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  Pharmaceutical Patents  

 

Title:  Prion inhibition
United States Patent: 
7,550,144
Issued: 
June 23, 2009

Inventors:
 Collinge; John (London, GB), Hawke; Simon (London, GB)
Assignee:
  D-Gen Limited (London, GB)
Appl. No.:
 10/535,938
Filed:
 November 28, 2003
PCT Filed:
 November 28, 2003
PCT No.:
 PCT/GB03/05225
371(c)(1),(2),(4) Date:
 June 02, 2006
PCT Pub. No.:
 WO2004/050120
PCT Pub. Date:
 June 17, 2004


 

Executive MBA in Pharmaceutical Management, U. Colorado


Abstract

The invention relates to the use of an agent such as an antibody capable of reacting with PrP in the prevention of prion replication in a subject, in the treatment or prevention of prion infection, in the treatment or prevention of neuropathology associated with prion infection or in the preparation of a medicament for the treatment or prevention of prion disease. Furthermore, the invention relates to methods of treatment of prion disease, methods of inhibiting prion replication and antibodies for use in such methods.

Description of the Invention

SUMMARY OF THE INVENTION

It is surprisingly shown herein that prion replication can be effectively inhibited in vivo. In contrast to existing studies, the present invention enables the inhibition of established and replicating populations of prions in vivo in whole organisms.

It is a core feature of the present invention that the methods and uses are effective in inhibiting replication of prions which have already entered the replication phase. Although it is advantageous to apply to the present invention to prophylactic and immumunisation applications, a key advantage of the present invention is that it enables the arrest/inhibition of established populations of prions ie. it is effective when applied to subjects after the time of exposure, inoculation or infection, for example when applied at least seven days (or later--see below) after the time of exposure, inoculation or infection. Prior art techniques do not produce this advantageous effect. It is also an advantageous feature of the present invention that in addition to delaying or postponing such as through increased incubation times, the present invention enables the prevention/inhibition of prion disease.

Accordingly the invention provides the use of an antibody capable of reacting with PrP in the prevention of prion replication in a subject.

In another aspect, the invention relates to the use of an antibody capable of reacting with PrP in the treatment or prevention of prion infection.

In another aspect, the invention relates to the use of an antibody capable of reacting with PrP in the treatment or prevention of neuropathology associated with prion infection.

In another aspect, the invention relates to the use of an antibody capable of reacting with PrP in the preparation of a medicament for the treatment or prevention of prion disease.

In another aspect, the invention relates to the use as described above wherein said medicament is a vaccine.

In another aspect, the invention relates to a method of treating prion infection in a subject comprising administering to said subject an effective amount of an antibody capable of reacting with PrP.

In another aspect, the invention relates to a method as described above wherein the antibody is administered after the subject has been exposed to prions.

In another aspect, the invention relates to a method as described above wherein the antibody is administered at least seven days after the subject has been exposed to prions.

In another aspect, the invention relates to a method as described above wherein the antibody is administered within 120 days after the subject has been exposed to prions.

In another aspect, the invention relates to a method as described above wherein antibody is administered after at least 4% of the total mean incubation time for said subject.

In another aspect, the invention relates to a method as described above wherein antibody is administered within 62% of the total mean incubation time for said subject.

In another aspect, the invention relates to a method of immunising a subject against prion infection comprising administering to said subject an effective amount of an antibody capable of reacting with PrP.

In another aspect, the invention relates to a use as described above or a method as described above wherein said antibody was raised against PrP 91-231.

In another aspect, the invention relates to a use or a method as described above wherein said antibody reacts with PrP.sup.Sc.

In another aspect, the invention relates to a use or a method as described above wherein said antibody reacts with PrP.sup.c and with PrP.sup.Sc.

In another aspect, the invention relates to a use or a method as described above wherein said antibody is an IgG.

In another aspect, the invention relates to a use or a method as described above wherein said antibody is ICSM18 or a fragment or fusion thereof.

