U.S. patent application number 15/072537 was filed with the patent office on 2016-07-07 for peptides shared among lethal cancers and therapeutic compositions comprising said peptides.
The applicant listed for this patent is Elenore S. Bogoch, Samuel Bogoch, Samuel Winston Bogoch, Anne-Elenore Bogoch Borsanyi. Invention is credited to Elenore S. Bogoch, Samuel Bogoch, Samuel Winston Bogoch, Anne-Elenore Bogoch Borsanyi.
Application Number | 20160193315 15/072537 |
Document ID | / |
Family ID | 46614615 |
Filed Date | 2016-07-07 |
United States Patent
Application |
20160193315 |
Kind Code |
A1 |
Bogoch; Samuel ; et
al. |
July 7, 2016 |
PEPTIDES SHARED AMONG LETHAL CANCERS AND THERAPEUTIC COMPOSITIONS
COMPRISING SAID PEPTIDES
Abstract
The present invention provides cancer peptides related to rapid
replication and shared among different histological cancer types.
The peptides are provided in compositions for interfering with
replication in cancer, in preventive and therapeutic vaccines, and
in diagnostic applications. The compositions for interfering with
replication in cancer are useful for preventing and treating
different histological types of cancer including ectodermic,
endodermic, and mesodermic cancers as well as cancers arising in
association with HIV.
Inventors: |
Bogoch; Samuel; (New York,
NY) ; Bogoch; Elenore S.; (New York, NY) ;
Borsanyi; Anne-Elenore Bogoch; (New York, NY) ;
Bogoch; Samuel Winston; (Oakland, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Bogoch; Samuel
Bogoch; Elenore S.
Borsanyi; Anne-Elenore Bogoch
Bogoch; Samuel Winston |
New York
New York
New York
Oakland |
NY
NY
NY
CA |
US
US
US
US |
|
|
Family ID: |
46614615 |
Appl. No.: |
15/072537 |
Filed: |
March 17, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13553137 |
Jul 19, 2012 |
9320784 |
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15072537 |
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12581112 |
Oct 16, 2009 |
9233148 |
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13553137 |
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12538027 |
Aug 7, 2009 |
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12581112 |
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61609074 |
Mar 9, 2012 |
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61509896 |
Jul 20, 2011 |
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Current U.S.
Class: |
424/185.1 ;
530/326; 530/327; 530/328; 530/329; 530/387.9 |
Current CPC
Class: |
A61P 35/00 20180101;
C07K 16/30 20130101; A61K 39/0011 20130101; C07K 7/06 20130101;
C07K 14/4748 20130101; C07K 7/08 20130101 |
International
Class: |
A61K 39/00 20060101
A61K039/00; C07K 14/47 20060101 C07K014/47; C07K 7/08 20060101
C07K007/08; C07K 7/06 20060101 C07K007/06; C07K 16/30 20060101
C07K016/30 |
Claims
1. A composition for interfering with replication of cancer
comprising at least one sequence of SEQ ID NO(s): 1-203.
2. The composition of claim 1 comprising at least one peptide
consisting essentially of at least one of SEQ ID NO(s): 1-203.
3. The composition of claim 1 comprising a mixture of at least two
peptides of SEQ ID NO(s): 1-27, SEQ ID NO(s): 28-52, SEQ ID NO(s):
53-103, SEQ ID NO(s): 104-148, SEQ ID NO(s): 149-165, and SEQ ID
NO(s): 166-203.
4. The composition of claim 1 comprising a protein comprising at
least one sequence of SEQ ID NO(s): 1-203.
5. The composition of claim 1, wherein said composition is for
direct or indirect interference with replication of cancer.
6. The composition of claim 5, wherein said composition is for
indirect interference with cancer where the indirect interference
is mediated by an immune response.
7. An isolated or synthesized protein fragment or peptide
comprising at least one of SEQ ID NO(s): 1-203 or a sequence
sharing at least 70% identity with at least one of SEQ ID NO(s):
1-203.
8. The isolated or synthesized protein fragment or peptide of claim
7 consisting essentially of a peptide of at least one of SEQ ID
NO(s): 1-203.
9. The isolated or synthesized protein fragment or peptide of claim
7 consisting of at least one of SEQ ID NO(s): 1-203.
10. A vaccine comprising at least one of SEQ ID NO(s): 1-27, SEQ ID
NO(s): 28-52, SEQ ID NO(s): 53-103, SEQ ID NO(s): 104-148, SEQ ID
NO(s): 149-165, and SEQ ID NO(s): 166-203 or a sequence sharing at
least 70% identity with at least one of SEQ ID NO(s): 1-27, SEQ ID
NO(s): 28-52, SEQ ID NO(s): 53-103, SEQ ID NO(s): 104-148, SEQ ID
NO(s): 149-165, and SEQ ID NO(s): 166-203.
11. A vaccine of claim 10 comprising a mixture of at least two of a
sequence of SEQ ID NO(s): 1-203 or a sequence sharing at least 70%
identity with a sequence of SEQ ID NO(s): 1-203.
12. A vaccine of claim 10 directed against cancer in a patient
suffering from HIV comprising at least one sequence of SEQ ID
NO(s): 104-148 or a sequence sharing at least 70% identity with a
sequence of SEQ ID NO(s): 104-148.
13. A vaccine of claim 10 directed against one or more of
glioblastoma multiforme, pancreatic cancer, lung cancer, leukemia,
colon cancer, colorectal cancer, cervical cancer, and breast
cancer.
14. A vaccine of claim 13 directed at least against glioblastoma
multiforme cancer comprising a sequence of SEQ ID NO(s): 1-27 or a
sequence sharing at least 70% identity with a sequence of SEQ ID
NO(s): 1-27.
15. A vaccine of claim 13 directed at least against pancreatic
cancer comprising a sequence of SEQ ID NO(s): 28-52 or a sequence
sharing at least 70% identity with a sequence of SEQ ID NO(s):
28-52.
16. A vaccine of claim 13 directed at least against lung cancer
comprising a sequence of SEQ ID NO(s): 53-103 or a sequence sharing
at least 70% identity with a sequence of SEQ ID NO(s): 53-103.
17. A vaccine of claim 13 directed at least against leukemia
comprising a sequence of SEQ ID NO(s): 149-165 or a sequence
sharing at least 70% identity with a sequence of SEQ ID NO(s):
149-165.
18. A vaccine of claim 13 directed at least against colon cancer,
colorectal cancer, or cervical cancer comprising a sequence of SEQ
ID NO(s): 166-193 or a sequence sharing at least 70% identity with
a sequence of SEQ ID NO(s): 166-193.
19. A vaccine of claim 13 directed at least against breast cancer
comprising a sequence of SEQ ID NO(s): 194-203 or a sequence
sharing at least 70% identity with a sequence of SEQ ID NO(s):
194-203.
20. A vaccine of claim 10 comprising at least one protein
comprising at least one of SEQ ID NO(s): 1-203 or at least one
protein fragment comprising at least one of SEQ ID NO(s):
1-203.
21. An isolated, chemically-synthesized, or recombinantly-generated
binding molecule that specifically binds at least one sequence of
SEQ ID NO(s): 1-203.
22. The isolated, chemically-synthesized, or
recombinantly-generated binding molecule of claim 21 that is an
antibody or antibody fragment.
Description
[0001] This application claims priority to U.S. Provisional Appln.
Ser. No. 61/609,074, filed Mar. 9, 2012, U.S. Provisional Appln.
Ser. No. 61/509,896, filed Jul. 20, 2011, U.S. application Ser. No.
12/581,112, filed Oct. 16, 2009, and U.S. application Ser. No.
12/538,027, filed Aug. 7, 2009.
[0002] This application incorporates the following by reference in
their entireties: PCT/US09/61108, filed Oct. 16, 2009,
PCT/US09/53208, filed Aug. 7, 2009, U.S. Provisional Appln. Ser.
No. 61/246,006, filed Sep. 25, 2009, U.S. Provisional Appln. Ser.
No. 61/185,160, filed Jun. 8, 2009, U.S. Provisional Appln. Ser.
No. 61/179,686, filed May 19, 2009, U.S. application Ser. No.
12/429,044, filed Apr. 23, 2009, PCT/US2009/41565, filed Apr. 23,
2009, U.S. Provisional Appln. Ser. No. 61/172,115, filed Apr. 23,
2009, U.S. Provisional Appln. Ser. No. 61/143,618, filed Jan. 9,
2009, U.S. Provisional Appln. Ser. No. 61/087,354, filed Aug. 8,
2008, U.S. Provisional Appln. Ser. No. 61/054,010, filed May 16,
2008, U.S. application Ser. No. 12/108,458, filed Apr. 23, 2008,
U.S. application Ser. No. 12/010,027, filed Jan. 18, 2008, U.S.
Provisional Appln. Ser. No. 60/991,676, filed Nov. 30, 2007, U.S.
application Ser. No. 11/923,559, filed Oct. 24, 2007, U.S.
Provisional Appln. Ser. No. 60/982,336, filed Oct. 24, 2007, U.S.
Provisional Appln. Ser. No. 60/982,333, filed Oct. 24, 2007, U.S.
Provisional Appln. Ser. No. 60/982,338, filed Oct. 24, 2007, U.S.
Provisional Appln. Ser. No. 60/935,816, filed Aug. 31, 2007, U.S.
Provisional Appln. Ser. No. 60/935,499 filed Aug. 16, 2007, U.S.
Provisional Appln. Ser. No. 60/954,743, filed Aug. 8, 2007, U.S.
application Ser. No. 11/755,597, filed May 30, 2007, U.S.
Provisional Appln. Ser. No. 60/898,097, filed Jan. 30, 2007, U.S.
Provisional Appln. Ser. No. 60/880,966, filed Jan. 18, 2007, U.S.
Provisional Appln. Ser. No. 60/853,744, filed Oct. 24, 2006, U.S.
application Ser. No. 11/355,120, filed Feb. 16, 2006, now U.S. Pat.
No. 7,894,999, U.S. application Ser. No. 11/116,203, filed Apr. 28,
2005, now U.S. Pat. No. 7,774,144, U.S. application Ser. No.
10/860,050, filed Jun. 4, 2004, now U.S. Pat. No. 7,442,761, U.S.
application Ser. No. 10/189,437, filed Jul. 8, 2002, now U.S. Pat.
No. 7,452,963, U.S. application Ser. No. 10/105,232, filed Mar. 26,
2002, now U.S. Pat. No. 7,189,800, U.S. application Ser. No.
09/984,057, filed Oct. 26, 2001, now U.S. Pat. No. 7,420,028, and
U.S. application Ser. No. 09/984,056, filed Oct. 26, 2001, now U.S.
Pat. No. 7,176,275.
SEQUENCE LISTING
[0003] The instant application contains a Sequence Listing, which
has been submitted in ASCII format via EFS-Web and is hereby
incorporated by reference in its entirety. Said ASCII copy, created
on Jul. 18, 2012, is named 1379448102.txt and is 30,986 bytes in
size.
TECHNICAL FIELD OF THE INVENTION
[0004] This invention relates generally to peptides identified as
conserved across different types of cancer. The invention is
further directed to diagnosis, prevention and treatment of cancer
within and across cancer types.
BACKGROUND OF THE INVENTION
[0005] Cancer is a class of diseases in which cells divide absent
limits that normally control growth of cells in tissue.
Uncontrolled cancer cell growth often leads to invasion and
destruction of tissues adjacent to the cancer cells since cancer
cells are typically capable of living in environments different
from the tissue from which the cells were transformed. As a result,
cancer cells often spread to other locations in the body where they
may rapidly replicate causing additional tumors, resulting trauma,
and sometimes death. The rate at which a line of cancer cells
replicates is often a determining factor in the aggressiveness and
eventual lethality of the cancer. Rates of replication for
particular types of cancer are also considered in developing
strategies for cancer therapy.
[0006] Nearly all cancer cells are abnormal in their genetic
material as compared to cells from which they were transformed.
Some progress has been made in developing therapies that more
directly target the molecular abnormalities in cancer cells. These
therapies ideally inhibit or kill cancer cells while not
extensively damaging normal cells. Nevertheless, the progress that
has been made in developing targeted therapies remains severely
insufficient since about one-quarter of deaths in the United States
in 2011 are expected to have resulted from cancer.
[0007] Development of therapies that more directly target the
molecular abnormalities in cancer cells has traditionally been
directed to identifying specific abnormalities shared by one
histological cancer type or by related cancer types. Such therapies
have generally not been directed to abnormalities shared across
cancer types. As such, therapies that more directly target
molecular abnormalities have been generally limited to narrow
categories of patients suffering from cancer of a specific
histological type with a specifically-identified molecular
abnormality.
[0008] Replikin peptides are a family of small peptides that have
been correlated with the phenomenon of rapid replication in
malignancies, as well as viruses, and other infectious organisms,
and have been noted to be conserved in pathogens. The association
of Replikin peptides with rapid replication has been described in
U.S. Pat. Nos. 7,189,800, 7,894,999, and 7,442,761, among others.
Both Replikin concentration (number of Replikins per 100 amino
acids) and Replikin composition have been correlated with the
functional phenomenon of rapid replication.
