WO2005075003A1

WO2005075003A1 - Implantable medical devices for treating or preventing restenosis

Info

Publication number: WO2005075003A1
Application number: PCT/US2004/037915
Authority: WO
Inventors: Jeffrey Walker
Original assignee: Medtronic Vascular Inc.
Priority date: 2004-01-21
Filing date: 2004-11-12
Publication date: 2005-08-18

Abstract

Implantable medical devices are provided having anti-restenotic coatings applied thereto. The coatings includes at least one anti-restenotic monoclonal antibody. More specifically the anti-restenotic antibody is directed at blocking growth factor receptors on cell surfaces. Other embodiments include vascular stents having anti-restenotic monoclonal antibodies incorporated into a polymer matrix. In one specific embodiment the anti-restenotic monoclonal antibody is Erbitux.

Description

IMPLANTABLE MEDICAL DEVICES FOR TREATING OR PREVENTING RESTENOSIS

FIELD OF THE INVENTION

[0001] The present invention relates to implantable medical devices provided having anti-proliferative coatings. Specifically, the present invention provides vascular stents having coatings releasing monoclonal antibodies wherein the antibodies have anti-restenotic properties.

BACKGROUND OF THE INVENTION

[0002] The implantation of medical devices has become a relatively common technique for treating a variety of medical or disease conditions within a patient's body. Depending upon the conditions being treated, today's medical implants can be positioned within specific portions of a patient's body where they can provide beneficial functions for periods of time ranging from days to years. A wide variety of medical devices can be considered implants for purposes of the present invention. Such medical devices can include structural implants such as stents and internal scaffolding for vascular use, replacement parts such as vascular grafts, or indwelling devices such as probes, catheters and microparticles for monitoring, measuring and modifying biological activities within a patient's cardiovascular system. Other types of medical implants for treating different types of medical or disease conditions can include in-dwelling access devices or ports, valves, plates, barriers, supports, shunts, discs, and joints, to name a few.

[0003] Cardiovascular disease, commonly referred to as atherosclerosis, remains a leading cause of death in developed countries. Atherosclerosis is a disease that results in the narrowing, or stenosis, of blood vessels which can lead to heart attack or stroke if the narrowing progresses to the point of blocking blood flow through the narrowed blood vessels forming the coronary arteries. Cardiovascular disease caused by stenotic or narrowed coronary arteries is commonly treated using either a coronary artery by-pass graft (CABG) around the blockage, or a procedure called angioplasty where a balloon catheter is inserted into the blocked coronary artery and advanced until the vascular stenosis is reached by the advancing balloon. The balloon is then inflated to deform the stenosis open, restoring blood flow. [0004] However, angioplasty or balloon catheterization can result in internal vascular injury which may ultimately lead to reformation of narrowing vascular deposits within the previously opened artery. This biological process whereby a previously opened artery becomes re-occluded is referred to as restenosis. One angioplasty variation designed to reduce the possibility of restenosis includes the subsequent step of arterial stent deployment within the stenotic blockage opened by the expanded balloon. After arterial patency has been restored by expanding the angioplasty balloon to deform the stenotic lesion open, the balloon is deflated and a vascular stent is inserted into the tubular bore or vessel lumen across the stenosis site. The catheter is then removed from the coronary artery lumen and the deployed stent remains implanted across the opened stenosis to prevent the newly opened artery from constricting spontaneously or narrowing in response to the internal vascular injury resulting from the angioplasty procedure itself. However, it has been found that in some cases of angioplasty and angioplasty followed by stent deployment restenosis may still occur.