In another aspect, the invention relates to a use or a method as described above wherein said antibody is ICSM35 or a fragment or fusion thereof.

In another aspect, the invention relates to a method of inhibiting prion replication comprising contacting said prion with ICSM 18 antibody.

In another aspect, the invention relates to a method of inhibiting prion replication comprising contacting said prion with ICSM 35 antibody.

In another aspect, the invention relates to an antibody or fragment thereof comprising CDR amino acid sequence encoded by at least one nucleotide sequence selected from the group consisting of SEQ ID NO 1, SEQ ID NO 2, SEQ ID NO 3, and SEQ ID NO 4, or a homologue thereof.

In another aspect, the invention relates to a use or a method as described above wherein the antibody is an antibody or fragment thereof comprising CDR amino acid sequence encoded by at least one nucleotide sequence selected from the group consisting of SEQ ID NO 1, SEQ ID NO 2, SEQ ID NO 3, and SEQ ID NO 4, or a homologue thereof.

In another aspect, the invention relates to a use or a method as described above wherein the subject is a mammal.

In another aspect, the invention relates to a use or a method as described above wherein the subject is a primate.

In another aspect, the invention relates to a use or a method as described above wherein the subject is a human.

DETAILED DESCRIPTION OF THE INVENTION

It is demonstrated herein that agents such as monoclonal antibodies used in accordance with the invention inhibit prion replication in vivo. Furthermore, agents such as monoclonal antibodies used in accordance with the invention delay the development of prion disease.

It is demonstrated herein using a murine scrapie model that agents such as anti-PrP mAbs have inhibitory effects on prion replication in vivo. It is further shown that peripheral PrP.sup.Sc levels and prion infectivity are dramatically reduced, even when the antibodies are first administered at the point of near maximal splenic PrP.sup.Sc accumulation.

Furthermore, every animal in which the treatment has been continued remains clinically healthy >200 days after equivalent untreated animals have succumbed to the disease. Thus the present invention provides immunotherapeutic strategies for prion diseases.

Thus in one embodiment the invention provides the use of agents such as antibodies in the prevention and/or treatment of prion disease.

Prevention and/or treatment is intended to embrace arrest, suspension, stopping, containment, freezing, inhibition of expansion, inhibition of replication, prevention of escalation or increase of prion load or similar effect in a subject. Preferably treatment/prevention of disease includes at least the delay, postponement or deferral of onset of clinical symptoms.

The subject is an organism, preferably a mammal, preferably a primate, preferably a human.

Agent

The agent according to the present invention is an entity which is capable of inhibiting the replication of prion(s) in vivo in a subject. The agent of the present invention may comprise one or more antibodies or antibody fragments capable of binding prion protein, mimetics thereof or small molecule(s) capable of binding prion protein or combinations thereof. Preferably the agent of the invention is an antibody or fragment thereof, preferably a monoclonal antibody or fragment thereof. Preferably the agent of the invention comprises an antibody or antibody fragment capable of binding prion protein.

Preferably the agent of the invention is an antibody or fragment thereof which was raised against PrP 91-231

Preferably the agent of the invention is an antibody or fragment thereof which reacts with PrP.sup.Sc

Preferably the agent of the invention is an antibody or fragment thereof which reacts with PrP.sup.c and with PrP.sup.Sc

Preferably the agent of the invention is an antibody or fragment thereof which is an IgG.

In another embodiment, the antibody is preferably raised against alpha PrP, preferably the antibody is raised against alpha PrP 91-231.

Preferably the antibody reacts with PrP.sup.Sc.

Preferably the antibody reacts with PrP.sup.c and with PrP.sup.Sc.

Preferably the antibody reacts with PrP epitope 146-159.

Preferably the antibody is IgG.

Preferably the antibody is of the IgG1 subclass.

Preferably the antibody comprises at least the CDRs of SEQ ID NO 3 and/or SEQ ID NO 4.

Preferably the antibody is ICSM18 or a fragment or fusion thereof.

