CN104395343A - Optimum dose regime of an anti-nogo-a antibody in the treatment of amyotrophic lateral sclerosis - Google Patents

Optimum dose regime of an anti-nogo-a antibody in the treatment of amyotrophic lateral sclerosis Download PDF

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CN104395343A
CN104395343A CN201380035806.8A CN201380035806A CN104395343A CN 104395343 A CN104395343 A CN 104395343A CN 201380035806 A CN201380035806 A CN 201380035806A CN 104395343 A CN104395343 A CN 104395343A
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antibody
nogo
limited
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dosage
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J.布尔曼
D.克鲁尔
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Glaxo Group Ltd
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Abstract

The invention relates to a method of treatment or prophylaxis of a neurological disorder, in particular but not exclusively amyotrophic lateral sclerosis (ALS), comprising administration of an anti-Nogo-A antibody.

Description

The optimal dose regime of anti-nogo-a antibody in amyotrophic lateral sclerosis treatment
Invention field
The present invention relates to treatment or prevention neurological disorder particularly but and be not exclusively the method for amyotrophic lateral sclerosis (ALS), it comprises using of anti-nogo-a antibody.
background of invention
Amyotrophic lateral sclerosis (ALS), also referred to as Lu Jia RD (Lou Gehrig's Disease) or charcot's disease (Maladie de Charcot), is the motor neuron of modal Adult Onset.Principal disease mark is the Progressive symmetric erythrokeratodermia regression of the intrafascicular upper and LM of corticospinal.The dysfunction trigger systemic of LM (in brain stem and spinal cord) is weak, amyotrophy and paralysis.The inefficacy of respiratory muscle is generally fatal event, occurs in morbidity 1-5.
ALS is modal motor neuron in adult, affects the U.S. about 30 every year, 000 people and Britain 5,000 people (Leigh and Swash, 1991).Typical case age of onset between 50 to 70 years old, although sometimes occurring more at an early age.Most of case (90-95%) is categorized as sporadic ALS (sALS), and remainder is genetic, and is called as familial ALS (fALS).Sporadic is that clinical relation is similar with familial type, prompting co-morbid mechanism people such as (, 2004) Bruijn.But the exact cause of most of case is still unknown, and there is not the effective therapeutics stopping this disease process.
Nogo also referred to as Reticulon-4 or neurite outgrowth inhibitor (Neurite outgrowth inhibitor), be in people by rTN4the protein of genes encoding, described in rTN4gene has been accredited as the inhibitor for the specific neurite outgrowth of central nervous system.
The people Nogo of three kinds of forms is identified: Nogo-A has 1192 amino-acid residues (GenBank accession number AJ251383); Nogo-B, lacks the splice variant (GenBank accession number AJ251384) of the residue 186 to 1004 in supposition extracellular domain; And shorter splice variant, Nogo-C, it also lacks residue 186 to 1004 and has less alternative amino terminal domain (GenBank accession number AJ251385) (people (2000) Nature 403,383-384 such as Prinjha R).The suppression of CNS arrestin matter such as Nogo can provide and improve Neuronal Damage and the methods for the treatment of promoting neurone reparation and growth, and the neuronal damage that potential help such as continues in apoplexy from neuronal damage thus recovers.The example of this type of Nogo inhibitor can comprise small molecules, peptide and antibody.
Report that the mouse monoclonal antibody IN-1 produced for NI-220/250 promotes axon regeneration (Caroni, P and Schwab, ME(1988) Neuron 1 85-96; Schnell, L and Schwab, ME(1990) Nature 343 269-272; Bregman, the people such as BS (1995) Nature 378 498-501 and Thallmair, the people such as M (1998) Nature Neuroscience 1 124-131), the myelin protein (and being later shown as the fragment of Nogo-A) of described NI-220/250 to be it be effective inhibitor of neurite outgrowth.Also report that Nogo-A is the antigen (people (2000) Nature 403 434-439 such as Chen) of IN-1.The using of IN-1 Fab fragment or humanization IN-1 strengthens recovery in the rat experiencing spinal cord transection art (people (2002) Protein Eng 15 931-941 such as Fiedler, M; The people such as Brosamle, C (2000) J. Neuroscience 20 8061-8068).
The monoclonal antibody be combined with Nogo describes in WO 2004/052932, WO 2005/028508, WO 2005/061544 and WO 2007/068750.WO 2004/052932 discloses the murine antibody 11C7 be combined with the people Nogo of some form with high-affinity.WO 2005/061544 also discloses high-affinity monoclonal antibody, comprise mouse monoclonal antibody 2A10, such as, and generally disclose its humanization variant, the sequence of H1 L11(H1 and L11 provides (only VH or VL sequence) respectively in SEQ ID NO. 33 and 34).Disclosed antibody is combined with people Nogo-A with high-affinity.WO 2007/068750 discloses much high-affinity humanization monoclonal anti Nogo antibody, and the sequence comprising H28L16(H28 and L16 provides (only VH or VL sequence) respectively in SEQ ID NO. 49 and 14).Disclosed antibody instruction can be used for treating nervous system disease.
