EP1223962A1 - Method and compositions for inhibiting adhesion formation - Google Patents
Method and compositions for inhibiting adhesion formationInfo
- Publication number
- EP1223962A1 EP1223962A1 EP00970476A EP00970476A EP1223962A1 EP 1223962 A1 EP1223962 A1 EP 1223962A1 EP 00970476 A EP00970476 A EP 00970476A EP 00970476 A EP00970476 A EP 00970476A EP 1223962 A1 EP1223962 A1 EP 1223962A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- accordance
- antagonist molecule
- monoclonal antibody
- composition
- molecule
- 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- Withdrawn
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
- C07K16/2848—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta3-subunit-containing molecules, e.g. CD41, CD51, CD61
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/043—Proteins; Polypeptides; Degradation products thereof
- A61L31/045—Gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/252—Polypeptides, proteins, e.g. glycoproteins, lipoproteins, cytokines
- A61L2300/256—Antibodies, e.g. immunoglobulins, vaccines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/424—Anti-adhesion agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/432—Inhibitors, antagonists
- A61L2300/436—Inhibitors, antagonists of receptors
Definitions
- This invention relates to the field of medicine and inhibition of post-operative/post-wounding adhesion formation. Background of the invention
- adhesion used in its medical sense refers to conglutination, the process of adhering or uniting of two surfaces or parts. For example, the union of the opposing surfaces of a wound, or opposing surfaces of peritoneum. Also, adhesions, in the plural, can refer to inflammatory bands that connect opposing serous surfaces.
- adhesion also includes fibrinous adhesions, which are adhesions that consist of fine threads of fibrin resulting from an exudate of plasma or lymph, or an extravasion of blood. Keloid, a smooth overgrowth of fibroblastic tissue that arises in an area of injury or, occasionally, spontaneously is also a form of adhesion.
- adhesion development is a major source of postoperative morbidity and mortality.
- the most frequent surgical procedures implicated in significant adhesion formation are gynecologic, cardiovascular, and general abdominal surgery. This is true for traditional surgery, as well as laparoscopic surgery.
- Complications of intraperitoneal adhesions include intestinal obstruction, chronic or recurrent pelvic pain, infertility in females, and prolonged surgical time and postoperative complications (when additional surgical procedures are needed).
- debilitating adhesions can be treated by adhesiotomy, surgical section or lysis of the adhesion (adhesiolysis).
- methods and compositions for inhibiting adhesion formation in patients would be most useful.
- InterceedTM (Johnson & Johnson Medical) is an oxidized regenerated cellulose; SeprafilmTM (Genzyme Corp.), is a modified hyaluronic acid complexed with modified carboxymethylcellulose and PrecludeTM, (W.L. Gore) is an expanded polytetraflurorethylene. InterceedTM is properly used in the absence of blood. PrecludeTM has been approved as a pericardial substitute, but is not bioresorbable. SeprafilmTM has been approved for use in abdominal wall and uterine incisions.
- Potential antiadhesion agents tested in a rat system include Ringer's lactate, 32% dextran 70 solution, and 1 % and 2% modified carboxymethylcellulose solution.
- One half of the solutions were applied to the defect, and the excess allowed to pool within the peritoneal cavity of the abdomen.
- Ringer's lactate was not effective since it was rapidly absorbed in the peritoneal cavity, and was, thus, not present during the full 36 hour critical period. The other, slightly viscous solutions were more effective.
- Hyaluronic acid has been used as a barrier in abdomino- pelvic and orthopedic surgery.
- Modified HA as a resorbable gel and, a hyaluronan-based gel of auto-crosslinked polysaccharides (ACP) have also been tested.
- the ACP, hyaluronic acid derivatives have been demonstrated to prevent laparoscopic adhesion formation in the rabbit model system, and has been reported by Delaco et al. , 1998, Fertility and Surgery. 69(2): 318-323.
- a chemically modified hyaluronate and carboxymethylcellulose (HA/CMC) gel formulation was applied in a rabbit models system by Leach et al. , 1998, Fertility and Surgery. 69(3): 415-418.