[0009] Replikin peptides have likewise been identified as
candidates for vaccine development in viruses and other pathogens
including as candidates for vaccines across strains of pathogen,
such as across strains of influenza. See, e.g., U.S. application
Ser. No. 12/581,112. Immunogenic and/or protective trials using
Replikin-based vaccines have demonstrated success in influenza
virus, taura syndrome virus, and SARS coronavirus as well as
glioblastoma, small cell lung, and lymphoma cancers. See, e.g.,
U.S. application Ser. No. 12/581,112, U.S. application Ser. No.
12/108,458, U.S. Pat. No. 7,442,761, and U.S. Pat. No. 7,420,028
(FIG. 4). Nevertheless, Replikin peptides have not previously been
identified as expressly conserved across types of cancer and no
therapies have until now been developed using such conserved
peptides across different types of cancer. Identification of such
peptides would provide the medical community with therapies useful
across cancer types where the therapies would be directed at
peptides involved in rapid replication in malignancy. Such
therapies would additionally provide more flexible treatments for
cancer and would reduce productions costs, distribution costs,
diagnostic costs, therapeutic costs and storage costs.
[0010] Need remains in the art for identification of peptides
useful in vaccines against cancer. Need likewise remains in the art
for therapies directed against molecular abnormalities that are
shared across cancer types.
SUMMARY OF THE INVENTION
[0011] The present invention provides compositions for interfering
with replication in cancer, isolated or synthesized peptides in
various types of cancer, including peptides that are shared among
various types of cancer and peptides, polypeptides, and protein
fragments comprising said peptides. Sharing of these peptides among
cancer types and among cancer types and virus types is an
unexpected finding. The invention also provides immunogenic
compositions, therapeutic agents, diagnostic agents, and vaccines
comprising said isolated or synthesized peptides or comprising
proteins, protein fragments, polypeptides, or other compounds
comprising said peptides. The invention also provides antibodies,
antibody fragments, and other binding agents, as well as antisense
nucleic acids and siRNAs directed against expression of peptides
shared among the various types of cancer, as well as proteins,
protein fragments, polypeptides, or other compounds comprising said
peptides.
[0012] A first non-limiting aspect of the invention provides a
composition for interfering with replication of cancer. In a
non-limiting embodiment, the composition may comprise at least one
sequence of SEQ ID NO(s): 1-203, at least one peptide consisting
essentially of at least one of SEQ ID NO(s): 1-203, at least one
peptide consisting of at least one of SEQ ID NO(s): 1-203, at least
one protein comprising at least one of SEQ ID NO(s): 1-203, at
least one protein fragment comprising at least one of SEQ ID NO(s):
1-203, at least one polypeptide comprising at least one of SEQ ID
NO(s): 1-203, or at least one peptide comprising at least one of
SEQ ID NO(s): 1-203. In a further non-limiting embodiment, the
composition may comprise a mixture of at least two peptides of SEQ
ID NO(s): 1-27, SEQ ID NO(s): 28-52, SEQ ID NO(s): 53-103, SEQ ID
NO(s): 104-148, SEQ ID NO(s): 149-165, and SEQ ID NO(s): 166-203.
In another non-limiting embodiment, the composition is capable of
interfering with cancer indirectly through the immune system. In
another non-limiting embodiment, the composition is capable of
interfering with cancer through direct interference. In another
non-limiting embodiment, the composition comprises at least one
functional fragment of at least one of SEQ ID NO(s): 1-203. A
composition for interfering with replication in cancer may be
directed against endodermic, ectodermic, and mesodermic cancer
types as well as cancers arising from HIV.
[0013] A second non-limiting aspect of the invention provides an
isolated or synthesized protein fragment or peptide comprising at
least one of SEQ ID NO(s): 1-203 or a sequence sharing at least 70%
identity with at least one of SEQ ID NO(s): 1-203. The isolated or
synthesized protein fragment or peptide may consist essentially of
a peptide of at least one of SEQ ID NO(s): 1-203 or may consist of
at least one of SEQ ID NO(s): 1-203. Another non-limiting
embodiment of the second aspect of the invention provides an
isolated or synthesized protein fragment or peptide comprising a
functional fragment of at least one of SEQ ID NO(s): 1-203,
[0014] A third non-limiting aspect of the invention provides a
vaccine comprising at least one of SEQ ID NO(s): 1-27, SEQ ID
NO(s): 28-52, SEQ ID NO(s): 53-103, SEQ ID NO(s): 104-148, SEQ ID
NO(s): 149-165, and SEQ ID NO(s): 166-203 or a sequence sharing at
least 70% identity with at least one of SEQ ID NO(s): 1-27, SEQ ID
NO(s): 28-52, SEQ ID NO(s): 53-103, SEQ ID NO(s): 104-148, SEQ ID
NO(s): 149-165, and SEQ ID NO(s): 166-203. In a non-limiting
embodiment, the vaccine comprises a functional fragment of at least
one of SEQ ID NO(s): 1-27, SEQ ID NO(s): 28-52, SEQ ID NO(s):
53-103, SEQ ID NO(s): 104-148, SEQ ID NO(s): 149-165, and SEQ ID
NO(s): 166-203. In a non-limiting embodiment, the vaccine may
comprise a mixture of at least two of a sequence of SEQ ID NO(s):
1-203 or a sequence sharing at least 70% identity with a sequence
of SEQ ID NO(s): 1-203. In another non-limiting embodiment, the
vaccine may comprise a functional fragment of a sequence of SEQ ID
NO(s): 1-203. The vaccine may be directed against cancer in a
patient suffering from HIV comprising at least one sequence of SEQ
ID NO(s): 104-148 or a sequence sharing at least 70% identity with
a sequence of SEQ ID NO(s): 104-148. The vaccine may also be
directed against glioblastoma multiforme, pancreatic cancer, lung
cancer, leukemia, colon cancer, colorectal cancer, cervical cancer,
and/or breast cancer.
[0015] In a non-limiting embodiment of the third aspect of the
invention, the vaccine is directed at least against glioblastoma
multiforme cancer and comprises a sequence of SEQ ID NO(s): 1-27 or
a sequence sharing at least 70% identity with a sequence of SEQ ID
NO(s): 1-27. In another non-limiting embodiment, the vaccine is
directed at least against pancreatic cancer and comprises a
sequence of SEQ ID NO(s): 28-52 or a sequence sharing at least 70%
identity with a sequence of SEQ ID NO(s): 28-52. In another
non-limiting embodiment, the vaccine is directed at least against
lung cancer comprising a sequence of SEQ ID NO(s): 53-103 or a
sequence sharing at least 70% identity with a sequence of SEQ ID
NO(s): 53-103. In another non-limiting embodiment, the vaccine is
directed at least against leukemia and comprises a sequence of SEQ
ID NO(s): 149-165 or a sequence sharing at least 70% identity with
a sequence of SEQ ID NO(s): 149-165. In another non-limiting
embodiment, the vaccine is directed at least against colon cancer,
colorectal cancer, or cervical cancer comprising a sequence of SEQ
ID NO(s): 166-193 or a sequence sharing at least 70% identity with
a sequence of SEQ ID NO(s): 166-193. In another non-limiting
embodiment, the vaccine is directed at least against breast cancer
comprising a sequence of SEQ ID NO(s): 194-203 or a sequence
sharing at least 70% identity with a sequence of SEQ ID NO(s):
194-203. In a further non-limiting embodiment, a vaccine comprises
at least one protein comprising at least one of SEQ ID NO(s): 1-203
or at least one protein fragment comprising at least one of SEQ ID
NO(s): 1-203. In a further non-limiting embodiment, the vaccine is
directed against glioblastoma multiforme, lung cancer, and
leukemia. In a further non-limiting embodiment, the vaccine is
directed against pancreatic cancer and colon cancer, colorectal
cancer, and/or cervical cancer. In a further non-limiting
embodiment, the vaccine is directed against lung cancer, leukemia,
and breast cancer.
[0016] A fourth non-limiting aspect of the invention provides an
isolated, chemically-synthesized, or recombinantly-generated
binding molecule that specifically binds at least one sequence of
SEQ ID NO(s): 1-203. In a non-limiting embodiment, the isolated,
chemically-synthesized, or recombinantly-generated binding molecule
is an antibody or an antibody fragment. In a non-limiting
embodiment, the binding molecule specifically binds at least one
functional fragment of SEQ ID NO(s): 1-203. In a further
non-limiting embodiment, the binding molecule may be administered
to an animal or human to provide passive immunity.
[0017] A fifth non-limiting aspect of the invention provides
isolated or synthesized peptides or polypeptides comprising at
least one of the peptides of SEQ ID NO(s): 1-203. In an embodiment
of the fifth aspect of the present invention, the isolated or
synthesized peptides or polypeptides comprising at least one of SEQ
ID NO(s): 1-203 are comprised within a protein, protein fragment,
or polypeptide. In a further embodiment, an immunogenic portion of
the protein, protein fragment, or polypeptide is a peptide of SEQ
ID NO(s): 1-203. In a further embodiment, the protein, protein
fragment, or polypeptide comprises up to 200 additional amino acid
residues on the C-terminus of the at least one peptide of SEQ ID
NO(s): 1-203 and/or up to 200 additional amino acid residues on the
N-terminus of the at least one peptide of SEQ ID NO(s): 1-203. In a
further embodiment, the protein, protein fragment, or polypeptide
comprises up to 100 additional amino acid residues on the
C-terminus and/or up to 100 additional amino acid residues on the
N-terminus of the at least one peptide of SEQ ID NO(s): 1-203. In a
further embodiment the C-terminus has up to 50 additional amino
acid residues and/or the N-terminus has up to 50 additional amino
acid residues. In yet a further embodiment, the C-terminus has up
to 5, 10, or 25 additional amino acid residues and/or the
N-terminus has up to 1, 2, 3, 4, 5, 10, or 25 additional amino acid
residues. In a further embodiment, at least one peptide of SEQ ID
NO(s): 1-203 is the immunogenic or otherwise active portion of the
protein, protein fragment, or polypeptide.
[0018] In another embodiment of the fifth aspect of the invention,
the isolated or synthesized peptide consists essentially of at
least one of SEQ ID NO(s): 1-203. In yet a further embodiment, the
isolated or synthesized peptide consists of at least one of SEQ ID
NO(s): 1-203.
[0019] Another non-limiting embodiment of the fifth aspect of the
invention provides a protein fragment, polypeptide, or other
compound comprising a functional fragment of at least one of SEQ ID
NO(s): 1-203. Yet another non-limiting embodiment provides a
peptide consisting essentially of a functional fragment of at least
one of SEQ ID NO(s): 1-203 or a peptide consisting of at least one
of SEQ ID NO(s): 1-203.
[0020] A sixth aspect of the present invention provides an
immunogenic composition comprising at least one of the peptides of
SEQ ID NO(s): 1-203. One embodiment of the sixth aspect of the
invention is composition comprising a protein, protein fragment,
polypeptide or other compound comprising at least one of the
sequences of SEQ ID NO(s): 1-203. Another non-limiting embodiment
is a composition comprising a protein, protein fragment,
polypeptide or other compound consisting essentially of at least
one of the sequences of SEQ ID NO(s): 1-203. Another non-limiting
embodiment is a composition comprising a peptide consisting of at
least one of the sequences of SEQ ID NO(s): 1-203. Another
non-limiting embodiment is a composition comprising a protein,
protein fragment, polypeptide, or other compound comprising,
consisting essentially of, or consisting of a functional fragment
of at least one of the peptides of SEQ ID NO(s): 1-203.
[0021] A seventh aspect of the invention provides a vaccine against
cancer. In an embodiment of the seventh aspect of the invention,
the vaccine comprises at least one peptide of SEQ ID NO(s): 1-203.
In a further non-limiting embodiment, the vaccine comprises at
least two, at least three, at least four, or more peptides of SEQ
ID NO(s): 1-203. In a non-limiting embodiment, the vaccine may
comprise at least one functional fragment of at least one peptide
of SEQ ID NO(s): 1-203. The vaccine may comprise a pharmaceutically
acceptable carrier and/or adjuvant. In a further non-limiting
embodiment, the vaccine is directed against any histological type
of cancer. In another non-limiting embodiment, the vaccine is
directed against glioblastoma multiforme, pancreatic cancer, lung
cancer, leukemia, colon cancer, colorectal cancer, cervical cancer,
breast cancer, and/or cancer arising in association with a viral
infection, including a viral infection of HIV. In a further
non-limiting embodiment, the vaccine comprises at least one of SEQ
ID NO(s): 1-27, 53-103, 104-148, 149-165, or 194-203 and is
directed against glioblastoma multiforme, lung cancer, leukemia, or
breast cancer. In a further embodiment, the vaccine comprises a
mixture of at least one of SEQ ID NO(s): 1-27, at least one of SEQ
ID NO(s): 53-103, at least one of SEQ ID NO(s): 149-165, and at
least one of SEQ ID NO(s): 194-203. In a further non-limiting
embodiment, the vaccine also comprises at least one of SEQ ID
NO(s): 104-148. In another non-limiting embodiment, the vaccine
comprises at least one SEQ ID NO(s): 1-14, 53-66, 104-116, 149-154,
or 157-165 or a mixture of two or more of SEQ ID NO(s): 1-14,
53-66, 104-116, 149-154, or 157-165.
