the individual antigens in the fusion protein can be interchanged, with the expectation that the fusion protein will exhibit comparable activity because each of the epitopes is still functionally available. In addition, truncated forms of proteins containing active epitopes can be used to construct functional proteins.

- Sequential protocol (1) Information about the sequence of SEQ ID NO: 1:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 766 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 1

CGAGGCACCG GTAGTTTGAA CCAAACGCAC AATCGACGGG CAAACGAACG GAAGAACACA 60 ACCATGAAGA TGGTGAAATC GATCGCCGCA GGTCTGACCG CCGCGGCTGC AATCGGCGCC 120 GCTGCGGCCG GTGTGACTTC GATCATGGCT GGCGGCCCGG TCGTATACCA GATGCAGCCG 180 GTCGTCTTCG GCGCGCCACT GCCGTTGGAC CCGGCATCCG CCCCTGACGT CCCGACCGCC 240 GCCCAGTTGA CCAGCCTGCT CAACAGCCTC GCCGATCCCA ACGTGTCGTT TGCGAACAAG 300 GGCAGTCTGG TCGAGGGCGG CATCGGGGGC ACCGAGGCGC GCATCGCCGA CCACAAGCTG 360 AAGAAGGCCG CCGAGCACGG GGATCTGCCG CTGTCGTTCA GCGTGACGAA CATCCAGCCG 420 GCGGCCGCCG GTTCGGCCAC CGCCGACGTT TCCGTCTCGG GTCCGAAGCT CTCGTCGCCG 480 GTCACGCAGA ACGTCACGTT CGTGAATCAA-GGCGGCTGGA TGCTGTCACG CGCATCGGCG 540 ATGGAGTTGC TGCAGGCCGC AGGGNAACTG ATTGGCGGGC CGGNTTCAGC CCGCTGTTCA 600 GCTACGCCGC CCGCCTGGTG ACGCGTCCAT GTCGAACACT CGCGCGTGTA GCACGGTGCG 660 GTNTGCGCAG GGNCGCACGC ACCGCCCGGT GCAAGCCGTC CTCGAGATAG GTGGTGNCTC 720 GNCACCAGNG ANCACCCCCN NNTCGNCNNT TCTCGNTGNT GNATGA (1) Sequence information of SEQ ID NO: 2: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 752 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2 766 ATGCATCACC ATCACCATCA CGATGAAGTC ACGGTAGAGA CGACCTCCGT CTTCCGCGCA 60 GACTTCCTCA GCGAGCTGGA CGCTCCTGCG CAAGCGGGTA CGGAGAGCGC GGTCTCCGGG 120 GTGGAAGGGC TCCCGCCGGG CTCGGCGTTG CTGGTAGTCA AACGAGGCCC CAACGCCGGG 180 TCCCGGTTCC TACTCGACCA AGCCATCACG TCGGCTGGTC GGCATCCCGA CAGCGACATA 240

0 0 0 0 0 0 · ···« ·· 00 0· 0 · ··

TTTCTCGACG ACGTGACCGT GAGCCGTCGC CATGCTGAAT TCCGGTTGGA AAACAACGAA 300 TTCAATGTCG TCGATGTCGG GAGTCTCAAC GGCACCTACG TCAACCGCGA GCCCGTGGAT 360 TCGGCGGTGC TGGCGAACGG CGACGAGGTC CAGATCGGCA AGCTCCGGTT GGTGTTCTTG 420 ACCGGACCCA AGCAAGGCGGA GGATGACGGG AGTACCGGGG GCCCGTGAGC GCACCCGATA 480 GCCCCGCGCT GGCCGGGATG TCGATCGGGG CGGTCCTCCG ACCTGCTACG ACCGGATTTT 540 CCCTGATGTC CACCATCTCC AAGATTCGAT TCTTGGGAGG CTTGAGGGTC NGGGTGACCC 600 CCCCGCGGGC CTCATTCNGG GGTNTCGGCN GGTTTCACCC CNTACCNACT GCCNCCCGGN 660 TTGCNAATTC NTTCTTCNCT GCCCNNAAAG GGACCNTTAN CTTGCCGCTN GAAANGGTNA 720 TCCNGGGCCC NTCCTNGAAN CCCCNTCCCC CT 752

(2) Information ο the sequence of SEQ ID NO: 3:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 813 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3

CATATGCATC ACCATCACA TCACACTTCT AACCGCCCAG CGCGTCGGGG GCGTCGAGCA 60 CCACGCGACA CCGGGCCCGA TCGATCTGCT AGCTTGAGTC TGGTCAGGCA TCGTCGTCAG . 120 CAGCGCGATG CCCTATGTTT GTCGTCACT CAGATATCGC GGCAATCCAA TCTCCCGCCT 180 GCGGCCGGCG GTGCTGCAAA CTACTCCCGG AGGAATTTCG ACGTGCGCAT CAAGATCTTC 240 ATGCTGGTCA CGGCTGTCGT TTTGCTCTGT TGTTCGGGTG TGGCCACGGC CGCGCCCAAG 300 ACCTACTGCG AGGAGTTGAA AGGCACCGAT ACCGGCCAGG CGTGCCAGAT TCAAATGTCC 360 GACCCGGCCT ACAACATCAA CATCAGCCTG CCCAGTTACT ACCCCGACCA GAAGTCGCTG 420 GAAAATTACA TCGCCCAGAC GCGCGACAAG TTCCTCAGCG CGGCCACATC GTCCACTCCA 480 CGCGAAGCCC CCTACGAATT GAATATCACC TCGGCCACAT ACCAGTCCGC GATACCGCCG 540 CGTGGTACGC AGGCCGTGGT GCTCAMGGTC TACCACAACG CCGGCGGCAC GCACCCAACG 600 ACCACGTACA AGGCCTTCGA TTGGGACCAG GCCTATCGCA AGCCAATCAC CTATGACACG 660 CTTGGGCAGG CTGACACCGA TCCGCTGCCA GTCGTCTTCC CCATTGTTGC AAGGTGAACT 720

GAGCAACGCA GACCGGGACA ACWGGTATCG ATAGCCGCCN AATGCCGGCT TGGAACCCNG 780

TGAAATTATC ACAACTTCGC AGTCACNAAA NAA 813 (2) Sequence Information SEQ ID NO: 4:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 447 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4:

CGGTATGAAC ACGGCCGCGT CCGATAACTT CCAGCTGTCC CAGGGTGGGC AGGGATTCGC 60 CATTCCGATC GGGCAGGCGA TGGCGATCGC GGGCCAGATC CGATCGGGTG GGGGGTCACC 120 CACCGTTCAT ATCGGGCCTA CCGCCTTCCT CGGCTTGGGT GTTGTCGACA ACAACGGCAA 180 CGGCGCACGA GTCCAACGCG TGGTCGGGAG CGCTCCGGCG GCAAGTCTCG GCATCTCCAC 240 CGGCGACGTG ATCACCGCGG TCGACGGCGC TCCGATCAAC TCGGCCACCG CGATGGGGA 300 CGCGCTTAAC GGGCATCATC CCGGTGACGT CATCTCGGTG AACTGGCAAA CCAAGTCGGG 360 CGGCACGCGT ACAGGGAACG TGACATGGC CGAGGGACCC CCGGCCTGAT TTCGTCGYGG 420 ATACCACCCG CCGGCCGGCC AATTGGA 447

(2) Sequence information of SEQ ID NO: 5:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 604 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5:

GTCCCACTGC GGTCGCCGAG TATGTCGCCC AGCAAATGTC TGGCAGCCGC CCAACGGAAT 60 CCGGTGATCC GACGTCGCAG GTTGTCGAAC CCGCCGCCGC GGAAGTATCG GTCCATGCCT 120 AGCCCGGCGA CGGCGAGCGC CGGAATGGCG CGAGTGAGGA GGCGGGCAAT TTGGCGGGGC 180

• · ·φ φ φ • · * φ φ φ • ·· · · ΦΦΦ

72 • · · φφφφ Φ Φ Φ φφφφ φ φ * · φφ φ Φ CCGGCGACGG NGAGCGCCGG AATGGCGCGA GTGAGGAGGT GGNCAGTCAT GCCCAGNGTG 240 ATCCAATCAA CCTGNATTCG GNCTGNGGGN CCATTTGACA ATCGAGGTAG TGAGCGCAAA 300 TGAATGATGG AAAACGGGŇG GNGACGTCCG NTGTTCTGGT GGTGNTAGGT GNCTGNCTGG 360 NGTNGNGGNT ATCAGGATGT TCTTCGNCGA AANCTGATGN CGAGGAACAG GGTGTNCCCG 420 NNANNCCNAN GGNGTCCNAN CCCNNNNTCC TCGNCGANAT CANANAGNCG NTTGATGNGA 480 NAAAAGGGTG GANCAGNNNN AANTNGNGGN CCNAANAANC NNNANNNNG NNAGNTNGNT 540 NNNTNTTNNC ANNNNNNNTG NNGNNGNNCN NNNCAANCNN NTNNNNNNAA NNGGNTTNTT 600 NAAT 604 Information about SEQ ID NO: 6: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 633 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6: TTGCANGTCG AACCACCTCA CTAAAGGGAA CAAAAGCTNG AGCTCCACCG CGGTGGCGG 60 CGCTCTAGAA CTAGTGKATM YYYCKGGCTG CAGSAATYCG GYACGAGCAT TAGGACAGTC 120 TAACGGTCCT GTTACGGTGA TCGAATGACC GACGACATCC TGCTGATCGA CACCGACGAA 180 CGGGTGCGAA CCCTCACCCT CAACCGGCCG CAGTCCCGYA ACGCGCTCTC GGCGGCTCTA 240 CGGGATCGGT TTTTCGCGGY GTTGGYCGAC GCCGAGGYCG ACGACGACAT CGACGTCGTC 300 ATCCTCACCG GYGCCGATCC GGTGTTCTGC GCCGGACTGG ACCTCAAGGT AGCTGGCCGG 360 GCAGACCGCG CTGCCGGACA TCTCACCGCG GTGGGCGGCC ATGACCAAGC CGGTGATCGG 420 CGCGATCAAC GGCGCCGCGG TCACCGGCGG GCTCGAACTG GCGCTGTACT GCGACATCCT 480 GATCGCCTCC GAGCACGCCC GCTTCGNCGA CACCCACGCC CGGGTGGGGC TGCTGCCCAC 540 CTGGGGACTC AGTGTGTGCT TGCCGCAAAA GGTCGGCATC GGNCTGGGCC GGTGGATGAG 600 CCTGACCGGC GACTACCTGT CCGTGACCGA CGC 633

(2) INFORMATION FOR SEQ ID NO:7:

(i) SEQUENCE CHARACTERISTICS:

• · • · · <1 · » • 9 · • · 9 9 99 • · · ···· ·· • 9 • · • · « ·

9··

9 9 999 9 9 « • · «

TGGCCAGAGT 60

GCCCGTCGCG 120

CGAGTTCGGC 180

CGCCGGCTGG 240 (2) Sequence Information SEQ ID NO: 7:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1362 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7:

CGACGACGAC GGCGCCGGAG AGCGGGCGCG AACGGCGATC GACGCGGCCC

CGGCACCACC CAGGAGGGAG TCGAATCATG AAATTTGTCA ACCATATTGA

CCCCGCCGAG CCGGCGGCGC GGTCGCCGAG GTCTATGCCG AGGCCCGCCG

CGGCTGCCCG AGCCGCTCGC CATGCTGTCC CCGGACGAGG GACTGCTCAC

GCGACGTTGC GCGAGACACT GCTGGTGGGC CAGGTGCCGC GTGGCCGCAA GGAAGCCGTC 300

GCCGCCGCCG TCGCGGCCAG CCTGCGCTGC CCCTGGTGCG TCGACGCACA CACCACCATG 360

CTGTACGCGG CAGGCCAAAC CGACACCGCC GCGGCGATCT TGGCCGGCAC AGCACCTGCC 420

GCCGGTGACC CGAACGCGGCC GTATGTGGCG TGGGCGGCAG GAACCGGGAC ACCGGCGGGA 480

CCGCCGGCAC CGTTCGGCCC GGATGTCGCC GCCGAATACC TGGGCACCGC GGTGCAATTC 540

CACTTCATCG CACGCCTGGT CCTGGTGCTG CTGGACGAAA CCTTCCTGCC GGGGGGCCCG .600

CGCGCCCAAC AGCTCATGCG CCGCGCCGGT GGACTGGTGT TCGCCCGCAA GGTGCGCGCG 660

GAGCATCGGC CGGGCCGCTC CACCCGCCGG CTCGAGCCGC GAACGCTGCC CGACGATCTG 720

GCATGGGCAA CACCGTCCGA GCCCATAGCA ACCGCGTTCG CCGCGCTCAG CCACCACCTG 780

GACACCGCGC CGCACCTGCC GCCACCGACT CGTCAGGTGG TCAGGCGGGT CGTGGGGTCG 840

TGGCACGGCG AGCCAATGCC GATGAGCAGT CGCTGGACGA ACGAGCACAC CGCCGAGCTG 900

CCCGCCGACC TGCACGCGCC CACCCGTCTT GCCCTGCTGA CCGGCCTGGC CCCGCATCAG 960

GTGACCGACG ACGACGTCGC CGCGGCCCGA TCCCTGCTCG ACACCGATGC GGCGCTGGTT 1020

GGCGCCCTGG CCTGGGCCGC CTTCACCGCC GCGCGGCGCA TCGGCACCTG GATCGGCGCC 1080

GCCGCCGAGG GCCAGGTGTC GCGGCAAAAC CCGACTGGGT GAGTGTGCGC GCCCTGTCGG 1140

TAGGGTGTCA TCGCTGGCCC GAGGGATCTC GCGGCGGCGA ACGGAGGTGG CGACACAGGT 1200

GGAAGCTGCG CCCACTGGCT TGCGCCCCAA CGCCGTCGTG GGCGTTCGGT TGGCCGCACT 1260

GGCCGATCAG GTCGGCGCCG GCCCTTGGCC GAAGGTCCAG CTCAACGTGC CGTCACCGAA 1320 ·· ·« ·· it »· it · it · · • this • ·· ·· ·· • · · it

1119 it · • · it ·

GGACCGGACG GTCACCGGGG GTCACCCTGC GCGCCCAAGG AA

1362 (2) Sequence information of SEQ ID NO: 8:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1458 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8:

GCGACGACCC CGATATGCCG GGCACCGTAG CGAAAGCCGT CGCCGACGCA CTCGGGCGCG 60 GTATCGCTCC CGTTGAGGAC ATTCAGGACT GCGTGGAGGC CCGGCTGGGG GAAGCCGGTC 120 TGGATGACGT GGCCCGTGTT TACATCATCT ACCGGCAGCG GCGCGCCGAG CTGCGGACGG 180 CTAAGGCCTT GCTCGGCGTG CGGGACGAGT T AAA G C T Gh G CTT'oGCGeCc GTGACGGTAC 240 TGCGCGAGCG CTATCTGCTG CACGACGAGC AGGGCCGGCC GGCCGAGTCG ACCGGGCGAGC 300 TGATGGACCG ATCGGCGCGC TGTGTCGCGG CGGCCGAGGA CCAGTATGAG CCGGGCTCGT 360 CGAGGCGGTG GGCCGAGCGG TTCGCCACGC TATTACGCAA CCTGGAATTC CTGCCGAATT 420 CGCCCACGTT GATGAACTCT GGCACCGACC TGGGACTGCT CGCCGGCTGT TTTGTTCTGC 480 CGATTGAGGA TTCGCTGCAA TCGATCTTTG CGACGCTGGG ACAGGCCGCC GAGCTGCAGC 540 GGGCTGGAGG CGGCACCGGA TATGCGTTCA GCCACCTGCG ACCCGCCGGG GATCGGGTGG 600 CCTCCACGGG CGGCACGGCC AGCGGACCGG TGTCGTTTCT ACGGCTGTAT GACAGTGCCG 660 CGGGTGTGGT CTCCATGGGC GGTCGCGGCC GTGGCGCCTG TATGGCTGTG CTTGATGTGT 720 CGCACCCGGA TATCTGTGAT TTCGTCACCG CCAAGGCCGA ATCCCCCAGC GAGCTCCCGC 780 ATTTCAACCT ATCGGTTGGT GTGACCGACG CGTTCCTGCG GGCCGTCGAA CGCAACGGCC 840 TACACCGGCT GGTCAATCCG CGAACCGGCA AGATCGTCGC GCGGATGCCC GCCGCCGAGC 900 TGTTCGACGC CATCTGCAAA GCCGCGCACG CCGGTGGCGA TCCCGGGCTG GTGTTTCTCG 960 ACACGATCAA TAGGGCAAAC CCGGTGCCGG GGAGAGGCCG CATCGAGGCG ACCAACCGT 1020 GCGGGGAGGT CCCACTGCTG CCTTACGAGT CATGTAATCT CGGCTCGATC AACCTCGCCC 1080 GGATGCTCGC CGACGGTCGC GTCGACTGGG ACCGGCTCGA GGAGGTCGCC GGTGTGGCGG 1140 TGCGGTTCCT TGATGACGTC ATCGATGTCA GCCGCTACCC CTTCCCGAA CTGGGTGAGG 1200

75 • this this • · · it • this it· · · • · « ···> ·· ·· ·· ·· • · · »· • · ··· _t * • · · · it ··· ·«·· * ·· ·♦ ·· ·· • · • that it·· • ·· CGGCCCGCGC CACCCGCAAG ATCGGGCTGG GAGTCATGGG TTTGGGGAA CTGCTTGCCG 1260 CACTGGGTAT TCCGTACGAC AGTGAAGAAG CCGTGCGGTT AGCCACCCGG CTCATGCGTC 1320 GCATACAGCA GGCGGCGCAC ACGGCATCGC GGAGGCTGGC CGAAGAGCGGG GGCGCATTCC 1380 CGGCGTTCAC CGATAGCCGG TTCGCGCGGT CGGGCCCGAG GCGCAACGCA CAGGTCACCT 1440 CCGTCGTCCC GACGGGCA .1458

(2) Sequence information of SEQ ID NO: 9:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 862 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9:

ACGGTGTAAT CGTGCTGGAT CTGGAACCGC GTGGCCCGCT ACCTACCGAG ATCTACTGGC 60 GGCG.CAGGGG GCTGGCCCTG GGCATCGCGG TCGTCGTAGT CGGGATCGCG GTGGCCATCG 120 TCATCGCCTT CGTCGACAGC AGCGCCGGTG CCAAACCGGT CAGCGCCGAC AAGCCGGCCT 180 CCGCCCAGAG CCATCCGGGC TCGCCGGCAC CCCAAGCACC CCAGCCGGCC GGGCAAACCG 240 AAGGTAACGC CGCCGCGGCC CCGCCGCAGG GCCAAAACCC CGAGACACCC ACGCCCACCG 300 CCGCGGTGCA GCCGCCGCCG GTGCTCAAGG AAGGGGACGA TTGCCCCGAT TCGACGCTGG 360 CCGTCAAAGG TTTGACCAAC GCGCCGCAGT ACTACGTCGG CGACCAGCCG AAGTTCACCA 420 TGGTGGTCAC CAACATCGGC CTGGTGTCCT GTAAACGCGA CGTTGGGGCC GCGGTGTTGG 480 CCGCCTACGT TTACTCGCTG GACAACAAGC GGTTGTGGTC CAACCTGGAC TGCGCGCCCT 540 CGAATGAGAC GCTGGTCAAG ACGTTTTCCC CCGGTGAGCA GGTAACGACC GCGGTGACCT 600 GGACCGGGAT GGGATCGGCG CCGCGCTGCC CATTGCCGCG GCCGGCGATC GGGCCGGGCA 660 CCTACAATCT CGTGGTACAA CTGGGCAATC TGCGCTCGCT GCCGGTTCCG TTCATCCTGA 720 ATCAGCCGCC GCCGCGCCC GGGCCGGTAC CCGCTCCGGG TCCAGCGCAG GCGCCTCCG 780 CGGAGTTCCC CGCGCAAGGC GGATAATTAT TGATCGCTGA TGGTCGATTC CGCCAGCTGT 840

GACAACCCCT CGCCTCGTGC CG

862

(2) Sequence information of SEQ ID NO: 10:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 622 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10:

TTGATCAGCA CCGGCAAGGC GTCACATGCC TCCCTGGGTG TGCAGGTGAC CAATGACAAA 60 GACACCCCGG GCGCCAAGAT CGTCGAAGTA GTGGCCGGTG GTGCTGCCGC GAACGCTGGA 120 GTGCCGAAGG GCGTCGTTGT CACCAAGGTC GACGACCGCC CGATCAACAG CGCGGACGCG 180 TTGGTTGCCG CCGTGCGGTC CAAAGCGCCG GGCGCCACGG TGGCGCTAAC CTTTCAGGAT 240 CCCTCGGGCG GTAGCCGCAC AGTGCAAGTC ACCCTCGGCA AGGCGGAGCA GTGATGAAGG 300 TCGCCGCGCA GTGTTCAAAG CTCGGATATA CGGTGGCACC CATGGAACAG CGTGCGGAGT 360 TGGTGGTTGG CCGGGCACTT GTCGTCGTCG TTGACGATCG CACGGCGCAC GGCGATGAAG 420 ACCACAGCGG GCCGCTTGTC ACCGAGCTGC TCACCGAGGC CGGGTTTGTT GTCGACGGCG 480 TGGTGGCGGT GTCGGCCGAC GAGGTCGAGA TCCGAAATGC GCTGAACACA GCGGTGATCG 540 GCGGGGTGGA CCTGGTGGTG TCGGTCGGCG GGACCGGNGT GACGNCTCGC GATGTCACCC 600 CGGAAGCCAC CCGNGACATT CT 622 ) SEQ ID NO: 11 sequence information: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1200 pairs are wanted (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11: GGCGCAGCGG TAAGCCTGTT. GGCCGCCGGC ACACTGGTGT TGACAGCATG CGGCGGTGGC 60 ACCAACAGCT CGTCGTCAGG CGCAGGCGGA ACGTCTGGGT CGGTGCACTG CGGCGGCAAG 120 AAGGAGCTCC ACTCCAGCGG CTCGACCGCA CAAGAAAATG CCATGGAGCA GTTCGTCTAT 180

» · · • · • · · · • ·

• ·

GCCTACGTGC GATCGTGCCC GGGCTACACG TTGGACTACA ACGCCAACGG GTCCGGTGCC 2.4 0 GGGGTGACCC AGTTTCTCAA CAACGAAACC GATTTCGCCG GCTCGGATGT CCCGTTGAAT 300 CCGTCGACCG GTCAACCTGA CCGGTCGGCG GAGCGGTGCG GTTCCCGGC ATGGGACCTG 360 CCGACGGTGT TCGGCCCGAT CGCGATCACCC TACAATATCA AGGGCGTGAG CACGCTGAAT 420 CTTGACGGAC CCACTACCGC CAAGATTTTC AACGGCACCA TCACCGTGTG GAATGATCCA 480 CAGATCCAAG CCCTCAACTC CGGCACCGAC CTGCCGCCAA CACCGATTAG CGTTATCTTC 540 CGCAGCGACA AGTCCGGTAC GTCGGACAAC TTCCAGAAAT ACCTCGACGG TGTATCCAAC 600 GGGGCGTGGG GCAAAGGCGC CAGCGAAACG TTCAGCGGGG GCGTCGGCGT CGGCGCCAGC 660 GGGAACAACG GAACGTCGGC CCTACTGCAG ACGACCGACG GGTCGATCAC CTACAACGAG 720 TGGTCGTTTG CGGTGGGTAA GCAGTTGAAC ATGGCCCAGA TCATCACGTC GGCGGGTCCG 780 GATCCAGTGG CGATCACCAC CGAGTCGGTC GGTAAGACAA TCGCCGGGGC CAAGATCATG 840 GGACAAGGCA ACGACCTGGT ATTGGACACG TCGTCGTTCT ACAGACCCAC CCAGCCTGGC 900 TCTTACCCGA TCGTGCTGGC GACCTATGAG ATCGTCTGCT CGAAATACCC GGATGCGACG - 960 ACCGGTACTG CGGTAAGGGC GTTTATGCAA GCCGCGATTG GTCCAGGCCA AGAAGGCCTG 1020 GACCAATACG GCTCCATTCC GTTGCCCAAA TCGTTCCAAG CAAAATTGGC GGCCGCGGTG 1080 AATGCTATTT CTTGACCTAG TGAAGGGAAAT TCGACGGTGA GCGATGCCGT TCCGCAGGTA 1140 GGGTCGCAAT TTGGGCCGTA TCAGCTATTG CGGCTGCTGG GCCGAGGCGGG GATGGGCGAG 1200

(2) Sequence information of SEQ ID NO: 12:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1155 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12:

GCAAGCAGCT GCAGGTCGTG CTGTTCGACG AACTGGGCAT GCCGAAGACC AAACGCACCA 60 AGACCGGCTA CACCACGGAT GCCGACGCGC TGCAGTCGT GTTCGACAAG ACCGGGCATC 120 CGTTTCTGCA ACATCTGCTC GCCCACCGCG ACGTCACCCG GCTCAAGGTC ACCGTCGACG 180

• ·

GGTTGCTCCA AGCGGTGGCC GCCGACGCC GCATCCACAC CACGTTCAAC CAGACGATCG 240 CCGCGACCGG CCGGCTTCCC TCGACCGAAC CCAACCTGCA GAACATCCCG ATCCGCACCG. 300 ACGCGGCCCG GCGGATCCGG GACGCGTTCG TGGTCGGGGGA CGGTTACGCC GAGTTGATGA 360 CGGCCGACTA CAGCCAGATC GAGATGCGGA TCATGGGGCA CCTGTCCGGG GACGAGGGCC 420 TCATCGAGGC GTTCAACACC GGGGAGGACC TGTATTCGTT CGTCGCGTCC CGGGTGTTCG 480 GTGTGCCCAT CGACGAGGTC ACCGGCGAGT TGCGGCGCCG GGTCAAGGCG ATGTCCTACG 540 GGCTGGTTTA CGGGTTGAGC GCCTACGGCC TGTCGCAGCA GTTGAAAATC TCCACCGAGG 600 AAGCCAACGA GCAGATGGAC GCGTATTTCG CCCGATTCGG CGGGGTGCGC GACTACCTGC 660 GCGCCGTAG CGAGCGGGCC CGCAAGGACG GCTACACCTC GACGGTGCTG GGCCGTCGCC 720 GCTACCTGCC CGAGCTGGAC AGCAGCAACC GTCAAGTGCG GGAGGCCGCC GAGCGGGCGG 780 CGCTGAACGC GCCGATCCAG GGCAGCGCGG CCGACATCAT CAAGGTGGCC ATGATCCAGG 840 TCGACAAGGC GCTCAACGAG GCACAGCTGG CGTCGCGCAT GCTGCTGCAG GTCCACGACG 900. AGCTGCTGTT CGAAATCGCC CCCGGTGAAC GCGAGCGGGT CGAGGCCCTG GTGCGCGACA 960 AGATGGGCGG CGCTTACCCG' CTCGACGTCC CGCTGGAGGT GTCGGTGGGC TACGGCCGCA 1020 GCTGGGACGC GGCGGCGCAC TGAGTGCCGA GCGTGCATCT GGGGGGGGAA TTCGGGGATT 1080 TTTCCGCCT GAGTTCACGC TCGGCGCAAT CGGGACCGAG TTTGTCCAGC GTGTACCCGT 1140 CGAGTAGCCT CGTCA 1155 2) Information about the sequence of SEQ ID NO: 13: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1771 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: GAGCGCCGTC TGGTGTTGA ACGGTTTTAC CGGTCGGCAT CGGCACGGGC GTTGCCGGGT 60 TCGGGCCTCG GGTTGGCGAT CGTCAAACAG GTGGTGCTCA ACCACGGCGGG ATTGCTGCGC 120 ATCGAAGACA CCGACCCAGG CGGCCAGCCC CCTGGAACGT CGATTTACGT GCTGCTCCCC 180

• · • ·

- 79 ·· ·· • · · · · • · · · • · · · · • · · · • · · · · · ·· ·· ·· • · · · • ··· · · • · · · · · · • · · · ·· ·· ·· • · • · • · • · · • • · GGCCGTCGGA TGCCGATTCC GCAGCTTCCC GGTGCGACGG CTGGCGCTCG GAGCACGGAC 240 ATCGAGAACT CTCGGGGTTC GGCGAACGTT ATCTCAGTGG AATCTCAGTC CACGCGCGCA 300 ACCTAGTTGT GCAGTTACTG TTGAAAGCCA CACCCATGCC AGTCCACGCA TGGCCAAGTT 360 GGCCCGAGTA GTGGGCCTAG TACAGGAAGA GCAACCTAGC GACATGACGA ATCACCCACG 420 GTATTGCCA CCGCCGCAGC AGCCGGGAAC CCCAGGTTAT GCTCAGGGGC AGCAGCAAAC 480 GTACAGCCAG CAGTTCGACT GGCGTTACCC ACCGTCCCCG CCCCCGCAGC CAACCCAGTA 540 CCGTCAACCC TACGAGGCGT TGGGTGGTAC CCGGCCGGGT CTGATACCTG GCGTGATTCC 600 GACCATGACG CCCCCTCCTG GGATGGTTCG CCAACGCCCT CGTGCAGGCA TGTTGGCCAT 660 CGGCGCGGTG ACGATAGCGG TGGTGTCCGC CGGCATCGGC GGCGCGGCCG CATCCCTGGT 720 CGGGTTCAAC CGGGGCACCCG CCGGCCCCAG CGGCGGCCCA GTGGCTGCCA GCGCGGCC 780 AAGCATCCCC GCAGCAAACA TGCCGCCGGG GTCGGTCGAA CAGGTGGCGG CCAAGGTGGT 840 GCCCAGTGTC GTCATGTTGG AAACCGATCT GGGCCGCCAG TCGGAGGAGG GCTCCGGCAT 900 CATTCTGTCT GCCGAGGGGCC TGATCTTGAC CAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA GTGATCGCGG CGGCCGCCAA 960 GCCTCCCCTG GGCAGTCCGC CGCCGAAAAC GACGGTAACC TTCTCTGACG GGCGGACCGC 1020 ACCCTTCACG GTGGGGGGGG CTGACCCCAC CAGTGATATC GCCGTCGTCC GTGTTCAGGG 1080 CGTCTCCGGG CTCACCCCGA TCTCCCTGGG TTCCTCTCCG GACCTGAGGG TCGGTCAGCC 1140 GGTGCTGGCG ATCGGGTCGC CGCTCGGTTT GGGGGGCACC GTGACCACGG GGATCGTCAG 1200 CGCTCTCAAC CGTCCAGTGT CGACGACCGG CGAGGCCGGC AACCAGAACA CCGTGCTGGA 1260 CGCCATTCAG ACCGACGCCG CGATCAACCC CGGTAACTCC GGGGGCCGGC TGGTGAACAT 1320 GAACGCTCAA CTCGTCGGAG TCAACTCGGC CATTGCCACG CTGGGCGCGG ACTCAGCCGA 1380 TGCGCAGAGC GGCTCGATCG GTCTCGGTTT TGCGATTCCA GTCGACCAGG CCAAGCGCAT 1440 CGCCGACGAG TTGATCAGCA CCGGCAAGGC GTCACATGCC TCCCTGGGTG TGCAGGTGAC 1500 CAATGACAAA GACACCCCGG GCGCCAAGAT CGTCGAAGTA GTGGCCGGTG GTGCTGCCGC 15.60 GAACGCTGGA GTGCCGAAGG GCGTCGTTGT CACCAAGGTC GACGACCGCC CGATCAACAG 1620 CGCGGACGCG TTGGTTGCCG CCGTGCGGTC CAAAGCGCCG GGCGCCACGG TGGCGCTAAC 1680 CTTTCAGGAT CCCTCGGGCG GTAGCCGCAC AGTGCAAGTC ACCCTCGGCA AGGCGGAGCA 1740

GTGATGAAGG TCGCCGCGCA GTGTTCAAAG C

1771

(2) Sequence information of SEQ ID NO: 14:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1058 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14:

CTCCACCGCG GTGGCGGCCG CTCTAGAACT AGTGGATCCC CCGGGCTGCA GGAATTCGGC 60 ACGAGGATCC GACGTCGCAG GTTGTCGAAC CCGCCGCCGC GGAAGTATCG GTCCATGCCT 120 AGCCCGGCGA CGGCGAGCGC CGGAATGGCG CGAGTGAGGA GGCGGGCAAT TTGGCGGGGC 180 CCGGCGACGG CGAGCGCCGG AATGGCGCGA GTGAGGAGGC GGGCAGTCAT GCCCAGCGTG 240 ATCCAATCAA CCTGCATTCG GCCTGCGGGC CCATTTGACA ATCGAGGTAG TGAGCGCAAA 300 TGAATGATGG AAAACGGGCG GTGACGTCCG CTGTTCTGGT GGTGCTAGGT GCCTGCCTGG 360 CGTTGTGGCT ATCAGGATGT TCTTCGCCGA AACCTGATGC CGAGGAACAG GGTGTTCCCG 420 TGAGCCCGAC GGCGTCCGAC CCCGCGCTCC TCGCCGAGAT CAGGCAGTCG CTTGATGCGA 480 CAAAAGGGTT GACCAGCGTG CACGTAGCGG TGCGAAAAAAC CGGGAAAGTC GACAGCTTGC 540 TGGGTATTAC CAGTGCCGAT GTCGACGTCC GGGCCAATCC GCTCGCGGCA AAGGGCGTAT 600 GCACCTACAA CGACGAGCAG GGTGTCCCGT TTCGGGTACA AGGCGACAAC ATCTCGGTGA 660 AACTGTTCGA CGACTGGAGC AATCTCGGCT CGATTTCTGA ACTGTCAACT TCACGCGTGC . 720 TCGATCCTGC CGCTGGGGTG ACGCAGCTGC TGTCCGGTGT CACGAACCTC CAAGCGCAAG 780 GTACCGAAGT GATAGACGGA ATTTCGACCA CCAAAATCAC CGGGACCATC CCGCGAGCT 840 CTGTCAAGAT GCTTGATCCT GGCGCCAAGA GTGCAAGGCC GGCGACCGTG TGGATTGCCC 900 AGGACGGCTC GCACCACCTC GTCCGAGCGA GCATCGACCT CGGATCCGGG TCGATTCAGC 960 TCACGCAGTC GAAATGGAAC GAACCCGTCA ACGTCGACTA GGCCGAAGTT GCGTCGACGC 1020

GTTGNTCGAA ACGCCCTTGT GAACGGTGTC AACGGNAC

1058 (2) Sequence information of SEQ ID NO: 15:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 542 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15:

GAATTCGGCA CGAGAGGTGA TCGACATCAT CGGGACCAGC CCCACATCCT GGGAACAGGC 60 GGCGGCGGAG GCGGTCCAGC GGGGCGGGGA TAGCGTCGAT GACATCCGCG TCGCTCGGGT 120 CATTGAGCAG GACATGGCCG TGGACAGCGC CGGCAAGATC ACCTACCGCA TCAAGCTCGA 180 AGTGTCGTTC AAGATGAGGC CGGCGCAACC GCGCTAGCAC GGGCCGGCGGA GCAAGACGCA 240 AAATCGCACG GTTTGCGGTT GATTCGTGCG ATTTTGTGTC TGCTCGCCGA GGCCTACCAG 300 GCGCGGCCCA GGTCCGCGTG CTGCCGTATC CAGGCGTGCA TCGCGATTCC GGCGGCCACG 360 CCGGAGTTAA TGCTTCCGGT CGACCCGAAC TGGGCGATCC GCCGGNGAGC TGATCGATGA 420 CCGTGGCCAG CCCGTCGATG CCCGAGTTGC C C G A.O Lj AAzi GTGCTGCCAG GCCGGTAGGA 480 AGCGTCCGTA GGCGGCGGTG CTGACCGGCT CTGCCTGCGC CCTCAGTGCG GCCAGCGAGC 540 GG 542 2) Sequence Information SEQ ID NO: 16: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 913 bp (B) TYPE: Nucleic Acid ¹ (C) STRAND TYPE: Single Strand (D) TOPOLOGY: Linear (xi) DESCRIPTION SEQUENCE: SEQ ID NO: 16:

CGGTGCCGCC CGCGCCTCCG TTGCCCCCAT TGCCGCCGTC GCCGATCAGC TGCGCATCGC 60 CACCATCACC GCCTTTGCCG CCGGCACCGC CGGTGGCCC GGGGCCGCCG ATGCCACCGC 120 TTGACCCTGG CCGCCGGCGC CGCCATTGCC ATACAGCACC CCGCCGGGGG CACCGTTACC 180 GCCGTCGCCA CCGTCGCCGC CGCTGCCGTT TCAGGCCGGG GAGGCCGAAT GAACCGCCGC 240 CAAGCCCGCC GCCGGCACCG TTGCCGCCTT TTCCGCCCGC CCCGCCGGCG CCGCCAATTG 300 CCGAACAGCC AMGCACCGTT GCCGCCAGCC CCGCCGCCGT TAACGGCGCT CCGGGGCGCC 360 GCCGCCGGAC CCGCCATTAC CGCCGTTCCC GTTCGGTGCC CCGCCGTTAC CGGCGCCGCC 420

• · • · ··· · ··

GTTTGCCGCC AATATTCGGC GGGCACCGCC AGACCCGCCG GGGCCACCAT TGCCGCCGGG 480 CACCGAAACA ACAGCCCAAC GGTGCCGCCG GCCCCGCCGT TTGCCGCCAT CACCGGCCAT 540 TCACCGCCAG CACCGCCGTT AATGTTTATG AACCCGGTAC CGCCAGCGCG GCCCCTATTG 600 CCGGGGCGCCG GAGNGCGTGC CCGCCGGCGC CGCCAACGCC CAAAGCCCG GGGTTGCCAC 660 CGGCCCCGCCC GGACCCACCG GTCCCGCCGA TCCCCCCGTT GCCGCCGGTG CCGCGCCAT 720 TGGTGCTGCT GAAGCCGTTA GCGCCGGTTC CGCSGGTTCC GGCGGTGGCG CCNTGGCCGC 780 CGGCCCCGCCC GTTGCCGTAC AGCCACCCCC CGGTGGCCC GTTGCCGCCA TTGCCGCCAT 840 TGCCGCCGTT GCCGCCATTG CCGCCGTTCC CGCCGCCACC GCCGGNTTGG CCGCCGGCGC 900 CGCCGGCGGC CGC 913

(2) Sequence information of SEQ ID NO: 17:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1872 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17:

GACTACGTTG GTGTAGAAAA ATCCTGCCGC CCGGACCCTT AAGGCTGGGA CAATTTCTGA 60

TAGCTACCCC GACACAGGAG GTTACGGGAT GAGCAATTCG CGCCGCCGCT CACTCAGGTG 120

GTCATGGTTG CTGAGCGTGC TGGCTGCCGT CGGGCTGGGC CTGGCCACGG CGCCGGCCCA 180

GGCGGCCCCG CCGGCCTTGT CGCAGGACCG GTTCGCCGAC TTCCCCGCGC TGCCCCTCGA 240

CCCGTCCGCG ATGGTCGCCC AAGTGGCGCC ACAGGTGGTC AACATCAACA CCAAACTGGG ·300

CTACAACAAC GCCGTGGGCG CCGGGACCGG CATCGTCATC GATCCCAACG GTGTCGTGCT 360

GACCAACAAC CACGTGATCG CGGGCGCCAC CGACATCAAT GCGTTCAGCG TCGGCTCCGG 420

CCAAACCTAC GGCGTCGATG TGGTCGGGTA TGACCGCACC CAGGATGTCG CGGTGCTGCA 480

GCTGCGCGGT GCCGGTGGCC TGCCGTCGGC GGCGATCGGT GGCGGCGTCG CGGTTGGTGA 540

GCCCGTCGTC GCGATGGGCA ACAGCGGTGG GCAGGGCGGA ACGCCCCGTG CGGTGCCTGG 600

CAGGGTGGTC GCGCTCGGCC AAACCGTGCA GGCGTCGGAT TCGCTGACCG GTGCCGAAGA 660 • · • · · ·

83 • · · · • · · · · · • · · · • · · · · · • • · GACATTGAAC GGGTTGATCC AGTTCGATGC CGCAATCCAG CCCGGTGATT CGGGCGGGCC 720 CGTCGTCAAC GGCCTAGGAC AGGTGGTCGG TATGAACACG GCCGCGTCCG ATAACTTCCA 780 GCTGTCCCAG GGTGGGCAGG GATTCGCCAT TCCGATCGGG CAGGCGATGG CGATCGCGGG 840 CCAAATCCGA TCGGGTGGG GGTCACCCAC CGTTCATATC GGGCCTACCG CCTTCCTCGG 900 CTTGGGTGTT GTCGACAACA ACGGCAACGG CGCACGAGTC CAACGCGTGG TCGGAAGCGC 960 TCCGGCGGCA AGTCTCGGCA TCTCCACCGG CGACGTGATC ACCGCGGTCG ACGGCGCTCC 1020 GATCAACTCG GCCACCGCGA TGGCGGACGC GCTTAACGGG CATCATCCCG GTGACGTCAT 1080 CTCGGTGAAC TGGCAAACCA AGTCGGGCGG CACGCGTACA GGGAACGTGA CATTGGCCGA 1140 GGGACCCCCG GCCTGATTTG TCGCGGATAC CACCCGCCGG CCGGCCAATT GGATTGGCGC 1200 CAGCCGTGAT TGCCGCGTGA GCCCCCGAGT TCCGTCTCCC GTGCCGGTGG CATTGTGGAA 1260 GCAATGAACG AGGCAGAACA CAGCGTTGAG CACCCTCCCG TGCAGGGCAG TTACGTCGAA. 1320 GGCGGTGTGG TCGAGCATCC GGATGCCAAG GACTTCGGCA GCGCGCGCGC CCTGCCCGCC 1380 GATCCGACCT GGTTTAAGCA CGCCGTCTTC TACGAGGTGC TGGTCCGGGC GTTCTTCGAC 1440 GCCAGCGCGG ACGGTTCCGN CGATCTGCGT GGACTCATCG ATCGCCTCGA CTACCTGCAG 1500 TGGCTTGGCA TCGACTGCAT CTGTTGCCGC CGTTCCTACG ACTCACCGCT GCGCGACGGC 1560 GGTTACGACA TTCGCGACTT CTACAAGGTG CTGCCCGAAT TCGGCACCGT CGACGATTTC 1620 GTCGCCCTGG TCGACACCGC TCACCGGCGA GGTATCCGCA TCATCACCGA CCTGGTGATG 1680 AATCACACCT CGGAGTCGCA CCCCTGGTTT CAGGAGTCCC GCCGCGACCC AGACGGACCG 1740 TACGGTGACT ATTACGTGTG GAGCGACAC AGCGAGCGCT ACACCGACGC CCGGATCATC 1800 TTCGTCGACA CCGAAGAGTC GAACTGGTCA TTCGATCCTG TCCGCCGACA GTTNCTACTG 1860 GCACCGATTC TT 1872

(2) Sequence information of SEQ ID NO: 18:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1482 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18:

• · • ·

• · · · • · · · · · • · · · • · · · · · • • · 84 CTTCGCCGAA ACCTGÁTGCC GAGGAACAGG GTGTTCCCGT GAGCCCGACG GCGTCCGACC 60 CCGCGCTCCT CGCCGAGATC AGGCAGTCGC TTGATGCGAC AAAAGGGTTG ACCAGCGTGC 120 ACGTAGCGGT CCGAACAACC GGGAAAGTCG ACAGCTTGCT GGGTATTACC AGTGCCGATG 180 TCGACGTCCG GGCCAATCCG CTCGCGGCAA AGGGCGTATG CACCTACAAC GACGAGCAGG 240 GTGTCCCGTT TCGGGTACAA GGCGACAACA TCTCGGTGAA ACTGTTCGAC GACTGGAGCA 300 ATCTCGGCTC GATTTCTGAA CTGTCAACTT CACGCGTGCT CGATCCTGCC GCTGGGGTGA 360 CGCAGCTGCT GTCCGGTGTC ACGAACCTCC AAGCGCAAGG TACCGAAGTG ATAGACGGAA 420 TTTCGACCAC CAAATCACC GGGACCATCC CCGCGAGCTC TGTCAAGATG CTTGATCCTG 480 GCGCCAAGAG TGCAAGGCCG GCGACCGTGT GGATTGCCCA GGACGGCTCG CACCACCTCG 540 TCCGAGCGAG CATCGACCTC GGATCCGGGT CGATTCAGCT CACGCAGTCG AAATGGAACG 600 AACCCGTCAA CGTCGACTAG GCCGAAGTTG CGTCGACGCG TTGCTCGAAA CGCCCTTGTG 660 AACGGTGTCA ACGGCACCCG AAAACTGACC CCCTGACGGC ATCTGAAAAT TGACCCCCTA 720 GACCGGGCGG TTGGTGGTTA TTCTTCGGTG GTTCCGGCTG GTGGGACGCG GCCGAGGTCG 780 CGGTCTTTGA GCCGGTAGCT GTCGCCTTTG AGGGCGACGA CTTCAGCATG GTGGACGAGG 840 CGGTCGATCA TGGCGGCAGC AACGACGTCG TCGCCGCCGA AAACCTCGCC CCACCGGCCG 900 AAGGCCTTAT TGGACGTGAC GATCAAGCTG GCCCGCTCAT ACCGGGGAGGA CACCAGCTGG 960 AAGAAGAGGT TGGCGGCCTC GGGCTCAAAC GGAATGTAAC CGACTTCGTC AACCACCAGG 1020 AGCGGATAGC GGCCAAACCG GGTGAGTTCG GCGTAGATGC GCCCGGCGTG GTGAGCCTCG 1080 GCGAACCGTG CTACCCATTC GGCGGCGGTG GCGAACAGCA CCCGATGACC GGCCTGACAC 1140 GCGCGTATCG CCAGGCCGAC CGCAAGATGA GTCTTCCCGG TGCCAGGCGG GGCCCAAAA 1200 CACGACGTTA TCGCGGGCGG TGATGAAATC CAGGGTGCCC AGATGTGCGA TGGTGTCGCG 1260 TTTGAGGCCA CGAGCATGCT CAAAGTCGAA CTCTTCCAAC GACTTCCGAA CCGGGAAGCG 1320 GGCGGCGCGG ATGCGGCCCT CACCACCATG GGACTCCCGG GCTGACACTT CCCGCTGCAG 1380 GCAGGCGGCC AGGTATTCT CGTGGCTCCA GTTCTCGGCG CGGGCGCGAT CGGCCAGCCG 1440

GGACACTGAC TCACGCAGGG TGGGAGCTTT CAATGCTCTT GT

1482 ·· ·· (2) Sequence information of SEQ ID NO: 19:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 876 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19:

GAATTCGGCA CGAGCCGGCG ATAGCTTCTG GGCCGCGGCC GACCAGATGG CTCGAGGGTT 60 CGTGCTCGGG GCCACCGCCG GGCGCACCAC CCTGACCGGT GAGGGCCTGC AACACGCCGA 120 CGGTCACTCG TTGCTGCTGG ACGCCACCAA CCGGCGGGTG GTTGCCTACG ACCCGGCCTT 180 CGCCTACGAA ATCGGCTACA TCGNGGAAAG CGGACTGGCC AGGATGTGCG GGGAGAACCC 240 GGAGAACATC TTCTTCTACA TCACCGTCTA CAACGAGCCG TACGTGCAGC CGCCGGAGCC 300 GGAGAACTTC GATCCCGAGG GCGTGCTGGG GGGTATCTAC CGNTATCACG CGGCCACCGA 360 GCAACGCACC AACAAGGNGC AGATCCTGGC CTCCGGGGTA GCGATGCCCG CGGCGCTCG 420 GGCAGCACAG ATGCTGGCCG CCGAGTGGGA TGTCGCCGCC GACGTGTGGT CGGTGACCAG 480 TTGGGGCGAG CTAAACCGCG ACGGGGTGGT CATCGAGACC GAGAAGCTCC GCCACCCCGA' 540 TCGGCCGGCG GGCGTGCCCT ACGTGACGAG AGCGCTGGAG AATGCTCGGG GCCCGGTGAT 600 CGCGGTGTCG GACTGGATGC GCGCGGTCCC CGAGCAGATC CGACCGTGGG TGCCGGGCAC 660 ATACCTCACG TTGGGCACCG ACGGGTTCGG TTTTTCCGAC ACTCGGCCCG CCGGTCGTCG 720 TTACTTCAC ACCGACGCCG AATCCCAGGT TGGTCGCGGT TTTGGGGGG GTTGGCCGGG. 780 TCGACGGGTG AATATCGACC CATTCGGTGC CGGTCGTGGG CCGCCCGCCC AGTTACCCGG 840 ATTCGACGAA GGTGGGGGGT TGCGCCCGAN TAAGTT 876

(2) Sequence information of SEQ ID NO: 20:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1021 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20

ATCCCCCCGG GCTGCAGGAA TTCGGCACGA GAGACAAAAT TCCACGCGTT AATGCAGGAA 60 • ··

86 • · · · ··· · ·· • · · · • · · · · · • « · CAGATTCATA ACGAATTCAC AGCGGCACAA CAATATGTCG CGATCGCGGT TTATTTCGAC 120 AGCGAAGACC TGCCGCAGTT GGCGAAGCAT TTTTACAGCC AAGCGGTCGA GGAACGAAAC 180 CATGCAATGA TGCTCGTGCA ACACCTGCTC GACCGCGACC TTCGTGTCGA AATTCCCGGC 240 GTAGACACGG TGCGAAACCA GTTCGACAGA CCCCGCGAGG CACTGGCGCT GGCGCTCGAT 300 CAGGAACGCA CAGTCACCGA CCAGGTCGGT CGGCTGACAG CGGTGGCCCG CGACGAGGGC 360 GATTTCCTCG GCGAGCAGTT CATGCAGTGG TTCTTGCAGG AACAGATCGA AGAGGTGGCC 420 TTGATGGCAA CCCTGGTGCG GGTTGCCGAT GGGGCCGGGG CCAACCTGTT CGAGCTAGAG 480 AACTTCGTCG CACGTGAAGT GGATGTGGCG CCGGCCGCAT CAGGCGCCCC GCACGCTGCC 540 GGGGGCCGCC TCTAGATCC TGGGGGGAT CAGCGAGTGG TCCCGTTCGC CCGCCCGTCT 600 TCCAGCCAGG CCTTGGTGCG GCCGGGGTGG TGAGTACCAA TCCAGGCCAC CCCGACCTCC 660 CGGNAAAAGT CGATGTCCTC GTACTCATCG ACGTTCCAGG AGTACACCGC CCGGCCCTGA 720 GCTGCCGAGC GGTCAACGAG TTGCGGATAT TCCTTTAACG CAGGCAGTGA GGGTCCCACG 780 GCGGTTGGCC CGACCGCCGT GGCCGCACTG CTGGTCAGGT ATCGGGGGGT CTTGGCGAGC 840 AACAACGTCG GCAGGAGGGG TGGAGCCCGC CGGATCCGCA GACCGGGGGG GCGAAAACGA 900 CATCAACACC GCACGGGATC GATCTGCGGA GGGGGGTGCG GGAATACCGA ACCGGTGTAG 960 GAGCGCCAGC AGTTGTTTTT CCACCAGCGA AGCGTTTTCG GGTCATCGGN GGCNNTTAAG 1020 T (2) Sequence information of SEQ ID NO: 21: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 321 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21 1021 CGTGCCGACG AACGGAAGAA CACAACCATG AAGATGGTGA AATCGATCGC CGCAGGTCTG 60 ACCGCCGCGG CTGCAATCGG CGCCGCTGCG GCCGGTGTGGA CTTCGATCAT GGCTGGCGGN 120 CCGGTCGTAT ACCAGATGCA GCCGGTCGTC TTCGGCGCGC CACTGCCGTT GGACCCGGNA 180

• · · · • · · · · 4 · ·· ··· ··· ······· · ·___.

