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WO1992004381A1 - Nouveaux anticorps pour le traitement et la prevention d'infections chez l'homme et l'animal - Google Patents

Nouveaux anticorps pour le traitement et la prevention d'infections chez l'homme et l'animal Download PDF

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Publication number
WO1992004381A1
WO1992004381A1 PCT/GB1991/001554 GB9101554W WO9204381A1 WO 1992004381 A1 WO1992004381 A1 WO 1992004381A1 GB 9101554 W GB9101554 W GB 9101554W WO 9204381 A1 WO9204381 A1 WO 9204381A1
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Prior art keywords
antibody
rsv
altered
human
approximately
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William J. Harris
Philip R. Tempest
Geraldine Taylor
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SCOTGEN Ltd
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SCOTGEN Ltd
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Priority to AU85058/91A priority Critical patent/AU654827B2/en
Publication of WO1992004381A1 publication Critical patent/WO1992004381A1/fr
Priority to KR1019930700750A priority patent/KR930702519A/ko
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2/00—Peptides of undefined number of amino acids; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1027—Paramyxoviridae, e.g. respiratory syncytial virus
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • RSV respiratory syncytial virus
  • This process may be used, for example, to substitute the CDRs from human heavy and light chain Ig variable region domains with alternative CDRs from murine variable region domains. These altered Ig variable regions may subsequently be combined with human Ig constant regions to create antibodies which are totally human in composition except for the substituted murine CDRs.
  • variable regions of heavy and light chains each comprise three looped structures (which include the CDRs) supported on a sheet-like structure termed the variable region framework.
  • variable region framework amino acid residues may be important in antigen binding through direct interaction with CDRs (See, Amit et al., Science, 233 (1986) pp 747-753; Queen et al., Proc. Natl. Acad. Sci., 86 (1989) pp10029- 10033; and Protein Design Labs, Patent Cooperation Treaty Patent
  • the present invention provides altered antibodies for prevention and treatment of infectious disease and a process for their production by introducing only critical variable region framework modifications.
  • RSV which is in the genus Pneumovirus of the Paramyxo ⁇ iridae family, is a major cause of lower respiratory tract infections in young children. Primary infection gives an incomplete immunity, and reinfection is frequently observed during childhood. The role of immune mechanisms in the human disease have not been clarified. Previous attempts to develop effective vaccines with attenuated or killed RSV have met with failure, i.e., not only were the children unprotected, but subsequent infections with RSV sometimes
  • RSV infection is also a major cause of respiratory infection in young cattle.
  • RSV fusion protein F
  • RSV attachment protein G
  • a and B Two antigenically distinct subgroups of human RSV, designated A and B, have been described.
  • the antigenic differences between A and B subgroups reside mainly on the RSV G protein.
  • the RSV F protein has a high degree of genetic and antigenic homology between the two subgroups, and various strains within these subgroups.
  • a neutralizing and protective epitope of an RSV viral antigen could prove useful in the generation of monoclonal antibodies useful for the prophylaxis and/or treatment of RSV infection.
  • the present invention provides such a novel epitope on the RSV F protein which is recognised by a neutralizing and protective antibody in vivo.
  • Figure 1 shows the DNA sequence and corresponding amino acid sequence of the RSV19 heavy chain variable region (VH).
  • the CDR sequences are boxed.
  • the first eight and last eleven amino acids, as underlined, correspond to sequences of the oligonucleotide primers used.
  • Figure 2 shows the DNA sequence and corresponding amino acid sequence of the RSV19 light chain variable region (VK).
  • VK light chain variable region
  • Figure 3 shows the basic plasmid pHuRSV19VH comprising a human Ig heavy chain variable region framework and CDRs derived from mouse RSV19.
  • Figure 4 shows the basic plasmid pHuRSV19VK comprising a human Ig light chain variable region framework and CDRs derived from mouse RSV19.
  • Figure 5 shows the derived Ig variable region amino acid sequences encoded by RSV19VH, RSV19VK, pHuRSWH and pHuRSV19VK, and derivations ofpHuRSV19VH.
  • Figure 6 shows an ELISA analysis of the binding of HuRSV19VH/VK antibody and its derivative, HuRSV19VHFNS/VK, to RSV antigen.
  • Figure 7 shows that mAb RSV19 binds to two synthetic peptides
  • the present invention relates to altered antibodies in which at least parts of the complementarity dete ⁇ nining regions (CDRs) in the light and/or heavy variable domains of an acceptor monoclonal antibody have been replaced by analagous parts of CDRs from one or more donor monoclonal antibodies, and in which there may or may not have been minimal alteration of the acceptor monoclonal antibody light and/or heavy variable domain
  • CDRs complementarity dete ⁇ nining regions
  • the present invention also relates to a process for preparing such altered antibodies; a pharmaceutical composition comprising a therapeutic, non-toxic amount of such altered antibodies and a pharmaceutically acceptable carrier or diluent; and a method of prophylactically or
  • the altered antibodies of the invention will be produced by recombinant DNA technology.
  • the altered antibody of the present invention may comprise a complete antibody molecule (having full length heavy and light chains) or any fragment thereof, such as the Fab or (Fab')2 fragment, a light chain or heavy chain dimer, or any minimal recombinant fragment thereof such as an Fv or a SCA (single-chian antibody) or any other molecule with the same specificity as the altered antibody of the invention.
  • the altered antibody of the invention may have attached to it an effector or reporter molecule.
  • the altered antibody of the invention may have a macrocycle, for chelating a heavy metal atom, or a toxin, such as ricin, attached to it by a covalent briding structure.
  • the procedure of recombinant DNA technology may be used to produce an altered antibody of the invention in which the Fc fragment or CH3 domain of a complete antibody molecule has been replaced by an enzyme or toxin molecule.
  • the remainder of the altered antibody may be derived from any suitable human iminunoglobulin. However, it need not comprise only protein sequences from the human immunoglobulin.
  • a gene may be constructed in which a DNA sequence encoding part of a human immunoglobulin chain is fused to a DNA sequence encoding the amino acid sequence of a polypeptide effector or reporter molecule.
  • Another aspect of this invention is the discovery of a specific epitope of the F (fusion) protein of RSV which has been demonstrated to be a target for monoclonal antibodies which both protect and cure mice of infection by RSV.
