WO1996025176A1 - Therapeutic inhibitor of vascular smooth muscle cells - Google Patents

Therapeutic inhibitor of vascular smooth muscle cells Download PDF

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Publication number
WO1996025176A1
WO1996025176A1 PCT/US1996/002125 US9602125W WO9625176A1 WO 1996025176 A1 WO1996025176 A1 WO 1996025176A1 US 9602125 W US9602125 W US 9602125W WO 9625176 A1 WO9625176 A1 WO 9625176A1
Authority
WO
WIPO (PCT)
Prior art keywords
smooth muscle
cells
stent
cytoskeletal inhibitor
analog
Prior art date
Application number
PCT/US1996/002125
Other languages
English (en)
French (fr)
Inventor
Lawrence L. Kunz
Original Assignee
Neorx Corporation
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=23539404&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO1996025176(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to AT96906490T priority Critical patent/ATE265233T1/de
Priority to AU49851/96A priority patent/AU4985196A/en
Priority to CA002212537A priority patent/CA2212537C/en
Priority to JP8525163A priority patent/JPH11500635A/ja
Priority to EP96906490A priority patent/EP0809515B1/en
Priority to DE69632310T priority patent/DE69632310T2/de
Application filed by Neorx Corporation filed Critical Neorx Corporation
Publication of WO1996025176A1 publication Critical patent/WO1996025176A1/en
Priority to US08/829,991 priority patent/US6306421B1/en
Priority to US08/829,685 priority patent/US5981568A/en
Priority to US09/361,194 priority patent/US6358989B1/en
Priority to US09/896,208 priority patent/US6491938B2/en
Priority to US09/995,490 priority patent/US6569441B2/en
Priority to US10/024,885 priority patent/US6663881B2/en
Priority to US11/650,059 priority patent/US8158670B2/en
Priority to US13/446,760 priority patent/US20120195951A1/en

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Definitions

  • This invention relates generally to therapeutic methods involving surgical or intravenous introduction of binding partners directed to certain target cell populations, such as smooth muscle cells, cancer cells, somatic cells requiring modulation to ameliorate a disease state and effector cells of the immune system, particularly for treating conditions such as stenosis following vascular trauma or disease, cancer, diseases resulting from hyperactivity or hyperplasia of somatic cells and diseases that are mediated by immune system effector cells.
  • Surgical or intravenous introduction of active agents capable of altering the proliferation or migration or contraction of smooth muscle proteins is also described.
  • the invention also relates to the direct or targeted delivery of therapeutic agents to vascular smooth muscle cells that results in dilation and fixation of the vascular lumen (biological stenting effect).
  • Combined administration of a cytocidal conjugate and a sustained release dosage form of a vascular smooth muscle cell inhibitor is also disclosed.
  • PTCA Percutaneous transluminal coronary angioplasty
  • PTCA Percutaneous transluminal coronary angioplasty
  • the use of this surgical procedure has grown rapidly, with 39,000 procedures performed in 1983, nearly 150,000 in 1987, 200,000 in 1988, 250,000 in 1989, and over 500,000 PTCAs per year are estimated by 1994 (1 , 2, 3).
  • Stenosis following PTCA remains a significant problem, with from 25% to 35% of the patients developing restenosis within 1 to 3 months. Restenosis results in significant morbidity and mortality and frequently necessitates further interventions such as repeat angioplasty or coronary bypass surgery. No surgical intervention or post-surgical treatment (to date) has proven effective in preventing restenosis.
  • Heparin is an example of one such compound, which reportedly inhibits smooth muscle cell proliferation in vitro but when used in vivo has the potential adverse side effect of inhibiting coagulation.
  • Heparin peptides while having reduced anti-coagulant activity, have the undesirable pharmacological property of having a short pharmacological half-life. Attempts have been made to solve such problems by using a double balloon catheter, i.e.. for regional delivery of the therapeutic agent at the angioplasty site (e.g., 8;
  • Verrucarins and Roridins are trichothecene drugs produced as secondary metabolites by the soil fungi Myrothecium verruc ⁇ ri ⁇ and
  • Verrucarin is a macrocyclic triester.
  • Roridin is a macrocyclic diester of verrucarol (10).
  • the trichothecenes are structurally related to sesquiterpenoid mycotoxins produced by several species of fungi and characterized by the 12,13-epoxytrichothec-9-ene basic structure. Their cytotoxic activity to eukaryotic cells is closely correlated with their ability to bind to the cell, to be internalized, and to inhibit protein and macromolecular synthesis in the cell.
  • inhibitory agents may have systemic toxicity that could create an unacceptable level of risk for patients with cardiovascular disease.
  • inhibitory agents might interfere with vascular wound healing following surgery and that could either delay healing or weaken the structure or elasticity of the newly healed vessel wall.
  • inhibitory agents killing smooth muscle cells could damage surrounding endothelium and/or other medial smooth muscle cells. Dead and dying cells also release mitogenic agents that might stimulate additional smooth muscle cell proliferation and exacerbate stenosis.
  • an inhibitory agent may be problematic from several standpoints: namely, a) delivery of a large number of molecules into the intercellular spaces between smooth muscle cells may be necessary, i.e., to establish favorable conditions for allowing a therapeutical ly effective dose of molecules to cross the cell membrane; b) directing an inhibitory drug into the proper intracellular compartment, i.e., where its action is exerted, may be difficult to control; and, c) optimizing the association of the inhibitory drug with its intracellular target, e.g, a ribosome, while minimizing intercellular redistribution of the drug, e.g. to neighboring cells, may be difficult.
  • therapeutic conjugates are provided for inhibiting vascular smooth muscle cells in a mammalian host.
  • the therapeutic conjugates contain a vascular smooth muscle binding protein or peptide that binds in a specific manner to the cell membranes of a vascular smooth muscle cell or an interstitial matrix binding protein/peptide that binds in a specific manner to interstitial matrix (e.g., collagen) of the artery wall, coupled to a therapeutic agent that inhibits the activity of the cell.
  • inhibition of cellular activity results in reducing, delaying, or eliminating stenosis after angioplasty or other vascular surgical procedures.
  • the therapeutic conjugates of the invention achieve these advantageous effects by associating with vascular smooth muscle cells and pericytes, which may transform into smooth muscle cells.
  • the therapeutic conjugate may contain: (1) therapeutic agents that alter cellular metabolism or are inhibitors of protein synthesis, cellular proliferation, or cell migration; (2) microtubule and microfilament inhibitors that affect
  • the conjugates include a cytotoxic therapeutic agent that is a sesquiterpenoid mycotoxin such as a verrucarin or a roridin.
  • cytostatic therapeutic agents that inhibit DNA synthesis and proliferation at doses that have a minimal effect on protein synthesis such as protein kinase inhibitors (e.g., staurosporin), suramin, and nitric oxide releasing compounds (e.g., nitroglycerin) or analogs or functional equivalents thereof.
  • therapeutic agents that inhibit the contraction or migration of smooth muscle cells and maintain an enlarged luminal area following, for example, angioplasty trauma e.g.. the cytochalasins, such as cytochalasin B,
  • cytochalasin C cytochalasin D or the like
  • vascular smooth muscle binding proteins that specifically associate with a chondroitin sulfate proteoglycan (CSPG) expressed on the membranes of a vascular smooth muscle cell, and in a preferred embodiment this CSPG has a molecular weight of about 250 kDaltons.
  • CSPG chondroitin sulfate proteoglycan
  • the vascular smooth muscle binding protein binds to a CSPG target on the cell surface with an association constant of at least 10 -4 M.
  • the vascular smooth muscle binding protein contains a sequence of amino acids found in the Fab, Fv or CDR (complementarity determining regions) of monoclonal antibody NR-AN-01 or functional equivalents thereof.
  • aspects of the invention include methods for inhibiting stenosis, e.g., following angioplasty in a mammalian host, by administering to a human or animal subject in need of such treatment a therapeutically effective dosage of a therapeutic conjugate of the invention.
  • stenosis e.g., following angioplasty in a mammalian host
  • the dosage of therapeutic conjugate may be administered with an infusion catheter, to achieve a 10 -3 M to 10 I2 M concentration of said therapeutic conjugate at the site of administration in a blood vessel.
  • the present invention also contemplates therapeutic methods and therapeutic dosage forms involving sustained release of therapeutic agent to target cells.
  • the target cells are vascular smooth muscle cells, cancer cells, somatic cells requiring modulation to ameliorate a disease state and cells involved in immune system-mediated diseases that are accessible by local administration of the dosage form. Consequently, the methods and dosage forms of this aspect of the present invention are useful for inhibiting vascular smooth muscle cells in a mammalian host, employing a therapeutic agent that inhibits the activity of the cell (e.g., proliferation, contraction, migration or the like) but does not kill the cell and a vascular smooth muscle cell binding protein.
  • a therapeutic agent that inhibits the activity of the cell (e.g., proliferation, contraction, migration or the like) but does not kill the cell and a vascular smooth muscle cell binding protein.
  • the methods and dosage forms of this aspect of the present invention are useful for inhibiting target cell proliferation or killing such target cells, employing a therapeutic agent that inhibits proliferation or is cytotoxic to the target cells and a target cell binding protein.
  • the methods and dosage forms of this aspect of the present invention are useful for delivering cytostatic, cytocidal or metabolism modulating therapeutic agents to target cells, such as effector cells of the immune system, that are accessible by local administration of the dosage form, employing a target cell binding protein.
  • dosage forms of the present invention are useful to reduce or eliminate pathological proliferation or hyperactivity of normal tissue (i.e., somatic cells).
  • one therapeutic method of the invention involves the in vivo placement of a metallic, plastic or biodegradable intravascular stent which comprises a therapeutic agent.
  • stents comprising a therapeutic agent.
  • a preferred embodiment of the invention is a stent which comprises a therapeutic agent such as a cytoskeletal inhibitor or an inhibitor of smooth muscle cell proliferation.
  • a preferred cytoskeletal inhibitor of the invention is a cytochalasin, such as cytochalasin B or a structural analog thereof that is functionally equivalent.
  • An alternative preferred cytoskeletal inhibitor of the invention is taxol or a structural analog thereof that is functionally equivalent.
  • the stents can comprise a biodegradable coating or a porous or permeable non-biodegradable coating.
  • a preferred embodiment of the invention is a stent comprising a biodegradable coating or a porous/permeable non-biodegradable coating comprising the therapeutic agent.
  • a more preferred embodiment of the invention is a stent comprising a biodegradable coating or a porous or non-biodegradable non-biodegradable coating comprising a sustained-release dosage form of the therapeutic agent.
  • a stent e.g., a biodegradable stent
  • a biodegradable stent with the therapeutic agent impregnated therein which is further coated with a biodegradable coating or with a porous or permeable non-biodegradable coating comprising a sustained release-dosage form of a therapeutic agent is also contemplated.
  • This embodiment of the invention can provide a differential release rate of the therapeutic agent, i.e., there would be a faster release of the therapeutic agent from the coating followed by delayed release of the therapeutic agent that is impregnated in the stent matrix upon degradation of the stent matrix.
