CN118450905A - Methods of using anti-amyloid beta protofibril antibodies and anti-tau antibodies - Google Patents
Methods of using anti-amyloid beta protofibril antibodies and anti-tau antibodies Download PDFInfo
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Abstract
Disclosed herein are antibodies, pharmaceutical formulations for treating or preventing alzheimer's disease, methods of treating or preventing alzheimer's disease, and kits comprising pharmaceutical formulations containing anti-aβ protofibril antibodies and anti-tau antibodies for treating or preventing alzheimer's disease.
Description
The present application claims priority from U.S. provisional application number 63/291,315, filed on 12 months 17 of 2021, and international application number PCT/IB2021/000937, filed on 12 months 17 of 2021, the contents of which are incorporated herein by reference in their entirety.
The present application comprises a sequence listing that has been electronically submitted in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy created at 12/3 of 2021 was named 08061_0053-00304_SL.txt and was 21,812 bytes in size.
The present invention was completed with government support under grant numbers U01AG042791, R01AG046179, R56AG053267, U01AG059798, R01AG053267 and R01AG068319 from the national institutes of health. The government has certain rights in the invention.
Alzheimer's Disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. In 2006, there were 2660 cases of AD (range: 1140-5940 tens of thousands) worldwide (Brookmeyer, R. et al, forecasting the global burden of Alzheimer's Disease [ global burden of predicting Alzheimer's Disease ]2007; 3:186-91), whereas more than 5 million people in the United states were reported to have AD (2010Alzheimer's Disease facts and figures. [ facts and data of Alzheimer's Disease in 2010 ] Alzheimer's Disease ]2010; 6:158-94). By 2050, it was predicted that the worldwide incidence of AD would increase to 1.068 billion (range: 4720 tens of thousands-2.212 billion), whereas the incidence in the united states alone is estimated to be 1100 tens of thousands to 1600 tens of thousands. (Brookmeyer, see above, and facts and data of Alzheimer's disease in 2010Alzheimer's disease facts and figures[2010 ], see above).
The disease generally involves an overall decline in cognitive function that slowly progresses and leaves the end-stage subject bedridden. AD subjects typically survive only 3 to 10 years after onset of symptoms, but the known extremes are 2 years and 20 years. (Hebert, L.E., et al, alzheimer DISEASE IN THE U.S. marketing: PREVALENCE ESTIMATES uses the 2000census. [ Alzheimer's disease in the U.S. population: prevalence estimate using general population screening in 2000 ] Arch Neurol. [ neurological literature ] 2003: 60:1119-1122.) AD remains the seventh cause of all deaths in the U.S. and is the fifth cause of death in Americans above 65 years despite the fact that death proves to be rarely attributed to AD due to death, and death due to AD is thus greatly underestimated. (facts and data of Alzheimer's disease in 2010Alzheimer's disease facts and figures[2010 years ], see above.)
Histologically, the disease is characterized by neuroinflammatory plaques, which are found mainly in the combined cortex, limbic system and basal ganglia. The main component of these plaques is amyloid β peptide (aβ). Aβ exists in various conformational states: monomers, oligomers, protofibrils, and insoluble fibrils.
In addition to aβ plaques, alzheimer's disease is also characterized by the presence of accumulation of tau-containing neurofibrillary tangles. Human tau protein is encoded by the microtubule associated protein tau protein gene MAPT located on chromosome 17q 21. Adult brain contains six major tau subtypes, which result from alternative splicing of exons 2 (E2), E3 and E10. These subtypes vary according to the number of repeat regions of 29 residues near the N-terminus. Tau protein subtypes containing 0, 1 or 2 inserts are referred to as 0N, 1N and 2N, respectively. The unprocessed tau protein subtype also contains 3 ("3R") or 4 ("4R") microtubule binding repeat domains. The second of these repeat domains is encoded by E10 and is not included in the 3R tau protein subtype.
Although tau is generally highly soluble, it can aggregate into paired helical filaments, neurofibrillary tangles, and other structures under pathological conditions that define a broad range of neurodegenerative diseases known as tauopathies. Thus, tauopathies refer to a class of neurodegenerative diseases associated with the aggregation of microtubule-associated protein tau protein, including Alzheimer's Disease (AD), progressive Supranuclear Palsy (PSP), and frontotemporal dementia (FTD).
Little is known about the details of the mechanistic relationships between Alzheimer's disease onset, abeta production and tau-mediated neurotoxicity. Improved therapies for both aβ production and tau-containing neurofibrillary tangles remain potential. Thus, there is a need for specific and effective therapeutic agents that target aβ and tau.
Provided herein are methods for treating and/or preventing alzheimer's disease comprising administering to a subject in need thereof an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils and an anti-tau protein antibody or antigen binding fragment thereof capable of binding to human tau protein.
In some embodiments, a method of treating or preventing alzheimer's disease in a subject in need thereof comprises administering to the subject:
(i) An isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 13, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 14, and
(Ii) An anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau protein, the anti-tau antibody or antigen-binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 15, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 16,
Wherein the anti-aβ protofibril antibody or fragment thereof is administered in combination (e.g., simultaneously or sequentially) with the anti-tau antibody or fragment thereof. In some embodiments, the isolated anti-aβ protofibril antibody or fragment thereof is administered once every two weeks. In some embodiments, the anti-tau antibody or fragment thereof is administered once every four weeks. In some embodiments, the anti-aβ protofibril antibody or fragment thereof is administered prior to initiation of treatment with the anti-tau antibody or fragment thereof, e.g., when the subject has symptoms of alzheimer's disease. In some embodiments, the anti-tau antibody or fragment thereof is administered prior to initiation of treatment with the anti-aβ protofibril antibody or fragment thereof, e.g., when the subject is free of symptoms of alzheimer's disease. In some embodiments, the anti-aβ protofibril antibody or fragment thereof is administered at a dose of 5mg/kg to 20mg/kg, for example, wherein the dose is 10mg/kg. In some embodiments, the anti-tau antibody or fragment thereof is administered in an amount of 1000-45000mg, e.g., wherein the dose is 1500mg. In some embodiments, the subject has a dominant inherited gene mutation of alzheimer's disease, e.g., wherein the subject has a gene mutation in at least one of the three genes PSEN1, PSEN2, or APP.
Also provided herein are kits and pharmaceutical combinations comprising
(I) An isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 13, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 14, and
(Ii) An anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau protein, the anti-tau antibody or antigen-binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 15, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 16,
Wherein the anti-aβ protofibril antibody or fragment thereof is administered in combination (e.g., simultaneously or sequentially) with the anti-tau antibody or fragment thereof.
Drawings
Fig. 1 depicts a randomization protocol for concurrent treatment with E2814 and lenkanesab (lecanemab).
Fig. 2 depicts E2814 or placebo and open label rankanamab treatment regimens.
Definition of the definition
The following are definitions of terms used in the present application.
As used herein, the singular terms "a" and "an" and "the" include plural referents unless the context clearly dictates otherwise.
As used herein, the phrase "and/or" means "either or both" of the elements so combined, i.e., elements that are present in combination in some cases and not in combination in others. Thus, as a non-limiting example, "a and/or B" when used in conjunction with an open language such as "comprising" may refer in some embodiments to a alone (optionally including elements other than B); in other embodiments, refer to B only (optionally including elements other than a); in yet other embodiments, both a and B (optionally including other elements); etc.
As used herein, "at least one" means one or more elements in the list of elements, but does not necessarily include at least one of each element specifically recited in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that elements may optionally be present other than the specifically identified elements within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, "at least one of a and B" (or equivalently, "at least one of a or B," or equivalently "at least one of a and/or B") may refer to at least one (optionally including more than one) a without B (and optionally including elements other than B) in one embodiment; in another embodiment, at least one (optionally including more than one) B without a (and optionally including elements other than a); in yet another embodiment, at least one (optionally including more than one) a, and at least one (optionally including more than one) B (and optionally including other elements); etc.
When numerical values are stated individually or as part of a range of numerical values, it is understood that the numerical values can vary with deviations from 10% above and below the stated values.
As used herein, the term "antibody" is broad and includes immunoglobulins or antibody molecules, including polyclonal antibodies, monoclonal antibodies, including murine, human-adapted, humanized and chimeric monoclonal antibodies and antibody fragments. Typically, an antibody is a protein or peptide chain that exhibits binding specificity for a particular antigen. Intact antibodies are typically heterotetrameric glycoproteins, consisting of two identical light chains and two identical heavy chains. Typically, each light chain is linked to one heavy chain by one covalent disulfide bond, and the number of disulfide bonds varies between heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bonds. Each heavy chain has a variable domain (variable region) (VH) at one end followed by multiple constant domains (constant regions). Each light chain has a variable domain (VL) at one end and a constant domain at the other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain and the variable domain of the light chain is aligned with the variable domain of the heavy chain. Based on the amino acid sequence of its constant domain, the antibody light chain of any vertebrate species can be classified into one of two distinct types (i.e., kappa and lambda).
Immunoglobulins can be assigned to five major classes or isotypes, igA, igD, igE, igG and IgM, depending on the type of constant domain they heavy chain have. Based on the amino acid sequence of the heavy chain constant domain. IgA and IgG are further subdivided into isotypes IgA1, igA2, igG1, igG2, igG3 and IgG4. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ and μ, respectively.
The immunoglobulin light chain variable region or heavy chain variable region consists of a "framework" region interrupted by three Complementarity Determining Regions (CDRs) that provide the primary determinants of antigen binding (Wu and Kabat, J.Exp.Med. [ journal of Experimental medicine ]132:211-250,1970). Typically, the antigen binding site has six CDRs; three of the VHs (HCDR 1, HCDR2, HCDR 3) and three of the VL (LCDR 1, LCDR2, LCDR 3) (Kabat et al Sequences of Proteins of Immunological Interest [ protein sequences with immunological significance ], 5 th edition Public HEALTH SERVICE, national Institutes of Health [ national institutes of health, public health, besseda, maryland, 1991). The CDRs may be determined according to the Kabat numbering scheme. SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST [ protein sequence of immunological significance ] (Kabat et al, 5 th edition, U.S. Pat. No. HEALTH AND Human Services [ U.S. department of health and Human Services ], NIH publication No. 91-3242,1991, hereinafter "Kabat report"). Alternatively, "IMGT-CDR" (Lefranc et al, dev. Comparat Immunol. [ developmental and comparative immunology ]27:55-77,2003) as set forth by Lefranc is based on a comparison of the V domains of immunoglobulins and T cell receptors. The International immunogenetics (ImMunoGeneTics, IMGT) database (http:// www_ imgt _org) provides standardized numbering and definition of these regions. The correspondence between CDR and IMGT descriptions is described in Lefranc et al, dev. Comparat. Immunol [ developmental and comparative immunology ]27:55-77,2003.
An antigen binding fragment is made up of the portion of the intact antibody that retains the antigen binding specificity of the parent antibody molecule. For example, an antigen binding fragment may comprise at least one variable region (heavy or light chain variable region) or one or more CDRs in an antibody known to bind a particular antigen. Examples of suitable antigen binding fragments include, but are not limited to, diabodies and single chain molecules as well as Fab, F (ab') 2, fc, fabc, and Fv molecules, single chain (Sc) antibodies, single antibody light chains, single antibody heavy chains, chimeric fusions between antibody chains or CDRs and other proteins, protein scaffolds, heavy chain monomers or dimers, light chain monomers or dimers, dimers composed of one heavy chain and one light chain, and the like. All antibody isoforms can be used to generate antigen binding fragments. In addition, antigen binding fragments may include a non-antibody protein framework that can successfully incorporate polypeptide segments in a direction that confers affinity for a given antigen of interest (e.g., a protein scaffold). Antigen binding fragments may be recombinantly produced or produced by enzymatic or chemical cleavage of intact antibodies. The phrase "antibody or antigen binding fragment thereof" may be used to refer to a given antigen binding fragment incorporating one or more amino acid segments of an antibody referred to in the phrase.
The term "subject" refers to human and non-human animals, including all vertebrates, e.g., mammals and non-mammals, e.g., non-human primates, mice, rabbits, sheep, dogs, cats, horses, cows, chickens, amphibians, and reptiles. In various embodiments of the method, the subject is a human.
In some embodiments, the subject has "elevated amyloid" or "moderate amyloid". In some embodiments, the level of amyloid is measured using amyloid PET. One of ordinary skill in the art will recognize that amyloid levels from amyloid PET can be reported in "percent units" (CL) using a percent unit method. (Klunk WE et al The Centiloid Project: standardizing quantitative amyloid plaque estimation by PET [ percent unit project: standardizing quantitative amyloid plaque estimation by PET ] Alzheimer's device [ Alzheimer's disease and dementia ]2015; 11:1-15e 1-4). The percent unit method measures tracers ranging from 0CL to 100CL, where 0 is considered the anchor point and represents the average of young healthy controls, and 100CL represents the average amyloid load present in subjects with mild to moderate severity dementia due to AD. As known to those of ordinary skill in the art, the percentile unit threshold may be varied, for example, modified based on new or additional scientific information. (see, e.g., http:// www.gaain.org/centiloid-project). ) Elevated amyloid levels may be set relative to a baseline threshold in healthy controls determined according to known methods of POSA. For example, a percent unit value of 32.5 may be used as a threshold for "elevated amyloid" and "moderate amyloid" levels may refer to aβ amyloid PET in the range of 20-32.5 CL. In another example, a percent unit value of 40 may be used as a threshold for "elevated amyloid" and "moderate amyloid" levels may refer to aβ amyloid PET in the range of 20-40 CL. Rowe et al Eur J Nucl Med Mol I [ journal of European Nuclear medicine and molecular imaging ]44,2053-2059 (2017); Salvad th et al, alzheimer's Res Ther [ Alzheimer's disease study and treatment ]11,27 (2019); sabri et al, alzheimers Dement [ Alzheimer's disease and dementia ]11:964-74 (2015); rowe et al, alzheimer 'S DEMENTIA [ Alzheimer's disease and dementia ]14, P634 (2018); amadoru et al, alzheimer's Res Ther [ Alzheimer's disease study and treatment ]12,22 (2020); Ro-Vellv e et al, alzheimer 'S DEMENTIA [ Alzheimer's disease and dementia ]16, (2020); bullich et al, alzheimer's Res Ther [ Alzheimer's disease research and treatment ]13,67 (2021).
