WO1995007717A1 - Procede pour inhiber la fixation de reticulocytes a l'endothelium par interference avec les interactions vla-4/vcam-1 - Google Patents

Procede pour inhiber la fixation de reticulocytes a l'endothelium par interference avec les interactions vla-4/vcam-1 Download PDF

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Publication number
WO1995007717A1
WO1995007717A1 PCT/US1994/010395 US9410395W WO9507717A1 WO 1995007717 A1 WO1995007717 A1 WO 1995007717A1 US 9410395 W US9410395 W US 9410395W WO 9507717 A1 WO9507717 A1 WO 9507717A1
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reticulocytes
vla
sickle
vcam
binding
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WO1995007717A9 (fr
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Robert A. Swerlick
James R. Eckman
Timothy M. Wick
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Emory University
Georgia Tech Research Institute
Georgia Tech Research Corp
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Emory University
Georgia Tech Research Institute
Georgia Tech Research Corp
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Priority to AU78352/94A priority Critical patent/AU7835294A/en
Priority to EP94929205A priority patent/EP0720486A1/fr
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Publication of WO1995007717A9 publication Critical patent/WO1995007717A9/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • 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
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/70542—CD106
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • C07K16/2842—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta1-subunit-containing molecules, e.g. CD29, CD49
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Definitions