  • the intravascular stent provides a mechanical means of providing an increase in luminal area of a vessel, in addition to that provided via the biological stenting action of the cytoskeletal inhibitor, such as cytochalasin B or taxol, releasably embedded therein. Furthermore, the placement of intravascular stents comprising a therapeutic agent which is an inhibitor of smooth muscle cell proliferation provides an increased efficacy by reducing or preventing intimal proliferation. This inhibition of intimal smooth muscle cells and stroma produced by the smooth muscle allows for more rapid and complete re-endothelization following the intraventional placement of the vascular stent. The increased rate of re-endothelization and stabilization of the vessel wall following stent placement can reduce the loss of luminal area and decreased blood flow which is the primary cause of vascular stent failures.
  • the cytoskeletal inhibitor such as cytochalasin B or taxol
  • the cytochalasins such as cytochalasin B, cytochalasin C, cytochalasin D or the like
  • suramin such as nitroglycerin
  • nitric oxide- releasing compounds such as nitroglycerin, or analogs or functional equivalents thereof.
  • useful therapeutic agents inhibit proliferation or are cytotoxic to the target cells.
  • Preferred therapeutic moieties for this purpose are Roridin A and Pseudomonas exotoxin. or analogs or functional equivalents thereof.
  • useful therapeutic agents deliver cytostatic, cytocidal or metabolism-modulating therapeutic agents to target cells that are accessible by local administration of the dosage form.
  • Preferred therapeutic moieties for this purpose are Roridin A, Pseudomonas exotoxin, suramin and protein kinase inhibitors (e.g., staurosporin), sphingosine, or analogs or functional equivalents thereof.
  • anti-proliferative agents or antimigration agents are preferred (e.g., cytochalasins, taxol, somatostatin, somatostatin analogs, N-ethylmaleimide, antisense
  • the dosage forms of the present invention are targeted to a relevant target cell population by a binding protein or peptide.
  • Preferred binding proteins/peptides of the present invention are vascular smooth muscle cell binding protein, tumor cell binding protein and immune system effector cell binding protein.
  • Preferred vascular smooth muscle cell binding proteins specifically associate with a chondroitin sulfate proteoglycan (CSPG) expressed on the membranes of a vascular smooth muscle cell, and in a preferred embodiment this CSPG has a molecular weight of about 250 kDaltons.
  • CSPG chondroitin sulfate proteoglycan
  • the vascular smooth muscle binding protein binds to a CSPG target on the cell surface with an association constant of at least 10 -4 M.
  • the present invention also provides therapeutic methods and
  • therapeutic dosage forms involving administration of free (i.e., non-targeted or non-binding partner associated) therapeutic agent to target cells.
  • the target cells are vascular smooth muscle cells and the therapeutic agent is an inhibitor of vascular smooth muscle cell contraction, allowing the normal hydrostatic pressure to dilate the vascular lumen.
  • Such contraction inhibition may be achieved by actin inhibition, which is preferably achievable and sustainable at a lower dose level than that necessary to inhibit protein synthesis. Consequently, the vascular smooth muscle cells synthesize protein required to repair minor cell trauma and secrete interstitial matrix, thereby facilitating the fixation of the vascular lumen in a dilated state near its maximal systolic diameter.
  • This phenomenon constitutes a biological stenting effect that diminishes or prevents the undesirable recoil mechanism that occurs in up to 25% of the angioplasty procedures classified as successful based on an initial post-procedural angiogram.
  • Cytochalasins which inhibit the polymerization of G- to F-actin which, in turn, inhibits the migration and contraction of vascular smooth muscle cells
  • Free therapeutic agent protocols of this type effect a reduction, a delay, or an elimination of stenosis after angioplasty or other vascular surgical procedures.
  • free therapeutic agent is administered directly or substantially directly to vascular smooth muscle tissue. Such administration is preferably effected by an infusion catheter, to achieve a 10 -3 M to 10 -12 M concentration of said therapeutic agent at the site of administration in a blood vessel.
  • a cytocidal targeted conjugate to destroy proliferating vascular smooth muscle cells involved in vascular stenosis.
  • the mitogenic agents released after this biological arteromyectomy are prevented from stimulating the remaining viable vascular smooth muscle cells to proliferate and restenose the vessel by administration of the anti-contraction (anti-migration) or anti-proliferative sustained release agents of the present invention.
  • FIGURE 1 is a photomicrograph of vascular smooth muscle cells in an artery of a 24-year-old male patient with vascular smooth muscle binding protein bound to the cell surface and membrane.
  • the patient received the vascular smooth muscle binding protein by i.v. administration 4 days before the arterial tissue was prepared for histology.
  • FIGURE 1B is a photomicrograph of vascular smooth muscle cells in an artery of a 24-year-old male patient with vascular smooth muscle binding protein bound to the cell surface and membrane. The section was reacted ex vivo with HRP-conjugated goat anti-mouse IgG. This reaction was visualized by adding 4-chloro-1-naphthol. The reaction product of the substrate forms an insoluble purple or dark brown precipitate at the reaction site (shown at #2). A counter stain was used to visualize cell nuclei (shown at #1).
  • FIGURE 2 depicts a first scheme for chemical coupling of a therapeutic agent to a vascular smooth muscle binding protein.
  • FIGURE 3 depicts a second scheme for chemical coupling of a therapeutic agent to a vascular smooth muscle binding protein.
  • FIGURE 4A graphically depicts experimental data showing rapid binding of vascular smooth muscle binding protein to marker-positive test cells in vitro.
  • FIGURE 4B graphically depicts experimental data showing rapid binding of vascular smooth muscle binding protein to vascular smooth muscle cells in vitro.
  • FIGURE 5 A presents graphically experimental data showing
  • RA-NR-AN-01 therapeutic conjugate
  • free RA therapeutic agent undesirable cytotoxicity of even low levels of therapeutic conjugate (i.e., RA-NR-AN-01), and the free RA therapeutic agent, when vascular smooth muscle cells were treated for 24 hours in vitro.
  • FIGURE 5B graphically presents experimental data showing the effects of RA-NR-AN-01 therapeutic conjugate on metabolic activity of marker-positive and -negative cells.
  • the data show undesirable nonspecific cytotoxicity of the conjugate for all these cells in a 24 hour treatment in vitro.
  • the non-specificity results from extracellular hydrolysis of the coupling ligand which exposes the tested cells to free drug.
  • FIGURE 6A graphically depicts experimental data showing undesirable nonspecific cytotoxicity of PE-NR-AN-01 therapeutic conjugate for marker-positive and marker-negative test cells after 24 hours of treatment in vitro, even though the 24 hour treatment was followed by an overnight recovery period prior to testing the metabolic activity.
  • FIGURE 6B depicts experimental data showing nonspecific
  • FIGURE 7A graphically presents experimental data showing that a short 5 minute "pulse” treatment, i.e., instead of 24 hours, followed by exposure to [3H]leucine, with free RA therapeutic agent being nonspecifically cytotoxic, i.e., for control HT29 marker-negative cells, but, in contrast, the RA-NR-AN-01 therapeutic conjugate is not cytotoxic in this "pulse" treatment.
  • FIGURE 7B presents graphically experimental data showing that free
  • RA-NRAN-01 therapeutic conjugate is not cytotoxic to cells.
  • FIGURE 7C presents graphically results of experiments showing that "pulse" treatment of cells in vitro with the RA-NR-AN-01 therapeutic conjugate inhibits cellular activity in marker-positive A375 cells, as measured by protein synthesis.
  • FIGURE 7D presents graphically experimental data showing that "pulse" treatment of cells in vitro with the RA-NR-AN-01 therapeutic conjugate did not exert long-lasting inhibitory effects on cellular activity in marker-positive cells, since protein synthesis in A375 cells was not inhibited when the cells were allowed an overnight recovery period prior to testing in vitro.
  • FIGURE 8A presents graphically experimental data showing that while a "pulse" treatment of cells in vitro with free RA therapeutic agent was non-specifically cytotoxic, the RA-NR-AN-01 therapeutic conjugate did not exert long-lasting inhibitory effects on cellular activity in vascular smooth muscle cells, as evidenced by metabolic activity in BO54 cells that were allowed a 48 hour recovery period prior to testing.
  • FIGURE 8B graphically depicts experimental data similar to those presented in FIGURE 8A, above, but using a second marker-positive cell type, namely A375.
  • the data show that "pulse" treatment with the RA-NR-AN-01 therapeutic conjugate did not exert long-lasting inhibitory effects on cellular activity, as measured by metabolic activity in A375 cells that were allowed a 48 hour recovery period prior to testing.
  • FIGURE 8C graphically depicts results similar to those presented in
  • the results show that the "pulse" treatment with the RA-NR-AN-01 therapeutic conjugate did not exert long-lasting inhibitory effects on the cellular activity of marker-negative control cells, as measured by metabolic activity in HT29 cells that were allowed a 48 hour recovery period prior to testing.
  • FIGURE 9A shows stenosis due to intimal smooth muscle cell proliferation in a histological section of an untreated artery 5 weeks after angioplasty in an animal model.
  • FIGURE 9B shows inhibition of stenosis in a histological section of an artery treated with therapeutic conjugate at 5 weeks after angioplasty in an animal model.
  • FIGURE 10A graphically depicts experimental data comparing protein synthesis and DNA synthesis inhibition capability of suramin with respect to vascular smooth muscle cells.
  • FIGURE 10B graphically depicts experimental data comparing protein synthesis and DNA synthesis inhibition capability of staurosporin with respect to vascular smooth muscle cells.
  • FIGURE 10C graphically depicts experimental data comparing protein synthesis and DNA synthesis inhibition capability of nitroglycerin with respect to vascular smooth muscle cells.
  • FIGURE 1 1 shows a tangential section parallel to the inner surface of a smooth muscle cell which is magnified 62,500 times and is characterized by numerous endocytic vesicles, several of which contain antibody coated gold beads in the process of being internalized by the cell in vitro.
  • FIGURE 12 shows a smooth muscle cell which is magnified 62,500 times and is characterized by a marked accumulation of gold beads in lysosomes at 24 hours following exposure of the cell to the beads in vitro.
  • FIGURE 14 depicts an in vivo dose response study of the effect of cytochalasin B on the luminal area of pig femoral arteries. Detailed Description of the Invention
  • “Therapeutic conjugate” means a vascular smooth muscle or an interstitial matrix binding protein coupled (e.g., optionally through a linker) to a therapeutic agent.
  • Target and marker are used interchangeably in describing the conjugate aspects of the present invention to mean a molecule recognized in a specific manner by the matrix or vascular smooth muscle binding protein, e.g., an antigen, polypeptide antigen or cell surface carbohydrate (e.g., a glycolipid. glycoprotein, or proteoglycan) that is expressed on the cell surface membranes of a vascular smooth muscle cell or a matrix structure.
  • an antigen, polypeptide antigen or cell surface carbohydrate e.g., a glycolipid. glycoprotein, or proteoglycan
  • Epitope is used to refer to a specific site within the “target” molecule that is bound by the matrix or smooth muscle binding protein, e.g., a sequence of three or more amino acids or saccharides.
  • Coupled is used to mean covalent or non-covalent chemical association (i.e., hydrophobic as through van der Waals forces or
  • the binding proteins will normally be associated with the
  • Linker means an agent that couples the matrix or smooth muscle binding protein to a therapeutic agent, e.g., an organic chemical coupler.
