Recombinant virus vectors encoding human papillomavirus proteins

The invention provides a recombinant virus vector for use as an immunotherapeutic or vaccine. The recombinant virus vector comprises at least one pair of nucleotide sequences heterologous to the virus and which have sufficient sequence homology that recombination between them might be expected. The pair of nucleotide sequences are arranged in the virus vector such that they are inverted with respect to each other. The virus vector is able to infect a mammalian host cell and express as polypeptide the heterologous nucleotide sequences in the host cell. For infection thought to be caused by HPV infection, the pair of nucleotide sequences encode part or all of human papillomavirus (HPV) wild-type proteins or mutant proteins immunologically cross-reactive therewith. For an immunotherapeutic or vaccine against cervical cancer, the recombinant virus vector encodes part or all of the HPV wild-type proteins HPV16E7 and HPV18E7 or mutant proteins immunologically cross-reactive therewith.

FIELD OF THE INVENTION 
This invention relates to recombinant virus vectors. In particular, it 
relates to recombinant virus vectors designed to overcome the problem of 
recombination between homologous nucleotide sequences. It also relates to 
recombinant virus vectors encoding human papillomavirus proteins; to 
immunotherapeutics and vaccines for conditions associated with HPV 
infection; to the production of a virus (e.g. vaccinia virus) engineered 
to express antigens encoded by human papillomavirus types 16 and 18 and to 
immunotherapeutics and vaccines for cervical cancer. 
BACKGROUND OF THE INVENTION 
In recent years, strong evidence has been adduced for a link between 
cervical carcinoma and infection with certain types of human 
papillomavirus (HPV), particularly with types 16, 18, 31, 33 and 35 
(Gissman et al., Cancer Cells 5,275, 1987). This is based on hybridisation 
studies which have indicated that more than 85-90% of biopsies from 
cervical tumours can be shown to contain papillomavirus DNA. HPV16 DNA is 
most commonly found (in about 60% of tumours) with HPV18 the next most 
frequent (about 20%) and the other types accounting for a further 5-10%. 
In many instances, tumour cells from the biopsies do not however, contain 
the complete genome, but rather a deleted form. The extent and location of 
the deleted information within the virus genome is variable, but a general 
feature is the retention of the part of the genome encoding the E7 protein 
(Schwarz et al., Nature 314, 111, 1985). In addition, the adjacent 
E6-encoding region is usually present. The ubiquitous presence of the 
E7-encoding region in tumour cells suggests that the protein product of 
this gene might play a role in the induction or maintenance of the 
transformed phenotype. Indeed in most cell lines established from tumour 
biopsies, expression of the E7 gene can be detected (Smotkin & Wettstein, 
PNAS, 83, 4680, 1986). Furthermore, it has been shown that the E7 gene 
product can bind to the retinoblastoma (Rb) gene product, a recognised 
"anti-oncogene" in normal human cells (Munger et al., EMBO J. 8,4099, 
1989). This strengthens the belief that E7 is directly involved in cell 
transformation. 
The presence and expression of the E7 and E6 genes in tumour cells derived 
from cervical carcinoma biopsies, suggests the possibility that these 
proteins could be potential targets for the immunological recognition of 
the tumour cells. It is well known that viral proteins produced inside 
mammalian cells can be processed through a host cell pathway to short 
peptides, which then form a complex with host Major Histocompatibility 
Complex (MHC) Class 1 molecules and are transported to the cell surface. 
These complexes may then present a target for recognition by the host 
immune system. Interaction of the complex with the receptor molecule on 
the surface of cytotoxic T cells (the T cell receptor) can then lead to 
activation of the T cells to proliferate or to destroy the recognised 
cell. It is possible, therefore, that the presence in the body of a 
population of cytotoxic T lymphocytes (CTLs) which are capable of 
recognising cells expressing the HPV E6 and/or E7 proteins could afford 
protection against the development and proliferation of cervical tumours. 
Indeed it has been reported that normally oncogenic mouse cells engineered 
to express the HPV E7 protein are unable to form tumours in mice which 
have been previously immunised with non-tumorigenic E7-expressing cells, 
and that this rejection is mediated by CD8+lymphocytes (CTLs) (Chen et 
al., PNAS 88, 110, 1991). Further, the generation of an active population 
of such cells subsequent to tumour initiation could result in regression 
of the tumour. 
There are numerous reports on the construction of recombinant viruses e.g. 
vaccinia viruses containing, and expressing foreign genes (Mackett & 
Smith, J. gen. Virol. 67,2067, 1986), and several reports of the use of 
these recombinant viruses to generate effective immune responses against 
the expressed foreign antigens. A particular advantage of this route for 
delivery of antigens for vaccination is that it may lead to the 
development of cellular as well as humoral immunity. This is because the 
foreign proteins will be produced inside cells of the infected individual 
in a manner similar to that which occurs during natural infection. This 
means that they should be processed through the correct pathway to allow 
generation of a CTL response. In several cases, it has been demonstrated 
directly that immunisation with the recombinant virus is capable of 
producing a cellular immune response in the form of foreign 
antigen-specific CTLs (Moss & Flexner, Ann. Rev. Immunol., 5,305, 1987). 
Furthermore, vaccination of animals with recombinant vaccinia viruses 
expressing certain tumour-specific antigens, such as the human 
melanoma-associated antigen P97 (Estin et al., PNAS, 85, 1052, 1988), the 
bovine papillomavirus E7 protein (Meneguzzi et al., Vaccine, 8, 199, 1990) 
and the human breast cancer-associated antigen ETA (Hareuveni et al., 
PNAS, 87, 9498, 1990) has been demonstrated to result in the induction of 
immunity against tumour initiation and progression. 
SUMMARY OF THE INVENTION 
The present applicants have recognised the desirability of producing a 
recombinant virus vector which is useful as an immunotherapeutic or 
vaccine for conditions caused by HPV infection, for example for cervical 
cancer. With respect to cervical cancer, the art at the time of the 
applicants making the present invention recognised the E7 gene as having 
the potential to immortalise cells. Therefore, it would be felt 
inappropriate to incorporate the E7 gene in an immunotherapeutic. The 
applicants however, have recognized the surprising usefulness of including 
the E7 gene in an immunotherapeutic. They have also recognized that the 
beneficial effects to be gained by treatment with an immunotherapeutic 
comprising the E7 gene are likely to outweigh by far any risk associated 
with the oncogenic activity of the E7 gene. Thus, an aspect of the 
applicants invention involves the use of a recombinant virus vector which 
expresses an E7 gene, as an immunotherapeutic or vaccine. Furthermore, the 
applicants provide embodiments of their invention in which these risks are 
reduced still further by specific alteration of the gene sequences in 
order to reduce the oncogenic potential of the E7 gene without 
compromising its ability to stimulate an appropriate immune response. 
The present applicants have also recognized that where a number of HPV 
proteins which may be encoded by different HPV strains are implicated as 
being associated with a particular HPV-associated condition (for example, 
cervical carcinoma, HPV16 and HPV18; genital warts, condyloma acuminata, 
respiratory papillomatosis, HPV6 and HPV11; squamous cell carcinoma in 
immunosuppressed individuals, HPV5 and HPV8), rather than produce a 
plurality of recombinant viruses engineered separately to express each of 
the implicated proteins, it would be advantageous to produce a single 
virus recombinant which is able to express part or all of the sequences of 
more than one of the proteins. Thus, with respect to cervical cancer, 
rather than produce four recombinant viruses engineered separately to 
express each of the potential targets for immunological recognition of 
cervical tumour cells i.e. the HPV16 E6, HPV16 E7, HPV18 E6 and HPV18 E7 
proteins, it would be especially advantageous to produce a single virus 
recombinant which is able to express the part or all of the sequences of 
more than one of the proteins, preferably at least two of the proteins and 
most preferably all four proteins. That the present applicants are able to 
achieve this is particularly surprising. This is because, the coding 
sequences for many HPV proteins are highly homologous to other equivalent 
HPV proteins (for example from other virus strains). Thus, the HPV16 E6 
and HPV18 E6 proteins show overall homology of 62% and comprise regions of 
very high homology. The same is true for HPV16 E7 and HPV18 E7 which show 
overall homology of 57%, with particular regions of very high homology. 
This means that one would expect recombination to create problems such as 
loss of gene sequences. The applicants have, however, devised a novel 
strategy designed to minimise the likelihood of such recombination events 
and to circumvent the deleterious effect of those events should they 
indeed arise. Thus, surprisingly, the invention provides recombinant virus 
vectors which comprise at least one pair of nucleotide sequences which 
have sufficient sequence homology that recombination between them might be 
expected. The at least one pair of nucleotide sequences may encode part or 
all of human papillomavirus (HPV) wild-type proteins or mutant proteins 
immunologically cross-reactive therewith. In particular, the invention 
provides a recombinant vector which can maintain stably, and express, part 
or all of four of the desired gene sequences from HPV16 and HPV18. 
Thus, the present invention provides a recombinant virus vector for use as 
an immunotherapeutic or vaccine which comprises at least one pair of 
nucleotide sequences heterologous to said virus and which have sufficient 
sequence homology that recombination between them might be expected 
wherein said pair of nucleotide sequences are arranged in said virus 
vector such that they are inverted with respect to each other to reduce 
the likelihood of recombination events leading to loss of part or all of 
said sequence and said virus vector is able to infect a mammalian host 
cell and express as polypeptide the heterologous nucleotide sequences in 
said host cell. 
BRIEF DESCRIPTION OF THE DRAWINGS

The at least one pair of nucleotide sequences may encode part or all of 
human papillomavirus (HPV) wild-type proteins or mutant proteins 
immunologically cross-reactive therewith. The pair of nucleotide sequences 
may encode part or all of the protein E7 from both HPV16 and HPV18 or 
functional equivalents thereof. The pair of nucleotide sequences may 
encode part or all of the proteins E6 from both HPV16 and HPV18 or 
functional equivalents thereof. 
The recombinant virus vector may comprise a further pair of nucleotide 
sequences heterologous to said virus and which (i) have sufficient 
sequence homology that recombination between them might be expected 
wherein said further pair of nucleotide sequences are arranged in said 
virus vector such that they are inverted with respect to each other and 
said virus vector is able to infect a mammalian host cell and express as 
polypeptide the further pair of heterologous nucleotide sequences in said 
host cell. 
The further pair of nucleotide sequences may encode part or all of HPV 
wild-type proteins or mutant proteins immunologically cross-reactive 
therewith. 
For example, the present invention also provides a recombinant virus vector 
which in addition to the E7 coding sequences, also comprises and is 
adapted to express genetic sequences encoding part or all of the protein 
E6 from both HPV16 and HPV18 or functional equivalents thereof. The 
genetic sequences may comprise sequences encoding HPV16 E6/E7 and HPV18 
E6/E7 as shown in FIGS. 1(a) (SEQ ID NOS:7-10) and 1(b) (SEQ ID NOS:11-14) 
respectively. 
The genetic sequences may encode an antigenic moiety of the said proteins. 
Either or both of the nucleotide sequences in a pair of nucleotide 
sequences may be altered to make them less homologous than an equivalent 
pair of nucleotide sequences encoding wild-type HPV proteins. The 
alteration in nucleotide sequence may be in an area of high sequence 
homology Preferably, the alteration in nucleotide sequence will not result 
in an alteration of the encoded amino acid sequence. 
Two or more nucleotide sequences each encoding separate proteins may be 
fused together to form a single open reading frame. Thus the genetic 
sequences encoding part or all of the proteins E6 and E7 from HPV16, may 
be fused together to form a single open reading frame. The genetic 
sequences encoding part or all of the proteins E6 and E7 from HPV18, may 
be fused together to form a single open reading frame. The genetic 
sequences encoding part or all of the proteins E6 and E7 from both HPV16 
and HPV18, may be fused together to form a single open reading frame. 
Thus, the recombinant virus vector may have the pairs of nucleotide 
sequences arranged according to any one of the options shown in FIG. 26. 
Where the recombinant virus vector comprises an open reading frame having 
a fused genetic sequence encoding part or all of the proteins E6 and E7 
from HPV16, and a separate open reading frame having fused genetic 
sequences encoding part or all of the proteins E6 and E7 from HPV18, the 
two open reading frames may be inverted with respect to one another. For 
example, the two open reading frames may be arranged in the recombinant 
virus vector adjacent to each other. The inversion may be such that the E6 
coding sequences of HPV16 and HPV18 are both located between the E7 coding 
sequences of HPV16 and HPV18. Alternatively, the inversion could be such 
that the E7 coding sequences of HPV16 and HPV18 are both located between 
the E6 coding sequences of HPV16 and HPV18. In particular the two open 
reading frames, each with its respective promoter, may be arranged next to 
each other in the recombinant vector. In this case the promoters may be 
located between the genes, which are transcribed outwardly, or the 
promoters may be located outside the genes, which are transcribed 
inwardly. 
Similarly, the genetic sequences encoding part or all of the E7 protein 
from HPV16 and the E7 protein from HPV18 may be fused together to form a 
single open reading frame. The genetic sequences encoding part or all of 
the E6 protein from HPV16 and the E6 protein from HPV18 may be fused 
together to form a single open reading frame. This leads to another range 
of arrangements similar to those shown in FIG. 26. The fusions may be via 
a single codon encoding a relatively small neutral amino acid e.g. 
glycine. 
Thus the present invention also provides a recombinant virus vector which 
comprises a first open reading frame having a fuse genetic sequence 
encoding part or all of the wild-type proteins E6 and E7 from HPV16; and a 
separate second open reading frame having a fused genetic sequence 
encoding part or all of the wild-type proteins E6 and E7 from HPV18; 
wherein the first and second open reading frames may be inverted with 
respect to one another whereby either: i) the E6 coding sequences of HPV16 
and HPV18 are both located between the E7 coding sequences of HPV16 and 
HPV18; or ii) the E7 coding sequences of HPV16 and HPV18 are both located 
between the E6 coding sequences of HPV16 and HPV18; and wherein any of 
said wild-type proteins may be replaced by a mutant protein 
immunologically cross-reactive therewith. 
Each of the first and second open reading frames may have a corresponding 
promoter and the two open reading frames each with its promoter, are 
arranged next to each other in the virus. 
