Methods for treating alzheimer's disease

Abstract

A method for treatment of a human subject for Alzheimer's disease (AD) comprises sequentially administering two or more doses of a recombinant, fully human, anti-amyloid beta monoclonal antibody to the human subject. In preferred embodiments, the antibody is administered subcutaneously in tissue near or at an abdomen of a human subject in increasing amounts over a period of time.

Description

METHODS FOR TREATING ALZHEIMER’S DISEASECROSS-REFERENCE

[0001] This application claims the benefit of priority from U.S. Provisional Application Nos. 63 / 539,897, filed September 22, 2023, and 63 / 651,787, filed May 24, 2024, each of which is incorporated by reference in its entirety.SEQUENCE LISTING

[0002] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14727-025-228_SEQ_LISTING.xml”, was created on September 19, 2024, and is 13,568 bytes in size.BACKGROUND

[0003] Alzheimer’s disease (AD) is a progressive neurodegenerative disorder clinically characterized by cognitive impairment, behavioral disturbances, psychiatric symptoms, and disability in activities of daily living. These clinical manifestations constitute AD dementia.

[0004] Alzheimer’s disease International estimates that the number of people living with dementia worldwide will increase from the current value of 47 million to 131 million by 2050. Being the most common cause of dementia, AD accounts for 60 to 80% of dementia cases. In the United States, it is estimated that 5.2 million Americans suffer from dementia caused by AD, and that by 2050 the prevalence will double or triple unless an effective treatment is found.

[0005] Thus, there exists an ongoing need for methods to treat AD patients.SUMMARY

[0006] Among other things, the present disclosure provides methods of treating Alzheimer’s disease (AD) not previously recognized and / or underappreciated in the art. In particular, the present disclosure provides an insight that an anti-beta amyloid (AP) monoclonal antibody or an A -binding fragment thereof administered subcutaneously near or at an abdomen of a subject may confer a comparable safety and / or tolerability profile as compared to the same anti -betaamyloid (AP) monoclonal antibody or an A -binding fragment thereof administered intravenously.

[0007] In some embodiments, disclosed methods include, in part, sequentially administering to a human subject two or more doses of a recombinant, fully human, anti -beta amyloid (AP) monoclonal antibody or an Ap-binding fragment thereof and the two or more doses are each administered subcutaneously near or at an abdomen of the human subject. In some embodiments, the two or more doses are administered in the lower abdomen quadrant of the human subject.

[0008] In some embodiments, sequential administration of an antibody or Ap-binding fragment thereof is performed using an auto-injector. In some embodiments, the auto-injector includes a syringe. In some embodiments, the syringe includes a finger flange, plunger rod, and a passive add-on needle guard. In some embodiments, the auto-injector further includes a mechanical spring.

[0009] The present disclosure describes, among other things, a dosing regimen comprising sequential administration of increasing doses of an anti-beta amyloid (AP) antibody or an AP- binding fragment thereof to treat AD. In some embodiments a dosing regimen includes: (A) administering 4 doses of an anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof to a human subject in an amount of about 70 mg about 2 weeks apart over about 8 weeks, (B) 2 weeks after step (A), administering 4 doses to the human subject in an amount of about 210 mg about 2 weeks apart over about 8 weeks, (C) 2 weeks after step (B), administering 4 doses to the human subject in an amount of about 420 mg about 2 weeks apart over about 8 weeks, and (D) 2 weeks after step (C), administering 4 doses to the human subject in an amount of about 700 mg about 2 weeks apart over about 26 weeks. In some embodiments, 26 total doses are administered about 2 weeks apart over about 50 weeks. In some embodiments, the dosing regimen further includes administering the antibody or Ap-binding fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.

[0010] The present disclosure describes, among other things, a method comprising sequential subcutaneous administration of increasing doses of an anti-beta amyloid (AP) antibody or an Ap- binding fragment thereof to treat AD. In some embodiments, the method of sequentially administering the anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof subcutaneously to the human subject to treat AD comprises administering a dose of a first dosage of about 70 mg, a dose of a second dosage of about 210 mg, a dose of a third dosage of about420 mg, and a dose of a fourth dosage of about 700 mg, of said anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof to said human subject. In some embodiments, the subcutaneously, sequentially administered doses are administered about two weeks apart. In some embodiments, the method disclosed herein comprises: (A) subcutaneously administering 4 doses of an anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof to a human subject in an amount of about 70 mg about 2 weeks apart over about 8 weeks, (B) after step (A), subcutaneously administering 4 doses to the human subject in an amount of about 210 mg about 2 weeks apart over about 8 weeks, (C) after step (B), subcutaneously administering 4 doses to the human subject in an amount of about 420 mg about 2 weeks apart over about 8 weeks, and (D) after step (C), subcutaneously administering 14 doses to the human subject in an amount of about 700 mg about 2 weeks apart over about 26 weeks. In some embodiments, 26 total doses are administered about 2 weeks apart over about 50 weeks. In some embodiments, the dosing regimen further includes subcutaneously administering the antibody or Ap-binding fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.

[0011] In some embodiments, the methods disclosed herein comprise sequentially administering the two or more doses subcutaneously, said method comprising (A) administering one or more doses of a first dosage, wherein each dose of the first dosage is administered about 2 weeks apart; (B) following step (A), administering one or more doses of a second dosage, wherein each dose of the second dosage is administered about 2 weeks apart; (C) following step (B), administering one or more doses of a third dosage, wherein each dose of the third dosage is administered about 2 weeks apart; and (D) following step (C), administering a plurality of doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart.

[0012] In some embodiments, the methods disclosed herein comprise sequentially administering the two or more doses subcutaneously, said method comprising (A) administering 4 doses of a first dosage, wherein each dose of the first dosage is administered about 2 weeks apart over a total of about 8 weeks; (B) following step (A), administering 4 doses of a second dosage, wherein each dose of the second dosage is administered about 2 weeks apart over a total of about 8 weeks; (C) following step (B), administering 4 doses of a third dosage, wherein each dose of the third dosage is administered about 2 weeks apart over a total of about 8 weeks; and (D) following step (C), administering 14 doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart over a total of about 28 weeks. In someembodiments, said method comprises administering 26 total doses with each dose administered about 2 weeks apart over a total of about 52 weeks. In some embodiments, step (D) comprises: following step (C), administering 27 doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart over a total of about 54 weeks. In some embodiments, said method comprises administering 39 total doses with each dose administered about 2 weeks apart over a total of about 78 weeks.

[0013] In some embodiments, the first dosage is about 70 mg. In some embodiments, the second dosage is about 210 mg. In some embodiments, the third dosage is about 420 mg. In some embodiments, the fourth dosage is about 700 mg.

[0014] In some embodiments, the methods disclosed herein comprise sequentially administering the two or more doses subcutaneously according to the regimen shown in FIG. 10.

[0015] In some embodiments, the dosing regimen of sequentially administering the anti -beta amyloid (A|3) antibody or an Ap-binding fragment thereof subcutaneously to the human subject to treat AD comprises administering a dose of about 210 mg, a dose of about 420 mg, and a dose of about 700 mg, of said anti-beta amyloid (Ap) antibody or an Ap-binding fragment thereof to said human subject. In some embodiments, the method is exclusive of administering a dose of about 70 mg. In some embodiments, each of the two or more subcutaneously, sequentially administered doses is administered about two weeks apart. In some embodiments, the method of sequentially administering the two or more doses of the antibody or Ap-binding fragment thereof disclosed herein subcutaneously comprises: (A) administering one or more doses of about 210 mg of the antibody or Ap-binding fragment thereof, wherein each dose is administered about 2 weeks apart; (B) following step (A), administering one or more doses of about 420 mg of the antibody or Ap-binding fragment thereof, wherein each dose is administered about 2 weeks apart; and (C) following step (B), administering a plurality of doses of about 700 mg of the antibody or Ap-binding fragment thereof, wherein each dose is administered about 2 weeks apart.

[0016] In some embodiments, according to the methods disclosed herein, the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously comprises a titration phase and a target phase. In some embodiments, the titration phase is followed by the target phase. In some embodiments, the method of sequentially administering the two or more doses of the antibody or Ap-binding fragment thereof disclosedherein subcutaneously comprises: (A) a titration phase, comprising: (i) administering one or more doses of a first titration dosage, wherein each dose of the first titration dosage is administered about 2 weeks apart; (ii) following step (A)(i), administering one or more doses of a second titration dosage, wherein each dose of the second titration dosage is administered about 2 weeks apart; and (B) following step (A)(ii), a target phase, comprising administering a plurality of doses of a target dosage, wherein each dose of the target dosage is administered about 2 weeks apart during the target phase. In some embodiments, the first titration dosage is about 210 mg. In some embodiments, the second titration dosage is about 420 mg. In some embodiments, the target dosage is about 700 mg. In some embodiments, the method of sequentially administering the two or more doses subcutaneously is exclusive of administering a dose of about 70 mg.

[0017] In some embodiments, according to the methods disclosed herein, the method of sequentially administering the two or more doses of the antibody or AP-binding fragment thereof disclosed herein subcutaneously comprises: (A) a titration phase, comprising: (i) administering 4 doses of a first titration dosage, wherein each dose of the first titration dosage is administered about 2 weeks apart over a total of about 8 weeks; (ii) following step (A)(i), administering 4 doses of a second titration dosage, wherein each dose of the second titration dosage is administered about 2 weeks apart over a total of about 8 weeks; and (B) following step (A)(ii), a target phase, comprising administering 31 doses of a target dosage, wherein each dose of the target dosage is administered about 2 weeks apart over a total of about 62 weeks during the target phase. In some embodiments, 39 total doses are administered with each dose administered about 2 weeks apart over a total of about 78 weeks. In some embodiments, the first titration dosage is about 210 mg. In some embodiments, the second titration dosage is about 420 mg. In some embodiments, the target dosage is about 700 mg. In some embodiments, the method of sequentially administering the two or more doses subcutaneously is exclusive of administering a dose of about 70 mg.

[0018] In some embodiments, according to the methods disclosed herein, the method comprises: a multiple dosage regimen administered to a human subject comprising, (A) administering 4 doses of a recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody or an AP-binding fragment thereof to the human subject in an amount of 210 mg about 2 weeks apart over about 8 weeks; (B) following step (A), administering 4 doses to the human subject in an amount of 420 mg about 2 weeks apart over about 8 weeks; and (C) following step(B), administering 31 doses to the human subject in an amount of 700 mg about 2 weeks apart over about 62 weeks; wherein 39 total doses are administered about 2 weeks apart over about 78 weeks, wherein the doses are each administered subcutaneously near or at an abdomen of the human subject; wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL); and wherein the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the method further comprises administering the antibody or AP-binding fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.

[0019] In some embodiments, according to the methods disclosed herein, the method of sequentially administering the two or more doses of said antibody or AP-binding fragment thereof subcutaneously is according to the regimen of FIG. 11 A.

[0020] In some embodiments, according to the methods disclosed herein, the method of sequentially administering the two or more doses of said antibody or AP-binding fragment thereof subcutaneously is according to the regimen of FIG. 1 IB.

[0021] The present disclosure describes, among other things, assessing a human subject following administration of an anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof. In some embodiments, a human subject is evaluated 18 weeks after a last dose. In some embodiments, an evaluation includes a drug and / or patient safety assessment. In some embodiments, an assessment includes a MRI.

[0022] In some embodiments, an antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), and the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth inSEQ ID NO: 8. In some embodiments, an antibody or A0-binding fragment thereof includes a human IgGl constant region. In some embodiments, an antibody or Ap-binding fragment thereof includes a heavy chain variable region (VH) and a light chain variable region (VL). In some embodiments, an antibody or Ap-binding fragment thereof includes a heavy chain variable region (VH) with the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) with the amino acid sequence set forth in SEQ ID NO: 2.

[0023] In some embodiments, two or more doses of the antibody or Ap-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates one or more similar pharmacokinetic / pharmacodynamics (PK / PD) parameter (s) as compared to the same antibody or Ap-binding fragment thereof when a single weight-based dose of the antibody or fragment thereof is administered. In some embodiments, a 700 mg dose of the antibody or Ap-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates one or more similar pharmacokinetic / pharmacodynamics (PK / PD) parameter as compared to the same antibody or Ap-binding fragment thereof when 10 mg / kg of the antibody or fragment thereof is administered. In some embodiments, one or more PK / PD parameter may include a measure of AUCinf, AUClast, AUC0-4wk, Cmax, Tmax, T! / 2, Vd, CL, anti-drug-antibodies (AD As), and / or adverse effects (e.g., headaches, injection site erythema, injection site reaction, injection site pruritus, and / or nausea).

[0024] In some embodiments, the subject treated according to the methods disclosed herein has a reduced number of incidences and / or a reduction in severity of one or more adverse events relative to a human subject after receiving doses of said anti -beta amyloid (AP) monoclonal antibody or said Ap-binding fragment thereof intravenously. In some embodiments, the human subject has a reduction in incidences of headaches and / or a reduction in severity of headaches after receiving the two or more doses subcutaneously of the anti-beta amyloid (AP) monoclonal antibody or the Ap-binding fragment thereof as compared to a human subject after receiving doses of said anti-beta amyloid (AP) monoclonal antibody or said Ap-binding fragment thereof intravenously.

[0025] In some embodiments, according to the methods disclosed herein, a low or minimal number of subjects treated with the subcutaneously administered anti-beta amyloid (AP) monoclonal antibody or Ap-binding fragment thereof develop a treatment-emergent antibodyagainst the subcutaneously administered anti -beta amyloid (A0) monoclonal antibody or the A0- binding fragment thereof. In some embodiments, according to the methods disclosed herein, the subject treated with the subcutaneously administered anti-beta amyloid (AP) monoclonal antibody or Ap-binding fragment thereof does not develop a treatment-emergent antibody against the subcutaneously administered anti-beta amyloid (AP) monoclonal antibody or the Ap- binding fragment thereof.

[0026] In some embodiment, a human subject is an ApoE4 carrier. In some embodiments, a human subject is not an ApoE4 carrier.

[0027] In some embodiments, method described herein may reduce susceptibility to amyloid related imaging abnormalities (ARIA) as compared to a reference. In some embodiments, method described herein may reduce susceptibility to vasogenic edema (VE) as compared to a reference. In some embodiments, method described herein may reduce susceptibility to cerebral microhemorrhages (mH) as compared to a reference. In some embodiments, an applicable reference is a historical reference. In some embodiments, a reference is a healthy human subject. In some embodiments, a reference comprises data from the human subject prior to treatment.

[0028] In some embodiments, methods described herein are a method for completely and / or partially preventing AD and / or symptoms thereof in the human subject. In some embodiments, methods described herein are a method for partially and / or completely curing AD and / or symptoms attributed to AD in the human subject. In some embodiments, according to the methods disclosed herein, the method is a method for treatment of a human patient for Alzheimer’s disease (AD).

[0029] In some embodiments, according to the methods disclosed herein, the method administers the recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody. In some embodiments, the recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody is aducanumab. In some embodiments, the method administers the Ap-binding fragment of said recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody. In some embodiments, the Ap-binding fragment of said recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody is Ap-binding fragment of aducanumab.

[0030] In some embodiments, the present disclosure provides for kits. In some embodiments, a kit includes an auto-injector and instruction for use. In some embodiments,an auto-injector includes at least one dose of a composition comprising an anti-beta amyloid (AP) monoclonal antibody or an A -binding fragment thereof. In some embodiments, an antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL). In some embodiments, an antibody or Ap-binding fragment thereof includes a human IgGl constant region. In some embodiments, an antibody or Ap- binding fragment thereof includes a heavy chain variable region (VH) and a light chain variable region (VL). In some embodiments, an antibody or Ap-binding fragment thereof includes a heavy chain variable region (VH) with the amino acid sequence set forth in SEQ ID NO: 1 and a light chain variable region (VL) with the amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody included in the kit is aducanumab. In some embodiments, the Ap-binding fragment of said recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody included in the kit is the Ap-binding fragment of aducanumab.

[0031] These and other features and advantages provided in the present disclosure will be more fully understood from the following detailed description taken together with the accompanying claims. It is noted that the scope of the claims is defined by the recitations therein and not by the specific discussion of features and advantages set forth in the present description.BRIEF DESCRIPTION OF THE DRAWING

[0032] FIG. 1 depicts an exemplary study design.

[0033] FIG. 2 shows an exemplary schematic of participants in the study.

[0034] FIG. 3 shows an exemplary pharmacokinetic (PK) analysis of arithmetic mean (±SE) serum concentration profiles for aducanumab.

[0035] FIG. 4 shows exemplary summary statistics of tested PK parameters.

[0036] FIG. 5 shows a comparison of exemplary PK parameters.

[0037] FIG. 6 shows exemplary safety results.

[0038] FIG. 7 shows exemplary safety and tolerability results.

[0039] FIG. 8 shows exemplary immunogenicity results.

[0040] FIGS. 9A-9C shows exemplary PK scatter plots by route and baseline weight: FIG.9A shows an exemplary scatter plot of AUCinf versus baseline weight; FIG. 9B shows an exemplary scatter plot of Cmax versus baseline weight; and FIG. 9C shows an exemplary scatterplot of Clearance versus baseline weight.

[0041] FIG. 10 depicts an exemplary dosing and assessment schedule.

[0042] FIG. 11A depicts an exemplary dosing scheme (Dosing Scheme 1); and FIG. 11B depicts an exemplary dosing scheme (Dosing Scheme 2).DETAILED DESCRIPTIONCertain Definitions

[0043] As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0044] Additionally, singular forms “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a method” includes one or more methods, and / or steps of the type described herein and / or which will become apparent to those persons skilled in the art upon reading this disclosure.

[0045] The term “about” or “approximately” includes being within a meaningful range of a value. The allowable variation encompassed by the term “about” or “approximately” depends on the particular system under study, and can be readily appreciated by one of ordinary skill in the art. For example, as used herein and unless otherwise specified, the terms “about” and “approximately,” when used in connection with a numeric value or a range of values which is provided to characterize a particular dose amount, such as, for example, a dose amount in terms of mg; a time period, such as, for example, a time period in terms of days, weeks, months, or years; or a score to evaluate a disease state level of a patient, for example, an MMSE score of an AD patient; indicate that the value or range of values may deviate to an extent deemed reasonable to one of ordinary skill in the art while still describing the particular dose amount, time period, or patient score, respectively. For example, in particular embodiments, the terms “about” and “approximately,” when used in this context, indicate that the numeric value or range of values may vary within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, or 0.25% of the recited value or range of values.

[0046] As used herein, the term “administering” or “administration” typically refers to the administration of a composition (e.g., comprising an anti-Ap antibody as described herein) to asubject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, e.g., a human subject. For example, in some embodiments, administration may be parenteral. In some embodiments, administration may involve a single dose or multiple doses. In some embodiments, administration may involve application of a fixed number of doses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period of time) dosing.

[0047] The term “determining” as used herein can utilize or be accomplished through use of any of a variety of techniques available to those skilled in the art, including for example specific techniques explicitly referred to herein. In some embodiments, determining involves manipulation of a physical sample. In some embodiments, determining involves consideration and / or manipulation of data or information. In some embodiments, determining involves receiving relevant information and / or materials from a source. In some embodiments, determining involves comparing one or more features of a sample or entity to a comparable reference.

[0048] As used herein, the terms “improve”, “increase”, “inhibit’, “reduce”, or grammatical equivalents thereof, indicate values that are relative to a baseline or other reference measurement. In some embodiments, an appropriate reference measurement may be or comprise a measurement in a particular system (e.g., in a single individual) under otherwise comparable conditions absent presence of (e.g., prior to and / or after) a particular agent or treatment, or in presence of an appropriate comparable reference agent. In some embodiments, an appropriate reference measurement may be or comprise a measurement in comparable system known or expected to respond in a particular way, in presence of the relevant agent or treatment.

[0049] As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder,and / or condition.Alzheimer ’s Disease

[0050] The present disclosure provides methods for treating patients having or suspected of having Alzheimer’s disease, abbreviated herein as “AD”. AD is a dementia that is primarily identified by clinical diagnosis and established by certain markers of the disease.

[0051] AD is a continuum having certain operationally defined stages of disease progression. AD pathology begins prior to the onset of clinical symptoms. For example, amyloid plaques, one marker of AD pathology, form 10-20 years prior to the onset of AD dementia. The currently recognized stages of AD include preclinical, prodromal, mild, moderate, and severe. These stages may be further divided into subcategories based on the severity of symptoms and measures of AD progression.

[0052] Because AD does not occur in discrete stages, those skilled in the art will recognize that the differences between patient groups may not be distinct in a particular clinical setting. Nevertheless, the clinical disease stage can be characterized by measures, and changes in these measures over time, such as amyloid-beta (A|3) accumulation (CSF / PET), synaptic dysfunction (FDG-PET / fMRI), tau-mediated neuronal injury (CSF), brain structure (volumetric MRI), cognition, and clinical function. (Jack CR, et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol., 2010; 9(1): 119-28).

[0053] Current core clinical criteria for all dementia, referred to as the NINCDS-ADRDA criteria (McKhann GM, V. diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Inst, on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia, 7 (2011) 263-269), are known in the art and can be employed in practicing this invention. They include cognitive or behavioral impairment involving impaired ability to acquire and remember new information, impaired reasoning and handling of complex tasks, impaired visuospatial abilities, impaired language functions (speaking, reading, writing), and changes in personality, behavior, or comportment. AD is currently diagnosed using the core criteria and is typically characterized by symptoms which have a gradual onset over months to years, not sudden over hours or days (insidious onset). There is usually a clear-cut history of worsening of cognition by report or observation in AD subjects.

[0054] Other diagnostic classification systems have evolved as new information on AD has become available. These systems include the International Working Group (IWG) new research criteria for diagnosis of AD (Dubois B et al., Lancet Neurol., 2007; 6(8):734-736), IWG research criteria, (Dubois et al., Lancet Neurol., 2010;9(l 1 ): 1118-27), NIA / AA Criteria (Jack CR et al. Alzheimer’s Dement., 201 l;7(3):257-62), and DSM-5 criteria (American Psychiatric Association, DSM-5, 2013). These classification systems can also be employed in diagnosing AD subjects for treatment according to the methods of this disclosure.