  • Microcyclic trichothecene is intended to mean any one of the group of structurally related sesquiterpenoid macrocyclic mycotoxins produced by several species of fungi and characterized by the 12,13-epoxytrichothec-9-ene basic structure, e.g., verrucarins and roridins that are the products of secondary metabolism in the soil fungi Myrothecium verrucaria and
  • sustained release means a dosage form designed to release a therapeutic agent therefrom for a time period ranging from about 3 to about 21 days. Release over a longer time period is also contemplated as a
  • Biodegradation rate directly impacts therapeutic agent release kinetics.
  • the biodegradation rate is regulable by alteration of the composition or structure of the sustained release dosage form.
  • alteration of the lactide/glycolide ratio in preferred dosage forms of the present invention can be conducted, as described by Tice et al., "Biodegradable Controlled-Release Parenteral Systems," Pharmaceutical Technology, pp. 26-35, 1984; by inclusion of polymer hydrolysis modifying agents, such as citric acid and sodium carbonate, as described by Kent et al., "Microencapsulation of Water Soluble Active Polypeptides," U.S. Patent No.
  • vascular smooth muscle binding proteins include antibodies (e.g., monoclonal and polyclonal affinity-purified antibodies, F(ab'), Fab', Fab. and Fv fragments and/or complementarity determining regions (CDR) of antibodies or functional equivalents thereof, (e.g., binding peptides and the like)); growth factors, cytokines, and polypeptide hormones and the like; and macromolecules recognizing extracellular matrix receptors (e.g., integrin and fibronectin receptors and the like).
  • antibodies e.g., monoclonal and polyclonal affinity-purified antibodies, F(ab'), Fab', Fab. and Fv fragments and/or complementarity determining regions (CDR) of antibodies or functional equivalents thereof, (e.g., binding peptides and the like)); growth factors, cytokines, and polypeptide hormones and the like; and macromolecules recognizing extracellular matrix receptors (e.g., integrin and fibronect
  • trichothecenes There are two broad classes of trichothecenes: those that have only a central sesquiterpenoid structure and those that have an additional macrocyclic ring (simple and macrocyclic trichothecenes, respectively).
  • the simple trichothecenes may be subdivided into three groups (i.e.. Group A, B, and C) as described in U.S. Patent Nos. 4,744,981 and 4.906,452 (incorporated herein by reference).
  • Representative examples of Group A simple trichothecenes include: Scirpene, Roridin C, dihydrotrichothecene. Scirpen-4. 8-diol,
  • Group C simple trichothecenes include: Crotocol and Crotocin.
  • Representative macrocyclic trichothecenes include Verrucarin A, Verrucarin B, Verrucarin J (Satratoxin C), Roridin A, Roridin D, Roridin E (Satratoxin D), Roridin H, Satratoxin F, Satratoxin G, Satratoxin H, Vertisporin, Mytoxin A, Mytoxin C, Mytoxin B, Myrotoxin A, Myrotoxin B, Myrotoxin C,
  • Preferred agents for these embodiments include Roridin A, Pseudomonas exotoxin, suramin, protein kinase inhibitors (e.g., staurosporin) and the like, or analogs or functional equivalents thereof.
  • compositions useful in the practice of the present invention include moieties capable of reducing or eliminating pathological proliferation, migration or hyperactivity of normal tissues.
  • exemplary of such therapeutic agents are those capable of reducing or eliminating hyperactivity of corneal epithelium and stroma, pathological proliferation or prolonged contraction of smooth muscle cells or pericytes of the intraocular vasculature implicated in degenerative eye disease resulting from hyperplasia or decreased vascular lumen area.
  • Preferred agents for this purpose are staurosporin and cytochalasin B.
  • Vascular smooth muscle binding proteins of the invention bind to targets on the surface of vascular smooth muscle cells.
  • targets e.g., polypeptides or carbohydrates, proteoglycans and the like, that are associated with the cell membranes of vascular smooth muscle cells are useful for selecting (e.g., by cloning) or constructing (e.g., by genetic engineering or chemical synthesis) appropriately specific vascular smooth muscle binding proteins.
  • Particularly useful "targets” are internalized by smooth muscle cells, e.g., as membrane constituent antigen turnover occurs in renewal. Internalization by cells may also be by mechanisms involving phagolysosomes, clathrin-coated pits, receptor-mediated redistribution or endocytosis and the like.
  • such a “target” is exemplified by chondroitin sulfate proteoglycans (CSPGs) synthesized by vascular smooth muscle cells and pericytes, and a discrete portion (termed an epitope herein) of the CSPG molecule having an apparent molecular weight of about 250 kD is especially preferred.
  • the 250 kD target is an N-linked glycoprotein that is a component of a larger 400 kD proteoglycan complex (14).
  • NR-ML-05 binding to smooth muscle cells has been disclosed (Fritzberg et al., U.S. Pat. No. 4,879.225).
  • Monoclonal antibody NR-ML-05 and subculture NR-ML-05 No. 85-41-4I-A2, freeze # A2106, have both been deposited with the American Type Culture Collection, Rockville, MD and granted Accession Nos. HB-5350 and HB-9350, respectively.
  • NR-ML-05 is the parent of, and structurally and functionally equivalent to, subclone
  • the binding-site amino acids and three dimensional model of the NR-AN-01 antigen binding site serve as a molecular model for constructing functional equivalents, e.g., short polypeptides ("minimal polypeptides"), that have binding affinity for a CSPG synthesized by vascular smooth muscle cells and pericytes.
  • functional equivalents e.g., short polypeptides ("minimal polypeptides")
  • binding proteins e.g., antibodies or fragments
  • selected binding proteins for use in the practice of the invention have a binding affinity of >10 4 liter/mole for the vascular smooth muscle 250 kD CSPG, and also the ability to be bound to and internalized by smooth muscle cells or pericytes.
  • murine monoclonal antibody may be "chimerized” by genetically recombining the nucleotide sequence encoding the murine Fv region (i.e., containing the antigen binding sites) with the nucleotide sequence encoding a human constant domain region and an Fc region, e.g., in a manner similar to that disclosed in European Patent Application No. 0,41 1,893 A2.
  • Humanized vascular smooth muscle binding partners will be recognized to have the advantage of decreasing the immunoreactivity of the antibody or polypeptide in the host recipient, which may thereby be useful for increasing the in vivo half-life and reducing the possibility of adverse immune reactions.
  • binding peptides localize to the surface membrane of intact cells and internal epitopes of disrupted cells, respectively, and deliver the therapeutic agent for assimilation into the target cells.
  • Minimal peptides, mimetic organic compounds and human or humanized antibodies that localize to the requisite tumor cell types are also useful as binding peptides of the present invention.
  • binding peptides may be identified and constructed or isolated in accordance with known techniques.
  • Preferred binding peptides of these embodiments of the present invention bind to a target epitope with an association constant of at least about 10 -6 M.
  • binding peptides are also useful as binding peptides of the present invention. Such binding peptides may be identified and constructed or isolated in accordance with known techniques. Preferred binding peptides of these embodiments of the present invention bind to a target epitope with an association constant of at least about 10 -6 M.
  • binding proteins or peptides useful in the practice of the present invention include moieties capable of localizing to pathologically proliferating normal tissues, such as pericytes of the intraocular vasculature implicated in degenerative eye disease.
  • the therapeutic agent is delivered to target cells for internalization therein by such sustained release dosage forms.
  • Minimal peptides, mimetic organic compounds and human or humanized antibodies that localize to the requisite pathologically proliferating normal cell types are also useful as binding peptides of the present invention.
  • binding peptides may be identified and constructed or isolated in accordance with known techniques.
  • Preferred binding peptides of these embodiments of the present invention bind to a target epitope with an association constant of at least about 10 -6 M.
  • Coupled methods for linking the therapeutic agent through covalent or non-covalent bonds to the vascular smooth muscle binding protein include chemical cross-linkers and heterobifunctional cross-linking compounds (i.e., "linkers") that react to form a bond between reactive groups (such as hydroxyl, amino, amido, or sulfhydryl groups) in a therapeutic agent and other reactive groups (of a similar nature) in the vascular smooth muscle binding protein.
  • This bond may be, for example, a peptide bond, disulfide bond, thioester bond, amide bond, thioether bond, and the like.
  • the sustained release embodiment of the present invention includes a therapeutic agent dispersed within a non-biodegradable or biodegradable polymeric structure. Such dispersion is conducted in accordance with the procedure described by Cowsar et al., "Poly(Lactide-Co-Glycolide)
  • nucleophilic groups include lysine epsilon amino groups (amide linkage), serine hydroxyl groups (ester linkage) or cysteine mercaptan groups (thioester linkage). Reactions with particular groups depend upon pH and the reduction state of the reaction conditions.
  • the benztriazole-derivatized particulates i.e., activated imidate-bearing moieties
  • a protein/peptide nucleophilic moiety such as an available epsilon amino moiety.
  • p-nitrophenol p-nitrophenol
  • binding protein/peptide nucleophilic moieties include hydroxyl groups of serine, endogenous free thiols of cysteine, thiol groups resulting from reduction of binding
  • lactic/glycolic acid particulates are activatable by reaction with thionyl chloride to form an acyl chloride derivatized moiety.
  • the derivatized particulates are then reacted with binding peptide/protein nucleophilic groups to form targeted dosage forms of the present invention.
  • the particulate carboxy groups are biotinylated (e.g., through carbodiimide activation of the carboxy group and subsequent reaction with amino alkyl biotinamide).
  • the biotinylated particulates are then incubated with a saturating concentration (i.e., a molar excess) of avidin or streptavidin to form protein coated particulates having free biotin binding sites.
  • a saturating concentration i.e., a molar excess
  • Such coated particulates are then capable of reaction with a molar excess of biotinylated binding protein formed as described above.
  • Another option involves avidin or streptavidin bound binding peptide or protein attachment to biotinylated particulates.
  • binding protein/peptide may be partially entrapped in the particulate polymeric matrix upon formation thereof.
  • entrapped binding protein/peptide provides residual selective binding character to the particulate. Mild particulate formation conditions, such as those employed by Cohen et al., Pharmaceutical Research, 8: 713-720 (1991), are preferred for this embodiment of the present invention. Such entrapped binding protein is also useful in target cell reattachment of a partially degraded particulate that has undergone exocytosis.
  • Other polymeric particulate dosage forms e.g., non-biodegradable dosage forms having different exposed functional groups can be bound to binding proteins or peptides in accordance with the principles discussed above.
  • targeting is specific for potentially proliferating cells that result in increased smooth muscle in the intimal region of a traumatized vascular site, e.g.. following angioplasty, e.g., pericytes and vascular smooth muscle cells.
  • angioplasty e.g., pericytes and vascular smooth muscle cells.
  • the therapeutic conjugates or dosage forms of the invention may be administered to the host using an infusion catheter, such as produced by C.R. Bard Inc., Billerica, MA, or that disclosed by Wolinsky (7; U.S. Patent No. 4,824,436) or Spears (U.S. Patent No. 4,512,762).
  • an infusion catheter such as produced by C.R. Bard Inc., Billerica, MA, or that disclosed by Wolinsky (7; U.S. Patent No. 4,824,436) or Spears (U.S. Patent No. 4,512,762).
