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WO1992007579A1 - Peptides solubles recepteurs de mannose - Google Patents

Peptides solubles recepteurs de mannose Download PDF

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Publication number
WO1992007579A1
WO1992007579A1 PCT/US1991/008320 US9108320W WO9207579A1 WO 1992007579 A1 WO1992007579 A1 WO 1992007579A1 US 9108320 W US9108320 W US 9108320W WO 9207579 A1 WO9207579 A1 WO 9207579A1
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WO
WIPO (PCT)
Prior art keywords
peptide
mannose receptor
ser
nucleic acid
leu
Prior art date
Application number
PCT/US1991/008320
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English (en)
Inventor
Raymond Alan Brian Ezekowitz
Original Assignee
The Children's Medical Center 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
Application filed by The Children's Medical Center Corporation filed Critical The Children's Medical Center Corporation
Priority to CA002095729A priority Critical patent/CA2095729A1/fr
Priority to JP4500952A priority patent/JPH06501620A/ja
Priority to EP19920900254 priority patent/EP0568539A4/en
Publication of WO1992007579A1 publication Critical patent/WO1992007579A1/fr

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • 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
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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 the general field of anti-microbial and anti-viral compounds, including diagnostic compounds, as well as to methods and reagents for making and using the compounds.
  • anti-microbial agents compounds that interfere with the metabolic processes of the infective cell.
  • antibacterial agents of the sulfonamide class as structural analogs of
  • p-aminobenzoic acid block purine nucleotide synthesis in susceptible microorganisms, while penicillin prevents the completion of the final stages of cell wall biosynthesis.
  • a number of antiviral agents such as AZT and suramin achieve their effect by targeting the uniquely retroviral enzyme reverse transcriptase.
  • AZT has been approved for treatment of patients with the Acquired Immune Deficiency Syndrome (AIDS), caused by the Human Immunodeficiency Virus Type 1 (HIV-1).
  • HIV-1 Human Immunodeficiency Virus Type 1
  • Another antiviral agent, the polyanionic compound dextran sulfate blocks binding of virions to target cells.
  • the soluble mannose-binding protein prevents infection of H9
  • lymphoblasts by HIV-1 by binding to the high mannose glycans expressed on the envelope glycoprotein of the retrovirus (Ezekowitz et al., J. Exp. Med. 169:185-196, 1989).
  • the invention features a soluble recombinant peptide comprising at least one (and
  • the peptide is capable of specifically targeting cells expressing mannose, N- acetylglucosamine, or fucose, by virtue of those
  • the MRP-derived carbohydrate recognition domain can specifically bind eucaryotic or procaryotic pathogenic cells (e.g., bacteria, fungi, or viruses) having exposed configurations of the specified sugar moieties on their cell wall or on the envelope glycoprotein.
  • a peptide containing the MRP-derived CRD can specifically target cancer cells which have any exposed mannose residues as a result of abberant glycosylation.
  • Peptides according to the invention offer a probe for such cells, or a tool for delivery of specific molecules (e.g., toxins or cell specific molecules such as the T-cell antigen, CD4) to those cells, or an in vivo marker for those cells to the immune system.
  • the domain(s) are said to be MRP-derived in that they generally contain at least 150, or preferably 300 contiguous amino acids homologous to a sequence of one or more carbohydrate recognition domains of the mannose receptor protein, shown in Fig. 3.
  • the soluble peptide lacks the transmembrane and
  • peptide is meant a chain of about ten or more amino acids, including larger polypeptides and proteins, that are useful in this invention.
  • the peptide may be glycosylated via O- or N- linkages.
  • recombinant peptide is meant a peptide that is expressed from engineered nucleic acid, defined below.
  • the invention features engineered nucleic acid (preferably cDNA) encoding such a soluble peptide.
  • engineered nucleic acid is meant nucleic acid removed from its natural environment (i.e., from naturally adjacent nucleic acid) by purification or recombinant DNA methodology; the term also includes synthetic nucleic acid or cDNA.
  • This nucleic acid may be a fragment of DNA or RNA, it may be present in a vector system (e.g., a plasmid, cosmid or phage), or it may be within the genome of an organism. In some cases, such nucleic acid is purified and includes a homogeneous preparation of desired nucleic acid.