As described herein, a subject "free of alzheimer's disease-like" is a cognitively normal subject with moderate or elevated amyloid levels in the brain, and can be identified by the presence or absence of memory impairment and emerging episodic memory and asymptomatic phases of executive function deficiency (e.g., based on accumulation of aβ in the brain and/or by CSF or blood-based biomarkers). Cognitive normal may include subjects with CDR 0, or subjects within the normal range of the cognitive test score. Asymptomatic AD occurs before significant irreversible neurodegeneration and cognitive impairment, and is typically characterized by the presence of molecular biomarkers in the body of AD and the absence of clinical symptoms. Asymptomatic AD biomarkers that can be indicative of developing alzheimer's disease include, but are not limited to, one or more of moderate or elevated amyloid and/or tau protein levels in the brain, e.g., as measured by: amyloid or tau Positron Emission Tomography (PET), aβ1-42 cerebrospinal fluid levels, total tau cerebrospinal fluid levels, neuroprolidin cerebrospinal fluid levels, neurofilament light chain cerebrospinal fluid levels, blood biomarkers as measured in serum or plasma (e.g., aβ1-42 levels, ratio of two forms of amyloid β peptide (aβ42/aβ40), a, Plasma levels of total tau protein (T-tau protein), levels of phosphorylated tau protein (P-tau protein) subtypes, including tau protein phosphorylated at 181 (P-tau protein 181), 217 (P-tau protein 217) and 231 (P-tau protein 231), and neurofilament light chain (NfL). for example, it has been found that subjects treated with alendronate (elenbecestat; E2609), which is a beta-site amyloid precursor protein cleaving enzyme (BACE) inhibitor, exhibit a maximal reduction in cognitive decline upon treatment, and that the amyloid baseline Positron Emission Tomography (PET) standard uptake value ratio (SUVr value) of the subject is 1.4 to 1.9. See Lynch, s.y. et al "Elenbecestat,a BACE inhibitor:results from a Phase 2study in subjects with mild cognitive impairment and mild-to-moderate dementia due to Alzheimer's disease.[, escitalopram, a BACE inhibitor: results of phase 2 studies from subjects with mild cognitive impairment and mild to moderate dementia due to alzheimer's disease ] "poster P4-389,Alzheimer's Association International Conference [ international conference on alzheimer's disease ], 7 months 22-26 days 2018, chicago, il. Likewise, it has been found that subjects with baseline flurbiproflumiapir (florbetapir) amyloid PET SUVr levels below 1.2 do not exhibit sufficient cognitive decline to be detectable, while subjects with SUVr levels above 1.6 appear to be associated with a plateau effect in which the amyloid levels have reached saturation levels and treatment does not cause a change in cognitive measures. See Dhadda, s. et al ,"Baseline florbetapir amyloid PET standard update value ratio(SUVr)can predict clinical progression in prodromal Alzheimer's disease(pAD).[ baseline flurbiptazicar amyloid PET standard update ratio (SUVr) can predict clinical progression of precursor alzheimer's disease (pAD), "poster P4-291,Alzheimer's Association International Conference [ international conference on alzheimer's disease ], 7 months 22-26 days 2018, chicago, il; SPERLING RA et al, alzheimer's disease and dementia 2011;7:280-92; jack C.R. et al, alzheimer's disease [ Alzheimer's disease and dementia ]2018;14:535-62.
As used herein, "early onset alzheimer's disease" refers to a cascade of severity of AD from mild cognitive impairment to mild alzheimer's dementia due to moderate likelihood of AD. Subjects with early onset AD include subjects with mild alzheimer's dementia as defined herein and subjects with Mild Cognitive Impairment (MCI) due to moderate likelihood of AD as defined herein. In some embodiments, a subject with early onset AD has a score of 22-30 and/or a total CDR range of 0.5 to 1.0 in a brief mental state examination (MMSE).
As used herein, a subject with "mild alzheimer's disease dementia" or "mild AD dementia" is a subject meeting the national institutes of aging and alzheimer's disease (NIA-AA) core clinical criteria for possible alzheimer's disease dementia in: diagnosis of dementia due to Alzheimer's disease by McKhann, G.M. et al ,"The diagnosis of dementia due to Alzheimer's disease:Recommendations from the National Institute on Aging–Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.[: advice from the national institutes of aging and the Alzheimer's disease diagnostic guidelines for Alzheimer's disease ] "Alzheimer's disease [ Alzheimer's disease and dementia ]2011;7:263-9. Also included herein are subjects with CDR scores of 0.5 to 1.0 and/or Memory Box score (Memory Box score) of 0.5 or higher at screening and baseline.
As used herein, a subject with "mild cognitive impairment due to moderate likelihood of AD" is a subject identified as such according to the NIA-AA core clinical criteria (see McKhann, supra) of mild cognitive impairment due to moderate likelihood of alzheimer's disease. For example, the subject may be symptomatic but without dementia, evidence of cerebral amyloid pathology makes them less heterogeneous in cognitive and functional decline and more similar to mild alzheimer's dementia subjects as measured by CDR scores of 0.5 and/or memory box scores of 0.5 or higher at screening and baseline. In addition, subjects reporting a history of subjective memory decline with gradual onset and slow progression (and confirmed by an knowledger) over the last 1 year prior to screening are also included herein.
The amyloid level of a subject can be detected by biomarkers such as, but not limited to: (a) Amyloid detected by PET scanning from visual readings or semi-quantitative thresholds (SUVr or percent units); (c) Cerebrospinal fluid (CSF) Aβ1-42 and/or Aβ1-42/1-40 ratio; and/or (d) a blood biomarker (i.e., plasma Aβ1-42, Aβ1-42/Aβ1-40, tau protein, total tau protein (T-tau protein), P-tau protein, and/or NfL). Secondary markers may confirm primary amyloid determination and include, but are not limited to: (a) tau protein detected by PET scanning; (b) CSF tau, phosphorylated tau (p-tau), neurofilament light chain peptide (NfL), and/or neuroparticulate proteins; (c) Other blood biomarkers (i.e., tau protein, total tau protein (T-tau protein), P-tau protein, and/or NfL).
"Amyloid" refers to unbranched fibers, usually extracellular, and found in vivo; in addition, the fiber-bound dye congo red and then exhibits green birefringence when viewed between crossed polarizers. Amyloid forming proteins have been identified and are associated with serious diseases, including amyloid β peptide (aβ) associated with Alzheimer's Disease (AD), islet amyloid polypeptide (IAPP) associated with type 2 diabetes, and prion protein (PrP) associated with spongiform encephalopathy. As used herein, "amyloid", "brain amyloid", and "amyloid β peptide (aβ)" are used interchangeably.
As used herein, the term "ARIA" refers to amyloid-related imaging abnormalities, as assessed using MRI. In some embodiments, the ARIA comprises amyloid-associated imaging abnormal edema/effusion (ARIA-E). In some embodiments, the ARIA comprises amyloid-associated imaging abnormal bleeding (ARIA-H). In some embodiments, subjects with ARIA experience headache, confusion, and/or epilepsy, and these may be used to identify subjects with ARIA or to indicate further evaluation of ARIA. In some embodiments, ARIA is evaluated at specified intervals during treatment. In some embodiments, ARIA is evaluated when the subject experiences symptoms of ARIA.
As used herein, the term "treatment" refers to achieving one or more beneficial or desired results, including but not limited to therapeutic benefit, which means eradicating or ameliorating the underlying disorder being treated or one or more physiological symptoms associated therewith. The term includes but does not require complete treatment.
As used herein, the term "preventing" refers to obtaining one or more beneficial or desired results, including but not limited to a prophylactic benefit. The benefit may include delaying the symptoms of the disease (e.g., one or more symptoms of Alzheimer's disease, such as progressive memory loss) or lessening the severity of the symptoms of the disease. For prophylactic benefit, subjects at risk for developing alzheimer's disease may be administered; to a subject having one or more preclinical symptoms but not clinical symptoms of alzheimer's disease; or administering the compound or formulation to a subject reporting one or more physiological symptoms of alzheimer's disease, even if a clinical diagnosis of alzheimer's disease has not been made. As used herein, "preventing" may further include therapeutic benefit, meaning eradicating or ameliorating the latent disorder being treated or one or more physiological symptoms associated therewith.
As will be appreciated by one of ordinary skill in the art, digital, computer, and/or conventional (e.g., pen and paper) cognitive tests may be used to detect early cognitive changes that may show mild cognitive impairment and/or risk of developing dementia, and thus may be used to identify a subject in need of treatment as disclosed herein. For example, such tests can screen for cognitive impairment and potentially identify subjects with MCI. The test may analyze the cognitive test results using artificial intelligence to determine if mild cognitive impairment cases will be upgraded to alzheimer's disease within one year. Early diagnosis of the condition before symptoms begin to appear can be used to help a physician identify a subject in need of treatment as disclosed herein earlier, potentially delaying the onset of or lessening the severity of the neurodegenerative disease.
As used herein, "MMSE" refers to a simple mental state examination, a cognitive tool commonly used for screening purposes, but also often measured longitudinally in AD clinical trials. MMSE is a 30 score scale, with higher scores indicating less damage and lower scores indicating more damage, ranging from 0 (maximum damage) to 30 (no damage). In some embodiments, measuring seven items of orientation, registration, recall, attention, language, and drawing of time and place may be evaluated as part of the MMSE score. ( Folstein, M.F. et al ,"Mini-mental state.A practical method for grading the cognitive state of patients for the clinician.[ simple mental state, a practical method for a clinician to score a patient's cognitive state, "J.Psychiatr.Res. [ journal of psychiatric study ]1975;12:189-98. )
As used herein, "ADAS-Cog" refers to Alzheimer's disease assessment scale-cognition (Alzheimer' S DISEASE ASSESSMENT SCALE-cognition). ADAS-Cog is a commonly used cognitive scale in Alzheimer's disease trials with a structural scale of evaluation memory (word recall, delayed word recall, and word recognition), reasoning (following commands), language (naming, understanding), orientation, concept practice (placing letters in envelopes), and construction practice (copying geometric design). (Rosen, W.G. et al, "A NEW RATING SCALE for Alzheimer's disease" [ New Alzheimer's disease rating scale ] "am.J. Psychiary [ journal of the United states of America ]1984; 141:1356-64.) can also obtain the ratings of spoken language, language understanding, word-calling difficulty, ability to remember test instructions, maze, and numerical marketing. In some embodiments, ADS-Cog refers to using the alzheimer's disease assessment scale-cognitive sub-scale 11 (ADAS-Cog 11). In some embodiments, ADAS-Cog 11 scores from 0 to 70, where a score of 0 indicates no damage and a score of 70 indicates maximum damage. In some embodiments, ADAS-Cog refers to using the alzheimer's disease assessment scale-cognitive sub scale 14(ADAS-Cog14). ADAS-Cog 14 includes 3 additional items: maze, digital scratch, and delayed recall test, and scored from 0 to 90, where a score of 0 indicates no damage and a score of 90 indicates maximum damage. In some embodiments, ADAS-Cog 14 tasks include memorization (word recall, delayed word recall, and word recognition), reasoning (follow command), language (naming, understanding), orientation, concept practice (placing letters in envelopes), construction practice (copy geometry design), spoken language understanding, word difficulty, ability to remember test instructions, maze, and number marketing (Rosen, W.G. et al, am.J. Psychiatry [ journal of psychiatry ]1984; 141:1356-64.).
As used herein, "CDR-SB" refers to clinical dementia assessment-box totals (CLINICAL DEMENTIA RATING-sum of boxes). The CDR is a clinical scale describing 5 degrees of impairment in performance of each of 6 functional categories including memory, targeting, judgment and problem solving, group transactions, home and hobbies, and personal care. (Berg, L.et al, "MILD SENILEDEMENTIA of the Alzheimer type:2.Longitudinal assessment. [ Alzheimer's disease type 2 mild senile dementia, longitudinal assessment ]" Ann. Neurol. [ neurological annual. 1988; 23:477-84.). The grade of the degree of impairment obtained for each of the 6 functional categories was synthesized as 1 total grade of dementia CDR scores (ranging from 0 to 3). The sum of the box scores provides an additional measure of variation, with each category having a maximum possible score of 3 points, and the total score being the sum of the categories of scores, resulting in a total possible score of 0 to 18, with higher scores indicating a higher degree of impairment. The total score may be used as a clinical measure of the severity of dementia.
In some embodiments, the efficacy of treatment for alzheimer's disease may be measured by any one or combination of medical observation, cognitive assessment, medical diagnosis, and medical imaging, for example. In some embodiments, therapeutic efficacy is determined by measuring tau protein diffusion via tau protein PET when isolated anti-tau protein antibodies or fragments thereof are administered concurrently with isolated anti-aβ protofibril antibodies or fragments thereof from week 24 to week 104 and week 208.
In some embodiments, when an isolated anti-tau antibody or fragment thereof is administered in parallel with an isolated anti-aβ protofibril antibody or fragment thereof, the efficacy of treatment in symptomatic patients is assessed by measuring the change from baseline in the sum of clinical dementia rating scale recordings (CDR-SB) after a period of treatment (e.g., change from week 24 to week 208). In some embodiments, when an isolated anti-tau antibody or fragment thereof is administered alone and then concurrently administered with an isolated anti-aβ protofibril antibody or fragment thereof, the efficacy of the treatment in asymptomatic patients is assessed by measuring the change in cerebrospinal fluid (CSF) phosphorylated tau protein (p-tau 217)/total tau protein (e.g., change from week 0 to week 104 and/or week 208) after a period of treatment.
In some embodiments, the efficacy of treatment in symptomatic patients is assessed by measuring at least one of: 1) When the isolated anti-tau antibody or isolated fragment thereof is administered in combination with the isolated anti-aβ protofibril antibody or fragment thereof, a change in the cognitive composite score (e.g., a change from week 24 to week 104 and/or week 208) after a period of treatment; 2) Changes in amyloid PET (e.g., changes from week 0 to week 24) after a period of treatment to assess the effect of isolated anti-aβ protofibril antibodies or fragments thereof when administered alone; 3) When the anti-aβ protofibril antibody or fragment thereof is administered alone, the generation of the anti-aβ protofibril antibody is evaluated for safety and tolerability after a period of treatment (e.g., change after 24 weeks); and 4) a change in CSF neurofilament light chain (NFL) from week 24 to week 104 and/or week 208 (e.g., a change from week 24 to weeks 104 and week 208) when the anti-tau antibody or fragment thereof is administered in combination with the anti-aβ protofibril antibody or fragment thereof.
In some embodiments, the efficacy of treatment in asymptomatic patients is determined by measuring at least one of: 1) When the anti-tau antibody or fragment thereof is administered alone, a change in CSF p-tau 217/total tau protein (e.g., a change from week 0 to week 52) after a period of treatment; 2) When an anti-tau antibody or fragment thereof is administered in combination with an anti-aβ protofibril antibody or fragment thereof, a change in CSF p-tau 217/total tau protein (e.g., a change from week 52 to week 104 and/or week 208) after a period of treatment; 3) When the anti-tau antibody or fragment thereof is administered alone, the anti-tau antibody is produced after a period of treatment (e.g., 52 weeks); 4) When an anti-tau antibody or fragment thereof is administered in combination with an anti-aβ protofibril antibody or fragment thereof, there is a change in CSF neurofilament light chain (NFL) after a period of treatment (e.g., a change from week 52 to week 104 and/or week 208).
Anti-Abeta-protofibril antibodies or antigen-binding fragments thereof
The methods, kits, and combinations disclosed herein include an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils.
In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils comprises six CDRs (HCDR 1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR 3) comprising an amino acid sequence of SEQ ID NO:1(HCDR1)、SEQ ID NO:2(HCDR2)、SEQ ID NO:3(HCDR3)、SEQ ID NO:4(LCDR1)、SEQ ID NO:5(LCDR2)、SEQ ID NO:6(LCDR3). See, e.g., table 11. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils comprises six CDRs (HCDR 1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR 3) from the heavy chain variable domain of SEQ ID NO:13 and the light chain variable domain of SEQ ID NO:14 (e.g., as defined by Kabat or IMGT). In some embodiments, an anti-Abeta-fibril antibody or antigen-binding fragment thereof capable of binding to human Abeta-fibrils comprises the heavy chain variable domain of SEQ ID NO. 13 and the light chain variable domain of SEQ ID NO. 14. See, e.g., table 12.
In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils comprises a human constant region. In some embodiments, the human constant region of the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils comprises a heavy chain constant region selected from the group consisting of: igG1, igG2, igG3, igG4, igM, igA, igE, and any allelic variation thereof as disclosed in Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the heavy chain constant region comprises SEQ ID NO. 17.
In some embodiments, the human constant region of the isolated anti-aβ protofibril antibody or antigen binding fragment thereof comprises a light chain constant region selected from the group consisting of kappa and lambda chain constant regions, and any allelic variation thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the light chain constant region comprises SEQ ID NO. 18.
In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is lenkanesab, also known as BAN2401. The rankazinab is a humanized IgG1 monoclonal form of mAb158, which mAb158 is a murine monoclonal antibody produced to target primary fibrils and disclosed in WO 2007/108756 and Journal of Alzheimer's Disease [ journal of alzheimer's Disease ]43:575-588 (2015). The lenKanesab is an isolated anti-aβ protofibril antibody, showing low affinity for aβ monomers while binding to soluble aβ aggregate species with high selectivity. For example, it has been reported that lenkanesab exhibits about 1000-fold and 5-fold to 10-fold higher selectivity for soluble aβ protofibrils than for aβ monomers or aβ insoluble fibrils, respectively. The full length sequences of the renkaempferide antibodies are described in WO 2007/108756 and Journal of Alzheimer's Disease [ J. Alzheimer's Disease ]43:575-588 (2015), the disclosures of which are incorporated herein by reference.