  • the invention relates to the inhibition of interactions between reticulocytes and activated endothelial cells. More particularly, the invention relates to treating human diseases associated with abnormal reticulocyte-endothelium interactions, by inhibiting these
  • Sickle cell anemia is a disease that is associated with various debilitating complications, including hemolytic anemia, increased infection, ischemic organ damage and episodes of severe pain. Pauling et al. (Science 10:543 (1949)) and Ingram (Nature 180:326 (1957)) teach that this disease and its complications are manifestations of homozygosity for a single amino acid substitution of valine for glutamic acid in the B6 position of the globin chain. Various researchers (including Hahn and Gillespie, Arch. Intern. Med. 39:233 (1927);
  • the primary pathologic event may be formation of mechanically rigid "sickled" cells with deoxygenation.
  • the sickled cells which cannot normally traverse the microvasculature, occlude small and large blood vessels, causing ischemic organ damage and episodes of pain.
  • VLA-4 receptor may mediate binding to the inducible endothelial cell adhesion
  • the invention demonstrates the mechanism by which a subpopulation of SSRBC bind to activated endothelial cells, thereby leading to increase in transit time and resulting in vascular occlusion in sickle cell disease.
  • the invention further provides a method for inhibiting such binding, thus preventing such vascular occlusion and its resulting complications.
  • This method comprises the step of administering a blocking agent of VLA-4 antigens on the surface of reticulocytes that express VLA-4, including sickle reticulocytes.
  • anti-VLA-4 or anti-VCAM-1 antibodies which may optionally be single chain, humanized or chimeric, Fab, Fab', F(ab') 2 or F(v) fragments thereof, heavy or light chain monomers or dimers thereof, or intermixtures of the same, soluble fibronectin, or soluble VCAM-1, bifunctional VCAM-1/Ig fusion proteins or VCAM-1 peptides.
  • the invention satisfies these objects by providing a method for blocking the binding interactions between VLA-4 expressing reticulocytes, including sickle reticulocytes and activated endothelial cells by administering a blocking agent of VLA-4 antigen on the surface of reticulocytes.
  • the invention clearly demonstrates, for the first time, that administration of such blocking agents is sufficient to prevent binding between sickle reticulocytes and activated endothelial cells.
  • Figure 1 shows the results of assays for Bi integrin expression by cells in venous blood, as described in Example 1.
  • Figure 2 shows the results of assays for reticulocyte counts and ⁇ , integrin expression
  • Example 2 by cells in venous blood, as described in Example 2.
  • Figure 3 shows the results of assays for alpha and beta integrin chain by SSRBC, as described in Example 3.
  • Figure 4 shows the results of assays for ⁇ j or ⁇ 4 integrin and glycophorin A expression by venous blood cells, as described in Example 4.
  • Figure 5 shows the results of assays for binding of erythrocytes to TNF- ⁇ -stimulated endothelial cells, as described in Example 5.
  • Figure 6 shows anti-VLA-4 and anti-VCAM-1 antibody inhibition of binding of
  • Figure 7 shows the nucleotide sequences encoding the variable regions of the heavy and light chains of anti-VLA-4 murine monoclonal antibody HP 1/2.
  • Panel A is the nucleotide sequence encoding the variable heavy region, with the first nucleotide representing the beginning of the first codon.
  • Panel B is the nucleotide sequence encoding the variable light region, with the first nucleotide representing the beginning of the first codon.
  • Figure 8 shows the nucleotide sequences of V H and V ⁇ -encoding regions having CDR-encoding sequences from murine HP 1/2 transplanted therein.
  • Panel A shows the transplanted V H sequence.
  • Panel B shows the transplanted V ⁇ sequence.
  • Figure 9 shows the nucleotide sequences encoding the variable regions of the heavy and light chains of the humanized anti-VLA-4 antibody hHPl/2.
  • Panel A is the nucleotide sequence encoding the V H region.
  • Panel B is the nucleotide sequence encoding the V ⁇ region.
  • Figure 10 shows the expression of adhesion proteins on erythrocytes from an infant with necrotizing enterocolitis.
  • Figure 11 shows the expression of adhesion proteins on erythrocytes from an infant with no known risk of necrotizing enterocolitis.
  • the invention relates to inhibition of binding interactions between VLA-4 expressing reticulocytes and activated endothelial cells. More particularly, the invention relates to the inhibition of . such binding interactions that are involved in the complications associated with human disease, especially sickle cell disease.
  • the invention provides an experimental model for studying the role of increased capillary transit time of sickle reticulocytes in common complications of sickle cell disease, such as vascular occlusion, hemolytic anemia, increased infection, ischemic organ damage and episodes of severe pain.
  • the invention further provides a method for preventing such complications in patients suffering from sickle cell disease.
  • the invention provides an experimental model for studying the role of increased capillary transit time of sickle reticulocytes in the complications associated with sickle cell disease.
  • the mechanism of such increased transit time has been poorly understood.
  • unclear or conflicting reports on the molecules involved in the binding interactions leading to increased transit time have not facilitated the discovery of means for blocking such binding.
