EP1430302A2 - Inhibiteurs de glycosaminoglycanes - Google Patents
Inhibiteurs de glycosaminoglycanesInfo
- Publication number
- EP1430302A2 EP1430302A2 EP02728711A EP02728711A EP1430302A2 EP 1430302 A2 EP1430302 A2 EP 1430302A2 EP 02728711 A EP02728711 A EP 02728711A EP 02728711 A EP02728711 A EP 02728711A EP 1430302 A2 EP1430302 A2 EP 1430302A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- cancer
- glycosaminoglycan
- peptide
- pep
- cell
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates generally to the fields of cancer, immunology and inflammatory diseases. More particularly, it concerns peptide inhibitors of glycosaminoglycans.
- the invention also provides therapeutic and preventive methods for the treatment of inflammatory diseases, autoimmune diseases and other glycosaminoglycan- associated diseases. Additionally, the invention provides anticancer therapies using glycosaminoglycan binding agents.
- Hyaluronan also known as hyaluronic acid or hyaluronate (HA)
- HA is a glycosaminoglycan lacking a protein core, and is one of the major non-structural elements of the extracellular matrix (Laurent et al., F.A.S.E.B. J. 6: 2397-2404, 1992; Aruffo et al. Cell. 61:1303-1313, 1990; Culty et al, J. Cell. Biol. 111:2765 1990; Underhill et al. Cell. Sci. 103, 293-298, 1992; Toole et al. Plenum Press, New York, 1384-1386,1991).
- HA also is involved in immune responses, for example, increased binding of HA to one of its receptors, CD44, has been shown to mediate the primary adhesion ("rolling") of lymphocytes to vascular endothelial cells under conditions of physiologic shear stress, and this interaction mediates activated T cell extravasation into an inflamed site in vivo in mice (DeGrendele et al. J.Exp.Med. 183:1119-1130, 1996; DeGrendele et al, J. Immunol. 159:2549-2553, 1997; DeGrendele, et al., Science. 278:672-675, 1997b).
- an artificial peptide multimer which comprises the structure (Z) n X(Y) m where X is any amino acid and each of Y and Z is an aliphatic or polar aliphatic amino acid of between 6 and 30 amino acid residues.
- the peptide multimer will bind a glycosaminoglycan or fragment thereof with a binding affinity K a of 5 x 10 s 1/mol or more.
- the structure (Z) n X(Y) m is comprised within a subunit of the multimer.
- the multimer may have two or more peptide units with the same amino acid sequence, or with different amino acid sequences.
- FIG 11. A-B. In vivo inhibition of DC-dependent T cell activation by PEG-Pep-1.
- Pep-1 a novel peptide that binds glycosaminoglycans, termed "Pep-1,” by using phage display technology.
- This peptide has the sequence GAHWQFNALTVR.
- Pep-1 showed specific binding to soluble, immobilized, and cell-associated forms of HA, and inhibited leukocyte adhesion to HA substrates almost completely.
- Systemic, local, or topical administration of Pep-1 inhibited the expression of contact hypersensitivity responses in mice by blocking skin-directed homing of inflammatory leukocytes.
- the peptide inhibitors of glycosaminoglycans are involved in various aspects of immune system function including, the control of activation, differentiation, proliferation, trafficking, release of cytokines and other regulatory/effector molecules by immune cells. Therefore, it is contemplated that the peptide inhibitors of gylcosaminoglycans will be effective therapeutic agents in a variety of immune disorders.
- Pep-1 and its derivatives are potent anti-inflammatory molecules by their ability to suppress immune system and more specifically by their ability to prevent leukocyte trafficking. Preventing leukocyte trafficking to and from sites of inflammation prevents the associated tissue damage.
- derivatives of the peptides of the invention can be chemically synthesized using of a peptide synthesizer and standard synthetic procedures.
- peptides can be synthesized on a solid support (resin) using either Boc or Fmoc chemistries.