  • Fab fragments of such monoclonal antibodies protect mice from in vivo infection.
  • the present invention also relates to such specific epitope of the F protein of RSV;
  • this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutic, non-toxic amount of such monoclonal antibodies or Fab fragments and a pharmaceutically acceptable carrier or diluent; and a method of prophylactically or
  • therapeutically treating RSV infection in a human or animal in need thereof which comprises administering an effective amount of such monoclonal antibodies or Fab fragments to such human or animal.
  • the present invention provides altered antibodies with specificity for microorganisms, and the DNA coding for such antibodies.
  • These antibodies comprise Ig constant regions and variable regions from one source, and one or more CDRs from a different source.
  • the invention also provides vectors producing the altered antibodies in mammalian cell hosts.
  • the present invention particularly applies to the provision of altered antibodies with the combination of properties required for the prevention and treatment of infections in animals and man.
  • non-human antibodies with specificity for micro organisms may be altered to produce "humanised” antibodies which elicit a minimal immune response in humans.
  • the invention provides "humanised” antibodies with specificity for RSV which are shown to be effective in an animal model for RSV infection in humans and to recognise a large variety of human clinical isolates of RSV.
  • the present invention also provides a method for effecting minimal modifications to the amino acids of variable region frameworks in order to retain the antigen binding capacity of CDRs from a different source.
  • the method involves step wise alteration and testing of individual amino acids in the variable region framework potentially critical for antigen binding affinity.
  • the method avoids major introduction of framework amino acids from the same source as CDRs.
  • humanized antibody refers to a molecule having its complementarity determining regions (and, perhaps, minimal portions of its light and/or heavy variable domain framework region) derived from an immunoglobulin from a non-human species, the remaining immunoglobulin- derived parts of the molecule being derived from a human immunoglobulin.
  • the present invention relates to altered antibodies in which at least parts of the complementarity determining regions (CDRs) in the light and/or heavy variable domains of an acceptor monoclonal antibody have been replaced by analagous parts of CDRs from one or more donor monoclonal antibodies, and in which there may or may not have been minimal alteration of the acceptor monoclonal antibody light and/or heavy variable domain
  • CDRs complementarity determining regions
  • the present invention also relates to a process for preparing such altered antibodies; a pharmaceutical composition comprising a therapeutic, non-toxic amount of such altered antibodies and a pharmaceutically acceptable carrier or diluent; and a method of prophylactically or
  • therapeutically treating a microorganism-induced disease state in a human or animal in need thereof which comprises administering an effective amount of such altered antibodies to such human or animal.
  • the altered antibodies of the invention may be produced by the following process:
  • variable domain (a) producing, by conventional techniques, in an expression vector an operon having a DNA sequence which encodes an antibody heavy or light chain wherein at least the CDRs (and those minimal portions of the acceptor monoclonal antibody light and/or heavy variable domain framework region required in order to retain donor monoclonal antibody binding specificity) of the variable domain are derived from a non-human immunoglobulin, such as that produced by RSV19, and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin, thereby producing the vector of the invention;
  • variable domain derived from a non-human immunoglobulin, such as that produced by RSV19, and the remaining immunoglobulin-derived parts of the antibody chain are derived from a human immunoglobulin, thereby producing another vector of the invention;
  • the host cell may be transfected with two vectors of the invention, the first vector containing an operon encoding a light chain-derived polypeptide and the second vector containing an operon encoding a heavy chain-derived plypeptide.
  • the vectors are identical except in so far as the coding sequences and selectable markers are concerned so to ensure as far as possible that each polypeptide chain is equally expressed.
  • a single vector of the invention may be used, the vector including the sequence encoding both light chain- and heavy chain-derived polypeptides.
  • the DNA in the coding sequences for the light and heavy chains may comprise cDNA or genomic DNA or both.
  • the host cell used to express the altered antibody of the invention is preferably a eukaryotic cell, most preferably a mammalian cell, such as a CHO cell or a myeloid cell.
  • the altered antibodies of the invention may be purified according to standard procedures of the art, including ammonium sulfate precipitation, affinity columns, column chromatography, gel electrophoresis and the like.
  • an example of the altered antibody of the invention are humanised antibodies derived from the murine monoclonal antibody RSV19 such as HuRSV19VH/VK and HuRSV19VHFNS/HuRSV19VK which are described in the Examples. Such antibodies are useful in treating, therapeutically or prophylactically, a human against human RSV infection. Therefore, this invention also relates to a method of treating, therapeutically or
  • human RSV infection in a human in need thereof which comprises administering an effective, human RSV infection treating dose such altered antibodies to such human.
  • the altered antibodies of this invention may also be used in conjunction with other antibodies, particularly human monoclonal antibodies reactive with other markers (epitopes) responsible for the disease against which the altered antibody of the invention is directed.
  • the altered antibodies of this invention may also be used as separately administered compositions given in conjunction with chemotherapeutic or immunosuppressive agents.
  • chemotherapeutic or immunosuppressive agents The appropriate combination of agents to utilized can readily be determined by one of skill in the art using
  • the altered antibody of the invention known as HuRSV19VHFNS/HuRSV19VK may be given in conjunction with the antiviral agent ribavirin in order to facilitate the treatment of RSV infection in a human.
  • One pharmaceutical composition of the present invention comprises the use of the antibodies of the subject invention in immunotoxins, i.e., molecules which are characterized by two components and are particularly useful for killing selected cells in vitro or in vivo.
  • immunotoxins i.e., molecules which are characterized by two components and are particularly useful for killing selected cells in vitro or in vivo.
  • One component is a cytotoxic agent which is usually fatal to a cell when attached or absorbed.
  • the second component known as the "delivery vehicle” provides a means for delivering the toxic agent to a particular cell type, such as cells comprising a
  • the two components are commonly chemically bonded together by any of a variety of well-known chemical procedures.
  • the linkage may be by way of heterobifunctional cross- linkers, e.g., carbodiimide, glutaraldehyde and the like, Production of various immunotoxins is well-known in the art.
  • cytotoxic agents are suitable for use in immunotoxins, and may include, among others, radionuclides, chemotherapeutic drugs such as methotrexate, and cytotoxic proteins such as ribosomal inhibiting proteins (e.g., rici n).
