WO1996011012A1 - Ligand pour l-selectine des cellules hematopoietiques (hll) et therapie associee - Google Patents

Ligand pour l-selectine des cellules hematopoietiques (hll) et therapie associee Download PDF

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Publication number
WO1996011012A1
WO1996011012A1 PCT/US1995/013736 US9513736W WO9611012A1 WO 1996011012 A1 WO1996011012 A1 WO 1996011012A1 US 9513736 W US9513736 W US 9513736W WO 9611012 A1 WO9611012 A1 WO 9611012A1
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Prior art keywords
cells
glycoprotein
set forth
selectin
kgla
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PCT/US1995/013736
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English (en)
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Robert Sackstein
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University Of South Florida
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention involves the development of compounds which can regulate and control the function of adhesion molecules.
  • the adhesion molecules are involved in the fundamental control of cell-cell interaction and cellular migration. Adhesion molecules regulate diverse processes in inflammation, hematopoiesis and tumor metastasis. (Woodruff, et al, 1987; Springer, et al, 1987; Sharon and Lie, 1993; Sca stein, 1993) For general reviews on adhesion molecules see Carlos and Harlan, 1994 and Chin et al, 1991. It would be useful to develop reagent ⁇ which can control and regulate the adhesion proteins, particularly within the selectin family.
  • the peripheral lymph node "homing receptor”, L-selectin (CD62L) is a -75 kDa glycoprotein which mediates attachment of lymphocytes to lymph node (LN) high endothelial venules (HEV) , an adhesive interaction which is the first step in the migration of lymphocytes from blood into lymphoid tissues (Gowans and Knight, 1964; Marchesi and Gowans, 1964). This trafficking of lymphocytes from blood into lymph nodes is markedly nonrandom and is initiated by specific adherence of the lymphocytes to HEV.
  • the "lymph node homing receptor” or L-selectin (LECAM-1) is the principal lymphocyte membrane glycoprotein mediating this attachment.
  • the L-selectin protein is recognized by a variety of monoclonal antibodies (mAbs) in humans ⁇ Gatenby et al., 1982 (Leu-8) ; Reinherz et al., 1982 (T -1); Tedder et al., 1990 (LAM) > and is a member of the selectin family of adhesion molecules, which includes P-selectin (CD62P) and E- selectin (CD62E) .
  • Selectins share a common structure consisting of an amino-terminal calcium- dependent lectin domain, an epidermal growth factor domain, a variable number of repeat sequences bearing homology to complement regulatory and catalytic proteins binding C3b or C4b, a transmembrane portion, and a C-terminal cytoplasmic tail (Bevilacqua and Nelson, 1993; Rosen, 1993).
  • the molecular weight varies among leukocytes due to posttranslational glycosylation among subsets of leukocytes. (Carlos and Harlan, 1994)
  • the lectin domain of these proteins directs their adhesion to carbohydrate molecules present on the cell surface.
  • lymphocytes and HEV have been extensively analyzed using an in vitro binding assay (Stamper and Woodruff, 1976) .
  • This assay is performed under shear at 4°C, whereby binding mediated by L- selectin is maximized and effects of other adhesion molecules are minimized (Shaw et al, 1986; Spertini et al., 1991).
  • L-selectin behaves as a lectin and recognizes sialylated, high mannose residues on its corresponding ligand which is identified by the monoclonal antibody MECA-79 (Sack ⁇ tein, 1993) .
  • MECA-79 identifies an L-selectin ligand on lymph node HEV and which cross-reacts with GLYCAM-1 and CD34.
  • L- selectin In vitro adherence of lymphocytes via L- selectin can be inhibited by carbohydrates such as mannose-6-phosphate (man-6-P) , PPME (Phospho annan monoester core from Hansenula hostii , a phosphomannosyl-rich polysaccharide) , and fucoidin (a sulfated, fucose-rich polysaccharide) (Stool an and Rosen, 1983).