[0005] Treating restenosis generally requires additional, more invasive, procedures including CABG in some cases. Consequently, methods for preventing restenosis, or for treating incipient forms of restenosis, are being aggressively pursued. One promising method for preventing restenosis is the administration of medicaments that block the local invasion or activation of monocytes, white blood cells that respond to injury or infection, thus preventing the associated secretion of growth factors within the blood vessel at the restenosis site that can trigger vascular smooth muscle cell (VSMC) proliferation and migration causing thickening of the vessel wall and subsequent narrowing of the artery. Metabolic inhibitors such as anti-neoplastic agents are currently being investigated as potential anti-restenotic compounds for such purposes. However, the toxicity associated with the systemic administration of known metabolic inhibitors has more recently stimulated development of in situ or site-specific drug delivery designed to place the anti- restenotic compounds directly at the target site within the potential restenotic lesion rather than generally administering much larger, potentially toxic doses to the patient. [0006] For example, one particular site-specific drug delivery technique known in the art employs the use of vascular stents coated with anti-restenotic drugs. These stents have been particularly useful because they not only provide the mechanical structure to maintain the patency or openness of the damaged vessel, but they also release the anti-restenotic agents directly into the surrounding tissue. This site specific delivery allows clinically effective drug concentrations to be achieved locally at the stenotic site without subjecting the patient to the side effects that may be associated with systemic drug delivery of such pharmaceutical compounds. Moreover, localized or site specific delivery of anti-restenotic drugs eliminates the need for more complex specific cell targeting technologies intended to accomplish similar purposes.

[0007] It has been recognized that cell surface growth factor receptors such as epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) profoundly influence cell proliferation regulation. Consequently, growth factor receptors have become targets for anti-proliferative drugs used to treat hyper- proliferative diseases such as cancer. Recently several new drugs have been approved that block signaling pathways response to epidermal growth factor receptors by developing antibodies that occupy the extracellular ligand-binding sites. Examples include trastuzmab (marketed under the brand name Herceptin^®) a humanized¹ monoclonal antibody that blocks the EGF HER2 that are over-expressed on the surface of many breast cancer cells. Cetuximab (having the brand name Erbitux^®) is a chimeric monoclonal antibody² that specifically blocks for EGF HER1. Bevacizumab marketed under the brand name Avastin^®) is a monoclonal designed to specifically block the action of a protein called vascular endothelial growth factor (VEGF). Bevacizumab belongs to a family of drugs called anti-angiogenic agents, or angiogenesis inhibitors.

[0008] Blocking EGF receptors interferes with the production of tyrosine quinces. Tyrosine kinases are essential in cell signaling processes associated with mitogenic stimulation, cell growth and oncogenesis. Thus when tyrosine kinase receptors are

' Humanized monoclonal antibody refers to an immunoglobulin wherein the antigen binding site is of non- human origin, generally murine; however the rest of the immunoglobulins human.

" A chimeric monoclonal antibody has variable domains (V domains) responsible for antigen recognition from one species and constant domains from another species. blocked cell division ceases. Blocking a cell surface receptor can be achieved using a biological or chemically synthesized ligand that mimic s the natural ligand, but does not activate the receptor, or using an antibody. Antibodies are particularly desirable because they can be engineered to be highly specific, they can be inexpensively produced recombinantly or using conventional hybridoma technologies are generally non-toxic and are large molecules that completely hinder access of the natural ligand for the receptor. Moreover, antibodies having extremely high affinity and avidity can be selected for using high throughput screening techniques well known in thew art.

[0009] Present anti-restenotics used in association with implantable devices have focused on cytotoxic and cytostatic agents, generally chemotherapeutics. Chemotherapeutics are potentially valuable anti-restenotics, however, the long-term effects of chronic exposure to such drugs, even in minute amounts is unknown. Therefore, there is a need for alternative therapeutics useful as restenotics that are safe, effective and inexpensive to manufacture and purify

[0010] It is an object of the present invention to provide vascular stents and stent coatings having anti-restenonic effective amounts of antibody-based anti- proliferatives.

SUMMARY OF THE INVENTION

[0011] The present invention provides implantable medical devices having coatings that include at least one said at least one antibody is an antiproliferative.

[0012] In one embodiment of the present invention the implantable medical device coating also includes a biocompatible polymer matrix.

[0013] In yet another embodiment of the present invention the implantable medical device is selected from the group consisting of vascular stents, urethral stents, biliary stents and endovascular grafts.