In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered twice daily. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered once daily. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered weekly. In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered twice weekly. In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered three times per week. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered every 2 weeks. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered monthly.
In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose ranging from 3mg/kg to 30 mg/kg. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 5mg/kg to 30 mg/kg. In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 10mg/kg to 30 mg/kg. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 15mg/kg to 30 mg/kg. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 20mg/kg to 30 mg/kg. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 25mg/kg to 30 mg/kg. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 5mg/kg to 25 mg/kg. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 5mg/kg to 20 mg/kg. In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 5mg/kg to 15 mg/kg. In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 5mg/kg to 10 mg/kg. In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 5mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, 25mg/kg or 30 mg/kg. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 10 mg/kg.
In some embodiments, an isolated anti-aβ protofibril antibody (e.g., lenkanesab) or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 10mg/kg every two weeks.
In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered until a change in the level of the biomarker in the sample is observed (e.g., an increase in the ratio is observed in a plasma or CSF sample relative to the ratio of aβ42/40 in the sample taken from the subject prior to administration). Methods for measuring the A.beta.42/40 ratio are known in the art, such as assays using LC MS/MS. Methods may include PRECIVITYAD TM assays for measuring aβ42 and aβ40 in a sample for calculating ratios (see, e.g., kirmess et al, j. Clinical CHIMICA ACTA journal of clinical chemistry 519:267-275 (2021)) and immunoassays using the HISCL TM platform (https:// www.eisai.com/news/2019/news201990. Html).
In some embodiments, the biomarker is brain amyloid level, e.g., as measured by PET SUVr. Methods for calculating PET SUVr are known in the art and may include those described herein. In some embodiments, the standard uptake value ratio quantitative analysis of amyloid levels is done using PMOD Biomedical Image Quantification software (PMOD technologies (PMOD Technologies), zurich, switzerland). In some embodiments, object motion of the PET images in X, Y and Z planes is first assessed and, if desired, motion correction is performed before individual images (e.g., 5 minute radiation frames) are averaged, for example, using a PMOD averaging function (averaging PET frames to increase signal-to-noise ratio). In some embodiments, corresponding MRI from the subject are prepared (e.g., using a matrix size reduction process, cropping MRI to include only brain, segmentation to separate images into binary maps of grey matter, white matter, and CSF, and stripping off images of the skull leaving only brain mask). In some embodiments, the averaged PET image and the prepared MRI are matched using a PMOD matching function, placing the images in the same orientation. In some embodiments, brain normalization functions, such as provided by PMOD software, are used, along with brain normalization and rigid matching transformation matrices, to produce an averaged PET. In some embodiments, this averaged PET is normalized with respect to MNInst space (Senjem et al, 2005) that is the same MRI orientation of the segmentation of the subject for quantitative analysis. In some embodiments, the PMOD mask function is used to mask the brain and the off-mask image is zeroed out to create normalized gray matter PET and normalized white matter PET. Standard Uptake Values (SUV) for all gray map areas and 3 white matter areas (pontic, cerebellar and subcortical) can be calculated using PMOD software, using normalized PET, subject weight and injected dose of tracer to arrive at the unit of SUV. In some embodiments SUVr is the ratio of the overall cortical average compared to the selected reference region. In some embodiments, a full cerebellum mask is used as the reference region. In some embodiments, the reference region is subcortical white matter, derived whole cerebellum, whole cerebellum corrected by subcortical white matter, cerebellum gray matter, and a composite reference region consisting of subcortical cortex, subcortical white matter, and cerebellum white matter.
In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is in the form of a pharmaceutical composition. In some embodiments, the pharmaceutical composition comprising the isolated anti-aβ protofibril antibody, or antigen binding fragment thereof, is administered via one or more syringes and/or auto-syringes. In some embodiments, administration is via any suitable route, e.g., intravenous.
The method of and including the use of the same are disclosed in U.S. provisional application No. 62/749,614 and PCT international application No. PCT/US2019/043067, both of which are incorporated herein by reference in their entireties.
Methods comprising the use of lenkanesab in subjects with preclinical AD are disclosed in CLINICAL TRIAL IDENTIFIER:nct04468659[ clinical trial identifier: NCT04468659] (clinical trimals. Gov), which is incorporated herein by reference in its entirety.
Anti-tau antibodies or antigen binding fragments thereof
The methods, kits and combinations disclosed herein include an anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau.
In some embodiments, an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau protein comprises six CDRs (HCDR 1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR 3) comprising the amino acid sequences of SEQ ID NO:7 (HCDR 1), SEQ ID NO:8 (HCDR 2), SEQ ID NO:9 (HCDR 3), SEQ ID NO:10 (LCDR 1), SEQ ID NO:11 (LCDR 2) and SEQ ID NO:12 (LCDR 3), as defined by Kabat. In some embodiments, an isolated anti-tau protein antibody or antigen binding fragment thereof capable of binding to human tau protein comprises six CDRs (HCDR 1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR 3) comprising the amino acid sequences of SEQ ID NO:24 (HCDR 1), SEQ ID NO:25 (HCDR 2), SEQ ID NO:26 (HCDR 3), SEQ ID NO:27 (LCDR 1), SEQ ID NO:28 (LCDR 2) and SEQ ID NO:29 (LCDR 3) as defined by IMGT see, e.g., table 11 in some embodiments, an isolated anti-tau protein antibody or antigen binding fragment thereof capable of binding to human tau protein comprises six CDRs (HCDR 1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR 3) from the heavy chain variable domain of SEQ ID NO:15 and the light chain variable domain of SEQ ID NO:16 in some embodiments, e.g., as defined by imkabat or table 11 in embodiments, may comprise the heavy chain variable domain of human tau protein or antigen binding to human chain variable domain of SEQ ID No. 16.
In some embodiments, an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau protein comprises a human constant region. In some embodiments, the human constant region comprises a heavy chain constant region selected from the group consisting of: igG1, igG2, igG3, igG4, igM, igA, igE, and any allelic variation thereof as disclosed in Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the heavy chain constant region comprises SEQ ID NO. 19.
In some embodiments, the human constant region of the isolated anti-tau antibody or antigen-binding fragment thereof comprises a light chain constant region selected from the group consisting of kappa and lambda chain constant regions, and any allelic variation thereof as discussed in the Kabat report. Any one or more of such sequences may be used in the present disclosure. In some embodiments, the light chain constant region comprises SEQ ID NO. 20.
In some embodiments, the anti-tau antibody or antigen-binding fragment comprises E2814 or an antigen-binding fragment thereof. E2814 is disclosed in US 2019/012364 A1 as clone 7G 6-HCzu/LCzu, the sequence of which is incorporated herein by reference.
In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is any of those disclosed in US 2019/012364 A1, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the anti-tau antibody or antigen binding fragment thereof comprises CDR and/or variable domain sequences from antibody clone 7G 6-HCzu/LCzu 18 as disclosed in US 2019/012364 A1, which are incorporated herein by reference. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is produced by an antibody-producing cell maintained at accession number PTA-124524 by the American type culture Collection (University Blvd, va.20110-2209, va.) on day 11.
In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered twice daily. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered once daily. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered weekly. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered twice weekly. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered three times per week. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered every 2 weeks. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered every four weeks or every month.
In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose in the range of 200mg to 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 500mg to 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 1000mg to 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 1500mg to 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 3000mg to 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 200mg to 3000 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 200mg to 1500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 200mg to 1000 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 200mg to 500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 200mg, 500mg, 1000mg, 1500mg, 2000mg, 2500mg, 3000mg, or 4500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 1500 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 3000 mg. In some embodiments, the anti-tau antibody or antigen-binding fragment thereof is administered at a dose of 4500 mg. Additional information regarding the administration and dosage forms of an anti-tau antibody (e.g., anti-tau antibody E2814) or antigen binding fragment thereof, which may be used in the methods disclosed herein, may be found in international application No. PCT/IB2022/060604, the contents of which are incorporated herein by reference in its entirety.
In some embodiments, the anti-tau antibody is E2814 or an antigen binding fragment thereof and is administered at a dose of 3000mg, e.g., once every four weeks.
In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered in combination with an isolated anti-tau antibody or antigen binding fragment thereof capable of binding to human tau protein, wherein the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered at a dose of 10mg/kg every two weeks and the isolated anti-tau antibody or antigen binding fragment thereof capable of binding to human tau protein is administered at a dose of 1500mg or 3000mg every four weeks.
In some embodiments, an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered until a change in the level of biomarker in the sample relative to the level in a sample taken from the subject prior to administration is observed (e.g., a decrease in phosphorylated tau 217 is observed in a plasma sample). In some embodiments, p-tau protein 217 can be measured from a sample taken from a subject at one point in time, and a second sample can be taken from the subject at a later point in time to measure changes in p-tau protein 217 in the subject. In some embodiments, the level of p-tau protein 217 in a sample taken from the subject after administration is reduced relative to the level of phosphorylated tau protein 217 in a sample taken from the subject prior to administration.
In some embodiments, administration of an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau protein is increased due to an increase in the amount of p-tau protein 217 in the subject. In some embodiments, administration of an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau protein is reduced due to a reduction in the amount of p-tau protein 217 in the subject. Methods for measuring phosphorylated tau 217 in plasma are known in the art, such as immunoassays. Tatebe et al, quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology, [ quantification of plasma phosphorylated tau for use as a biomarker for pathology of brain Alzheimer's disease ]12Molecular Neurodegeneration [ molecular neurodegeneration ]63 (2017, 9, 4).
In some embodiments, an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered until a change in tau protein diffusion as measured by PET is detected. In some embodiments, tau PET may be used to confirm the presence of tau protein in the brain of AD subjects and/or to measure its amount. In some embodiments, a tau PET scan may be performed at one time point and a second tau PET scan may be performed at a second, later time point to measure tau diffusion in the subject. In some embodiments, administration of an isolated anti-tau antibody or antigen binding fragment thereof capable of binding to human tau is increased as tau protein diffusion as measured by PET is observed in the patient. In some embodiments, the tau PET is MK-6240 tau PET.
Application of
In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered simultaneously with an isolated anti-tau antibody or antigen binding fragment thereof capable of binding to human tau protein. In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils and the isolated anti-tau antibody or antigen binding fragment thereof capable of binding to human tau protein are administered from the same vial. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils and an isolated anti-tau antibody or antigen binding fragment thereof capable of binding to human tau protein are administered from separate vials.
In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered for a period of time prior to administration of the isolated anti-tau antibody or antigen binding fragment thereof capable of binding to human tau. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered for a period of time prior to administration of the isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibrils. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered for fifty-two weeks prior to administration of the isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibrils. In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered for twenty weeks prior to administration of the isolated anti-tau antibody or antigen binding fragment thereof capable of binding to human tau.
In some embodiments, an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and an isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibrils are administered during the same clinical visit. In some embodiments, an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and an isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibrils are administered during separate clinical visits. In some embodiments, an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and an isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibrils are administered intravenously to the subject. In some embodiments, the timing of administration of an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and an isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibrils depends on whether the human is symptomatic or asymptomatic of alzheimer's disease.
In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered to a patient symptomatic of alzheimer's disease prior to administration of the isolated anti-tau antibody or antigen binding fragment thereof capable of binding to human tau. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered to a patient with symptoms of alzheimer's disease for 24 weeks until the isolated anti-tau antibody or antigen binding fragment thereof capable of binding to human tau and the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils are administered in combination. In some embodiments, an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered to a patient with symptoms of alzheimer's disease for 24 weeks followed by a combination of an isolated anti-tau antibody or antigen binding fragment thereof capable of binding to human tau and an isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils administered from 24 weeks to 52 weeks and/or 24 weeks to 208 weeks.
In some embodiments, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human tau is administered to a patient without symptoms of alzheimer's disease prior to administration of the isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibril. In some embodiments, the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered to a patient without symptoms of alzheimer's disease for 52 weeks prior to the combined administration of the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and the isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibrils. In some embodiments, an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau is administered to a patient without symptoms of alzheimer's disease for 52 weeks, followed by co-administration of the isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and the isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibril from week 52 to week 208.
Family history and dominant inherited Alzheimer's disease
In some embodiments, the subject has a family history of alzheimer's disease, e.g., family members are diagnosed with a medical history of alzheimer's disease before 60 years of age.
In some embodiments, the subject has Dominant Inherited Alzheimer's Disease (DIAD). In some embodiments, the subject has a mutation in at least one of the following three genes: amyloid Precursor Protein (APP), presenilin 1 (PSEN 1) or presenilin 2 (PSEN 2). In some embodiments, the subject has a mutation in the APP gene. In some embodiments, the subject has a mutation in the PSEN1 gene. In some embodiments, the subject has a mutation in the PSEN2 gene. Specific mutations in the APP, PSEN1 or PSEN2 genes that contribute to DIAD are known in the art (e.g., cruts and Van Broeckhoven,1998; cruts, theruns and Van Broeckhoven,2012; ryman et al 2014; sherva and Kowall, 2018).
Treating outcome
In some embodiments, the score of the subject is improved relative to the CDR-SB score prior to administration of an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and/or an isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibrils according to the methods disclosed herein. In some embodiments, the score of the subject is improved relative to an ADAS-cog score prior to administration of an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and/or an isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibrils according to the methods disclosed herein. In some embodiments, the score of the subject is improved relative to the MMSE score prior to administration of an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and/or an isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibrils according to the methods disclosed herein. In some embodiments, the score of the subject is improved relative to the CDR score prior to administration of an isolated anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau and/or an isolated anti-aβ protofibril antibody or antigen-binding fragment thereof capable of binding to human aβ protofibrils according to the methods disclosed herein.
Pharmaceutical combination and kit
In some embodiments, an isolated anti-tau antibody or antigen-binding fragment thereof described herein that is capable of binding to human tau and/or an isolated anti-aβ protofibril antibody or antigen-binding fragment thereof that is capable of binding to human aβ protofibrils is presented in a pharmaceutical combination. In some embodiments, the isolated anti-tau antibodies or antigen-binding fragments thereof described herein that are capable of binding to human tau and/or the isolated anti-aβ protofibril antibodies or antigen-binding fragments thereof that are capable of binding to human aβ protofibrils are presented in the form of a kit, e.g., comprising one or more vials containing these antibodies or antigen-binding fragments and instructions for administration (e.g., concurrent administration). In some embodiments, the antibody or antigen binding fragment in the kit is formulated for administration, e.g., intravenous administration, e.g., as disclosed above.
Subcutaneous administration
In some embodiments, a dose of anti-aβ protofibril antibody or antigen binding fragment thereof is administered subcutaneously to the subject. For example, 400mg to 800mg or 400mg to 1500mg (e.g., 720 mg) of an anti-aβ protofibril antibody or antigen binding fragment thereof may be administered to a subject. The antibody may be lenkazinab. Antibodies may be administered at a particular frequency, e.g., twice weekly, weekly (QW), biweekly (biweekly or Q2W), or monthly, for a period of time, e.g., for at least 52 weeks or 18 months, or until a particular criterion (e.g., a particular behavioral and/or biomarker criterion) is met. In some embodiments, a maintenance dose of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is then administered to the subject, e.g., at a specific frequency and for a period of time or until a specific standard is reached. The dose, frequency, time period of administration, and criteria may be the same as or different from the previous therapeutic dose, frequency, time period of administration, and/or criteria.