The present invention also provides a recombinant virus vector wherein 
either: i) the promoters are located between the first and second reading 
frames whereby the open reading frames are transcribed outwardly; or ii) 
the promoters are located outside the first and second open reading frames 
whereby the open reading frames are transcribed inwardly. 
The present invention also provides a recombinant virus vector which 
comprises a first open reading frame having a fused genetic sequence 
encoding part or all of the wild-type proteins E6 and E7 from HPV16; and a 
separate second open reading frame having a fused genetic sequence 
encoding part or all of the wild-type proteins E6 and E7 from HPV18; 
wherein the E6 coding sequences of HPV16 and HPV18 are both located 
between the E7 coding sequences of HPV16 and HPV18; and each open reading 
frame has a corresponding promoter, the promoters being located between 
the first and second open reading frames whereby the open reading frames 
are transcribed outwardly; and wherein any of said wild-type proteins may 
be replaced by a mutant protein immunologically cross-reactive therewith. 
The wild-type proteins HPV16E7 and HPV18E7 may be replaced with mutant 
proteins which are substantially homologous to said wild-type proteins and 
in which the residues cys 24 and glu 26 of wild-type protein HPV16E7 and 
the residues cys 27 and glu 29 of wild-type protein HPV18E7 are replaced 
with glycine residues. 
The recombinant virus vector may be derivable from vaccinia virus. 
The applicants have also recognized that for effective function as an 
immunotherapeutic, it is desirable for the recombinant virus to retain its 
ability to replicate and thereby generate an active infection in order 
that a cellular immune response may be mounted against the virus-encoded 
proteins. Thus, the applicants propose that the foreign gene sequences 
should be inserted into the vector virus at sites, the disruption of which 
by the insertion of the heterologous gene sequences will not substantially 
interfere with, and therefore have a substantially adverse affect on any 
viral functions which relate to the replicative ability of the virus in 
the infected host animal. The applicants have named these sites `neutral 
sites` (although the term `neutral` should not be interpreted strictly as 
it is acknowledged that the disruption of these sites may have a small, 
but relatively speaking inconsequential adverse affect on replicative 
ability). 
DNA sequences which affect virus replication can fall into several 
categories: 
i) protein coding sequences; 
ii) elements involved in control of gene expression; 
and 
iii) elements involved in virus DNA replication A non-essential and neutral 
insertion site must therefore avoid such regions, and, such sites have 
been identified on the basis of nucleotide sequencing studies. Thus the 
genetic sequences may be inserted into neutral sites within the virus 
genome. One or more genetic sequences may be inserted into the same 
neutral site. 
Neutral sites can be easily tested for according to techniques well known 
in the art. For example, a site may be selected, interrupted or deleted 
using standard methodologies and the resultant recombinant virus placed in 
conditions which normally support growth of the wild type virus vector, to 
assess the effect of the manipulations. The pathogenicity of the virus may 
be further compared with that of the unmodified virus vector strain in 
animal models, in order to assess its level of attenuation. 
In the present invention, the virus vector may be vaccinia virus. The 
vaccinia virus may be attenuated or disabled so that it is unable to fully 
replicate and establish an extensive infection of host cells. 
Vaccinia virus has been used extensively in the past for vaccination 
against smallpox, and its use worldwide has led to the complete 
eradication of the disease (Bhebehami, Microbiol. Rev., 47, 455, 1983). 
During the World Health Organisation (WHO) campaign to eradicate smallpox, 
several different strains of vaccinia virus were used as vaccines. In 1984 
a meeting was sponsored by the WHO to discuss the use of vaccinia virus as 
live virus vectors (Bulletin of the WHO 63(3): 471-477). The data in this 
report indicates that the number of complications associated with 
vaccination was lowest for the Wyeth strain of vaccinia virus, and so this 
strain has been chosen as a basis for the construction of the recombinant 
virus according to an embodiment of the present invention. 
It is well known that insertion of foreign DNA into the genome of vaccinia 
virus at certain favoured sites, such as the thymidine kinase gene locus, 
can reduce dramatically the ability of the virus to replicate in vivo. As 
discussed above, the aim of the therapeutic approach described here is to 
generate an active in vivo infection, so that a cellular immune response 
may be mounted against the virus encoded proteins. The present invention 
provides a method for inserting foreign genes at neutral sites within the 
genome of a virus, the disruption of which sites by the insertion will not 
interfere with and therefore have a substantially adverse affect on virus 
replication. 
Where the virus is vaccinia virus, the neutral site may be identified 
herein within the Wyeth strain of vaccinia virus on the basis of the 
related WR strain nucleotide sequence. Alternatively, where other vaccinia 
virus strains are used, sites equivalent to those sites identified above 
may be used. The neutral sites may be any as identified hereinafter as A 
(SEQ ID NO:03), B (SEQ ID NO:04), C (SEQ ID NOS:05), and D (SEQ ID NO:06), 
or a functional equivalent. 
For successful expression of foreign proteins by the recombinant virus 
vector the foreign genes must be placed under the control of a promoter 
sequence which is operable by the virus. Thus the recombinant virus vector 
may comprise a single promoter which controls the expression of all the 
heterologous genetic sequences within a single open reading frame. 
Alternatively, where the recombinant virus vector encodes more than one 
open reading frame containing heterologous genetic sequences, the virus 
may comprise a first promoter which controls the expression of the genetic 
sequences from a first open reading frame, and one or more further 
promoters which control the expression of the genetic sequences from one 
or more further open reading frames. The promoter sequence may be 
virus--specific and several have been characterised so far (Davison & 
Moss, J. Mol. Biol., 210, 749, 1989; Davison & Moss, J. Mol. Biol., 210, 
771, 1989). The single promoter and the first and one or more further 
promoters may be the p 7.5 promoter. There have been reports that the 
induction of foreign antigen-specific CTLs requires expression of the 
antigen early in the virus replication cycle (Coupar et al., Eur. J. 
Immunol., 16, 1479, 1986). Therefore, a recombinant virus as provided by 
the present invention may involve the use of the p7.5 promoter (Venkatesan 
et al., Cell, 125, 805, 1981) and/or the H6 promoter (Rosel et al., J. 
Virol, 60, 436, 1988), both of which are active both early and late in 
infection. 
As mentioned earlier, it has been reported that the E7 gene on its own has 
the potential to immortalise cells (Phelps et al., Cell 53, 539, 1988). In 
an embodiment of the present invention, the strategy for expression of the 
protein involves production of E7 as a fusion protein with E6, which is 
unlikely to retain biological function. Embodiments of the invention 
provide for reducing this risk still further, by making changes within the 
E7 gene which are known to destroy its oncogenic capacity (Chesters et 
al., J. Gen Virol. 71, 449. 1990). Thus in the recombinant virus vectors 
of the present invention, the genetic sequences encoding part or all of 
the E7 proteins may be altered from the equivalent wild type sequences, in 
order to render the sequences, used in the recombinant virus vectors less 
oncogenic than their equivalent wild type sequences. 
The present invention also provides pharmaceuticals comprising recombinant 
virus vectors as herein defined. The pharmaceutical may be for use against 
a condition caused by HPV infection which comprises an 
immunotherapeutically effective amount of a recombinant virus vector. The 
pharmaceutical may be for use against cervical cancer. 
The pharmaceutical may be a vaccine to immunise against a condition caused 
by HPV infection which comprises an amount of recombinant virus vector as 
herein provided which when administered to a recipient can specifically 
activate cells of the immune system to HPV proteins. The vaccine may be 
for immunisation against cervical cancer. 
The pharmaceuticals may comprise one or more excipients. The present 
invention also provides methods of using the recombinant virus vectors as 
herein defined to make medicaments for use as immunotherapeutics or 
vaccines against conditions thought to be caused by HPV infection. For 
example for the prophylaxis and treatment of cervical cancer. 
The present invention also provides methods of treating mammalian patients 
with recombinant virus vectors and pharmaceuticals as herein provided. 
The present invention also provides a method of determining a neutral site 
in a virus vector, the disruption of which by the insertion of 
heterologous gene sequences will not interfere with, and therefore, have a 
substantially adverse affect on viral function which relates to the 
replicative ability of the virus. The method for this determination 
comprises: (a) analysing a viral genome to identify open reading frames 
which are likely to encode functional genes, by looking for expected codon 
usage between spaced apart start and stop codons; and (b) selecting sites 
which are not in such open reading frames, likely to encode functional 
genes, as identified in (a) This may include selecting sites between open 
reading frames for sequences of functional genes and selecting sites which 
are in open reading frames which have some functional gene 
characteristics, such as an expected codon usage, but have lost other 
essential characteristics such as a start codon. The method may also 
comprise interrupting or deleting the selected sites from the viral genome 
and placing the resultant virus in conditions which normally support 
growth of the wild type virus. 
The present invention also provides neutral sites identified by use of the 
above methods. 
The present invention provides an embodiment which shows a way of inducing 
a cellular immune response against the papillomavirus proteins usually 
expressed in cervical tumour cells by the creation of a recombinant 
vaccinia virus, which has been engineered to produce the HPV E6 and E7 
proteins, or proteins containing HPV E6 and E7 sequences, during its 
replication cycle. This therapeutic vaccinia virus contains the E6 and E7 
genes from both HPV16 and HPV18, the viruses most commonly associated with 
cervical carcinoma. Vaccination with this single virus may thus stimulate 
immunity to the E6 and E7 proteins of the HPV types associated with more 
than 80% of cervical tumours. Expression of all four gene sequences (e.g. 
HPV16 E6 and E7; HPV18 E6 and E7) in a single virus however presents a 
problem, because of the likelihood of loss of genetic sequences through 
recombination. The present invention provides a method for circumventing 
this difficulty, firstly through specific sequence alteration, in order to 
reduce sequence homology and secondly through their insertion into the 
vaccinia virus genome in such a way that if such recombination were to 
occur, it would not lead to loss of sequences (i.e. in inverted 
orientation with respect to each other). Expression of the desired four 
gene sequences in the vaccinia virus genome could also be difficult 
(though not impossible) to achieve as independent expression units, and so 
the invention provides that instead, the E6 and E7 open reading frames may 
be fused together. A problem with standard methods for insertion of 
foreign information into the vaccinia virus genome is that the use of 
selectable markers to increase the efficiency of recombination results in 
the ultimate presence in the recombinant virus also of the selectable 
marker gene itself. Methods for insertion have been developed however, 
which allow subsequent elimination of these extraneous sequences (Falkner 
& Moss J. Virol., 64, 3108, 1990) and these are used in an embodiment of 
the present invention to ensure that the final recombinant vaccinia virus 
has only those additional sequences which are necessary for its required 
function. 
All cloning procedures are carried out according to the protocols described 
in "Molecular Cloning", A Laboratory Manual, eds. Sambrook, Fritsch and 
Maniatis, Cold Spring Harbor Laboratory Press, 1989. All plasmids on which 
site directed mutagenesis is performed are of the "phagemid" type, which 
may be converted to single-stranded DNA by superinfection with the 
bacteriophage fl. Preparation and site directed mutagenesis of 
single-stranded DNA, is carried out as described by Brierley et al., Cell, 
57, 537, 1989. The sequence of all the synthetic oligonucleotides used are 
provided in FIG. 18. 
Preparation of the E6 and E7 genes from HPV16 and HPV18 for insertion into 
vaccinia virus Cloning of the HPV16 and HPV18 E6 and E7 
A fragment of DNA containing the HPV16 E6/7 coding region is prepared by 
polymerase chain reaction (PCR) amplification from the plasmid 
pBR322/HPV16 (Durst et al., PNAS, 80, 3812, 1983) using the 
oligonucleotides SO5 and SO6. A fragment containing the same region from 
HPV18 is prepared by the same procedure from plasmid pBR322/HPV16 (Boshart 
et al., EMBO J. 3,1151) using the oligonucleotides SO1 and S02. Plasmids 
pBR322/HPV16 and pBR322/HPV18 are both available from Behringwerke AG, 
P.O. Box 1140 D-3550, Marburg, Germany (alternatively the necessary 
sequences can be created synthetically from the sequence information 
provided by the present application). 
In each case, this produces a DNA fragment of about 800 base pairs (bp) 
with a site for the restriction enzyme Nco 1 (CCATGG) located exactly at 
the beginning of the E6 gene, and a Smal site immediately downstream of 
the termination codon for the E7 gene (FIGS. 1(a) and (b)). The products 
are then digested with Ncol and Smal , and cloned into Ncol-Smal digested 
plasmid pUC118NS (a modified version of the "phagemid" pUC118 (Viera & 
Messing, Methods Enzymol., 153,3, 1987) in which Ncol and Smal sites have 
been created by site-directed mutagenesis within the poly-linker region) 
to generate the plasmid p1MS7, containing the HPV16 sequences, and pIMS8 
containing the HPV18 sequences (FIG. 2). The use of pUC118 is not crucial 
to the present strategy as any plasmid which can be manipulated by site 
directed mutagenesis can be successfully used. 
Fusion of the E6 and E7ORFs 
For insertion into vaccinia virus, the E6 and E7 genes from each HPV type, 
are first fused together to form a single continuous ORF. This is achieved 
by site-directed mutagenesis as follows: 
(i) The termination codon TAA of HPV16 E6 in pIMS7 is altered using the 
oligonucleotide S20 to the sequence GGAA. This is in order to convert the 
normally separate ORFs for HPV16 E6 and E7 into a single ORF 
(pIMS7.1--FIG. 2). 
(ii) The termination codon TAA of HPV18 E6 in pIMS8 is altered using the 
oligonucleotide S21 to the sequence GGAA. This is in order to convert the 
normally separate ORFs for HPV18 E6 and E7 into a single ORF 
(pIMS8.1--FIG. 2). 5 
Abolition of the immortalising potential of E7 
In order to destroy the immortalising properties of each of the E7 
proteins, two key codons within the HPV16 E7 coding sequence, (cys24 and 
glu26 --FIG. 1(a)) and the equivalent codons from HPV18 E7 (cys27 and 
glu29--FIG. 1(b)), are altered to glycine residues by site directed 
mutagenesis as follows. 
(i) The sequence of the E7 gene is altered in pIMS7 to encode glycine at 
codons 24 and 26 (normally encoding cysteine and glutamate respectively, 
using oligonucleotide S22 (pIMS7.2--FIG. 2). 