- Any type of automated synthesizer may be used including batch synthesizers and a continuos-flow synthesizers.
- a manual synthetic approach may be used to prepare the peptides of the invention.
- solution phase peptide synthesis methods can also be used.
- the peptide will have the core sequence of general formula
- Non-classical amino acids include but are not limited to the D-isomers of the common amino acids, ⁇ - amino isobutyric acid, 4-amino-butyric acid, 2-amino butyric acid, ⁇ -amino butyric acid, ⁇ -6- amino hexanoic acid, 2-amino isobutyric acid, 3 -amino propionic acid, ornithine, norleucine, norvaline, hydroxyproline, sarcosine, citrulline, cysteic acid, t-butylglycine, t-butylalanine, phenylglycine, cyclohexylalanine, ⁇ -alanine, fluoro-amino acids, designer amino acids such as ⁇ -methyl amino acids, C ⁇ -methyl amino acids, N ⁇ -methyl amino acids, and amino acid analogs in general.
- the amino acid can be either of the optical isomers, D (dextrorotary) or L (levorotary).
- the subunit may further comprises an N- or C-terminal extension W p , wherein W is any basic or neutral amino acid, and p is an integer between 3 and 13, for example, wherein W is arginine or glycine independently.
- the peptide subunit also may comprise a terminal serine.
- the extension is a C-terminal GGGS.
- PEP 1 can have of at least about 65%, preferably at least about 80%, more preferably at least about 85%, and can be about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO:l or 2.
- An exemplary hetero-bifunctional cross-linker contains two reactive groups: one reacting with primary amine group (e.g., N-hydroxy succinimide) and the other reacting with a thiol group (e.g., pyridyl disulfide, maleimides, halogens, etc.).
- primary amine group e.g., N-hydroxy succinimide
- a thiol group e.g., pyridyl disulfide, maleimides, halogens, etc.
- the cross-linker may react with the lysine residue(s) of one protein (e.g., the selected antibody or fragment) and through the thiol reactive group, the cross- linker, already tied up to the first protein, reacts with the cysteine residue (free sulfhydryl group) of the other protein (e.g., the selective agent).
- cross-linker having reasonable stability in blood will be employed.
- Numerous types of disulfide-bond containing linkers are known that can be successfully employed to conjugate targeting and therapeutic/preventative agents. Linkers that contain a disulfide bond that is sterically hindered may prove to give greater stability in vivo, preventing release of the targeting peptide prior to reaching the site of action. These linkers are thus one group of linking agents.
- SMPT cross-linking reagent
- Another cross-linking reagent is SMPT, which is a bifunctional cross-linker containing a disulfide bond that is "sterically hindered" by an adjacent benzene ring and methyl groups. It is believed that steric hindrance of the disulfide bond serves a function of protecting the bond from attack by thiolate anions such as glutathione which can be present in tissues and blood, and thereby help in preventing decoupling of the conjugate prior to the delivery of the attached agent to the target site.
- thiolate anions such as glutathione which can be present in tissues and blood
- HA has ' several other ligands including, RHAMM, aggrecan, versican, link protein, the LEC HA receptor, hyaluronection, inter- ⁇ -trypsin inhibitor-related proteins, BEHAB, CD38, CD54, and hyaluronidase (HAase). Therefore, the peptide derivatives that bind glycosaminoglycans, provided herein, are envisioned to be useful in potentiating or inhibiting glycosaminoglycan-mediated activities through these receptor molecules as well. The skilled artisan will recognize that the peptide derivatives provided here will be useful as therapeutic agents in various pathologies and that the scope of the invention is not limited to the diseases and conditions mentioned here. C. HA Metabolism
- HAases degrades HA polysaccharides to oligosaccharides while ⁇ -D-glucuronidase and ⁇ -N-acetyl-D- hexosaminidase degrades oligosaccharides into monosaccharides (glucuronic acid and N- acetyglucosamine).