  • the peptide and nucleic acid encoding it are further characterized by at least 75% identity at the amino acid level to a sequence of at least 150, and preferably 300, contiguous amino acids of one or more carbohydrate recognition domains of mannose receptor protein most preferably the peptide includes the entire extracellular region of mannose receptor protein.
  • the nucleic acid is characterized by at least 75% identity at the amino acid level to a sequence of at least 150, and preferably 300, contiguous amino acids of one or more carbohydrate recognition domains of mannose receptor protein most preferably the peptide includes the entire extracellular region of mannose receptor protein.
  • nucleic acid is ligated to nucleic acid encoding the toxic part of a toxin molecule (e.g., AZT, ricin, or cholera toxin), or to nucleic acid encoding a peptide capable of fixing complement.
  • a toxin molecule e.g., AZT, ricin, or cholera toxin
  • the hybrid peptides encoded by such ligated nucleic acid are especially useful for causing an effector molecule to be targeted to an undesired cell or other organism, such as a virus.
  • peptides described above, and antibodies to those peptides may be used in therapeutic or diagnostic agents.
  • the peptide is purified, that is, the peptide is substantially separated from contaminating peptides. Most preferably it is provided as a homogenous preparation admixed in a carrier substance suitable for therapeutic use.
  • therapeutic agent is meant a
  • diagnostic agent a substance relating to the detection of a disease or disorder.
  • the invention features methods for treating an animal, e.g., a human, infected with a bacterium, fungus, or virus.
  • a bacterium, fungus, or virus is meant to include any type of
  • One such method includes
  • a therapeutically effective amount of a therapeutic agent or peptide including a soluble extracellular portion of mannose receptor protein capable of specifically targeting cells expressing mannose, N-acetylglucosamine, or fucose causes direct inhibition of growth of the infective organism, or causes host defensive cells, e.g., macrophages, to be attracted to the pathogenic organisms which are thereby inactivated.
  • host defensive cells e.g., macrophages
  • a therapeutically effective amount is that quantity which produces a significant physiological effect in the patient and is recognized by those of ordinary skill in the art to depend upon the size and weight of the animal as well as other well known factors.
  • the peptide is a therapeutically effective fragment of the soluble extracellular portion of mannose receptor protein; the peptide is able to inhibit (e.g., reduce or prevent) growth of, or infection by, the bacterium, fungus, or virus, and is a peptide as described above.
  • the animal is human; the infection is one that results in a bacteremia or local bacterial
  • the route of administration is either intravenous, intramuscular, oral, or local, e.g., in the form of a powder, or lotion, preferably at 5-100 ⁇ g/ml, more preferably at 25 ⁇ g/ml; or the virus is HIV or a related virus, and the peptide lowers the rate of infection of eucaryotic cells by the virus; the protein or peptide is provided at 1-500 ⁇ g/ml (preferably 100-150 ⁇ g/ml) final concentration in human serum or tissue.
  • lipid vesicles, or lyposomes, containing toxins or antibiotics are coated with the peptide and administered directly to the patient.
  • Such lyposomes will be targeted to the infected area by the peptide and the content of the lyposomes released, thereby specifically retarding or preventing growth of the targeted cells or organisms in the targeted area.
  • the invention features a coated catheter, useful for long-term administration of fluids to a patient.
  • the catheter is coated with one of the above-described peptides, e.g., by impregnating the catheter material with the peptide.
  • the peptide lowers the rate of bacterial, fungal or viral infection of the patient through the catheter.
  • the invention features a method for diagnosing infection by a bacterium, fungus or virus.
  • the method includes detecting the serum level of a pathogen that expresses one of the target glycoproteins recognized by MRP, by measuring the amount of binding of a peptide according to the invention to a sample of the serum.
  • the detected pathogen level reflects the
  • the method comprises:
  • the invention features a purified antibody specifically recognizing a peptide according to the invention.
  • the antibody is preferably provided as a homogeneous preparation of a monoclonal or polyclonal antibody.