4··4 44 44 44 44 44

TCCGCCCCTG ANGTCCCGAC CGCCGCCCAG TGGACCAGNC TGCTCAACAG NCTCGNCGAT 240 CCCAACGTGT CGTTTGNGAA CAAGGGNAGT CTGGTCGAGG GNGGNATCGG NGGNANCGAG 300 GGGNGNATC GNCGANCACA AND 321

(2) Information ο the sequence of SEQ ID NO: 22:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 373 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22:

TCTTATCGGT TCCGGTTGGC GACGGGTTTT GGGNGCGGGT GGTTAACCCG CTCGGCCAGC 60

CGATCGACGG GCGCGGAGAC GTCGACTCCG ATACTCGGCG CGCGCTGGAG CTCCAGGCGC 120

CCTCGGTGGT GNACCGGCAA GGCGTGAAGG AGCCGTTGNA GACCGGGATC AAGGCGATTG 180

ACGCGATGAC CCCGATCGGC CGCGGGCAGC GCCAGCTGAT CATCGGGGAC CGCAAGACCG 240

GCAAAACCG CCGTCTGTGT CGGACACCAT CCTCAAACCA GCGGGAAGAA CTGGGAGTCC 300

GGTGGATCCC AAGAAGCAGG TGCGCTTGTG TATACGTTGG CCATCGGGCA AGAAGGGGAA' 360 CTTACCATCG CCG 373 (2) Sequence Information SEQ ID NO: 23:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 352 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23:

GTGACGCCGT GATGGGATTC CTGGGCGGGG CCGGTCCGCT GGCGGTGGTG GATCAGCAAC 60 TGGTTACCCG GGTGCCGCAA GGCTGGTCGT TTGCTCAGGC AGCCGCTGTG CCGTTGACGGC CTGGTACGGG TTGGCCGATT TAGCCGAGAT CAAGGCGGC GAATCGGTGC 180 TGATCCATGC CGGTACCGGC GGTGTGGGCA TGGCGGCTGT GCAGCTGGCT CGCCAGTGGG 240 • · « · < · • · · · » · · 0 ·«·· ·· ·· ·· ··

GCGTGGAGGT TTTCGTCACC GCCAGCCGTG GNAAGTGGGGA CACGCTGCGC GCCATNGNGT 300 TTGACGACGA NCCATATCGG NGATTCCCNC ACATNCGAAG TTCCGANGGA GA 352 (2) Sequence information of SEQ ID NO: 24: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 726 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24: GAAATCCGCG TTCATTCCGT TCGACCAGCG GCTGGCGATA ATCGACGAAG TGATCAAGCC 60 GCGGTTCGCG GCGCTCATGG GTCACAGCGA GTAATCAGCA AGTTCTCTGG TATATCGCAC 120 CTAGCGTCCA GTTGCTTGCC AGATCGCTTT CGTACCGTCA TCGCATGTAC CGGTTCCGGT 180 GCCGCACGCT CATGCTGGCG GCGTGCATCC TGGCCACGGG TGTGGCGGGT CTCGGGGTC 240 GCGCGCAGTC CGCAGCCCAA ACCGCGCGG TGCCCGACTA CTACTGGTGC CCGGGGCAGC 300 CTTTCGACCC CGCATGGGG CCCAACTGGG ATCCCTACAC CTGCCATGAC GACTTCCACC 360 GCCAGCGA CGGCCCCGAC CACAGCCGCG ACTACCCCGG ACCCATCCTC GAAGGTCCCG 420 TGCTTGACGA TCCCGGTGCT GCGCGCGCGC CCCCGGCTGC CGGTGGCGG GCATAGCGCT 480 CGTTGACCGG GCCGCATCAG CGAATACGCG TATAAACCCG GGCGTGCCCC CGGCAAGCTA 540 CGACCCCCGG CGGGGCAGAT TTACGCTCCC GTGCCGATGG ATCGCGCCGT CCGATGACAG 600 AAAAATAGGCG ACGGTTTTGG CAACCGCTTG GAGGACGCTT GAAGGGAACC TGTCATGAAC 660 GGCGACAGCG CCTCCACCAT CGACATCGAC AAGGTTGTTA CCCGCACACC CGTTCGCCGG 720 ATCGTG 726

(2) Sequence information of SEQ ID NO: 25:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 580 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 25:

» * φ« ·· «··« · · · » · * · • «« * · ··· · » · · • · · · · * · ·· »·· «»« ···«*· · 9 · ······ · · 99 9 9 99

CGCGACGACG ACGAACGTCG GGCCCACCAC CGCCTATGCG TTGATGCAGG CGACCGGGAT 60 GGTCGCCGAC CATATCCAAG CATGCTGGGT GCCCACTGAG CGACCTTTTG ACCAGCCGGG . 120 CTGCCCGATG GCGGCCCGGT GAAGTCATTG CGCCGGGGCT TGTGCACCTG ATGAACCCGA 180 ATAGGGAACA ATAGGGGGGT GATTTGGCAG TTCAATGTCG GGTATGGCTG GAAATCCAAT 240 GGCGGGGCAT GCTCGGCGCC GACCAGGCTC GCGCAGGCGG GCCAGCCCGA ATCTGGAGGG 300 AGCACTCAAT GGCGGCGATG AAGCCCCGGA CCGGCGACGG TCCTTTGGAA GCAACTAAGG 360 AGGGGCGCGG CATTGTGATG CGAGTACCAC TTGAGGGTGG CGGTCGCCTG GTCGTCGAGC 420 TGACACCCGA CGAAGCCGCC GCACTGGGTG ACGAACTCAA AGGCGTTACT AGCTAAGACC 480 AGCCCAACGG CGAATGGTCG GCGTTACGCG CACACCTTCC GGTAGATGTC CAGTGTCTGC 540 TCGGCGATGT ATGCCCAGGA GAACTCTTGG ATACAGCGC? (2) Sequence information of SEQ ID NO: 26: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 160 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26: 580

AACGGAGGCG CCGGGGGTTT TGGCGGGGCC GGGGCGGTCG GCGGCAACGG CGGGGCCGGC 60 GGTACCGCCG GGTTGTTCGG TGTCGGCGGG GCCGGTGGGG CCGGAGGCAA CGGCATCGCC 120 GGTGTCACGG GTACGTCGGC CAGCACACCG GGTGGATCCG 160

(2) Information ο the sequence of SEQ ID NO: 27:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 272 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27:

φφφφ φφ • · φφ • φ « • · «φ φφ φφ

ΦΦΦ • · • · • Φ φφ φφ • · · φ • · · · • φφ ΦΦΦ φ φ φφ φφ

GACACCGATA CGATGGTGAT GTACGCCAAC GTTGTCGACA CGCTCGAGGC GTTCACGATC 60 CAGCGCACAC CCGACGGCGT GACCATCGGC GATGCGGCCC CGTTCGCGGA GGCGGCTGCC 120 AAGGCGATGG GAATCGACAA GCTGCGGGTA ATTCATACCG GAATGGACCC CGTCGTCGCT 180 GAACGCGAAC AGTGGGACGA CGGCAACAAC ACGTTGGCGT TGGCGCCCGG TGTCGTTGTC 240 GCCTACGAGC GCAACGTACA GACCAACGCC CG 272

(2) Information ο the sequence of SEQ ID NO: 28:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 317 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 28:

GCAGCCGGTG GTTCTCGGAC TATCTGCGCA CGGTGACGCA GCGCGACGTG CGCGAGCTGGA 60 AGCGGATCGA GCAGACGGAT CGCCTGCCGC GGTTCATGCG CTACCTGGCC GCTATCACCG 120 CGCAGGAGCT GAACGTGGCC GAAGCGGCGC GGGTCATCGG GGTCGACGCG GGGACGATCC 180 GTTCGGATCT GGCGTGGTTC GAGACGGTCT ATCTGGTACA TCGCCTGCCC GCCTGGTCGC 240 GGAATCTGAC CGCGAAGATC AAGAAGCGGT CAAAGATCCA CGTCGTCGAC AGTGGCTTCG 300 CGGCCTGGTT GCGCGGG 317

(2) Sequence information of SEQ ID NO: 29:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 182 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 29:

GATCGTGGAG CTGTCGATGA ACAGCGTTGC CGGACGCGCG GCGGCCAGCA CGTCGGTGTA 60 • · · · • · • · · · · · · ··· · · ·· · ·

GCAGCGCCGG ACCACCTCGC CGGTGGGCAG CATGGTGATG ACCACGTCGG CCTCGGCCAC 120 CGCTTCGGGC GCGCTACGAA ACACCGCGAC ACCGTGCGCG GCGGCGCCGG ACGCCGCCGT 180 GG 182

(2) Sequence information of SEQ ID NO: 30:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 308 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30:

GATCGCGAAG TTTGGTGAGC AGGTGGTCGA CGCGAAAGTC TGGGCGCCTG CGAAGCGGGT 60 CGGCGTTCAC GAGGCGAAGA CACGCCTGTC CGAGCTGCTG CGGCTCGTCT ACGGCGGGCA 120 GAGGTTGAGA TTGCCCGCCG CGGCGAGCCG GTAGCAAAGC TTGTGCCGCT GCATCCTCAT 180 GAGACTCGGC GGTTAGGCAT TGACCATGGC GTGTACCGCG TGCCCGACGA TTTGGACGCT' 240 CCGTTGTCAG ACGACGTGCT CGAACGCTTTT CACCGGTGAA GCGCTACCTC ATCGACACCC 300

ACGTTTGG (2) Sequence Information SEQ ID NO: 31:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 267 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31:

CCGACGACGA GCAACTCACG TGGATGATGG TCGGCAGCGG CATTGAGGAC GGAGAGAATC 60 CGGCCGAAGC TGCCGCGCGG CAAGTGCTCA TÁGTGACCGG CCGTAGAGGG CTCCCCCGAT 120 GGCACCGGAC TATTCTGGTG TGCCGCTGGC CGGTAAGAGC GGGTAAAAA ATGTGAGGGG 180 ACACGATGAG CAATCACACC TACCGAGTGA TCGAGATCGT CGGGACCTCCG CCCGACGGCG 240

TCGACGCGGC AATCCAGGGC GGTCTGG

267 • · • · • ·

• · · · · · · ···· ·· ·· ·· • · • · · · 92 2) Information about the sequence of SEQ ID NO: 32: - (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1539 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32:

CTCGTGCCGA AAGAATGTGA GGGGACACGA TGAGCAATCA CACCTACCGA GTGATCGAGA 60 TCGTCGGGAC CTCGCCCGAC GGCGTCGACG CGGCAATCCA GGGCGGTCTG GCCCGAGCTG 120 CGCAGACCAT GCGCGCGCTG GACTGGTTCG AAGTACAGTC AATTCGAGGC CACCTGGTCG 180 ACGGAGCGGT CGCGCACTTC CAGGTGACTA TGAAAGTCGG CTTCCGCTGG AGGATTCCTG 240 AACCTTCAAG CGCGGCCGAT AACTGAGGTG Qů *7QZ. ^-Ίη . - Ί CGACTTTTCC AGAACATCCT 300 GACGCGCTCG AAACGCGTT CAGCCGACGG TGGCTCCGCC GAGGCGCTGC CTCCAAAATC 360 CCTGCGACAA TTCGTCGCG GCGCCTACAA GGAAGTCGGT GCTGAATTCG TCGGGTATCT 420 GGTCGACCTG TGTGGGCTGC AGCCGGACGA AGCGGTGCTC GACGTCGGCT GCGGCTCGGG 480 GCGGATGGCG TTGCCGCTCA CCGGCTATCT GAACAGCGAG GGACGCTACG CCGGCTTCGA 540 TATCTCGCAG AAAGCCATCG CGTGGTGCCA GGAGCACATC ACCTCGGGC ACCCCAACTT 600 CCAGTTCGAG GTCTCCGACA TCTACAACTC GCTGTACAAC CCGAAAGGGA AATACCAGTC 660 ACTAGACTTT CGCTTTCCAT ATCCGGATGC GTCGTTCGAT GTGGTGTTTC TTACCTCGGT 720 GTTCACCCAC ATGTTTCCGC CGGACGTGGA GCACTATCTG GACGAGATCT CCCGCGTGCT 780 GAAGCCCGGC GGACGATGCC TGTGCACGTA CTTCTTGCTC AATGACGAGT CGTTAGCCCA 840 CATCGCGGAA GGAAAGAGTG CGCACAACTT CCAGCATGAG GGACCGGGTT ATCGGACAAT 900 CCACAAGAAG CGGCCCGAAG AAGCAATCGG CTTGCCGGAG ACCTTCTCA GGGATGTCTA 960 TGGCAAGTTC GGCCTCGCCG TGCACGAACC ATTGCACTAC GGCTCATGGA GTGGCCGGGA 1020 ACCACGCCTA AGCTTCCAGG ACATCGTCAT CGCGACCAAA ACCGCGAGCT AGGTCGGCAT 1080 * CCGGGAAGCA TCGCGACACC GTGGCGCCGA GCGCCGCTGC CGGCAGGCCG ATTAGGCGGG 1140 - CAGATTAGCC CGCCGCGGCT CCCGGCTCCG AGTACGGCGC CCCGAATGGC GTCACCGGCT 1200 GGTAACCACG CTTGCGCGCC TGGGCGGCGG CCTGCCGGAT CAGGTGGTAG ATGCCGACAA 1260

• · · · · · • ·

AGCCTGCGTG ATCGGTCATC ACCAACGGTG ACAGCAGCCG GTTGTGCACC AGCGCGAACG 1320

CCACCCCGGT CTCCGGGTCT GTCCAGCCGA TCGAGCCGCC CAAGCCCACA TGACCAAACC 1380

CCGGCATCAC GTTGCCGATC GGCATACCGT GATAGCCAAG ATGAAAATT AAGGGCACCA 1440

ATAGATTTCG ATCCGGCAGA ACTTGCCGTC GGTTGCGGGT CAGGCCCGTG ACCAGCTCCC 1500

GCGACAAGAA CCGTATGCCG TCGATCTCGC CTCGTGCCG 1539 (2) Sequence Information SEQ ID NO: 33:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 851 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33:

CTGCAGGGTG GCGTGGATGA GCGTCACCGC GGGGCAGGCC GAGCTGACCG CCGCCCAGGT 60 CCGGGTTGCT GCGGCGGCCT ACGAGACGGC GTATGGGCTG ACGGTGCCCC CGCCGGTGAT 120 CGCCGAGAAC CGTGCTGAAC TGATGATTCT GATAGCGACC AACCTCTTGG GGCAAAAAC 180 CCCGGCGATC GCGGTCAACG AGGCCGAATA CGGCGAGATG TGGGCCCAAG ACGCCGCCGC 240 GATGTTTGGC TACGCCGCGG CGACGGCGAC GGCGACGGCG ACGTTGCTGC CGTTCGAGGA 300 GGCGCCGGAG ATGACCAGCG CGGGTGGGCT CCTCGAGCAG GCCGCGCGG TCGAGGAGGC 360 CTCCGACACC GCCGCGGCGGA ACCAGTTGAT GAACAATGTG CCCCAGGCGC TGAACAGTT 420 GGCCCAGCCC ACGCAGGGCA CCACGCCTTC TTCCAAGCTG GGTGGCCTGT GGAAGACGGT 480 CTCGCCGCAT CGGTCGCCGA TCAGCAACAT GGTGTCGATG GCCAACAACC ACATGTCGAT 540 GACCAACTCG GGTGTGTCGA TGACCAACAC CTTGAGCTCG ATGTTGAAGG GCTTTGCTCC 600 GGCGGCGGCC GCCCAGGCCG TGCAAACCGC GGCGCAAAAC GGGGTCCGGG CGATGAGCTC 660 GCTGGGCAGC TCGCTGGGTT CTTCGGGTCT GGGCGGTGGG GTGGCCGCCA ACTTGGGTCG 720 GGCGGCTCCG GTACGGTATG GTCACCGGGA TGGCGGAAAAA TATGCANAGT CTGGTCGGCG 780 GAACGGTGGT CCGGCGTAAG GTTTACCCCC GTTTTCTGGA TGCGGTGAAC TTCGTCAACG 840

GAAACAGTTA C

851 • · · · · · (2) Sequence information of SEQ ID NO: 34:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 254 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34:

GATCGATCGG GCGGAAATTT GGACCAGATT CGCCTCCGGC GATAACCCAA TCAATCGAAC 60 CTAGATTTAT TCCGTCCAGG GGCCCGAGTA ATGGCTCGCA GGAGAGGAAC CTTACTGCTG 120 CGGGCACCTG TCGTAGGTCC TCGATACGGC GGAAGGCGTC GACATTTTCC ACCGACACCC 180 CCATCCAAAC GTTCGAGGGC CACTCCAGCT TGTGAGCGAG GCGACGCAGT CGCAGGCTGC 240 GCTTGGTCAA GATC 254 (2) SEQ ID sequence information NO: 35: (and) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 1227 pairs of strands (B) TYPE: nuclear acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xii) DESCRIPTION OF THE SEQUENCE: SEQ : ID NO: 35:

GATCCTGACC GAAGCGGCCG CCGCCAAGGC GAAGTCGCTG TTGGACCAGG AGGGACGGGA 60

CGATCTGGCG CTGCGGATCG CGGTTCAGCC GGGGGGGTGC GCTGGATTGC GCTATAACCT 120

TTTCTTCGAC GACCGGACGC TGGATGGTGA CCAAACCGCG GAGTTCGGTG GTGTCAGGTT 180

GATCGTGGAC CGGATGAGCG CGCCGTATGT GGAAGGCGCG TCGATCGATT TCGTCGACAC 240

TATTGAGAAG CAAGGTTCAC CATCGACAAT CCCAACGCCA CCGGCTCCTG CGCGTGCGGG 300

GATTCGTTCA ACTGATAAAA CGCTAGTACG ACCCCCGCGGT GCGCAACACG TACGAGCACA 360

CCAAGACCTG ACCGCGCTGG AAAAGCAACT GAGCGATGCC TTGCACCTGA CCGCGTGGCG 420

GGCCGCCGGC GGCAGGTGTC ACCTGCATGG TGAACAGCAC CTGGGCCTGA TATTGCGACC 480

AGTACACGAT TTTGTCGATC GAGGTCACTT CGACCTGGGA GAACTGCTTG CGGAACGCGT 540

• 4 · · · • · · 4 • · · · ···· 4 4 4 · 95 • · · 4 · 4 4 4 4 4 4 44 4 4 4 4 4 4 44 44 44 CGCTGCTCAG CTTGGCCAAG GCCTGATCGG AGCGCTTGTC GCGCACGCCG TCGTGGATAC 600 CGCACAGCGC ATTGCGAACG ATGGTGTCCA CATCGCGGTT CTCCAGCGCG TTGAGGTATC 660 CCTGAATCGC GGTTTTGGCC GGTCCCTCCG AGAATGTGCC TGCCGTGTTG GCTCCGTTGG 720 TGCGGACCCC GTATATGATC GCCGCCGTCA TAGCCGACAC CAGCGCGAGG GCTACCACAA 780 TGCCGATCAG CAGCCGCTTG TGCCGTCGCT TCGGGTAGGA CACCTGCGGC GGCACGCCGG 840 GATATGCGGC GGGCGGCAGC GCCGCGTCGT CTGCCGGTCC CGGGGCGAAG GCCGGTTCGG 900 CGGCGCCGAG GTCGTGGGGG TAGTCCAGGG CTTGGGGTTC GTGGGATGAG GGCTCGGGGTT 960 ACGGCGCCGG TCCGTTGGTG CCGACACCGG GGTTCGGCGA GTGGGGACCG GGCATTGTGG 1020 TTCTCCTAGG GTGGTGGACG GGACCAGCTG CTAGGGCGAC AACCGCCCGT CGCGTCAGCC' 1080 GGCAGCATCG GCAATCAGGT GAGCTCCCTA GGCAGGCTAG CGCAACAGCT GCCGTCAGCT 1140 CTCAACGCGA CGGGGCGGGC CGCGGCGCCG ATAATGTTGA AAGACTAGGC AACCTTAGGA 1200 ACGAAGGACG GAGATTTTGT GACGATC 1227 (2) SEQ ID sequence information NO: 36: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 181 pairs of strands (B) TYPE: nuclear acid (C) TYPE OF CHAIN: j single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36: GCGGTGTCGG CGGATCCGGC GGGTGGTTGA ACGGCAACGG CGGGGCCGGC GGGGCCGGCG 60 GGACCGGCGC TAACGGTGGT GCCGGCGGCA ACGCCTGGTT GTTCGGGGCC GGCGGGTCCG 120 GCGGNGCCGG CACCAATGGT GGNGTCGGCG GGTCCGGCGG ATTTGTCTAC GGCAACGGCG 180 G 181

(2) Sequence information of SEQ ID NO: 37:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 290 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37:

GCGGTGTCGG CGGATCCGGC GGGTGGTTGA ACGGCAACGG CGGTGTCGGC GGCCGGGGCG 60 GCGACGGCGT CTTTGCCGGT GCCGGCGGCC AGGGCGGCCT CGGTGGGCAG GGCGGCAATG 120 GCGGCGGCTC CACCGGCGGC AACGCGGTCC TTGGCGGCGC GGGCGGTGGC GGAGGCAACG 180 CCCCGGACGG CGGCTTCGGT GGCAACGGCG GTAAGGGTGG CCAGGGCGGN ATTGGCGGCG 240 GCACTCAGAG CGCGACCGGC CTCGGNGGTG ACGGCGGTGA CGGCGGTGAC 290

(2) Sequence information of SEQ ID NO: 38:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 34 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38:

GATCCAGTGG CATGGNGGGT GTCAGTGGAA GCAT 34 (2) Sequence Information SEQ ID NO: 39:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 155 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39:

GATCGCTGCT CGTCCCCCCC TTGCCGCCGA CGCCACCGGT CCCACCGTTA CCGAACAAGC 60

TGGCGTGGTC GCCAGCACCC CCGGCACCGC CGACGCCGGA GTCGAACAAT GGCACCGTCG 120

TATCCCCACC ATTGCCGCCG GNCCCACCGG CACCG

155 • · this • · » this this · · (2) Sequence information of SEQ ID NO: 40:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 53 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 40:

ATGGCGTTCA CGGGGCGCCG GGGACCGGGC AGCCCGGNGG GGCCGGGGGG TGG (2) Sequence Information SEQ ID NO: 41:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 132 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41:

GATCCACCGC GGGTGCAGAC GGTGCCCGCG GCGCCACCCC GACCAGCGGC GGCAACGGCG 60 GCACCGGCGG CAACGGCGCG AACGCCACCG TCGTCGGNGG GGCCGGCGGG GCCGGCGGCA 120 AGGGCGGCAA CG 132

(2) Sequence information of SEQ ID NO: 42:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 132 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42:

GATCGGCGGC

CCNGCCAAGA

CGGNACGGNC

ATCCTCCGNG

GGGGACGGCG GGAAGGGCGG

TCCNCCAATG GCGCGAATGG

NAACGGGGGC

CGGACAGGGC

GCCGNÁGCCA

GGCAACGGCG

120

GCANCGGCGG CA

132 • · (2) Sequence information of SEQ ID NO: 43:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 702 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43:

CGGCACGAGG ATCGGTACCC CGCGGCATCG GCAGCTGCCG ATTCGCCGGG TTTCCCCACCC 60 CGAGGAAAGC CGCTACCAGA TGGCGCTGCC GAAGTAGGGC GATCCGTTCG CGATGCCGGC 120 ATGAACGGGC GGCATCAAAT TAGTGCAGGA ACCTTTCAGT TTAGCGACGA TAATGGCTAT 180 AGCACTAAGG AGGATGATCC GATATGACGC AGTCGCAGAC CGTGACGGTG GATCAGCAAG 240 AGATTTTGAA CAGGGCCAAC GAGGTGGAGG CCCCGATGGC GGACCCACCG ACTGATGTCC 300 CCATCACACC GTGCGAACTC ACGGNGGNTA AAAACGCCC-C CCA-.CAGNTG GTNTTGTCCG 360 CCGACAACAT GCGGGAATAC CTGGCGGCCG GTGCCAAAGA GCGGCAGCGT CTGGCGACCT 420 CGCTGCGCAA CGCGGCCAAG GNGTATGGCG AGGTTGATGA GGAGGCTGCG ACCGCGCTGG' 480 ACAACGACGG CGAAGGAACT GTGCAGGCAG AATCGGCCGG GGCCGTCGGA GGGGACAGTT 540 CGGCCGAACT AACCGATACG CCGAGGGTGG CCACGGCCGG TGAACCCCAAC TTCATGGATC 600 TCAAAGAAGC GGCAAGGAAG CTCGAAACGG GCGACCAAGG CGCATCGCTC GCGCACTNG 660 GGGATGGGTG GAACACTTNC ACCCTGACGC TGCAAGGCGGA CG 702 ) Information of SEQ ID NO :44:

(i) SEQUENCE CHARACTERISTICS:

(AND) LENGTH: 702 pairs of threads (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) DESCRIPTION ; SEQUENCE: SEQ ID NO: 44:

GAAGCCGCAG CGCTGTCGGG CGACGTGGCG GTCAAAGCGG CATCGCTCG TGGCGGTGGA 60 GGCGGCGGGG TGCCGTCGGC GCCGTTGGGA TCCGCGATCG GGGGCGCCGA ATCGGTGCGG 120 CCCGCTGGCG CTGGTGACAT TGCCGGCTTA GGCCAGGAA GGGCCGGCGGG CGGCGCCGCG 180

• · • · ·*··*·· · · • ·· · · · fl 9 9 9 9 9 9

CTGGGCGGCG GTGGCATGGG AATGCCGATG GGTGCCGCGC ATCAGGGACA AGGGGGCGCC 240

AAGTCCAAGG GTTCTCAGCA GGAAGACGAG GCGCTCTACA CCGAGGATCC TCGTGCCG 298 (2) INFORMATION FOR SEQ ID NO:45:

(2) Sequence information of SEQ ID NO: 45:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1058 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45:

GCACTGCACC AGTGGAGGAG ⁶⁰ CCATGACCTA CTCGCCGGGT AACCCCGGAT ACCCGCAAGC GCAGCCCGCA GGCTCCTACG 120 GAGGCGTCAC ACCTCGTTC GCCCACGCCG ATGAGGGTGC GAGCAAGCTA CCGATGTACC 180 TGAACATCGC GGTGGCAGTG CTCGGTCTGG CTGCGTACTT CGCCAGCTTC GGCCCAATGT 240 TCACCCTCAG TACCGAACTC GGGGGGGGTG ATGGCGCAC-T GTCCGGTGAC ACTGGGCTGC 300 CGGTCGGGGTT GGCTCTGCTG GCTGCGCTGC TTGCCGGGGTT GGTTCTGGTG CCTAAGGCCA 360 AGAGCCATGT GACGGTAGTT GCGGTGCTCG GGGTACTCG CGTATTTCTG ATGGTCTCGG 420 CGACGTTTAA CAAGCCCAGC GCCTATTGA CCGGTTGGGC ATTGTGGGTT GTGTTGGCTT 480 TCATCGTGTT CCAGGCGGTT GCGGCAGTCC TGGCGCTCTT GGTGGAGACC GGCGCTATCA 540 CCGCGCGGCC GCCGCGGCC AAGTTCGACC CGTATGGACA GTACGGGCGGG TACGGGCAGT 600 ACGGGCAGTA CGGGGTGCAG CCGGGTGGGT ACTACGGTCA GCAGGGTGCT CAGCAGGCCG 660 CGGGACTGCA GTCGCCCGGC CCGCAGCAGT CTCCGCAGCC TCCCGGATAT GGGTCGCAGT 720 ACGGCGGCTA TTCGTCCAGT CCGAGCCAAT CGGGCAGTGG ATACACTGCT CAGCCCCGG 780 CCCAGCCGCC GGCGCAGTCC GGGTCGCAAC AATCGCACCA GGGCCCATCC ACGCCACCTA 840 CCGGCTTTCC GAGCTTCAGC CCACCACCAC ČGGTCAGTGC CGGGACGGGG TCGCAGGCTG 900 GTTCGGCTCC AGTCAACTAT TCAAACCCCA GCGGGGGCGA GCAGTCGTCG TCCCCCGGGG 960 GGGCGCCGGT CTAACCGGGC GTTCCCGCGT CCGGTCGCGC GTGTGCGCGA AGAGTGAACA 1020

GGGTGTCAGC AAGCGCGGAC GATCCTCGTG CCGAATTC

1058

100 (2) Information on the sequence of SEQ ID NO: 46:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 327 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46:

CGGCACGAGA GACCGATGCC GCTACCCTCG CGCAGGAGGC AGGTAATTTC GAGCGGATCT 60 CCGGCGACCT GAAAACCCAG ATCGACCAGG TGGAGTCGAC GGCAGGTTCG TTGCAGGGCC 120 AGTGGCGCGG CGCGCGGGGG ACGGCCGCCC AGGCCGCGGTT GGTGCGCTTC CAAGAAGCAG 180 CCAATAAGCA GAAGCAGGAA CTCGACGAGA TCTCGACGAA TATTCGTCAG GCCGGCGTCCC 240 AATACTCGAG GGCCGACGAG GAGCAGCAGC AGGCGC i ό i CTCGCAAATG GGCTTCTGAC 300 CCGCTAATAC GAAAAAAAAC GGAGCAA 327

(2) Sequence information of SEQ ID NO: 47:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 170 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47:

CGGTCGCGAT GATGGCGTTG TCGAACGTGA CCGATTCTGT ACCGCCGTCG TTGAGATCAA 60 CCAACAACGT GTTGGCGTCG GCAAATGTGC CGNACCGTG GATCTCGGTG ATCTTGTTCT 120 TCTTCATCAG GAAGTGCACA CCGGCCACCC TGCCCTCGGGN TACCTTTCGG 170

(2) Sequence information of SEQ ID NO: 48:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 127 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48:

101

GATCCGGCGG CACGGGGGGT GCCGGCGGCA GCACCGCTGG CGCTGGCGGC AACGGCGGGG 60

CCGGGGGTGG CGGCGGAACC GGTGGGTTGC TCTTCGGCAA CGGCGGTGCC GGCGGGCACG 120

127 (2) Information on the sequence of SEQ ID NO: 49:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 81 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49:

CGGCGGCAAG GGCGGCACCG CCGGCAACGG GAGCGGCGCG GCCGGCGGCA ACGGCGGCAA

CGGCGGCTCC GGCCTCAACG G (2) Sequence Information SEQ ID NO: 50:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 149 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50:

GATCAGGGCT GGCCGGCTCC GGCCAGAAGG GCGGTAACGG AGGAGCTGCC GGATTGTTTG 60

GCAACGGCGG GGCCGGNGGT GCCGGCCGGT CCAACCAAGC CGGTAACGGC GGNGCCGGCG 120

GAAACGGTGG TGCCGGTGGG CTGATCTGG

149

102 • ft ft ftft • ··· ft · · · · · · • ••ft ftft ftft ·· (2) Sequence information of SEQ ID NO: 51:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 355 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51:

CGGCACGAGA TCACACCTAC CGAGTGATCG AGATCGTCGG GACCTCGCCC GACGGTGTCG 60 ACGCGGNAAT CCAGGGCGGT CTGGCCCGAG CTGCGCAGAC CATGCGCGCG CTGGACTGGT 120 TCGAAGTACA GTCAATTCGA GGCCACCTGG TCGACGGAGC GGTCGCGCAC TTCCAGGTGA 180 CTATGAAAGT CGGCTTCCGC CTGGAGGATT CCTGAACCTT CAAGCGCGGC CGATAACTGA 240 GGTGCATCAT TAAGCGACTT TTCCAGAACA TCCTGACGCG CTCGAAACGC GGTTCAGCCG 300 ACGGTGGCTC CGCCGAGGCG CTGCCTCCAA AATCCCTGCG ACAATTCGTC GGGGG 355

feet* 2) Information about the sequence of SEQ ID NO: 52: (i) SEQUENCE CHARACTERISTICS: (AND) LENGTH: 999 pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) DESCRIPTION SEQUENCE: SEQ ID NO: 52:

ATGCATCACC ATCACCATCA CATGCATCAG GTGGACCCCA ACTTGACACG TCGCAAGGGA. 60 CGATTGGCGG CACTGGCTAT CGCGGCGATG GCCAGCGCCA GCCTGGTGAC CGTTGCGGTG 120 CCCGCGACCG CCAACGCCGA TCCGGAGCCA GCGCCCCCGG TACCCACAAC GGCCGCTCCG 180 CCGCCGTCGA CCGCTGCAGC GCCACCCGCCA CCGGCGACAC CTGTTGCCCC CCCACCACCG 240 GCCGCGCCA ACACGCCGAA TGCCCAGCCG GGCGATCCCA ACGCAGCACC TCCGCCGGCC 300 GACCCGAACG CACCGCCGCC ACCTGTCATT GCCCCAAACG CACCCCAACC TGTCCGGATC 360 GACAACCCGG TTGGAGGATT CAGCTTCGCG CTGCCTGCTG GCTGGGTGGA GTCTGACGCC 420 GCCCACTTCG ACTACGGTTC AGCACTCCTC AGCAAAACCA CCGGGGACCC GCCATTTCCC 480 GGACAGCCGC CGCCGGTGGC CAATGACACC CGTATCGTGC TCGGCCGGCT AGACCAAAAAG 540 CTTTACGCCA GCGCCGAAGC CACCGACTCC AAGGCCGCGG CCGGTTGGG CTCGGACATG 600 GGTGAGTTCT ATATGCCCTA CCCGGGCACC CGGATCAACC AGGAAACCGT CTCGCTCGAC 660

103 • · · · · • · · · • · · · 9··· 44 4 · · 9 9 9 9999 9 99 9 9 9 9 9 » · ·· • • · GCCAACGGGG TGTCTGGAAG CGCGTCGTAT TACGAAGTCA AGTTCAGCGA TCCGAGTAAG 720 CCGAACGGCC AGATCTGGAC GGGCGTAATC GGCTCGCCCG CGGCGAACGC ACCGGACGCC 780 GGGCCCCCTC AGCGCTGGTT TGTGGTATGG CTCGGGACCG CCAACAACCC GGTGGACAAG 840 GGCGCGGCCA AGGCGCTGGC CGAATCGATC CGGCCTTTGG TCGCCCCGCC GCCGGCGCCG 900 GCACCGGCTC CTGCAGAGCC CGCTCCGGCG CCGGCGCCGG CCGGGGAAGT CGCTCCTACC 960 CCGACGACAC CGACACCGCA GCGGACCTTA CCGGCCTGA 999

(2) Sequence information of SEQ ID NO: 53:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 332 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO : 53: Met His His His His His His Met His Gin Wall' Asp For Association Leo Thr 1 5 10 15 Arg Arg Fox Glee Arg Leo Alas Alas Leo Alas How many Alas Alas Met Alas Ser 20 25 30 Alas Ser Leo Wall Thr Wall Alas Wall For Alas Thr Alas Association Alas Asp For 35 40 45 Gosh For Alas For For Wall For Thr Thr Alas Alas Ser For For Ser Thr 50 55 60 Alas Alas Alas For For Alas For Alas Thr For Wall Alas For For For For 65 70 75 80 Alas Alas Alas Association Thr For Association Alas Gin For Glee Asp For Association Alas Alas 85 90 95 For For For Alas Asp For Association Alas For For For For Wall How many Alas For 100 105 110 Association Alas For Gin For Wall Arg How many Asp Association For Wall Glee Glee Phew Ser 115 120 125 Phew Alas Leo For Alas Glee Suffering Wall Gosh Ser Asp Alas Alas His Phew Asp 130 135 140

Tyr Gly Ser Ala Leu Leu Ser Lys Thr Thr Gly Asp Pro Pro Phe Pro

104 ·· ·· • 0 • 0 • 0 0 0 0 0 0 · 0 0 0 0 0* 0 0 0 0 0 0 00 0 0 0 00 0 0 00 0 0 0 0 0 00 0 0 0 • 0 • 0 • · • 0 • · • ·» 0 • 0 • 0 0 0 145 150 155 160 Glee Gin For For For Wall Alas Association Asp Thr Arg How many Wall Leo Glee Arg 165 170 175 Leo Asp Gin Fox Leo Tire Alas Ser Alas Gosh Alas Thr Asp Ser Fox Alas 180 185 190 Alas Alas Arg Leo Glee Ser Asp Met Glee Gosh Phew Tire Met For Tire For 195 200 205 Glee Thr Arg How many Association Gin Gosh Thr Wall Ser Leo Asp Alas Association Glee Wall 210 215 220 Ser Glee Ser Alas Ser Tire Tire Gosh Wall Fox Phew Ser Asp For Ser Fox 225 230 235 240 For Association Glee Gin How many Suffering Thr Glee Wall How many Glee Ser For Alas Alas Association 245 250 255 Alas For Asp Alas Glee For For Gin Arg Suffering Phew Wall Wall Suffering Leo Glee 260 265 270 Thr Alas Association Association For Wall Asp Fox Glee Alas Alas Fox Alas Leo Alas Gosh 275 280 285 Ser How many Arg For Leo Wall Alas For For For Alas For Alas For Alas For 290 295 300 Alas Gosh For Alas For Alas For Alas For Alas Glee Gosh Wall Alas For Thr 305 310 315 320 For Thr Thr For Thr For Gin Arg Thr Leo For Alas 325 330

(2) Sequence information of SEQ ID NO: 54:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 54:

Asp Pro Val Asp Ala Val Ile Asn Thr Thr Xaa Asn Tyr Gly Gin Val 1 5 10 15

Val Ala Ala Leu 20

99

105 (2) Sequence information of SEQ ID NO: 55:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 55:

Ala Val Glu Ser Gly Met Leu Ala Leu Gly Thr Pro Ala Pro Ser η 5 ^{10 15} (2)

Information (including:

(xi) about the sequence of SEQ ID NO: 56: CHARACTERISTICS OF THE SEQUENCE:

(A) LENGTH: 19 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear SEQUENCE DESCRIPTION: SEQ ID NO: 56:

Ala Ala Met Lys Pro Arg Thr Gly Asp Gly Pro Leu Glu Ala Ala Lys ! 5 10 15

Glu Gly Arg (2) Sequence Information SEQ ID NO: 57:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57:

Tvr Tyr Trp Cys Pro Gly Gin Pro Phe Asp Pro Ala Trp Gly Pro 1 5 10 ¹⁵ ·· fr « ·* «· • * • · ·· • 9· · ·1

106 (2) Information on the sequence of SEQ ID NO: 58:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 14 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58:

Asp Ile Gly Ser Glu Ser Thr Glu Asp Gin Gin Xaa Ala Val ¹ 5 10 (2) Sequence Information SEQ ID NO: 59:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 59:

Ala Glu Glu Ser Ile Ser Thr Xaa Glu Xaa Ile Val Pro 15 10 (2) Sequence Information SEQ ID NO: 60:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 60:

Asp Pro Glu Pro Ala Pro Pro Vál Pro Thr Ala Ala Ala Ala Pro Pro 1 5 10 15

Ala *· «· ·* ·« ·· • it · · this* it·· ««· · · · ·» · ·· • 99 9 9 9 9 9

9999 99 9 9 99 99

Λ

107 (2) Sequence information of SEQ ID NO: 61:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61:

Ala Pro Lys Thr Tyr Xaa Glu Glu Leu Lys Gly Thr Asp Thr Gly 1 5 10 I ⁵ (2) Sequence Information SEQ ID NO: 62:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 30 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 62:

Asp For Ala Ser Alas For Asp Wall For Thr Alas Alas Gin Gin Thr Ser 1 5 10 15 . Leu Leu Assn Association Leo Alas Asp For Asp Wall Ser Phew Alas Asp 20 25 30 (2) Information 0 sequence SEQ id NO: 63:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 24 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi! SEQUENCE DESCRIPTION: SEQ ID NO: 63:

Gly Cys Gly Asp Arg Ser Gly Gly Asn Leu Asp Gin lle Arg Leu Arg 15 10 15

Arg Asp Arg Ser Gly Gly Asn Leu 20 ·· »9 • · · · • ·· • · · • · · ·*·· ·« ·· ·· ·· ·· • · · · · · • · · ·· · · · 9 • · · · · ··· ··· • · · · · · ·» ·· ·· ··

108 (2) Information on the sequence of SEQ ID NO: 64:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 187 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64:

Thr Gly 1 Ser Leo Association 5 Gin Thr His Asn Arg Arg Ala Asn Glu Arg Fox 10 15 Association Thr Thr Met Fox Met Wall Fox Ser lle Alas Alas Glee Leo Thr Alas 20 25 30 Alas Alas Alas lle Glee Alas Alas Alas Alas Glee Wall Thr Ser lle Met Alas 35 40 45 Glee Glee For Wall Wall Tire Gin Met Gin For Wall Wall Phew Glee Alas For 50 55 60 Leo For Leo Asp For Alas Ser Alas For Asp Wall For Thr Alas Alas Gin 65 70 75 80 Leo Thr Ser Leo Leo Association Ser Leo Alas Asp For Association Wall Ser Phew Alas 85 90 95 Association Fox Glee Ser Leo Wall Gosh Glee Glee lle Glee Glee Thr Gosh Alas Arg 100 105 110 lle Alas Asp His Fox Leo Fox Fox Alas Alas Gosh His Glee Asp Leo For 115 120 125 Leo Ser Phew Ser Wall Thr Association lle Gin For Alas Alas Alas Glee Ser Alas 130 135 140 Thr Alas Asp Wall Ser Wall Ser Glee For Fox Leo Ser Ser For Wall Thr 145 150 155 160 Gin Association Wall Thr Phew Wall Association Gin Glee Glee Suffering Met Leo Ser Arg Alas 165 170 175 Ser Alas Met Gosh Leo Leo Gin Alas Alas Glee Xaa

180 185 • · • · · · • · ······· · · • · · · ·· · · · · ·· ··

109 (2) Sequence information of SEQ ID NO: 65:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 148 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65:

Asp Glu 1 Wall Thr Val Glu Thr Thr Ser Val Phew Arg Ala Asp Phew 15 Leo 5 10 Ser Gosh Leo Asp Alas For Alas Gin Alas Glee Thr Gosh Ser Alas Wall Ser 20 25 30 Glee Wall Gosh Glee Leo For For Glee Ser Alas Leo Leo Wall Wall Fox Arg 35 40 45 Glee For Association Alas Glee Ser Arg Phew Leo Leo Asp Gin Alas How many Thr Ser 50 55 60 Alas Glee Arg His For Asp Ser Asp How many Phew Leo Asp Asp Wall Thr Wall 65 70 75 80 Ser Arg Arg His Alas Gosh Phew Arg Leo Gosh Association Association Gosh Phew Association Wall 85 90 95 Wall Asp Wall Glee Ser Leo Association Glee Thr Tire Wall Association Arg Gosh For Wall 100 105 110 Asp Ser Alas Wall Leo Alas Association Glee Asp Gosh Wall Gin How many Glee Fox Leo 115 120 125 Arg Leo Wall Phew Leo Thr Glee For Fox Gin Glee Gosh Asp Asp Glee Ser 130 135 140

Thr Gly Gly Pro 145 (2) Sequence Information SEQ ID NO: 66:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 230 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66:

Thr Ser Asn Arg Pro Ala Arg Arg Gly Arg Arg Ala Pro Arg Asp Thr 15 10 15 • ·

110

Gly Pro Asp Arg Ser Ala Ser Leu Ser Leu Val Arg His Arg Arg Gin 20 25 30

Gin Arg Asp Ala Leu Cys Leu Ser Ser Thr Gin lle Ser Arg Gin Ser 35 40 45

Asn Leu Pro Pro Ala Ala Gly Gly Ala Ala Asn Tyr Ser Arg Arg Asn 50 55 60

100

115

130

145

180

195

210

165

Fox lle Phew Met Leo Wall Thr Alas Wall Wall Leo 70 75 80 Wall Alas Thr Alas Alas For Fox Thr Tire Cys Gosh 90 95 Asp Thr Glee Gin Alas Cys Gin lle Gin Met Ser 105 110 lle Association lle Ser Leo For Ser Tire Tire For Asp 120 125 Association Tire lle Alas Gin Thr Arg Asp Fox Phew Leo 135 140 Ser Thr For Arg Gosh Alas For Tire Gosh Leo Association 150 155 160 Tire Gin Ser Alas lle For For Arg Glee Thr Gin 170 175 Wall Tire His Association Alas Glee Glee Thr His For Thr 185 190 Phew Asp Suffering Asp Gin Alas Tire Arg Fox For lle 200 205 Suffering Gin Alas Asp Thr Asp For Leo For Wall Wall

215

220

Phe Prolle Val Ala Arg 225 230 (2) SEQ ID NO: 67 Sequence Information:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 132 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67:

• ·

111

Thr 1 Alas Alas Ser Asp Asn Phe Gin Leu Ser Gin Gly Gly Gin Gly Phew 5 10 15 Alas How many For How many Glee Gin Alas Met Alas How many Alas Glee Gin How many Arg Ser 20 25 30 Glee Glee Glee Ser For Thr Wall His How many Glee For Thr Alas Phew Leo Glee 35 40 45 Leo Glee Wall Wall Asp Association Association Glee Association Glee Alas Arg Wall Gin Arg Wall 50 55 60 Wall Glee Ser Alas For Alas Alas Ser Leo Glee How many Ser Thr Glee Asp Wall 65 70 75 80 How many Thr Alas Wall Asp Glee Alas For How many Association Ser Alas Thr Alas Met Alas 85 90 95 Asp Alas Leo Association Glee His His For Glee Asp Wall How many Ser Wall Association Suffering 100 105 110 Gin Thr Fox Ser Glee Glee Thr Arg Thr Glee Association Wall Thr Leo Alas Gosh 115 120 - 125 Glee For For Alas -

130 (2) Information on the sequence of SEQ ID NO: 68:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 100 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68:

Wall For Leo Arg Ser For Ser Met Ser For Ser Fox Cys Leo Alas Alas 1 5 10 15 Alas Gin Arg Association For Wall How many Arg Arg Arg Arg Leo Ser Association For For 20 25 30 For Arg Fox Tire Arg Ser Met For Ser For Alas Thr Alas Ser Alas Glee

40 45

Met Ala Arg Val Arg Arg Arg Ala Ile Trp Arg Gly Pro Ala Thr Xaa 50 55 60 ··· ···· · • · · · ·· ·· ·· · · ·«

112

Ser Ala Gly Met Ala Arg Val Arg Arg Trp Xaa Val 75 Met For Xaa Wall 80 65 70 How many Gin Ser Thr Xaa How many Arg Xaa Xaa Glee For Phew Asp Association Arg Glee 85 90 95 Ser Gosh Arg Fox

100 (2) Information on the sequence of SEQ ID NO: 69:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 163 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69:

Met 1 Thr Asp Asp How many 5 Leo Leo How many Asp Thr 10 Asp Gosh Arg Wall Arg ¹⁵ Thr Leo' Thr Leo Association 20 Arg For Gin Ser Arg 25 Association Alas Leo Ser Alas 30 Alas Leo Arg Asp Arg 35 Phew Phew Alas Xaa Leo 40 Xaa Asp Alas Gosh Xaa 45 Asp Asp Asp How many Asp 50 Wall Wall How many Leo Thr 55 Glee Alas Asp For Wall 60 Phew Cys Alas Glee Leo 65 Asp Leo Fox Wall Alas 70 Glee Arg Alas Asp Arg 75 Alas Alas Glee His Leo 80 Thr Alas Wall Glee Glee 85 His Asp Gin Alas Glee 90 Asp Arg Arg Asp Gin 95 Arg Arg Arg Glee His 100 Arg Arg Alas Arg Thr 105 Glee Alas Wall Leo Arg 110 His For Asp Arg Leo 115 Arg Alas Arg For Leo 120 Arg Arg His For Arg 125 For Glee Glee Alas Alas 130 Alas His Leo Glee Thr 135 Gin Cys Wall Leo Alas 140 Alas Fox Glee Arg His Arg Xaa Glee For Wall Asp Gosh For Asp Arg Arg Leo For Wall Arg

145 150 155 160

Asp Arg Arg • · · • · · · • · · · · · · ···· ·· ·· · · ··

113 (2) Sequence information of SEQ ID NO: 70:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 344 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 70:

Met 1 Fox Phew Wall Asn His 5 lle Gosh For Val Ala 10 For Arg Arg Alas 15 Glee Alas Wall Alas Gosh Wall Tire Alas Gosh Alas Arg Arg Gosh Phew Glee 20 25 30 Leo For Gosh For Leo Alas Met Leo Ser For Asp Gosh Glee Leo Leo 35 40 45 Alas Glee Suffering Alas Thr Leo Arg Gosh Thr Leo Leo Wall Glee Gin Wall 50 55 60 Arg Glee Arg Fox Gosh Alas Wall Alas Alas Alas Wall Alas Alas Ser Leo 65 70 75 Cys For Suffering Cys Wall Asp Alas His Thr Thr Met Leo Tire Alas Alas 85 90 95 Gin Thr Asp Thr Alas Alas Alas lle Leo Alas Glee Thr Alas For Alas 100 105 110 Glee Asp For Association Alas For Tire Wall Alas Suffering Alas Alas Glee Thr Glee 115 120 125 For Alas Glee For For Alas For Phew Glee For Asp Wall Alas Alas Gosh 130 135 140 Leo Glee Thr Alas Wall Gin Phew His Phew lle Alas Arg Leo Wall Leo 145 150 155 Leo Leo Asp Gosh Thr Phew Leo For Glee Glee For Arg Alas Gin Gin 165 170 175 Met Arg Arg Alas Glee Glee Leo Wall Phew Alas Arg Fox Wall Arg Alas 130 185 190 His Arg For Glee Arg Ser Thr Arg Arg Leo Gosh For Arg Thr Leo 195 200 205 Asp Asp Leo Alas Suffering Alas Thr For Ser Gosh For lle Alas Thr Alas

Glee

Arg

Thr

For

Arg

Glee

Alas

Thr

Tire

Wall

160

Leo

Gosh

For

Phe • · · · ···· · ·· · • · ··· ·· ·· · · · · · · ··«···· · · ···· · · ·· ·· · · · ·

114

210 215 220

Ala Ala Leu Ser His His Leu Asp Thr Ala Pro His Leu Pro Pro Pro

225 230 235 240

Thr Arg Gin Val Val Arg Arg Val Val Gly Ser Trp His Gly Glu Pro

245 250 255

Met Pro Met Ser Ser Arg Trp Thr Asn Glu His Thr Ala Glu Leu Pro 260 265 270

Ala Asp Leu His Ala Pro Thr Arg Leu Ala Leu Leu Thr Gly Leu Ala 275 280 285

Pro His Gin Val Thr Asp Asp Asp Val' Ala Ala Ala Arg Ser Leu Leu 290 295 300

Asp Thr Asp Ala Ala Leu Val Gly Ala Leu Ala Trp Ala Ala Phe Thr

305 310 315 320

Ala Ala Arg Arg Ile Gly Thr Trp Ile Gly Ala Ala Ala Glu Gly Gin

325 330 335

Val Ser Arg Gin Asn Pro Thr Gly 340 (2) Sequence Information SEQ ID NO: 71:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 485 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 71:

Asp 1 Asp For Asp Met 5 For Glee Thr Wall Alas 10 Fox Alas Wall Alas Asp 15 Alas Leo Glee Arg Glee 20 How many Alas For Wall Gosh 25 Asp How many Gin Asp Cys 30 Wall Gosh Alas Arg Leo 35 Glee Gosh Alas Glee Leo 4O Asp Asp Wall Alas Arg 45 Wall Tire How many How many Tire 50 Arg Gin Arg Arg Alas 55 Gosh Leo Arg Thr Alas 60 Fox Alas Leo Leo Glee 65 Wall Arg Asp Gosh Leo 70 Fox Leo Ser Leo Alas 75 Alas Wall Thr Wall Leo 80

• · • · · ·

115 • · · · · · • · • · • · • · Arg Glu Arg Tyr Leu Leu His Asp Glu Gin Gly Arg For Alas Gosh Ser 85 90 95 Thr Gly Glu Leu Met Asp Arg Ser Ala Arg Cys Val Alas Alas Alas Gosh 100 105 110 Asp Gin Tyr Glu For Gly Ser Ser Arg Arg Trp Ala Gosh Arg Phew Alas 115 120 125 Thr Leu Leu Arg Asn Leu Glu Phe Leu For Asn Ser For Thr Leo Met 130 135 140 Asn Ser Gly Thr Asp Leu Gly Leu Leu Ala Gly Cys Phew Wall Leo For 145 150 155 160 lle Glu Asp Ser Leu Gin Ser lle Phe Ala Thr Leu Glee Gin Alas Alas 165 170 175 Glu Leu Gin Arg Ala Gly Gly Gly Thr Gly Tyr Ala Phew Ser His Leo 180 185 190 Arg Pro Ala Gly Asp Arg Val Ala Ser Thr Gly Gly Thr Alas Ser Glee 195 200 205 For Val Ser Phe Leu Arg Leu Tyr Asp Ser Ala Ala Glee Wall Wall Ser 210 215 220 Met Gly Gly Arg Arg Arg Gly Ala Cys Met Ala Val Leo Asp Wall Ser 225 230 235 240 His Pro Asp lle Cys Asp Phe Val Thr Ala Lys Ala Gosh Ser For Ser 245 250 255 Glu Leu For His Phe Asn Leu Ser Val Gly Val Thr Asp Alas Phew Leo 260 '265 270 Arg Ala Val Glu Arg Asn Gly Leu His Arg Leu Val Association For Arg Thr 275 280 285 Gly Lys lle Val Ala Arg Met For Ala Ala Glu Leu Phew Asp Alas lle 290 295 300 Cys Lys Ala Ala His Ala Gly Gly Asp For Gly Leu Wall Phew Leo Asp 305 310 315 320 Thr lle Asn Arg Ala Asn Pro Val Pro Gly Arg Gly Arg lle Gosh Alas 325 330 335 Thr Asn Pro Cys Gly Glu Val Pro Leu Leu For Tyr Gosh Ser Cys Association 340 345 350 Leu Gly Ser lle Asn Leu Ala Arg Met Leu Ala Asp Glee Arg Wall Asp 355 360 365

Trp Asp Arg Leu Glu Glu Val Ala Gly Val Ala Val Arg Phe Leu Asp • ·· · ···· · ·· · ······· · · ···· ·· ·· ·· ·· · ·

116

370 375 380

Asp Val Ile Asp Val Ser Arg Tyr Pro Phe Pro Glu Leu Gly Glu Ala

3Q5 390 395 400

Ala Arg Ala Thr Arg Lys Ile Gly Leu Gly Val Met Gly Leu Ala Glu

405 410 415

Leu Leu Ala Ala Leu Gly Ile Pro Tyr Asp Ser Glu Glu Ala Val Arg 420 425 430

Leu Ala Thr Arg Leu Met Arg Arg Ile Gin Gin Ala Ala His Thr Ala 435 440 445

Ser Arg Arg Leu Ala Glu Glu Arg Gly Ala Phe Pro Ala Phe Thr Asp 450 455 460

Ser Arg Phe Ala Arg Ser Gly Pro Arg Arg Asn Ala Gin Val Thr Ser 465 470 475 480

Val Ala Pro Thr Gly 485 (2) Sequence Information SEQ ID NO: 72:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 267 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 72:

Gly Val Ile Val Leu Asp Leu Glu Pro Arg Gly Pro Leu Pro Thr Glu

5 10 15

Ile Tyr Trp Arg Arg Arg Gly Leu Ala Leu Gly Ile Ala Val Val Val

25 30

Val Gly Ile Ala Val Ala Ile Val Ile Ala Phe Val Asp Ser Ser Ala 35 40 45

Gly Ala Lys Pro Val Ser Ala Asp Lys Pro Ala Ser Ala Gin Ser His 50 55 60

Pro Gly Ser Pro Ala Pro Gin Ala Pro Gin Pro Ala Gly Gin Thr Glu

70 75 80

Gly Asn Ala Ala Ala Ala Pro Pro Gin Gly Gin Asn Pro Glu Thr Pro

90 95 • ·

• • · · 117 • · · • • · · • • · • · • · • · • · ' · • · • · • • · • · • • · Thr For Thr Alas Alas Wall Gin For For For Wall Leo Fox Gosh Glee Asp 100 105 110 Asp Cys For Asp Ser Thr Leo Alas Wall Fox Glee Leo Thr Association Alas For 115 120 125 Gin Tire Tire Wall Glee Asp Gin For Fox Phew Thr Met Wall Wall Thr Association 130 135 140 How many Glee Leo Wall Ser Cys Fox Arg Asp Wall Glee Alas Alas Wall Leo Alas 145 150 155 160 Alas Tire Wall Tire Ser Leo Asp Association Fox Arg Leo Suffering Ser Association Leo Asp 165 170 175 Cys Alas For Ser Association Gosh Thr Leo Wall Fox Thr Phew Ser For Glee Gosh 180 185 190 Gin Wall Thr Thr Alas Wall Thr Suffering Thr Glee Met Glee Ser Alas For Arg 195 200 205 Cys For Leo For Arg For Alas How many Glee For Glee Thr Tire Association Leo Wall 210 215 220 Wall Gin Leo Glee Association Leo Arg Ser Leo For Wall For Phew How many Leo Association 225 230 235 240 Gin For For For For For Glee For Wall For Alas For Glee For Alas Gin 245 250 255 Alas For For For Gosh Ser For Alas Gin Glee Glee

260 265 (2) Sequence Information SEQ ID NO: 73:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 97 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73:

Leo How many Ser Thr Glee Fox Alas Ser His Alas Ser Leo Glee Wall Gin Wall 1 5 10 15 Thr Association Asp Fox Asp Thr For Glee Alas Fox How many Wall Gosh Wall Wall Alas 20 25 30 Glee Glee Alas Alas Alas Association Alas Glee Wall For Fox Glee Wall Wall Wall Thr 35 40 45

·····*· · · ···· ·· ·· ·· ·· ··

118

Fox Wall 50 Asp Asp Arg For How many 55 Association Ser Alas Asp Alas 60 Leo Wall Alas Alas Wall 65 Arg Ser Fox Alas For 70 Glee Alas Thr Wall Alas 75 Leo Thr Phew Gin Asp 80 For Ser Glee Glee Ser 85 Arg Thr Wall Gin Wall 90 Thr Leo Glee Fox Alas 95 Gosh

Gin (2) Sequence Information SEQ ID NO: 74:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 364 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 74:

Gly Ala Ala Val Ser Leu Leu Ala Ala Gly Thr Leu Val Leu Thr Ala

5 10 15

Cys Gly Gly Gly Thr Asn Ser Ser Ser Ser Gly Ala Gly Gly Thr Ser

25 30

Gly Ser Val His Cys Gly Gly Lys Lys Glu Leu His Ser Ser Gly Ser 35 40 45

Thr Ala Gin Glu Asn Ala Met Glu Gin Phe Val Tyr Ala Tyr Val Arg 50 55 60

Ser Cys Pro Gly Tyr Thr Leu Asp Tyr Asn Ala Asn Gly Ser Gly Ala

70 75 80

Gly Val Thr Gin Phe Leu Asn Asn Glu Thr Asp Phe Ala Gly Ser Asp

90 95

Val Pro Leu Asn Pro Ser Thr Gly Gin Pro Asp Arg Ser Ala Glu Arg 100 105 HO

Cys Gly Ser Pro Ala Trp Asp Leu Pro Thr Val Phe Gly Pro Ile Ala 115 120 125

Ile Thr Tyr Asn Ile Lys Gly Val Ser Thr Leu Asn Leu Asp Gly Pro 130 135 140

Thr Thr Ala Lys Ile Phe Asn Gly Thr Ile Thr Val Trp Asn Asp Pro

WO 98/16645 119 • · • · « • ' · · · • · • · • · PCT/USa7yi8214 145 150 155 160 Gin lle Gin Ala Leu Asn Ser Gly Thr Asp Leo For For Thr For lle 165 170 175 Ser Val lle Phe Arg Ser Asp Lys Ser Glee Thr Ser Asp Association Phew Gin 180 185 190 Lys Tyr Leu Asp Gly Val Ser Asn Gly Alas Suffering Glee Fox Glee Ala Ser 195 200 205 Glu Thr Phe Ser Gly Gly Val Gly Val Glee Alas Ser Glee Association Asn Gly 210 215 220 Thr Ser Ala Leu Leu Gin Thr Thr Asp Glee Ser lle Thr Tire Asn Glu 225 230 235 240 Trp Ser Phe Ala Val Gly Lys Gin Leu Association Met Alas Gin lle lle Thr 245 250 255 Ser Ala Gly Pro Asp Pro Val Ala lle Thr Thr Gosh Ser Wall Gly Lys 260 265 270 Thr lle Ala Gly Ala Lys lle Met Gly Gin Glee Association Asp Leo Val Leu 275 280 285 Asp Thr Ser Ser Phe Tyr Arg For Thr Gin For Glee Ser Tire For lle 290 295 300 Val Leu Ala Thr Tyr Glu lle Val Cys Ser Fox Tire For Asp Ala Thr 305 310 315 • 320 Thr Gly Thr Ala Val Arg Ala Phe Met Gin Alas Alas lle Glee For Gly 325 330 335 Gin Glu Gly Leu Asp Gin Tyr Gly Ser The floor For Leo For Fox Sir Phe 340 345 350 Gin Ala Lys Leu Ala Ala Ala Val Asn Alas lle Ser 355 360

(2) Sequence information of SEQ ID NO: 75:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 309 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 75:

• · ···*··· · · ···· ·· ·· ·· ·· ··

120

Gin 1 Ala Ala Ala Glee 5 Arg Ala Val Arg Arg Thr Gly His Ala Glu Asp 10 15 Gin Thr His Gin Asp Arg Leo His His Glee Cys Arg Arg Alas Alas Wall 20 25 30 Wall Wall Arg Gin Asp Arg Alas Ser Wall Ser Alas Thr Ser Alas Arg For 35 40 45 For Arg Arg His For Alas Gin Glee His Arg Arg Arg Wall Alas For Ser 50 55 60 Glee Glee Arg Arg Arg For His For His His Wall Gin For Asp Asp Arg 65 70 75 80 Arg Asp Arg For Alas Leo Leo Asp Arg Thr Gin For Alas Gosh His For 85 90 95 Asp For His Arg Arg Glee For Alas Asp For Glee Arg Wall Arg Glee Arg 100 105 110 Glee Arg Leo Arg Arg Wall Asp Asp Glee Arg Leo Gin For Asp Arg Asp 115 120 125 Alas Asp His Glee Alas For Wall Arg Glee Arg Glee For His Arg Glee Wall 130 135 140 Gin His Arg Glee Glee For Wall Phew Wall Arg Arg Wall For Glee Wall Arg 145 150 155 160 Cys Alas His Arg Arg Glee His Arg Arg Wall Alas Alas For Glee Gin Glee 165 170 175 Asp Wall Leo Arg Alas Glee Leo Arg Wall Gosh Arg Leo Arg For Wall Alas 180 185 190 Alas Wall Gosh Association Leo His Arg Glee Ser Gin Arg Alas Asp Glee Arg Wall 195 200 205 Phew Arg For How many Arg Arg Glee Alas Arg Leo For Alas Arg Arg Ser Arg 210 215 220 Alas Glee For Gin Glee Arg Leo His Leo Asp Glee Alas Glee For Ser For 225 230 235 240 Leo For Alas Arg Alas Glee Gin Gin Gin For Ser Ser Alas Glee Glee Arg 245 250 255 Arg Alas Glee Glee Alas Gosh Arg Alas Asp For Glee Gin Arg Glee Arg His 260 265 270 His Gin Glee Glee His Asp For Glee Arg Gin Glee Alas Gin Arg Glee Thr 275 280 285

Ala Gly Val Ala His Ala Ala Ala Gly Pro Arg Arg Ala Ala Val Arg • · • · · · • ·

290

295

121

300

Asn Arg Pro Arg Arg 305 (2) Sequence Information SEQ ID NO: 76:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 580 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 76:

Ser Alas Wall Suffering Cys Leo Association Glee Phew Thr Glee Arg His Arg His Glee 1 5 10 15 Arg Cys Arg Wall Arg Alas Ser Glee Suffering Arg Ser Ser Association Arg Suffering Cys 20 25 30 Ser Thr Thr Alas Asp Cys Cys Alas Ser Fox Thr For Thr Gin Alas Alas 35 40 45 Ser For Leo Gosh Arg Arg Phew Thr Cys Cys Ser For Alas Wall Glee Cys 50 55 60 Arg Phew Arg Ser Phew For Wall Arg Arg Leo Alas Leo Glee Alas Arg Thr 65 70 75 80 Ser Arg Thr Leo Glee Wall Arg Arg Thr Leo Ser Gin Suffering Association Leo Ser 85 90 95 For Arg Alas Gin For Ser Cys Alas Wall Thr Wall Gosh Ser His Thr His 100 105 110 Alas Ser For Arg Met Alas Fox Leo Alas Arg Wall Wall Glee Leo Wall Gin 115 120 125 Gosh Gosh Gin For Ser Asp Met Thr Association His For Arg Tire Ser For For 130 135 140 For Gin Gin For Glee Thr For Glee Tire Alas Gin Glee Gin Gin Gin Thr 145 150 155 160 Tire Ser Gin Gin Phew Asp Suffering Arg Tire For For Ser For For For Gin 165 170 175 For Thr Gin Tire Arg Gin For Tire Gosh Alas Leo Glee Glee Thr Arg For 180 185 190

·····«· · · ···· ·· ·· «· ·· ··

122

Gly Leu How many 195 For Gly Wall How many For Thr Met 200 Thr For For 205 For Glee Met Wall Arg Gin Arg For Arg Alas Glee Met Leo Alas How many Glee Alas Wall Thr 210 215 220 lle Alas Wall Wall Ser Alas Glee How many Glee Glee Alas Alas Alas Ser Leo Wall 225 230 235 240 Glee Phew Association Arg Alas For Alas Glee For Ser Glee Glee For Wall Alas Alas 245 250 255 Ser Alas Alas For Ser How many For Alas Alas Association Met For For Glee Ser Wall 260 265 270 Gosh Gin Wall Alas Alas Fox Wall Wall For Ser Wall Wall Met Leo Gosh Thr 275 280 285 Asp Leo Glee Arg Gin Ser Gosh Gosh Glee Ser Glee How many How many Leo Ser Alas 290 295 300 Gosh Glee Leo How many Leo Thr Association Association His Wall How many Alas Alas Alas Al a Fox 305 310 315 320 For For Leo Glee Ser For For For Fox Thr Thr Wall Thr Phew Ser Asp 325 330 335 Glee Arg Thr Alas For Phew Thr Wall Wall Glee Alas Asp For Thr Ser Asp 340 345 350 lle Alas Wall Wall Arg Wall Gin Glee Wall Ser Glee Leo Thr For How many Ser 355 360 365 Leo Glee Ser Ser Ser Asp Leo Arg Wall Glee Gin For Wall Leo Alas How many 370 375 380 Glee Ser For Leo Glee Leo Gosh Glee Thr Wall Thr Thr Glee How many Wall Ser 385 390 395 400 Alas Leo Association Arg For Wall Ser Thr Thr Glee Gosh Alas Glee Association Gin Association 405 410 415 Thr Wall Leo Asp Alas How many Gin Thr Asp Alas Alas How many Association For Glee Association 420 425 430 Ser Glee Glee Alas Leo Wall Association Met Association Alas Gin Leo Wall Glee Wall Association 435 4.40 445 Ser Alas How many Alas Thr Leo Glee Alas Asp Ser Alas Asp Alas Gin Ser Glee 450 455 460 Ser How many Glee Leo Glee Phew Alas How many For Wall Asp Gin Alas Fox Arg How many 4 65 4 70 475 480

Ala Asp Glu Leu lle Ser Thr Gly Lys Ala Ser His Ala Ser Leu Gly » · • 4 • 4 4«

I · 4 » · · 4 · ► 4 4 and » <4 «

444 444

123

485 490 495

Wall Gin Wall Thr 500 Association Asp Fox Asp Thr 505 For Glee Alas Fox lle 510 Wall Gosh Wall Wall Alas 515 Glee Glee Alas Alas Alas 520 Association Alas Glee Wall For 525 Fox Glee Wall Wall Wall 530 Thr Fox Wall Asp Asp 535 Arg For lle Association Ser 540 Alas Asp Alas Leo Wall 545 Alas Alas Wall Arg Ser 550 Fox Alas For Glee Alas 555 Thr Wall Alas Leo Thr 560 Phew Gin Asp For Ser Glee Glee Ser Arg Thr Wall Gin Wall Thr Leo Glee

565 570 575

Lys Ala Glu Gin 580 (2) Sequence Information SEQ ID NO: 77:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 233 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77:

Met 1 Assn Asp Glee Fox 5 Arg Alas Wall Thr Ser 10 Alas Wall Leo Wall Wall 15 Leo Glee Alas Cys Leo 20 Alas Leo Suffering Leo Ser 25 Glee Cys Ser Ser For 30 Fox For Asp Alas Gosh 35 Gosh Gin Glee Wall For 40 Wall Ser For Thr Alas 45 Ser Asp For Alas Leo 50 Leo Alas Gosh lle Arg 55 Gin Ser Leo Asp Alas 60 Thr Fox Glee Leo Thr 65 Ser Wall His Wall Alas 70 Wall Arg Thr Thr Glee 75 Fox Wall Asp Ser Leo 80 Leo Glee lle Thr Ser 85 Alas Asp Wall Asp Wall 90 Arg Alas Association For Leo 95 Alas Alas Fox Glee Wall 100 Cys Thr Tire Association Asp 105 Gosh Gin Glee Wall For 110 Phew Arg

·· ·· «« • · · » « · · • «« · · « • · ·· ·» • · « · * 9 « · • · · 9 9 9 9

999 9 9 9 99 99

124

Wall Gin Gly Asp Asn lle Ser Val Lys Lew Phew Asp Asp 125 Trp Ser Association 115 120 Leo Glee Ser lle Ser Gosh Leo Ser Thr Ser Arg Wall Leo Asp For Alas 130 135 140 Alas Glee Wall Thr Gin Leo Leo Ser Glee Wall Thr Association Leo Gin Alas Gin 145 150 155 160 Glee Thr Gosh Wall lle Asp Glee lle Ser Thr Thr Fox lle Thr Glee Thr 165 170 175 lle For Alas Ser Ser Wall Fox Met Leo Asp For Glee Alas Fox Ser Alas 180 185 190 Arg For Alas Thr Wall Suffering lle Alas Gin Asp Glee Ser His His Leo Wall 195 200 205 Arg Alas Ser lle Asp Leo Glee Ser Glee Ser lle Gin Leo Thr Gin Ser 210 215 220 Fox Suffering Association Gosh For Wall Association Wall Asp 225 230 Information about sequence SEQ id NO: 78:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 66 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 78:

Wall 1 lle Asp lle lle 5 Glee Thr Ser For Thr 10 Ser Suffering Gosh Gin Alas 15 Alas Alas Gosh Alas Wall 20 Gin Arg Alas Arg Asp 25 Ser Wall Asp Asp lle 30 Arg Wall Alas Arg Wall 35 lle Gosh Gin Asp Met 40 Alas Wall Asp Ser Alas 45 Glee Fox lle Thr Tire Arg lle Fox Leo Gosh Wall Ser Phew Fox Met Arg For Alas Gin

55 60

For Arg 65 ·· ·« • · · * • ·· • · · • · * ···· ·· ·* • · · • · ··· • · · » • · · · ·· *· ·· • · • · • ··· ♦ · ··

With • · ··· • t

125 (2)

Sequence Information SEQ ID NO: 79:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 69 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79:

Wall 1 For For Al For 5 For Leo For For Leo 10 For For Ser For How many 15 Ser Cys Alas Sir Pro 20 For Ser For For Leo 25 For For Alas For For 30 Wall Alas For Glee For Pro 35 Met For For Leo 40 Asp For Suffering For For 45 Alas For For Leo For 50 Tyr Ser Thr For For 55 Glee Alas For Leo For 60 For Ser For For Ser For For Lea For 65 2) Information about the sequence SEQ ID NO: 80:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 355 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 80:

Met 1 Ser Association Ser Arg 5 Arg Arg Ser Leo Arg 10 Suffering Ser Suffering Leo Leo 15 Ser Wall Leo Alas Alas 20 Wall Glee Leo Glee Leo 25 Alas Thr Alas For Alas 30 Gin Alas Alas For For 35 Alas Leo Ser Gin Asp 40 Arg Phew Alas Asp Phew 45 For Alas Leo For Leo Asp For Ser Alas Met Wall Alas Gin Wall Alas For Gin Wall Wall

55 60

Asn Ile Asn Thr Lys Leu Gly Tyr Asn Asn Ala Val Gly Ala Gly Thr 65 70 75 80

126

Gly Ile Val Ile Asp 85

Ile Ala Gly Ala Thr 100

Thr Tyr Gly Val Asp 115

Val Leu Gin Leu Arg 130

Gly Gly Val Ala Val 145

Gly Gin Gly Gly Thr 165

Gly Gin Thr Val Gin 180

Leu Asn Gly Leu Ile 195

Gly Gly Pro Val Val 210

Ala Ala Ser Asp Asn 225

Ile Pro Ile Gly Gin 245

Gly Gly Ser Pro Thr 260

Gly Val Val Asp Asn 275

Gly Ser Ala Pro Ala 290

Thr Ala Val Asp Gly 305

Ala Leu Asn Gly His 325

Thr Lys Ser Gly Gly 340

For Asn Gly Val Val 90

Asp Ile Asn Ala Phe 105

Val Val Gly Tyr Asp 120

Gly Ala Gly Gly Leu 135

Gly Glu Pro Val Val 150

Pro Arg Ala Val Pro 170

Ala Ser Asp Ser Leu 185

Gin Phe Asp Ala Ala

200

Asn Gly Leu Gly Gin 215

Phe Gin Leu Ser Gin 230

Ala Met Ala Ile Ala 250

Val His Ile Gly Pro 265

Asn Gly Asn Gly Ala 280

Ala Ser Leu Gly Ile 295

Ala Pro Ile Asn Ser 310

His Pro Gly Asp Val 330

Thr Arg Thr Gly Asn 345

Leu Thr Asn Asn His Val 95

Ser Val Gly Ser Gly Gin 110

Arg Thr Gin Asp Val Ala 125

For Ser Ala Ala Ile Gly 140

Ala Met Gly Asn Ser Gly 155 160

Gly Arg Val Val Ala Leu 175

Thr Gly Ala Glu Glu Thr 190

Ile Gin Pro Gly Asp Ser

205

Val Val Gly Met Asn Thr 220

Gly Gly Gin Gly Phe Ala 235 240

Gly Gin Ile Arg Ser Gly 255

Thr Ala Phe Leu Gly Leu 270

Arg Val Gin Arg Val Val 285

Ser Thr Gly Asp Val Ile 300

Ala Thr Ala Met Ala Asp 315 320

Ile Ser Val Asn Trp Gin 335

Val Thr Leu Ala Glu Gly 350

Pro Pro Ala 355 • · • · ··· ···· · ···· ·· · 9 ·· ·· · ·

127 (2) Information on the sequence of SEQ ID NO: 81:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 205 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 81:

Ser 1 For Lys For Asp Ala Glu Glu Gin Gly Val For Wall Ser For 15 Thr 5 10 Alas Ser Asp For Alas Leo Leo Alas Gosh How many Arg Gin Ser Leo Asp Alas 20 25 30 Thr Fox Glee Leo Thr Ser Wall His Wall Alas Wall Arg Thr Thr Glee Fox 35 40 45 Wall Asp Ser Leo Leo Glee How many Thr Ser Alas Asp Wall Asp Wall Arg Alas 50 55 60 Association For Leo Alas Alas Fox Glee Wall Cys Thr Tire Association Asp Gosh Gin Glee 65 70 75' 80 Wall For Phew Arg Wall Gin Glee Asp Association How many Ser Wall Fox Leo Phew Asp 85 90 95 Asp Suffering Ser Association Leo Glee Ser How many Ser Gosh Leo Ser Thr Ser Arg Wall 100 105 110 Leo Asp For Alas Alas Glee Wall Thr Gin Leo Leo Ser Glee Wall Thr Association 115 120 125 Leo Gin Alas Gin Glee Thr Gosh Wall How many Asp Glee How many Ser Thr Thr Fox 130 135 140 How many Thr Glee Thr How many For Alas Ser Ser Wall Fox Met Leo Asp For Glee 145 150 155 160 Alas Fox Ser Alas Arg For Alas Thr Wall Suffering How many Alas Gin Asp Glee Ser 165 170 175 His His Leo Wall Arg Alas Ser How many Asp Leo Glee Ser Glee Ser How many Gin 180 185 190

Leu Thr Gin Ser Lys Trp Asn Glu Pro Val Asn Val Asp 195 200 205 • · · · · ·

128 (2) Sequence information of SEQ ID NO: 82:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 286 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 82

Gly Asp 1

Leu Gly

His Ala

Val Ala 50

Ser Gly 65

Tyr Ile

Asn Phe

Ala Thr

Ala Met 130

Asp Val 145

Arg Asp

For Al

For Val

Arg Pro

210

Gly Phe

Sir Phe

Ala Thr 20

Asp Gly 35

Tyr Asp

Leo Ala

Thr Val

Asp Pro 100

Glu Gin 115

For Al

Ala Ala

Gly Val

Gly Val 180

Ile Ala 195

Trp Val

Ser Asp

Trp Ala 5

Ala Gly

His Ser

For Al

Arg Met 70

Tire Asn 85

Glu Glu

Arg Thr

Alas Leo

Asp Val 150

Val Ile 165

For Tyr

Val Ser

For Gly

Thr Arg

Ala Ala

Arg Thr

Leu Leu 40

Phe Ala 55

Cys Gly

Glu Pro

Val Leu

Asn Lys 120

Arg Ala 135

Trp Ser

Glu Thr

Val Thr

Asp Trp

200

Thr Tyr 215

For Al

Asp Gin 10

Thr Leu 25

Leu Asp

Tyr Glu

Glu Assn

Tire Val 90

Gly Gly 105

Xaa Gin

Ala Gin

Val Thr

Glu Lys 170

Arg Ala 185

Met Arg

Leu Thr

Gly Arg

Met Ala

ThrGly

Ala Thr

Ile Gly 60

For Glu 75

Gin Pro

Ile Tyr

How much Leu

Met Leu 140

Ser Trp 155

Leu Arg

Leu Glu

Ala Val

Leu Gly 220

Arg Tyr

Arg Gly

Glu Gly 30

Asn Pro 45

Tyr Ile

Asn Ile

For Glu

Arg Tyr 110

Ala Ser 125

Ala Ala

Glu Glu

His Pro

Asn Ala 190

For Glu 205

Thr Asp

Phe Assn

Phe Val 15

Leo Gin

Ala Val

Xaa Glu

Phew Phew. 80

For Glu ⁹⁵

His Ala

Gly Val

Glu Trp

Leu Asn 160

Asp Arg 175

Arg Gly

Gin Ile

Gly Phe

Thr Asp • ·

129

225 230 235 240 Alas Gosh Ser Gin Wall 245 Glee Arg Glee Phew Glee 250 Arg Glee Suffering For Glee 255 Arg Arg Wall Association How many 260 Asp For Phew Glee Alas 265 Glee Arg Glee For For 270 Alas Gin Leo For Glee Phew Asp Gosh Glee Glee Glee Leo Arg For Xaa Fox

275 280 285 (2) Sequence information of SEQ ID NO: 83:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 173 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 83:

Thr Lys 1 Phew His Ala 5 Leo Met Gin Glu Gin Ile His Asn Glu Phe Thr ¹⁰ .15 Alas Alas Gin Gin Tire Wall Alas How many Alas Wall Tire Phew Asp Ser Gosh Asp 20 25 30 Leo For Gin Leo Alas Fox His Phew Tire Ser Gin Alas Wall Gosh Gosh Arg 35 40 45 Association His Alas Met Met Leo Wall Gin His Leo Leo Asp Arg Asp Leo Arg 50 55 60 Wall Gosh How many For Glee Wall Asp Thr Wall Arg Association Gin Phew Asp Arg For 65 70 75 80 Arg Gosh Alas Leo Alas Leo Alas Leo Asp Gin Gosh Arg Thr Wall Thr Asp 85 90 95 Gin Wall Glee Arg Leo Thr Alas Wall Alas Arg Asp Gosh Glee Asp Phew Leo 100 105 110 Glee Gosh Gin Phew Met Gin Suffering Phew Leo Gin Gosh Gin How many Gosh Gosh Wall 115 120 125 Alas Leo Met Alas Thr Leo Wall Arg Wall Alas Asp Arg Alas Glee Alas Association 130 135 140 Leo Phew Gosh Leo Gosh Association Phew Wall Alas Arg Gosh Wall Asp Wall Alas For 145 150 155 160

130

Ala Ala Ser Gly Ala Pro His Ala Ala Gly Gly Arg Leu 165 170 (2) Sequence Information SEQ ID NO: 84:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 107 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 84:

Arg 1 Alas Asp Gosh Arg 5 Fox Association Thr Thr Met 10 Fox Met Wall Fox Ser 15 How many Alas Alas Glee Leo 20 Thr Alas Alas Alas Alas 25 How many Glee Alas Alas Alas 30 Alas Glee Wall Thr Ser 35 How many Met Alas Glee Glee 40 For Wall Wall Tire Gin 45 Met Gin For Wall Wall 50 Phew Glee Alas For Leo 55 For Leo Asp For Xaa 60 Ser Alas For Xaa Wall 65 For Thr Alas Alas Gin 70 Suffering Thr Xaa Leo Leo 75 Association Xaa Leo Xaa Asp 80 For Association Wall Ser Phew 85 Xaa Association Fox Glee Ser 90 Leo Wall Gosh Glee Glee 95 How many

Gly Gly Xaa Glu Gly Xaa Xaa Arg Arg Xaa Gin 100 105 (2) Sequence Information SEQ ID NO: 85:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 125 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 85:

Val Leu Ser Val Pro Val Gly Asp Gly Phe Trp Xaa Arg Val Val Asn 15 10 15

Pro Leu Gly Gin Pro Ile Asp Gly Arg Gly Asp Val Asp Ser Asp Thr • ·

131

25 30

Arg Arg Alas Leo Gosh Leo Gin Alas For Ser Wall Wall Xaa Arg Gin Glee 35 40 4 5 Wall Fox Gosh For Leo Xaa Thr Glee lle Fox Alas lle Asp Alas Met Thr 50 55 60 For lle Glee Arg Glee Gin Arg Gin Leo lle lle Glee Asp Arg Fox Thr 65 70 75 80 Glee Fox Association Arg Arg Leo Cys Arg Thr For Ser Ser Association Gin Arg Gosh 85 90 95 Gosh Leo Glee Wall Arg Suffering lle For Arg Ser Arg Cys Alas Cys Wall Tire 100 105 110 Wall Glee His Arg Alas Arg Arg Glee Thr Tire His Arg Arg 115 120 125

(2) Sequence information of SEQ ID NO: 86:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 117 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 86:

Cys 1 Asp Alas Wall Met 5 Glee Phew Leo Wall Asp Gin Gin 20 Leo Wall Thr Arg Gin Alas Alas 35 Alas Wall For Wall Wall 40 Alas Asp 50 Leo Alas Gosh lle Fox 55 Alas Glee 65 Thr Glee Glee Wall Glee 70 Met Alas Glee Wall Gosh Wall Phew 85 Wall Thr Alas Arg Alas Xaa Xaa Phew Asp Asp Xaa

100

Gly Gly Ala Gly Pro Leu Ala Val 10 15

Val Pro Gin Gly Trp Ser Phe Ala 25 30

Phe Leu Thr Ala Trp Tyr Gly Leu 45

Gly Glu Ser Val Leu lle His Ala 60

Ala Val Gin Leu Ala Arg Gin Trp 75 80

Ser Arg Gly Lys Trp Asp Thr Leu 90 95

For Tyr Arg Xaa Phe For His Xaa

105 110

132

Arg Ser Ser Xaa Gly 115 (2) Sequence Information SEQ ID NO: 87:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 103 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 87:

Met 1 Tire Arg Phew Alas 5 Cys Arg Thr Leo Met 10 Leo Alas Alas Cys lle 15 Leo Alas Thr Glee Wall 20 Alas Glee Leo Glee Wall 25 Glee Alas Gin Ser Alas 30 Alas Gin Thr Alas For 35 Wall For Asp Tire Tire 40 Suffering Cys For Glee Gin 45 For Phew Asp For Alas 50 Suffering Glee For Association Suffering 55 Asp For Tire Thr Cys 60 His Asp Asp Phew His 65 Arg Asp Ser Asp Glee 70 For Asp His Ser Arg 75 Asp Tire For Glee For 80 lle Leo Gosh Glee For 85 Wall Leo Asp Asp For 90 Glee Alas Alas For For 95 For

For Ala Ala Gly Gly Gly Ala 100 (2) Sequence Information SEQ ID NO: 88:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 88 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 88:

Val Gin Cys Arg Val Trp Leu Glu lle Gin Trp Arg Gly Met Leu Gly 1 5 10 15 • · • ·

133

Alas Asp Gin Alas Arg Alas Glee Glee For Alas Arg How many Suffering Arg 20 25 30 Ser Met Alas Alas Met Fox For Arg Thr Glee Asp Glee For Leo 35 40 45 Thr Fox Gosh Glee Arg Glee How many Wall Met Arg Wall For Leo Gosh 50 55 60 Glee Arg Leo Wall Wall Gosh Leo Thr For Asp Gosh Alas Alas Alas 65 70 75 Asp Gosh Leo Fox Glee Wall Thr Ser 85 Information about sequence SEQ id NO: 89:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 95 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 89:

Thr 1 Asp Alas Alas Thr 5 Leo Alas Gin Gosh Alas 10 Glee Association Phew Gosh Arg 15 How many Ser Glee Asp Leo 20 Fox Thr Gin How many Asp 25 Gin Wall Gosh Ser Thr 30 Alas Glee Ser Leo Gin 35 Glee Gin Suffering Arg Glee 40 Alas Alas Glee Thr Ala ⁴⁵ Alas Gin Alas Alas Wall 50 Wall Arg Phew Gin Gosh 55 Alas Alas Association Fox Gin 60 Fox Gin Gosh Leo Asp 65 Gosh How many Ser Thr Association 70 How many Arg Gin Alas Glee 75 Wall Gin Tire Ser Arg 80 Alas Asp Gosh Gosh Gin 85 Gin Gin Alas Leo Ser 90 Ser Gin Met Glee Phew 95

(2) Sequence information of SEQ ID NO: 90:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 166 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 90:

• · • · • · · · · · · · ···· ·· ·· ·· ··

134

Met Thr Gin Ser Gin Thr Wall Thr Wall Asp Gin Gin Gosh How many Leo Association 1 5 10 15 Arg Alas Association Gosh Wall Gosh Alas For Met Alas Asp For For Thr Asp Wall 20 25 30 For How many Thr For Cys Gosh Leo Thr Xaa Xaa Fox Association Alas Alas Gin Gin 35 40 45 Xaa Wall Leo Ser Alas Asp Association Met Arg Gosh Tire Leo Alas Alas Glee Alas 50 55 60 Fox Gosh Arg Gin Arg Leo Alas Thr Ser Leo Arg Association Alas Alas Fox Xaa 65 70 75 80 Tire Glee Gosh Wall Asp Gosh Gosh Al a Alas Thr Alas Leo Asp Association Asp Glee 85 90 95 Gosh Glee Thr Wall Gin Alas Gosh Ser Alas Glee Alas Wall Glee Glee Asp Ser 100 105 110 Ser Alas Gosh Leo Thr Asp Thr For Arg Wall Alas Thr Alas Glee Gosh For 115 120 125 Association Phew Met Asp Leo Fox Gosh Alas Alas Arg Fox Leo Gosh Thr Glee Asp 130 135 140 Gin Glee Alas Ser Leo Alas His Xaa Glee Asp Glee Suffering Association Thr Xaa Thr 145 150 155 160 Leo Thr Leo Gin Glee Asp

165 (2) Information on the sequence of SEQ ID NO: 91:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 5 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 91:

Arg Ala Glu Arg Met 1 5 • ·

135 (2) Sequence information of SEQ ID NO: 92:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 263 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 92:

Wall 1 Alas Suffer Met Ser Val 5 Thr Ala Gly Gin Ala Glu Leu Thr Ala Ala 10 15 Gin Wall Arg Wall Alas Alas Alas Alas Tire Gosh Thr Alas Tire Glee Leo Thr 20 25 30 Wall For For For Wall How many Alas Gosh Association Arg Alas Gosh Leo Met How many Leo 35 40 45 How many Alas Thr Association Leo Leo Glee Gin Association Thr For Alas How many Alas Wall Association 50 55 60 Gosh Alas Gosh Tire Glee Gosh Met Suffering Alas Gin Asp Alas Alas Alas Met Phew 65 70 75 80 Glee Tire Alas Alas Alas Thr Alas Thr Alas Thr Alas Thr Leo Leo For Phew 85 90 95 Gosh Gosh Alas For Gosh Met Thr Ser Alas Glee Glee Leo Leo Gosh Gin Alas 100 105 110 Alas Alas Wall Gosh Gosh Alas Ser Asp Thr Alas Alas Alas Association Gin Leo Met 115 120 125 Association Association Wall For Gin Alas Leo Fox Gin Leo Alas Gin For Thr Gin Glee 130 135 140 Thr Thr For Ser Ser Fox Leo Glee Glee Leo Suffering Fox Thr Wall Ser For 145 150 155 160 His Arg Ser For How many Ser Association Met Wall Ser Met Alas Association Association His Met 165 170 175 Ser Met Thr Association Ser Glee Wall Ser Met Thr Association Thr Leo Ser Ser Met 180 185 190 Leo Fox Glee Phew Alas For Alas Alas Alas Alas Gin Alas Wall Gin Thr Alas 195 200 205 Alas Gin Association Glee Wall Arg Alas Met Ser Ser Leo Glee Ser Ser Leo Glee

• · • ·

136

210 215 220 Ser 225 Ser Glee Leo Glee Glee 230 Glee Wall Alas Alas Association 235 Leo Glee Arg Alas Alas 240 Ser Wall Arg Tire Glee 245 His Arg Asp Glee Glee 250 Fox Tire Alas Xaa Ser 255 Glee Arg Arg Association Glee 260 Glee For Alas

(2) Sequence information of SEQ ID NO: 93:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 303 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 93:

Met Thr Tyr Ser Pro Gly Asn Pro Gly Tyr Pro Gin Ala Gin Pro Ala

5 10 15

Gly Ser Tyr Gly Gly Val Thr Pro Ser Phe Ala His Ala Asp Glu Gly

25 30

Ala Ser Lys Leu Pro Met Tyr Leu Asn Ile Ala Val Ala Val Leu Gly 35 40 45

Leu Ala Ala Tyr Phe Ala Ser Phe Gly Pro Met Phe Thr Leu Ser Thr 50 55 60

Glu Leu Gly Gly Gly Asp Gly Ala Val Ser Gly Asp Thr Gly Leu Pro

70 75 80

Val Gly Val Ala Leu Leu Ala Ala Leu Leu Ala Gly Val Val Leu Val

90 95

Pro Lys Ala Lys Ser His Val Thr Val Val Ala Val Leu Gly Val Leu 100 105 110

Gly Val Phe Leu Met Val Ser Ala Thr Phe Asn Lys Pro Ser Ala Tyr 115 120 125

Ser Thr Gly Trp Ala Leu Trp Val Val Leu Ala Phe Ile Val Phe Gin 130 135 140

Ala Val Ala Ala Val Leu Ala Leu Leu Val Glu Thr Gly Ala Ile Thr 145 150 155 160 • 9

99 99 ·9 • · · · · « · ·

9 9 · 9 9 9 9 · • 9 · · · · · 9 • · · · · 9 9 9 9 9 ··

137

Alas For Alas For Arg 165 For Lys Phew Asp Pro Tyr Gly Gin Tyr Gly Arg 170 175 Tire Glee Gin Tire Glee Gin Tire Glee Wall Gin For Glee Glee Tire Tire Glee 180 185 190 Gin Gin Glee Alas Gin Gin Alas Alas Glee Leo Gin Ser For Glee For Gin 195 200 205 Gin Ser For Gin For For Glee Tire Glee Ser Gin Tire Glee Glee Tire Ser 210 215 220 Ser Ser For Ser Gin Ser Glee Ser Glee Tire Thr Alas Gin For For Alas 225 230 235 240 Gin For For Alas Gin Ser Glee Ser Gin Gin Ser His Gin Glee For Ser 245 250 255 Thr For For Thr Glee Phew For Ser Phew Ser For For For For Wall Ser 260 2 65 270 Alas Glee Thr Glee Ser Gin Alas Glee Ser Alas For Wall Association Tire Ser Association 275 280 285 For Ser Glee Glee Gosh Gin Ser Ser Ser For Glee Glee ala' For Wall

290 295 300 (2) Information about the sequence of SEQ ID NO: 94:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 507 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 94:

ATGAAGATGG TGAAATCGAT CGCCGCAGGT CTGACCGCCG CGGCTGCAAT CGGCGCCGCT 60 GCGGCCGGTG TGACTTCGAT CATGGCTGGC GGCCCGGTCG TATACCAGAT GCAGCCGGTC 120 GTCTTCGGCG CGCCACTGCC GTTGGACCCG GCATCCGCCC CTGACGTCCC GACCGCCGCC 180 CAGTTGACCA GCCTGCTCAA CAGCCTCGCCC GATCCAACG TGTCGTTTGC GAACAAGGGC 240 AGTCTGGTCG AGGGCGGCAT CGGGGGCACC GAGGCGCGCA TCGCCGACCA CAAGCTGAAG 300 AAGGCCGCCG AGCACGGGGA TCTGCCGCTG TCGTTCAGCG TGACGAACAT CCAGCCGGCG 360 GCCGCCGGTT CGGCCACGC CGACGTTTCC GTCTCGGGTC CGAAGCTCTC GTCGCCGGTC' 420

• · • · • · · · • ·· · · ··· 4 ······· · » ·♦♦· ·· ·· 99 49 99

138

ACGCAGAACG TCACGTTCGT GAATCAAGGC GGCTGGATGC TGTCACGCGC ATCGGCGATG 480

GAGTTGCTGC AGGCCGCAGG GAACTGA 507 (2) Sequence Information SEQ ID NO: 95:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 168 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 95:

Met 1 Fox Met Wall Fox 5 Ser Ile Ala Alas Gly Leu 10 Thr Alas Alas Alas 15 Alas How many Glee Alas Alas Alas Alas Glee Wall Thr Ser How many Met Alas Glee Glee For 20 25 30 Wall Wall Tire Gin Met Gin For Wall Wall Phew Glee Alas For Leo For Leo 35 40 45 Asp For Alas Ser Alas For Asp Wall For Thr Alas Alas Gin Leo Thr Ser 50 55 60 Leo Leo Association Ser Leo Alas Asp For Association Wall Ser Phew Alas Association Fox Glee 65 70 75 80 Ser Leo Wall Gosh Glee Glee How many Glee Glee Thr Gosh Alas Arg How many Alas Asp 85 90 95 His Fox Leo Fox Fox Alas Alas Gosh His Glee Asp Leo For Leo Ser Phew 100 105 110 Ser Wall Thr Association How many Gin For Alas Alas Alas Glee Ser Alas Thr Alas Asp 115 120 125 • Wall Ser Wall Ser Glee For Fox Leo Ser Ser For Wall Thr Gin Association Wall 130 135 140 Thr Phew Wall Association Gin Glee Glee Suffering Met Leo Ser Arg Alas Ser Alas Met 145 150 155 160

Glu Leu Leu Gin Ala Ala Gly Asn 165

139 (2) Sequence information of SEQ ID NO: 96:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 500 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 96:

CGTGGCAATG TCGTTGACCG TCGGGGCCGG GGTCGCTCCC GCAGATCCCG TGGACGCGGT 60 CATTAACACC ACCTGCAATT ACGGGCAGGT AGTAGCTGCG CTCAACGCGA CGGATCCGGG 120 GGCTGCCGCA CAGTTCAACG CCTCACCGGT GGCGCAGTCC TATTTGCGCA ATTTCCTCGC 180 CGCACCGCCA CCTCAGCGCG CTGCCATGGC CGCGCAATTG CAAGCTGTGC CGGGGGCGGC 240 ACAGTACATC GGCCTTGTCG AGTCGGTTGC CGGCTCCTGC AACAACTATT AAGCCCATGC 300 GGGCCCCATC CCGCGACCCG GCATCGTCGC CGGGGCTAG CCGATTGCC CCGCTCCTCA 360 ACGGGCCGCA TCCCGCGACC CGGCATCGTC GCCGGGGCT GGCCAGATTG CCCCGCTCCT 420 CAACGGGCCG CATCTCGTGC CGAATTCCTG CAGCCGGGG GATCCACTAG TTCTAGAGCG 480 GCCGCCACCG CGGTGGAGCT 500

(2) Sequence information of SEQ ID NO: 97:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 96 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 97:

Wall 1 Alas Met Ser Leo 5 Thr Wall Glee Alas Glee 10 Wall Alas Ser Alas Asp 15 For Wall Asp Alas Wall 20 How many Association Thr Thr Cys 25 Association Tire Glee Gin Wall 30 Wall Alas Alas Leo Association 35 Alas Thr Asp For Glee 40 Alas Alas Alas Gin Phew 45 Association Alas Ser For Wall Alas Gin Ser Tire Leo Arg Association Phew Leo Alas Alas For For For

55 60

• · · · · · · 4 ···· ·· ·· ·· ·· ··

140

Gin 65 Arg Alas Alas Met Alas 70 Alas Gin Leo Gin Alas 75 Wall For Gly Ala Alas 80 Gin Tire lle Glee Leo Wall Gosh Ser Wall Alas Glee Ser Cys Assn Assn Tire

(2) Sequence information of SEQ ID NO: 98:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 154 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 98:

ATGACAGAGC AGCAGTGGAA TTTCGCGGGT ATCGAGGCCG CGGCAAGCGC AATCCAGGGA

AATGTCACGT CCATTCATTC CCTCCTTGAC GAGGGGAAGC AGTCCCTGAC CAAGCTCGCA

GCGGCCTGGG GCGGTAGCGG TTCGGAAGCG TACC (2) Sequence Information SEQ ID NO: 99:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 51 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 99:

Met 1 Thr Gosh Gin Gin 5 Suffering Association Phew Alas Glee 10 lle Gosh Alas Alas Alas 15 Ser Alas lle Gin Glee 20 Association Wall Thr Ser lle 25 His Ser Leo Leo Asp 30 Gosh Glee Fox Gin Ser Leo Thr Fox Leo Alas Alas Alas Suffering Glee Glee Ser Glee Ser

40 45

Glu Ala Tyr 50

141 (2) Sequence information of SEQ ID NO: 100:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 282 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 100:

CGGTCGCGCA CTTCCAGGTG ACTATGAAAG TCGGCTTCCG NCTGGAGGAT TCCTGAACCT 60 TCAAGCGCGG CCGATAACTG AGGTGCATCA TTAAGCGACT TTTCCAGAAC ATCCTGACGC 120 GCTCGAAACG CGGCACAGCC GACGGTGGCT CCGNCGAGGC GCTGNCTCA AAATCCTGA 180 GACAATTCGN CGGGGGCGCC TACAAGGAAG TCGGTGCTGA ATTCGNCGNG TATCTGGTCG 240 ACCTGTGTGG TCTGNAGCCG GACGAAGCGG TGCTCGACGT CG 282 (2) Sequence information of SEQ ID NO: 101: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 3058 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 101: - GATCGTACCC GTGCGAGTGC TCGGGCCGTT TGAGGATGGA GTGCACGTGT CTTTCGTGAT 60 GGCATACCCA GAGATGTTGG CGGCGGCGG TGACACCCTG CAGAGCATCG GTGCTACCAC 120 TGTGGCTAGC AATGCCGCTG CGGCGGCCCC GACGACTGGG GTGGTGCCCC CCGCTGCCGA 180 TGAGGTGTCG GCGCTGACTG CGGCGCACTT CGCCGCACAT GCGGCGATGT ATCAGTCCGT 240 GAGCGCTCGG GCTGCTGCGA TTCATGACCA GTTCGTGGCC ACCCTTGCCA GCAGCGCCAG 300 CTCGTATGCG GCCACTGAAG TCGCCAATGC GGCGGCGGCC AGCTAAGCCA GGAACAGTCG 360 GCACGAGAAA CCACGAGAAA TAGGGACACG TAATGGTGGA TTTCGGGGCG TTACCACCGG 420 AGATCAACTC CGCGAGGATG TACGCCGGCC CGGGTTCGGC CTCGCTGGTG GCCGCGGCTC 480 AGATGTGGGA CAGCGTGGCG AGTGACCTGT TTTCGGCCGC GTCGGCTTTT CAGTCGGTGG 540 TCTGGGGTCT GACGGTGGGGG TCGTGGATAG GTTCGTCGGC GGGTCTGATG GTGGCGGCGG 600

»··· *·«’ *·„·

142

CCTCGCCGTA TGTGGCGTGG ATGAGCGTCA CCGCGGGGCA GGCCGAGCTG ACCGCCGCCC 660 AGGTCCGGGT TGCTGCGGCG GCCTACGAGA CGGCGTATGG GCTGACGGTG CCCCCGCCGG 720 TGATCGCCGA GAACCGTGCT GAACTGATGA TTCTGATAGC GACCAACCTC TTGGGGCAAA 780 ACACCCCGGC GATCGCGGTC AACGAGGCCG AATACGGCGA GATGTGGGCC CAAGACGCCG 840 CCGCGATGTT TGGCTACGCC GCGGCGACGG CGACGGCGAC GGCGACGTTG CTGCCGTTCG 900 AGGAGGCGCC GGAGATGACC AGCGCGGGTG GGCTCCTCGA GCAGGCCGCC GCGGTCGAGG 960 AGGCTCCCGA CACCGCCGCG GCGAACCAGT TGATGAACAA TGTGCCCCAG GCGCTGCAAC 1020 AGCTGGCCCA GCCCACGCAG GGCACCACGC CTTCTTCCAA GCTGGGTGGC CTGTGGAAGA 1080 CGGTCTCGCC GCATCGGTCG CCGATCAGCA ACATGGTGTC GATGGCCAAC AACCACATGT 1140 CGATGACCAA CTCGGGTGTG TCGATGACCA ACACCTTGAG CTCGATGTTG AAGGGCTTTG 1200 CTCCGGCGGC GGCCGCCCAG GCCGTGCAAA CCGCGGCGCA AAACGGGGTC CGGGCGATGA 1260 GCTCGCTGGG CAGCTCGCTG GGTTCTTCGG GTCTGGGCGG TGC-GGTGGCC GCCAACTTGG 1320 GTCGGGCGGC CTCGGTCGGT TCGTTGTCGG TGCCGCAGGC CTGGGCCGCG GCCAACCAGG 1380 CAGTGACCCC GGCGGCGCGG GCGCTGCCGC TGACCAGCCT GACCAGCGCC GCGGAAAGAG 1440 GGCCCGGGCA GATGCTGGGC GGGCTGCCGG TGGGGCAGAT GGGCGCCAGG GCCGGTGGGTG 1500 GGCTCAGTGG TGTGCTGCGT GTTCCGCCGC GACCCTATGT GATGCCGCAT TCTCCGGCGG 1560 CCGGCTAGGA GAGGGGGCGC AGACTGTCGT TATTTGACCA GTGATCGGCG GTCTCGGTGT 1620 TTCCGCGGCC GGCTATGACA ACAGTCAATG TGCATGACAA GTTACAGGTA TTAGGTCCAG 1680 GTTCAACAAG GAGACAGGCA ACATGGCCTC ACGTTTTATG ACGGATCCGC ACGCGATGCG 1740 GGACATGGCG GGCCGTTTTG AGGGTCACGC CCAGACGGTG GAGGACGAGG CTCGCCGGAT 1800 GTGGGCGTCC GCGCAAAACA TTTCCGGTGC GGGCTGGAGT GGCATGGCCG AGGCGACCTC 1860 GCTAGACAC ATGGCCCAGA TGAATCAGGC GTTTCGCAAC ATCGTGAACA TGCTGCACGG 1920 GGTGCGTGAC GGGCTGGTTC GCGACGCCAA CAACTACGAG CAGCAAGAGC AGGCCTCCCCA 1980 GCAGATCCTC AGCAGCTAAC GTCAGCCGCT GCAGCACAAT ACTTTTACAA GCGAAGGAGA 2040 ACAGGTTCGA TGACCATCAA CTATCAATTC GGGGATGTCG ACGCTCACGG CGCCATGATC 2100 CGCGCTCAGG CCGGGTTGCT GGAGGCCGAG CATCAGGCCA TCATTCGTGA TGTGTTGACC 2160 GCGAGTGACT TTTGGGGGG CGCCGGTTCG GCGGCCTGCC AGGGGTTCAT TACCCAGTTG 2220 GGCCGTAACT TCCAGGTGAT CTACGAGCAG GCCAACGCCC ACGGGCAGAA GGTGCAGGCT 2280

tt

143

GCCGGCAACA ACATGGCGCA AACCGACAGC GCCGTCGGCT CCAGCTGGGC CTGACACCAG 2340

GCCAAGGCCA GGGACGTGGT GTACGAGTGGA AGTTCCTCGC GTGATCCTTC GGGTGGCAGT 2400

CTAAGTGGTC AGTGCTGGGG TGTTGGTGGT TTGCTGCTTG GCGGGTTCTT CGGTGCTGGT 2460

CAGTGCTGCT CGGGCTCGGG TGAGGACCTC GAGGCCCAGG TAGCGCCGTC CTTCGATCCA 2520

TTCGTCGTGT TGTTCGGCGA GGACGGCTCC GACGAGGCGG ATGATCGAGG CGCGGTCGGG 2580

GAAGATGCCC ACGACGTCGG TTCGGCGTCG TACCTCTCGG TTGAGGCGTT CCTGGGGGTT 2640

GTTGGACCAG ATTTGGCGCC AGATCTGCTT GGGGAAGGCG GTGAACGCCA GCAGGTCGGT 2700

GCGGGCGGTG TCGAGGTGCT CGGCCACCGC GGGGAGTTTG TCGGTCAGAG CGTCGAGTAC 2760

CCGATCATAT TGGGCAACAA CTGATTCGGC GTCGGGCTGG TCGTAGATGG AGTGCAGCAG 2820

GGTGCGCACC CACGGCCAGG AGGGCTTCGG GGTGGCTGCC ATCAGATTGG CTGCGTAGTG 2880

GGTTCTGCAG CGCTGCCAGG CCGCTGCGGG CAGGGTGGCG CCGATCGCGG CCACCAGGCC 2940

GGCGTGGGCG TCGCTGGTGA CCAGCGCGAC CCCGGACAGG CCGCGGGCGA CCAGGTCGCG 3000

GAAGAACGCC AGCCAGCCGG CCCCGTCCTC GGCGGAGGTG ACCTGGATGC CCAGGATC 3058 (2) Sequence Information SEQ ID NO: 102:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 391 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 102:

Met 1 Wall Asp Phew Glee 5 Alas Leo For For Gosh 10 How many Association Ser Alas Arg 15 Met Tire Alas Glee For 20 Glee Ser Alas Ser Leo 25 Wall Alas Alas Alas Gin 30 Met Suffering Asp Ser Wall 35 Alas Ser Asp Leo Phew 40 Ser Alas Alas Ser Alas 45 Phew Gin Ser Wall Wall 50 Suffering Glee Leo Thr Wall 55 Glee Ser Suffering How many Glee 60 Ser Ser Alas Glee Leo Met Wall Alas Alas Alas Ser For Tire Wall Alas Suffering Met Ser Wall Thr

• · · « ··· »· ·« ··

144

Ala Gly Gin Ala Glu Leu Thr Ala Ala Gin Val Arg Val Ala Ala Ala 85 90 95

Ala Tyr Glu Thr Ala Tyr Gly Leu Thr Val Pro Pro Pro Val Ile Ala 100 105 110

Glu Asn Arg Ala Glu Leu Met Ile Leu Ile Ala Thr Asn Leu Leu Gly 115 120 125

Gin Asn Thr Pro Ala Ile Ala Val Asn Glu Ala Glu Tyr Gly Glu Met 130 135 140

Trp Ala Gin Asp Ala Ala Ala Met Phe Gly Tyr Ala Ala Ala Thr Ala

145 150 155 160

Thr Ala Thr Ala Thr Leu Leu Pro Phe Glu Glu Ala Pro Glu Met Thr

165 170 175

Ser Ala Gly Gly Leu Leu Glu Gin Ala Ala Ala Val Glu Glu Ala Ser 180 185 190

Asp Thr Ala Ala Ala Asn Gin Leu Met Asn Asn Val Pro Gin Ala Leu 195 200 205

Gin Gin Leu Ala Gin Pro Thr Gin Gly Thr Thr Pro Ser Ser Lys Leu 210 215 220

Gly Gly Leu Trp Lys Thr Val Ser Pro His Arg Ser Pro Ile Ser Asn

225

230

235

240

Met Val Ser Met Ala Asn Asn His Met Ser Met Thr Asn Ser Gly Val 245 250 255

Ser Met Thr Asn Thr Leu Ser Ser Met Leu Lys Gly Phe Ala Pro Ala 260 265 270

Ala Ala Ala Gin Ala Val Gin Thr Ala Ala Gin Asn Gly Val Arg Ala 275 280 285

Met Ser Ser Leu Gly Ser Ser Leu Gly Ser Ser Gly Leu Gly Gly Gly 290 295 300

Val Ala Ala Asn Leu Gly Arg Ala Ala Ser Val Gly Ser Leu Ser Val

305 310 315 320

Pro Gin Ala Trp Ala Ala Ala Asn Gin Ala Val Thr Pro Ala Ala Arg

325 330 335

Ala Leu Pro Leu Thr Ser Leu Thr Ser Ala Ala Glu Arg Gly Pro Gly 340 345 350

Gin Met Leu Gly Gly Leu Pro Val Gly Gin Met Gly Ala Arg Ala Gly 355 360 365 ·· ···♦ ·« ·· ··

F · · ► · · · · ► · · 4 » · · 4 ·· 4«

145

Gly Gly Leu Ser Gly Val Leu Arg Val Pro Pro Arg Pro Tyr Val Met 370 375 380

Pro His Ser Pro Ala Ala Gly 385 390 (2) Sequence Information SEQ ID NO: 103:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1725 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 103:

GACGTCAGCA CCCGCCGTGC AGGGCTGGAG CGTGGTCGGT TTTGATCTGC GGTCAAGGTG 60

ACGTCCCTCG GCGTGTCGCC GGCGTGGATG CAGACTCGAT GCCGCTCTTT AGTGCAACTA 120

ATTTCGTTGA AGTGCCTGCG AGGTATAGGA CTTCACGATT GGTTAATGTA GCGTTCACCC 180

CGTGTTGGGG TCGATTTGGC CGGACCAGTC GTCACCAACG CTTGGCGTGC GCGCCAGGCG 240

GGCGATCAGA TCGCTTGACT ACCAATCAAT CTTGAGCTCC CGGGCCGATG CTCGGGCTAA 300

ATGAGGAGGA GCACGCGTGT CTTTCACTGC GCAACCGGAG ATGTTGGCGG CCGCGGCTGG 360

CGAACTTCGT TCCCTGGGGG CAACGCTGAA GGCTAGCAAT GCCGCCGCAG CCGTGCCGAC 420

GACTGGGGTG GTGCCCCCGG CTGCCGACGA GGTGTCGCTG CTGCTTGCCA CACAATTCCG 480

TACGCATGCG GCGACGTATC AGACGGCCAG CGCCAAGGCC GCGGTGATCC ATGAGCAGTT 540

TGTGACCACG CTGGCCACCA GCGCTAGTTC ATATGCGGAC ACCGAGGCCG CCAACGCTGT 600

GGTCACCGGC TAGCTGACCT GACGGTATTC GAGCGGAAGG ATTATCGAAG TGGTGGATTT 660

CGGGGCGTTA CCACCGGAGA TCAACTCCGC GAGGATGTAC GCCGGCCCGG GTTCGGCCTC 720

GCTGGTGGCC GCCGCGAAGA TGTGGGACAG CGTGGCGAGT GACCTGTTTT CGGCCGCGTC 780

GGCGTTTCAG TCGGTGGTCT GGGGTCTGAC GGTGGGGTCG TGGATAGGTT CGTCGGCGGG 840

TCTGATGGCG GCGGCGGCCT CGCCGTATGT GGCGTGGATG AGCGTCACCG CGGGGCAGGC 900

CCAGCTGACC GCCGCCCAGG TCCGGGTTGC TGCGGCGGCC TACGAGACAG CGTATAGGCT 960

GACGGTGCCC CCGCCGGTGA TCGCCGAGAA CCGTACCGAA CTGATGACGC TGACCGCGAC 1020

CAACCTCTTG GGGCAAAACA CGCCGGCGAT CGAGGCCAAT CAGGCCGCAT ACAGCCAGAT 1080 ·· ·· ·· • · · · · · • ·· · '· • · · « · 9 • · 9 · 9

9999 99 99 ···

9 9 9

9 9 9 • 9 ··· 999 • 9 9

99 99

146

GTGGGGCCAA GACGCGGAGG CGATGTATGG CTACGCCGCC ACGGCGGCGA CGGCGACCGA 1140 GGCGTTGCTG CCGTTCGAGG ACGCCCACT GATCACCAAC CCGGCGGGCC TCCTTGAGCA 1200 GGCCGTCGCG GTCGAGGAGG CCATCGACAC CGCCGCGGCG AACCAGTTGA TGAAACAATGT 1260 GCCCCAAGCG CTGCAACAGC TGGCČCAGCC AGCGCAGGGC GTCGTACCTT CTTCCAAGCT 1320 GGGTGGGCTG TGGACGGGG TCTCGCCGCA TCTGTCGCCG CTCAGCAACG TCAGTTCGAT 1380 AGCCAACAAC CACATGTCGA TGATGGGCAC GGGTGTGTCG ATGACCAACA CCTTGCACTC 1440 GATGTTGAAG GGCTTAGCTC CGGCGGCGG TCAGGCCGTG GAAACCGCGG CGGAAAACGG 1500 GGTCTGGGCG ATGAGCTCGC TGGGCAGCCA GCTGGGTTCG TCGCTGGGTT CTTCGGGTCT 1560 GGGCGCTGG GTGGCCGCCA ACTTGGGTCG GGCGGCTCCG GTCGGTTCGT TGTCGGTGCC 1620 GCCAGCATGG GCCGCGGCCCA ACCAGGCGGT CACCCCGGCG GCGCGGGCGC TGCCGCTGAC 1680 CAGCCTGACC AGCGCCGCCC AAACCGCCC CGGACACATG CTGGG 1725

(2) Sequence information of SEQ ID NO: 104:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 359 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 104:

Val Val Asp Phe Gly Ala Leu Pro Pro Glu Ile Asn Ser Ala Arg Met 15 10 15

Tyr Ala Gly Pro Gly Ser Ala Ser Leu Val Ala Ala Ala Lys Met Trp 20 25 30

Asp Ser Val Ala Ser Asp Leu Phe Ser Ala Ala Ser Ala Phe Gin Ser 35 40 45 .

Val Val Trp Gly Leu Thr Val Gly Ser Trp Ile Gly Ser Ser Ala Gly 50 55 60

Leu Met Ala Ala Ala Ala Ser Pro Tyr Val Ala Trp Met Ser Val Thr

70 75 80

Ala Gly Gin Ala Gin Leu Thr Ala Ala Gin Val Arg Val Ala Ala Ala

90 95 • · · · • · · · · · · · • ··· ·· ·· · · · · ·«

147 Alas Tire Gosh Thr Alas Tire Arg Leo Thr Wall For For For Wall How many Alas 100 105 110 Gosh Association Arg Thr Gosh Leo Met Thr Leo Thr Alas Thr Association Leo Leo Glee 115 120 125 Gin Association Thr For Alas How many Gosh Alas Association Gin Alas Alas Tire Ser Gin Met 130 135 140 Suffering Glee Gin Asp Alas Gosh Alas Met Tire Glee Tire Alas Alas Thr Alas Alas 145 150 155 160 Thr Alas Thr Gosh Alas Leo Leo For Phew Gosh Asp Alas For Leo How many Thr 165 170 175 Association For Glee Glee Leo Leo Gosh Gin Alas Wall Alas Wall Gosh Gosh Alas How many 180 185 190 Asp Thr Alas Alas Alas Association Gin Leo Met Association Association Wall For Gin Alas Leo 195 200 205 Gin Gin Leo Alas Gin For Alas Gin Glee Wall Wall For Ser Ser Fox Leo 210 215 220 Glee Glee Leo Suffering Thr Alas Wall Ser For His Leo Ser For Leo Ser Association 225 230 235 240 Wall Ser Ser How many Alas Association Association His Met Ser Met Met Glee Thr Glee Wall 245 250 255 Ser Met Thr Association Thr Leo His Ser Met Leo Fox Glee Leo Alas For Alas 260 265 270 Alas Alas Gin Alas Wall Gosh Thr Alas Alas Gosh Association Glee Wall Suffering Alas Met 275 280 285 Ser Ser Leo Glee Ser Gin Leo Glee Ser Ser Leo Glee Ser Ser Glee Leo 290 295 300 Glee Alas Glee Wall Alas Alas Association Leo Glee Arg Alas Alas Ser Wall Glee Ser 305 310 315 320 Leo Ser Wall For For Alas Suffering Alas Alas Alas Association Gin Alas Wall Thr For 325 330 335 Alas Alas Arg Alas Leo For Leo Thr Ser Leo Thr Ser Alas Alas Gin Thr 340 345 350

Ala Pro Gly His Met Leu Gly 355

148 (2) Information on the sequence of SEQ ID NO: 105:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 3027 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 105:

AGTTCAGTCG AGAATGATAC TGACGGGCTG TATCCACGAT GGCTGAGACA ACCGAACCAC 60 CGTCGGACGC GGGGACATCG CAAGCCGACG CGATGGCGTT GGCCGCCGAA GCCGAAGCCG 120 CCGAAGCCGA AGCGCTGGCC GCCGCGGGC GGGCCCGTGC CCGTGCCGCC CGGTTGAAGC 180 GTGAGGCGCT GGCGATGGCC CCAGCCGAGG ACGAGAACGT CCCCGAGGAT ATGCAGACTG 240 GGAAGACGCC GAAGACTATG ACGACTATGA CGACTATGAG GCCGCAGACC AGGAGGCCGC 300 ACGGTCGGCA TCCTGGCGAC GGCGGTTGCG GGTGCGGTTA CCAAGACTGT CCACGATTGC 360 CATGGCGCC GCAGTCGTCA TCATCTGCGG CTTCACCGGG CTCAGCGGAT ACATTGTGTG 420 GCAACACCAT GAGGCCACCG AACGCCAGCA GCGCGCCGCG GCGTTCGCCG CCGGAGCCAA 480 GCAAGGTGTC ATCAACATGA CCTCGCTGGA CTTCAACAAG GCCAAAAAG ACGTCGCGCG 540 TGTGATCGAC AGCTCCACCG GCGAATTCAG GGATGACTTC CAGCAGCGGG CAGCCGATTT 600 CACCAAGGTT GTCGAACAGT CCAAAGTGGT CACCGAAGGC ACGGTGAACG CGACAGCCGT 660 CGAATCCATG AACGAGCATT CCGCCGTGGT GCTCGTCGCG GCGACTTCAC GGGTCACCAA 720 TTCCGCTGGG GCGAAAGACG AACCACGTGC GTGGCGGCTC AAAGTGACCG TGACCGAAGA 780 GGGGGGACAG TACAAGATGT CGAAAGTTGA GTTCGTACCG TGACCGATGA CGTACGCGAC 840 GTCAACACCG AAACCACTGA CGCCACCGAA GTCGCTGAGA TCGACTCAGC CGCAGGCGAA 900 GCCGGTGATT CGGCGACCGA GGCATTTGAC ACCGACTCTG CAACGGAATC TACCGCGCAG 960 AAGGGTCAGC GGCACCGTGA CCTGTGGCGA ATGCAGGTTA CCTTGAAACC CGTTCCGGTG 1020 ATTCTCATCC TGCTCATGTT GATCTCTGGG GGCGCGACGG GATGGCTATA CCTTGAGCAA 1080 TACGACCCGA TCAGCAGACG GACTCCGGCG CCGCCCGTGC TGCCGTCGCC GCGGCGTCTG 1140 ACGGGACAAT CGCGCTGTTG TGTATTCACC CGACACGTCG ACCAAGACTT CGCTACCGCC 1200 AGGTCGCACC TCGCCGGCGA TTTCCTGTCC TATACGACCA GTTCACGCAG CAGATCGTGG 1260 CTCCGGCGGC CAAACAGAAG TCACTGAAAA CCACCGCCAA GGTGGTGCGC GCGGCCGTGT 1320 CGGAGCTACA TCCGGATTCG GCCGTCGTTC TGGTTTTTGT CGACCAGGC ACTACCAGTA 1380

• ·

149 • · • 999 • · · · · ·· 9 · · 9 • this it AGGACAGCCC CAATCCGTCG ATGGCGGCCA GCAGCGTGAT GGTGACCCTA GCCAAGGTCG 1440 ACGGCAATTG GCTGATCACC AAGTTCACCC CGGTTTAGGT TGCCGTAGGC GGTCGCCAAG 1500 TCTGACGGGG GCGCGGGTGG CTGCTCGTGC GAGATACCGG CCGTTCTCCG GACAATCACG 1560 GCCCGACCTC AAACAGATCT CGGCCGCGT CTAATCGGCC GGGTTATTTA AGATTAGTTG 1620 CCACTGTATT TACCTGATGT TCAGATTGTT CAGCTGGATT TAGCTTCGCG GCAGGGCGGC 1680 TGGTGCACTT TGCATCTGGG GTTGTGACTA CTTGAGAGAA TTTGACCTGT TGCCGACGTT 1740 GTTTGCTGTC CATCATTGGT GCTAGTTATG GCCGAGCGGA AGGATTATCG AAGTGGTGGA 1800 CTTCGGGGCG TTACCACCGG AGATCAACTC CGCGAGGATG TACGCCGGCC CGGGTTCGGC 1860 CTCGCTGGTG GCCGCGCCA AGATGTGGGA CAGCGTGGCG AGTGACCTGT TTTCGGCCGC 1920 GTCGGCTTTT CAGTCGGTGG TCTGGGGTCT GACGACGGGA TCGTGGATAG GTTCGTCGGC 1980 GGGTCTGATG GTGGCGGCGG CCTCGCCGTA TGTGGCGTGG ATGAGCGTCA CCGCGGGGCA 2040 GGCCGAGCTG ACCGCCGCCC AGGTCCGGGT TGCTGCGGCG GCCTACGAGA CGGCGTATGG 2100 GCTGACGGTG CCCCCGCCGG TGATCGCCGA GAACCGTGCT GAACTGATGA TTCTGATAGC 2160 GACCAACCTC TTGGGGCAAA ACACCCCGGC GATCGCGGTC AACGAGGCCG AATACGGGGA 2220 GATGTGGGCC CAAGACGCCG CCGCGATGTT TGGCTACGCC GCCACGGCGGG CGACGGCGAC 2280 CGAGGCGTTG CTGCCGTTCG AGGACGCCCC ACTGATCACC AACCCCGGCG GGCTCCTTGA 2340 GCAGGCCGTC GCGGTCGAGG AGGCCATCGA CACCGCCGCG GCGAACCAGT TGATGAACAA 2400 TGTGCCCCAA GCGCTGCAAC AACTGGCCCA GCCCACGAAA AGCATCTGGC CGTTCGACCA 2460 ACTGAGTGAA CTCTGGAAAG CCATCTCGCC GCATCTGTCG CCGCTCAGCA ACATCGTGTC 2520 GATGCTCAAC AACCACGTGT CGATGACCAA CTCGGGTGTG TCGATGGCCA GCACCTTGCA 2580 CTCAATGTTG AAGGGCTTTG CTCCGGCGGC GGCTCAGGCC GTGGAAACCG CGGCGCAAAA 2640 CGGGGTCCAG GCGATGAGCT CGCTGGGCAG CCAGCTGGGT TCGTCGCTGG GTTCTTCGGG 2700 TCTGGGCGCT GGGGTGGCCG CCAACTTGGG TCGGGCGGCC TCGGTCGGTT CGTTGTCGGT 2760 GCCGCAGGCC TGGGCCGCGG CCAACCAGGC GGTCACCCCG GCGGCGCGGG CGCTGCCGCT 2820 GACCAGCCTG ACCAGCGCCG CCCAAACCGC CCCCGGACAC ATGCTGGGCG GGCTACCGCT 2880 GGGGCAACTG ACCAATAGCG GCGGCGGGTT CGGCGGGGTT AGCAATGCGT TGCGGATGCC 2940 GCCGGGGGCG TACGTAATGC CCCGTGTGCC CGCCGCCGGG TAACGCCGAT CCGCACGCAA 3000

• ·

WO 98/16645 • · · · · · · · • · · · · · · · · ·· · .· : : · :pcuus5?7/isTfit ··:

···· ·· ·· ·· . tt 'tt

150

TGCGGCCCT CTATGCGGGC AGCGATC

3027 (2) Sequence Information SEQ ID NO: 106:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 396 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106:

Wall 1 Wall Asp Phew Glee 5 Alas Leo For For Gosh 10 Ile Asn Ser Ala Arg 15 Met Tire Alas Glee For Glee Ser Alas Ser Leo Wall Alas Alas Alas Fox Met Suffering 20 25 30 Asp Ser Wall Alas Ser Asp Leo Phew Ser Alas Alas Ser Alas Phew Gin Ser 35 40 45 Wall Wall Suffering Glee Leo Thr Thr Glee Ser Suffering How many Glee Ser Ser Alas Glee 50 55 60 Leo Met Wall Alas Alas Alas Ser For Tire Wall Alas Suffering Met Ser Wall Thr 65 70 75 80 Alas Glee Gin Alas Gosh Leo Thr Alas Alas Gin Wall Arg Wall Alas Alas Alas 85 90 95 Alas Tire Gosh Thr Alas Tire Glee Leo Thr Wall For For For Wall How many Alas 100 105 110 Gosh Association Arg Alas Gosh Leo Met How many Leo How many Alas Thr Association Leo Leo Glee 115 120 125 Gin Association Thr For Alas How many Alas Wall Association Gosh Alas Gosh Tire Glee Gosh Met 130 135 140 Suffering Alas Gin Asp Alas Alas Alas Met Phew Glee Tire Alas Alas Thr Alas Alas 145 150 155 160 Thr Alas Thr Gosh Alas Leo Leo For Phew Gosh Asp Alas For Leo How many Thr 165 170 175 Association For Glee Glee Leo Leo Gosh Gin Alas Wall Alas Wall Gosh Gosh Alas How many 180 185 190 Asp Thr Alas Alas Alas Association Gin Leo Met Association Association Wall For Gin Alas Leo 195 200 205

• · • · » · · » · · • · · 4 • · · · · · · ······ ·* »»

151

Gin Gin Leu Ala Gin Pro Thr Lys Ser lle Trp Pro Phe Asp Gin Leu 210 215 220

Ser Glu Leu Trp Lys Ala lle Ser Pro His Leu Ser Pro Leu Ser Asn

225 230 235 240 lle Val Ser Met Leu Asn Asn His Val Ser Met Thr Asn Ser Gly Val

245 250 255

Ser Met Ala Ser Thr Leu His Ser Met Leu Lys Gly Phe Ala Pro Ala 260 265 270

Ala Ala Gin Ala Val Glu Thr Ala Ala Gin Asn Gly Val Gin Ala Met 275 280 285

Ser Ser Leu Gly Ser Gin Leu Gly Ser Ser Leu Gly Ser Ser Gly Leu 290 295 300

Gly Ala Gly Val Ala Ala Asn Leu Gly Arg Ala Ala Ser Val Gly Ser

305 310 315 320

Leu Ser Val Pro Gin Ala Trp Ala Ala Ala Asn Gin Ala Val Thr Pro

325. 330 335

Ala Ala Arg Ala Leu Pro Leu Thr Ser Leu Thr Ser Ala Ala Gin Thr 340 345 350

Ala Pro Gly His Met Leu Gly Gly Leu Pro Leu Gly Gin Leu Thr Asn 355 360 365

Ser Gly Gly Gly Phe Gly Gly Val Ser Asn Ala Leu Arg Met Pro Pro 370 375 380

Arg Ala Tyr Val Met Pro Arg Val Pro Ala Ala Gly 385 390 395 (2) Sequence Information SEQ ID NO: 107:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1616 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 107:

CATCGGGAGGG AGTGATCACC ATGCTGTGGC ACGCAATGCC ACCGGAGTAA ATACCGCACG 60 GCTGATGGCC GGCGCGGGTC CGGCTCCAAT GCTTGCGGCG GCCGGGGGAT GGCAGACGCT 120 TTCGGCGCT CTGGACGCTC AGGCCGTCGA GTTGACCGCG CGCCTGAACT CTCTGGGAGA 180

• ·

152

AGCCTGGACT GGAGGTGGGCA GCGACAAGGC GCTTGCGGCT GCAACGCCGA TGGTGGTCTG 240 GCTACAAACC GCGTCAACAC AGGCCAAGAC CCGTGCGATG CAGGCGACGG CGCAAGCCGC 300 GGCATACACC CAGGCCATGG CCACGACGCC GTCGCTGCCG GAGATCGCCG CCAACCACAT 360 CACCCAGGCC GTCCTTACGG CCACCAACTT CTTCGGTATC AACACGATCC CGATCGCGTT 420 GACCGAGATG GATTATTTCA TCCGTATGTG GAACCAGGCA GCCCTGGCAA TGGAGGTCTA 480 CCAGGCCGAG ACCGCGGTTA ACACGCTTTT CGAGAAGCTC GAGCCGATGG CGTCGATCCT 54 0 TGATCCCGGC GCGAGCCAGA GCACGACGAA CCCGATCTTC GGAATGCCCT CCCCTGGCAG 600 CTCAACACCG GTTGGCCAGT TGCCGCCGGC GGCTACCCAG ACCCTCGCC AACTGGGTGA 660 GATGAGCGGC CCGATGCAGC AGCTGACCCA GCCGCTGCAG CAGGTGACGT CGTTGTTCAG 720 CCAGGTGGGC GGCACCGGCG GCGGCAACCC AGCCGACGAG GAAGCCGCGC AGATGGGCCT 780 GCTCGGCACC AGTCCGCTGT CGAACCATCC GCTGGCTGGT GGATCAGGCC CCAGCGCGGG 840 CGCGGGCCTG CTGCGCGCGG AGTCGCTACC TGGCGCAGGT GGGTCGTTGA CCCGCACGCC 900 GCTGATGTCT CAGCTGATCG AAAAAGCCGGT TGCCCCTCCG GTGATGCCGG CGGCTGCTGC 960 CGGATCGTCG GCGACGGGTG GCGCCGTCCC GGTGGGTGCG GGAGCGATGG GCCAGGGTGC 1020 GCAATCCGGC GGCTCCACCA GGCCGGGTCT GGTCGCGCCG GCACCGCTCG CGCAGGAGCG 1080 TGAAGAAGAC GACGAGGACG ACTGGGACGA AGAGGACGAC TGGTGAGCTC CCGTAATGAC 1140 AACAGACTTC CCGGCCACCC GGGCCGGAAG ACTTGCCAAC ATTTTGGCGA GGAAGGTAAAA 1200 GAGAGAAAGT AGTCCAGCAT GGCAGAGATG AAGACCGATG CCGCTACCCT CGCGCAGGAG 1260 GCAGGTAATT TCGAGCGGAT CTCCGGCGAC CTGAAAACCC AGATCGACCA GGTGGAGTCG 1320 ACGGCAGGTT CGTTGCAGGG CCAGTGGCGC GGCGCGGCGG GGACGGCCGC CCAGGCCGCG 1380 GTGGTGCGCT TCCAAGAAGC AGCCAATAAG CAGAAGCAGG AACTCGACGA GATCTCGACG 1440 AATATTCGTC AGGCCGGCGT CCAATACTCG AGGGCCGACG AGGAGCAGCA GCAGGCGCTG 1500 TCCTCGCAAA TGGGCTTCTG ACCGCTAAT ACGAAAAGAA ACGGAGCAAA AACATGACAG 1560 AGCAGCAGTG GAATTTCGCG GGTATCGAGG CČGCGGCAAG CGCAATCCAG GGAAAT 1616

(2) Sequence information of SEQ ID NO: 108:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 432 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 108:

• ·

153

CTAGTGGATG GGACCATGGC CATTTTCTGC AGTCTCACTG CCTTCTGTGT TGACATTTTG 60 GCACGCCGGC GGAAACGAAG CACTGGGGTC GAAGAACGGC TGCGCTGCCA TATCGTCCGG 120 AGCTTCCATA CCTTCGTGCG GCCGGAAGAG CTTGTCGTAG TCGGCCGCCA TGACAACCTC 180 TCAGAGTGCG CTCAAACGTA TAAACACGAG AAAGGGGGG ACCGACGGAA GGTCGAACTC 240 GCCCGATCCC GTGTTTCGCT ATTCTACGCG AACTCGGCGT TGCCCTATGC GAACATCCCA 300 GTGACGTTGC CTTCGGTCGA AGCCATTGCC TGACCGGCTT CGCTGATCGT CCGCGCCAGG 360 TTCTGCAGCG CGTTGTTCAG CTCGGTAGCC GTGGCGTCCC ATTTTTGCTG GACACCCTGG 420 TACGCCTCCG AA 432

(2) Information ο the sequence of SEQ ID NO: 109:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 368 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 109:

Met Leu Trp His Ala Met Pro Pro Glu Xaa Asn Thr Ala Arg Leu Met 15 10 15

Ala Gly Ala Gly Pro Ala Pro Met Leu Ala Ala Ala Ala Gly Trp Gin 20 25 30

Thr Leu Ser Ala Ala Leu Asp Ala Gin Ala Val Glu Leu Thr Ala Arg 35 ' 40 45

Leu Asn Ser Leu Gly Glu Ala Trp Thr Gly Gly Gly Ser Asp Lys Ala 50 55 60

Leu Ala Ala Ala Thr Pro Met Val Val Trp Leu Gin Ťhr Ala Ser Thr

70 75 80

Gin Ala Lys Thr Arg Ala Met Gin Ala Thr Ala Gin Ala Ala Ala Tyr

90 95 • ·· · ···· · · · · • · · · · · · ·· ··· ··· • •••••ft · · ···· ·· ·» ·· ·· ··

