CN117279938A - anti-N3 pGlu amyloid beta antibodies and uses thereof - Google Patents
anti-N3 pGlu amyloid beta antibodies and uses thereof Download PDFInfo
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- CN117279938A CN117279938A CN202280021001.7A CN202280021001A CN117279938A CN 117279938 A CN117279938 A CN 117279938A CN 202280021001 A CN202280021001 A CN 202280021001A CN 117279938 A CN117279938 A CN 117279938A
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Abstract
Methods of treating, preventing and/or delaying the progression of cognitive decline in human subjects having diseases characterized by aβ deposition in the brain, including alzheimer's disease, down's syndrome, and cerebral amyloid angiopathy, using anti-N3 pGlu aβ antibodies.
Description
The present invention relates to the field of medicine. More particularly, the invention relates to the prevention or treatment of diseases characterized by amyloid β (aβ) deposition in human subjects, including Alzheimer's Disease (AD), down's syndrome, and Cerebral Amyloid Angiopathy (CAA). Aspects of the invention relate to the use of anti-aβ antibodies (including anti-N3 pGlu aβ antibodies) for the treatment or prevention of diseases characterized by aβ deposition. In a further aspect, the invention relates to the treatment or prevention of a disease characterized by aβ deposition in a human subject, wherein the human subject for treatment or prevention is selected based on the level/burden of neurogenic tau and/or the rate of cognitive decline of the human subject. In some aspects, the invention relates to slowing the progression of disease in AD. In some embodiments, the invention relates to the use of an anti-N3 pGlu antibody described herein to treat/prevent/slow disease progression in patients with neuropathological evidence of AD and Mild Cognitive Impairment (MCI) or mild dementia stages of AD.
Accumulation of amyloid- β (aβ) peptides in the form of brain amyloid deposits is an early and important event in Alzheimer's Disease (AD), leading to neurodegeneration and thus to the onset of clinical symptoms: cognitive and functional disorders (Selkoe, "The Origins of Alzheimer Disease: A is for Amyloid," JAMA 283:1615-7 (2000); hardy et al, "The Amyloid Hypothesis of Alzheimer's Disease: progress and Problems on the Road to Therapeutics," Science 297:353-6 (2002); masters et al, "Alzheimer's Disease," Nat. Rev. Dis. Primers Sichuan 5056 (2015); and Selkoe et al, "The Amyloid Hypothesis of Alzheimer's Disease at 25years," EMBO mol. Med.8: 595-608 (2016)). Studies of rare gene variants that increase or decrease Abeta deposition support the role of amyloid deposits in driving disease progression (Fleisher et al, "Associations Between Biomarkers and Age in the Presenilin 1 E280AAutosomal Dominant Alzheimer Disease Kindred:A Cross-sectional Study," JAMA neuron 72:316-24 (2015); jonsson et al, "A Mutation in APP Protects Against Alzheimer's Disease and Age-related CognitiVe Decline," Nature 488:96-9 (2012)). Furthermore, the presence of early Amyloid deposits in the disease increases the likelihood of Mild Cognitive Impairment (MCI) progressing to AD dementia (Doraiswamy et al, "Amyloid-. Beta. Assessed by Florbetapir F18PET and 18-month Cognitive Decline: A Multicenter Study," Neurology 79:1636-44 (2012)). It is speculated that interventions aimed at removing aβ deposits (including amyloid plaques) slow down the clinical progression of AD.
Some known anti-aβ antibodies include bapineuzumab, more poncirumab (ganenumab), al Du Nashan antibody (aducanaumab), GSK933776, su Lanzu mab (solanezumab), critiuximab (crenezumab), ponentuzumab (ponenzumab), and rankaempferide mab (lecanemab) (BAN 2401). Antibodies targeting aβ have shown promise as therapeutic agents for alzheimer's disease in preclinical and clinical studies. Despite this prospect, several amyloid-targeting antibodies failed to reach the therapeutic endpoint in several clinical trials. The history of anti-amyloid clinical Trials has been over the last twenty years and to a large extent doubts have raised the potential for such therapies to effectively treat AD (Aisen et al, "The Future of Anti-amyloid three," The Journal of Prevention of Alzheimer's Disease 7:146-151 (2020)). To date, only a few treatments for AD have been approved. The utility of such treatments is limited because they provide only partial symptomatic relief and do not alter the progression of AD. See also Budd et al, "Clinical Development of Aducanumab, an Anti-Abeta Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease," The Journal of Prevention of 4lzheimer's Disease 4 (4): 255-263 (2017) and Klein et al, "Gantenerumab Reduces Amyloid-beta Plaques in Patients with Prodromal to Moderate Alzheimer's Disease: a PET Substudy Interim Analysis, "Alzheimer's Research & Therapy 11.1:1-12 (2019).
Amyloid deposits found in human patients include heterogeneous mixtures of aβ peptides. N3pGlu A beta (also known as N3pG A beta, N3pE A beta, A beta pE3-42 or A beta p 3-42) is a truncated form of A beta peptide and is found only in amyloid deposits. The N3pGlu aβ lacks the first two amino acid residues at the N-terminus of human aβ and has pyroglutamic acid derived from glutamic acid at the third amino acid position of aβ. Although the N3pGlu aβ peptide is a minor component of the deposition aβ in the brain, studies have shown that the N3pGlu aβ peptide has positive aggregation properties and accumulates early in the deposition cascade.
Antibodies to aβ peptides are known in the art, such as us patent No. 7,195,761;8,591,894; and 8,066,999). Anti-aβ antibodies to N3pGlu aβ are known in the art, for example, U.S. patent No. 8,679,498 (which is incorporated herein by reference in its entirety, including the anti-N3 pGlu aβ antibodies disclosed therein) discloses anti-N3 pGlu aβ antibodies and methods of treating diseases such as alzheimer's disease with the antibodies. Passive immunization against antibodies to aβ found in deposits (including N3pGlu aβ) has been shown to disrupt aβ aggregates and promote plaque clearance in the brain in various animal models by chronic administration over a long period of time. Donepezil (disclosed in us patent No. 8,679,498) is a pyroglutamic acid modified antibody directed against the third amino acid of the amyloid β (N3 pGlu aβ) epitope present only in brain amyloid plaques. The mechanism of action of donepezil is to target and remove existing amyloid plaques, a key pathological hallmark of AD.
To date, the clinical focus of treatment with donepezil is especially directed to patients with early symptoms of AD with existing brain amyloid burden. However, the second neuropathological marker of AD is the presence of intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. Current disease models suggest that aβ triggers tau pathology, where more complex and synergistic interactions between aβ and tau occur later and drive disease progression (Busche et al, "Synergy Between Amyloid- β and Tau in Alzheimer's disease," Nature Neuroscience 23:1183-93 (2020)).
There is currently no disease-modifying therapy for AD. Thus, there is a need for improved methods of treating diseases characterized by aβ deposition in human subjects, including AD. Such methods should help identify patients based on whether such patients are likely to receive therapeutic benefits from such treatment. Such treatments and methods should not be further accompanied by increased cytotoxicity or other known adverse events. The present invention meets one or more of these needs.
