LV13419B

LV13419B - Synthetic peptides and uses thereof for the prevention and therapy of cancer invasion and metastasis

Info

Publication number: LV13419B
Application number: LVP-05-134A
Authority: LV
Inventors: Matthias Rath; Aleksandra Niedzwiecki; Shrirang Netke
Original assignee: Matthias Rath
Priority date: 2002-01-23
Filing date: 2005-10-17
Publication date: 2006-09-20
Also published as: NO20034146L; DE60326539D1; ATE425247T1; EP1468085B1; RU2004125599A; PL371254A1; CN101007844A; RU2346043C2; KR20040077764A; WO2003062413A1; ZA200405328B; NO20034146D0; ES2324027T3; MXPA04007170A; US8012935B2; LV13289B; YU76403A; PL209827B1; BR0302819A; US20030139345A1

Description

SYNTHETIC PEPTIDES AND METHOD FOR PREVENTIVE AND THERAPEUTIC USE IN CANCER INVASION AND METASTASIS

FIELD OF THE INVENTION

The present invention reiates to synthetic peptides that exhibit inhibitory activity towards cancer invasion and metastasis. The peptides of the invention comprises PRKPKWDK (SEQ ID: 2) peptide corresponding to amino acids of 85 to 92 of the matrix metalloproteinase-2 (MM P-2), and fragments, analogs and homologs of SEQ ID: 2). The invention also reiates to the uses of such peptides as inhibitory of human cancer invasion and metastasis and further to the therapeutic use in preventing and treating cancer and other pathological conditions related to the degradation of extracellular matrix by MMPs.

BACKGROUND OF THE INVENTION

A variety of pathological conditions including neoplastic diseases are associated with an increased activity of matrix metalloproteinases (MMPs). MMPs are a group of serine proteinases that can degrade extracellular matrix (ECM). MMPs are secreted in the extracellular matrix in their zymogen form. Upon activation, MMPs enzymatic activity becomes active and digest ECM, a process that is shovvn to piay a major role in cancer metastasis.

They are at least a few members of proteinases within the MMP family, and they include MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-13. In cancer MMP-2 is implicated in primary tumour growth as well as in tumour metastasis. This particular MMP is able to digest collagen and other extracellular matrix (ECM) proteīns as a precondition for the spreading of cancer for its invasion and metastasis.

Although a great deal of effort is being directed to design and testing of anticancer aģents, there is a continuing need for a non-toxic therapeutic aģent that can effectively block MMPmediated digestion of ECM, thereby attenuating the spreading of cancer and other diseases.

SUMMARY OF THE INVENTION

The present invention embodies synthetic peptides vvhich can effectively block cancer celi invasion. The benefits of these aģents and the antibodies to them are the utility in clinical applications for blocking cancer invasion and metastasis.

-2An object of the present invention is to provide a synthetic oligopeptide having the amino acid sequence analogous to specific amino sequence of the matrix metalloproteinase 2 sequence (85-92) that is effective in blocking cancer invasion and cancer metastasis.

An object of the present invention is to provide synthetic peptides that are useful in blocking cancer invasion and metastasis having an amino acid sequence PRKPKWEDK.

Another object of the present invention is a process of utilizing synthetic peptides as disclosed in this application to prevent and treat cancer diseases. It is a further aspect of the embodiment that an effective amount of synthetic peptides is used to achieve blockade of cancer invasion and metastasis.

Another object of the present invention provides an oligopeptide having PRKPKWDK (SEQ. ID. No. 2).

Preferably, the oligopeptide is of about 6 to about 20 residues. Most preferably, the oligopeptide is of about 8 to about 10 residues.

Preferably, the concentration of the synthetic peptide ranges from 1 μΜ to 500 μΜ. Most 20 preferablv, the concentration of synthetic peptides ranges from 50 μΜ to 200 μΜ.

