WO1991004745A1 - Compositions pour inhiber l'adherence cellulaire et methodes d'utilisation - Google Patents

Compositions pour inhiber l'adherence cellulaire et methodes d'utilisation Download PDF

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Publication number
WO1991004745A1
WO1991004745A1 PCT/US1990/005105 US9005105W WO9104745A1 WO 1991004745 A1 WO1991004745 A1 WO 1991004745A1 US 9005105 W US9005105 W US 9005105W WO 9104745 A1 WO9104745 A1 WO 9104745A1
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WIPO (PCT)
Prior art keywords
amino acid
acid sequence
cadherin
cell
cell adhesion
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PCT/US1990/005105
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English (en)
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Lee L. Rubin
Chen W. Liaw
Kevin J. Tomaselli
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Athena Neurosciences, Inc.
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Application filed by Athena Neurosciences, Inc. filed Critical Athena Neurosciences, Inc.
Publication of WO1991004745A1 publication Critical patent/WO1991004745A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to compositions that transiently and reversibly dissociate the blood-brain barrier. More particularly, the invention relates to compositions that dissociate tight junctions between brain capillary endothelial cells that constitute the physiological barrier between the general circulation and the brain.
  • CNS central nervous system
  • the brain and spinal cord The entry of drugs from the blood stream to the central nervous system (CNS), i.e., the brain and spinal cord, is restricted by the presence of high resistance tight junctions between brain capillary cells and by the apparently low rate of transport across these endothelial cells (Betz, A.L., et al., Ann. Rev. Physiol., 48:241 (1986); Pardridge, W.M., Ann. Rev. Pharmacol. Toxicol., 28:25 (1988)).
  • the tight junctions of the blood brain barrier prevent diffusion of molecules and ions around the brain capillary endothelial cells.
  • the only substances that can readily pass from the luminal core of the capillary to the abluminal tissues that surround the capillary are those molecules for which selective transport systems exist in the endothelial cells, as well as those compounds that are lipophilic (i.e., hydrophobic).
  • drugs, peptides and other molecules that are neither lipophilic nor transported by specific carrier proteins are barred from entry into the brain, or their rates of entry are too low to be useful, thereby imposing a severe limitation upon the physician's ability to treat CNS disorders
  • the carrier-mediated transcellular transport system mentioned above may have limited usefulness for therapeutic modalities under some circumstances.
  • Transcytotic transport in general, involves, first, the binding of molecules to specific carrier proteins on the surface of endothelial cells, and, second, the delivery of such molecules across the endothelial cells.
  • Limitations on the usefulness of such a system for treatment of CNS disorders are based on the
  • physiological carrier proteins may not function efficiently, or at all, with non-physiological drugs; (2) even where function occurs, the rate of transport of therapeutic agents will be limited by the rate of transport of the
  • macromolecules may be simply too low to achieve
  • concentrated sugar solutions may not be innocuous, and might be expected to have undesirable side effects.
  • chemical agents may not be useful for the treatment of chronic neurological disease, their effects on tight junctions are not always reversible, and, as they all are
  • 7-fluorouracil is a powerful inhibitor of pyrimidine synthesis, and thus nucleic acid biosynthesis, in animals cells.
  • junctions of the BBB in order that administered drugs can reach the brain from the general circulation, and which have no undesirable side effects of their own in the subject.
  • CAM cell adhesion molecules
  • cadherin is the term applied to a family of glycoproteins found in most kinds of mammalian tissues and thought to be responsible for Ca 2+ - dependent cell-cell adhesion, (Takeichi, M.,
  • E-cadherin from epithelial tissues
  • P-cadherin from placental tissues
  • N-cadherin from neural tissues
  • the different cadherins exhibit distinct tissue distribution patterns (Takeichi, U., (1988) above). E-cadherin, which was found to be distributed
  • N-cadherin which is expressed in various neural tissues including astrocytes (Hatta, K., et al., Devel. Biol., 120:215 (1987); Matsunega, M., et al., Nature. 334:62 (1988); Tomaselli, K.J., Neuron, 1:33 (1988)), shows 92% amino acid sequence homology between
  • Placental P-cadherin has also been cloned, and the deduced amino acid sequence of this glycoprotein was found to exhibit about 58% homology with epithelial E-cadherin (Nose, A., et al., EMBO J., 12:3655 (1987)).