In some embodiments, the therapeutic dose is administered subcutaneously in two simultaneous or sequential injections, e.g., at a total dose of 720mg per week. In some embodiments, the treatment lasts for at least 52 weeks, or for at least 18 months. In some embodiments, the treatment is administered by subcutaneous injection. In some embodiments, the treatment is administered by a subcutaneous auto-injector.
In some embodiments, the maintenance dose is administered subcutaneously, e.g., twice weekly or weekly, e.g., 720mg per dose, after a period of time, e.g., 18 months, after receiving the therapeutic dose (e.g., two simultaneous or sequential subcutaneous injections, e.g., at a total dose of 720mg per week). In some embodiments, more than one therapeutic dose and more than one maintenance dose of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils are administered, wherein the maintenance dose is administered in a lower amount and/or with a reduced frequency relative to the therapeutic dose. In some embodiments, the criteria for switching to a maintenance dose or selecting a lower amount or frequency of maintenance doses may include a change in the biomarker, such as an increase in the aβ42/40 ratio observed in the sample (e.g., plasma sample) relative to that in a sample taken from the subject prior to treatment, a decrease in the level of pτ 217 or pτ 181 in a sample taken from the subject after treatment, and/or a decrease in amyloid PET SUVr after treatment.
In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is in the form of a pharmaceutical composition. In some embodiments, a pharmaceutical composition comprising an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered via one or more syringes and/or auto-syringes. In some embodiments, a pharmaceutical composition comprising an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered to the abdomen.
In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of at least 80 mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of at least 100 mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of at least 200 mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of at least 250 mg/mL. In some embodiments, the antibody is present in the pharmaceutical composition at a concentration of 80mg/mL to 300mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of 85mg/mL to 275 mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of 90mg/mL to 250 mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of 95mg/mL to 225 mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of 100mg/mL to 200 mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of ：80mg/mL、90mg/mL、100mg/mL、110mg/mL、120mg/mL、130mg/mL、140mg/mL、150mg/mL、160mg/mL、170mg/mL、180mg/mL、190mg/mL、200mg/mL、210mg/mL、220mg/mL、230mg/mL、240mg/mL、250mg/mL、260mg/mL、270mg/mL、280mg/mL、290mg/mL or 300mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of 100 mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of 200 mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of 250 mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present in the pharmaceutical composition at a concentration of 300mg/mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is trastuzumab.
In some embodiments, the pharmaceutical composition comprising an anti-aβ protofibril antibody, or antigen binding fragment thereof, further comprises at least one additional component. In some embodiments, at least one additional component of the pharmaceutical composition is selected from pharmaceutically acceptable buffers. In some embodiments, the pharmaceutically acceptable buffer is a citrate buffer. In some embodiments, the pharmaceutically acceptable buffer is a histidine buffer. In some embodiments, at least one additional component in the pharmaceutical composition is selected from emulsifiers. In some embodiments, at least one additional component in the pharmaceutical composition is selected from citric acid (or citric acid monohydrate), sodium chloride, histidine (and/or histidine hydrochloride), arginine (and/or arginine hydrochloride), and polysorbate 80. In some embodiments, at least one additional component in the pharmaceutical composition is selected from citric acid (and/or citric acid monohydrate), arginine (and/or arginine hydrochloride), and polysorbate 80. In some embodiments, the at least one additional component in the pharmaceutical composition is selected from histidine (and/or histidine hydrochloride), arginine (and/or arginine hydrochloride), and polysorbate 80.
In some embodiments, the pharmaceutical composition comprising an anti-aβ protofibril antibody or antigen binding fragment thereof comprises arginine (and/or arginine hydrochloride). In some embodiments, the concentration of arginine (and/or arginine hydrochloride) in the pharmaceutical composition is in the range of 100mM to 400 mM. In some embodiments, the concentration of arginine (and/or arginine hydrochloride) in the pharmaceutical composition is in the range of 110mM to 380mM, 120mM to 360mM, 125mM to 350mM, 140mM to 340mM, 160mM to 325mM, 175mM to 300mM, or 200mM to 250 mM. In some embodiments, the concentration of arginine (and/or arginine hydrochloride) in the pharmaceutical composition is in the range of 110mM to 150mM, 150mM to 200mM, 200mM to 250mM, 250mM to 300mM, 300mM to 350mM, or 350mM to 380 mM. In some embodiments, the concentration of arginine (and/or arginine hydrochloride) is 125mM. In some embodiments, the concentration of arginine (and/or arginine hydrochloride) is 200mM. In some embodiments, the concentration of arginine (and/or arginine hydrochloride) is 350mM.
In some embodiments, the pharmaceutical composition comprising an anti-aβ protofibril antibody or antigen binding fragment thereof comprises histidine. In some embodiments, the concentration of histidine in the pharmaceutical composition is in the range of 10mM to 100 mM. In some embodiments, the concentration of histidine in the pharmaceutical composition is in the range of 10mM to 100mM, 12mM to 80mM, 14mM to 60mM, 15mM to 55mM, 15mM to 35mM, or 15mM to 25mM. In some embodiments, the concentration of histidine is 25mM. In some embodiments, the concentration of histidine is 50mM.
In some embodiments, the pharmaceutical composition comprising an anti-aβ protofibril antibody, or antigen binding fragment thereof, comprises polysorbate 80. In some embodiments, the concentration of polysorbate 80 in the pharmaceutical composition is in the range of 0.01% w/v to 0.1% w/v, 0.01% w/v to 0.08% w/v, 0.02% w/v to 0.08% w/v, 0.03% w/v to 0.07% w/v, or 0.04% w/v to 0.06% w/v. In some embodiments, polysorbate 80 is present in the pharmaceutical composition at a concentration of 0.01% w/v, 0.02% w/v, 0.03% w/v, 0.04% w/v, 0.05% w/v, 0.06% w/v, 0.07% w/v, or 0.08% w/v. In some embodiments, polysorbate 80 is present in the pharmaceutical composition at a concentration of 0.02% w/v. In some embodiments, polysorbate 80 is present in the pharmaceutical composition at a concentration of 0.05% w/v.
In some embodiments, the pharmaceutical composition comprising an anti-aβ protofibril antibody, or antigen binding fragment thereof, comprises citric acid monohydrate. In some embodiments, the concentration of citric acid monohydrate in the pharmaceutical composition is in the range of 10mM to 100 mM. In some embodiments, the concentration of citric acid monohydrate in the pharmaceutical composition is in the range of 10mM to 100mM, 10mM to 90mM, 15mM to 85mM, 20mM to 80mM, 25mM to 75mM, 30mM to 70mM, 30mM to 60mM, or 30mM to 50mM. In some embodiments, the concentration of citric acid monohydrate in the pharmaceutical composition is 50mM.
In some embodiments, the pharmaceutical composition comprising an anti-aβ protofibril antibody, or antigen binding fragment thereof, has a pH in the range of 4.5 to 5.5. In some embodiments, the pH in the pharmaceutical composition is in the range of 4.0 to 6.0, 4.2 to 5.8, 4.3 to 5.7, 4.4 to 5.6, or 4.5 to 5.5. In some embodiments, the pH is 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, or 5.5. In some embodiments, the pH is 5.0.
In some embodiments, the pharmaceutical composition comprising the anti-aβ protofibril antibody, or antigen binding fragment thereof, may be in the form of a solution and/or any other suitable liquid formulation deemed suitable by one of ordinary skill in the art. In some embodiments, the pharmaceutical composition is formulated as a sterile pyrogen-free liquid for subcutaneous administration. In some embodiments, the pharmaceutical composition is a saline solution.
In some embodiments, the pharmaceutical composition comprising an anti-aβ protofibril antibody or antigen binding fragment thereof is a liquid dosage form comprising an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils (such as lenkanesab) bound to aβ protofibrils and further comprising, for example, citric acid monohydrate, arginine hydrochloride, and polysorbate 80.
In some embodiments, the pharmaceutical composition comprises 100mg/mL of an anti-aβ protofibril antibody or antigen binding fragment thereof (e.g., lenkazinab), 50mM citric acid monohydrate, 110mM arginine, 240mM arginine hydrochloride, and 0.05% (w/v) polysorbate 80, and has a pH of 5.0±0.4.
In some embodiments, the pharmaceutical composition comprising an anti-aβ protofibril antibody or antigen binding fragment thereof is a liquid dosage form comprising an anti-aβ protofibril antibody (such as lenkanesab) that binds to aβ protofibrils and further comprising, for example, histidine, arginine hydrochloride, and polysorbate 80. In some embodiments, the pharmaceutical composition comprises 100mg/mL or 200mg/mL of an anti-aβ protofibril antibody that binds to aβ protofibrils (e.g., lenKanesab), 25mM histidine and histidine hydrochloride, 200mM arginine hydrochloride, and 0.05% (w/v) polysorbate 80, and has a pH of 5.0±0.4. In some embodiments, the pharmaceutical composition comprises 200mg/mL of rankaempferide, 200mM arginine, 25mM histidine and histidine hydrochloride, 0.05% (w/v) polysorbate 80 as a sterile aqueous solution.
In some embodiments, the pharmaceutical composition is a liquid dosage form comprising an anti-aβ protofibril antibody (such as lenKanesab) that binds to aβ protofibrils, and further comprising, for example, histidine hydrochloride, arginine hydrochloride, and polysorbate 80. In some embodiments, the pharmaceutical composition comprises 200mg/mL of an anti-aβ protofibril antibody that binds to aβ protofibrils (e.g., lenKanesab), 50mM histidine and histidine hydrochloride, 125mM arginine hydrochloride, and 0.02% (w/v) polysorbate 80, and has a pH of 5.0±0.4.
In some embodiments, the pharmaceutical composition is a liquid dosage form comprising an anti-aβ protofibril antibody (such as lenKanesab) that binds to aβ protofibrils, and further comprising, for example, histidine hydrochloride, arginine hydrochloride, and polysorbate 80. In some embodiments, the pharmaceutical composition comprises 200mg/mL of an anti-aβ protofibril antibody that binds to aβ protofibrils (such as lenkanesab), 50mM citric acid (and/or citric acid monohydrate), 125mM arginine (and/or arginine hydrochloride), and 0.02% (w/v) polysorbate 80, and has a pH of 5.0±0.4.
Exemplary formulations for subcutaneous administration are also disclosed in PCT/IB2021/000155, the contents of which are incorporated herein by reference in their entirety.
As used herein, the term "maintenance dose" refers to the dose administered to a subject in order to maintain a desired therapeutic effect. In some embodiments, the maintenance dose of the subject is the same as the dose during the treatment period. In some embodiments, the maintenance dose is administered subcutaneously. In some embodiments, the maintenance dose is administered one or more times. In some embodiments, the maintenance dose is administered weekly, biweekly, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks (three months or quarters), 16 weeks, 24 weeks (six months or half a year), 48 weeks, monthly, 2 months, 3 months, 4 months, 6 months, or 12 months. In some embodiments, the maintenance dose comprises an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils. In some embodiments, the maintenance dose is 300mg to 800mg, 300mg to 400mg, 400mg to 500mg, 400mg to 450mg, 450mg to 500mg, 500mg to 600mg, 500mg to 550mg, 550mg to 600mg, 600mg to 700mg, 600mg to 650mg, 650mg to 700mg, 700mg to 800mg, 700mg to 750mg, or 750mg to 800mg. In some embodiments, the maintenance dose is 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, or 390mg. In some embodiments, the maintenance dose is 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, or 490mg. In some embodiments, the maintenance dose is 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, or 590mg. In some embodiments, the maintenance dose is 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, or 690mg. In some embodiments, the maintenance dose is 700mg, 710mg, 720mg, 730mg, 740mg, 750mg, 760mg, 770mg, 780mg, or 790mg. In some embodiments, the maintenance dose is 800mg to 1600mg, 800mg to 1000mg, 800mg to 900mg, 900mg to 1000mg, 1000mg to 1200mg, 1000mg to 1100mg, 1100mg to 1200mg, 1200mg to 1400mg, 1200mg to 1300mg, 1300mg to 1400mg, 1400mg to 1600mg, 1400mg to 1500mg, or 1500mg to 16000mg. In some embodiments, the maintenance dose is 800mg, 820mg, 840mg, 860mg, 880mg, 900mg, 920mg, 940mg, 960mg, or 980mg. In some embodiments, the maintenance dose is 1000mg, 1020mg, 1040mg, 1060mg, 1080mg, 1100mg, 1120mg, 1140mg, 1160mg, or 1180mg. In some embodiments, the maintenance dose is 1200mg, 1220mg, 1240mg, 1260mg, 1280mg, 1300mg, 1320mg, 1340mg, 1360mg, or 1380mg. In some embodiments, the maintenance dose is 1400mg, 1420mg, 1440mg, 1460mg, 1480mg, 1500mg, 1520mg, 1540mg, 1560mg, or 1580mg. In some embodiments, the maintenance dose is provided in a single administration, e.g., as a single 1440mg subcutaneous injection administration, or in two or more administrations, two administrations of 720mg to achieve a total of 1440mg, four administrations of 360mg to achieve a total of 1440mg. In some embodiments, the maintenance dose is 3600mg. In some embodiments, the maintenance dose is 440mg. In some embodiments, the maintenance dose is 580mg. In some embodiments, the maintenance dose is 720mg. In some embodiments, a maintenance dose of 720mg is administered in a single administration or in two administrations of 360 mg. In some embodiments, the maintenance dose is 1440mg. In some embodiments, the maintenance dose is provided in a single administration, e.g., as a single 720 or 1440mg subcutaneous injection administration, or in two or more administrations, e.g., two concurrent administrations of 360mg to a total of 720mg or two administrations of 720mg to a total of 1440mg, or four administrations of 360mg to a total of 1440mg. In some embodiments, the maintenance dose is 120mg. In some embodiments, the maintenance dose is 180mg. In some embodiments, the maintenance dose is 240mg. In some embodiments, the maintenance dose is 360mg. In some embodiments, the maintenance dose is 440mg. In some embodiments, the maintenance dose is 480mg. In some embodiments, the maintenance dose is 540mg. In some embodiments, the maintenance dose is 440mg. In some embodiments, the maintenance dose is 580mg. In some embodiments, the maintenance dose is 600mg. In some embodiments, the maintenance dose is 720mg. In some embodiments, the maintenance dose is 840mg. In some embodiments, the maintenance dose is 900mg. In some embodiments, the maintenance dose is 960mg. In some embodiments, the maintenance dose is 1080mg. In some embodiments, the maintenance dose is 1200mg. In some embodiments, the maintenance dose is 1260mg. In some embodiments, the maintenance dose is 1320mg. In some embodiments, the maintenance dose is 1440mg. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per week. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per week, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as a 720mg subcutaneous injection every two weeks. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections every two weeks, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as a subcutaneous injection of 1440mg every two weeks. In some embodiments, the maintenance dose is provided in a single 1440mg administration every two weeks, including two concurrent (e.g., two sequential) administrations of 720mg subcutaneous formulation to achieve a total of 1440mg or four sequential administrations of 360mg to achieve a total of 1440mg.
In some embodiments, the maintenance dose is administered one or more times. In some embodiments, the maintenance dose is administered at a lower dose than during the earlier treatment session and/or at a lower frequency than during the earlier treatment session.
In some embodiments, the therapeutic dose is administered as a subcutaneous injection. In some embodiments, the therapeutic dose is administered as a weekly subcutaneous injection. In some embodiments, the therapeutic dose is administered as a subcutaneous injection every two weeks. In some embodiments, the therapeutic dose is administered as a monthly subcutaneous injection. In some embodiments, the therapeutic dose is administered as a subcutaneous injection every quarter.
In some embodiments, the maintenance dose is administered as a subcutaneous injection. In some embodiments, the maintenance dose is administered as a weekly subcutaneous injection. In some embodiments, the maintenance dose is administered as a subcutaneous injection every two weeks. In some embodiments, the maintenance dose is administered as a monthly subcutaneous injection. In some embodiments, the maintenance dose is administered as a subcutaneous injection every quarter.