[0055] In some embodiments, AD is mild AD, early AD, prodromal AD, mild AD dementia, mild cognitive impairment due to AD, mid-stage AD, or late-stage AD.Patients

[0056] As used herein, the terms “patient”, “subject”, or “human subject”, includes any human subject who may benefit from therapy with an anti -beta-amyloid antibody. In some embodiments, a patient has or is suspected of having a disease associated with the accumulation and deposition of beta amyloid, such as Alzheimer's disease (AD), Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia.

[0057] In some embodiments, a patient is one for whom diagnosis, prognosis, prevention, or therapy for AD is desired, and includes a human subject in need of treatment. Those in need of treatment include those already with AD, as well as those prone to have AD, or those in which the manifestation of AD is to be prevented. Typical patients will be men or women aged 40 to 90 (e.g., 45 to 90, 50 to 90, 55 to 90, 60 to 90). In some embodiments, a patient is aged > 65 years. In some embodiments, a patient is aged 65 to 74 years. In some embodiments, a patient is aged > 75 years.

[0058] In some embodiments, the disclosure provides a method of treating a patient with AD (including, without limitation, patients with preclinical, prodromal, mild, moderate, or severe AD). In certain instances, the disclosure provides a method of treating a patient with prodromal AD. In some instances, the disclosure provides a method of treating a patient with early AD. In some instances, the disclosure provides a method of treating a patient to reduce clinical decline in AD. In some embodiments, a patient with AD also has Down’s syndrome.

[0059] In some instances, the disclosure provides a method of treating a patient with mild cognitive impairment due to AD. In other instances, the disclosure provides a method of treating a patient with mild AD dementia. In some embodiments, the patient has amyloid pathology confirmed, e.g., by positron emission tomography (PET) imaging. In some cases, amyloid P pathology is confirmed by [18F] -fl orb etapir PET imaging. In some cases, amyloid pathology is confirmed by [18F]-flutemetomol PET imaging. In some cases, amyloid P pathology is confirmed by [18F]-florbetaben PET imaging. In some cases, amyloid P pathology is confirmed by CSF amyloid P analysis. In some cases, amyloid P pathology is confirmed by blood amyloid P analysis. In some cases, amyloid P pathology is confirmed by Congo red staining and birefringence under polarized microscopy. In some cases, amyloid P pathology is confirmed by immunohistochemistry (IHC), electron microscopy, or mass spectrometry. In some cases, amyloid P pathology is confirmed by any method to assess levels of amyloid p.

[0060] In some instances, the disclosure provides a method of treating a patient with Down’s syndrome that also has or is suspected of having an accumulation of beta amyloid deposits. In some embodiments, a patient with Down’s syndrome has a confirmed amyloid pathology. In some embodiments, a patient with Down’s syndrome has been diagnosed with AD.

[0061] In certain instances, a patient to be treated has a mini-mental state examination (MMSE) score between 24-30 (inclusive). In some instances, the patient to be treated has a CDR global score of 0.5. In some instances, the patient to be treated has a RBANS score of less than or equal to 85 (based upon Delayed Memory Index score). In some instances, the patient to be treated has at least 6 years of work experience. In some cases, the patient to be treated has an MMSE score between 24-30 (inclusive); a CDR global score of 0.5; and a RBANS score of less than or equal to 85 (based upon Delayed Memory Index score). In certain instances, the patient is an ApoE carrier (e.g., ApoE4 positive). In certain instances, the patient is an ApoE noncarrier (e.g., ApoE4 negative).

[0062] In some embodiments, the patient to be treated has mid-stage AD, characterized by a MMSE score of about 10-20 or equivalent score on other scales. In some embodiments, latestage AD is characterized by a MMSE score of about 9 or less or equivalent score on other scales.

[0063] In some embodiments, a patient has p-tau tangles, p-tau threads, and / or p-tau neuritic plaques. In some embodiments, a patient has neocortical p-tau tangles, neocortical p-tau threads,and / or neocortical p-tau neuritic plaques. In some embodiments, p-tau tangles, p-tau threads, and / or p-tau neuritic plaques are detected in a patient by positron emission tomography (PET) scanning of the human subject’s brain. In some embodiments, p-tau tangles, p-tau threads, and / or p-tau neuritic plaques are detected in a patient by analysis of the amount of p-tau and / or t-tau in the human subject’s CSF and / or plasma.

[0064] AD patients in need of treatment range from subjects with amyloid P pathology and early neuronal degeneration to subjects with widespread neurodegeneration and irreversible neuronal loss with progressive cognitive and functional impairment to subjects with dementia.

[0065] Patients with preclinical AD can be identified by asymptomatic stages with or without memory complaints and emerging episodic memory and executive function deficits. This stage is typically characterized by the appearance of in vivo molecular biomarkers of AD and the absence clinical symptoms.

[0066] Prodromal AD patients are pre-dementia stage characterized predominantly by cognitive deficits and emerging functional impairment with disease progression. Prodromal AD patients typically have mini-mental state examination (MMSE) scores between 24-30 (inclusive), a spontaneous memory complaint, objective memory loss defined as a free recall score of <27 on the Free and Cued Selective Reminding Test (FCSRT), a global Clinical Dementia Rating (CDR) score of 0.5, absence of significant levels of impairment in other cognitive domains, and essentially preserved activities of daily living, and an absence of dementia.

[0067] Patients with mild AD typically have MMSE scores between 20-26 (inclusive), a global CDR of 0.5 or 1.0, and meet the National Institute on Aging-Alzheimer’s Association core clinical criteria for probable AD (see Section 22).

[0068] Basing AD diagnosis on clinical symptoms, mild stage AD patients will exhibit conspicuous behavior at work, forgetfulness, mood swings, and attention disturbances. Moderate stage AD patients will exhibit cognitive deficits, restricted everyday activities, orientation disturbance, apraxia, agnosia, aphasia, and behavioral abnormalities. Severe stage AD patients are characterized by loss of independence, decay of memory and speech, and incontinence.

[0069] In certain embodiments, treatment is of earlier-stage patients who are amyloid positive as assessed by [18F]-florbetapir PET scans. In certain embodiments, treatment is of earlier-stage patients who are amyloid positive as assessed by18F-flutemetomol PET scans. In certain embodiments, treatment is of earlier-stage patients who are amyloid positive as assessedby 18F-florbetaben PET scans. In certain instances, the human subject is confirmed to have a brain amyloid beta pathology prior to the initiation of treatment. The patient may be asymptomatic for, or exhibit only transient symptoms of, headache, confusion, gait difficulties, or visual disturbances. The patient may or may not be an ApoE carrier (e.g., ApoE4 carrier) as determined by ApoE genotyping.

[0070] In other embodiments, treatment is of patients having any medical or neurological condition (other than AD) that might be a contributing cause of the subject's cognitive impairment, such as stroke or other cerebrovascular condition, other neurodegenerative disease, a history of clinically significant psychiatric illness, acute or sub-acute micro- or macro hemorrhage, prior macrohemorrhage, or superficial siderosis. These patients can be treated following screening and selection by a qualified clinician.

[0071] In some embodiments, the patient is an ApoE4 carrier. In some embodiments, the patient is not an ApoE4 carrier. In some embodiments, the patient has a reduced susceptibility to amyloid related imaging abnormalities (ARIA) as compared to a reference. In some embodiments, the patient’s susceptibility to vasogenic edema (VE) is reduced as compared to a reference. In some embodiments, the patient’s susceptibility to cerebral microhemorrhages (mH) is reduced as compared to a reference. In some embodiments, the reference is a historical reference. In some embodiments, the reference is a healthy human patient. In some embodiments, the reference comprises data from the human patient prior to treatment.Anti-Aft Antibodies

[0072] In some embodiments, an anti-beta amyloid antibody used in a method of the present disclosure comprises aducanumab (also known as BIIB037). Aducanumab is an anti-Ap antibody that recognizes aggregated forms of A , including plaques. BIIB037 contains a human kappa light chain. BIIB037 consists of 2 heavy and 2 human kappa light chains connected by interchain disulfide bonds. By “BIIB037” or “aducanumab” is meant an anti-Ap antibody comprising the amino acid sequences set forth in SEQ ID NOs: 10 and 11.

[0073] In vitro characterization studies have established that antibody BIIB037 recognizes a conformational epitope present in Ap aggregates, the accumulation of which is believed to underlie the development and progression of AD.

[0074] In vivo pharmacology studies indicate that a murine IgG2a chimeric version of the antibody (ch 12F6A) with similar properties significantly reduces amyloid plaque burden in the brains of aged Tg2576 mice, a mouse model of AD. The reduction in parenchymal amyloid was not accompanied by a change in vascular amyloid, as has been reported for certain anti-Ap antibodies (Wilcock OM, Colton CA. Immunotherapy, vascular pathology, and microhemorrhages in transgenic mice. CNS & Neurological Disorders Drug Targets, 2009 Mar;8(l):50-64).

[0075] The VH and VL of antibody BIIB037 have amino acid sequences that are identical to the amino acid sequence of the VH and VL of antibody NI-101.12F6A described in US Patent No. 8,906,367 see, Tables 2-4; incorporated by reference in its entirety herein). Specifically, antibody BIIB037 has an antigen binding domain comprising VH and VL variable regions depicted in Table 1 (VH) and Table 2 (VL), corresponding complementarity determining regions (CDRs) depicted in Table 3, and heavy and light chains depicted in Table 4 (H) and Table 5 (L).Table 1: Amino acid sequences of the VH region of anti-Ap antibody BIIB037 (VH CDRs (Kabat definition) underlined).Table 2: Amino acid sequences of the VL region of anti-Ap antibody BIIB037.Table 3: Denomination of CDR protein sequences in Kabat Nomenclature of VH and VL regions of anti-Ap antibody BIIB037 .

[0076] The amino acid sequence of the mature heavy chain of BIIB037 is provided in Table4 below.

[0077] Table 4: Amino acid sequences of the heavy chain of anti-Ap antibody BIIB037(heavy chain CDRs (Kabat definition) underlined).

[0078] The amino acid sequence of the mature light chain of BIIB037 is provided in Table 5 below.

[0079] Table 5: Amino acid sequences of the light chain of anti-Ap antibody BIIB037(light chain CDRs (Kabat definition) underlined).

[0080] In addition to antibody BIIB037, this disclosure contemplates the use of the other anti-Ap antibodies, such as antibodies comprising either a VH comprising or consisting of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 1 or a VL comprising or consisting an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 2, or antibodies comprising a VH comprising or consisting of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 1 and a VL comprising or consisting an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 2, wherein the VH and / or VL regions have one or moresubstitutions, deletions, and / or insertions. In some embodiments, these VH and VL regions may have up to 25, up to 20, up to 15, up to 10, up to 5, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions and still bind beta-amyloid. In specific embodiments, these amino acid substitutions occur only in the framework region. In some embodiments, the amino acid substitution(s) is / are conservative amino acid substitutions. In some embodiments, the VH and VL regions may include 1 to 5 (1, 2, 3, 4, 5) amino acid deletions and / or additions and still bind beta-amyloid. In some embodiments, these deletions and / or additions are made at the N- and / or C-terminus of the VH and / or VL regions. In some embodiments, one amino acid is deleted and / or added at the N and / or C-terminus of the VH region. In some embodiments, one amino acid is deleted and / or added at the N and / or C-terminus of the VL region.

[0081] Other antibodies contemplated for use in the disclosure include antibodies comprising the variable heavy chain (VH) CDRs and the variable light chain (VL) CDRs in Table 3. In some aspects, the anti-Ap antibody or A -binding fragment thereof comprises a VH CDR1 comprising or consisting of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 3, a VH CDR2 comprising or consisting of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 4; and a VH CDR3 comprising or consisting of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 5. In some embodiments, the anti-Ap antibody or Ap-binding fragment thereof comprises a VL CDR1 comprising or consisting of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 6, a VL CDR2 comprising or consisting of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 7; and a VL CDR3 comprising or consisting of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 8. Thus, the anti-Ap antibody or Ap-binding fragment thereof comprises the CDRs comprising or consisting of amino acid sequences having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with any one of SEQ ID NOs: 3 to 8. In some embodiments, the anti-beta amyloid antibodies comprise the CDRs comprising or consisting of the amino acid sequences of SEQ ID NOs.: 4-8 and include asVH CDR1 an amino acid sequence comprising or consisting of GFAFSSYGMH (SEQ ID NO:9). In some instances, the disclosure encompasses anti-Ap antibodies comprising the VH and VL CDRs of BIIB037 based on any CDR definition (e.g., Kabat, Chothia, enhanced Chothia, AbM, or contact definition). See, e.g., http: / / www.bioinf.org.uk / abs / index.html. In some embodiments, the disclosure encompasses anti-Ap antibodies comprising the VH and VL CDRs of BIIB037 based on the Chothia definition. In some embodiments, the disclosure encompasses anti-Ap antibodies comprising the VH and VL CDRs of BIIB037 based on the enhanced Chothia definition. In some embodiments, the disclosure encompasses anti-Ap antibodies comprising the VH and VL CDRs of BIIB037 based on the AbM definition. In yet another embodiment, the disclosure encompasses anti-Ap antibodies comprising the VH and VL CDRs of BIIB037 based on the contact definition.

[0082] In some embodiments, the anti-Ap antibody or AP-binding fragment thereof comprises a heavy chain (HC) that comprises or consists of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 10. In some embodiments, the HC regions may have up to 25, up to 20, up to 15, up to 10, up to 5, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions and still bind beta-amyloid.

[0083] In some embodiments, the anti-Ap antibody or AP-binding fragment thereof comprises a light chain (LC) comprising or consisting of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 11. In some embodiments, the LC regions may have up to 25, up to 20, up to 15, up to 10, up to 5, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions and still bind beta-amyloid.

[0084] In some embodiments, the anti-Ap antibody or Ap-binding fragment thereof comprises a HC comprising or consisting of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 10 and a LC comprising or consisting of an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 11.

[0085] In some embodiments, the anti-Ap antibody or Ap-binding fragment thereof comprises:

[0086] (A) an immunoglobulin heavy chain variable domain comprising complementarity determining regions (CDRs), wherein: a first CDR comprises an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 3; a second CDR comprises an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 4; a third CDR comprises an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 5; and

[0087] (B) an immunoglobulin light chain variable domain comprising CDRs, wherein: a first CDR comprises an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 6; a second CDR comprises an amino acid sequence having at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 7; and a third CDR comprises an amino acid sequence that is at least 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99.5%, or 99.9% sequence identity with SEQ ID NO: 8.

[0088] Antibody BIIB037 and other antibodies employed in the invention can be prepared using known methods. In some embodiments, the antibody is expressed in a Chinese hamster ovary (CHO) cell line.

[0089] Antibody BIIB037 and other antibodies employed in the invention can be prepared using known methods. In some embodiments, the antibody is expressed in an appropriate Chinese hamster ovary cell line.

[0090] In some embodiments, the anti-Ap antibody is aducanumab. In some embodiments, the A -binding fragment of said anti-Ap antibody is the AP-binding fragment of aducanumab.Treatment

[0091] The present disclosure provides, among other things, methods and compositions for treatment of a disease associated with the accumulation and deposition of beta amyloid, such as Alzheimer's disease (AD), Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia. In some embodiments, a method of treatment of AD described herein includes: (a) inhibiting AD, e.g. arresting its development; (b) relieving AD, e.g. causing regression of AD; or (c) prolonging survival as compared to expected survival if not receiving treatment. Aducanumab, a human immunoglobulin gamma 1monoclonal antibody, was granted accelerated approval by the FDA for the treatment of patients with early AD and is administered as an intravenous (IV) infusion. Subcutaneous (SC) administration of an anti-beta amyloid antibody, such as aducanumab, may offer an alternative, less burdensome route of administration, reducing the need for health care visits and dependence on medical professionals.

[0092] In some embodiments, the treatment is therapeutic. In some embodiments, treatment has a disease modifying effect. A disease modifying effect, as used herein, means that the treatment slows or delays the underling pathological or pathophysiological disease processes and / or there is an improvement in clinical signs and symptoms of AD relative to placebo.

[0093] In some embodiments, treatment results in symptomatic improvement. This may consist of enhanced cognition, more autonomy, and / or improvement in neuropsychiatric and behavioral dysfunction, even if for only a limited duration.

[0094] In some embodiments, the disclosure relates to methods for delaying clinical decline or progression of disease, or relief of symptoms. Delaying clinical decline or disease progression directly impacts the patient and care-givers. It delays disability, maintains independence, and allows the patient to live a normal life for a longer period of time. Relief of symptoms to the best degree possible can incrementally improve cognition, function, and behavioral symptoms, as well as mood.

[0095] The present disclosure describes, among other things, a titration regimen (sequential administration of increasing doses of an anti-beta amyloid antibody) to treat AD. In some instances, the AD is mild AD, early AD, prodromal AD, mild AD dementia, or mild cognitive impairment due to AD.

[0096] In some provided methods of treatment of AD, the anti-beta amyloid antibody is administered to a human patient in increasing amounts over a period of time. This procedure of sequentially administering the antibody to the patient is referred to herein as “titration” because it involves administering a standardized pharmaceutical of known concentrations in carefully measured amounts until completion of the procedure.

[0097] One of the advantages of the titration regimen of the invention is that it makes it possible to administer higher doses of the anti-Ap antibody to AD patients without incurring the same extent of ARIA observed with a standard dose regimen. In certain embodiments, the higher dose comprises a dose or doses of the anti-Ap antibody of 700 mg. Without intending to belimited to any particular mechanism, it is believed that titration results in lower initial amyloid removal and slower removal during the overall treatment.

[0098] Titration of the anti-Ap antibody (e.g., BIIB037) is carried out in multiple doses.

[0099] For example, two or more doses of the antibody can be administered to the patient in an amount per dose that is less than the minimum therapeutic amount, followed by a dose of the antibody in an amount per dose that is about equal to the minimum therapeutic amount. This regime can then be followed by two or more doses in an amount per dose that is more than the minimum therapeutic amount, but less than the maximum tolerated amount until there is an acceptable change in AD in the patient. Progress can be monitored by periodic assessment (e.g., MRI). In some embodiments, according to the methods disclosed herein, the human subject is evaluated 18 weeks after a last dose. In some embodiments, the evaluation comprises a drug and / or patient safety assessment. In some embodiments, the assessment comprises a MRI.

[0100] In some embodiments, the method of sequentially administering the anti-beta amyloid (AP) antibody or an AP-binding fragment thereof subcutaneously to the human subject to treat AD comprises administering a dose of a first dosage of about 70 mg, a dose of a second dosage of about 210 mg, a dose of a third dosage of about 420 mg, and a dose of a fourth dosage of about 700 mg, of said anti-beta amyloid (AP) antibody or an AP-binding fragment thereof to said human subject. In some embodiments, the subcutaneously, sequentially administered doses are administered about two weeks apart.

[0101] In some embodiments, the method of sequentially administering the two or more doses subcutaneously comprises: (A) administering one or more doses of a first dosage, wherein each dose of the first dosage is administered about 2 weeks apart; (B) following step (A), administering one or more doses of a second dosage, wherein each dose of the second dosage is administered about 2 weeks apart; (C) following step (B), administering one or more doses of a third dosage, wherein each dose of the third dosage is administered about 2 weeks apart; and (D) following step (C), administering a plurality of doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart.

[0102] In some embodiments, according to the methods disclosed herein, the one or more doses of the first dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first dosage. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first dosage are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks,about 14 weeks, or about 16 weeks, respectively. Tn some embodiments, a first dose of the first dosage is administered on Day 1. In some embodiments, a second dose, a third dose, and a fourth dose of the first dosage are administered at about 2 weeks, about 4 weeks, and about 6 weeks, following Day 1, respectively. In some embodiments, for example, 2 doses of the first dosage are administered over a total of about 4 weeks, 3 doses of the first dosage are administered over a total of about 6 weeks, 4 doses of the first dosage are administered over a total of about 8 weeks, or 5 doses of the first dosage are administered over a total of about 10 weeks. In some embodiments, the one or more doses of the second dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second dosage.

[0103] In some embodiments, according to the methods disclosed herein, 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second dosage are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively. In some embodiments, a first dose of the second dosage is administered about 2 weeks following administration of a final dose of the first dosage. In some embodiments, a first dose, a second dose, a third dose, and a fourth dose of the second dosage are administered about 8 weeks, about 10 weeks, about 12 weeks, and about 14 weeks, following Day 1, respectively. In some embodiments, for example, 2 doses of the second dosage are administered over a total of about 4 weeks, 3 doses of the second dosage are administered over a total of about 6 weeks, 4 doses of the second dosage are administered over a total of about 8 weeks, or 5 doses of the second dosage are administered over a total of about 10 weeks.

[0104] In some embodiments, according to the methods disclosed herein, the one or more doses of the third dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the third dosage. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 doses of the third dosage are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively. In some embodiments, a first dose of the third dosage is administered about 2 weeks following administration of a final dose of the second dosage. In some embodiments, a first dose, a second dose, a third dose, and a fourth dose of the third dosage are administered about 16 weeks, about 18 weeks, about 20 weeks, and about 22 weeks, following Day 1, respectively. In some embodiments, for example, 2 doses of the third dosage are administered over a total of about 4 weeks, 3 doses of the third dosage are administered over a total of about 6 weeks, 4 doses of the third dosage are administered over atotal of about 8 weeks, or 5 doses of the third dosage are administered over a total of about 10 weeks.

[0105] In some embodiments, according to the methods disclosed herein, a first dose of the fourth dosage is administered about 2 weeks following administration of a final dose of the third dosage. In some embodiments, a first dose of the fourth dosage is administered about 24 weeks following Day 1. In some embodiments, the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of at least 4 weeks. In some embodiments, the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 weeks. In some embodiments, the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of about 26, 52, 78, 104, 130, 156, 182, or 208 weeks. In some embodiments, the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of about 1-20 years. In some embodiments, the plurality of doses of the fourth dosage are administered indefinitely in about 2 week intervals.

[0106] An exemplary protocol according to the disclosure, designated Protocol A, comprises:(A) administering 4 doses of an anti-beta amyloid (A0) antibody or an AP-binding fragment thereof to a human subject in an amount of about 70 mg about 2 weeks apart over about 8 weeks,(B) 2 weeks after step (A), administering 4 doses to the human subject in an amount of about 210 mg about 2 weeks apart over about 8 weeks,(C) 2 weeks after step (B), administering 4 doses to the human subject in an amount of about 420 mg about 2 weeks apart over about 8 weeks, and(D) 2 weeks after step (C), administering 4 doses to the human subject in an amount of about 700 mg about 2 weeks apart over about 26 weeks, wherein 26 total doses are administered about 2 weeks apart over about 50 weeks, wherein the doses are each administered subcutaneously near or at an abdomen of the human subject.