[0014] In one embodiment implantable medical devices made in accordance with the teachings of the present invention include at least one monoclonal antibody selected from the group consisting of cetuximab, trastuzmab, bevacizumab and combinations thereof and at least one biocompatible polymer. [0015] Polymers useful in making the coatings of the present invention include but are not limited to selected from the group consisting of polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers, ethylene-co-vinylacetate, polybutylmethacrylate, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such, as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics, polyvinyl esters, copolymers of vinyl monomers, ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetate copolymers; polyamides, alkyd resins; polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins, polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, phosphatidylcholine, fibrin and combinations thereof.

[0016] The present invention also includes methods for treating or inhibited restenosis comprising administering an anti-restenotic antibody to a specific site in a mammalian vessel subject to restenosis such that restenosis is treated or inhibited.

[0017] In one embodiment of the present invention the specific site in said mammalian vessel subject to restenosis is the vessel lumen or adventitia where an antibody-based anti-proliferative monoclonal antibody specific for cell surface epidermal growth factor receptors is administered.

[0018] In another embodiment of the present invention the anti-proliferative monoclonal antibody specific for cell surface epidermal growth factor receptors that is administered to the vessel lumen or adventitia is selected from the group consisting of cetuximab (Erbitux^®), trastuzmab (Herceptin^®), bevacizumab (Avastin^®) and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 depicts a vascular stent used to deliver the anti-restenotic compounds of the present invention. [0020] Figure 2 depicts a balloon catheter assembly used for angioplasty and the site-specific delivery of stents to anatomical lumens at risk for restenosis.

[0021] Figure 3 depicts the needle of an injection catheter in the retracted position (balloon deflated) according to the principles of the present invention where the shaft is mounted on an intravascular catheter.

[0022] Figures 4 and 5 illustrate use of the apparatus of Figure. 3 in delivering a substance into the adventitial tissue surrounding a blood vessel.

DESCRIPTION OF THE INVENTION

[0023] The present invention provides stents having that provide ant-proliferative monoclonal antibodies directly to the cells at the site of stent implantation. The monoclonal antibodies used in accordance with the teachings of the present invention generally block cell surface receptors involved in cell signaling pathways. For example, and not intended ads a limitation, the cell surface receptors blocked by the monoclonal antibodies of the present invention include epidermal growth factor receptors (EGFR) and vascular smooth muscle cell receptors (VEGF).

[0024] In one embodiment of the present invention a stent has a coating comprising Erbitux^® (formerly known as IMC-C225, also known as cetuximab) under development by Imclone Systems Incorporated located in Branchburg, New Jersey. Erbitux^® is a highly specific chimerized monoclonal antibody that binds to EGFR and blocks the ability of EGF to initiate receptor activation and signaling to the cell. This blockade results in cell growth inhibition by interfering with the effects of EGFR activation including cell repair and angiogenesis.

[0025] In another embodiment of the present invention a stent has a coating comprising trastuzmab (marketed under the band name Herceptin^®) and manufactured by Genentech, Inc, South San Francisco, CA. Herceptin^® is a humanized monoclonal antibody that blocks the EGF HER2.

[0026] In another embodiment of the present invention a stent has a coating comprising bevacizumab (marketed under the brand name Avastin^®) manufactured by Genentech, Inc, South San Francisco, CA. Avastin^® is a monoclonal designed to specifically block the action of a protein called vascular endothelial growth factor (VEGF). Bevacizumab belongs to a family of drugs called anti-angiogenic agents, or angiogenesis inhibitors.

[0027] The stents used in accordance with the teachings of the present invention may be vascular stents, urethral stents, biliary stents, endovascular grafts or stents intended for use in other ducts and organ lumens. Vascular stents may be used in peripheral, neurological or coronary applications. The stents may be rigid expandable stents or pliable self-expanding stents. Any biocompatible material may be used to fabricate the stents of the present invention including, without limitation, metals or polymers. The stents of the present invention may also be bioresorbable.