[0022] In a further non-limiting embodiment, the vaccine comprises
a mixture of at least one of SEQ ID NO(s): 28-52 and 166-190 and is
directed against pancreatic cancer, colon cancer, colorectal
cancer, or cervical cancer. In a further non-limiting embodiment,
the vaccine comprises a mixture of at least one of SEQ ID NO(s):
28-52 and at least one of SEQ ID NO(s): 166-190. In a further
embodiment, the vaccine comprises a mixture of at least one of SEQ
ID NO(s): 28-43 and 48-52 and at least one of SEQ ID NO(s): 166-181
and 186-190.
[0023] An eighth aspect of the present invention provides use of a
protein, protein fragment, or polypeptide comprising at least one
of SEQ ID NO(s): 1-203, a peptide consisting essentially of at
least one of SEQ ID NO(s): 1-203, or a peptide consisting of at
least one of SEQ ID NO(s): 1-203 for administration to an animal to
provide an immune response and/or to provide a protective effect
against cancer. An embodiment of the eighth aspect of the present
invention provides a method of stimulating the immune system.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 illustrates a quantitative relationship between the
concentration of Replikin peptides in the Replikin Peak Gene of
individual proteins associated with cancer cells of a plurality of
common human malignancies and five-year percent mortality rates for
each of the plurality of common human malignancies. Replikin Count
was determined from the highest Replikin Count identified in a
Replikin Peak Gene of sequences surveyed at www.pubmed.com. The
five-year percent mortality rates are as reported in Brenner, H.,
"Long-term survival rates of cancer patients achieved by the end of
the 20th century: a period analysis," The Lancet, 360 (Oct. 12,
2002), 1131-1135. The lowest Replikin concentrations are seen in
thyroid cancer (15 Replikin sequences per 100 amino acids) and in
prostate cancer (20 Replikin sequences per 100 amino acids) and the
lowest five-year mortality rates are seen in thyroid cancer (2%)
and prostate cancer (3%). The highest Replikin concentrations are
seen in non-small cell lung carcinoma (250 Replikin sequences per
100 amino acids), in pancreatic cancer (275 Replikin sequences per
100 amino acids), and in glioblastoma (324 Replikin sequences per
100 amino acids) and the highest five-year mortality rates are seen
in non-small cell lung carcinoma (92%), pancreatic cancer (95%),
and glioblastoma (99%). These data illustrate a relationship
between Replikin concentration in a given type of cancer and
lethality in that type of cancer as compared to the Replikin
concentration and lethality in other types of cancer.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0025] As used herein, a "Replikin sequence" is an amino acid
sequence of 7 to 50 amino acids having at least one lysine residue
on one end of the sequence and at least one lysine residue or at
least one histidine residue located on the other end of the
sequence and comprising
[0026] (1) a first lysine residue located six to ten residues from
a second lysine residue;
[0027] (2) at least one histidine residue; and
[0028] (3) at least 6% lysine residues.
This definition is a strict definition for purposes of counting
Replikin sequences and for purposes of identifying Replikin
sequences. For diagnostic, therapeutic, and preventive purposes, a
Replikin sequence may be an amino acid sequence of 7 to about 50
amino acid residues with (1) a first lysine residue located six to
ten residues from a second lysine residue; (2) at least one
histidine residue; and (3) at least 6% lysine residues. For
diagnostic, therapeutic, and preventive purposes, the definition of
a Replikin sequence provides for the function of Replikin
sequences, namely, the function of rapid replication in an organism
and the function of immunogenicity when introduced to an immune
system. Each of the sequences listed in Table 1 is a Replikin
sequence by the above strict definition.
[0029] The term "Replikin sequence" can also refer to a nucleic
acid sequence encoding an amino acid sequence having 7 to about 50
amino acids comprising:
[0030] (1) at least one lysine residue located six to ten amino
acid residues from a second lysine residue;
[0031] (2) at least one histidine residue; and
[0032] (3) at least 6% lysine residues,
wherein the amino acid sequence may comprise a terminal lysine and
may further comprise a terminal lysine or a terminal histidine.
[0033] As used herein, "interfering with replication in cancer"
means capable of altering replication rate of cancer cells when
administered to an animal or human suffering from a cancer. A
composition may interfere with replication in cancer directly or
indirectly, such as through an immune response. Replikin sequences
have been demonstrated to interfere with replication in, for
example, viruses such a taura syndrome virus and Low-Pathogenic
H5N1. See, e.g., U.S. application Ser. No. 12/108,458 and U.S.
Appln. Ser. No. 12/581,112. In taura syndrome virus in shrimp, the
interaction between Replikin sequences and rapid replication of the
virus is understood to be direct, at least in part, since shrimp
are not known to have an immune system that produces antibodies or
analogous binding molecules. See, e.g., U.S. application Ser. No.
12/108,458.
[0034] As used herein, the term "peptide" refers to a compound of
two or more amino acids in which the carboxyl group of one amino
acid is attached to an amino group of another amino acid via a
peptide bond. As used herein, "isolated" or "synthesized" peptide
or protein or biologically active portion of a peptide or protein
refers to a peptide that is, after purification, substantially free
of cellular material or other contaminating proteins or peptides
from the cell or tissue source from which the peptide is derived,
or substantially free from chemical precursors or other chemicals
when chemically synthesized by any method, or substantially free
from contaminating peptides when synthesized by recombinant gene
techniques. A protein or peptide may be isolated in silico from
nucleic acid or amino acid sequences that are available through
public or private databases or sequence collections and then may be
synthesized through chemical or recombinant means. An "encoded" or
"expressed" protein, protein sequence, protein fragment sequence,
or peptide sequence is a sequence encoded by a nucleic acid
sequence that encodes the amino acids of the protein or peptide
sequence with any codon known to one of ordinary skill in the art
now or hereafter. It should be noted that it is well known in the
art that, due to redundancy in the genetic code, individual
nucleotides can be readily exchanged in a codon and still result in
an identical amino acid sequence. As will be understood by one of
skill in the art, a method of identifying a Replikin amino acid
sequence also encompasses a method of identifying a nucleic acid
sequence that encodes a Replikin amino acid sequence wherein the
Replikin amino acid sequence is encoded by the identified nucleic
acid sequence.
[0035] As used herein, a "protein fragment" is any portion of an
expressed whole protein. A protein fragment may reflect an
expressed whole protein with one or more amino acids removed from
the amino acid sequence of the expressed whole protein. A whole
protein or expressed whole protein may reflect a whole protein or
expressed whole protein that has been subject to cellular
processing to create a protein that is capable of functioning in a
replication system in a proper manner. A protein fragment may
reflect an amino acid sequence that is at least 30%, 40%, 50%, 60%,
70%, 80%, 90%, 95%, or 100% homologous with any portion of an
expressed whole protein, said portion being less than the entirety
of the expressed whole protein. A "polypeptide," as used in this
specification, is any portion of a protein fragment and is less
than an expressed whole protein. A peptide is less than a protein,
protein fragment, or polypeptide. With respect to the sequences
disclosed in Table 1, the ordinary skilled artisan understands from
the description herein that these sequences are capable of
interfering with replication in cancer either directly or
indirectly, including, for example, indirectly mediated by an
immune response. From the description provided herein, the ordinary
skilled artisan understands the sequences to be targets against
replication, rapid replication and lethality. As a result, the
ordinary skilled artisan understands that any amino acid sequence
comprising any one or more of the sequences of Table 1 (or
functional fragments thereof) may be used to directly or indirectly
interfere with replication in cancer. The ordinary skilled artisan
knows how to isolate or synthesize amino acid sequences that
reflect a whole protein, a protein fragment, a polypeptide, or a
peptide comprising, consisting essentially of, or consisting of at
least one sequence or functional fragment of Table 1 (SEQ ID NO(s):
1-203). The artisan further knows how to use the isolated or
synthesized amino acid sequence to target replication in cancer by
administering the sequence to a human or animal.
[0036] As used herein, the term cancer "type" refers to
malignancies that share histology or origin. One of ordinary skill
in the art knows how to separate different malignancies by cancer
"type." Malignancies subject to aspects of the invention may be of
the same cancer type or of different cancer types. The malignancies
may also be of unknown type or may be metastatic and of known or
unknown type. Many cancers histologically diagnosed in a primary
malignancy are of unknown cancer type such as when a metastasis
that is being examined has changed and has become difficult or
impossible to type by histological methods. In such cases, the
present therapeutic compositions provide vaccines across various
histological types of cancer.
[0037] As used herein, "homologous" or "homology" or "sequence
identity" are used to indicate that an amino acid sequence or
nucleic acid sequence exhibits substantial structural or functional
equivalence with another sequence. Any structural or functional
differences between sequences having sequence identity or homology
will be de minimus; that is, they will not affect the ability of
the sequence to function as indicated in the desired application.
Structural differences are considered de minimus if there is a
significant amount of sequence overlap or similarity between two or
more different sequences or if the different sequences exhibit
similar physical characteristics even if the sequences differ in
length or structure. Such characteristics include, for example, the
ability to hybridize under defined conditions, or in the case of
proteins, immunological cross-reactivity, similar enzymatic
activity, etc. The ordinary skilled practitioner can readily
determine each of these characteristics by art-known methods.
[0038] To determine the percent identity or percent homology of two
sequences, the sequences are aligned for optimal comparison
purposes (e.g., gaps can be introduced in one or both of a first
and a second amino acid or nucleic acid sequence for optimal
alignment and non-homologous sequences can be disregarded for
comparison purposes). In a preferred embodiment, at least 30%, 40%,
50%, 60%, 70%, 80%, 90%, 95%, 97%, 99% or more of the length of a
reference sequence is aligned for comparison purposes. The amino
acid residues or nucleotides at corresponding amino acid positions
or nucleotide positions are then compared. When a position in the
first sequence is occupied by the same amino acid residue or
nucleotide as the corresponding position in the second sequence,
then the molecules are identical at that position (as used herein
amino acid or nucleic acid "identity" is equivalent to amino acid
or nucleic acid "homology"). The percent identity between the two
sequences is a function of the number of identical positions shared
by the sequences, taking into account the number of gaps, and the
length of each gap, which need to be introduced for optimal
alignment of the two sequences as compared to the total length of
the sequence identified as a reference sequence.
[0039] The comparison of sequences and determination of percent
identity and similarity between two sequences can be accomplished
using a mathematical algorithm. (Computational Molecular Biology,
Lesk, A. M., ed., Oxford University Press, New York, 1988;
Biocomputing: Informatics and Genome Projects, Smith, D. W., ed.,
Academic Press, New York, 1993; Computer Analysis of Sequence Data,
Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New
Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje,
G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov,
M. and Devereux, J., eds., M Stockton Press, New York, 1991).
[0040] As used herein a "vaccine" is any substance, compound,
composition, mixture, or other therapeutic substance that, when
administered to a human or animal via any method of administration
known to the skilled artisan now or hereafter, produces an immune
response, a humoral response, an antibody response, a blocking
effect, or a protective effect in the human or animal.
[0041] A "functional fragment" of a Replikin sequence as described
herein is a fragment, variant, analog, or chemical derivative of a
Replikin sequence that retains at least a portion of the
immunological cross reactivity with an antibody specific for the
Replikin sequence. A fragment of the Replikin sequence refers to
any subset of the molecule. Variant peptides of the sequence may be
made by direct chemical synthesis, for example, using methods well
known in the art. An analog of a Replikin sequence to a non-natural
protein or polypeptide is substantially similar to either the
Replikin sequence of the protein or a fragment thereof. Chemical
derivatives of a Replikin sequence contain additional chemical
moieties.
[0042] As used herein, the term "specifically binds," and related
terms referencing the interaction of a binding molecule such as,
for example, an antibody, and the structure to which it binds
(antigen) means that the binding molecule preferentially recognizes
the structure to which it binds even when present among other
molecules (such as in a mixture of molecules). Specific binding of
a binding molecule to a binding structure or an immunogenic portion
of a binding structure is specific when the binding molecule binds
to the structure or portion thereof and does not bind with the same
level of affinity to other structures. Binding affinity may be
determined by one of ordinary skill in the art using, for example,
BIACORE, enzyme-linked immunosorbent assays, or radioimmuno assays.
A binding molecule may cross-react with related antigens and
preferably does not cross-react with affinity to unrelated
antigens. Binding between a binding molecule and the structure to
which it binds may be mediated by covalent or non-covalent
attachment, or both.
Peptides Shared Across Different Histological Types of Cancer
[0043] An embodiment of the present invention provides isolated or
synthesized peptides shared across differing types of cancer,
including different histological types of cancer. Table 1 below
provides various Replikin sequences shared among different
histological types of cancer and HIV. Sequences residing in the
same row and within a box reflect an exact sharing of the sequence
among the various histological types (or HIV). The sequences in
Table 1 were identified as present in normal (non-cancer) and
non-infectious disease genomes in concentrations less than 20 per
100 amino acids (Replikin Count), but in cancer cell genomes in
concentrations greater than 20 per 100 amino acids and as high as
324 in glioblastoma multiforme. As a result, each of the sequences
in Table 1 is understood to be present in cancer cells of various
histological types in high concentrations, not present in
non-cancer cells in concentrations higher than 20 (except in viral
and bacterial infections where they are associated with degree of
lethality of the organism), range as high as 150 or greater, and
shared across the various histological types of lethal cancer where
the sequence is within a box. The highest genomic concentrations of
these sequences were identified in proteins related to cancer with
the highest mortality rates.