Doody et al, "Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease," NEJM,370;4,311-321 (2014) states that "no significant differential therapeutic effect on efficacy measurements was observed between APOE epsilon 4 carrier and non-carrier". It has now been found that administration of an anti-N3 pGlu aβ antibody to a human subject having one or two APOE 4 alleles (e.g., a carrier of APOE 4) provides unexpected and surprising efficacy compared to a non-carrier having one or more of these alleles. Thus, embodiments of the invention relate to administering a dose of anti-N3 pGlu aβ antibodies to patients with such genes as a means to slow down cognitive decline in these patients. In particular, APOE 4 carriers have been found to be more effective than non-carriers when anti-N3 pGlu aβ antibodies are administered to patients. This means that patients with APOE 4 had less cognitive decline than non-carriers when measured using various clinical measurement methods and at various endpoints.
According to an embodiment, the present invention provides a method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have a high neurological tau load, the method comprising administering a therapeutically effective amount of an anti-aβ antibody. In addition, according to a specific embodiment, the present invention provides a method of treating or preventing a disease characterized by aβ deposits in the brain of a human subject that has been determined to have a posterolateral temporal lobe tau burden, the method comprising administering a therapeutically effective amount of an anti-aβ antibody.
According to a specific embodiment, the present invention provides a method of treating or preventing a disease characterized by amyloid (aβ) deposits in the brain of a human subject that has been determined to have a high neurological tau load and to have one or both alleles of the epsilon-4 allele of apolipoprotein E (referred to herein as APOE4 or APOE 4), comprising administering a therapeutically effective amount of an anti-aβ antibody. In addition, according to a specific embodiment, the present invention provides a method of treating or preventing a disease characterized by AO deposits in the brain of a human subject that has been determined to have a posterolateral temporal lobe tau burden, the method comprising administering a therapeutically effective amount of an anti-aβ antibody.
According to some embodiments, the present invention provides an anti-aβ antibody for use in the treatment or prevention of a disease characterized by aβ deposits in the brain of a human subject that has been determined to have a high neurological tau burden, the method comprising administering a therapeutically effective amount of an anti-aβ antibody. In some embodiments, the human subject has been determined to have a high neurological tau load and to have one or both alleles of APOE 4.
In some embodiments, the invention provides an anti-aβ antibody for use in the treatment or prevention of a disease characterized by aβ deposits in the brain of a human subject that has been determined to have a posterolateral temporal lobe tau burden. In some embodiments, the human subject has been determined to have a posterolateral temporal lobe tau load and to have one or both alleles of APOE 4.
In addition, in some embodiments, the invention provides an anti-aβ antibody for treating, preventing or delaying the progression of Alzheimer's Disease (AD) in a human subject who has been determined to have a slow progression of AD cognitive decline. Some embodiments of the invention provide an anti-aβ antibody for use in treating, preventing or delaying the progression of Alzheimer's Disease (AD) in a human subject who has been determined to have a slow progression of AD cognitive decline and one or both alleles of APOE 4.
Furthermore, according to some embodiments, the present invention provides the use of an anti-aβ antibody in the manufacture of a medicament for the treatment or prevention of a disease characterized by aβ deposits in the brain of a human subject that has been determined to have one or both alleles of i) high neuropathic tau burden or ii) high neuropathic tau burden and APOE 4. In some embodiments, the invention provides the use of an anti-aβ antibody in the manufacture of a medicament for the treatment or prevention of a disease characterized by aβ deposits in the brain of a human subject that has been determined to have i) a posterolateral temporal lobe tau load or ii) one or both alleles of a posterolateral temporal lobe tau load and APOE 4. And in a further embodiment, the invention provides the use of an anti-aβ antibody in the manufacture of a medicament for treating, preventing or delaying the progression of Alzheimer's Disease (AD) in a human subject who has been determined to have i) a slow progression of AD cognitive decline or ii) one or both alleles of apoe 4 and a slow progression of AD cognitive decline.
According to some embodiments provided herein, the human subject has been determined to have posterolateral temporal lobe and occipital lobe tau loads. In some embodiments, the human subject has been determined to have posterolateral temporal lobe, occipital lobe, and parietal lobe tau loads. In some embodiments, the human subject has been determined to have posterolateral temporal lobe, occipital lobe, parietal lobe, and frontal lobe tau loads. In some embodiments, the human subject has been determined to have one or more of posterolateral temporal lobe, occipital lobe, parietal lobe, and/or frontal lobe tau burden by neurological PET imaging. In some embodiments, one or more of the posterolateral temporal lobe, occipital lobe, parietal lobe, and/or frontal lobe tau loads corresponds to a neuropathic tau load greater than 1.46 SUVr.
According to some embodiments provided herein, a human subject has been determined to have one or both alleles of APOE 4 and posterolateral temporal and occipital tau loads. In some embodiments, the human subject has been determined to have one or both alleles of APOE 4 and posterolateral temporal, occipital and parietal tau loads. In some embodiments, the human subject has been determined to have one or both alleles of APOE 4 and posterolateral temporal, occipital, parietal and frontal lobe tau loads. In some embodiments, the human subject has been determined by neurological PET imaging to have one or more of posterolateral temporal, occipital, parietal and/or frontal lobe tau burden and one or both alleles of APOE 4. In some embodiments, one or more of the posterolateral temporal lobe, occipital lobe, parietal lobe, and/or frontal lobe tau loads corresponds to a neuropathic tau load greater than 1.46 SUVr.
According to a further embodiment, the invention provides a method of treating, preventing or delaying the progression of Alzheimer's Disease (AD) in a human subject who has been determined to have a slow progression of AD cognitive decline, comprising administering a therapeutically effective amount of an anti-aβ antibody. According to some embodiments, the human subject has been determined to have a high neuropathic tau load. According to some embodiments, the human subject has been determined to have one or both alleles of APOE 4. In some embodiments, the human subject has been determined to have a posterolateral temporal lobe tau load. In some embodiments, the human subject has been determined to have a posterolateral temporal lobe and occipital lobe tau load. In some embodiments, the human subject has been determined to have posterolateral temporal lobe, occipital lobe, and parietal lobe tau loads. In some embodiments, the human subject has been determined to have posterolateral temporal lobe, occipital lobe, parietal lobe, and frontal lobe tau loads. In some embodiments, the human subject has been determined to have one or both alleles of posterolateral temporal lobe tau burden and APOE 4. In some embodiments, the human subject has been determined to have one or both alleles of apoe 4 and posterolateral temporal lobe and occipital tau burden. In some embodiments, the human subject has been determined to have one or both alleles of apoe 4 and posterolateral temporal, occipital and parietal tau loads. In some embodiments, the human subject has been determined to have one or both alleles of APOE 4 and posterolateral temporal, occipital, parietal and frontal lobe tau loads.