Although provides the art the anti-Nogo antibody of the high-affinity being used for the treatment of neurological disorder, the treatment plan optimizing this type of obstacle is still the target of high expectations.
summary of the invention
According to a first aspect of the invention, provide the method for the neurological disorder in treatment or prevention patient, described method comprises uses anti-nogo-a antibody or its function fragment to described patient, and its dosage realizes and maintains the common position level that described antibody and people Nogo-A are greater than 90% on the cytolemma of described patient.
According to a second aspect of the invention, provide the anti-nogo-a antibody of the neurological disorder being used for the treatment of or preventing in patient, described treatment or prevention comprise uses described anti-nogo-a antibody or its function fragment, and its dosage realizes and maintains the common position level that described antibody and people Nogo-A are greater than 90% on the cytolemma of described patient.
According to a third aspect of the present invention, provide the pharmaceutical composition of the neurological disorder being used for the treatment of or preventing in patient, described pharmaceutical composition comprises anti-nogo-a antibody or its function fragment, described treatment or prevention comprise uses described anti-nogo-a antibody or its function fragment, and its dosage realizes and maintains the common position level that described antibody and people Nogo-A are greater than 90% on the cytolemma of described patient.
accompanying drawing is sketched
fig. 1:laser scanning Cytometry (LSC) fully scans, and with appraisement organization's section (gray image), and four regions (blue-greenish colour frame) is placed in each section.High resolving power field scan produces the site plan picture of three kinds of dyestuffs.Various protein dye is blue (γ sarcoglycan), red (Nogo A) and green (H28L16).
Figure 2:event colony gate (before administration biopsy samples).Produce scatter diagram with based on fluorescence intensity with regard to feature differentiation dyestuff pixel.
fig. 3:event colony gate (before administration biopsy samples).This figure is the field picture of display " background gate (back gating) " process, and described " background gate " is for showing gated events on tissue sections.
fig. 4:event colony gate (after administration biopsy samples).As produced scatter diagram in Fig. 2, but, after with 15 mg/kg H28L16 administrations.
fig. 5:event colony gate (after administration biopsy samples).Background gate as carried out in Fig. 3, but, after with 15 mg/kg H28L16 administrations.
fig. 6:nogoA/H28L16 expresses (γ sarcoglycan passage is not shown).Show each fluorescence channel.First trip is display target (Nogo A) only, and the second row only shows H28L16, and the third line display Nogo A and H28L16.
fig. 7:the Nogo A per-cent that film is located altogether with H28L16.Show the Nogo A per-cent of locating altogether with H28L16 on sarcolemma.The frame highlighting " 15mg/kg " shows and realizes being total to the maximum of locating after with 15 mg/kg H28L16 administrations.Every post represents a section.
fig. 8:the intermediate value per-cent of the film Nogo-A located altogether with H28L16.Data are from 2.5 mg/kg repeated doses (left figure), 15 mg/kg repeated doses (middle 3 figure) and 15 mg/kg single doses (right figure).From the triplicate section of the biopsy samples of repeated doses group, together with the intermediate value of the single section of the biopsy samples from single dose group.
Figure 9:blood plasma H28L16 concentration and and the H28L16 film Nogo-A per-cent of locating altogether between model estimate relation (Emax).
figure 10:about prediction intermediate value (the 5th percentile and the 95th percentile) the H28L16 Plasma concentration time overview of the 15mg/kg H28L16 that every 4 weeks use.
figure 11:about prediction intermediate value (the 5th percentile and the 95th percentile) the H28L16 Plasma concentration time overview of the 15mg/kg H28L16 that every 2 weeks use.
Figure 12:the Weight variable sequence of H28L16 antibody and variable light district.
detailed Description Of The Invention
According to a first aspect of the invention, provide the method for the neurological disorder in treatment or prevention patient, described method comprises uses anti-nogo-a antibody or its function fragment to described patient, and its dosage realizes and maintains the common position level that described antibody and people Nogo-A are greater than 90% on the cytolemma of described patient.
Be to be understood that and mention that " altogether location " refers to locate with anti-nogo-a antibody, be connected (associated with) or combine the membrane-bound Nogo-A ratio of (bound to) herein.Such as, the value of 100% altogether location equals all film Nogo-A and anti-nogo-a antibody is located altogether.Technician is to be understood that common location is not equal to target and occupies, but it provides measuring, to determine optimal dose regime of very useful possible drug action really.
The data acknowledgement presented herein Nogo-A and anti-nogo-a antibody on cytolemma are located altogether with the level being greater than 90% and are realized maximum drug action.
Mention that " anti-nogo-a antibody " refers to any antibody or its variant form herein, include but not limited to antibody fragment, domain antibodies or the single-chain antibody that can be combined with Nogo-A.Anti-nogo-a antibody can be neutrality anti-nogo-a antibody.Anti-nogo-a can be mouse, chimeric, humanization or human antibody or its fragment." neutralization " and grammatical variants thereof refer to any Nogo function, and more specifically, all or part of suppression of any Nogo-A function.