  • mannose-6-phosphate mannose-6-phosphate
  • PPME Phospho annan monoester core from Hansenula hostii , a phosphomannosyl-rich polysaccharide
  • fucoidin a sulfated, fucose-rich polysaccharide
  • Ligands for L-selectin have thus far been characterized on murine endothelial cells utilizing a murine L-selectin IgG chimera molecule as a probe.
  • This approach has identified two proteins, GlyCAM-1 (Sgp50) (Imai et al., 1991) and CD34 (Sgp90) (Baumhueter et al., 1993) , present on endothelial cells.
  • GlyCAM-1 is a novel sialomucin, and its role as a ligand for L- selectin is its only known function (Lasky et al., 1992) .
  • CD34 Although present on endothelial cells in most tissues (Beschorner et al., 1985), CD34 is best known for its expression on the earliest multilineage colony-forming hematopoietic stem cells (Civin et al., 1984).
  • L-selectin plays a role in hematopoiesi ⁇ (Terstappen et al., 1993; Kobayashi et al., 1994).
  • the characterization of L-selectin and its ligands among progenitor cells is of considerable interest as adhesion proteins regulate cell-cell and cell-stromal interactions fundamental to hematopoiesis.
  • lymphocyte migration can occur secondary to the effect of pharmacologic agents used in posttransplant therapy such as corticosteroids (Sackstein, 1993) . It would be useful to have an agent which can assist in reestablishing lymphocyte trafficking and so immune function following bone marrow transplantation.
  • adhesion molecules in controlling and directing the inflammatory process indicates that a reagent which interferes with the process, i.e. anti-adhesive, could have anti- inflammatory properties.
  • glycoproteins are characterized by being expressed on at least primative hematopoietic cells, and being a ligand for L-selectin.
  • the binding of ligand to L- selectin is not inhibited by anti-CD34 antibodies nor by MECA-79 monoclonal antibody.
  • FIGURE 1A-B are photomicrographs of cytospin preparations of KGla cells demonstrating adherence of lymphocytes (small dark dots) , ( ⁇ ) Lymphocytes adhere to KGla in the presence of CD45 or isotype control Abs, (B) Lymphocyte binding assay in the presence of LAM1-3 Ab (anti-L- selectin) ;
  • FIGURE 2 is FACS profiles of lymphocytes used in the binding assay after incubation with isotope-matched IgG control, LAMl-3, or anti-CD45
  • FIGURE 3A-D are FACS profiles of KGla cells sorted by FACS prior to the binding assay into CD34+ and CD34- fractions using mAb HPCA-2PE, sorted cell fractions were restained for CD34 using mAb QBEND10-FITC and analyzed, positive and negative sorted fractions were >90% and ⁇ 10% positive for CD34, respectively, results shown are representative of 3 independent experiments;
  • FIGURE 4 is a photomicrograph showing the lymphocyte adherence assay performed on the sorted cells, and no differences in lymphocyte adherence were evident among the CD34+ and CD34- populations, adherence to the CD34 negative fraction is shown; and FIGURE 5A-F are FACS profiles of COS-7 cells were transfected with either CD34-pCDM8 (E,F) or pCDM8 (mock, C,D) , then analyzed by FACS and compared to KGla (A,B) for CD34 expression, Abs used were isotype-matched IgG ⁇ control and anti- CD34 mAb QBEND10, Lymphocytes did not adhere to CD34-transfected COS-7 cells, despite higher levels of CD34 expression as compared to KGla cells. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
  • the present invention provides an isolated and purified glycoprotein and functional analogs thereof.
  • Analog is defined as a molecule that will be generally at least 70% homologous over any portion that is functionally relevant.
  • the homology will be at least 80% and can approach 95% homology to the amino acid sequence of the protein segment of the glycoprotein.
  • the homology will extend over a region of at least 8 contiguous amino acids to 80 contiguous amino acids.
  • the amino acid sequence of an analog may differ from that of the glycoprotein of the present invention when at least one residue is deleted, inserted or substituted.