(ii) The sequence of the E7 gene is altered in pIMS8 to encode glycine at 
codons 27 and 29 (normally encoding cysteine and glutamate respectively, 
using oligonucleotide S23 (pIMS8.1B --FIG. 2). 
Reduction in intertypic recombination potential of HPV16 and HPV18 E6 and 
E7 sequence and elimination of potential vaccinia virus transcription 
termination signal 
A potential difficulty with the presence of both HPV16 and HPV18 E6 and E7 
specific DNA within the genome of a single virus, is that recombination 
between the two sets of related sequences could lead to loss or 
rearrangement of information such that expression of the required proteins 
is disrupted. The invention provides ways of minimising this risk. 
Firstly, by inserting the two sets of genetic information in the vaccinia 
genome in opposite orientation to each other (so that recombination will 
result not in the loss of sequence information, but rather in its 
inversion). Secondly, by creating specific changes in the E6/7 sequence of 
one of the HPV virus strains at sites where the homology is greatest. 
These changes however are made in such a way that the amino acid coding 
potential of the genes remains unaltered. 
The HPV18 E6 sequences is therefore altered by site-directed mutagenesis as 
follows: 
The sequence TTTTTATTCTAGAATTAGAG (SEQ ID NO:01) (which begins 210 
nucleotides from the start of E6--underlined in FIG. 1(b)) is mutated, 
using oligonucleotide S24 to the sequence TTTCTACAGTAGAATCAGAG (SEQ ID 
NO:02)(pIMS8.2--FIG. 2) (changed nucleotides are in bold type). 
A second aim of this change is to eliminate from the HPV18 E6 sequence, the 
sequence TTTTTAT, which is a potential termination signal for the early 
vaccinia virus transcription enzyme (Rohrmann et al., Cell., 46, 1029, 
1986). 
Source and propagation of vaccinia virus 
The Wyeth strain of vaccinia virus is used for construction of the 
therapeutic virus. It is propagated in Vero cells for the purposes of 
genetic manipulation, and in the human diploid fibroblast cell line MRC5 
for the production of the final therapeutic virus stock. Both cell lines 
are obtained from the National Institute of Biological Standards and 
Control, South Mims, U.K. The Wyeth strain of vaccinia virus, Vero cells 
and the cell line MRC5 are also available from the American Type Culture 
Collection, 12301 Parklawn Drive, Rockville, Md. 20852, U.S.A. 
Identification and of neutral sites from the vaccinia virus Description of 
neutral sites 
For the purpose of insertion of papillomavirus genes within the vaccinia 
virus genome, sites have been chosen to have two characteristics. 
Firstly, they should be non-essential regions, i.e. insertion of foreign 
genes at these points, will not disrupt any functions of the vaccinia 
virus to the extent that the virus can no longer grow in tissue culture. 
Secondly, they should be neutral sites, i.e. insertion of foreign genes all 
these points, will not increase or decrease the level of attenuation of 
the vaccinia virus. 
The difference between these two factors can be seen by looking at the 
thymidine kinase (TK) gene of vaccinia virus. It is a non-essential 
region, and hence viruses with genes inserted in the TK gene can grow well 
in tissue culture (Mackett at al., J. Virol., 49, 857, 1984). However, 
such viruses have been found to be greatly attenuated in vivo (Buller et 
al., Nature 317, 813, 1985). For the purpose of prophylactic vaccination, 
such increased attenuation might be desirable. However, for an 
immunotherapeutic strategy where the danger from the disease to be treated 
clearly outweighs the risk of vaccine associated complications, use of an 
attenuated virus is considered undesirable since it could compromise the 
immunological response to the papillomavirus antigens. Hence, the 
applicants have identified sites which they judge will not attenuate the 
virus any further, and have termed them `neutral sites`. Such sites have 
been identified within the virus genome by careful analysis of the DNA 
sequence of the WR strain. The WR strain was originally derived from the 
Wyeth strain by passage in mouse brain. Therefore the two strains are 
closely related. The nucleotide sequence of three regions of the WR genome 
which contain the selected neutral sites are shown in FIGS. 19, 20 and 21. 
Four neutral sites (A-D) have been chosen on the above discussed criteria 
as follows: 
Site A: gap between SalF17R and SalF19R 
Site B: gap between SalF19R and SalF20.5R 
Site C: in SalG2R, a potential non-functional gene Site D: in HindB3.5R, a 
potential non-functional gene 
These sites (A-D) can be identified by the following stretches of DNA 
sequence, each of which is 40 nucleotides in length. 
A CTATCTACCAGATTATTATGTGTTATAAGGTACTTTTTCT (SEQ ID NO:03) 
B TATTGTGCTACTGATTCTTCACAGACTGAAGATTGTTGAA (SEQ ID NO:04) 
C TCTCTTAAAATGGTTGAGACCAAGCTTCGTTGTAGAAACA (SEQ ID NO:05) 
D TGAGGCTACCTCGACATACGTGTGCGCTATCAAAGTGGAA (SEQ ID NO:06) 
In other strains these sequences may vary, while still having substantial 
homology with those given above. In particular a site may have at least 
90%, more preferably 95%, homology with the sequence given above. 
FIGS. 3-5 show the distribution of initiation codons and open reading 
frames (ORFs) in the regions of the vaccinia virus genome shown in FIGS. 
19, 20 and 21. 
FIGS. 6-8 show the same regions with a plot showing to what extent each 
reading frame conforms to the pattern of codon usage expected for vaccinia 
genes. A graph of codon usage is plotted for each of the three possible 
reading frames in each direction (Staden, R., Nucl. Acids Res., 12, 521, 
1984; Staden, R., Nucl. Acids Res., 12, 551, 1984). In these codon usage 
plots, the short vertical bar lines extending from the horizontal axes 
represent start codons. The longer vertical bar lines placed above the 
horizontal axes represent stop codons. This sort of plot is a useful way 
of helping to determine whether a particular ORF is a genuine vaccinia 
gene. Where there is a likely genuine gene, the graph of codon usage will 
rise between a start codon and a stop codon. For example, in FIG. 7, it 
can be seen that the graph of codon usage rises over the region of the 
SalG2R ORF (the dotted line shows that this frame conforms most of the 
expected codon usage). For the other two frames the graphs show that they 
do not conform to vaccinia codon usage. The peak labelled `part of gk`, 
and marked with a dashed line, also conforms well to vaccinia codon usage. 
In summary, a genuine gene must start with an initiation (start) codon, 
end with a termination (stop) codon, and should conform well to vaccinia 
codon usage along its length. In most cases the conformation to the 
vaccinia codon usage drops off sharply outside the gene. The neutral sites 
are further described as follows 
Site A. Gap between SalF17R and SalF19R 
Site A is marked on FIGS. 3 and 6. FIG. 9 (SEQ ID NO:15-17) shows the 
actual DNA sequence with a translation of the ORFs on either side of the 
site. It can be seen that Site A is placed in an intergenic region between 
SalF17R and SalF19R. It is placed some 195 bases upstream of SalF19R to 
avoid any promoter elements associated with that gene. The sequence 
TTTTTCT (shown in italics) will act as a terminator of early RNA 
transcription for the SalF17R gene if it is an early gene. However, the 
site is placed downstream of the first of these, so it will not affect 
early termination of transcription if it occurs. Examination of FIG. 6 
shows that there is no recognisable gene on the opposite strand at this 
point, and hence this sequence location is suitable as a neutral insertion 
site. 
Site B. Gap between SalF19R and SalF20.5R 
Site B is marked on FIGS. 3 and 6. FIG. 10 (SEQ ID NOS:18-20)shows the 
actual DNA sequence with a translation of the ORFs on either side of the 
site. It can be seen that Site B is placed in an intergenic region between 
SalF19R and SalF20.5R. FIG. 6 shows that it is within a region of high 
vaccinia codon usage, but that this region does not form a genuine gene, 
having no initiation codon. In addition, FIG. 6 suggests that Sal20.5R is 
not a complete gene, as the conformation to vaccinia codon usage drops off 
dramatically at the start of the gene. In the event that SalF20.5R is a 
genuine gene, Site B is placed some 70 bases upstream of SalF20.5R which 
may well avoid any promoter elements associated with that gene. (Note: 
many vaccinia promoter elements are located in approximately 35 bases 
upstream of the start of the gene.) In addition SalF20R has no TTTTTNT 
(N=any nucleotide) transcription termination signal with which Site B 
could interfere. Hence this sequence location is suitable as a neutral 
insertion site. 
Site C. Within SalG2R, a potential non-functional gene 
Site C is marked on FIG. 4. The ORF SalG2R has considerable similarity to 
the guanylate kinase (GK) gene of yeast. This similarity is shown in FIG. 
11. Sequence upstream of the SalG2R ORF (but in a different frame) has 
been added on to SalG2R, to see if the match to GK extends beyond the 
boundaries of the original open reading frame. The match appears to extend 
beyond the 5' and of the SalG2R 0RF. In particular, an important site in 
the yeast GK gene, the ATP/GTP binding site (shown underlined) only 
matches in the out of frame sequence upstream of the SalG2R ORF. Hence, it 
is very likely that the SalG2R gene is not active as a guanylate kinase 
and can be referred to as a `pseudogene`. If the gene is inactive as the 
applicants deduce, then it will serve as a neutral insertion site. 
Site D. Within HindB3.5R, a potential non-functional gene 
FIG. 5 shows that site D lies within the region designated HindB3.5R. This 
region, although conforming to vaccinia codon usage, has no start codon 
and is therefore not a genuine gene. The codon usage plot shown in FIG. 8 
indicates that it probably was once a functional gene, and may well have 
been attached to HindB3R (a shift in the codon usage preference occurs 
here well away from the termination codon of the HindB3R ORF which 
suggests that the last section of HindB3R is not properly part of this 
gene.) Hence it is likely that HindB3.5R is not active as a gene and can 
be used as a neutral insertion site. FIG. 12 (SEQ ID NOS:23-25) shows the 
actual DNA sequence with a translation of the ORFs on either side of the 
site. It can be seen that site D is placed in an intergenic region between 
HindB3R and HindB4R as well as being within the non-functional HindB3.5R. 
Preparation of vector for cloning of neutral sites 
In order to insert foreign genetic information into the neutral sites 
described above, DNA copies of the neutral sites, together with an 
appropriate amount of flanking DNA from the vaccinia genome (approximately 
500 bases on either side) must first be cloned into a plasmid vector. 
These plasmids may then be used to introduce the foreign DNA into the 
vaccinia virus genome; the vaccinia virus `flanking sequences` around the 
inserted gene serve to allow homologous recombination between the plasmid 
DNA and the viral DNA, with the consequent insertion of the foreign gene 
at the desired location. 
Cloning of neutral site sequences 
Plasmids containing flanking regions from the neutral sites are constructed 
as follows. DNA is prepared from the Wyeth strain of vaccinia virus by the 
method of Esposito et al., (J. Virol. Meth. 2: 175, 1981). The polymerase 
chain reaction (PCR) is used to remove an approximately 1000 base pair 
(bp) fragment from DNA of the Wyeth strain of vaccinia virus. Pairs of 
oligonucleotides are chosen approximately 500 bp either side of the chosen 
neutral site. These oligonucleotides are based on the sequence of the WR 
strain, but are chosen in regions where the sequence of the WR strain is 
identical to that of the Copenhagen strain (Goebel et al., Virology 
179:247, 1990). The oligonucleotides incorporate restriction enzyme 
recognition sequences so that they can be cloned easily into a plasmid. 
For neutral sites A (SEQ ID NO:03), B (SEQ ID NO:04), and D (SEQ ID NO:06) 
the restriction sites are EcoR1 and HindIII. For neutral site C (SEQ ID 
NO:05) the HindIII site is replaced by an Sphl site, since there is an 
internal HindIII site in the chosen flanking sequences. 
The oligonucleotides used for PCR are listed below: 
Site A (SEQ ID NO:03) leftMB 16 
Site A (SEQ ID NO:03) rightMB 17 
Site B (SEQ ID NO:04) leftMB 24 
Site B (SEQ ID NO:04) rightMB 25 
Site C (SEQ ID NO:05) leftMB 18 
Site C (SEQ ID NO:05) rightMB 19 
Site D (SEQ ID NO:06) leftMB 22 
Site D (SEQ ID NO:06) rightMB 23 
DNA fragments of approximately lkb are then prepared using these pairs of 
oligonucleotides by PCR amplification, digested with EcoRI and HindIII 
(for site A (SEQ NO:03), B (SEQ ID NO:04) and D (SEQ ID NO:06) or with 
EcoRI and Sphl (for site C (SEQ ID NO:05)) and cloned into HindIII and 
EcoRI-digested pUC118 (FIG. 13) to generate the plasmids pIMMC7a, pIMMC7b, 
pIMMC7c and pIMMC7d. 
Creation of unique restriction sites for insertion at the neutral sites 
A suitable restriction enzyme site is then introduced at the selected 
location within each of the plasmids. This is achieved using site directed 
mutagenesis using an oligonucleotide containing the desired new unique 
site and flanked by 15 bases of sequence to either side (see below). The 
plasmids modified in this fashion are designated pIMMC8a-d (FIG. 13). 
______________________________________ 
original oligonucleotidesite new plasmid 
plasmid introduced 
______________________________________ 
pIMMC7a MB35SnaB1 pIMMC8a 
pIMMC7b MB36Hpa1 pIMMCb 
pIMMC7c MB37Stu1 pIMMC8c 
pIMMC7d MB38SnaB1 pIMMC8d 
______________________________________ 
Cloning of the vaccinia virus early/late promoter sequences 
The p7.5 and H6 promoters from vaccinia virus genomic DNA are prepared by 
PCR amplification as described below. 
A pair of complementary oligonucleotides (S7 and S8) is synthesised to 
include the following restriction enzyme sites, HindIII, Snal Hpal, 
HindIII, Sall, Ncol, Smal, SnaBl and EcoRl such that the pair, after 
annealing, present at one end HindIII compatible overhanging ends, and at 
the other, EcoRl compatible overhanging ends. The two oligonucleotides are 
allowed to anneal and are inserted into pUC118 cut with EcoRl and HindIII 
(FIG. 14). The resulting vector is called pIMMC3. 
