EP1945667A1 - Composition et procede destines au traitement d'une infection virale au moyen d'anticorps de camelides a chaine lourde - Google Patents

Composition et procede destines au traitement d'une infection virale au moyen d'anticorps de camelides a chaine lourde

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Publication number
EP1945667A1
EP1945667A1 EP06809738A EP06809738A EP1945667A1 EP 1945667 A1 EP1945667 A1 EP 1945667A1 EP 06809738 A EP06809738 A EP 06809738A EP 06809738 A EP06809738 A EP 06809738A EP 1945667 A1 EP1945667 A1 EP 1945667A1
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EP
European Patent Office
Prior art keywords
influenza
heavy chain
antibody
virus
camelid
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EP06809738A
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German (de)
English (en)
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Patrick T. Prendergast
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Individual
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Individual
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Publication of EP1945667A1 publication Critical patent/EP1945667A1/fr
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    • 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
    • C07K16/1018—Orthomyxoviridae, e.g. influenza virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • the present invention relates to compositions and methods for use of the same for the treatment and prophylaxis of viral infections.
  • the present invention relates to Camelid heavy chain antibodies and antigen binding portions thereof that specifically bind to the influenza Neuraminidase enzyme, and which function to inhibit Neuraminidase function.
  • the invention further extends to the use of said Camelid antibodies in the inhibition of a broad spectrum of avian orthomyxovirus infections, more specifically type A influenza viruses of the family orthomyxoviridae, most specifically Influenza virus A, subtypes H5N1 , H5N2, H7 and H9 (commonly termed "avian influenza" or "bird flu”).
  • the Camilidae In addition to the production of classical four chain heterotetrameric immunoglobulins, comprised of a dimerisation of 2 heavy chains and 2 light chains, the Camilidae produce a further subset of antibodies known as heavy chain antibodies.
  • variable domain of the Camilidae heavy chain antibody differs in both structure and function to the variable heavy domain of the classical 4 chain antibody. Unlike the variable domain present in the heavy chain of a heterotetrameric antibody, the variable domain of the Camilidae heavy chain (referred to as VHH) has no interaction with the variable light chain domain, as this is absent. Further, the CH1 constant domain is also absent from the Camelid heavy chain antibody structure.
  • variable domain (VHH) of the heavy chain contains the antigen binding sites of the antibody, these being the areas of the antibody which confer its binding specificity.
  • the binding epitope of the heavy chain antibody is thus formed solely from the variable domain as opposed to being derived from a complex of the light and heavy variable domains as is the case in the classical antibody structure.
  • Avian influenza is commonly known as "avian flu” or "bird flu”.
  • the avian influenza virus was first isolated from birds in South Africa in 1961. Wild birds are the natural host of the virus, with the virus circulating amongst birds worldwide. The virus is extremely contagious and can be deadly to birds, particularly domesticated chickens. Fifteen subtypes of the influenza virus are known to infect avians. Although primarily associated with the occurrence of illness and infection in avians, there have been previous instances of certain subtypes of avian influenza strains "jumping" the species barrier and causing infection in humans.
  • Incidences of disease outbreaks include an outbreak of H5N1 in Hong Kong in 1997 causing infections in both poultry and humans; an H9N2 outbreak in China and Hong Kong in 1999, an H7N2 outbreak in Virginia in 2002, and reported case of; H7N7 in the Netherlands (2003), H9N2 in Hong Kong (2003), H7N2 in New York (2003), and H5N1 in Thailand and Vietnam (2004).
  • outbreaks of highly pathogenic influenza A (H5N1 ) in Asia were first reported by the World Health Organization, this was followed by reported cases of H7N3 in Canada in in February 2004.
  • Subsequently cases of H5N1 were reported in Thailand and Vietnam in June 2004, this outbreak extending to several countries in Asia.
  • the new outbreaks of H5N1 in poultry in Asia were followed by renewed sporadic reporting of human cases of H5N1 infection in Vietnam and Thailand beginning in August and continuing into 2005.
  • Seasonal influenza epidemics in humans are associated with amino acid changes in antigenic sites in the haemagglutinin and neuraminidase proteins, in a process termed 'antigenic drift'.
  • Major pandemics are associated with the introduction of new haemagglutinin and neuraminidase genes from animal-derived influenza viruses, by reassortment, into the genetic background of a currently circulating human virus - called 'antigenic shift'.
  • H5N1 mutates rapidly and has a documented propensity to acquire genes from viruses infecting other animal species. Its ability to cause severe disease in humans has now been documented on two occasions. In addition, laboratory studies have demonstrated that isolates from this virus have a high pathogenicity and can cause severe disease in humans. Birds that survive infection excrete virus for at least 10 days, orally and in faeces, thus facilitating further spread at live poultry markets and by migratory birds.