  • the antibody is useful for
  • the invention features a purified soluble peptide comprising the extracellular portion of mannose receptor protein, said peptide lacking the mannose receptor protein transmembrane and
  • Fig. la shows the nucleotide base sequence and the corresponding amino acid sequence of the extracellular portion of the mannose receptor protein, described herein as nucleotides 1-4212 of SEQ ID NO: 1.
  • Fig. lb shows the nucleotide base sequence and the corresponding amino acid sequence of the transmembrane and cytoplasmic portions of the mannose receptor protein, described herein as nucleotides 1-4212 of SEQ ID NO: 2.
  • Fig. 2 is a schematic diagram including the functional regions of the extracellular portion of the mannose receptor protein.
  • Fig. 3 shows the correspondance of the amino acid sequence of the various carbohydrate recognition domains of the mannose receptor, using the single letter amino acid code.
  • Soluble recombinant peptides derived from an extracellular portion of the mannose receptor that contains one or more carbohydrate recognition domains (CRDs) are able to recognize carbohydrates with a
  • Such soluble mannose receptor peptides can be immobilized or attached to a portion of another molecule without losing effective carbohydrate recognition capacity.
  • Exposed sugars like mannose and N- acetylglucosamine are a feature of the cell walls of many pathogens, whereas higher organisms, including humans and animals, tend to have masked internal mannose residues that are not recognized by the mannose receptor.
  • soluble mannose receptor peptides are useful in therapeutic agents in that they specifically bind mannose-rich pathogens, including bacteria, fungi, yeasts, parasites, or the envelope glycoproteins of certain viruses.
  • mannose-rich pathogens including bacteria, fungi, yeasts, parasites, or the envelope glycoproteins of certain viruses.
  • Such peptides can also specifically target cancer cells having exposed mannose residues as a result of abberant glycosylation.
  • the peptides can direct removal of such pathogens from the patient.
  • the soluble peptides can direct removal of such pathogens from the patient.
  • the first domain is comprised of 134 amino acids at the NH 2 terminus. Without being bound to any theory, it appears that this cysteine-rich region is not essential to mannose targeting according to the invention, and, therefore, it may be deleted without departing from the spirit of the invention. Preferred soluble peptides according to the invention, however, include this domain.
  • the second domain spans from residues 135-188.
  • this domain appears to be related to fibronectin type II, and it may play a role in interaction with the extracellular matrix and
  • the second domain is not essential to the practice of the invention, but preferred peptides include it.
  • Carbohydrate recognition domains comprise the remainder of the extracellular portion of the
  • CCDs C-type carbohydrate recognition domains
  • a transmembrane region and a COOH-terminal cytoplasmic domain are truncated from the receptor in peptides according to the invention to enhance solubility and facilitate therapeutic application of such peptides.
  • the molecule retains carbohydrate binding capacity effective for various purposes discussed elsewhere in this application.
  • Preferred peptides according to the invention include at least one or more, and preferably four or more, of the eight carbohydrate recognition domains
  • a peptide according to the invention includes multiple (two or more and, preferably, four or more) CRDs of mannose receptor protein.
  • individual CRDs can be repeated to further increase the carbohydrate binding capacity of the peptide according to the invention.
  • the peptide can include multiple copies of one or more of the specific CRDs of the mannose receptor, shown in Fig. 3.
  • Isolated nucleic acid encoding a CRD of mannose receptor protein is useful for producing recombinant peptide fragments of the protein.
  • the nucleic acid can be modified by standard techniques in order to express the same or modified peptides; e.g., by conservative base substitution the nucleic acid can be modified and still encode the same amino acid sequence, or the nucleic acid can be modified to encode a
  • MRP mannose receptor protein
  • Example 1 Cloning of Full Length MRP and Processing of MRP cDNA to encode and express peptides of the invention
  • Sequences for probes were determined by obtaining sequence information from purified receptor.
  • Receptor was purified from alveolar macrophages or human placenta as described (Lennartz et al., J. Biol. Chem. 262:9942, 1987).