Another object of the present invention is an immunogenic oligopeptide that is included in pharmaceutical compositions comprising a pharmaceutically acceptable carrier and the oligopeptides. The oligopeptide can be used as a vaccine. The pharmaceutical composition comprising oligopeptide can be used to inducē an immune response against a protein comprising an epitope having the sequence of the oligopeptide (e.g., SEQ. ID. 2).

Another object of the present invention is that the compositions and processes be accomplished both in vivo and in vitro.

The present invention provides a synthetic oligopeptide having amino acid sequence analogous to human MMP-2.

-3The present invention further provides a modification of oligopeptides that block cancer celi invasion and metastasis by omitting one or more of the amino residues at the N-terminal end.

The present invention provides a modification of oligopeptides that block cancer celi 5 invasion and metastasis by omitting one or more amino acid residues at the C-terminal end.

The present invention provides a modification of oligopeptides that block cancer celi invasion and metastasis by omitting one or more amino acid residues at the N-terminal and the C-terminal end.

The present invention provides a modification of oligopeptides that block cancer celi invasion and metastasis by substituting one or more of the amino acid residues vvithin the given sequence vvithout consideration of charge and polarity of the substitution residue.

The present invention provides a modification of oligopeptides that block cancer celi invasion and metastasis by substituting one or more of the amino acid residues vvithin the given sequence vvith amino acid residues vvith similar charge and/or polarity.

The present invention provides a modification of oligopeptides that block cancer celi invasion and metastasis by omitting one or more amino acid residues vvithin the given sequence.

The present invention provides a modification of oligopeptides that block cancer celi invasion and metastasis by tvvo or more of the modifications.

The present invention provides a modification of oligopeptides that block cancer celi invasion and metastasis by repeating the oligopeptides sequence one or more times each of them covalently bound to one or more oligopeptides repeat(s).

Another object of the present invention is using the synthetic peptides as an immunogen to generate antibodies so that such generated antibodies can effectively block cancer invasion and metastasis.

-4The present invention provides a preventive or therapeutic use of one or more of the oligopeptides to directly and competitively reduce or block the metabolic action or interaction of MMP-2 by intravenous application or in another therapeutically acceptable way.

The present invention provides a preventive or therapeutic use of one or more of the oligopeptides to indirectly reduce or block the metabolic action or interaction of MMPs by appiying them as vaccines by subcutaneous application or in another acceptable way to stimulate a specific immune response vvhich can partially or completely block the metabolic interaction of MMP5. An preferred embodiment includes MMP-2.

The present invention provides a preventive and therapeutic use of one or more of the oligopeptides vvhere the oligopeptides are coupled to haptens to enhance immune response and thereby therapeutic efficacy. ļ ļ

i ļ

The present invention provides a preventive or therapeutic use of one or more of the !

oligopeptides to function as feed-back regulators to specifically prevent or reduce the synthesis rāte of MMP-2 proteins at the cellular Ievel.

The present invention provides one of more oligopeptides that can block cancer celi invasion and metastasis as vaccines for the production of specific antibodies for the diagnosis of a disease involving MMP-2 or the clinical monitoring of the progression or regression of this disease.

The present invention provides the use of one or more of oligopeptides that block cancer celi invasion and metastasis for the prevention or therapy of cancer.

The present invention provides the use of one or more of oligopeptides that block cancer celi invasion and metastasis, where these oligopeptides can be applied to a patient as a vaccine, as injections, infusions, inhalations, suppositories or other pharmaceutically acceptable carriers and/or means of delivery.

-5BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the amino acid sequence of the enzyme MMP2. The amino acid sequences selected for inhibitory activity studies have been boxed for easy Identification. The amino acid sequence TMRKPRCGNPDVAN (also boxed) which vvas shovvn to inhibit the activity of MMP2 by others (Loitta and Associates) vvas used a reference.

FIG. 2 depicts the comparative inhibitory effects of various oligopeptides tested.

Oligopeptide PRKPKWDK is highly effective in blocking cancer celi invasion using Matrigel assay with human melanoma cancer celis A2058.

FIG. 3 depicts an inhibitory effect of oligopeptide PRK.PK.WDK. in blocking cancer celi invasion using Matrigel assay vvith human melanoma cancer celis A2058.