A DNA molecule of approximately 180 bp containing the H6 promoter is 
removed from the WR strain of vaccinia virus by PCR amplification using 
the oligonucleotides MB15 (anneals upstream and includes a 5'-Sall site) 
and MB7 (anneals downstream and includes a 5'-HindIII site). This is 
cloned into pIMMC3 cleaved with HindIII and Sall to create pIMMC4a (FIG. 
14). A DNA molecule of approximately 200 bp containing the p7.5 promoter 
is then removed from the WR strain of vaccinia virus by PCR amplification 
using the oligonucleotides MB32 (anneals upstream and includes a 5'-Sall 
site) and MB33 (anneals downstream and includes a 5'Ncol site). This is 
cloned into pIMMC3 cleaved with Ncol and Sall to create pIMMC14b. 
Construction of the therapeutic virus 
The strategy required to generate a recombinant vaccinia virus containing 
and expressing the E6-E7 proteins from HPV16 and HPV18, based on the 
elements described above involves five main stages as outlined below. 
i) Cloning of the modified E6-7 genes downstream of vaccinia early promoter 
sequences 
A DNA fragment containing the modified HPV16 E6-7 sequence is excised from 
pIMS7.2 by digestion with HindIII and Smal, and cloned into HindIII and 
Hpal-digested pIMMC4a to generate pIMS12 (FIG. 15). 
A DNA fragment containing the modified HPV18 E6-7 sequence is excised from 
pIMS8.2 by digestion with Ncol and Smal, and cloned into Ncol and 
Smal-digested pIMMC14b to generate pIMS14 (FIG. 15). 
ii) Preparation of a plasmid vector containing both HPV16 and HPV18 E6-7 
sequences together with their upstream vaccinia promoters. 
A DNA fragment containing the HPV18 E6-7 region together with the upstream 
p7.5 promoter is excised from pIMS14 with Sall and Smal and inserted into 
Sall and Smal-digested pIMS12 to generate pIMS15 (FIG. 15) 
iii) Insertion of the HPV E6-7/promoter "double" cartridge into the neutral 
site containing plasmids. 
A DNA fragment containing both the HPV16 and HPV18 E6-7 coding regions 
together with their upstream promoter elements is excised from pIMS15 with 
SnaB1 and inserted into the appropriately-digested neutral site-containing 
plasmids pIMMC7a-d. This step is shown in FIG. 16, and the resulting 
plasmids are designated pIMMC9a-d. 
iv) Introduction via homologous recombination of the neutral site DNA, 
together with the intervening HPV sequences, into the vaccinia virus 
genome to create a recombinant virus expressing the two modified HPV E6-7 
sequences. 
The recombinant plasmids pIMMC9a-d are purified and allowed to recombine 
into vaccinia (FIG. 17) using standard protocols (Mackett et al., in D. M. 
Glover (ed) DNA Cloning: a Practical Approach, Oxford and Washington D.C., 
IRL Press, 1985). Viruses which have acquired the HPV sequences are 
identified by probing with radiolabelled HPV specific sequences. Viral 
plaques are lifted onto nitrocellulose (Villareal and Berg, Science 196, 
183, 1977) and probed with radiolabelled NcoI-SmaI fragment from pIMS14 
containing the HPV18 E67 gene. Recombinant viruses are then isolated from 
the agarose overlay and plaque purified three times. They are checked for 
the presence of the appropriate DNA sequences by Southern blotting of 
purified virus DNA using DNA probes derived from the HPV E6 and E7 genes, 
and for expression of the appropriate sequences by western blotting using 
antisera specific for the HPV E6 and E7 proteins. 
Cloning of the therapeutic virus in MRC5 cells 
Stocks of the final recombinant virus are prepared by growth in Vero cells, 
and are used to infect MRC5 cells deemed suitable for the preparation of 
material suitable for use as human vaccines. The virus is plaque-purified 
three times by standard methods, and finally a stock prepared for clinical 
use. 
Confirmation of presence of the correct HPV DNA insert 
A sample of this stock virus is checked once again for the presence of 
correctly configured virus DNA, and for expression of the correct virus 
proteins. FIG. 22 shows the analysis by PCR, of a recombinant vaccinia 
virus (v9a.1) in which the HPV DNA cassette is inserted at Site A. The 
diagram shown in panel (a) indicates the DNA fragments expected if 
insertion of the correct DNA has occurred. It can be seen in panel (b) 
that the actual pattern of PCR products generated is consistent with that 
expected. 
Confirmation of expression of the HPV DNA insert 
The recombinant viruses are then checked for expression of the expected HPV 
proteins. An example of this analysis is shown in FIG. 23. Vero cells are 
infected with recombinant virus v9a.1 (HPV DNA inserted at Site A), and 
the cells examined by western blotting for the presence of the HPV E67 
fusions proteins using monoclonal antibodies specific for the HPV16 E7 
protein (camvir3) and for the HPV18 E7 protein (7E10). It can be seen that 
both monoclonal antibodies recognise specifically proteins of the expected 
size in cells infected with the recombinant virus v9a.1, but not in cells 
infected with the control parent virus Wyeth strain. These recognised 
proteins co-migrate with proteins synthesised by in vitro translation of 
mRNA encoding the expected HPV fusion proteins (HPV 16 E67 and HPV18 E67). 
This experiment indicates successful expression of the heterologous gene 
sequences from the recombinant virus. 
Stability of the HPV DNA insert 
For the recombinant virus to be of use clinically, it is important that the 
inserted sequences remain genetically stable over multiple virus passage, 
and the DNA insert was carefully designed to promote this genetic 
instability. To confirm the stability of the HPV information within the 
recombinant virus genome, the virus is subjected to 9 serial passages, 
(multiplicity of infection=10 pfu/cell) in Vero cells. Subsequently 20 
plaque isolates are picked, and analysed for the presence of the correct 
HPV DNA insert by PCR analysis as described in FIG. 22. The data obtained 
for recombinant virus A are shown in FIG. 24. All 20 virus isolates 
retained the HPV information in the expected Genetic arrangement 
indicating a considerable degree of genetic stability. 
Animal experiments 
The virulence of the recombinant virus is compared in animal experiments 
with that of the parental Wyeth strain. Groups of 20 mice are inoculated 
intranasally each with 10.sup.7 pfu of Wyeth strain or recombinant virus 
in a total volume of 20 .mu.l . Two mice are sacrificed at 1 day, 3 days 
and 5 days following inoculation, and the lungs dissected out. The amount 
of virus present in the lungs is then measured by grinding the tissue, and 
assay of the homogenate by standard vaccinia virus plaque assay. The 
results of such an experiment for the recombinant virus v9a.1 (HPV 
infromation inserted at site A (SEQ ID NO:03) are shown in FIG. 25. It can 
be seen that the recombinant virus retains the ability to replicate in 
mice, and that the level of virus produced in the lungs of the infected 
animals is similar to that seen with the parental Wyeth strain. 
Therapeutic Use 
A stock of the recombinant virus is prepared by infection of MRC5 cells, 
and adjusted to a concentration of not less than 10.sup.8 pfu/ml. 20 .mu.l 
of this material is applied to the arm of the patient, which is then 
scarified through the virus droplet with a bifurcated needle, according to 
the standard procedure used for vaccination against smallpox. 
__________________________________________________________________________ 
SEQUENCE LISTING 
(1) GENERAL INFORMATION: 
(iii) NUMBER OF SEQUENCES: 70 
(2) INFORMATION FOR SEQ ID NO:1: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 20 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: 
TTTTTATTCTAGAATTAGAG20 
(2) INFORMATION FOR SEQ ID NO:2: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 20 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: 
TTTCTACAGTAGAATCAGAG20 
(2) INFORMATION FOR SEQ ID NO:3: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 40 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: 
CTATCTACCAGATTATTATGTGTTATAAGGTACTTTTTCT40 
(2) INFORMATION FOR SEQ ID NO:4: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 40 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: 
TATTGTGCTACTGATTCTTCACAGACTGAAGATTGTTGAA40 
(2) INFORMATION FOR SEQ ID NO:5: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 40 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: 
TCTCTTAAAATGGTTGAGACCAAGCTTCGTTGTAGAAACA40 
(2) INFORMATION FOR SEQ ID NO:6: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 40 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: 
TGAGGCTACCTCGACATACGTGTGCGCTATCAAAGTGGAA40 
(2) INFORMATION FOR SEQ ID NO:7: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 790 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: 
ATCCCATGGACCAAAAGAGAACTGCAATGTTTCAGGACCCACAGGAGCGACCCAGAAAGT60 
TACCACAGTTATGCACAGAGCTGCAAACAACTATACATGATATAATATTAGAATGTGTGT120 
ACTGCAAGCAACAGTTACTGCGACGTGAGGTATATGACTTTGCTTTTCGGGATTTATGCA180 
TAGTATATAGAGATGGGAATCCATATGCTGTATGTGATAAATGTTTAAAGTTTTATTCTA240 
AAATTAGTGAGTATAGACATTATTGTTATAGTTTGTATGGAACAACATTAGAACAGCAAT300 
ACAACAAACCGTTGTGTGATTTGTTAATTAGGTGTATTAACTGTCAAAAGCCACTGTGTC360 
CTGAAGAAAAGCAAAGACATCTGGACAAAAAGCAAAGATTCCATAATATAAGGGGTCGGT420 
GGACCGGTCGATGTATGTCTTGTTGCAGATCATCAAGAACACGTAGAGAAACCCAGCTGT480 
AATCATGCATGGAGATACACCTACATTGCATGAATATATGTTAGATTTGCAACCAGAGAC540 
AACTGATCTCTACTGTTATGAGCAATTAAATGACAGCTCAGAGGAGGAGGATGAAATAGA600 
TGGTCCAGCTGGACAAGCAGAACCGGACAGAGCCCATTACAATATTGTAACCTTTTGTTG660 
CAAGTGTGACTCTACGCTTCGGTTGTGCGTACAAAGCACACACGTAGACATTCGTACTTT720 
GGAAGACCTGTTAATGGGCACACTAGGAATTGTGTGCCCCATCTGTTCTCAGAAACCATA780 
ACCCGGGTGA790 
(2) INFORMATION FOR SEQ ID NO:8: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 263 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..263 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: 
IleProTrpThrLysArgGluLeuGlnCysPheArgThrHisArgSer 
151015 
AspProGluSerTyrHisSerTyrAlaGlnSerCysLysGlnLeuTyr 
202530 
MetIleXaaTyrXaaAsnValCysThrAlaSerAsnSerTyrCysAsp 