In some embodiments, the frequency of maintenance doses is weekly. In some embodiments, the maintenance dose is every two weeks (every two weeks). In some embodiments, the maintenance dose is weekly (monthly). In some embodiments, the subcutaneous maintenance dose is administered every six weeks. In some embodiments, the subcutaneous maintenance dose is administered every eight weeks (2 months). In some embodiments, the maintenance dose is every three months (every twelve weeks or quarterly). In some embodiments, the maintenance dose is every six months (every 24 weeks or every half year). In some embodiments, the maintenance dose of the subject is the same as the dose during the treatment period. In some embodiments, the maintenance dose is the same dose amount as the dose prior to administration of the maintenance dose. In some embodiments, the maintenance dose is lower in dose than before the maintenance dose is administered. In some embodiments, the maintenance dose has the same dose frequency as the dose prior to administration of the maintenance dose. In some embodiments, the maintenance dose is less frequent than the dose prior to administration of the maintenance dose.
In some embodiments, the maintenance dose is administered as a subcutaneous injection of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils. In some embodiments, the maintenance dose is administered subcutaneously weekly as a formulation of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per week, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per month, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per quarter, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections every two weeks, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per month, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per quarter, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the subcutaneous maintenance dose is administered weekly. In some embodiments, the subcutaneous maintenance dose is administered every two weeks. In some embodiments, the subcutaneous maintenance dose is administered every four weeks (monthly). In some embodiments, the subcutaneous maintenance dose is administered every six weeks. In some embodiments, the subcutaneous maintenance dose is administered every eight weeks (2 months). In some embodiments, the subcutaneous maintenance dose is administered every three months (twelve weeks or quarterly). in some subcutaneous embodiments, the maintenance dose is administered weekly, biweekly, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 16 weeks, 24 weeks, 48 weeks, monthly, 2 months, 3 months, 4 months, 6 months, or 12 months. In some embodiments, the subcutaneous maintenance dose comprises a dose of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils of: 300mg to 800mg, 300mg to 400mg, 400mg to 500mg, 400mg to 450mg, 450mg to 500mg, 500mg to 600mg, 500mg to 550mg, 550mg to 600mg, 600mg to 700mg, 600mg to 650mg, 650mg to 700mg, 700mg to 800mg, 700mg to 750mg, Or 750mg to 800mg. In some embodiments, the maintenance dose is 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, or 390mg. In some embodiments, the maintenance dose is 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, or 490mg. In some embodiments, the maintenance dose is 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, or 590mg. In some embodiments, the maintenance dose is 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, or 690mg. In some embodiments, the maintenance dose is 700mg, 710mg, 720mg, 730mg, 740mg, 750mg, 760mg, 770mg, 780mg, or 790mg. In some embodiments, the maintenance dose is 800mg to 1600mg, 800mg to 1000mg, 800mg to 900mg, 900mg to 1000mg, 1000mg to 1200mg, 1000mg to 1100mg, 1100mg to 1200mg, 1200mg to 1400mg, 1200mg to 1300mg, 1300mg to 1400mg, 1400mg to 1600mg, 1400mg to 1500mg, or 1500mg to 16000mg. In some embodiments, the maintenance dose is 800mg, 820mg, 840mg, 860mg, 880mg, 900mg, 920mg, 940mg, 960mg, or 980mg. In some embodiments, the maintenance dose is 1000mg, 1020mg, 1040mg, 1060mg, 1080mg, 1100mg, 1120mg, 1140mg, 1160mg, or 1180mg. In some embodiments, the maintenance dose is 1200mg, 1220mg, 1240mg, 1260mg, 1280mg, 1300mg, 1320mg, 1340mg, 1360mg, or 1380mg. in some embodiments, the maintenance dose is 1400mg, 1420mg, 1440mg, 1460mg, 1480mg, 1500mg, 1520mg, 1540mg, 1560mg, or 1580mg. In some embodiments, the maintenance dose is provided in a single administration, e.g., as a single 720 or 1440mg subcutaneous injection administration, or in two or more administrations, e.g., two concurrent administrations of 360mg to a total of 720mg or two administrations of 720mg to a total of 1440mg, or four administrations of 360mg to a total of 1440mg. In some embodiments, the maintenance dose is 440mg. In some embodiments, the maintenance dose is 580mg. In some embodiments, the maintenance dose is administered as 720mg for a single administration or 360mg for two administrations. In some embodiments, the maintenance dose is 1440mg. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per week. In some embodiments, the maintenance dose is administered as a 360mg subcutaneous injection per week. In some embodiments, the maintenance dose is administered as a 720mg subcutaneous injection every two weeks. In some embodiments, the maintenance dose is administered as a subcutaneous injection of 1440mg every two weeks. in some embodiments, the maintenance dose is provided in a single administration of 1440mg every two weeks, including two concurrent (e.g., sequential) administrations of 720mg subcutaneous formulation to achieve a total of 1440mg.
In some embodiments, the treatment comprises subcutaneously administering an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils prior to conversion to an intravenous maintenance dose. In some embodiments, the treatment comprises subcutaneous administration of the rankazinab weekly, e.g., subcutaneous injection of 720mg, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL), e.g., until the patient is amyloid negative or for a period of time, e.g., at least 18 months. In some embodiments, the treatment comprises subcutaneous administration of the rankazinab weekly, e.g., at a dose of 720mg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converted to a maintenance dose. In some embodiments, the treatment comprises subcutaneous administration of the rankazinab weekly, e.g., at a dose of 720mg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converted to an intravenous maintenance dose of 10mg/kg weekly. In some embodiments, the treatment comprises subcutaneous administration of the rankazinab weekly, e.g., at a dose of 720mg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then switching to an intravenous maintenance dose of 10mg/kg every two weeks. In some embodiments, the treatment comprises subcutaneous administration of the rankazinab weekly, e.g., at a dose of 720mg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converted to an intravenous maintenance dose of 10mg/kg per month. In some embodiments, the treatment comprises subcutaneous administration of the rankazinab weekly, e.g., at a dose of 720mg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then switching to an intravenous maintenance dose of 10mg/kg every six weeks. In some embodiments, the treatment comprises subcutaneous administration of the rankazinab weekly, e.g., at a dose of 720mg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then switching to an intravenous maintenance dose of 10mg/kg every eight weeks. In some embodiments, the treatment comprises subcutaneous administration of the rankazinab weekly, e.g., at a dose of 720mg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then switching to an intravenous maintenance dose of 10mg/kg quarterly. In some embodiments, the maintenance dose of the subject is administered in the same amount and/or frequency as the dose during the treatment period. In some embodiments, the maintenance dose of the subject is 50% of the dose during the treatment period.
In some embodiments, the maintenance dose is administered intravenously, for example, after an intravenous treatment period as disclosed above. In some embodiments, an intravenous maintenance dose, e.g., a 10mg/kg administration of rankazinab, is administered weekly, biweekly, monthly, bi-monthly, or tri-monthly (quarterly). In some embodiments, the intravenous maintenance dose is administered every two weeks. In some embodiments, an intravenous maintenance dose is administered every four weeks. In some embodiments, the intravenous maintenance dose is administered every six weeks. In some embodiments, the intravenous maintenance dose is administered every eight weeks (2 months). In some embodiments, the intravenous maintenance dose is administered every three months (quarterly). In some embodiments, the intravenous maintenance dose is administered every 24 weeks (every six months or every half year). In some embodiments, the intravenous maintenance dose is 2.5mg/kg to 10mg/kg. In some embodiments, the maintenance dose is administered every two weeks as an intravenous dose of 10mg/kg of rankazinoki mab. In some embodiments, the maintenance dose is administered every four weeks (monthly) as an intravenous dose of 10mg/kg. In some embodiments, the maintenance dose is administered every six weeks as an intravenous dose of 10mg/kg. In some embodiments, the maintenance dose is administered every eight weeks (2 months) as an intravenous dose of 10mg/kg. In some embodiments, the maintenance dose is administered every twelve weeks (every three months or quarters) as an intravenous dose of 10 mg/kg. In some embodiments, the maintenance dose is administered every 24 weeks (every six months or every half year) as an intravenous dose of 10 mg/kg. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a weekly intravenous maintenance dose. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to an intravenous maintenance dose every two weeks. in some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils at 10mg/kg every two weeks, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a monthly intravenous maintenance dose. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils at 10mg/kg every two weeks, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to an intravenous maintenance dose every six weeks. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils at 10mg/kg every two weeks, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to an intravenous maintenance dose every eight weeks. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a quarterly intravenous maintenance dose.
In some embodiments, the patient begins intravenous maintenance dose, e.g., administration of 10mg/kg of rankazinoki mab as disclosed above, and then transitions to subcutaneous maintenance dose, e.g., subcutaneous injection of 720mg, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) of the subcutaneous formulation. In some embodiments, the patient begins a subcutaneous maintenance dose, e.g., 720mg, comprising two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) of the subcutaneous formulation, followed by a transition to an intravenous maintenance dose, e.g., administration of 10mg/kg of rankazinab as disclosed above.
In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered Subcutaneously (SC). In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered in an injection solution having a volume of 1.1 mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered in an injection solution having a volume of 1.4 mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered in an injection solution having a volume of 1.45 mL. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered in an injection solution having a volume of 1.8 mL.
In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered once daily. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered twice daily. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered one or more times; for example, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered as a single administration of 720mg or as two administrations of 720mg (1440 mg total). In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered one or more times; for example, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered as a single administration of 720mg or as two administrations of 360mg (720 mg total). In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered weekly. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered weekly. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered three times per week. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered every 2 weeks. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered monthly. In some embodiments, the dose amount and/or dose frequency may be reduced after the desired therapeutic effect is achieved. The frequency of decrease may be every two weeks, or every 4 weeks, every 6 weeks, every 8 weeks, every 10 weeks, every 12 weeks, every 16 weeks, monthly, every 2 months, every 3 months, every 4 months, every 6 months, or every 12 months. In some embodiments, the desired therapeutic effect associated with dose amount or dose frequency reduction may be one or more selected from the group consisting of: cerebral amyloid reduction, amyloid PET SUVr reduction, increased plasma aβ42/40 ratio, reduced plasma p-tau 181, and changes to achieve sufficient or predetermined levels of other biomarkers associated with cerebral amyloid reduction. In some embodiments, administration of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is discontinued when the desired therapeutic effect is maintained after a reduced dose amount or frequency of administration. In some embodiments, if the desired therapeutic effect or an expected sufficient or predetermined level is not achieved in the subject, discontinuing administration of the anti-aβ protofibril antibody or antigen binding fragment thereof that binds to human aβ protofibrils, the desired therapeutic effect may be assessed by one or more selected from the group consisting of: cerebral amyloid reduction, amyloid PET SUVr reduction, increased plasma aβ42/40 ratio, reduced plasma p-tau 181, and changes in other biomarkers associated with cerebral amyloid reduction.
In some embodiments, the treatment comprises subcutaneous administration of the rankazinab weekly, e.g., at a dose of 720mg, e.g., for at least 18 months. In some embodiments, the treatment comprises subcutaneous administration of the rankazinab twice a week, e.g., at 720mg per dose, e.g., for at least 18 months. In some embodiments, treatment is continued until a desired improvement in one or more biomarkers or other measure of treatment outcome is achieved, e.g., when an increase in the aβ42/40 ratio in the sample (e.g., plasma sample) is observed relative to the ratio in a sample taken from the subject prior to treatment (e.g., 18 months prior to treatment). In some embodiments, the subject has been diagnosed with early stage AD. In some embodiments, the subject has been diagnosed with mild cognitive impairment due to moderate likelihood of alzheimer's disease, and/or has been diagnosed with mild alzheimer's disease dementia.
In some embodiments, the method of treatment comprises measuring the concentration of amyloid beta 1-42 (aβ42) and the concentration of amyloid beta 1-40 (aβ40) in a first blood sample obtained from the subject to determine a first ratio of aβ42 to aβ40 (aβ42/40 ratio). In some embodiments, a therapeutically effective dose of an anti-amyloid β (aβ) protofibril antibody is then administered to the subject. In some embodiments, a second blood sample is obtained after the first sample to determine a second aβ42/40 ratio. In some embodiments, the second blood sample is obtained from the subject after cessation or reduction of treatment. In some embodiments, a change in the aβ42/40 ratio is used to determine a second therapeutically effective dose. In some embodiments, a second therapeutically effective dose comprising the same or lower amount of anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils than the first dose of the subject is administered to a subject having a second ratio that is increased relative to the first ratio. In some embodiments, a second therapeutically effective dose comprising a higher amount of anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils than the first dose is administered to a subject having a second ratio that is lower relative to the first ratio. In some embodiments, a different treatment for AD is administered to subjects with a second ratio that is lower relative to the first ratio. After measuring the second aβ42/40 ratio, the first therapeutically effective dose may be administered multiple times (e.g., every two weeks or month for 6-18 months) before changing to the second therapeutically effective dose or dosing regimen. In some embodiments, a first therapeutically effective dose may be administered for at least 18 months and then converted to a maintenance dose. In some embodiments, a first therapeutically effective dose may be administered until the patient is amyloid negative and then converted to a maintenance dose. in some embodiments, a first therapeutically effective dose may be administered until the patient is amyloid negative (e.g., as measured by amyloid or tau Positron Emission Tomography (PET), cerebrospinal fluid Aβ1-42 levels and/or Aβ1-42/1-40 ratios, cerebrospinal fluid total tau levels, cerebrospinal fluid neuroproteins levels, cerebrospinal fluid neurofilament light chain peptide (NfL) levels, and blood biomarkers as measured in serum or plasma (e.g., Aβ1-42 levels, ratio of two forms of amyloid βpeptide (Aβ1-42/1-40 ratios), a, Plasma levels of total plasma tau (T-tau), levels of phosphorylated tau (P-tau) isoforms (including tau phosphorylated at 181 (P-tau 181), 217 (P-tau 217), and 231 (P-tau 231)), glial Fibrillary Acidic Protein (GFAP), and/or neurofilament light chain (NfL)), and then converted to maintenance doses. in some embodiments, the first therapeutically effective dose may be administered until the patient is amyloid negative, e.g., as measured by a aβ42/40 ratio equal to or higher than 0.092-0.094 (e.g., equal to or higher than 0.092) or flurbipetapirn amyloid PET SUVr negative equal to or lower than 1.17, and then converted to a maintenance dose. In some embodiments, the first therapeutically effective dose may be administered until the patient is amyloid negative, e.g., as measured by a aβ42/40 ratio of greater than 0.092 or equal to or less than 1.17 for flurbiptapidine amyloid PET SUVr negative, and then converted to a maintenance dose. In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or e.g., until the patient is amyloid negative, and then converting to a maintenance dose.
In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or e.g., until the patient is amyloid negative, and then switching to an intravenous maintenance dose (e.g., at 10mg/kg, e.g., every two weeks or every 4, 6, 8, 10, or 12 weeks). In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or e.g., until the patient is amyloid negative, and then converting to an intravenous maintenance dose every two weeks. In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg (e.g., administration of lenkazin mab at 10 mg/kg), e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a monthly intravenous maintenance dose. In some embodiments, the first therapeutically effective dose comprises administering the anti-aβ protofibril antibody intravenously every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then switching to an intravenous maintenance dose every six weeks. In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg (e.g., administration of lenkazin mab at 10 mg/kg), e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to an intravenous maintenance dose every eight weeks. In some embodiments, the first therapeutically effective dose comprises intravenous administration of anti-aβ protofibril antibody at 10mg/kg every two weeks, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then switching to a maintenance dose every two months. In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg (e.g., administration of lenkazinoki mab at 10 mg/kg), e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a quarterly intravenous maintenance dose.
In some embodiments, the first therapeutically effective dose comprises administering 720mg of anti-aβ protofibril antibody subcutaneously weekly, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then switching to a subcutaneous maintenance dose (e.g., at 720mg, e.g., weekly, biweekly, or every 4, 6, 8, 10, or 12 weeks). In some embodiments, the maintenance dose is 360mg per week.