In another embodiment, the antibody is preferably raised against beta PrP, preferably raised against beta PrP 91-231.

Preferably the antibody reacts with PrP.sup.Sc.

Preferably the antibody reacts with PrP.sup.c and with PrP.sup.Sc.

Preferably the antibody reacts with PrP epitope 91-110.

Preferably the antibody is IgG.

Preferably the antibody is of the IgG2b subclass.

Preferably the antibody comprises at least the CDRs of SEQ ID NO 1 and/or SEQ ID NO 2.

Preferably the antibody is ICSM35 or a fragment or fusion thereof.

Advantageously when the agent is an antibody, said antibody is a humanised antibody. Humanisation of antibodies is well known in the art and can be easily accomplished by the skilled worker. For example, ICSM18 and/or ICSM35 may each be advantageously humanised with reference to the sequences encoding the CDRs presented herein. In this regard, SEQ ID NO 1 corresponds to ICSM35VH; SEQ ID NO: 2 corresponds to ICSM35VK; SEQ ID NO: 3 corresponds to ICSM18VH; SEQ ID NO: 4 corresponds to ICSM181c.

Guidance regarding humanisation may be found for example in the literature as published by Greg Winter et al., and techniques for the manipulation and production of recombinant antibodies may be found in Harlow and Lane `Antibodies-A Laboratory Manual`, Cold Spring Harbour press.

In one embodiment, the antibodies (or fragments) may advantageously be humanised by manufacture of chimaeric antibodies. In another embodiment, the antibodies (or fragments) may advantageously be CDR-grafted.

In another embodiment, the antibodies (or fragments) may advantageously be fully humanised to the extent that the technology permits.

Pharmaceutical Compositions

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the agent(s) of the present invention and a pharmaceutically acceptable carrier, diluent or excipient (including combinations thereof).

The pharmaceutical compositions may be for human or animal usage in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier, or excipient. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as--or in addition to--the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).

Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.

There may be different composition/formulation requirements dependent on the different delivery systems. By way of example, the pharmaceutical composition of the present invention may be formulated to be administered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route. Alternatively, the formulation may be designed to be administered by a number of routes.

Where the agent is to be administered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.

Where appropriate, the pharmaceutical compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, the compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration the compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.

If the agent is a protein, then said protein may be prepared in situ in the subject being treated. In this respect, nucleotide sequences encoding said protein may be delivered by use of non-viral techniques (e.g. by use of liposomes) and/or viral techniques (e.g. by use of retroviral vectors) such that the said protein is expressed from said nucleotide sequence.

In a preferred embodiment, the pharmaceutical of the present invention is administered topically.

Hence, preferably the pharmaceutical is in a form that is suitable for topical delivery.

Administration

The term "administered" includes delivery by viral or non-viral techniques. Viral delivery mechanisms include but are not limited to adenoviral vectors, adeno-associated viral (AAV) vectos, herpes viral vectors, retroviral vectors, lentiviral vectors, and baculoviral vectors. Non-viral delivery mechanisms include lipid mediated transfection, liposomes, immunoliposomes, lipofectin, cationic facial amphiphiles (CFAs) and combinations thereof.

The components of the present invention may be administered alone but will generally be administered as a pharmaceutical composition--e.g. when the components are is in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

For example, the components can be administered (e.g. orally or topically) in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

If the pharmaceutical is a tablet, then the tablet may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

The routes for administration (delivery) include, but are not limited to, one or more of: oral (e.g. as a tablet, capsule, or as an ingestable solution), topical, mucosal (e.g. as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g. by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, vaginal, epidural, sublingual.

In a preferred aspect, the pharmaceutical composition is delivered topically.

It is to be understood that not all of the components of the pharmaceutical need be administered by the same route. Likewise, if the composition comprises more than one active component, then those components may be administered by different routes.

If a component of the present invention is administered parenterally, then examples of such administration include one or more of: intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the component; and/or by using infusion techniques.

For parenteral administration, the component is best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.