354045 
ValArgTyrMetThrLeuLeuPheGlyIleTyrAlaXaaTyrIleGlu 
505560 
MetGlyIleHisMetLeuTyrValIleAsnValXaaSerPheIleLeu 
65707580 
LysLeuValSerIleAspIleIleValIleValCysMetGluGlnHis 
859095 
XaaAsnSerAsnThrThrAsnArgCysValIleCysXaaLeuGlyVal 
100105110 
LeuThrValLysSerHisCysValLeuLysLysSerLysAspIleTrp 
115120125 
ThrLysSerLysAspSerIleIleXaaGlyValGlyGlyProValAsp 
130135140 
ValCysLeuValAlaAspHisGlnGluHisValGluLysProSerCys 
145150155160 
AsnHisAlaTrpArgTyrThrTyrIleAlaXaaIleTyrValArgPhe 
165170175 
AlaThrArgAspAsnXaaSerLeuLeuLeuXaaAlaIleLysXaaGln 
180185190 
LeuArgGlyGlyGlyXaaAsnArgTrpSerSerTrpThrSerArgThr 
195200205 
GlyGlnSerProLeuGlnTyrCysAsnLeuLeuLeuGlnValXaaLeu 
210215220 
TyrAlaSerValValArgThrLysHisThrArgArgHisSerTyrPhe 
225230235240 
GlyArgProValAsnGlyHisThrArgAsnCysValProHisLeuPhe 
245250255 
SerGluThrIleThrArgVal 
260 
(2) INFORMATION FOR SEQ ID NO:9: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 263 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..263 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: 
SerHisGlyProLysGluAsnCysAsnValSerGlyProThrGlyAla 
151015 
ThrGlnLysValThrThrValMetHisArgAlaAlaAsnAsnTyrThr 
202530 
XaaTyrAsnIleArgMetCysValLeuGlnAlaThrValThrAlaThr 
354045 
XaaGlyIleXaaLeuCysPheSerGlyPheMetHisSerIleXaaArg 
505560 
TrpGluSerIleCysCysMetXaaXaaMetPheLysValLeuPheXaa 
65707580 
AsnXaaXaaValXaaThrLeuLeuLeuXaaPheValTrpAsnAsnIle 
859095 
ArgThrAlaIleGlnGlnThrValValXaaPheValAsnXaaValTyr 
100105110 
XaaLeuSerLysAlaThrValSerXaaArgLysAlaLysThrSerGly 
115120125 
GlnLysAlaLysIleProXaaTyrLysGlySerValAspArgSerMet 
130135140 
TyrValLeuLeuGlnIleIleLysAsnThrXaaArgAsnProAlaVal 
145150155160 
IleMetHisGlyAspThrProThrLeuHisGluTyrMetLeuAspLeu 
165170175 
GlnProGluThrThrAspLeuTyrCysTyrGluGlnLeuAsnAspSer 
180185190 
SerGluGluGluAspGluIleAspGlyProAlaGlyGlnAlaGluPro 
195200205 
AspArgAlaHisTyrAsnIleValThrPheCysCysLysCysAspSer 
210215220 
ThrLeuArgLeuCysValGlnSerThrHisValAspIleArgThrLeu 
225230235240 
GluAspLeuLeuMetGlyThrLeuGlyIleValCysProIleCysSer 
245250255 
GlnLysProXaaProGlyXaa 
260 
(2) INFORMATION FOR SEQ ID NO:10: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 182 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..182 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: 
ProMetAspGlnLysArgThrAlaMetPheGlnAspProGlnGluArg 
151015 
ProArgLysLeuProGlnLeuCysThrGluLeuGlnThrThrIleHis 
202530 
AspIleIleLeuGluCysValTyrCysLysGlnGlnLeuLeuArgArg 
354045 
GluValTyrAspPheAlaPheArgAspLeuCysIleIleSerGluTyr 
505560 
ArgHisTyrCysTyrSerLeuTyrGlyThrThrLeuGluGlnGlnTyr 
65707580 
GluGluLysGlnArgHisLeuAspLysLysGlnArgPheHisAsnIle 
859095 
ArgGlyArgTrpSerCysMetGluIleHisLeuHisCysMetAsnIle 
100105110 
CysXaaIleCysAsnGlnArgGlnValGlnLeuAspLysGlnAsnArg 
115120125 
ThrGluProIleThrIleLeuXaaProPheValAlaSerValThrLeu 
130135140 
ArgPheGlyCysAlaTyrLysAlaHisThrXaaThrPheValLeuTrp 
145150155160 
LysThrCysXaaTrpAlaHisXaaGluLeuCysAlaProSerValLeu 
165170175 
ArgAsnHisAsnProGly 
180 
(2) INFORMATION FOR SEQ ID NO:11: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 817 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: 
ATCCCATGGCGCGCTTTGAGGATCCAACACGGCGACCCTACAAGCTACCTGATCTGTGCA60 
CGGAACTGAACACTTCACTGCAAGACATAGAAATAACCTGTGTATATTGCAAGACAGTAT120 
TGGAACTTACAGAGGTATTTGAATTTGCATTTAAAGATTTATTTGTGGTGTATAGAGACA180 
GTATACCCCATGCTGCATGCCATAAATGTATAGATTTTTATTCTAGAATTAGAGAATTAA240 
GACATTATTCAGACTCTGTGTATGGAGACACATTGGAAAAACTAACTAACACTGGGTTAT300 
ACAATTTATTAATAAGGTGCCTGCGGTGCCAGAAACCGTTGAATCCAGCAGAAAAACTTA360 
GACACCTTAATGAAAAACGACGATTTCACAACATAGCTGGGCACTATAGAGGCCAGTGCC420 
ATTCGTGCTGCAACCGAGCACGACAGGAACGACTCCAACGACGCAGAGAAACACAAGTAT480 
AATATTAAGTATGCATGGACCTAAGGCAACATTGCAAGACATTGTATTGCATTTAGAGCC540 
CCAAAATGAAATTCCGGTTGACCTTCTATGTCACGAGCAATTAAGCGACTCAGAGGAAGA600 
AAACGATGAAATAGATGGAGTTAATCATCAACATTTACCAGCCCGACGAGCCGAACCACA660 
ACGTCACACAATGTTGTGTATGTGTTGTAAGTGTGAAGCCAGAATTGAGCTAGTAGTAGA720 
AAGCTCAGCAGACGACCTTCGAGCATTCCAGCAGCTGTTTCTGAACACCCTGTCCTTTGT780 
GTGTCCGTGGTGTGCATCCCAGCAGTAACCCGGGTGA817 
(2) INFORMATION FOR SEQ ID NO:12: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 272 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..272 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: 
IleProTrpArgAlaLeuArgIleGlnHisGlyAspProThrSerTyr 
151015 
LeuIleCysAlaArgAsnXaaThrLeuHisCysLysThrXaaLysXaa 
202530 
ProValTyrIleAlaArgGlnTyrTrpAsnLeuGlnArgTyrLeuAsn 
354045 
LeuHisLeuLysIleTyrLeuTrpCysIleGluThrValTyrProMet 
505560 
LeuHisAlaIleAsnValXaaIlePheIleLeuGluLeuGluAsnXaa 
65707580 
AspIleIleGlnThrLeuCysMetGluThrHisTrpLysAsnXaaLeu 
859095 
ThrLeuGlyTyrThrIleTyrXaaXaaGlyAlaCysGlyAlaArgAsn 
100105110 
ArgXaaIleGlnGlnLysAsnLeuAspThrLeuMetLysAsnAspAsp 
115120125 
PheThrThrXaaLeuGlyThrIleGluAlaSerAlaIleArgAlaAla 
130135140 
ThrGluHisAspArgAsnAspSerAsnAspAlaGluLysHisLysTyr 
145150155160 
AsnIleLysTyrAlaTrpThrXaaGlyAsnIleAlaArgHisCysIle 
165170175 
AlaPheArgAlaProLysXaaAsnSerGlyXaaProSerMetSerArg 
180185190 
AlaIleLysArgLeuArgGlyArgLysArgXaaAsnArgTrpSerXaa 
195200205 
SerSerThrPheThrSerProThrSerArgThrThrThrSerHisAsn 
210215220 
ValValTyrValLeuXaaValXaaSerGlnAsnXaaAlaSerSerArg 
225230235240 
LysLeuSerArgArgProSerSerIleProAlaAlaValSerGluHis 
245250255 
ProValLeuCysValSerValValCysIleProAlaValThrArgVal 
260265270 
(2) INFORMATION FOR SEQ ID NO:13: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 272 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..272 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: 
SerHisGlyAlaLeuXaaGlySerAsnThrAlaThrLeuGlnAlaThr 
151015 
XaaSerValHisGlyThrGluHisPheThrAlaArgHisArgAsnAsn 
202530 
LeuCysIleLeuGlnAspSerIleGlyThrTyrArgGlyIleXaaIle 
354045 
CysIleXaaArgPheIleCysGlyValXaaArgGlnTyrThrProCys 
505560 
CysMetProXaaMetTyrArgPheLeuPheXaaAsnXaaArgIleLys 
65707580 
ThrLeuPheArgLeuCysValTrpArgHisIleGlyLysThrAsnXaa 
859095 
HisTrpValIleGlnPheIleAsnLysValProAlaValProGluThr 
100105110 
ValGluSerSerArgLysThrXaaThrProXaaXaaLysThrThrIle 
115120125 
SerGlnHisSerTrpAlaLeuXaaArgProValProPheValLeuGln 
130135140 
ProSerThrThrGlyThrThrProThrThrGlnArgAsnThrSerIle 
145150155160 
IleLeuSerMetHisGlyProLysAlaThrLeuGlnAspIleValLeu 
165170175 
HisLeuGluProGlnAsnGluIleProValAspLeuLeuCysHisGlu 
180185190 
GlnLeuSerAspSerGluGluGluAsnAspGluIleAspGlyValAsn 
195200205 
HisGlnHisLeuProAlaArgArgAlaGluProGlnArgHisThrMet 
210215220 
LeuCysMetCysCysLysCysGluAlaArgIleGluLeuValValGlu 
225230235240 
SerSerAlaAspAspLeuArgAlaPheGlnGlnLeuPheLeuAsnThr 
245250255 
LeuSerPheValCysProTrpCysAlaSerGlnGlnXaaProGlyXaa 
260265270 
(2) INFORMATION FOR SEQ ID NO:14: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 271 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..271 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: 
ProMetAlaArgPheGluAspProThrArgArgProTyrLysLeuPro 
151015 
AspLeuCysThrGluLeuAsnThrSerLeuGlnAspIleGluIleThr 
202530 
CysValTyrCysLysThrValLeuGluLeuThrGluValPheGluPhe 
354045 
AlaPheLysAspLeuPheValValTyrArgAspSerIleProHisAla 
505560 
AlaCysHisLysCysIleAspPheTyrSerArgIleArgGluLeuArg 
65707580 
HisTyrSerAspSerValTyrGlyAspThrLeuGluLysLeuThrAsn 
859095 
ThrGlyLeuTyrAsnLeuLeuIleArgCysLeuArgCysGlnLysPro 
100105110 
LeuAsnProAlaGluLysLeuArgHisLeuAsnGluLysArgArgPhe 
115120125 
HisAsnIleAlaGlyHisTyrArgGlyGlnCysHisSerCysCysAsn 
130135140 
ArgAlaArgGlnGluArgLeuGlnArgArgArgGluThrGlnValXaa 
145150155160 
TyrXaaValCysMetAspLeuArgGlnHisCysLysThrLeuTyrCys 
165170175 
IleXaaSerProLysMetLysPheArgLeuThrPheTyrValThrSer 
180185190 
AsnXaaAlaThrGlnArgLysLysThrMetLysXaaMetGluLeuIle 
195200205 
IleAsnIleTyrGlnProAspGluProAsnHisAsnValThrGlnCys 
210215220 
CysValCysValValSerValLysProGluLeuSerXaaXaaXaaLys 
225230235240 
AlaGlnGlnThrThrPheGluHisSerSerSerCysPheXaaThrPro 
245250255 
CysProLeuCysValArgGlyValHisProSerSerAsnProGly 
260265270 
(2) INFORMATION FOR SEQ ID NO:15: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 540 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: 
GATTGTGTGCATGCGTGGTAGATGTTTGGAGAAATGAGAAACTGTTTTCTAGATGGAAAT60 
ATTGTTTACGAGCTATTAAACTGTTTATTAATGATCACATGCTTGATAAGATAAAATCTA120 
TACTGCAGAATAGACTAGTATATGTGGAAATGTCATAGAAAGTTAAAAGTTAATGAGAGC180 
AAAAATATATAAGGTTGTATTCCATATTTGTTATTTTTTCTGTAATAGTTAGAAAAATAC240 
ATTCGATGGTCTATCTACCAGATTATTATGTGTTATAAGGTACTTTTTCTCATAATAAAC300 
TAGAGTATGAGTAAGATAGTGTTTTTCAAAACATATAAATCTAAAATTGATGGATGAGAT360 
ATACAGCTATTAATTTCGAAAATATATTTTAATCTGATAACTTTAAACATGGATTTTTGA420 
TGGTGGTTTAACGTTTTAAAAAAAGATTTTGTTATTGTAGTATATGATAATATTAAAAGA480 
TGGATATAAAGAATTTGCTGACTGCATGTACTATTTTTTACATTACTACATTGGCTACGG540 
(2) INFORMATION FOR SEQ ID NO:16: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 52 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein (B) LOCATION: 1..52 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: 
LeuCysAlaCysValValAspValTrpArgAsnGluLysLeuPheSer 
151015 
ArgTrpLysTyrCysLeuArgAlaIleLysLeuPheIleAsnAspHis 
202530 
MetLeuAspLysIleLysSerIleLeuGlnAsnArgLeuValTyrVal 
354045 
GluMetSerXaa 
50 
(2) INFORMATION FOR SEQ ID NO:17: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 26 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: 
MetIleIleLeuLysAspGlyTyrLysGluPheAlaAspCysMetTyr 
151015 
TyrPheLeuHisTyrTyrIleGlyTyrGly 
2025 
(2) INFORMATION FOR SEQ ID NO:18: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 540 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: 
TGCCAAGGTTAGATGTAATGGTAACGATAACACAAAATGTGAACGCTGCCCACCTCATAC60 
ATATACCACAATCCCAATTATTCTAATGGATGTCATCAATGTAGAAAATGCCCAACCGGA120 
TCATTTGATAAGGTAAAGTGTACCGGAACACAGAACAGTAAATGTTCGTGTCTTCCTGGT180 
TGGTATTGTGCTACTGATTCTTCACAGACTGAAGATTGTTGAAATTGTGTACCAAAAAGG240 
AGATGTCCATGCGGATACTTTGGTGGAATAGATGAACAAGGAAATCCTATTTGTAAATCG300 
TGTTGTGTTGGTGAATATTGCGACTACCTACGTAATTATAGACTTGATCCATTTCCTCCA360 
TGCAAACTATCTAAATGTAATTAATTATGATTTTGATGATAATGTTACCATACATTATAT420 
CGCTACTTGGTTAGTGTATTATTCAGTATGAAGACCTATTAATAATTACTTATCTTTTGA480 
CGATCTTGTTATAATTATAATATAAAAATACTTATGGCATAGTAACTCATAATTGCTGAC540 
(2) INFORMATION FOR SEQ ID NO:19: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 45 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..45 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: 
AlaLysValArgCysAsnGlyAsnAspAsnThrLysCysGluArgCys 