- the invention provides needed compositions and methods useful for inhibiting or ameliorating adhesion formation in mammals, including humans.
- Adhesions resulting from wounding or surgical procedures can be inhibited or at least ameliorated by treating a wound or surgical site with an antagonist molecule that interacts with alpha V beta 3 ( ⁇ v ⁇ 3) integrin, or with the integrin binding site of an extracellular matrix protein to block an v ⁇ 3 integrin from binding to an extracellular matrix protein in a mammalian body.
- Suitable antagonist molecules for this purpose are proteins, peptides (linear as well as cyclic) and peptidomimetics that mimic the ⁇ v ⁇ 3 integrin binding site on an extracellular matrix protein, e.g. , fibronectin, or that bind to the ⁇ v ⁇ 3 integrin itself so as to interfere with its binding to an extracellular matrix protein.
- v ⁇ 3 antagonist molecules are monoclonal antibodies and bioactive portions or fragments thereof that include, mimic, or block the ⁇ v ⁇ 3 binding site on an extracellular matrix protein, or that specifically bind to an antigenic epitope of the ⁇ v ⁇ 3 molecule so that inhibition of ⁇ v ⁇ 3 integrin binding to an extracellular matrix protein is achieved.
- One such monoclonal antibody is LM609 in its entirety, as well as its bioactive antigen binding portions or fragments such as Fab, Fab2, Fv, and mixtures thereof. Both the murine as well as the humanized versions of monoclonal antibody LM609 are suitable for the present purposes.
- fibronectin fragments that include amino acid residue sequences corresponding to the v ⁇ 3 integrin binding site on fibronectin, and which may for example include the amino acid residue sequence Arg-Gly-Asp- Ser (RGDS) or bioequivalents thereof, can be utilized as ⁇ v ⁇ 3 antagonist molecules for the purposes of the present invention to interfere with an ⁇ v ⁇ 3 integrin binding to fibronectin or any other extracellular matrix protein that has a binding site defined by the amino acid residue sequence RGDS or bioequivalents thereof.
- RGDS amino acid residue sequence Arg-Gly-Asp- Ser
- peptidomimetics i.e. , non-peptidic organic compounds that mimic the aforementioned peptides vis-a-vis interaction with ⁇ v ⁇ 3 integrins so as to interfere with the ⁇ v ⁇ 3 integrin binding to an extracellular matrix protein, e.g. , fibronectin, and the like.
- Adhesion formation is inhibited, or at least minimized, by applying to the surgical site an adhesion-inhibiting amount of at least one of the aforementioned ⁇ v ⁇ 3 antagonist molecules, directly or in a physiologically compatible carrier vehicle.
- Application of these antagonists is readily accomplished via intraperitoneal (i.p.) administration, subcutaneous (s.c.) injection, intravenous (i.v.) administration, or other suitable route of administration.
- Suitable carrier vehicles can be liquids as well as physiologically acceptable absorbable pastes and solids.
- the antagonist molecule can be applied as an antagonist composition with the antagonist molecule dissolved in an aqueous vehicle or present as a suspension therein, usually at a concentration of at least about 50 micrograms per milliliter ( ⁇ g/ml).
- the antagonist composition can be an absorbable paste or a solid constituted by the inhibitor molecule in solution or suspension, and an absorbable gelatin sponge or powder, or as an absorbable dried hydrogel, absorbable hyaluronic acid derivatives, and the like, as the carrier vehicle.
- the ⁇ v ⁇ 3 antagonist composition can be packaged in appropriately sized dosage forms provided with a label which indicates that the inhibitor composition contained within the package can be used to inhibit adhesion formation.
- the ⁇ v ⁇ 3 antagonists contemplated by the present invention can either bind to the extracellular matrix protein, or to the ⁇ v ⁇ 3 integrin molecule; however, to be effective such binding must interfere with the normal interaction between v ⁇ 3 integrin and its binding site on an extracellular matrix protein.