  • a therapeutically effective dosage of the therapeutic conjugate will be typically reached when the concentration of conjugate in the fluid space between the balloons of the catheter is in the range of about 10 -3 to 10 -12 M.
  • therapeutic conjugates of the invention may only need to be delivered in an anti-proliferative therapeutic dosage sufficient to expose the proximal (6 to 9) cell layers of the intimal or tunica media cells lining the lumen to the therapeutic anti-proliferative conjugate, whereas the anti-contractile therapeutic dosage needs to expose the entire tunica media, and further that this dosage can be determined empirically, e.g., by a) infusing vessels from suitable animal model systems and using immunohistochemical methods to detect the conjugate and its effects (e.g., such as exemplified in the EXAMPLES below); and b) conducting suitable in vitro studies such as exemplified in EXAMPLES 3, 4, and 5, below).
  • this therapeutically effective dosage is achieved by preparing 10 ml of a 200 ⁇ g/ml therapeutic conjugate solution, wherein the vascular smooth muscle protein binding protein is NR-AN-01 and the therapeutic agent is Roridin A, a trichothecene drug.
  • 10 ml will commonly be sufficient volume to fill the catheter and infuse 1 to 1.5 ml into one to three traumatic lesion sites in the vessel wall.
  • Sustained release dosage forms of an embodiment of the invention may only need to be delivered in an anti-proliferative therapeutic dosage sufficient to expose the proximal (6 to 9) cell layers of the tunica media smooth muscle cells lining the lumen to the dosage form.
  • This dosage is determinable empirically, e.g., by a) infusing vessels from suitable animal model systems and using immunohistochemical, fluorescent or electron microscopy methods to detect the dosage form and its effects; and b) conducting suitable in vitro studies.
  • this therapeutically effective dosage is achieved by determining in smooth muscle cell tissue culture the pericellular agent dosage, which at a continuous exposure results in a therapeutic effect between the toxic and minimal effective doses.
  • This therapeutic level is obtained in vivo by determining the size, number and therapeutic agent concentration and release rate required for particulates infused between the smooth muscle cells of the artery wall to maintain this pericellular therapeutic dosage.
  • the dosage form should release the therapeutic agent at a rate that approximates the pericellular dose of the following exemplary therapeutic agents: from about 0.01 to about 100 micrograms/ml nitroglycerin, from about 1.0 to about 1000 micrograms/ml of suramin, from about 0.001 to about 100 micrograms/ml for cytochalasin. and from about 0.01 to about 10 5 nanograms/ml of staurosporin.
  • therapeutically effective dosages of the sustained release dosage form of the invention will be dependent on several factors, including, e.g.: a) the binding affinity of the binding protein associated with the dosage form; b) the atmospheric pressure and duration of the infusion; c) the time over which the dosage form administered resides at the target site; d) the rate of therapeutic agent release from the particulate dosage form; e) the nature of the therapeutic agent employed; f) the nature of the trauma and/or therapy desired; and/or g) the intercellular and/or intracellular localization of the particulate dosage form.
  • Those skilled practitioners trained to deliver drugs at therapeutically effective dosages are capable of determining the optimal dosage for an individual patient based on experience and professional judgment.
  • about 0.3 atm (i.e., 300 mm of Hg) to about 3 atm of pressure applied for 15 seconds to 3 minutes to the arterial wall is adequate to achieve infiltration of a sustained release dosage form bound to the NR-AN-01 binding protein into the smooth muscle layers of a mammalian artery wall.
  • Wolinsky et al. "Direct Intraarterial Wall Injection of Microparticles Via a Catheter: A Potential Drug Delivery Strategy Following Angioplasty," Am. Heart Jour., 122(4):1 136-1 140, 1991.
  • Those skilled in the art will recognize that infiltration of a sustained release dosage form into a target cell population will probably be variable and will need to be determined on an individual basis.
  • therapeutic conjugates radiolabeled with alpha-, beta- or gamma-emitters of known specific activities are useful for determining the therapeutically effective dosage by using them in animal studies and human trials with quantitative imaging or autoradiography of histological tissue sections to determine the concentration of therapeutic conjugate that is required by the therapeutic protocol.
  • a therapeutically effective dosage of the therapeutic conjugate or dosage form will be reached when at least three conditions are met: namely.
  • the therapeutic dosage required to achieve the desired inhibitory activity for a therapeutic conjugate or dosage form can also be anticipated through the use of in vitro studies.
  • the infusion catheter may be conveniently a double balloon or quadruple balloon catheter with a permeable membrane.
  • a therapeutically effective dosage of a therapeutic conjugate or dosage form is useful in treating vascular trauma resulting from disease (e.g., atherosclerosis, aneurysm, or the like) or vascular surgical procedures such as angioplasty, atheroectomy, placement of a stent (e.g., in a vessel), thrombectomy, and grafting.
  • Atheroectomy may be performed, for example, by surgical excision, ultrasound or laser treatment, or by high pressure fluid flow.
  • Grafting may be, for example, vascular grafting using natural or synthetic materials or surgical anastomosis of vessels such as, e.g., during organ grafting.
  • a therapeutic conjugate containing Roridin A and NR-AN-01 achieved a therapeutically effective dosage in vivo at a concentration which inhibited cellular protein synthesis in test cells in vitro by at least 5 to 50%, as judged by incorporation of radiolabeled amino acids.
  • cell migration and cell adherence in in vitro assays may be used for determining the concentration at which a therapeutically effective dosage will be reached in the fluid space created by the infusion catheter in the vessel wall.
  • While one representative embodiment of the invention relates to therapeutic methods employing an infusion catheter, it will be recognized that other methods for drug delivery or routes of administration may also be useful, e.g., injection by the intravenous, intralymphatic, intrathecal.
  • intraarterial local delivery by implanted osmotic pumps or other intracavity routes.
  • nanoparticulate dosage forms of the present invention are preferred.
  • Intravenous administration of nanoparticulates is useful, for example, where vascular permeability is increased in tumors for leakage, especially in necrotic areas of tumors having damaged vessels which allow the leakage of particles into the interstitial fluid, and where artery walls have been denuded and traumatized allowing the particles to enter the interstitial area of the tunica media.
  • non-coupled vascular smooth muscle cell binding protein e.g., free NR-AN-01 antibody
  • non-coupled vascular smooth muscle cell binding protein is administered prior to administration of the therapeutic agent conjugate or dosage form to provide a blocker of non-specific binding to cross-reactive sites. Blocking of such sites is important because vascular smooth muscle cell binding proteins will generally have some low level of cross-reactivity with cells in tissues other than the desired smooth muscle cells. Such blocking can improve localization of the therapeutic conjugate or dosage form at the specific vascular site, e.g., by making more of the therapeutic conjugate available to the cells.
  • non-coupled vascular smooth muscle binding protein is administered from about 5 minutes to about 48 hours, most preferably from about 5 minutes to about 30 minutes, prior to administration of the therapeutic conjugate or dosage form.
  • the unlabeled specific "blocker" is a monovalent or bivalent form of an antibody (e.g., a whole antibody or an F(ab)' 2 , Fab. Fab', or Fv fragment of an antibody).
  • the monovalent form of the antibody has the advantage of minimizing displacement of the therapeutic conjugate or dosage form while maximizing blocking of the non-specific cross-reactive sites.
  • the non-coupled vascular smooth muscle cell binding protein is administered in an amount effective to blocking binding of a least a portion of the non-specific cross-reactive sites in a patient. The amount may vary according to such factors as the weight of the patient and the nature of the binding protein. In general, about 0.06 mg to 0.20 mg per kg body weight or more of the unlabeled specific blocker is administered to a human.
  • a second irrelevant vascular smooth muscle cell binding protein may optionally be administered to a patient prior to administration of the therapeutic conjugate or dosage form to reduce non-specific binding of the therapeutic conjugate or dosage form to tissues.
  • the irrelevant binding protein may be an antibody which does not bind to sites in the patient through antigen-specific binding, but instead binds in a non-specific manner, e.g., through Fc receptor binding reticuloendothelial cells, asialo-receptor binding, and by binding to ubiquitin-expressing cells.
  • the irrelevant "blocker” decreases non-specific binding of the therapeutic conjugate or dosage form and thus reduces side-effects, e.g., tissue toxicity, associated with the use of the therapeutic conjugate or dosage form.
  • the irrelevant "blocker” is advantageously administered from 5 minutes to
  • irrelevant "blockers” include antibodies that are nonreactive with human tissues and receptors or cellular and serum proteins prepared from animal sources that when tested are found not to bind in a specific manner (e.g., with a Ka ⁇ 10 3 M -1 ) to human cell membrane targets.
  • conjugates and dosage forms of the invention are not restricted in use for therapy following angioplasty; rather, the usefulness of the therapeutic conjugates and dosage forms will be proscribed by their ability to inhibit cellular activities of smooth muscle cells and pericytes in the vascular wall.
  • other aspects of the invention include therapeutic conjugates and dosage forms and protocols useful in early therapeutic intervention for reducing, delaying, or eliminating (and even reversing) atherosclerotic plaques and areas of vascular wall hypertrophy and/or hyperplasia.
  • Therapeutic conjugates and dosage forms of the invention also find utility for early intervention in pre-atherosclerotic conditions, e.g., they are useful in patients at a high risk of developing atherosclerosis or with signs of hypertension resulting from atherosclerotic changes in vessels or vessel stenosis due to hypertrophy of the vessel wall.
  • the stent preferably comprises a biodegradable coating or a porous or permeable non-biodegradable coating comprising the therapeutic agent.
  • a more preferred embodiment of the invention is a coated stent wherein the coating comprises a sustained-release dosage form of the therapeutic agent.
  • a biodegradable stent may also have the therapeutic agent impregnated therein, i.e., in the stent matrix.
  • the intravascular stent thus provides a mechanical means of providing an increase in luminal area of a vessel, in addition to that provided via the biological stenting action of the cytoskeletal inhibitor, such as cytochalasin B or taxol, releasably embedded therein.
  • the cytoskeletal inhibitor such as cytochalasin B or taxol
  • intravascular stents comprising a therapeutic agent which is an inhibitor of smooth muscle cell proliferation
  • a stent which further comprises a cytochalasin to inhibit the proliferation and migration of pericytes, which can transform into smooth muscle cells and contribute to intimal thickening, is also an embodiment of the invention.
  • This inhibition of intimal smooth muscle cells and stroma produced by the smooth muscle and pericytes can allow more rapid and complete re-endothelization following the intraventional placement of the vascular stent.
  • the increased rate of re-endothelization and stabilization of the vessel wall following stent placement can reduce the loss of luminal area and decreased blood flow which is the primary cause of vascular stent failures.
  • the biodegradable microparticles containing the therapeutic agent are from about 1 to 50 microns.
  • the microparticles would biodegrade over a period of 30 to 120 days, releasing into the tunica media and intima a sustained cellular concentration of approximately from about 0.05 ⁇ g/ml to about 0.25 ⁇ g/ml of cytochalasin B into the cytosol, thus providing the diffusion of therapeutic levels of cytochalasin B without toxicity to cells adjacent to the stent/vessel wall interface.