[0107] In some instances, the exemplary protocol according to the disclosure, designated Protocol A, comprises the dosing and assessment schedule according to FIG. 10.

[0108] In some embodiments, according to the methods disclosed herein, the method of sequentially administering the two or more doses of the antibody or AP-binding fragment thereof disclosed herein subcutaneously comprises: (A) subcutaneously administering 4 doses of a first dosage, wherein each dose of the first dosage is administered about 2 weeks apart over a total ofabout 8 weeks; (B) following step (A), subcutaneously administering 4 doses of a second dosage, wherein each dose of the second dosage is administered about 2 weeks apart over a total of about 8 weeks; (C) following step (B), subcutaneously administering 4 doses of a third dosage, wherein each dose of the third dosage is administered about 2 weeks apart over a total of about 8 weeks; and (D) following step (C), subcutaneously administering 14 doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart over a total of about 28 weeks. In some embodiments, 26 total doses are administered with each dose administered about 2 weeks apart over a total of about 52 weeks. In some embodiments, the first dosage is about 70 mg. In some embodiments, the second dosage is about 210 mg. In some embodiments, the third dosage is about 420 mg. In some embodiments, the fourth dosage is about 700 mg.

[0109] In some embodiments, according to the methods disclosed herein, the method of sequentially administering the two or more doses of the antibody or Ap-binding fragment thereof disclosed herein subcutaneously comprises: (A) administering 4 doses of a first dosage, wherein each dose of the first dosage is administered about 2 weeks apart over a total of about 8 weeks; (B) following step (A), administering 4 doses of a second dosage, wherein each dose of the second dosage is administered about 2 weeks apart over a total of about 8 weeks; (C) following step (B), administering 4 doses of a third dosage, wherein each dose of the third dosage is administered about 2 weeks apart over a total of about 8 weeks; and (D) following step (C), administering 27 doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart over a total of about 54 weeks. In some embodiments, 39 total doses are administered with each dose administered about 2 weeks apart over a total of about 78 weeks. In some embodiments, the first dosage is about 70 mg. In some embodiments, the second dosage is about 210 mg. In some embodiments, the third dosage is about 420 mg. In some embodiments, the fourth dosage is about 700 mg.

[0110] Unexpectedly, methods of sequentially administering the anti-beta amyloid (AP) antibody or an AP-binding fragment thereof subcutaneously to a human subject, as disclosed herein, which begin treatment by utilizing an expedited titration phase that comprises a first dose of at least 150 mg or at least 200 mg, provides a safe and effective method of treating AD in the subject. For example, methods of sequentially administering the anti -beta amyloid (AP) antibody or an Ap-binding fragment thereof subcutaneously to a human subject, which begin treatment by utilizing an expedited titration phase that comprises a first dose of about 210 mg,followed by a dose of about 420 mg, and a dose of about 700 mg, and without administering a dose of about 70 mg, as disclosed herein, provides a safe and effective method of treating AD in the subject. For example, methods of sequentially administering the anti-beta amyloid ( A|3) antibody or an Ap-binding fragment thereof subcutaneously to a human subject, which begin treatment by utilizing an expedited titration phase (comprising a first dose of about 210 mg, followed by a dose of about 420 mg, and a dose of about 700 mg, and without administering a dose of about 70 mg) followed by a target phase, as disclosed herein, unexpectedly provided a safe and effective method of treating AD in the subject. For example, methods of sequentially administering the anti-beta amyloid (AP) antibody or an AP-binding fragment thereof subcutaneously to a human subject to treat AD in the subject, which begin treatment by utilizing an expedited titration phase (comprising a first dose of about 210 mg, followed by a dose of about 420 mg, and a dose of about 700 mg, and without administering a dose of about 70 mg) followed by a target phase, as disclosed herein, maximize duration of time administering an efficacious target dose during the target phase and unexpectedly results in a lower incidence of ARIA. In some embodiments, the method of sequentially administering the anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof subcutaneously to the human subject to treat AD, as disclosed herein, comprises administering a dose of about 210 mg, a dose of about 420 mg, and a dose of about 700 mg, of said anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof to said human subject. In some embodiments, the method of sequentially administering the two or more doses subcutaneously is exclusive of administering a dose of about 70 mg. In some embodiments, each of the two or more subcutaneously, sequentially administered doses is administered about two weeks apart. In some embodiments, the method of sequentially administering the two or more doses of the antibody or Ap-binding fragment thereof disclosed herein subcutaneously comprises: (A) administering one or more doses of about 210 mg of the antibody or Ap-binding fragment thereof, wherein each dose is administered about 2 weeks apart; (B) following step (A), administering one or more doses of about 420 mg of the antibody or Ap-binding fragment thereof, wherein each dose is administered about 2 weeks apart; and (C) following step (B), administering a plurality of doses of about 700 mg of the antibody or Ap-binding fragment thereof, wherein each dose is administered about 2 weeks apart.

[0111] In some embodiments, according to the methods disclosed herein, 1, 2, 3, 4, 5, 6, 7, or 8 doses of the about 210 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively. In some embodiments, a first dose of the about 210 mg of the antibody or Ap-binding fragment thereof is administered on Day 1. In some embodiments, a second dose, a third dose, and a fourth dose of the about 210 mg of the antibody or Ap-binding fragment thereof are administered at about 2 weeks, about 4 weeks, and about 6 weeks, following Day 1, respectively. In some embodiments, for example, 2 doses of the about 210 mg of the antibody or AP-binding fragment thereof are administered over a total of about 4 weeks, 3 doses of the about 210 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 6 weeks, or 4 doses of the about 210 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 8 weeks.

[0112] In some embodiments, according to the methods disclosed herein, 1, 2, 3, 4, 5, 6, 7, or 8 doses of the about 420 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively. In some embodiments, a first dose of the about 420 mg of the antibody or Ap-binding fragment thereof is administered about 2 weeks following administration of a final dose of the about 210 mg dosage. In some embodiments, a first dose, a second dose, a third dose, and a fourth dose of the about 420 mg of the antibody or AP-binding fragment thereof are administered about 8 weeks, about 10 weeks, about 12 weeks, and about 14 weeks, following Day 1, respectively. In some embodiments, for example, 2 doses of the about 420 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 4 weeks, 3 doses of the about 420 mg of the antibody or Ap- binding fragment thereof are administered over a total of about 6 weeks, or 4 doses of the about 420 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 8 weeks.

[0113] In some embodiments, according to the methods disclosed herein, a first dose of the about 700 mg of the antibody or Ap-binding fragment thereof is administered about 2 weeks following administration of a final dose of the about 420 mg dosage. In some embodiments, a first dose of the about 700 mg of the antibody or Ap-binding fragment thereof is administered about 16 weeks following Day 1. In some embodiments, the plurality of doses of the about 700mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of at least 4 weeks. In some embodiments, the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 weeks. In some embodiments, the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of about 26, 52, 78, 104, 130, 156, 182, or 208 weeks. In some embodiments, the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of about 1-20 years. In some embodiments, the plurality of doses of the about 700 mg of the antibody or AP-binding fragment thereof are administered indefinitely in about 2 week intervals.

[0114] In some embodiments, according to the methods disclosed herein, the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously comprises a titration phase and a target phase. In some embodiments, the titration phase is followed by the target phase. In some embodiments, the method of sequentially administering the two or more doses of the antibody or Ap-binding fragment thereof disclosed herein subcutaneously comprises: (A) a titration phase, comprising: (i) administering one or more doses of a first titration dosage, wherein each dose of the first titration dosage is administered about 2 weeks apart; (ii) following step (A)(i), administering one or more doses of a second titration dosage, wherein each dose of the second titration dosage is administered about 2 weeks apart; and (B) following step (A)(ii), a target phase, comprising administering a plurality of doses of a target dosage, wherein each dose of the target dosage is administered about 2 weeks apart during the target phase. In some embodiments, the first titration dosage is about 210 mg. In some embodiments, the second titration dosage is about 420 mg. In some embodiments, the target dosage is about 700 mg. In some embodiments, the method of sequentially administering the two or more doses subcutaneously is exclusive of administering a dose of about 70 mg.

[0115] In some embodiments, according to the methods disclosed herein, the titration phase begins with administration of a first dose of the first titration dosage on Day 1. In some embodiments, the one or more doses of the first titration dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first titration dosage. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first titration dosage are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively. Insome embodiments, a first dose of the first titration dosage is administered on Day 1 . In some embodiments, a second dose, a third dose, and a fourth dose of the first titration dosage are administered at about 2 weeks, about 4 weeks, and about 6 weeks, following Day 1, respectively. In some embodiments, 2 doses of the first titration dosage are administered over a total of about 4 weeks, 3 doses of the first titration dosage are administered over a total of about 6 weeks, 4 doses of the first titration dosage are administered over a total of about 8 weeks, or 5 doses of the first titration dosage are administered over a total of about 10 weeks. In some embodiments, the first titration dosage is about 210 mg.

[0116] In some embodiments, according to the methods disclosed herein, the one or more doses of the second titration dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second titration dosage. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second titration dosage are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively. In some embodiments, a first dose of the second titration dosage is administered about 2 weeks following administration of a final dose of the first titration dosage. In some embodiments, a first dose, a second dose, a third dose, and a fourth dose of the second titration dosage are administered about 8 weeks, about 10 weeks, about 12 weeks, and about 14 weeks, following Day 1, respectively. In some embodiments, 2 doses of the second titration dosage are administered over a total of about 4 weeks, 3 doses of the second titration dosage are administered over a total of about 6 weeks, 4 doses of the second titration dosage are administered over a total of about 8 weeks, or 5 doses of the second titration dosage are administered over a total of about 10 weeks. In some embodiments, the second titration dosage is about 420 mg.

[0117] In some embodiments, according to the methods disclosed herein, the target phase begins with administration of a first dose of the target dosage about 16 weeks following Day 1. In some embodiments, a first dose of the target dosage is administered about 2 weeks following administration of a final dose of the second titration dosage. In some embodiments, a first dose of the target dosage is administered about 16 weeks following Day 1. In some embodiments, the plurality of doses of the target dosage are administered about 2 weeks apart over a total of at least 4 weeks. In some embodiments, the plurality of doses of the target dosage are administered about 2 weeks apart over a total of about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 weeks. In some embodiments, the plurality of doses of the target dosage are administered about 2 weeksapart over a total of about 26, 52, 78, 104, 130, 1 6, 182, or 208 weeks. In some embodiments, the plurality of doses of the target dosage are administered about 2 weeks apart over a total of about 1-20 years. In some embodiments, the plurality of doses of the target dosage are administered indefinitely in about 2 week intervals. In some embodiments, the target dosage is about 700 mg.

[0118] In some embodiments, according to the methods disclosed herein, the method of sequentially administering the two or more doses of the antibody or Ap-binding fragment thereof disclosed herein subcutaneously comprises: (A) a titration phase, comprising: (i) administering 4 doses of a first titration dosage, wherein each dose of the first titration dosage is administered about 2 weeks apart over a total of about 8 weeks; (ii) following step (A)(i), administering 4 doses of a second titration dosage, wherein each dose of the second titration dosage is administered about 2 weeks apart over a total of about 8 weeks; and (B) following step (A)(ii), a target phase, comprising administering 31 doses of a target dosage, wherein each dose of the target dosage is administered about 2 weeks apart over a total of about 62 weeks during the target phase. In some embodiments, 39 total doses are administered with each dose administered about 2 weeks apart over a total of about 78 weeks. In some embodiments, the first titration dosage is about 210 mg. In some embodiments, the second titration dosage is about 420 mg. In some embodiments, the target dosage is about 700 mg. In some embodiments, the method of sequentially administering the two or more doses subcutaneously is exclusive of administering a dose of about 70 mg.

[0119] In some embodiments, according to the methods disclosed herein, the method comprises: a multiple dosage regimen administered to a human subject comprising, (A) administering 4 doses of a recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody or an Ap-binding fragment thereof to the human subject in an amount of 210 mg about 2 weeks apart over about 8 weeks; (B) following step (A), administering 4 doses to the human subject in an amount of 420 mg about 2 weeks apart over about 8 weeks; and (C) following step (B), administering 31 doses to the human subject in an amount of 700 mg about 2 weeks apart over about 62 weeks; wherein 39 total doses are administered about 2 weeks apart over about 78 weeks, wherein the doses are each administered subcutaneously near or at an abdomen of the human subject; wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL); and wherein the VH comprises acomplementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the method further comprises administering the antibody or AP-binding fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.

[0120] In some embodiments, according to the methods disclosed herein, the method of sequentially administering the two or more doses of said antibody or AP-binding fragment thereof subcutaneously is according to the regimen of FIG. 11A.

[0121] In some embodiments, according to the methods disclosed herein, the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously is according to the regimen of FIG. 1 IB.

[0122] In some embodiments, according to the methods disclosed herein, the method is a method for completely and / or partially preventing AD and / or symptoms thereof in the human subject. In some embodiments, the method is a method for partially and / or completely curing AD and / or symptoms attributed to AD in the human subject. In some embodiments, according to the methods disclosed herein, the method is a method for treatment of a human patient for Alzheimer’s disease (AD).

[0123] In some embodiments, according to the methods disclosed herein, the use of a titration phase reduces the incidence of ARIA-E, for example, in ApoE s4 carriers.

[0124] In some instances, the anti-Ap antibody of the protocols and methods above comprises a VH and VL comprising the six CDRs of BIIB037. In certain instances, the anti-Ap antibody comprises the VH and VL of BIIB037. In other instances, the anti-Ap antibody comprises the heavy and light chains of BIIB037. In some instances, the anti-Ap antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region (VHCDR1) with the amino acid sequence of SEQ ID NO:3, a VHCDR2 with the amino acid sequence of SEQ ID NO:4, and a VHCDR3 with the amino acid sequence of SEQ ID NO:5, and wherein the VL comprises a VLCDR1 with the amino acid sequence of SEQ ID NO:6, a VLCDR2 with the amino acidsequence of SEQ ID NO:7, and a VLCDR3 with the amino acid sequence of SEQ ID NO:8. In some instances, the anti-Ap antibody comprises a VH comprising or consisting of SEQ ID NO:1; and a VL comprising or consisting of SEQ ID NO:2. In some cases, the anti-Ap antibody comprises a heavy chain and a light chain, wherein: the heavy chain comprises or consists of SEQ ID NO: 10; and the light chain comprises or consists of SEQ ID NO: 11.

[0125] In some embodiments, the method administers the recombinant, fully human, antibeta amyloid (AP) monoclonal antibody. In some embodiments, the recombinant, fully human, anti -beta amyloid (AP) monoclonal antibody is aducanumab. In some embodiments, the method administers the AP-binding fragment of said recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody. In some embodiments, the AP-binding fragment of said recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody is Ap-binding fragment of aducanumab.

[0126] The patient’s response to treatment according to the invention is generally dosedependent. One embodiment of the invention comprises administering at least one dose of the anti-Ap antibody to the patient in an amount that is less than the minimum therapeutic amount required to treat the patient for AD. This is followed by at least one dose administered to the patient in an amount that is about equal to the minimum therapeutic amount required to treat the patient for AD. And then at least one dose is administered to the patient in an effective amount that is more than the minimum therapeutic amount, but less than the maximum tolerated amount required to treat the patient for AD. In a preferred embodiment, cerebral amyloid burden is reduced. In a further preferred embodiment, the susceptibility of the patient to ARIA is reduced.

[0127] A therapeutically effective amount refers to the amount of the antibody sufficient to ameliorate a symptom or condition associated with AD. Therapeutic efficacy and toxicity of the monoclonal antibody can be determined by standard pharmaceutical procedures. Ideally, the monoclonal antibody is employed in an amount sufficient to restore normal behavior and / or cognitive properties in case of AD, or at least delay or prevent the progression of AD in the patient.

[0128] In some embodiments, the method of treating includes monitoring and management of ARIA. For example, in some embodiments, the methods disclosed herein further include a schedule of safety MRIs similar to the scheme detailed by the FDA for administration of the IV formulation of aducanumab and lecanemab, including MRIs prior to dose escalation steps (priorto the 5th and 9th administration) and once the target dose has been achieved (prior to the 13th administration). In some embodiments, if a human subject experiences symptoms that could be suggestive of ARIA, clinical evaluation should be performed, including MRI testing if indicated. If the human subject is determined to be suffering from ARIA, the method may further comprise determining whether it is ARIA-E or ARIA-H, and the severity of the ARIA-E or the ARIA-H.

[0129] In some embodiments, if the method of treatment administrations are temporarily suspended due to ARIA, the time will elapse / will be held on a Schedule of Assessments, and the dosing according to the method of treatment disclosed here may resume at the same dose level after clinical symptoms and / or radiographic findings have been assessed.

[0130] ARIA-E

[0131] In some embodiments, human subjects who develop asymptomatic or clinically mild, radiographically mild ARIA-E on MRI will continue the method of treatment as disclosed herein uninterrupted per a Schedule of Assessments.

[0132] In some embodiments, human subjects who develop ARIA-E associated with > moderate clinical symptom severity or > moderate imaging severity will have treatment administrations temporarily stopped. In some embodiments, the human subjects will undertake follow-up unscheduled visits (USV) with MRIs every 4 weeks (± 5 days) until symptoms and radiographic evidence of ARIA have resolved.

[0133] In some embodiments, human subjects who develop ARIA-E (of any radiographic severity) that is considered serious at any time during the study, should permanently discontinue treatment.

[0134] ARIA-H

[0135] In some embodiments, human subjects who develop asymptomatic ARIA-H of cerebral microhemorrhages or asymptomatic superficial siderosis, will continue the method of treatment as disclosed herein uninterrupted per the Schedule of Assessments and do not require additional MRI follow-up outside the regularly scheduled assessments.

[0136] In some embodiments, human subjects who develop a single macrohemorrhage (>10 mm at greatest diameter; symptomatic or not), multiple (>10) cerebral microhemorrhages cumulatively (symptomatic or not), symptomatic cerebral microhemorrhages, or symptomatic superficial siderosis, will have the method of treatment administration as disclosed herein temporarily stopped. In some embodiments, the human subjects will undertake USV with MRIsevery 4 weeks (± 5 days) until radiographic evidence of ARIA-H have stabilized.

[0137] In some embodiments, human subjects who develop ARIA-H (of any radiographic severity) that is considered serious at any time during the method of treatment as disclosed herein, should permanently discontinue treatment.

[0138] In some embodiments, resumption of the method of treatment as disclosed herein following the occurrence of ARIA-H of symptomatic cerebral microhemorrhages, symptomatic superficial siderosis, or any macrohemorrhage can only occur twice, after which the participant must be discontinued from the treatment. For participants who already have ARIA-H of >10 cerebral microhemorrhages, should further new microhemorrhages develop after resumption of treatment, the participant must be discontinued from the treatment.

[0139] Objectives and Endpoints

[0140] In some embodiments, the effectiveness of the method of treating disclosed herein may be evaluated, measured, and / or determined by one or more objectives and / or endpoints disclosed herein. In some embodiments, the effectiveness of the method of treating disclosed herein may be evaluated, measured, and / or determined according to a primary objective, a key secondary objective, a secondary objective, an exploratory objective, or a combination thereof. For example, in some embodiments, the effectiveness of the method of treating disclosed herein may be evaluated, measured, and / or determined by: CDR-SB, iADRS, ADCS-ADL-MCI, ADAS-Cogl3, MMSE, NPI-10, or amyloid PET imaging, or combinations thereof.

[0141] In some embodiments, the primary objective is evaluated, measured, and / or determined by: CDR-SB, iADRS, ADCS-ADL-MCI, ADAS-Cogl3, MMSE, NPI-10, or amyloid PET imaging, or combinations thereof.

[0142] In some embodiments, the primary objective is evaluated, measured, and / or determined by CDR-SB. In some embodiments, the effectiveness of the method of treating disclosed herein may be evaluated, measured, and / or determined according to a primary objective. In some embodiments, the primary objective is to confirm the clinical benefit of the subcutaneously administered antibody or A -binding fragment thereof in slowing cognitive and functional impairment as measured by changes in the CDR-SB score as compared with placebo in participants with early Alzheimer’s disease. In some embodiments, a primary endpoint for determining the primary objective is the change from baseline in CDR-SB score at Week 78.

[0143] In some embodiments, the effectiveness of the method of treating disclosed hereinmay be evaluated, measured, and / or determined according to a key secondary objective. In some embodiments, the key secondary objective is evaluated, measured, and / or determined by: CDR- SB, iADRS, ADCS-ADL-MCI, ADAS-Cogl3, MMSE, NPI-10, or amyloid PET imaging, or combinations thereof. In some embodiments, the key secondary objective is evaluated, measured, and / or determined by: iADRS, ADCS-ADL-MCI, ADAS-Cogl3, MMSE, or NPI-10, or combinations thereof.

[0144] In some embodiments, the key secondary objective is to assess the effect of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo on clinical decline as measured by the iADRS. In some embodiments, a key secondary endpoint for determining the primary objective is the change from baseline in iADRS score at Week 78.

[0145] In some embodiments, the key secondary objective is to assess the effect of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo on clinical decline as measured by the ADCS-ADL-MCI. In some embodiments, a key secondary endpoint for determining the primary objective is the change from baseline in ADCS-ADL-MCI score at Week 78.

[0146] In some embodiments, the key secondary objective is to assess the effect of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo on clinical decline as measured by the ADAS-Cogl3. In some embodiments, a key secondary endpoint for determining the primary objective is the change from baseline in ADAS- Cogl3 score at Week 78.

[0147] In some embodiments, the key secondary objective is to assess the effect of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo on clinical decline as measured by the MMSE. In some embodiments, a key secondary endpoint for determining the primary objective is the change from baseline in MMSE score at Week 78.

[0148] In some embodiments, the key secondary objective is to assess the effect of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo on clinical decline as measured by the NPI-10. In some embodiments, a key secondary endpoint for determining the primary objective is the change from baseline in NPI-10 score at Week 78.

[0149] In some embodiments, the effectiveness of the method of treating disclosed herein may be evaluated, measured, and / or determined according to a secondary objective. In some embodiments, the secondary objective is evaluated, measured, and / or determined by: CDR-SB, iADRS, ADCS-ADL-MCI, ADAS-Cogl3, MMSE, NPI-10, or amyloid PET imaging, or combinations thereof. In some embodiments, the secondary objective is evaluated, measured, and / or determined by amyloid PET imaging. In some embodiments, a secondary endpoint for determining the primary objective is the change from baseline in amyloid PET signal at Week 52 and / or Week 78.