154

Thr Gin Alas Met 100 Alas Thr Thr For Ser 105 Leo For Gosh How many Alas 110 Alas Association - His How many Thr Gin Alas Wall Leo Thr Alas Thr Association Phew Phew Glee How many Association 1 115 120 125 Thr How many For How many Alas Leo Thr Gosh Met Asp Tire Phew How many Arg Met Suffering - 130 135 140 Association Gin Alas Alas Leo Alas Met Gosh Wall Tire Gin Alas Gosh Thr Alas Wall 145 150 155 160 Association Thr Leo Phew Gosh Fox Leo Gosh For Met Alas Ser How many Leo Asp For 165 170 175 Glee Alas Ser Gin Ser Thr Thr Association For How many Phew Glee Met For Ser For 180 185 190 Glee Ser Ser Thr For Wall Glee Gin Leo For For Alas Alas Thr Gin Thr 195 200 205 Leo Glee Gin Leo Glee Gosh Met Ser Glee For Met Gin Gin Leo Thr Gin 210 215 220 For Leo Gin Gin Wall Thr Ser Leo Phew Ser Gin Wall Glee Glee Thr Glee 225 230 235 240 Glee Glee Association For Alas Asp Gosh Gosh Alas Alas Gin Met Glee Leo Leo Glee 245 250 255 Thr Ser For Leo Ser Association His For Leo Alas Glee Glee Ser Glee For Ser 260 265 270 Alas Glee Alas Glee Leo Leo Arg Alas Gosh Ser Leo For Glee Alas Glee Glee 275 280 285 Ser Leo Thr Arg Thr For Leo Met Ser Gin Leo How many Gosh Fox For Wall 290 295 300 Alas For Ser Wall Met For Alas Alas Alas Alas Glee Ser Ser Alas Thr Glee 305 310 315 320 Glee Alas Alas For Wall Glee Alas Glee Alas Met Glee Gin Glee Alas Gin Ser 325 330 335 Glee Glee Ser Thr Arg For Glee Leo Wall Alas For Alas For Leo Alas Gin

340 345 350

Glu Arg Glu Glu Asp Asp Glu Asp Asp Trp Asp Glu Glu Asp Asp Trp 355 360 365 • 0 0

0 • · · 0·00 ···· 00 00 ·»

155 (2) Sequence information of SEQ ID NO: 110:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 100 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 110:

Met 1 Ala Glu Met Lys Thr Asp Ala Ala Thr Leu Ala Gin Glu Ala Glee 5 10 15 Association Phew Gosh Arg How many Ser Glee Asp Leo Fox Thr Gin How many Asp Gin Wall 20 25 30 Gosh Ser Thr Alas Glee Ser Leo Gin Glee Gin Suffering Arg Glee Alas Alas Glee 35 40 45 Thr Alas Alas Gin Alas Alas Wall Wall Arg Phew Gin Gosh Alas Alas Association Fox 50 55 60 Gin Fox Gin Gosh Leo Asp Gosh How many Ser Thr Association How many Arg Gin Alas Glee 65 70 75 80 Wall Gin Tire Ser Arg Alas Asp Gosh Gosh Gin Gin Gin Alas Leo Ser Ser

90 . 95

Gin Met Gly Phe 100 (2) Sequence Information SEQ ID NO: 111:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 396 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111:

GATCTCCGGC GACCTGAAAA CCCAGATCGA CCAGGTGGAG TCGACGGCAG GTTCGTTGCA 60 GGGCCAGTGG CGCGGCGCGGG CGGGGACGGC CGCCCAGGCC GCGGTGGTGC GCTTCCAAGA 120 AGCAGCCAAT AAGCAGAAGC AGGAACTCGA CGAGATCTCG ACGAATATTC GTCAGGCCGG ' 180 CGTCCAATAC TCGAGGGCCG ACGAGGAGCA GCAGCAGGCG CTGTCCTCGC AAATGGGCTT 240

156

CTGACCCGCT AATACGAAAA GAAACGGAGC AAAAACATGA CAGAGCAGCA GTGGAATTTC 300

GCGGGTATCG AGGCCGCGGC AAGCGCAATC CAGGGAAATG TCACGTCCAT TCATTCCCTC 360

CTTGACGAGG GGAAGCAGTC CCTGACCAAG CTCGCA 396 (2) Sequence Information SEQ ID NO: 112:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 80 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 112:

How many 1 Ser Glee Asp Leo 5 Fox Thr Gin How many Asp 10 Gin Wall Gosh Ser Thr 15 Alas Glee Ser Leo Gin 20 Glee Gin Suffering Arg Glee 25 Alas Alas Glee Thr Alas 30 Alas Gin Alas Alas Wall 35 .Wall Arg Phew Gin Gosh 40 Alas Alas Association Fox Gin 45 Fox Gin Gosh Leo Asp 50 Gosh How many Ser Thr Association 55 How many Arg Gin Alas Glee 60 Wall Gin Tire Ser Arg Alas Asp Gosh Gosh Gin Gin Gin Alas Leo Ser Ser Gin Met Glee Phew

70 75 80 (2) Sequence information of SEQ ID NO: 113:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 387 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 113:

GTGGATCCCG ATCCCGTGTT TCGCTATTCT ACGCGAACTC GGCGTTGCCC TATGCGAACA 60 TCCCAGTGAC GTTGCCTTCG GTCGAAGCCA TTGCCTGACC GGCTTCGCTG ATCGTCCGCG 120 CCAGGTTCTG CAGCCGGTTG TTCAGCTCGG TAGCCGTGGC GTCCCATTTT TGCTGGACAC 180

157

CCTGGTACGC CTCCGAACCG CTACCGCCCC AGGCCGCTGC GAGCTTGGTC AGGGACTGCT 240 TCCCCTCGTC AAGGAGGGAA TGAATGGACG TGACATTTCC CTGGATTGCG CTTGCCGCGG 300 CCTCGATACC CGCGAAATTC CACTGCTGCT CTGTCATGTT TTTGCTCCGT TTCTTTTCGT 360 ATTAGCGGGT CAGAAGCCCA TTTGCGA 387

(2) Sequence information of SEQ ID NO: 114:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 272 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 114:

CGGCACGAGG ATTCCGGTTG GCCCAACGGC GCTGGCGAGG GCTCCGTTCC GGGGGCGAGC 60 TGCGCGCCGG ATGCTTCCTC TGCCCGCAGC CGCGCCTGGA TGGATGGACC AGTTGCTACC 120 TTCCCGACGT TTCGTTCGGT GTCTGTGCGA TAGCGGTGAC CCCGCGCGC ACGTCGGGAG 180 TGTTGGGGGG CAGGCCGGGT CGGTGGTTCG GCCGGGGACG CAGACGGTCT GGACGGAACG 240 GGCGGGGGTT CGCCGATTGG CATCTTTGCC ca 272

(2) Sequence information of SEQ ID NO: 115:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 115:

Asp Pro Val Asp Ala Val Ile Asn Thr Thr Cys Asn Tyr Gly Gin Val 15 10 15

Val Ala Ala Leu 20 • · · ·

158 (2) Sequence information of SEQ ID NO: 116:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 116:

Ala Val Glu Ser Gly Met Leu Ala Leu Gly Thr Pro Ala Pro Ser 15 10 15 (2) Sequence Information SEQ ID NO: 117:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 19 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 117:

Ala Ala Met Lys Pro Arg Thr Gly Asp Gly Pro Leu Glu Ala Ala Lys 15 10 15

Glu Gly Arg (2) SEQ ID NO: 118 Sequence Information:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 118:

Tyr Tyr Trp Cys Pro Gly Gin Pro Phe Asp 15 10

Pro Ala Trp Gly Pro 15 • · · · · · · · · · · ··· · ···· · ·· · ······· · · ···· ·· ·· ·· ·· ··

159 (2) Information on the sequence of SEQ ID NO: 119:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 14 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 119:

Asp Ile Gly Ser Glu Ser Thr Glu Asp Gin Gin Xaa Ala Val 1 5 10 (2) Sequence Information SEQ ID NO: 120:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 13 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 120:

Ala Glu Glu Ser 1

Ile Ser Thr Xaa Glu 5

Xaa Ile Val Pro 10 (2) Sequence Information SEQ ID NO: 121:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 17 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 121:

Asp Pro Glu Pro Ala Pro Pro Val Pro Thr Thr Ala Ala Ser Pro Pro 1 5 ^{10 15}

Ser • this this this • · · • · · · ··

160 (2) Sequence information of SEQ ID NO: 122:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids (E) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 122:

Ala Pro Lys Thr Tyr Xaa Glu Glu Leu Lys Gly Thr Asp Thr Gly 15 10 15 (2) Sequence Information SEQ ID NO: 123:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 30 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 123:

Asp 1 For Al Ser Alas 5 For Asp Val For Thr Ala Ala 10 Gin Leo Thr Ser 15 Leo Leo Association Ser Leo Ala Asp For Association Wall Ser Phew Alas Association 20 25 30

(2) Sequence information of SEQ ID NO: 124:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 124:

Asp Pro Pro Asp Pro His Gin Xaa Asp Met Thr Lys Gly Tyr Tyr Pro 15 10 15

Gly Gly Arg Arg Xaa Phe 20 ·· ··

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161 (2) Sequence information of SEQ ID NO: 125:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 125:

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:125:

Asp Pro Gly Tyr Thr Pro Gly 1 5 (2) Sequence Information SEQ ID NO: 126:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 10 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: Linear (ix) FEATURES:

(D) OTHER INFORMATION: (note = "the second residue can be either Pro or Thr (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 126:

Xaa Xaa Gly Phe Thr Gly Pro Gin Phe Tyr 15 10 (2) Sequence Information SEQ ID NO: 127:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: Linear (ix) FEATURES:

(D) OTHER INFORMATION: (note = “the third residue can be either Gin or Leu (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 127:

For Xaa Val Thr Ala Tyr Ala Gly 5

Xaa • · • · · ···· · ···· ·· ·· ·· ·· ··

162 (2) Sequence information of SEQ ID NO: 128:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 9 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 128:

Xaa Xaa Xaa Glu Lys Pro Phe Leu Arg 1 5 (2) Sequence Information SEQ ID NO: 129:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 129:

Xaa Asp Ser Glu Lys Ser Ala Thr Ile Lys Val Thr Asp Ala Ser 15 10 15 (2) Sequence information of SEQ ID NO: 130:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 130:

Ala Gly Asp Thr Xaa Ile Tyr Ile Val Gly Asn Leu Thr Ala Asp 1 5 10 15 • · ···· ··· ····

99 9 9 999 9 9 9 9 • · ··· ·· «· ·«· ·«· ······· · · ···· ·· ·· 99 99 99

163 (2) Sequence information of SEQ ID NO: 131:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 131:

Ala Pro Glu Ser Gly Ala Gly Leu Gly Gly Thr Val Gin Ala Gly 1 5 10 15 (2) Sequence information of SEQ ID NO: 132:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 132

Xaa Tyr Ile Ala Tyr Xaa Thr Thr Ala Gly Ile Val Pro Gly Lys Ile 15 10 15

Asn Val His Leu Val 20 (2) Sequence Information SEQ ID NO: 133:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 882 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 133:

GCAACGCTGT CGTGGCCTTT GCGGTGATCG GTTTCGCCTC GCTGGCGGTG GCGGTGGCGG 60 TCACCATCCG ACCGACCGCG GCCTCAAAAC CGGTAGAGGG ACACCAAAAC GCCCAGCCAG 120 GGAAGTTCAT GCCGTTGTTG CCGACGCAAC AGCAGGCGCC GGTCCCGCCG CCTCCGCCCG 180 ATGATCCCAC CGCTGGATTC CAGGGCGGCA CCATTCCGGC TGTACAGAAC GTGGTGCCGC 240

• · • · • · • ···

GGCCGGGTAC CTCACCCGGG GTGGGTGGGA

CCGTGCCCGG TGTTGTGCCT GCCCCGGTGC

TCCCGGGTTG GCAGCCTGGA ATGCCGACCA

CCACGTCGGC GACGACGCCG CCGACCACGC

CGACGCCGCČ GACCACGCCG GTGACCACGC

CCACGCCACC AACGACCGTC GCCCCGACGA

CCGTCGCCCC GACCACGGTC GCTCCAGCCA

CGACGCAGCA GCCCACGCAA CAACCAACCC

CCCCGCAGAC GGTGGCGCCG GCTCCGCAGC

GGGGCGACTT ATTCGGCGGG TTCTGATCAC

GGCCGGTGAT GCGGTGACGG TGGTGCTGCC

164

CGCCGGCTTC

CAATCCCGGT

TCCCCACCGC

CGCCGACCAC

CGCCAACGAC

CCGTCGCCCC

CCGCCACGCC

AACAGATGCC

CGCCGTCCGG

GGTCGCGGCT

CTGTCTCAAC

GCCTGCGCCG GAAGCGCCGG 300 CCCGATCATC ATTCCCCCGT 360 ACCGCCGACG ACGCCGGTGA 420 GCCGGTGACCC ACGCCGCCAA 480 GCCGCCGACC ACGCCGGTGA 540 GACGACGGTC GCTCCGACCA 600 GACGACCGTC GCTCCGCAGC 660 AACCCAGCAG CAGACCGTGG 720 TGGCCGCAAC GGCAGCGGCG 780 TCACTACGGT CGGAGGACAT 840 GA 882

(2) INFORMATION FOR SEQ ID NO:134:

(2) Sequence information of SEQ ID NO: 134:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 815 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: DNA (genomic)

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 134: CCATCAACCA ACCGCTCGCG CCGCCCGCGC CGCCGGATCC GCCGTCGCCG CCACGCCCGC 60 CGGTGCCTC GGTGCCCCCG TTGCCGCCGT CGCCGCCGTC GCCGCCGACC GGCTGGGTGC 120 CTAGGGCGCT GTTACCGCCC TGGTTGGCGG GGACGCCGCC GGCACCACCG GTACCGCCGA 180 TGGCGCCGTT GCCGCCGGCG GCACCGTTGC CACCGTTGCC ACCGTTGCCA CCGTTGCCGA 240 CCAGCCACCC GCCGCGACCA CCGGCACCGC CGGCGCCGCC CGCACCGCCG GCGTGCCCGT 300 TCGTGCCCGT ACCGCCGGCA CCGCCGTTGC CGCCGTCACC GCCGACGGAA CTACCGGCGG 360 ACGCGGCCTG CCCGCCGGCG CCGCCCGCAC CGCCATTGGC ACCGCCGTCA CCGCCGGCTG 420 GGAGTGCCGC GATTAGGGCA CTGACCGGCG CAACCAGCGC AAGTACTCTC GGTCACCGAG 480 CACTTCCAGA CGACACCACA GCACGGGGTT GTCGGCGGAC TGGGTGAAAT GGCAGCCGAT 540

• 4

165 4 4 • 4 • • 4 • · 4 4 • 4 44*4 • · 4 4 4 ·· · · 4·· 4 4 4 4 4 4 4 • ♦ · 4 4 4 ·· *· 44 4· 4 4 • 4 • «44 • 4 · AGCGGCTAGC TGTCGGCTGC GGTCAACCTC GATCATGATG TCGAGGTGAC CGTGACCGCG 600 CCCCCCGAAG GAGGCGCTGA ACTCGGCGTT GAGCCGATCG GCGATCGGTT GGGGCAGTGC 660 CCAGGCCAAT ACGGGGATAC CGGGTGTCNA AGCCGCCGCG AGCGCAGCTT CGGTTGCGCG 720 ACNGTGGTCG GGGTGGCCTG TTACGCCGTT GTCNTCGAAC ACGAGTAGCA GGTCTGCTCC ¹ 780 GGCGAGGGCA TCCACCACGC GTTGCGTCAG CTCGT 815

(2) Sequence information of SEQ ID NO: 135:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1152 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 135:

ACCAGCCGCC GGCTGAGGTC TCAGATCAGA GAGTTCCCGG ACTCACCGGG GCGGTTCAGC 60 CTTCTCCCAG AACAACTGCT GAAGATCCTC GCCCGCGAAA CAGGCGCTGA TTTGACGCTC 120 TATGACCGGT TGAACGACGA GATCATCCGG CAGATTGATA TGGCACCGCT GGGCTAACAG 180 GTGCGCAAGA TGGTGCAGCT GTATGTCTCG GACTCCGTGT CGCGGATCAG CTTTGCCGAC 240 GGCCGGGTGA TCGTGTGGAG CGAGGAGCTC GGCGAGAGCC AGTATCCGAT CGAGACGCTG 300 GACGGCATCA CGCTGTTTGG GCGGCCGACG ATGACAACGC CCTTCATCGT TGAGATGCTC 360 AAGCGTGAGC GCGACATCCA GCTCTTCACG ACCGACGGCC ACTACCAGGG CCGGATCTCA 420 ACACCCGACG TGTCATACGC GCCGCGGCTC CGTCAGCAAG TTCACCGCAC CGACGATCCT 480 GCGTTCTGCC TGTCGTTAAG CAAGCGGATC GTGTCGAGGA AGATCCTGAA TCAGCAGGCC 540 TTGATTCGGG CACACACGTC GGGGCAAGAC GTTGCTGAGA GCATCCGCAC GATGAAGCAC 600 TCGCTGGCCT GGGTCGATCG ATCGGGCTCC CTGGCGGAGT TGAACGGGTT CGAGGGAAAT 660 GCCGCAAAGG CATACTTCAC CGCGCTGGGG CATCTCGTCC CGCAGGAGTT CGCATTCCAG 720 GGCCGCTCGA CTCGGCCGCC GTTGGACGCC TTCAACTCGA TGGTCAGCCT CGGCTATTCG 780 CTGCTGTACA AGAACATCAT AGGGGCGATC GAGCGTCACA GCCTGAACGC GTATATCGGT 840 TTCCTACACC AGGATTCACG AGGGCACGCA ACGTCTCGTG CCGAATTCGG CACGAGCTCC 900

• 44 ··· • » · · · 9 a tl 4 4 • « · 4 t 4 4 4«

4444444 4 4

444444 44 44 44 44

166

GCTGAAACCG CTGGCCGGCT GCTCAGTGCC CGTACGTAAT CCGCTGCGCC CAGGCCGGCC 960

CGCCGGCCGA ATACCAGCAG ATCGGACAGC GAATTGCCGC CCAGCCGGTT GGAGCCGTGC 1020

ATACCGCCGG CACACTCACC GGCAGCGAAC AGGCCTGGCA CCGTGGCGGC GCCGGTGTCCC 1080

GCGTCTACTT CGACACCGCC CATCACGTAG TGACACGTCG GCCCGACTTC CATTGCCTGC 1140

GTTCGGCACG AG 1152 (2) Sequence Information SEQ ID NO: 136:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 655 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 136:

CTCGTGCCGA TTCGGCAGGG TGTACTTGCC GGTGGTGTAN GCCGCATGAG TGCCGACGAC 60 CAGCAATGCG GCAACAGCAC GGATCCCGGT CAACGACGCC ACCCGGTCCA CGTGGGCGAT 120 CCGCTCGAGT CCGCCCTGGG CGGCTCTTTC CTTGGGCAGG GTCATCGAC GTGTTTCCGC 180 CGTGGTTTGC CGCCATTATG CCGGCGCGCC GCGTCGGGCG GCCGGTATGG CCGAANGTCG 240 ATCAGCACAC CCGAGATACG GGTCTGTGCA AGCTTTTTGA GCGTCGCGCG GGGCAGCTTC 300 GCCGGCAATT CTACTAGCGA GAAGTCTGGC CCGATACGGA TCTGACCGAA GTCGCTGCGG 360 TGCAGCCCAC CCTCATTGGC GATGGCGCCG ACGATGGCGC CTGGACCGAT CTTGTGCCGC 420 TTGCCGACGG CGACGCGGTA GGTGGTCAAG TCCGGTCTAC GCTTGGGCCT TTGCGGACGG 480 TCCCGACGCT GGTCGCGGTT GCGCCGCGAA AGCGGCGGGT CGGGTGCCAT CAGGAATGCC 540 TCACCGCCGC GGCACTGCAC GGCCAGTGCC GCGGCGATGT CAGCCATCGG GACATCATGC 600 TCGCGTTCAT ACTCCTCGAC CAGTCGGCGG AACAGCTCGA TTCCCGGACC GCCCA 655

(2) Sequence information of SEQ ID NO: 137:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 267 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: DNA (genomic) (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 137:

»· ·· ·· ·« ·· ,· ···· »·· ··«* . · ·· · · ··· · · · · • · ··· ·· »« «·· ««· ······· · and ···· ·» »· ·· ·· ,,

167

Association Alas Wall Wall Alas Phew Alas Wall How many Glee Phew Alas Ser Leo Alas Wall 1 5 10 15 Alas Wall Alas Wall Thr How many Arg For Thr Alas Alas Ser Fox For Wall Gosh 20 25 30 Glee His Gin Association Alas Gin For Glee Fox Phew Met For Leo Leo For Thr 35 40 45 Gin Gin Gin Alas For Wall For For For For For Asp Asp For Thr Alas 50 55 60 Glee Phew Gin Glee Glee Thr How many For Alas Wall Gin Association Wall Wall For Arg 65 70 75 80 For Glee Thr Ser For Glee Wall Glee Glee Thr For Alas Ser For Alas For 85 90 95 Gosh Alas For Alas Wall For Glee Wall Wall For Alas For Wall For How many For 100 105 110 Wall For How many How many How many For For Phew For Glee Suffering Gin For Glee Met For 115 120 125 Thr How many For Thr Alas For For Thr Thr For Wall Thr Thr Ser Alas Thr 130 135 140 Thr For For Thr Thr For For Thr Thr For Wall Thr Thr For For Thr 145 150 155 160 Thr For For Thr Thr For Wall Thr Thr For For Thr Thr For For Thr 165 170 175 Thr For Wall Thr Thr For For Thr Thr Wall Alas For Thr Thr Wall Alas 180 185 190 For Thr Thr Wall Alas For Thr Thr Wall Alas For Thr Thr Wall Alas For 195 200 205 Alas Thr Alas Thr For Thr Thr Wall Alas For Gin For Thr Gin Gin For 210 215 220 Thr Gin Gin For Thr Gin Gin Met For Thr Gin Gin Gin Thr Wall Alas 225 230 235 240

Pro Gin Thr Val Ala Pro Ala Pro Gin Pro Pro Ser Gly Gly Arg Asn 245 250 255 ·· ·· ·· • · · ···· ··

Gly Ser Gly Gly Gly Asp Leu Phe Gly Gly Phe

260 265 ·· • 9 • ··· • · 4 • · 4 ft ··

168 (2, SEQ ID NO: 138 Sequence Information:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 174 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 138:

How many 1 Association Gin For Leo 5 Alas For For Alas For 10 For Asp For For Ser 15 For For Arg For For 20 Wall For For Wall For 25 For Leo For For Ser 30 For For Ser For For 35 Thr Glee Suffering Wall For 40 Arg Alas Leo Leo For 45 For Suffering Leo Alas Glee 50 Thr For For Alas For 55 For Wall For For Met 60 Alas For Leo For For 65 Alas Alas For Leo For 70 For Leo For For Leo 75 For For Leo For Thr 80 Ser His For For Arg 85 For For Alas For For 90 Alas For For Alas For 95 For Alas Cys For Phew 100 Wall For Wall For For 105 Alas For For Leo For 110 For Ser For For Thr 115 Gosh Leo For Alas Asp 120 Alas Alas Cys For For 125 Alas For For Alas For 130 For Leo Alas For For 135 Ser For For Alas Glee 140 Ser Alas Alas How many Arg 145 Alas Leo Thr Glee Alas 150 Thr Ser Alas Ser Thr 155 Leo Glee His Arg Alas 160

Leu Pro Asp Asp Thr Thr Ala Arg Gly Cys Arg Arg Thr Gly 165 170 • ·

169 (2) Information on the sequence of SEQ ID NO: 139:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 35 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 139:

Gin 1 For For Alas Gosh 5 Wall Ser Asp Gin Arg 10 Wall Ser Glee Leo Thr 15 Glee Alas Wall Gin For Ser For Arg Thr Thr Alas Gosh Asp For Arg For Arg

25 30

Asn Arg Arg 35 (2) Sequence Information SEQ ID NO: 140:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 104 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 140:

Arg 1 Alas Asp Ser Alas 5 Glee Cys Thr Cys Arg 10 Suffering Cys Xaa For His 15 Gosh Cys Arg Arg For 20 Alas Met Arg Gin Gin 25 His Glee Ser Arg Ser 30 Thr Thr For For Glee 35 For Arg Glee Arg Ser 40 Alas Arg Wall Arg For 45 Glee Arg Leo Phew For 50 Suffering Alas Glee Ser Ser 55 Asp Wall Phew For For 60 Suffering Phew Alas Alas How many 65 Met For Alas Arg Arg 70 Wall Glee Arg For Wall 75 Suffering For Xaa Wall Asp 80 Gin His Thr Arg Asp Thr Glee Leo Cys Fox Leo Phew Gosh Arg Arg Alas

90 95

Gly Gin Leu Arg Arg Gin Phe Tyr

100

170 (2) Sequence information of SEQ ID NO: 141:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 53 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: other nucleic acid (A) DESCRIPTION: PCR primer (vi) ORIGINAL SOURCE:

(A) ORGANISM: Mycobacterium tuberculosis (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 141:

GGATCCATAT GGGCCATCAT CATCATCATC ACGTGATCGA CATCATCGGG ACC (2) Sequence Information SEQ ID NO: 142:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 42 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: other nucleic acid (A) DESCRIPTION: PCR primer (vi) ORIGINAL SOURCE:

(A) ORGANISM: Mycobacterium tuberculosis (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 142:

CCTGAATTCA GGCCTCGGTT GCGCCGGCCT CATCTTGAAC GA (2) Sequence Information SEQ ID NO: 143:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 31 nucleic acid (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: other nucleic acid (A) DESCRIPTION: PCR primer (vi) ORIGINAL SOURCE:

(A) ORGANISM: Mycobacterium tuberculosis (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 143:

171

GGATCCTGCA GGCTCGAAAC CACCGAGCGG T (2)

Information (i) about the sequence of SEQ ID NO: 144:

CHARACTERISTICS OF THE SEQUENCE:

(A) LENGTH: 31 nucleic acid (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear TYPE OF MOLECULE: other nucleic acid (A) DESCRIPTION: PCR primer (vi) ORIGINAL SOURCE:

(A) ORGANISM: Mycobacterium tuberculosis (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 144:

(ii:

CTCTGAATTC AGCGCTGGAA ATCGTCGCGA T (2) Sequence Information SEQ ID NO: 145:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 33 nucleic acid (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: other nucleic acid (A) DESCRIPTION: PCR primer (vi) ORIGINAL SOURCE:

(A) ORGANISM: Mycobacterium tuberculosis (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 145:

GGATCCAGCG CTGAGATGAA GACCGATGCC GCT (2) Sequence Information SEQ ID NO: 146:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 33 nucleic acid (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: other nucleic acid (A) DESCRIPTION: PCR primer (vi) ORIGINAL SOURCE:

(A) ORGANISM: Mycobacterium tuberculosis (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 146:

······* · · ···· ·· ·· ··. «· ··

172

GAGAGAATTC TCAGAAGCCC ATTTGCGAGG ACA (2) Sequence Information SEQ ID NO: 147:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1993 nucleic acid (B) TYPE: nucleic acid (C) TYPE OF STRAND: single stranded (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: DNA (genomic) (vi) ORIGINAL SOURCE:

(A) ORGANISM: Mycobacterium tuberculosis (ix) FEATURES:

(A) NAME/KEY: CDS (B) POSITION: 152..1237

(xi) DESCRIPTION SEQUENCE: ; SEQ ID NO: 147: TGTTCTTCGA CGGCAGGCTG GTGGAGGAAG GGCCCACCGA ACAGCTGTTC TCCTCGCCGA 60 AGCATGCGGA AACCGCCCGA TACGTCGCCG GACTGTCGGG GGACGTCAAG GACGCCAAGC 120 GCGGAAATTG AAGAGCACAG AAAGGTATGG C GTG AAA Val Lys 1 ATT CGT TTG Ile Arg Leu 5 CAT ACG His Thr 172

CTG TTG Leu Leu GCC GTG Ala Val 10 TTG Leo ACC GCT GCG CCG CTG CTG CTA GCA GCG GCG Alas GGC Glee 220 Thr Alas Alas 15 For Leo Leu Leu Ala 20 Alas TGT GGC TCG AAA Approx CCG AGC GGT TCG CCT GAA ACG GGC GCC GGC GCC 268 Cys Glee Ser Fox For For Ser Glee Ser For Gosh Thr Glee Alas Glee Alas 25 30 35 GGT ACT GTC GCG ACT acc CCC GCG TCG TCG CCG GTG ACG TTG GCG GAG 316 Glee Thr Wall Alas Thr Thr For Alas Ser Ser For Wall Thr Leo Alas Gosh 40 45 50 55 acc GGT AGC ACG CTG CTC TRAY CCG CTG TTC AAC CTG TGG GGT CCG GCC 364 Thr Glee Ser Thr Leo Leo Tire For Leo Phew Association Leo Suffering Glee For Alas

65 70 ·····»· · · ···· ·· ·· ·· *· ·«

173

TTT Phew CAC GAG AGG TAT CCG AAC GTC ACG ATC ACC GCT CAG GGC ACC GGT Glee 412 His Glu Arg 75 Tire Pro Association Wall Thr Ile 80 Thr Ala Gin Glee 85 Thr TCT GGT GCC GGG ATC GCG CAG GCC GCC GCC GGG ACG GTC AAC ATT GGG 4 60 Ser Glee Alas Glee How many Alas Gin Alas Alas Alas Glee Thr Wall Association How many Glee 90 95 100 GCC TCC GAC GCC MELT CTG TCG GAA GGT GAT ATG GCC GCG CAC AAG GGG 508 Alas Ser Asp Alas Tire Leo Ser Gosh Glee Asp Met Alas Alas His Fox Glee 105 110 115 CTG ATG AAC ATC GCG CTA GCC ATC TCC GCT CAG CAG GTC AAC TRAY AAC 556 Leo Met Association How many Alas Leo Alas How many Ser Alas Gin Gin Wall Association Tire Association 120 125 130 135 CTG CCC GGA GTG AGC GAG CAC CTC AAG CTG AAC GGA AAA GTC CTG GCG 604 Leo For Glee Wall Ser Gosh His Leo Fox Leo Association Glee Fox Wall Leo Alas 140 145 150 GCC ATG TRAY CAG GGC acc ATC AAA acc TGG GAC GAC CCG CAG ATC GCT 652 Alas Met Tire Gin Glee Thr How many Fox Thr Suffering Asp Asp For Gin How many Alas 155 160 165 GCG CTC AAC CCC GGC GTG AAC CTG CCC GGC acc GCG GTA GTT CCG CTG 700 Alas Leo Association For Glee Wall Association Leo For Glee Thr Alas Wall Wall For Leo 170 175 180 CAC CGC TCC GAC GGG TCC GGT GAC acc TTC TTG TTC acc CAG TRAY CTG 748 His Arg Ser Asp Glee Ser Glee Asp Thr Phew Leo Phew Thr Gin Tire Leo 185 190 195 TCC AAG CAA GAT CCC GAG GGC TGG GGC AAG TCG CCC GGC TTC GGC acc 796 Ser Fox Gin Asp For Gosh Glee Suffering Glee Fox Ser For Glee Phew Glee Thr 200 205 210 215 acc GTC GAC TTC CCG GCG GTG CCG GGT GCG CTG GGT GAG AAC GGC AAC 844 Thr Wall Asp Phew For Alas Wall For Glee Alas Leo Glee Gosh Association Glee Association 220 225 230 GGC GGC ATG GTG acc GGT TGC GCC GAG ACA CCG GGC TGC GTG GCC MELT 892 Glee Glee Met Wall Thr Glee Cys Alas Gosh Thr For Glee Cys Wall Alas Tire 235 240 245 ATC GGC ATC AGC TTC CTC GAC CAG GCC AGT CAA CGG GGA CTC GGC GAG 940 How many Glee How many Ser Phew Leo Asp Gin Alas Ser Gin Arg Glee Leo Glee Gosh 250 255 260 GCC CAA CTA GGC AAT AGC TCT GGC AAT TTC TTG TTG CCC GAC GCG CAA 988 Alas Gin Leo Glee Association Ser Ser Glee Association Phew Leo Leo For Asp Alas Gin 265 270 275 AGC ATT CAG GCC GCG GCG GCT GGC TTC GCA TCG AAA acc CCG GCG AAC 1036 Ser How many Gin Alas Alas Alas Alas Glee Phew Alas Ser Fox Thr For Alas Association

• · · · · · ···· ·· · · · ·

174

280 285 290 295 CAG GCG ATT TCG ATG ATC GAC GGG CCC GCC CCG GAC GGC TRAY CCG ATC 1084 Gin Alas lle Ser Met lle Asp Glee For Alas For Asp Glee Tire For lle 300 305 310 ATC AAC TRAY GAG TRAY GCC ATC GTC AAC AAC CGG CAA AAG GAC GCC GCC 1132 lle Association Tire Gosh Tire Alas lle Wall Association Association Arg Gin Fox Asp Alas Alas 315 320 - 325 acc GCG CAG acc TTG CAG GCA TTT CTG CAC TGG GCG ATC acc GAC GGC 1180 Thr Alas Gin Thr Leo Gin Alas Phew Leo His Suffering Alas lle Thr Asp Glee 330 335 340 AAC AAG GCC TCG TTC CTC GAC CAG GTT CAT TTC CAG CCG CTG CCG CCC 1228 Association Fox Alas Ser Phew Leo Asp Gin Wall His Phew Gin For Leo For For

345 350 355 GCG GTG GTG AAG TTG TCT GAC GCG Ala Val Val Lys Leu Ser Asp Ala : 360 365 TTG ATC GCG Leu lle Ala 370 ACG ATT TCC AGC Thr lle Ser Ser 1273 TAGCCTCGTT GACCACCACG CGACAGCAAC CTCCGTCGGG CCATtGGGCT GCTTTGCGGA 1333 GCATGCTGGC CCGTGCCGGT GAAGTCGGCC GCGCTGGCCC GGCCATCCGG TGGTTGGGTG 1393 GGATAGGTGC GGTGATCCCG CTGCTTGCGC TGGTCTTGGT GCTGGTGGTG CTGGTCATCG 1453 AGGCGATGGG TGCGATCAGGG CTCAACGGGT TGCATTTCTT CACCGCCACC GAATGGAATC 1513 CAGGCAACAC CTACGGCGAA ACCGTTGTCA CCGACGCGTC GCCCATCCGG TCGGCGCCTA 1573 CTACGGGGCG TTGCCGCTGA TCGTCGGGAC GCTGGCGACC TCGGCAATCG CCCTGATCAT 1633 CGCGGTGCCG GTTCCTGTAG GAGCGGCGCT GGTGATCGTG GAACGGCTGC CGAAACGTT 1693 GGCCGAGGCT GTGGGAATAG TCCTGGAATT GCTCGCCGGA ATCCCCAGCG TGGTCGTCGG 1753 TTTGTGGGGG GCAATGACGT TCGGGCCGTT CATCGCTCAT CACATCGCTC CGGTGATCGC 1813 TCACAACGCT CCCGATGTGC CGGTGCTGAA CTACTTGCGC GGCGACCCGG GCAACGGGGA 1873 GGGCATGTTG GTGTCCGGTC TGGTGTTGGC GGTGATGGTC GTTCCCATTA TCGCCACCAC 1933 CACTCATGAC CTGTTCCGGC AGGTGCCGGT GTTGCCCCGG GAGGGGCGGA TCGGGAATTC 1993

(2) Sequence information of SEQ ID NO: 148:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 374 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: protein (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 148:

• · ······· · · ···· ·· ·· ·· ·· ··

175

Val Lys 1 Ile Arg Leo 5 His Thr Leu Leu Ala Val Leu Thr Ala Ala For 10 15 Leo Leo Leo Alas Alas Alas Glee Cys Glee Ser Fox For For Ser Glee Ser 20 25 30 For Gosh Thr Glee Alas Glee Alas Glee Thr Wall Alas Thr Thr For Alas Ser 35 40 45 Ser For Wall Thr Leo Alas Gosh Thr Glee Ser Thr Leo Leo Tire For Leo 50 55 60 Phew Association Leo Suffering Glee For Alas Phew His Gosh Arg Tire For Association Wall Thr 65 70 75 80 How many Thr Alas Gin Glee Thr Glee Ser Glee Alas Glee How many Alas Gin Alas Alas 85 90 95 Alas Glee Thr Wall Association How many Glee Alas Ser Asp Al a Tire Leo Ser Gosh Glee 100 105 110 Asp Met Alas Alas His Fox Glee Leo Met Association How many Alas Leo Alas How many Ser 115 120 125 Alas Gin Gin Wall Association Tire Association Leo For Glee Wall Ser Gosh His Leo Fox 130 135 140 Leo Association Glee Fox Wall Leo Alas Alas Met Tire Gin Glee Thr How many Fox Thr 145 150 155 160 Suffering Asp Asp For Gin How many Alas Alas Leo Association For Glee Wall Association Leo For 165 170 175 Glee Thr Alas Wall Wall For Leo His Arg Ser Asp Glee Ser Glee Asp Thr 180 185 190 Phew Leo Phew Thr Gin Tire Leo Ser Fox Gin Asp For Gosh Glee Suffering Glee 195 200 205 Fox Ser For Glee Phew Glee Thr Thr Wall Asp Phew For Alas Wall For Glee 210 215 220 Alas Leo Glee Gosh Association Glee Association Glee Glee Met Wall Thr Glee Cys Alas Gosh 225 230 235 240 Thr For Glee Cys Wall Alas Tire How many Glee How many Ser Phew Leo Asp Gin Alas 245 250 255 Ser Gin Arg Glee Leo Glee Gosh Alas Gin Leo Glee Association Ser Ser Glee Association 260 265 270

• · ·«·«·>· · · • ··· · ·· · · ·· ··

176

Phew Leo Leo 275 For Asp Alas Gin Ser 280 lle Gin Alas Alas Alas 285 Alas Glee Phew Alas Ser 290 Fox Thr For Alas Association 295 • Gin Alas lle Ser Met 300 lle Asp Glee For Alas 305 For Asp Glee Tire For 310 lle lle Association Tire Gosh 315 Tire Alas lle Wall Association 320 Association Arg Gin Fox Asp 325 Alas Alas Thr Alas Gin 330 Thr Leo Gin Alas Phew 335 Leo His Suffering Alas lle 340 Thr Asp Glee Association Fox 345 Alas Ser Phew Leo Asp 350 Gin Wall His Phew Gin 355 For Leo For For Alas 360 Wall Wall Fox Leo Ser 365 Asp Alas Leo lle Alas 370 Thr lle Ser Ser

(2) Sequence information of SEQ ID NO: 149:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1993 base pairs (B) TYPE: nucleic acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 149:

TGTTCTTCGA CGGCAGGCTG GTGGAGGAAG GGCCCACCGA ACAGCTGTTC TCCTCGCCGA 60 AGCATGCGGA AACCGCCCGA TACGTCGCCG GACTGTCGGG GGACGTCAAG GACGCCAAGC 120 GCGGAAATTG AAGAGCACAG AAAGGTATGG CGTGAAAATT CGTTTGCATA CGCTGTTGGC 180 CGTGTTGACC GCTGCGCCGC TGCTGCTAGC AGCGGCGGGC TGTGGCTCGA AACCACGAG 240 CGGTTCGCCT GAAACGGGCG CCGGCGCCGG TACTGTCGCG ACTACCCCCG CGTCGTCGCC 300 GGTGACGTTG GCGGAGACCG GTAGCACGCT GCTCTACCCG CTGTTCAACC TGTGGGGTCC 360 GGCCTTTCAC GAGAGGTATC CGAACGTCAC GATCACCGCT CAGGGCACCG GTTCTGGTGC 420 CGGGATCGCG CAGGCCGCCG CCGGGACGGT CAACATTGGG GCTCCCGACG CCTATCTGTC 480 GGAAGGTGAT ATGGCCGCGC ACAAGGGGCT GATGAACATC GCGCTAGCCA TCTCCGCTCA 540 GCAGGTCAAC TACAACCTGC CCGGAGTGAG CGAGCACCTC AAGCTGAACG GAAAAGTCCT 600

• · • ·

177

GGCGGCCATG TACCAGGGCA CCATCAAAAC CTGGGACGAC CCGCAGATCG CTGCGCTCAA 660 CCCCGGCGTG AACCTGCCCG GCACCGCGGT AGTTCCGCTG CACCGCTCCG ACGGGTCCGG 720 TGACACCTTC TTGTTCACCC AGTACCTGTC CAAGCAAGAT CCCGAGGGCT GGGGCAAGTC 780 GCCCGGCTTC GGCACCACCG TCGACTTCCC GGCGGTGCCG GGTGCGCTGG GTGAGAACGG 840 CAACGGCGGC ATGGTGACCG GTTGCGCCGA GACACCGGGC TGCGTGGCCT ATATCGGCAT 900 CAGCTTCCTC GACCAGGCCA GTCAACGGGG ACTCGGCGAG GCCCAACTAG GCAATAGCTC 960 TGGCAATTTC TTGTTGCCCG ACGCGCAAAG CATTCAGGCC GCGGCGGCTG GCTTCGCATC 1020 GAAAACCCCG GCGAACCAGG CGATTTCGAT GATCGACGGG CCCGCCCCGG ACGGCTACCC 1080 GATCATCAAC TACGAGTACG CCATCGTCAA CAACCGGCAA AAGGACGCCG CCACCGCGCA 1140 GACCTTGCAG GCATTTCTGC ACTGGGCGAT CACCGACGGC AACAAGGCCT CGTTCCTCGA 1200 CCAGGTTCAT TTCCAGCCGC TGCCGCCCGC GGTGGTGAAG TTGTCTGACG CGTTGATCGC 1260 GACGATTTCC AGCTAGCCTC GTTGACCACC ACGCGACAGC AACCTCCGTC GGGCCATCGG 1320 GCTGCTTTGC GGAGCATGCT GGCCCGTGCC GGTGAAGTCG GCCGGCCTGG CCCGGCCATC 1380 CGGTGGTTGG GTGGGATAGG TGCGGTGATC CCGCTGCTTG CGCTGGTCTT GGTGCTGGTG 1440 GTGCTGGTCA TCGAGGCGAT GGGTGCGATC AGGCTCAACG GGTTGCATTT CTTCACCGCC 1500 ACCGAATGGA ATCCAGGCAA CACCTACGGC GAAACCGTTG TCACCGACGC GTCGCCCATC 1560 CGGTCGGCGC CTACTACGGG GCGTTGCCGC TGATCGTCGG GACGCTGGCG ACCTCGGCAA 1620 TCGCCCTGAT CATCGCGGTG CCGGTCTCTG TAGGAGCGGC GCTGGTGATC GTGGAACGGC 1680 TGCCGAAACG GTTGGCCGAG GCTGTGGGAA TAGTCCTGGA ATTGCTCGCC GGAATCCCCA 1740 GCGTGGTCGT CGGTTTGTGG GGGGCAATGA CGTTCGGGCC GTTCATCGCT CATCACATCG 1800 CTCCGGTGAT CGCTCACAAC GCTCCCGATG TGCCGGTGCT GAACTACTTG CGCGGCGACC 1860 CGGGCAACGG GGAGGGCATG TTGGTGTCCG GTCTGGTGTT GGCGGTGATG GTCGTTCCCA 1920 TTATCGCCAC CACCACTCAT GACCTGTTCC GGCAGGTGCC GGTGTTGCCC CGGGAGGCG 1980 CGATCGGGAA TTC 1993

(2) Sequence information of SEQ ID NO: 150:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 374 amino acids (B) TYPE: amino acid (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 150:

--

• · · · ·» ·· · · · · · «

179

Ser Gin Arg Gly Leo Gly Glu Ala Gin 265 Leo Glee Association Ser Ser 270 Glee Association 260 Phew Leo Leo For Asp , Ala Gin Ser How many Gin Alas Alas Alas Alas Glee Phew 275 280 285 Alas Ser Fox Thr For Alas Association Gin Alas How many Ser Met How many Asp Glee For 290 295 300 Alas For Asp Glee Tire For How many How many Association Tire Gosh Tire Alas How many Wall Association 305 310 315 320 Association Arg Gin Fox Asp Alas Alas Thr Alas Gin Thr Leo Gin Alas Phew Leo 325 330 335 His Suffering Alas How many Thr Asp Glee Association Fox Alas Ser Phew Leo Asp Gin Wall 340 345 350 His Phew Gin For Leo For For Alas Wall Wall Fox Leo Ser Asp Alas Leo 355 360 365 How many Alas Thr How many Ser Ser

370 (2) Sequence information of SEQ ID NO: 151:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1777 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 151:

GGTCTTGACC ACCACCTGGG TGTCGAAGTC GGTGCCCGGA TTGAAGTCCA GGTACTCGTG 60 GGTGGGGCGG GCGAAACAAT AGCGACAAGC ATGCGAGCAG CCGCGGTAGC CGTTGACGGT 120 GTAGCGAAAAC GGCAACGCGG CCGCGTTGGG CACCTTGTTC AGCGCTGATT TGCACAACAC 180 CTCGTGGAAG GTGATGCCGT CGAATTGTGG CGCGCGAACG CTGCGGACCA GGCCGATCCG 240 CTGCAACCCG GCAGCGCCCG TCGTCAACGG GCATCCCGTT CACCGCGACG GCTTGCCGGG 300 CCCAACGCAT ACCATTATTC GAACAACCGT TCTATACTTT GTCAACGCTG GCCGCTACCG 360 AGCGCCGCAC AGGATGTGAT ATGCCATCTC TGCCCGCACA GACAGGAGCC AGGCCTTATG 420 ACAGCATTCG GCGTCGAGCC CTACGGGCAG CCGAAGTACC TAGAAATCGC CGGGAAGCGC 480 ATGGCGTATA TCGACGAAGG CAAGGGTGAC GCCATCGTCT TTCAGCACGG CAACCCCACG 540

• · • · · · • ·

180 • · · • · · » · · • · é · · • · · · · · • • · TCGTCTTACT TGTGGCGCAA CATCATGCCG CACTTGGAAG GGCTGGCCCG GCTGGTGGCC 600 TGCGATCTGA TCGGGATGGG CGCGTCGGAC AAGCTCAGCC CATCGGGACC CGACCGCTAT 660 AGCTATGGCG AGCAACGAGA CTTTTTGTTC GCGCTCTGGG ATGCGCTCGA CCTCGGCGAC 720 CACGTGGTAC TGGTGCTGCA CGACTGGGGC TCGGCGCTCG GCTTCGACTG GGCTAACCAG 780 CATCGCGACC GAGTGCAGGG GATCGCGTTC ATGGAAGCGA TCGTCACCCC GATGACGTGG 840 GCGGACTGGC CGCCGGCCGT GCGGGGTGTG TTCCAGGGTT TCCGATCGCC TCAAGGCGAG 900 CCAATGGCGT TGGAGCACAA CATCTTTGTC GAACGGGTGC TGCCCGGGGC GATCCTGCGA 960 CAGCTCAGCG ACGAGGAAAT GAACCACTATE CGGCGGCCAT TCGTGAACGG CGGCGAGGAC 1020 CGTCGCCCCA CGTTGTCGTG GCCACGAAAC CTTCCAATCG ACGGTGAGCC CGCCGAGGTC 1080 GTCGCGTTGG TCAACGAGTA CCGGAGCTGG CTCGAGGAAA CCGACATGCC GAAACTGTTC 1140 ATCAACGCCG AGCCCGGCGC GATCATCACC GGCCGCATCC GTGACTATGT CAGGAGCTGG 1200 CCCAACCAGA CCGAAATCAC AGTGCCCGGC GTGCATTTCG TTCAGGAGGA CAGCGATGGC 1260 GTCGTATCGT GGGCGGGCGC TCGGCAGCAT CGGCGACCTG GGAGCGCTCT CATTTCACGA 1320 GACCAAGAAT GTGATTTCCG GCGAAGGCGG CGCCTGCTT GTCAACTCAT AAGACTTCCT 1380 GCTCCGGGCA GAGATTCTCA GGGAAAAGGG CACCAATCGC AGCCGCTTCC TTCGCAACGA 1440 GGTCGACAAA TATACGTGGC AGGACAAAGG TCTTCCTATT TGCCCAGCGA ATTAGTCGCT 1500 GCCTTTCTAT GGGCTCAGTT CGAGGAAGCC GAGCGGATCA CGCGTATCCG ATTGGACCTA 1560 TGGAACCGGT ATCATGAAAG CTTCGAATCA TTGGAACAGC GGGGGCTCCT GCGCCGTCCG 1620 ATTCCCCC AGGGCTGCTC TCACAACGCC CACATGTACT ACGTGTTACT AGCGCCCAGC 1680 GCCGATCGGG AGGAGGTGCT GGCGCGTCTG ACGAGCGAAG GTATAGGCGC GGTCTTTCAT 1740 TACGTGCCGC TTCACGATTC GCCGGCCGGG CGTCGCT 1777