As indicated, the component(s) of the present invention can be administered intranasally or by inhalation and is conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA 134A.TM.) or 1,1,1,2,3,3,3-heptafluoropropane (HFA 227EA.TM.), carbon dioxide or other suitable gas. In the case of a pressurised aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount The pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g. using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g. sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insuffilator may be formulated to contain a powder mix of the agent and a suitable powder base such as lactose or starch.

Alternatively, the component(s) of the present invention can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The component(s) of the present invention may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route. For ophthalmic use, the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

For application topically to the skin, the component(s) of the present invention can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, it can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Advantageously the agent of the present invention is administered in such a way as to contact tissue(s) in which prions may accumulate. This may conveniently be accomplished by direct injection of a suitable formulation into the subject.

Approximately 0.1% of agent administered into a subject can be passively transported into the spinal fluid. This proportion may vary depending upon the exact mode of administration and the exact nature of the agent. Advantageously, techniques may be used in order to increase this proportion. Advantageously, direct application of the agent into the spinal fluid may be performed.

Clearly, it is advantageous for the agent to contact neural tissues in which prions are known to accumulate. For example, it is advantageous for the agent to be administered in such a way as to contact brain tissues. Crossing the Blood-Brain Barrier (BBB) is a problem known in the art and can be overcome by a person skilled in the art.

For example, the agent may be directly administered into the brain. This could be accomplished by direct infusion using a Omayer reservoir extending into the lateral ventricle in a manner similar to that used in the treatment of metastatic cancers such as testicular cancer.

In another example, the agent may be linked preferably covalently linked to a carrier peptide such as a ligand for the transferrin receptor such as an anti-transferrin receptor mAb or transferrin or a part thereof. In a preferred embodiment this linkage is achieved by fusion of the agent such as an antibody to the carrier such as transferrin. This may be advantageously accomplished by production and expression of a recombinant gene fusion encoding transferrin and the antibody or fragment of interest. In this manner, the agent may be administered to the subject via any suitable route and the subject's own transport mechanism(s) will allow the agent to cross the blood-brain barrier by action of the transferrin receptor.

In another example, the agent may be administered into the brain by use of non-virulent neurotropic viruses. One or more of these viruses are inoculated or infected into the subject. The blood brain barrier is then able to permit passive transfer of agent such as antibody into the brain. These regimes may be simply based on known systems such as those used in clearing alpha-virus and/or influenza-virus from the brain using antibodies. Agent(s) according to the present invention such as anti-PrP antibodies as described herein are simply substituted for the antiviral antibodies used in the existing techniques.

Timing of Administration

It is an advantage of the invention that the agent may be administered after exposure to prions.

Preferably the agent is administered as soon as is practical after exposure to prions.

Preferably the agent is administered before the onset of clinical symptoms.

Preferably the agent is administered before neuroinvasion (ie. before prions have populated the brain).

Preferably the agent is administered before peripheral neuroinvasion (ie. before prions have populated the spinal cord and/or the peripheral nerves.)

Preferably the agent is administered within 120 days of exposure, preferably within 117 days of exposure, preferably within 100 days of exposure, preferably within 80 days of exposure, preferably within 60 days of exposure, preferably within 40 days of exposure, preferably within 30 days of exposure, preferably within 20 days of exposure, preferably within 7 days of exposure.

More preferably the timing of administration is expressed in terms of a percentage of the total incubation period (mean incubation period). This enables different species' incubation times to be taken into account and appropriate adjustments made to the timing of administration. Advantageously the mouse mean total incubation time of 195 days as a calibration with reference to the Examples.

Preferably the agent is administered within 62% of the total incubation time, preferably within 60% of the total incubation time, preferably within 52% of the total incubation time, preferably within 41% of the total incubation time, preferably within 31% of the total incubation time, preferably within 21% of the total incubation time, preferably within 16% of the total incubation time, preferably within 11% of the total incubation time, preferably within 4% of the total incubation time.

If the exact time of the exposure to prions is not known then it will be apparent that an estimated time of exposure to prions should be used in the estimation of the total incubation times and therefore the timing of the administration.