According to embodiments of the invention provided herein, a human subject has been determined to have a slow-progressing cognitive decline in AD by ADAS-Cog, iADL, CDR-SB, MMSE, APOE-4 genotyping, tau levels, P-tau levels, and/or iADRS. In some embodiments, the human subject has been determined to have a slow-progressing cognitive decline in AD by iADRS. In some embodiments, iADRS has been reduced by less than 20. In some embodiments, iADRS has decreased by less than 20 over a period of 6 months. In some embodiments, iADRS has decreased by less than 20 over a 12 month period. In some embodiments, iADRS has decreased by less than 20 over a period of 18 months. In some embodiments, iADRS has decreased by less than 20 over a 24 month period. In some embodiments, the human subject has been determined to have a slow-progressing cognitive decline in AD by APOE-4 genotyping. In some embodiments, the human subject has been determined to be APOE-4 heterozygous. In some embodiments, the human subject has been determined to be APOE-4 homozygous negative. In some embodiments, a human subject has been determined to have a slow-progressing cognitive decline in AD by MMSE. In some embodiments, the human subject has been determined to have an MMSE above 27. In some embodiments, MMSE has been reduced by less than 3. In some embodiments, MMSE has fallen less than 3 over a period of 6 months. In some embodiments, MMSE has fallen less than 3 over a 12 month period. In some embodiments, MMSE has fallen less than 3 over a period of 18 months. In some embodiments, MMSE has fallen less than 3 over a 24 month period.
According to embodiments of the invention provided herein, human subjects have been determined to have high neurological tau burden by neurological PET imaging. In some embodiments, the human subject has been determined to have a high neurogenic tau load of greater than 1.46SUVr by neurological PET imaging. In some embodiments, a human subject has been determined to have a high neurological tau load by quantification of threonine at residue 217 phosphorylated human tau ("hTau-pT 217"). In some embodiments, hTau-pT217 is quantified in a biological sample from a human subject. In some embodiments, the biological sample is cerebrospinal fluid. In some embodiments, the biological sample is one of blood, plasma, or serum.
According to embodiments of the invention provided herein, the anti-aβ antibodies comprise anti-N3 pG aβ antibodies. In some embodiments, the anti-N3 pgaβ antibody comprises a Light Chain Variable Region (LCVR) and a Heavy Chain Variable Region (HCVR), wherein the LCVR and HCVR are selected from the group consisting of: (a) a polypeptide comprising SEQ ID NO:1 and an LCVR comprising the amino acid sequence of SEQ ID NO:2, HCVR of the amino acid sequence of seq id no; or (b) comprises a sequence identical to SEQ ID NO:1 and an LCVR comprising an amino acid sequence having at least 95% homology to the amino acid sequence of SEQ ID NO:2, and an amino acid sequence having at least 95% homology.
According to some embodiments of the invention provided herein, administering an anti-N3 pG aβ antibody comprises: i) Administering to a human subject one or more first doses of about 100mg to about 700mg of anti-N3 pG aβ antibody, wherein each first dose is administered about once every 4 weeks; and ii) about 4 weeks after administration of the one or more first doses, administering to the human subject one or more second doses of greater than 700mg to about 1400mg of anti-N3 pG aβ antibody, wherein each second dose is administered about once every 4 weeks. In some embodiments, the first dose is administered to the human subject once, twice or three times before the second dose is administered. In some embodiments, a first dose of about 700mg is administered to a human subject. In some embodiments, one or more second doses of about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, or about 1400mg are administered to a human subject. In some embodiments, one or more second doses of about 1400mg are administered to the human subject. In some embodiments, the anti-N3 pGlu aβ antibody is administered to the human subject for a duration of up to 72 weeks.
According to embodiments of the invention provided herein, the disease characterized by aβ deposition in the brain of a human subject is selected from preclinical Alzheimer's Disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy. In some embodiments, the human subject is an AD patient with early symptoms. In some embodiments, the human subject has pre-AD and/or mild dementia due to AD.
For the purposes of the present invention, tau levels or loads (as used interchangeably herein) of a human subject may be determined using techniques or methods such as detecting or quantifying i) neurological or brain tau deposition, ii) tau in blood, serum, and/or plasma, or iii) tau in cerebrospinal fluid. In some embodiments, the neuropathic tau load (whether determined by PET or by blood, serum, plasma, or cerebrospinal fluid assays) can be used to stratify subjects based on the neuropathic tau load (e.g., low, medium, or high neuropathic tau load).
The neural tau loading may be applied using methods such as using radiolabeled PET compounds (including [ inclusive. ] 18 F]Fluoxelopirox, a PET ligand) is determined by tau imaging (Leuzy et al, "Diagnostic Performance)of RO 948F 18 Tau Positron EmissionTomography in the Differentiation of Alzheimer Disease from Other Neurodegeneratice Disorders, "JAMA Neurology 77.8:955-965 (2020); ossenkoppele et al, "Discriminative Accuracy of ] 18 F]Flortaucipir Positron Emission Tomography for Alzheimer Disease vs Other Neurodegenerative Disorders, "JAMA 320, 1151-1162, doi:10.1001/jama.2018.12917 (2018), which is incorporated herein by reference in its entirety). For example, the patient may be assessed by published methods (Pontecorevo et al, "A Multicentre Longitudinal Study ofFlortaucipir (18F) in Normal imaging, mild Cognitice Impairment and Alzheimer's DiseaseDementia," Brain 142:1723-35 (2019); devous et al, "Test-RetestReproducibility for the Tau PET Imaging Agent Flortaucipir F18," Journal of Nuclear Medicine 59:937-43 (2018); southekal et al, "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J.Nucl. Med.59:944-51 (2018), which are incorporated herein by reference in their entirety) and/or visually, for example, to determine whether the patient has an AD pattern (Fleisher et al, "PositronEmission Tomography Imaging With [ 35 ] 18 F]Flortaucipir and PostmortemAssessment of Alzheimer Disease Neuropathologic Changes, "JAMA Neurology 77:829-39 (2020), which is incorporated herein by reference in its entirety), petttau images are quantitatively evaluated to evaluate SUVr. Lower SUVr values represent less tau load, while higher SUVr values represent higher tau load. In one embodiment, the quantitative evaluation by flutoxion scan is by, for example, southekal et al, "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," j.nucl. Med.59:944-951 (2018), which is incorporated by reference herein in its entirety, is done by an automated image processing pipeline as described in this document. In some embodiments, counts within a specific target region of interest in the brain (e.g., multi-block barycentric discriminant analysis or MUBADA, see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F," J.Nucl. Med.59:937-943 (2018), which is incorporated by reference herein in its entiretyIncorporated herein in its entirety) with a reference region, such as the whole cerebellum (whorl core), cerebellum GM (cereCrus), a profile-based white matter (atlas WM), a subject-specific WM (ssWM, e.g., parameter estimation using reference signal intensity (PERSI), see Southekal et al, "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," j.nucleic.med.59: 944-951 (2018), which is incorporated herein by reference in its entirety). An example method of determining tau load is quantitative analysis reported as a normalized uptake value ratio (SUVr), which represents counts (e.g., MUBADA) within a particular target region of interest in the brain when compared to a reference region (e.g., using PERSI).
In some embodiments, phosphorylated tau (P-tau; phosphorylated at threonine 181 or 217, or a combination thereof) may be used to measure tau load/burden for purposes of the present invention (Barthelemy et al, "Cerebrospinal Fluid Phospho-tau T217Outperforms T181as a Biomarker for the Differential Diagnosis of Alzheimer's Disease and PET Amyloid-positive Patient Identification," Alzheimer's Res. Ther.12, 26, doi:10.1186/s13195-020-00596-4 (2020); mattsson et al, "Abeta Deposition is Associated with Increases in Soluble and Phosphorylated Tau that Precede a Positive Tau PET in Alzheimer's Disease," Science Advances 6, eaaz2387 (2020), which are incorporated herein by reference in their entirety). In one particular embodiment, antibodies to human tau phosphorylated by threonine at residue 217 may be used to measure tau load/burden in a subject (see international patent application publication No. WO 2020/242963, which is incorporated by reference in its entirety). In some embodiments, the invention includes the use of an anti-tau antibody disclosed in WO 2020/242963 to measure tau load in a subject. The anti-tau antibodies disclosed in WO 2020/242963 are directed against isoforms of human tau expressed in the CNS (e.g., recognize isoforms expressed in the CNS and do not recognize isoforms of human tau expressed exclusively outside the CNS).