As used herein, mention that " treatment " refers to reduction or the elimination of the reason of the disease symptoms relevant to amyotrophic lateral sclerosis and/or amyotrophic lateral sclerosis, comprise the intrafascicular neuronic Progressive symmetric erythrokeratodermia sex change of corticospinal, the reduction of myofiber denervation and/or myasthenia and/or spasticity or elimination.As used herein, mention " prevention " refer to the disease symptoms relevant to amyotrophic lateral sclerosis delay, prevent or drop to minimum, comprise the intrafascicular neuronic Progressive symmetric erythrokeratodermia sex change of corticospinal, myofiber denervation and/or myasthenia and/or spasticity delay, prevent or drop to minimum.
Be to be understood that selection is greater than 90% to guarantee realization and to maintain on cytolemma with the common location of Nogo-A by amount and the frequency of anti-nogo-a antibody to be administered.
WO 2010/004031 discloses the suitable dose of the anti-nogo-a antibody being used for the treatment of ALS in people or other nervous system diseases by the scope of 0.1 mg/kg to 300 mg/kg, is generally about 2 mg/kg to about 40 mg/kg.Therefore, in one embodiment, the dosage of anti-nogo-a antibody is 0.1 mg/kg to 300 mg/kg.In further embodiment, the dosage of anti-nogo-a antibody is 2 mg/kg to 40 mg/kg.
In addition, WO 2007/068750 discloses the suitable dose of the anti-nogo-a antibody being used for the treatment of apoplexy in people and other nervous system diseases by the scope of 700 mg to 3500 mg/70 kg body weight.Therefore, in one embodiment, the dosage of anti-nogo-a antibody is 10 mg/kg to 50 mg/kg.
In a particular of the present invention, the dosage of anti-nogo-a antibody is 15 mg/kg.The data presented herein show the advantageous results of 15 mg/kg dosage surprisingly.Especially, this dosage complies with dose frequency easily especially, is total to the threshold value of the present invention of locating to realize being greater than on cytolemma with 90% of Nogo-A.
Present the data of the particularly advantageous 15 mg/kg dosage of the present invention herein, its display, for the time length of using latter 8 days, cytolemma is increased to the common location of Nogo-A and is greater than 90%, and after application between 22 to 27 days, be down to about 70%.Therefore, in one embodiment, when dosage is 15 mg/kg, maintenance is greater than 90% suitable dose of locating altogether and is spaced apart 8 to 22 days.In further embodiment, when dosage is 15 mg/kg, maintenance is greater than 90% suitable dose of locating altogether and is spaced apart 10 to 18 days.
In a particular of the present invention, when dosage is 15 mg/kg, maintenance is greater than 90% suitable dose of locating altogether and is spaced apart 14 days.Be to be understood that the slight change of 14 days spacing of doses will be acceptable, and administration by 14 days +/-before or after 14 days spacing of doses of the best until 3 days time occur.Therefore, in one embodiment, when dosage is 15 mg/kg, maintains the suitable dose being greater than 90% altogether location and be spaced apart 11 days to 17 days (namely before or after 14 days spacing of doses of the best 3 days).In an alternative embodiment, when dosage is 15 mg/kg, maintains the suitable dose being greater than 90% altogether location and be spaced apart 12 days to 16 days (namely before or after 14 days spacing of doses of the best 2 days).In an alternative embodiment, when dosage is 15 mg/kg, maintains the suitable dose being greater than 90% altogether location and be spaced apart 13 days to 15 days (namely before or after 14 days spacing of doses of the best 1 day).
According to further aspect of the present invention, provide the method for the neurological disorder in treatment or prevention patient, it comprises the anti-nogo-a antibody that every 14 days (+/-3 days) is 15 mg/kg to described patient at dosage.
The example of the anti-nogo-a antibody that can use according to the present invention describes in WO 2004/052932, WO 2005/028508, WO 2005/061544 and WO 2007/068750, and the anti-nogo-a antibody of described patent is incorporated to herein by reference.
In one embodiment, anti-nogo-a antibody is monoclonal antibody.
In one embodiment, anti-nogo-a antibody is humanized antibody.Mention that term " humanized antibody " refers to such class engineered antibody herein, it has the CDR deriving from non-human donor immunoglobulin, and the residual immunity sphaeroprotein derivative moiety of this molecule derives from one (or more) human normal immunoglobulin.In addition, can framework support residues be changed, to preserve binding affinity (see people such as such as Queen, Proc. Natl Acad Sci USA, 86:10029-10032(1989), the people such as Hodgson, Bio/Technology, 9:421(1991)).Suitable people's receptor antibody can be by with donor antibody (in this case, mouse donor antibody 2A10) Nucleotide and the homology of aminoacid sequence, be selected from the antibody of routine data storehouse such as KABAT database, Los Alamos database and Swiss Protein database.The people's antibody characterized by the homology (on amino acid basis) of the framework region with donor antibody may be applicable to providing CH and/or weight chain variable framework region for inserting donor CDR.The suitable acceptor antibody of constant region of light chain or variable framework region can be contributed to be selected in a similar manner.Should be understood that receptor antibody weight and light chain are without the need to being derived from same receptor antibody.EP-A-0239400 and EP-A-054951 particularly depict the several method producing this type of humanized antibody.
Term " donor antibody " refers to non-human antibody, it contributes the aminoacid sequence of its variable region, CDR or its other function fragments or analogue to humanized antibody, and thus provides the humanized antibody of antigen-specific and the Neutralization effect feature with donor antibody.