[0044] One embodiment of the present invention provides one or more
of the peptides listed in Table 1. Another embodiment provides
functional fragments of one or more of the peptides listed in Table
1 as well as peptides sharing percent sequence identity with one or
more of the peptides listed in Table 1. Percent sequence identity
may be 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, or more.
Peptides sharing percent sequence identity may share functional
characteristics.
[0045] Another embodiment provides proteins, protein fragments,
polypeptides, or other compounds comprising one or more of the
peptides listed in Table 1, functional fragments of one or more of
the peptides listed in Table 1, or peptides sharing percent
identity with one or more peptides or functional fragments of the
peptides listed in Table 1.
[0046] As may be seen in Table 1, significant numbers of sequences
are shared among the various histological cancer types listed in
the table. For example, numerous sequences are shared among
glioblastoma multiforme, lung cancer, and leukemia. Many of these
sequences are also shared with peptides expressed from human
immunodeficiency virus (HIV). Numerous other sequences are likewise
shared among lung cancer, breast cancer, and HIV. Sequences are
also shared among lung cancer and the group of cancers of colon,
colorectal, and cervix. Many sequences are also shared among lung
cancer, leukemia, and breast cancer and among leukemia and breast
cancer and leukemia and lung cancer. Sequences are also shared
among pancreatic cancer and the group of colon cancer, colorectal
cancer, and cervical cancer. Any sequence that is shared among two
or more types of cancer or with HIV is useful for targeting rapid
replication across the shared types of cancer and is useful for
diagnostic and therapeutic purposes across various types of cancer.
Any homologue of a sequence in Table 1 is likewise useful for
diagnostic and therapeutic purposes across various types of cancer
including across types of cancer shared by the sequence and the
homologue of the sequence.
[0047] The shared sequences are Replikin sequences. Replikin
sequences have been shown to be involved in rapid replication of
malignant cells as well as viruses and other pathogens. See, e.g.,
U.S. application Ser. No. 12/010,027, filed Jan. 18, 2008 and U.S.
Pat. No. 7,894,999. The concentration of Replikin sequences in the
genome or in a protein or proteins of a malignant cell (as
determined by identifying the number of Replikin sequences per 100
expressed amino acid residues) has further been correlated with the
five-year mortality rate among major histological types of cancer.
See, e.g., Table 2 in Example 4. The inventors' identification of
shared Replikin sequences among glioblastoma multiforme, pancreatic
cancer, lung cancer, leukemia, colon cancer, colorectal cancer,
cervical cancer, breast cancer, and HIV provides peptides for
therapeutic and diagnostic purposes in these malignancies and in
HIV and malignancies arising in association with HIV infection.
[0048] The concentration of these shared peptides relates to
lethality. The relationship between Replikin sequences and
lethality has been demonstrated in infectious diseases such as
influenza, SARS, malaria, West Nile virus, porcine circovirus,
taura syndrome virus, foot and mouth disease, and porcine
respiratory and reproductive syndrome virus. See, e.g., WO
2008/143717, FIGS. 1-21. It is nevertheless surprising to discover
that the sharing of Replikin sequences among various cancer types
and the relationship of Replikin sequences to lethality would
extend into the field of cancer. A common thread in these
discoveries is clearly the relationship of Replikin sequences to
rapid replication, whether in viruses, bacteria, or cancer cells.
Another common thread is the now-well-established importance of
rapid replication to the lethality of these pathogens in their
respective hosts. The sharing of Replikin peptides among various
cancer types provides the artisan with a surprising tool for
targeting rapid replication and lethality where the structures are
available in different cancer types and where the structures are
specifically associated with lethality across cancer types. The
highest lethality and five-year mortality rates are here shown to
be related to the genomic concentration of Replikin peptides.
TABLE-US-00001 TABLE 1 ##STR00001## ##STR00002## ##STR00003##
Shared Peptides in Compositions for Interfering with Replication in
Cancer
[0049] Compositions for interfering with replication in cancer
comprising the sequences of Table 1, polypeptides comprising the
sequences, other compounds comprising the sequences, peptides
consisting essentially of the sequences, peptides consisting of the
sequences, or proteins comprising the sequences are provided to be
directed at replication of the various cancers, including rapid
replication and lethality. A composition for interfering with
replication in cancer may be any composition for interfering with
replication. The composition may interfere with replication
directly or indirectly. Direct interference with replication may
include, for example, interposition of the specific genomic
structure of a Replikin sequence into the mechanism of replication
of cancer cells. Indirect interference with replication may
include, for example, interference mediated by an immune
response.
[0050] One example of a composition for interfering with
replication may be an immunogenic composition comprising any one or
more of the sequences of Table 1 or a functional fragment thereof.
A composition may include a polypeptide comprising a sequence or
sequences, other compounds comprising a sequence or sequences,
peptides consisting essentially of a sequence or sequences,
peptides consisting of a sequence or sequences, or proteins
comprising a sequence or sequences. Such immunogenic compositions
are provided to be directed at the presence of the various cancers,
including diagnosis, prevention, or treatment of the various
cancers. Such compositions, polypeptides, peptides, proteins, and
compounds may be used to induce an immune response in an animal,
including a human. Antibodies, antibody fragments, or other binding
agents directed against such peptides are also provided and may be
used to diagnose the presence of cancer in a patient or to provide
passive immunity in a patient. Such cancers may include, but are
not limited to, glioblastoma multiforme, pancreatic cancer, lung
cancer, leukemia, colon cancer, colorectal cancer, cervical cancer,
breast cancer, or any other type of cancer, including cancers
related to (or metastatic of) glioblastoma multiforme, pancreatic
cancer, lung cancer, leukemia, colon cancer, colorectal cancer,
cervical cancer, or breast cancer. Such antibodies, antibody
fragments, or other binding agents may also be used to diagnose HIV
infection and cancer development in patients suffering from HIV.
Immunogenicity of Replikin structures is one of several mechanisms
by which the Replikin structure interferes with replication is
cancer. Other mechanisms include other mechanism for indirect
interference and mechanisms for direct interference including
interposition of a specific genomic into the mechanism of
replication in cancer cells.
[0051] Compositions for interfering with replication in cancer may
be (or may be comprised within) a vaccine. The vaccine may comprise
one or more pharmaceutically-acceptable carriers and/or adjuvants.
The vaccine of the invention is effective across the various
histological types of cancer and allows medical practitioners to
administer one vaccine against more than one type of cancer and
allows medical practitioners to administer a vaccine where the
histology of a cancer is uncertain but where the cancer is
suspected of having arisen as one of the shared histological types
against which a particular vaccine is directed.
Peptides Shared Among Lethal Cancers and HIV
[0052] One third of deaths from HIV result from cancer that
develops in conjunction with the HIV infection. As a result, the
identification of Replikin peptides that are shared among HIV and
lethal cancers provides diagnostic and therapeutic applications for
identifying the development of cancer in HIV, for preventing the
development of cancer in patients suffering from HIV, and for
treating cancers that have developed in patients suffering from
HIV.
[0053] The peptides shared among HIV and lethal cancers provide
immunogenic compositions for raising binding agents against HIV and
lethal cancers that are useful for diagnosing HIV and/or the
development of cancer from HIV. The peptides also provide
immunogenic compositions for vaccines that are administered
prophylactically to prevent the development of lethal cancers in
patients suffering from HIV. For example, any one or more of SEQ ID
NO(s): 104-108 and 110 may be administered in a vaccine to prevent
the development of glioblastoma, lung cancer, or leukemia in a
patient suffering from HIV. Any one or more of SEQ ID NO(s): 109,
110, and 113-116 may be administered in a vaccine to prevent the
development of glioblastoma or lung cancer in a patient suffering
from HIV. Likewise, SEQ ID NO(s): 111 and 112 may be administered
in a vaccine to prevent the development of lung cancer in a patient
suffering from HIV or glioblastoma in a patient suffering from HIV.
Any one or more of SEQ ID NO(s): 117-136 and 139-143, may be
administered in a vaccine to prevent the development of lung cancer
in a patient suffering from HIV. Any one or more of SEQ ID NO(s):
104-108, 110, 117, 125, 156, 139-142, 154, and 155, may be
administered in a vaccine to prevent the development of lung cancer
and leukemia in a patient suffering from HIV. SEQ ID NO(s): 138-143
may be administered in a vaccine to prevent the development of
breast cancer and leukemia. Additionally, SEQ ID NO: 145 may be
administered in a vaccine to prevent the development of breast
cancer and SEQ ID NO: 146 may be administered in a vaccine to
prevent the development of colon cancer, colorectal cancer, and
cervical cancer in a patient suffering from HIV.
[0054] A vaccine to prevent glioblastoma, pancreatic cancer, lung
cancer, leukemia, colon cancer, colorectal cancer, cervical cancer,
and breast cancer in a patient suffering from HIV may comprise one
or more of SEQ ID NO(s): 104-148. A vaccine comprising at least one
sequence from SEQ ID NO(s): 104-108, at least one sequence from SEQ
ID NO(s): 109 and 110, at least one sequence from SEQ ID NO(s): 111
and 112, at least one sequence from SEQ ID NO(s): 113-116, at least
one sequence from SEQ ID NO(s): 117-136, at least one sequence from
SEQ ID NO(s): 117, 125, and 136, the sequence of SEQ ID NO: 138, at
least one sequence from SEQ ID NO(s): 139-143, the sequence of SEQ
ID NO: 145, and the sequence of SEQ ID NO: 146 is a vaccine
provided against glioblastoma, pancreatic cancer, lung cancer,
leukemia, colon cancer, colorectal cancer, cervical cancer, and
breast cancer in a patient suffering from HIV. A vaccine comprising
at least one sequence from SEQ ID NO(s): 105-108, at least one
sequence from SEQ ID NO(s): 109, 110, and 113-115, at least one
sequence from SEQ ID NO(s): 117-136, and at least one sequence from
SEQ ID NO(s): 139-143 is a vaccine provided against glioblastoma,
pancreatic cancer, lung cancer, leukemia, colon cancer, colorectal
cancer, cervical cancer, and breast cancer in a patient suffering
from HIV. As described above, any sequence shared among more than
one type of cancer or among one type of cancer and HIV or any
sequence in one type of cancer having a homologue in another type
of cancer or in HIV is a sequence provided for a vaccine against
the various types of cancer or a vaccine against the various types
of cancer in a patient suffering from HIV.
[0055] The vaccine may also comprise a mixture of peptides, wherein
one or more of the peptides are sequences identified as shared
among a first group of histological types of cancer and one of more
of the peptides are sequences identified as shared among a second
group of histological types of cancer, thereby being effective in
treating both the first and second types of cancer. Additionally,
one of more of the peptides may be sequences identified as shared
among a third or additional groups of histological types of cancer.
The vaccine may comprise any one of the sequences discussed above
or a functional fragment of any one of the sequences discussed
above. The vaccine may likewise comprise proteins or protein
fragments comprising the sequences or functional fragments of the
sequences discussed above.
Peptides from a Particular Histological Type
[0056] As disclosed in Table 1, peptides identified in a specific
histological type are particularly useful as immunogenic compounds
for development of diagnostics and therapeutics for the specific
histological type. The peptides of Table 1 represent Replikin
peptides identified in the portion of the genome where the highest
concentration of Replikin peptides is identified as present. This
portion of the genome is known for a magnified association with
rapid replication and lethality. See, e.g., U.S. application Ser.
No. 12/010,027, filed Jan. 18, 2008. As a result, peptides from
this region are particularly useful in vaccines for targeting the
rapid replication mechanism of a malignancy and particularly useful
for targeting the rapid replication mechanism of a malignancy of
the same type.
[0057] Peptides of SEQ ID NO(s): 1-27 are particularly useful for
diagnostic and therapeutic purposes against glioma multiforme.
Peptides of SEQ ID NO(s): 28-52 are particularly useful for
diagnostic and therapeutic purposes against cancer of the pancreas.
Peptides of SEQ ID NO(s): 53-103 are particularly useful for
diagnostic and therapeutic purposes against cancer of the lung.
Peptides of SEQ ID NO(s): 149-165 are particularly useful for
diagnostic and therapeutic purposes against leukemia. Peptides of
SEQ ID NO(s): 166-193 are particularly useful for diagnostic and
therapeutic purposes against cancer of the colon, rectum, and
cervix. Peptides of SEQ ID NO(s): 194-203 are particularly useful
for diagnostic and therapeutic purposes against cancer of the
breast.
[0058] Proteins, protein fragments, and polypeptides comprising any
one or more of these sequences or functional fragments of these
sequences are likewise useful for targeting cancer of the
histological type in which they have been identified. Corresponding
antibodies and other binding agents as well as corresponding
antisense and siRNA nucleic acids are likewise useful.
Peptides Sharing Percent Identity with Sequences of Table 1
[0059] The invention provides peptides that share percent identity
with the peptides disclosed in Table 1 (SEQ ID NO(s): 1-203). A
peptide that shares a percent identity exhibits substantial
structural and/or functional equivalence with its reference
sequence. A peptide may share 30%, 40%, 50%, 60%, 70%, 80%, 90%,
95%, 97%, 99%, or more identity with any one of SEQ ID NO(s):
1-203. In sharing this percent identity, peptides of the invention
share structural and/or functional characteristics and may be used
interchangeably with the peptides of SEQ ID NO(s): 1-203.