In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or e.g., until the patient is amyloid negative, and then converting to a weekly subcutaneous maintenance dose (e.g., at a dose of 720 mg). In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or e.g., until the patient is amyloid negative, and then converting to a weekly subcutaneous maintenance dose (e.g., at a dose of 360 mg). In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or e.g., until the patient is amyloid negative, and then converting to a sub-dermal maintenance dose every two weeks (e.g., at a dose of 720mg or at a dose of 360 mg). In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or e.g., until the patient is amyloid negative, and then converting to a monthly subcutaneous maintenance dose (e.g., at a dose of 720mg or at a dose of 360 mg). In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg (e.g., administration of lenkazin mab at 10 mg/kg), e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then switching to a subcutaneous maintenance dose every six weeks (e.g., at a dose of 720mg or at a dose of 360 mg). In some embodiments, the first therapeutically effective dose comprises intravenous administration of anti-aβ protofibril antibody at 10mg/kg every two weeks, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then switching to a subcutaneous maintenance dose every eight weeks (e.g., at a dose of 720mg or at a dose of 360 mg). In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or e.g., until the patient is amyloid negative, and then switching to a subcutaneous maintenance dose every two months (e.g., at a dose of 720mg or at a dose of 360 mg). In some embodiments, the first therapeutically effective dose comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or e.g., until the patient is amyloid negative, and then converting to a quarterly subcutaneous maintenance dose (e.g., at a dose of 720mg or at a dose of 360 mg).
In some embodiments, the first therapeutically effective dose comprises weekly subcutaneous administration of anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, e.g., subcutaneous injection of 720mg, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) of a subcutaneous formulation within a given week, e.g., for at least 18 months or, for example, until the patient is amyloid negative, and then conversion to a weekly subcutaneous maintenance dose (e.g., at a dose of 720mg or at a dose of 360 mg). In some embodiments, the first therapeutically effective dose comprises weekly subcutaneous administration of anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, e.g., subcutaneous injection of 720mg, comprising two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) of a subcutaneous formulation within a given week, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, followed by conversion to a weekly subcutaneous maintenance dose (e.g., at a dose of 720 mg). In some embodiments, the first therapeutically effective dose comprises weekly subcutaneous administration of anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, e.g., subcutaneous injection of 720mg, comprising two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) of a subcutaneous formulation within a given week, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, followed by conversion to a weekly subcutaneous maintenance dose (e.g., as a single dose of 360 mg). In some embodiments, the first therapeutically effective dose comprises weekly subcutaneous administration of anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, e.g., subcutaneous injection of 720mg, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) of a subcutaneous formulation within a given week, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, followed by conversion to a monthly subcutaneous maintenance dose (e.g., at a dose of 720 mg). In some embodiments, the first therapeutically effective dose comprises weekly subcutaneous administration of anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, e.g., subcutaneous injection of 720mg, comprising two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) of a subcutaneous formulation within a given week, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, followed by conversion to a subcutaneous maintenance dose (e.g., at a dose of 720 mg) every six weeks. In some embodiments, the first therapeutically effective dose comprises weekly subcutaneous administration of anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, e.g., subcutaneous injection of 720mg, comprising two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) of a subcutaneous formulation within a given week, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, followed by conversion to a subcutaneous maintenance dose (e.g., at a dose of 720 mg) every eight weeks. In some embodiments, the first therapeutically effective dose comprises weekly subcutaneous administration of anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, e.g., subcutaneous injection of 720mg, comprising two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) of a subcutaneous formulation within a given week, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, followed by conversion to a subcutaneous maintenance dose (e.g., at a dose of 720 mg) every two months. In some embodiments, the first therapeutically effective dose comprises weekly subcutaneous administration of anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, e.g., subcutaneous injection of 720mg, comprising two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) of a subcutaneous formulation within a given week, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, followed by conversion to a quarterly subcutaneous maintenance dose (e.g., at a dose of 720 mg).
In some embodiments, the treatment comprises intravenous administration of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils at 10mg/kg every two weeks, e.g., for at least 18 months. In some embodiments, the treatment comprises intravenous administration of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, which is then converted to a maintenance dose. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months, and then converting to a maintenance dose. In some embodiments, the subject converts to the maintenance dose without employing an initial step-by-step adjustment step for the maintenance dose. In some embodiments, the subject is converted to a maintenance dose using at least one step adjustment step for the maintenance dose, e.g., the subject's administration dose or frequency may be reduced in multiple steps until a final maintenance dosing regimen is achieved (e.g., step down from a weekly 720mg subcutaneous treatment dosing regimen to a weekly 360mg or biweekly 720mg maintenance dosing regimen via intermediate dosing in an intermediate amount or period of time (e.g., 540mg per week or 720mg per 10 days)). In some embodiments, the maintenance dose of the subject is the same as the dose during the treatment period. In some embodiments, the maintenance dose of the subject is 50% of the dose during the treatment period.
In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a weekly intravenous maintenance dose. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to an intravenous maintenance dose every two weeks. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils at 10mg/kg every two weeks, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a monthly intravenous maintenance dose. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a quarterly intravenous maintenance dose.
In some embodiments, the maintenance dose is administered subcutaneously (e.g., as a subcutaneous injection). In other embodiments, the treatment comprises subcutaneously administering an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils prior to switching to the intravenous maintenance dose. In some embodiments, the treatment comprises intravenous administration of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, which is then converted to a subcutaneous maintenance dose. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a subcutaneous maintenance dose. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a weekly subcutaneous maintenance dose. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months, e.g., until the patient is amyloid negative, and then converting to a 360mg subcutaneous maintenance dose per week. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a 720mg subcutaneous maintenance dose per week. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a subcutaneous maintenance dose of 720mg every two weeks. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a monthly 720mg subcutaneous maintenance dose. In some embodiments, the treatment comprises administering intravenously an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils every two weeks at 10mg/kg, e.g., for at least 18 months or, e.g., until the patient is amyloid negative, and then converting to a subcutaneous maintenance dose of 720mg quarterly.
In some embodiments, the patient will begin a treatment comprising intravenous administration of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils at a dose of 10mg/kg and then switch to a treatment comprising subcutaneous administration of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, e.g., at a dose of 720 mg. In some embodiments, the patient will begin to include a 10mg/kg every two weeks intravenous administration of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, and then switch to a treatment that includes, for example, a 720mg dose of weekly subcutaneous administration of lenkaempferon, for example, for a total of at least 18 months of treatment period or until the patient is amyloid negative. In some embodiments, the patient will begin a treatment comprising intravenous administration of anti-aβ protofibril antibodies or antigen binding fragments thereof capable of binding to human aβ protofibrils at 10mg/kg every two weeks, then switch to a treatment comprising subcutaneous administration of, for example, lenkazinab weekly at a dose of 720mg, then switch to a subcutaneous maintenance dose of 360mg weekly. In some embodiments, the patient will begin to be treated comprising intravenous administration of anti-aβ protofibril antibodies or antigen binding fragments thereof capable of binding to human aβ protofibrils at 10mg/kg every two weeks, then be converted to a treatment comprising subcutaneous administration of, for example, lenkazinab at a dose of 720mg weekly, then be converted to a subcutaneous maintenance dose of 720mg monthly.
In some embodiments, the maintenance dose is administered as a subcutaneous injection of an anti-aβ protofibril antibody or antigen binding fragment thereof (e.g., lenkanesab) capable of binding to human aβ protofibrils. In some embodiments, the maintenance dose is administered subcutaneously weekly as a formulation of an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per week, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per month, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per quarter, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections every two weeks, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per month, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation. In some embodiments, the maintenance dose is administered as 720mg subcutaneous injections per quarter, including two concurrent (e.g., sequential) injections of 360mg (2 x 1.8mL of 400mg/2 mL) subcutaneous formulation.
In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose ranging from 300mg to 800mg or from 400 to 1500 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 300mg to 400 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 400mg to 500 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 400mg to 450 mg. in some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 450mg to 500 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 500mg to 600 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 500mg to 550 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 550mg to 600 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 600mg to 700 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 600mg to 650 mg. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 650mg to 700 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 700mg to 800 mg. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 700mg to 750 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 750mg to 800 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, or 390 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, or 490 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, or 590 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, or 690 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 700mg, 710mg, 720mg, 730mg, 740mg, 750mg, 760mg, 770mg, 780mg, or 790 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 440 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 580 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 720 mg.
In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose ranging from 800mg to 1600 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 800mg to 1000 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 800mg to 900 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 900mg to 1000 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1000mg to 1200 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1000mg to 1100 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1100mg to 1200 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1200mg to 1400 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1200mg to 1300 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1300mg to 1400 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1400mg to 1600 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1400mg to 1500 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1500mg to 1600 mg. In some embodiments, the anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is present at 800mg, 820mg, 840mg, 860mg, 880mg, 900mg, 920mg, 940mg, 960mg, or 960mg. In some embodiments, the anti-aβ protofibrils capable of binding to human aβ protofibrils are administered subcutaneously at a dose of 1000mg, 1020mg, 1040mg, 1060mg, 1080mg, 1100mg, 1120mg, 1140mg, 1160mg, or 1180 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1200mg, 1220mg, 1240mg, 1260mg, 1280mg, 1300mg, 1320mg, 1340mg, 1360mg, or 1380 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1400mg, 1440mg, 1460mg, 1480mg, 1500mg, 1520mg, 1540mg, 1560mg, or 1580 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 880 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1160 mg. In some embodiments, an anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils is administered subcutaneously at a dose of 1440 mg.
Additional exemplary subcutaneous doses, dosing frequencies, maintenance doses, and formulations for subcutaneous administration that may be used in the methods discussed herein are disclosed in international application No. PCT/US 2022/04926, the contents of which are incorporated herein by reference in their entirety.
In some embodiments, the anti-aβ protofibril antibodies or antigen binding fragments thereof used in the methods disclosed herein are delivered by an auto-injector. In some embodiments, the auto-injector delivers the anti-aβ protofibril antibody, or antigen binding fragment thereof, subcutaneously. In some embodiments, the auto-injector delivers an injection volume of 1.1 mL. In some embodiments, the auto-injector delivers an injection volume of 1.4 mL. In some embodiments, the auto-injector delivers an injection volume of 1.8 mL. In some embodiments, the auto-injector delivers about 400-800mg (e.g., 360 mg) of the anti-aβ protofibril antibody, or antigen binding fragment thereof, subcutaneously.
Examples
The disclosure is further illustrated by the following examples, which should not be construed as limiting. The contents of all references, patents and published patent applications cited throughout this application are incorporated herein by reference in their entirety for all purposes.
Example 1: administration of Lekanolamine in combination with E2814 for the treatment of Alzheimer's disease
1.1 Double blind phase dose selection
1.1.1E2814
1500Mg of E2814 (anti-tau antibody or antigen binding fragment thereof) is administered Intravenously (IV) every 4 weeks. Higher dose (3000 mg or 4500 mg) studies can be considered in future protocol revisions based on higher dose safety, PK and TE data.
1.1.2. Lekanepab
The treatment with rankazinab will be administered via intravenous infusion Q2W at a dose of 10 mg/kg.
1.2 Drug-specific study design
This is a placebo-controlled, double-blind phase II/III study of safety, tolerability, biomarkers, cognitive and clinical efficacy for evaluating the therapeutic effect of E2814 alone or in combination with rankazinokamab.
Inclusion criteria included:
● Individuals between 18-80 years of age;
● Individuals who are known to have mutations that cause Alzheimer's disease;
● Within-10 to +10 years of the predicted or actual age of onset of cognitive symptoms;
● Cognitive normal or mild cognitive impairment or mild dementia, clinical dementia assessment (CDR) of 0-1 (inclusive);
● Fluent approved test language and evidence of adequate pre-onset intellectual function;
● Magnetic Resonance Imaging (MRI), lumbar Puncture (LP), positron Emission Tomography (PET) can be performed and all tests and evaluations related to the study are completed.
● For women with fertility, if the partner is not sterile, the participants must agree to use effective contraceptive measures (hormonal contraception, intrauterine contraceptive device, sexual abstinence, barrier methods using spermicides);
● Sufficient visual and auditory capabilities to perform all aspects of cognitive and functional assessment;
● There are study partners that, at the discretion of the researcher, are able to provide accurate information about the subject's cognitive and functional abilities and agree to provide information at study visit, which requires information input to complete the scale.
The exclusion criteria included:
● Currently or during the course of a study, obvious neurological or psychiatric disorders (other than AD) that may affect cognition or affect the ability of the participants to complete the study;
● The risk of suicide is high, for example, there is a clear suicidal ideation or attempt in the last 12 months, and the current stable mild depression or the current use of antidepressants is not precluded;
● Indicating the history or presence of any other clearly abnormal brain MRI scan;
● Substance or alcohol use disorders present or within the last 1 year;
● The presence of pacemakers, aneurysm clips, prosthetic heart valves, ear implants or foreign metal objects in the eye, skin or body would prevent MRI scanning;
● A clinically significant history or presence of cardiovascular disease, liver/kidney disorder, infectious disease or immune disorder or metabolic/endocrine disorder;
● Anticoagulants other than low-dose (325 mg or less) aspirin are being used;
● Monoclonal antibodies directed against amyloid beta peptides were contacted over the past six months;
● A history of cancer has been in the past 5 years, except basal cell carcinoma, non-squamous skin carcinoma, prostate cancer, or carcinoma in situ, which did not progress significantly in the past 2 years;
● Urine or serum pregnancy tests are positive or planned or are intended to be pregnant during the course of the test;
● The subject is unable to complete all study-related tests, including the inability to remove implanted metals for MRI scanning, the need for anticoagulation, and pregnancy.
Approximately 168 participants were blinded to study drug group E2814, with 84 participants in each of the two cohorts. All 168 participants within-10 to +10 years of the estimated years of symptom onset (EYO) will be divided into 2 cohorts according to their baseline (week 0) CDR scores, as follows:
Symptomatic population (cohort 1): at least 84 participants with cdr=0.5-1 (with symptoms of mild cognitive impairment)
Asymptomatic group (cohort 2): at least 84 participants with cdr=0 (cognitive normal)
The participants will randomize with placebo at 1:1 activity E2814 via a minimization algorithm (fig. 1) that includes the following factors when randomized:
1. Clinical dementia assessment-Box Total (CDR-SB; 0,0.5 to 1,1.5 to 3, > 3)
2. Estimated years from onset of symptoms (EYO) (-10 to-5, -4 to-1, 0 to 4,5 to 10)
3. Genotype (APP, PSEN1, PSEN 2)
4. Education years (< 12, 13 to 16, > 16)
5. Age (18 to 40 years, 41 to 55 years, 56 to 80 years)
6. Presence of APOE4 allele (APOE 4 positive, APOE4 negative)
7. Region (U.S./Australia/Canada, europe, and other parts of the world)
8. Study site, and
9. Sex (male, female).
To achieve the following two goals, a minimum randomization algorithm will be employed: 1) Balancing prognostic factors that affect clinical and cognitive progression or non-prognostic factors that may affect clinical and cognitive progression (these factors include baseline CDR-SB, EYO, age at randomization, education age and region), and 2) balancing factors that may affect adverse events or interfere with drug action (these factors include genotype, APOE4 allele and sex).
E2814 or placebo will be administered in parallel with the open label rankazinab as part of the E2814 blinded study drug group. E2814 or placebo will be administered intravenously at a dose of 1500mg every 4 weeks (Q4W) and rankazinab at 10mg/kg every two weeks (Q2W), with each cohort beginning the respective treatment at a different time point, as specified in fig. 2. The participants will continue to receive treatment until all participants who have entered the group receive treatment for at least 4 years (week 210) or exit (common shutdown). Each cohort will begin treatment with E2814 or placebo and with rankazinab for concurrent administration as follows:
Symptomatic group (queue 1)
At week 0, the participants will receive 10mg/kg of the open label rankazinokamamide administered intravenously every two weeks (Q2W) throughout the treatment period.