  • H5N1 avian influenza virus The direct infection of the H5N1 avian influenza virus into humans presents a high risk potential for progression to pandemic spread amongst humans. Repeated chances at replication in humans may allow this virus to become better adapted to humans and allow efficient human to human transmission. The importance of establishing a reliable treatment for not only sporadic outbreaks of H5N1 in humans, but also for use in the event that a pandemic situation arises, is clearly evident.
  • H5N1 has crossed the species barrier. It is clear that upon crossing the species barrier, pathogenicity of H5N1 is high.
  • the H5N1 virus comes in two forms, one demonstrating low pathogenicity in chickens, and the second being the highly virulent form known as "highly pathogenic avian influenza". There is mounting evidence that this strain has the unique capacity to jump the species barrier causing the severe disease, with high mortality, recently observed in humans.
  • Oseltamivir and Zanamivir block the action of neuraminidase to prevent release of newly formed virus from the infected cell and its spread within the host.
  • Oseltamivir oseltamivir phosphate
  • Zanamivir (4- guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid) is a recognised neuraminidase inhibitor useful in the treatment or prevention of influenza virus infection.
  • Zanamivir is generally thought to have poor oral bioavailability due to poor dissolution in the gastrointestinal tract.
  • Oseltamivir reduces the severity of some symptoms, it does not reduce nasal congestion or the production of excessive mucous in the respiratory tract to the same degree that an H1 histamine receptor antagonist does. Consequently, nasal congestion or the production of excessive mucous in the respiratory tract lingers in patients having been administered Oseltamivir.
  • Ribavirin is a broad spectrum anti-viral agent based on a purine nucleoside analogue and is the standard treatment regimen for hepatitis C. Ribavirin is known to be active against various RNA viruses by inducing lethal mutagenesis of the viral RNA genome. Although Ribavirin has a marked anti-viral activity against a number of viruses, it is not acknowledged as a medicament for influenza infections.
  • the heavy chain antibody is at least one Camelid heavy chain antibody.
  • the term “heavy chain Camelid antibody” or “Camelid heavy chain antibody” means an antibody which comprises only heavy chains, that is it is lacking in light chains commonly associated with classical heterotetrameric antibodies. Further, the heavy chain antibody lacks the CH1 constant domain.
  • the viral infection is an influenza virus infection, in particular a type A Influenza viral infection.
  • the Influenza A virus is of the subtype H5, H7, H11 or H9.
  • the type A Influenza subtype may be of the strain H5N1 , H5N2, H9N2, H7N2 or H7N7.
  • the type A influenza subtype may be H6N1 , H5N3, H8N4, H14N5, H4N6, H7N7, H4N4 or H11N9.
  • the Camelid heavy chain antibody has binding specificity for the neuraminidase enzyme and binds thereto.
  • the binding of the Camelid heavy chain antibody serves to inhibit the action of the neuraminidase enzyme.
  • the neuraminidase enzyme may be any neuraminidase subtype, particularly of subtypes N1 to N9.
  • the Camelid heavy chain antibody comprises a polyclonal mixture of antibodies.
  • the polyclonal mixture preparation of antibodies comprises antibodies of the class lgG2 and / or lgG3.
  • the Camelid (which may further be defined as a Camelidae) is a Camel, specifically Camelus bactrianus or Camelus dromderius.
  • the Camelidae is a Llama such as Lama Paccos, Lama Glama or Lama Vicugna.
  • the Camelid antibodies are obtained from Camelids following their inoculation with a known strain of type A influenza.
  • the strain of Influenza A administered to the Camelid should be provided in an attenuated or inactivated form such that is does not cause infection in the host, while at the same time, being identified as being foreign by the host's immune system such that a protective immune response is mounted there against.
  • the antibodies are derived from Camelids which have been inoculated with H5N2 strain of Influenza A.
  • an inactivated avian influenza type A, H5N2 virus coded and identified as A/Chicken/Mexico/232-CPA/94 is provided for by the present invention.
  • the Camelid heavy chain antibodies are those derived from a Camelid following the inoculation of the Camelid with Influenza H5, an inactivated avian influenza type A, H5N2 virus coded and identified as A/Chicken/Mexico/232-CPA/94.
  • the Camelid antibodies which are obtained are polyclonal antibodies.
  • the antibodies have specificity for H5N2, the inventors have surprisingly identified that the antibodies generated in the Camelid following inoculation with H5N2 are cross-reactive to other subtypes of influenza, particularly H5N1.
  • the method further comprises the step of administering a therapeutically effective amount of an antibody preparation comprising at least one antibody with binding specificity for TNF-alpha (tumour necrosis factor alpha) in combination with said heavy chain Camelid antibodies.
  • the method comprises the further step of administering a therapeutically effective amount of an inhibitor of TNF- alpha activity, with such an inhibitor being selected from the group comprising: Thaliomide, Butyrate Hydroxy Toluene (BHT) or Quinine Sulphate in combination with the administration of said heavy chain Camelid antibodies.