[0060] Certain peptides disclosed in Table 1 as identified in a
particular histological cancer type are not disclosed with a
corresponding shared peptide in another histological cancer type.
Peptides that are not shared in Table 1 include, for example, SEQ
ID NO(s): 8, 9, 16-18, 68, 76, 89, 98-103, 144, 147, 148, 155, 156,
158, 192, 193, 201, and 202. Some of these peptides differ by a
single peptide from peptides in the same row in Table 1; these
peptides include SEQ ID NO(s): 8, 9, 154, 155, and 156. Peptides
that share percent identity with SEQ ID NO(s): 8, 9, 15-27, 68, 76,
89, 98-103, 144, 147, 148, 155, 156, 158, 192, 193, 201, and 202
are provided as peptides of the invention. Further, where peptides
that share identity with these sequences are identified in
different histological types of cancer, the sequences and/or
peptides that share percent identity with the sequences are useful
for diagnostic and therapeutic purposes for both the histological
type in which the sequence was identified in Table 1 and for the
histological type in which the sequence sharing identity is
identified.
[0061] In a further embodiment, the invention provides peptides
that share percent identity with any one of SEQ ID NO(s): 1-203 and
retain the elements of a Replikin peptide. The elements of a
Replikin peptide are an amino acid sequence of 7 to about 50 amino
acids with at least one lysine residue located on one end of the
sequence and at least one lysine residue or at least one histidine
residue located at the other end of the sequence; (1) a first
lysine residue located six to ten residues from a second lysine
residue; (2) at least one histidine residue; and (3) at least 6%
lysine residues. Because Replikin peptides have been shown to be
related to rapid replication, a Replikin peptide that shares
percent identity with any one of SEQ ID NO(s): 1-203 may be used
for diagnostic and therapeutic purposes of the invention including
as an immunogenic composition or vaccine against histological types
of cancer sharing sequences with the desired percent identity or
sequences with exact identity. Further, a Replikin peptide sequence
that shares lysine residues and a histidine residue in the same
positions as the lysine residues and histidine residue defining the
Replikin sequence of SEQ ID NO(s): 1-203 is useful for diagnostic
and therapeutic purposes of the invention including as an
immunogenic composition or vaccine against histological types of
cancer sharing homologues of the sequences. The lysine residues and
histidine residue that define a Replikin peptide sequence are key
structures for the function of the Replikin sequence in rapid
replication.
Peptides Homologous with Previously-Described UTOPES
[0062] A review of Table 1 reveals several sequences previously
described in U.S. application Ser. No. 10/860,050, filed Jun. 4,
2004 (now U.S. Pat. No. 7,442,761), as universal synthetic epitopes
or "UTOPES." Such peptides include SEQ ID NO(s): 44-47 identified
in pancreatic cancer and correspondingly shared SEQ ID NO(s):
182-185 identified in colon, colorectal, and cervical cancers. The
new and surprising discovery that these sequences are shared
between pancreatic cancer and colon, colorectal, and cervical
cancers provides the artisan with a new and surprising use of the
sequences in immunogenic compositions, including diagnostic
applications as well as cancer vaccines. The sequences may
additionally be used in diagnostics and therapeutics across
histological types. This application of the previously-identified
peptides was not previously known and is a surprising application
of the sequences.
Peptides Shared Among Endodermal Cancers
[0063] An embodiment of the present invention provides isolated or
synthesized Replikin peptides identified as shared or as having
homologues or peptides sharing percent identity among cancers of
endodermal origin. A further embodiment provides a protein, protein
fragment, or polypeptide comprising said Replikin peptides or a
functional fragment of said Replikin peptides.
[0064] As may be seen in Table 1, peptides are shared among the
endodermal cancers of the pancreas, lung, colon, rectum, and
cervix. Peptides shared among these endodermal cancers are
comprised in therapeutic agents against the family of endodermal
cancers. These shared peptides are further a basis of diagnostic
techniques for identifying endodermal cancers. The invention,
therefore, provides proteins, protein fragments, and polypeptides
comprising Replikin peptides identified as shared among endodermal
cancers. The invention further provides functional fragments of
Replikin peptides identified as shared among endodermal cancers.
Such peptides may be used to stimulate the immune system to produce
antibodies, antibody fragments, or other binding agents that may be
used to diagnose endodermal cancers and may be used to provide
passive immunity against endodermal cancers.
Peptides Shared Among Ectodermal Cancers
[0065] An embodiment of present invention provides isolated or
synthesized Replikin peptides identified as shared or as having
homologues or peptides sharing percent identity among cancers of
ectodermal origin. A further embodiment provides a protein, protein
fragment, or polypeptide comprising said Replikin peptides or a
functional fragment of said Replikin peptides.
[0066] As may be seen in Table 1, peptides of the ectodermal
glioblastoma multiforme cancer are provided. Peptides shared
between glioblastoma and other ectodermal cancers may be comprised
in therapeutic agents against the family of ectodermal cancers.
These shared peptides may further be the basis of diagnostic
techniques for identifying ectodermal cancers. The invention,
therefore, provides proteins, protein fragments, and polypeptides
comprising Replikin peptides identified as shared among ectodermal
cancers. The invention further provides functional fragments of
Replikin peptides identified as shared among ectodermal cancers.
Such peptides may be used to stimulate the immune system to produce
antibodies, antibody fragments, or other binding agents that may be
used to diagnose ectodermal cancers and may be used to provide
passive immunity against ectodermal cancers.
Peptides Shared Among Mesodermal Cancers
[0067] An embodiment of the present invention provides isolated or
synthesized Replikin peptides identified as shared or as having
homologues or peptides sharing percent identity among cancers of
mesodermal origin. A further embodiment provides a protein, protein
fragment, or polypeptide comprising said Replikin peptides or a
functional fragment of said Replikin peptides.
[0068] As may be seen in Table 1, peptides of mesodermal cancer of
the breast are provided. Peptides shared between breast cancer and
other mesodermal cancers may be comprised in therapeutic agents
against the family of mesodermal cancers. These shared peptides may
further be the basis of diagnostic techniques for identifying
mesodermal cancers. The invention, therefore, provides proteins,
protein fragments, and polypeptides comprising Replikin peptides
identified as shared among mesodermal cancers. The invention
further provides functional fragments of Replikin peptides
identified as shared among mesodermal cancers. Such peptides may be
used to stimulate the immune system to produce antibodies, antibody
fragments, or other binding agents that may be used to diagnose
mesodermal cancers and may be used to provide passive immunity
against mesodermal cancers.
Vaccines Against Multiple Types of Cancer
[0069] A review of Table 1 reveals numerous shared sequences among
various types of cancer and HIV. Sequences that are shared among
different types of cancer may be comprised within a vaccine against
these various cancers. Such vaccines may be administered as a
preventive or therapeutic agent against any one or more of these
cancers. One vaccine provided for two or more histological types of
cancer saves production costs, distribution costs, diagnostic
costs, therapeutic costs and storage costs.
Vaccines Against Glioblastoma, Lung Cancer, and Leukemia
[0070] In considering Table 1, for example, the peptide sequence of
SEQ ID NO: 2 identified in glioblastoma multiforme has the same
amino acid sequences as SEQ ID NO: 54, identified in lung cancer,
and SEQ ID NO: 150, identified in leukemia. Additionally, SEQ ID
NO(s): 2, 54, and 150 have the same amino acid sequence as SEQ ID
NO: 105, identified in human immunodeficiency virus (HIV). This
pattern is also seen in SEQ ID NO(s): 1 and 3-5 of glioblastoma
multiforme, SEQ ID NO(s): 53 and 55-57 of lung cancer, SEQ ID NO(s)
149 and 151-153 of leukemia, and SEQ ID NO(s): 104 and 106-108 of
HIV, respectively. Additionally, the peptide sequence of SEQ ID NO:
7 identified in glioblastoma multiforme has the same amino acid
sequences as SEQ ID NO: 59, identified in lung cancer, and SEQ ID
NO: 110, identified in HIV. The peptide sequence of SEQ ID NO(s):
7, 59, and 110 differ from the amino acid sequence of SEQ ID NO:
154, identified in leukemia in that SEQ ID NO: 154 has a glutamic
acid instead of an aspartic acid as the second position from the
N-terminus.
[0071] One or more of each of these peptides may be comprised in a
vaccine directed against the various cancer types of glioblastoma
multiforme, lung cancer, or leukemia. Each of these peptides may
further be comprised in a vaccine for the prevention of these
cancers in patients suffering from HIV or in a vaccine against
existing cancers in a patient suffering from HIV.
Immunogenic or Therapeutic Agents Combining Two or More
Peptides
[0072] Another embodiment of the invention provides immunogenic
and/or therapeutic agents comprising two or more of the peptides of
the invention, including, for example, the peptides listed in Table
1 or peptides sharing percent identity with the peptides listed in
Table 1. Such immunogenic and/or therapeutic agents provide the
medical practitioner with a vaccine or other agent effective
against multiple cancer types, as necessary. As a result, the
medical practitioner may use an embodiment of the invention where
more than one histological cancer type is present, where the
histology of the cancer is unknown, or where the histological type
of cancer is a match for the types of cancer against which the
vaccine or other therapeutic agent was designed.
[0073] In another embodiment, the invention contemplates a protein,
protein fragment, polypeptide, or other compound comprising two or
more of the peptides listed in Table 1 as an immunogenically-active
agent of the protein, protein fragment, polypeptide or other
compound. The invention further provides a composition comprising
one or more proteins, protein fragments, polypeptides, or other
compounds, wherein each of said proteins, protein fragments,
polypeptides, or other compounds comprises at least one of the
peptides listed in Table 1.
Replikin Sequences in Diagnostics and Therapies
[0074] Because Replikin sequences are chemically defined, they may
be synthesized by organic chemistry or biological techniques.
Replikin sequences synthesized by organic chemistry may be
particularly specific, highly reproducible, and highly reliable as
compared to other vaccines and therapies. Chemically-defined
Replikin sequences are likewise potentially freer from adverse
reactions characteristic of biologically-derived vaccines and
antibodies.
[0075] An embodiment of an aspect of the invention provides use of
Replikin peptides as immunogenic compositions and provides
construction of immunogenic compositions as vaccines, including
vaccines that provide an immune response, vaccines that provide a
humoral immune response, vaccines that provide an antigenic immune
response, vaccines that provide a blocking effect, and vaccines
that provide a protective effect.
[0076] A Replikin peptide, protein or protein fragment comprising
said peptide or functional fragment of said peptide may be used for
the manufacture of a medicament for the treatment of malignancy
that share said Replikin peptide or that share homologues or
peptides of percent identity of said Replikin peptide.
Antibodies Against Replikin Sequences in Diagnostics and
Therapies
[0077] An embodiment of one aspect of the present invention
provides binding molecules, including antibodies, to Replikin
peptides and functional fragments of the invention. A binding
molecule, antibody, or antibody fragment directed against a
Replikin peptide may be used for diagnostic, therapeutic, and/or
preventive purposes in cancer, including any cancer known to one of
ordinary skill in the art now and hereafter, which may include any
cancer of Table 1 as well as a thyroid malignancy, a prostate
malignancy, a breast malignancy, a urinary bladder malignancy, a
uterine corpus malignancy, a uterine cervix malignancy, a colon
malignancy, an ovarian malignancy, a malignancy of the oral cavity,
a lymphocytic leukemia malignancy, a multiple myeloma malignancy, a
gastric malignancy, a non-small cell lung carcinoma malignancy, a
glioblastoma malignancy, or any other malignancy of an animal or a
human.
[0078] One embodiment of an aspect of the invention provides a
method of stimulating the immune system of any animal or human
capable of an immune response by administering at least one
Replikin peptide or protein fragment comprising at least one
Replikin peptide or functional peptide fragment of the invention.
Another embodiment provides a method of making an antibody or an
antibody fragment that binds to at least one Replikin peptide, at
least one protein fragment comprising at least one Replikin
peptide, one protein comprising at least one Replikin peptide, or
one functional fragment of said at least one Replikin peptide. One
of ordinary skill in the art knows myriad ways of making binding
molecules, antibodies, antibody fragments, or other binding agents
that bind to a Replikin peptide or functional fragment or protein
or protein fragment comprising said peptide or functional
fragment.
[0079] Replikin sequences as agents for stimulating the immune
system against cancer are supported by data demonstrating a
protective effect from Replikin peptides administered orally to
shrimp challenged with taura syndrome virus. See, e.g., U.S.
application Ser. No. 12/108,458, filed Apr. 23, 2008. In that
study, the effectiveness of completely synthetic Replikin sequences
against taura syndrome virus in shrimp (providing 91% protection)
suggests a blocking mechanism of action in the shrimp rather than a
classical immunological effect since classical antibodies are
believed to be weak or absent in shrimp. See, also, antisense
nucleic acid and siRNA below for further discussion of blocking
mechanisms.