  • oligonucleotide probes were synthesized on a Dupont oligonucleotide synthesizer, purified by gel filtration, and labeled with 32 p-ATP and polynucleotide kinase. Radiolabled probe was used to screen a pCDM8 placental cDNA library (gift of Dr. B. Seed, Harvard Medical School) by colony hybridization. Twenty-five positive clones were isolated by two rounds of
  • placental mannose receptor Teylor et al., J. Biol. Chem. 265:12156, 1990. This 3.3kb placental derived clone was radiolabeled and used as a probe to isolate the
  • macrophage mannose receptor cDNAs from a 7 day macrophage cDNA library (Ezekowitz et al., J. Exp. Med., in press, December, 1990).
  • a 750bp cDNA derived from the 5' extent of the placental mannose receptor cDNA was utilized to isolate 5' clones from the macrophage library.
  • a full- length cDNA was then assembled in a CDM8 expression vector.
  • the sequence of macrophage mannose receptor is identical to the placental form except for a C to T polymorphism at nucleotide 2284.
  • the initial placental clone was sequenced by double stranded sequencing using a modified T7 polymerase, Sequenase ® (U.S. Biochemical, Cleveland, Ohio) based on the Sanger chain termination method (Sanger et al., Proc. Natl. Acad. Sci., USA
  • the encoded protein sequence deduced from the nucleotide sequence is shown in Figs, 1a and 1b (SEQ ID NO: 1).
  • the open reading frame predicts a protein of 1438 amino acids which is consistent with the estimated molecular weight of the receptor polypeptide (150kD) after the N-linked sugars have been removed. (Lennartz et al., J. Biol. Chem. 264:2385, 1989; Taylor et al., J. Biol. Chem. 265:12156, 1990; Ezekowitz et al., J. Exp. Med., in press, December, 1990).
  • the features of the membrane bound mannose receptor protein are depicted in a schematic diagram (Fig. 2) and include (i) a typical hydrophobic signal peptide; (ii) a cysteine rich NH 2 terminal region; (iii) a fibronectin type II domain; (iv) eight carbohydrate recognition domains; (v) a hydrophobic transmembrane region; and (vi) a cytoplasmic tail.
  • the NH 2 terminal amino acid is defined by an N-terminus peptide as Leu, which is preceded by Ala-Val-Leu, a typical recognition sequence for a signal peptidase (Von Heijne, Eur. J.
  • cDNA encoding the full length mannose receptor protein (MRP) was first derived in a CDM8 plasmid
  • a construct of the cDNA encoding soluble mannose receptor peptide was then prepared in a CDM8 plasmid by a multiple step procedure, as follows.
  • an antisense primer was designed from a 3' end, at base pair 4169, to a 5' end, at base pair 4201, to contain a Hpal site.
  • the sense primer was prepared from a 5' end at base pair 3475 and encompassed the Nsil site base pair 3510.
  • the primers were annealed to full length mannose receptor cDNA, and a 726 base pair fragment was amplified using the polymerase chain reaction technique (PCR).
  • the full length cDNA mannose receptor in CDM8 was then digested with Nsil and Hpal which released a fragment from the unique Nsil site in the cDNA to the Hpal site in the vector, thereby removing (see Figs, la and 2) the last three amino acids of the ectodomain, the entire transmembrane region, the entire cytoplasmic domain, and some vector sequence.
  • This fragment was replaced with the 726 bp PCR fragment, thereby creating a clone (SMR), confirmed by sequence analysis, which contained cDNA encoding the signal peptide and the entire ectodomain of the mannose receptor (except for the last three amino acids).
  • This clone is capable of generating a soluble mannose receptor peptide.
  • This construct can be
  • transfected stably or ransiently into a mammalian expression system and the soluble receptor peptide expressed is secreted into the medium.
  • ATCC as ATCC No. 6843 a series of truncated forms of soluble mannose receptor peptide containing various numbers of carbohydrate recognition domains can be constructed by standard molecular biological techniques, either by using the polymerase chain reaction or convenient restriction enzyme sites to create molecules that can be secreted.
  • standard molecular biological techniques may be used to isolate other nucleic acid (especially cDNA) clones encoding the extracellular portion of the mannose receptor protein by procedures analogous to those described above.
  • Expression vectors suitable for peptide expression also include standard bacterial, yeast, and viral
  • soluble human mannose receptor peptides by these vectors and organisms can be followed using a mannan affinity column such as sepharose-mannose.