  • an inhibitor of TNF- alpha activity selected from the group comprising: Thaliomide, Butyrate Hydroxy Toluene (BHT) or Quinine Sulphate in combination with the administration of said heavy chain Camelid antibodies.
  • an isolated heavy chain Camelid antibody or an antigen binding portion thereof for use in the prophylaxis and/or treatment of mammalian infection with type A Influenza.
  • the polyclonal preparation of antibodies comprises antibodies of the class lgG2 and / or lgG3.
  • Camelid is a Camel, specifically Camelus bactrianus or Camelus dromderius.
  • the mammalian is a human.
  • the isolated heavy chain Camelid antibody or an antigen binding portion thereof is obtained following the inoculation of the Camelid with Influenza H5, an inactivated avian influenza type A, H5N2 virus coded and identified as A/Chicken/Mexico/232-CPA/94.
  • the Camelid antibodies which are obtained are polyclonal antibodies.
  • an isolated heavy chain Camelid antibody or an antigen binding portion thereof in the preparation of a medicament for the treatment or prevention of infection with a type A Influenza virus.
  • the Influenza A virus is of the subtype H5, H7, H11 or H9.
  • the type A Influenza subtype is of the strain H5N1 , H5N2, H9N2, H7N2 or H7N7.
  • the type A influenza subtype may be H6N1 , H5N3, H8N4, H14N5, H4N6, H7N7, H4N4 or H11 N9.
  • the polyclonal preparation of antibodies comprises antibodies of the class lgG2 and / or lgG3.
  • the medicament may further comprise an antibody which binds to or inhibits the activity of TNF-alpha.
  • the medicament may further comprise an inhibitor of TNF- alpha activity such as Thaliomide, Butyrate Hydroxy Toluene (BHT) or Quinine Sulphate.
  • the isolated heavy chain Camelid antibody or an antigen binding portion thereof is obtained following the inoculation of the Camelid with Influenza H5, an inactivated avian influenza type A, H5N2 virus coded and identified as A/Chicken/Mexico/232-CPA/94.
  • the Camelid antibodies which are obtained are polyclonal antibodies. Therefore the antibodies have specificity for H5N2 but are cross-reactive to other subtypes of influenza, particularly H5N1.
  • a yet further aspect of the present invention provides a method of treating influenza A viral infection in a subject in need thereof, comprising the step of administering to said subject a polyclonal Camelid heavy chain immunoglobulin preparation wherein said antibody or antigen-binding portion binds to Neuraminidase.
  • a still further aspect of the present invention provides a method for producing a polyclonal Camelid heavy chain immunoglobulin preparation which specifically binds Neuraminidase, comprising the steps of: (a) immunizing a Camelid that is capable of producing heavy chain antibodies with a strain of influenza A virus, with an immunogenic portion of an influenza A virus or with a cell or tissue expressing an influenza A virus; (b) allowing the Camelid to mount an immune response to the influenza A virus, and (c) collecting and purifying the produced antibodies.
  • the Influenza A virus is of the subtype H5, H7, H11 or H9.
  • the type A Influenza subtype is of the strain H5N1 , H5N2, H9N2, H7N2 or H7N7.
  • the type A influenza subtype may be H6N1 , H5N3, H8N4, H14N5, H4N6, H7N7, H4N4 or H11N9.
  • the present invention further extends to a monoclonal Camelid heavy chain antibody which has specificity for the Neuraminidase molecule and which is capable of binding and inhibition of Neuraminidase enzyme activity.
  • a monoclonal antibody can be generated, using methods commonly known to the person skilled in the art, through the selection of an antibody producing B cells of single specificity from the polyclonal antibody response generated following the immunisation of a Camelid and the resulting production of a polyclonal antibody inhibitors to Neuraminidase.
  • a further aspect of the present invention provides a monoclonal antibody which is derived from a Camelid heavy chain antibody which is specific for Neuraminidase.
  • the neuraminidase may be of any subtype, preferably N1 to N11. Specifically the antibody serves to inhibit the function of the neuraminidase.
  • an isolated cell line that produces such a monoclonal antibody or an antigen-binding portion thereof.
  • an isolated nucleic acid molecule comprising a nucleotide sequence that encodes the heavy chain or an antigen-binding portion thereof of the monoclonal antibody.
  • a vector comprising the nucleic acid molecule which encodes the monoclonal antibody.
  • the vector optionally comprises an expression control sequence operably linked to the nucleic acid molecule.
  • a host cell comprising the vector or the nucleic acid molecule may also be provided.
  • a yet further aspect of the invention provides a method of treating a subject in need thereof with a Camelid heavy chain monoclonal antibody or an antigen-binding portion thereof that specifically binds to and/or inhibits Neuraminidase, comprising the steps of:
  • a method of preventing or treating human infection with type A Influenza virus including the step of administering a therapeutically useful amount of an isolated heavy chain Camelid antibody or an antigen binding portion thereof to a subject in need of treatment along with a therapeutically useful amount of a suitable anti-viral compound.