[0150] In some embodiments, the effectiveness of the method of treating disclosed herein may be evaluated, measured, and / or determined according to an exploratory objective. In some embodiments, the exploratory objective is evaluated, measured, and / or determined by: CDR-SB, iADRS, ADCS-ADL-MCI, ADAS-Cogl3, MMSE, NPLIO, GST composite z-score, MoCA, EQ-5D-5L and QoL-AD, ZBI-22, or disease-related biomarkers or treatment-related biomarkers in blood, or combinations thereof.

[0151] In some embodiments, the exploratory objective is to assess the effect of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo on early clinical decline as measured by CDR-SB, ADAS-Cogl3, ADCS-ADL- MCRI, NPI-10 and / or MMSE. In some embodiments, an exploratory endpoint for determining the exploratory objective is the change from baseline in CDR-SB, ADAS-Cogl3, ADCS-ADL- MCRI, NPI-10 and / or MMSE score at Week 52, respectively.

[0152] In some embodiments, the exploratory objective is to assess the effect of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo on clinical decline as measured by the GST composite z-score. In some embodiments, an exploratory endpoint for determining the exploratory objective is the change from baseline in GST composite z-score (based on CDR-SB, ADAS-Cogl3, and ADCS-ADL- MCI) at Week 52 and / or Week 78.

[0153] In some embodiments, the exploratory objective is to assess the effect of biweekly doses of the subcutaneously administered antibody or AP-binding fragment thereof as compared with placebo on clinical decline as measured by the MoCA. In some embodiments, an exploratory endpoint for determining the exploratory objective is the change from baseline in MoCA score at Week 78.

[0154] In some embodiments, the exploratory objective is to assess the effect of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo on patient-reported quality of life as measured by EQ-5D-5L and / or QoL-AD. In some embodiments, an exploratory endpoint for determining the exploratory objective is the change from baseline in EQ-5D-5L score at Week 78, and / or the change from baseline in QoL- AD score at Week 78, respectively.

[0155] In some embodiments, the exploratory objective is to assess the effect of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo on informant health status as measured by the ZB 1-22. In some embodiments, an exploratory endpoint for determining the exploratory objective is the change from baseline in informant-rated ZBL22 score at Weeks 78.

[0156] In some embodiments, the exploratory objective is to assess the effect of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo on disease-related biomarkers or treatment-related biomarkers in blood. In some embodiments, an exploratory endpoint for determining the exploratory objective is the change from baseline over time in disease-related biomarkers or treatment-related biomarkers in blood.

[0157] In some embodiments, the effectiveness of the method of treating disclosed herein may be evaluated, measured, and / or determined according to a safety objective. In some embodiments, the safety objective is evaluated, measured, and / or determined by: safety, tolerability, or immunogenicity, of the subcutaneously administered antibody or AP-binding fragment thereof as compared with placebo, or combinations thereof.

[0158] In some embodiments, the safety objective is to assess the safety and / or tolerability of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo. In some embodiments, a safety endpoint for determining the safety objective is the incidence of TEAEs and treatment-emergent SAEs; the incidence of asymptomatic and symptomatic ARIA; or changes from baseline in physical examination, vital signs, clinical laboratory tests, and 12 lead ECGs, or combinations thereof.

[0159] In some embodiments, the safety objective is to assess the immunogenicity of biweekly doses of the subcutaneously administered antibody or Ap-binding fragment thereof as compared with placebo. In some embodiments, a safety endpoint for determining the safety objective is the ADA incidence, response and titer.

[0160] In some embodiments, the methods of sequentially administering the anti-beta amyloid (AP) antibody or an A -bindin fragment thereof subcutaneously to a human subject to treat AD in the subject, as disclosed herein, results in a reduced rate of immunogenicity, relative to a rate of immunogenicity resulting from a method of intravenously administering the anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof. For example, in some embodiments, the methods of sequentially administering the anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof subcutaneously to a human subject to treat AD in the subject, which begin treatment by utilizing an expedited titration phase that comprises a first dose of about 210 mg, followed by a dose of about 420 mg, and a dose of about 700 mg, and without administering a dose of about 70 mg, as disclosed herein, results in a reduced rate of immunogenicity, relative to a rate of immunogenicity resulting from a method of intravenously administering the anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof. In some embodiments, the methods of sequentially administering the anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof subcutaneously to a human subject to treat AD in the subject, which begin treatment by utilizing an expedited titration phase (comprising a first dose of about 210 mg, followed by a dose of about 420 mg, and a dose of about 700 mg, and without administering a dose of about 70 mg) followed by a target phase, as disclosed herein, results in a reduced rate of immunogenicity, relative to a rate of immunogenicity resulting from a method of intravenously administering the anti -beta amyloid (AP) antibody or an Ap-binding fragment thereof. For example, in some embodiments, the rate of immunogenicity resulting from the methods of sequentially subcutaneously administering the anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof to a human subject to treat AD in the subject, as disclosed herein, is reduced by at least 20%, such as by at 30% or by at least 40%, relative to intravenously administering said anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof. In some embodiments, the titer of antibodies against the subcutaneously administered anti-beta amyloid (AP) antibody or an AP- binding fragment thereof, according to the methods disclosed herein, is reduced by at least 20%, such as by at 30% or by at least 40%, relative to intravenously administering said anti-beta amyloid (AP) antibody or an Ap-binding fragment thereof.

[0161] In some embodiments, the effectiveness of the method of treating disclosed herein may be evaluated, measured, and / or determined according to a pharmacokinetic objective. In some embodiments, the pharmacokinetic objective is to collect and characterize the PKparameters of biweekly doses of the subcutaneously administered antibody or AP-binding fragment thereof in the serum of the treated human subject. In some embodiments, a pharmacokinetic endpoint for determining the safety objective is serum concentrations and PK parameters of the subcutaneously administered antibody or A -binding fragment over time in the treated human subject.

[0162] Inclusion criteria

[0163] In some embodiments, the human subject treated according to the methods disclosed herein is 60-85 years old.

[0164] In some embodiments, the human subject treated according to the methods disclosed herein who is a woman of childbearing potential practices effective contraception during the study and for 5 times the half-life or 24 weeks (whichever is longer) after their last dose of the treatment.

[0165] In some embodiments, the human subject treated according to the methods disclosed herein has adequate literacy, vision, and hearing for neuropsychological testing in the opinion of the treating physician at the time of screening.

[0166] In some embodiments, the human subject treated according to the methods disclosed herein must have confirmed amyloid beta pathology by blood biomarker, CSF (historical CSF test results not allowed) or amyloid PET. In some embodiments, if providing only a screening amyloid PET scan for amyloid positivity, a historical, amyloid PET scan obtained within 18 months of Screening Visit 2 is permissible. In the case of discordant results between CSF and PET, PET results will be used to assess eligibility.

[0167] In some embodiments, the human subject treated according to the methods disclosed herein must have a history of subjective memory decline with gradual onset and slow progression over the last 12 months before Screening.

[0168] In some embodiments, the human subject treated according to the methods disclosed herein must meet all of the following clinical criteria for MCI due to Alzheimer’s disease or mild Alzheimer’s disease according to NIA-AA criteria, including having (i) an MMSE score between 22 and 30 inclusive, (ii) a CDR memory score > 0.5, (iii) a CDR-GS of 0.5 or 1.0, (iv) an RBANS score of 85 or lower indicative of objective cognitive impairment (based upon the DMI score), or (v) an objective impairment in episodic memory as indicated by at least 1 standard deviation below age-adjusted mean in the Wechsler Memory Scale IV-Logical Memory(subscale) II (WMS-IV LMII), as follows: a) <15 for age 50 to 64 years, b) <12 for age 65 to 69 years, c) <11 for age 70 to 74 years, d) <9 for age 75 to 79 years, and e) <7 for age 80 to 90 years, or combination thereof.

[0169] In some embodiments, the human subject treated according to the methods disclosed herein must be in good health, apart from a clinical diagnosis of early Alzheimer’s disease, as determined by the Investigator based on medical history and screening assessments.

[0170] In some embodiments, the human subject treated according to the methods disclosed herein must have one informant / care partner who, in the physician’s opinion, has frequent and sufficient contact with the subject (at least 10 hours / week in person or by phone) as to be able to provide accurate information about the subject’s cognitive and functional abilities over time. The informant / care partner ideally has known the subject prior to their cognitive decline to have a reference point for change across time. The informant / care partner must be available by phone to provide information to the physician and staff about the participant as well as agree to attend in-person clinic visits that require partner input for scale completion. The informant / care partner must be literate and provide informed consent and should be available for the duration of the treatment. The same informant / care partner is required to be consistent across all study visits except under rare, unavoidable circumstances (e.g., unexpected informant health crisis) that are approved by the physician.

[0171] In some embodiments, the human subject treated according to the methods disclosed herein, if receiving an approved AD treatment, such as AChEIs, or memantine, or both for AD, must be on a stable dose for at least 12 weeks prior to Baseline. Treatment-naive subjects for AD can treated according to the methods disclosed herein. Unless otherwise stated, subjects must have been on stable doses of all other (i.e., non-AD-related) permitted concomitant medications for at least 4 weeks prior to Baseline.

[0172] In some embodiments, the human subject treated according to the methods disclosed herein is treatment naive to all A0-directed monoclonal antibodies, including aducanumab.

[0173] Exclusion criteria

[0174] In some embodiments, the human subject treated according to the methods disclosed herein cannot have one or more of the following Medical History and Current Health Status criteria:Any neurological condition that may be contributing to cognitive impairmentabove and beyond that caused by the subject’s AD.• Any psychiatric diagnosis or symptoms (eg, hallucinations, major depression, or delusions) that could interfere with study procedures in the subject.• Answer “yes” to C-SSRS suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months prior to informed consent or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening.• History of transient ischemic attack or stroke or any unexplained loss of consciousness within 1 year prior to Screening.• Other significant pathological findings on brain MRI at Screening, including but not limited to: more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter); a single macrohemorrhage greater than 10 mm at greatest diameter; an area of superficial siderosis; evidence of vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations, or infective lesions; evidence of multiple lacunar infarcts or stroke involving a major vascular territory, severe small vessel, or white matter disease; space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and less than 1 cm at their greatest diameter need not be exclusionary).• Evidence of other clinically significant lesions on brain MRI at Screening that could indicate a dementia diagnosis other than AD.• Any finding that, in the opinion of the Investigator, might be a contributing cause of participant’s dementia, might pose a risk to the participant, or might prevent a satisfactory MRI assessment for safety monitoring• Any local or diffuse skin disorder that could impair absorption of study drug at the site of SC administration (e.g., the abdomen).• History of bleeding disorder or predisposing conditions, blood clotting, or clinically significant abnormal results on coagulation profile at Screening as determined by the Investigator.• Presence of diabetes mellitus that, in the judgment of the Investigator, cannot be controlled or adequately managed.• Any other clinically significant abnormalities in physical examination, vital signs, laboratory tests, or ECG at Screening or Baseline which in the opinion of the PI requirefurther investigation or treatment or which may interfere with study procedures or safety.• Uncontrolled hypertension with a history of blood pressure consistently above 165 / 100 mm Hg at Screening• Subjects with malignant neoplasms within 3 years of Screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male subjects). Subjects who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before Screening need not be excluded.• History of seizures or new-onset seizures within 10 years prior to Screening.• Indication of impaired liver function as shown by an abnormal liver function profile at Screening (e.g., repeated values of AST and ALT > 2.5 x the upper limit of normal).• Any immunological disease which is not adequately controlled, or which requires treatment with biologic drugs during the study.• Recent history (within 1 year of Screening) of alcohol or substance abuse as determined by the Investigator, or a positive urine drug test (due to a nonprescription drug and without a clear justification of the results according to the Investigator) at Screening.• Within 30 days of Screening, clinically significant systemic illness or infection that requires hospitalization or that, in the opinion of the Investigator, is impacting the patient’s usual performance in function or cognition.• History of or known seropositivity for HIV.• Current hepatitis B infection (defined as positive for HBsAg and total anti-HBc). Participants with immunity to hepatitis B from previous natural infection (defined as negative HBsAg, positive anti-HBc, and positive anti-HBs) or vaccination (defined as negative HBsAg, negative anti-HBc, and positive anti-HBs) are eligible to participate in the study.• Current hepatitis C virus infection (defined as positive HCV antibody and detectable HCV RNA). Participants with positive HCV Ab and undetectable HCV RNA are eligible to participate in the study.• History of severe allergic or anaphylactic reactions or of hypersensitivity to any of the inactive ingredients in the drug product. (Refer to the Investigator’ s Brochure forinformation on the clinical formulation.)• Any other medical conditions (eg, cardiac, respiratory, gastrointestinal, renal disease) which are not stably and adequately controlled, or which in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments.

[0175] In some embodiments, the human subject treated according to the methods disclosed herein cannot have one or more of the following Medication criteria:• Participation in any active immunotherapy study targeting Ap unless documentation of receipt of placebo is available.• Participation in any passive immunotherapy study targeting Ap within 12 months of Screening unless documentation of receipt of placebo is available.• Participation in any study with purported disease-modifying effect in Alzheimer’s disease within 12 months prior to Screening unless documentation of receipt of placebo is available.• Use of any medications that, in the opinion of the Investigator, may contribute to cognitive impairment, put the participant at higher risk for AEs, or impair the participant’s ability to perform cognitive testing or complete study procedures.• Subjects who are taking prohibited medications.• Use of allowed chronic concomitant medications that affect cognition (e.g., antidepressants, anticonvulsants, atypical and typical antipsychotics, short- / medium- acting benzodiazepines) at doses that have not been stable for at least 8 weeks prior to Screening Visit 2 and during Screening up to Day 1.• Use of long-acting benzodiazepines (allowed only for sedation prior to MRI / PET scans or LP for participants requiring sedation).• Use of medications with antiplatelet or anticoagulant properties (acetylsalicyclic acid [aspirin] is allowed at a dose < 325 mg per day).• Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening. Subjects who test positive for benzodiazepines or opioids in urine drug testing need not be excluded if in the clinical opinion of the investigator, this is due to the subject taking prior / concomitant medications containing benzodiazepines or opioids for a medical condition and not due to drug abuse.• Use of any investigational drug.• Prior exposure to the subcutaneously administered antibody or Ap-binding fragment thereof disclosed herein either commercially or by participation in a previous study. (Participants are eligible if they did not receive the active antibody or Ap-binding fragment thereof.)• Participated in any other investigational medication or device study in the 8 weeks or 5 half-lives (whichever is longer) of the medication before randomization unless it can be documented that the subject was in a placebo treatment arm.

[0176] In some embodiments, the human subject treated according to the methods disclosed herein cannot have one or more of the following Study Procedures criteria:• Contraindications to having a brain MRI (e.g., pacemaker; MRI-incompatible aneurysm clips, artificial heart valves, or other metal foreign body; or claustrophobia that cannot be medically managed).

[0177] In some embodiments, the human subject treated according to the methods disclosed herein cannot have one or more of the following Other criteria:• Female participants who are pregnant or currently breastfeeding.• Inability to comply with study requirements.• Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the participant unsuitable for enrollment.• For PET-substudy: Contraindications to PET (e.g., inability to lie flat or still for the duration of the scan) or intolerance to previous PET scans (i.e., previous hypersensitivity reactions to any PET ligand or imaging agent or failure to participate in and comply with previous PET scans); the participant has had or plans to have exposure to experimental radiation within 12 months prior to Screening such that radiodosimetry limits would be exceeded by participating in this study. Participants with a history of excised or treated basal cell or squamous carcinoma of the skin.Compositions

[0178] In some embodiments, the present disclosure provides compositions comprising an anti-Ap antibody. In some embodiments, the present disclosure provides compositions comprising an anti-Ap antibody for use in treating a human subject with a disease associatedwith the accumulation and deposition of beta amyloid, such as Alzheimer's disease (AD), Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia.

[0179] In some embodiments, a human subject has one or more characteristics. In some embodiments, a human subject is an ApoE carrier. In some embodiments, a human subject that has Down’s syndrome. In some embodiments, a human subject is aged > 65 years. In some embodiments, a human subject is aged 65 to 74 years. In some embodiments, a human subject is aged > 75 years.

[0180] In some embodiments, the present disclosure provides compositions for use in treating a human subject with AD, wherein a level of plasma and / or cerebrospinal fluid (CSF) p- tau has been determined prior to the treating. In some embodiments, a human subject has a plasma and / or cerebrospinal fluid (CSF) p-tau level prior to administration that is at or above a reference or threshold level. In some embodiments, a p-tau level in plasma and / or cerebrospinal fluid (CSF) comprises p-tau181and / or p-tau217. In some embodiments, the p-tau level is a plasma and / or cerebrospinal fluid (CSF) p-tau181level.

[0181] In some embodiments, the present disclosure provides compositions for use in treating a human subject with AD, wherein a level of plasma and / or cerebrospinal fluid (CSF) p- tau has been determined at a first time point that occurs prior to the treating and at a second time point. In some embodiments, a second time point for determining a p-tau level is after the human subject has received at least one dose of the anti-Ap antibody. In some embodiments, the present disclosure provides compositions for treating a human subject whose change in plasma and / or cerebrospinal fluid (CSF) p-tau level between the first and second time point meets or exceeds a reference or threshold level. In some embodiments, a p-tau level in plasma and / or cerebrospinal fluid (CSF) comprises p-tau181and / or p-tau217. In some embodiments, the p-tau level is a plasma and / or cerebrospinal fluid (CSF) p-tau181level.

[0182] In some embodiments, provided compositions comprise an anti-Ap antibody at a concentration of 50 mg / ml to 250 mg / ml; methionine at a concentration of 5 mM to 150 mM; Arg.HCl at a concentration of 50 mM to 200 mM; histidine at a concentration of 10 mM to 30 mM; PS80 at a concentration of 0.01% to 0.1%; and a thiol-containing antioxidant at a concentration of 0.02 mM to 4 mM. In some embodiments, a composition has a pH of 5.2 to 6.2. In some embodiments, a composition has a pH of 5.2 to 6.0. In some embodiments, acomposition has a pH of 5.3 to 5.7. Tn some embodiments, a composition has a pH of 5.5. In some instances, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, the combination of GSH and GSSG, cystine, cysteine, and the combination of cysteine and cystine. In some embodiments, the thiol-containing antioxidant is GSH. In some instances, the thiol-containing antioxidant is GSSG. In some instances, the thiol-containing antioxidant is the combination of GSH and GSSG.

[0183] In some embodiments, a composition comprises an anti-Ap antibody at a concentration of 175 mg / ml; Arg.HCl at a concentration of 150 mM; methionine at a concentration of 10 mM; histidine at a concentration of 10 mM to 30 mM; PS80 at a concentration of 0.01% to 0.1%; and a thiol-containing antioxidant at a concentration of 0.02 mM to 4 mM. In some embodiments, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, the combination of GSH and GSSG, cystine, cysteine, and the combination of cysteine and cystine. In some instances, the thiol-containing antioxidant is GSH. In some instances, the thiol-containing antioxidant is GSSG. In some instances, the thiol- containing antioxidant is the combination of GSH and GSSG.

[0184] In some embodiments, a composition comprises an anti-Ap antibody at a concentration of 175 mg / ml; Arg.HCl at a concentration of 150 mM; methionine at a concentration of 10 mM; histidine at a concentration of 20 mM; a thiol-containing antioxidant at a concentration of 0.4 mM; and PS80 at a concentration of 0.05%. In some embodiments, the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, the combination of GSH and GSSG, cystine, cysteine, and the combination of cysteine and cystine. In some instances, the thiol-containing antioxidant is GSH. In some instances, the thiol- containing antioxidant is GSSG. In some instances, the thiol-containing antioxidant is the combination of GSH and GSSG.Methods

[0185] In some embodiments, the present disclosure provides methods of treating, monitoring, and / or evaluating a disease associated with the accumulation and deposition of beta amyloid, such as Alzheimer's disease (AD), Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia.

[0186] In some embodiments, provided methods include methods of treating a human subject. In some embodiments, provided methods include methods of monitoring treatment response in a human subject. In some embodiments, provided methods include methods of determining a treatment plan for a human subject. In some embodiments, provided methods include methods of monitoring the cognitive state of a human subject.

[0187] In some embodiments, the present disclosure provides methods for selecting a patient for treatment with an anti-Ap antibody. In some embodiments, the present disclosure provides methods for selecting a patient for treatment with an anti-Ap antibody comprising determining a p-tau level in plasma and / or cerebrospinal fluid (CSF) of a human subject.

[0188] In some embodiments, the present disclosure provides methods for determining a dose of an anti-Ap antibody to be administered to a human subject. In some embodiments, the present disclosure provides methods for determining a dose of an anti-Ap antibody to be administered to a human subject comprising determining a p-tau level in plasma and / or cerebrospinal fluid (CSF) of a human subject.

[0189] In some embodiments, the present disclosure provides methods for selecting a patient receiving an anti-Ap antibody for cognitive support services. In some embodiments, the present disclosure provides methods for selecting a patient receiving an anti-Ap antibody for cognitive support services comprising determining a p-tau level in plasma and / or cerebrospinal fluid (CSF) of a human subject.

[0190] In some embodiments, provided methods include methods of characterizing or assessing efficacy of an anti-Ap antibody in a human subject. In some embodiments, provided methods include methods of characterizing or assessing efficacy of an anti-Ap antibody in a human subject comprising determining a p-tau level in plasma and / or cerebrospinal fluid (CSF) of a human subject.

[0191] In some embodiments, provided methods include methods of characterizing or assessing efficacy of an anti-Ap antibody in a human subject comprising determining one or more pharmacokinetic / pharmacodynamics (PK / PD) parameters. In a non-limiting list, one or more PK / PD parameter comprises a measure of AUCinf, AUClast, AUC0-4wk, Cmax, Tmax, T’A, Vd, CL, anti-drug-antibodies (AD As), and / or adverse effects (e.g., headaches, injection site erythema, injection site reaction, injection site pruritus, and / or nausea).