FIG. 4 depicts an inhibitory effect of oligopeptide PRKPKWDK in blocking cancer celi 15 invasion using Matrigel assay vvith human breast cancer celis MCF7.

DETAILED DESCRIPTION OF THE INVENTION

Definitions: As used herein, the term peptide» refers to organic compounds comprising two or more amino acids covalently joined by peptide bonds; peptides may be a dipeptide (which contains two amino acid residues), a tripeptide (three amino acids etc.).

As used herein, the term oligopeptide” refers to a peptide that contains typically less than 30 residues in length. The length of oligopeptides is not critical to the invention so long as the correct epitope is maintained. Desirably, the oligopeptide can be as smali as possible vvhile stili maintaining substantially ali the biological activity of the large oligopeptide and that it is effective in blocking cancer celi invasion and metastasis.

Oligopeptide” is used interchangeable vvith ”synthetic peptide” in this application. The oligopeptide used in this invention is an ‘isolated” but ”biologically pure synthetic peptides.

As used herein, the one-letter symbols for amino acid residues are: A (alanine); R (arginine);

N (asparagine); D (aspartic acid); C (cysteine); Q (glutamine); E (glutamic acid); G (glycine);

-6H (histidine); I (isoleucine); L (leucine); K (lysine); M (methionine); F (phenylalanine);

P (proline); S (serine);T (threonine); W (tryptophan); and Y (tyrosine).

Amino acid substitutions are typically of single residues. Substitutions, deletions, insertions 5 or any combination thereof may be combined to arrive at a oligopeptide. Conserved amino acid substitutions consists of replacing one or more amino acids with amino acids vvith similar charge, size and/or hydrophobicity characteristics, such as, for example, a glutamic acid (E) to aspartic acid (D) amino acid subsitution. Nonconserved substitutions consist of replacing one or more amino acids vvith amino acids possessing dissimilar charge, size, and/or hydrophobicity, such as, for example, a glutamic acid (E) to valine (V) substitution. The present invention is intended to encompass conservative changes of oligopeptide vvith respect to substitutions, deletions, insertions or any combination thereof so long as the effectiveness of blocking cancer celi invasion and metastasis is substantially unchanged.

Rath et al. (J Applied Nutr. 44:62-69,1992; J Orthomolecular Med. 8:11-20, 1993) has postulated that oligopeptide sequences vvith high hydrophilicity maxima and conformation and electric charge mediate pathogenesis of multitude of diseases. According to the postulation, selected sequence of amino acid in the MMP enzyme may block the action of the enzyme by attaching itself to the complimentary sequence in the substrate. This concept is entirely different than the one detailed by Liotta and associates (U.S. Pat. No. 5,372,809) in vvhich the oligopeptide blocks the zinc molecule in the enzyme. The experimental evidence indicating that complexes of different types of protein in the celis can modify the activity of the proteins in the celi (Gavin and Associates, Nature 415:141-147, 2002) is in essence confirmation of the postulate. The references cited herein are incorporated by reference in its entirety.

In the present invention, we identified possible oligopeptide sequences in the amino acid sequence of MMP-2 and found that these oligopeptide sequences effectively interfere vvith the functional activity of MMP-2 using in vitro invasion of ECM by cancer celis as tēst modei.

-7Not limited by any theory or mechanism of actions, the present invention provides oligopeptides that can effectively block cancer celi invasion and metastasis.

One mechanism of action may be that MMP-2 binds to the target ECM molecules via 5 specific binding sites. Blocking these binding sites may therefore prevent MMP-2 from binding to its ECM substrate molecules, inhibits the destruction of the ECM and thereby prevents cancer and other diseases from spreading throughout the body.

Several potential binding sites vvithin the MMP-2 protein have been identified, the present invention provides that synthetic analogs to these oligopeptides sequences are effective to prevent ECM destruction. One of the therapeutic oligopeptides is PRK.PK.WDK., vvhich is shovvn to inhibit the invasion of cancer celis by about 90 %.