Term " receptor antibody " refers to the antibody with donor antibody allos, and described antibody on human source antibody provides its heavy and/or light chain framework regions and/or its aminoacid sequence that is heavy and/or constant region of light chain.Receptor antibody can derive from any Mammals, and condition is that its right and wrong in people is immunogenic.In one embodiment, receptor antibody is people's antibody.
Or humanization can be realized by " veneer (veneering) " method.Unique people and rat immune globulin is heavy and the statistical study of variable region of light chain discloses: the accurate model of exposed residue is different in people and murine antibody, and each surface location of great majority to have for a small amount of different residue strong preferred (see people such as Padlan E.A.; (1991) people (1994) the J. MoI. Biol. 235 such as Mol.lmmunol.28,489-498 and Pedersen J.T.; 959-973).Therefore, by replacing in its framework region those the exposed residue being different from and usually finding in people's antibody, the immunogenicity of inhuman Fv can be reduced.Because proteantigen can associate with surperficial accessibility, so the replacement of surface residue may be enough to cause mouse variable region to human immune system " invisible " (also see people (1994) such as Mark G. E. in Handbook of Experimental Pharmacology the 113rd volume: The pharmacology of monoclonal Antibodies, Springer-Verlag, 105-134 page).This humanization program is called as " veneer ", because only change the surface of antibody, supports that residue keeps interference-free.Further alternative is set forth in WO 2004/006955.
" CDR " is defined as the complementary determining region aminoacid sequence of antibody, its hypervariable region that is heavy for immunoglobulin (Ig) and light chain.See people such as such as Kabat, Sequences of Proteins of Immunological Interest, the 4th edition, U.S. Department of Health and Human Services, National Institutes of Health(1987).Three heavy chains and three light chain CDR(or CDR district is there is) in the variable part of immunoglobulin (Ig).Therefore, as used herein " CDR " refers to all three heavy chain CDR, or all three light chain CDR(or suitably time, all heavy chain CDR and all light chain CDR).The structure of antibody and protein folding can mean the part that other residues are considered as antigen binding domain, and technician will so understand.See people such as such as Chothia, (1989) Conformations of immunoglobulin hypervariable regions; Nature 342,877-883 page.
In one embodiment, anti-nogo-a antibody is neutrality anti-nogo-a antibody or its fragment, and such as murine antibody 2A10,15C3 and 2C4(such as its content is incorporated to described in WO 2005/016544 herein with its entirety by reference).
In one embodiment, anti-nogo-a antibody is that the content of patent described in WO 2004/052932(is incorporated to herein with its entirety by reference) described in any antibody.Disclosed in WO 2004/052932, the example of antibody is 11C7, comprises its humanization variant.
In one embodiment, anti-nogo-a antibody is that the content of patent as described in WO 2005/028508 and WO 2009/056509(is incorporated to herein with its entirety by reference) described in anyone anti-nogo-a antibody.In further embodiment, anti-nogo-a antibody is the people's anti-nogo-a antibody 6A3 as described in WO 2009/056509.
In one embodiment, anti-nogo-a antibody comprises the anti-nogo-a antibody described in WO 2007/068750.In further embodiment, anti-nogo-a antibody comprises the humanization variant of humanized antibody such as 2A10, such as H20L16, H28L16, H28L13 and H27L16(such as its content is incorporated to described in WO 2007/068750 herein with its entirety by reference), people's antibody or its fragment.
In further embodiment, anti-nogo-a antibody comprises SEQ ID NO:48 and the SEQ ID NO:14 of H27L16(WO 2007/068750), the SEQ ID NO:49 of H28L13(WO 2007/068750 and SEQ ID NO:13) or the SEQ ID NO:49 of H28L16(WO 2007/068750 and SEQ ID NO:14).In further embodiment, anti-nogo-a antibody comprises SEQ ID NO:49 and the SEQ ID NO:14 of H28L16(WO 2007/068750, is respectively SEQ ID NO:1 herein and SEQ ID NO:2).
In further embodiment, anti-nogo-a antibody comprises SEQ ID NO:54 and the SEQ ID NO:18 of H27FL L16FL(WO 2007/068750), the SEQ ID NO:55 of H28FL L13FL(WO 2007/068750 and SEQ ID NO:17) or the SEQ ID NO:55 of H28FL L16FL(WO 2007/068750 and SEQ ID NO:18).In further embodiment, anti-nogo-a antibody comprises SEQ ID NO:55 and the SEQ ID NO:18 of H28FL L16FL(WO 2007/068750).
In further embodiment, anti-nogo-a antibody comprises SEQ ID NO:49 and the SEQ ID NO:14 of H28L16(WO 2007/068750) or the SEQ ID NO:55 of H28FL L16FL(WO 2007/068750 and SEQ ID NO:18).In further embodiment, anti-nogo-a antibody comprises SEQ ID NO:49 and the SEQ ID NO:14 of H28L16(WO 2007/068750).
In further embodiment, it is one or more that anti-nogo-a antibody or its fragment comprise in the CDR of 2A10, H28L16 or 6A3, optional six.In further embodiment, anti-nogo-a antibody or its fragment are if H28L16 is in conjunction with identical people Nogo-A epi-position (people Nogo-A 610-621aa, it comprises the SEQ ID NO:6 from WO 2010/004031) or the antibody with H28L16 competition binding people Nogo-A.