  • the therapeutic conjugates and dosage forms of the invention may also be used in therapeutic modalities for enhancing the regrowth of endothelial cells in injured vascular tissues and in many kinds of wound sites including epithelial wounds.
  • the therapeutic conjugates and dosage forms of the invention find utility in inhibiting the migration and/or proliferation of smooth muscle cells or pericytes. Smooth muscle cells and pericytes have been implicated in the production of factors in vitro that inhibit endothelial cell proliferation, and their proliferation can also result in a physical barrier to establishing a continuous endothelium.
  • the therapeutic conjugates and dosage forms of the invention find utility in promoting neo-angiogenesis and increased re-endothelialization, e.g.. during wound healing, vessel grafts and following vascular surgery.
  • the dosage forms may also release therapeutic modalities that stimulate or speed up re-endothelialization of the damaged vessel wall.
  • An exemplary therapeutic agent for this purpose is vascular permeability factor.
  • Still other aspects of the invention relate to therapeutic modalities for enhancing wound healing in a vascular site and improving the structural and elastic properties of healed vascular tissues.
  • these therapeutic modalities using the therapeutic conjugate or dosage form of the invention i.e.. to inhibit the migration and proliferation of smooth muscle cells or pericytes in a vessel wall
  • the strength and quality of healing of the vessel wall are improved.
  • Smooth muscle cells in the vascular wound site contribute to the normal process of contraction of the wound site which promotes wound healing. It is presently believed that migration and proliferation of smooth muscle cells and matrix secretion by transformed smooth muscle cells may detract from this normal process and impair the long-term structural and elastic qualities of the healed vessel.
  • other aspects of the invention provide for therapeutic conjugates and dosage forms that inhibit smooth muscle and pericyte proliferation and migration as well as morphological transformation, and improve the quality of the healed vasculature.
  • one embodiment of the present invention comprises the in vivo or ex vivo infusion of a solution of a therapeutic agent such as cytochalasin B into the walls of isolated vessels (arteries or veins) to be used for vascular grafts.
  • a therapeutic agent such as cytochalasin B
  • the vessel that is to serve as the graft is excised or isolated and subsequently distended by an infusion of a solution of a therapeutic agent.
  • the infusion is accomplished by a pressure infusion at a pressure of about 0.2 to 1 atmosphere for a time period of from about 2 to about 4 minutes. This infusion regime will result in the penetration of an efficacious dose of the therapeutic agent to the smooth muscle cells of the vessel wall.
  • the therapeutic agent will be at a concentration of from about 0.1 ⁇ g/ml to about 0.8 ⁇ g/ml of infusate.
  • the therapeutic agent will be a cytochalasin, and most preferably, the therapeutic agent employed will be cytochalasin B, or a functionally equivalent analogue thereof.
  • cytochalasin B in this manner will prevent the constriction or spasm that frequently occurs after vascular grafts are anastomosed to both their proximal and distal locations, that can lead to impaired function, if not total failure, of vascular grafts.
  • the vessel stenting produced by cytochalasin b should decrease the incidence of spasms, which can occur from a few days to several months following the graft procedure.
  • the present invention also provides a combination therapeutic method involving a cytocidal therapeutic conjugate and a cytostatic therapeutic agent.
  • the cytocidal conjugate includes a binding partner (such as a protein or peptide) capable of specifically localizing to vascular smooth muscle cells and an active agent capable of killing such cells.
  • the cytocidal conjugate is administered, preferably intravenously or through any other convenient route therefor, localizes to the target smooth muscle cells, and destroys proliferating cells involved in stenotic or restenotic events. This cellular destruction causes the release of mitogens and other metabolic events, which events generally lead, in turn, to vascular smooth muscle cell proliferation.
  • the present invention also provides methods for the treatment of cancer and immune system-mediated diseases through local administration of a targeted particulate dosage form.
  • the particulate dosage form is, for example, administered locally into primary and/or metastatic foci of cancerous target cells.
  • Local administration is preferably conducted using an infusion needle or intraluminal administration route, infusing the particulate dosage form in the intercellular region of the tumor tissue or in luminal fluid surrounding the tumor cells.
  • Primary foci introduction is preferably conducted with respect to target cells that are generally situated in confined areas within a mammal, e.g., ovarian carcinomas located in the abdominal cavity.
  • the dosage form of the present invention binds to the target cell population and, optionally, is internalized therein for release of the therapeutic agent over time.
  • Local administration of dosage forms of the present invention to such primary foci results in a localized effect on such target cells, with limited exposure of other sensitive organs, e.g., the bone marrow and kidneys, to the therapeutic agent.
  • the administered microparticles and larger nanoparticles are primarily bound to the target cells situated near the infusion site and are, optionally, internalized for release of the therapeutic agent, thereby generating a marked and localized effect on the target cells immediately surrounding the infusion site.
  • smaller nanoparticles follow interstitial fluid flow or lymphatic drainage channels and bind to target cells that are distal to the infusion site and undergoing lymphatic metastasis.
  • the targeted dosage forms of this embodiment of the present invention can be used in combination with more commonly employed immunoconjugate therapy.
  • the immunoconjugate achieves a systemic effect within the limits of systemic toxicity, while the dosage form of the present invention delivers a concentrated and sustained dose of therapeutic agent to the primary and metastatic foci, which often receive an inadequate therapeutic dose from such "systemic" immunoconjugate administration alone, and avoids or minimizes systemic toxic effects.
  • target cell population can be accessed by local
  • the dosage forms of the present invention are utilized to control immune system-mediated diseases.
  • diseases are arthritis, sprue, uveitis, endophthalmitis, keratitis and the like.
  • the target cell populations implicated in these embodiments of the present invention are confined to a body cavity or space, such as joint capsules, pleural and abdominal cavity, eye and sub-conjunctival space, respectively.
  • Local administration is preferably conducted using an infusion needle for a intrapleural, intraperitoneal, intraocular or sub-conjunctival administration route.
  • This embodiment of the present invention provides a more intense, localized modulation of immune system cells with minimal effect on the systemic immune system cells.
  • the systemic cells of the immune system are simultaneously treatable with a chemotherapeutic agent conjugated to a binding protein or peptide.
  • a conjugate preferably penetrates from the vascular lumen into target immune system cells.
  • the local particulate dosage form administration may also localize to normal tissues that have been stimulated to proliferate, thereby reducing or eliminating such pathological (i.e., hyperactive) conditions.
  • An example of this embodiment of the present invention involves intraocular administration of a particulate dosage form coated with a binding protein or peptide that localizes to pericytes and smooth muscle cells of neovascularizing tissue. Proliferation of these pericytes causes degenerative eye disease.
  • Preferred dosage forms of the present invention release compounds capable of suppressing the pathological proliferation of the target cell population.
  • the preferred dosage forms can also release compounds that increase vessel lumen area and blood flow, reducing the pathological alterations produced by this reduced blood supply.
  • Still another aspect of the present invention relates to therapeutic modalities for maintaining an expanded luminal volume following angioplasty or other vessel trauma.
  • a therapeutic agent capable of inhibiting the ability of vascular smooth muscle cells to contract.
  • agents useful in the practice of this aspect of the present invention are those capable of causing a traumatized artery to lose vascular tone, such that normal vascular hydrostatic pressure (i.e., blood pressure) expands the flaccid vessel to or near to its maximal physiological diameter.
  • Loss of vascular tone may be caused by agents that interfere with the formation or function of contractile proteins (e.g., actin, myosin, tropomyosin, caldesmon, calponin or the like). This interference can occur directly or indirectly through, for example, inhibition of calcium modulation, phosphorylation or other metabolic pathways implicated in contraction of vascular smooth muscle cells.
  • Inhibition of cellular contraction may operate through two mechanisms to reduce the degree of vascular stenosis.
  • Second, inhibition of cellular contraction causes the smooth muscle wall to relax and dilate under normal vascular hydrostatic pressure (i.e., blood pressure).
  • the clinician can eliminate over-inflation and its resultant trauma shock as a means to diminish or delay the vessel spasm or elastic recoil. Reduction or elimination of over-inflation decreases trauma to the muscular wall of the vessel, thereby reducing the determinants of smooth muscle cell proliferation in the intima and, therefore, reducing the incidence or severity of restenosis.
  • Cytochalasins are exemplary therapeutic agents capable of generating a biological stenting effect on vascular smooth muscle cells. Cytochalasins are thought to inhibit both migration and contraction of vascular smooth muscle cells by interacting with actin. The cytochalasins interact with the ends of filamentous actin to inhibit the elongation of the actin filaments. Low doses of cytochalasins (e.g., cytochalasin B) also disrupt microfilament networks of actin. In vitro data indicate that after vascular smooth muscle cells clear cytochalasin B, the cells regenerate enough polymerized actin to resume migration within about 24 hours. In vivo assessments reveal that vascular smooth muscle cells regain vascular tone within 2 to 4 days. It is during this recuperative period that the lumen diameter fixation and biological stenting effect occurs.
  • cytochalasins are thought to inhibit both migration and contraction of vascular smooth muscle cells by interacting with actin. The cytochalasins interact with the ends of filamentous
  • the therapeutic agent may be targeted, but is preferably administered directly to the traumatized vessel following the angioplasty or other traumatic event.
  • the biological stenting effect of cytochalasin B is achievable using a single infusion of the therapeutic agent into the traumatized region of the vessel wall at a dose concentration ranging from about 0.1 microgram/ml to about 1.0 micrograms/ml.
  • vascular smooth muscle cell migration has been demonstrated in the same dose range (Example 1 1 ); however, a sustained exposure of the vessel to the therapeutic agent is preferable in order to maximize these anti-migratory effects. If the vascular smooth muscle cells cannot migrate into the intima, they cannot proliferate there. Should vascular smooth muscle cells migrate to the intima, a subsequently administered anti-proliferative sustained release dosage form inhibits the intimal proliferation.
  • the sustained release dosage form of the present invention incorporating a cytochalasin or other anti-proliferative therapeutic agent, can be administered in combination with a free cytochalasin therapeutic agent. In this manner, the biological stenting effect, as well as an anti-proliferative or anti-migratory effect, can be achieved in a single administration protocol.
  • Agents useful in the protocols of the present invention are identifiable. for example, in accordance with the following procedures.
  • a potential agent for free agent (i.e., non-targeted) administration exhibits one or more of the following characteristics:
  • angioplasty e.g., PTCA, percutaneous transluminal angioplasty (PTA) or the like
  • PTA percutaneous transluminal angioplasty
  • atheroectomy e.g., rotoblater, laser and the like
  • coronary artery bypass procedures e.g., coronary artery bypass procedures or the like
  • vascular disease e.g., atherosclerosis, eye diseases secondary to vascular stenosis or atrophy, cerebral vascular stenotic diseases or the like
  • a therapeutic agent employed herein will have all four properties; however, the first and third are more important than the second and fourth for practice of the present invention.
  • Cytochalasin B for example, was evaluated to determine suitability for use in free therapeutic agent protocols. The biological stenting effect of cytochalasin B is achievable using a single infusion of the therapeutic agent into the traumatized region of the vessel wall at a dose concentration ranging from about 0.1 microgram/ml to about 1.0 micrograms/ml.