(2) Sequence information of SEQ ID NO: 152:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 324 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 152:

• ·

I • · · ·

• · · · · · · ···· · · ·· ·· • · • · · · 181

GAGATTGAAT CGTACCGGTC TCCTTAGCGGG CTCCGTCCCG TGAATGCCCA TATCACGCAC 60 GGCCATGTTC TGGCTGTCGA CCTTCGCCCC ATGCCCGGAC GTTGGTAAAC CCAGGGTTTG 120 ATCAGTAATT CCGGGGGACG GTTGCGGGAA GGCGGCCAGG ATGTGCGTGA GCCGCGGGC 180 CGCCGTCGCC CAGGCGACCG CTGGATGCTC AGCCCCGGTG CGGCGACGTA GCCAGCGTTT 240 GGCGCGTGTC GTCCACAGTG GTACTCCGGT GACGACGCGG CGCGGTGCCT GGGTGAAGAC 300 CGTGACCGAC GCCGCCGATT CAG 324

(2) Sequence information of SEQ ID NO: 153:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1338 pairs of strands

(B) TYPE: nuclear acid (C) TYPE OF CHAIN: j single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 153:

GCGGTACCGC CGCGTTGCGC TGGCACGGGA CCTGTACGAC CTGAACCACT TCGCCTCGCG 60 AACGATTGAC GAACCGCTCG TGCGGCGGCT GTGGGTGCTC AAGGTGTGGG GTGATGTCGT 120 CGATGACCGG CGCGGCACCC GGCCACTACG CGTCGAAGAC GTCCTCGCCG CCCGCAGCGA 180 GCACGACTTC CAGCCCGACT CGATCGGCGT GCTGACCCGT CCTGTCGCTA TGGCTGCCTG 240 GGAAGCTCGC GTTCGGAAGC GATTTGCGTT CCTCACTGAC CTCGACGCCG ACGAGCAGCG 300 GTGGGCCGCC TGCGACGAAC GGCACCGCCG CGAAGTGGAG AACGCGCTGG CGGTGCTGCG 360 GTCCTGATCA ACCTGCCGGC GATCGTGCCG TTCCGCTGGC ACGGTTGCGG CTGGACGCGG 420 CTGAATCGAC TAGATGAGAG CAGTTGGGCA CGAATCCGGC TGTGGTGGTG AGCAAGACAC 480 GAGTACTGTC ATCACTATTG GATGCACTGG ATGACCGGCC TGATTCAGCA GGACCAATGG 540 AACTGCCCGG GGCAAAACGT CTCGGAGATG ATCGGCGTCC CCTCGGAACC CTGCGGTGCT 600 GGCGTCATTC GGACATCGGT CCGGCTCGCG GGATCGTGGT GACGCCAGCG CTGAAGGAGT 660 GGAGCGCGGC GGTGCACGCG CTGCTGGACG GCCGGCAGAC GGTGCTGCTG CGTAAGGGCG 720 GGATCGGCGA GAAGCGCTTC GAGGTGGCGG CCCACGAGTT CTTGTTGTTC CCGACGGTCG 780 CGCACAGCCA CGCCGAGCGG GTTCGCCCCG AGCACCGCGA CCTGCTGGGC CCGGCGGCCG 840

182

CCGACAGCAC CGACGAGTGT GTGCTACTGC GGGCCGCAGC GAAAGTTGTT GCCGCACTGC 900

CGGTTAACCG GCCAGAGGGT CTGGACGCCA TCGAGGATCT GCACATCTGG ACCGCCGAGT 960

CGGTGCGCGC CGACCGGCTC GACTTTCGGC CCAAGCACAA ACTGGCCGTC TTGGTGGTCT 1020

CGGCGATCCC GCTGGCCGAG CCGGTCCGGC TGGCGCGTAG GCCCGAGTAC GGCGGTTGCA 1080

CCAGCTGGGT GCAGCTGCCG GTGACGCCGA CGTTGGCGGC GCCGGTGCAC GACGAGGCCG 1140

CGCTGGCCGA GGTCGCCGCC CGGGTCCGCG AGGCCGTGGG TTGACTGGGC GGCATCGCTT 1200

GGGTCTGAGC TGTACGCCCA GTCGGCGCTG CGAGTGATCT GCTGTCGGTT CGGTCCCTGC 1260

TGGCGTCAAT TGACGGCGCG GGCAACAGCA GCATTGGCGG CGCCATCCTC CGCGCGGCCG 1320

GCGCCCACCG CTACAACC 1338 (2) Sequence Information SÉQ ID NO: 154:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 321 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 154:

CCGGCGGCAC CGGCGGCACC GGCGGTACCG GCGGCAACGG CGCTGACGCC GCTGCTGTGG 60 TGGGCTTCGG CGCGAACGGC GACCCTGGCT TCCGTGGCGG CAAAGGCGGT AACGGCGGAAA 120 TAGGTGGGGC CGCGGTGCA GGCGGGGTCG CCGGCGACGG CGGCACCGGC GGCAAAGGTG 180 GCACCGGCGG TGCCGGCGGC GCCGGCAACG ACGCCGGCAG CACCGGCAAT CCCGGCGGTA 240 AGGGCGGCGA CGGCGGGATC GGCGGTGCCG GCGGGGCCGG CGGCGCGGCC GGCACCGGCA 300 ACGGCGGCCA TGCCGGCAAC C 321

(2) Sequence information of SEQ ID NO: 155:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 492 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 155:

• · • ·

183 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:155:

GAAGACCCGG CCCCGCCATA TCGATCGGCT CGCCGACTAC TTTCGCCGAA CGTGCACGCG 60 GCGGCGTCGG GCTGATCATC ACCGGTGGCT ACGGCCCCAA CCGCACCGGA TGGCTGCTG 120 CGTTCGCTC CGAACTCGTC ACTTCGGCGC AAGCCCGACG GCACCGCCGA ATCACCAGGG 180 CGGTCCACGA TTCGGGTGCA AAGATCCTGC TGCAAATCCT GCACGCCGGA CGCTACGCCT 240 ACCACCCACT TGCGGTCAGC GCCTCGCCGA TCAAGGCGCC GATCACCCCG TTTCGTCCGC 300 GAGCACTATC GGCTCGGGGG GTCGAAGCGA CCATCGCGGA TTTCGCCCGC TGCGCGCAGT 360 TGGCCCGGA TGCCGGCTAC GACGGCGTCG AAAATCATGGG CAGCGAAGGG TATCTGCTCA 420 ATCAGTTCCT GGCGCGCGC ACCAACAAGC GCACCGACTC GTGGGGCGGC ACACCGGCCA 480 ACCGTCGCCG GT 4 92

(2) Sequence information of SEQ ID NO: 156:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 536 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 156:

Phe Ala Gin His Leu Val Glu Gly Asp Ala Val Glu Leu Trp Arg Ala 15 10 15

Asn Ala Ala Asp Gin Ala Asp Pro Leu Gin Pro Gly Ser Ala Arg Arg 20 25 30

Gin Arg Ala Ser Arg Ser Pro Arg Arg Leu Ala Gly Pro Asn Ala Tyr 35 40 45

His Tyr Ser Asn Asn Arg Ser Ile Leu Cys Gin Arg Trp Pro Leu Pro 50 55 . 60

Ser Ala Ala Gin Asp Val Ile Cys His Leu Cys Pro His Arg Gin Glu

70 75 80

Pro Gly Leu Met Thr Ala Phe Gly Val Glu Pro Tyr Gly Gin Pro Lys

90 95

Tyr Leu Glu Ile Ala Gly Lys Arg Met Ala Tyr Ile Asp Glu Gly Lys

184

100 105 110

Glee Asp Ala 115 Ile Val Phe Gin His Gly Asn Pro Thr Ser Ser Tyr Leo 120 125 Suffering Arg Association How many Met For His Leo Gosh Glee Leo Glee Arg Leo Wall Alas 130 135 140 Cys Asp Leo How many Glee Met Glee Alas Ser Asp Fox Leo Ser For Ser Glee 145 150 155 160 For Asp Arg Tire Ser Tire Glee Gosh Gin Arg Asp Phew Leo Phew Alas Leo 165 170 175 Suffering Asp Alas Leo Asp Leo Glee Asp His Wall Wall Leo Wall Leo His Asp 180 185 190 Suffering Glee Ser Alas Leo Glee Phew Asp Suffering Alas Association Gin His Arg Asp Arg 195 200 205 Wall Gin Glee How many Alas Phew Met Gosh Alas How many Wall Thr For Met Thr Suffering 210 215 220 Alas Asp Suffering For For Alas Wall Arg Glee Wall Phew Gin Glee Phew Arg Ser 225 230 235 240 For Gin Glee Gosh For Met Alas Leo Gosh His Association How many Phew Wall Gosh Arg 245 250 255 Wall Leo For Glee Alas How many Leo Arg Gin Leo Ser Asp Gosh Gosh Met Association 260 265 270 His Tire Arg Arg For Phew Wall Association Glee Glee Gosh Asp Arg Arg For Thr 275 280 285 Leo Ser Suffering For Arg Association Leo For How many Asp Glee Gosh For. Alas Gosh Wall 290 295 300 Wall Alas Leo Wall Association Gosh Tire Arg Ser Suffering Leo Gosh Gosh Thr Asp Met 305 310 315 320 For Fox Leo Phew How many Association Alas Gosh For Glee Alas How many How many Thr Glee Arg 325 330 335 How many Arg Asp Tire Wall Arg Ser Suffering For Association Gin Thr Gosh How many Thr Wall 340 345 350 For Glee Wall His Phew Wall Gin Gosh Asp Ser Asp Glee Wall Wall Ser Suffering 355 360 365 Alas Glee Alas Arg Gin His Arg Arg For Glee Ser Alas Leo How many Ser Arg 370 375 380 Asp Gin Gosh Cys Asp Phew Arg Arg Arg Arg Arg For Alas Cys Gin Leo 385 390 395 400

• ·

0 0 0 0 0 0 0 ···· ·· ·0 00 00 00

185

How many Arg Leo For Alas 405 For Glee Arg Asp Ser 410 Gin Glee Fox Glee His 415 Gin Ser Gin For Leo 420 For Ser Gin Arg Gly Arg 425 Gin How many Tire Wall 430 Alas Glee Gin Arg Ser 435 Ser Tire Leo For Ser 440 Gosh Leo Wall Alas Alas 445 Phew Leo Suffering Alas Gin Phew Gosh Gosh Alas Gosh Arg How many Thr Arg How many Arg Leo Asp Leo

450 455 460

Trp Asn Arg Tyr His Glu Ser Phe Glu Ser Leu Glu Gin Arg Gly Leu 465 470 475 480

Leo Arg Arg Pro How many 485 How many For Gin Glee Cys 490 Ser His Association Alas His 495 Met Tire Tire Val Leu 500 Leo Alas For Ser Alas 505 Asp Arg Gosh Gosh Wall 510 Leo Alas Arg Leo Thr Ser 515 Gosh Glee How many Glee 520 Alas Vci Phew His Tire 525 Wall For Leo His Asp 530 Sir Pro Alas Glee Arg 535 Arg Information about the sequence SEQ ID : NO: 157:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 284 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 157:

Association 1 Gosh Ser Alas For 5 Arg Ser For Met Leo 10 For Ser Alas Arg For 15 Arg Tire Asp Alas How many 20 Alas Wall Leo Leo Association 25 Gosh Met His Alas Glee 30 His Cys Asp Phew Glee 35 Leo Wall Glee For Alas 40 For Asp How many Wall Thr 45 Asp Alas Alas Glee Asp 50 Asp Arg Alas Glee Leo 55 Glee Wall Asp Gosh Gin 60 Phew Arg His Wall Glee Phew Leo Gosh For Alas For Wall Leo Wall Asp Gin Arg Asp Asp Leo

000 0000 0 0000 00 00 00 00 00

186

65 70 75 80 Glee Glee Leo Thr Wall Asp Suffering Fox Wall Ser Suffering For Arg Gin Arg Glee 85 90 95 Alas Thr Wall Leo Alas Alas Wall His Gosh Suffering For For How many Wall Wall His 100 105 110 Phew Leo Wall Alas Gosh Leo Ser Gin Asp Arg For Glee Gin His For Phew 115 120 125 Asp Fox Asp Wall Wall Leo Gin Arg His Suffering Leo Alas Leo Arg Arg Ser 130 135 140 Gosh Thr Leo Gosh His Thr For His Glee Arg Arg For Wall Arg For Arg 145 150 155 160 His Arg Glee Asp Asp Arg Phew His Gosh Arg Asp For Leo His Ser Wall 165 170 175 Alas Met Leo Wall Ser For Wall Gosh Alas Gosh Arg Arg Alas For Wall Wall 180 185 190 Gin His Gin Tire His Wall Wall Alas Gosh Wall Gosh Arg How many For Gosh Arg 195 200 205 Gosh Gin Fox Wall Ser Leo Leo Alas How many Alas How many Alas Wall Glee Ser Arg 210 215 220 Suffering Alas Gosh Leo Wall Arg Arg Alas His For Asp Gin How many Alas Glee His 225 230 235 240 Gin For Alas Gin For Phew Gin Wall Arg His Asp Wall Alas For Gin Wall 245 250 255 Arg Arg Arg Glee Wall Alas Wall Leo Fox Asp Asp Glee Wall Thr Leo Alas 260 265 270 Phew Wall Asp How many Arg His Alas Leo For Glee Asp Phew

275,280 (2) Sequence information of SEQ ID NO: 158:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 264 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 158:

< · that that · · ·

187 • ·· • that's it • it· · ·· • ···· · · • · · · · ·· ·· ·· • that • that's it ATGAACATGT CGTCGGTGGT GGGTCGCAAG GCCTTTGCGC GATTCGCCGG CTACTCCTCC 60 GCCATGCACCG CGATCGCCGG TTTCTCCGAT GCGTTGCGCC AAGAGCTGCG GGGTAGCGGA 120 ATCGCCGTCT CGGTGATCCA CCCGGCCTG ACCCAGACAC CGCTGTTGGC CAACGTCGAC 180 CCCGCCGACA TGCCGCCGCC GTTTCGCAGC CTCACGCCCA TTCCCGTTCA CTGGGTCGCG 240 GCAGCGGTGC TTGACGGTGT GGCG 264 (2) Sequence information of SEQ ID NO: 159: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1171 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 159:

TAGTCGGCGA CGATGACGTC GCGGTCCAGG CCGACCGCTT CAAGCACCAG CGCGACCACG 60 AAGCCGGTGC GATCCTTACC CGCGAAGCAG TGGGTGAGCA CCGGGCGTCC GGCGGCAAGC 120 AGTGTGACGA CACGATGTAG CGCGCGCTGT GCTCCATTGC GCGTTGGGAA TTGGCGATAC 180 TCGTCGGTCA TGTAGCGGGT GGCCGCGTCA TTTATCGACT GGCTGGATTC GCCGGACTCG 240 CCGTTGGACC CGTCATTGGT TAGCAGCCTC TTGAATGCGG TTTCGTGCGG CGCTGAGTCG 300 TCGGCGTCAT CATCGGCGAG GTCGGGGAAC GGCAGCAGGT GGACGTCGAT GCCGTCCGGA 360 ACCCGTCCTG GACCGCGGCG GGCAACCTCC CGGGACGACC GCAGGTCGGC AACGTCGGTG 420 ATCCCCAGCC GGCGCAGCGT TGCCCCTCGT GCCGAATTCG GCACGAGGCT GGCGAGCCAC 480 CGGGCATCAC CAAGCAACGC TTGCCCAGTA CGGATCGTCA CTTCCGCATC CGGCAGACCA 540 ATCTCCTCGC CGCCCATCGT CAGATCCCGC TCGTGCGTTG ACAAGAACGG CCGCAGATGT 600 GCCAGCGGGT ATCGGAGATT GAACCGCGCA CGCAGTTCTT CAATCGCTGC GCGCTGCCGC 660 ACTATTGGCA CTTTCCGGCG GTCGCGGTAT TCAGCAAGCA TGCGAGTCTC GACGAACTCG 720 CCCCACGTAA CCCACGGCGT AGCTCCCGGC GTGACGCGGA GGATCGGCGG GTGATCTTTG 780 CCGCCACGCT CGTAGCCGTT GATCCACCGC TTCGCGGTGC CGGCGGGGAG GCCGATCAGC 840 TTATCGACCT CGGCGTATGC CGACGGCAAG CTGGGCGCGT TCGTCGAGGT CAAGAACTCC 900 ACCATCGGCA CCGGCACCAA GGTGCCGCAC CTGACCTACG TCGGCGACGC CGACATCGGC 960

• ·

188

GAGTACAGCA ACATCGGCGC CTCCAGCGTG TTCGTCAACT ACGACGGTAC GTCCAAACGG 1020 CGCACCACCG TCGGTTCGCA CGTACGGACC GGGTCCGACA CCATGTTCGT GGCCCCAGTA 1080 ACCATCGCG ACGGCGCGTA TACCGGGGCC GGCACAGTGG TGCGGGAGGA TGTCCCGCCG 1140 GGGGCGCTGG CAGTGTCGGC GGGTCCGCAA C 1171

(2) Information ο the sequence of SEQ ID NO: 160:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 227 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 160:

GCAAAGGCGG CACCGGCGGG GCCGGCATGA ACAGCCTCGA CCCGCTGCTA GCCGCCCAAG 60 ACGGCGGCCA AGGCGGCACC GGCGGCACCG GCGGCAACGC CGGCGCCGGC GGCACCAGCT 120 TCACCCAAGG CGCCGACGGC AACGCCGGCA ACGGCGGTGA CGGCGGGGTC GGCGGCAACG 180 GCGGAAACGG CGGAAACGGC GCAGACAACA CCACCACCGC CGCCGCC 227

(2) Sequence information of SEQ ID NO: 161:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 304 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 161:

CCTCGCCACC ATGGGCGGGC AGGGCGGTAG CGGTGGCGCC GGCTCTACCC CAGGCGCCAA 60 GGGCGCCCAC GGCTTCACTC CAACCAGCGG CGGCACGGC GGCGACGGCG GCAACGGCGG 120 CAACTCCCAA GTGGTCGGCG GCAACGGCGG CGACGGCGGC AATGGCGGCA ACGGCGGCAG 180 CGCCGGCACG GGCGGCAACG GCGGCCGCGG CGGCGACGGC GCGTTTGGTG GCATGAGTGC 240 CAACGCCACC AACCCTGGTG AAAACGGGCC AAACGGTAAC CCCGGCGGCA ACGGTGGCGC 300

189

CGGC ³⁰⁴ (2) SEQ ID NO: 162 Sequence Information:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 1439 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 162:

GTGGGACGCT GCCGAGGCTG TATAACAAGG ACAACATCGA CCAGCGCCGG CTCGGTGAGC 60 TGATCGACCT ATTTAACAGT GCGCGCTTCA GCCGGCAGGG CGAGCACCGC GCCCGGGATC 120 TGATGGGTGA GGTCTACGAA TACTTCCTCG GCAATTTCGC TCGCGCGGAA GGGAAGCGGG 180 GTGGCGAGTT CTTTACCCCG CCCAGCGTGG TCAAGGTGAT CGTGGAGGTG CTGGAGCCGT 240 CGAGTGGGCG GGTGTATGAC CCGTGCTGCG GTTCCGGAGG CATGTTTGTG CAGACCGAGA 300 AGTTCATCTA CGAACACGAC GGCGATCCGA AGGATGTCTC GATCTATGGC CAGGAAAGCA' 360 TTGAGGAGAC CTGGCGGATG GCGAAGATGA ACCTCGCCAT CCACGGCATC GACAACAAGG 420 GGCTCGGCGC CCGATGGAGT GATACCTTCG CCGCGACCCA GCACCCGGAC GTGCAGATGG 480 ACTACGTGAT GGCCAATCCG CCGTTCAACA TCAAAGACTG GGCCCGCAAC GAGGAAGACC 540 CACGCTGGCG CTTCGGTGTT CCGCCCGCCA ATAACGCCAA CTACGCATGG ATTCAGCACA 600 TCCTGTACAA CTTGGCGCCG GGAGGTCGGG CGGGCGTGGT GATGGCCAAC GGGTCGATGT 660 CGTCGAACTC CAACGGCAAG GGGGATATTC GCGCGCAAAT CGTGGAGGCG GATTTGGTTT 720 CCTGCATGGT CGCGTTACCC ACCCAGCTGT TCCGCAGCAC CGGAATCCCG GTGTGCCTGT 780 GGTTTTTCGC CAAAAACAAG. GCGGCAGGTA AGCAAGGGTC TATCAACCGG TGCGGGCAGG 840 TGCTGTTCAT CGACGCTCGT GAACTGGGCG ACCTAGTGGA CCGGGGCCGAG CGGGCGCTGA 900 CCAACGAGGA GATCGTCCGC ATCGGGGATA CCTTCCACGC GAGCACGACC ACCGGCAACG 960 CCGGCTCCGG TGGTGCCGGC GGTAATGGGG GCACTGGCCT CAACGGCGCG GGCGGTGCTG 1020 GCGGGGCCGG CGGCAACGCG GGTGTCGCCG GCGTGTCCTT CGGCAACGCT GTGGGGCGCG 1080 ACGGCGGCAA CGGCGGCAAC GGCGGCCACG GCGGCGACGG CACGACGGGC GGCGCCGGCG 1140 GCAAGGGCGG CAACGGCAGC AGCGGTGCCG CCAGCGGCTC AGGCGTCGTC AACGTCACCG 1200

• · · · • · ····«·· · « • · ♦ · ·· ·· · * · · · ·

190

CCGGCCACGG CGGCAACGGC GGCAATGGCG GCAACGGCGG CAACGGCTCC GCGGGCGCCG 1260 GCGGCCAGGG CGGTGCCGGC GGCAGCGCCG GCAACGGCGG CCACGGCGGC GGTGCCACCG' 1320 GCGGCGCCAG CGGCAAGGGC GGCAACGGCA CCAGCGGTGC CGCCAGCGGC TCAGGCGTCA 1380 TCAACGTCAC CGCCGGCCAC GGCGGCAACG GCGGCAATGG CCGCAACGGC GGCAACGGC 1439

(2) Sequence information of SEQ ID NO: 163:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 329 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 163:

GGGCCGGCGGG GGCCGGATTT TCTCGTGCCT TGATTGTCGC TGGGGATAAC GGCGGTGATG 60 GTGGTAACGG CGGGATGGGC GGGGCTGGCG GGGCTGGCGG CCCCGGCGGG GCCGGCGGCC 120 TGATCAGCCT GCTGGGCGGC CAAGGCGCCG GCGGGGCCGG CGGGACCGGC GGGGCCGGCG 180 GTGTTGGCGG TGACGGCGGG GCCGGCGGCC CCGGCAACCA GGCCTTCAAC GCAGGTGCCG 240 GCGGGGCCGG CGGCCTGATC AGCCTGCTGG GCGGCCAAGG CGCCGGCGGG GCCGGCGGGGA 300 CCGGCGGGGC CGGCGGTT GGCGGTGAC 329

(2) Sequence information of SEQ ID NO: 164:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 80 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 164:

GCAACGGTGG CAACGGCGGC ACCAGCACGA CCGTGGGGAT GGCCGGAGGT AACTGTGGTG 60

CCGCCGGGCT GATCGGCAAC

4 · • · · 4 • * · ·· ·· » · 9 · » · · · ··· · ··

191 (2) Information on the sequence of SEQ ID NO: 165:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 392 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 165:

GGGCTGTGTC GCACTCACAC CGCCGCATTC GGCGACGTTG GCCGCCCAAT ATCCAGCTCA 60 AGGCCTACTA CTTACCGTCG GAGGACCGCC GCATCAAGGT GCGGGTCAGC GCCCAAGGAA 120 TCAAGGTCAT CGACCGCGAC GGGCATCGAG GCCGTCGTCG CGCGGCTCGG GCAGGATCCG 180 CCCCGGCGCA CTTCGCCGGC CAAGCGGGCT CATCGCTCCG AACGCGCGCG ATCCTGTGAG 240 CACAACTGAT GGCGCGCAAC GAGATTCGTC CAATTGTCAA GCCGTGTTCG ACCGCAGGGA 300 CCGGTTATAC GTATGTCAAC CTATGTCACT CGCAAGAACC GGCATAACGA TCCCGTGATC 360 CGCCGACAGC CCACGAGTGC AAGACCGTTA ca 392

(2) Sequence information of SEQ ID NO: 166:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 535 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 166:

ACCGGCCCCA CCGGCGGCAC CGGGTTCGCC GGTGGCGCCG GCGGGGCCGG CGGGCAGGGC 60 GGTATCAGCG GTGCCGGCGG CACCAACGGC TCTGGTGGCG CTGGCGGCAC CGGCGGACAA 120 GGCGGCGCCG GGGGCGCTGG CGGGGCCGGC GCCGATAACC CCACCGGCAT CGGCGGCC 180 GGCGGCACCG GCGGCACCGG CGGAGCGGCC GGAGCCGGCG GGGCCGGTGGG CGCCATCGGT 240 ACCGGCGGCA CCGGCGGCGC GGTGGGCAGC GTCGGTAACG CCGGGATCGG CGGTACCGGC 300 GGTACGGGTG GTGTCGGTGG TGCTGGTGGT GCAGGTGCGG CTGCGGCCGC TGGCAGCAGC 360 GCTACCGGTG GCGCCGGGTT CGCCGGCGGC GCCGGCGGG AAGGCGGACC GGGCGGCAAC 420 AGCGGTGTGG GCGGCACCAA CGGCTCCGGC GGCGCCGGCG GTGCAGGCGG CAAGGGCGGC 480

·· • ·

·· ·· ·· ·· • · · · · · · • · ··· · · · · • · · · · ··· · ·· • · · · · · ·« 99 99.. 99

192

ACCGGAGGTG CCGGCGGGTC CGGCGCGGAC AACCCCACCG GTGCTGGTTT CGCCG 535 (2) Sequence Information SEQ ID NO: 167:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 690 base pairs, (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 167:

CCGACGTCGC CGGGGCGATA CGGGGGTCAC CGACTACTAC ATCATCCGCA CCGAGAATCG 60 GCCGCTGCTG CAACCGCTGC GGGCGGTCCC GGTCATCGGA GATCCGCTGG CCGACCTGAT 120 CCAGCCGAAC CTGAAGGTGA TCGTCAACCT GGGCTACGGC GACCCGAACT ACGGCTACTC 180 GACGAGCTAC GCCGATGTGC GAACGCCGTT CGGGCTGTGG CCGAACGTGC CGCCTCAGGT 240 CATCGCCGAT GCCCTGGCCG CCGGAACACA AGAAGGCATC CTTGACTTCA CGGCCGACCT 300 GCAGGCGCTG TCCGCGCAAC CGCTCACGCT CCCGCAGATC CAGCTGCCGC AACCCGCCGA 360 TCTGGTGGCC GCGGTGGCCG CCGCACCGAC GCCGGCCGAG GTGGTGAACA CGCTCGCCAG 420 GATCATCTCA ACCAACTACG CCGTCCTGCT GCCCACCGTG GACATCGCCC TCGCCTGGTC 480 ACCACCCTGC CGCTGTACAC CACCCAACTG TTCGTCAGGC AACTCGCTGC GGGCAATCTG 540 ATCAACGCGA TCGGCTATCC CCTGGCGGCC ACCGTAGGTT TAGGCACGAT CGATAGCGGG 600 CGGCGTGGAA TTGCTCACCC TCCTCGCGGC GGCCTCGGAC ACCGTTCGAA ACATCGAGGG 660 CCTCGTCACC TAACGGATTC CCGACGGCAT 690

(2) Sequence information of SEQ ID NO: 168:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 407 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 168:

• ·» · • ·· • · · • · · ···· »· ·· ·· ·· ·· • · · · · · · • · ··· · · · · • · · · · ·· · ··· • · · · · · ·· ·«.____ ·· «·

193

ACGGTGACGG CGGTACTGGC GGCGGCCACG GCGGCAACGG CGGGAATCCC GGGTGGCTCT 60 TGGGCACAGC CGGGGGTGGC GGCAACGGTG GCGCCGGCAG CACCGGTACT GCAGGTGGCG 120 GCTCTGGGGG CACCGGCGGC GACGGCGGGA CCGGCGGGCG TGGCGGCCTG TTAATGGGCG 180 CCGGCGCCGG CGGGCACGGT GGCACTGGCG GCGCGGGCGG TGCCGGTGTC GACGGTGGCG 240 GCGCCGGCGGG GGCCGGCGGG GCCGGCGGCA ACGGCGGCGC CGGGGGTCAA GCCGCCCTGC 300 TGTTCGGGCG CGGCGGCACC GGCGGAGCCG GCGGCTACGG CGGCGATGGC GGTGGCGGCG 360 GTGACGGCTT CGACGGCACG ATGGCCGGCC TGGGTGGTAC CGGTGGC 407

(2) Sequence information of SEQ ID NO: 169:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 468 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 169:

GATCGGTCAG CGCATCGCCC TCGGCGCAA GCGATTCCGC GGTCTCACCG AAGAACATCG 60 TGCACGCGGC GGCGCGGACC AGCCCGCTGC GCTGCGGCGC GTCGAACGCC TCCAGCAGGC 120 ACAGCCAGTC CTTGGCGGCC TGCGAGGCGGA ACACGTCGGT GTCACCGGTG TAGATCGCCG 180 GGATGCCCGC CTCCGCCAAC GCATTCCGGC ACGCCCGCGC GTCTTTGTGA TGCTCGACGA 240 TCACCGCGAT GTCTGCGGCC ACCACGGGCC GCCCGGCGAA GGTGGCCCCG CTGGCCAGTA 300 GCGCCGCGAC GTCGGCGGCC AGGTCGTCGG GGATGTGCCG GCGCAGCGCT CCGGCGCGAC 360 GCCCGAAAAA CGACCCCTCA CCCAGCTGGG TCCCGCTGGC ATATCCCTTG CCGTCCTGGG 420 CGATATTGGA CGCGCATGCC CCGACCGCGT ACAGGCCGGC CACCACCG 468

(2) Sequence information of SEQ ID NO: 170;

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 219 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 170:

• · · · ··· · · · · ··· · ···· · ·· · • · · · · 9 9 9 9 999 999

9 9 9 9 9 9 9.9

9999 99 99 99 ~ 99 99

194 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:170:

GGTGGTAACG GCGGCCAGGG TGGCATCGGC GGCGCCGGCG AGAGAGGCGC CGACGGCGCC 60 GGCCCCAATG CTAACGGCGC AAACGCGAG AACGGCGGTA GCGGTGGTAA CGGTGGGAC 120 GGCGGCGCCG GCGGCAATGG CGGCGCGGGC GGCAACGGCGC AGGCGGCCGG GTACACCGAC 180 GGCGCCACGG GCACCGGCGG CGACGGCGGC AACGGCGGC 219

(2) Sequence information of SEQ ID NO: 171:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 494 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 171:

TAGCTCCGGC GAGGGCGGCA AGGGCGGCGA CGGTGGCCAC GGCGGTGACG GCGTCGGCGG 60 CAACAGTTCC GTCACCCAAG GCGGCAGCGG CGGTGGCGG GGCGCCGGCG GCGCCGGCGGG 120 CAGCGGCTTT TTCGGCGCA AGGGCGGCTT CGGCGGCGAC GGCGGTCAGG GCGGCCCCAA 180 CGGCGGCGGT ACCGTCGGCA CCGTGGCCGG TGGCGGCGG AACGCGGGTG TCGGCGGCCG 240 GGGCGGGAC GGCGTCTTTG CCGGTGCCGG CGGCCAGGGC GGCCTCGGTG GGCAGGGCGG 300 CAATGGCGGC GGCTCCACCG GCGGCAACGG CGGCCTTGGC GGCGCGGGCG GTGGCGGAGG 360 CAACGCCCCG GCTCGTGCCG AATCCGGGCT GACCATGGAC AGCGCGGCCA AGTTCGCTGC 420 CATCGCATCA GGCCGGTACT GCCCCGAACA CCTGGAACAT CACCCGAGTT AGCGGGCGGC 480 ATTTCCTGAT CACC 494

(2) Sequence information of SEQ ID NO: 172:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 220 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 172:

• ·

195 • 9 9 • · · 9 · 9 9 9 » • 9 9 9 9 · · 9 9 9 9 · • · 9 9 9 9 • · - 9 - - • 9 GGGCCGGTGGG TGCCGCGGGC CAGCTCTTCA GCGCCGGAGG CGCGGCGGGT GCCGTTGGGG 60 TTGGCGGCAC CGGCGGCCAG GGTGGGGCTG GCGGTGCCGG AGCGGCCGGC GCCGACGCCC 120 CCGCCAGCAC AGGTCTAACC GGTGGTACCG GGTTCGCTGG CGGGGCCGGC GGCGTCGGCG 180 GCCAGAGCGG CAACGCCATT GCCGGCGGCA TCAACGGCTC 220

(2) Sequence information of SEQ ID NO: 173:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 388 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 173:

ATGGCGGCAA CGGGGGCCCC GGCGGTGCTG GCGGGGCCGG CGACTACAAT TTCCAACGGC 60 GGGCAGGGTG GTGCCGGCGG CCAAGGCGGC CAAGGCGGCC TGGGCGGGGC AAGCACCACC' 120 TGATCGGCCT AGCCGCACCC GGGAAAGCCG ATCCAACAGG CGACGATGCC GCCTTCCTTG 180 CCGCGTTGGA CCAGGCCGGC ATCACCTACG CTGACCCAGG CCACGCCATA ACGGCCGCCA 240 AGGCGATGTG TGGGCTGTGT GCTAACGGCG TAACAGGTCT ACAGCTGGTC GCGGACCTGC 300 GGGACTACAA TCCCGGGCTG ACCATGGACA GCGCGGCCAA GTTCGCTGCC ATCGCATCAG 360 GCGCGTACTG CCCCGAACAC CTGGAACA 388

(2) Sequence information of SEQ ID NO: 174:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 400 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 174:

GCAAAGGCGG CACCGGCGGG GCCGGCATGA ACAGCCTCGA CCCGCTGCTA GCCGCCCAAG 60

ACGGCGGCCA AGGCGGCACC GGCGGCACCG GCGGCAACGC CGGCGCCGGC GGCACCAGCT - 120 • · • · · ·

• · · • · · · · · • · · · · • · · · · · • • · 196 TCACCCAAGG CGCCGACGGC AACGCCGGCA ACGGCGGTGA CGGCGGGGTC GGCGGCAACG 180 GCGGAAACGG CGGAAACGGC GCAGACAACA CCACCACCGC CGCCGCCGGC ACCACAGGCG' 240 GCGACGGCGG GGCCGGCGGG GCCGGCGGAA CCGGCGGAAC CGGCGGAGCC GCCGGCACCG 300 GCACCGGCGG CCAACAAGGC AACGGCGGCA ACGGCGGCAC CGGCGGCAAA GGCGGCACCG 360 GCGGCGACGG TGCACTCTCA GGCAGCACCG GTGGTGCCGG 400 (2) Sequence information of SEQ ID NO: 175: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 538 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 175:

GGCAACGGCG GCAACGGCGG CATCGCCGGC ATTGGGCGGC AACGGCGTTC CGGGACGGGC 60 AGCGGCAACG GCGGCCAACG GCGGCAGCGG CGGCAACGGC GGCAACGCCG GCATGGGCGG 120 CAACAGCGGC ACCGGCAGCG GCGACGGCGG TGCCGGCGGG AACGGCGGCG CGGCGGGCAC 180 GGGCGGCACC GGCGGCGACG GCGGCCTCAC CGGTACTGGC GGCACCGGCG GCAGCGGTGG 240 CACCGGCGGT GACGGCGGTA ACGGCGGCAA CGGAGCAGAT AACACCGCAA ACATGACTGC 300 GCAGGCGGGC GGTGACGGTG GCAACGGCGG CGACGGTGGC TTCGGCGGCG GGGCCGGGGCC 360 CGGCGGCGGT GGCTTGACCG CTGGCGCCAA CGGCACCGGC GGGCAAGGCG GCGCCGGCGGG 420 CGATGGCGGAC AACGGGGCCA TCGGCGGCCA CGGCCCACTC ACTGACGACC CCGGCGGCAA 480 CGGGGGCACC GGCGGCAACG GCGGCACCGG CGGCACCGGC GGCGCGGGCA TCGGCAGC 538 (2) Sequence information of SEQ ID NO: 176:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 239 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 176:

197 • · · • · · · · · • · · · • · · · • · • * · · (xi) SEQUENCE DESCRIPTION: SEQ ID NO:176: GGGCCGGTGG TGCCGCGGGC CAGCTCTTCA GCGCCGGAGG CGCGGCGGGT GCCGTTGGGG 60 TTGGCGGCAC CGGCGGCCAG GGTGGGGCTG GCGGTGCCGG AGCGGCCGGC GCCGACGCC 120 CCGCCAGCAC AGGTCTAACC GGTGGTACCG GGTTCGCTGG CGGGGCCGGC GGCGTCGGCG 180 GCCACGGCGG CAACGCCATT GCCGGCGGCA TCAACGCTC CGGTGGTGCC (2) Sequence information of SEQ ID NO: 177: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 985 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 177: GGCGGCACC 239 AGCAGCGCTA CCGGTGGCGC CGGGTTCGCC GGCGGCGCCG GCGGAGAAGG CGGAGCGGGC 60 GGCAACAGCG GTGTGGGCGG CACCAACGGC TCCGGCGGCG CCGGCGGTGC AGGCGGCAAG 120 GGCGGCACCG GAGGTGCCGG CGGGTCCGGC GCGGACAACC CCACCGGTGC TGGTTTCGCC 180 GGTGGCGCCG GCGGCACAGG TGGCGCGGCC GGCGCCGGCG GGGCCGGCGGG GGCGACCGGT 240 ACCGGCGGCCA CCGGCGGCGT TGTCGGCGCC ACCGGTAGTG CAGGCATCGG CGGGGCCGGC 300 GGCCGCGGCG GTGACGGCGG CGATGGGGCC AGCGGTTCCG GCCTGGGCCT CTCCGGCTTT 360 GACGGCGGCC AAGGCGGCCA AGGCGGGGCC GGCGGCAGCG CCGGCGCCGG CGGCATCAAC 420 GGGGCCGGCG GGGCCGGCGG CAACGGCGGC GACGGCGGGG ACGGCGCAAC CGGTGCCGCA 480 GGTCTCGGCG ACAACGGCGG GGTCGGCGGT GACGGTGGGG CCGGTGGCGC CGCCGGCAAC 540 GGCGGCAACG CGGGCGTCGG CCTGACAGCC AAGGCCGGCG ACGGCGGCGC CGCGGGCAAT 600 GGCGGCAACG GGGGCGCCGG CGGTGCTGGC GGGGCCGGCG ACAACAATTT CAACGGCGGC 660 CAGGGTGGTG CCGGCGGCCA AGGCGGCCAA GGCGGCTTGG GCGGGGCAAG CACCACCTGA 720 TCGGCCTAGC CGCACCCGGG AAAGCCGATC CAACAGGCGA CGATGCCGCC TTCCTTGCCG 780 CGTTGGACCA GGCCGGCATC ACCTACGCTG ACCCAGGCCA CGCCATAACG GCCGCCAAGG 840 CGATGTGTGGCTGTGTGCT AACGGCGTAA CAGGTCTACA GCTGGTCGCG GACCTGCGGG 900 AATACAATCC CGGGCTGACC ATGGACAGCG CGGCCAAGTT CGCTGCCATC GCATCAGGCG 960

• · • · · ·

• · · · · · 198 • · · · • · · · CGTACTGCCC CGAACACCTG GAACA 985 (2) Sequence information of SEQ ID NO: 178: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 2138 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 178:

CGGCACGAGG ATCGGTACCC CGCGGCATCG GCAGCTGCCG ATTCGCCGGG TTTCCCCACCC 60 CGAGGAAAGC CGCTACCAGA TGGCGCTGCC GAAGTAGGGC GATCCGTTCG CGATGCCGGC 120 ATGAACGGGC GGCATCAAAT TAGTGCAGGA ACCTTTCAGT TTAGCGACGA TAATGGCTAT 180 AGCACTAAGG AGGATGATCC GATATGACGC AGTCGCAGAC CGTGACGGTG GATCAGCAAG 240 AGATTTTGAA CAGGGCCAAC GAGGTGGAGG CCCCGATGGC GGACCCACCG ACTGATGTCC 300 CCATCACACC GTGCGAACTC ACGGCGGCTA AAAAACGCCGC CCAACAGCTG GTATTGTCCG 360 CCGACAACAT GCGGGAATAC CTGGCGGCCG GTGCCAAAGA GCGGCAGCGT CTGGCGACCT 420 CGCTGCGCAA CGCGGCCAAG GCGTATGGCG AGGTTGATGA GGAGGCTGCG ACCGCGCTGG 480 ACAACGACGG CGAAGGAACT GTGCAGGCAG AATCGGCCGG GGCCGTCGGA GGGGACAGTT 540 CGGCCGAACT AACCGATACG CCGAGGGTGG CCACGGCCGG TGAACCCCAAC TTCATGGATC 600 TCAAAGAAGC GGCAAGGAAG CTCGAAACGG GCGACCAAGG CGCATCGCTC GCGCACTTTG 660 CGGATGGGTG GAACACTTTC AACCTGACGC TGCAAGGCGGA CGTCAAGCGG TTCCGGGGGT 720 TTGACAACTG GGAAGGCGAT GCGGCTACCG CTTGCGAGGC TTCGCTCGAT CAACAACGGC 780 AATGGATACT CCACATGGCC AAATTGAGCG CTGCGATGGC CAAGCAGGCT CAATATGTCG 840 CGCAGCTGCA CGTGTGGGCT AGGCGGGAAC ATCCGACTTA TGAAGACATA GTCGGGCTCG 900 AACGGCTTTTA CGCGGAAAAC CCTTCGGCCC GCGACCAAAT TCTCCCGGTG TACGCGGAGT 960 ATCAGCAGAG GTCGGAGAAG GTGCTGACCG AATACAACAA CAAGGCAGCC CTGGAACCGG 1020 TAAACCCGCC GAAGCCTCCC CCGCCATCA AGATCGACCC GCCCCCGCCT CCGCAAGAGC 1080 AGGGATTGAT CCCTGGCTTC CTGATGCCGC CGTCTGACGG CTCCGGTGTG ACTCCCGGTA 1140

······· · · ···· · · · · 9 · · · ··

199

CCGGGATGCC AGCCGCACCG ATGGTTCCGC CTACCGGATC GCCGGGTGGT GGCCTCCCGG 1200 CTGACACGGC GGCGCAGCTG ACGTCGGCTG GGCGGGAAGC CGCAGCGCTG TCGGGCGACG 1260 TGGCGGTCAA AGCGGCATCG CTCGGTGGCG GTGGAGGCGG CGGGGTGCCG TCGGCGCCGT 1320 TGGGATCCGC GATCGGGGGC GCCGAATCGG TGCGGCCGC TGGCGCTGGT GACATTGCCG 1380 GCTTAGGCCA GGGAAGGGCC GGCGGCGGCG CCGCGCTGGG CGGCGGTGGC ATGGGAATGC 1440 CGATGGGTGC CGCGCATCAG GGACAAGGGG GCGCCAAGTC CAAGGGTTCT CAGCAGGAAG 1500 ACGAGGCGCT CTACACCGAG GATCGGGCAT GGACCGAGGC CGTCATTGGT AACCGTCGGC 1560 GCCAGGACAG TAAGGAGTCG AAGTGAGCAT GGACGAATTG GACCCGCATG TCCGCCGGGC 1620 GTTGACGCTG GCGGCGCGGT TTCAGTCGGC CCTAGACGGG ACGCTCAATC AGATGAACAA 1680 CGGATCCTTC CGCGCCACCG ACGAAGCCGA GACCGTCGAA GTGACGATCA ATGGGCACCA 1740 GTGGCTCACC GGCCTGCGCA TCGAAGATGG TTTGCTGAAG AAGCTGGGTG CCGAGGCGGT 1800 GGCTCAGCGG GTCAACGAGG CGCTGCACAA TGCGCAGGCC GCGGCGTCCG CGTATAACGA 1860 CGCGGCGGGC GAGCAGCTGA CCGCTGCGTT ATCGGCCATG TCCCGCGCGA TGAACGAAGG 1920 AATGGCCTAA GCCCATTGTT GCGGTGGGTAG CGACTACGCA CCGAATGAGC GCCGCAATGC 1980 GGTCATTCAG CGCGCCCGAC ACGGCGTGAG TACGCATTGT CAATGTTTTG ACATGGATCG 2040 GCCGGGTTCG GAGGGCCCCA TAGTCCTGGT CGCCAATATT GCCGCAGCTA GCTGGTCTTA 2100 GGTTCGGTTA CGCTGGTTAA TTATGACGTC CGTTACCA 2138

(2) Sequence information of SEQ ID NO: 179:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 460 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 179:

Met Thr Gin Ser Gin Thr Wall Thr Wall Asp Gin Gin Gosh lle Leo Association 1 5 10 15 Arg Alas Association Gosh Wall Gosh Alas For Met Alas Asp For For Thr Asp Wall