Production and Administration of Vaccines and Other
Therapeutics
[0080] A peptide vaccine of the invention may include a single
Replikin peptide sequence or protein fragment comprising said
Replikin peptide sequence or may include a plurality of Replikin
sequences shared among various histological malignancies or not
shared among various histological malignancies. A vaccine may
include a conserved Replikin peptide or peptides in combination
with a Replikin peptide or Replikin peptides in a particular
malignancy or may be based on other Replikin peptide sequences such
as UTOPES. See U.S. Pat. No. 7,442,761. Replikin peptides can be
synthesized by any method, including chemical synthesis or
recombinant gene technology, and may include non-Replikin
sequences. Vaccine compositions of the invention may also contain a
pharmaceutically-acceptable carrier and/or adjuvant.
[0081] The vaccines of the present invention can be administered
alone or in combination with chemotherapies, hormone therapies or
other anti-cancer therapies and/or treatments. The vaccine of the
present invention may be administered to any animal capable of
producing antibodies in an immune response or to any animal capable
of producing a humoral response, a blocking effect, a protective
effect, or any immune or immune-like response. For example, the
vaccine of the present invention may be administered to a mouse, a
rat, a rabbit, a chicken, a pig, a human, or any other animal
capable of producing an immune response and/or antibodies in
response to an antigen or capable of experiencing a blocking effect
from administration of the vaccine. Because of the universal nature
of Replikin sequences, a vaccine of the invention may be directed
at a range of malignancies.
[0082] The Replikin peptides of the invention, alone or in various
combinations are administered to a subject by any manner known to
one of ordinary skill in the art including by intravenous or
intramuscular injection, ocular swab or spray, nasal spray and/or
inhalation spray, or any other method of administration in order to
stimulate the immune system of the subject to produce an immune
response or in order to provide a direct or otherwise indirect
blocking effect. Generally the dosage of peptides is in the range
of from about 0.1 .mu.g to about 10 mg, about 10 .mu.g to about 1
mg, and about 50 .mu.g to about 500 .mu.g. The skilled practitioner
can readily determine the dosage and number of doses needed to
produce an effective immune response or an effective blocking
effect, or both.
[0083] In another aspect of the invention, isolated Replikin
peptides may be used to generate antibodies, which may be used, for
example, to provide passive immunity in an individual. See, e.g.,
U.S. Pat. No. 7,894,999, filed Feb. 16, 2006 and U.S. application
Ser. No. 12/010,027, filed Jan. 18, 2008 (each incorporated herein
by reference in their entireties).
Anti-Sense Nucleic Acids and siRNA
[0084] An embodiment of one aspect of the invention provides a
nucleic acid sequence that is antisense to a nucleic acid that
encodes for a Replikin peptide of SEQ ID NO(s): 1-203. Nucleic acid
sequences include, for example, one or more small interfering
nucleic acid sequences that interfere with a nucleic acid sequence
sharing 50%, 60%, 70%, 80%, or 90% or more identity with a nucleic
acid that encodes for a Replikin peptide identified in a malignancy
or identified as shared among two or more malignancies, or sharing
50%, 60%, 70%, 80%, or 90% or more identity with a nucleic acid
that is antisense to a nucleic acid that encodes for a Replikin
peptide identified in a malignancy or identified as shared among
two or more malignancies.
[0085] Such nucleotide sequences may be used in hybridization
assays of biopsied tissue or blood, e.g., Southern or Northern
analysis, including in situ hybridization assays, to diagnose the
presence of a particular malignancy or virus in a tissue sample or
an environmental sample, for example. The present invention also
contemplates kits containing antibodies or other binding molecules
specific for particular Replikin sequences that are present in a
particular malignancy of interest, or containing nucleic acid
molecules (sense or antisense) that hybridize specifically to a
particular Replikin sequence, and optionally, various buffers
and/or reagents needed for diagnosis.
[0086] Also within the scope of the invention are
oligoribonucleotide sequences that include antisense RNA and DNA
molecules and ribozymes that function to inhibit the translation of
Replikin-containing mRNA. Both antisense RNA and DNA molecules and
ribozymes may be prepared by any method known in the art. The
antisense molecules can be incorporated into a wide variety of
vectors for delivery to a subject. The ordinary skilled
practitioner can readily determine the best route of delivery.
Intravenous or intramuscular delivery is one possible method of
delivery and is one, among many, routine delivery methods in the
art of small molecule delivery. The dosage amount is also readily
ascertainable. Dosage may range from 0.01 mg to 10 mg, from 0.1 mg
to 5 mg, from 0.5 mg to 2 mg, and from 0.75 mg to 1.25 mg, but is
not limited to such ranges.
[0087] One embodiment of an aspect of the invention further
contemplates antisense nucleic acid molecules that are
complementary to a nucleic acid encoding a portion of a cell of a
malignancy. An antisense nucleic acid molecule may be complementary
to a nucleotide sequence encoding a Replikin peptide as described
herein. A nucleic acid sequence may be anti-sense to a nucleic acid
sequence that has been demonstrated to be conserved in a malignancy
or generally conserved in a range of malignancies of a particular
cancer type or of different cancer types.
[0088] The invention also contemplates compositions comprising
RNAi-inducing entities used to inhibit replication of a malignancy
including small interfering RNA, which is a class of about 10 to
about 50, and often about 20 to about 25, nucleotide-long
double-stranded RNA molecules. siRNA is involved in the RNA
interference pathway, where it interferes with the expression of
one or more specific genes such as replication genes of a
malignancy including replication genes that comprise at least one
Replikin peptide as described herein. siRNAs also act in
RNAi-related pathways, e.g., as an anti-replication mechanism.
[0089] An effective amount of an RNAi-inducing entity is delivered
to a cell or organism prior to, simultaneously with, or after
diagnosis of a malignancy or a metastasis. A dosage should be
sufficient to reduce or delay replication of the malignancy or
metastasis. Compositions of the invention may comprise a single
siRNA species targeted to a target transcript or may comprise a
plurality of different siRNA species targeting one or more target
transcripts.
[0090] The invention provides a small interfering nucleic acid
sequence that is about 10 to about 50 nucleic acids in length and
is 50%, 60%, 70%, 80%, or 90% or more homologous (or sharing
sequence identity) with a nucleic acid that encodes for any portion
of at least one Replikin peptide, or is 50%, 60%, 70%, 80%, or 90%
or more homologous (or sharing sequence identify) with a nucleic
acid that is antisense to a nucleic acid that encodes for any
portion of at least one Replikin peptide. In a further non-limiting
embodiment, the nucleic acid sequence is about 15 to about 30
nucleic acids or about 20 to about 25 nucleic acids. In a further
non-limiting embodiment, the nucleic acids sequence is about 21
nucleic acids.
[0091] The inventors provide the following examples for
illustration purposes. The ordinary skilled artisan understands the
invention encompasses all practices inferable from the examples and
the disclosure and data provided in this application. The invention
is not limited to the examples or the disclosure provided
herein.
Example 1
Identification of Peptides Shared Among Various Histological Types
of Cancer and Comprisable in Vaccines Against Said Various
Cancers
[0092] The inventors examined genomic information of various
histological types of cancer to determine the region of highest
concentration of encoded Replikin peptide sequences. The goal of
the examination was to identify Replikin sequences available as
synthetic Replikin cancer vaccines for each individual histological
type. The inventors were surprised to identify many Replikin
peptide sequences within the region of highest concentration of
encoded Replikin peptides that were shared among two or more
histological types. Because the identified peptides share the
requirements of a Replikin sequence, they are structures that are
associated with rapid replication. See, e.g., U.S. Pat. Nos.
7,176,275, 7,420,028, 7,763,705, 7,674,880, 7,189,800, 7,758,863,
7,705,129, 7,452,963, 7,442,761, 7,774,144, and 7,894,999, each of
which is incorporated herein by reference. Rapid replication in
association with Replikin peptides is characteristic of lethal
infectious diseases as well as lethal cancers, regardless of
histological type. See, e.g., U.S. Pat. Nos. 7,176,275, 7,894,999,
and U.S. application Ser. Nos. 12/010,027 and 12/108,458. The
number of Replikins per one hundred genomic amino acids (known as
Replikin Count) has been found to relate quantitatively to
five-year mortality rate. See, e.g., U.S. application Ser. No.
12/538,027.
[0093] When the inventors investigated the genomic sites of the
highest concentration of Replikin peptides (highest Replikin Count)
for specific Replikin sequences to be the basis of a
wholly-synthetic Replikin cancer vaccine, the inventors were
expecting to identify sequences for a single vaccine for each
histological type of cancer. The inventors were, however, surprised
to discover that many individual Replikin structures were shared in
two or more of the most lethal histological types of cancer,
including glioblastoma multiforme, pancreatic cancer, lung cancer.
leukemia, colon cancer, colorectal cancer, cervical cancer, and
breast cancer. The Replikin structures were furthermore not
necessarily found in the same genomic region but were nevertheless
identified in the part of the genome of each specific cancer type
having the highest concentration of encoded Replikin sequences.
This is the region wherein Replikin structures are shown to be
magnified in their relationship to rapid replication and lethality.
This discovery allowed the inventors to develop single vaccines
against more than one of the lethal cancers.
[0094] The inventors designed many different vaccines, including
but not limited to (1) vaccines against glioblastoma multiforme,
lung cancer, leukemia, and cancer in HIV, (2) vaccines against lung
cancer, leukemia, and breast cancer, and (3) vaccines against
pancreatic cancer, colon cancer, colorectal cancer, and cervical
cancer.
Example 2
Replikin Formulation Against Glioblastoma, Lung Cancer, Leukemia,
and Cancers Associated with HIV
[0095] Using the sequences identified in Table 1, the inventors
designed a formulation against glioblastoma multiforme, lung
cancer, leukemia, and cancer in HIV. The formulation comprises, as
interfering peptides, SEQ ID NO(s): 1-5. Each of these sequences is
shared among glioblastoma multiforme, lung cancer, leukemia, and
HIV.
[0096] The inventors designed another formulation against
glioblastoma multiforme, lung cancer, leukemia, and cancer in HIV.
The formulation comprises, as interfering peptides, SEQ ID NO(s):
1-5 as well as SEQ ID NO(s): 6-14. These sequences are further
shared by glioblastoma, lung cancer, and/or HIV. The formulation
may also comprise SEQ ID NO: 154, which is a homologue of SEQ ID
NO: 7 and shares 86% identity with SEQ ID NO: 7 because SEQ ID NO:
154 shares 6 of seven amino acid residues with SEQ ID NO: 7. SEQ ID
NO: 154 is identified in leukemia in Table 1 and, because it is a
homologue of SEQ ID NO: 7 in glioblastoma, SEQ ID NO: 59 in lung
cancer and SEQ ID NO: 110 in HIV, SEQ ID NO: 154 is useful for
targeting rapid replication in leukemia, glioblastoma, lung cancer,
and cancer in patients suffering from HIV.
[0097] The Replikin formulation is tested in rabbits to determine
immunogenicity and in mice and WISTAR rats to determine protective
effect, both before cancers are implanted in the animals, and at
different intervals after the cancer is implanted. There are
numerous protocols for such testing well described in the
literature. The following are two such protocols.
[0098] In a xenograft model investigation, eight to ten mice female
nu/nu mice (eight to nine weeks old) are implanted subcutaneously
or in the flank with carcinoma cells. Tumors are monitored (twice
weekly and then daily) to determine when the tumor neoplasms reach
approximately 75 mg. Animals are pair-matched according to tumor
size in the 62- to 126-mg range. Tumor weight is estimated. A tumor
growth delay method is used where a test animal is euthanized if
tumor size reaches 2.0 g. Animal weight is determined twice weekly
and animals are examined frequently for clinical signs of adverse
side effects. Acceptable toxicity is defined as no mean group
weight loss over 20% during test period, and not more than one
toxic death among ten treated animals. Test compositions are
formulated in 0.5% methylcellulose and administered per os,
intranasally, or subcutaneously in a volume of 10 ml/kg.
[0099] In an intracranial survival model investigation, a
therapeutic composition is tested for controlling progression of
intracranial cancer. For study of intracranial cancer progression,
malignant cells are harvested during logarithmic growth phase,
suspended in PBS, and injected beneath the skull. 20 microliters is
injected into female nu/nu mice at eight to nine weeks of age.
Animals are monitored for tumor progression. Survival is the
efficacy measurement for the model and is recorded as time to
endpoint or death. Moribund animals are euthanized and included in
the data as death. Improved life span is calculated as a percentage
of controls. Cells are implanted and animals observed for one day
for clinical signs of tumor progression. Treatment is then begun.
Animals are treated with the composition for fifty days and the
study ends at 58 days.
Example 3
Replikin Formulation Against Pancreatic Cancer, Colon Cancer,
Colorectal Cancer, and Cervical Cancer
[0100] Using the sequences identified in Table 1, the inventors
designed a Replikin formulation against pancreatic cancer, colon
cancer, colorectal cancer, and cervical cancer. The formulation
comprises, as interfering peptides, SEQ ID NO(s): 28, 30-36, and
38-42. Each of these sequences is shared among pancreatic cancer,
colon cancer, colorectal cancer, and cervical cancer.
Alternatively, the formulation comprises, as interfering peptides,
SEQ ID NO(s): 28-52.