At week 24, participants will be randomized at a 1:1 ratio to receive Q4W intravenous 1500mg e2814 or placebo in a blinded fashion for the remainder of their treatment period.
Asymptomatic group (queue 2)
At week 0, participants will randomize at a 1:1 ratio to blindly receive either Q4W intravenous 1500mg e2814 or placebo throughout the treatment period.
At week 52, all participants will begin Q2W intravenous administration of 10mg/kg of open label rankanaimab at the rest of their treatment period.
By staggering the administration of each drug in this manner, the effect of the individual rankazinokamamide and E2814 can be evaluated, followed by the evaluation of the drug co-effect.
1.3 Theory of biomarker targets and endpoints based on
According to the pathophysiological evolution of tau in the different phases of DIAD, the primary study endpoint for the symptomatic population (cohort 1) is tau PET, and the key secondary study endpoint for the asymptomatic population (cohort 2) is the cerebrospinal fluid (CSF) phosphorylated tau (pτ 217)/total tau ratio (p- τ 217/total tau ratio).
Following a single infusion of E2814 at 3, 10 and 30mg/kg, a dose-related decrease in free MTBR-tau protein was present, confirming that E2814 was able to reduce MTBR-tau protein levels in CSF. Target conjugation (TE) was estimated using E2814-bound and free MTBR-tau as fraction (%) of bound MTBR-tau relative to total MTBR-tau (free plus bound). These preliminary data indicate that the dose-related increases in TE are about 26%, 45% and 60% (3, 10 and 30mg/kg, respectively) with TE continued until day 29.
1.4 Principal study objectives and endpoints
The primary study endpoint was to determine if E2814 is better than placebo in terms of variation in tau protein diffusion (as measured by tau protein PET) from week 24 to week 104 (phase analysis) and week 208 (end analysis) when each was administered in parallel with rankanab in the symptomatic population (cohort 1).
1.5 Secondary study endpoint
1.5.1 Critical secondary endpoint
The key secondary endpoints are as follows:
symptomatic population (cohort 1): when each was administered in parallel with rankazinab, it was determined whether E2814 was better than placebo in terms of the total sum of clinical dementia rating scale recordings (CDR-SB) change from week 24 to week 208.
Asymptomatic group (cohort 2): when each was administered alone and then concurrently with the rankanolamide, it was determined whether E2814 is superior to placebo in terms of the change in cerebrospinal fluid (CSF) phosphorylating tau protein (p-tau protein 217)/total tau protein from week 0 to week 104 (the mid-period analysis) and week 208 (the final analysis).
1.5.2 Additional secondary endpoints
Additional secondary endpoints of the individual or combined population queues are as follows:
Symptomatic population (cohort 1): 1) When each was administered in parallel with the rankanolamide, it was determined whether E2814 is better than placebo in terms of the change in cognitive composite score from week 24 to weeks 104 and 208; 2) When administered alone, the effect of the rankanolamide mab was evaluated in terms of amyloid PET change from week 0 to week 24; 3) When administered alone or with placebo, it was determined whether the rankanemab was superior to the external control in terms of CDR-SB change from week 0 to week 208; 4) Safety and tolerability of the rankanolamide mab was assessed when administered alone for 24 weeks, including immunogenicity (production of anti-rankanolamide mab); and 5) determining whether E2814 is superior to placebo in terms of changes in CSF neurofilament light chain (NFL) from week 24 to weeks 104 and 208 when each is administered in parallel with the rankanolamab.
Asymptomatic group (cohort 2): 1) When each was administered alone, it was evaluated whether E2814 is better than placebo in terms of CSF p-tau 217/total tau protein change from week 0 to week 52; 2) When each was administered in parallel with the rankanolamab, it was determined whether E2814 is superior to placebo in terms of CSF p-tau 217/total tau change from week 52 to week 104 (interim analysis) and week 208 (final analysis); 3) When administered alone for 52 weeks, the safety and tolerability of E2814 was assessed, including the immunogenicity (production of anti-E2814 antibodies); 4) When each was administered in parallel with rankanolamine, it was determined whether E2814 is superior to placebo in terms of changes in CSF neurofilament light chain (NFL) from week 52 to weeks 104 and 208.
1.6 Exploratory endpoint
The exploratory endpoints of each group cohort in the E2814 group studied were as follows:
Symptomatic population (cohort 1):
evaluation of E2814 effect compared to placebo in terms of the change in CSF p-tau protein 217/total tau protein decreasing from week 24 to week 104 and week 208 when each was administered in parallel with rankanolamab
When administered alone, the effect of rankanemab was evaluated in terms of changes in tau protein PET, CSF and blood biomarkers (amyloid beta [ Ab ]42, ab 40, p-tau, total tau, NFL) from week 0 to week 24
Asymptomatic group (cohort 2):
When each was administered in parallel with rankanolamab, it was evaluated whether E2814 was better than placebo in terms of CSF p-tau 217/total tau change from week 52 to weeks 104 and 208
Evaluation of E2814 effect compared to placebo in terms of change in cognitive composite score from week 52 to weeks 104 and 208 when each was administered in parallel with rankazinab
Evaluation of E2814 effect compared to placebo in terms of a change in decreasing brain tau protein diffusion measured by tau protein PET from week 52 to week 104 and 208 Zhou Ru when each was administered in parallel with Lekanolamab
When administered alone, it was evaluated whether E2814 is superior to placebo in terms of changes from week 0 to week 52 tau PET, CSF biomarkers (NFL and MTBR-tau) and blood biomarkers (p-tau 217/total tau and NFL)
Symptomatic (cohort 1) and asymptomatic (cohort 2):
Evaluation of E2814 effect compared to placebo in terms of CDR-SB changes from week 24 to week 104 (cohort 1) and from week 52 to weeks 104 and week 208 (cohort 2) when each was administered in parallel with rankazinab
When each was administered in parallel with rankanolamab, the effect of E2814 compared with placebo was evaluated in terms of changes in CSF microtubule binding region (MTBR) -tau protein from week 24 to week 104 and week 208 (cohort 1) and from week 52 to week 104 and week 208 (cohort 2)
When each was administered in parallel with rankanolamide, it was evaluated whether E2814 is superior to placebo in terms of changes in plasma NFL from week 24 to week 104 and week 208 (cohort 1) and from week 52 to week 104 and week 208 (cohort 2)
When each was administered in parallel with rankanolamab, it was evaluated whether E2814 was superior to placebo in terms of changes in CSF and blood biomarkers (other than those already listed above) from week 24 to week 104 and week 208 (cohort 1) and from week 52 to week 104 and week 208 (cohort 2) of neurodegeneration, neuroinflammation, amyloid and tau
When each was administered in parallel with the rankanolamide, the effect of E2814 compared to placebo was evaluated in terms of the change in cognitive and functional endpoints from week 24 to week 208 (cohort 1) and from week 52 to week 208 (cohort 2), including the following:
■ Senior depression scale (GDS)
■ Neuropsychiatric questionnaire (NPI-Q)
■ Function evaluation scale (FAS)
■ Simple mental state examination (MMSE)
■ DIAN memory complaint questionnaire (MAC-Q)
■ Buschke and Grober free and clue Selective recall test-immediate recall (FCSRT-IR)
■ Webster memory table revision (WMS-R) logical memory/paragraph memory (immediate and delayed recall), alternate paragraph-version A (immediate and delayed) of logical memories I and II, alternate paragraph-version B (immediate and delayed) of logical memories I and II
■ Fluency in category (animals)
■ Webster adult Intelligence development (WAIS-R) with numeric symbol substitution test
■ Wire test sections A and B
■ Webster memory table revision (WMS-R), forward and backward digital space spans
■ Cognitive dynamic research (ARC), smartphone-based cognitive assessment (grid, price, sign)
When each was administered in parallel with the rankanolamide mab, the effect of E2814 compared to placebo was evaluated in terms of the change in imaging metrics from week 24 to week 104 and week 208 (cohort 1) and from week 52 to week 104 and week 208 (cohort 2), including the following:
■ Amyloid burden based on (11) C-labeled Pittsburgh compound B ([ 11C ] PiB) PET
■ Fluorodeoxyglucose (FDG) -PET metabolism at specific regions of interest (e.g., anterior wedge lobes)
■ Brain atrophy as measured by cortical thickness of the region of interest, including whole brain volume and ventricle volume (volume magnetic resonance imaging [ vMRI ])
■ Functional connection MRI (fc-MRI)
■ Parameters in Diffusion Tensor Imaging (DTI) MRI, including diffusion-based spectral imaging (DBSI)
■ Blood flow measurement by Arterial Spin Labeling (ASL) MRI
■ Assessment of clinical MRI features such as micro-hemorrhage (MCH), white matter high signal (WMH), cerebral infarction and amyloid-related imaging abnormalities (ARIA) using conventional MRI sequences
Evaluation of population Pharmacokinetics (PK) of E2814 in plasma and serum
Evaluation of Rinkanemab in serum population PK
Exploring the relationship of PK (E2814/rankazinab exposure) to Pharmacodynamics (PD) (CSF, blood and imaging biomarkers)
Collecting a Pharmacogenomics (PG) sample for future analysis
1.7 Security target and endpoint
The present study will evaluate the safety and tolerability of treatment with E2814 and rankazinab in individuals with DIAD. Safety endpoints include AE, clinical laboratory results, vital signs, ECG, CSSRS, and physical and neurological examination.
Immunogenicity was assessed for concurrent administration of E2814 and rankaempferide (production of anti-E2814 antibodies and anti-rankaempferide antibodies).
Safety measures related to plasma fibrinogen binding include monitoring functional fibrinogen using the Clauss method.
Safety MRI for monitoring ARIA will also be evaluated.
1.8 Drug specific test
1.8.1 Pharmacokinetic assessment
1.8.1.1E2814 blood PK of Lekanimazethapyr
Blood samples for E2814 (plasma and serum) and rankazinab (serum) PK assessment will be collected prior to dosing, i.e. immediately prior to starting any drug administration at this visit; and post-dose collection at any time 30 minutes after completion of all drug administration at this visit. Based on the assigned queue as described below, blood will collect in the first year and approximately every 26 weeks (about 6 months) until the 4 th year, after which it will collect annually and at the time of safety follow-up. Samples should also be collected if the participants terminate prematurely.
TABLE 1E2814 and Lekananemab blood PK-queue specific collection schedules
Serum and plasma concentrations of E2814 will be measured by validated Electrochemiluminescence (ECL) assay methods.
1.8.1.2E2814 and Lekanolamine mab cerebrospinal fluid (CSF) PK-queue specific collection schedules
CSF samples for E2814 and rankazinab PK assessment will be collected on a distributed queue at the visit specified below via Lumbar Puncture (LP) prior to dosing.
TABLE 2 CSF PK-queue specific collection schedules for E2814 and rankazinab
The CSF concentration of E2814 will be measured by a validated Electrochemiluminescence (ECL) assay method. The CSF concentration of the rankazinab will be measured by validated immunoprecipitation-liquid chromatography-tandem mass spectrometry (IP/LC-MS/MS) methods.
1.8.2 Immunogenicity assessment
Blood samples for immunogenicity will be collected immediately prior to LP at the time of the annual visit to LP and immediately prior to drug administration at all other visits. Immunogenicity will be assessed by measuring the presence of anti-E2814 antibodies and anti-rankaneamide antibodies in serum based on a partitioned cohort as described below, approximately every 26 weeks (approximately 6 months) until year 4 and until premature termination (ET) occurs.
TABLE 3 specific collection schedules for anti-E2814 and anti-rankaneamide antibody queues
For participants with significant immunogenicity at the last collected evaluation (week 208 or ET visit), the evaluation of anti-E2814 antibody or anti-rankaneazumab antibody will continue every 24 weeks until regression (where possible/possible). In addition, clinical measurements (e.g., CRP) can be made to monitor inflammation that may be associated with immunogenicity.
Serum anti-E2814 antibodies were measured by properly validated ECL assay methods. Serum anti-rankanaimab antibodies will use validated Meso Scale(MSD) bridging assay.
1.8.3 Pharmacodynamic and biomarker assessment
Blood samples for plasma Pharmacodynamic (PD) biomarkers will be collected immediately prior to LP at the time of annual visit to LP and immediately prior to drug administration at all other visits. Samples will be collected according to the same schedule for both queues as follows: at year 1, about every 12 weeks, about every 26 weeks (about every 6 months) up to year 4, and thereafter each year, including safety follow-up.
● Year 1: week 0 (V2), week 12 (V5), week 24 (V8), week 36 (V11), week 52 (V15)
● Year 2: week 76 (V21) and week 104 (V28)
● Year 3: week 128 (V34) and week 156 (V41)
● Year 4: week 180 (V47) and week 208 (V54)
● Year 5: week 260 (V67) (if applicable)
● Year 6: week 312 (V80) (if applicable)
● Year 7: week 364 (V93) (if applicable)
● Security follow-up
● Early termination (if applicable)
CSF samples of PD biomarkers will be collected via lumbar puncture prior to dosing at the following visit:
● Week 0 (V2), baseline
● Week 24 (V8) -queue 1 only
● Week 52 (V15)
● Week 104 (V28)
● Week 208 (V54) or ET
● 260 Th week (V67)
● Early termination (if terminated before week 260) (V67)
CSF and blood concentrations of AD related biomarkers (including, but not limited to aβ [1-42], neuroparticulate proteins, neurofilament light chain [ NFL ], MTBR-tau [ bound, free and total ], total tau [ t-tau ], and phosphorylated tau [ p-tau ]) will be measured.
1.8.4 Genomic DNA blood samples for pooling
The pharmacogenomic and biomarker samples obtained from the participants of the present study may be analyzed by global proteomics, metabolomics, or lipidomics, as well as single or multiplex assays, in an attempt to identify predictive biomarkers of PK and PD. In addition, biomarkers identified in other clinical studies can also be evaluated in samples collected from participants enrolled in the study.
Example 2: combination of rankazinab with E2814 for subcutaneous administration for the treatment of Alzheimer's disease
Double blind phase dose selection
E2814: 3000mg of E2814 (anti-tau antibody or antigen binding fragment thereof) is administered Intravenously (IV) every 4 weeks. Higher dose (4500 mg) studies can be considered in future protocol revisions based on higher dose safety, PK and TE data.
Lekanepab: the treatment of the rankanolamide will be administered subcutaneously using two autoinjectors, each delivering 360mg of rankanolamide, with a total dose of 720mg of rankanolamide. The patient will receive two 360mg doses weekly or biweekly.
Symptomatic population (cohort 1): at week 0, the participants will receive 720mg (two consecutive 360mg doses delivered using an auto-injector throughout the treatment period) of open label rankazinab administered subcutaneously.
At week 24, participants will be randomized at a 1:1 ratio to receive Q4W intravenous 3000mg E2814 or placebo in a blinded fashion for the remainder of their treatment period.
Asymptomatic group (cohort 2): at week 0, participants will randomize at a 1:1 ratio to blindly receive either Q4W intravenous 3000mg e2814 or placebo throughout the treatment period.
At week 52, all participants will begin to receive 720mg (two consecutive 360mg doses delivered using an auto-injector during the rest of their treatment period) of open label rankaspiumab administered subcutaneously.
Examples
Example 1: lemcanemab background anti-amyloid therapies in next generation clinical trials evaluating tau-targeting research therapies for dominant inherited Alzheimer's disease (tau NexGen trial)
People with mutations in the gene of DIAD are known to develop AD and are likely to develop symptoms at about the same age as their parents develop symptoms, typically at their ages of 50, 40 or even 30. The purpose of the tau NexGen assay is to assess the safety, tolerability, biomarkers and cognitive efficacy of the study therapy in humans with gene mutations that cause Alzheimer's disease. This test will evaluate whether treatment with the study drug would slow down the rate of progression of cognitive impairment and improve disease-related biomarkers.