- Glucuronic acid is converted through a series of enzymatic reactions to D-glucose-6-phosphate.
- the D-glucose-6-phosphate then funnels into the glycolytic pathway.
- N-acetyglucosamine is phosphorylated in an ATP-dependent reaction to yield N- acetyglucosamine-6-phosphate.
- the peptides of the invention can facilitate a decrease in pressure upon myocardial tissues, prevent tissue necrosis, and relieve edema (Maclean et al. Science. 194:199-200, 1976; Opie et al. Am. Heart. J. 100:531-52, 1980).
- Non-limiting examples include, ibuprofen, ketoprofen, piroxicam, naproxen, naproxen sodium, sulindac, celecoxib, aspirin, choline subsalicylate, diflunisal, oxaprozin, diclofenac sodium delayed release, diclofenac potassium immediate release, etodolac, ketorolac, fenoprofen, flurbiprofen, indomethacin, fenamates, meclofenamate, mefenamic acid, nabumetone, oxicam, piroxicam, salsalate, tolmetin, and magnesium salicylate.
- Another important embodiment of the invention provides, for the first time, a successful anti-cancer effect by altering glycosaminoglycan functions.
- the invention envisions anticancer-therapies utilizing any agent that is capable of inhibiting glycosaminoglycan function or expression.
- therapies for the treatment of cancers associated with increased levels of HA or other glycosaminoglycans, or of cancers that are associated with altered glycosaminoglycan function comprising providing to a patient in need thereof a agent that inhibits a glycosaminoglycan.
- Such an agent can include among others any peptide or non-peptide glycosaminoglycan inhibitor.
- cancer therapies may be used in combination with the anticancer peptides of the present invention.
- anticancer peptides of the present invention may be desirable to combine these compositions with other agents effective in the treatment of cancer such as but not limited to those described below.
- some of the patient's blood may be removed and heated before being perfused into an area that will be internally heated.
- Whole-body heating may also be implemented in cases where cancer has spread throughout the body. Warm-water blankets, hot wax, inductive coils, and thermal chambers may be used for this purpose.
- Hormonal therapy may also be used in conjunction with the present invention or in combination with any other cancer therapy previously described.
- the use of hormones may be employed in the treatment of certain cancers such as breast, prostate, ovarian, or cervical cancer to lower the level or block the effects of certain hormones such as testosterone or estrogen. This treatment is often used in combination with at least one other cancer therapy as a treatment option or to reduce the risk of metastasis. 5.
- Other Therapeutic Uses are also be used in conjunction with the present invention or in combination with any other cancer therapy previously described.
- composition must be stable under the conditions of manufacture and storage, and preserved against the contaminating action of microorganisms, such as bacteria and fungi. It will be appreciated that endotoxin contamination should be kept minimally at a safe level, for example, less that 0.5 ng/mg protein.
- prolonged absorption of an injectable composition can be brought about by the use in the compositions of agents delaying absorption, such as, for example, aluminum monostearate, gelatin or combinations thereof.
- the present invention further comprises methods for identifying modulators of glycosaminoglycan metabolism.
- These assays may comprise random screening of large libraries of candidate substances; alternatively, the assays may be used to focus on particular classes of compounds selected with an eye towards structural attributes that are believed to make them more likely to modulate glycosaminoglycan metabolism.
- a method generally comprises: providing a candidate modulator; admixing the candidate modulator with a cell, tissue or a suitable experimental animal; measuring one or more aspects of glycosaminoglycan metabolism in the tissue cell or animal in step; and comparing the aspect measured in step (c) with the aspect of the cell, tissue or animal in the absence of said candidate modulator, wherein a difference between the aspect indicates that said candidate modulator is, indeed, a modulator of glycosaminoglycan metabolism.
- Assays may be conducted in cell free systems as well.