  • CAMs independent of Ca 2+ are also known, for example, the 125K glycoprotein of Urushihara et al. (Urushihara, H., et al., Cell, 20:363 (1980)); N-CAM (Rutishauser, U., Nature. Lond., 310:549 (1984));
  • Ng-CAM (Grunet, M. et al., Proc. Nat'l. Acad. Sci.
  • PECAM-1 CD 31
  • Ca 2+ -independent CAMs are known to exhibit certain properties of the Ca 2+ -dependent CAMs.
  • N-CAM and N-cadherin both promote retinal neurite outgrowth on astrocytes (Neugebauer, K.M., et al., J. Cell Biol., 107:1177 (1985)), and on Schwann cells (Bixby, J.L. et al., J. Cell Biol., 107:353 (1988)).
  • Monoclonal antibodies raised against epithelial E-type cadherins such as uvomorulin are known to disrupt the adhesion of several cell types, including embryo cells, cultured teratocarcinoma cells,
  • cadherins had not been found in brain capillary or other endothelial cells (see, Takeichi, et al. (1988), above). Further, the CAMs of microvascular endothelial cells had not yet been identified, nor had such molecules been localized specifically to brain capillary endothelial cells.
  • junctions between microvascular endothelial cells including those of the BBB, based upon an attack upon the CAM'S of such cells that are responsible for tight junction formation and maintenance.
  • CAR cell adhesion recognition
  • RGD which is found in laminin, fribronectin and other basement membrane components that are
  • cadherin cell adhesion molecules homologous to, and immunologically related to, cadherin cell adhesion molecules are present on brain and non- brain microvascular endothelial cells, such that
  • junctions between such endothelial cells can be reversibly opened so as to permit passage of
  • therapeutic drugs by the use of polypeptide and antibody compositions that compete with such cell adhesion molecules for binding to such cells.
  • Another object of this invention is to provide DNA sequences of genes, and plasmids containing same, coding for the expression of all or a cell-binding portion of microvascular endothelial cell adhesion molecules.
  • Yet another object of this invention is to provide means to identify those sequences of cell adhesion molecules responsible for the tight binding of
  • a further object is to provide therapeutic
  • compositions comprising polypeptides derived from cell adhesion molecules that reversibly disrupt cell-cell adhesion.
  • Still another object of this invention is to provide therapeutic compositions comprising polyclonal or monoclonal antibodies or fragments thereof directed against endothelial cell adhesion molecules, or against polypeptides representing cell binding regions thereof, that reversibly disrupt endothelial cell-cell adhesion.
  • Yet another object of this invention is to provide therapeutic formulations comprising therapeutic drugs conjugated with blood-brain barrier-disrupting
  • compositions of this invention that are capable of entering the central nervous system following
  • Figure 1 illustrates the partial cDNA sequence for bovine endothelial cell adhesion molecule homologous to chicken N-cadherin.
  • Figure 2 illustrates the partial cDNA sequence for bovine endothelial cell adhesion molecule homologous to mouse P-cadherin.
  • Figure 3 illustrates the cDNA sequence for the MDCK cell adhesion molecule homologous to mouse
  • Figure 4 illustrates the restriction sites in the bovine endothelial cell N- (4-1 to 4-5) and P-cadherin (4-6 to 4-8) cDNA sequences and in the MDCK E-cadherin (4-9 to 4-14) cDNA sequence.
  • Figure 5 shows the staining of a mouse brain thin section by an antibody raised against a fusion protein derived from amino acids 9-96 of MDCK E-cadherin containing an HAV region.
  • Figure 6 is a repeat of the experiment of Fig. 5, except that the antibody was raised against the entire E-cadherin molecule.
  • Figure 7 illustrates the effects of an 18-mer HAV- containing polypeptide on the resistance of tight junction monolayers of MDCK epithelial cells.
  • Figure 8 illustrates the effects of 11-mer and 18-mer HAV-containing polypeptides on the resistance of tight junction monolayers MDCK epithelial cells.