  • the molecular weight of the glycoprotein may vary between the analog and the present invention due to carbohydrate differences. Differences in glycosylation may be present between the analog and the present invention.
  • the glycoprotein has the following functional characteristics. It is expressed on at least primative hematopoietic cells.
  • the glycoprotein is a ligand for L-selectin.
  • the ligand binding to L-selectin is not inhibited by anti-CD34 antibodies and is not recognized by the MECA-79 monoclonal antibody.
  • the glycoprotein is designated hereinafter as hematopoietic cell L- selectin ligand, HLL.
  • the glycoprotein is isolated by immunoprecipitation of KGla membrane lysates as is standard in the art and used for the production of further antibodies as needed.
  • Such methods can be found described Sambrook et al, Molecular Cloning: A Laboratory Manual , Cold Springs Harbor, New York, 1989, as well as additional methods of isolation and purification as are known in the art.
  • the antibodies may be prepared against a synthetic peptide based on the sequence, or prepared recombinantly by cloning techniques or the natural gene product and/or portions thereof may be isolated and used as the immunogen.
  • proteins or peptides can be used to produce antibodies by standard antibody production technology well known to those skilled in the art as described generally in Harlow and Lane, Antibodies: A Laboratory Manual , Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 1988.
  • a host such as a rabbit or goat, is immunized with the protein or peptide, generally with an adjuvant and, if necessary, coupled to a carrier; antibodies to the protein are collected from the sera.
  • the technique involves hyperimmunization of an appropriate donor with the protein or peptide fragment, generally a mouse, and isolation of splenic antibody producing cells. These cells are fused to a cell having immortality, such as a myeloma cell, to provide a fused cell hybrid which has immortality and secretes the required antibody. The cells are then cultured, in bulk, and the monoclonal antibodies harvested from the culture media for use.
  • the antibody can be bound to a solid support substrate or conjugated with a detectable moiety or be both bound and conjugated as is well known in the art.
  • toxins such as ricin A chain, p ⁇ eudomonas exotoxin A, diphtheria toxin, other plant and bacterial toxins as well as chemotherapeutic compounds can be coupled in the present invention forming an immunotoxin.
  • toxins such as ricin A chain, p ⁇ eudomonas exotoxin A, diphtheria toxin, other plant and bacterial toxins as well as chemotherapeutic compounds can be coupled in the present invention forming an immunotoxin.
  • a toxin bound antibody can be administered to the appropriate patient and targeted cells killed in vivo.
  • the immunotoxin is administered and dosed in accordance with good medical practice, taking into account the clinical condition of the individual patient, the site and method of administration, scheduling of administration, and other factors known to medical practitioners.
  • the "effective amount" for purposes herein is thus determined by such considerations as are known in the art. The amount must be effective to achieve at least 25% of the treated patients exhibit improvement including but not limited to improved survival
  • cells can be removed from the patient and treated ex vivo selectively.
  • cells expressing HLL can be removed through complement-mediated lysis from the ex vivo population and the remaining cells returned to the patient. Additional cell removal can be undertaken
  • SUBSTITUTE SHFET 26 utilizing cell sorting, “panning” and magnetic bead separation. Further, utilizing cell sorting, “panning”, magnetic bead separation and the like cell populations can be enriched for HLL bearing cells and this enriched cell population returned to the patient.
  • the targeted cells to be removed are cells expressing HLL and can be selected from the group consisting of leukemic cells, malignant hemopoietic progenitor cells, or any malignant cell expressing the marker.
  • the present invention also provides a method of regulating hematopoiesis, particularly in reconstitution of the immune system following bone marrow transplantation.
  • the present invention includes the steps of selecting those cells with high(+) or low(-) expression of HLL depending on the growth characteristics associated with the marker density needed by the patient.
  • the selection procedure utilizes ex vivo methods as described herein. After selection, the selected cell type is cultured in vitro, if needed to expand the population using standard methods known in the art. The patient is then infused with the expanded, enriched HLL+ or HLL- population as needed.