- the goal of rational drug design is to produce structural analogs of biologically active polypeptides or target compounds. By creating such analogs, it is possible to fashion drugs, which are more active or stable than the natural molecules, which have different susceptibility to alteration or which may affect the function of various other molecules. In one approach, one would generate a three-dimensional structure for a target molecule, or a fragment thereof. This could be accomplished by x-ray crystallography, computer modeling or by a combination of both approaches.
- Anti-idiotypes may be generated using the methods described herein for producing antibodies, using an antibody as the antigen.
- the Pep-1 dimer was soluble in the absence of added solvents such as DMSO and exhibited significant biological activities to prevent HA- mediated leukocyte adhesion. As the Pep-1 dimer formulation has a high solubility it is an ideal choice for local administration in therapeutic applications.
- Pep-1 Tetramer This Pep-1 tetramer obtained by PEG- conjugated Pep-1 remained soluble in the absence of added solvents (e.g., DMSO) and exhibited significant biological activities to prevent HA-mediated leukocyte adhesion.
- the PEG-conjugated Pep-1 was also found to be at least 10-fold more active than Pep-1 in its capacity to inhibit in vitro adhesion of B16F10 melanoma cells to the HA-coated substrates.
- the inventors have therefore demonstrated that lung metastasis of B16-F10 mouse melanoma cell line can be inhibited by simultaneous administration of Pep-1. These results have revealed an additional pharmacological activity of Pep-1 to specifically prevent tumor metastasis. The inventors will also examine the prophylactic and therapeutic potentials of multimeric Pep-1 formulations and other chemically modified Pep-1 derivatives using this animal model of melanoma metastasis.
- compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
Abstract
L'invention concerne des dérivés peptidiques présentant une affinité spécifique pour les molécules de glycosaminoglycane. Ces dérivés peptidiques comprennent des mulitmères ainsi que des peptides modifiés chimiquement et peuvent être préparés par divers procédés. Les peptides décrits ont de nombreuses fonctions, et peuvent être utilisés notamment, mais non exclusivement, comme inhibiteurs des événements de signalisation régulés par le glycosaminoglycane, et comme agents de ciblage. Les peptides décrits peuvent être dirigés contre un glycosaminoglycane quelconque, notamment l'acide hyalonurique, le chondroïtine sulfate A, le dermatane sulfate, l'héparine, le kératane sulfate, le kératosulfate, la chitine, le chitosane 1 et le chitosane 2. Les dérivés peptidiques décrits ont également des applications thérapeutiques dans le traitement et la prévention de pathologies telles que les maladies inflammatoires, le cancer, les métastases cancéreuses, les maladies auto-immunes etc.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US27779001P | 2001-03-21 | 2001-03-21 | |
US277790P | 2001-03-21 | ||
PCT/US2002/011167 WO2002076173A2 (fr) | 2001-03-21 | 2002-03-20 | Inhibiteurs de glycosaminoglycanes |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1430302A2 true EP1430302A2 (fr) | 2004-06-23 |
EP1430302A4 EP1430302A4 (fr) | 2007-08-22 |
Family
ID=23062353
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02728711A Withdrawn EP1430302A4 (fr) | 2001-03-21 | 2002-03-20 | Inhibiteurs de glycosaminoglycanes |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1430302A4 (fr) |
JP (1) | JP2004532203A (fr) |
AU (1) | AU2002258749A1 (fr) |