  • the delivery component of the immunotoxin will include the human-like immunoglobulins of the present invention. Intact immunoglobulins or their binding fragments, such as Fab, are preferably used. Typically, the antibodies in the immunotoxins will be of the human IgM or IgG isotype, but other mammalian constant regions may be utilized if desired.
  • the altered antibodies and pharmaceutical compositions of the invention are particularly useful for parenteral administration, i.e., subcutaneously, intramuscularly or intravenously.
  • the compositions for parenteral administration will commonly comprise a solution of the altered antibody of the invention or a cocktail thereof dissolved in an acceptable carrier, preferably an aqueous carrier.
  • an acceptable carrier preferably an aqueous carrier.
  • aqueous carriers may be employed, e.g., water, buffered water, 0.4% saline, 0.3% glycine, and the like. These solutions are sterile and generally free of particulate matter. These solutions may be sterilized by conventional, well known sterilization techniques.
  • the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, etc.
  • concentration of the altered antibody of the invention in such pharmaceutical formulation can vary widely, i.e., from less than about 0.5%, usually at or at least about 1% to as much as 15 or 20% by weight and will be selected primarily based on fluid volumes, viscosities, etc., according to the particular mode of
  • a pharmaceutical composition of the invention for intramuscular injection could be prepared to contain 1 mL sterile buffered water, and 50 mg of an altered antibody of the invention.
  • a pharmaceutical composition of the invention for intravenous infusion could be made up to contain 250 ml of sterile Ringer's solution, and 150 mg of an altered antibody of the invention.
  • Actual methods for preparing parenterally administrate compositions are well known or will be apparent to those skilled in the art and are described in more detail in, for example,
  • the altered antibodies of the invention can be lyophilized for storage and reconstituted in a suitable carrier prior to use. This technique has been shown to be effective with conventional immune globulins and art-known lyophilization and reconstitution techniques can be employed.
  • the pharmaceutical composition of the invention can be administered for prophylactic and/or therapeutic treatments.
  • compositions are administerd to a patient already suffering from a disease, in an amount sufficient to cure or at least partially arrest the disease and its complications.
  • compositions containing the present antibodies or a cocktail thereof are administered to a patient not already in a disease state to enhance the patient's resistance.
  • Single or multiple administrations of the pharmaceutical compositions can be carried out with dose levels and pattern being selected by the treating physician.
  • the pharmaceutical composition of the invention should provide a quantity of the altered antibodies of the invention sufficient to effectively treat the patient.
  • Another aspect of this invention is the discovery of a specific epitope of the F (fusion) protein of RSV which has been demonstrated to be a target for monoclonal antibodies which both protect and cure mice of infection by RSV.
  • Fab fragments of such monoclonal antibodies protect mice from in vivo infection.
  • the present invention also relates to such specific epitope of the F protein of RSV;
  • this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutic, non-toxic amount of such monoclonal antibodies or Fab fragments and a pharmaceutically acceptable carrier or diluent; and a method of prophylactically or
  • therapeutically treating RSV infection in a human or animal in need thereof which comprises administering an effective amount of such monoclonal antibodies or Fab fragments to such human or animal.
  • the present invention provides altered antibodies with specificity for microorganisms, and the DNA coding for such antibodies.
  • These antibodies comprise Ig constant regions and variable regions from one source, and one or more CDRs from a difference source.
  • the invention also provides vectors producing the altered antibodies in mammalian cell hosts.
  • the present invention particularly applies to the provision of altered antibodies with the combination of properties required for the prevention and treatment of infections in animals and man.
  • non-human antibodies with specificity for micro organisms may be altered to produce "humanised” antibodies which elicit a minimal immune response in humans.
  • the invention provides "humanised” antibodies with specificity for RSV which are shown to be effective in an animal model for RSV infection in humans and to recognise a large variety of human clinical isolates of RSV.
  • the present invention also provides a method for effecting minimal modifications to the amino acids of variable region frameworks in order to retain the antigen binding capacity of CDRs from a different source.
  • the method involves stepwise alteration and testing of individual amino acids in the variable region framework potentially critical for antigen binding affinity.
  • the method avoids major introduction of framework amino acids from the same source as CDRs.
  • Maniatis et. al. published by Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (hereinafter referred to as "Maniatis et al.”).
  • the following abbreviations may be employed: dCTP deoxycytidine triphosphate
  • Examples 1-3 describe the preparation of the altered antibodies of the invention.
  • the source of the donor CDRs utilized to prepare these altered antibodies was a murine monoclonal antibody, RSV19, specific for the fusion (F) protein of RSV.
  • the RSV19 hybridoma cell line was obtained from Dr.
  • Cytoplasmic RNA was prepared by the method of Favaloro et. al., (1980)
  • VH1FOR (5TGAGGAGACGGTGACCGTGGTCCCTTGGCCCCAG3') was used, and
  • the primer for the Ig light chain variable region (VK), the primer
  • VK1FOR (5'GTTAGATCTCCAGCTTGGTCCC3')
  • cDNA synthesis reactions consisted of 20mg RNA, 0.4mM VH1FOR or VKIFOR, 250mM each of dATP, dCTP, dGTP and dTTP, 50mM Tris-HCl pH 7.5, 75mM KCl, 10mM DTT, 3mM MgCl 2 and 27 units RNase inhibitor (Pharmacia, Milton Keynes, United Kingdom) in a total volume of 50ml. Samples were heated at 70°C for 10 minutes (min) and slowly cooled to 42°C over a period of 30 min. Then, 100m MMLV reverse transcriptase (Life Technologies, Paisley, United Kingdom) was added and incubation at 42°C continued for 1 hour.
  • VH and VK cDNAs were then amplified using the polymerase chain reaction (PCR) as described by Saiki, et al., Science. 239 (1988). p487-491.
  • PCR polymerase chain reaction
  • the primers used were:
  • DNA/primer mixtures consisted of 5ml
  • RNA/cDNA hybrid RNA/cDNA hybrid
  • VHIFOR and VHIBACK primers 0.5mM VHIFOR and VHIBACK primers.
  • DNA/primer mixtures consisted of 5ml RNA/cDNA hybrid, and 0.5mM VHIFOR and VKIBACK primers.