  • the column is first contacted With the expressed
  • Soluble mannose receptor peptides expressed as described above are useful for specifically targeting (or specifically recognizing) cells expressing carbohydrates such as mannose, N-acetylglucosamine, or fucose on their surface.
  • these peptides are useful in agents for diagnosing or treating infection by a wide variety of pathogenic organisms, e.g., Leishmania proamastigotes, Pneumocystis carinii, Candida albicans, Microbacteria tuberculosis (and other atypical mycobacteria), Human Immunodeficiency Virus Type l (HIV-1) or influenza virus.
  • Such agents are also useful for treating opportunistic infections such as those that arise in patients with cancer, patients undergoing chemotherapy or bone marrow transplants, or patients suffering from congenital or acquired immune deficiency diseases, such as AIDS.
  • agents can specifically target cancer cells having exposed mannose residues as a result of abberant glycosylation.
  • removing by host defense mechanisms is achieved by directing attachment of a soluble mannose receptor peptide, in conjunction with the cell attachment site of a receptor such as the mannose- binding protein, to the surface of phagocytic cells, thereby enhancing the clearance of the pathogens from the circulation by causing the phagocytes to recognize the pathogens.
  • a soluble mannose receptor peptide in conjunction with the cell attachment site of a receptor such as the mannose- binding protein
  • direct inactivation of the virus and viral infected cells is accomplished by attaching toxins, such as ricin, cholera, diphtheria, or pertussis, or
  • antimetabolic drugs such as AZT
  • AZT antimetabolic drugs
  • the hybrid peptide thus formed can serve to kill or inhibit growth of the target cell, such as HIV.
  • nucleic acid encoding such toxins can be ligated by well known
  • nucleic acid encoding a soluble mannose receptor peptide according to the invention, and the fused nucleic acid can be expressed as a single entity toform a hybrid peptide (for example, as described by
  • nucleic acid encoding a complement- fixing region e.g., the complement-fixing region of the immunoglobulin heavy chain or of the mannose-binding protein
  • nucleic acid encoding a soluble mannose receptor protein can be engineered by standard techniques to form a hybrid molecule with nucleic acid encoding a soluble mannose receptor protein.
  • the expression product of such nucleic acid can be used to target cells with exposed surface carbohydrate moieties and then to interact with complement components and activate complement. Activated complement will then stimulate binding of macrophages to the targeted pathogenic cells and their subsequent ingestion by the macrophages.
  • a soluble mannose receptor peptide-immunoglobulin fusion protein can be prepared by digesting cDNA encoding soluble mannose receptor peptide and inserting an
  • oligonucleotide linker e.g., a BamHl linker
  • the resulting plasmid can be digested with BamHl, and the portion encoding the entire extracellular domain can be ligated to the synthetic splice donor sequence of an immunoglobulin (e.g., human IgG1) expression plasmid
  • expression vectors contain in their 3' region the
  • immunoglobulin heavy chain constant regions two and three which have the capacity to fix complement.
  • a fusion protein expressed from such a fused cDNA sequence would contain a complement-fixing region at the 3' end of a soluble mannose receptor peptide.
  • fusion protein expressed from such a cDNA sequence would contain a complement-fixing region in the amino terminal portion of the molecule, preceding the carbohydrate recognition domains.
  • Soluble mannose receptor peptides according to the invention may be administered by routine methods in pharmaceutically acceptable carrier substances, i.e., inert substances suitable for pharmaceutical use such as the dispensing of drugs or medicine.
  • pharmaceutically acceptable carrier substances i.e., inert substances suitable for pharmaceutical use such as the dispensing of drugs or medicine.
  • they can be administered in an aerosol form to treat, e.g., Pneumocystis carinii.
  • they may be administered in an aerosol form to treat, e.g., Pneumocystis carinii.
  • they may be administered in an aerosol form to treat, e.g., Pneumocystis carinii.
  • they may be administered in an aerosol form to treat, e.g., Pneumocystis carinii.
  • they may be administered in an aerosol form to treat, e.g., Pneumocystis carinii.
  • they may be
  • administered orally or parenterally e.g., they can be injected directly into the blood stream of an animal, especially humans, to a level of between 1-500 ⁇ g/ml serum (most preferably, 100-150 ⁇ g/ml) final
  • the peptides can be administered prophylactically or after infection.