151015 
ProProHisThrTyrThrThrIleProIleIleLeuMetAspValIle 
202530 
AsnValGluAsnAlaGlnProAspHisLeuIleArgXaa 
354045 
(2) INFORMATION FOR SEQ ID NO:20: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 60 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..60 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: 
MetAsnLysGluIleLeuPheValAsnArgValValLeuValAsnIle 
151015 
AlaThrThrTyrValIleIleAspLeuIleHisPheLeuHisAlaAsn 
202530 
TyrLeuAsnValIleAsnTyrAspPheAspAspAsnValThrIleHis 
354045 
TyrIleAlaThrTrpLeuValTyrTyrSerValXaa 
505560 
(2) INFORMATION FOR SEQ ID NO:21: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 194 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: 
MetSerGlyIleValLysSerIleIleLeuSerGlyProSerGlyLeu 
151015 
GlyLysThrAlaIleAlaLysArgLeuMetGlyIleTyrLeuAspLeu 
202530 
TrpCysProIleProLeuAspPheLeuValLeuMetGluArgGluGly 
354045 
ValAspTyrHisTyrValAsnArgGluAlaIleTrpLysGlyIleAla 
505560 
AlaGlyAsnPheLeuGluHisThrGluPheLeuGlyAsnIleTyrGly 
65707580 
ThrSerLysThrAlaValAsnThrAlaAlaIleAsnAsnArgIleCys 
859095 
ValMetAspLeuAsnIleAspGlyValArgSerLeuLysAsnThrTyr 
100105110 
LeuMetProTyrSerValTyrIleArgProThrSerLeuLysMetVal 
115120125 
GluThrLysLeuArgCysArgAsnThrGluAlaAsnAspGluIleHis 
130135140 
ArgArgValIleLeuAlaLysThrAspMetAspGluAlaAsnGluAla 
145150155160 
GlyLeuPheAspThrIleIleIleGluAspAspValAsnLeuAlaTyr 
165170175 
SerLysLeuIleGlnIleLeuGlnAspArgIleArgMetTyrPheAsn 
180185190 
ThrAsn 
(2) INFORMATION FOR SEQ ID NO:22: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 186 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: 
SerArgProIleValIleSerGlyProSerGlyThrGlyLysSerThr 
151015 
LeuLeuLysLysLeuPheAlaGluTyrProAspSerPheGlyPheSer 
202530 
ValSerSerThrThrArgThrProArgAlaGlyGluValAsnGlyLys 
354045 
AspTyrAsnPheValSerValAspGluPheLysSerMetIleLysAsn 
505560 
AsnGluPheIleGluTrpAlaGlnPheSerGlyAsnTyrTyrGlySer 
65707580 
ThrValAlaSerValLysGlnValSerLysSerGlyLysThrCysIle 
859095 
LeuAspIleAspMetGlnGlyValLysSerValLysAlaIleProGlu 
100105110 
LeuAsnAlaArgPheLeuPheIleAlaProProSerValGluAspLeu 
115120125 
LysLysArgLeuGluGlyArgGlyThrGluThrGluGluSerIleAsn 
130135140 
LysArgLeuSerAlaAlaGlnAlaGluLeuAlaTyrAlaGluThrGly 
145150155160 
AlaHisAspLysValIleValAsnAspAspLeuAspLysAlaTyrLys 
165170175 
GluLeuLysAspPheIlePheAlaGluLys 
180185 
(2) INFORMATION FOR SEQ ID NO:23: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 720 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: 
CTAAGAACACGTATACGGCAGCAGCTTCCTTTATACTCTCATCTTTTACCAACACAAAGG60 
GTGGATATTTGTTCATTGGAGTTGATAATAATACACACAAAGTAATTGGATTCACGGTGG120 
GTCATGACTACCTCAGACTGGTAGAGAATGATATAGAAAAGCATATCAAAAGACTTCGTG180 
TTGTGCATTTCTGTGAGAAGAAAGAGGACATCAAGTACACGTGTCGATTCATCAAGGTAT240 
ATAAACCTGGGGATGAGGCTACCTCGACATACGTGTGCGCTATCAAAGTGGAAAGATGCT300 
GTTGTGCTGTGTTTGCAGATTGGCCAGAATCATGGTATATGGATACTAATGGTATCAAGA360 
AGTATTCTCCAGATGAATGGGTGTCACATATAAAATTTTAATTAATGTAATAGAGAACAA420 
ATAATAAGGTTGTAATATCATATAGACAATAACTAACAATTAATTAGTAACTGTTATCTC480 
TTTTTTAACTAACCAACTAACTATATACCTATTAATACATCGTAATTATAGTTCTTAACA540 
TCTATTAATCATTAATTCGCTTCTTTAATTTTTTATAAACTAACATTGTTAATTGAAAAG600 
GGATAACATGTTACAGAATATAAATTATATATGGATTTTTTTAAAAAGGAAATACTTGAC660 
TGGAGTATATATTTATCTCTTCATTATATAGCACGCGTGTTTTCCAATTTTTCCACATCC720 
(2) INFORMATION FOR SEQ ID NO:24: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 35 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..35 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: 
LeuArgThrArgIleArgGlnGlnLeuProLeuTyrSerHisLeuLeu 
151015 
ProThrGlnArgValAspIleCysSerLeuGluLeuIleIleIleHis 
202530 
ThrLysXaa 
35 
(2) INFORMATION FOR SEQ ID NO:25: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 30 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: 
MetAspPhePheLysLysGluIleLeuAspTrpSerIleTyrLeuSer 
151015 
LeuHisTyrIleAlaArgValPheSerAsnPheSerThrSer 
202530 
(2) INFORMATION FOR SEQ ID NO:26: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: 
TCAGGATCCCACATGAGCGAAAAATACATCG31 
(2) INFORMATION FOR SEQ ID NO:27: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: 
TCAAAGCTTATTACGATACAAACTTAACGGA31 
(2) INFORMATION FOR SEQ ID NO:28: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 32 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: 
TCAGTTAACATAAAAAGAACAACGCCCGGCAG32 
(2) INFORMATION FOR SEQ ID NO:29: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 32 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: 
TCAAGGGCCTCTATATAGTAATACCAATACTC32 
(2) INFORMATION FOR SEQ ID NO:30: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:30: 
TCAGTCGACTTACAAACAACTAGGAAATTGG31 
(2) INFORMATION FOR SEQ ID NO:31: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: 
TCAGAATTCTATGTACAGAGGTCTATTAGGC31 
(2) INFORMATION FOR SEQ ID NO:32: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: 
TCAAAGCTTGTATGAGGTGGGCAGCGTTCAC31 
(2) INFORMATION FOR SEQ ID NO:33: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: 
TCAGAATTCTTAATTATATTGTCGGCCGTGG31 
(2) INFORMATION FOR SEQ ID NO:34: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: 
TCAGCATGCATGATCCGTTAGCTTTGGGCTC31 
(2) INFORMATION FOR SEQ ID NO:35: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:35: 
TCAGAATTCGAAGCTCTAGAGTATCTTAGCG31 
(2) INFORMATION FOR SEQ ID NO:36: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:36: 
TCAAAGCTTTCCTGTATTATATGGGATGTGG31 
(2) INFORMATION FOR SEQ ID NO:37: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: 
TCAGAATTCATTGATGGATGAGATATACAGC31 
(2) INFORMATION FOR SEQ ID NO:38: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 20 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: 
TCAAAGCTTTCACAAAATCG20 
(2) INFORMATION FOR SEQ ID NO:39: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: 
TCAGAATTCCACGTATACGGCAGCAGCTTCC31 
(2) INFORMATION FOR SEQ ID NO:40: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:40: 
TCAAAGCTTTGTTCTACGTCCATTTTCAAGC31 
(2) INFORMATION FOR SEQ ID NO:41: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:41: 
TCAGTCGACATACCAATACTCAAGACTACGA31 
(2) INFORMATION FOR SEQ ID NO:42: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 33 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:42: 
TCACCATGGATTGCTATTGATTGAGTACTGTTC33 
(2) INFORMATION FOR SEQ ID NO:43: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 30 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: 
AGTACCTTATAATACGTAATAATCTGGTAG30 
(2) INFORMATION FOR SEQ ID NO:44: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 30 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: 
AATCTTCAGTCTGTTAACAATCAGTAGCAC30 
(2) INFORMATION FOR SEQ ID NO:45: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 30 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:45: 
TACAACGAAGCTAGGCCTCAACCATTTTAA30 
(2) INFORMATION FOR SEQ ID NO:46: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 30 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:46: 
TTTGATAGCGCATACGTATGTCGAGGTAGC30 
(2) INFORMATION FOR SEQ ID NO:47: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 30 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:47: 
AATAGGTATATAGTTAACTGGTTAGTTAAA30 
(2) INFORMATION FOR SEQ ID NO:48: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 28 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: 
ATCCCATGGCGCGCTTTGAGGATCCAAC28 
(2) INFORMATION FOR SEQ ID NO:49: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: 
TCACCCGGGTTACTGCTGGGATGCACACCAC31 
(2) INFORMATION FOR SEQ ID NO:50: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 33 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:50: 
ATCCCATGGACCAAAAGAGAACTGCAATGTTTC33 
(2) INFORMATION FOR SEQ ID NO:51: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 31 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:51: 
TCACCCGGGTTATGGTTTCTGAGAACAGATG31 
(2) INFORMATION FOR SEQ ID NO:52: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 47 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: 
AGCTCTACGTAGTTAACAAGCTTGTCGACCCATGGCCCGGGTACGTA47 
(2) INFORMATION FOR SEQ ID NO:53: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 47 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: 
AATTTACGTACCCGGGCCATGGGTCGACAAGCTTGTTAACTACGTAG47 
(2) INFORMATION FOR SEQ ID NO:54: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 26 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:54: 
GAAACCCAGCTGGGAATCATGCATGG26 
(2) INFORMATION FOR SEQ ID NO:55: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 27 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:55: 
GAAACACAAGTAGGAATATTAAGTATG27 
(2) INFORMATION FOR SEQ ID NO:56: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 30 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:56: 
GATCTCTACGGTTATGGGCAATTAAATGAC30 
(2) INFORMATION FOR SEQ ID NO:57: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 30 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:57: 
GACCTTCTAGGTCACGGGCAATTAAGCGAC30 
(2) INFORMATION FOR SEQ ID NO:58: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 36 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:58: 
ATGTATAGATTTCTACAGTAGAATCAGAGAATTAAG36 
(2) INFORMATION FOR SEQ ID NO:59: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 1250 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:59: 
TATTGTTTACGAGCTATTAAACTGTTTATTAATGATCACATGCTTGATAAGATAAAATCT60 
ATACTGCAGAATAGACTAGTATATGTGGAAATGTCATAGAAAGTTAAAAGTTAATGAGAG120 
CAAAAATATATAAGGTTGTATTCCATATTTGTTATTTTTTCTGTAATAGTTAGAAAAATA180 
CATTCGATGGTCTATCTACCAGATTATTATGTGTTATAAGGTACTTTTTCTCATAATAAA240 
CTAGAGTATGAGTAAGATAGTGTTTTTCAAAACATATAAATCTAAAATTGATGGATGAGA300 
TATACAGCTATTAATTTCGAAAATATATTTTAATCTGATAACTTTAAACATGGATTTTTG360 
ATGGTGGTTTAACGTTTTAAAAAAAGATTTTGTTATTGTAGTATATGATAATATTAAAAG420 
ATGGATATAAAGAATTTGCTGACTGCATGTACTATTTTTTACATTACTACATTGGCTACG480 
GCAGATATACCTACTCCGCCACCAACGGGTCATGTGACAAGGGAGAATATCTTGATAAGA540 
GGCATAATCAATGTTGTAATCGGTGTCCACCTGGAGAATTTGCCAAGGTTAGATGTAATG600 
GTAACGATAACACAAAATGTGAACGCTGCCCACCTCATACATATACCACAATCCCAATTA660 
TTCTAATGGATGTCATCAATGTAGAAAATGCCCAACCGGATCATTTGATAAGGTAAAGTG720 
TACCGGAACACAGAACAGTAAATGTTCGTGTCTTCCTGGTTGGTATTGTGCTACTGATTC780 