CA (1) | CA2439409A1 (fr) |
WO (1) | WO2002076173A2 (fr) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2720587A1 (fr) | 2008-04-09 | 2009-10-15 | Francis Barany | Coferons et leurs procedes de fabrication et d'utilisation |
CA2774476A1 (fr) | 2009-10-07 | 2011-04-14 | Francis Barany | Coferons et procedes de fabrication et d'utilisation de ceux-ci |
EP2804586A4 (fr) * | 2012-01-19 | 2016-03-16 | Univ Johns Hopkins | Biomatériaux comprenant des peptides se liant à l'acide hyaluronique et des molécules biopolymères bifonctionnelles pour des applications de rétention d'acide hyaluronique et d'ingénierie tissulaire |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996040189A1 (fr) * | 1995-06-07 | 1996-12-19 | Glaxo Group Limited | Peptides et composes se fixant a un recepteur |
EP0950708A2 (fr) * | 1997-12-19 | 1999-10-20 | Cangene Corporation | Peptides se liant à l'hyaluronane avec une affinité augmentée |
WO2000057896A1 (fr) * | 1999-03-26 | 2000-10-05 | The University Of Texas System | Modulateurs de polysaccharides et leurs utilisations |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5643575A (en) * | 1993-10-27 | 1997-07-01 | Enzon, Inc. | Non-antigenic branched polymer conjugates |
WO1997009051A1 (fr) * | 1995-09-05 | 1997-03-13 | Cambridge Neuroscience, Inc. | Analogues pour interactions specifiques oligosaccharide-neureguline et leurs utilisations |
EP1169048A4 (fr) * | 1998-07-06 | 2002-07-17 | Glenn D Prestwich | Analogues d'acide hyaluronique et procedes correspondants |
AU4529800A (en) * | 1999-05-05 | 2000-11-21 | Neurochem, Inc. | Stereoselective antifibrillogenic peptides and peptidomimetics thereof |
-
2002
- 2002-03-20 WO PCT/US2002/011167 patent/WO2002076173A2/fr active Search and Examination
- 2002-03-20 EP EP02728711A patent/EP1430302A4/fr not_active Withdrawn
- 2002-03-20 JP JP2002574703A patent/JP2004532203A/ja active Pending
- 2002-03-20 CA CA002439409A patent/CA2439409A1/fr not_active Abandoned
- 2002-03-20 AU AU2002258749A patent/AU2002258749A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996040189A1 (fr) * | 1995-06-07 | 1996-12-19 | Glaxo Group Limited | Peptides et composes se fixant a un recepteur |
EP0950708A2 (fr) * | 1997-12-19 | 1999-10-20 | Cangene Corporation | Peptides se liant à l'hyaluronane avec une affinité augmentée |
WO2000057896A1 (fr) * | 1999-03-26 | 2000-10-05 | The University Of Texas System | Modulateurs de polysaccharides et leurs utilisations |
Non-Patent Citations (4)
Title |
---|
CARRITHERS M D ET AL: "SYNTHESIS AND CHARACTERIZATION OF BIVALENT PEPTIDE LIGANDS TARGETED TO G-PROTEIN-COUPLED RECEPTORS" CHEMISTRY AND BIOLOGY, CURRENT BIOLOGY, LONDON, GB, vol. 3, no. 5, May 1996 (1996-05), pages 537-542, XP000945385 ISSN: 1074-5521 * |
MUMMERT M E ET AL: "Development of a peptide inhibitor of hyaluronan-mediated leukocyte trafficking." THE JOURNAL OF EXPERIMENTAL MEDICINE 18 SEP 2000, vol. 192, no. 6, 18 September 2000 (2000-09-18), pages 769-779, XP009081295 ISSN: 0022-1007 * |
See also references of WO02076173A2 * |
TAKASHIMA A ET AL: "NEW TECHNOLOGIES TO PREVENT AND TREAT CONTACT HYPERSENSITIVITY RESPONSES" ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, NEW YORK ACADEMY OF SCIENCES, NEW YORK, NY, US, vol. 919, 2000, pages 205-213, XP009060432 ISSN: 0077-8923 * |
Also Published As
Publication number | Publication date |
---|---|
WO2002076173A2 (fr) | 2002-10-03 |
JP2004532203A (ja) | 2004-10-21 |
AU2002258749A1 (en) | 2002-10-08 |
CA2439409A1 (fr) | 2002-10-03 |
EP1430302A4 (fr) | 2007-08-22 |
WO2002076173A3 (fr) | 2004-04-08 |
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