The example of the neurological disorder can treated according to dosage of the present invention is selected from: apoplexy (ischemia or hemorrhagic), traumatic brain injury, Spinal injury, Alzheimer, frontotemporal dementia (Tau albumen is sick), peripheral neuropathy, Parkinson's disease, creutzfeldt-Jacob disease (CJD), schizophrenia, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Huntington's disease, multiple sclerosis, inclusion body myositis, polymyositis, dermatomyositis, the non-specific myopathy of form (morphologically nonspecific myopathies), congestive heart failure and neuropathic pain.
In one embodiment, neurological disorder is amyotrophic lateral sclerosis (ALS).
The mode of administration of anti-nogo-a antibody of the present invention or its fragment can be to any suitable pathways of host by drug delivery.Antibody of the present invention and pharmaceutical composition can be used in particular for parenteral administration, namely subcutaneous (s.c), in sheath, in intraperitoneal (i.p.), intramuscular (i.m.), intravenously (i.v.) or nose (i.n.).In one embodiment, anti-nogo-a antibody or its fragment intravenously are used.In an alternative embodiment, anti-nogo-a antibody or its fragment subcutaneous administration.
According to a second aspect of the invention, provide the anti-nogo-a antibody of the neurological disorder being used for the treatment of or preventing in patient, described treatment or prevention comprise uses described anti-nogo-a antibody or its function fragment, and its dosage realizes and maintains the common position level that described antibody and people Nogo-A are greater than 90% on the cytolemma of described patient.
According to a third aspect of the present invention, provide the pharmaceutical composition of the neurological disorder being used for the treatment of or preventing in patient, described pharmaceutical composition comprises anti-nogo-a antibody or its function fragment, described treatment or prevention comprise uses described anti-nogo-a antibody or its function fragment, and its dosage realizes and maintains the common position level that described antibody and people Nogo-A are greater than 90% on the cytolemma of described patient.
The of the present invention antibody of pharmaceutical composition of the present invention usually containing the significant quantity in pharmaceutically acceptable carrier is as activeconstituents.In prevention medicament of the present invention, preferably usually cushion at physiological ph, with prepare for injection form containing the aq suspension of engineered antibody or solution.The composition of parenteral administration is generally comprised within the solution of antibody of the present invention or its mixture (cocktail) dissolved in pharmaceutically acceptable carrier (being generally aqueous carrier).Multiple aqueous carrier can be adopted, such as 0.9% salt solution, 0.3% glycine etc.These solution are aseptic and generally do not contain particulate matter.These solution can carry out sterilizing by conventional, well-known sterilising technology (such as filtering).Said composition can contain close to the pharmaceutically acceptable auxiliary substance needed for physiological condition, such as pH adjusting agent and buffer reagent etc.The concentration of the antibody of the present invention in this type of pharmaceutical preparation can extensively change, namely from being less than about 0.5 % by weight (be generally or at least about 1 % by weight) to nearly 15 or 20 % by weight, and by according to selected concrete method of application, mainly selected based on fluid volume, viscosity etc.
Therefore, the pharmaceutical composition of the present invention for intramuscularly can be prepared as containing 1 mL sterile buffered water, and about 1 ng to about 100 mg, such as about 50 ng to about 30 mg or more, the antibody of the present invention of such as about 5 mg to about 25 mg.Similarly, pharmaceutical composition of the present invention for intravenous infusion can be prepared as containing 250 ml 0.9% physiological saline (sodium-chlor) solution of having an appointment, and about 1 is generally 5 mg to about 25 mg engineered antibody/ml 0.9% of the present invention physiological saline (sodium-chlor) solution to about 30.Preparation can the practical methods of composition of parenteral administration be that those skilled in the art are well-known or apparent, and such as at Remington's Pharmaceutical Science, 15th edition, Mack Publishing Company, describe in more detail in Easton, Pennsylvania.About of the present invention can the intravenously preparation of antibody preparation of using, see Lasmar U and Parkins D " The formulation of Biopharmaceutical products ", Pharma. Sci.Tech.today, 129-137 page, 3rd volume (on April 3rd, 2000), Wang, W " Instability, stabilisation and formulation of liquid protein pharmaceuticals ", Int. J. Pharm 185(1999) 129-188, Stability of Protein Pharmaceuticals Part A and B ed Ahem T.J., Manning M. C, New York, NY:Plenum Press(1992), Akers.M.J. " Excipient-Drug interactions in Parenteral Formulations ", J.Pharm Sci 91(2002) 2283-2300, Imamura, the people such as K " Effects of types of sugar on stabilization of Protein in the dried state ", J Pharm Sci 92(2003) 266-274, lzutsu, Kkojima, S. " Excipient crystalinity and its protein-structure-stabilizing effect during freeze-drying ", J Pharm. Pharmacol, 54(2002) 1033-1039, Johnson, R, " Mannitol-sucrose mixtures-versatile formulations for protein lyophilization ", J. Pharm. Sci, 91(2002) 914-922. Ha, E Wang W, Wang YJ. " Peroxide formation in polysorbate 80 and protein stability ", J. Pharm Sci, 91, 2252-2264, (2002), its complete content is incorporated to by reference herein and reader can specifically reference.