  • soluble mannose receptor peptides may be used to coat intravenous or urethral catheters (e.g., by chemical impregnation of the catheter material, with the peptide) to prevent infection in immunocompromised patients (e.g., cancer patients subjected to long term intravenous chemotherapy).
  • catheters will bind infective organisms and prevent their entry into the patient.
  • the soluble mannose receptor peptide may be applied topically in powder or lotion form (at a concentration of between 56-100 ⁇ g/ml), for example, to treat local infections, such as bacterial infection, yeast infection, or infection with
  • Soluble mannose receptor peptides can also be used as a diagnostic tool, e.g., for the diagnosis of fungal diseases. Fungi infecting an animal will shed a mannose- rich polysaccharide into the serum. A sample of serum from a patient (e.g., 100 ⁇ l) can be analyzed with
  • the degree of binding of the soluble mannose receptor peptide can be detected by using a labelled antibody that
  • the invention generally features peptides that include a MRP-derived carbohydrate recognition domain.
  • the genetic material encoding soluble mannose receptor peptide (deposited as described above as ATCC No. 68430) can be used to generate a large number of recombinant peptides by fragmenting the full- length nucleic acid and expressing candidate fragments.
  • standard molecular biological techniques may be used to isolate other proteins.
  • nucleic acid especially cDNA
  • clones encoding soluble mannose receptor peptides. These clones can also be used to express candidate fragment peptides. As described, preferred fragments are those containing multiple CRDs.
  • Various assays may be used to determine whether a
  • particular candidate peptide has carbohydrate recognition ability.
  • Another assay invokes binding and uptake of I 125 -labeled mannose-BSA. Specifically,
  • mannose-BSA EY Labs, CA
  • EY Labs, CA mannose-BSA
  • binding and uptake of radiolabled ligand is performed on COS-I cells transfected with cloned cDNA encoding the candidate peptide.
  • COS-I cells transfected with CD64 serve as controls, and thioglycollate elicited mouse peritoneal macrophages serve as a positive control.
  • Another assay utilizes antibody that specifically recognizes a soluble mannose receptor peptide.
  • the antibody may be linked with a fluorescent tag and
  • antibody-peptide binding identified flow cytometrically.
  • the antibody may be immobilized for assay use or employed in an enzyme linked immunosorbent assay or ELIZA test.
  • ATCC American Type Culture Collection
  • Applicant's assignee Children's Medical Center Corporation, represents that the ATCC is a depository affording permanence of the deposit and ready
  • GGC AAT GCC AAT GGA GCA ACC TGT GCA TTC CCG TTC AAG TTT GAA AAC 591 Gly Asn Ala Asn Gly Ala Thr Cys Ala Phe Pro Phe Lys Phe Glu Asn
  • ATC CAC ACC ATC GAG GAA TTG GAC TTT ATT ATC TCC CAG CTA GGA TAT 1311 lle His Thr lle Glu Glu Leu Asp Phe lle lle Ser Gln Leu Gly Tyr
  • GAG CCA AAT GAC GAA TTG TGG ATC GGC TTA AAT GAC ATT AAG ATT CAA 1359 Glu Pro Asn Asp Glu Leu Trp lle Gly Leu Asn Asp lle Lys lle Gln
  • AGT AAA CGA GGC TAC ATA TGC CAG ACA CGA TCC GAC CCT TCC TTG ACT 3327 Ser Lys Arg Gly Tyr lle Cys Gln Thr Arg Ser Asp Pro Ser Leu Thr
  • TTGTTTCCCC CAAGAGAGTT TTACAGGCTG AGTGTTGCAA ATGTGTTCTT TGTCCTGTTA 5024

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Abstract

L'invention concerne des peptides purifiés recombinés solubles dérivés d'une partie extracellulaire de la protéine réceptrice de mannose ainsi que de fragments de celle-ci, contenant un ou plusieurs domaines de reconnaissance de glucides, un acide nucléique produisant ces fragments, ainsi que des vecteurs et des cellules comprenant ledit acide nucléique. Les peptides sont utiles dans le traitement de maladies.