  • the invention provides the necessary information for producing an experimental model for studying the involvement of increased capillary transit time in complications arising from sickle cell disease.
  • ⁇ ] integrin chain but do not express either the ⁇ 2 or ⁇ 3 integrin chain.
  • the expression of the ⁇ , integrin chain is found almost exclusively on reticulocytes and the population of reticulocytes demonstrating the greatest expression of ⁇ , integrin stain brightest with thiazole orange, suggesting that only the youngest reticulocytes express ⁇ , integrin. No detectable
  • erythrocyte integrin expression is found in normal controls with reticulocyte counts less than 5%, although a small population of ⁇ j expressing reticulocytes is detected in blood from non- sickle patients with reticulocyte counts greater than 5%, particularly in neonates with elevated reticulocyte counts.
  • Reticulocyte counts in 25 samples obtained from 22 sickle cell disease patients range from 4% to 45% with a mean and standard deviation of 18 ⁇ 11%. Since ⁇ , expression is limited to the reticulocyte fraction, the total SSRBC expressing ⁇ , ranges from 0.3% to 11.2%.
  • ⁇ 4 and ⁇ , expressing cells are erythrocytes, rather than leukocytes or platelets, and that reticulocytes in the peripheral circulation may express the ⁇ 4 ⁇ , integrin complex commonly known as VLA-4.
  • Tumor necrosis factor (TNF) ⁇ stimulation of endothelial cell monolayers which is associated with VCAM-1 induction, results in markedly increased binding of SSRBC to the monolayers, relative to unstimulated endothelial cell monolayer controls, with only a small number of SSRBC or normal RBC binding to unstimulated human umbilical vein endothelial cells.
  • the increase in SSRBC binding parallels VCAM-1 induction.
  • stimulation of the endothelial cells by TNF ⁇ causes only a small increase in binding of RBC from normal individuals.
  • VLA-4 expressed by sickle reticulocytes in the binding of these cells to activated endothelium is supported by monoclonal antibody (mAb) blocking studies.
  • mAb monoclonal antibody
  • Preincubation of TNF ⁇ -stimulated endothelial cells with anti-VCAM-1 mAb, or of SSRBC ⁇ with anti- ⁇ 4 integrin mAb causes up to 75% inhibition of binding of SSRBC to endothelial cells.
  • a control mAb that recognizes intercellular adhesion molecule 1 (ICAM-1) does not inhibit SSRBC binding to activated endothelial cells.
  • the invention provides a method for preventing increased capillary transit time and the resultant vascular occlusion in patients suffering from sickle cell anemia.
  • the irreversibly sickled cell was initially believed to play a central role in the development of vascular complications, more recent clinical studies suggest that the frequency and severity of vascular complications is inversely related to the per centage of these cells and instead is closely correlated with the per centage of young deformable cells (see e.g.. Ballas et al., Blood 72:1216 (1988)).
  • VLA-4/VCAM-1 interactions are responsible for binding of sickle reticulocytes to activated endothelial cells, and that administration of blocking agents of VLA-4 antigen on the surface of sickle reticulocytes can prevent this binding, indicates that the method according to this aspect of the invention can prevent vascular occlusion in patients suffering from sickle cell anemia.
  • the method according to this aspect of the invention comprises the step of administering to a patient suffering form sickle cell anemia a blocking agent of VLA-4 on the surface of sickle reticulocytes.
  • a blocking agent of VLA-4 antigens is intended to mean an agent that is capable of interfering with interactions between VLA-4 antigens and ligands on endothelial cells or in the extracellular matrix, including but not limited to either VCAM-1 or fibronectin on the surface of activated endothelial cells.
  • VCAM-1 fibronectin
  • any agent that can block VLA-4 antigens can be successfully used in the method of the invention.
  • any agent capable of blocking VLA-4 antigens on the surface of sickle reticulocytes is considered to be an equivalent of the monoclonal antibody used in the examples herein.
  • the invention contemplates as equivalents at least peptides, peptide mimetics, carbohydrates and small molecules capable of blocking VLA-4 antigens on the surface of sickle reticulocytes.
  • the blocking agent that is used in the method of the invention to block VLA-4 antigens on the surface of sickle reticulocytes is a monoclonal antibody or antibody derivative.
  • Preferred antibody derivatives include humanized antibodies, chimeric antibodies, single chain antibodies, Fab, Fab', F(ab') 2 and F(v) antibody fragments, and monomers or dimers of antibody heavy or light chains or intermixtures thereof.
  • monoclonal antibody OKT3 to control allograft rejection indicates that, although humanized antibodies are preferable, murine monoclonal antibodies can be effective in therapeutic
  • Monoclonal antibodies against VLA-4 are a preferred blocking agent in the
  • Human monoclonal antibodies against VLA-4 are another preferred blocking agent in the method according to the invention. These can be prepared using in vitro-primed human splenocytes, as described by Boerner et al., J. Immunol. 147:86- 95 (1991). Alternatively, they can be prepared by repertoire cloning as described by Persson
  • Another preferred blocking agent in the method of the invention is a chimeric antibody having anti-VLA-4 specificity and a human antibody constant region.
  • These preferred blocking agents can be prepared according to art-recognized techniques, as exemplified in U.S. Patent No. 4,816,397 and in Morrison et al., Proc. Natl. Acad. Sci. USA £1:6851-6855 (1984).
  • Yet another preferred blocking agent in the method of the invention is a humanized antibody having anti-VLA-4 specificity.