When detecting aβ or using a method such as amyloid imaging using a radiolabeled PET compound or usingDiagnostic methods for Abeta biomarkers amyloid deposits in a subject are positive when amyloid is detected in the brain. Exemplary methods that may be used to measure brain amyloid load include, for example, fluroprolol Bei Ping (Carpenter et al, "The Use of the Exploratory IND in the Evaluation and Development of) 18 F-PET Radiopharmaceuticals for Amyloid Imaging in the Brain: a Review of One Company's Experience, "The Quarterly Journal of Nuclear Medicine and Molecular Imaging 53.4.53.4: 387 (2009), which is incorporated herein by reference in its entirety); fluobetaban (Syed et al, "[ A ] 18 F]Florsetaben: a Review in β -Amyloid PET Imaging in Cognitive Impairment, "CNSDrugs 29, 605-613 (2015), which is incorporated herein by reference in its entirety); flumetaphenol (heuling et al, "Imaging beta-amylase Using ] 18 F]Flutemetamol Positron Emission Tomography: from Dosimetry to Clinical Diagnosis, "European Journal of Nuclear Medicine and Molecular Imaging 43.2.2: 362-373 (2016), which are incorporated herein by reference in their entirety). [ 18 F]Florol Bei Ping may provide a qualitative and quantitative measure of the plaque burden in the brain of patients (including those with pre-AD or mild AD dementia), and may also be used to assess the reduction of amyloid plaques in the brain.
Furthermore, beta-amyloid analysis based on cerebrospinal fluid or plasma can also be used to measure amyloid load. For example, abeta42 can be used to measure cerebral amyloid (Palmqvist, S.et al, "Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid Beta-amyoid 42: a Cross-validation Study Against Amyloid Positron Emission Tomonograph. JAMA Neurol71, 1282-1289 (2014), which is incorporated herein by reference in its entirety). In some embodiments, the ratio of Abeta42/Abeta40 or Abeta42/Abeta38 can be used as a biomarker for amyloid beta (Janelided et al, "CSF Abeta42/Abeta40 and Abeta42/Abeta38Ratios: better Diagnostic Markers of Alzheimer Disease," Ann Clin TranslNeurol, 154-165 (2016), which is incorporated herein by reference in its entirety). In some embodiments, cerebral amyloid plaques or aβ deposited in CSF or plasma can be used to stratify subjects into groups based on amyloid load/burden.
As used herein, "anti-N3 pGlu aβ antibody", "anti-N3 pG antibody" or "anti-N3 pE antibody" are used interchangeably to refer to antibodies that preferentially bind N3pGlu aβ over aβ1-40 or aβ1-42. Those of ordinary skill in the art will understand and appreciate that "anti-N3 pGlu aβ antibodies" and several specific antibodies, including "hE8L", "B12L" and "R17L" are identified and disclosed in U.S. patent No. 8,679,498 B2 (which is incorporated herein by reference in its entirety) (along with methods of making and using such antibodies). See, for example, table 1 of U.S. patent No. 8,679,498 B2. Each of the antibodies disclosed in U.S. patent No. 8,679,498 B2, including the "hE8L", "B12L" and "R17L" antibodies, may be used as the anti-N3 pGlu aβ antibodies of the invention or in place of the anti-N3 pGlu aβ antibodies described in various aspects of the invention. Other representative classes of anti-N3 pGlu aβ antibodies include, but are not limited to, the antibodies disclosed below: U.S. patent No. 8,961,972; U.S. patent No. 10,647,759; U.S. patent No. 9,944,696; WO 2010/009987A2; WO 2011/151076A2; WO 2012/136552A1 and its equivalents, for example according to 35 u.s.c. 112 (f).
One of ordinary skill in the art will understand and recognize the "anti-N3 pGlu aβ antibody" and several specific antibodies in U.S. patent No. 8,961,972 (which is incorporated herein by reference in its entirety); U.S. patent No. 10,647,759 (which is incorporated herein by reference in its entirety); and U.S. patent No. 9,944,696, which is incorporated herein by reference in its entirety, are identified and disclosed (along with methods of making and using such antibodies). U.S. patent No. 8,961,972;9,944,696; and 10,647,759 may be used as the anti-N3 pGlu aβ antibody of the invention or in place of the anti-N3 pGlu aβ antibody described in the various aspects of the invention.
Those of ordinary skill in the art will understand and appreciate that "anti-N3 pGlu aβ antibodies" and several specific antibodies, including "antibody VI", "antibody VII", "antibody VIII" and "antibody IX" are identified and disclosed in WO2010/009987A2 (which is incorporated herein by reference in its entirety) (along with methods for making and using such antibodies). Each of these four antibodies (e.g., "antibody VI", "antibody VII", "antibody VIII" and "antibody IX") may be used as the anti-N3 pGlu aβ antibody of the invention or in place of the anti-N3 pGlu aβ antibody described in the various aspects of the invention.
Those of ordinary skill in the art will understand and appreciate that "anti-N3 pGlu aβ antibodies" and several specific antibodies, including "antibody X" and "antibody XI" are identified and disclosed in WO 2011-51076 A2 (which is incorporated herein by reference in its entirety) (along with methods of making and using such antibodies). Each of these two antibodies (e.g., "antibody X" and "antibody XI") may be used as the anti-N3 pGlu aβ antibody of the invention or in place of the anti-N3 pGlu aβ antibody described in the various aspects of the invention.
Those of ordinary skill in the art will understand and appreciate that "anti-N3 pGlu aβ antibodies" and several specific antibodies, including "antibody XII" and "antibody XIII" are identified and disclosed in WO 2012/136552A1 (which is incorporated herein by reference in its entirety) (along with methods of making and using the antibodies). Each of these two antibodies (e.g., "antibody XII" and "antibody XIII") can be used as the anti-N3 pGlu aβ antibody of the invention or in place of the anti-N3 pGlu aβ antibody described in the various aspects of the invention.
As used herein, an "antibody" is an immunoglobulin molecule comprising two HCs and two LCs that are linked to each other by disulfide bonds. The amino-terminal portion of each LC and HC includes a variable region that is responsible for antigen recognition via the Complementarity Determining Regions (CDRs) contained therein. CDRs are interleaved with more conserved regions called framework regions. Amino acids are assigned to CDR domains within the LCVR and HCVR regions of the antibodies of the disclosure based on: kabat numbering convention (Kabat et al, ann.NYAcad. Sci.190:382-93 (1971); kabat et al, sequences of Proteins of Immunological Interest, fifth edition, U.S. device of Health and Human Services, NIH publication No. 91-3242 (1991)), and North numbering convention (North et al, A New Clustering of Antibody CDR Loop Conformations, journal of Molecular Biology,406:228-256 (2011)). Following the above method, the CDRs of the antibodies of the invention were determined.