  • To these mixtures was added 200 mM each of dATP, dCTP, dGTP and dTTP, 10mM Tris-HCl pH 8.3, 50mM KCl, 1.5mM MgCl 2 , 0.01% (w/v) gelatin, 0.01% (v/v) Tween 20, 0.01% (v/v) Nonidet P40 and 2 units Taq DNA polymerase (United
  • VH DNA was either directly ligated into the Smal site of M13 mp18/19 (Pharmacia-Milton Keynes, UK) or, following digestion with PstI, into the PstI site of M13tg131 (Amersham International-Little
  • VK was similarly gel purified and cloned by the following alternatives:
  • VHCDR1 5'CTGTCTCACCCAGTGCATATAGTAGTCGCTGAAGGTGAA
  • VHCDR2 5'CATTGTCACTCTGCCCTGGAACTTCGGGGCATATGGAA
  • VKCDR35' CCCTTGGCCGAACGTCCGAGGAAGATGTGAACCTTGAA
  • AGCAGTAGTAGGT3' The DNA templates for mutagenesis comprised human framework regions derived from the crystallographically solved proteins, NEW ( described by Saul, et al., J. Biol., Chem., 53 (1978), p585-597) with a substitution of amino acid 27 from serine to phenylalanine (See, Riechmann et al., loc. cit.) and REI (described by Epp et al, Eur J. Biochem, 45 (1974), p513-524) for VH and VK domains, respectively.
  • NEW described by Saul, et al., J. Biol., Chem., 53 (1978), p585-597
  • REI described by Epp et al, Eur J. Biochem, 45 (1974), p513-524
  • Oligonucleotide site directed mutagenesis of the human VH and VK genes was based on the method of Nakamaye et al., Nucl. Acids Res, 14 (1986) p9679-9698.
  • VH or VK single-stranded DNA in M13 was added a two-fold molar excess of each of the three VH or VK phosphorylated oligonucleotides encoding the three mouse CDR (complementarity deterniining region) sequences.
  • Primers were annealed to the template by heating to 70°C and slowly cooled to 37°C. To the annealed DNA was added 6u Klenow
  • dATP nucleoside triphosphates
  • dGTP nucleoside triphosphates
  • dTTP 2'-deoxycytidine 5'-0-(1- thiotriphosphate)
  • thiodCTP nucleoside triphosphates
  • 60mM Tris-HCl pH 8.0
  • 6mM MgCl 2 5mM DTT (Sigma, Poole, UK)
  • 10mM ATP in a reaction volume of 50ml. This mixture was incubated at 16°C for 15 hours (h).
  • the DNA was then ethanol precipitated and digested with 5 units Neil (life Technologies, Paisley, UK) which nicks the parental strand but leaves the newly synthesised strand containing thiodCTP intact.
  • the parental strand was then removed by digesting for 30 min with 100 units exonuclease III (Pharmacia, Milton Keynes, United Kingdom) in 50 ml of 60mM Tris-HCl (pH 8.0), 0.66mM MgCl 2 , and ImM DTT.
  • the DNA was then repaired through addition of 3 units of DNA polymerase I (Life Technologies, Paisley, UK), 2 units T4 DNA ligase in 50 ml of 60mM Tris-HCl (pH 8.0), 6mM MgCl 2 , 5mM DTT, 10mM ATP and 0.5mM each of dATP, dCTP, dGTP and dTTP.
  • the DNA was transformed into competent E.
  • coli TGI cells (Amersham International, Little Chalfont, UK) by the method of Maniatis et al. Single-stranded DNA was prepared from individual plaques and sequenced by the method of Messing (1983) Methods in Enzymology, 101, p. 20-78. If only single or double mutants were obtained, then these were subjected to further rounds of mutagenesis (utilizing the methodology described above) by using the appropriate oligonucleotides until the triple CDR mutants were obtained.
  • pHuRSV19VH and pHuRSV19VK For pHuRSV19VH, the
  • pHuRSV19VK plasmid The construction of the pHuRSV19VK plasmid was essentially the same except that the gpt gene was replaced by the hygromycin
  • YB2/0 cells from the American Type Culture Collection, Rockville, Maryland, USA
  • 0.5ml DMEM Gibco, Paisley, UK
  • the cells were given a single pulse of 170V at 960uF (Gene-Pulser, Bio-Rad-Richmond, California, USA) and left in ice for a further 20 min.
  • the cells were then put into 20 ml DMEM plus 10% foetal calf serum and allowed to recover for 48h.
  • the cells were distributed into a 24-well plate and selective medium applied (DMEM, 10% foetal calf serum, 0.8mg/ml mycophenolic acid, and 2 ⁇ 0mg/ml xanthine). After 3-4 days, the medium and dead cells were removed and replaced with fresh selective medium. Transfected clones were visible with the naked eye 10-12 days later.
  • DMEM 10% foetal calf serum, 0.8mg/ml mycophenolic acid, and 2 ⁇ 0mg/ml xanthine
  • Micro-titre plates were coated overnight at 4°C with goat anti-human IgG (gamma chain specific) antibodies (Sera-Lab- LtdL, Crawley Down, UK) at 1 mg per well. After washing with PBST (phosphate buffered saline containing 0.02% Tween 20x (pH7.5)), 100ml of culture medium from the wells containing transfectants was added to each microtitre well for lh at 37°C.
  • PBST phosphate buffered saline containing 0.02% Tween 20x (pH7.5)
  • pHuRSVVK was purified on Protein-A agarose columns
  • Antigen consisted of calf kidney (CK) cells infected with RSV (A2 strain of RSV obtained from a child in Australia and described by Lewis et al., Med. J. Australia, 48, 932- 933 (1961)) and treated with 0.5% (v/v) NP40 detergent to yield a cell lysate.
  • a control cell lysate was similarly prepared using uninfected CK cells. Microtitre plate wells were coated with either infected or control cell lysate.
  • Antigen coated plates were blocked with PBST for 1 hour at 37°C, washed with PBST, and thereafter humanised antibody was applied (i.e., HuRSV19VH/VK). After 1 hour at 37°C, the wells were emptied, washed with PBST and 200 ng goat anti-human IgG antibodies (Sera Lab-Ltd., Crawley Down, UK) added per well. After 1 hour at 37°C, the wells were emptied, washed with PBST and 200ml of a 1:1000 dilution of horseradish peroxidase conjugated rabbit anti-goat IgG antibodies (Sigma-Poole, UK) were added.
  • HuRSVV H/VK bound to RSV although with an affinity less than the murine RSV19 antibody.