PCT/US1991/008320 1990-11-06 1991-11-06 Peptides solubles recepteurs de mannose WO1992007579A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002095729A CA2095729A1 (fr) 1990-11-06 1991-11-06 Peptides solubles du recepteur du mannose
JP4500952A JPH06501620A (ja) 1990-11-06 1991-11-06 可溶性マンノース受容体ペプチド
EP19920900254 EP0568539A4 (en) 1990-11-06 1991-11-06 Soluble mannose receptor peptides

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US609,915 1984-05-14
US60991590A 1990-11-06 1990-11-06

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WO (1) WO1992007579A1 (fr)

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US6395476B1 (en) 1995-07-27 2002-05-28 Imperial College Of Science Technology & Medicine Methods of predicting the outcome of HBV infection
EP1008351A4 (fr) * 1997-08-21 2004-11-10 Takara Bio Inc Agents cancerostatiques
US7560534B2 (en) 2000-05-08 2009-07-14 Celldex Research Corporation Molecular conjugates comprising human monoclonal antibodies to dendritic cells
US7563876B2 (en) 2000-05-08 2009-07-21 Celldex Therapeutics, Inc. Human monoclonal antibodies to dendritic cells
US8236318B2 (en) 2007-11-07 2012-08-07 Celldex Therapeutics Inc. Antibodies that bind human dendritic and epithelial cell 205 (DEC-205)
US9243064B2 (en) 2003-01-31 2016-01-26 Celldex Therapeutics Inc. Antibody vaccine conjugates and uses therefor
US9259459B2 (en) 2003-01-31 2016-02-16 Celldex Therapeutics Inc. Antibody vaccine conjugates and uses therefor
WO2019086513A1 (fr) * 2017-10-31 2019-05-09 The University Court Of The University Of Aberdeen Traitement et diagnostic de l'anémie
WO2022002982A1 (fr) 2020-06-30 2022-01-06 Henriques Normark Birgitta Peptides dérivés du récepteur de mannose pour neutraliser des toxines formant des pores pour des utilisations thérapeutiques

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US7563876B2 (en) 2000-05-08 2009-07-21 Celldex Therapeutics, Inc. Human monoclonal antibodies to dendritic cells
US8142790B2 (en) 2000-05-08 2012-03-27 Celldex Research Corporation Methods of using molecular conjugates comprising monoclonal antibodies to dendritic cells
US7560534B2 (en) 2000-05-08 2009-07-14 Celldex Research Corporation Molecular conjugates comprising human monoclonal antibodies to dendritic cells
US9243064B2 (en) 2003-01-31 2016-01-26 Celldex Therapeutics Inc. Antibody vaccine conjugates and uses therefor
US9259459B2 (en) 2003-01-31 2016-02-16 Celldex Therapeutics Inc. Antibody vaccine conjugates and uses therefor
US8236318B2 (en) 2007-11-07 2012-08-07 Celldex Therapeutics Inc. Antibodies that bind human dendritic and epithelial cell 205 (DEC-205)
US8362214B2 (en) 2007-11-07 2013-01-29 Celldex Therapeutics Inc. Antibodies that bind human dendritic and epithelial cell 205 (DEC-205)
US8586720B2 (en) 2007-11-07 2013-11-19 Celldex Therapeutics Inc. Antibodies that bind human dendritic and epithelial cell 205 (DEC-205)
US9624300B2 (en) 2007-11-07 2017-04-18 Celldex Therapeutics Inc. Antibodies that bind human dendritic and epithelial cell 205 (DEC-205)
WO2019086513A1 (fr) * 2017-10-31 2019-05-09 The University Court Of The University Of Aberdeen Traitement et diagnostic de l'anémie
WO2022002982A1 (fr) 2020-06-30 2022-01-06 Henriques Normark Birgitta Peptides dérivés du récepteur de mannose pour neutraliser des toxines formant des pores pour des utilisations thérapeutiques

Also Published As

Publication number Publication date
EP0568539A1 (fr) 1993-11-10
JPH06501620A (ja) 1994-02-24
CA2095729A1 (fr) 1992-05-07
EP0568539A4 (en) 1994-07-06
AU9040591A (en) 1992-05-26

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