  • Figure 9 illustrates the effects of 11-mer and 18- mer HAV-containing polypeptides on the resistance of tight-junction monolayers of brain microvascular endothelial cells.
  • a polypeptide composition comprising cell binding domains of endothelial cell adhesion molecules may compete against such molecules for binding to such cells, such that by this means the junctions between such cells could be reversibly opened, thereby permitting penetration by therapeutic agents.
  • the present invention also discloses that polyclonal or monoclonal antibodies (or fragments thereof) raised against endothelial cell adhesion molecules or cell-binding domains thereof may also compete for endothelial cell surface binding sites, and, by this means, reversibly disrupt junctions between endothelial cells, thereby permitting entry into the central nervous system of therapeutic agents.
  • the endothelial cell cadherins disclosed herein exhibit one or more of several characteristics of E-, P- and N- cadherins, including: characteristics of a transmembrane integral protein, with cytoplasmic, hydrophobic plasma membrane, and extracellular regions; intraspecies DNA sequence homologies of greater than about 50% for the entire molecule; immunological cross- reactivity with antibodies raised against non- endothelial cell cadherins; and containing cell-binding domains. "Immunologically related to" means that these cadherin-like molecules cross-react with antibodies raised against non-endothelial cell cadherins.
  • E-cadherin-like molecules were localized in brain by immunofluorescence. Cryostat sections of mouse brain were labeled with a rabbit antibody prepared against E-cadherin, and then with fluorescein
  • microvascular endothelial cell (BMEC) cadherins were cloned and sequenced as described below, and the partial sequence of N-cadherin and P-cadherin are disclosed herein in Figures 1 and 2, respectively.
  • MDCK dog kidney epithelial cells are known to employ E-cadherin to form high resistance tight junctions, and as the present invention discloses that brain capillary endothelial cell adhesion molecules include E-type cadherin, the DNA of this cadherin was also cloned; its complete DNA sequence is disclosed herein (Fig. 3).
  • N-, P- and E-cadherin-type clones described herein were deposited in the American Type Culture Collection on September 26, 1989, and were assigned the following accession numbers:
  • transmembrane glycoproteins the cytoplasmic domains of which are highly conserved, that is, are highly homologous.
  • 42-amino acid coding region in the cytoplasmic domain were selected to serve as primers for polymerase chain reaction (PCR) using either BMEC cDNA or MDCK cDNA as templates.
  • PCR polymerase chain reaction
  • BMEC cadherins are of two types - one homologous to chicken N-cadherin (neuronal type, see, e.g., Hatta, K., et al., J. Cell Biol., 106:873 (1988)) and the other homologous to mouse
  • P-cadherin placental type, see e.g., Nose, A., et al., (1987) above. It has also been found that there are two species of cadherins in MDCK cells - one homologous to mouse E-cadherin (see, e.g., Nagafuchi, A., et al., Nature, 329:341 (1987)) and the other homologous to mouse P-cadherin (Nose, et al. (1987), above).
  • PCR products were then used as probes to isolate the BMEC and MDCK cadherin cDNA clones as follows.
  • a cDNA library was constructed essentially according to Gubler et al . (Gubler, U. et al., Gene, 25:263 (1983), which is incorporated herein by
  • the partial restriction maps for each cDNA clone based on their sequences are shown in Fig. 4. Some of these restriction sites were confirmed by restriction enzyme digestions, including Hind III, Pst I, Kpn I, Bgl II for N-cadherin; Pvu II, Sac I and Pst I for P-cadherin; Pst I, Pvu II, BamH I, and Sac I for
  • E-cadherin cDNA contains all the information necessary for cadherin function
  • full-length E-cadherin cDNA joined to a suitable promoter may be introduced into mouse L-cells that have very little endogenous cadherin activity (Nagafuchi, et al. (1987), supra).
  • transfected L-cells may be tested for Ca 2+ -dependent aggregating activity. The extent of this aggregating activity should be closely correlated with the amount of E-cadherin expressed (Takeichi, M. (1988), supra).