[0192] In some embodiments, the subject treated according to the methods disclosed herein has a reduced number of incidences and / or a reduction in severity of one or more adverse events relative to a human subject after receiving doses of said anti -beta amyloid ( A|3) monoclonal antibody or said Ap-binding fragment thereof intravenously. In some embodiments, the human subject has a reduction in incidences of headaches and / or a reduction in severity of headaches after receiving the two or more doses subcutaneously of the anti-beta amyloid (A0) monoclonal antibody or the Ap-binding fragment thereof as compared to a human subject after receiving doses of said anti-beta amyloid (AP) monoclonal antibody or said Ap-binding fragment thereof intravenously. In some embodiments, the reduction in incidences of headaches is about 10% or more, about 25% or more, about 40% or more, or about 50% or more. In some embodiments, the reduction in severity of headaches is about 10% or more, about 25% or more, about 40% or more, or about 50% or more.

[0193] In some embodiments, according to the methods disclosed herein, a low or minimal number of subjects treated with the subcutaneously administered anti-beta amyloid (AP) monoclonal antibody or Ap-binding fragment thereof develop a treatment-emergent antibody against the subcutaneously administered anti-beta amyloid (AP) monoclonal antibody or the Ap- binding fragment thereof. In some embodiments, about 25% or less, about 20% or less, about 15% or less, about 10% or less, or about 5% or less of patients treated according to the method test positive for a treatment-emergent antibody against the subcutaneously administered anti-beta amyloid (AP) monoclonal antibody or the AP-binding fragment thereof. For example, in some embodiments, about 4.8% of patients treated according to the method test positive for a treatment-emergent antibody against the subcutaneously administered anti-beta amyloid (AP) monoclonal antibody or the Ap-binding fragment thereof. In some embodiments, according to the methods disclosed herein, the subject treated with the subcutaneously administered anti -beta amyloid (AP) monoclonal antibody or Ap-binding fragment thereof does not develop a treatment-emergent antibody against the subcutaneously administered anti-beta amyloid (AP) monoclonal antibody or the Ap-binding fragment thereof.

[0194] In some embodiments, the present disclosure provides methods of monitoring treatment response in a human subject having or suspected of having a disease associated with the accumulation and deposition of beta amyloid, such as AD, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia. Insome embodiments, the present disclosure provides methods of monitoring treatment response in a human subject having or suspected of having a disease associated with the accumulation and deposition of beta amyloid, such as AD, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia comprising determining a p-tau level in plasma and / or cerebrospinal fluid (CSF) of a human subject.

[0195] In some embodiments, the present disclosure provides methods of reducing plasma p- tau in a human subject having or suspected of having a disease associated with the accumulation and deposition of beta amyloid, such as AD, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and / or multi-infarct dementia.

[0196] In some embodiments, provided methods comprise administering to a human subject an effective amount of an anti-Ap antibody. The route of administration of an anti-Ap antibody of the present disclosure may be subcutaneous. In some embodiments, an anti-Ap antibody is administered to a human subject by subcutaneous injection(s) near or at an abdomen of a human subject.

[0197] In some embodiments, the present disclosure provides methods that include administering an effective amount of an anti-Ap antibody to a human subject, where a level of plasma p-tau level has been or will be determined in the human subject.

[0198] In some embodiments, an anti-Ap antibody is administered to a subject in one or more doses. In some embodiments, an anti-Ap antibody is administered to a subject as a multidose regimen.Measurement and Reduction in the Symptoms of Alzheimer ’s Disease (AD)

[0199] Measurement of the risk, existence, severity, and progression of Alzheimer’s Disease (AD) can be determined by clinical diagnosis over time; assessment of the global functional level of the patient; evaluation of the daily living capacities or behavioral deficits; volumetric analysis of brain structures; in vivo measurement of pathological deposits of abnormal proteins in brain (e g. PET beta-amyloid imaging), or biochemical variables in body fluids (e.g. tau proteins or Abeta peptides); and by comparison to the natural course / hi story of the disease.

[0200] The following clinical assessments can be employed in determining the stage of AD in the patient: CDR, FCSRT, Neuropsychiatric Inventory-Questionnaire (NPI-Q), and a neuropsychological test battery comprising Rey Auditory Verbal Learning Test (RA VLT)Immediate and Delayed Recall, Wechsler Memory Scale (WMS) Verbal Pair Associate Learning Test Immediate and Delayed Recall, Delis-Kaplan Executive Function System Verbal Fluency Conditions 1 and 2, and the Wechsler Adult Intelligence Scale Fourth Edition Symbol Search and Coding Subsets; and the Cognitive Drug Research computerized test battery.

[0201] A preferred diagnostic regime comprises determining the change from baseline on the Clinical Dementia Rating (CDR) Scale, a neuropsychological test battery, Cognitive Drug Research computerized test battery, the Free and Cued Selective Reminding Test (FCSRT), Mini Mental State Examination (MMSE), Columbia Suicide Severity Rating Scale (C-SSRS), and Neuropsychiatric Inventory-Questionnaire (NPI-Q).

[0202] Biomarkers have emerged as essential for defining AD and for staging of the disease along its spectrum. Biomarker phenotypes can bridge the gap between clinical phenotypes and neuropathology phenotypes, such as amyloid plaques, neurofibrillary tangles, inflammation, and neurodegeneration. Biomarkers of AD include ApoE isotype, CSF A 42, amyloid PET, CSF Tau, and hippocampal volumetric (HCV) MRI.

[0203] Amyloid plaque burden in certain areas of the brain can be measured by 18F-AV-45 PET. 18F-AV-45 is an amyloid ligand developed by Avid Radiopharmaceuticals (Philadelphia, Pennsylvania). It binds to fibrillar A with a high affinity (Kd = 3.1 nM). Results with 18F-AV- 45 PET imaging have shown that patients with AD have selective retention of tracer in cortical areas expected to be high in amyloid deposition, whereas healthy controls have shown rapid washout from these areas, with only minimal cortical tracer retention. A significant difference in mean uptake of 18F-AV-45 has been observed between AD and age-matched control subjects. Test-retest variance of 18F-AV-45 PET imaging is low (less than 5%) in both AD patients and cognitively healthy controls. Visual interpretation of the 18F-AV-45 PET images and mean quantitative estimates of cortical uptake correlate with presence and quantity of amyloid pathology at autopsy as measured by immunohistochemistry and silver stain neuritic plaque score [Clark et al. 2011],

[0204] Radiation dosimetry of 18F-AV-45 is in the range of typical PET ligands. The average human whole body effective dose is estimated to be 0.019 mSv / MBq. A dose of 370 MBq per injection has also been shown to yield good imaging results.

[0205] Patients with AD have characteristic reductions in FDG PET measurements of regional glucose metabolism, which are related to progressive impairment of cognitive function[Landau 2011 ; Mielke 1994], The effect of BIIB037 in halting the progression of glucose metabolic deficit can be periodically assessed using FDG PET measurements. Radiation dosimetry of FDG is in the range of typical PET ligands. The average human whole body effective dose is estimated to be 0.019 mSv / MBq. The standard FDG imaging protocol uses a dose of 185 MBq per injection. In this invention, patients can typically receive up to 185 MBq with each scan.

[0206] Measurement of Api-42 and T-Tau or P-Tau levels in CSF are gaining acceptance as predictive biomarkers of AD. Evidence suggests that Tau aggregation pathology is a very early event in pathogenesis. Duyckaerts (2011) Lancet Neurol. 10, 774-775, and Braak et al., (2013), Acta Neuropath., 126:631-41.

[0207] AD-related biomarkers can also be employed. These include, but are not limited, to pyroglutamate- Ap, Ap40, and Ap42 in blood, and total Tau, phospho-Tau, pyroglutamate-Ap AP40, and Ap42 in CSF.

[0208] Morphometric MRI measures can also aid in the assessment of AD. These include whole brain volume, hippocampal volume, ventricle volume, and cortical gray matter volume. Cerebral blood flow as measured by ASL-MRI and functional connectivity as measured by tf- fMRI can be included in the assessment protocols.

[0209] Use of antibody BIIB037 for the treatment of AD patients according to the invention results in an improvement in one or more of these parameters over baseline measurements or at least prevents or slows the progression of AD from one stage to the next stage.Syringe

[0210] Compositions of the present invention may be fdled into a syringe for administration to a subject. Any syringe known in the art for use in delivering compounds (e.g., pharmaceutical compounds) to a subject may be used.

[0211] In some embodiments, the syringe may comprise a needle and a plunger rod. In such a syringe, the composition may be administered by contacting the subject at the injection site with the needle, depressing the plunger until the complete injection of the syringe contents is complete, and then withdrawing the needle from the subject.

[0212] The composition may be administered by the subject or by a third person (e.g. doctor).

[0213] In some embodiments, the syringe may also comprise a finger flange.

[0214] In some embodiments, the syringe may also comprise a passive add-on needle guard.

[0215] Parameters such as needle gauge, needle length, and syringe barrel size can potentially impact injection time and depth.

[0216] In certain embodiments, the syringe is a 2.25 mb Type 1 borosilicate glass PFS with a ' / 2-in ch 27-gauge special thin wall staked stainless steel needle.

[0217] Although anti-A[3 antibodies and fragments thereof are typically delivered in intravenous formulations in doses that depend on body weight, flat (weight-independent) dosing may be justified for subcutaneous administration. This is because monoclonal antibodies typically distribute into compartments such as plasma and extracellular fluids that are not greatly impacted by body weight. Flat dosing may simplify treatment by eliminating the need for dose calculations and associated dosing errors.

[0218] It may be desirable to keep the volume of the injection constant. Thus, in some embodiments, syringes used may contain a constant volume of a composition but the various injections may contain compositions containing different concentrations of the antibody or fragment thereof.

[0219] In certain embodiments, the syringe is contained in an auto-injector. Any autoinjector known in the art for use in delivering compounds (e.g., pharmaceutical compounds) to a subject may be used.

[0220] In certain embodiments, the auto-injector is a single-use, disposable auto-injector containing a prefilled staked-needle syringe. In certain such embodiments, the staked needle is about ’A inch, the needle diameter is 27G STW 0.28 mm, the syringe volume is about 2.25 ml, and / or the syringe material is glass.

[0221] In some embodiment methods described herein comprise: removing a cap from the auto-injector, the removal thereof serving to remove a needle shield that shields a needle; aligning the auto-injector over an injection site of the patient; pressing the auto-injector, thereby inserting the needle subcutaneously into the patient; and, following completion of the injection, withdrawing the needle by lifting the auto-injector away from the injection site wherein, following withdrawal, a needle cover extends to cover the needle.

[0222] The auto-injector may be used by the subject to self-administer the composition or may be used by a third person (e.g., doctor, caregiver, or relative) to administer the composition to the subj ect.Kits

[0223] Also provided by the present disclosure are kits comprising an auto-injector, a composition comprising an anti-Ap antibody for administration to a human subject, and instructions for use. In some embodiments, an auto-injector comprises a composition comprising an anti-Ap antibody for administration to a human subject. In some embodiments, the instructions direct administration to a human subject that has one or more characteristics. In some embodiments, the instructions direct administration to a human subject that is an ApoE carrier. In some embodiments, the instructions direct administration to a human subject that has Down’s syndrome. In some embodiments, the instructions direct administration to a human subject that is aged > 65 years. In some embodiments, the instructions direct administration to a human subject that is aged 65 to 74 years. In some embodiments, the instructions direct administration to a human subject that is aged > 75 years.

[0224] In some embodiments, the instructions direct administration to a human subject that has a plasma p-tau level is above a reference or threshold level. In some embodiments, a p-tau level in plasma comprises p-tau181and / or p-tau217. In some embodiments, the p-tau level is a plasma p-tau181level.

[0225] In some embodiments, kits for use in accordance with the present disclosure may include, instructions for administration, processing samples, performing tests on samples, instructions for interpreting the results, etc.

[0226] In some embodiments, the instructions to determine a p-tau level in plasma and / or cerebrospinal fluid (CSF) of a human subject at a first and second time point. In some embodiments, a first time point for determining a p-tau level is prior to the human subject receiving a dose of the anti-Ap antibody. In some embodiments, a second time point for determining a p-tau level is after the human subject has received at least one dose of the anti-Ap antibody.

[0227] In some embodiments, the recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody included in the kit is aducanumab. In some embodiments, the AP-binding fragment of said recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody included in the kit is the Ap-binding fragment of aducanumab.EXAMPLESExample 1: Pharmacokinetics (PK) studies in healthy volunteers

[0228] The present disclosure demonstrates that subcutaneous (SC) administration of aducanumab may exhibit comparable pharmacokinetics (PK) to intravenously administered aducanumab.Methods:

[0229] An exemplary study design is shown in FIG. 1. In short, an open-label, parallel-arm study compared a single weight-based 10 mg / kg IV dose of aducanumab (Arm 1) with two 700 mg SC doses of aducanumab administered 2 weeks apart (Arm 2). 124 healthy volunteers (Arm 1 n=61, Arm 2 n=63) were randomized and dosed with study treatment. 120 participants (60 participants in Arm 1 and 60 participants in Arm 2) were included in the PK Analysis Set. The planned total study duration for participants was approximately 19 weeks, with participants in Arm 1 having 11 visits and participants in Arm 2 having 15 visits concluded by a 14 week outpatient monitoring period. The participants in Arm 1 received a single, weight-based dose of aducanumab as 10 mg / kg IV on Day 1. The participants in Arm 2 received 2 fixed doses of aducanumab as 700 mg SC in the lower abdomen on Days 1 and 15, respectively. As shown in the exemplary schematic of FIG. 2, two participants in the study withdrew from the study due to relocation, one participant withdrew due to study visit burden / scheduling conflicts, and one participant withdrew for other reasons unrelated to AEs. PK sampling was intensive on Day 1 with sparse collection up to day 99 in both arms to ensure adequate calculation of PK parameters. Key inclusion criteria included age 40-70 years, body mass index (BMI) between 18-30 kg / m2, and participants required to be in good health. For Japanese participants, both biological parents and all 4 grandparents were of Japanese descent. Japanese participants were included to better understand any potential PK differences between Japanese and non-Japanese populations. Key exclusion criteria included: MMSE score <27 at screening; brain MRI (at screening or <1 year of Day -1) evidence of acute or subacute hemorrhage, prior microhemorrhage or prior subarachnoid hemorrhage, >4 microhemorrhages, cortical infarct, >1 lacunar infarct, or any focal area of superficial siderosis; history of or positive test for HIV or HCV; current HBV infection; symptoms of bacterial, fungal, or viral infection; or prior aducanumab exposure. Study endpoints included a Primary endpoint (PK comparability of SCvs TV administration as measured by the geometric mean ratio of AUCinf) and Secondary endpoints (incidence of adverse events with treatment route and characterization of additional PK parameters). The baseline participant demographics of the participants, which were similar across treatment groups, is provided in Table 6 below. The mean age of the participants was 52.6 years and a total of 21 (16.9%) participants were Japanese.Table 6: Baseline participant demographics - full analysis set*Participants who reported multiple categories of race were counted in each reported category.Results’.

[0230] Aducanumab was well tolerated in healthy volunteers. The overall incidence (%[n]) of adverse events (AEs) was 50.8%

[0031] in Arm 1 and 30.2%

[0019] in Arm 2. Headache was the most common AE in both arms (Arm 1 : 32.8%

[0020] vs Arm 2: 7.9%[5]). General disorders and administration site conditions included injection site erythema (Arm 1 : 0%[0], Arm 2: 6.3%[4]), injection site reaction (Arm 1: 0%[0], Arm 2: 4.8%[3]), adverse drug reaction (Arm 1 : 0%[0], Arm 2: 1 ,6%[1]), injection site pruritis (Arm 1 : 0%[0], Arm 2: 1 ,6%[1]), and oedema peripheral (Arm 1 : 1 ,6%[1], Arm 2: 0%[0]). All AEs of injection site erythema, injection site reaction, and injection site pruritis were assessed by the investigator as related to study treatment, mild in severity, and resolved. One serious AE (SAE) was reported in this study. The SAE (enterocolitis)occurred in an Arm 2 participant (onset of 1 day after first dose) and led to study treatment discontinuation. The investigator assessed the SAE as severe in severity, related to treatment, and resolved 8 days after onset. All other AEs reported during the study were assessed by the investigator as mild or moderate in severity and resolved (except for two AEs assessed as recovering). No deaths occurred during the study. The incidence of treatment-emergent (TE) anti-aducanumab antibodies (ADA) was low; 3 participants (4.8%) in Arm 2 tested positive for TE ADA during the study, as shown in FIG. 8. A summary of the incidences of adverse events, safety results, and tolerability results are provided in Table 7 below, and in FIG. 6 and FIG. 7.Table 7: Incidence of adverse events - safety analysis set**AEs are MedDRA v25.0 preferred terms within a system organ class (MedDRA v25.0).

[0231] An arithmetic mean (±SE) serum concentration profile for 10 mg / kg IV aducanumab (Arm 1) and 700 mg SC aducanumab injections (Arm 2) is provided in FIG. 3. As shown in FIG.3, in participants treated with 10 mg / kg IV aducanumab (Arm 1), mean serum aducanumab concentrations reached peak exposure at the end of the 1-hour IV infusion and declined rapidly thereafter, reaching exposure levels comparable to those of participants treated with two 700 mg SC aducanumab injections around Day 8 (Arm 2). A summary of the tested pharmacokineticparameters of the participants in Arm 1 and Arm 2 is provided in FIG. 4. Based on geometric means, Cmax was approximately 5-fold lower in the SC arm (Arm 2) compared to the IV arm (Arm 1). A statistical comparative analysis of the pharmacokinetic results of the participants in Arm 1 and Arm 2 is provided in FIG. 5. A series of exemplary PK scatter plots by route (participants in Arm 1 and Arm 2) and baseline weight are provided in FIGS. 9A-9C. FIG. 9A shows an exemplary scatter plot of AUCinf (by route) versus baseline weight. FIG. 9B shows an exemplary scatter plot of Cmax (by route) versus baseline weight. FIG. 9C shows an exemplary scatter plot of Clearance (by route) versus baseline weight. Aducanumab AUCinf in participants treated with 2 aducanumab 700 mg SC injections (Arm 2) and participants treated with aducanumab 10 mg / kg IV (Arm 1) were comparable, with a geometric LS mean ratio of 93.9% (0.939, 90% CI [0.863, 1.022]).

[0232] Thus, the present example demonstrates that Aducanumab administered as two doses of 700 mg SC demonstrates a high degree of PK comparability to aducanumab administered as a single weight-based 10 mg / kg IV dose and is well tolerated in healthy volunteersEquivalents Exemplary Embodiments