  • the present invention further provides a method of regulating inflammatory response by interrupting cellular migration into lymph nodes and sites of both acute and chronic inflammation including the step of administering to the patient antibody directed agains HLL thereby disturbing cellular migration mediated by HLL by blocking the the lymphocyte attachment site and can be injected directly at the inflammed site if needed.
  • the regulation of the inflammatory response would be useful in autoimmune disorders, post-ischemic tissue injury and sepsis (Calos and Harlan, 1994) .
  • Administration and effective dose are as described for immunotoxins hereinabove.
  • COS-7 cells were incubated for 4 hours at 37°C with 10 ml of transfection solution containing 20-40 ⁇ g of plasmid DNA, 10% Nu Serum (Collaborative Biomedical Products, Bedford, MA) , 400 ⁇ g/ml DEAE Dextran (Sigma) , and 100 ⁇ chloroquine (Sigma) in Dulbecco's Modified Eagles Medium (Gibcon-BRL) . Cells were then rinsed and treated with 10% DMSO (Sigma) in PBS for two minutes at room temperature, rinsed in PBS, and incubated in tissue culture media for 3 days.
  • 10% DMSO Sigma
  • trypsinization was avoided by growing transfected cells directly on glass slides for subsequent use in the binding assay or for analysis of CD34 expression by fluorescence microscopy.
  • COS-7 cells grown on 10 cm plates were removed with trypsin/EDTA (0.25%/lmM, Gibco-BRL) , then analyzed for CD34 expression by flow cytometry. These trypsinized cells were then placed on slides by cytospin for use in the lymphocyte binding assay.
  • Antibodies did Not Inhibit Adherence of Lymphocytes. Cytospin preps of KGla were preincubated with anti-CD34 Abs and the binding assay was performed in the presence of the Abs. Monoclonal ABS to four different CD34 epitopes were used alone or in combination, including the clones MylO, QBENDIO, 8gl2, and 12.8, in amounts ranging from 0.2 to 17 ⁇ g/slide. Anti-CD45 (irrelevant control) and IgG j ⁇ (isotype control) Abs were also tested. None of the anti-CD34 Abs inhibited lymphocyte binding to KGla, despite immunohistochemical evidence of extensive Ab binding to the glutaraldehyde-fixed KGla sections.
  • CD34+ and CD34- KGla cells were separated by fluorescence activated cell sorting and cytospin preparations of each population were made.
  • the in vitro adherence of lymphocytes was identical in the CD34+ and CD34- populations despite an enrichment of >90% and ⁇ 10% CD34+ cells in the respective populations (Fig. 3 and 4; Table 2).
  • Cowing C, Chapdelaine JM T cells discriminate between la antigens expressed on allogeneic accessory cells and B cells: a potential function for carbohydrate side chains on la molecules. Proc Natl Acad Sci USA 80:6000, 1983.
  • Huff TF, Uede T, Iwata M, Ishizaka K Modulation of the biologic activities of IgE-binding factors. III. switching of a T cell hybrid clone from the formation of IgE-suppressive factor to the formation of IgE-potentiating factor. J Immunol 131:1090, 1983.
  • Lewinsohn DM Bagatze RR, Butcher EC: Leukocyte- endothelial cell recognition: evidence of a common molecular mechanism shared by neutrophils, lymphocytes, and other leukocytes.
  • Ramakrishnan S Current status of antibody-toxin conjugates for tumor therapy. Targeted Diagn Ther 3:189, 1990. /11012
  • Leukocyte adhesion molecule-1 (LAM-1, L-selectin) interacts with an inducible endothelial cell ligand to support leukocyte adhesion. J Immunol 147:222565, 1991.
  • Butcher EC A tissue-specific endothelial cell molecule involved in lymphocyte homing. Nature 331:41, 1988.