The antibodies of the invention are monoclonal antibodies ("mabs"). Monoclonal antibodies can be produced, for example, by hybridoma technology, recombinant technology, phage display technology, synthetic technology such as CDR-grafting, or combinations of such or other technologies known in the art. The monoclonal antibodies of the invention are human or humanized. Humanized antibodies may be engineered to contain one or more human framework regions (or substantially human framework regions) around CDRs derived from a non-human antibody. The human framework germline sequence can be accessed via its website http: the circuits. Fr is obtained from ImunoGeneTics (INGT) or The Immunoglobulin FactsBook by Marie-Paule Lefranc and Gerard Lefranc, academic 25Press,2001,ISBN 012441351. Techniques for the generation of human or humanized antibodies are well known in the art. In another embodiment of the invention, the antibody or nucleic acid encoding the same is provided in isolated form. As used herein, the term "isolated" refers to a protein, peptide, or nucleic acid that is not found in nature and is free or substantially free of other macromolecular species found in the cellular environment. As used herein, "substantially free" means that the protein, peptide or nucleic acid of interest comprises more than 80% (on a molar basis), preferably more than 90% and more preferably more than 95% of the macromolecular species present.
The antibodies of the invention are administered as pharmaceutical compositions. Pharmaceutical compositions comprising an antibody of the invention may be administered to a subject by a parenteral route (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular) that is at risk of, or exhibits, a disease or disorder as described herein. Subcutaneous and intravenous routes are preferred.
The terms "treatment", "treatment" or "to treatment" and the like include inhibiting, slowing or stopping the progression or severity of an existing symptom, condition, disease or disorder in a subject. The term "subject" refers to a human.
The term "preventing" means that the antibodies of the invention are administered prophylactically to an asymptomatic subject or a subject with preclinical alzheimer's disease to prevent the onset or progression of the disease.
As used herein, the term "delay of progression of … …" means delay or prevention of progression of a disease or symptom thereof in a subject.
The term "disease characterized by deposition of aβ" or "disease characterized by aβ deposits" is used interchangeably and refers to a disease characterized pathologically by aβ deposits in the brain or in the brain vasculature. This includes diseases such as Alzheimer's disease, down's syndrome and cerebral amyloid angiopathy. Clinical diagnosis, staging or progression of Alzheimer's disease can be readily determined by an attending diagnostician or health care professional as a person skilled in the art by using known techniques and by observing the results. This generally includes brain plaque imaging, mental or cognitive assessment (e.g., clinical dementia assessment-sum of cases (CDR-SB), brief mental state checklist (MMSE) or Alzheimer's disease assessment scale-cognition (ADAS-Cog)), or functional assessment (e.g., alzheimer's disease collaboration study-activities of daily living (Alzheimer's Disease Cooperative Study-Activities ofDaily Living) (ADCS-ADL)), cognition and functional assessment can be used to determine changes in a patient's cognition (e.g., cognitive decline) and function (e.g., functional decline). In another exemplary embodiment, "slow-progressing" cognitive decline may be identified by APOE-4 genotyping, wherein the subject is APOE-4 homozygous negative or APOE-4 heterozygous, wherein "slow-progressing" cognitive decline may be identified by MMSE, wherein the subject has been determined to have an MMSE of about 27 or an MMSE decline of less than about 3 for a given period of time (e.g., 6, 12, 18, or 24 months), "clinical Alzheimer ' as used herein is a diagnostic stage of Alzheimer's disease, including a diagnostic stage of Alzheimer's disease as a precursor, mild alzheimer's disease, moderate alzheimer's disease and severe alzheimer's disease. The term "preclinical alzheimer's disease" refers to a stage prior to clinical alzheimer's disease in which measurable changes in biomarkers (e.g., CSF aβ42 levels or brain plaques deposited by amyloid PET) indicate the earliest signs of patients with alzheimer's pathology progressing to clinical alzheimer's disease. This usually occurs before symptoms such as memory loss and confusion appear. Preclinical alzheimer's disease also includes presymptomatic autosomal dominant carriers, as well as patients at higher risk of developing AD due to carrying one or two APOE 4 alleles.
The reduction or alleviation of cognitive decline may be measured by cognitive assessment, such as clinical dementia assessment-box sum, simple mental state checklist or Alzheimer's disease assessment scale-cognition. The reduction or alleviation of functional decline may be measured by functional assessment such as ADCS-ADL.
As used herein, "mg/kg" refers to the amount (in milligrams) of antibody or drug administered to a subject based on the body weight (in kilograms) of the subject. One dose is administered at a time. For example, for a subject weighing 70kg, a 10mg/kg dose of antibody would be a single 700mg dose of antibody administered in a single administration. Similarly, for a subject weighing 70kg, the 20mg/kg dose of antibody would be 1400mg dose of antibody administered in a single administration.
As used herein, if used is based on 18 Quantitative analysis of F-fluotuxepime, tau load less than 1.10SUVr (< 1.10 SUVr), then human subjects have a "very low tau" load, where quantitative analysis refers to calculation of SUVr, and SUVr represents counts within a specific target region of interest in the brain when compared to a reference region (parameter estimation of reference signal intensity or PERSI, see Sonchekal et al, "Flortaupir F18 Quantitation Using Parametric Estimation of RefeFence SignalIntensity," J.Nucl. Med.59:944-951 (2018)), see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F," J.Nucl. Med.59:937-943 (2018)). As used herein, if Using 18F-fluotuximide based quantitative analysis, tau load is less than or equal to 1.46SUVr (i.e. < 1.46 SUVr), then the human subject has a "very low tau to moderate tau" load, where quantitative analysis refers to calculation of SUVr, which represents the count within a specific target region in the brain when compared to a reference region (PERSI, see Southekal et al, "flortuscipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," j.nucl. Med.59:944-951 (2018 ")) (MUBADA, see devaus et al," Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18, "j.nucl. Med.59:937-943 (2018)).
As used herein, if used is based on 18 Quantitative analysis of F-flutoxipiride, tau load greater than or equal to 1.10 to less than or equal to 1.46SUVr (i.e. 1.10SUVr to 1.46 SUVr), then human subjects have a "low to moderate tau" load, where quantitative analysis refers to calculation of SUVr, and SUVr refers to a count within a specific target region in the brain when compared to a reference region (PERSI, see Southekal et al, "Flortaupir F8 Quantitation Using Parametric Estimation of Reference Signal Intensity," J.Nucl.Med.59:944-951 (2018)) (MUBADA, see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F," J.Nucl.Med.59:937-943 (2018)). Human subjects with "low to moderate tau" loads may also be referred to as having "moderate" tau loads.
As used herein, if used is based on 18 Quantitative analysis of F-flutoxipiride, tau load greater than 1.46SUVr (i.e. > 1.46 SUVr), then human subjects have a "high tau" load, where quantitative analysis refers to calculation of SUVr, and SUVr represents counts within a specific target region of interest in the brain when compared to a reference region (PERSI, see Southekal et al, "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity," J.Nucl.Med.59:944-951 (2018)), see Devous et al, "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18," J.Nucl.Med.59:937-943 (2018)).
As used herein, the term "about" means up to ± 10%.
The terms "human subject" and "patient" are used interchangeably throughout this disclosure.