[0233] One or more than one (including for instance all) of the following exemplary Embodiments may comprise each of the other embodiments or parts thereof.1. In an Embodiment, a method comprising: sequentially administering to a human subject two or more doses of a recombinant, fully human, anti-beta amyloid (A ) monoclonal antibody or an AP-binding fragment thereof, wherein the two or more doses are each administered subcutaneously near or at an abdomen of the human subject, wherein the antibody or AP-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO:6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8.2. The method of Embodiment 1, wherein sequential administration is performed using an auto-injector.3. The method of Embodiment 2, wherein the auto-injector further comprises a syringe.4. The method of Embodiment 3, wherein the syringe comprises a finger flange, plunger rod, and a passive add-on needle guard.5. The method of any one of Embodiments 2-4, wherein the auto-injector further comprises a mechanical spring.6. The method of any one of the preceding Embodiments, wherein the two or more doses are administered in the lower abdomen quadrant of the human subject.7. The method of any one of the preceding Embodiments, further comprising:(A) administering 4 doses of a first dosage about 2 weeks apart over about 8 weeks,(B) after step (A), administering 4 doses of a second dosage about 2 weeks apart over about 8 weeks,(C) after step (B), administering 4 doses of a third dosage about 2 weeks apart over about 8 weeks, and(D) after step (C), administering 14 doses of a fourth dosage about 2 weeks apart over about 26 weeks, wherein 26 total doses are administered about 2 weeks apart over about 50 weeks.8. The method of Embodiment 7, wherein the first dosage is at least about 70 mg.9. The method of Embodiment 7, wherein the second dosage is at least about 210 mg.10. The method of Embodiment 7, wherein the third dosage is at least about 420 mg.11. The method of Embodiment 7, wherein the fourth dosage is at least about 700 mg.12. The method of any one of the preceding Embodiments, further comprising administering the antibody or AP-bindin fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.13. The method of any one of Embodiments 7-12, wherein the human subject is evaluated 18 weeks after a last dose.14. The method of Embodiment 13, wherein the evaluation comprises a drug and / or patient safety assessment.15. The method of Embodiment 14, wherein the assessment comprises a MRI.16 The method of any one of the preceding Embodiments, wherein the antibody or Ap- binding fragment thereof comprises a human IgGl constant region.17. The method of any one of the preceding Embodiments, wherein the antibody or AP- binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO: 1, and the VL comprises SEQ ID NO: 2.18. The method of any one of the preceding Embodiments, wherein two or more doses of the antibody or Ap-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates one or more similar pharmacokinetic / pharmacodynamics (PK / PD) parameter(s) as compared to the same antibody or Ap-binding fragment thereof when a single weight-based dose of the antibody or fragment thereof is administered.19. The method of any one of Embodiments 1-17, wherein a 700 mg dose of the antibody or Ap-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates one or more similar pharmacokinetic / pharmacodynamics (PK / PD) parameter(s) as compared to the same antibody or Ap-binding fragment thereof when 10 mg / kg of the antibody or fragment thereof is administered.20. The method of Embodiment 18 or 19, wherein the one or more PK / PD parameter comprises a measure of AUCinf, AUClast, AUC0-4wk, Cmax, Tmax, T’ / z, Vd, CL, anti-drug- antibodies (AD As), and / or adverse effects (e.g., headaches, injection site erythema, injection site reaction, injection site pruritus, and / or nausea).21. The method of any one of the preceding Embodiments, wherein the human subject is an ApoE4 carrier.22. The method of any one of Embodiments 1-20, wherein the human subject is not an ApoE4 carrier.23. The method of any one of the preceding Embodiments, wherein the human subject has a reduced susceptibility to amyloid related imaging abnormalities (ARIA) as compared to a reference.24. The method of any one of Embodiments 1-23, wherein the human subject’s susceptibility to vasogenic edema (VE) is reduced as compared to a reference.25. The method of any one of Embodiments 1-24, wherein the human subject’s susceptibility to cerebral microhemorrhages (mH) is reduced as compared to a reference.26. The method of any one of Embodiments 23-25, wherein the reference is a historical reference.27. The method of any one of Embodiments 23-25, wherein the reference is a healthy human subject.28. The method of any one of Embodiments 23-25, wherein the reference comprises data from the human subject prior to treatment.29. The method of any one of Embodiments 1-28, wherein the method is a method for completely and / or partially preventing AD and / or symptoms thereof in the human subject.30. The method of any one of Embodiments 1-28, wherein the method is a method for partially and / or completely curing AD and / or symptoms attributed to AD in the human subject.31. In an Embodiment, a method comprising: a multiple dosage regimen administered to a human subject comprising,(A) administering 4 doses of a recombinant, fully human, anti-beta amyloid ( A0) monoclonal antibody or an Ap-binding fragment thereof to the human subject in an amount of 70 mg about 2 weeks apart over about 8 weeks,(B) after step (A), administering 4 doses to the human subject in an amount of 210 mg about 2 weeks apart over about 8 weeks,(C) after step (B), administering 4 doses to the human subject in an amount of 420 mg about 2 weeks apart over about 8 weeks, and(D) after step (C), administering 14 doses to the human subject in an amount of 700 mg about 2 weeks apart over about 26 weeks, wherein 26 total doses are administered about 2 weeks apart over about 50 weeks, wherein the doses are each administered subcutaneously near or at an abdomen of the human subject, wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL),wherein the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8.32. In an Embodiment, a recombinant, fully human, anti-amyloid beta monoclonal antibody for use in a method comprising: sequentially administering to a human subject two or more doses of a recombinant, fully human, anti-beta amyloid (A0) monoclonal antibody or an Ap-binding fragment thereof, wherein the two or more doses are each administered subcutaneously near or at an abdomen of the human subject, wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8.33. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 32, wherein sequential administration is performed using an auto-injector.34. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 33, wherein the auto-injector further comprises a syringe.35. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 34, wherein the syringe comprises a finger flange, plunger rod, and a passive add-on needle guard.36. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 32-35, wherein the auto-injector further comprises a mechanical spring.37. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding Embodiments, wherein the two or more doses are administered in the lower abdomen quadrant of the human subject.38. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding Embodiments, further comprising:(A) administering 4 doses of a first dosage about 2 weeks apart over about 8 weeks,(B) after step (A), administering 4 doses of a second dosage about 2 weeks apart over about 8 weeks,(C) after step (B), administering 4 doses of a third dosage about 2 weeks apart over about 8 weeks, and(D) after step (C), administering 14 doses of a fourth dosage about 2 weeks apart over about 26 weeks, wherein 26 total doses are administered about 2 weeks apart over about 50 weeks.39. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 38, wherein the first dosage is at least about 70 mg.40. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 38, wherein the second dosage is at least about 210 mg.41. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 38, wherein the third dosage is at least about 420 mg.42. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 38, wherein the fourth dosage is at least about 700 mg.43. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding Embodiments, further comprising administering the antibody or A ~ binding fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.44. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 38-43, wherein the human subject is evaluated 18 weeks after a last dose.45. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 44, wherein the evaluation comprises a drug and / or patient safety assessment.46. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 45, wherein the assessment comprises a MRI.47. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding Embodiments, wherein the antibody or A^-binding fragment thereof comprises a human IgGl constant region.48. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding Embodiments, wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO: 1, and the VL comprises SEQ ID NO: 2.49. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding Embodiments, wherein two or more doses of the antibody or AP- binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates similar pharmacokinetic parameter(s) as compared to the same antibody or AP-binding fragment thereof when a single weight-based dose of the antibody or fragment thereof is administered.50. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 32-48, wherein a 700 mg dose of the antibody or AP-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates similar one or more pharmacokinetic / pharmacodynamics (PK / PD) parameter as compared to the same antibody or Ap-binding fragment thereof when 10 mg / kg of the antibody or fragment thereof is administered.51. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 49 or 50, wherein the one or more PK / PD parameter comprises a measure of AUCinf, AUClast, AUC0-4wk, Cmax, Tmax, T'A, Vd, CL, anti-drug-antibodies (ADAs), and / or adverse effects (e.g., headaches, injection site erythema, injection site reaction, injection site pruritus, and / or nausea).52. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding Embodiments, wherein the human subject is an ApoE4 carrier.53. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 32-51, wherein the human subject is not an ApoE4 carrier.54. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding Embodiments, wherein the human subject has a reduced susceptibility to amyloid related imaging abnormalities (ARIA) as compared to a reference.55. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 32-54, wherein the human subject’s susceptibility to vasogenic edema (VE) is reduced as compared to a reference.56. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 32-55, wherein the human subject’s susceptibility to cerebral microhemorrhages (mH) is reduced as compared to a reference.57. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 54-56, wherein the reference is a historical reference.58. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 54-56, wherein the reference is a healthy human subject.59. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 54-56, wherein the reference comprises data from the human subject prior to treatment.60. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 32-59, wherein the method is a method for completely and / or partially preventing AD and / or symptoms thereof in the human subject.61. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 32-59, wherein the method is a method for partially and / or completely curing AD and / or symptoms attributed to AD in the human subject.62. In an Embodiment, a kit comprising, at least one dose of a composition comprising an anti-beta amyloid (AP) monoclonal antibody or an AP-binding fragment thereof and instruction for use.63. The kit of Embodiment 62, further comprising an auto-injector.64. The kit of Embodiment 63, wherein the auto-injector comprises the composition comprising an anti-beta amyloid (AP) monoclonal antibody or an AP-binding fragment thereof.65. The kit of any one of Embodiments 62-64, wherein the antibody or AP-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL),wherein the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8.66. The method of any one of Embodiments 1-6, wherein the method of sequentially administering the two or more doses of said antibody or A -binding fragment thereof subcutaneously comprises administering a dose of a first dosage of about 70 mg, a dose of a second dosage of about 210 mg, a dose of a third dosage of about 420 mg, and a dose of a fourth dosage of about 700 mg.67. The method of any one of Embodiments 1-6 or 66, wherein each of the two or more subcutaneously, sequentially administered doses is administered about two weeks apart, optionally wherein each of the two or more subcutaneously, sequentially administered doses is administered in intervals of about two weeks apart.68. The method of any one of Embodiments 1-6, 66 or 67, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) administering one or more doses of a first dosage, wherein each dose of the first dosage is administered about 2 weeks apart;(B) following step (A), administering one or more doses of a second dosage, wherein each dose of the second dosage is administered about 2 weeks apart;(C) following step (B), administering one or more doses of a third dosage, wherein each dose of the third dosage is administered about 2 weeks apart; and(D) following step (C), administering a plurality of doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart.69. The method of any one of Embodiments 1-6 or 66-68, wherein the one or more doses of the first dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first dosage.70. The method of any one of Embodiments 1-6 or 66-69, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first dosage are administered over a total of or within about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.71 . The method of any one of Embodiments 1-6 or 66-70, wherein a first dose of the first dosage is administered on Day 1.72. The method of any one of Embodiments 1-6 or 66-71, wherein a second dose, a third dose, and a fourth dose of the first dosage are administered at about 2 weeks, about 4 weeks, and about 6 weeks, following Day 1, respectively.73. The method of any one of Embodiments 1-6 or 66-72, wherein 2 doses of the first dosage are administered over a total of or within about 4 weeks.74. The method of any one of Embodiments 1-6 or 66-73, wherein 3 doses of the first dosage are administered over a total of or within about 6 weeks.75. The method of any one of Embodiments 1-6 or 66-74, wherein 4 doses of the first dosage are administered over a total of or within about 8 weeks.76. The method of any one of Embodiments 1-6 or 66-75, wherein 5 doses of the first dosage are administered over a total of or within about 10 weeks.77. The method of any one of Embodiments 1-6 or 66-76, wherein the one or more doses of the second dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second dosage.78. The method of any one of Embodiments 1-6 or 66-77, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second dosage are administered over a total of or within about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.79. The method of any one of Embodiments 1-6 or 66-78, wherein a first dose of the second dosage is administered about 2 weeks following administration of a final dose of the first dosage.80. The method of any one of Embodiments 1-6 or 66-79, wherein a first dose, a second dose, a third dose, and a fourth dose of the second dosage are administered about 8 weeks, about 10 weeks, about 12 weeks, and about 14 weeks, following Day 1, respectively.81. The method of any one of Embodiments 1-6 or 66-80, wherein 2 doses of the second dosage are administered over a total of or within about 4 weeks.82. The method of any one of Embodiments 1-6 or 66-81, wherein 3 doses of the second dosage are administered over a total of or within about 6 weeks.83. The method of any one of Embodiments 1-6 or 66-82, wherein 4 doses of the second dosage are administered over a total of or within about 8 weeks.84. The method of any one of Embodiments 1-6 or 66-83, wherein 5 doses of the second dosage are administered over a total of or within about 10 weeks.85. The method of any one of Embodiments 1-6 or 66-84, wherein the one or more doses of the third dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the third dosage.86. The method of any one of Embodiments 1-6 or 66-85, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the third dosage are administered over a total of or within about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.87. The method of any one of Embodiments 1-6 or 66-86, wherein a first dose of the third dosage is administered about 2 weeks following administration of a final dose of the second dosage.88. The method of any one of Embodiments 1-6 or 66-87, wherein a first dose, a second dose, a third dose, and a fourth dose of the third dosage are administered about 16 weeks, about 18 weeks, about 20 weeks, and about 22 weeks, following Day 1, respectively.89. The method of any one of Embodiments 1-6 or 66-88, wherein 2 doses of the third dosage are administered over a total of or within about 4 weeks.90. The method of any one of Embodiments 1-6 or 66-89, wherein 3 doses of the third dosage are administered over a total of or within about 6 weeks.91. The method of any one of Embodiments 1-6 or 66-90, wherein 4 doses of the third dosage are administered over a total of or within about 8 weeks.92. The method of any one of Embodiments 1-6 or 66-91, wherein 5 doses of the third dosage are administered over a total of or within about 10 weeks.93. The method of any one of Embodiments 1-6 or 66-92, wherein a first dose of the fourth dosage is administered about 2 weeks following administration of a final dose of the third dosage.94. The method of any one of Embodiments 1-6 or 66-93, wherein a first dose of the fourth dosage is administered about 24 weeks following Day 1.95. The method of any one of Embodiments 1-6 or 66-94, wherein the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of at least 4 weeks.96. The method of any one of Embodiments 1-6 or 66-95, wherein the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of or within about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 weeks.97. The method of any one of Embodiments 1-6 or 66-96, wherein the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of or within about 26, 52, 78, 104, 130, 156, 182, or 208 weeks.98. The method of any one of Embodiments 1-6 or 66-97, wherein the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of or within about 1-20 years.99. The method of any one of Embodiments 1-6 or 66-98, wherein the plurality of doses of the fourth dosage are administered indefinitely in about 2 week intervals.100. The method of any one of Embodiments 1-6 or 66-99, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) administering 4 doses of a first dosage, wherein each dose of the first dosage is administered about 2 weeks apart over a total of or within about 8 weeks;(B) following step (A), administering 4 doses of a second dosage, wherein each dose of the second dosage is administered about 2 weeks apart over a total of or within about 8 weeks;(C) following step (B), administering 4 doses of a third dosage, wherein each dose of the third dosage is administered about 2 weeks apart over a total of or within about 8 weeks; and(D) following step (C), administering 14 doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart over a total of or within about 28 weeks.101. The method of Embodiment 100, wherein 26 total doses are administered with each dose administered about 2 weeks apart over a total of or within about 52 weeks.102. The method of any one of Embodiments 1-6 or 66-99, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) administering 4 doses of a first dosage, wherein each dose of the first dosage is administered about 2 weeks apart over a total of or within about 8 weeks;(B) following step (A), administering 4 doses of a second dosage, wherein each dose of the second dosage is administered about 2 weeks apart over a total of or within about 8 weeks;(C) following step (B), administering 4 doses of a third dosage, wherein each dose of the third dosage is administered about 2 weeks apart over a total of or within about 8 weeks; and(D) following step (C), administering 27 doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart over a total of or within about 54 weeks.103. The method of Embodiment 102, wherein 39 total doses are administered with each dose administered about 2 weeks apart over a total of or within about 78 weeks.104. The method of any one of Embodiments 1-6 or 66-103, wherein the first dosage is about 70 mg.105. The method of any one of Embodiments 1-6 or 66-104, wherein the second dosage is about 210 mg.106. The method of any one of Embodiments 1-6 or 66-105, wherein the third dosage is about 420 mg.107. The method of any one of Embodiments 1-6 or 66-106, wherein the fourth dosage is about 700 mg.108. The method of any one of Embodiments 1-107, wherein the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously is according to the regimen of FIG. 10.109. The method of any one of Embodiments 1-6, wherein the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously comprises administering a dose of about 210 mg, a dose of about 420 mg, and a dose of about 700 mg.110. The method of any one of Embodiments 1-6 or 109, wherein each of the two or more subcutaneously, sequentially administered doses is administered about two weeks apart, optionally wherein each of the two or more subcutaneously, sequentially administered doses is administered in intervals of about two weeks apart.111. The method of any one of Embodiments 1 -6, 109 or 110, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) administering one or more doses of about 210 mg of the antibody or Ap-binding fragment thereof, wherein each dose is administered about 2 weeks apart;(B) following step (A), administering one or more doses of about 420 mg of the antibody or AP-binding fragment thereof, wherein each dose is administered about 2 weeks apart; and(C) following step (B), administering a plurality of doses of about 700 mg of the antibody or AP-binding fragment thereof, wherein each dose is administered about 2 weeks apart.112. The method of any one of Embodiments 1-6 or 109-111, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the about 210 mg of the antibody or AP-binding fragment thereof are administered over a total of or within about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.113. The method of any one of Embodiments 1-6 or 109-112, wherein a first dose of the about 210 mg of the antibody or Ap-binding fragment thereof is administered on Day 1.114. The method of any one of Embodiments 1-6 or 109-113, wherein a second dose, a third dose, and a fourth dose of the about 210 mg of the antibody or Ap-binding fragment thereof are administered at about 2 weeks, about 4 weeks, and about 6 weeks, following Day 1, respectively.115. The method of any one of Embodiments 1-6 or 109-114, wherein 2 doses of the about210 mg of the antibody or Ap-binding fragment thereof are administered over a total of or within about 4 weeks.116. The method of any one of Embodiments 1-6 or 109-115, wherein 3 doses of the about 210 mg of the antibody or Ap-binding fragment thereof are administered over a total of or within about 6 weeks.117. The method of any one of Embodiments 1-6 or 109-116, wherein 4 doses of the about 210 mg of the antibody or Ap-binding fragment thereof are administered over a total of or within about 8 weeks.118. The method of any one of Embodiments 1-6 or 109-117, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the about 420 mg of the antibody or Ap-binding fragment thereof are administered overa total of or within about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.119. The method of any one of Embodiments 1-6 or 109-118, wherein a first dose of the about 420 mg of the antibody or Ap-binding fragment thereof is administered about 2 weeks following administration of a final dose of the about 210 mg dosage.120. The method of any one of Embodiments 1-6 or 109-119, wherein a first dose, a second dose, a third dose, and a fourth dose of the about 420 mg of the antibody or AP-binding fragment thereof are administered about 8 weeks, about 10 weeks, about 12 weeks, and about 14 weeks, following Day 1, respectively.121. The method of any one of Embodiments 1-6 or 109-120, wherein 2 doses of the about420 mg of the antibody or Ap-binding fragment thereof are administered over a total of or within about 4 weeks.122. The method of any one of Embodiments 1-6 or 109-121, wherein 3 doses of the about420 mg of the antibody or Ap-binding fragment thereof are administered over a total of or within about 6 weeks.123. The method of any one of Embodiments 1-6 or 109-122, wherein 4 doses of the about 420 mg of the antibody or Ap-binding fragment thereof are administered over a total of or within about 8 weeks.124. The method of any one of Embodiments 1-6 or 109-123, wherein a first dose of the about 700 mg of the antibody or AP-binding fragment thereof is administered about 2 weeks following administration of a final dose of the about 420 mg dosage.125. The method of any one of Embodiments 1-6 or 109-124, wherein a first dose of the about 700 mg of the antibody or Ap-binding fragment thereof is administered about 16 weeks following Day 1.126. The method of any one of Embodiments 1-6 or 109-125, wherein the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of at least 4 weeks.127. The method of any one of Embodiments 1-6 or 109-126, wherein the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of or within about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 weeks.128. The method of any one of Embodiments 1-6 or 109-127, wherein the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of or within about 26, 52, 78, 104, 130, 156, 182, or 208 weeks.129. The method of any one of Embodiments 1-6 or 109-128, wherein the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of or within about 1-20 years.130. The method of any one of Embodiments 1-6 or 109-129, wherein the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered indefinitely in about 2 week intervals.131. The method of any one of Embodiments 1 -6, 109 or 110, wherein the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously comprises a titration phase and a target phase.132. The method of Embodiment 131, wherein the titration phase is followed by the target phase.133. The method of any one of Embodiments 1-6, 109-110, or 131-132, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) a titration phase, comprising:(i) administering one or more doses of a first titration dosage, wherein each dose of the first titration dosage is administered about 2 weeks apart;(ii) following step (A)(i), administering one or more doses of a second titration dosage, wherein each dose of the second titration dosage is administered about 2 weeks apart; and(B) following step (A)(ii), a target phase, comprising administering a plurality of doses of a target dosage, wherein each dose of the target dosage is administered about 2 weeks apart during the target phase.134. The method of any one of Embodiments 1-6, 109-110, or 131-133, wherein the titration phase begins with administration of a first dose of the first titration dosage on Day 1.135. The method of any one of Embodiments 1-6, 109-110, or 131-134, wherein the one or more doses of the first titration dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first titration dosage.136. The method of any one of Embodiments 1-6, 109-110, or 131-135, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first titration dosage are administered over a total of or within about 2weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.137. The method of any one of Embodiments 1-6, 109-110, or 131-136, wherein a first dose of the first titration dosage is administered on Day 1.138. The method of any one of Embodiments 1-6, 109-110, or 131-137, wherein a second dose, a third dose, and a fourth dose of the first titration dosage are administered at about 2 weeks, about 4 weeks, and about 6 weeks, following Day 1, respectively.139. The method of any one of Embodiments 1-6, 109-110, or 131-138, wherein 2 doses of the first titration dosage are administered over a total of or within about 4 weeks.140. The method of any one of Embodiments 1-6, 109-110, or 131-139, wherein 3 doses of the first titration dosage are administered over a total of or within about 6 weeks.141. The method of any one of Embodiments 1-6, 109-110, or 131-140, wherein 4 doses of the first titration dosage are administered over a total of or within about 8 weeks.142. The method of any one of Embodiments 1-6, 109-110, or 131-141, wherein 5 doses of the first titration dosage are administered over a total of or within about 10 weeks.143. The method of any one of Embodiments 1-6, 109-110, or 131-142, wherein the one or more doses of the second titration dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second titration dosage.144. The method of any one of Embodiments 1-6, 109-110, or 131-143, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second titration dosage are administered over a total of or within about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.145. The method of any one of Embodiments 1-6, 109-110, or 131-144, wherein a first dose of the second titration dosage is administered about 2 weeks following administration of a final dose of the first titration dosage.146. The method of any one of Embodiments 1-6, 109-110, or 131-145, wherein a first dose, a second dose, a third dose, and a fourth dose of the second titration dosage are administered about 8 weeks, about 10 weeks, about 12 weeks, and about 14 weeks, following Day 1, respectively.147. The method of any one of Embodiments 1-6, 109-110, or 131-146, wherein 2 doses of the second titration dosage are administered over a total of or within about 4 weeks.148. The method of any one of Embodiments 1-6, 109-110, or 131-147, wherein 3 doses of the second titration dosage are administered over a total of or within about 6 weeks.149. The method of any one of Embodiments 1-6, 109-110, or 131-148, wherein 4 doses of the second titration dosage are administered over a total of or within about 8 weeks.150. The method of any one of Embodiments 1-6, 109-110, or 131-149, wherein 5 doses of the second titration dosage are administered over a total of or within about 10 weeks.151. The method of any one of Embodiments 1-6, 109-110, or 131-150, wherein the target phase begins with administration of a first dose of the target dosage about 16 weeks following Day 1.152. The method of any one of Embodiments 1-6, 109-110, or 131-151, wherein a first dose of the target dosage is administered about 2 weeks following administration of a final dose of the second titration dosage.153. The method of any one of Embodiments 1-6, 109-110, or 131-152, wherein a first dose of the target dosage is administered about 16 weeks following Day 1.154. The method of any one of Embodiments 1-6, 109-110, or 131-153, wherein the plurality of doses of the target dosage are administered about 2 weeks apart over a total of at least 4 weeks.155. The method of any one of Embodiments 1-6, 109-110, or 131-154, wherein the plurality of doses of the target dosage are administered about 2 weeks apart over a total of or within about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 weeks.156. The method of any one of Embodiments 1-6, 109-110, or 131-155, wherein the plurality of doses of the target dosage are administered about 2 weeks apart over a total of or within about 26, 52, 78, 104, 130, 156, 182, or 208 weeks.157. The method of any one of Embodiments 1-6, 109-110, or 131-156, wherein the plurality of doses of the target dosage are administered about 2 weeks apart over a total of or within about 1-20 years.158. The method of any one of Embodiments 1-6, 109-110, or 131-157, wherein the plurality of doses of the target dosage are administered indefinitely in about 2 week intervals.159. The method of any one of Embodiments 1-6, 109-110, or 131-158, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) a titration phase, comprising:(i) administering 4 doses of a first titration dosage, wherein each dose of the first titration dosage is administered about 2 weeks apart over a total of or within about 8 weeks;(ii) following step (A)(i), administering 4 doses of a second titration dosage, wherein each dose of the second titration dosage is administered about 2 weeks apart over a total of or within about 8 weeks; and(B) following step (A)(ii), a target phase, comprising administering 31 doses of a target dosage, wherein each dose of the target dosage is administered about 2 weeks apart over a total of or within about 62 weeks during the target phase.160. The method of Embodiment 159, wherein 39 total doses are administered with each dose administered about 2 weeks apart over a total of or within about 78 weeks.161. The method of any one of Embodiments 1 -6, 109- 110, or 131 - 160, wherein the first titration dosage is about 210 mg.162. The method of any one of Embodiments 1-6, 109-110, or 131-161, wherein the second titration dosage is about 420 mg.163. The method of any one of Embodiments 1-6, 109-110, or 131-162, wherein the target dosage is about 700 mg.164. The method of any one of Embodiments 109-163, wherein the method of sequentially administering the two or more doses subcutaneously is exclusive of administering a dose of about 70 mg.165. The method of any one of Embodiments 66-164, wherein the human subject is evaluated 18 weeks after a last dose.166. The method of Embodiment 165, wherein the evaluation comprises a drug and / or patient safety assessment.167. The method of Embodiment 166, wherein the assessment comprises a MRI.168. The method of any one of Embodiments 66-167, wherein the antibody or AP-binding fragment thereof comprises a human IgGl constant region.169. The method of any one of Embodiments 66-168, wherein the antibody or AP-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO: 1, andthe VL comprises SEQ ID NO: 2.170. The method of any one of Embodiments 66-169, wherein two or more doses of the antibody or Ap-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates one or more similar pharmacokinetic / pharmacodynamics (PK / PD) parameter(s) as compared to the same antibody or AP-binding fragment thereof when a single weight-based dose of the antibody or fragment thereof is administered.171. The method of any one of Embodiments 66-170, wherein a 700 mg dose of the antibody or AP-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates one or more similar pharmacokinetic / pharmacodynamics (PK / PD) parameter(s) as compared to the same antibody or Ap-binding fragment thereof when 10 mg / kg of the antibody or fragment thereof is administered.172. The method of Embodiment 170 or Embodiment 171, wherein the one or more PK / PD parameter comprises a measure of AUCinf, AUClast, AUC0-4wk, Cmax, Tmax, T'A, Vd, CL, anti-drug-antibodies (AD As), and / or adverse effects (e.g., headaches, injection site erythema, injection site reaction, injection site pruritus, and / or nausea).173. The method of any one of Embodiments 66-172, wherein the human subject is an ApoE4 carrier.174. The method of any one of Embodiments 66-172, wherein the human subject is not an ApoE4 carrier.175. The method of any one of Embodiments 66-174, wherein the human subject has a reduced susceptibility to amyloid related imaging abnormalities (ARIA) as compared to a reference.176. The method of any one of Embodiments 66-175, wherein the human subject’s susceptibility to vasogenic edema (VE) is reduced as compared to a reference.177. The method of any one of Embodiments 66-176, wherein the human subject’s susceptibility to cerebral microhemorrhages (mH) is reduced as compared to a reference.178. The method of any one of Embodiments 175-177, wherein the reference is a historical reference.179. The method of any one of Embodiments 175-177, wherein the reference is a healthy human subject.180. The method of any one of Embodiments 175-177, wherein the reference comprises data from the human subject prior to treatment.181. The method of any one of Embodiments 66-180, wherein the method is a method for completely and / or partially preventing AD and / or symptoms thereof in the human subject.182. The method of any one of Embodiments 66-180, wherein the method is a method for partially and / or completely curing AD and / or symptoms attributed to AD in the human subject.183. In an Embodiment, a method comprising: a multiple dosage regimen administered to a human subject comprising,(A) administering 4 doses of a recombinant, fully human, anti-beta amyloid (Ap) monoclonal antibody or an Ap-binding fragment thereof to the human subject in an amount of 210 mg about 2 weeks apart over or within about 8 weeks;(B) following step (A), administering 4 doses to the human subject in an amount of 420 mg about 2 weeks apart over or within about 8 weeks; and(C) following step (B), administering 31 doses to the human subject in an amount of 700 mg about 2 weeks apart over or within about 62 weeks; wherein 39 total doses are administered about 2 weeks apart over or within about 78 weeks, wherein the doses are each administered subcutaneously near or at an abdomen of the human subject; wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL); and wherein the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8.184. The method of Embodiment 183, further comprising administering the antibody or Ap~ binding fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.185. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 32-37, wherein the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously comprises:(A) administering 4 doses of an about 210 mg dosage about 2 weeks apart over or within about 8 weeks;(B) following step (A), administering 4 doses of an about 420 mg dosage about 2 weeks apart over or within about 8 weeks; and(C) following step (B), administering 31 doses of an about 700 mg dosage about 2 weeks apart over or within about 62 weeks; wherein 39 total doses are administered about 2 weeks apart over or within about 78 weeks.186. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use of Embodiment 185, wherein the method further comprises administering said antibody or Ap- binding fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.187. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use of Embodiment 185 or Embodiment 186, wherein the human subject is evaluated 18 weeks after a last dose.188. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 187, wherein the evaluation comprises a drug and / or patient safety assessment.189. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 188, wherein the assessment comprises a MRI.190. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 185-189, wherein the antibody or Ap-binding fragment thereof comprises a human IgGl constant region.191. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 185-190, wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO: 1, and the VL comprises SEQ ID NO: 2.192. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 185-191, wherein two or more doses of the antibody or Ap-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates similar pharmacokinetic parameter(s) as compared to the same antibody or Ap-binding fragment thereof when a single weight-based dose of the antibody or fragment thereof is administered.193. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 185-191, wherein a 700 mg dose of the antibody or Ap-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates similar one or more pharmacokinetic / pharmacodynamics (PK / PD) parameter as compared to the same antibody or Ap-binding fragment thereof when 10 mg / kg of the antibody or fragment thereof is administered.194. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to Embodiment 192 or Embodiment 193, wherein the one or more PK / PD parameter comprises a measure of AUCinf, AUClast, AUC0-4wk, Cmax, Tmax, TA, Vd, CL, anti-drug-antibodies (AD As), and / or adverse effects (e.g., headaches, injection site erythema, injection site reaction, injection site pruritus, and / or nausea).195. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 185-194, wherein the human subject is an ApoE4 carrier.196. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 185-194, wherein the human subject is not an ApoE4 carrier.197. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 185-196, wherein the human subject has a reduced susceptibility to amyloid related imaging abnormalities (ARIA) as compared to a reference.198. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 185-197, wherein the human subject’s susceptibility to vasogenic edema (VE) is reduced as compared to a reference.199. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 185-198, wherein the human subject’s susceptibility to cerebral microhemorrhages (mH) is reduced as compared to a reference.200. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 197-199, wherein the reference is a historical reference.201. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 197-199, wherein the reference is a healthy human subject.202. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 197-199, wherein the reference comprises data from the human subject prior to treatment.203. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 185-202, wherein the method is a method for completely and / or partially preventing AD and / or symptoms thereof in the human subject.204. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of Embodiments 185-203, wherein the method is a method for partially and / or completely curing AD and / or symptoms attributed to AD in the human subject.205. The method of any one of Embodiments 183-204, wherein the method is exclusive of administering a dose of about 70 mg.206. The method of any one of Embodiments 109-205, wherein the method of sequentially administering the two or more doses of said antibody or A0-binding fragment thereof subcutaneously is according to the regimen of FIG. 11 A or FIG. 1 IB; optionally wherein the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously is according to the regimen of FIG. 1 IB.207. The method of any one of Embodiments 1-206, wherein the method is a method for treatment of a human patient for Alzheimer’s disease (AD).208. The method of any one of Embodiments 1-207, wherein about 25% or less, about 20% or less, about 15% or less, about 10% or less, or about 5% or less of patients treated according to the method test positive for a treatment-emergent antibody against the subcutaneously administered anti-beta amyloid (A ) monoclonal antibody or the Ap-binding fragment thereof.209. The method of Embodiment 208, wherein about 4.8% of patients treated according to the method test positive for a treatment-emergent antibody against the subcutaneously administered anti-beta amyloid (AP) monoclonal antibody or the Ap-binding fragment thereof.210. The method of any one of Embodiments 1-209, wherein the human subject has a reduction in incidences of headaches and / or a reduction in severity of headaches after receivingthe two or more doses subcutaneously of the anti -beta amyloid (AP) monoclonal antibody or the Ap-binding fragment thereof as compared to a human subject after receiving doses of said antibeta amyloid (AP) monoclonal antibody or said Ap-binding fragment thereof intravenously.211. The method of Embodiment 210, wherein the reduction in incidences of headaches is about 10% or more, about 25% or more, about 40% or more, or about 50% or more.212. The method of Embodiment 210 or Embodiment 211, wherein the reduction in severity of headaches is about 10% or more, about 25% or more, about 40% or more, or about 50% or more.213. The method of any one of Embodiments 1-212, wherein the method administers the recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody.214. The method of Embodiment 213, wherein the recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody is aducanumab.215. The method of any one of Embodiments 1-212, wherein the method administers the Ap- binding fragment of said recombinant, fully human, anti-beta amyloid ( AP) monoclonal antibody.216. The method of Embodiment 215, wherein the Ap-binding fragment of said recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody is Ap-binding fragment of aducanumab.217. The method of any one of Embodiments 1-216, wherein the method results in a reduced rate of immunogenicity, relative to intravenously administering said anti-beta amyloid (AP) antibody or Ap-binding fragment thereof; optionally wherein the method results in a rate of immunogenicity that is reduced by at least 20%, such as by at 30% or by at least 40%, relative to intravenously administering said anti-beta amyloid (AP) antibody or Ap-binding fragment thereof.218. The method of any one of Embodiments 1-217, wherein the method results in a titer of antibodies against the subcutaneously administered anti-beta amyloid (AP) antibody or Ap- binding fragment thereof that is reduced, relative to intravenously administering said anti-beta amyloid (AP) antibody or Ap-binding fragment thereof; optionally wherein the method results in a titer of antibodies against the subcutaneously administered anti-beta amyloid (AP) antibody or Ap-binding fragment thereof that is reduced by at least 20%, such as by at 30% or by at least40%, relative to intravenously administering said anti-beta amyloid (A[3) antibody or A -binding fragment thereof.