  • the method of this invention involves the following order of steps of alteration and testing: 1. Individual framework amino acid residues which are known to be critical for interaction with CDRs are compared in the primary antibody and the altered CDR-replacement antibody. For example, heavy chain amino acid residue 94 (Kabat numbering- see Kabat et al., cited above) is compared in the primary (donor) and altered antibodies. An arginine residue at this position is thought to interact with the invariant heavy chain CDR aspartic acid residue at position 101.
  • amino acid 94 comprises arginine in the framework of the primary antibody but not in the framework of the altered antibody
  • an alternative heavy chain gene comprising arginine 94 in the altered antibody is produced.
  • the altered antibody framework comprises an ajginine residue at position 94 but the primary antibody does not
  • an alternative heavy chain gene comprising the original amino acid at position 94 is produced.
  • alternative plasmids produced on this basis are tested for production of high affinity altered antibodies.
  • Framework amino acids within 4 residues of the CDRs as defined according to Kabat are compared in the primary antibody and altered CDR-replacement antibody. Where differences are present, then for each region (e.g., upstream of VHCDR1) the specific amino acids of that region are substituted for those in the corresponding region of the altered antibody to provide a small number of altered genes. Alternative plasmids produced on this basis are then tested for production of high affinity antibodies.
  • Alternative plasmids are produced on this basis with the individual highlighted amino acids represented by the corresponding amino acids of the primary antibody and such alternative plasmids are tested for production of high affinity antibodies.
  • the method is exemplified by the production of a high affinity altered antibody derivative of HuRSVVH/VK (See, Example 1) specific for RSV.
  • Comparison of VH gene sequences between RSV19VH and pHuRSV19VH indicates that 3 out of 4 amino acid differences occur between amino acids 27 to 30 and between amino acids 91 to 94.
  • pHuRSV19VHNlK and pHuRSV19VHFNS were produced with framework amino acids 27 to 30 and 91 to 94 in the former, and amino acids 91 and 94 in the latter, represented as in the primary RSV19VH.
  • oligonucleotide site directed mutagenesis as described in Example 1, the following oligonucleotides were used for mutagenesis of the HuRSV19VH gene in M13:
  • pHuRSV19VHNIK 5'ATATAGTAGTCTTTAATGTTGAAGCCAGA CA3'
  • Humanised HuRSV19VHFNS/HuRSV19VK antibody was tested in an ELISA assay as detailed in Example 1 for analysis of binding to RSV antigen prepared from detergent-extracted, virus-infected cells.
  • Figure 6 shows that the substitution of VH residues 91 to 94 in HuRSV19VH/VK with VH residues from mouse RSV19VH partially restored antigen binding levels. Additional analysis of HuFNS binding properties was performed using an ELISA assay in which intact Type A RS virus (Long strain) was used as the antigen.
  • Specifidty of HuRSV19VHFNS/HuRSV19VK for RSV F protein was shown by conventional Western blot analysis using a truncated soluble F protein construct expressed in CHO cells.
  • HuRSV19VHFNS/HuRSV19VK HuRSV19VHFNS/HuRSV19VK, or the murine antibody RSV19
  • HuRSV19VHFNS/HuRSV19VK or the murine antibody RSV19
  • fluorescein-conjugated rabbit anti-mouse IgG Nadic Laboratories- Tilburg, The Netherlands
  • fluorescein-conjugated goat anti- human IgGl Southern Biotechnology, Birmingham, Alabama, USA
  • cells were mounted in glycerol and examined under UV light.
  • Table I shows the results of comparative immunofluorescence for the humanised antibody, HuRSV19VHFNS/HuRSV19VK, and the murine antibody RSV19. This data indicates that 100% of clinical isolates are recognised by both the humanised and murine antibodies.
  • the humanised antibody has the potential for recognition of most clinical isolates comprising both of the major RSV subgroups.
  • * +,++,+++ and ++++ refer to relative numbers of fluorescing cells observed and represent the proportion of cells infected
  • the humanised antibody, HuRSV19VHFNS/HuRSV19VK was next tested for biological activity in vitro in a fusion inhibition assay. A suspension of MA104 cells was infected with RSV at an m.o.i.
  • HuRSV19VHFNS/HuRSV19VK in inhibiting Type A RSV induced cell fusion. It should be noted that additional studies showed that the fusion inhibition titres for RSV19 versus
  • HuRSV19VHFNS/HuRSV19VK were comparable, providing additional evidence that affinity for the native viral antigen was fully restored in HuRSV19VHFNS/HuRSV19VK
  • the humanized antibody HuRSV19VHFNS/HuRSV19VK has also been shown, (using methodology analogous to that utilized above for showing inhibition of Type A RSV induced cell fusion), to exhibit a dose dependent inhibition of Type B RSV (strain 8/60) induced giant cell fusion.
  • the humanised antibody, HuRSV19VHFNS/HuRSV19VK was next tested for biological activity in vivo in an RSV-mouse infection model.
  • BALB/c mice obtained from Charles Rivers: spe ⁇ fic pathogen free category 4 standard
  • 10 4 PFU of the A2 strain of human RSV as described by
  • mice were administered with 25mg of humanised antibody either one day prior to virus infection or 4 days following infection. Administration of antibody was either by the intranasal (i.n.) or intraperitoneal (i.p.) routes, 5 days after RSV infection, mice were sacrificed and lungs were assayed for RSV PFU (see, Taylor et al., Infection and Immunity, 43 (1984) p649-655).
  • Table III shows that HuRSV19VHFNS/HuRSV19VK at a single dose of 25mg per mouse is extremely effective in prevention and treatment of RSV infection.
  • * -1 refers to administration of HuRSV19VHFNS/HuRSV19VK antibody 1 day prior to RSV infection
  • +4 refers to administration of antibody 4 days post infection
  • HuRSV19VHFNS/HuRSV19VK was also shown to be active in vivo when administered prophylactically to mice challenged with Type B RSV (strain 8/60) using methodology similar to that described above.
  • the humanized antibody HuRSV19VH/VK was also shown to be active in vivo when administered prophylactically to mice challenged with Type B RSV (strain 8/60) using
  • This invention also relates to a method of preventing human RSV infection in a human in need thereof which comprises
  • This invention also relates to a method of therapeutically treating human RSV infection in a human in need thereof which comprises administering to such human an effective, human RSV infection therapeutic dose of an altered antibody of this invention for which RSV19 or RSV20 was the donor monoclonal antibody.