Antibody described herein freeze-drying can be used for storage and reconstructs in suitable carrier before use.This technology has shown for conventional immune globulins effective, and the freeze-drying that field can be adopted known and reconfiguration technique.
In one embodiment, anti-nogo-a antibody and further therapeutic combination are used.In further embodiment, further therapeutical agent is the medicament of the effect had for amyotrophic lateral sclerosis (ALS).In further embodiment, the medicament had for the effect of amyotrophic lateral sclerosis (ALS) is dexpramipexole (dexpramipexole).Dexpramipexole (KNS-760704; ( r)- n 6-propyl group-4,5,6,7-tetrahydro benzo [ d] thiazole-2,6-diamines) be the medicine developed by Knopp Biosciences and Biogen.Relate to slowing down of the II clinical trial phase display ALS progression of disease in 2010 of 102 patients, and the III phase tests underway at present.
In one embodiment, anti-nogo-a antibody is used together with having the compound of antiglutamic acid activity.In a particular embodiment, the compound with antiglutamic acid activity is Riluzole (riluzole).In another embodiment, the compound with antiglutamic acid activity is ampa receptor antagonist, such as 2,3-blood metabolites (2,3-benzodiazepine compound), particularly Talampanel.In another embodiment, the compound with antiglutamic acid activity is TRO 19622 or ceftriaxone.Anti-nogo-a antibody and have antiglutamic acid activity compound can simultaneously, continuously or separate administration in patient.When the compound with antiglutamic acid activity is Riluzole, about 50mg can daily in patient to about 150 or 200mg Riluzole, and usual 100mg Riluzole is daily in patient.Riluzole is normally Orally administered.When the compound with antiglutamic acid activity is Talampanel, Talampanel is usually Orally administered once to five times for every day with about 10mg to about 250mg.In one embodiment, Talampanel with the dosage of 25mg or 50mg daily once to five times, optional every day three times.
The present invention is illustrated with reference to following research:
the common positioning analysis of embodiment 1:Nogo A and H28L16
Laser scanning Cytometry (LSC) uses laser to carry out fluorescence excitation dyestuff, and to produce the image of the position of dyestuff in biological cells and tissues section, this allows to measure the expression in described position.Dyestuff is connected to the antibody be combined with targeting proteins matter.Be connected to the target of business anti-nogo-a antibody for the identification of H28L16 of Alexa 647 dyestuff.The use of business Nogo A antibody allows to measure the target in tissue slice.Also expect to know that how many targets (Nogo A) are positioned on sarcolemma.This is by carrying out with the section of the antibody staining for the anti-γ sarcoglycan of sarcolemma protein being connected to Alexa 488 dyestuff.
This allow qualification and measure and sarcolemma locate altogether and no the amount of the target (Nogo A) of locating altogether with film.Next, the H28L16 amount quantitatively in the muscle section of administration and the common location with its target (Nogo A) is needed.In order to provide, H28L16's is quantitatively this, is used for marker muscle section with the non-neutral antiidiotypic antibody for H28L16 of Alexa 555 dye marker.Once three kinds of components, three kinds of different dyes mark, LSC software just may be used for distinguishing and measures often kind of feature.
Carry out fully scanning with appraisement organization's section (gray image), and four regions (blue-greenish colour frame) is placed in each section.High resolving power field scan produces the site plan picture of three kinds of dyestuffs.
Fig. 1 shows the LSC area image wherein color being assigned to each passage.Such as, various protein staining is blue (γ sarcoglycan), red (Nogo A) and green (H28L16).Profile is the rectangle frame of white is each field picture forming area image.Each area image contains 10 field picture.
Produce scatter diagram with based on fluorescence intensity with regard to feature differentiation dyestuff pixel.Pixel uses the threshold value (ground unrest and specific signals are distinguished) being called the method for " gate ".Gate is illustrated on scatter diagram as multi-color cord, and according to the order that door produces, door is labeled as R1, R2 and R3 ... Deng (Fig. 2).The scatter diagram of Fig. 2 is by producing for marking and drawing two passages each other.The film of tissue and non-diaphragm area are by distinguishing for " green intensity " plotting " green maximum pixel ".Brightest pixel in R1 is on the film with γ sarcoglycan antibody labeling.In R5 is unlabelled fiber compared with duskiness pixel.Long red intensity value is marked and drawed for film value (green maximum pixel), to obtain the amount of the Nogo A located altogether with film R2.In order to obtain the medication amount on film, green maximum pixel is marked and drawed for yellow intensity.Because this is biopsy samples before administration, so if present, in R3, there is not the event that can contain the medicine on film.Last figure shows the medicine that will be positioned at altogether with Nogo A on film.
Can be illustrated on image as colored box in the intragroup pixel groups of gate.The method is called as " background gate ".The most accurately placing of checking door is quality control tasks (Fig. 3).Gate colony in scatter diagram in Fig. 2 is illustrated in the image of Fig. 3.Be it should be noted that by Fig. 3, these data, from the patient only using vehicle administration, therefore exist with the minimum background stainings of the antiidiotypic antibody for H28L16 and little evidence (red block) of locating altogether with Nogo-A.