TTCACAGACTGAAGATTGTTGAAATTGTGTACCAAAAAGGAGATGTCCATGCGGATACTT840 
TGGTGGAATAGATGAACAAGGAAATCCTATTTGTAAATCGTGTTGTGTTGGTGAATATTG900 
CGACTACCTACGTAATTATAGACTTGATCCATTTCCTCCATGCAAACTATCTAAATGTAA960 
TTAATTATGATTTTGATGATAATGTTACCATACATTATATCGCTACTTGGTTAGTGTATT1020 
ATTCAGTATGAAGACCTATTAATAATTACTTATCTTTTGACGATCTTGTTATAATTATAA1080 
TATAAAAATACTTATGGCATAGTAACTCATAATTGCTGACGCGATAAATTCGTAATAATC1140 
TGTTTTGTTCAAATTTTTATAAGGAATCTACAGGCATAAAAATAAAAATATAATTTATAA1200 
TATACTCTTACAGCGCGCCATCATGAATAACAGCAGTGAATTGATTGCTG1250 
(2) INFORMATION FOR SEQ ID NO:60: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 416 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..416 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:60: 
TyrCysLeuArgAlaIleLysLeuPheIleAsnAspHisMetLeuAsp 
151015 
LysIleLysSerIleLeuGlnAsnArgLeuValTyrValGluMetSer 
202530 
XaaLysValLysSerXaaXaaGluGlnLysTyrIleArgLeuTyrSer 
354045 
IlePheValIlePheSerValIleValArgLysIleHisSerMetVal 
505560 
TyrLeuProAspTyrTyrValLeuXaaGlyThrPheSerHisAsnLys 
65707580 
LeuGluTyrGluXaaAspSerValPheGlnAsnIleXaaIleXaaAsn 
859095 
XaaTrpMetArgTyrThrAlaIleAsnPheGluAsnIlePheXaaSer 
100105110 
AspAsnPheLysHisGlyPheLeuMetValValXaaArgPheLysLys 
115120125 
ArgPheCysTyrCysSerIleXaaXaaTyrXaaLysMetAspIleLys 
130135140 
AsnLeuLeuThrAlaCysThrIlePheTyrIleThrThrLeuAlaThr 
145150155160 
AlaAspIleProThrProProProThrGlyHisValThrArgGluAsn 
165170175 
IleLeuIleArgGlyIleIleAsnValValIleGlyValHisLeuGlu 
180185190 
AsnLeuProArgLeuAspValMetValThrIleThrGlnAsnValAsn 
195200205 
AlaAlaHisLeuIleHisIleProGlnSerGlnLeuPheXaaTrpMet 
210215220 
SerSerMetXaaLysMetProAsnArgIleIleXaaXaaGlyLysVal 
225230235240 
TyrArgAsnThrGluGlnXaaMetPheValSerSerTrpLeuValLeu 
245250255 
CysTyrXaaPhePheThrAspXaaArgLeuLeuLysLeuCysThrLys 
260265270 
LysGluMetSerMetArgIleLeuTrpTrpAsnArgXaaThrArgLys 
275280285 
SerTyrLeuXaaIleValLeuCysTrpXaaIleLeuArgLeuProThr 
290295300 
XaaLeuXaaThrXaaSerIleSerSerMetGlnThrIleXaaMetXaa 
305310315320 
LeuIleMetIleLeuMetIleMetLeuProTyrIleIleSerLeuLeu 
325330335 
GlyXaaCysIleIleGlnTyrGluAspLeuLeuIleIleThrTyrLeu 
340345350 
LeuThrIleLeuLeuXaaLeuXaaTyrLysAsnThrTyrGlyIleVal 
355360365 
ThrHisAsnCysXaaArgAspLysPheValIleIleCysPheValGln 
370375380 
IlePheIleArgAsnLeuGlnAlaXaaLysXaaLysTyrAsnLeuXaa 
385390395400 
TyrThrLeuThrAlaArgHisHisGluXaaGlnGlnXaaIleAspCys 
405410415 
(2) INFORMATION FOR SEQ ID NO:61: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 416 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..416 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:61: 
IleValTyrGluLeuLeuAsnCysLeuLeuMetIleThrCysLeuIle 
151015 
ArgXaaAsnLeuTyrCysArgIleAspXaaTyrMetTrpLysCysHis 
202530 
ArgLysLeuLysValAsnGluSerLysAsnIleXaaGlyCysIlePro 
354045 
TyrLeuLeuPhePheLeuXaaXaaLeuGluLysTyrIleArgTrpSer 
505560 
IleTyrGlnIleIleMetCysTyrLysValLeuPheLeuIleIleAsn 
65707580 
XaaSerMetSerLysIleValPhePheLysThrTyrLysSerLysIle 
859095 
AspGlyXaaAspIleGlnLeuLeuIleSerLysIleTyrPheAsnLeu 
100105110 
IleThrLeuAsnMetAspPheXaaTrpTrpPheAsnValLeuLysLys 
115120125 
AspPheValIleValValTyrAspAsnIleLysArgTrpIleXaaArg 
130135140 
IleCysXaaLeuHisValLeuPhePheThrLeuLeuHisTrpLeuArg 
145150155160 
GlnIleTyrLeuLeuArgHisGlnArgValMetXaaGlnGlyArgIle 
165170175 
SerXaaXaaGluAlaXaaSerMetLeuXaaSerValSerThrTrpArg 
180185190 
IleCysGlnGlyXaaMetXaaTrpXaaArgXaaHisLysMetXaaThr 
195200205 
LeuProThrSerTyrIleTyrHisAsnProAsnTyrSerAsnGlyCys 
210215220 
HisGlnCysArgLysCysProThrGlySerPheAspLysValLysCys 
225230235240 
ThrGlyThrGlnAsnSerLysCysSerCysLeuProGlyTrpTyrCys 
245250255 
AlaThrAspSerSerGlnThrGluAspCysXaaAsnCysValProLys 
260265270 
ArgArgCysProCysGlyTyrPheGlyGlyIleAspGluGlnGlyAsn 
275280285 
ProIleCysLysSerCysCysValGlyGluTyrCysAspTyrLeuArg 
290295300 
AsnTyrArgLeuAspProPheProProCysLysLeuSerLysCysAsn 
305310315320 
XaaLeuXaaPheXaaXaaXaaCysTyrHisThrLeuTyrArgTyrLeu 
325330335 
ValSerValLeuPheSerMetLysThrTyrXaaXaaLeuLeuIlePhe 
340345350 
XaaArgSerCysTyrAsnTyrAsnIleLysIleLeuMetAlaXaaXaa 
355360365 
LeuIleIleAlaAspAlaIleAsnSerXaaXaaSerValLeuPheLys 
370375380 
PheLeuXaaGlyIleTyrArgHisLysAsnLysAsnIleIleTyrAsn 
385390395400 
IleLeuLeuGlnArgAlaIleMetAsnAsnSerSerGluLeuIleAla 
405410415 
(2) INFORMATION FOR SEQ ID NO:62: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 416 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..416 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:62: 
LeuPheThrSerTyrXaaThrValTyrXaaXaaSerHisAlaXaaXaa 
151015 
AspLysIleTyrThrAlaGluXaaThrSerIleCysGlyAsnValIle 
202530 
GluSerXaaLysLeuMetArgAlaLysIleTyrLysValValPheHis 
354045 
IleCysTyrPhePheCysAsnSerXaaLysAsnThrPheAspGlyLeu 
505560 
SerThrArgLeuLeuCysValIleArgTyrPhePheSerXaaXaaThr 
65707580 
ArgValXaaValArgXaaCysPheSerLysHisIleAsnLeuLysLeu 
859095 
MetAspGluIleTyrSerTyrXaaPheArgLysTyrIleLeuIleXaa 
100105110 
XaaLeuXaaThrTrpIlePheAspGlyGlyLeuThrPheXaaLysLys 
115120125 
IleLeuLeuLeuXaaTyrMetIleIleLeuLysAspGlyTyrLysGlu 
130135140 
PheAlaAspCysMetTyrTyrPheLeuHisTyrTyrIleGlyTyrGly 
145150155160 
ArgTyrThrTyrSerAlaThrAsnGlySerCysAspLysGlyGluTyr 
165170175 
LeuAspLysArgHisAsnGlnCysCysAsnArgCysProProGlyGlu 
180185190 
PheAlaLysValArgCysAsnGlyAsnAspAsnThrLysCysGluArg 
195200205 
CysProProHisThrTyrThrThrIleProIleIleLeuMetAspVal 
210215220 
IleAsnValGluAsnAlaGlnProAspHisLeuIleArgXaaSerVal 
225230235240 
ProGluHisArgThrValAsnValArgValPheLeuValGlyIleVal 
245250255 
LeuLeuIleLeuHisArgLeuLysIleValGluIleValTyrGlnLys 
260265270 
GlyAspValHisAlaAspThrLeuValGluXaaMetAsnLysGluIle 
275280285 
LeuPheValAsnArgValValLeuValAsnIleAlaThrThrTyrVal 
290295300 
IleIleAspLeuIleHisPheLeuHisAlaAsnTyrLeuAsnValIle 
305310315320 
AsnTyrAspPheAspAspAsnValThrIleHisTyrIleAlaThrTrp 
325330335 
LeuValTyrTyrSerValXaaArgProIleAsnAsnTyrLeuSerPhe 
340345350 
AspAspLeuValIleIleIleIleXaaLysTyrLeuTrpHisSerAsn 
355360365 
SerXaaLeuLeuThrArgXaaIleArgAsnAsnLeuPheCysSerAsn 
370375380 
PheTyrLysGluSerThrGlyIleLysIleLysIleXaaPheIleIle 
385390395400 
TyrSerTyrSerAlaProSerXaaIleThrAlaValAsnXaaLeuLeu 
405410415 
(2) INFORMATION FOR SEQ ID NO:63: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 1000 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:63: 
ATATTTGGTATTACCGCATTAATTATATTGTCGGCCGTGGCAATTTTCTGTATTACATAT60 
TATATATATAATAAACGTTCACGTAAATACAAAACAGAGAACAAAGTCTAGATTTTTGAC120 
TTACATAAATGTCTGGGATAGTAAAATCTATCATATTGAGCGGACCATCTGGTTTAGGAA180 
AGACAGCCATAGCCAAAAGACTATGGGAATATATTTGGATTTGTGGTGTCCCATACCACT240 
AGATTTCCTCGTCCTATGGAACGAGAAGGTGTTGATTACCATTACGTTAACAGAGAGGCC300 
ATCTGGAAGGGAATAGCCGCCGGAAACTTTCTAGAACATACTGAGTTTTTAGGAAATATT360 
TACGGAACTTCTAAAACAGCTGTGAATACAGCGGCTATTAATAATCGTATTTGTGTGATG420 
GATCTAAACATCGACGGTGTTAGAAGTCTTAAAAATACGTACCTAATGCCTTACTCGGTG480 
TATATAAGACCTACCTCTCTTAAAATGGTTGAGACCAAGCTTCGTTGTAGAAACACTGAA540 
GCTAACGATGAGATTCATCGTCGCGTGATATTGGCAAAAACGGATATGGATGAGGCCAAC600 
GAAGCAGGTCTATTCGACACTATTATCATTGAAGATGATGTGAATTTAGCATATAGTAAG660 
TTAATTCAGATACTACAGGACCGTATTAGAATGTATTTTAACACTAATTAGAGACTTAAG720 
ACTTAAAACTTGATAATTAATAATATAACTCGTTTTTATATGTGGCTATTTCAACGTCTA780 
ATGTATTAGTTAAATATTAAAACTTACCACGTAAAACTTAAAATTTAAAATGATATTTCA840 
TTGACAGATAGATCACACATTATGAACTTTCAAGGACTTGTGTTAACTGACAATTGCAAA900 
AATCAATGGGTCGTTGGACCATTAATAGGAAAAGGTGGATTCGGTAGTATTTATACTACT960 
AATGACAATAATTATGTAGTAAAAATAGAGCCCAAAGCTA1000 
(2) INFORMATION FOR SEQ ID NO:64: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 333 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..333 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:64: 
IlePheGlyIleThrAlaLeuIleIleLeuSerAlaValAlaIlePhe 
151015 
CysIleThrTyrTyrIleTyrAsnLysArgSerArgLysTyrLysThr 
202530 
GluAsnLysValXaaIlePheAspLeuHisLysCysLeuGlyXaaXaa 
354045 
AsnLeuSerTyrXaaAlaAspHisLeuValXaaGluArgGlnProXaa 
505560 
ProLysAspTyrGlyAsnIlePheGlyPheValValSerHisThrThr 
65707580 
ArgPheProArgProMetGluArgGluGlyValAspTyrHisTyrVal 
859095 
AsnArgGluAlaIleTrpLysGlyIleAlaAlaGlyAsnPheLeuGlu 
100105110 
HisThrGluPheLeuGlyAsnIleTyrGlyThrSerLysThrAlaVal 
115120125 
AsnThrAlaAlaIleAsnAsnArgIleCysValMetAspLeuAsnIle 
130135140 
AspGlyValArgSerLeuLysAsnThrTyrLeuMetProTyrSerVal 
145150155160 
TyrIleArgProThrSerLeuLysMetValGluThrLysLeuArgCys 
165170175 
ArgAsnThrGluAlaAsnAspGluIleHisArgArgValIleLeuAla 
180185190 
LysThrAspMetAspGluAlaAsnGluAlaGlyLeuPheAspThrIle 
195200205 
IleIleGluAspAspValAsnLeuAlaTyrSerLysLeuIleGlnIle 
210215220 
LeuGlnAspArgIleArgMetTyrPheAsnThrAsnXaaArgLeuLys 
225230235240 
ThrXaaAsnLeuIleIleAsnAsnIleThrArgPheTyrMetTrpLeu 
245250255 
PheGlnArgLeuMetTyrXaaLeuAsnIleLysThrTyrHisValLys 
260265270 
LeuLysIleXaaAsnAspIleSerLeuThrAspArgSerHisIleMet 
275280285 
AsnPheGlnGlyLeuValLeuThrAspAsnCysLysAsnGlnTrpVal 
290295300 
ValGlyProLeuIleGlyLysGlyGlyPheGlySerIleTyrThrThr 
305310315320 
AsnAspAsnAsnTyrValValLysIleGluProLysAla 
325330 
(2) INFORMATION FOR SEQ ID NO:65: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 333 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..333 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:65: 
TyrLeuValLeuProHisXaaLeuTyrCysArgProTrpGlnPheSer 
151015 
ValLeuHisIleIleTyrIleIleAsnValHisValAsnThrLysGln 
202530 
ArgThrLysSerArgPheLeuThrTyrIleAsnValTrpAspSerLys 
354045 
IleTyrHisIleGluArgThrIleTrpPheArgLysAspSerHisSer 
505560 
GlnLysThrMetGlyIleTyrLeuAspLeuTrpCysProIleProLeu 
65707580 
AspPheLeuValLeuTrpAsnGluLysValLeuIleThrIleThrLeu 
859095 
ThrGluArgProSerGlyArgGluXaaProProGluThrPheXaaAsn 
100105110 
IleLeuSerPheXaaGluIlePheThrGluLeuLeuLysGlnLeuXaa 
115120125 
IleGlnArgLeuLeuIleIleValPheValXaaTrpIleXaaThrSer 
130135140 
ThrValLeuGluValLeuLysIleArgThrXaaCysLeuThrArgCys 
145150155160 
IleXaaAspLeuProLeuLeuLysTrpLeuArgProSerPheValVal 
165170175 
GluThrLeuLysLeuThrMetArgPheIleValAlaXaaTyrTrpGln 
180185190 
LysArgIleTrpMetArgProThrLysGlnValTyrSerThrLeuLeu 
195200205 
SerLeuLysMetMetXaaIleXaaHisIleValSerXaaPheArgTyr 
210215220 
TyrArgThrValLeuGluCysIleLeuThrLeuIleArgAspLeuArg 
225230235240 
LeuLysThrXaaXaaLeuIleIleXaaLeuValPheIleCysGlyTyr 
245250255 
PheAsnValXaaCysIleSerXaaIleLeuLysLeuThrThrXaaAsn 
260265270 
LeuLysPheLysMetIlePheHisXaaGlnIleAspHisThrLeuXaa 
275280285 
ThrPheLysAspLeuCysXaaLeuThrIleAlaLysIleAsnGlySer 
290295300 
LeuAspHisXaaXaaGluLysValAspSerValValPheIleLeuLeu 