  • L-cells may be first transfected as above with a cDNA of a size sufficient to cause Ca 2+ -mediated aggregation of transfectants.
  • a series of deletion mutants comprising truncated cDNA species missing different regions of the extracellular domain may be prepared by restriction enzyme digestion and proper end filling or exonuclease digestion to make the deletions in the proper coding frames. These deletion mutants can then be tested for their ability to express in L-cells a protein causing Ca 2+ -dependent aggregation. By correlating a loss of aggregation with deletion of particular fragments, the regions important for cell binding may be determined.
  • polypeptides corresponding to binding regions of cadherins may be synthesized chemically using an automated peptide synthesizer such as that of Applied Biosystems, Inc., Foster City, CA, or expressed by recombinant DNA methods.
  • Effective polypeptides may be of varying lengths, depending upon the natures of junctions being disrupted and the cell adhesion
  • sequences of cadherins may be analyzed to detect homologous regions.
  • this technique to bovine endothelial cell N- and P-cadherins and to epithelial cell E-cadherin, we have determined that, in the amino acid 80 region of each of these cadherins, there is conserved a triplet HAV (His-Ala-Val) region.
  • HAV His-Ala-Val
  • this HAV region may be a common cell adhesions recognition (CAR) sequence.
  • Polyclonal antibodies raised in rabbits and monoclonal antibodies derived from hybridomas may be generated against each of the chemically-synthesized polypeptides by standard methods. (Harlow, E., et al.,
  • recombinant antibodies may be prepared. Fragments of antibodies, e.g., Fc, Fab, F(ab)', may be prepared by standard methods.
  • CAM-derived polypeptides containing cell-binding domains, and the corresponding polyclonal and monoclonal antibodies, of the invention to disrupt tight junctions may be tested in in vitro and in vivo models of high resistance tight junctions and in animal models.
  • Monolayers of MDCK dog kidney epithelial cells, that are known to contain high resistance tight junctions (Gumbiner, B., J. Cell Biol., 102:457
  • Polyclonal antibodies prepared as described above may also be used in conjunction with Western blotting (Old, R.W., et al., Principles of Gene Manipulation, 3d ed., Blackwell, Oxford, 1985, p. 10) and a variety of tissue extracts in order to identify cell adhesion glycoproteins in such extracts.
  • Another embodiment of the present invention is in drug delivery systems.
  • Conjugates between therapeutic drugs and agents that affect cell adhesion molecule function in brain capillary endothelial cells may be used to deliver therapeutic drugs to the CNS.
  • a polypeptide derived from a cell adhesion molecule that contains within its amino acid sequence a cell-binding domain, or antibodies thereto may be conjugated in biologically-active form to a therapeutic modality.
  • Such conjugates may have the dual effect of opening the BBB and delivering the therapeutic agent to the brain side of the BBB. Delivery of therapeutic drugs to the CNS, either alone or conjugated to agents that disrupt cell-cell adhesion, may be accomplished by administering such drugs to a subject either
  • modalities that may be delivered to the brain by the cell adhesion disruption compositions of this invention include Nerve Growth Factor, anti-Parkinsonian drugs, and brain enzymes known to be missing in
  • sphingolipidoses e.g., Tay-Sachs disease.
  • the integrity of the therapeutic agent is not compromised and such that the therapeutic agent is readily cleaved from the carrier by enzymes present on or within endothelial cells (e.g., amidases, esterases,
  • disulfide-cleaving enzymes are well known in the art. It is also apparent that these therapeutic conjugates may be delivered to endothelial cells in encapsulated form (e.g., in liposomes) or as microsuspensions stabilized by pharmacological excipients.
  • compositions that disrupt the junctions between the two tumors develop internal barriers, including high pressure zones and collapsed blood vessels, that make it difficult for blood-borne chemotherapeutic agents to reach the tumor's inner core.
  • the barrier problem is particularly troublesome with therapeutic products drawn from the human immune system, such as monoclonal antibodies conjugated with chemotherapeutic agents, interleukin-2, interferon and activated killer T-lymphocytes, because of their large size.
  • endothelial cells particularly the relatively small peptides that contain one or more cell-binding regions of cell adhesion macromolecules, may be used to enhance drug delivery to tumors with depressed blood flow.