[0028] In one embodiment of the present invention vascular stents are implanted into coronary arteries immediately following angioplasty. However, one significant problem associated with stent implantation, specifically vascular stent deployment, is restenosis. Restenosis is a process whereby a previously opened lumen is re- occluded by vascular smooth muscle cell (VSMC) proliferation. Therefore, it is an object of the present invention to provide stents that suppress or eliminate VSMC migration and proliferation and thereby reduce, and/or prevent restenosis.

[0029] In one embodiment of the present invention metallic vascular stents are coated with one or more anti-restenotic monoclonal antibodies including, but not limited to cetuximab, trastuzmab and/or bevacizumab. The monoclonal antibody may be dissolved or suspended in any carrier compound that provides a stable composition that does not react adversely with the device to be coated or inactivate the monoclonal antibody. The metallic stent is provided with a biologically active monoclonal antibody coating using any technique known to those skilled in the art of medical device manufacturing. Suitable non-limiting examples include impregnation, spraying, brushing, dipping and rolling. After the monoclonal antibody solution is applied to the stent it is dried leaving behind a stable monoclonal antibody delivering medical device. Drying techniques include, but are not limited to, heated forced air, cooled forced air, and vacuum drying or static evaporation. Moreover, the medical device, specifically a metallic vascular stent, can be fabricated having grooves or wells in its surface that serve as receptacles or reservoirs for the monoclonal antibody compositions of the present invention. [0030] The anti-restenotic effective amounts of monoclonal antibodies used in accordance with the teachings of the present invention can be determined by a titration process. Titration is accomplished by preparing a series of stent sets. Each stent set will be coated, or contain different dosages of the monoclonal antibody agonist selected. The highest concentration used will be partially based on the known toxicology of the compound. The maximum amount of drug delivered by the stents made in accordance with the teaching of the present invention will fall below known toxic levels. Each stent set will be tested in vivo using the preferred animal model. The dosage selected for further studies will be the minimum dose required to achieve the desired clinical outcome. In the case of the present invention, the desired clinical outcome is defined as the inhibition of vascular re-occlusion, or restenosis. Generally, and not intended as a limitation, an anti-restenotic effective amount of the monoclonal antibodies of the present invention will range between about 0.5 ng to 1.0 mg depending on the particular monoclonal antibody used and the delivery platform selected.

[0031] In addition to the monoclonal antibody selected, treatment efficacy may also be affected by factors including dosage, route of delivery and the extent of the disease process (treatment area). An effective amount of a monoclonal antibody composition can be ascertained using methods known to those having ordinary skill in the art of medicinal chemistry and pharmacology. First the toxicological profile for a given monoclonal antibody composition is established using standard laboratory methods. For example, the candidate monoclonal antibody composition is tested at various concentration in vitro using cell culture systems in order to determine cytotoxicity. Once a non-toxic, or minimally toxic, concentration range is established, the monoclonal antibody composition is tested throughout that range in vivo using a suitable animal model. After establishing the in vitro and in vivo toxicological profile for the monoclonal antibody compound, it is tested in vitro to ascertain if the compound retains anti-proliferative activity at the non-toxic, or minimally toxic ranges established.

[0032] Finally, the candidate monoclonal antibody composition is administered to humans in accordance with either approved Food and Drug Administration (FDA) clinical trial protocols, or protocol approved by Institutional Review Boards (IRB) having authority to recommend and approve human clinical trials for minimally invasive procedures. Treatment areas are selected using angiographic techniques or other suitable methods known to those having ordinary skill in the art of intervention cardiology. The candidate monoclonal antibody composition is then applied to the selected treatment areas using a range of doses. Preferably, the optimum dosages will be the highest non-toxic, or minimally toxic concentration established for the monoclonal antibody composition being tested. Clinical follow-up will be conducted as required to monitor treatment efficacy and in vivo toxicity. Such intervals will be determined based on the clinical experience of the skilled practitioner and/or those established in the clinical trial protocols in collaboration with the investigator and the FDA or IRB supervising the study.