The present invention additionally provides a therapeutic use of the oligopeptide in other

MMP-related diseases. Because MMP-2 may use the same sites to bind to its target molecules vvithin the ECM, the oligopeptide disclosed in the present invention can similarly interfere other diseases. Thus, the preventive and therapeutic use of the synthetic oligopeptides claimed here are not limited to cancer but can also be used in cardiovascular disease and other pathological conditions associated vvith the destruction of the ECM by

MMPs. These oligopeptides can be applied to a patient as a vaccine, as injections, infusions, inhalations, suppositories or other pharmaceutically acceptable carriers and/or means of delivery.

The method of administering peptides and formulations of the present invention employs any of a number of knovvn administrative routes such as oral, IV, subcutaneous, transcutaneous and topical administration. A preferred method of the present invention employs a pharmaceutical composition for parenteral administration.

The present invention provides oligopeptides that can also be used as vaccines to raise antibodies for assays used to diagnose diseases involving MMPs (in particular, MMP-2) as vvell as the clinical monitoring of the progression or regression of this disease through blood essays or in other suitable diagnostic essays.

-8The present invention embodies synthetic peptides effective in blocking cancer celi invasion. The benefits of these aģents and the antibodies to them are the utility in clinical applications for preventing and treating cancer invasion and metastasis. Preferably, synthetic oligopeptides vvhich have the amino acid of SEQ ID. 2 are useful in blocking cancer invasion and metastasis. More preferably, the synthetic peptides are ineluded in a pharmaceutical formulation for blocking cancer invasion and metastasis.

The oligopeptide may be of about 6 to about 20 residues. Most preferably, the oligopeptide is of about 8 to about 10 residues. Most preferably, the synthetic oligopeptide contains 8 amino acid residues in length.

Preferably, the concentration of synthetic peptides ranges from 1 μΜ to 500 μΜ. Most preferably, the concentration of synthetic peptides ranges from 50 μΜ to 200 μΜ.

Preferably, the synthetic oligopeptide contains 8 amino acid residues in length. Another object of the present invention is an immunogenic oligopeptide that is ineluded in pharmaceutical composition comprising a pharmaceutically acceptabie carrier and the oligopeptides. The oligopeptide can be used as a vaccine. The pharmaceutical composition comprising oligopeptide can be used to inducē an immune response against a protein comprising an eptiope having the sequence of the oligopeptide (e.g., SEQ. ID. 2).

The present invention provides a synthetic oligopeptide having amino acid sequence analogous to an amino acid sequence vvithin the protein of human MMP-2.

-9The amino- and/or carboxy-termini of the synthetic oligopeptide can comprise an amino group (-NH2) or a carboxy (-COOH) group, respectively. Alternatively, the oligopeptide amino-terminus may, for example, represent a hydrophobic group, including but not limited to carbobenzyl, dansyl, t-butoxycarbonyl, decanoyl, napthoyl or other carbohydrate group; an acetyl group; 9-fluorenylmethoxy-carbonyl (FMOC) group; or a modified, non-naturally occurring amino acid residue. Alternatively, the synthetic oligopeptide carboxy-terminus can, for example, represent an amido group; a t-butoxycarbonyl group; or a modified nonnaturally occurring amino acid residue. Alternatively, the present invention encompasses synthetic oligopeptides that block cancer celi invasion and metastasis by omitting an amino residue at the N-terminal end or the C-terminal end. The present invention also provides a modification of oligopeptides that block cancer celi invasion and metastasis by substituting an amino acid residue within the given sequence vvithout consideration of charge and polarity of the substitution residue.

It is to be understood that the present invention also contemplates peptide analogues vvherein one or more amide linkage is optionally replaced with a linkage other than amide, preferably a substituted amide or an isostere of amide. Thus, while the amino acid residues within peptides are generally described in terms of amino acids, and preferred embodiments of the invention are exemplified by way of peptides, one having skiil in the art vvili recognize that in embodiments having non-amide linkages, the term amino acid or residue as used herein refers to other bifunctional moieties bearing groups similar in structure to the side chains of the amino acids. In addition the amino acid residues may be blocked or unblocked.