- extracellular matrix proteins are fibronectin, fibrinogen, vitronectin, von Willebrand Factor, laminin, collagen, tenascin, osteopontin, thrombospondin, and the like.
- a preferred method for inhibiting post-operative adhesion formation comprises administering to a surgical patient (human as well as veterinary) an adhesion inhibiting amount of an ⁇ v ⁇ 3 integrin inhibitor molecule.
- Such administration encompasses application of an aliquot of the inhibitor composition to a tissue surface to be protected from adhesion formation either directly, or as an aerosol spray, or via a pad, gel, solution, suspension, or the like, as a suitable carrier vehicle.
- Adhesion formation occurs as an aberration of the wound healing cascade involving cell adhesion and migration of fibroblasts. Adhesions often occur as a result of trauma or bleeding at the time of surgery when the interruption of a peritoneal surface results in the exposure of the underlying stromal layers. Subsequently, this exposure leads to the release of kinins and histamine which, in turn, increase capillary permeability and allow serosanguinous exudate containing inflammatory cells to be released. This exudate, rich in fibrin, leads to clotting on the injured surface. Without dissolution of the clot, inflammatory cells and fibroblasts infiltrate the fibrin rich extracellular matrix which results in the formation of adhesions.
- the extracellular matrix is composed of an interactive network of proteins which forms the meshwork upon which cells adhere to organize tissues.
- the macromolecules that constitute the extracellular matrix are mainly secreted locally by cells in the matrix. In most connective tissues these macromolecules are secreted largely by fibroblasts or cells from the fibroblast family, such as chondroblasts or osteoblasts.
- the two main classes of extracellular macromolecules that make up the matrix are polysaccharide glycosaminoglycans (GAGs), which are usually found covalently linked to protein in the form of proteoglycans, and fibrous proteins.
- the fibrous proteins are usually considered as one of two functional types: mainly structural (for example collagen and elastin) or mainly adhesive (for example fibronectin and laminin).
- structural for example collagen and elastin
- adhesive for example fibronectin and laminin.
- Cell adhesion regulates cell migration, growth and differentiation in embryonic tissues, and in the extracellular matrix, as well as contributes to the formation of malignancies, inflammation, immune regulation and hemostasis.
- integrins Mediators of cell adhesion, transmembrane cellular receptors, include integrins, immunoglobulin supergene family, cadherins, selectins, CD- 44 related molecules, and transmembrane proteoglycans.
- Integrins are an important class of binding protein which interact with many ligands.
- the v ⁇ 3 integrin is a membrane-bound glycoprotein identified as important for cell-cell adhesion and migration. Integrins bind to diverse ligands including components of the extracellular matrix, cell surface immunoglobulin (Ig) superfamily receptors, surface components of microorganisms, and certain plasma proteins.
- Ig immunoglobulin
- Murine monoclonal (mAb) IgG antibody LM609 produced by the hybridoma cell line LM 609, is specific for integrin v ⁇ 3 (Cheresh et al. , 1987, J. Biol. Chem.. 262: 17703-17711).
- Murine hybridoma LM609 has been deposited with the American Type Culture Collection (ATCC, Rockville, MD, USA) as the International Depository Authority under the Budapest Treaty, and assigned the ATCC Designation HB 9537, on September 15, 1987.
- LM609 cDNA has been cloned, and soluble Fab portions thereof have been made from transformed host cells.
- LM609 antibody also has been humanized to reduce its immunogenicity, (WO 99/29888).
- Proteins and peptides suitable for use as ⁇ v ⁇ 3 antagonist molecules are those that include the v ⁇ 3 complementary binding site on fibronectin, the amino acid residue sequence RGDS, or bioequivalents thereof.
- the peptides can be linear or cyclic.
- non-toxic, non-peptide organic compounds that define a region that is substantially complementary to the ⁇ v ⁇ 3 integrin binding site or to the binding site on the extracellular matrix protein for the ⁇ v ⁇ 3 integrin.