  • the Influenza A virus is of the subtype H5, H7 or H9.
  • the type A Influenza subtype is of the strain H5N1 , H5N2, H9N2, H7N2 or H7N7.
  • the type A influenza subtype may be H6N1 , H5N3, H8N4, H14N5, H4N6, H7N7, H4N4 or H11 N9.
  • the anti-viral compound is ribavirin, amantadine, rimantadine, oseltamivir or zanamivir.
  • an isolated heavy chain Camelid antibody or an antigen binding portion thereof and an anti-viral compound in the preparation of a combined medicament for the treatment or prevention of infection with type A Influenza virus.
  • H5N1 , H5N2, H9N2, H7N2 or H7N7 may be H6N1 , H5N3, H8N4, H14N5, H4N6, H7N7, H4N4 or H11 N9.
  • the anti-viral compound is ribavirin, amantadine, rimantadine, oseltamivir or zanamivir.
  • H5 There are 3 prominent subtypes of avian influenza virus; H5, H7 and H9. Each of these 3 viral subtypes can potentially be combined with any one of the 9 neuraminidase surface proteins, hence there is the potential for up to 9 different forms of each subtype, for example H7N1 , H7N2 ... H7N9.
  • Influenza A viruses are found in many different animals, including ducks, chickens, pigs, whales, horses, and seals. However, certain subtypes of influenza A virus are specific to certain species, except for birds which are hosts to all subtypes of influenza A.
  • H5N1 avian influenza was responsible for a recent outbreak of bird flu in the human population, while H7N7, H9N2 and H7N2 subtypes have also been associated with transmission over the species barrier and resultant infection in humans.
  • Avian influenza viruses may be transmitted to humans in two main ways; (i) directly from birds or from avian virus-contaminated environments to people, (ii) through an intermediate host, such as a pig.
  • Influenza viruses have eight separate gene segments. The segmented genome allows viruses from different species to mix and create a new influenza A virus if viruses from two different species infect the same person or animal. For example, if a pig were infected with a human influenza virus and an avian influenza virus at the same time, the viruses could reassort and produce a new virus that had most of the genes from the human virus, but a hemagglutinin and/or neuraminidase from the avian virus. The resulting new virus might then be able to infect humans and spread from person to person, but it would have surface proteins (hemagglutinin and/or neuraminidase) not previously seen in influenza viruses that infect humans.
  • Antigenic shift results when a new influenza A subtype to which most people have little or no immune protection infects humans. If this new virus causes illness in people and can be transmitted easily from person to person, an influenza pandemic can occur.
  • influenza A viruses with a hemagglutinin against which humans have little or no immunity that have reassorted with a human influenza virus are more likely to result in sustained human-to-human transmission and pandemic influenza.
  • an isolated heavy chain Camelid antibody or an antigen binding portion thereof in the preparation of a medicament for the prevention and treatment of human infection with type A Influenza subtype which has resulted from natural reassortment of influenza variants.
  • the present invention extends to the use of an isolated 2 chain Camelid antibody or an antigen binding portion thereof in the preparation of a medicament for the prevention and treatment of a novel influenza subtype which has resulted from natural reassortment of human influenza and avian influenza variants.
  • a yet further aspect of the present invention provides a method for the treatment and / or prophylaxis of human infection with a type A Influenza subtype which has resulted from natural reassortment of influenza variants, the method including the step of administering a therapeutically useful amount of an isolated heavy chain Camelid antibody or an antigen binding portion thereof to a subject in need of treatment.
  • the present invention further provides an isolated antibody that specifically binds Neuraminidase, wherein at least the complementarity determining regions (CDR) sequences of said antibody are Cameiid CDR sequences derived from a Camelid heavy chain antibody, or an antigen- binding portion of said antibody.
  • CDR complementarity determining regions
  • the invention also provides nucleic acid molecules encoding the heavy chain of said anti-Neuraminidase antibody or the variable region thereof or antigen-binding portion thereof.
  • the invention further provides vectors and host cells comprising said nucleic acid molecules, as well as methods of recombinantly producing the polypeptides encoded by the nucleic acid molecules.
  • treatment is used herein to refer to any regime that can benefit a human or non-human animal.
  • the treatment may be in respect of an existing condition or may be prophylactic (preventative treatment).
  • treatment means therapeutic treatment.
  • References herein to "therapeutic” and “prophylactic” treatment is to be considered in its broadest context.
  • the term “therapeutic” does not necessarily imply that a subject is treated until total recovery.
  • “prophylactic” does not necessarily mean that the subject will not eventually contract a disease condition.
  • therapeutic and prophylactic treatment includes amelioration of the symptoms of a particular condition or preventing or otherwise reducing the risk of developing a particular condition.
  • the term “prophylactic” may be considered as reducing the severity or the onset of a particular condition.