  • compositions of this invention may also be used to provide penetration for chemotherapeutic agents of other well-known blood- tissue barriers, such as blood-testis barriers and blood-retina barriers.
  • the latter barrier is known to prevent the efficient transport of, for example, administered antibiotics to the retina from the general circulation.
  • the cell adhesion disrupting compositions of this invention may, thus, be used in conjunction with the administration of antibiotics to treat retinal infections.
  • the polypeptide was added to the cells either from the apical side (top) or basolateral side (bottom), as shown in the following sketch.
  • BASOLATERAL Figure 7 illustrates the effects of various concentrations of the aforementioned 18-mer polypeptide on resistance of MDCK epithelial cells. At the lowest concentration tested, 0.5 mg/ml, resistance was
  • the polypeptide was more effective when added from the basolateral side, but at high concentrations was quite effective even when added from the apical side. These data indicate that the 18-mer is effective in making tight junctions permeable. The 20-mer was similarly effective, and a 17-mer less effective.
  • Figure 9 illustrates the effect of 1 mg/ml of the 11-mer and 18-mer on high resistance monolayer cultures of brain endothelial cells (see copending United States Serial No. 07/413,332 for method of preparation).
  • the 11-mer (and the 6-mer) failed to reduce resistance values over a 48-hour period of observation.
  • the 18-mer (as well as the 20-mer) decreased resistance values markedly when added from either the basolateral or apical side, but the effect of the polypeptide was more rapid and more pronounced when it was added from the basolateral side; the 17-mer was less effective.

Abstract

Sont présentées des compositions destinées à briser les jonctions étroites de cellules épithéliales et endothéliales, ainsi que leurs méthodes d'utilisation. De telles compositions comprennent des agents qui inhibent la liaison à des cellules des molécules d'adhérence cellulaire. De tels agents d'inhibition comprennent des molécules d'adhérence cellulaire, des fragments de molécules d'ahdérence cellulaire qui enferment un domaine de liaison cellulaire, comme la HAV, et des anticorps s'opposant aux molécules d'adhérence cellulaire et aux fragments de ces dernières. Sont également présentées des compositions libérant un médicament comprenant un médicament thérapeutique associé à un agent empêchant les jonctions serrées de cellules.
PCT/US1990/005105 1989-09-27 1990-09-13 Compositions pour inhiber l'adherence cellulaire et methodes d'utilisation WO1991004745A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US41333289A 1989-09-27 1989-09-27
US413,332 1989-09-27
US57126790A 1990-08-23 1990-08-23
US571,267 1995-12-12

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EP (1) EP0494175A4 (fr)
JP (1) JPH05500504A (fr)
CA (1) CA2067183A1 (fr)
WO (1) WO1991004745A1 (fr)

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EP0493444A1 (fr) * 1989-09-27 1992-07-08 Athena Neurosciences, Inc. Modele de barriere hemato-encephalique
WO1994011401A1 (fr) * 1992-11-17 1994-05-26 Yale University Homologue humain du gene de la cadherine e et procedes d'utilisation
WO1994014960A2 (fr) * 1992-12-29 1994-07-07 Doheny Eye Institute Protocaherines, leurs anticorps et emplois
US5340800A (en) * 1990-08-27 1994-08-23 Liu David Y Peptide medicaments for the treatment of disease
WO1995013820A1 (fr) * 1993-11-19 1995-05-26 Eisai Co., Ltd. Utilisation d'un agent modulateur de la phosphorylation par la tyrosine, afin de moduler la permeabilite d'une barriere physiologique
US5597725A (en) * 1992-04-17 1997-01-28 Doheny Eye Institute Cadherin-specific antibodies and hybridoma cell lines
US5639634A (en) * 1992-04-17 1997-06-17 Doheny Eye Institute Cadherin polynucleotides
US5646250A (en) * 1992-04-17 1997-07-08 Doheny Eye Institute Cadherin polypeptides