In the modified tau NexGen trial, symptomatic participants would be administered with lenKanesab for six months and then randomized to receive E2814 or placebo. Since amyloid plaques accumulate prior to tau entanglement in AD, this experimental design allows researchers to assess whether amyloid removal has cleared the way for anti-tau drugs to function most effectively. Pre-symptomatic participants will be randomized to receive either anti-tau drug E2814 or placebo for one year, followed by onset of administration of the rankanaissance. Interleaving the drugs in this way will allow the effect of the anti-tau drug to be assessed separately and then the effect of the two drugs together. The rankazinab will be administered at a dose of 10mg/kg every two weeks, which does not require stepwise adjustment of dosing, and the incidence of amyloid-related image abnormalities is 9.9% with less than 2% of people having symptoms. The primary endpoint was a slowing of tau accumulation in the brain of symptomatic participants (as a function of the addition of E2814), as seen by PET brain scans. The secondary endpoint will be the effect on the levels of a specific type of tau protein (phosphorylated tau protein 217) in the cerebrospinal fluid (CSF) of the symptomatic participants (effect of E2814 alone or in combination with rankanesab). If these primary and secondary endpoints are reached in the assay two years after the start of the trial, the trial will be extended two more years to assess whether the drug slows cognitive decline and has a further impact on tau pathology.
Selected sequences
TABLE 11 amino acid sequences of mAb CDRs
TABLE 12 amino acid sequences of mAb variable regions
TABLE 13 amino acid sequence of mAb constant regions
TABLE 14 amino acid sequences of biomarkers
Claims (66)
1. A method for treating or preventing alzheimer's disease in a subject in need thereof, the method comprising administering to the subject:
(i) An isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 13, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 14, and
(Ii) An anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau protein, the anti-tau antibody or antigen-binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 15, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 16,
Wherein the anti-aβ protofibril antibody or fragment thereof is administered in combination (e.g., simultaneously or sequentially) with the anti-tau antibody or fragment thereof.
2. The method of claim 1, wherein the isolated anti-aβ protofibril antibody or fragment thereof comprises
(I) A heavy chain comprising the amino acid sequence of SEQ ID NO. 17, and
(Ii) A light chain comprising the amino acid sequence of SEQ ID NO. 18.
3. The method of any one of claims 1 or 2, wherein the anti-tau antibody or fragment thereof comprises
(I) A heavy chain comprising the amino acid sequence of SEQ ID NO. 19, and
(Ii) A light chain comprising the amino acid sequence of SEQ ID NO. 20.
4. The method of any one of claims 1-3, wherein the isolated anti-aβ protofibril antibody or fragment thereof is administered once weekly or once every two weeks.
5. The method of any one of claims 1-4, wherein the isolated anti-aβ protofibril antibody or fragment thereof is administered intravenously, e.g., at a dose of 5mg/kg to 20mg/kg (e.g., 10 mg/kg).
6. The method of any one of claims 1-5, wherein the isolated anti-aβ protofibril antibody or fragment thereof is administered intravenously at a dose of 10mg/kg every two weeks, e.g., for at least 52 weeks.
7. The method of any one of claims 1-4, wherein the isolated anti-aβ protofibril antibody or fragment thereof is administered subcutaneously, e.g., in a weekly manner, comprising two consecutive subcutaneous injections, e.g., 360mg, of the isolated anti-aβ protofibril antibody or fragment thereof, for a total dose of 720mg, e.g., for at least 52 weeks.
8. The method of any one of claims 1-4 or 7, wherein the isolated anti-aβ protofibril antibody or fragment thereof is administered subcutaneously for a period of time, e.g., at least 52 weeks or 18 months, followed by administration of a maintenance dose.
9. The method of claim 8, wherein the maintenance dose comprises administering 720mg subcutaneously weekly or biweekly.
10. The method of claim 8, wherein the maintenance dose comprises intravenous administration of 10mg/kg once every two weeks, once every four weeks, or once every twelve weeks.
11. The method of any one of claims 1-10, wherein the anti-tau antibody or fragment thereof is administered once every four weeks.
12. The method of any one of claims 1-11, wherein the anti-tau antibody or fragment thereof is administered in an amount of 1000-4500mg (e.g., 1500, 3000, 4500 mg) once every four weeks.
13. The method of any one of claims 1-12, wherein the anti-tau antibody or fragment thereof is administered in an amount of 1500mg once every four weeks.
14. The method of claims 1-12, wherein the anti-tau antibody or fragment thereof is administered in an amount of 3000mg once every four weeks.
15. The method of any one of claims 1-11, wherein the anti-tau protein antibody or fragment thereof is administered at a dose of 3, 10 or 30mg/kg once every four weeks.
16. The method of any one of claims 1-15, wherein the anti-tau antibody or fragment thereof is administered intravenously.
17. The method of any one of claims 1-16, wherein the anti-aβ protofibril antibody or fragment thereof is administered prior to initiating treatment with the anti-tau antibody or fragment thereof.
18. The method of any one of claims 1-17, wherein the anti-aβ protofibril antibody or fragment thereof is administered for at least 10 weeks (e.g., at least 15, 20, 24, or 25 weeks) before treatment with the anti-tau antibody or fragment thereof begins.
19. The method of claim 17 or 18, wherein the subject has symptoms of alzheimer's disease.
20. The method of claim 19, wherein the subject has early-onset alzheimer's disease.
21. The method of claim 16, wherein the anti-tau antibody or fragment thereof is administered alone for 52 weeks before commencing combination therapy with the anti-tau antibody or fragment thereof and the anti-aβ protofibril antibody or fragment thereof.
22. The method of any one of claims 1-16, wherein the anti-tau antibody or fragment thereof is administered prior to commencing treatment with the anti-aβ protofibril antibody or fragment thereof.
23. The method of any one of claims 1-16, wherein the anti-tau antibody or fragment thereof is administered for at least 25 weeks (e.g., at least 30, 40, 50, or 52 weeks) prior to administration of the anti-aβ protofibril antibody or fragment thereof.
24. The method of claim 22 or 23, wherein the subject is free of symptoms of alzheimer's disease.
25. The method of any one of claims 1-24, wherein the subject has a dominant inherited gene mutation of alzheimer's disease, e.g., wherein the subject has a gene mutation in at least one of three genes-PSEN 1, PSEN2, or APP.
26. The method of claim 25, wherein the subject has a mutation in APP.
27. The method of any one of claims 1-26, wherein the subject has a family history of alzheimer's disease, e.g., family members were diagnosed with a medical history of alzheimer's disease before 60 years of age.
28. The method of any one of claims 1-27, wherein tau protein diffusion, e.g., as measured by tau protein PET (e.g., MK-6240 tau protein-PET) and/or MRI, is reduced after administration compared to untreated control subjects.
29. The method of any one of claims 1-28, wherein the level of phosphorylated tau protein 217 in a sample (e.g., cerebrospinal fluid or blood sample) taken from the subject after administration is reduced relative to the level of phosphorylated tau protein 217 in a sample taken from the subject prior to administration.
30. The method of any one of claims 1-29, wherein the subject's clinical dementia rating scale score sum score is improved after administration relative to the subject's score prior to administration.
31. The method of any one of claims 1-30, wherein the subject has improved ADAS-cog (alzheimer's disease assessment scale-cognition sub-scale), MMSE (simple mental state assessment), and/or clinical dementia assessment (CDR) scores after administration relative to scores prior to administration.
32. The method of any one of claims 1-31, wherein the ratio of aβ42/40 in a sample (e.g., a blood sample, such as a plasma sample, or CSF sample) collected from the subject after administration is increased relative to the ratio in a sample collected from the subject prior to administration.
33. The method of any one of claims 1-32, wherein the level of aβ protofibrils in the subject after administration is reduced compared to the level of aβ protofibrils in the subject prior to administration and/or compared to an untreated control or subject, e.g., as measured by PET (e.g., FDG-PET) and/or MRI.
34. A kit, the kit comprising:
(i) An isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 13, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 14, and
(Ii) An anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau protein, the anti-tau antibody or antigen-binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 15, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 16.
35. The kit of claim 34, wherein the anti-aβ protofibril antibody or fragment thereof is present in an amount suitable for intravenous administration at a dose of 10mg/kg or suitable for subcutaneous administration of two consecutive 360mg doses, the total dose being 720mg, and the anti-tau protein antibody or fragment thereof is present in an amount suitable for administration at a dose of 1500 or 3000 mg.
36. The kit of any one of claims 34 or 35, wherein the anti-aβ protofibril antibody or fragment thereof is present in an amount suitable for subcutaneous administration of two consecutive 360mg doses, a total dose of 720mg, and the anti-tau protein antibody or fragment thereof is present in an amount suitable for administration at a dose of 3000 mg.
37. The kit of any one of claims 34-36, wherein the anti-aβ protofibril antibody or fragment thereof and the anti-tau antibody or antigen binding fragment thereof are formulated in separate containers within the kit.
38. The kit of any one of claims 34-37, wherein the isolated anti-aβ protofibril antibody, or fragment thereof, comprises
(I) A heavy chain comprising the amino acid sequence of SEQ ID NO. 17, and
(Ii) A light chain comprising the amino acid sequence of SEQ ID NO. 18.
39. The kit of any one of claims 34-38, wherein the anti-tau antibody or fragment thereof comprises
(I) A heavy chain comprising the amino acid sequence of SEQ ID NO. 19, and
(Ii) A light chain comprising the amino acid sequence of SEQ ID NO. 20.
40. A pharmaceutical combination comprising:
(i) An isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 13, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 14, and
(Ii) An anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau protein, the anti-tau antibody or antigen-binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 15, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 16.
41. The pharmaceutical combination of claim 40, wherein the anti-aβ protofibril antibody or fragment thereof is present in an amount suitable for intravenous administration at a dose of 10mg/kg or suitable for subcutaneous administration at a dose of 720mg and the anti-tau protein antibody or fragment thereof is present in an amount suitable for administration at a dose of 1500 or 3000 mg.
42. Use of an anti-aβ protofibril antibody or fragment thereof and an anti-tau antibody or fragment thereof for the treatment or prevention of alzheimer's disease, wherein:
(i) An isolated anti-aβ protofibril antibody or antigen binding fragment thereof capable of binding to human aβ protofibrils, the isolated anti-aβ protofibril antibody or antigen binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 13, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 14, and
(Ii) An anti-tau antibody or antigen-binding fragment thereof capable of binding to human tau protein, the anti-tau antibody or antigen-binding fragment thereof comprising
(A) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO. 15, and
(B) A light chain variable domain comprising the amino acid sequence of SEQ ID NO. 16.
43. The use of claim 42, wherein the anti-aβ protofibril antibody or fragment thereof is present in an amount suitable for intravenous administration at a dose of 10mg/kg or suitable for subcutaneous administration at a dose of 720mg and the anti-tau protein antibody or fragment thereof is present in an amount suitable for intravenous administration at a dose of 1500 or 3000 mg.
44. The use according to any one of claims 42 or 43 for the treatment or prevention of early-onset alzheimer's disease in a subject.
45. The use of any one of claims 42-44, wherein the isolated anti-aβ protofibril antibody or fragment thereof is administered once weekly or once every two weeks.
46. The use of any one of claims 42-45, wherein the isolated anti-aβ protofibril antibody or fragment thereof is administered intravenously at a dose of 10 mg/kg.
47. The use of any one of claims 42-45, wherein the isolated anti-aβ protofibril antibody or fragment thereof is administered subcutaneously in two consecutive 360mg doses, a total dose of 720mg.
48. The use of any one of claims 42-47, wherein the anti-tau antibody or fragment thereof is administered once every four weeks.
49. The use of any one of claims 42-48, wherein the anti-tau protein antibody or fragment thereof is administered intravenously every four weeks at a dose of 1500 or 3000 mg.
50. The use of any one of claims 42-49, wherein the anti-tau protein antibody or fragment thereof is administered intravenously at a dose of 3000mg every four weeks.
51. The use of any one of claims 42-48, wherein the anti-tau protein antibody or fragment thereof is administered intravenously every four weeks at a dose of 3, 10, or 30 mg/kg.
52. The use of any one of claims 42-51, wherein the anti-aβ protofibril antibody or fragment thereof is administered prior to initiation of treatment with the anti-tau antibody or fragment thereof.
53. The use of any one of claims 42-52, wherein the anti-aβ protofibril antibody or fragment thereof is administered for at least 10 weeks (e.g., at least 15, 20, 24, or 25 weeks) before treatment with the anti-tau antibody or fragment thereof begins.
54. The use of any one of claims 42-53, wherein the anti-tau antibody or fragment thereof is administered alone for 52 weeks before commencing combination therapy with the anti-tau antibody or fragment thereof and the anti-aβ protofibril antibody or fragment thereof.
55. The use of any one of claims 42-51, wherein the anti-tau antibody or fragment thereof is administered prior to onset of treatment with the anti-aβ protofibril antibody or fragment thereof.
56. The use of any one of claims 42-51 or 55, wherein the anti-tau antibody or fragment thereof is administered for at least 25 weeks (e.g., at least 30, 40, 50 or 52 weeks) prior to administration of the anti-aβ protofibril antibody or fragment thereof.
57. The use of any one of claims 42-56, wherein the subject has a dominant inherited gene mutation of alzheimer's disease, e.g., wherein the subject has a gene mutation in at least one of the three genes PSEN1, PSEN2 or APP.
58. The use of any one of claims 42-57, wherein the subject has a family history of alzheimer's disease, e.g., family members were diagnosed with a medical history of alzheimer's disease before 60 years of age.
59. The use of any one of claims 42-58, wherein tau protein diffusion, e.g., as measured by tau protein PET (e.g., MK-6240 tau protein-PET) and/or MRI, is reduced after administration compared to untreated control subjects.
60. The use of any one of claims 42-59, wherein the level of phosphorylated tau protein 217 in a sample (e.g., cerebrospinal fluid or blood sample) taken from the subject after administration is reduced relative to the level of phosphorylated tau protein 217 in a sample taken from the subject prior to administration.
61. The use of any one of claims 42-60, wherein the subject's clinical dementia rating scale score sum score is improved after administration relative to the subject's score prior to administration.
62. The use of any one of claims 42-61, wherein the subject has improved ADAS-cog (alzheimer's disease assessment scale-cognition sub-scale), MMSE (simple mental state assessment) and/or clinical dementia assessment (CDR) scores after administration relative to scores prior to administration.
63. The use of any one of claims 42-62, wherein the ratio of aβ42/40 in a sample (e.g., a blood sample, such as a plasma sample, or CSF sample) collected from the subject after administration is increased relative to the ratio in a sample collected from the subject prior to administration.
64. The use of any one of claims 42-63, wherein the level of aβ protofibrils in the subject after administration is reduced compared to the level of aβ protofibrils in the subject prior to administration and/or compared to an untreated control or subject, e.g., as measured by PET (e.g., FDG-PET) and/or MRI.
65. The use of any one of claims 42-64, wherein the isolated anti-aβ protofibril antibody or fragment thereof comprises
(I) A heavy chain comprising the amino acid sequence of SEQ ID NO. 17, and
(Ii) A light chain comprising the amino acid sequence of SEQ ID NO. 18.
66. The use of any one of claims 42-65, wherein the anti-tau antibody or fragment thereof comprises
(I) A heavy chain comprising the amino acid sequence of SEQ ID NO. 19, and
(Ii) A light chain comprising the amino acid sequence of SEQ ID NO. 20.
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| US202163291315P | 2021-12-17 | 2021-12-17 | |
| IBPCT/IB2021/000937 | 2021-12-17 | ||
| US63/291,315 | 2021-12-17 | ||
| PCT/US2022/079509 WO2023114586A1 (en) | 2021-12-17 | 2022-11-08 | Methods of using an anti-amyloid beta protofibril antibody and anti-tau antibody |
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