  • “Therapeutic” may also reduce the severity of an existing condition.
  • an “antibody” is an immunoglobulin, whether natural or partly or wholly synthetically produced.
  • the term also covers any polypeptide, protein or peptide having a binding domain that is, or is homologous to, an antibody binding domain. These can be derived from natural sources, or they may be partly or wholly synthetically produced.
  • Camelid heavy chain antibodies due to the differences in their structure, and in particular the specific absence of a light chain and a CH 1 constant domain, mean that many of the fragments which result in classical 4 chain antibodies cannot be extended to Camelid heavy chain antibodies.
  • fragments and antigen binding portions of Camelid heavy chain antibodies can be produced such as chimeric antibodies and diabodies as well as polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide.
  • An antibody may have one or more binding sites. If there is more than one binding site, the binding sites may be identical to one another or may be different. For instance, a naturally-occurring immunoglobulin has two identical binding sites, a single-chain antibody or Fab fragment has one binding site, while a "bispecific” or “bifunctional” antibody (diabody) has two different binding sites.
  • Chimeric and bispecific antibodies can be generated from Camelid heavy chain antibodies.
  • a chimeric antibody may be made that comprises CDRs and framework regions from different antibodies.
  • the CDRs of the chimeric antibody comprises all of the CDRs of the variable region of the heavy chain of a camelid anti-Neuraminidase antibody, while the framework regions are derived from one or more different antibodies.
  • the CDRs of the chimeric antibody comprise all of the CDRs of the variable regions of the heavy chain of a Camelid anti-Neuraminidase antibody.
  • the framework regions may be from another species and may, in a preferred embodiment, be humanized. Alternatively, the framework regions may be from another human antibody.
  • a bispecific antibody can be generated that binds specifically to Neuraminidase through one binding domain and to a second molecule through a second binding domain.
  • the bispecific antibody can be produced through recombinant molecular biological techniques, or may be physically conjugated together.
  • a single chain antibody containing more than one VHH may be generated that binds specifically to Neuraminidase and to another molecule.
  • Such bispecific antibodies can be generated using techniques that are well known for example see, e.g., Fanger et al., Immunol Methods 4: 72-81 (1994) and Wright and Harris, supra, and in connection with (iii) see, e.g., Traunecker et al., Int. J. Cancer (Suppl.) 7: 51-52 (1992).
  • antibody should be construed as covering any binding member or substance having a binding domain with the required specificity.
  • the antibody of the invention may be a monoclonal antibody, or a fragment, derivative, functional equivalent or homologue thereof.
  • the term includes any polypeptide comprising an immunoglobulin binding domain, whether natural or wholly or partially synthetic.
  • a fragment of an antibody or of a polypeptide for use in the present invention generally means a stretch of amino acid residues of at least 5 to 7 contiguous amino acids, often at least about 7 to 9 contiguous amino acids, typically at least about 9 to 13 contiguous amino acids, more preferably at least about 20 to 30 or more contiguous amino acids and most preferably at least about 30 to 40 or more consecutive amino acids.
  • antibody includes antibodies which have been "humanised”. Methods for making humanised antibodies are known in the art. Methods are described, for example, in Winter, U.S. Patent No. 5,225,539.
  • a humanised antibody may be a modified antibody having the hypervariable region or the variable region of a Camelid monoclonal antibody and the constant region of a human antibody.
  • the binding member may comprise a human constant region.
  • variable region other than the hypervariable region may also be derived from the variable region of a human antibody and/or may also be derived from a monoclonal antibody. In such case, the entire variable region may be derived from a Camelid antibody and the antibody is said to be chimerised.
  • Methods for making chimerised antibodies are known in the art. Such methods include, for example, those described in U.S. patents by Boss (Celltech) and by Cabilly (Genentech). See U.S. Patent Nos. 4,816,397 and 4,816,567, respectively.
  • the antibodies or antibody fragments of and for use in the present invention may be generated wholly or partly by chemical synthesis.
  • the antibodies can be readily prepared according to well-established, standard liquid or, preferably, solid-phase peptide synthesis methods, general descriptions of which are broadly available (see, for example, in J. M. Stewart and J. D. Young, (1984), in M. Bodanzsky and A. Bodanzsky,
  • Another convenient way of producing antibodies or antibody fragments suitable for use in the present invention is to express nucleic acid encoding them, by use of nucleic acid in an expression system.
  • the present invention further provides the use of an isolated nucleic acid encoding antibodies or antibody fragments which bind to influenza neuraminidase.
  • Nucleic acid for use in accordance with the present invention may comprise DNA or RNA and may be wholly or partially synthetic.
  • nucleic acid for use in the invention codes for antibodies or antibody fragments of the invention as defined above. The skilled person will be able to determine substitutions, deletions and/or additions to such nucleic acids which will still provide an antibody or antibody fragment of the present invention.