  • Humanized antibodies can be prepared according to art-recognized techniques, as exemplified in Jones et al., Nature 321:522 (1986); Riechmann, Nature 332:323 (1988); Queen et al., Proc. Natl. Acad. Sci. USA 86:10029 (1989); and Orlandi et al., Proc. Natl. Acad. Sci. USA 86:3833 (1989).
  • Those skilled in the art will be able to produce all of these preferred blocking agents, based upon the nucleotide sequence encoding the heavy and light chain variable regions of HP1/2 [SEQ.
  • Two other preferred blocking agents are single chain antibodies, which can be prepared as described in U.S. Patent No. 4,946,778, the teachings of which are hereby incorporated by reference; and biosynthetic antibody binding sites, which can be prepared as described in U.S. Patent No. 5,091,513, the teachings of which are hereby incorporated by reference.
  • any of the above-identified antibody or antibody derivative blocking agents can also act in the method of the invention by binding the receptor for VLA-4, thus acting as agents for blocking the VLA-4 antigen on the surface of sickle reticulocytes, within the meaning of this term for purposes of the invention.
  • antibody and antibody derivative blocking agents according to the invention include embodiments having binding specificity for VCAM-1 or fibronectin, since these molecules are likely to be important in the adhesion between sickle reticulocytes and activated endothelial cells.
  • the blocking agents used in the method according to the invention are not antibodies or antibody derivatives, but rather are soluble forms of the natural binding proteins for VLA-4.
  • These blocking agents include soluble VCAM-1, bifunctional VCAM-1/Ig fusion proteins, or VCAM-1 peptides as well as fibronectin, fibronectin having an alternatively spliced non-type DI connecting segment. These blocking agents will act by competing with the activated endothelial cell-bound binding protein for VLA-4 on the surface of sickle reticulocytes.
  • blocking agents are preferably administered parenterally.
  • the blocking agents are preferably administered as a sterile pharmaceutical composition containing a pharmaceutically acceptable carrier, which may be any of the numerous well known carriers, such as water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, or combinations thereof.
  • a pharmaceutically acceptable carrier such as water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, or combinations thereof.
  • the blocking agent if an antibody or antibody derivative, will be administered at a dose between
  • administration should be at a molar equivalency to that of the antibody binding sites at the above-described concentrations.
  • the invention provides an experimental model for studying other diseases involving increased reticulocyte counts and/or vaso-occlusion.
  • a condition is severe hereditary spherocytosis, which results in a poorly understood occurrence of leg ulceration and dermatitis.
  • These complications have previously been attributed to increased blood viscosity and reduced tissue oxygen delivery caused by rigid microspherocytes.
  • these attributions are called into question by the observation that the leg ulcers improve or disappear after splenectomy.
  • Splenectomy predictably results in increased erythrocyte counts and circulating microspherocytes, which should aggravate leg ulcers if increased blood viscosity alone is responsible for ulceration and dermatitis.
  • VLA-4 expressing reticulocytes plays a role in the pathophysiology of skin complications in sever .
  • hereditary spherocytosis since splenectomy invariably decreases reticulocyte counts.
  • invention thus provides a method for studying the potential role of VLA-4 expression by reticulocytes in the complications by administering to the cells blocking agents of VLA-4 antigen on the surface of reticulocytes in in vitro and/or in vivo studies.
  • erythrocytes parasitized by Plasmodium falciparum bind to endothelial cells, and vascular occlusive complications characteristic of malaria are thought to be mediated by this binding (see MacPherson et al., Am. J. Pathol. 119:385 (1985); Oo et al., J. Neuropathol. Exp. Neurol. 46:223 (1987); Pongponrantn et al., Am. J. Trop. Med. Hyg. 44:168 (1991)).
  • the factors that predispose certain individuals to the most catastrophic complication of cerebral malaria are not well understood.
  • Necrotizing enterocolitis in infants is another pathologic condition in which abnormal interactions between endothelial cells and erythrocytes have been pathophysiologically implicated. Abnormal binding of red cells to bowel endothelial cells results in vascular compromise, occlusion, and a clinical syndrome marked by colitis and bowel infarction.
  • the following examples are intended to further illustrate certain aspects of preferred . embodiments of the invention, and are not limiting in nature.
  • Example 1 Expression of ⁇ , Integrin by a Subpopulation of Reticulocytes
  • Venous blood samples anticoagulated with EDTA were collected from patients with sickle cell anemia during routine follow up visits to the Grady Memorial Hospital Sickle Cell
  • Erythrocytes were identified by forward and side scatter and 50,000 events were collected per tube. Reticulocytes were identified by green fluorescence (FL1) and cell surface expression was detected by yellow fluorescence (FL2). The results are shown in Figure 1. Erythrocytes from the normal control (A) (reticulocyte count 1.6%:% ⁇ , expressing cells 0.2%) did not express ⁇ ,.
  • erythrocytes from a newborn (reticulocyte count 10%, % ⁇ , expressing cells 1.5%) and from a patient with sickle cell anemia (C) (reticulocyte count 16.5%, % ⁇ -, expressing cells 4%) both expressed the ⁇ , integrin chain.