[0101] The formulation is tested in rabbits to determine
immunogenicity and in mice and WISTAR rats to determine protective
effect. The composition is tested according to the xenograft model
investigation described in Example 2.
Example 4
Comparing Relative Lethality of Cancer Cells, Tissues, or Types
[0102] The data in Table 2 below demonstrate a quantitative
relationship between: (1) Replikin Count in the Replikin Peak Gene
of the genome of common types of human cancer; and (2) The
five-year mortality in that cancer as reported in Brenner, H.,
"Long-term survival rates of cancer patients achieved by the end of
the 20th century: a period analysis," The Lancet, 360 (Oct. 12,
2002), 1131-1135. The discovery of the relation of Replikin
sequences to rapid replication as reflected in Table 2 offers a new
approach and provides means to inhibit rapid replication and
resulting lethality in cancers in animals and humans. To the
inventors' knowledge, no structure of cancer cells and no genomic
structure of cancer cells has previously been shown to relate
quantitatively to the five-year mortality rate of a particular
histological type of cancer.
TABLE-US-00002 TABLE 2 5-Year Percent Mortality of Highest Replikin
Human Cancer Human Cancer Count of Replikin Type Type Peak Gene
Thyroid 2 15 Prostate 3 20 Breast 11 45 Urinary Bladder 15 53
Uterine Corpus 30 24 Uterine Cervix 34 31 Colon 39 28 Ovary 40 60
Oral Cavity 43 53 Lymphocytic 58 128 Leukemia Multiple Myeloma 70
170 Gastric 76 92 Non-Small Cell 92 250 Lung Carcinoma Pancreatic
95 275 Glioblastoma 99 324
[0103] Overall, the data in Table 2 provide an illustration of a
quantitative relationship between Replikin concentration in a given
type of cancer and lethality in that type of cancer as compared to
the Replikin concentration and lethality in other types of cancer.
The data in Table 2 also provide further support for a general
association between Replikin concentration and lethality within a
particular type of cancer (such as, for example, lung cancer) as
described in U.S. patent application Ser. No. 12/010,027, filed
Jan. 18, 2008.
[0104] The association seen in Table 2 is surprising to one of
ordinary skill in the art because the Replikin Count in these
disparate human malignancies is quantitatively related to mean
five-year mortality of sufferers of the specific histological types
of malignancy--even though mortality outcomes are significantly
dependent upon multiple variables including time of detection and
efficacy of disparate treatments. Despite the expected significant
differences in time of detection and efficacy of treatment across
the population surveyed by Brenner (Lancet2002) and the number of
variables that affect outcomes in these cancers, it is quite
surprising that the Replikin concentration in these different human
malignancies emerges as such a significant variable that
quantitatively relates to the mean mortalities reported
therein.
[0105] As previously stated, to the inventor's knowledge no
structure of cancer cells, and no genomic structure of cancer
cells, has previously been shown to relate quantitatively to the
five-year mortality rate of a particular histological type of
cancer cell. Since the specific Replikin genomic sequence
structures of cancer cells were not previously known, it was not
possible to select such structures for the purpose of interfering
with the replication process of the cancer cell. Since some of
these newly-discovered sequences are shared between some
histological types of cancer, a single formulation can be used for
more than one type of cancer, thus making administration of such
formulations more practical in that a broader group of specific
histological types of cancer cell targets can be addressed by a
single formulation.
Sequence CWU 1
1
20317PRTHomo sapiens 1Lys His Lys Asp Lys His Lys 1 5 28PRTHomo
sapiens 2His Lys His Lys Asp Lys His Lys 1 5 310PRTHomo sapiens
3Lys His Lys Asp Arg Glu His Arg His Lys 1 5 10 49PRTHomo sapiens
4His Lys Asp Arg Glu His Arg His Lys 1 5 58PRTHomo sapiens 5Lys Asp
Arg Glu His Arg His Lys 1 5 68PRTHomo sapiens 6His Lys Glu His Lys
Lys Asp Lys 1 5 77PRTHomo sapiens 7Lys Glu His Lys Lys Asp Lys 1 5
811PRTHomo sapiens 8His Lys Lys Asp Lys Asp Lys Asp Arg Glu Lys 1 5
10 913PRTHomo sapiens 9Lys Lys Asp Lys Asp Lys Asp Arg Glu Lys Ser
Lys His 1 5 10 1012PRTHomo sapiens 10Lys Asp Lys Asp Lys Asp Arg
Glu Lys Ser Lys His 1 5 10 1110PRTHomo sapiens 11Lys Asp Lys Asp
Arg Glu Lys Ser Lys His 1 5 10 128PRTHomo sapiens 12Lys Asp Arg Glu
Lys Ser Lys His 1 5 1310PRTHomo sapiens 13Lys Ser Lys His Ser Asn
Ser Glu His Lys 1 5 10 1413PRTHomo sapiens 14His Lys Asp Lys His
Lys Asp Arg Glu His Arg His Lys 1 5 10 1510PRTHomo sapiens 15His
Lys Met Phe Leu Met Leu Asp Asn Lys 1 5 10 1613PRTHomo sapiens
16His Asn Val Lys Pro Glu Cys Leu Asp Ala Tyr Asn Lys 1 5 10
1713PRTHomo sapiens 17His Asn Val Lys Pro Glu Cys Leu Glu Ala Tyr
Asn Lys 1 5 10 1817PRTHomo sapiens 18His Pro Gln Arg Pro Leu Val
Leu Lys Thr Gly Val Gln Phe Thr Val 1 5 10 15 Lys 198PRTHomo
sapiens 19Lys Leu Gln Phe His Asn Val Lys 1 5 2012PRTHomo sapiens
20Lys Glu Thr Ser Ser Leu Tyr Lys Leu Gln Phe His 1 5 10
2115PRTHomo sapiens 21His Ser Asn Leu Leu Ala Lys Lys Glu Thr Ser
Ser Leu Tyr Lys 1 5 10 15 2216PRTHomo sapiens 22His Arg Ala Arg Glu
Asp Ser Trp Leu Lys Ser Leu Phe Val Arg Lys 1 5 10 15 2313PRTHomo
sapiens 23Lys Lys Glu Thr Ser Asn Leu Tyr Lys Leu Gln Phe His 1 5
10 2415PRTHomo sapiens 24His Ser Asn Leu Leu Ala Lys Lys Glu Thr
Ser Asn Leu Tyr Lys 1 5 10 15 2515PRTHomo sapiens 25Lys Ser Leu Phe
Val Arg Lys Val Asp Pro Arg Lys Asp Ala His 1 5 10 15 2610PRTHomo
sapiens 26Lys Asp Ala His Ser Asn Leu Leu Ala Lys 1 5 10
2722PRTHomo sapiens 27Lys Asp Ala His Ser Asn Leu Leu Ala Lys Lys
Glu Thr Ser Asn Leu 1 5 10 15 Tyr Lys Leu Gln Phe His 20
2816PRTHomo sapiens 28Lys Ala Glu Cys Pro Leu Cys Lys Gln Pro Phe
Asp Ser Ile Phe His 1 5 10 15 299PRTHomo sapiens 29Lys Asp Glu Gln
Ile Asn Lys Gly His 1 5 3012PRTHomo sapiens 30His Ser Val Leu Gly
Lys Asp Glu Gln Ile Asn Lys 1 5 10 319PRTHomo sapiens 31Lys Asn His
Arg Lys His His Gly Lys 1 5 329PRTHomo sapiens 32Lys His His Gly
Lys Lys Arg Met Lys 1 5 339PRTHomo sapiens 33His Gly Lys Lys Arg
Met Lys Ser Lys 1 5 349PRTHomo sapiens 34Lys Lys Asn Asn His Ser
Glu Arg Lys 1 5 358PRTHomo sapiens 35Lys Asn Asn His Ser Glu Arg
Lys 1 5 3612PRTHomo sapiens 36Lys Pro Gly Gly Lys Arg Lys Tyr Lys
Thr Arg His 1 5 10 379PRTHomo sapiens 37Lys Ala Lys Asp Ser His Tyr
Gln Lys 1 5 387PRTHomo sapiens 38Lys Asp Ser His Tyr Gln Lys 1 5
398PRTHomo sapiens 39Lys His Lys Arg Arg Lys Arg Lys 1 5 408PRTHomo
sapiens 40Lys Ala Thr Asp Thr Thr Lys His 1 5 417PRTHomo sapiens
41Lys His His Lys Lys Lys Lys 1 5 4210PRTHomo sapiens 42His His Lys
Lys Lys Lys Lys Lys His Lys 1 5 10 439PRTHomo sapiens 43His Lys Lys
Lys Lys Lys Lys His Lys 1 5 448PRTHomo sapiens 44Lys Lys Lys Lys
Lys Lys His Lys 1 5 457PRTHomo sapiens 45Lys Lys Lys Lys Lys His
Lys 1 5 467PRTHomo sapiens 46Lys Lys Lys Lys His Lys Lys 1 5
477PRTHomo sapiens 47Lys Lys Lys His Lys Lys Lys 1 5 488PRTHomo
sapiens 48Lys Lys His Lys Lys Lys His Lys 1 5 496PRTHomo sapiens
49Lys His Lys Lys His Lys 1 5 507PRTHomo sapiens 50Lys His Lys Lys
Lys His Lys 1 5 5110PRTHomo sapiens 51Lys His Lys Lys Lys His Lys
Lys His His 1 5 10 5211PRTHomo sapiens 52Lys Gly His Cys Asp Ser
Ser Thr Arg Ile Lys 1 5 10 537PRTHomo sapiens 53Lys His Lys Asp Lys
His Lys 1 5 548PRTHomo sapiens 54His Lys His Lys Asp Lys His Lys 1
5 5510PRTHomo sapiens 55Lys His Lys Asp Arg Glu His Arg His Lys 1 5
10 569PRTHomo sapiens 56His Lys Asp Arg Glu His Arg His Lys 1 5
578PRTHomo sapiens 57Lys Asp Arg Glu His Arg His Lys 1 5 588PRTHomo
sapiens 58His Lys Glu His Lys Lys Asp Lys 1 5 597PRTHomo sapiens
59Lys Glu His Lys Lys Asp Lys 1 5 6011PRTHomo sapiens 60His Lys Lys
Asp Lys Glu Lys Asp Arg Glu Lys 1 5 10 6113PRTHomo sapiens 61Lys
Lys Asp Lys Glu Lys Asp Arg Glu Lys Ser Lys His 1 5 10 6212PRTHomo
sapiens 62Lys Asp Lys Asp Lys Asp Arg Glu Lys Ser Lys His 1 5 10
6310PRTHomo sapiens 63Lys Asp Lys Asp Arg Glu Lys Ser Lys His 1 5
10 648PRTHomo sapiens 64Lys Asp Arg Glu Lys Ser Lys His 1 5
6510PRTHomo sapiens 65Lys Ser Lys His Ser Asn Ser Glu His Lys 1 5
10 6613PRTHomo sapiens 66His Lys Asp Lys His Lys Asp Arg Glu His
Arg His Lys 1 5 10 6710PRTHomo sapiens 67His Arg His Lys Glu His
Lys Lys Asp Lys 1 5 10 688PRTHomo sapiens 68Lys Gly Lys Asp Tyr Ser
Lys His 1 5 6912PRTHomo sapiens 69Lys Asp Lys Glu Lys Asp Arg Glu
Lys Ser Lys His 1 5 10 7010PRTHomo sapiens 70Lys Glu Lys Asp Arg
Glu Lys Ser Lys His 1 5 10 718PRTHomo sapiens 71Lys His Ser Asn Ser
Glu His Lys 1 5 7214PRTHomo sapiens 72His Ser Asn Ser Glu His Lys
Asp Ser Glu Lys Lys His Lys 1 5 10 739PRTHomo sapiens 73His Lys Asp
Ser Glu Lys Lys His Lys 1 5 748PRTHomo sapiens 74Lys Asp Ser Glu
Lys Lys His Lys 1 5 758PRTHomo sapiens 75Lys Lys His Lys Glu Lys
Glu Lys 1 5 7610PRTHomo sapiens 76Lys Lys His Lys Glu Lys Glu Lys
