Therapeutic use of bispecific anti-Aβ / TfR antibodies

Abstract

We provide therapeutic antibodies for the treatment of neurological diseases, particularly Alzheimer's disease. [Solution] A bispecific anti-Aβ / TfR antibody is provided for use as a pharmaceutical in the treatment of Alzheimer's disease, which specifically binds to human Aβ protein and human transferrin receptor (bispecific anti-Aβ / TfR antibody), and the antibody is administered intravenously once every four weeks at a dose of 0.2 mg / kg to 7.2 mg / kg.

Description

Technical Field

[0001] The present invention is in the field of therapeutic antibodies for the treatment of neurological diseases, particularly Alzheimer's disease. More specifically, the present specification reports the therapeutic use of troncimab, a bispecific anti-Aβ / TfR antibody that targets human Aβ protein and has active blood-brain barrier passage by binding to the human transferrin receptor (TFR).

Background Art

[0002] The World Health Organization (WHO) estimates that over 55 million people worldwide live with dementia and 10 million new cases are diagnosed each year (World Health Organization (2023)). The total number of people with dementia is estimated to reach 78 million by 2030 and 139 million by 2050 (Alzheimer's Disease International (2022)). Alzheimer's disease (AD) is the most common form of dementia, accounting for 60% - 70% of cases (World Health Organization 2023). The prevalence of AD increases with age, and the global prevalence in people aged 60 and over is 5% - 8%.

[0003] Although AD was identified over 100 years ago, despite significant efforts to develop disease-modifying therapeutics, the cognitive decline in AD has remained unsatisfactory (Zhao et al., Int. J. Nanomed. 18 (2023) 7825 - 7845).

[0004] Alzheimer's disease is clinically characterized by progressive cognitive impairment, resulting in a decline in function and a gradual loss of independence (Mesterton, J., et al., Curr. Alz. Res. 7 (2010) 358-367). There is significant inter-individual variability (IIV) in the progression of AD, and survival rates depend on many factors, including age at onset. Generally, the clinical picture progresses from "predementia" or "prodromal AD" to mild, moderate, and then severe AD. In the early stages of AD, slight impairments in memory, language, and visuospatial function can be observed. As AD progresses, patients gradually experience impairments not only in cognitive functions but also in daily living activities, significantly increasing the burden on caregivers. The median survival time after diagnosis of AD depends on the patient's age at diagnosis, ranging from 8.3 years for those diagnosed at age 65 to 3.4 years for those diagnosed at age 90 (Brookmeyer, R., et al., Arch. Neurol. 59 (2002) 1764-1767). On average, individuals survive for 6 years after diagnosis of AD (Helzner, EP, et al., Neurol. 71 (2008) 1489-1495).

[0005] Due to its increasing prevalence, human burden, long duration, and high treatment costs, Alzheimer's disease (AD) is expected to remain a major public health problem.

[0006] The neuropathological features of Alzheimer's disease (AD) include extracellular amyloid plaques formed from entanglements of neurofibrillary fibers within neurons, consisting of insoluble amyloid-beta (Aβ) protein and hyperphosphorylated tau filaments (Bloom, GS, JAMA Neurol. 71(2014) 505-508). Although the etiology of AD is not fully understood, current research suggests that Aβ protein processing and deposition play a crucial role in a cascade of biological events involved in the development of pathological Aβ protein, which is presumed to be the primary cause of memory loss and cognitive deterioration in the early stages of AD. New evidence from several independent amyloid-removing mAbs has identified a relationship between reduced Aβ plaques and improved cognition (see, e.g., Selkoe, D.J. and Hardy, J., EMBO Molec. Med. 8(2016) 595-608; Kulic, L., et al. AD / PD 2021, presented at virtual conference). Aβ proteins originate from the proteolytic processing of amyloid-beta precursor protein (APP). These proteins exist in two main forms: Aβ1-40 and Aβ1-42 (Citron, M., Trends Pharmacol. Sci. 25(2004) 92-97). Accumulation in the brain begins up to 20 years before the onset of clinical dementia in Alzheimer's disease (AD), triggering a series of downstream events resulting in synaptic dysfunction, inflammation, neurodegeneration, and clinical symptoms (Selkoe, D.J. and Hardy, J., EMBO Mol.). Consequently, therapies targeting this process, particularly Aβ proteins, have the potential to significantly alter disease progression.