- the ⁇ v ⁇ 3 integrin antagonist molecule can be applied to a surgical site directly, as an aerosol powder, or in a physiologically compatible carrier vehicle which can be a liquid, such as water, alone or together with an absorbable powder in the form of a paste.
- sterile gelatin powder commercially available under the designation GELFOAM ® (Upjohn Co.).
- the v ⁇ 3 integrin antagonist molecule can be delivered to the surgical site on a sterile gelatin foam or sponge, on a dried, absorbable hydrogel of the type described in U.S. Patent No. 5,409,703 to McAualley et al. , or on a hyaluronic acid derivative.
- the preferred carrier vehicle is an aqueous vehicle such as water, or an aqueous saline solution.
- a rabbit sidewall model of adhesion formation has been previously described (Rogers et al. , 1996, J. Invest. Surg.. 9:388-91; Rodgers et al. , 1998, supra). Rabbits were anesthetized with a mixture of 55 mg ketamine hydrochloride per kg rabbit body weight, and 5 mg xylazine per kg intramuscularly. Following preparation for sterile surgery, a midline laparotomy was performed. The cecum and bowel were exteriorized, and digital pressure was exerted to create subserosal hemorrhages over all surfaces that could be in contact with the area of sidewall injury. The damaged intestine was then lightly abraded with 4" 4x4-ply sterile gauze until punctate bleeding was observed. The cecum and bowel were then returned to their normal anatomical position.
- This rabbit model is very similar to a standardized rat model for adhesion formation described by Harris et al. (1995, supra).
- this rat model an abdominal wall defect and cecal abrasion were created, air dried for 10 minutes, and the two injured surfaces placed into contact before closure.
- the rats were anesthetized with intraperitoneal sodium pentobarbital (43 mg/kg).
- the ventral abdomen was prepared and given an iodophor scrub, and rinsed with 70% alcohol. A 6 cm midline skin incision was made, and the skin retracted. A 4 cm midline abdominal wall incision was made, and the right abdominal wall was rejected.
- a 1 x 2 cm segment of parietal peritoneum was sharply excised from the wall including a superficial layer of underlying muscle, 1 cm lateral to the midline incision.
- the cecum was then elevated and positioned so that at closure the cecum would contact the abdominal wall defect. Thereafter, the cecum was abraded in a standard manner by scraping with a scalpel blade so that a homogeneous surface of petechial hemorrhages was created over a 1 x 2 cm area.
- the abdominal wall defect was also abraded. Both the abdominal wall and cecal defects were exposed to air for 10 minutes. The defects were then placed in contact, the midline incision was closed with a running 4-0 polypropylene suture and the skin closed with 4-0 silk (Harris et al. , 1995, supra).
- rabbit uterine horn model Another rabbit system for studying reproductive organ adhesions is the rabbit uterine horn model.
- a midline incision is made and the uterine horns are brought through the incision.
- An approximately 5 cm long areas around the entire circumference of the uterine horns are abraded using surgical gauze, and by scraping 12 times with a scalpel blade. This injury results in generalized erythema without areas of active bleeding.
- the horns are then replaced in the abdominal cavity and the wound closed.
- a standardized injury to the peritoneum or internal surfaces can be induced by denuding a 2 x 2 cm area of the right uterine horn for 30 seconds with forceps, making a 1-cm incision in the distal right uterine horn, denuding a 5 x 5 cm area of the peritoneum of the abdominal wall in front of the previous lesions.
- Administration of whole murine LM 609 mAb to the surgical site of a patient is possible, but may be precluded for long-term, or multiple, uses lest a host immune reaction is triggered against the murine LM 609 protein (i.e. , Human anti-mouse antibody, HAMA in human patients; Cat or Dog anti- mouse antibody and other reactions in other treated animals).
- LM 609 that has been truncated, either into Fab, Fab2, or Fv constructs or mixtures thereof.
- the generation of antibody fragments such as Fab, Fab2 or Fv is known in the art and is taught for example by French (1998, Methods in Molecular Biology. Immunochemical Protocols, 2nd Ed. , 80: 121-134).