  • Nucleic acid sequences encoding antibodies or antibody fragments for use with the present invention can be readily prepared by the skilled person using the information and references contained herein and techniques known in the art (for example, see Sambrook et al.(1989), and Ausubel et al, (1992)), given the nucleic acid sequences and clones available.
  • DNA encoding antibody fragments may be generated and used in any suitable way known to those of skill in the art, including by taking encoding DNA, identifying suitable restriction enzyme recognition sites either side of the portion to be expressed, and cutting out said portion from the DNA. The portion may then be operably linked to a suitable promoter in a standard commercially available expression system.
  • Another recombinant approach is to amplify the relevant portion of the DNA with suitable PCR primers. Modifications to the sequences can be made, e.g. using site directed mutagenesis, to lead to the expression of modified peptide or to take account of codon preferences in the host cells used to express the nucleic acid.
  • the nucleic acid may be comprised as constructs in the form of a plasmid, vector, transcription or expression cassette which comprises at least one nucleic acid as described above.
  • the construct may be comprised within a recombinant host cell which comprises one or more constructs as above. Expression may conveniently be achieved by culturing under appropriate conditions recombinant host cells containing the nucleic acid. Following production by expression the antibody or antibody fragments may be isolated and/or purified using any suitable technique, then used as appropriate.
  • Systems for cloning and expression of a polypeptide in a variety of different host cells are well known. Suitable host cells include bacteria, mammalian cells, yeast, and baculovirus systems.
  • Mammalian cell lines available in the art for expression of a heterologous polypeptide include Chinese hamster ovary (CHO) cells, HeLa cells, baby hamster kidney cells, NSO mouse myeloma cells.
  • a common, preferred bacterial host is E. coli.
  • antibodies or antibody fragments for use in the invention may be produced in transgenic organisms, for example mammals, Camelids, avians, fish, insects or plants using methods known in the art.
  • nucleic acid encoding the binding member(s) may be introduced to the cell or embryo by methods including but not limited to direct injection, electroporation, nuclear transfer techniques or by use of vectors, e.g. viral vectors such as lentiviral vectors.
  • Suitable vectors can be chosen or constructed, containing appropriate regulatory sequences, including promoter sequences, terminator sequences, polyadenylation sequences, enhancer sequences, marker genes and other sequences as appropriate.
  • Vectors may be plasmids, viral e.g. 'phage, or phagemid, as appropriate.
  • plasmids viral e.g. 'phage, or phagemid, as appropriate.
  • Many known techniques and protocols for manipulation of nucleic acid for example in preparation of nucleic acid constructs, mutagenesis, sequencing, introduction of DNA into cells and gene expression, and analysis of proteins, are described in detail in Ausubel et al. eds., (1992).
  • the nucleic acid may be introduced into a host cell by any suitable means.
  • the introduction may employ any available technique.
  • suitable techniques may include calcium phosphate transfection, DEAE-Dextran, electroporation, liposome-mediated transfection and transduction using retrovirus or other virus, e.g. vaccinia or, for insect cells, baculovirus.
  • suitable techniques may include calcium chloride transformation, electroporation and transfection using bacteriophage.
  • Marker genes such as antibiotic resistance or sensitivity genes may be used in identifying clones containing nucleic acid of interest, as is well known in the art.
  • the introduction may be followed by causing or allowing expression from the nucleic acid, e.g. by culturing host cells under conditions for expression of the gene.
  • the nucleic acid may be integrated into the genome (e.g. chromosome) of the host cell. Integration may be promoted by inclusion of sequences which promote recombination with the genome in accordance with standard techniques.
  • the nucleic acid may be on an extra-chromosomal vector within the cell, or otherwise identifiably heterologous or foreign to the cell.
  • Antibodies of and for use in the present invention may be administered alone but will preferably be administered as a pharmaceutical composition, which will generally comprise a suitable pharmaceutical excipient, diluent or carrier selected dependent on the intended route of administration.
  • Antibodies of and for use in the present invention may be administered to a patient in need of treatment via any suitable route.
  • Camelid antibodies of the invention may be administered orally without the conditions of the stomach or gastro-intestinal tract adversely affecting the ability of the antibody to effect its use as defined herein.
  • Some suitable routes of administration include (but are not limited to) oral, rectal, nasal, topical (including buccal and sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration or administration via oral or nasal inhalation.
  • the composition is deliverable as an injectable composition, is administered orally, is administered to the lungs as an aerosol via oral or nasal inhalation.
  • the active ingredient will be in a suitable pharmaceutical formulation and may be delivered using a mechanical form including, but not restricted to an inhaler or nebuliser device.
  • administration is by a SPAG (small particulate aerosol generator) may be used.
  • Intravenous administration For intravenous injection, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability.
  • isotonic vehicles such as sodium chloride injection, Ringer's injection, Lactated Ringer's injection.
  • Preservatives, stabilisers, buffers, antioxidants and/or other additives may be included, as required.