25 30

Pro lle Thr Pro Cys Glu Leu Thr Ala Ala Lys Asn Ala Ala Gin Gin

• ·

201

- Alas Gin Leu Thr Ser Ala Gly Arg Glu Ala Ala Ala Leu Ser Gly Asp 340 345 350 Wall Alas Wall Fox Alas Alas Ser Leo Glee Glee Glee Glee Glee Glee Glee Wall - 355 360 365 For Ser Alas For Leo Glee Ser Alas lle Glee Glee Alas Gosh Ser Wall Arg 370 375 380 For Alas Glee Alas Glee Asp lle Alas Glee Leo Glee Gin Glee Arg Alas Glee 385 390 395 400 Glee Glee Alas Alas Leo Glee Glee Glee Glee Met Glee Met For Met Glee Alas 405 410 415 Alas His Gin Glee Gin Glee Glee Alas Fox Ser Fox Glee Ser Gin Gin Gosh 420 425 430 Asp Gosh Alas Leo Tire Thr Gosh Asp Arg Alas Suffering Thr Gosh Alas Wall lle 435 440 445 Glee Association Arg Arg Arg Gin Asp Ser Fox Gosh Ser Fox 450 455 460

(2) Sequence information of SEQ ID NO: 180:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 277 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 180:

Ala Gly 1 Asn Val Thr 5 Ser Ala Ser Gly Pro His Arg Phe Giy Ala For 10 15 Asp Arg Glee Ser Gin Arg Arg Arg Arg His For Alas Alas Ser Thr Alas 20 25 30 - Thr Gosh Arg Cys Arg Phew Asp Arg His Wall Alas Arg Gin Arg Cys Glee 35 40 45 Phew For For Ser Arg Arg Gin Leo Arg Arg Arg Wall Ser Arg Gosh Alas 50 55 60 Thr Thr Arg Arg Ser Glee Arg Arg Association His Arg Cys Glee Suffering His For 65 70 75 80

Gly Thr Gly Ser His Thr Gly Ala Val Arg Arg Arg His Gin Glu Ala

202

90 95

Arg Asp Gin Ser Leu Leu Leu Arg Arg Arg Gly Arg Val Asp Leu Asp 100 105 110 Glee Glee Glee Arg Leo Arg Arg Wall Tire Arg Phew Gin Glee Cys Leo Wall 115 120 125 Wall Wall Phew Glee Gin His Leo Leo Arg For Leo Leo How many Leo Arg Wall 130 135 140 His Arg Gosh Association Leo Wall Alas Glee Arg Arg Wall Phew Arg Wall Fox For 145 150 155 160 Phew Gosh For Asp Tire Wall Phew How many Ser Arg Met Phew For For Ser For 165 170 175 His Wall Gin Leo Arg Asp How many Leo Ser Leo Leo Glee His Arg Ser Alas 180 185 190 Gin Phew Glee His Wall Gosh Tire For Leo For Leo Leo How many Gosh Arg Ser 195 200 205 Leo Alas Ser Glee Ser Arg How many Alas Phew For Wall Wall Fox For For Gosh 210 215 220 For Leo Asp Wall Alas Leo Gin Arg Gin Wall Gosh Ser Wall For For How many 225 230 235 240 Arg Fox Wall Arg Gosh Arg Cys Alas Leo Wall Alas Arg Phew Gosh Leo For 245 250 255 Cys Arg Phew Phew Gosh How many His Gosh Wall Glee Phew Thr Glee Arg Glee His

260 265 270

For Arg Arg Ile Gly 275 (2) Sequence Information SEQ ID NO: 181:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 192 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO:.181:

Arg Val Ala Ala Ser Phe Ile Asp Trp Leu Asp Ser Pro Asp Ser Pro 1 5 10 15 • · · ·

203 • • · · • • · · « · • · • · · • • • • · Leo Asp For Ser Leo Wall Ser Ser Leo Leo Association Alas Wall Ser Cys Glee 20 25 30 Alas Gosh Ser Ser Alas Ser Ser Ser Alas Arg Ser Glee Association Glee Ser Arg 35 40 45 Suffering Thr Ser Met For Ser Glee Thr Arg For Glee For Arg Arg Alas Thr 50 55 60 Ser Arg Asp Asp Arg Arg Ser Alas Thr Ser Wall How many For Ser Arg Arg 65 70 75 80 Ser Wall Alas For Arg Alas Gosh Phew Glee Thr Arg Leo Alas Ser His Arg 85 90 95 Alas Ser For Ser Association Alas Cys For Wall Arg How many Wall Thr Ser Alas Ser 100 105 110 Glee Arg For How many Ser Ser For For How many Wall Arg Ser Arg Ser Cys Wall 115 120 125 Asp Fox Association Glee Arg Arg Cys Alas Ser Glee Tire Arg Arg Leo Association Arg 130 135 140 Alas Arg Ser Ser Ser How many Alas Alas Arg Cys Arg Thr How many Glee Thr Phew 145 150 155 160 Arg Arg Ser Arg Tire Ser Alas Ser Met Arg Wall Ser Thr Association Ser For 165 170 175 His Wall Thr His Glee Wall Alas For Glee Wall Thr Arg Arg How many Glee Glee

180 185 190 (2) Sequence information of SEQ ID NO: 182:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 196 amino acids (B) TYPE: amino acid' (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 182:

Gin Gosh Arg For Gin Met Cys Gin Arg Wall Ser Gosh How many Gosh For Arg 1 5 10 15 Thr Gin Phew Phew Association Arg Cys Alas Leo For His Tire Suffering His Phew For 20 25 30 Alas Wall Alas Wall Phew Ser Fox His Alas Ser Leo Asp Gosh Leo Alas For

204

40 45

Arg Association 50 For Arg Arg Ser Ser 55 Arg Arg Asp Alas Gosh 60 Asp Arg Arg Wall How many 65 Phew Alas Alas Thr Leo 70 Wall Alas Wall Asp For 75 For Leo Arg Glee Alas 80 Glee Glee Gosh Alas Asp 85 Gin Leo How many Asp Leo 90 Glee Wall Cys Arg Arg 95 Gin Alas Glee Arg Wall 100 Arg Arg Glee Gin Gosh 105 Leo His His Arg His 110 Arg His Gin Glee Alas 115 Alas For Asp Leo Arg 120 Arg Arg Arg Arg His 125 Arg Arg Wall Gin Gin 130 His Arg Arg Leo Gin 135 Arg Wall Arg Gin Leo 140 Arg Arg Tire Wall Gin 145 Thr Alas His His Arg 150 Arg Phew Alas Arg Thr 155 Asp Arg Wall Arg His 160 His Wall Arg Glee For 165 Ser Association His Arg Arg 170 Arg Arg Wall Tire Arg 175 Glee Arg His Ser Glee Alas Glee Glee Cys For Alas Glee Glee Alas Glee Ser Wall

180 185 190

Gly Gly Ser Ala 195 (2) Sequence Information SEQ ID NO: 183:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 311 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 183:

Wall 1 Arg Cys Glee Thr 5 Leo Wall For Wall For 10 Met Wall Gosh Phew Leo 15 Thr Ser Thr Association Alas 20 For Ser Leo For Ser 25 Alas Tire Alas Gosh Wall 30 Asp Fox Leo How many Glee Leo For Alas Glee Thr Alas Fox Arg Suffering How many Association Glee Tire

40 45

• 9

9.99 9 9 9 9 9 ·

--- 9999 99 99 99 99 99

206 (2) Sequence information of SEQ ID NO: 184:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2072 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 184:

CTCGTGCCGA TTCGGCACGA GCTGAGCAGC CCAAGGGGCC GTTCGGCGAA GTCATCGAGG 60 CATTCGCCGA CGGGCTGGCC GGCAAGGGTA AGCAAATCAA CACCACGCTG AACAGCCTGT 120 CGCAGGCGTT GAACGCCTTG AATGAGGGCC GCGGCGACTT CTTCGCGGTG GTACGCAGCC 180 TGGCGCTATT CGTCAACGCG CTACATCAGG ACGACCAACA GTTCGTCGCG TTGAACAAGA 240 ACCTTGCGGA GTTCACCGAC AGGTTGACCC ACTCCGATGC GGACCTGTCG AACGCCATCC 300 AGCAATTCGA CAGCTTGCTC GCCGTCGCGC GCCCGTTCTT CGCCAAGAAC CGCGAGGTGC 360 TGACGCATGA CGTCAATAAT CTCGCGACCG TGACCACCAC GTTGCTGCAG CCCGATCCGT 420 TGGATGGGTT GGAGACCGTC CTGCACATCT TCCCGACGCT GGCGGCGAAC ATTAACCAGC 480 TTTACCATCC GACACACGGT GGCGTGGTGT CGCTTTCCGC GTTCACGAAT TTCGCCAACC 540 CGATGGAGTT CATCTGCAGC TCGATTCAGG CGGGTAGCCG GCTCGGTTAT CAAGAGTCGG 600 CCGAACTCTG TGCGCAGTAT CTGGCGCCAG TCCTCGATGC GATCAAGTTC AACTACTTTC 660 CGTTCGGCCT GAACGTGGCC AGCACCGCCT CGACACTGCC TAAAGAGATC GCGTACTCCG 720 AGCCCCGCTT GCAGCCGCCC AACGGGTACA AGGACACCAC GGTGCCCGGC ATCTGGGTGC 780 CGGATACGCC GTTGTCACAC CGCAACACGC AGCCCGGTTG GGTGGTGGCA CCCGGGATGC 840 AAGGGGTTCA GGTGGGACCG ATCACGCAGG GTTTGCTGAC GCCGGAGTCCC CTGGCCGAAC 900 TCATGGGTGG TCCCGATATC GCCCCTCCGT CGTCAGGGCT GCAAACCCCG CCCGGACCCC 960 CGAATGCGTA CGACGAGTAC CCCGTGCTGC CGCCGATCGG TTTACAGGCC CCACAGGTGC 1020 CGATACCACC GCCGCCTCCT GGGCCCGACG TAATCCCGGG TCCGGTGCCA CCGGTCTTGG 1080 CGGCGATCGT GTTCCCAAGA GATCGCCCGG CAGCGTCGGA AAACTTCGAC TACATGGGCC 1140 TCTTGTTGCT GTCGCCGGGC CTGGCGACCT TCCTGTTCGG GGTGTCATCT AGCCCCGCCC 1200 GTGGAACGAT GGCCGATCGG CACGTGTTGA TACCGGCGAT CACCGGCCTG GCGTTGATCG 1260 CGGCATTCGT CGCACATTCG TGGTACCGCA CAGAACATCC GCTCATAGAC ATGCGCTTGT 1320 TCCAGAACCG AGCGGTCGCG CAGGCCAACA TGACGATGAC GGTGCTCTCC CTCGGGCTGT 1380

— 207 • · · · • · · • · · 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4444 4 4 4 4 •4 44 44 ··· • 4 4 4 4 • 4 44 44 • 4 4 • • 4 TTGGCTCCTT CTTGCTGCTC CCGAGCTACC TCCAGCAAGT GTTGCACCAA TCACCGATGC 1440 AATCGGGGGT GCATATCATC CCACAGGGCC TCGGTGCCAT GCTGGCGATG CCGATCGCCG 1500 GAGCGATGAT GGACCGACGG GGACCGGCCA AGATCGTGCT GGTTGGGATC ATGCTGATCG 1560 CTGCGGGGTT GGGCACCTTC GCCTTTGGTG TCCGCGGGCA AGCGACTAC TTACCCATTC 1620 TGCCGACCGG GCTGGCAATC ATGGGCATGG GCATGGGCTG CTCCATGATG CCACTGTCCG 1680 GGGCGGCAGT GCAGACCCTG GCCCCACATC AGATCGCTCG CGGTTCGACG CTGATCAGCG 1740 TCAACCAGCA GGTGGGCGGT TCGATAGGGA CCGCACTGAT GTCGGTGCTG CTCACCTACC 1800 AGTTCAATCA CAGCGAAATC ATCGCTACTG CAAAAAAAGT CGCACTGACC CCAGAGAGTG 1860 GCGCCGGGCG GGGGGCGGCG GTTGACCCTT CCTCGCTACC GCGCCAAACC AACTTCGCGG 1920 CCCAACTGCT GCATGACCTT TCGCACGCCT ACGCGGTGGT ATTCGTGATA GCGACCGCGC 1980 TAGTGGTCTC GACGCTGATC CCCGCGGCAT TCCTGCCGAA ACAGCAGGCT AGTCATCGAA 2040 GAGCACCGTT GCTATCCGCA TGACGTCTGC TT (2) Sequence information of SEQ ID NO: 185: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 1923 pairs of strands (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single chain (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 185: 2072

TCACCCCGGA GAAGTCGTTC GTCGACGACC TGGACATCGA CTCGCTGTCG ATGGTCGAGA 60 TCGCCGTGCA GACCGAGGAC AAGTACGGCG TCAAGATCCC CGACGAGGAC CTCGCCGGTC 120 TGCGTACCGT CGGTGACGTT GTCGCCTACA TCCAGAAGCT CGAGGAAGAA AACCCGGAGG 180 CGGCTCAGGC GTTGCGCGCG AAGATTGAGT CGGAGAACCC CGATGCGGCA CGAGCAGATC 240 GGTGCGTTTC ACCCACATCG CAAGCTCGAG AČGCCCGTCG TCCTCTTGCA CGCTCAGCCA 300 GGTTGGCGTG TCGCCGCCTT CCAGCAAGTG TTCCCACCAC ACGAAGGGAC CCTCGCGAAA 360 GGTGACTGAT CCGCGGACCA CATAGTCGAT GCCACCGTGG CTGACAATTG CGCCGGGTCC 420 GAGTTGGCGG GGGCCGAATT GCGGCATTGC GTCGAAGGCC AGCGGATCCC GGCGCCCGCC 480

• · • ·

208

CGGCGTGGCT GGTGTTTTGG GCCGCCGGAT GGCCACGACG AGAACGACGA TGGCGGCGAT 540 GAACAGCGCC ACGGCAATCA CGACCAGCAG ATTTCCCACG CATACCCTCT CGTACCGCTG 600 CGCCGCGGTT GGTCGATCGG TCGCATATCG ATGGCGCCGT TTAACGTAAC AGCTTTCGCG 660 GGACCGGGG TCACAACGGG CGAGTTGTCC GGCCGGGAAC CCGGCAGGTC TCGGCCGCGG 720 TCACCCCAGC TCACTGGTGC ACCATCCGGG TGTCGGTGAG CGTGCAACTC AAACACACTC 780 AACGGCAACG GTTTCTCAGG TCACCAGCTC AACCTCGACC CGCAATCGCT CGTACGTTTC 840 GACCGCGCGC AGGTCGCGAG TCAGCAGCTT TGCGCCGGCA GCTTTCGCCG TGAAGCCGAC 900 CAGGGCATCG TAGGTTGCGC CACCGGTGAC ATCGTGCTCG GCGAGGTGGT CGGTCAAGCC 960 GCGATATGAG CAGGCATCCA GTGCCAGGTA GTTGCTGGAG GTGATGTCCG CCAAGTAGGC 1020 GTGGACGGCA ACAGGGGCAA TACGATGCGG CGGTGGTAGC CGGGTCAAGA CCGAATAGGT 1080 TTCCACAGCC GCGTGCGCGA TCAGATGGAC GCCACGGTTG AGCGCGCGCA CGGCGGCCTC 1140 GTGCCCTTCG TGCCAGGTCG CGAATCCGGC AACCAGCACG CTGGTGTCTG GTGCGATCAC 1200 CGCCGTGTGC GATCGAGCGT TTCCCGAACG ATTTCGTCGG TCAACGGGGG CAGGGGACGT 1260 TCTGGCCGTG CGACGAGAAC CGAGCCTTCC CGAACGAGTT CGACACCGGT CGGGGCCGGC 1320 TCAATCTCGA TGCGCCCATC GCGCTCGGTG ATTCCCACCT GGTCGTTCCC GCGCAAGCCA 1380 AGGCGCTCGC GAATCCGCTT GGGAATCACC AGACGTCCTG CGACATCGAT GGTTGTTCGC 1440 ATGGTAGGAA ATTTACCATC GCACGTTCCA TAGGCGTGTC CTGCGCGGGA TGTCGGGACG 1500 ATCCGCTAGC GTATCGAACG ATTGTTTCGG AAATGGCTGA GGGAGCGTGC GGTGCGGGTG 1560 ATGGGTGTCG ATCCCGGGTT GACCCGATGC GGGCTGTCGC TCATCGAGAG TGGGCGTGGT 1620 CGGCAGCTCA CCGCGCTGGA TGTCGACGTG GTGCGCACAC CGTCGGATGC GGCCTTGGCG 1680 CAGCGCCTGT TGGCCATCAG CGATGCCGTC GAGCACTGGC TGGCACCCA TCATCCGGAG 1740 GTGGTGGCTA TCGAACGGGT GTTCTCTCAG CTCAACGTGA CCACGGTGAT GGGCACCGCG 1800 CAGGCCGGCG GCGTGATCGC CCTGGCGGCG GCCAAACGTG GTGTCGACGT GCATTTCCAT 1860 ACCCCCAGCG AGGTCAAGGC GGCGGTCACT GGCAACGGTT CCGCAGACAA GGCTCAGGTC 1920

acc

1923 • · • · • ·

209 (2) Sequence information of SEQ ID NO: 186:

(i) SEQUENCE CHARACTERISTICS: :

(A) LENGTH: 1055 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear

(xi) DESCRIPTION SEQUENCE: SEQ ID NO: 186: CTGGCGTGCC AGTGTCACCG GCGATATGAC GTCGGCATTC AATTTCGCGG CCCCGCCGGA 60 CCCGTCGCCA CCCAATCGG ACCACCCGGT CCGTCAATTG CCGAAGGTCG CCAAGTGCGT 120 GCCCAATGTG GTGCTGGGTT TCTTGAACGA AGGCCTGCCG TATCGGGTGC CCTACCCCCA 180 AACAAGCCA GTCCAGGAAT CCGGTCCCGC GCGGCCGATT CCCAGCGGCA TCTGCTAGCC 240 GGGGATGGTT CAGACGTAAC GGTTGGCTAG GTCGAAACCC GCGCCAGGGC CGCTGGACGG 300 GCTCATGGCA GCGAAATTAG AAAAACCGGGG ATATTGTCCG CGGATTGTCA TACGATGCTG 360 AGTGCTTGGT GGTTCGTGTT TAGCCATTGA GTGTGGATGT GTTGAGACCC TGGCCTGGAA 420 GGGGACAACG TGCTTTTGCC TCTTGGTCCG CCTTTGCCGC CCGACGCGGT GGTGGCGAAA 480 CGGGCTGAGT CGGGAATGCT CGGCGGGTTG TCGGTTCCGC TCAGCTGGGG AGTGGCTGTG 540 CCACCCGATG ATTATGACCA CTGGGCGCCT GCGCCGGAGG ACGGCGCCGA TGTCGATGTC 600 CAGGCGGCCG AAGGGGGGGA CGCAGAGGCC GCGGCCATGG ACGAGTGGGA TGAGTGGCAG 660 GCGTGGAACG AGTGGGTGGC GGAGAACGCT GAACCCCGCT TTGAGGTGCC ACGGAGTAGC 720 AGCAGCGTGA TTCCGCATTC TCCGGCGGCC GGCTAGGAGA GGGGGCGCAG ACTGTCGTTA 780 TTTGACCAGT GATCGGCGGT CTCGGTGTTC CCGCGGCCGG CTATGACAAC AGTCAATGTG 840 CATGACAAGT TACAGGTATT AGGTCCAGGT TCAACAAGGA GACAGGCAAC ATGGCAACAC 900 GTTTTATGAC GGATCCGCAC GCGATGCGGG ACATGGCGGG CCGTTTTGAG GTGCACGCCC 960 AGACGGTGGA GGACGAGGCT CGCCGGATGT GGGCGTCCGC GCAAAACATC TCGGGNGCGG 1020 GCTGGAGTGG CATGGCCGAG GCGACCTCGC TAGAC 1055

(2) Sequence information of SEQ ID NO: 187:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 359 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 187:

• 4 • 44 4

4444444 4 4

210 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:187:

CCGCTCGTT GTTGGCATAC TCCGCCGCGG CCGCTCGAC CGCACTGGCC GTGGCGTGTG 60 TCCGGGCTGA CCACCGGGAT CGCCGAACCA TCCGAGATCA CCTCGCAATG ATCCACCTCG 120 CGCAGCTGGT CACCCAGCCA CCGGGCGGTG TGCGACAGCG CCTGCATCAC CTTGGTATAG 180 CCGTCGCGCC CCAGCCGCAG GAAGTTGTAG TACTGGCCCA CCACCTGGTT ACCGGGACGG 240 GAGAAGTTCA GGGTGAAGGT CGGCATGTCG CCGCCGAGGT AGTTGACCCG GAAAACCAGA 300 TCCTCCGGCA GGTGCTCGGG CCCGCGCCAC ACGACAAACC CGACGCCGGG ATAGGTCAG 359

(2) Sequence information of SEQ ID NO: 188:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 350 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 188:

AACGGGCCCG TGGGCACCGC TCCTCTAAGG GCTCTCGTTG GTCGCATGAA GTGCTGGAAG 60 GATGCATCTT GGCAGATTCC CGCCAGAGCA AAACAGCCGC TAGTCCTAGT CCGAGTCGCC 120 CGCAAAGTTC CTCGAATAAC TCCGTACCCG GAGCGCCAAA CCGGGTCTCC TTCGCTAAGC 180 TGCGCGAACC ACTTGAGGTT CCGGGACTCC TTGACGTCCA GACCGATTCG TTCGAGTGGC 240 TGATCGGTTC GCCGCGCTGG CGCGAATCCG CCGCCGAGCG GGGTGATGTC AACCCAGTGG 300 GTGGCCTGGA AGAGGTGCTC TACGAGCTGT CTCCGATCGA GGACTTCTCC 350

(2) Sequence information of SEQ ID NO: 189:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 679 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 189:

·· ·· this this ·· ' ·· • this · · · this · this this this this • ·« this t ttt · this this ·« · « · «· ·· ··· ··· • · · this it · it · · • it·· ·· ·· ·· ·· ··

211

Glu Gin 1 For Fox Glee 5 For Phew Glu Glu Wall 10 How many Gosh Alas Phew Alas 15 Asp Glee Leo Alas Glee Fox Glee Fox Gin How many Association Thr Thr Leo Association Ser Leo 20 25 30 Ser Gin Alas Leo Association Alas Leo Association Gosh Glee Arg Glee Asp Phew Phew Alas 35 40 45 Wall Wall Arg Ser Leo Alas Leo Phew Wall Association Alas Leo His Gin Asp Asp 50 55 60 Gin Gin Phew Wall Alas Leo Association Fox Association Leo Alas Gosh Phew Thr Asp Arg 65 70 75 80 Leo Thr His Ser Asp Alas Asp Leo Ser Association Alas How many Gin Gin Phew Asp 85 90 95 Ser Leo Leo Alas Wall Alas Arg For Phew Phew Alas Fox Association Arg Gosh Wall 100 105 110 Leo Thr His Asp Wall Association Association Leo Alas Thr Wall Thr Thr Thr Leo Leo 115 120 125 Gin For Asp For Leo Asp Glee Leo Gosh Thr Wall Leo His How many Phew For 130 135 140 Thr Leo Alas Alas Association How many Association Gin Leo Tire His For Thr His Glee Glee 145 150 155 160 Wall Wall Ser Leo Ser Alas Phew Thr Association Phew Alas Association For Met Gosh Phew 165 170 175 How many Cys Ser Ser How many Gin Alas Glee Ser Arg Leo Glee Tire Gin Gosh Ser 180 185 190 Alas Gosh Leo Cys Alas Gin Tire Leo Alas For Wall Leo Asp Alas How many Fox 195 200 205 Phew Association Tire Phew For Phew Glee Leo Association Wall Alas Ser Thr Alas Ser Thr 210 215 220 Leo For Fox Gosh How many Alas Tire Ser Gosh For Arg Leo Gin For For Association 225 230 235 240 Glee Tire Fox Asp Thr Thr Wall For Glee How many Suffering Wall For Asp Thr For 245 250 255 Leo Ser His Arg Association Thr Gin For Glee Suffering Wall Wall Alas For Glee Met 260 265 270 Gin Glee Wall Gin Wall Glee For How many Thr Gin Glee Leo Leo Thr For Gosh 275 280 285

·· ·· »· ·· ·· ·· ···· «·· ···· • »· · · ··· · · · · ·· ··· ·· 4 · 444 444

4444444 4 4

4444 44 44 44 44 44

212

Ser Leu Ala Glu Leu Met Gly Gly Pro Asp Ile Ala Pro Pro Ser Ser 290 295 300

Gly Leu Gin Thr Pro Pro Gly Pro Pro Asn Ala Tyr Asp Glu Tyr Pro

305 310 315 320

Val Leu Pro Pro Ile Gly Leu Gin Ala Pro Gin Val Pro Ile Pro Pro

325 330 335

Pro Pro Pro Gly Pro Asp Val Ile Pro Gly Pro Val Pro Pro Val Leu 340 345 350

Ala Ala Ile Val Phe Pro Arg Asp Arg Pro Ala Ala Ser Glu Asn Phe 355 360 365

Asp Tyr Met Gly Leu Leu Leu Leu Ser Pro Gly Leu Ala Thr Phe Leu 370 375 380

Phe Gly Val Ser Ser Ser Pro Ala Arg Gly Thr Met Ala Asp Arg His

385 390 395 400

Val Leu Ile Pro Ala Ile Thr Gly Leu Ala Leu Ile Ala Ala Phe Val

405 410 415

Ala His Ser Trp Tyr Arg Thr Glu His Pro Leu Ile Asp Met Arg Leu 420 425 430

Phe Gin Asn Arg Ala Val Ala Gin Ala Asn Met Thr Met Thr Val Leu 435 440 445

Ser Leu Gly Leu Phe Gly Ser Phe Leu Leu Leu Pro Ser Tyr Leu Gin 450 455 460

Gin Val Leu His Gin Ser Pro Met Gin Ser Gly Val His Ile Ile Pro

465 470 475 480

Gin Gly Leu Gly Ala Met Leu Ala Met Pro Ile Ala Gly Ala Met Met

485 490 495

Asp Arg Arg Gly Pro Ala Lys Ile Val Leu Val Gly Ile Met Leu Ile 500 505 510

Ala Ala Gly Leu Gly Thr Phe Ala Phe Gly Val Ala Arg Gin Ala Asp 515 520 525

Tyr Leu Pro Ile Leu Pro Thr Gly Leu Ala Ile Met Gly Met Gly Met 530 535 540

Gly Cys Ser Met Met Pro Leu Ser Gly Ala Ala Val Gin Thr Leu Ala

545 550 555 560

Pro His Gin Ile Ala Arg Gly Ser Thr Leu Ile Ser Val Asn Gin Gin

565 570 575

Val Gly Gly Ser Ile Gly Thr Ala Leu Met Ser Val Leu Leu Thr Tyr

213

580 585 590 Gin Phew Association His Ser Gosh How many How many Alas Thr Alas Fox Fox Wall Alas Leo 595 600 605 Thr For Gosh Ser Glee Alas Glee Arg Glee Alas Alas Wall Asp For Ser Ser 610 615 620 Leo For Arg Gin Thr Association Phew Alas Alas Gin Leo Leo His Asp Leo Ser 625 630 635 640 His Alas Tire Alas Wall Wall Phew Wall How many Alas Thr Alas Leo Wall Wall Ser 645 650 655 Thr Leo How many For Alas Alas Phew Leo For Fox Gin Gin Alas Ser His Arg 660 665 670 Arg Alas For Leo Leo Ser Alas

675 (2) Information on the sequence of SEQ ID NO: 190:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 120 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi.). SEQUENCE DESCRIPTION: SEQ ID NO: 190:

Thr Pro 1

Met Val

For Asp

Tyr Ile 50

Arg Ala 65

Cys Val

Arg Ser

Glu Lys

Glu Ile 20

Glu Asp 35

Gin Lys

Lys Ile

Sir Pro

Ala Arg 100

Ser Phe Val Asp Asp Leu Asp Ile Asp Ser Leu Ser 5 10 15

Ala Val Gin Thr Glu Asp Lys Tyr Gly Val Lys Ile 25 30

Leu Ala Gly Leu Arg Thr Val Gly Asp Val Val Tkla 40 45

Leu Glu Glu Glu Asn Pro Glu Ala Ala Gin Ala Leu 55 60

Glu Ser Glu Asn Pro Asp Ala Ala Arg Ala Asp Arg 70 75 80

Thr Ser Gin Ala Arg Asp Ala Arg Arg Pro Leu Ala 85 90 95

Leu Ala Cys Arg Arg Leu Pro Ala Ser Val Pro Thr 105 110 • ·

214

Thr Arg Arg Asp Pro Arg Glu Arg 115 120 (2) Sequence Information SEQ ID NO: 191:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 89 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 191:

Leo Alas Cys Gin Cys His Arg Arg Tire Asp Wall Glee How many Gin Phew Arg 1 5 10 15 Glee For Alas Glee For Wall Alas Thr Gin Ser Glee For For Glee For Ser 20 25 30 How many Alas Gosh Glee Arg Gin Wall Arg Alas Gin Cys Glee Alas Glee Phew Leo 35 40 45 Gosh Arg Arg For Alas Wall Ser Glee Alas Leo For For Association Association Alas Ser 50 55 60 For Glee How many Arg Ser Arg Alas Alas Asp Ser Gin Arg His Leo Leo Alas 65 70 75 80 Glee Asp Glee Ser Asp Wall Thr Wall Glee

(2) Sequence information of SEQ ID NO: 192:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 119 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 192:

Alas Ser Leo Leo Ala Tyr Ser Alas Alas Ala Ala Ser Thr Alas Leo Alas 1 5 10 15 Wall Alas Cys Wall Arg Ala Asp His Arg Asp Arg Arg Thr How many Arg Asp

25 30 • ·

215

His Leo Alas 35 Met How many His Leo Alas 40 Gin Leo Wall Thr Gin 45 For For Glee Glee Wall 50 Arg Gin Arg Leo His 55 His Leo Glee How many Ala Val 60 Alas For Gin For 65 Gin Gosh Wall Wall Wall 70 Leo Alas His His Leo 75 Val Thr Glee Thr Glee 80 Gosh Wall Gin Glee Gosh 85 Glee Arg His Wall Alas 90 Alas Glu Val Wall Asp 95 For Gosh Association Gin How many 100 Leo Arg Gin Wall Leo 105 Glee For Ala·Pro His 110 Asp Fox For Asp Alas Glee How many Glee Gin

115 (2) Sequence information of SEQ ID NO: 193:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 116 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 193:

Arg Ala Arg Gly His Arg Ser Ser Lys Gly Ser Arg Trp Ser His Glu 1 5 10 15 Wall Leo Gosh Glee Cys How many Leo Alas Asp Ser Arg Gin Ser Fox Thr Alas 20 25 30 Alas Ser For Ser For Ser Arg For Gin Ser Ser Ser Association Association Ser Wall 35 40 45 For Glee Alas For Association Arg Wall Ser Phew Alas Fox Leo Arg Gosh For Leo 50 55 60 Gosh Wall For Glee Leo Leo Asp Wall Gin Thr Asp Ser Phew Gosh Suffering Leo 65 70 75 80 How many Glee Ser For Arg Suffering Arg Ola Ser Alas Alas Gosh Arg Glee Asp Wall 85 90 95 Association For Wall Glee Glee Leo Gosh Gosh Wall Leo Tire Gosh Leo Ser For' How many 100 105 110 Gosh Asp Phew Ser

115 • · · • · · · ····· ···· ·· ·· ·♦

216 (2) Sequence information of SEQ ID NO: 194:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 811 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 194:

TGCTACGCAG CAATCGCTTT GGTGACAGAT

GTGAAAGCCG

GTGCGGGCCG

GCCGGTGTTC

TCATCGGGTC

ACGCGCTGCT

TCGACGTGCG

ACCAGGCCGC

ACAACGATTT

TGGTGCTGGC

GACCGGTCGA

GTTGCCCGGG

GCCCGCGCAG

GGAAACGAAT (2)

CCGACGTGTT

CCATCGATCG

CGTTGCCGTT

GCGCGTGGAT

GCCCGCCGCG

CGACGCCAGC

CATGGTGGGGT

CGCCACCACG

GTCGTCGATG

CCCGCTGCCG

GTGCGGCGAG

CCTGTACGCG

GGGCGTTCCG

CGCCGCATTC

GGTCGCCGAC

CGAGCTGCCA

GCGGCGTTAC

CACGGGCCAA

GCGCTGGCCC

GCCGGCGTCCA

GTGCTGCTGG

GTGGTTTACG

CGGCGCGAG

CCAGTCTT

GCAGCAAGAC

TGGTGGCGTT

GTGGATGCCG GCGTCGCTGC TGGCGATGGC 60 GGGGAGAACA TCGAACTGCT CAAAAGGCTG 120 GAGCGCACGT GCACGCACTG TCAACACCAC 180 TGAGGGTGCT GCTGACCGGC GCGGCCGGCT 240 GGGCTGCGGG TCACGACGTG GTGGGCGTCG 300 ACCCGGTGCT GCCACCGGGC TGCCAGCGGG 360 CGTTGTTGGC CGGTGTCGAT CTGGTGTGTC 420 ACGCCGCCGA CGCACCCGCC TATGGCGGCC 480 CGCAGATGTT CGCCGCCGGG GTCCGCCGTT 540 GGCAGGGGCG CTATGACTGT CCCCAGCATG 600 CCGACCTGGA CAATGGGGTC TTCGAGCACC 660 GGCAATTGGT CGACGAAGAT GCCCCGTTGC 720 CGCGCAGGAG CACTACGCGC TGGCGTGGTC 780 G 811

Sequence Information SEQ ID NO: 195:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 966 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 195:

217 • · · • · · • · • ·'· · · · • · · · • · · · · • · · · · • · · · • · · • · · • • · · · GTCCCGCGAT GTGGCCGAGC ATGACTTTCG GCAACACCGG CGTAGTAGTC GAAGATATCG 60 GACTTTGTGG TCCCGGTGGC GGGATAGAGC ACCTGTCGGC GTTGGTCAGC GTCACCCGTT 120 GCTCGGACGC CGAACCCCATG CTTTCAACGT AGCCTGTCGG TCACACAAGT CGCGAGCGTA 180 ACGTCACGGT CAAATATCGC GTGGAATTTC GCCGTGACGT TCCGCTCGCG GACAATCAAG 240 GCATACTCAC TTACATGCGA GCCATTTGGA CGGGTTCGAT CGCCTTCGGG CTGGTGAACG 300 TGCCGGTCAA GGTGTACAGC GCTACCGCAG ACCACGACAT CAGGTTCCAC CAGGTGCACG 360 CCAAGGACAA CGGACGCATC CGGTACAAGC GCGTCTGCGA GGCGTGTGGC GAGGTGGTCG 420 ACTACCGCGA TCTTGCCCGG GCCTACGAGT CCGGCGACGG CCAAATGGTG GCGATCACCG 480 ACGACGACAT CGCCAGCTTG CCTGAAGAAC GCAGCCGGGA GATCGAGGTG TTGGAGTTCG 540 TCCCCGCCGC CGACGTGGAC CCGATGATGT TCGACCGCAG CTACTTTTTG GAGCCTGATT 600 CGAAGTCGTC GAAATCGTAT GTGCTGCTGG CTAAGACACT CGCCGAGACC GACCGGATGG 660 CGATCGTGGA TCGCCCCACC GGCCGTGAAT GCAGGAAAAA TAAGAGCCGC TATCCACAAT 720 TCGGCGTCGA GCTCGGCTAC CACAAACGGT AGAACGATCG AGACATTCCC GAGCTGAAGT 780 GCGGCGCTAT AGAAGCCGCT CTGCGCGATT ATCAAACGCA AAATACGCTT ACTCATGCCA 840 TCGGCGCTGC TCACCCGATG CGACGTTTTT GCCACGCTCCC ACCGCCTGCC GCGCGACCTC 900 AAGTGGGCAT GCATCCCACC CGTTCCCGGA AACCGGTTCC GGCGGGTCGG CTCATCGCTT 960 CATCCT 966

(2) Sequence information of SEQ ID NO: 196:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2367 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 196:

CCGCACCGCC GGCAATACCG CCAGCGCCAC CGTTACCGCC GTTTGCGCCG TTGCCCCCGT 60 TGCCGCCCGT CCCGCCGGCC CCGCCGATGG AGTTCTCATC GCCAAAAGTA CTGGCGTTGC 120 CACCGGAGCC GCCGTGCCG CCGTCACCGC CAGCCCCGCC GACTCCACCG GCCCCACCGA 180

218 • · · • · · • · · · · · • · · · · · ·· · • · · · • · this • · • · · · CTCCGCCGCT GCCACCGTTG CCGCCGTTGC CGATCAACAT GCCGCTGGCG CCACCCTTGC 240 CACCCACGCC ACCGGCTCCG CCCACCCCGC CGACACCAAG CGAGCTGCCG ČCGGAGCCAC 300 CATCACCACC TACGCCACCG ACCGCCCAGA CACCAGCGAC CGGGTCTTCG TGAAACGTCG 360 CGGTGCCACCC ACCGCCGCCG TTACCGCCAA CCCCACCGGC AACGCCGGCG CCGCCATCCC 420 CGCCGGCCCC GGCGTTGCCG CCGTTGCCGC CGTTGCCGAA CAACAACCCG CCGGCGCCGC 480 CGTTGCCGCC CGCGCCGCCG GTCCCGCCGG CGCCGCCGAC GCCAAGGCCG CTGCCGCCCT 540 TGCCGCCATC ACCACCCTTG CCGCCGACCA CATCGGGTTC TGCCTCGGGG TCTGGGCTGT 600 CAAACCTCGC GATGCCAGCG TTGCCGCGC TTCCCCGGGG CCCCCCCGTG GCGCCGTCAC 660 CACCGATACC ACCCGCCA CCGGCGCCAC CGTTGCCGCC ATCACCGAAT AGCAACCCGC 720 CGGCGCCACC ATTGCCGCCA GCTCCCCCTG CGCCACCGTC GGCGCCGGAG GCGGCACTGG 780 CAGCCCCGTT ACCACCCGAAA CCGCCGCTAC CACCGGTAGA GGTGGCAGTG GCGATGTGTA 840 CGAAAGCGCC GCCTCCGGCG CCGCCGCTAC CACCCCCACT GCCGGCGGCT ACACCGTCGG 900 ACCCGTTGCC ACCATCACCG CCAAAGGCGC TCGCAATGTC GCCCTGCGCG ACTCCGCCGT 960 CGCCGCCGTT GCCGCCGCCG CCACCGGCAG CGGCGGTACC GCCGTCACCA CCGGCACCGC 1020 CGGTGGCCTT GCCCGAGCCT GCCGTCGCGG TGGCACCGTC GCCGCCGGTG CCACCGGTCG 1080 GCGTGCCGGC AGTGCCATGG CCGCCCGTGC CGCCGTCGCC GCCGGTTTGA TCACCGATGC 1140 CGGACACATC TGCCGGGCTG TCCCCGGTGC TGGCCGCGGG GCCGGGGCGTG GGATTGACCC 1200 CGTTTGCCCC GGCGAGGCCG GCGCCGCCGG TACCACCGGC GCCGCCATGG CCGAACAGCC 1260 CGGCGTTGCC GCCGTTACCG CCCGCACCCC CGATGCCTGC GGCCACGCTG GTGCCGCCGA 1320 CACCGCCGTT GCCGCCGTTG CCCCACAACC ACCCCCCGTT CCCACCGGCA CCGCCGGCCG 1380 CGCCGGTACC ACCGGCCCCG CCGTTGCCGC CGTTGCCGAT CAACCCGGCC GCGCCTCCG 1440 TGCCGCCGGT TTGACCGAAC CCGCCAGCCG CGCCGTTGCC ACCGTTGCCA AACAGCAACC 1500 CGCCGGCCGC GCCAGGCTGC CCGGGTGCCG TCCCGTCGGC GCCGTTTCCG ATCAACGGGC 1560 GCCCCAAAAAG CGCCTCGGTG GGCGCATTCA CČGCACCCAG CAGACTCCGC TCAACAGCGG 1620 CTTCAGTGCT GGCATACCGA CCCGCGCCG CAGTCAACGC CTGCACAAAC TGCTCGTGAA 1680 ACGCTGCCAC CTGTACGCTG AGCGCCTGAT ACTGCCGAGC ATGGGCCCG AACAACCCG 1740 CAATCGCCGC CGACACTTCA TCGGCAGCCG CAGCCACCAC TTCCGTCGTC GGGATCGCCG 1800

• ·

219

CGGCCGCATT AGCCGCGCTC ACCTGCGAAC CAATAGTCGA TAAATCCAAA GCCGCAGTTG 1860 CCAGCAGCTG CGGCGTCGCG ATCACCAAGG ACACCTCGCA CCTCGGATA CCCCATATCG 1920 CCGCACCGTG TCCCCAGCGG CCACGTGACC TTTGGTCGCT GGCTGGCGGC CCTGACTATG 1980 GCCGCGACGG CCCTCGTTCT GATTCGCCCC GGCGCGCAGC TTGTTGCGCG AGTTGAAGAC 2040 GGGAGGACAG GCCGAGCTTG GTGTAGACGT GGGTCAAGTG GGAATGCACG GTCCGCGGCG 2100 AGATGAATAG GCGGACGCCG ATTCCCTTGT TGCTGAGTCC CTCACCGACC AGTAGAGCCA 2160 CCTCAAGCTC TGTCGGTGTC AACGCGCCCC AGCCACTTGT CGGGCGTTTC CGTGCACCGC 2220 GGCCTCGTTG CGCGTACGCG ATCGCCTCAT CGATCGATAA CGCAGTTCCT TCGGCCCAGG 2280 CATCGTCGAA CTCGCTGTCA CCCATGGATT TTCGAAGGGT GGCTAGCGAC GAGTTACAGC 2340 CCGCCTGGTA GATCCCGAAG CGGACCG 2367

(2) Sequence information of SEQ ID NO: 197:

(i) CHARACTERISTICS. SEQUENCE:

(A) LENGTH: 376 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 197:

Gin 1 For Alas Glee Alas 5 Thr How many Alas Alas Ser 10 Ser For Cys Alas Thr 15 Wall Glee Alas Glee Glee 20 Glee Thr Glee Ser For 25 Wall Thr Thr Gosh Thr 30 Alas Alas Thr Thr Glee 35 Arg Glee Glee Ser Glee 40 Asp Wall Tire Gosh Ser 45 Alas Alas Ser Glee Alas 50 Alas Alas Thr Thr For 55 Thr Alas Glee Glee Tire 60 Thr Wall Glee For Wall 65 Alas Thr How many Thr Alas 70 Fox Glee Alas Arg Association 75 Wall Alas Leo Arg Asp 80 Ser Alas Wall Alas Alas 85 Wall Alas Alas Alas Alas 90 Thr Glee Ser Glee Glee 95 Thr Alas Wall Thr Thr Glee Thr Alas Glee Glee Leo Alas Arg Alas Cys Arg Arg

1Q0 105 110

130

145

210

225

290

305

370 • · e . ·· ·· ·· ·· ·· ···· ··· ···< ··· · ···· · · · < • · ··· *· ·· ··· · · I ·· · ···· and ·

115

195

275

355

220 • · · · • · • · • · • · Wall Alas Alas Glee Ala Thr Glee Arg Arg Alas Glee Ser Alas 120 125 Arg Alas Alas Wall Ala Ala Glee Leu lle Thr Asp Alas Glee 135 140 Arg Alas Wall For Gly Ala Glee Arg Gly Alas Glee Arg Glee 150 155 160 Wall Cys For Glee Glu Ala Glee Ala Ala Glee Thr Thr Glee 165 170 175 Alas Gosh Gin For Gly Val Alas Ala Val Thr Alas Arg Thr 180 185 190 Cys Glee His Alas Gly Ala Alas Asp Thr Alas Wall Alas Alas 200 205 Gin For For For Val Pro Thr Gly Thr Alas Glee Arg Alas 215 220 Glee For Alas Wall Ala Ala Wall Ala Asp Gin For Glee Arg 230 235 240 Alas Alas Glee Leo Thr Glu For Ala Ser- Arg Alas Wall Alas 245 250 255 Fox Gin Gin For Ala Gly Arg Ala Arg Leo For Glee Cys 260 265 270 Glee Alas Wall Ser Asp Gin Arg Ala Pro Gin Fox Arg Leo 280 285 lle His Arg Thr Gin Gin Thr For Lea Association Ser Glee Phew 295 300 lle For Thr Arg Gly Arg Ser Gin Arg Leo His Fox Leo 310 315 320 Arg Cys His Leo Tire Ala Gosh Arg Leu lle Leo For Ser 325 330 335 Gosh Gin For Arg Asn Arg Arg Arg His Phew lle Glee Ser 340 345 350 His Phew Arg Arg Arg Asp Arg Arg Gly Arg lle Ser Arg 360 365 Arg Thr Association Ser Arg

375 • · • ·

221 (2) Information on the sequence of SEQ ID NO: 198:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 2852 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 198:

GGCCAAAACG CCCCGGCGAT CGCGGCCACCC GAGGCCGCCT ACGACCAGAT GTGGGCCCAG 60 GACGTGGCGG CGATGTTGG CTACCATGCC GGGGCTTCGG CGGCCGTCTC GGCGTTGACA 120 CCGTTCGGCC AGGCGCTGCC GACCGTGGCG GGCGGCGGTG CGCTGGTCAG CGCGGCCGCG 180 GCTCAGGTGA CCACGCGGGT CTTCCGCAAC CTGGGCTTGG CGAACGTCCG CGAGGGCAAC 240 GTCCGCAACG GTAATGTCCG GAACTTCAAT CTCGGCTCGG CCAACATCGG CAACGGCAAC 300 ATCGGCAGCG GCAACATCGG CAGCTCCAAC ATCGGGTTTG GCAACGTGGG TCCTGGGTTG 360 ACCGCAGCGC TGAACAACAT CGGTTTCGGC AACACCGGCA GCAACAACAT CGGGTTTGGC 420 AACACCGGCA GCAACAACAT CGGGTTCGGC AATACCGGAG ACGGCAACCG AGGTATCGGG 480 CTCACGGGTA GCGGTTTGTT GGGGTTCGGC GGCCTGAACT CGGGCACCGG CAACATCGGT 540 CTGTTCAACT CGGGCACCGG AAACGTCGGC ATCGGCAACT CGGGTACCGG GAACTGGGGC 600 ATTGGCAACT CGGGCAACAG CTACAACACC GGTTTTGGCA ACTCCGGCGA CGCCAACACG 660 GGCTTCTTCA ACTCCGGAAT AGCCAACACC GGCGTCGGCA ACGCCGGCAA CTACAACACC· 720 GGTAGCTACA ACCCGGGCAA CAGCAATACC GGCGGCTTCA ACATGGGCCA GTACAACACG 780 GGCTACCTGA ACAGCGGCAA CTACAACACC GGCTTGGCAA ACTCCGGCAA TGTCAACACC 840 GGCGCCTTCA TTACTGGCAA CTTCAACAAC GGCTTCTTGT GGCGCGGCGA CCACCAAGGC 900 CTGATTTTCG GGAGCCCCGG CTTCTTCAAC TCGACCAGTG CGCCGTCGTC GGGATTCTTC 960 AACAGCGGTG CCGGTAGCGC GTCCGGCTTC CTGAACTCCG GTGCCAACAA TTCTGGCTTC 1020 TTCAACTCTT CGTCGGGGGC CATCGGTAAC TCCGGCCTGG CAAACCGGGGG CGTGCTGGTA 1080 TCGGGCGTGA TCAACTCGGG CAACACCGTA TCGGGTTTGT TCAACATGAG CCTGGTGGCC 1140 ATCACAACGC CGGCCTTGAT CTCGGGCTTC TTCAACACCG GAAGCAACAT GTCGGGATTT 1200 TTCGGTGGGCC CACCGGTCTT CAATCTCGGC CTGGCAAACC GGGGCGTCGT GAACATTCTC 1260 GGCAACGCCA ACATCGGGCAA TTACAACATT CTCGGCAGCG GAAACGTCGG TGACTTCAC 1320 ATCCTTGGCA GCGGCAACCT CGGCAGCCAA AACATCTTGG GCAGCGGCAA CGTCGGCAGC 1380