  • Yamashita K, Hitoi A, Tateishi N, Higashi T, Sakamoto Y, Kobata A The structures of the carbohydrate moieties of mouse kidney gamma- glutamyltranspeptidase: occurrence of X-antigenic determinants and bisecting N-acetylglucosamine residues. Arch Biochem Biophys 240:573, 1985.

Abstract

L'invention concerne une glycoprotéine isolée et purifiée et des analogues fonctionnels. Les glycoprotéines sont caractérisées en ce qu'elles sont exprimées sur au moins des cellules hématopoïétiques primitives, et qu'elles constituent un ligand pour L-sélectine. La liaison du ligand sur L-sélectine n'est pas empêchée par des anticorps anti-CD34 ni par l'anticorps monoclonal MECA 79.
PCT/US1995/013736 1994-10-11 1995-10-10 Ligand pour l-selectine des cellules hematopoietiques (hll) et therapie associee WO1996011012A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1421174A2 (fr) * 2000-10-18 2004-05-26 The Brigham And Women's Hospital, Inc. Polypeptides ligands de e-selection/l-selectine et methodes d'utilisation associees
US7816500B2 (en) 2006-06-02 2010-10-19 Robert Sackstein Antibody SACK-1 that binds CD44 glycoforms

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5130144A (en) * 1984-02-06 1992-07-14 The Johns Hopkins University Human stem cells and monoclonal antibodies

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5130144A (en) * 1984-02-06 1992-07-14 The Johns Hopkins University Human stem cells and monoclonal antibodies
US5130144B1 (en) * 1984-02-06 1995-08-15 Univ Johns Hopkins Human stem cells and monoclonal antibodies

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
EXPERIMENTAL HEMATOLOGY, Volume 22, issued 1994, SACKSTEIN, "L-Selectin Mediates Lymphocyte Adhesion to KG1A Cells by Binding to a Ligand Other than CD34", page 788, Abstract 414. *
HEMATOPOIETIC CELL PROLIFERATION AND DIFFERENTIATION II, Volume 82, issued 1993, KRAUSE et al., "Two Forms of CD34 Protein Are Expressed in Human KMT2 and KG1a Cells", page 110a, Abstract 427. *
HISTOCHEMISTRY, Volume 100, issued 1993, ROSEN, "L-Selectin and Its Biological Ligands", pages 185-191. *
SCIENCE, Volume 262, issued 15 October 1993, BAUMHUETER et al., "Binding of L-Selectin to the Vascular Sialomucin CD34", pages 436-438. *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1421174A2 (fr) * 2000-10-18 2004-05-26 The Brigham And Women's Hospital, Inc. Polypeptides ligands de e-selection/l-selectine et methodes d'utilisation associees
EP1421174A4 (fr) * 2000-10-18 2004-09-22 Brigham & Womens Hospital Polypeptides ligands de e-selection/l-selectine et methodes d'utilisation associees
US7875585B2 (en) 2000-10-18 2011-01-25 Robert Sackstein Hematopoietic cell E-selectin / L-selectin ligand glycosylated CD44 polypeptide
US9523078B2 (en) 2000-10-18 2016-12-20 Robert Sackstein Method for increasing the E-selectin binding affinity of a population of cells expressing a CD44 polypeptide
US10370642B2 (en) 2000-10-18 2019-08-06 Robert Sackstein Hematopoietic progenitor cell populations having affinity for E-selectin / L-selectin
US7816500B2 (en) 2006-06-02 2010-10-19 Robert Sackstein Antibody SACK-1 that binds CD44 glycoforms
US8084236B2 (en) 2006-06-02 2011-12-27 Robert Sackstein Compositions and methods for modifying cell surface glycans
US8728810B2 (en) 2006-06-02 2014-05-20 Robert Sackstein Methods for modifying cell surface glycans
US8852935B2 (en) 2006-06-02 2014-10-07 Robert Sackstein Compositions and methods for modifying cell surface glycans
US11535831B2 (en) 2006-06-02 2022-12-27 Robert Sackstein Compositions and methods for modifying cell surface glycans

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