  • compositions for oral administration may be in tablet, capsule, powder or liquid form.
  • a tablet may comprise a solid carrier such as gelatin or an adjuvant.
  • Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.
  • composition may also be administered via microspheres, liposomes, other microparticulate delivery systems or sustained release formulations placed in certain tissues including blood.
  • sustained release carriers include semipermeable polymer matrices in the form of shared articles, e.g. suppositories or microcapsules.
  • Implantable or microcapsular sustained release matrices include polylactides (US Patent No.
  • the present invention extends to a pharmaceutical composition for the treatment of Influenza virus A, subtypes H5N1 , H7 and H9 (commonly termed "avian influenza” or “bird flu”) in humans, wherein the composition comprises at least one isolated Camelid heavy chain antibody.
  • Pharmaceutical compositions according to the present invention, and for use in accordance with the present invention may comprise, in addition to active ingredient (i.e. one or more isolated heavy chain Camelid antibody), a pharmaceutically acceptable excipient, carrier, buffer stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be, for example, oral, intravenous, intranasal or via oral or nasal inhalation.
  • the formulation may be a liquid, for example, a physiologic salt solution containing non-phosphate buffer at pH 6.8-7.6, or a lyophilised or freeze dried powder.
  • the isolated antibody or antibodies of the invention or the pharmaceutical composition which may be dived there from is preferably administered to an individual in a "therapeutically effective amount", this being sufficient to show benefit to the individual.
  • the actual amount administered, and rate and time-course of administration, will depend on the nature and severity of what is being treated. Prescription of treatment, e.g. decisions on dosage etc, is ultimately within the responsibility and at the discretion of general practitioners and other medical doctors, and typically takes account of the disorder to be treated, the condition of the individual patient, the site of delivery, the method of administration and other factors known to practitioners.
  • the optimal dose can be determined by physicians based on a number of parameters including, for example, age, sex, weight, severity of the condition being treated, the active ingredient being administered and the route of administration.
  • An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of an antibody or antibody portion of the invention is 0.025 to 50 mg/kg, more preferably 0.1 to 50 mg/kg, more preferably 0.1- 25, 0.1 to 10 or 0.1 to 3 mg/kg.
  • a formulation contains 5 mg/mL of antibody in a buffer of 20 mM sodium acetate, pH 5.5, 140 mM NaCI, and 0.2 mg/mL polysorbate 80. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated.
  • a yet further aspect of the present invention advantageously provides an isolated heavy chain Camelid antibody or an antigen binding portion thereof for the effective clearance of avian influenza from humans, said effective clearance resulting when said antibodies are administered at a clinically effective concentration.
  • an assay method for determining the efficacy of a candidate agent in the treatment of Influenza virus A, subtypes H5N1 , H7, H9 and H11 (commonly termed "avian influenza” or "bird flu") in humans, wherein the assay method includes the steps of; (i) incubating virus infected cells in the presence of the candidate agent, and (ii) determining the degree of inhibition of the cytopathic effect of the virus on the cells.
  • the method further includes the step of comparing the degree of inhibition obtained using the candidate agent with the degree of inhibition obtainable with incubation with an isolated heavy chain Camelid antibody or an antigen binding portion thereof.
  • Preferred assays for use in the assay methods of the invention include cytopathic endpoint assays and plaque reduction assays.
  • kits comprising an anti- Neuraminidase Camelid heavy chain antibody or binding fragment derived there from or a composition comprising such an antibody.
  • a kit may include, in addition to the antibody or composition, diagnostic or therapeutic agents.
  • a kit can also include instructions for use in a diagnostic or therapeutic method.
  • an in-vitro assay method for the determination of the level of neuraminidase in an individual comprising the steps of:
  • sample from a subject, said sample preferably being derived from nasal discharge or other suitable discharge,
  • the assay method is a rapid assay method, which may be performed at the point of care, thus providing the advantage that a result can be provided immediately and further that said sample from the individual does not have to be taken, stored and transported to a further location for testing.
  • a rapid antibody based assay test will be well known to the person skilled in the art, who will be aware that said test can take the form of a dipstick test or the like.
  • the antigen used for the Camelidae inoculation programme was NobilisTM Influenza H5, an inactivated avian influenza type A, H5N2 virus coded and identified as A/Chicken/Mexico/232-CPA/94, it is a water and oil emulsion vaccine manufactured by Intervet International, Boxmeer, the Netherlands.
  • Isolation of immunoglobulin concentrate from the Camelidae blood Isolation of immunoglobulin may be achieved by utilizing the following procedure.
  • Anticoagulant is added to whole blood after it is extracted from the jugular vein of the animal. The blood is centrifuged to separate the plasma. Any anticoagulant may be used for this purpose, including sodium citrate and heparin. Calcium is then added to the plasma to promote clotting, the conversion of fibrinogen to fibrin; however other methods known to the skilled person are also acceptable. This mixture is then centrifuged to remove the fibrin portion. Once the fibrin is removed from plasma resulting in serum, the serum can be used as a principal source of IgG. Alternatively, this portion of the clotting mechanism may be inactivated through the use of various anticoagulants.