As used herein, "method of treatment" is equally applicable to the use of the composition for treating a disease or disorder described herein and/or the use of the composition for use and/or the use of the composition in the manufacture of a medicament for treating a disease or disorder described herein.
The following examples further illustrate the invention. However, it should be understood that the embodiments are set forth by way of illustration and not limitation, and that various modifications may be made by one of ordinary skill in the art.
Examples
Example 1: expression and purification of engineered N3pGlu A beta antibodies
Antibodies to N3pGlu aβ are known in the art. For example, U.S. patent No. 8,679,498 and U.S. patent No. 8,961,972, which are incorporated herein by reference in their entireties, disclose anti-N3 pGlu aβ antibodies, methods of making antibodies, antibody formulations, and methods of treating diseases such as alzheimer's disease with such antibodies.
Exemplary methods for expressing and purifying the anti-N3 pGlu aβ antibodies of the invention are as follows. Using the best predetermined HC: LC vector ratio or single vector system encoding both HC and LC, appropriate host cells, such as HEK 293EBNA or CHO, are transiently or stably transfected with an expression system for secretion of antibodies. The clarified medium into which the antibodies have been secreted is purified using any of a number of commonly used techniques. For example, the medium can be conveniently applied to a protein a or G sepharose ff column, which has been equilibrated with a compatible buffer, such as phosphate buffered saline (ph 7.4). The column is washed to remove non-specific binding components. The bound antibodies are eluted, for example, by a pH gradient (e.g., 0.1M sodium phosphate buffer pH 6.8 to 0.1M sodium citrate buffer (pH 2.5). The antibody fractions are detected, for example, by SDS-PAGE and pooled.
Example 2: comparison of neurogenic tau load with cognitive changes
In contrast to cognitive changes, the evaluation of neurological tau load (both overall and frontal lobes) was measured essentially as follows. At baseline, subjects were assessed for neurological tau load (both overall and frontal lobes) by flutoxion as described herein. In addition, at baseline, subjects were subjected to cognitive assessment according to one of iADRS or CDR-SB, as known in the art. The subject may be cognitively reevaluated at a given point in time thereafter, e.g., at 26 weeks, 52 weeks, 78 weeks, or 104 weeks, e.g., according to one of iADRS or CDR-SB. The change in cognitive assessment with respect to neuropathic tau load can be plotted as shown in figures 1, 2 and 3.
Figures 1, 2 and 3 demonstrate that lower cognitive decline is associated with lower tau load at baseline. Furthermore, figures 1, 2, and 3 demonstrate the heterogeneity of cognitive decline in patients determined to have higher tau loads (e.g., SUVR greater than about 1.4) at baseline. Figure 1 shows the overall tau load change at baseline relative to iADRS over 18 months. Figure 2 shows the change in frontal lobe tau load at baseline relative to iADRS over 18 months. FIG. 3 shows changes in frontal lobe tau load at baseline relative to CDR-SB over 76 weeks.
Example 3: treatment of subjects identified as having high neuropathic tau burden
According to the methods described herein, including PET imaging, including using flutoxion, and human pTau217 evaluation, a subject may be determined to have a high neurological tau load at baseline. The neurological tau burden may be assessed overall or based on regional brain lobe burden, such as posterolateral temporal lobe, occipital lobe, parietal lobe and/or frontal lobe. Patients identified as having a high neurological tau burden may be treated with the N3pG antibodies described herein and according to the dosage regimen described herein.
In addition, the subject may be subjected to cognitive assessment at baseline, including by one or more of ADAS-Cog, iADL, CDR-SB, MMSE, APOE-4 genotyping and/or iADRS, in the manner described herein. After treatment with the N3pG abs described herein and according to the dosage regimen described herein, the subject may be subjected to cognitive reevaluation, e.g. at 26 weeks, 52 weeks, 78 weeks or 104 weeks. Patients exhibiting slow or not rapid cognitive decline, including those identified as having a high neurological tau load, may continue to be treated with the N3pG antibodies described herein.
Sequence (underlined indicates CDR)
SEQ ID NO:1, a step of; light Chain Variable Region (LCVR)
SEQ ID NO:2; heavy Chain Variable Region (HCVR)
SEQ IS NO:3, a step of; light Chain (LC)
SEQ IS NO:4, a step of; heavy Chain (HC)
SEQ ID NO:5, a step of; light chain complementarity determining region 1 (LCDR 1)
KSSQSLLYSRGKTYLN
SEQ ID NO:6, preparing a base material; light chain complementarity determining region 2 (LCDR 2)
AVSKLDS
SEQ ID NO:7, preparing a base material; light chain complementarity determining region 3 (LCDR 3)
VQGTHYPFT
SEQ ID NO:8, 8; heavy chain complementarity determining region 1 (HCDR 1)
GYDFTRYYIN
SEQ ID NO:9, a step of performing the process; heavy chain complementarity determining region 2 (HCDR 2)
WINPGSGNTKYNEKFKG
SEQ ID NO:10; heavy chain complementarity determining region 3 (HCDR 3)
FGITVY
SEQ ID NO:11; SEQ ID NO:1, a step of; nucleotide sequence of Light Chain Variable Region (LCVR)
SEQ ID NO.12; SEQ ID NO:2; nucleotide sequence of Heavy Chain Variable Region (HCVR)
SEQ ID NO.13; SEQ ID NO:3, a step of; nucleotide sequence of Light Chain (LC)
SEQ ID NO.14; SEQ ID NO:4, a step of; nucleotide sequence of Heavy Chain (HC)
/>
SEQ ID NO:15; amino acid sequence of light chain of Su Lanzu monoclonal antibody
SEQ ID NO:16; amino acid sequence of heavy chain of Su Lanzu monoclonal antibody
/>
Sequence listing
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Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
305 310 315 320
Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
325 330 335
Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
340 345 350
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys
355 360 365
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln
370 375 380
Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
385 390 395 400
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln
405 410 415
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
420 425 430
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
435 440
<210> 5
<211> 16
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<400> 5
Lys Ser Ser Gln Ser Leu Leu Tyr Ser Arg Gly Lys Thr Tyr Leu Asn
1 5 10 15
<210> 6
<211> 7
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<400> 6
Ala Val Ser Lys Leu Asp Ser
1 5
<210> 7
<211> 9
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<400> 7
Val Gln Gly Thr His Tyr Pro Phe Thr
1 5
<210> 8
<211> 10
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<400> 8
Gly Tyr Asp Phe Thr Arg Tyr Tyr Ile Asn
1 5 10
<210> 9
<211> 17
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<400> 9
Trp Ile Asn Pro Gly Ser Gly Asn Thr Lys Tyr Asn Glu Lys Phe Lys
1 5 10 15
Gly
<210> 10
<211> 6
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<400> 10
Glu Gly Ile Thr Val Tyr
1 5
<210> 11
<211> 336
<212> DNA
<213> artificial sequence
<220>
<223> synthetic construct DNA sequence of SEQ ID NO. 1
<400> 11
gatattgtga tgactcagac tccactctcc ctgtccgtca cccctggaca gccggcctcc 60
atctcctgca agtcaagtca gagcctctta tatagtcgcg gaaaaaccta tttgaattgg 120