  • HuRSV19VHFNS/HuRSV19VK should be administered
  • parenterally preferably i.v. (intravenously) or i.m.
  • HuRSV19VHFNS/HuRSV19VK should be administered
  • the altered antibodies of the invention may also be administered by inhalation.
  • inhalation is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • a composition for administration by inhalation for an aerosol container with a capadty of 15-20 ml: Mix 10 mg of an altered antibody of this invention with 0.2-0.2% of a lubricating agent, such as polysorbate 85 or oleic add, and disperse such mixture in a propellant, such as freon, preferably in a combination of (1,2 dichlorotetrafluoroethane) and difluorochloromethane and put into an appropriate aerosol container adaped for either intranasal or oral inhalation administration.
  • a propellant such as freon
  • a composition for administration by inhalation for an aerosol container with a capadty of l ⁇ -20 ml: Dissolve 10 mg of an altered antibody of this invention in ethanol (6-8 ml), add 0.1-0.2% of a lubricating agent, such as polysorbate 8 ⁇ or oleic add; and disperse such in a propellant, such as freon, preferably a combination of (1.2 dichlorotetrafluoroethane) and difluorochloromethane, and put into an appropriate aerosol container adapted for either intranasal or oral inhalation administration.
  • a propellant such as freon
  • the preferred daily dosage amount to be employed of an altered antibody of the invention to prophylactically or therapeutically treat RSV infection in a human in need thereof to be administered by inhalation is from about 0.1 mg to about 10 mg/kg per day).
  • Examples 1-3 show that altered antibodies for prevention and treatment of infection can be produced with variable region frameworks potentially recognised as "self" by redpients of the altered antibody. Minor modifications to the variable region frameworks can be implemented to effect large increases in antigen binding without appredable increased immunogenidty for the redpient. Such altered antibodies can effectively prevent and eradicate infection.
  • the present invention provides an altered antibody in which complementarity determining regions (CDRs) in the heavy or light chain variable domains have been replaced by analogous parts of CDRs from a different source resulting in antibodies possessing the combination of properties required for effective prevention and treatment of infectious disease in animals or man.
  • CDRs complementarity determining regions
  • the entire CDRs have been replaced.
  • the variable domains in both heavy and light chains have been altered by CDR
  • the CDRs from a mouse antibody are grafted onto the framework regions of a human antibody.
  • the altered antibody preferably has the structure of a natural antibody or a fragment thereof.
  • a preferred antibody is one directed against respiratory syncytial virus (RSV), preferably one specific for the fusion (F) protein of RSV.
  • RSV respiratory syncytial virus
  • F fusion protein of RSV.
  • a particularly preferred antibody of this kind has the following N-terminal variable domain amino add sequences (see the Amino Add Shorthand Table immediately following) in its heavy and light chains: heavy:
  • an altered antibody may be further altered by changes in variable domain amino adds without necessarily affecting the specifidty of the antibody for the fusion (F) protein of RSV, and it is antidpated that even as many as 25% of heavy and light chain amino adds may be substituted by other amino adds either in the variable domain frameworks or CDRs or both.
  • Such altered antibodies can be effective in prevention and treatment of respiratory syncytial virus (RSV) infection in animals and man.
  • the invention also includes a recombinant plasmid containing the coding sequence of the altered antibody of the invention, and a mammalian cell-line transfected with a recombinant plasmid containing the coding sequence of the altered antibodies hereof.
  • Such a vector is prepared by conventional techniques and suitably comprises DNA sequences encoding immunoglobulin domains including variable region frameworks and CDRs derived from a different source and a suitable promoter operationally linked to the DNA sequences which encode the altered antibody.
  • Such a vector is transfected into a transfected mammalian cell via conventional techniques.
  • epitope 417-438 This novel epitope (which may be referred to herein as “epitope 417-438”) is a suitable target for screening for other neutralizing epitopes, for protective and therapeutic agents against RSV, and in particular, for monoclonal antibodies against this epitope. Knowledge of this epitope enables one of skill in the art to define synthetic peptides which would be suitable as vacdnes against RSV. Epitope 417-438 is also useful for generating monodonal antibodies which will be useful in the treatment, therapeutic and/or prophylactic, of human RSV infection in humans.
  • the present invention also applies to the use of Fab fragments derived from monodonal antibodies directed against such novel epitope as protective and therapeutic agents against in vivo infection by viruses, and particularly relates to the protection against RSV.
  • the invention also includes a recombinant plasmid containing the coding sequence of a monodonal antibody generated against the 417-438 epitope, and a mammalian cell-line transfected with a recombinant plasmid containing such coding sequence.
  • a vector is prepared by conventional techniques and suitably comprises DNA sequences encoding immunoglobulin domains including variable region frameworks and CDRs and a suitable promoter operationally linked to the DNA sequences which encode the antibody.
  • Such a vector is transfected into a mammalian cell via conventional techniques.
  • Murine monodonal antibodies 19 and 20 were produced as follows. BALB/c mice (obtained from Charles Rivers-spedfic pathogen free) were inoculated intranasally (i.n.) on two occasions, 3 weeks apart, with 1x10 4 PFU of the A2 strain of human (H) RSV (described by Lewis et al., 1961, Med. J. Australia, 48, 932-933). After an interval of 4 months, the mice were inoculated
  • the immunoglobulin isotype of the mAbs was determined by immunodiffusion using a radial immunodiffusion kit (Serotec, Kidlington, Oxfordshire, UK).
  • virus infected cells bovine nasal mucosa cells persistently infected with BRSV
  • mAb and rabbit complement 3Percent specific chromium release from virus infected cells (bovine nasal mucosa cells persistently infected with BRSV) by 1/100 dilution of mAb and rabbit complement.
  • intranasal challenge expressed as log 10 pfu.
  • mAbs 19 and 20 recognized the fusion (F) glycoprotein. This was confirmed by a Western blot of non-reduced and reduced lysates of cells infected with RSV. The blots were probed with HRP- conjugated goat anti-mouse IgG (Kpl, Gaithersburg, Maryland, USA). mAbs 19 and 20 recognized the 140k F protein dimer and the 70K monomer present in the native F protein antigen and the 46K Fl fragment in antigen denatured by boiling in 2- mercaptoethanol.