  • the defibrinated plasma was next treated with an amount of salt compound or polymer sufficient to precipitate the albumin or globulin fraction of the plasma.
  • salt compound or polymer examples include all polyphosphates, including sodium hexametaphosphate and potassium polyphosphate.
  • the globulin may also be precipitated through the addition of polyethylene glycol or ammonium sulfate.
  • the pH of the plasma solution is lowered to stabilize the albumin precipitate. The pH should not be lowered below 3.5, as this will cause the proteins in the plasma to become damaged. Any type of acid can be used for this purpose, so long as it is compatible with the plasma solution.
  • Suitable acids are HCI, acetic acid, H 2 SO 4 , citric acid, and H 2 PO 4 .
  • the acid is added in an amount sufficient to lower the pH of the plasma to the designated range. Generally, this amount will range from a ratio of about 1 :4 to 1 :2 acid to plasma.
  • the plasma is then centrifuged to separate the globulin fraction from the albumin fraction.
  • IgG immunoglobulin G
  • VHH fragments isolated from the serum were concentrated and varying amounts of this pool of antibody fragments, range zero to 350 ⁇ g/ml were used to determine their ability to inhibit Neuraminidase activity.
  • NA activity was determined by using 2 1 -(4-methylumbelliferyl)- -D-N-acetylneuraminic acid (MUN; Sigma Chemical Co., St. Louis, Mo.) as a substrate.
  • MUN 2 1 -(4-methylumbelliferyl)- -D-N-acetylneuraminic acid
  • Viruses used in the NA assay were grown in embryonated chicken eggs and were obtained from the allantoic fluid after centrifugation at 2,000 x g for 10 minutes. The NA activity of each virus was determined before it was used in NA inhibition tests.
  • NA inhibition was assayed by determining the camel antibody concentration required to reduce NA activity to 50% of control NA activity (IC50).
  • IC50 camel antibody concentration required to reduce NA activity to 50% of control NA activity.
  • Fourfold dilutions ranging from 10 ⁇ g to 300 ⁇ g of CC07 were made, and 10 ⁇ l of each dilution was incubated with 10 ⁇ l of virus- containing allantoic fluid at a standard amount of NA activity (100 to 150 relative fluorescence units). The mixture was shaken at 37°C for 30 minutes to allow interaction of antibody and the virus.
  • the enzymatic reaction was initiated by adding 30 ⁇ l of substrate in enzyme buffer at a final concentration of 100 ⁇ M. The reaction was stopped after 1 hour of incubation at 37°C.
  • Standard curves were constructed by plotting the percentage of fluorescence inhibition relative to the activity of controls against the logs of inhibitor concentrations.
  • the IC 5 oS, as shown in Table A were obtained from the graphs by extrapolation, and the means were calculated on the basis of three independent experiments.
  • MUN final concentration of 100 ⁇ M was used as the substrate. Values are means of at least three independent determinations.
  • CC07 is a Camelidae Antibody VHH fragment affinity purified to the A/chicken/mexico232-CPA/94 viral strain.

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Abstract

La présente invention concerne un procédé pour traiter ou prévenir une infection humaine par la grippe de type A, qui consiste à administrer une quantité thérapeutiquement utile d'un anticorps de camélidés à chaîne lourde isolée, ou un antigène se liant à une partie de celui-ci, à un sujet nécessitant un tel traitement. L'invention concerne aussi un anticorps de camélidés à chaîne lourde isolée ou un antigène se liant à une partie de celui-ci, destiné à la prévention ou au traitement d'une infection humaine par la grippe de type A, de même qu'un procédé pour préparer une immunoglobuline polyclonale de camélidés à chaîne lourde, qui lie spécifiquement la neuraminidase ainsi qu'un procédé pour traiter l'infection virale par la grippe de type A, qui comprend les stades d'administration de ladite préparation d'immunoglobulines, ou de leur partie liant les antigènes, à un sujet nécessitant une telle thérapie.
EP06809738A 2005-11-03 2006-11-03 Composition et procede destines au traitement d'une infection virale au moyen d'anticorps de camelides a chaine lourde Withdrawn EP1945667A1 (fr)

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GBGB0522460.5A GB0522460D0 (en) 2005-11-03 2005-11-03 Composition and method for the treatment of avian influenza
PCT/IE2006/000126 WO2007052242A1 (fr) 2005-11-03 2006-11-03 Composition et procede destines au traitement d'une infection virale au moyen d'anticorps de camelides a chaine lourde

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EP2125886A2 (fr) 2007-03-13 2009-12-02 Humabs LLC Anticorps humains contre les souches h5n1 du virus a de la grippe
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