ctcctgcaga agccaggcca atctccacag ctcctaattt atgcggtgtc taaactggac 180
tctggggtcc cagacagatt cagcggcagt gggtcaggca cagatttcac actgaaaatc 240
agcagggtgg aggccgaaga tgttggggtt tattactgcg tgcaaggtac acattaccca 300
ttcacgtttg gccaagggac caagctggag atcaaa 336
<210> 12
<211> 345
<212> DNA
<213> artificial sequence
<220>
<223> synthetic construct DNA sequence of SEQ ID NO. 2
<400> 12
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtt 60
tcctgcaagg catctggtta cgacttcact agatactata taaactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg attaatcctg gaagcggtaa tactaagtac 180
aatgagaaat tcaagggcag agtcaccatt accgcggacg aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagaaggc 300
atcacggtct actggggcca agggaccacg gtcaccgtct cctca 345
<210> 13
<211> 657
<212> DNA
<213> artificial sequence
<220>
<223> synthetic construct DNA sequence of SEQ ID NO. 3
<400> 13
gatattgtga tgactcagac tccactctcc ctgtccgtca cccctggaca gccggcctcc 60
atctcctgca agtcaagtca gagcctctta tatagtcgcg gaaaaaccta tttgaattgg 120
ctcctgcaga agccaggcca atctccacag ctcctaattt atgcggtgtc taaactggac 180
tctggggtcc cagacagatt cagcggcagt gggtcaggca cagatttcac actgaaaatc 240
agcagggtgg aggccgaaga tgttggggtt tattactgcg tgcaaggtac acattaccca 300
ttcacgtttg gccaagggac caagctggag atcaaacgaa ctgtggctgc accatctgtc 360
ttcatcttcc cgccatctga tgagcagttg aaatctggaa ctgcctctgt tgtgtgcctg 420
ctgaataact tctatcccag agaggccaaa gtacagtgga aggtggataa cgccctccaa 480
tcgggtaact cccaggagag tgtcacagag caggacagca aggacagcac ctacagcctc 540
agcagcaccc tgacgctgag caaagcagac tacgagaaac acaaagtcta cgcctgcgaa 600
gtcacccatc agggcctgag ctcgcccgtc acaaagagct tcaacagggg agagtgc 657
<210> 14
<211> 1332
<212> DNA
<213> artificial sequence
<220>
<223> synthetic construct DNA sequence of SEQ ID NO. 4
<400> 14
caggtgcagc tggtgcagtc tggggctgag gtgaagaagc ctgggtcctc agtgaaggtt 60
tcctgcaagg catctggtta cgacttcact agatactata taaactgggt gcgacaggcc 120
cctggacaag ggcttgagtg gatgggatgg attaatcctg gaagcggtaa tactaagtac 180
aatgagaaat tcaagggcag agtcaccatt accgcggacg aatccacgag cacagcctac 240
atggagctga gcagcctgag atctgaggac acggccgtgt attactgtgc gagagaaggc 300
atcacggtct actggggcca agggaccacg gtcaccgtct cctcagcctc caccaagggc 360
ccatcggtct tcccgctagc accctcctcc aagagcacct ctgggggcac agcggccctg 420
ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgcc 480
ctgaccagcg gcgtgcacac cttcccggct gtcctacagt cctcaggact ctactccctc 540
agcagcgtgg tgaccgtgcc ctccagcagc ttgggcaccc agacctacat ctgcaacgtg 600
aatcacaagc ccagcaacac caaggtggac aagaaagttg agcccaaatc ttgtgacaaa 660
actcacacat gcccaccgtg cccagcacct gaactcctgg ggggaccgtc agtcttcctc 720
ttccccccaa aacccaagga caccctcatg atctcccgga cccctgaggt cacatgcgtg 780
gtggtggacg tgagccacga agaccctgag gtcaagttca actggtacgt ggacggcgtg 840
gaggtgcata atgccaagac aaagccgcgg gaggagcagt acaacagcac gtaccgtgtg 900
gtcagcgtcc tcaccgtcct gcaccaggac tggctgaatg gcaaggagta caagtgcaag 960
gtctccaaca aagccctccc agcccccatc gagaaaacca tctccaaagc caaagggcag 1020
ccccgagaac cacaggtgta caccctgccc ccatcccggg acgagctgac caagaaccag 1080
gtcagcctga cctgcctggt caaaggcttc tatcccagcg acatcgccgt ggagtgggag 1140
agcaatgggc agccggagaa caactacaag accacgcccc ccgtgctgga ctccgacggc 1200
tccttcttcc tctatagcaa gctcaccgtg gacaagagca ggtggcagca ggggaacgtc 1260
ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa gagcctctcc 1320
ctgtctccgg gt 1332
<210> 15
<211> 219
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<400> 15
Asp Val Val Met Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Leu Gly
1 5 10 15
Gln Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Ile Tyr Ser
20 25 30
Asp Gly Asn Ala Tyr Leu His Trp Phe Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Arg Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ser Gln Ser
85 90 95
Thr His Val Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 16
<211> 442
<212> PRT
<213> artificial sequence
<220>
<223> synthetic construct
<400> 16
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Tyr
20 25 30
Ser Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val
35 40 45
Ala Gln Ile Asn Ser Val Gly Asn Ser Thr Tyr Tyr Pro Asp Thr Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Ser Gly Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
100 105 110
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys
115 120 125
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
130 135 140
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
145 150 155 160
Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser
165 170 175
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr
180 185 190
Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys
195 200 205
Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
210 215 220
Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro
225 230 235 240
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
245 250 255
Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp
260 265 270
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu
275 280 285
Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu
290 295 300
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn
305 310 315 320
Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly
325 330 335
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
340 345 350
Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr
355 360 365
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn
370 375 380
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
385 390 395 400
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn
405 410 415
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr
420 425 430
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440
Claims (53)
1. A method of treating or preventing a disease characterized by amyloid β (aβ) deposits in the brain of a human subject that has been determined to have i) a high neurological tau load or ii) one or both alleles of high neurological tau load and/or APOE 4, the method comprising administering a therapeutically effective amount of an anti-aβ antibody.
2. A method of treating or preventing a disease characterized by aβ deposits in the brain of a human subject that has been determined to have i) posterolateral temporal lobe tau burden or ii) posterolateral temporal lobe tau burden and/or one or both alleles of APOE 4, the method comprising administering a therapeutically effective amount of an anti-aβ antibody.
3. The method of claim 2, wherein the human subject has been determined to have posterolateral temporal lobe and occipital lobe tau loads.
4. The method of claim 3, wherein the human subject has been determined to have posterolateral temporal, occipital and parietal tau loads.
5. The method of claim 4, wherein the human subject has been determined to have posterolateral temporal lobe, occipital lobe, parietal lobe, and frontal lobe tau loads.
6. The method of any one of claims 2-5, wherein the human subject has been determined by neurological PET imaging to have one or more of posterolateral temporal lobe, occipital lobe, parietal lobe, and/or frontal lobe tau burden.
7. The method of claim 6, wherein one or more of posterolateral temporal, occipital, parietal and/or frontal lobe tau loads correspond to a neuropathic tau load greater than 1.46 SUVr.
8. A method of treating, preventing or delaying progression of Alzheimer's Disease (AD) in a human subject who has been determined to have i) a slow-progressing decline in AD cognition or ii) a slow-progressing decline in AD cognition and/or one or both alleles of APOE 4, the method comprising administering a therapeutically effective amount of an anti-aβ antibody.