  • An agent useful in the sustained release embodiments of the present invention exhibits one or more of the following characteristics:
  • angioplasty e.g., PTCA, percutaneous transluminal angioplasty (PTA) or the like
  • PTA percutaneous transluminal angioplasty
  • atheroectomy e.g., rotoblater, laser and the like
  • coronary artery bypass procedures e.g., coronary artery bypass procedures or the like
  • vascular disease e.g., atherosclerosis, eye diseases secondary to vascular stenosis or atrophy, cerebral vascular stenotic diseases or the like
  • target cell proliferation e.g., following 5 minute and 24 hour exposure to the agent, in vitro vascular smooth muscle tissue cultures demonstrate a level of inhibition of 3 H-thymidine uptake and. preferably, display relatively less inhibition of 3 H-leucine uptake;
  • (v) is cytostatic.
  • the agent Upon identification of a therapeutic agent exhibiting one or more of the preceding attributes, the agent is subjected to a second testing protocol that involves longer exposure of vascular smooth muscle cells to the therapeutic agent.
  • FIGURE 3 shows diagrammatically the second reaction scheme for synthesis of Roridin A hemisuccinyl succinimidate (RA-HS-NHS) through a five step process with reagents: t-butyl dimethyl silyl chloride (TBMS-C1) and imidazole in dimethylformamide (DMF) at room temperature (RT); acetic anhydride, triethylamine (TEA), and diethylaminopyridine in dichloromethane (CH 2 Cl 2 ) at RT; succinic anhydride, triethylamine (TEA) and
  • the binding of the NR-AN-01 MAb to the A375 cells was quantified by washing to remove unbound antibody, adding HRP-conjugated goat anti-mouse IgG to react with the cell-bound MAb, washing to remove unbound goat second antibody, and adding 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) substrate for peroxidase. Color development was monitored after 30 minutes at both 415 nm and 490 nm (ABS415.490).
  • the HT29 and Ml 4 cells were seeded in 96-well microtiter plates at a concentration of 5.0 ⁇ 10 3 cells/well, and the BO54 cells were seeded at 2.5 ⁇ 10 3 cells/well.
  • Serial two-fold dilutions of free Roridin A and 2'RA-HS-NR-AN-01 i.e., Roridin A coupled through a hemisuccinate (HS) coupling agent at the 2' position to NR-AN-01
  • HS hemisuccinate
  • RA-conjugate concentration of >10 ng/ml.
  • PE Pseudomonas exotoxin
  • FIGURE 6B graphically depicts the results of in vitro studies conducted in manner similar to those discussed above in regard to FIGURE 6A. but designed to compare the effects obtained with free PE (PE) to those obtained above, i.e., in FIGURE 6A. with PE-NR-AN-01.
  • PE free PE
  • FIGURE 6B graphically depicts the results of in vitro studies conducted in manner similar to those discussed above in regard to FIGURE 6A. but designed to compare the effects obtained with free PE (PE) to those obtained above, i.e., in FIGURE 6A. with PE-NR-AN-01.
  • the cells, culture conditions, calculations, and presentation of the results are the same as in FIGURE 6A, above.
  • FIGURE 7A graphically depicts the results of in vitro studies conducted to investigate the effects on control HT29 marker-negative cells of a 5 minute exposure to different concentrations of Roridin A (Free RA; open squares, FIGURE 7A), or 2'RA-NR-AN-01 (2'RA-NRAN01 ; closed squares, FIGURE 7A), or 13'RA-NR-AN-01 (13'RA-NRAN01 ; closed triangles, FIGURE 7A) conjugates.
  • Roridin A Free RA; open squares, FIGURE 7A
  • 2'RA-NR-AN-01 (2'RA-NRAN01 ; closed squares, FIGURE 7A
  • 13'RA-NR-AN-01 13'RA-NRAN01 ; closed triangles, FIGURE 7A
  • the concentrations of Free RA, 2'RA-NR-AN-01 or 13'NR-AN-01 are expressed as the calculated concentration of Roridin A in the assay (in ⁇ g/ml plotted on a log scale), i.e., rather than the total ⁇ g/ml of NR-AN-01 protein, so that direct comparisons of the results can be made.
  • the cells were treated for 5 minutes, washed, and then returned to culture for 4 hours, during which time cellular protein synthesis was evaluated by adding 0.5 mCi/ml of 3 H-leucine to the culture medium. At the end of the 4 hour period, cellular proteins were collected and radioactivity was determined. The results are expressed as the percentage of the radioactivity recorded in a control (non-treated) HT29 cell culture (i.e., %control).
  • FIGURE 7B graphically depicts the results of in vitro studies investigating the effects on control HT29 marker-negative cells of a 5 minute expose to different concentrations of Free RA (open squares,FIGURE 7B), 2'RA-NRAN01 ( closed squares, FIGURE 7B), or 13'RA-NRAN01 ( closed triangles, FIGURE 7B), as described above in regard to FIGURE 7A, but in the present experiments the cells were incubated for a 16-18 hour recovery period (i.e., overnight; o/n) prior to testing protein synthesis in a four hour 3 H-leucine protein synthesis assay. The results are presented in a manner similar to those above in FIGURE 7A.
  • FIGURE 7D graphically depicts the results of in vitro studies investigating the effects on A375 m/ml marker-positive cells of a 5 minute exposure to different concentrations of Free RA (open squares ,FIGURE 7D), 2'RA-NRAN01 (closed squares, FIGURE 7D), 13'RA-NRAN01 (closed triangles, FIGURE 7D), as described above in regard to FIGURE 7B.
  • the A375 cells were incubated for 5 minutes in the test agent, washed, and then returned to culture for a 16-18 hour recovery period (i.e., overnight; o/n Recovery), after which time protein synthesis was evaluated during a 4 hour 3 H-leucine protein synthesis assay.
  • the results of the experiments are plotted in a manner similar to those described above in regard to FIGURE 7A.
  • FIGURE 7A and FIGURE 7B, above that its effect on the cells is manifest even after a 16-18 hour recovery period.
  • the specific effects of the RA-NR-AN-01 conjugates on target cells during a "pulse" treatment appear to be a property of the NR-AN-01 binding protein.
  • MTT assays were conducted at 48 hours following a 5-minute exposure of target and non-target cells to RA or RA-NR-AN-01 conjugates.
  • Target cells in these studies included BO54 and A375, and non-target cells included HT29 cells.
  • Sterile 96 well microtiter plates were seeded with 2500 cells/well, wrapped in aluminum foil and incubated in a humidified chamber containing 5% CO 2 /95% air for 16-18 hours.
  • the plates were covered and incubated at 37°C for 4 hours and then the reaction was developed as described above (see EXAMPLE 4, above).
  • the dark blue solubilized formazan reaction product was developed at room temperature after a 16-18 hour incubation.
  • the samples were quantified using an ELISA microtiter plate reader at an absorbance of 570 nm.
  • FIGURE 8A graphically depicts the results of in vitro studies investigating the effects on BO54 marker-positive smooth muscle cells of a 5 minute exposure to different concentrations of Roridin A (open squares, FIGURE 8A), 2'RA-NR-AN-01 (NRAN01-2'RA; closed diamonds, FIGURE 8A), or 13' RA-NR-AN-01 (NRAN01-13'RA; closed squares, FIGURE 8A).
  • the experiments were conducted in a manner similar to those described above in regard to FIGURE 7B, but metabolic activity was assayed by MTT assay, i.e., rather than protein synthesis as in FIGURE 7B, and cells were also given 48 hours to recover (rather than 24 hours, as in FIGURE 7B).
  • the results of the experiments are plotted in a manner similar to those described (above) in regard to FIGURE 7A .
  • FIGURE 8B graphically depicts the results of in vitro studies investigating the effects on A375 m/m marker-positive cells of a 5 minute exposure to different concentrations of Roridin A (open squares, FIGURE 8B), 2'RA-NR-AN-01 (NRAN01-2'RA; closed diamonds, FIGURE 8B), 13'RA-NR-AN-01 (NRAN01-13'RA; closed squares, FIGURE 8B).
  • the experiments were conducted (and the results plotted) in a manner similar to those described above in regard to FIGURE 8A.
  • FIGURE 8C graphically depicts the results of in vitro studies investigating the effects on HT29 marker-negative cells of a 5 minute exposure to different concentrations of Roridin A (open squares, FIGURE 8C), 2'RA-NR-AN-01 (NRAN01 -2'RA; closed diamonds, FIGURE 8C), 13'RA-NR-AN-01 (NRAN01-13'RA; closed squares, FIGURE 8C).
  • the experiments were conducted (and the results plotted) in a manner similar to those described above in regard to FIGURE 8A.
  • FIGURES 8A-8C show slight differences between the different RA-NR-AN-01 conjugates at the highest doses, but at the lower doses the 2' and 13'RA-NR-AN-01 did not significantly inhibit target cell (i.e., BO54 and A375) or non-target cell (i.e., HT29) metabolic activity over the long-term (i.e., 48 hours).
  • target cell i.e., BO54 and A375
  • non-target cell i.e., HT29
  • the therapeutic conjugates of the invention are useful for inhibiting stenosis following vascular trauma or disease.
  • vascular trauma that is induced during angioplasty is treated during the surgical procedure by removing the catheter used to perform the angioplasty, and inserting a balloon infusion catheter into the vessel.
  • the infusion catheter is positioned with the instillation port (or, alternatively, a permeable membrane region) in the traumatized area of the vessel, and then pressure is applied to introduce the therapeutic conjugate.
  • an infusion catheter with two balloons may be used, and when one balloon is inflated on either side of the trauma site a fluid space is created that can be filled with a suitable infusion fluid containing the therapeutic conjugate.
  • HRP horseradish peroxidase
  • the coronary and femoral arteries of domestic pigs or non-human primates were infused with NR-AN-01 for 45 seconds to 3 minutes at multiple pressures in the range of about
  • NR-AN-01 target antigen with man.
  • NR-AN-01 could bind in a specific manner to its target antigen in vivo
  • the coronary and femoral arteries of domestic pigs were infused with therapeutic conjugates using an infusion catheter, the infusion sites were flushed with sterile saline, the surgical sites were then closed, and the animals were maintained for an additional 3-5 days.
  • the vascular infusion sites were excised and prepared for immunohistology, once again using goat anti-mouse IgG to identify
  • NR-AN-01 was identified in the vessel wall of swine coronary and femoral arteries 3-5 days after surgery, and the NR-AN-01 appeared to be associated only with vascular smooth muscle cells. These findings suggest that NR-AN-01 is capable of specifically binding to its target antigen in vivo.
  • Intimal smooth muscle proliferation that follows balloon catheter-induced trauma is a good model to evaluate the therapeutic efficacy of conjugates for inhibiting smooth muscle cell activity in vivo in response to vascular trauma, including restenosis following angioplasty.
  • Domestic pigs were used to study the effects of NR-AN-01 (i.e., termed vascular smooth muscle binding protein or simply VSMBP in these studies; and therapeutic conjugates with Roridin A are termed VSMBP - RA).
  • VSMBP - RA vascular smooth muscle binding protein
  • test protocol was conducted in domestic pigs with NR-AN-01-Roridin A conjugates.