When with display come personal 15 mg/kg H28L16 administrations patient data Figure 4 and 5 compared with time, should be understood that background gate demonstrates display nothe green frame of the position of the H28L16 located altogether with Nogo A, and display H28L16 withthe red block that Nogo A locates altogether.Therefore, Figure 4 and 5 show the common location of positive drug event in R3 and medicine and Nogo A.
Fig. 6 shows each fluorescence channel.Before administration, biopsy samples is red, and compared with biopsy samples after administration, there is not orange/yellow fluorescence, the common location that after described administration, biopsy samples shows H28L16 and Nogo A and the excessive H28L16 do not located altogether with Nogo A.High positioned edge tunica fibrosa altogether occurs.
Fig. 7 is the figure being presented at the Nogo A per-cent that sarcolemma is located altogether with H28L16.Cut three sections and assess each patient's biopsy samples (by medicine or placebo administration front and rear).More visible low-level location altogether in the biopsy samples from non-administration experimenter (before administration or placebo administration), the antiidiotypic antibody visible non-specific background represented with locating altogether with Nogo-A dyes.Higher levels of antiidiotype dyeing and visible all the time in sample after being positioned at drug administration altogether, wherein locating and displaying dose-dependently increase altogether.The section highlighted shows the common location of H28L16 and the Nogo A of highest level on muscle film, and this is in the biopsy samples collected from the experimenter of 8 days after with 15mg/kg H28L16 administration.
embodiment 2: use positioning experiment altogether to study the optimal dose regime of H28L16 for amyotrophic lateral sclerosis (ALS)
When there is not the direct measurement of replying the drug effect of the H28L16 in muscle, use the target site place of H28L16 on the film of Skeletal Muscle Cell and the common location of Nogo-A, to inform dosage choice, as described in example 1 above.Such as, in order to assess the muscle level of Nogo-A and H28L16 to the bio distribution of skeletal muscle, muscle biopsy is collected from the designated groups (cohort) in " among people first " (FTiH) research.Quantity is enough to support that the antibody of freezing biopsy samples (mainly from 0.5 mg/kg, 2.5 mg/kg and 15 mg/kg groups) for Nogo-A of immunohistochemical analysis, the antiidiotypic antibody for H28L16 and anti-γ sarcoglycan (to define muscle film) dye.Use fluorescently-labeled secondary antibody to develop to express, and use laser scanning Cytometry (LSC) quantitative.Use the method, Nogo-A on muscle film can be evaluated and express, and be different from Nogo-A in cell by the common location with γ sarcoglycan and express.In addition, measure the estimated value of the H28L16 level in muscle, and derive the estimated value of the common location degree of Nogo-A and H28L16 on muscle film.
Use the H28L16 level in antiidiotype staining evaluation muscle, the dose-dependently observed in medicine dyeing increases, wherein when 0.5 mg/kg without measurable dyeing, and upon administration during 22-27 days, visible the highest dyeing (measuring consistent with the immunoassay of the levels of drugs in muscle) in the biopsy samples from 15 mg/kg administration experimenters.The biopsy samples collection time point changed in 15 mg/kg repeated doses groups (group 8) allow to evaluate upon administration medicine to the chorologic time course of muscle.These data presentation the 1st day time in muscle the H28L16 of initial lower level, increase until the 8th day, then again slightly declined by 23-24 days.
The other measurement of the film Nogo-A level in these biopsy samples allows to evaluate upon administration in the common location degree of target site place Nogo-A and H28L16.Fig. 8 illustrates the intermediate value per-cent (wherein 100% will equal all film Nogo-A all locate altogether with H28L16) of the Nogo-A that muscle cell membrane place after the administration deriving from 2.5 mg/kg and 15 mg/kg groups in biopsy samples and H28L16 locate altogether.
Altogether locate degree closely follow the H28L16 level measured in muscle, wherein in the biopsy samples of the experimenter from 15 mg/kg process visible level higher than the biopsy samples from 2.5 mg/kg groups.In 15 mg/kg repeated doses groups, altogether location again with H28L16 horizontal relevance, had the 1st day time ~ 50% intermediate value locates altogether, upon administration the 8th day time the Nogo-A that locates altogether with drugs on muscle film increase to >90%, then to fall back to when 22-27 days ~ 70%.
Although common location is not equal to target and occupies, think that the >90% of muscle film Nogo-A and H28L16 locates altogether on whole spacing of doses required, to realize maximum drug action.Based on LSC data, need the dosage level of 15 mg/kg H28L16 with realize upon administration the 8th day time film Nogo-A and H28L16 >90% locate altogether, although this altogether the degree of locating be not maintained to 23-24 days.Exploratory PK-PD modeling is shown, to study the blood plasma H28L16 concentration (using colony PK model) and corresponding potential relation altogether between position level estimated when examination of living tissue in Fig. 9.To the EC that these market demands Emax model is estimated in ~ 18 μ g/mL regions 50with the EC of ~ 160 μ g/mL 90.