9. The method of claim 8, wherein the human subject has been determined to have a high neurological tau load.
10. The method of claim 9, wherein the human subject has been determined to have a posterolateral temporal lobe tau load.
11. The method of claim 10, wherein the human subject has been determined to have posterolateral temporal lobe and occipital lobe tau loads.
12. The method of claim 11, wherein the human subject has been determined to have posterolateral temporal, occipital and parietal tau loads.
13. The method of claim 12, wherein the human subject has been determined to have posterolateral temporal lobe, occipital lobe, parietal lobe, and frontal lobe tau loads.
14. The method of any one of claims 8-13, wherein the human subject has a slow-progressing cognitive decline in AD has been determined by one or more of ADAS-Cog, iADL, CDR-SB, MMSE, APOE-4 genotyping, tau levels, P-tau levels, and/or iADRS.
15. The method of claim 14, wherein the human subject has been determined by iADRS to have a slow-progressing cognitive decline in AD.
16. The method of claim 15, wherein iADRS has been reduced by less than 20.
17. The method of claim 15, wherein iADRS has fallen less than 20 over a period of 6 months.
18. The method of claim 15, wherein iADRS has fallen less than 20 over a period of 12 months.
19. The method of claim 15, wherein iADRS has fallen less than 20 over a period of 18 months.
20. The method of claim 15, wherein iADRS has fallen less than 20 over a 24 month period.
21. The method of claim 14, wherein the human subject has a slow-progressing cognitive decline in AD as determined by APOE-4 genotyping.
22. The method of claim 21, wherein the human subject has been determined to be APOE-4 heterozygous.
23. The method of claim 21, wherein the human subject has been determined to be APOE-4 homozygous negative.
24. The method of claim 14, wherein the human subject has been determined to have a slow-progressing cognitive decline in AD by MMSE.
25. The method of claim 24, wherein the human subject has been determined to have an MMSE above 27.
26. The method of claim 24 wherein MMSE has fallen less than 3.
27. The method of claim 24 wherein MMSE has fallen less than 3 over a 6 month period.
28. The method of claim 24 wherein MMSE has fallen less than 3 over a 12 month period.
29. The method of claim 24 wherein MMSE has fallen less than 3 over a period of 18 months.
30. The method of claim 24 wherein MMSE has fallen less than 3 over a 24 month period.
31. The method of claim 1 or claim 9, wherein the human subject has been determined to have a high neurological tau burden by neurological PET imaging.
32. The method of claim 31, wherein the human subject has been determined to have a high neurological tau load of greater than 1.46SUVr by neurological PET imaging.
33. The method of claim 1 or claim 9, wherein the human subject has been determined to have a high neurogenic tau load by quantification of threonine at residue 217 phosphorylated human tau ("hTau-pT 217").
34. The method of claim 33, wherein the human subject is quantitatively determined in a biological sample of hTau-pT 217.
35. The method of claim 34, wherein the biological sample is cerebrospinal fluid.
36. The method of claim 34, wherein the biological sample is one of blood, plasma, or serum.
37. The method of any one of claims 1-36, wherein the anti-aβ antibody comprises an anti-N3 pG aβ antibody.
38. The method of claim 37, wherein the anti-N3 pG aβ antibody comprises a Light Chain Variable Region (LCVR) and a Heavy Chain Variable Region (HCVR), wherein the LCVR and HCVR are selected from the group consisting of:
(a) Comprising SEQ ID NO:1 and an LCVR comprising the amino acid sequence of SEQ ID NO:2, HCVR of the amino acid sequence of seq id no; or (b)
(b) Comprising a sequence identical to SEQ ID NO:1 and an LCVR comprising an amino acid sequence having at least 95% homology to the amino acid sequence of SEQ ID NO:2, and an amino acid sequence having at least 95% homology.
39. The method of any one of claims 1-38, wherein the step of administering comprises:
i) Administering to the human subject one or more first doses of about 100mg to about 700mg of anti-N3 pG aβ antibody, wherein each first dose is administered about once every 4 weeks; and
ii) administering to the human subject one or more second doses of greater than 700mg to about 1400mg of anti-N3 pG aβ antibody about 4 weeks after administration of the one or more first doses, wherein each second dose is administered about once every 4 weeks.
40. The method of claim 39, wherein the first dose is administered once, twice or three times to the human subject prior to the administration of the second dose.
41. The method of claim 40, wherein the human subject is administered a first dose of about 700 mg.
42. The method of any one of claims 39-41, wherein the human subject is administered one or more second doses of about 800mg, about 900mg, about 1000mg, about 1100mg, about 1200mg, about 1300mg, or about 1400 mg.
43. The method of any one of claims 39-42, wherein one or more second doses of about 1400mg are administered to the human subject.
44. The method of any one of claims 39-43, wherein the anti-N3 pGlu aβ antibody is administered to the human subject for a duration of up to 72 weeks.
45. The method of any one of claims 1 to 44, wherein the disease characterized by aβ deposits in the brain of the human subject is selected from preclinical Alzheimer's Disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, down's syndrome, clinical cerebral amyloid angiopathy, or preclinical cerebral amyloid angiopathy.
46. The method of any one of claims 1-45, wherein the human subject is an early symptomatic AD patient.
47. The method of claim 46, wherein the human subject has pre-AD and/or mild dementia due to AD.
48. An anti-aβ antibody for use in the treatment or prevention of a disease characterized by aβ deposits in the brain of a human subject that has been determined to have i) a high neurological tau load or ii) one or both alleles of high neurological tau load and/or APOE 4, comprising administering a therapeutically effective amount of an anti-aβ antibody.
49. An anti-aβ antibody for use in the treatment or prevention of a disease characterized by aβ deposits in the brain of a human subject that has been determined to have one or both alleles of i) posterolateral temporal lobe tau load or ii) posterolateral temporal lobe tau load and/or APOE 4.
50. An anti-aβ antibody for use in the treatment, prevention or delay of progression of Alzheimer's Disease (AD) in a human subject who has been determined to have i) a slow-progressing decline in AD cognition or ii) a slow-progressing decline in AD cognition and/or one or both alleles of APOE 4.
51. Use of an anti-aβ antibody in the manufacture of a medicament for the treatment or prevention of a disease characterized by aβ deposits in the brain of a human subject that has been determined to have i) a high neurological tau load or ii) one or both alleles of high neurological tau load and/or APOE 4.
52. Use of an anti-aβ antibody in the manufacture of a medicament for the treatment or prevention of a disease characterized by aβ deposits in the brain of a human subject that has been determined to have one or both alleles of i) posterolateral temporal lobe tau load or ii) posterolateral temporal lobe tau load and/or APOE 4.
53. Use of an anti-aβ antibody in the manufacture of a medicament for treating, preventing or delaying the progression of Alzheimer's Disease (AD) in a human subject who has been determined to have i) a slow-progressing cognitive decline in AD or ii) a slow-progressing cognitive decline in AD and/or one or both alleles of APOE 4.
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US63/160490 | 2021-03-12 | ||
US202163192288P | 2021-05-24 | 2021-05-24 | |
US63/192288 | 2021-05-24 | ||
PCT/US2022/019903 WO2022192639A2 (en) | 2021-03-12 | 2022-03-11 | Anti-n3pglu amyloid beta antibodies and uses thereof |
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