  • Localized administration of the test conjugates i.e., through a catheter into a region of traumatized vessel confined by temporary slip ligatures, was designed to reduce systemic toxicity while providing a high level of exposure for the target smooth muscle cells.
  • This intra-artery route of administration in animal model studies simulates the proposed route in human coronary arteries.
  • the test protocol was designed as an initial in vivo screening of intra-arteriolar, site specific, catheter
  • vascular smooth muscle binding protein VSMBP conjugates.
  • Toxicity of free drug was also evaluated, i.e., for pathobiological effects on arteriolar smooth muscle cells.
  • the therapeutically effective dosage of the Roridin A-NR-AN-01 conjugate was determined by in vitro studies, and the proper intra-arteriolar administration pressure was determined by administering free MAb and MAb conjugates to animals, as described above in Example 7.
  • Test conjugates and control compounds were administered as a single intra-artery infusion at the site of endothelial denuding and trauma induced by a balloon catheter. Both the carotid and femoral arteries were abraded over 1 cm to 2 cm of endothelium by intraluminal passage of a 23 cm, size 3 (femoral) and size 4 (carotid) Uresil Vascu-Flo® silicone occlusion balloon catheter (Uresil Technology Center, Skokie, IL), sufficiently distended with saline to generate slight resistance. This technique produced slight distension of the artery.
  • proximal and distal slip ligatures were placed near the ends of the abraded region, and a size 8 French, Infant Feeding Catheter (Cutter-Resiflex. Berkeley, CA) attached to an Inflation Pro® (USCI, C.R. Bard, Inc., Billerica, MA) pressure syringe was used to administer the test conjugates and control compounds directly to the denuded segment at a pressure of three atmospheres for three minutes.
  • the slip ligatures were removed after the three minute exposure period and arterial blood flow was re-established.
  • branches of the femoral or carotid arteries were ligated with 00 silk suture as required to attain pressurized infusion in the treated region.
  • the largest distal branch of the femoral artery (the saphenous artery) was incised and used as an entry site for the catheters which were then passed into the main femoral artery. Following this catheterization procedure in the main femoral artery, the secondary branch was ligated. In these cases, ligation or incision was used to allow entry of the catheters and the opening was then closed with 3 to 4 sutures of
  • the pigs were kept in 3 ⁇ 5 foot indoor runs with cement floors during the quarantine and surgical recovery periods. They were then transferred to indoor/outdoor pens for the remainder of the five week healing period prior to collection of tissues for histology.
  • the animals recovered normally from surgery with no evidence of hemorrhage or inflammation at the surgical sites. All six animals were examined 5 to 6 days after treatment with a doppler stethoscope, and all arteries in each of the animals were patent. Post treatment all animals had normal appetite, activity and weight gain.
  • heparinized i.v. 2 ml sodium heparin, 1000 units/ml
  • euthanized by i.v. pentobarbital Both the right and left carotid and femoral arteries were removed with normal vessel included both proximal and distal to the treated segment. The arteries were measured and the location of ligatures and gross abnormalities noted. The arteries were transected at 2 mm intervals and arranged in order in cryomolds with O.C.T. (optimum cutting temperature) compound (Tissue Tek®, Miles Laboratories Inc., Elkhart, IN) and frozen in liquid nitrogen. The blocks were sectioned at 5 microns and stained with
  • Sections were also used for immunohistological staining of vascular smooth muscle.
  • FIGURES 9A and 9B are identical to FIGURES 9A and 9B.
  • FIGURE 9A show (at 160x magnification) a cross-sectional of an untreated artery 5 weeks after angioplasty.
  • Dominant histological features of the artery include displacement of the endothelium (see #1 in FIGURE 9A) away from the internal elastic lamina (see #2, FIGURE 9A), apparently due to intimal smooth muscle proliferation (see #3, FIGURE 9A).
  • FIGURE 9B show (at 160x magnification) a cross-section of a treated artery 5 weeks after angioplasty and infusion of the RA-NR-AN-01 therapeutic conjugate.
  • the vessel in this section was subjected to greater mechanical stresses than the vessel shown in FIGURE 9A, with multiple sites where the external elastic membrane was ruptured and associated proliferation of smooth muscle cells in the outer layers of the media was observed (i.e., see #4 in FIGURE 9B).
  • Treatment with therapeutic conjugate inhibited intimal hypertrophy, as evidenced by the lack of displacement of the endothelium (see #1 , FIGURE 9B) from the internal elastic lamina (see #2, FIGURE 9B).
  • this inhibitory effect on intimal smooth muscle cells was accomplished without inhibiting hypertrophy of medial smooth muscle cells in the areas where the external elastic membrane was ruptured (see #4, FIGURE 9B).
  • FIGURE 9B therapeutic conjugate administered at the site following angioplasty resulted in approximately 95% inhibition of the smooth muscle hypertrophy that restricted the lumen of the untreated vessel
  • FIG. 9A Significantly, the therapeutic conjugate exerted its effects on the smooth muscle cells migrating from the medial smooth muscle layers into the intima, without affecting either endothelium, or producing any signs of necrosis (i.e., cell death) in the smooth muscle cells in the medial layers of the arterial wall. Studies also failed to show any histological signs of
  • H-leucine uptake Vascular smooth muscle cells at 40,000 cells/ml were seeded in sterile 24 well plates at 1 ml/well. The plates were incubated overnight at 37°C, 5% CO 2 , 95% air in a humidified atmosphere (saturation). Log dilutions of the therapeutic agent of interest were incubated with the vascular smooth muscle cells for 5 minutes or 24 hours. Samples of the therapeutic agents were diluted in DMEM :F- 12 medium (Whittaker Bioproducts, Walkersville, Maryland) with 5% fetal bovine serum (FBS, Gibco BRL, Gaithersburg, MD) and 5% Serum Plus® (JRH Biosciences, Lenexa, KS).
  • micrograms/ml transferrin (5 micrograms/ml) and sodium selenite (5 nanograms/ml), available from Sigma Chemical, St. Louis, Missouri) was added. Cells were incubated in this medium for 24 hours. For a 5 minute therapeutic agent exposure, log dilutions of the therapeutic agent were incubated with the cells in complete medium. After 5 minutes and medium aspiration, 1 ml/well of 1.0 microcurie/ml 3 H-thymidine dispersed in complete medium was added. The 24 hour exposure involved incubation of the cells with 1 ml/well of 1.0 microcurie/ml of 3 H-thymidine dispersed in complete medium and log dilutions of the therapeutic agent being tested.
  • Vascular smooth muscle cells were seeded at 4.0 ⁇ 10 4 cells/ml medium/well on a commercially prepared four well slide (Nunc. Inc., Naperville. Illinois).
  • the therapeutic agent medium was aspirated from each well, including the untreated well.
  • One milliliter of fresh medium was then added to replace the aspirated medium.
  • Re-incubation followed until each of the incremented evaluation points were achieved.
  • the medium was aspirated and subsequently replaced with 1 ml of 10% neutral buffered formalin for one hour to allow for proper fixation.
  • These fixed slides were stained by hematoxylin (nuclear) and cosin (cytoplasmic) for morphologic evaluation and grading.
  • results of the 24 hour 3 H-leucine protein inhibition assay and the 24 hour 3 H-thymidine DNA synthesis inhibition assay are shown in Figs. 10A-10D for suramin, staurosporin. nitroglycerin and cytochalasin B. respectively. All of the tested compounds showed an available therapeutic range (area under the curve of 3 H-leucine assay is greater than that resulting from the 3 H-thymidine assay), indicating usefulness in the practice of sustained release dosage form embodiments of the present invention. More specifically, the compounds inhibited the ability of vascular smooth muscle cells to undergo DNA synthesis in the presence of 5% FBS to a greater extent than they inhibited protein synthesis of vascular smooth muscle cells.
  • the protein and DNA synthesis inhibitory effects of suramin, staurosporin, nitroglycerin and cytochalasin B during a 5 minute and 24 hour pulsed exposure are shown in Figure 10 A-D, respectively.
  • vascular smooth muscle cells The ability of vascular smooth muscle cells to bind and internalize particles coated with binding protein or peptide was demonstrated with monoclonal antibody (NR-AN-01 ) coated gold beads both in vitro and in vivo.
  • the cells were exposed to the beads as monolayer and cell suspension cultures, and were examined at six time points (i.e.. 1 minute, 5 minutes, 15 minutes, 30 minutes. 60 minutes and 24 hours) for binding and internalization by electron microscopy.
  • Table 3 shows the results of the experimentation, indicating that the binding to the cell surface is specific.
  • NR-AN-01 internalized by macro and micro phagocytosis. When the cells were maintained in a cell suspension, non-specific internalization was minimal or absent. Non-specific adherence of gold beads devoid of NR-AN-01 to surface mucin produced by HT29 cells was observed, resulting in modest non-specific internalization thereof. Vascular smooth muscle cell uptake of NR-AN-01 targeted gold beads was highly specific in cell suspension cultures.
  • FIGURE 1 1 shows a tangential section parallel to the inner surface of a smooth muscle cell characterized by numerous endocytic vesicles, several of which contain antibody coated gold beads in the process of being internalized by the cell. These endocytic vesicles with particles attached to cell surface antigens were stimulated to fuse with lysosomes at a higher than expected rate for normal cell surface membrane recycling. The resultant marked
  • NR-AN-01 coated gold beads were infused via intravascular catheter, open ended with treated area occluded proximally and distally with slip ligatures, at 3 atm pressure applied for 3 minutes into the wall of a pig femoral artery
  • FIGURE 13 shows particulate concentration in the lysosomes in vivo at one week following bead
  • Vascular smooth muscle cells at 40.000-50,000 cells/ml were seeded and processed as described in Example 8. "5 minute exposure; 3 H-leucine uptake.”
  • Log dilutions of staurosporin 200 ng/ml, 20 ng/ml, 2 ng/ml, 0.2 ng/ml and 0.02 ng/ml
  • cytochalasin B log dilutions at 20 ⁇ g/ml, 2.0 ⁇ g/ml, 0.2 ⁇ g/ml, 0.02 ⁇ g/ml and 0.002 ⁇ g/ml were dispersed in complete medium. Complete medium was then added to the control wells.
  • Protein Synthesis Assay vascular smooth muscle (BO54) cells at 20,000 cells/ml were seeded in sterile 24 well plates and incubated in complete medium (1 ml/well) overnight at 37°C, 5% CO 2 , 95% air in a humidified atmosphere (saturation). Log dilutions of staurosporin (100 ng/ml, 10 ng/ml, 1 ng/ml, 0.1 ng/ml and 0.01 ng/ml) were dispersed sequentially in the two media, as described below.
  • cytochalasin B log dilutions at 10 ⁇ g/ml, 1.0 ⁇ g/ml, 0.1 ⁇ g/ml, 0.01 ⁇ g/ml and 0.001 ⁇ g/ml were dispersed sequentially in the two media, as described below:
  • each therapeutic agent was diluted in Medium (2), as noted above.
  • Medium (1) was aspirated from the wells, and aliquots of therapeutic agent dilutions in Medium (2) were added in
  • each therapeutic agent was diluted in Medium (1), as noted above.