  • Both mAb 19 and 20 were identified as IgG2a, and their ELISA titres against the A2 and 8/60 strains of HRSV were similar to the ELISA titres against the 127 strain of BRSV, indicating that the epitopes recognized by these mAbs were conserved amongst strains of human and bovine RSV. Both mAB 19 and 20 neutralized RSV infectivity and inhibited the formation of multinucleated giant cells in MA104 cells infected with RSV. In contrast to mAb 19, mAb 20 lysed RSV-infected cells in the presence of rabbit complement.
  • mice 20 to protect against RSV infection was assessed by challenging mice i.n. with approximately 10 4 PFU of RSV 24 h after i.p.
  • mice inoculation of mAbs 19 and 20.
  • the lungs of untreated mice killed 5 days after challenge contained 5.5 log 10 PFU of RSV/g tissue whereas virus was not detected in the lungs of mice given either mAb 19 or 20.
  • This example describes methods of isolating mutants of RSV which are resistant to inhibition by mAbS 19 and 20 generated in
  • Example 4 Mutant RS viruses refractory to neutralization by mAbs 19 and 20 were produced using a plaque reduction technique with the A2 strain of HRSV as follows. Confluent monolayers of CK cells, in a tissue culture flask, were infected with the A2 strain of HRSV at a MOI of 0.1. Starting 24 hours after infection and continuing for 3 to 5 days, the culture medium was replaced daily with fresh medium containing 10% mAb. Virus was harvested when a cytopathic effect was observed. Virus prepared in this way was mixed with an equal volume of either undiluted mAb 19 or 20, or medium alone for 1 hour at room temperature and inoculated onto
  • Putative mutant viruses were plaque picked again and inoculated into tubes containing covershps of calf testes cells. After 4 to 6 days incubation, the covershps were removed and stained with mAb 19 and 20 and FITC-labelled rabbit anti-mouse Ig (Nordic Labs, Tilburg, The Netherlands). As a positive control, coverslips were stained with polyclonal bovine antiserum to RSV (produced at Institute for Animal Health- Compton form a gnotobiotic calf hyperimmunised with RSV), and FITC-labelled rabbitt anit-bovine Ig (obtained from Nordic
  • RS viruses that failed to react by immunofluorescence to mAb 19 or 20 were classed as mutant viruses and were used to infect monolayers of Hep-2 cells to produce antigen for ELISA.
  • RS viruses that failed to react by immunofluorescence to mAb 19 or 20 were classed as mutant viruses and were used to infect monolayers of Hep-2 cells to produce antigen for ELISA.
  • 3 to 4 days after RSV infection cells were scraped into the medium, spun at 400 g for 5 mins, resuspended in distilled water, and treated with 0.5% (v/v) NP40 detergent to yield a cell lysate.
  • a control cell lysate was made in a similar way using uninfected Hep-2 cells.
  • the binding of a panel of mAbs to the F protein of RSV to the mutant viruses was examined by ELISA.
  • Microtitre plate wells were coated with 50 ul of either infected or control cell lysate overnight at 37°C, incubated with blocking buffer consisting of 5% normal pig serum in PBS and 0.05% Tween 20 for 1 h at room temperature and washed 5x with PBS/TWEEN. Serial dilutions (three times) of the mAbs were added to the wells and the plates were incubated for 1 hour. After washing 5 times with PBS/Tween, HRP-conjugated goat anti-mouse IgG (Kpl, Gaithersburg, Maryland, USA), diluted 1:2000, was added to each well.
  • blocking buffer consisting of 5% normal pig serum in PBS and 0.05% Tween 20 for 1 h at room temperature and washed 5x with PBS/TWEEN.
  • Serial dilutions (three times) of the mAbs were added to the wells and the plates were incubated for 1 hour. After washing 5 times with PBS/Tween
  • This example describes the identification of an amino acid sequence within the F protein which binds protective monoclonal antibodies and demonstrates that arginine 429 is essential for binding protective mabs to this amino acid sequence.
  • Poly(A) + RNAs isolated from cells infected with either the A2 strain of HRSV or each of the mutants described in Example 5, were used to sequence the F protein mRNA. These sequences were determined by the dideoxy method (cited above) using 5'- 32 P.
  • oligonucleotide primers synthesized according to the previously reported F-protein sequence of the Long strain of RSV (see, Lopez, et al., 1988, Virus Res.10, 249-262), followed by a chase with terminal deoxynucleotide transferase (see, DeBorde, et al., 1986, Anal Biochem. 157, 275-282). Three mutants were selected with mAb 19 and three were selected with mAb 20. All such mutants showed a single transversion (C to G) at nucleotide 1298 compared with the parent A2 strain. This nucleotide substitution changes the amino acid residue at position 429 of the F protein from arginine to serine. Since mAbs 19 reacted in Western blot with the F 1 subunit, it is likely that the antibody-binding site is determined by a linear sequence of contiguous amino acids in which residue 429 of the F 1 subunit plays an essential role.
  • Synthetic peptides corresponding to amino acids residues 417-432, 422-438, 417-438 and 421-450 of the F protein were examined for their ability to react with mAbs 19 and 20 in ELISA.
  • mAbs 19 and 20 reacted with peptides 417-432 (F417), 417-438 and with 422-438 (F422) but not with peptide 431-450.
  • the binding of mAb 19 to peptides 417-432 and 422-438 (2ug/well) either coated onto microtitre plate wells overnight at 37°C (“dry") or coated onto the wells for lh at room temperature (“wet”) is shown in Figure 7. It should be noted that mAb 20 gave essentially the same results.
  • Example 7 This example shows that Fab fragments derived from mAbs 19 and 20 can protect and treat mice infected by RSV.
  • mAbs 19 and 20 were purified from ascitic fluid using Protein A Sepharose (Pharmacia, Milton Keynes, United Kingdom).
  • the purified IgG and the papain cleaved fragments were evaluated for anti-RSV activity by ELISA with HRSV strain A2 infected and uninfected Hep-2 cells as antigen, and HRP-goat anti-mouse Fab (Sigma Chemical Co., St. Louis, Mi, USA) and HRP-goat anti-mouse Fc (ICN ImmunoBiologicals, Illinois).