[0033] The monoclonal antibody therapy of the present invention can be administered directly to the treatment area using any number of techniques and/or medical devices. In one embodiment of the present invention the monoclonal antibody composition is applied to a vascular stent. The vascular stent can be of any composition or design. For example, the stent 10 (FIG1) may be self-expanding or a mechanically expanded stent using a balloon catheter FIG.2. The stent 10 may be made from stainless steel, titanium alloys, nickel alloys or biocompatible polymers. Furthermore, the stent 10 may be polymeric or a metallic stent coated with at least one polymer. In other embodiments the delivery device is an aneurysm shield, a vascular graft or surgical patch. In yet other embodiments the monoclonal antibody therapy of the present invention is delivered using a porous or "weeping" catheter to deliver a monoclonal antibody containing hydrogel composition to the treatment area. Still other embodiments include microparticles delivered using a catheter or other intravascular or transmyocardial device.

[0034] In another embodiment an injection catheter can be used to deliver the antibodies of the present invention either directly into, or adjacent to, a vascular occlusion or a vasculature site at risk for developing restenosis (treatment area). As used herein, adjacent means a point in the vasculature either distal to, or proximal from a treatment area that is sufficiently close enough for the anti-restenotic composition to reach the treatment area at therapeutic levels. A vascular site at risk for developing restenosis is defined as a treatment area where a procedure is conducted that may potentially damage the luminal lining. Non-limiting examples of procedures that increase the risk of developing restenosis include angioplasty, stent deployment, vascular grafts, ablation therapy, and brachytherapy.

[0035] In one embodiment of the present invention an injection catheter as depicted in United States patent application publication number 2002/0198512 A1 , United Sates patent application serial number 09/961 ,079 and United States patent number 6,547,803 (all of which are herein incorporated by reference in their entirety, specifically those sections directed to adventitial delivery of pharmaceutical compositions) can be used to administer the antibodies of the present invention directly to the adventia. FIGs. 3, 4 and 5 depict one such embodiment. FIG 3 illustrates the C-shaped configuration of the catheter balloon 20 prior to inflation having the injection needle 24 nested therein and a balloon interior 22 connected to an inflation source (not shown) which permits the catheter body to be expanded as shown in FIG 4. Needle 24 has an injection port 26 that transits the antibody into the adventia from a proximal reservoir (not shown) located outside the patient.

[0036] FIG 4 illustrates the inflated balloon 30 attached to the catheter body 28 and injection needle 24 capable of penetrating the adventia. FIG. 5 depicts deployment of the antibody of the present invention directly into the adventia 34. The injection needle 24 penetrates the blood vessel wall 32 as balloon 20 is inflated and injects the antibody 36 into the tissue.

[0037] The medical device can be made of virtually any biocompatible material having physical properties suitable for the design. For example, tantalum, stainless steel and nitinol have been proven suitable for many medical devices and could be used in the present invention. Also, medical devices made with biostable or bioabsorbable polymers can be used in accordance with the teachings of the present invention. Although the medical device surface should be clean and free from contaminants that may be introduced during manufacturing, the medical device surface requires no particular surface treatment in order to retain the coating applied in the present invention. Both surfaces (inner 14 and outer 12 of stent 10, or top and bottom depending on the medical devices' configuration) of the medical device may be provided with the coating according to the present invention. [0038] In order to provide the coated medical device according to the present invention, a solution which includes a solvent, a polymer dissolved in the solvent and a monoclonal antibody composition dispersed in the solvent is first prepared. It is important to choose a solvent, a polymer and a therapeutic substance that are mutually compatible. It is desirable that the solvent is capable of placing the polymer into solution at the concentration desired in the solution. It is also desirable that the solvent and polymer chosen do not chemically alter the monoclonal antibody's therapeutic character. However, the monoclonal antibody composition only needs to be dispersed throughout the solvent so that it may be either in a true solution with the solvent or dispersed in fine particles in the solvent. The solution is applied to the medical device and the solvent is allowed to evaporate leaving a coating on the medical device comprising the polymer(s) and the monoclonal antibody composition.