  • Medium (1) was aspirated from the wells, and aliquots of therapeutic agent dilutions in Medium (1 ) were added in quadruplicate to the appropriate wells.
  • Medium (1 ) was then added to the control wells. The medium was changed every 24 hours, and fresh therapeutic agent was added to the test wells.
  • each therapeutic agent was diluted in Medium (2), as noted above.
  • Medium (1 ) was aspirated from the wells, and aliquots of therapeutic agent dilutions in Medium (2) were added in quadruplicate to the appropriate wells.
  • Medium (2) was then added to the control wells.
  • test agents in 3 H-leucine were incubated overnight at 37°C, 5% CO 2 in a humidified atmosphere.
  • the toxic effect of the therapeutic agents was then determined, as described in the 5 Minute
  • the minimum effective dose (MED) of each agent was determined as a percentage of the control that was treated with medium only; 50% of control values was chosen as the cytotoxicity benchmark.
  • MED minimum effective dose
  • staurosporin demonstrated an MED of 100 ng/ml in the protein synthesis assay and 1 ng/ml in the DNA assay.
  • the 24 hour MED for staurosporin was 10 ng/ml in the protein synthesis assay and 1 ng/ml in the DNA synthesis assay. Both assays gave an MED of 1 ng/ml for a 120 hour exposure of staurosporin.
  • cytochalasin B demonstrated an MED of 10 ⁇ g/ml in the protein synthesis assay as well as in the DNA assay.
  • the 24 hour MED for cytochalasin B was 1.0 ⁇ g/ml in the protein synthesis assay and 0.1 ⁇ g/ml in the DNA synthesis assay. Both assays gave an MED of approximately 0.1 ⁇ g/ml for a 120 hour exposure of staurosporin.
  • Cytochalasin C and cytochalasin D therapeutic agents were tested at 24 and 48 hour exposures using the same dilutions as described for cytochalasin B, above.
  • cytochalasin C demonstrated an MED of 1.0 ⁇ g/ml in the protein synthesis assay and an MED of 0.01 ⁇ g/ml in the DNA synthesis assay.
  • cytochalasin C demonstrated an MED of 0.1 ⁇ g/ml in the protein synthesis assay and 0.01 ⁇ g/ml in the DNA synthesis assay.
  • Cytochalasin D demonstrated an MED of 1.0 ⁇ g/ml in the 24 hour protein synthesis assay and an MED of 0.1 ⁇ g/ml in the 24 hr DNA synthesis assay.
  • a 48 hour exposure to cytochalasin D gave an MED ranging between 0.1 and 0.01 ⁇ g/ml in both the protein synthesis and DNA synthesis assays.
  • Vascular smooth muscle cells were derived from explants of baboon aortic smooth muscle, as described in Example 10. The cells were grown in flat bottom, six well tissue culture plates, which hold about 5 ml of medium. The vascular smooth muscle cells were plated at 200,000 cells/well and placed at 37°C in a humidified 5% CO 2 incubator for 18 hours. The wells were then scratched with a sterile portion of a single edge razor blade that was held by clamp or pliers and was brought aseptically into contact with the bottom of the well at a 90° angle. The cells from a small area along the scratch were removed by a sterile cotton tipped applicator while the blade was in contact with the bottom of the well. After incubation, the presence of cells in the "scratched" area is indicative of cell migration across the scratch line. A control incubation showed significant cellular migration, and serves as the standard against which the migration of cells exposed to the therapeutic agent is compared.
  • cytochalasin B Sigma Chemical Co.
  • DMSO dimethyl sulfoxide
  • a set Test agent exposure for 1 , 3, 6, 8 and 10 days only; and B set: Test agent exposure for 1, 3, 6, 8 and 10 days, followed by a seven day recovery time with control medium.
  • Both sets of plates were fixed (10% formalin in PBS) and stained (0.02% crystal violet) at the end of the timed exposures.
  • Test concentrations for cytochalasin B were 1, 0.1 and 0.01 ⁇ g/ml, and a negative medium control was included. Fresh medium and drug were supplied 3 times per week.
  • Table 4 shows the results of these experiments.
  • the migration results are expressed as "Grade in the Cleared Area of the Well / Grade in an Undisturbed Region of the Well.”
  • the toxicity values represent a grade for all cells in each well.
  • BRDU assay In vivo vascular smooth muscle proliferation was quantitated by measuring incorporation of the base analog 5-bromo-2'-deoxyuridine (BRDU. available from Sigma Chemical Co.) into DNA during cellular DNA synthesis and proliferation. BRDU incorporation was demonstrated histochemically using commercially available anti-BRDU monoclonal antibodies. The 1 hour pulse labeling permits assessment of the number of cells undergoing division during the pulse period.
  • BRDU base analog 5-bromo-2'-deoxyuridine
  • BRDU was then administered intravenously via the lateral ear vein.
  • Two ml of BRDU at a concentration of 50 mg/ml was administered to each 30-40 lb pig.
  • Test artery segments were then removed (a segment included normal vessel located proximally and, if possible, distally with respect to the treated artery segment).
  • the artery segments were transected at 2 mm intervals; arranged in order in cryomolds with O.C.T.
  • BRDU-labeled cell detection After BRDU (1 g BRDU diluted in 17 ml sterile water and 3 ml 1 N NaOH) pulse labeling and test artery segment removal and sectioning (as above), immunohistochemical staining with anti-BRDU monoclonal antibody provides a visual means of determining a mitotic index over a specified time period.
  • the immunohistochemical staining method was performed as follows:
  • test artery 5 ⁇ m sections of test artery were dehydrated in cold acetone (- 20°C) for 10 minutes;
  • Sections were mounted on glass microscope slides, and the slides were dried in a 37°C oven for 10 minutes;
  • Balloon traumatized pig arteries that had been treated with cytochalasin B displayed a larger luminal area at the 4 day and 3 week post-treatment time points, as compared to arteries treated with other test agents or controls.
  • Ten femoral arteries two arteries obtained from each of the 5 pigs that were treated according to the single dose protocol described in Example 7) were evaluated histologically. The maximal luminal area of each artery was measured and calculated from digitized microscopic images by a BQ System IV computerized morphometric analysis system (R & M Biometrics, Inc., Nashville, TN).
  • the luminal area of the traumatized and cytochalasin B-treated segments of the arteries were also compared to the luminal area of the normal, untreated region of the femoral artery proximal to the test area.
  • the results showed that the lumen area in the test region was approximately two times as large as the area of the normal control segment of the same artery.
  • the negative control agents, PBS and monoclonal antibody NR-AN-01 showed no increase or a slight decrease in lumen area as compared to the normal control segment of the same artery.
  • cytochalasin B dose response study was then conducted on 10 pigs, following the experimental protocol described in Example 7. Briefly, both arteries in each of 2 pigs were treated with one of the following doses of cytochalasin B: 0.0 ⁇ g/ml (i.e., PBS negative control); 0.01 ⁇ g/ml; 0.10 ⁇ g/ml; 1.0 ⁇ g/ml; and 10.0 ⁇ g/ml.
  • the agent was delivered by intraluminal catheter at 1 atm pressure for 3 min. and the arteries were evaluated 3 weeks later by the morphometric analysis system described above. The ratio of treated artery luminal area to proximal normal artery luminal area was determined as a percent change in treated vs. normal area.
  • Antibody-coated latex particles (a model of an antibody- coated, sustained release dosage form) may be obtained using the following aseptic technique:
  • Sizing Particle size homogeneity is assessed by laser anisotropy or, for particles larger than 1 ⁇ m, by microscopic examination.
  • Specific Binding Assessment Specific binding to smooth muscle cells is determined by histological examination of tissue or cell pellet microtome slices after incubation of protein/peptide conjugates with conjugated particles, with or without blocker protein/peptide included in the incubation mixture.
  • Preferred detection techniques include second antibody assays (i.e., anti-mouse Ig) or competition assays (i.e., radioscintigraphic detection in conjunction with radioisotopically labeled protein/peptide conjugates).

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PCT/US1996/002125 1992-09-25 1996-02-15 Therapeutic inhibitor of vascular smooth muscle cells WO1996025176A1 (en)

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AT96906490T ATE265233T1 (de) 1995-02-15 1996-02-15 Therapeutische inhibitoren der zellen der glatten gefässmuskulatur
AU49851/96A AU4985196A (en) 1995-02-15 1996-02-15 Therapeutic inhibitor of vascular smooth muscle cells
CA002212537A CA2212537C (en) 1995-02-15 1996-02-15 Therapeutic inhibitor of vascular smooth muscle cells
JP8525163A JPH11500635A (ja) 1995-02-15 1996-02-15 血管平滑筋細胞の治療インヒビター
EP96906490A EP0809515B1 (en) 1995-02-15 1996-02-15 Therapeutic inhibitor of vascular smooth muscle cells
DE69632310T DE69632310T2 (de) 1995-02-15 1996-02-15 Therapeutische inhibitoren der zellen der glatten gefässmuskulatur
US08/829,685 US5981568A (en) 1993-01-28 1997-03-31 Therapeutic inhibitor of vascular smooth muscle cells
US08/829,991 US6306421B1 (en) 1992-09-25 1997-03-31 Therapeutic inhibitor of vascular smooth muscle cells
US09/361,194 US6358989B1 (en) 1993-05-13 1999-07-26 Therapeutic inhibitor of vascular smooth muscle cells
US09/896,208 US6491938B2 (en) 1993-05-13 2001-06-29 Therapeutic inhibitor of vascular smooth muscle cells
US09/995,490 US6569441B2 (en) 1993-01-28 2001-11-27 Therapeutic inhibitor of vascular smooth muscle cells
US10/024,885 US6663881B2 (en) 1993-01-28 2001-12-18 Therapeutic inhibitor of vascular smooth muscle cells
US11/650,059 US8158670B2 (en) 1995-02-15 2007-01-04 Therapeutic inhibitor of vascular smooth muscle cells
US13/446,760 US20120195951A1 (en) 1995-02-15 2012-04-13 Therapeutic Inhibitor of Vascular Smooth Muscle Cells

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US20120195951A1 (en) 2012-08-02
US8097642B2 (en) 2012-01-17
US20070148207A1 (en) 2007-06-28
JP2007075623A (ja) 2007-03-29
ATE265233T1 (de) 2004-05-15
EP1669091A2 (en) 2006-06-14
US6599928B2 (en) 2003-07-29
US20020040064A1 (en) 2002-04-04
EP0809515B1 (en) 2004-04-28
US8158670B2 (en) 2012-04-17
DE69635968T2 (de) 2007-01-25
ES2217306T3 (es) 2004-11-01
JPH11500635A (ja) 1999-01-19
DE69632310D1 (de) 2004-06-03
US20110300221A1 (en) 2011-12-08
AU4985196A (en) 1996-09-04
US6171609B1 (en) 2001-01-09
ATE321573T1 (de) 2006-04-15
US20070134314A1 (en) 2007-06-14
CA2212537A1 (en) 1996-08-22
DE69635968D1 (de) 2006-05-18
EP1407786B1 (en) 2006-03-29
EP0809515A1 (en) 1997-12-03
EP1669091A3 (en) 2009-06-17
US6515009B1 (en) 2003-02-04
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CA2212537C (en) 2006-12-19

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