[0234] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the claims set forth below.INCORPORATION BY REFERENCE

[0235] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entireties to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Such citations or identifications of any publication, patent, or patent application in this application is not to be construed as an admission that it is prior art to the present application. In case of conflict, the present application, including any definitions herein, will control.

Claims

ClaimsWe claim:

1. A m ethod compri si n : sequentially administering to a human subject two or more doses of a recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody or an A -binding fragment thereof, wherein the two or more doses are each administered subcutaneously near or at an abdomen of the human subject, wherein the antibody or AP-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8.

2. The method of claim 1, wherein sequential administration is performed using an autoinjector.

3. The method of claim 2, wherein the auto-injector further comprises a syringe.

4. The method of claim 3, wherein the syringe comprises a finger flange, plunger rod, and a passive add-on needle guard.

5. The method of any one of claims 2-4, wherein the auto-injector further comprises a mechanical spring.

6. The method of any one of the preceding claims, wherein the two or more doses are administered in the lower abdomen quadrant of the human subject.

7. The method of any one of the preceding claims, further comprising:(A) administering 4 doses of a first dosage about 2 weeks apart over about 8 weeks,(B) 2 weeks after step (A), administering 4 doses of a second dosage about 2 weeks apart over about 8 weeks,(C) 2 weeks after step (B), administering 4 doses of a third dosage about 2 weeks apart over about 8 weeks, and(D) 2 weeks after step (C), administering 4 doses of a fourth dosage about 2 weeks apart over about 26 weeks, wherein 26 total doses are administered about 2 weeks apart over about 50 weeks.

8. The method of claim 7, wherein the first dosage is at least about 70 mg.

9. The method of claim 7, wherein the second dosage is at least about 210 mg.

10. The method of claim 7, wherein the third dosage is at least about 420 mg.

11. The method of claim 7, wherein the fourth dosage is at least about 700 mg.

12. The method of any one of the preceding claims, further comprising administering the antibody or Ap-binding fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.

13. The method of any one of claims 7-12, wherein the human subject is evaluated 18 weeks after a last dose.

14. The method of claim 13, wherein the evaluation comprises a drug and / or patient safety assessment.

15. The method of claim 14, wherein the assessment comprises a MRI.16 The method of any one of the preceding claims, wherein the antibody or A -binding fragment thereof comprises a human IgGl constant region.

17. The method of any one of the preceding claims, wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO: 1, and the VL comprises SEQ ID NO: 2.

18. The method of any one of the preceding claims, wherein two or more doses of the antibody or Ap-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates one or more similar pharmacokinetic / pharmacodynamics (PK / PD) parameter(s) as compared to the same antibody or Ap-binding fragment thereof when a single weight-based dose of the antibody or fragment thereof is administered.

19. The method of any one of claims 1-17, wherein a 700 mg dose of the antibody or AP- binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates one or more similar pharmacokinetic / pharmacodynamics (PK / PD)param eter(s) as compared to the same antibody or Ap-binding fragment thereof when 10 mg / kg of the antibody or fragment thereof is administered.

20. The method of claim 18 or 19, wherein the one or more PK / PD parameter comprises a measure of AUCinf, AUClast, AUC0-4wk, Cmax, Tmax, T’A, Vd, CL, anti-drug-antibodies (ADAs), and / or adverse effects (e.g., headaches, injection site erythema, injection site reaction, injection site pruritus, and / or nausea).

21. The method of any one of the preceding claims, wherein the human subject is an ApoE4 carrier.

22. The method of any one of claims 1-20, wherein the human subject is not an ApoE4 carrier.

23. The method of any one of the preceding claims, wherein the human subject has a reduced susceptibility to amyloid related imaging abnormalities (ARIA) as compared to a reference.

24. The method of any one of claims 1-23, wherein the human subject’s susceptibility to vasogenic edema (VE) is reduced as compared to a reference.

25. The method of any one of claims 1-24, wherein the human subject’s susceptibility to cerebral microhemorrhages (mH) is reduced as compared to a reference.

26. The method of any one of claims 23-25, wherein the reference is a historical reference.

27. The method of any one of claims 23-25, wherein the reference is a healthy human subject.

28. The method of any one of claims 23-25, wherein the reference comprises data from the human subject prior to treatment.

29. The method of any one of claims 1-28, wherein the method is a method for completely and / or partially preventing AD and / or symptoms thereof in the human subject.

30. The method of any one of claims 1-28, wherein the method is a method for partially and / or completely curing AD and / or symptoms attributed to AD in the human subject.

31. A method comprising: a multiple dosage regimen administered to a human subject comprising,(A) administering 4 doses of a recombinant, fully human, anti-beta amyloid (A ) monoclonal antibody or an Ap-binding fragment thereof to the human subject in an amount of 70 mg about 2 weeks apart over about 8 weeks,(B) 2 weeks after step (A), administering 4 doses to the human subject in an amount of 210 mg about 2 weeks apart over about 8 weeks,(C) 2 weeks after step (B), administering 4 doses to the human subject in an amount of 420 mg about 2 weeks apart over about 8 weeks, and(D) 2 weeks after step (C), administering 4 doses to the human subject in an amount of 700 mg about 2 weeks apart over about 26 weeks, wherein 26 total doses are administered about 2 weeks apart over about 50 weeks, wherein the doses are each administered subcutaneously near or at an abdomen of the human subject, wherein the antibody or AP-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8.

32. A recombinant, fully human, anti-amyloid beta monoclonal antibody for use in a method comprising: sequentially administering to a human subject two or more doses of a recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody or an AP-binding fragment thereof, wherein the two or more doses are each administered subcutaneously near or at an abdomen of the human subject, wherein the antibody or AP-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8.

33. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 32, wherein sequential administration is performed using an auto-injector.

34. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 33, wherein the auto-injector further comprises a syringe.

35. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 34, wherein the syringe comprises a finger flange, plunger rod, and a passive add-on needle guard.

36. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 32-35, wherein the auto-injector further comprises a mechanical spring.

37. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding claims, wherein the two or more doses are administered in the lower abdomen quadrant of the human subject.

38. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding claims, further comprising:(A) administering 4 doses of a first dosage about 2 weeks apart over about 8 weeks,(B) 2 weeks after step (A), administering 4 doses of a second dosage about 2 weeks apart over about 8 weeks,(C) 2 weeks after step (B), administering 4 doses of a third dosage about 2 weeks apart over about 8 weeks, and(D) 2 weeks after step (C), administering 4 doses of a fourth dosage about 2 weeks apart over about 26 weeks, wherein 26 total doses are administered about 2 weeks apart over about 50 weeks.

39. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 38, wherein the first dosage is at least about 70 mg.

40. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 38, wherein the second dosage is at least about 210 mg.

41. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 38, wherein the third dosage is at least about 420 mg.

42. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 38, wherein the fourth dosage is at least about 700 mg.

43. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding claims, further comprising administering the antibody or AP-binding fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.

44. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 38-43, wherein the human subject is evaluated 18 weeks after a last dose.

45. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 44, wherein the evaluation comprises a drug and / or patient safety assessment.

46. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 45, wherein the assessment comprises a MRI.

47. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding claims, wherein the antibody or AP-binding fragment thereof comprises a human IgGl constant region.

48. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding claims, wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO: 1, and the VL comprises SEQ ID NO: 2.

49. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding claims, wherein two or more doses of the antibody or Ap- binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates similar pharmacokinetic param eter(s) as compared to the same antibody or Ap-binding fragment thereof when a single weight-based dose of the antibody or fragment thereof is administered.

50. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 32-48, wherein a 700 mg dose of the antibody or Ap-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates similar one or more pharmacokinetic / pharmacodynamics (PK / PD)parameter as compared to the same antibody or Ap-binding fragment thereof when 10 mg / kg of the antibody or fragment thereof is administered.

51. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 49 or 50, wherein the one or more PK / PD parameter comprises a measure of AUCinf, AUClast, AUC0-4wk, Cmax, Tmax, T’A, Vd, CL, anti-drug-antibodies (ADAs), and / or adverse effects (e.g., headaches, injection site erythema, injection site reaction, injection site pruritus, and / or nausea).

52. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding claims, wherein the human subject is an ApoE4 carrier.

53. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 32-51, wherein the human subject is not an ApoE4 carrier.

54. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of the preceding claims, wherein the human subject has a reduced susceptibility to amyloid related imaging abnormalities (ARIA) as compared to a reference.

55. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 32-54, wherein the human subject’s susceptibility to vasogenic edema (VE) is reduced as compared to a reference.

56. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 32-55, wherein the human subject’s susceptibility to cerebral microhemorrhages (mH) is reduced as compared to a reference.

57. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 54-56, wherein the reference is a historical reference.

58. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 54-56, wherein the reference is a healthy human subject.

59. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 54-56, wherein the reference comprises data from the human subject prior to treatment.

60. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 32-59, wherein the method is a method for completely and / or partially preventing AD and / or symptoms thereof in the human subject.

61. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 32-59, wherein the method is a method for partially and / or completely curing AD and / or symptoms attributed to AD in the human subject.

62. A kit comprising, at least one dose of a composition comprising an anti -beta amyloid (AP) monoclonal antibody or an A -binding fragment thereof and instruction for use.

63. The kit of claim 62, further comprising an auto-injector.

64. The kit of claim 63, wherein the auto-injector comprises the composition comprising an anti-beta amyloid (AP) monoclonal antibody or an Ap-binding fragment thereof.

65. The kit of any one of claims 62-64, wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8.

66. The method of any one of claims 1-6, wherein the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously comprises administering a dose of a first dosage of about 70 mg, a dose of a second dosage of about 210 mg, a dose of a third dosage of about 420 mg, and a dose of a fourth dosage of about 700 mg.

67. The method of any one of claims 1-6 or 66, wherein each of the two or more subcutaneously, sequentially administered doses is administered about two weeks apart.

68. The method of any one of claims 1-6, 66 or 67, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) administering one or more doses of a first dosage, wherein each dose of the first dosage is administered about 2 weeks apart;(B) following step (A), administering one or more doses of a second dosage, wherein each dose of the second dosage is administered about 2 weeks apart;(C) following step (B), administering one or more doses of a third dosage, wherein each dose of the third dosage is administered about 2 weeks apart; and(D) following step (C), administering a plurality of doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart.

69. The method of any one of claims 1-6 or 66-68, wherein the one or more doses of the first dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first dosage.

70. The method of any one of claims 1-6 or 66-69, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first dosage are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.

71. The method of any one of claims 1-6 or 66-70, wherein a first dose of the first dosage is administered on Day 1.

72. The method of any one of claims 1-6 or 66-71, wherein a second dose, a third dose, and a fourth dose of the first dosage are administered at about 2 weeks, about 4 weeks, and about 6 weeks, following Day 1, respectively.

73. The method of any one of claims 1-6 or 66-72, wherein 2 doses of the first dosage are administered over a total of about 4 weeks.

74. The method of any one of claims 1-6 or 66-73, wherein 3 doses of the first dosage are administered over a total of about 6 weeks.

75. The method of any one of claims 1-6 or 66-74, wherein 4 doses of the first dosage are administered over a total of about 8 weeks.

76. The method of any one of claims 1-6 or 66-75, wherein 5 doses of the first dosage are administered over a total of about 10 weeks.

77. The method of any one of claims 1-6 or 66-76, wherein the one or more doses of the second dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second dosage.

78. The method of any one of claims 1-6 or 66-77, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second dosage are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.

79. The method of any one of claims 1-6 or 66-78, wherein a first dose of the second dosage is administered about 2 weeks following administration of a final dose of the first dosage.

80. The method of any one of claims 1-6 or 66-79, wherein a first dose, a second dose, a third dose, and a fourth dose of the second dosage are administered about 8 weeks, about 10 weeks, about 12 weeks, and about 14 weeks, following Day 1, respectively.

81. The method of any one of claims 1-6 or 66-80, wherein 2 doses of the second dosage are administered over a total of about 4 weeks.

82. The method of any one of claims 1-6 or 66-81, wherein 3 doses of the second dosage are administered over a total of about 6 weeks.

83. The method of any one of claims 1-6 or 66-82, wherein 4 doses of the second dosage are administered over a total of about 8 weeks.

84. The method of any one of claims 1-6 or 66-83, wherein 5 doses of the second dosage are administered over a total of about 10 weeks.

85. The method of any one of claims 1-6 or 66-84, wherein the one or more doses of the third dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the third dosage.

86. The method of any one of claims 1-6 or 66-85, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the third dosage are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.

87. The method of any one of claims 1-6 or 66-86, wherein a first dose of the third dosage is administered about 2 weeks following administration of a final dose of the second dosage.

88. The method of any one of claims 1-6 or 66-87, wherein a first dose, a second dose, a third dose, and a fourth dose of the third dosage are administered about 16 weeks, about 18 weeks, about 20 weeks, and about 22 weeks, following Day 1, respectively.

89. The method of any one of claims 1-6 or 66-88, wherein 2 doses of the third dosage are administered over a total of about 4 weeks.