US5708143A (en) * 1992-12-29 1998-01-13 Doheny Eye Institute Protocadherin materials and methods
WO1998002452A2 (fr) * 1996-07-12 1998-01-22 Mcgill University Composes et procedes pour la modulation de l'adherence cellulaire
WO1998045319A2 (fr) * 1997-04-10 1998-10-15 Mcgill University COMPOSES ET PROCEDES PERMETTANT D'INHIBER L'INTERACTION ENTRE L'α-CATENINE ET LA β-CATENINE
US5827819A (en) * 1990-11-01 1998-10-27 Oregon Health Sciences University Covalent polar lipid conjugates with neurologically active compounds for targeting
WO1999016791A2 (fr) * 1997-09-29 1999-04-08 Adherex Inc. Composes et procedes de regulation d'adherence cellulaire
WO1999033875A1 (fr) * 1997-12-23 1999-07-08 Mcgill University Composes et procedes servant a moduler la stabilite synaptique
WO1999057149A2 (fr) * 1998-05-05 1999-11-11 Adherex Technologies, Inc. Composes et procedes servant a moduler des fonctions etablies par l'intermediaire de cadherine non classique
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US6033665A (en) * 1989-09-27 2000-03-07 Elan Pharmaceuticals, Inc. Compositions and methods for modulating leukocyte adhesion to brain endothelial cells
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US6358920B1 (en) 1998-05-05 2002-03-19 Adherex Technologies Compounds and methods for modulating nonclassical cadherin-mediated functions
US6417325B1 (en) 1996-07-12 2002-07-09 Mcgill University Compounds and methods for cancer therapy
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US6465007B1 (en) 1998-07-02 2002-10-15 Genzyme Corporation Transgene expression in polarized cells
US6562786B1 (en) 1996-07-12 2003-05-13 Mcgill University Compounds and methods for modulating apoptosis
US6593297B2 (en) 1998-05-05 2003-07-15 Adherex Technologies, Inc. Compounds and methods for inhibiting cancer metastasis
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WO2006088491A2 (fr) * 2004-06-29 2006-08-24 Massachusetts Institute Of Technology Procedes et compositions concernant la modulation de jonctions intercellulaires
US7122623B2 (en) 1996-07-12 2006-10-17 Adherex Technologies, Inc. Compounds and methods for modulating cell adhesion
US7268115B2 (en) 2000-01-24 2007-09-11 Adherex Technologies, Inc. Peptidomimetic modulators of cell adhesion
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EP0493444A1 (fr) * 1989-09-27 1992-07-08 Athena Neurosciences, Inc. Modele de barriere hemato-encephalique
US6033665A (en) * 1989-09-27 2000-03-07 Elan Pharmaceuticals, Inc. Compositions and methods for modulating leukocyte adhesion to brain endothelial cells
EP0493444A4 (en) * 1989-09-27 1994-11-09 Athena Neurosciences Inc Blood-brain barrier model
US5340800A (en) * 1990-08-27 1994-08-23 Liu David Y Peptide medicaments for the treatment of disease
US5827819A (en) * 1990-11-01 1998-10-27 Oregon Health Sciences University Covalent polar lipid conjugates with neurologically active compounds for targeting
US6339060B1 (en) 1990-11-01 2002-01-15 Oregon Health & Science University Conjugate of biologically active compound and polar lipid conjugated to a microparticle for biological targeting
US6436437B1 (en) 1990-11-01 2002-08-20 Oregon Health And Science University Covalent polar lipid conjugates with neurologically active compounds for targeting
US6858582B2 (en) 1990-11-01 2005-02-22 Oregon Health And Sciences University Composition containing porous microparticle impregnated with biologically-active compound for treatment of infection
US6024977A (en) * 1990-11-01 2000-02-15 Oregon Health Sciences University Covalent polar lipid conjugates with neurologically active compounds for targeting
EP2325203A2 (fr) 1992-04-17 2011-05-25 Doheny Eye Institute Eléments et procédés permettant la production de cadherines
US5597725A (en) * 1992-04-17 1997-01-28 Doheny Eye Institute Cadherin-specific antibodies and hybridoma cell lines
US5639634A (en) * 1992-04-17 1997-06-17 Doheny Eye Institute Cadherin polynucleotides
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