Dose Levels

Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.

Depending upon the need, the agent may be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight. Preferably dosage may be estimated according to the dosages used in the accompanying Examples. For example, dosages from 500 um to 2 mg per administration per mouse (weighing approx. 25-30 gm, most often approx. 30 gm) can be extrapolated for subjects of different weights such as primates especially humans using their weights and scaling accordingly.

Formulation

The component(s) of the present invention may be formulated into a pharmaceutical composition, such as by mixing with one or more of a suitable carrier, diluent or excipient, by using techniques that are known in the art.

Pharmaceutically Active Salt

The agent of the present invention may be administered as a pharmaceutically acceptable salt. Typically, a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base, as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.

Treatment

It is to be appreciated that all references herein to treatment include one or more of curative, palliative and prophylactic treatment. Preferably, the term treatment includes at least curative treatment and/or prophylactic treatment.

The treatment may be of one or more of prion disease (including prion infection), or related complaint.

Therapy

The agents of the present invention may be used as therapeutic agents--i.e. in therapy applications.

As with the term "treatment", the term "therapy" includes curative effects, alleviation effects, and prophylactic effects.

The therapy may be on humans or animals.

The therapy can include the treatment of one or more of prion disease/prion infection, or related complaint.

Sequence Homology

Fragments, mutants, alleles and other derivatives of the sequences of interest preferably retain substantial homology with said sequence. As used herein, "homology" means that the two entities share sufficient characteristics for the skilled person to determine that they are similar. Preferably, homology is used to refer to sequence identity. Thus, the derivatives of the sequences of interest preferably retain substantial sequence identity with said sequence.

Thus the present invention also relates to agents such as antibodies having CDR sequences homologous to those presented in the sequence listing, and to the uses of such antibodies and to methods involving their use as described herein.

In the context of the present invention, a homologous sequence is taken to include any sequence which is at least 60, 70, 80 or 90% identical, preferably at least 95 or 98% identical over at least 5, preferably 8, 10, 15, 20, 30, 40 or even more residues or bases with the sequence of interest, for example as shown in the sequence listing herein. In particular, homology should typically be considered with respect to those regions of the sequence of interest which may be known to be functionally important ie. the complementarity determining regions (CDRs) rather than non-essential neighbouring sequences such as framework regions, except of course where framework residues contribute to complementarity when such residues would be regarded as functionally important also. Homology comparisons can be conducted by eye, or more usually, with the aid of readily available sequence comparison programs. In some aspects of the present invention, no gap penalties are used when determining sequence identity.

Relative sequence identity may be determined by computer programs which can calculate the percentage identity between two or more sequences using any suitable algorithm for determining identity, using for example default parameters. A typical example of such a computer program is CLUSTAL (see Thompson et al., 1994 (NAR 22: 4673-80). Advantageously, the BLAST algorithm is employed, with parameters set to default values. The BLAST algorithm is described in detail at the Pubmed NIH website. Other computer programs used to determine identity and/or similarity between sequences include but are not limited to the GCG program package (Devereux et al 1984 Nucleic Acids Research 12: 387), FASTA (Atschul et al 1990 J Mol Biol 403-410) and the GENEWORKS suite of comparison tools. Preferably, sequence comparisons are conducted using the simple BLAST search algorithm.

Although in general the techniques mentioned herein are well known in the art, reference may be made in particular to Sambrook et al., Molecular Cloning, A Laboratory Manual (1989) and Ausubel et al., Short Protocols in Molecular Biology (1999) 4.sup.th Ed, John Wiley & Sons, Inc.
 

Claim 1 of 12 Claims

1. An isolated PrP binding antibody or antigen or antigen binding fragment thereof comprising a heavy chain variable domain sequence encoded by the nucleic acid sequence of SEQ ID NO: 1 and a light chain variable domain sequence encoded by the nucleic acid sequence of SEQ ID NO: 2.

____________________________________________
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