[0007] Unfortunately, the binding of Aβ proteins, i.e., therapeutic targets, is associated with adverse events. More specifically, recently approved standard monoclonal anti-Aβ antibodies show only effective amyloid reduction and a moderate progression delay of 27–35% with an ARIA rate of 13–25% within 1.5 years of treatment. Therefore, there is a high unmet need for more effective, safer, and more convenient treatments.

[0008] Zhao et al. reported that the recent successive approvals of anti-amyloid-beta monoclonal antibodies as disease-modifying therapies for Alzheimer's disease have strengthened confidence in the development of anti-Alzheimer's therapies. However, current treatments still face the dilemma of significant adverse reactions and limited efficacy (Int.J.Nanomed.18(2023)7825-7845).

[0009] The current opinion in this field is that rapid and efficient clearance of aggregated Aβ proteins is a necessary condition for achieving significant clinical effects. [Overview of the Initiative]

[0010] The aforementioned shortcomings of current anti-Aβ protein therapies are overcome by the present invention.

[0011] This invention is at least in part based on the finding that intravenous administration of trontinemab at a dose of 1.8 mg / kg once every four weeks results in a mean change from baseline of -65.3 centiloids (range -102.8 to -42.6) by the nominal visit after nominal dose 3 has already been administered (mean number of given doses: 2.8).

[0012] Therefore, it was found that rapid amyloid plaque (Aβ protein plaque) clearance can be achieved at remarkably lower dose levels than with standard typical anti-Aβ monoclonal antibodies using the Brainshuttle® approach of transferrin receptor-based (TfR-based) trontinemab. Brainshuttle® technology has been shown to enable higher brain exposure and broader CNS distribution compared to standard IgG, i.e., non-Brainshuttle® antibodies.

[0013] Therefore, trontinemab, along with its structural and functional equivalents, may be the best amyloid-reducing treatment for this disease, possessing superior efficacy, safety, and convenience compared to standard antibodies, by slowing the rate of disease progression, for example, by at least half, and keeping the risk of ARIA relatively low. For example, one aspect of the present invention relates to a bispecific antibody (bispecific anti-Aβ / TfR antibody) that specifically binds to human Aβ protein and human transferrin receptor for use as a pharmaceutical in the treatment of Alzheimer's disease, wherein the antibody is administered intravenously once every four weeks at a dose of 0.2 mg / kg to 7.2 mg / kg.

[0014] An exemplary aspect of the present invention relates to a pharmaceutical composition for treating prodromal to mild Alzheimer's disease (AD), comprising administering a bispecific anti-Aβ / TfR antibody in an intravenous dose of 0.2 mg / kg to 7.2 mg / kg once every four weeks to a patient / animal having prodromal to mild Alzheimer's disease.

[0015] An exemplary embodiment of the present invention relates to a bispecific anti-Aβ / TfR antibody for use in the treatment of Alzheimer's disease, wherein the antibody is administered intravenously at a dose of 0.2 mg / kg to 7.2 mg / kg once every four weeks.

[0016] In one embodiment, administration of a bispecific anti-Aβ / TfR antibody composition results in at least 30% of subjects being amyloid-negative, as determined by visual reading of amyloid PET images after 3 months of administration (3 doses) of the antibody composition. Therefore, in one embodiment, administration of the antibody composition results in the subjects being determined to be amyloid-negative, as determined by visual reading of amyloid PET images after 3 months of administration (3 doses) of the antibody composition. Preferably, 30-70% of subjects are amyloid-negative, as determined by visual reading of amyloid PET images after 3-6 months of administration (3-6 doses) of the antibody composition. Therefore, in one embodiment, administration of the antibody composition results in the subjects being determined to be amyloid-negative, as determined by visual reading of amyloid PET images after 3-6 months of administration (3-6 doses) of the antibody composition.