Dosage regimen is studied to maintain blood plasma H28L16 concentration more than EC based on colony PK modeling and follow-up simulation 90, it is evident that, the dosage regimen (every 4 weeks one time 15 mg/kg) utilized in FTiH research predicts the plasma concentration completely on average do not maintained more than 160 μ g/mL on dosing interval.But, administration frequency is increased to every 2 weeks one time 15 mg/kg and predicts the concentration on average maintained more than 160 μ g/mL on dosing interval.Blood plasma H28L16 concentration-time overview about every 15mg/kg prediction of using for 2 and 4 weeks is hereafter being showed in Figure 10 and Figure 11 respectively.With regard to the proposal dosage regimen of every 2 weeks 15 mg/kg, the H28L16 plasma exposure (C of prediction maxand AUC (0-tau)) be showed in table 1.
The 15mg/kg H28L16 that table 1 was used about every 2 weeks, intermediate value (the 5th percentile and the 95th percentile) the H28L16 plasma C max and AUC(0-tau of prediction).
With every 2 weeks frequencies once with 15 mg/kg repeat administrations after, the prediction people systemic exposure when stable state approximately doubles after single 15 mg/kg dosage.
Evidence display H28L16 from the FTiH research in ALS patient tolerated during 15 mg/kg dosage once completely at every 4 weeks.At every 14 days intravenous administrations up in long-term 12 months toxicity research in the cynomolgus monkey of 500 mg/kg, do not observe remarkable toxicity.Based on the 15 mg/kg dosage that every 2 weeks use, relative in the 2 phases research proposed the human plasma of steady state predictions expose to expose boundary (margins of exposure) to the monkey of H28L16 to people be (i) based on 33 times of dose ratio, (ii) based on 10 times of stable state AUC ratio, (iii) based on stable state C max27 times of ratio.
Based on from the security of non-clinical study and systemic exposure boundary; From clinical safety, the PK positioning relation data altogether of FTiH research; And colony PK modeling, the optimal dose of H28L16 looks like every 2 weeks one time 15 mg/kg.Although expection exceedes the exposure level reached in clinical studies up to now, this dosage is fully supported by non-clinical safety evaluation data, and makes the effect chance of sending in ALS patient reach maximum.

Claims (20)

1. the method for the treatment of or preventing the neurological disorder in patient, described method comprises uses anti-nogo-a antibody or its function fragment to described patient, and its dosage realizes and maintains the common position level that described antibody and people Nogo-A are greater than 90% on the cytolemma of described patient.
2. the method as limited in claim 1, wherein said anti-nogo-a antibody dosage is 0.1 mg/kg to 300 mg/kg.
3. the method as limited in claim 2, wherein said anti-nogo-a antibody dosage is 15 mg/kg.
4. the method as limited in claim 3, is wherein saidly greater than 90% and locates maintenance 8 to 22 days altogether.
5. the method as limited in claim 4, is wherein saidly greater than 90% and locates maintenance 10 to 18 days altogether.
6. the method as limited in claim 5, is wherein saidly greater than 90% and locates maintenance 11 to 17 days altogether.
7. the method as limited in claim 6, is wherein saidly greater than 90% and locates maintenance 12 to 16 days altogether.
8. the method as limited in claim 6, is wherein saidly greater than 90% and locates maintenance 13 to 15 days altogether.
9. the method as limited in claim 8, is wherein saidly greater than 90% and locates maintenance 14 days altogether.
10. treat or prevent a method for the neurological disorder in patient, described method comprises every 14 days +/-and uses anti-nogo-a antibody or its function fragment with the dosage of 15 mg/kg to described patient in 3 days.
The method of 11. middle restrictions any one of claim 1-10, wherein said anti-nogo-a antibody is monoclonal antibody.
The method of 12. middle restrictions any one of claim 1-11, wherein said anti-nogo-a antibody is humanized antibody.
The method of 13. middle restrictions any one of claim 1-12, wherein said anti-nogo-a antibody comprises H28L16.
The method of 14. middle restrictions any one of claim 1-13, wherein said neurological disorder is selected from apoplexy (ischemia or hemorrhagic), traumatic brain injury, Spinal injury, Alzheimer, frontotemporal dementia (Tau albumen is sick), peripheral neuropathy, Parkinson's disease, creutzfeldt-Jacob disease (CJD), schizophrenia, amyotrophic lateral sclerosis (ALS), multiple sclerosis, Huntington's disease, multiple sclerosis, inclusion body myositis, polymyositis, dermatomyositis, the non-specific myopathy of form, congestive heart failure and neuropathic pain.
15. as in claim 14 limit method, wherein said neurological disorder is amyotrophic lateral sclerosis (ALS).
The method of 16. middle restrictions any one of claim 1-15, it comprises further uses with further therapeutic combination.
17. as in claim 16 limit method, wherein said further therapeutical agent is the medicament of the effect had for amyotrophic lateral sclerosis (ALS).
18. as in claim 17 limit method, the wherein said medicament had for the effect of amyotrophic lateral sclerosis (ALS) is dexpramipexole.
19. as in claim 16 limit method, wherein said further therapeutical agent is the compound with antiglutamic acid activity.
20. as in claim 19 limit method, the wherein said compound with antiglutamic acid activity is Riluzole.
CN201380035806.8A 2012-07-05 2013-07-03 Optimum dose regime of an anti-nogo-a antibody in the treatment of amyotrophic lateral sclerosis Pending CN104395343A (en)

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