- Also known is the use of recombinant DNA methods to prepare these antigen binding proteins and artificial constructs (i.e. single chain Fv, scFv, scAb; Molecular Recognition Units, MRUs), see for example Verhoeyen et al.
- the murine LM 609 antibody can be humanized by the judicious substitution of amino acid residues in the protein structure to alter the immunogenic epitopes of the antibody surface to appear as human protein to the treated host, wherein the antigen specificity of the binding active site, including complementarity determining region (CDR) amino acid residues, are conserved to maintain antigen epitope binding specificity.
- CDR complementarity determining region
- Patent 5,502,167 describe a humanized antibody in which the amino acid sequence of the CDRs is derived from the sequence of CDRs of a monoclonal antibody having the specificity of binding to resting and activated T-cells.
- Hoogenboom et al. U.S. Patent 5,565,332 describe methods for producing antibodies with increased human characteristics involving selective mutation of either heavy or light chains, recombination of the mutated chains, and antigen selective screening for binding activity.
- Adair et al., (U.S. Patent 5,859,205) describe specific methods for grafting the CDR of antibody heavy and light chains to acceptor framework regions.
- any resultant reduction in affinity that may occur by this process, and, thus, reduction in binding efficiency, can be minimized by screening with antigen to select better binding constructs, and by generating multi-valent binding constructs.
- compositions of the invention by generating antibodies that interfere with, or otherwise block, the binding of ⁇ v ⁇ 3 integrin to fibronectin or other extracellular matrix protein, thus interfering with the formation of the contacts needed for the development of adhesions.
- suitable animals can be immunized to stimulate the generation of antibodies specific for the v ⁇ 3 integrin or to the ⁇ v ⁇ 3 binding site of fibronectin or other extracellular matrix protein.
- Suitable such antibodies can be selected by antigen screening using routine methods known in the art.
- the generation of monoclonal antibodies from suitably selected clones is also well known and can be utilized for the production of suitable ⁇ v ⁇ 3 inhibitor molecules.
- Antagonist molecules suitable for inhibition of ⁇ v ⁇ 3 binding in addition to those described herein above can also be easily selected by routine screening.
- an in vitro screening assay can be constructed utilizing cell adhesion to a prepared extracellular matrix comprising fibronectin or other suitable matrix component.
- candidate molecules can be administered, and the subsequent behavior of the cells scored. Reduction in binding to the substrate, or inhibition of proliferation of matrix components mirroring adhesion formation, indicates a promising candidate for further study.
- the initial screening can be conducted with mixtures of compounds so as to reduce screening time and effort by performing batch screens. Specific binding inhibition of specific compound mixtures can be individually assayed once any initial results indicate success. Such screening can be fully automated, if desired.
- inhibiting molecules are found, it is envisioned that they will be suitably formulated into a composition of the invention for use in the method of the invention. Ideally the optimal concentration for use of any such compound is at least comparable to that for LM 609 antibody, and minimizes any potential adverse or toxic effects.
- Antagonist molecules that specifically bind to, or interfere with, the v ⁇ 3 integrin binding site of an extracellular matrix protein molecule are also suitable for practicing the invention.
- a midline laparotomy was performed on the experimental animals, and the sidewalls, bladder, uterus and fallopian tubes were abraded with 200 grit sandpaper until punctate bleeding occurred.
- the abdominal wall was closed in two layers using 3.0 polyglactin 910 (Vicryl) for the muscle and 4.0 polyglactin 910 to close the skin in a subcuticular fashion.
- the animals were housed with a 12 hour light/dark cycle and fed
- a filmy adhesion was defined as one that could easily be disrupted.
- a dense adhesion was one that was not easily separated.