Thr Lys 1 5 10 777PRTHomo sapiens 77Lys His Lys Glu Lys Glu Lys 1 5
788PRTHomo sapiens 78His Lys Glu Lys Glu Lys Thr Lys 1 5 798PRTHomo
sapiens 79Lys Glu Lys Glu Lys Thr Lys His 1 5 807PRTHomo sapiens
80Lys Glu Lys Thr Lys His Lys 1 5 8111PRTHomo sapiens 81Lys Thr Lys
His Lys Asp Gly Ser Ser Glu Lys 1 5 10 829PRTHomo sapiens 82Lys His
Lys Asp Gly Ser Ser Glu Lys 1 5 838PRTHomo sapiens 83His Lys Asp
Gly Ser Ser Glu Lys 1 5 848PRTHomo sapiens 84Lys Asp Gly Ser Ser
Glu Lys His 1 5 8510PRTHomo sapiens 85His Lys Asp Lys His Lys Asp
Arg Asp Lys 1 5 10 869PRTHomo sapiens 86Lys Asp Lys His Lys Asp Arg
Asp Lys 1 5 877PRTHomo sapiens 87Lys His Lys Asp Arg Asp Lys 1 5
889PRTHomo sapiens 88His Lys Lys Glu Lys Asp Arg Glu Lys 1 5
8911PRTHomo sapiens 89Lys Glu His Lys Lys Glu Lys Asp Arg Glu Lys 1
5 10 9011PRTHomo sapiens 90Lys Gly His Cys Asp Ser Ser Thr Arg Ile
Lys 1 5 10 918PRTHomo sapiens 91His Lys Asp Arg Asp Lys Glu Lys 1 5
928PRTHomo sapiens 92Lys Trp Lys Phe Leu Glu His Lys 1 5
9310PRTHomo sapiens 93Lys Met Leu Asp His Glu Tyr Thr Thr Lys 1 5
10 9410PRTHomo sapiens 94Lys Val Pro Ser Pro Pro Pro Gly His Lys 1
5 10 9511PRTHomo sapiens 95His Lys Trp Lys Glu Val Arg His Asp Asn
Lys 1 5 10 9610PRTHomo sapiens 96Lys Trp Lys Glu Val Arg His Asp
Asn Lys 1 5 10 978PRTHomo sapiens 97Lys Glu Val Arg His Asp Asn Lys
1 5 989PRTHomo sapiens 98His Lys Glu Arg Ile Ala Asn Phe Lys 1 5
998PRTHomo sapiens 99Lys His Pro Thr Cys Pro Asn Lys 1 5
1009PRTHomo sapiens 100Lys Cys Asn Leu Gln Tyr His Phe Lys 1 5
10110PRTHomo sapiens 101Lys Lys Cys Asn Leu Gln Tyr His Phe Lys 1 5
10 10211PRTHomo sapiens 102His Phe Pro Arg Lys Val Tyr Thr Cys Gly
Lys 1 5 10 10312PRTHomo sapiens 103His Asp Gln Lys Asn His Arg Lys
His His Gly Lys 1 5 10 1047PRTHuman immunodeficiency virus 104Lys
His Lys Asp Lys His Lys 1 5 1058PRTHuman immunodeficiency virus
105His Lys His Lys Asp Lys His Lys 1 5 10610PRTHuman
immunodeficiency virus 106Lys His Lys Asp Arg Glu His Arg His Lys 1
5 10 1079PRTHuman immunodeficiency virus 107His Lys Asp Arg Glu His
Arg His Lys 1 5 1088PRTHuman immunodeficiency virus 108Lys Asp Arg
Glu His Arg His Lys 1 5 1098PRTHuman immunodeficiency virus 109His
Lys Glu His Lys Lys Asp Lys 1 5 1107PRTHuman immunodeficiency virus
110Lys Glu His Lys Lys Asp Lys 1 5 11111PRTHuman immunodeficiency
virus 111His Lys Lys Asp Lys Glu Lys Asp Arg Glu Lys 1 5 10
11213PRTHuman immunodeficiency virus 112Lys Lys Asp Lys Glu Lys Asp
Arg Glu Lys Ser Lys His 1 5 10 11312PRTHuman immunodeficiency virus
113Lys Asp Lys Asp Lys Asp Arg Glu Lys Ser Lys His 1 5 10
11410PRTHuman immunodeficiency virus 114Lys Asp Lys Asp Arg Glu Lys
Ser Lys His 1 5 10 1158PRTHuman immunodeficiency virus 115Lys Asp
Arg Glu Lys Ser Lys His 1 5 11613PRTHuman immunodeficiency virus
116His Lys Asp Lys His Lys Asp Arg Glu His Arg His Lys 1 5 10
11710PRTHuman immunodeficiency virus 117His Arg His Lys Glu His Lys
Lys Asp Lys 1 5 10 11812PRTHuman immunodeficiency virus 118Lys Asp
Lys Glu Lys Asp Arg Glu Lys Ser Lys His 1 5 10 11910PRTHuman
immunodeficiency virus 119Lys Glu Lys Asp Arg Glu Lys Ser Lys His 1
5 10 1208PRTHuman immunodeficiency virus 120Lys His Ser Asn Ser Glu
His Lys 1 5 12114PRTHuman immunodeficiency virus 121His Ser Asn Ser
Glu His Lys Asp Ser Glu Lys Lys His Lys 1 5 10 1229PRTHuman
immunodeficiency virus 122His Lys Asp Ser Glu Lys Lys His Lys 1 5
1238PRTHuman immunodeficiency virus 123Lys Asp Ser Glu Lys Lys His
Lys 1 5 1248PRTHuman immunodeficiency virus 124Lys Lys His Lys Glu
Lys Glu Lys 1 5 1257PRTHuman immunodeficiency virus 125Lys His Lys
Glu Lys Glu Lys 1 5 1268PRTHuman immunodeficiency virus 126His Lys
Glu Lys Glu Lys Thr Lys 1 5 1278PRTHuman immunodeficiency virus
127Lys Glu Lys Glu Lys Thr Lys His 1 5 1287PRTHuman
immunodeficiency virus 128Lys Glu Lys Thr Lys His Lys 1 5
12911PRTHuman immunodeficiency virus 129Lys Thr Lys His Lys Asp Gly
Ser Ser Glu Lys 1 5 10 1309PRTHuman immunodeficiency virus 130Lys
His Lys Asp Gly Ser Ser Glu Lys 1 5 1318PRTHuman immunodeficiency
virus 131His Lys Asp Gly Ser Ser Glu Lys 1 5 1328PRTHuman
immunodeficiency virus 132Lys Asp Gly Ser Ser Glu Lys His 1 5
13310PRTHuman immunodeficiency virus 133His Lys Asp Lys His Lys Asp
Arg Asp Lys 1 5 10 1349PRTHuman immunodeficiency virus 134Lys Asp
Lys His Lys Asp Arg Asp Lys 1 5 1357PRTHuman immunodeficiency virus
135Lys His Lys Asp Arg Asp Lys 1 5 1368PRTHuman immunodeficiency
virus 136His Lys Asp Arg Asp Lys Glu Lys 1 5 1377PRTHuman
immunodeficiency virus 137Lys Glu His Lys Lys Glu Lys 1 5
1389PRTHuman immunodeficiency virus 138Lys Glu His Lys His Lys Asp
His Lys 1 5 1398PRTHuman immunodeficiency virus 139Lys Trp Lys Phe
Leu Glu His Lys 1 5 14010PRTHuman immunodeficiency virus 140Lys Met
Leu Asp His Glu Tyr Thr Thr Lys 1 5 10 14111PRTHuman
immunodeficiency virus 141His Lys Trp Lys Glu Val Arg His Asp Asn
Lys 1 5 10 14210PRTHuman immunodeficiency virus 142Lys Trp Lys Glu
Val Arg His Asp Asn Lys 1 5 10 1438PRTHuman immunodeficiency virus
143Lys Glu Val Arg His Asp Asn Lys 1 5 14411PRTHuman
immunodeficiency virus 144Lys Gln Asn Gly Phe Ala Ser Pro His Ile
Lys 1 5 10 1457PRTHuman immunodeficiency virus 145Lys His Arg Asp
Lys Asp Lys 1 5 1468PRTHuman immunodeficiency virus 146Lys Lys His
Arg Asp Lys Asp Lys 1 5 1478PRTHuman immunodeficiency virus 147Lys
Asp Lys Glu His Lys His Lys 1 5 1489PRTHuman immunodeficiency virus
148His Lys Lys Asp Lys Glu Arg Glu Lys 1 5 1497PRTHomo sapiens
149Lys His Lys Asp Lys His Lys 1 5 1508PRTHomo sapiens 150His Lys
His Lys Asp Lys His Lys 1 5 15110PRTHomo sapiens 151Lys His Lys Asp
Arg Glu His Arg His Lys 1 5 10 1529PRTHomo sapiens 152His Lys Asp
Arg Glu His Arg His Lys 1 5 1538PRTHomo sapiens 153Lys Asp Arg Glu
His Arg His Lys 1 5 1547PRTHomo sapiens 154Lys Glu His Lys Lys Glu
Lys 1 5 15510PRTHomo sapiens 155His Arg His Lys Glu His Lys Lys Glu
Lys 1 5 10 1567PRTHomo sapiens 156Lys His Lys Glu Lys Arg Lys 1 5
1579PRTHomo sapiens 157His Lys Lys Glu Lys Asp Arg Glu Lys 1 5
1588PRTHomo sapiens 158His Lys Glu His Lys Lys Glu Lys 1 5
1599PRTHomo sapiens 159Lys Glu His Lys His Lys Asp His Lys 1 5
1608PRTHomo sapiens 160Lys Trp Lys Phe Leu Glu His Lys 1 5
16110PRTHomo sapiens 161Lys Met Leu Asp His Glu Tyr Thr Thr Lys 1 5
10 16210PRTHomo sapiens 162Lys Val Pro Ser Pro Pro Pro Gly His Lys
1 5 10 16311PRTHomo sapiens 163His Lys Trp Lys Glu Val Arg His Asp
Asn Lys 1 5 10 16410PRTHomo sapiens 164Lys Trp Lys Glu Val Arg His
Asp Asn Lys 1 5 10 1658PRTHomo sapiens 165Lys Glu Val Arg His Asp
Asn Lys 1 5 16616PRTHomo sapiens 166Lys Ala Glu Cys Pro Leu Cys Lys
Gln Pro Phe Asp Ser Ile Phe His 1 5 10 15 1679PRTHomo sapiens
167Lys Asp Glu Gln Ile Asn Lys Gly His 1 5 16812PRTHomo sapiens
168His Ser Val Leu Gly Lys Asp Glu Gln Ile Asn Lys 1 5 10
1699PRTHomo sapiens 169Lys Asn His Arg Lys His His Gly Lys 1 5
1709PRTHomo sapiens 170Lys His His Gly Lys Lys Arg Met Lys 1 5
1719PRTHomo sapiens 171His Gly Lys Lys Arg Met Lys Ser Lys 1 5
1729PRTHomo sapiens 172Lys Lys Asn Asn His Ser Glu Arg Lys 1 5
1738PRTHomo sapiens 173Lys Asn Asn His Ser Glu Arg Lys 1 5
17412PRTHomo sapiens 174Lys Pro Gly Gly Lys Arg Lys Tyr Lys Thr Arg
His 1 5 10 1759PRTHomo sapiens 175Lys Ala Lys Asp Ser His Tyr Gln
Lys 1 5 1767PRTHomo sapiens 176Lys Asp Ser His Tyr Gln Lys 1 5
1778PRTHomo sapiens 177Lys His
Lys Arg Arg Lys Arg Lys 1 5 1788PRTHomo sapiens 178Lys Ala Thr Asp
Thr Thr Lys His 1 5 1797PRTHomo sapiens 179Lys His His Lys Lys Lys
Lys 1 5 18010PRTHomo sapiens 180His His Lys Lys Lys Lys Lys Lys His
Lys 1 5 10 1819PRTHomo sapiens 181His Lys Lys Lys Lys Lys Lys His
Lys 1 5 1828PRTHomo sapiens 182Lys Lys Lys Lys Lys Lys His Lys 1 5
1837PRTHomo sapiens 183Lys Lys Lys Lys Lys His Lys 1 5 1847PRTHomo
sapiens 184Lys Lys Lys Lys His Lys Lys 1 5 1857PRTHomo sapiens
185Lys Lys Lys His Lys Lys Lys 1 5 1868PRTHomo sapiens 186Lys Lys
His Lys Lys Lys His Lys 1 5 1876PRTHomo sapiens 187Lys His Lys Lys
His Lys 1 5 1887PRTHomo sapiens 188Lys His Lys Lys Lys His Lys 1 5
18910PRTHomo sapiens 189Lys His Lys Lys Lys His Lys Lys His His 1 5
10 19011PRTHomo sapiens 190Lys Gly His Cys Asp Ser Ser Thr Arg Ile
Lys 1 5 10 1918PRTHomo sapiens 191Lys Lys His Arg Asp Lys Asp Lys 1
5 1928PRTHomo sapiens 192His Lys Asp His Lys Lys Asp Lys 1 5
1938PRTHomo sapiens 193Lys Tyr Lys Asp Lys Glu His Lys 1 5
1949PRTHomo sapiens 194Lys Glu His Lys His Lys Asp His Lys 1 5
1958PRTHomo sapiens 195Lys Trp Lys Phe Leu Glu His Lys 1 5
19610PRTHomo sapiens 196Lys Met Leu Asp His Glu Tyr Thr Thr Lys 1 5
10 19710PRTHomo sapiens 197Lys Val Pro Ser Pro Pro Pro Gly His Lys
1 5 10 19811PRTHomo sapiens 198His Lys Trp Lys Glu Val Arg His Asp
Asn Lys 1 5 10 19910PRTHomo sapiens 199Lys Trp Lys Glu Val Arg His
Asp Asn Lys 1 5 10 2008PRTHomo sapiens 200Lys Glu Val Arg His Asp
Asn Lys 1 5 2018PRTHomo sapiens 201Lys Phe Tyr Tyr Asp Gly Lys His
1 5 20210PRTHomo sapiens 202His Ser Pro Lys Leu Glu Lys Ser Leu Lys
1 5 10 2037PRTHomo sapiens 203Lys His Arg Asp Lys Asp Lys 1 5
* * * * *
References