The present invention provides a modification of oligopeptides that block cancer celi invasion and metastasis by repeating the oligopeptide sequence one or more times each of them covalently bound to one or more oligopeptide repeat(s).

The present invention provides a preventive or therapeutic use of one or more of the oligopeptides to directly and competitively reduce or block the metabolic action or interaction of MMP-2 by intravenous application or in another therapeutically acceptable way.

- 10The present invention provides a preventive or therapeutic use of one or more of the oligopeptides to indirectly reduce or block the metabolic action or interaction of MMPs by applying them as vaccines by subcutaneous application or in another acceptable wav to stimulate a specific immune response which can partially or completely block the metabolic interaction of MMPs. An preferred embodiment includes MMP-2.

The present invention provides a preventive and therapeutic use of one or more of the oligopeptides where the oligopeptides are coupled to haptens to enhance immune response and thereby therapeutic efficacy.

The present invention provides a preventive or therapeutic use of one or more of the oligopeptides to function as feedback regulators to specifically prevent or reduce the synthesis rāte of MMP-2 proteins at the cellular Ievel.

The present invention provides the use of one or more of oligopeptides that block a human disease including, but not limited to cancer celi invasion and metastasis for the prevention or therapy of cancer; for example, prevention or therapy of infectious diseases, cardiovascular diseases and degenerative diseases.

The present invention provides the use of one or more of oligopeptides that block cancer celi invasion and metastasis for the prevention or therapy of diseases involving MMP-2.

The present invention provides the use of one or more of oligopeptides that block cancer celi invasion and metastasis, vvhere these oligopeptides can be applied to a patient as a vaccine, as injections. infusions, inhalations, suppositories or other pharmaceutically acceptable carriers and/or means of delivery.

- 11 Compositions of the present invention may be in the form of a peptide or peptides in combination vvith at Ieast one other aģent, such as stabilizing compound, vvhich may be administered in any sterile, bio-compatible pharmaceutical carrier, including, but not limited to, saline, buffered saline, dextrose, and vvater. The compositions may be administered to a patient alone, or in combination vvith other aģents, drugs or hormones. Pharmaceuticallyacceptable carriers may also be comprised of excipients and auxiliaries vvhich facilitate processing of the active compounds into preparations vvhich can be used pharmaceutically. Further details on techniques for formulation and administration may be found in the latest edition of ”Remington's Pharmaceutical Sciences”, Mack Publishing Co., Easton, Pa., vvhich content is incorporated by reference in its entirety. The pharmaceutical composition may be provided as a salt and can be formed vvith many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.

The follovving examples are intended as illustrations of the practice of this and are not meant to limit the scope of the invention.

Oligopeptide Seguences

The amino acid sequence of MMP-2 regarding reģions of high hydrophilicity maxima enriched vvith charged amino acids vvere identified vvith a softvvare program. The oligopeptides of the present invention may be synthesized or prepared by techniques vvell knovvn in the art. (See, for example, Creighton, 1983, Proteins: Structures and Molecular Principles, W.H. Freeman and Co., Ν.Υ.,) vvhich is incorporated herein by reference in its entirety. The oligopeptides prepared and used in the present invention are listed in Table 1.

The inhibitory effects of these oligopeptides on the Matrigel invasion and migration through

- 12the Matrigel membrane by various cancer celis vvere evaluated using ”improved Matrigel Invasion Chamber” (Becton Dickinson, USA). The oligopeptide TMRKPRCGNPDVAN vvhich vvas shovvn to have anti-MMP-2 activity by Liotta and Associates vvas used as a Standard reference for oligopeptides.

Table 1: Various Oligopeptide Seguences Identified and Use In the Studies

Oligopeptide	Sequence Number
GDVAPKTDKE	SEQ ID. 1
PRKPKWDK	SEQ ID. 2
EDYDRDKKY	SEQ ĪD. 3
GRSDGLM	SEQ ID. 4
NYDDDRKW	SEQ ID. 5
LPPDVQRVD	SEQ ID. 6
RYNEVKKKMDP	SEQ ID. 7

General Experimental Conditions

The identified oligopeptīds vvere custom synthesized. They vvere then used for Matrigel invasion studies.