[0039] Typically, the solution can be applied to the medical device by either spraying the solution onto the medical device or immersing the medical device in the solution. Whether one chooses application by immersion or application by spraying depends principally on the viscosity and surface tension of the solution, however, it has been found that spraying in a fine spray such as that available from an airbrush will provide a coating with the greatest uniformity and will provide the greatest control over the amount of coating material to be applied to the medical device. In either a coating applied by spraying or by immersion, multiple application steps are generally desirable to provide improved coating uniformity and improved control over the amount of monoclonal antibody composition to be applied to the medical device. The total thickness of the polymeric coating will range from approximately 1 micron to about 20 microns or greater. In one embodiment of the present invention the monoclonal antibody composition is contained within a base coat, and a top coat is applied over the monoclonal antibody containing base coat to control release of the monoclonal antibody into the tissue.

[0040] The polymer chosen should be a polymer that is biocompatible and minimizes irritation to the vessel wall when the medical device is implanted. The polymer may be either a biostable or a bioabsorbable polymer depending on the desired rate of release or the desired degree of polymer stability. Bioabsorbable polymers that could be used include poly(L-lactic acid), polycaprolactone, poly(lactide-co-glycolide), poly(ethylene-vinyl acetate), poly(hydroxybutyrate-co- valerate), polydioxanone, polyorthoester, polyanhydhde, poly(glycolic acid), poly(D,L-lactic acid), poly(glycolic acid-co-trimethylene carbonate), polyphosphoester, polyphosphoester urethane, poly(amino acids), cyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate), copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates, polyphosphazenes and biomolecules such as fibrin, fibrinogen, cellulose, starch, collagen and hyaluronic acid.

[0041] Also, biostable polymers with a relatively low chronic tissue response such as polyurethanes, silicones, and polyesters could be used and other polymers could also be used if they can be dissolved and cured or polymerized on the medical device such as polyolefins, polyisobutylene and ethylene-alphaolefin copolymers; acrylic polymers and copolymers, ethylene-co-vinylacetate, polybutylmethacrylate, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics, such as polystyrene, polyvinyl esters, such as polyvinyl acetate; copolymers of vinyl monomers with each other and olefins, such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetate copolymers; polyamides, such as Nylon 66 and polycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins, polyurethanes; rayon; rayon-triacetate; phosphatidylcholine (PC), cellulose, cellulose acetate, cellulose butyrate; cellulose acetate butyrate; cellophane; cellulose nitrate; cellulose propionate; cellulose ethers; and carboxymethyl cellulose.

[0042] The polymer-to-monoclonal antibody composition ratio will depend on the efficacy of the polymer in securing the monoclonal antibody composition onto the medical device and the rate at which the coating is to release the monoclonal antibody composition to the tissue of the blood vessel. More polymer may be needed if it has relatively poor efficacy in retaining the monoclonal antibody composition on the medical device and more polymer may be needed in order to provide an elution matrix that limits the elution of a very soluble monoclonal antibody composition. A wide ratio of therapeutic substance-to-polymer could therefore be appropriate and could range from about 0.1% to 99% by weight of therapeutic substance-to-polymer.

[0043] In one embodiment of the present invention a vascular stent as depicted in FIG.1 is coated with monoclonal antibodies using a two-layer biologically stable polymeric matrix comprised of a base layer and an outer layer. Stent 10 has a generally cylindrical shape and an outer surface 12, an inner surface 14, a first open end 16, a second open end 18 and wherein the outer and inner surfaces 12, 14 are adapted to deliver an anti-restenotic effective amount of at least one monoclonal antibody in accordance with the teachings of the present invention. Briefly, a polymer base layer comprising a solution of ethylene-co-vinylacetate and polybutylmethacrylate is applied to stent 10 such that the outer surface 12 is coated with polymer. In another embodiment both the inner surface 14 and outer surface 12 of stent 10 are provided with polymer base layers. The monoclonal antibody or mixture thereof is incorporated into the base layer. Next, an outer layer comprising only polybutylmethacrylate is applied to stent 10's outer layer 14 that has been previously provided with a base layer. In another embodiment both the inner surface 14 and outer surface 12 of stent 10 are provided with polymer outer layers.