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US40552299A | 1999-09-23 | 1999-09-23 | |
US405522 | 1999-09-23 | ||
PCT/US2000/026095 WO2001021196A1 (en) | 1999-09-23 | 2000-09-22 | Method and compositions for inhibiting adhesion formation |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1223962A1 true EP1223962A1 (en) | 2002-07-24 |
EP1223962A4 EP1223962A4 (en) | 2004-01-21 |
Family
ID=23604048
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00970476A Withdrawn EP1223962A4 (en) | 1999-09-23 | 2000-09-22 | Method and compositions for inhibiting adhesion formation |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1223962A4 (en) |
JP (1) | JP2003509468A (en) |
KR (1) | KR20020048941A (en) |
CN (1) | CN1399554A (en) |
AU (1) | AU781442B2 (en) |
BR (1) | BR0014222A (en) |
CA (1) | CA2384812A1 (en) |
MX (1) | MXPA02003079A (en) |
WO (1) | WO2001021196A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2025685B1 (en) | 2007-08-15 | 2013-06-19 | Canadian Blood Services | Monoclonal antibodies against BETA3 integrins |
CN109641084A (en) | 2016-07-13 | 2019-04-16 | 持田制药株式会社 | It is anti-sticking that composition is used in conjunction |
WO2019138583A1 (en) * | 2018-01-15 | 2019-07-18 | 持田製薬株式会社 | Anti-adhesion composition |
KR102318958B1 (en) * | 2019-08-08 | 2021-10-27 | 고려대학교 산학협력단 | Pharmaceutical Composition for Preventing or Treating Tissue Adhesion Comprising Integrin α2β1 Inhibitors |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990014103A1 (en) * | 1989-05-17 | 1990-11-29 | Scripps Clinic And Research Foundation | Polypeptide-antibody conjugate for inhibiting cell adhesion |
US5753230A (en) * | 1994-03-18 | 1998-05-19 | The Scripps Research Institute | Methods and compositions useful for inhibition of angiogenesis |
WO1999009982A1 (en) * | 1997-08-25 | 1999-03-04 | Harold Brem | Prevention of adhesions and excessive scar formation using angiogenesis inhibitors |
-
2000
- 2000-09-22 JP JP2001524620A patent/JP2003509468A/en active Pending
- 2000-09-22 KR KR1020027003796A patent/KR20020048941A/en not_active Application Discontinuation
- 2000-09-22 MX MXPA02003079A patent/MXPA02003079A/en unknown
- 2000-09-22 WO PCT/US2000/026095 patent/WO2001021196A1/en active IP Right Grant
- 2000-09-22 BR BR0014222-0A patent/BR0014222A/en not_active IP Right Cessation
- 2000-09-22 CN CN00816148A patent/CN1399554A/en active Pending
- 2000-09-22 CA CA002384812A patent/CA2384812A1/en not_active Abandoned
- 2000-09-22 EP EP00970476A patent/EP1223962A4/en not_active Withdrawn
- 2000-09-22 AU AU79850/00A patent/AU781442B2/en not_active Ceased
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990014103A1 (en) * | 1989-05-17 | 1990-11-29 | Scripps Clinic And Research Foundation | Polypeptide-antibody conjugate for inhibiting cell adhesion |
US5753230A (en) * | 1994-03-18 | 1998-05-19 | The Scripps Research Institute | Methods and compositions useful for inhibition of angiogenesis |
WO1999009982A1 (en) * | 1997-08-25 | 1999-03-04 | Harold Brem | Prevention of adhesions and excessive scar formation using angiogenesis inhibitors |
Non-Patent Citations (2)
Title |
---|
PIRISI A: "Postsurgical adhesions reduced with antibody" LANCET (NORTH AMERICAN EDITION), vol. 354, no. 9185, 2 October 1999 (1999-10-02), page 1184 XP001156012 ISSN: 0099-5355 * |
See also references of WO0121196A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU781442B2 (en) | 2005-05-26 |
EP1223962A4 (en) | 2004-01-21 |
CA2384812A1 (en) | 2001-03-29 |
BR0014222A (en) | 2003-02-25 |
JP2003509468A (en) | 2003-03-11 |
MXPA02003079A (en) | 2004-04-21 |
AU7985000A (en) | 2001-04-24 |
CN1399554A (en) | 2003-02-26 |
WO2001021196A1 (en) | 2001-03-29 |
KR20020048941A (en) | 2002-06-24 |
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