90. The method of any one of claims 1-6 or 66-89, wherein 3 doses of the third dosage are administered over a total of about 6 weeks.

91. The method of any one of claims 1-6 or 66-90, wherein 4 doses of the third dosage are administered over a total of about 8 weeks.

92. The method of any one of claims 1-6 or 66-91, wherein 5 doses of the third dosage are administered over a total of about 10 weeks.

93. The method of any one of claims 1-6 or 66-92, wherein a first dose of the fourth dosage is administered about 2 weeks following administration of a final dose of the third dosage.

94. The method of any one of claims 1-6 or 66-93, wherein a first dose of the fourth dosage is administered about 24 weeks following Day 1.

95. The method of any one of claims 1-6 or 66-94, wherein the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of at least 4 weeks.

96. The method of any one of claims 1-6 or 66-95, wherein the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 weeks.

97. The method of any one of claims 1-6 or 66-96, wherein the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of about 26, 52, 78, 104, 130, 156, 182, or 208 weeks.

98. The method of any one of claims 1-6 or 66-97, wherein the plurality of doses of the fourth dosage are administered about 2 weeks apart over a total of about 1-20 years.

99. The method of any one of claims 1-6 or 66-98, wherein the plurality of doses of the fourth dosage are administered indefinitely in about 2 week intervals.

100. The method of any one of claims 1-6 or 66-99, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) administering 4 doses of a first dosage, wherein each dose of the first dosage is administered about 2 weeks apart over a total of about 8 weeks;(B) following step (A), administering 4 doses of a second dosage, wherein each dose of the second dosage is administered about 2 weeks apart over a total of about 8 weeks;(C) following step (B), administering 4 doses of a third dosage, wherein each dose of the third dosage is administered about 2 weeks apart over a total of about 8 weeks; and(D) following step (C), administering 14 doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart over a total of about 28 weeks.

101. The method of claim 100, wherein 26 total doses are administered with each dose administered about 2 weeks apart over a total of about 52 weeks.

102. The method of any one of claims 1-6 or 66-99, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) administering 4 doses of a first dosage, wherein each dose of the first dosage is administered about 2 weeks apart over a total of about 8 weeks;(B) following step (A), administering 4 doses of a second dosage, wherein each dose of the second dosage is administered about 2 weeks apart over a total of about 8 weeks;(C) following step (B), administering 4 doses of a third dosage, wherein each dose of the third dosage is administered about 2 weeks apart over a total of about 8 weeks; and(D) following step (C), administering 27 doses of a fourth dosage, wherein each dose of the fourth dosage is administered about 2 weeks apart over a total of about 54 weeks.

103. The method of claim 102, wherein 39 total doses are administered with each dose administered about 2 weeks apart over a total of about 78 weeks.

104. The method of any one of claims 1-6 or 66-103, wherein the first dosage is about 70 mg.

105. The method of any one of claims 1-6 or 66-104, wherein the second dosage is about 210 mg.

106. The method of any one of claims 1-6 or 66-105, wherein the third dosage is about 420 mg.

107. The method of any one of claims 1-6 or 66-106, wherein the fourth dosage is about 700 mg.

108. The method of any one of claims 1-107, wherein the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously is according to the regimen of FIG. 10.

109. The method of any one of claims 1-6, wherein the method of sequentially administering the two or more doses of said antibody or A -binding fragment thereof subcutaneously comprises administering a dose of about 210 mg, a dose of about 420 mg, and a dose of about 700 mg.

110. The method of any one of claims 1-6 or 109, wherein each of the two or more subcutaneously, sequentially administered doses is administered about two weeks apart.

111. The method of any one of claims 1-6, 109 or 110, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) administering one or more doses of about 210 mg of the antibody or Ap-binding fragment thereof, wherein each dose is administered about 2 weeks apart;(B) following step (A), administering one or more doses of about 420 mg of the antibody or AP-binding fragment thereof, wherein each dose is administered about 2 weeks apart; and(C) following step (B), administering a plurality of doses of about 700 mg of the antibody or Ap-binding fragment thereof, wherein each dose is administered about 2 weeks apart.

112. The method of any one of claims 1-6 or 109-111, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the about 210 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.

113. The method of any one of claims 1-6 or 109-112, wherein a first dose of the about 210 mg of the antibody or Ap-binding fragment thereof is administered on Day 1 .

114. The method of any one of claims 1-6 or 109-113, wherein a second dose, a third dose, and a fourth dose of the about 210 mg of the antibody or Ap-binding fragment thereof are administered at about 2 weeks, about 4 weeks, and about 6 weeks, following Day 1, respectively.

115. The method of any one of claims 1-6 or 109-114, wherein 2 doses of the about 210 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 4 weeks.

116. The method of any one of claims 1-6 or 109-115, wherein 3 doses of the about 210 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 6 weeks.

117. The method of any one of claims 1-6 or 109-116, wherein 4 doses of the about 210 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 8 weeks.

118. The method of any one of claims 1-6 or 109-117, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the about 420 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.

119. The method of any one of claims 1-6 or 109-118, wherein a first dose of the about 420 mg of the antibody or Ap-binding fragment thereof is administered about 2 weeks following administration of a final dose of the about 210 mg dosage.

120. The method of any one of claims 1-6 or 109-119, wherein a first dose, a second dose, a third dose, and a fourth dose of the about 420 mg of the antibody or AP-binding fragment thereof are administered about 8 weeks, about 10 weeks, about 12 weeks, and about 14 weeks, following Day 1, respectively.

121. The method of any one of claims 1-6 or 109-120, wherein 2 doses of the about 420 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 4 weeks.

122. The method of any one of claims 1-6 or 109-121, wherein 3 doses of the about 420 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 6 weeks.

123. The method of any one of claims 1-6 or 109-122, wherein 4 doses of the about 420 mg of the antibody or Ap-binding fragment thereof are administered over a total of about 8 weeks.

124. The method of any one of claims 1-6 or 109-123, wherein a first dose of the about 700 mg of the antibody or Ap-binding fragment thereof is administered about 2 weeks following administration of a final dose of the about 420 mg dosage.

125. The method of any one of claims 1-6 or 109-124, wherein a first dose of the about 700 mg of the antibody or Ap-binding fragment thereof is administered about 16 weeks following Day 1.

126. The method of any one of claims 1-6 or 109-125, wherein the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of at least 4 weeks.

127. The method of any one of claims 1-6 or 109-126, wherein the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 weeks.

128. The method of any one of claims 1-6 or 109-127, wherein the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of about 26, 52, 78, 104, 130, 156, 182, or 208 weeks.

129. The method of any one of claims 1-6 or 109-128, wherein the plurality of doses of the about 700 mg of the antibody or Ap-binding fragment thereof are administered about 2 weeks apart over a total of about 1-20 years.

130. The method of any one of claims 1-6 or 109-129, wherein the plurality of doses of the about 700 mg of the antibody or AP-binding fragment thereof are administered indefinitely in about 2 week intervals.

131. The method of any one of claims 1-6, 109 or 110, wherein the method of sequentially administering the two or more doses of said antibody or AP-binding fragment thereof subcutaneously comprises a titration phase and a target phase.

132. The method of claim 131, wherein the titration phase is followed by the target phase.

133. The method of any one of claims 1-6, 109-110, or 131-132, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) a titration phase, comprising:(i) administering one or more doses of a first titration dosage, wherein each dose of the first titration dosage is administered about 2 weeks apart;(ii) following step (A)(i), administering one or more doses of a second titration dosage, wherein each dose of the second titration dosage is administered about 2 weeks apart; and(B) following step (A)(ii), a target phase, comprising administering a plurality of doses of a target dosage, wherein each dose of the target dosage is administered about 2 weeks apart during the target phase.

134. The method of any one of claims 1-6, 109-110, or 131-133, wherein the titration phase begins with administration of a first dose of the first titration dosage on Day 1.

135. The method of any one of claims 1-6, 109-110, or 131-134, wherein the one or more doses of the first titration dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first titration dosage.

136. The method of any one of claims 1-6, 109-110, or 131-135, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the first titration dosage are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.

137. The method of any one of claims 1-6, 109-110, or 131-136, wherein a first dose of the first titration dosage is administered on Day 1.

138. The method of any one of claims 1-6, 109-110, or 131-137, wherein a second dose, a third dose, and a fourth dose of the first titration dosage are administered at about 2 weeks, about 4 weeks, and about 6 weeks, following Day 1, respectively.

139. The method of any one of claims 1-6, 109-110, or 131-138, wherein 2 doses of the first titration dosage are administered over a total of about 4 weeks.

140. The method of any one of claims 1-6, 109-110, or 131-139, wherein 3 doses of the first titration dosage are administered over a total of about 6 weeks.

141. The method of any one of claims 1-6, 109-110, or 131-140, wherein 4 doses of the first titration dosage are administered over a total of about 8 weeks.

142. The method of any one of claims 1-6, 109-110, or 131-141, wherein 5 doses of the first titration dosage are administered over a total of about 10 weeks.

143. The method of any one of claims 1-6, 109-110, or 131-142, wherein the one or more doses of the second titration dosage is 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second titration dosage.

144. The method of any one of claims 1-6, 109-110, or 131-143, wherein 1, 2, 3, 4, 5, 6, 7, or 8 doses of the second titration dosage are administered over a total of about 2 weeks, about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, or about 16 weeks, respectively.

145. The method of any one of claims 1-6, 109-110, or 131-144, wherein a first dose of the second titration dosage is administered about 2 weeks following administration of a final dose of the first titration dosage.

146. The method of any one of claims 1-6, 109-110, or 131-145, wherein a first dose, a second dose, a third dose, and a fourth dose of the second titration dosage are administered about 8 weeks, about 10 weeks, about 12 weeks, and about 14 weeks, following Day 1, respectively.

147. The method of any one of claims 1-6, 109-110, or 131-146, wherein 2 doses of the second titration dosage are administered over a total of about 4 weeks.

148. The method of any one of claims 1-6, 109-110, or 131-147, wherein 3 doses of the second titration dosage are administered over a total of about 6 weeks.

149. The method of any one of claims 1-6, 109-110, or 131-148, wherein 4 doses of the second titration dosage are administered over a total of about 8 weeks.

150. The method of any one of claims 1-6, 109-110, or 131-149, wherein 5 doses of the second titration dosage are administered over a total of about 10 weeks.

151. The method of any one of claims 1-6, 109-110, or 131-150, wherein the target phase begins with administration of a first dose of the target dosage about 16 weeks following Day 1.

152. The method of any one of claims 1-6, 109-110, or 131-151, wherein a first dose of the target dosage is administered about 2 weeks following administration of a final dose of the second titration dosage.

153. The method of any one of claims 1-6, 109-110, or 131-152, wherein a first dose of the target dosage is administered about 16 weeks following Day 1.

154. The method of any one of claims 1-6, 109-110, or 131-153, wherein the plurality of doses of the target dosage are administered about 2 weeks apart over a total of at least 4 weeks.

155. The method of any one of claims 1-6, 109-110, or 131-154, wherein the plurality of doses of the target dosage are administered about 2 weeks apart over a total of about 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 weeks.

156. The method of any one of claims 1-6, 109-110, or 131-155, wherein the plurality of doses of the target dosage are administered about 2 weeks apart over a total of about 26, 52, 78, 104, 130, 156, 182, or 208 weeks.

157. The method of any one of claims 1-6, 109-110, or 131-156, wherein the plurality of doses of the target dosage are administered about 2 weeks apart over a total of about 1-20 years.

158. The method of any one of claims 1-6, 109-110, or 131-157, wherein the plurality of doses of the target dosage are administered indefinitely in about 2 week intervals.

159. The method of any one of claims 1-6, 109-110, or 131-158, wherein the method of sequentially administering the two or more doses subcutaneously comprises:(A) a titration phase, comprising:(i) administering 4 doses of a first titration dosage, wherein each dose of the first titration dosage is administered about 2 weeks apart over a total of about 8 weeks;(ii) following step (A)(i), administering 4 doses of a second titration dosage, wherein each dose of the second titration dosage is administered about 2 weeks apart over a total of about 8 weeks; and(B) following step (A)(ii ), a target phase, comprising administering 31 doses of a target dosage, wherein each dose of the target dosage is administered about 2 weeks apart over a total of about 62 weeks during the target phase.

160. The method of claim 159, wherein 39 total doses are administered with each dose administered about 2 weeks apart over a total of about 78 weeks.

161. The method of any one of claims 1-6, 109-110, or 131-160, wherein the first titration dosage is about 210 mg.

162. The method of any one of claims 1 -6, 109- 110, or 131-161, wherein the second titration dosage is about 420 mg.

163. The method of any one of claims 1-6, 109-110, or 131-162, wherein the target dosage is about 700 mg.

164. The method of any one of claims 109-163, wherein the method of sequentially administering the two or more doses subcutaneously is exclusive of administering a dose of about 70 mg.

165. The method of any one of claims 66-164, wherein the human subject is evaluated 18 weeks after a last dose.

166. The method of claim 165, wherein the evaluation comprises a drug and / or patient safety assessment.

167. The method of claim 166, wherein the assessment comprises a MRI.

168. The method of any one of claims 66-167, wherein the antibody or Ap-binding fragment thereof comprises a human IgGl constant region.

169. The method of any one of claims 66-168, wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO: 1, and the VL comprises SEQ ID NO: 2.

170. The method of any one of claims 66-169, wherein two or more doses of the antibody or Ap-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates one or more similar pharmacokinetic / pharmacodynamics (PK / PD) parameter(s) as compared to the same antibody or Ap-binding fragment thereof when a single weight-based dose of the antibody or fragment thereof is administered.

171. The method of any one of claims 66-170, wherein a 700 mg dose of the antibody or AP- binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates one or more similar pharmacokinetic / pharmacodynamics (PK / PD)param eter(s) as compared to the same antibody or Ap-binding fragment thereof when 10 mg / kg of the antibody or fragment thereof is administered.

172. The method of claim 170 or claim 171, wherein the one or more PK / PD parameter comprises a measure of AUCinf, AUClast, AUC0-4wk, Cmax, Tmax, T'A, Vd, CL, anti-drug- antibodies (ADAs), and / or adverse effects (e.g., headaches, injection site erythema, injection site reaction, injection site pruritus, and / or nausea).

173. The method of any one of claims 66-172, wherein the human subject is an ApoE4 carrier.

174. The method of any one of claims 66-172, wherein the human subject is not an ApoE4 carrier.

175. The method of any one of claims 66-174, wherein the human subject has a reduced susceptibility to amyloid related imaging abnormalities (ARIA) as compared to a reference.

176. The method of any one of claims 66-175, wherein the human subject’s susceptibility to vasogenic edema (VE) is reduced as compared to a reference.

177. The method of any one of claims 66-176, wherein the human subject’s susceptibility to cerebral microhemorrhages (mH) is reduced as compared to a reference.

178. The method of any one of claims 175-177, wherein the reference is a historical reference.

179. The method of any one of claims 175-177, wherein the reference is a healthy human subject.

180. The method of any one of claims 175-177, wherein the reference comprises data from the human subject prior to treatment.

181. The method of any one of claims 66-180, wherein the method is a method for completely and / or partially preventing AD and / or symptoms thereof in the human subject.

182. The method of any one of claims 66-180, wherein the method is a method for partially and / or completely curing AD and / or symptoms attributed to AD in the human subject.

183. A method comprising: a multiple dosage regimen administered to a human subject comprising,(A) administering 4 doses of a recombinant, fully human, anti-beta amyloid (A ) monoclonal antibody or an Ap-binding fragment thereof to the human subject in an amount of 210 mg about 2 weeks apart over about 8 weeks;(B) following step (A), administering 4 doses to the human subject in an amount of 420 mg about 2 weeks apart over about 8 weeks; and(C) following step (B), administering 31 doses to the human subject in an amount of 700 mg about 2 weeks apart over about 62 weeks; wherein 39 total doses are administered about 2 weeks apart over about 78 weeks, wherein the doses are each administered subcutaneously near or at an abdomen of the human subject; wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL); and wherein the VH comprises a complementarity determining region 1 (HCDR1) with the amino acid sequence set forth in SEQ ID NO: 3, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 4, and a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 5, and wherein the VL comprises a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 6, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 7, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 8.

184. The method of claim 183, further comprising administering the antibody or Ap-binding fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.

185. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 32-37, wherein the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously comprises:(A) administering 4 doses of an about 210 mg dosage about 2 weeks apart over about 8 weeks;(B) following step (A), administering 4 doses of an about 420 mg dosage about 2 weeks apart over about 8 weeks; and(C) following step (B), administering 31 doses of an about 700 mg dosage about 2 weeks apart over about 62 weeks; wherein 39 total doses are administered about 2 weeks apart over about 78 weeks.

186. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use of claim 185, wherein the method further comprises administering said antibody or Ap-binding fragment thereof to the human subject in 2 week intervals indefinitely in an amount of 700 mg.

187. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use of claim 185 or claim 186, wherein the human subject is evaluated 18 weeks after a last dose.

188. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 187, wherein the evaluation comprises a drug and / or patient safety assessment.

189. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 188, wherein the assessment comprises a MRI.

190. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 185-189, wherein the antibody or Ap-binding fragment thereof comprises a human IgGl constant region.

191. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 185-190, wherein the antibody or Ap-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises SEQ ID NO: 1, and the VL comprises SEQ ID NO: 2.

192. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 185-191, wherein two or more doses of the antibody or Ap- binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates similar pharmacokinetic param eter(s) as compared to the same antibody or Ap-binding fragment thereof when a single weight-based dose of the antibody or fragment thereof is administered.

193. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 185-191, wherein a 700 mg dose of the antibody or Ap-binding fragment thereof, when sequentially administered in tissue near or at an abdomen of the human subject, demonstrates similar one or more pharmacokinetic / pharmacodynamics (PK / PD) parameter as compared to the same antibody or Ap-binding fragment thereof when 10 mg / kg of the antibody or fragment thereof is administered.

194. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to claim 192 or claim 193, wherein the one or more PK / PD parameter comprises a measure of AUCinf, AUClast, AUC0-4wk, Cmax, Tmax, T’A, Vd, CL, anti-drug-antibodies(AD As), and / or adverse effects (e.g., headaches, injection site erythema, injection site reaction, injection site pruritus, and / or nausea).

195. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 185-194, wherein the human subject is an ApoE4 carrier.

196. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 185-194, wherein the human subject is not an ApoE4 carrier.

197. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 185-196, wherein the human subject has a reduced susceptibility to amyloid related imaging abnormalities (ARIA) as compared to a reference.

198. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 185-197, wherein the human subject’s susceptibility to vasogenic edema (VE) is reduced as compared to a reference.

199. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 185-198, wherein the human subject’s susceptibility to cerebral microhemorrhages (mH) is reduced as compared to a reference.

200. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 197-199, wherein the reference is a historical reference.

201. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 197-199, wherein the reference is a healthy human subject.

202. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 197-199, wherein the reference comprises data from the human subject prior to treatment.

203. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 185-202, wherein the method is a method for completely and / or partially preventing AD and / or symptoms thereof in the human subject.

204. The recombinant, fully human, anti-amyloid beta monoclonal antibody for use according to any one of claims 185-203, wherein the method is a method for partially and / or completely curing AD and / or symptoms attributed to AD in the human subject.

205. The method of any one of claims 183-204, wherein the method is exclusive of administering a dose of about 70 mg.

206. The method of any one of claims 109-205, wherein the method of sequentially administering the two or more doses of said antibody or Ap-binding fragment thereof subcutaneously is according to the regimen of FIG. 11A or FIG. 1 IB; optionally wherein the method of sequentially administering the two or more doses of said antibody or A -binding fragment thereof subcutaneously is according to the regimen of FIG. 1 IB.

207. The method of any one of claims 1-206, wherein the method is a method for treatment of a human patient for Alzheimer’s disease (AD).

208. The method of any one of claims 1-207, wherein about 25% or less, about 20% or less, about 15% or less, about 10% or less, or about 5% or less of patients treated according to the method test positive for a treatment-emergent antibody against the subcutaneously administered anti-beta amyloid (AP) monoclonal antibody or the Ap-binding fragment thereof.

209. The method of claim 208, wherein about 4.8% of patients treated according to the method test positive for a treatment-emergent antibody against the subcutaneously administered anti-beta amyloid (AP) monoclonal antibody or the Ap-binding fragment thereof.

210. The method of any one of claims 1-209, wherein the human subject has a reduction in incidences of headaches and / or a reduction in severity of headaches after receiving the two or more doses subcutaneously of the anti-beta amyloid (AP) monoclonal antibody or the Ap- binding fragment thereof as compared to a human subject after receiving doses of said anti -beta amyloid (AP) monoclonal antibody or said Ap-binding fragment thereof intravenously.

211. The method of claim 210, wherein the reduction in incidences of headaches is about 10% or more, about 25% or more, about 40% or more, or about 50% or more.

212. The method of claim 210 or claim 211, wherein the reduction in severity of headaches is about 10% or more, about 25% or more, about 40% or more, or about 50% or more.

213. The method of any one of claims 1-212, wherein the method administers the recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody.

214. The method of claim 213, wherein the recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody is aducanumab.

215. The method of any one of claims 1-212, wherein the method administers the Ap-binding fragment of said recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody.

216. The method of claim 215, wherein the Ap-binding fragment of said recombinant, fully human, anti-beta amyloid (AP) monoclonal antibody is Ap-binding fragment of aducanumab.

217. The method of any one of claims 1-216, wherein the method results in a reduced rate of immunogenicity, relative to intravenously administering said anti-beta amyloid (A ) antibody or AP-binding fragment thereof; optionally wherein the method results in a rate of immunogenicity that is reduced by at least 20%, such as by at 30% or by at least 40%, relative to intravenously administering said anti-beta amyloid (AP) antibody or AP-binding fragment thereof.

218. The method of any one of claims 1-217, wherein the method results in a titer of antibodies against the subcutaneously administered anti-beta amyloid (AP) antibody or Ap- binding fragment thereof that is reduced, relative to intravenously administering said anti-beta amyloid (AP) antibody or AP-binding fragment thereof; optionally wherein the method results in a titer of antibodies against the subcutaneously administered anti-beta amyloid (AP) antibody or Ap-binding fragment thereof that is reduced by at least 20%, such as by at 30% or by at least 40%, relative to intravenously administering said anti-beta amyloid (AP) antibody or AP- binding fragment thereof.

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