  • HRSV strain A2 infected and uninfected Hep-2 cells as antigen
  • HRP-goat anti-mouse Fab Sigma Chemical Co., St. Louis, Mi, USA
  • HRP-goat anti-mouse Fc ICN ImmunoBiologicals, Illinois
  • the concentration of antibody in undigested mAbs 19 and 20 were adjusted to give ELISA titres similar to those of the Fab fragments and examined for their ability to protect against RSV infection in BALB/c mice. Groups of 5 mice were inoculated i.n. with
  • Fab fragments of mAbs 19 and 20 were highly effective both in preventing RSV infection and in clearing an established infection.
  • This invention relates to the 417-438 epitope.
  • This invention also relates to monoclonal antibodies generated against the 417-438 epitope. Such monoclonal antibodies are produced by conventional techniques and include, without limitation, murine monoclonal antibodies, human monoclonal antibodies, and bovine monoclonal antibodies.
  • Such monoclonal antibodies may comprise a complete antibody molecule (having full length heavy and light chains) or any fragment thereof, such as the Fab or (Fab') 2 fragment, a light chain or heavy chain dimer, or any minimal recombinant fragment thereof such as an Fv or a SCA (single-chian antibody) or any other molecule with the same specificity as the monoclonal antibody.
  • a complete antibody molecule having full length heavy and light chains
  • any fragment thereof such as the Fab or (Fab') 2 fragment, a light chain or heavy chain dimer, or any minimal recombinant fragment thereof such as an Fv or a SCA (single-chian antibody) or any other molecule with the same specificity as the monoclonal antibody.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a monoclonal antibody generated against the 417-438 epitope and a pharmaceutically acceptable carrier or diluent.
  • This invention also relates to a method of preventing human RSV infection in a human in need thereof which comprises
  • This invention also relates to a method of therapeutically treating human RSV infection in a human in need thereof which comprises administering to such human an effective, human RSV infection therapeutic dose of a monoclonal antibody generated against the 417-438 epitope.
  • i.v. intravenously
  • i.m. intramuscularly
  • one dose of approximately 200 ug/kg to approximately 2 mg/kg of such antibody should be administered i.n. (intranasally).
  • such dose should be repeated every six (6) weeks starting at the beginning of the RSV season (October- November) until the end of the RSV season (March- April).
  • one dose of approximately 5 mg/kg to approximately 100 mg/kg of a monoclonal antibody generated against the 417-438 epitope should be administered at the beginning of the RSV season.
  • one dose of approximately 2 mg/kg to approximately 20 mg/kg of a monoclonal antibody generated against the 417-438 epitope should be administered parenterally., preferably i.v. or i.m.; or
  • a monoclonal antibody generated against the 417-438 epitope may also be administered by inhalation.
  • inhalation is meant intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • a composition for administration by inhalation for an aerosol container with a capacity of 15-20 ml: Mix 10 mg of a monoclonal antibody generated against the 417-438 epitope with 0.2-0.2% of a lubricating agent, such as polysorbate 85 or oleic acid, and disperse such mixture in a propellant, such as freon, preferably in a combination of (1,2 dichlorotetrafluoroethane) and difluorochloromethane and put into an appropriate aerosol container adaped for either intranasal or oral inhalation
  • a propellant such as freon
  • composition for administration by inhalation for an aerosol container with a capacity of 15-20 ml: Dissolve 10 mg of a monoclonal antibody generated against the 417-438 epitope in ethanol (6-8 ml), add 0.1- 0.2% of a lubricating agent, such as polysorbate 85 or oleic acid; and disperse such in a propellant, such as freon, preferably a
  • the preferred daily dosage amount to be employed of a monoclonal antibody generated against the 417-438 epitope to prophylactically or therapeutically treat RSV infection in a human in need thereof to be administered by inhalation is from about 0.1 mg to about 10 mg/kg per day.

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Abstract

On décrit des anticorps modifiés dans lesquels au moins certaines parties des régions déterminant la complémentarité (CDR) dans les domaines variables légers et/ou lourds d'un anticorps monoclonal récepteur ont été remplacées par des parties analogues de régions CDR provenant d'un ou plusieurs anticorps monoclonaux donneurs, et dans lesquels l'altération de la région cadre du domaine variable léger et/ou lourd de l'anticorps monoclonal récepteur a été minime afin de conserver la spécificité de la liaison de l'anticorps monoclonal donneur, lesdits anticorps donneurs ayant une spécificité pour les microorganismes, et en particulier une spécificité pour le virus respiratoire syncytial (RSV); un procédé de préparation de tels anticorps modifiés; une composition pharmaceutique comprenant une quantité non toxique à effet thérapeutique de tels anticorps modifiés et un vecteur ou diluant acceptable en pharmacologie; une méthode de traitement prophylactique ou thérapeutique d'une maladie induite par microorganisme chez l'homme ou l'animal, qui consiste à administrer à l'homme ou l'animal atteint une quantité efficace de tels anticorps modifiés; un déterminant antigénique spécifique de la protéine F du RSV; des anticorps monoclonaux dirigés contre un tel déterminant antigénique; des fragments Fab de tels anticorps monoclonaux; une composition pharmaceutique comprenant une quantité non toxique à effet thérapeutique de tels anticorps monoclonaux ou fragments Fab et un vecteur ou diluant acceptable en pharmacologie; et une méthode de traitement prophylactique ou thérapeutique de l'infection RSV chez l'homme ou l'animal, qui consiste à administrer à l'homme ou l'animal atteint une quantité efficace de tels anticorps monoclonaux ou fragments Fab.
PCT/GB1991/001554 1990-09-11 1991-09-11 Nouveaux anticorps pour le traitement et la prevention d'infections chez l'homme et l'animal Ceased WO1992004381A1 (fr)

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CA2091335A1 (fr) 1992-03-12
JPH06501152A (ja) 1994-02-10
NZ239728A (en) 1995-07-26
PT98944A (pt) 1992-08-31
KR930702519A (ko) 1993-09-09
AU654827B2 (en) 1994-11-24
MX9101046A (es) 1992-05-04
EP0548190A1 (fr) 1993-06-30
AU8505891A (en) 1992-03-30
PT98944B (pt) 1999-02-26
ZA917170B (en) 1992-07-29
GB9019812D0 (en) 1990-10-24
IE913177A1 (en) 1992-03-11

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