(a) Matrigel Invasion Studies

The studies vvere conducted using Improved Matrigel Invasion Chambers» (Becton Dickinson, USA).

In studies vvith human melanoma celis, human fibroblasts- NHDF (Clonetics) vvere seeded on 20 Matrigel” insert and vvere allovved to reach confluence. This vvas done to closely simulate the in vivo conditions surrounding the cancer celis in the body. The human melanoma celis A2058 vvere then seeded on the insert. Conditioned media from the fibroblast culture supplemented vvith various Ievels of chosen oligopeptide vvas added to the chamber. The system vvas incubated for about 24 hours. At the end of the period the celis on the upper

- 13 surface of the insert vvere wiped off. The celis that had invaded the Matrigel membrane and had migrated to the lovver surface of the insert vvere stained vvith ”quick stain“ and vvere counted under the microscope. The percent inhibition vvas calculated by the number of celis that failed to migrate through the membrane as compared to control (”0”Ievel of oligopeptide). The inhibitory activity of the control vvas considered as ”0‘,. The s media from invasion assays vvas saved for zymogram studies.

In studies vvith human breast cancer celis MCF7 the procedure vvas essentially similar to that used for melanoma celis, except that MRC5 (ATCC) fibroblasts vvere used in place of

NHDF.

In studies vvith human breast cancer celis MDA-MB 231 the fibroblast-MRC5 (ATCC) celis vvere plated in the vvells. Rest of the procedure remained the same as in studies vvith MCF7 celis.

(b) Zvmogram Studies

The media (25-30 μΐ) from various vvells in invasion studies vvere applied to Novex” zymogram gels (Invitrogen). The gels vvere developed and stained as recommended by the manufacturer. The matrix metalloproteinases (MMPs) vvere identified on the basis of their knovvn molecular vveights.

Example 1

Inhibitorv effects of various oligopeptide seguences on Matrigel invasion and migration by melanoma celis A2058

Seven (7) oligopeptides (see Table 1 for their amino acid sequences) vvere tested for inhibiting invasion of human melanoma cancer celis. Oligpeptide having the amino acid sequence PRKPKWDK shovved blocking activity. Oligopeptide having

TMRKPRCGNPDVAN shovved about 11% inhibition as compared to 73% shovvn by PRK.PK.WDK (Fig 1).

- 14Oligopeptide VI having the amino acid sequence LPPDVQRVD also had some blocking activity (i.e., about 20%). Oligopeptide’T’ having the amino acid sequence GDVAPK.TDKE did not show any activity up tom 100 μΜ concentration (not shovvn in Fig.2). as against 63 % shovvn by PRKPKVVDK at the same concentration.

Example 2

Inhibitory effects of oligopeptide PRKPKWDK on Matrigel invasion and migration by melanoma celis A2058

In these studies the concentration of PRKPKWDK in the medium vvas varied betvveen 0 to 150 μΜ. it vvas seen that the oligopeptide progressively inhibited the invasion by the melanoma celis (Fig. 3) from about 37% at 50 μΜ concentration to 73% at 150 μΜ.

The Matrigel membrane is analogus to ECM and the ability of cancer celis to breakthrough and migrate to the other side of the membrane represents the ability of the cancer celis to metastasize in the body. The oligopeptide was able to significantly reduce invasion of three different types of cancer celis. In this tēst system the activity vvas directed against ECM. We conclude that our studies therefore clearly indicate that the oligopeptide can interfere vvith degradation of ECM in the body and thereby adversely affect the progression of diseases in vvhich breakdovvn of ECM is the basie lesion.