  • Washed erythrocytes were incubated within antibody recognizing CD8 or mAb recognizing the integrin chains ⁇ instruct ⁇ ! (mAb TS 2/7 Dr. Martin Hemler, Dana Farber Cancer
  • Example 5 Binding of SSRBC. but not Normal Erythrocytes to TNF- ⁇ Stimulated Endothelial Cells
  • HUVEC Human umbilical vein endothelial cells
  • TNF ⁇ stimulated endothelial cells were left untreated or preincubated with mAb recognizing VCAM-1 (mAb BBA 6, 10 ⁇ g/ml, R&D Systems, Minneapolis, MN) or ICAM-1 (mAb 84H10, tissue culture supernatants.
  • Sickle RBC were untreated or preincubated with anti- ⁇ 4 (50 ⁇ g/ml, mAb HP2/1. The results are shown in Figure 6.
  • CDRs complementarity determining regions
  • anti-VLA-4 monoclonal antibody HP 1/2 were determined according to the sequence alignment
  • the CDRs of murine HP1/2 V H correspond to the residues identified in the humanized V H sequences disclosed herein as amino acids 31-35 (CDRl), 50-66 (CDR2) and 99-110 (CDR3), which respectively correspond to amino acids 31-35, 50-65 and 95-102 in the Kabat alignment.
  • the CDRs of murine HP1/2 V ⁇ correspond to the residues identified in the humanized V ⁇ sequences disclosed herein as amino acids 24-34 (CDRl), 50-56 (CDR2) and 89-97 (CDR3), and to the same residues in the Kabat alignment.
  • the Kabat NEWM framework was chosen to accept the heavy chain CDRs and the Kabat REI framework was chosen to accept the kappa chain CDRs.
  • Transplantation of the CDRs into the human frameworks was achieved by using M13 mutagenesis vectors and synthetic oligonucleotides containing the HP 1/2 CDR-encoding sequences flanked by short sequences derived from the frameworks.
  • the V H mutagenesis vector, M13VHPCR1 contains the NEWM framework and has been described by Orlandi et al., Proc. Natl. Acad. Sci USA 86:3833-3837 (1989).
  • the V ⁇ mutagenesis vector, M13VKPCR2 contains essentially the REI framework and is identical to the M13VKPCR1 , vector described by Orlandi et al., except that there is a single amino acid change from Val to
  • V H and V ⁇ regions of humanized HP1/2 were cloned into appropriate expression vectors.
  • the appropriate human IgGl, IgG4 or kappa constant region was then added to the vector in appropriate reading frame with respect to the murine variable regions.
  • the vectors were cotransfected into YB2/0 ray myeloma cells (available from ATCC), which were then selected for the presence of both vectors.
  • ELISA analysis of cell supernatants demonstrated that the humanized antibody produced by these cells was at least equipotent with murine HP1/2.
  • the cell line expressing this humanized antibody was deposited with the ATCC on November 3, 1992 and given accession number CRL 11 175.
  • Necrotizing enterocolitis is the most common serious acquired gastrointestinal tract disorder in the neonatal intensive care unit, responsible for an increasing number of infectious disease associated deaths in low birth weight babies. It has been estimated that
  • NEC affects at least 25,000 newborn children in the United States annually and carries an
  • NEC Newcastle disease virus
  • NEC represents a final common pathway of response of the immature intestine to injury which may be initiated by multiple factors.
  • Prematurity is recognized as the primary risk factor which predisposes infants to NEC. Disturbed hemodynamics associated with hyperviscosity has been implicated as a primary factor in the development of intestinal injury. However, explanations relying on hyperviscosity often suggest that erythrocytes are merely passive participants in vaso- occlusive disease.
  • Adherence of erythrocytes may initiate microvascular complications in diseases such as sickle cell anemia and diabetes.
  • the primary event may be the binding of adhesion protein expressing reticulocytes to vascular endothelial cells. Vessels partially occluded by bound reticulocytes may be completely occluded by trapping of dense, sickled cells.
  • Reticulocytes may bind to endothelial cells after opsonization with thrombospondin (TSP-1) or multimers of von Willebrand factor. Additionally, reticulocytes are capable of binding directly to endothelial cell surface ligands.
  • Reticulocyte expression of CD36 is important in TSP-1 mediated binding of erythrocytes to endothelial cells and erythrocyte express of the a4bl integrin complex can mediate binding to the inducible endothelial cell adhesion molecule VCAM-1 on cytokine activated endothelial cells.
  • VCAM-1 inducible endothelial cell adhesion molecule
  • the expression of CD36 and the a4bl integrin complex is not limited to reticulocytes of patients with sickle cell anemia.
  • neonates with elevated reticulocyte counts also demonstrate similar, if not higher percentages of CD36 and a4bl expressing red cells.
  • NEC may be a clinical manifestation of this predisposition.
  • the mucosal ischemia proposed as an initiating event in NEC may not be due to an abrupt cessation of mesenteric blood flow, but rather due to vascular compromise induced by the binding of "sticky" erythrocytes to activated endothelium.
  • Adherent erythrocytes may serve as a nidus for platelet activation of the clotting cascade with resultant complete occlusion and bowel necrosis.
  • LPS bacterial lipopolysaccharide
  • ICAM-1 Intercellular adhesion molecule -1
  • TNF tumor necrosis factor
  • IL-1 interleukin 1
  • IFN- g interferon g
  • VCAM-1 molecule 1
  • VCAM-1 can be induced de novo on endothelial cells. These may serve as ligands for adhesion receptors on the surface of a variety of cells. In fact, all three adhesion receptors have been shown to play a role in red cell binding to endothelial cells under certain clinical circumstances.
  • MOLECULE TYPE cDNA
  • HYPOTHETICAL NO
  • ANTI-SENSE NO