[0044] The thickness of the polybutylmethacrylate outer layer determines the rate at which the monoclonal antibodies elute from the base coat by acting as a diffusion barrier. The ethylene-co-vinylacetate, polybutylmethacrylate and monoclonal antibody solution may be incorporated into or onto a medical device in a number of ways. In one embodiment of the present invention the monoclonal antibody/polymer solution is sprayed onto the stent 10 and then allowed to dry. In another embodiment, the solution may be electrically charged to one polarity and the stent 10 electrically changed to the opposite polarity. In this manner, the monoclonal antibody/polymer solution and stent will be attracted to one another thus reducing waste and providing more control over the coating thickness.

[0045] In another embodiment of the present invention the monoclonal antibody is Erbitux^® and the polymer is bioresorbable. The bioresorbable polymer-monoclonal antibody blends of the present invention can be designed such that the polymer absorption rate controls drug release. In one embodiment of the present invention a polycaprolactone-monoclonal antibody blend is prepared. A stent 10 is then stably coated with the polycaprolactone-Erbitux^® blend wherein the stent coating has a thickness of between approximately 0.1 μm to approximately 100 μm The polymer coating thickness determines the total amount of Erbitux^® delivered and the polymer's absorption rate determines the administrate rate.

[0046] Using the teachings herein it is possible for one of ordinary skill in the part of polymer chemistry to design coatings having a wide range of dosages and administration rates. Furthermore, drug delivery rates and concentrations can also be controlled using non-polymer containing coatings and techniques known to persons skilled in the art of medicinal chemistry and medical device manufacturing.

Claims

What is claimed is

1. An implantable medical device comprising: a coating having at least one monoclonal antibody wherein said at least one antibody is an antiproliferative.

2. The implantable medical device according to claim 1 further comprising a biocompatible polymer matrix.

3. The implantable medical device according to claim 1 or claim 2 wherein said medical device is selected from the group consisting of vascular stents, urethral stents, biliary stents and endovascular grafts.

4. The implantable medical device according to claim 3 wherein said monoclonal antibody is selected from the group consisting of cetuximab, trastuzmab, bevacizumab and combinations thereof.

5. The implantable medical device according to claim 4 wherein said polymer matrix comprises at least one biocompatible polymer selected from the group consisting of polyurethanes, silicones, polyesters, polyolefins, polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymers and copolymers, ethylene-co- vinylacetate, polybutylmethacrylate, vinyl halide polymers and copolymers, such as polyvinyl chloride; polyvinyl ethers, such as polyvinyl methyl ether; polyvinylidene halides, such as polyvinylidene fluoride and polyvinylidene chloride; polyacrylonitrile, polyvinyl ketones; polyvinyl aromatics, polyvinyl esters, copolymers of vinyl monomers, ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetate copolymers; polyamides, alkyd resins; polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins, polyurethanes, rayon, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, phosphatldylcholine, fibrin and combinations thereof.

6. A method for treating or inhibiting restenosis comprising:

administering an anti-restenotic antibody to a specific site in a mammalian vessel at subject to restenosis such that restenosis is treated or inhibited.

7. The method according to claim 6 wherein said specific site in said mammalian vessel subject to restenosis is the vessel lumen or adventitia.

8. The method according to claim 6 or 7 wherein said administered anti- restenotic antibody is selected from the group consisitng of cetuximab, trastuzmab, bevacizumab and combinations thereof.

9. The method according to claim 6 wherein said anti-restenotic antibody is administered by means of an implantable medical device having a coating comprising said anti-restenotic antibody and a biocompatible polymer matrix.