Example3

In these studies vve determined the inhibitory effects of PRKPKWDK on the Matrigel invasion and migration by h'uman breast cancer celis MCF7 (ATCC). As vvith melanoma celis this oligopeptide inhibited the cancer celi invasion. The inhibition at 150 μΜ concentration vvas about 70%. It increased to about 90% at 200 μΜ concentration (Fig. 4).

Example 4

In these studies vve investigated the inhibitory activity of PRKPKWDK vvith another human

- 15 breast cancer celis- MDA-MB 231. The inhibition at 150 μΜ concentration was about 94%.

Example 5

We next assessed it the oligopeptides can interfere vvith the action of the enzyme after it vvas secreted. Zymogram studies did not shovv any inhibitory effect of the PR.KPK.WDK on the amount of MMP-2 secreted by the various cancer celis (data not shovvn).

A number of embodiments of the invention have been described. Nevertheless, it vvill be understood that various modifications may be made vvithout departing from the spirit and scope of the invention. Accordingly, other embodiments are vvithin the scope of the present claimed invention.

While the foregoing has been set forth in considerable detail, the sequences are presented for elucidation, and not limitation. Modifications and improvements, inciuding equivalents, of the technology disclosed above vvhich are vvithin the purvievv and abilities of those in the art are included vvithin the scope of the claims appended hereto. It vvill be readily apparent to those skilled in the art that numerous modifications, alterations and changes can be made vvith respect to the specifics of the above deseription vvithout departing from the inventive concept described herein. For example, modification (either Chemical or enzymatic) of the basie sequences described herein are also vvithin the purvievv of the present invention. For example, the disclosed sequence can be a dipeptide or tripeptide. Also, the disclosed sequences may be modified to inciude this residue at either the amino or carboxyl ends of the peptides. The sequences may also be chemically modified to increase their activity (e.g., amidation of the carboxyl terminus portion of a sequence). The peptides may be chemically modified to increase their activitv (e.g., amidation of the carboxy terminus portion of a sequence or inciuding a glycine or alanine residue at either end). Accordingly, it is understood that various modifications may be made vvithout departing from the spirit and scope of the invention and that such variances should be vievved as being vvithin the scope of the present invention as set forth in the claims belovv.

Claims

1. An oligopeptide comprising an oligopeptide sequence selected from the group consisting of:

a) an oligopeptide sequence as shovvn in SEQ ID No: 6;

b) an oligopeptide capable of inducing an immune response against the epitope of SEQ ID No: 6;

c) an oligopeptide sequence of 8 to 10 amino acid residues in length comprising any one of the sequences of a) or b);

d) an oligopeptide sequence comprising the oligopeptide sequence of any one of a) to c), vvherein one or more amino acids are replaced by amino acids vvith similar charge, size, and/or hydrophobicity characteristics provided that the oligopeptide sequence is capable of blocking cancer celi invasion and metastasis;

e) an oligopeptide sequence comprising the oligopeptide sequence of any one of a) to d), vvherein an amino acid residue at the N- or C-terminal end is omitted provided that the oligopeptide sequence is capable of blocking cancer celi invasion and metastasis; and

f) an oligopeptide sequence comprising one or more repeats of the oligopeptide sequence of any one of a) to e) covalently bound to each other.

2. The oligopeptide of claim 1, vvherein said oligopeptide is coupled to haptens enhancing immune response.

3. A pharmaceutical composition comprising the oligopeptide of claim 1 or 2.

4. A diagnostic composition comprising the oligopeptide of claim 1 or 2.

5. A vaccine comprising the oligopeptide of claim 1 or 2.

6. Use of the oligopeptide of claim 1 or 2 for the preparation of a pharmaceutical composition for preventing or treating cancer, infectious diseases, cardiovascular diseases, degenerative diseases, or pathological conditions associated with the destruction of the ECM by MMPs.

7. The use of claim 6, vvherein said pharmaceutical composition is to be administered to a patient as a vaccine, as injection, infusion, inhalation or suppository.

8. The use of claim 6 or 7, vvherein said oligopeptide is to be formulated in a concentration ranging from 1 μΜ to 500 μΜ or 50 μΜ to 200 μΜ.