• · • ·

222 • · • · · · « · • · · · · ·· ·· • ·· ·· TTCAATATCG GCAGTGGAAA CATCGGAGTA TTCAATGTCG GTTCCGGAAG CCTGGGAAAC 1440 TACAACATCG GATCCGGAAA CCTCGGGATC TACAACATCG GTTTTGGAAA CGTCGGCGAC 1500 TACAACGTCG GCTTCGGGAA CGCGGGCGAC TTCAACCAAG GCTTTGCCAA CACCGGCAAC 1560 AACAACATCG GGTTCGCCAA CACCGGCAAC AACAACATCG GCATCGGGCT GTCCGGCGAC 1620 AACCAGCAGG GCTTCAATAT TGCTAGCGGC TGGAACTCG GCACCGGCAA CAGCGGCCTG 1680 TTCAATTCGG GCACCAATAA CGTTGGCATC TTCAACGCGGG GCACCGGAAA CGTCGGCATC 1740 GCAAACTCG GCACCGGGAA CTGGGGTATC GGGAACCCGG GTACCGACAA TACCGGCATC 1800 CTCAATGCTG GCAGCTACAA CACGGGCATC CTCAACGCCG GCGACTTCAA CACGGGCTTC 1860 TACAACACGG GCAGCTACAA CACCGGCGGC TTCAACGTCG GTAACACCAA CACCGGCAAC 1920 TTCAACGTGG GTGACACCAA TACCGGCAGC TATAACCCGG GTGACACCAA CACCGGCTTC 1980 TTCAATCCCG GCAACGTCAA TACCGGCGCT TTCGACACGG GCGACTTCAA CAATGGCTTC 2040 TTGGTGGCGG GCGATAACCA GGGCCAGATT GCCATCGATC TCTCGGTCAC CACTCCATTC 2100 ATCCCCATAA ACGAGCAGAT GGTCATTGAC GTACACAACG TAATGACCTT CGGCGGCAAC 2160 ATGATCACGG TCACCGAGGC CTCGACCGTT TTCCCCCAAA CCTTCTATCT GAGCGGTTTG 2220 TTCTTCTTCG GCCCGGTCAA TCTCAGCGCA TCCACGCTGA CCGTTCCGAC GATCACCCTC 2280 ACCATCGCG GACCGACGGT GACCGTCCCC ATCAGCATTG TCGGTGCTCT GGAGAGCCGC 2340 ACGATTACCT TCCTCAAGAT CGATCGGCG CCGGGCATCG GAAAATTCGAC CACCAACCCC 2400 TCGTCCGGCT TCTTCAACTC GGGCACCGGT GGCACATCTG GCTTCCAAAA CGTCGGCGGC 2460 GGCAGTTCAG GCGTCTGGAA CAGTGGTTTG AGCAGCGCGA TAGGGAATTC GGGTTTCCAG 2520 AACCTCGGCT CGCTGCAGTC AGGCTGGGCG AACCTGGGCA ACTCCGTATC GGGCTTTTTC 2580 AACACCAGTA CGGTGAACCT CTCCACGCCG GCCAATGTCT CGGGCCTGAA CAACATCGGC 2640 ACCAACCTGT CCGGCGTGTT CCGCGGTCCG ACCGGGACGA TTTTCAACGC GGGCCTTGCC 2700 AACCTGGGCC AGTTGAACAT CGGCAGCGCC TCGTGCCGAA TTCGGCACGA GTTAGATACG 2760 GTTTCAACAA TCATATCCGC GTTTTGCGGC ÁGTGCATCAG ACGAATCGAA CCCGGGAAGC 2820

GTAAGCGAAT AAACCGAATG GCGGCCTGTC AT

2852

0 • 000000 0 0 0000 0 0. 00 0 0 00 00

223 (2) Information on the sequence of SEQ ID NO: 199:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 943 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN:

(D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 199:

Glee 1 Gin Association Alas For 5 Alas How many Alas Alas Thr 10 Gosh Alas Alas Tire Asp 15 Gin Met Suffering Alas Gin 20 Asp Wall Alas Alas Met 25 Phew Glee Tire His Alas 30 Glee Alas Ser Alas Alas 35 Wall Ser Alas Leo Thr 40 For Phew Glee Gin Alas 45 Leo For Thr Wall Alas 50 Glee Glee Glee Alas Leo 55 Wall Ser Alas Alas Alas 60 Alas Gin Wall Thr Thr 65 Arg Wall Phew Arg Association 70 Leo Glee Leo Al a Association 75 Wall Arg Gosh Glee Association 80 Wall Arg Association Glee Association 85 Wall Arg Association Phew Association 90 Leo Glee Ser Alas Association 95 How many Glee Association Glee Association 100 How many Glee Ser Glee Association 105 How many Glee Ser Ser Association 110 How many Glee Phew Glee Association 115 Wall Glee For Glee Leo 120 Thr Alas Alas Leo Association 125 Association How many Glee Phew Glee 130 Association Thr Glee Ser Association 135 Association How many Glee Phew Glee 140 Association Thr Glee Ser Association 145 Association How many Glee Phew Glee 150 Association Thr Glee Asp Glee 155 Association Arg Glee How many Glee 160 Leo Thr Glee Ser Glee 165 Leo Leo Glee Phew Glee 170 Glee Leo Association Ser Glee 175 Thr Glee Association How many Glee 180 Leo Phew Association Ser Glee 185 Thr Glee Association Wall Glee 190 How many Glee Association Ser Glee 195 Thr Glee Association Suffering Glee 200 How many Glee Association Ser Glee 205 Association Ser Tire Association Thr 210 Glee Phew Glee Association Ser 215 Glee Asp Alas Association Thr 220 Glee Phew Phew Association

Ser Gly Ile Ala Asn Thr Gly Val Gly Asn Ala Gly Asn Tyr Asn Thr 225 230 235 240 • · ·· ·· ·· ·« • · · · 9 • · · · · · · · ·

224

305

385

465

Ser Tire Association For Glee Association Ser Association Thr Glee Glee Phew Association Met Glee 245 250 255 Tire Association Thr Glee Tire Leo Association Ser Glee Association Tire Association Thr Glee Leo 260 265 270 Association Ser Glee Association Wall Association Thr Glee Alas Phew How many Thr Glee Association Phew 275 280 285 Association Glee Phew Leo Suffering Arg Glee Asp His Gin Glee Leo How many Phew Glee 290 295 300 For Glee Phew Phew Association Ser Thr Ser Alas For Ser Ser Glee Phew Phew 310 315 320 Ser Glee Alas Glee Ser Alas Ser Glee Phew Leo Association Ser Glee Alas Association 325 330 335 Ser Glee Phew Phew Association Ser Ser Ser Glee Alas How many Glee Association Ser Glee 340 '345 350 Alas Association Alas Glee Wall Leo Wall Ser Glee Wall How many Association Ser Glee Association 355 360 365 Wall Ser Glee Leo Phew Association Met Ser Leo Wall Alas How many Thr Thr For 370 375 380 Leo How many Ser Glee Phew Phew Association Thr Glee Ser Association Met Ser Glee Phew 390 395 400 Glee Glee For For Wall Phew Association Leo Glee Leo Alas Association Arg Glee Wall 405 410 415 Association How many Leo Glee Association Alas Association How many Glee Association Tire Association How many Leo Glee 420 425 430 Glee Association Wall Glee Asp Phew Association How many Leo Glee Ser Glee Association Leo Glee 435 440 445 Gin Association How many Leo Glee Ser Glee Association Wall Glee Ser Phew Association How many Glee 450 455 460 Glee Association How many Glee Wall Phew Association Wall Glee Ser Glee Ser Leo Glee Association 470 475 480 Association How many Glee Ser Glee Association Leo Glee How many Tire Association How many Glee Phew Glee 485 4 90 495 Wall Glee Asp Tire Association Wall Glee Phew Glee Association Alas Glee Asp Phew Association 500 505 510 Glee Phew Alas Association Thr Glee Association Association Association How many Glee Phew Alas Association Thr 515 520 525

Gly Asn Asn Asn Ile Gly Ile Gly Leu Ser Gly Asp Asn Gin Gin Gly * · . to· ·· »« ·· «ι • · · · ··· ··· · ·· · ···· · · >

··· · · ♦ · · ···· ·· «« ·« ·« ««

225

530

535

540

Phe Asn lle Ala Ser Gly Trp Asn Ser Gly Thr Gly Asn Ser Gly Leu

545 550 555 560

Phe Asn Ser Gly Thr Asn Asn Val Gly lle Phe Asn Ala Gly Thr Gly

565 570 575

Asn Val Gly lle Ala Asn Ser Gly Thr Gly Asn Trp Gly lle Gly Asn 580 585 590

Pro Gly Thr Asp Asn Thr Gly Tle Leu Asn Ala Gly Ser Tyr Asn Thr 595 600 605

Gly lle Leu Asn Ala Gly Asp Phe Asn Thr Gly Phe Tyr Asn Thr Gly 610 615 620

Ser Tyr Asn Thr Gly Gly Phe Asn Val Gly Asn Thr Asn Thr Gly Asn

625 630 635 640

Phe Asn Val Gly Asp Thr Asn Thr Gly Ser Tyr Asn Pro Gly Asp Thr

645 650 655

Asn Thr Gly Phe Phe Asn Pro Gly Asn Val Asn Thr Gly Ala Phe Asp 660 665 670

Thr Gly Asp Phe Asn Asn Gly Phe Leu Val Ala Gly Asp Asn Gin Gly 675 680 685

Gin lle Ala lle Asp Leu Ser Val Thr Thr Pro Phe lle Pro lle Asn 690 695 700

Glu Gin Met Val lle Asp Val His Asn Val Met Thr Phe Gly Gly Asn

705 710 715 720

Met lle Thr Val Thr Glu Ala Ser Thr Val Phe Pro Gin Thr Phe Tyr

725 730 735

Leu Ser Gly Leu Phe Phe Phe Gly Pro Val Asn Leu Ser Ala Ser Thr 740 745 750

Leu Thr Val Pro Thr lle Thr Leu Thr lle Gly Gly Pro Thr Val Thr 755 760 765

Val Pro lle Ser lle Val Gly Ala Leu Glu Ser Arg Thr lle Thr Phe 770 775 780

Leu Lys lle Asp Pro Ala Pro Gly lle Gly Asn Ser Thr Thr Asn Pro

785,790,795,800

Ser Ser Gly Phe Phe Asn Ser Gly Thr Gly Gly Thr Ser Gly Phe Gin

805 810 815

Asn Val Gly Gly Gly Ser Ser Gly Val Trp Asn Ser Gly Leu Ser Ser 820 825 830 . . . . *· ·· ·· »· • ! · · « « · · « · <

• ·· » · ··· · · , , • J ϊ*· · · · · ·»· ··« ······· .· « ···♦ ·· ·· ·· ·< « <

226

Alas How many Glee Association Ser Glee Phew Gin Association Leo Gly Ser Leo Gin Ser Glee 835 840 845 Suffering Alas Association Leo Glee Association Ser Wall Ser Glee Phew Phew Association Thr Ser Thr 850 855 860 Wall Association Leo Ser Thr For Alas Association Wall Ser Glee Leo Association Association How many Glee 865 870 875 880 Thr Association Leo Ser Glee Wall Phew Arg Glee For Thr Glee Thr How many Phew Association 885 890 895 Alas Glee Leo Alas Association Leo Glee Gin Leo Association How many Glee Ser Alas Ser Cys 900 905 910 Arg How many Arg His Gosh Leo Asp Thr Wall Ser Thr How many How many Ser Alas Phew 915 920 925 Cys Glee Ser Alas Ser Asp Gosh Ser Association For Glee Ser Wall Ser Gosh

930

935

940 (2) Information about the sequence of SEQ ID NO: 200:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 53 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 200:

GGATCCATAT GGGCCATCAT CATCATCATC ACGTGATCGA CATCATCGGG ACC (2) Sequence Information SEQ ID NO: 201:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 42 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 201:

CCTGAATTCA GGCCTCGGTT GCGCCGGCCT CATCTTGAAC GA • ·· · ·· ··

227 (2) Information on the sequence of SEQ ID NO: 202:

·· ·· • φ • ··· (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 31 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 202:

GGATCCTGCA GGCTCGAAAC CACCGAGCGG T (2) Sequence Information SEQ ID NO: 203:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 31 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 203:

CTCTGAATTC AGCGCTGGAA ATCGTCGCGA T (2) Sequence Information SEQ ID NO: 204:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 33 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 204:

GGATCCAGCG CTGAGATGAA GACCGATGCC GCT

228 (2) Sequence information of SEQ ID NO: 205:

{i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 38 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 205:

GGATATCTGC AGAATTCAGG TTTAAAGCCC ATTTGCGA 38 (2) Sequence Information SEQ ID NO: 206:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 30 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 206:

CCGCATGCGA GCCACGTGCC CACAACGGCC (2) Sequence Information SEQ ID NO: 207:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 37 base pairs (B) TYPE: nucleic acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 207:

CTTCATGGAA TTCTCAGGCC GGTAAGGTCC GCTGCGG 37 (2) Sequence Information SEQ ID NO: 208:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 7676 base pairs (B) TYPE: nucleic acid (C) TYPE OF STRAND: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 208:

TGGCGAATGG GACGCGCCCT GTAGCGGGC ATTAAGCGCG GCGGGTGTGG TGGTTACGCG 60 • · ·

• · · • · · · it· • · · · ·· ·· • · • · · · 229 CAGCGTGACC GCTACACTTG CCAGCGCCCT AGCGCCCGCT CCTTTCGCTT TCTTCCCTTC 120 CTTTCTCGCC ACGTTCGCCG GCTTTCCCCG TCAAGCTCTA AATCGGGGGC TCCCTTTAG 180 GTTCCGATTT AGTGCTTTÁC GGCACCTCGA CCCCAAAAAA CTTGATTAGG GTGATGGTTC 240 ACGTAGTGGG CCATCGCCCT GATAGACGGT TTTTCGCCCT TTGACGTTGG AGTCCACGTT 300 CTTTATAGT GGACTCTTGT TCCAAACTGG AACAACACTC AACCCTATCT CGGTCTATTC 360 TTTTGATTTA TAAGGGATTT TGCCGATTTC GGCCTATTGG TTAAAAAT AGCTGATTTA 420 ACAAAAAATT AACGCGAATT TTAAAAAAAT ATTAACGTTT ACAATTTCAG GTGGCACTTT 480 TCGGGGAAAT GTGCGCGGAA CCCCTATTTG TTTTTTTTC TAAATACATT CAAATATGTA 540 TCCGCTCATG AATTAATTCT TAGAAAAACT CATCGAGCAT CAAATGAAAC TGCAATTTAT 600 TCATATCAGG ATTATCAATA CCATATTTTT GAAAAAGCCG TTTCTGTAAT GAAGGAGAAA 660 ACTCACCGAG GCAGTTCCAT AGGATGGCAA GATCCTGGTA TCGGTCTGCG ATTCCGACTC 720 GTCCAACATC AATACAACCT ATTAATTTCC CCTCGTCAAA AATAAGGTTA TCAAGTGAGA 780 AATCACCATG AGTGACGACT GAATCCGGTG AGAATGGCAA AAGTTTATGC ATTTCTTTCC 840 AGACTTGTTC AACAGGCCAG CCATTACGCT CGTCATCAAA ATCACTCGCA TCAACCAAAC 900 CGTTATTCAT TCGTGATTGC GCCTGAGCGA GACGAAATAC GCGATCGCTG TTAAAAAGGAC 960 AATTACAAAC AGGAATCGAA TGCAACCGGC GCAGGAACAC TGCCAGCGCA TCAACAATAT 1020 TTTCACCTGA ATCAGGATAT TCTTCTAATA CCTGGAATGC TGTTTTCCCG GGGATCGCAG 1080 TGGTGAGTAA CCATGCATCA TCAGGAGTAC GGATAAAATG CTTGATGGTC GGAAGGAGGCA 1140 TAAATTCCGT CAGCCAGTTT AGTCTGACCA TCTCATCTGT AACATCATTG GCAACGCTAC 1200 CTTTGCCATG TTTCAGAAAC AACTCTGGCG CATCGGGCT CCCATACAAT CGATAGATTG 1260 TCCGACCTGA TTGCCCGACA TTATCGCGAG CCCATTTATA CCCATATAAA TCAGCATCCA 1320 TGTTGGAATT TAATCGCGGC CTAGAGCAAG ACGTTTCCCG TTGAATATGG CTCATAACAC 1380 CCCTTGTATT ACTGTTTATG TAAGCAGACA GTTTTATTGT TCATGACCAA AATCCCTTAA 1440 CGTGAGTTTT CGTTCCACTG AGCGTCAGAC ČCCGTAGAAA AGATCAAAGG ATCTTCTTGA 1500 GATCCTTTT TTCTGCCGGT AATCTGCTGC TTGCAAACAA AAAAACCACC GCTACCAGCG 1560 GTGGTTTGTT TGCCGGATCA AGAGCTACCA ACTCTTTTTC CGAAGGTAC TGGCTTCAGC 1620 AGAGCGCAGA TACCAAATAC TGTCCTTCTA GTGTAGCCGT AGTTAGGCCA CCACTTCAG 1680

• · • · ······· · · • · · · ·· ·· ·· ·· · ·

230

AACTCTGTAG CACCGCCTAC ATACCTCGCT CTGCTAATCC TGTTACCAGT GGCTGCTGCC 1740 AGTGGCGATA AGTCGTGTCT TACCGGGTTG GACTCAAGAC GATAGTTACC GGATAAGGCG 1800 CAGCGGTCGG GCTGAACGGG GGGTTCGTGC ACACAGCCCA GCTTGGAGCG AACGACCTAC 1860 ACCGAACTGA GATACCTACA GCGTGAGCTA TGAGAAAGCG CCACGCTTCC CGAAGGGGAGA 1920 AAGGCGGACA GGTATCCGGT AAGCGGCAGG GTCGGAACAG GAGAGCGCAC GAGGGAGCTT 1980 CCAGGGGGAA ACGCCTGGTA TCTTTATAGT CCTGTCGGGT TTCGCCACCT CTGACTTGAG 2040 CGTCGATTTT TGTGATGCTC GTCAGGGGGG CGGAGCCTAT GGAAAAACGC CAGCAACGCG 2100 GCCTTTTTAC GGTTCCTGGC CTTTTGCTGG CCTTTTGCTC ACATGTTCTT TCCTGCGTTA 2160 TCCCCTGATT CTGTGGATAA CCGTATTACC GCCTTTGAGT GAGCTGATAC CGCTCGCCGC 2220 AGCCGAACGA CCGAGCGCAG CGAGTCAGTG AGCGAGGAAG CGGAAGAGCG CCTGATGCGG 2280 TATTTTCTCC TTACGCATCT GTGCGGTTATT TCACACCGCA TATATGGTGC ACTCTCAGTA 2340 CAATCTGCTC TGATGCCGCA TAGTTAAGCC AGTATACACT CCGCTATCGC TACGTGACTG 2400 GGTCATGGCT GCGCCCCGAC ACCCGCCAAC ACCCGCTGAC GCGCCCTGAC GGGCTTGTCT 2460 GCTCCCGGCA TCCGCTTACA GACAAGCTGT GACCGTTCCC GGGAGCTGCA TGTGTCAGAG 2520 GTTTTCACCG TCATCACCGA AACGCGCGAG GCAGCTGCGG TAAAGCTCAT CAGCGTGGTC 2580 GTGAAGCGAT TCACAGATGT CTGCCTGTTC ATCCGCGTCC AGCTCGTTGA GTTTCTCCAG 2640 AAGCGTTAAT GTCTGGCTTC TGATAAAGCG GGCCATGTTA AGGGCGGTTT TTTCCTGTTT 2700 GGTCACTGAT GCCTCCGTGT AAGGGGGATT TCTGTTCATG GGGGTAATGA TACCGATGAA 2760 ACGAGAGAGG ATGCTCACGA TACGGGTTAC TGATGATGAA CATGCCCGGT TACTGGAACG 2820 TTGTGAGGGT AAACAACTGG CGGTATGGAT GCGGCGGGAC CAGAGAAAAA TCACTCAGGG 2880 TCAATGCCAG CGCTTCGTTA ATACAGATGT AGGTGTTCCA CAGGGTAGCC AGCAGCATCC 2940 TGCGATGCAG ATCCGGAACA TAATGGTGCA GGGCGCTGAC TTCCGCGTTT CCAGACTTTA ' 3000 CGAAACACGG AAACCGAAGA CCATTCATGT TGTTGCTCAG GTCGCAGACG TTTTGCAGCA 3060 GCAGTCGCTT CACGTTCGCT CGCGTATCGG TGATTCATTC TGCTAACCAG TAAGGCAACC 3120 CCGCCAGCCT AGCCGGGTCC TCAACGACAG GAGCACGATC ATGCGCACCC GTGGGGCCGC 3180 CATGCCGGCG ATAATGGCCT GCTTCTCGCC GAAACGTTTG GTGGCGGGAC CAGTGACGAA 3240 GGCTTGAGCG AGGGCGTGCA AGATTCCGAA TACCGCAAGC GACAGGCCGA TCATCGTCGC 3300 GCTCCAGCGA AAGCGGTCCT CGCCGAAAAT GACCCAGAGC GCTGCCGGCA CCTGTCCTAC 3360

• · • · ··· · ···· · ·· ·

231 • · · • « · · · · • · · · • · · · • · • » · · GAGTTGCATG ATAAAGAAAA CAGTCATAAG TGCGGCGACG ATAGTCATGC CCCGCGCCCA 3420 CCGGAAGGAG CTGACTGGGT TGAAGGCTCT CAAGGGCATC GGTCGAGATC CCGGTGCCTA 3480 ATGAGTGAGC TAACTTACAT TAATTGCGTT GCGCTCACTG CCCGCTTTCC AGTCGGGAAA 3540 CCTGTCGTGC CAGCTGCATT AATGAATCGGG CCAACGCGCG GGGAGAGGCG GTTTGCGTAT 3600 TGGGCGCCAG GGTGGTTTTT CTTTTCACCA GTGAGACGGG CAACAGCTGA TTGCCCTTCA 3660 CCGCCTGGCC CTGAGAGAGT TGCAGCAAGC GGTCCACGCT GGTTTGCCCC AGCAGGCGAA 3720 AATCCTGTTT GATGGTGGTT AAGGCGGGGA TATAACATGA GCTGTCTTCG GTATCGT 3780 ATCCACTAC CGAGATATCC GCACCAACGC GCAGCCCGGA CTCGGTAATG GCGCGCATTG 3840 CGCCCAGCGC CATCTGATCG TTGGCAACCA GCATCGCAGT GGGAACGATG CCCTCATTCA 3900 GCATTTGCAT GGTTTGTTGA AAACCGGACA TGGCACTCCA GTCGCCTTCC CGTTCCGCTA 3960 TCGGCTGAAT TTGATTGCGA GTGAGATATT TATGCCAGCC AGCCAGACGC AGACGCGCCG 4020 AGACAGAACT TAATGGGCCC GCTAACAGCG CGATTTGCTG GTGACCCAAT GCGACCAGAT 4080 GCTCCACGCC CAGTCGCGTA CCGTCTTCAT GGGAAAAAAT AATACTGTTG ATGGGTGTCT 4140 GGTCAGAGAC ATCAAGAAAT AACGCCGGAA CATTAGTGCA GGCAGCTTCC ACAGCAATGG 4200 CATCCTGGTC ATCCAGCGGA TAGTTAATGA TCAGCCCACT GACGCGTTGC GCGAGAAGAT 4260 TGTGCACCGC CGCTTTACAG GCTTCGACGC CGCTTCGTTC TACCATCGAC ACCACCACGC 4320 TGGCACCAG TTGATCGGCG CGAGATTTAA TCGCCGCGAC AATTTGCGAC GGCGCGTGCA 4380 GGGCCAGACT GGAGGTGGGCA ACGCCAATCA GCAACGACTG TTTGCCCGCC AGTTGTTGTG 4440 CCACGCGGTT GGGAATGTAA TTCAGCTCCG CCATCGCCGC TTCCACTTTT TCCCGCGTTT 4500 TCGCAGAAAAC GTGGCTGGCC TGGTTCACCA CGCGGGAAAC GGTCTGATAA GAGACACCGG 4560 CATACTCTGC GACATCGTAT AACGTTACTG GTTTCACATT CACCACCCTG AATTGACTCT 4620 CTTCCGGGCG CTATCATGCC ATACCGCGAA AGGTTTTGCG CCATTCGATG GTGTCCGGGA 4680 TCTCGACGCT CTCCCTTATG CGACTCCTGC ATTAGGAAGC AGCCCAGTAG TAGGTTGAGG 4740 CCGTTGAGCA CCGCCGCCGC AAGGAATGGT GCATGCAAGG AGATGGCGCC CAACAGTCCC 4800 CCGGCCACGG GGCCTGCCAC CATACCCACG CCGAAACAAG CGCTCATGAG CCCGAAGTGGG 4860 CGAGCCCGAT CTTCCCCATC GGTGATGTCG GCGATATAGG CGCCAGCAAC CGCACCTGTG 4920 GCGCCGGTGA TGCCGGCCAC GATGCGTCCG GCGTAGAGGA TCGAGATCTC GATCCCGCGA 4980

• · · · ······· · · ···· ·· ·· ·· ·· ··

232

AATTAATACG ACTCACTATA GGGGAATTGT GAGCGGATAA CAATTCCCCT CTAGAAATAA 5040 TTTTGTTTAA CTTTAAGAAG GAGATATACA TATGGGCCAT CATCATCATC ATCACGTGAT 5100 CGACATCATC GGGACCAGCC CCACATCCTG GGAACAGGCG GCGGCGGAGG CGGTCCAGCG 5160 GGCGCGGGAT AGCGTCGATG ACATCCGCGT CGCTCGGGTC ATTGAGCAGG ACATGGCCGT 5220 GGACAGCGCC GGCAAGATCA CCTACCGCAT CAAGCTCGAA GTGTCGTTCA AGATGAGGCC 5280 GGCGCAACCG AGGGGCTCGA AACCACGAG CGGTTCGCCT GAAACGGGCG CCGGCGCCGG 5340 TACTGTCGCG ACTACCCCCG CGTCGTCGCC GGTGACGTTG GCGGAGACCG GTAGCACGCT 5400 GCTCTACCCG CTGTTCAACC TGTGGGGTCC GGCCTTTCAC GAGAGGTATC CGAACGTCAC 5460 GATCACCGCT CAGGGCACCG GTTCTGGTGC CGGGATCGCG CAGGCCGCCG CCGGGACGGT 5520 CAACATTGGG GCTCCCGACG CCTATCTGTC GGAAGGTGAT ATGGCCGCGC ACAAGGGGCT 5580 GATGAACATC GCGCTAGCCA TCTCCGCTCA GCAGGTCAAC TACAACCTGC CCGGAGTGAG 5640 CGAGCACCTC AAGCTGAACG GAAAAGTCCT GGCGGCCATG TACCAGGGCA CCATCAAAAC 5700 CTGGGACGAC CCGCAGATCG CTGCGCTCAA CCCCGGCGTG AACCTGCCCG GCACCGCGGT 5760 AGTTCCGCTG CACCGCTCCG ACGGGTCCGG TGACACCTTC TTGTTCACCC AGTACCTGTC 5820 CAAGCAAGAT CCCGAGGGCT GGGGCAAGTC GCCCGGCTTC GGCACCACCG TCGACTTCCC 5880 GGCGGTGCCG GGTGCGCTGG GTGAGAACGG CAACGGCGGC ATGGTGACCG GTTGCGCCGA 5940 GACACCGGGC TGCGTGGCCT ATATCGGCAT CAGCTTCCTC GACCAGGCCA GTCAACGGGG 6000 ACTCGGCGAG GCCCAACTAG GCAATAGCTC TGGCAATTTC TTGTTGCCCG ACGCGCAAAG 6060 CATTCAGGCC GCGGCGCTG GCTTCGCATC GAAAACCCCG GCGAACCAGG CGATTTCGAT 6120 GATCGACGGG CCCGCCCCGG ACGGCTACCC GATCATCAAC TACGAGTACG CCATCGTCAA 6180 CAACCGGCAA AAGGACGCCG CCACCGCGCA GACCTTGCAG GCATTTCTGC ACTGGGCGAT 6240 CACCGACGGC AACAAGGCCT CGTTCCTCGA CCAGGTTCAT TTCCAGCCGC TGCCGCCCGC 6300 GGTGGTGAAG TTGTCTGACG CGTTGATCGC GACGATTTCC AGCGCTGAGA TGAAGACGA 6360 TGCCGCTACC CTCGCGCAGG AGGCAGGTAA TTTCGAGCGG ATTCCCGGCG ACCTGAAAAAC 6420 CCAGATCGAC CAGGTGGAGT CGACGGCAGG TTCGTTGCAG GGCCAGTGGC GCGGCGCGGC •6480 GGGGACGGCC GCCCAGGCCG CGGTGGTGCG CTTCCAAGAA GCAGCCAATA AGCAGAAGCA 6540 GGAACTCGAC GAGATCTCGA CGAATATTCG TCAGGCCGGC GTCCAATACT CGAGGGCCGA 6600 CGAGGAGCAG CAGCAGGCGC TGTCTCCGCA AATGGGCTTT GTGCCCACAA CGGCCGCTC 6660

233

GCCGCCGTCG ACCGCTGCAG CGCCACCCGC ACCGGCGACA CCTGTTGCCC CCCCACCACC . 6720 GGCCGCCGCC AACACGCCGA ATGCCCAGCC GGGCGATCCC AACGCAGCAC CTCCGCCGGC 6780 CGACCCGAAC GCACCGCCGC CACCTGTCAT TGCCCCAAAC GCACCCCAAC CTGTCCGGAT 6840 CGACAACCCG GTTGGAGGAT TCAGCTTCGC GCTGCCTGCT GGCTGGGTGG AGTCTGACGC 6900 CGCCCACTTC GACTACGGTT CAGCACTCCT CAGCAAAACC ACCGGGGACC CGCATTTCC 6960 CGGACAGCCG CCGCCGGTGG CCAATGACAC CCGTATCGTG CTCGGCCGGC TAGACCAAAA 7020 GCTTTACGCC AGCGCCGAAG CCACCGACTC CAAGGCCGCG GCCCGGTTGG GCTCGGACAT 7080 GGGTGAGTTC TATATGCCCT ACCCGGGCAC CCGGATCAAC CAGGAAACCG TCTCGCTTGA 7140 CGCCAACGGG GTGTCTGGAA GCGCGTCGTA TTACGAAGTC AAGTTCAGCG ATCCGAGTAA 7200 GCCGAACGGC CAGATCTGGA CGGGCGTAAT CGGCTCGCCC GCGGCGAACG CACCGGACGC 7260 CGGGCCCCCT CAGCGCTGGT TTGTGGTATG GCTCGGGACC GCCAACAACC CGGTGGACAA 7320 GGGCGCGGCC AAGGCGCTGG CCGAATCGAT CCGGCCTTTG GTCGCCCCGC CGCCGGCGCC 7380 GGCACCGGCT CCTGCAGAGC CCGCTCCGGC GCCGGCGCCG GCCGGGGAAG TCGCTCCTAC 7440 CCCGACGACA CCGACACCGC AGCGGACCTT ACCGGCCTGA GAATTCTGCA GATATCCATC 7500 ACACTGGGG CCGCTCGAGC ACCACACCA CCACCACTGA GATCCGGCTG CTAACAAAGC 7560 CCGAAAGGAA GCTGAGTTGG CTGCTGCCAC CGCTGAGCAA TAACTAGCAT AACCCCTTGG 7620 GGCCTCTAAA CGGGTCTTGA GGGGTTTTTT GCTGAAAGGA GGAACTATAT CCGGAT 7676

(2) Sequence information of SEQ ID NO: 209:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 802 amino acids (B) TYPE: amino acid (C) TYPE OF CHAIN: single-stranded (D) TOPOLOGY: linear (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 209:

Met Gly His His His His His His Val Ile Asp Ile Ile Gly Thr Ser 1 5 10 15 For Thr Ser Suffering Gosh Gin Alas Alas Alas Gosh Alas Wall Gin Arg Alas Arg 20 25 30

1/My, 237

OK

soluble antigens

Claims (54)

PATENTOVÉ NÁR A polypeptide comprising an antigenic portion M. tuberculosis or a variant of said antigens that differ only in conservative substitutions and / or modifications, said antigen having an N-terminal sequence selected from the group consisting of: (a) Asp-Pro-Val-Asp-Ala-Val-Ile-Asn-Thr-Thr-Cys-Asn-Tyr-GlyGln-Val-Val-Ala-Ala-Leu (SEQ ID NO: 115); (b) Ala-Val-Glu-Ser-Gly-Met-Leu-Ala-Leu-Gly-Thr-Pro-Ala-ProSer (SEQ ID NO: 116); (c) Ala-Ala-Met-Lys-Pro-Arg-Thr-Gly-Asp-Gly-Pro-Leu-Glu-AlaAla-Lys-Glu-Gly-Arg (SEQ ID NO: 17); (d) Tyr-Tyr-Trp-Cys-Pro-Gly-Gln-Pro-Phe-Asp-Pro-Ala-Trp-GlyPro (SEQ ID NO: 118); (e) Asp-Ile-Gly-Ser-Glu-Ser-Thr-Glu-Asp-Gln-Gln-Xaa-Ala-Val (SEQ ID NO: 119); (f) Ala-Glu-Glu-Ser-Ile-Ser-Thr-Xaa-Glu-Xaa-Ile-Val-Pro (SEQ ID NO: 120); (g) Asp-Pro-Glu-Pro-Ala-Pro-Pro-Val-Pro-Thr-Thr-Ala-Ala-Ser-Pro-Pro-Ser (SEQ ID NO: 121); (h) Ala-Pro-Lys-Thr-Tyr-Xaa-Glu-Glu-Leu-Lys-Gly-Thr-Asp-ThrGly (SEQ ID NO: 122); (i) Asp-Pro-Ala-Ser-Ala-Asp-Val-Pro-Thr-Ala-Ala-Gln-LeuThr-Ser-Leu-Leu-Asn-Ser-Leu-Ala-Asp-Pro-Asn -Val-Ser-PheAla-Asn (SEQ ID NO: 123) and (j) Ala-Pro-Glu-Ser-Gly-Ala-Gly-Leu-Gly-Gly-Thr-Val-Gln-AlaGly (SEQ ID NO. : 131), wherein Xaa can be any amino acid. 2. A polypeptide comprising an immunogenic portion of M. tuberculosis antigens or a variant of said antigens that differs only in conservative substitutions and / or modifications; 238 wherein said antigen has an N-terminal sequence selected from the group consisting of: (a) Asp-Pro-Pro-Asp-Pro-His-Gln-Xaa-Asp-Met-Thr-Lys-Gly-TyrTyr-Pro-Gly-Gly-Arg-Arg-Xaa-Phe (SEQ ID NO: 124 ) and (b) Xaa-Tyr-Ile-Ala-Tyr-Xaa-Thr-Thr-Ala-Gly-Ile-Val-Pro-GlyLys-Ile-Asn-Val-His-Leu-Val (SEQ ID NO: 132) wherein Xaa can be any amino acid. A polypeptide comprising an antigenic portion of a soluble M. tuberculosis antigen or variant of said antigen that differs only in conservative substitutions and / or modifications, said antigen comprising an amino acid sequence encoded by a DNA sequence selected from the group consisting of the sequences set forth in SEQ ID NO: 1, 2, 4 to 10, 13 to 25, 52, 94 and 96, the complements of said sequences, and DNA sequences which hybridize to the sequences set forth in SEQ ID NOs: 1, 2, 4 to 10, 13 to 25, 52, 94 and 96 or a complement thereof under moderately stringent conditions. 4. A polypeptide comprising an antigenic portion of an M. antigen. tuberculosis or a variant of said antigen that differs only in conservative substitutions and / or modifications, said antigen comprising an amino acid sequence encoded by a DNA sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 26 to 51, 133, 134, 158- 178 and 196, the complements of said sequences and the DNA sequences which hybridize to the sequences set forth in SEQ ID NOs: 26 to 51, 133, 134, 158-178 and 196 or their complement under moderately stringent conditions. A DNA molecule comprising a nucleotide sequence encoding a polypeptide according to any one of claims 1 to 4. 239 • · • ··· 6. A recombinant expression vector comprising the DNA molecule of claim 5. 7. A host cell characterized in that it is transformed with the expression vector of claim 6. 8. The host cell of claim 7, wherein said host cell is selected from the group consisting of E. coli cells, yeast cells, and mammalian cells. 9. A method for detecting an M. tuberculosis infection in a biological sample, comprising: (a) contacting the biological sample with one or more polypeptides of any one of claims 1 to 4; and (b) detecting the presence of antibodies in the sample that bind to at least one of the polypeptides thereby detecting M. tuberculosis infection in the biological sample. 10. A method of detecting a M. tuberculosis infection in a biological sample, the method comprising: (a) contacting the biological sample with a polypeptide having an N-terminal sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 129 and 130; and (b) detecting the presence of antibodies in the sample that bind to at least one of the polypeptides thereby the biological sample detects M. tuberculosis infection. 11. A method for detecting a M. tuberculosis infection in a biological sample, comprising: (a) contacting the biological sample with one or more polypeptides encoded by a DNA sequence selected from the group consisting of SEQ ID NOs: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198, the complements and DNA sequences that hybridize to the sequence 240, as shown in SEQ ID NO: 3, 11, &lt; tb &gt; &gt;, &lt; tb &gt; 12, 135, 136, 151-155, 184-188, 194-195 and 198, and (b) detecting the presence of antibodies in the sample that bind to at least one of the polypeptides, thereby detecting M. tuberculosis infection in the biological sample. The method of any one of claims 9 to 11, wherein the step described in (a) additionally comprises contacting the biological sample with a M. tuberculosis 38 kD antigen, and the step described in (b) additionally comprising detecting the presence of antibodies in the sample that bind to M. tuberculosis 38 kD antigen. The method of any one of claims 9 to 11, wherein the polypeptide (s) are bound to a solid support. 14. The method of claim 13, wherein the solid support comprises a nitrocellulose, latex or plastic material. The method of any one of claims 9 to 11, wherein the biological sample is selected from the group consisting of whole blood, serum, plasma, saliva, cerebrospinal fluid, and urine. 16. The method of claim 15, wherein the biological sample is whole blood or serum. 17. A method for detecting a M. tuberculosis infection in a biological sample, comprising: (a) contacting the sample in a polymerase chain reaction with at least two oligonucleotide primers, wherein at least 241 • 44 • ··· (B) one of the nucleotide primers is specific for the DNA molecule of claim 5 and detects a DNA sequence in the sample that is amplified in the presence of oligonucleotide primers, thereby detecting M. tuberculosis infection. The method of claim 17, wherein at least one of the oligonucleotide primers comprises at least about ten contiguous nucleotides of the DNA molecule of claim 5. 19. A method for detecting a M. tuberculosis infection in a biological sample, comprising: (a) contacting the sample in a polymerase chain reaction with at least two oligonucleotide primers, wherein at least one of the oligonucleotide primers is specific for a DNA sequence selected from the group consisting of SEQ ID NOs: 3, 11, 12, 135, 136, 151 to 155, 184 to 184; 188, 194-195 and 198; and (b) detecting a DNA sequence in the sample that is amplified in the presence of the first and second oligonucleotide primers, thereby detecting M. tuberculosis infection. 20. The method of claim 19, wherein at least one of the oligonucleotide primers comprises at least about ten contiguous nucleotides of a DNA sequence selected from the group consisting of SEQ ID NOs: 3, 11, 12, 135, 136, 151 to 155, 184 to 188, 194 to 195 and 198. The method of claim 17 or 19, wherein the biological sample is selected from the group consisting of whole blood, sputum, serum, plasma, saliva, cerebrospinal fluid, and urine. 242 • · · ·· · φ « 22. A method of detecting a M. tuberculosis infection in a biological sample, comprising: (a) contacting the sample with one or more oligonucleotide probes specific for the DNA molecule of claim 5, and (b) detecting a DNA sequence in the sample that hybridizes to the oligonucleotide probe, thereby detecting M. tuberculosis infection. 23. The method of claim 22, wherein the probe comprises at least about 15 contiguous nucleotides of the DNA molecule of claim 5. 24. A method for detecting a M. tuberculosis infection in a biological sample, comprising: (a) contacting the sample with one or more oligonucleotide probes specific for a DNA sequence selected from the group consisting of SEQ ID NOs: 3, 11, 12, 135, 136, 151-155, 184188, 194-195 and 198; and (b) detecting the sequence DNA in a sample that hybridizes to an oligonucleotide probe to detect M. tuberculosis infection. 25. The method of claim 24, wherein the oligonucleotide probe comprises at least about 15 contiguous nucleotides of a DNA sequence selected from the group consisting of SEQ ID NOs: 3, 11, 12, 135, 136, 151-155, 184-188 , 194-195 and 198. 26. The method of claim 22 or 24, wherein the biological sample is selected from the group consisting of whole blood, sputum, serum, plasma, saliva, cerebrospinal fluid, and urine. «· · 243 27. A method of detecting a M. tuberculosis infection in a biological sample, the method comprising: (a) contacting the biological sample with a binding agent capable of binding to the polypeptide of any one of claims 1 to 4; and (b) detecting a protein or polypeptide in the sample that binds to the binding agent to detect M. tuberculosis infection. 28. A method of detecting a M. tuberculosis infection in a biological sample, comprising: (a) contacting the biological sample with a binding agent capable of binding to a polypeptide having an N-terminal sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 129 and 130; and (b) detecting the protein or polypeptide in the sample that it is capable of binding to a binding agent, thereby detecting M. tuberculosis infection in the biological sample. 29. A method of detecting a M. tuberculosis infection in a biological sample, comprising: (a) contacting the biological sample with a binding agent capable of binding to a polypeptide encoded by a DNA sequence selected from the group consisting of SEQ ID NOs: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195, and 198 and complements of said sequences and DNA sequences that hybridize to the sequence set forth in SEQ ID NOs: 3, 11, 12, 135, 136, 151155, 184-188, 194-195 and 198; and (b) detecting the protein or polypeptide in the sample which is capable of binding to a binding agent, thereby detecting M. tuberculosis infection in the biological sample. ··· 244 ··················· ·· The method of any one of claims 27 to 29, wherein the binding agent is a monoclonal antibody. The method of any one of claims 27 to 29, wherein the binding agent is a polyclonal antibody. 32. A diagnostic kit comprising: (a) one or more polypeptides of any one of claims 1 to 4; and (b) a detection reagent. 33. A diagnostic kit comprising: (a) one or more polypeptides having an N-terminal sequence selected from the group consisting of the sequences set forth in SEQ ID NOs: 129 and 130; and (b) a detection reagent. 34. A diagnostic kit comprising: (a) one or more polypeptides encoded by a DNA sequence selected from the group consisting of SEQ ID NOs: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198, the complements of said sequences and DNA sequences which hybridize to the sequence set forth in SEQ ID NOs: 3, 11, 12, 135, 136, 151155, 184-188, 194-195 and 198; and (b) a detection reagent. Kit according to any one of claims 32 to 34, characterized in that the polypeptide (s) are immobilized on a solid support. 245 • · ······························ Kit according to claim 35, characterized in that the solid support comprises nitrocellulose, latex or plastic material. Kit according to any one of claims 32 to 34, characterized in that the detection reagent comprises a reporter group associated with the binding agent. 38. The kit of claim 37, wherein the binding agent is selected from the group consisting of anti-immunoglobins, protein G, protein A, and lectins. 39. The kit of claim 37, wherein the reporter group is selected from the group consisting of radioisotopes, fluorescent groups, luminescent groups, enzymes, biotin, and dye particles. 40. A diagnostic kit comprising at least two oligonucleotide primers, wherein at least one of the oligonucleotide primers is specific for the DNA molecule of claim 5. 41. The diagnostic kit of claim 40, wherein at least one of the oligonucleotide primers comprises at least about 10 contiguous nucleotides of the DNA molecule of claim 5. 42. A diagnostic kit comprising at least two oligonucleotide primers, wherein at least one of the primers is specific for a DNA sequence selected from the group consisting of SEQ ID NOs: 3, 11, 12, 135, 136, 151-155, 184- 188, 194-195 and 198. • · • · 246 43. The diagnostic kit of claim 42, wherein at least one of the oligonucleotide primers comprises about 10 contiguous nucleotides of a DNA sequence selected from the group consisting of SEQ ID NOs: 3, 11, 12, 135, 136, 151-155, 184-188 , 194-195 and 198. 44. A diagnostic kit comprising at least one oligonucleotide probe, wherein the oligonucleotide probe is specific for the DNA molecule of claim 5. 45. The kit of claim 44, wherein the oligonucleotide probe comprises at least about 15 contiguous nucleotides of the DNA molecule of claim 5. 46. A diagnostic kit comprising at least one oligonucleotide probe that is specific for a DNA sequence selected from the group consisting of SEQ ID NOs: 3, 11, 12, 135, 136, 151-155, 184-188, 194- 195 and 198. 47. The kit of claim 46, wherein the oligonucleotide probe comprises at least about 15 contiguous nucleotides of a DNA sequence selected from the group consisting of SEQ ID NOs: 3, 11, 12, 135, 136, 151-155, 184-188, 194-195 and 198. Monoclonal antibodies that bind to a polypeptide of any one of claims 1 to 4. A polyclonal antibody that binds to a polypeptide of any one of claims 1 to 4. 247 ··································· A fusion protein comprising two or more polypeptides according to any one of claims 1 to 4. A fusion protein comprising two or more polypeptides according to any one of claims 1 to 4 and ESAT-6 (SEQ ID NO: 99). 52. A fusion protein comprising a polypeptide having an Interminal Sequence selected from the group of SEQ ID NOS: 129 and 130. A fusion protein comprising two or more polypeptides according to any one of claims 1 to 4 and a 38 kD antigen (SEQ ID NO: 150) of M. tuberculosis. 54. A diagnostic kit comprising: (a) one or more of the fusion proteins of any one of claims 50 to 53, and (b) a detection reagent.