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Abstract

L'invention décrit un modèle expérimental pour l'étude du rôle du temps de transit capillaire augmenté des réticulocytes falciformes dans les complications de l'anémie falciforme, ainsi qu'un procédé pour la prévention de ces complications chez les patients atteints d'anémie falciforme. L'invention prévoit également un procédé de traitement de l'entérocolite nécrosante et d'autres maladies caractérisées par des anomalies des interactions entre les érythrocytes et l'endothélium vasculaire.
PCT/US1994/010395 1993-09-15 1994-09-15 Procede pour inhiber la fixation de reticulocytes a l'endothelium par interference avec les interactions vla-4/vcam-1 Ceased WO1995007717A1 (fr)

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AU78352/94A AU7835294A (en) 1993-09-15 1994-09-15 Peripheralization of hematopoietic stem cells
EP94929205A EP0720486A1 (fr) 1993-09-15 1994-09-15 Peripherisation des cellules souches hematopoietiques

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US12222893A 1993-09-15 1993-09-15
US08/122,228 1993-09-15

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230212295A1 (en) * 2016-05-27 2023-07-06 Albert Einstein College Of Medicine Methods of treatment by targeting vcam1 and maea

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WO1991003252A1 (fr) * 1989-09-01 1991-03-21 Fred Hutchinson Cancer Research Center Inhibition de l'adhesion de lymphocytes sur l'endothelium vasculaire au moyen d'une nouvelle interaction entre le recepteur matriciel extra-cellulaire et son ligand
WO1993013798A1 (fr) * 1992-01-13 1993-07-22 Biogen, Inc. Traitement de l'asthme
WO1993015764A1 (fr) * 1992-02-12 1993-08-19 Biogen, Inc. Traitement de l'inflammation intestinale

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991003252A1 (fr) * 1989-09-01 1991-03-21 Fred Hutchinson Cancer Research Center Inhibition de l'adhesion de lymphocytes sur l'endothelium vasculaire au moyen d'une nouvelle interaction entre le recepteur matriciel extra-cellulaire et son ligand
WO1993013798A1 (fr) * 1992-01-13 1993-07-22 Biogen, Inc. Traitement de l'asthme
WO1993015764A1 (fr) * 1992-02-12 1993-08-19 Biogen, Inc. Traitement de l'inflammation intestinale

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230212295A1 (en) * 2016-05-27 2023-07-06 Albert Einstein College Of Medicine Methods of treatment by targeting vcam1 and maea
US12173073B2 (en) * 2016-05-27 2024-12-24 Albert Einstein College Of Medicine Methods of treatment by targeting VCAM1 and MAEA

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AP9400679A0 (en) 1996-03-13

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