305310315320 
MetThrIleIleMetXaaXaaLysXaaSerProLysLeu 
325330 
(2) INFORMATION FOR SEQ ID NO:66: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 333 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..333 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:66: 
IleTrpTyrTyrArgIleAsnTyrIleValGlyArgGlyAsnPheLeu 
151015 
TyrTyrIleLeuTyrIleXaaXaaThrPheThrXaaIleGlnAsnArg 
202530 
GluGlnSerLeuAspPheXaaLeuThrXaaMetSerGlyIleValLys 
354045 
SerIleIleLeuSerGlyProSerGlyLeuGlyLysThrAlaIleAla 
505560 
LysArgLeuTrpGluTyrIleTrpIleCysGlyValProTyrHisXaa 
65707580 
IleSerSerSerTyrGlyThrArgArgCysXaaLeuProLeuArgXaa 
859095 
GlnArgGlyHisLeuGluGlyAsnSerArgArgLysLeuSerArgThr 
100105110 
TyrXaaValPheArgLysTyrLeuArgAsnPheXaaAsnSerCysGlu 
115120125 
TyrSerGlyTyrXaaXaaSerTyrLeuCysAspGlySerLysHisArg 
130135140 
ArgCysXaaLysSerXaaLysTyrValProAsnAlaLeuLeuGlyVal 
145150155160 
TyrLysThrTyrLeuSerXaaAsnGlyXaaAspGlnAlaSerLeuXaa 
165170175 
LysHisXaaSerXaaArgXaaAspSerSerSerArgAspIleGlyLys 
180185190 
AsnGlyTyrGlyXaaGlyGlnArgSerArgSerIleArgHisTyrTyr 
195200205 
HisXaaArgXaaCysGluPheSerIleXaaXaaValAsnSerAspThr 
210215220 
ThrGlyProTyrXaaAsnValPheXaaHisXaaLeuGluThrXaaAsp 
225230235240 
LeuLysLeuAspAsnXaaXaaTyrAsnSerPheLeuTyrValAlaIle 
245250255 
SerThrSerAsnValLeuValLysTyrXaaAsnLeuProArgLysThr 
260265270 
XaaAsnLeuLysXaaTyrPheIleAspArgXaaIleThrHisTyrGlu 
275280285 
LeuSerArgThrCysValAsnXaaGlnLeuGlnLysSerMetGlyArg 
290295300 
TrpThrIleAsnArgLysArgTrpIleArgXaaTyrLeuTyrTyrXaa 
305310315320 
XaaGlnXaaLeuCysSerLysAsnArgAlaGlnSerSer 
325330 
(2) INFORMATION FOR SEQ ID NO:67: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 1500 base pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: cDNA 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:67: 
ACCATCGAGGTAACCACCTCTCTGGAAGACAGCGTGAATAATGTACTCATGAAACGTTTG60 
GAAACTATACGCCATATGTGGTCTGTCGTATATGATCATTTTGATATTGTGAATGGTAAA120 
GAATGCTGTTATGTGCATACGCATTTGTCTAATCAAAATCTTATACCGAGTACTGTAAAA180 
ACAAATTTGTACATGAAGACTATGGGATCATGCATTCAAATGGATTCCATGGAAGCTCTA240 
GAGTATCTTAGCGAACTGAAGGAATCAGGTGGATGGAGTCCCAGACCAGAAATGCAGGAA300 
TTTGAATATCCAGATGGAGTGGAAGACACTGAATCAATTGAGAGATTGGTAGAGGAGTTC360 
TTCAATAGATCAGAACTTCAGGCTGGTGAATCAGTCAAATTTGGTAATTCTATTAATGTT420 
AAACATACATCTGTTTCAGCTAAGCAACTAAGAACACGTATACGGCAGCAGCTTCCTTTA480 
TACTCTCATCTTTTACCAACACAAAGGGTGGATATTTGTTCATTGGAGTTGATAATAATA540 
CACACAAAGTAATTGGATTCACGGTGGGTCATGACTACCTCAGACTGGTAGAGAATGATA600 
TAGAAAAGCATATCAAAAGACTTCGTGTTGTGCATTTCTGTGAGAAGAAAGAGGACATCA660 
AGTACACGTGTCGATTCATCAAGGTATATAAACCTGGGGATGAGGCTACCTCGACATACG720 
TGTGCGCTATCAAAGTGGAAAGATGCTGTTGTGCTGTGTTTGCAGATTGGCCAGAATCAT780 
GGTATATGGATACTAATGGTATCAAGAAGTATTCTCCAGATGAATGGGTGTCACATATAA840 
AATTTTAATTAATGTAATAGAGAACAAATAATAAGGTTGTAATATCATATAGACAATAAC900 
TAACAATTAATTAGTAACTGTTATCTCTTTTTTAACTAACCAACTAACTATATACCTATT960 
AATACATCGTAATTATAGTTCTTAACATCTATTAATCATTAATTCGCTTCTTTAATTTTT1020 
TATAAACTAACATTGTTAATTGAAAAGGGATAACATGTTACAGAATATAAATTATATATG1080 
GATTTTTTTAAAAAGGAAATACTTGACTGGAGTATATATTTATCTCTTCATTATATAGCA1140 
CGCGTGTTTTCCAATTTTTCCACATCCCATATAATACAGGATTATAATCTCGTTCGAACA1200 
TACGAGAAAGTGGATAAAACAATAGTTGATTTTTTATCTAGGTTGCCAAATTTATTCCAT1260 
ATTTTAGAATATGGGGAAAATATTCTACATATTTATTCTATGGATGATGCTAATACGAAT1320 
ATTATAATTTTTTTTCTAGATAGAGTATTAAATATTAATAAGAACGGGTCATTTATACAC1380 
AATCTCAGGTTATCATCATCCATTAATATAAAAGAATATGTATATCAATTAGTTAATAAT1440 
GATCATCCAGATAATAGGATAAGACTAATGCTTGAAAATGGACGTAGAACAAGACATTTT1500 
(2) INFORMATION FOR SEQ ID NO:68: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 500 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..500 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:68: 
ThrIleGluValThrThrSerLeuGluAspSerValAsnAsnValLeu 
151015 
MetLysArgLeuGluThrIleArgHisMetTrpSerValValTyrAsp 
202530 
HisPheAspIleValAsnGlyLysGluCysCysTyrValHisThrHis 
354045 
LeuSerAsnGlnAsnLeuIleProSerThrValLysThrAsnLeuTyr 
505560 
MetLysThrMetGlySerCysIleGlnMetAspSerMetGluAlaLeu 
65707580 
GluTyrLeuSerGluLeuLysGluSerGlyGlyTrpSerProArgPro 
859095 
GluMetGlnGluPheGluTyrProAspGlyValGluAspThrGluSer 
100105110 
IleGluArgLeuValGluGluPhePheAsnArgSerGluLeuGlnAla 
115120125 
GlyGluSerValLysPheGlyAsnSerIleAsnValLysHisThrSer 
130135140 
ValSerAlaLysGlnLeuArgThrArgIleArgGlnGlnLeuProLeu 
145150155160 
TyrSerHisLeuLeuProThrGlnArgValAspIleCysSerLeuGlu 
165170175 
LeuIleIleIleHisThrLysXaaLeuAspSerArgTrpValMetThr 
180185190 
ThrSerAspTrpXaaArgMetIleXaaLysSerIleSerLysAspPhe 
195200205 
ValLeuCysIleSerValArgArgLysArgThrSerSerThrArgVal 
210215220 
AspSerSerArgTyrIleAsnLeuGlyMetArgLeuProArgHisThr 
225230235240 
CysAlaLeuSerLysTrpLysAspAlaValValLeuCysLeuGlnIle 
245250255 
GlyGlnAsnHisGlyIleTrpIleLeuMetValSerArgSerIleLeu 
260265270 
GlnMetAsnGlyCysHisIleXaaAsnPheAsnXaaCysAsnArgGlu 
275280285 
GlnIleIleArgLeuXaaTyrHisIleAspAsnAsnXaaGlnLeuIle 
290295300 
SerAsnCysTyrLeuPhePheAsnXaaProThrAsnTyrIleProIle 
305310315320 
AsnThrSerXaaLeuXaaPheLeuThrSerIleAsnHisXaaPheAla 
325330335 
SerLeuIlePheTyrLysLeuThrLeuLeuIleGluLysGlyXaaHis 
340345350 
ValThrGluTyrLysLeuTyrMetAspPhePheLysLysGluIleLeu 
355360365 
AspTrpSerIleTyrLeuSerLeuHisTyrIleAlaArgValPheSer 
370375380 
AsnPheSerThrSerHisIleIleGlnAspTyrAsnLeuValArgThr 
385390395400 
TyrGluLysValAspLysThrIleValAspPheLeuSerArgLeuPro 
405410415 
AsnLeuPheHisIleLeuGluTyrGlyGluAsnIleLeuHisIleTyr 
420425430 
SerMetAspAspAlaAsnThrAsnIleIleIlePhePheLeuAspArg 
435440445 
ValLeuAsnIleAsnLysAsnGlySerPheIleHisAsnLeuArgLeu 
450455460 
SerSerSerIleAsnIleLysGluTyrValTyrGlnLeuValAsnAsn 
465470475480 
AspHisProAspAsnArgIleArgLeuMetLeuGluAsnGlyArgArg 
485490495 
ThrArgHisPhe 
500 
(2) INFORMATION FOR SEQ ID NO:69: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 500 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..500 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:69: 
ProSerArgXaaProProLeuTrpLysThrAlaXaaIleMetTyrSer 
151015 
XaaAsnValTrpLysLeuTyrAlaIleCysGlyLeuSerTyrMetIle 
202530 
IleLeuIleLeuXaaMetValLysAsnAlaValMetCysIleArgIle 
354045 
CysLeuIleLysIleLeuTyrArgValLeuXaaLysGlnIleCysThr 
505560 
XaaArgLeuTrpAspHisAlaPheLysTrpIleProTrpLysLeuXaa 
65707580 
SerIleLeuAlaAsnXaaArgAsnGlnValAspGlyValProAspGln 
859095 
LysCysArgAsnLeuAsnIleGlnMetGluTrpLysThrLeuAsnGln 
100105110 
LeuArgAspTrpXaaArgSerSerSerIleAspGlnAsnPheArgLeu 
115120125 
ValAsnGlnSerAsnLeuValIleLeuLeuMetLeuAsnIleHisLeu 
130135140 
PheGlnLeuSerAsnXaaGluHisValTyrGlySerSerPheLeuTyr 
145150155160 
ThrLeuIlePheTyrGlnHisLysGlyTrpIlePheValHisTrpSer 
165170175 
XaaXaaXaaTyrThrGlnSerAsnTrpIleHisGlyGlySerXaaLeu 
180185190 
ProGlnThrGlyArgGluXaaTyrArgLysAlaTyrGlnLysThrSer 
195200205 
CysCysAlaPheLeuXaaGluGluArgGlyHisGlnValHisValSer 
210215220 
IleHisGlnGlyIleXaaThrTrpGlyXaaGlyTyrLeuAspIleArg 
225230235240 
ValArgTyrGlnSerGlyLysMetLeuLeuCysCysValCysArgLeu 
245250255 
AlaArgIleMetValTyrGlyTyrXaaTrpTyrGlnGluValPheSer 
260265270 
ArgXaaMetGlyValThrTyrLysIleLeuIleAsnValIleGluAsn 
275280285 
LysXaaXaaGlyCysAsnIleIleXaaThrIleThrAsnAsnXaaLeu 
290295300 
ValThrValIleSerPheLeuThrAsnGlnLeuThrIleTyrLeuLeu 
305310315320 
IleHisArgAsnTyrSerSerXaaHisLeuLeuIleIleAsnSerLeu 
325330335 
LeuXaaPhePheIleAsnXaaHisCysXaaLeuLysArgAspAsnMet 
340345350 
LeuGlnAsnIleAsnTyrIleTrpIlePheLeuLysArgLysTyrLeu 
355360365 
ThrGlyValTyrIleTyrLeuPheIleIleXaaHisAlaCysPhePro 
370375380 
IlePheProHisProIleXaaTyrArgIleIleIleSerPheGluHis 
385390395400 
ThrArgLysTrpIleLysGlnXaaLeuIlePheTyrLeuGlyCysGln 
405410415 
IleTyrSerIlePheXaaAsnMetGlyLysIlePheTyrIlePheIle 
420425430 
LeuTrpMetMetLeuIleArgIleLeuXaaPhePhePheXaaIleGlu 
435440445 
TyrXaaIleLeuIleArgThrGlyHisLeuTyrThrIleSerGlyTyr 
450455460 
HisHisProLeuIleXaaLysAsnMetTyrIleAsnXaaLeuIleMet 
465470475480 
IleIleGlnIleIleGlyXaaAspXaaCysLeuLysMetAspValGlu 
485490495 
GlnAspIleIle 
500 
(2) INFORMATION FOR SEQ ID NO:70: 
(i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 500 amino acids 
(B) TYPE: amino acid 
(C) STRANDEDNESS: single 
(D) TOPOLOGY: linear 
(ii) MOLECULE TYPE: protein 
(ix) FEATURE: 
(A) NAME/KEY: Protein 
(B) LOCATION: 1..500 
(D) OTHER INFORMATION: /note= "Xaa refers to stop codon in 
the open reading frame." 
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:70: 
HisArgGlyAsnHisLeuSerGlyArgGlnArgGluXaaCysThrHis 
151015 
GluThrPheGlyAsnTyrThrProTyrValValCysArgIleXaaSer 
202530 
PheXaaTyrCysGluTrpXaaArgMetLeuLeuCysAlaTyrAlaPhe 
354045 
ValXaaSerLysSerTyrThrGluTyrCysLysAsnLysPheValHis 
505560 
GluAspTyrGlyIleMetHisSerAsnGlyPheHisGlySerSerArg 
65707580 
ValSerXaaArgThrGluGlyIleArgTrpMetGluSerGlnThrArg 
859095 
AsnAlaGlyIleXaaIleSerArgTrpSerGlyArgHisXaaIleAsn 
100105110 
XaaGluIleGlyArgGlyValLeuGlnXaaIleArgThrSerGlyTrp 
115120125 
XaaIleSerGlnIleTrpXaaPheTyrXaaCysXaaThrTyrIleCys 
130135140 
PheSerXaaAlaThrLysAsnThrTyrThrAlaAlaAlaSerPheIle 
145150155160 
LeuSerSerPheThrAsnThrLysGlyGlyTyrLeuPheIleGlyVal 
165170175 
AspAsnAsnThrHisLysValIleGlyPheThrValGlyHisAspTyr 
180185190 
LeuArgLeuValGluAsnAspIleGluLysHisIleLysArgLeuArg 
195200205 
ValValHisPheCysGluLysLysGluAspIleLysTyrThrCysArg 
210215220 
PheIleLysValTyrLysProGlyAspGluAlaThrSerThrTyrVal 
225230235240 
CysAlaIleLysValGluArgCysCysCysAlaValPheAlaAspTrp 
245250255 
ProGluSerTrpTyrMetAspThrAsnGlyIleLysLysTyrSerPro 
260265270 
AspGluTrpValSerHisIleLysPheXaaLeuMetXaaXaaArgThr 
275280285 
AsnAsnLysValValIleSerTyrArgGlnXaaLeuThrIleAsnXaa 
290295300 
XaaLeuLeuSerLeuPheXaaLeuThrAsnXaaLeuTyrThrTyrXaa 
305310315320 
TyrIleValIleIleValLeuAsnIleTyrXaaSerLeuIleArgPhe 
325330335 
PheAsnPheLeuXaaThrAsnIleValAsnXaaLysGlyIleThrCys 
340345350 
TyrArgIleXaaIleIleTyrGlyPhePheXaaLysGlyAsnThrXaa 
355360365 
LeuGluTyrIlePheIleSerSerLeuTyrSerThrArgValPheGln 
370375380 
PhePheHisIleProTyrAsnThrGlyLeuXaaSerArgSerAsnIle 
385390395400 
ArgGluSerGlyXaaAsnAsnSerXaaPhePheIleXaaValAlaLys 
405410415 
PheIleProTyrPheArgIleTrpGlyLysTyrSerThrTyrLeuPhe 
420425430 
TyrGlyXaaCysXaaTyrGluTyrTyrAsnPhePheSerArgXaaSer 
435440445 
IleLysTyrXaaXaaGluArgValIleTyrThrGlnSerGlnValIle 
450455460 
IleIleHisXaaTyrLysArgIleCysIleSerIleSerXaaXaaXaa 
465470475480 
SerSerArgXaaXaaAspLysThrAsnAlaXaaLysTrpThrXaaAsn 
485490495 
LysThrPhePhe 
500 
__________________________________________________________________________