[0017] In one exemplary embodiment, administration of the antibody composition results in at least 70% of subjects being amyloid-negative, as determined by visual reading of amyloid PET images after 4–6 months of administration (3–6 doses) of the antibody composition. Therefore, in one embodiment, administration of the antibody composition results in the subjects being determined to be amyloid-negative, as determined by visual reading of amyloid PET images after 4–6 months of administration (3–6 doses) of the antibody composition.

[0018] In one embodiment, the bispecific anti-Aβ / TfR antibody is i) Form a binding site that specifically binds to human Aβ protein fragments Aβ1-42, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, ii) Form a binding site that specifically binds to human transferrin receptor 1, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including Includes.

[0019] In one embodiment, the bispecific anti-Aβ / TfR antibody is trontinemab (RG6102). In one embodiment, trontinemab uses receptor-mediated transcellular transport to cross the blood-brain barrier. In one embodiment, trontinemab uses a transcellular pathway to cross the blood-brain barrier.

[0020] In one embodiment, the treatment is for a subject diagnosed with mild Alzheimer's disease.

[0021] In one embodiment, the treatment is for a subject diagnosed with mild to moderate Alzheimer's disease.

[0022] In one embodiment, the treatment is the treatment of a subject diagnosed with prodromal Alzheimer's disease.

[0023] In certain embodiments, administration of the bispecific anti-Aβ / TfR antibody reduces amyloid levels from amyloid positive to amyloid negative when determined by PET imaging within 12 weeks. PET imaging is performed using florbetapir or florbetaben in certain embodiments. Administration is performed once every 4 weeks (Q4W) in certain embodiments. Administration is performed intravenously in certain embodiments. In certain embodiments, rapid amyloid plaque clearance with troncizumab is achieved at significantly lower dose levels than typical anti-amyloid monoclonal antibodies. Typical anti-amyloid antibodies are aducanumab or / and lecanemab in certain embodiments.

[0024] In certain embodiments, administration of the bispecific anti-Aβ / TfR antibody reduces amyloid levels from, for example, 50 centiloids or more as determined by PET imaging before the start of administration to, for example, 24 centiloids or less as determined by the same PET imaging within 12 weeks after the start of administration. PET imaging is performed using florbetapir or florbetaben in certain embodiments. Administration is performed once every 4 weeks (Q4W) in certain embodiments. Administration is performed intravenously in certain embodiments. In certain embodiments, rapid amyloid plaque clearance is achieved at significantly lower dose levels than typical anti-amyloid monoclonal antibodies. Typical anti-amyloid antibodies are aducanumab or / and lecanemab in certain embodiments.

[0025] In certain embodiments, administration of the bispecific anti-Aβ / TfR antibody reduces amyloid levels by at least 40 centiloids relative to placebo when determined by visual reading of amyloid PET.

[0026] In certain embodiments, administration of the bispecific anti-Aβ / TfR antibody reduces amyloid levels within 3 months after the start of antibody administration.

[0027] In one embodiment, no further Alzheimer's disease drugs other than trontinemab are administered.

[0028] In one embodiment, the bispecific anti-Aβ / TfR antibody is administered in doses of 1.8 mg / kg to 7.2 mg / kg.

[0029] In one embodiment, the bispecific anti-Aβ / TfR antibody is administered at a dose of 1.8 mg / kg to 3.6 mg / kg.

[0030] In one embodiment, Aβ is human Aβ protein fragments 1-42, and the transferrin receptor is human transfer receptor 1.

[0031] In one embodiment, the bispecific anti-Aβ / TfR antibody is administered at lower doses of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject after several doses. In one embodiment, the number of doses is 3 to 60.

[0032] In some embodiments, administration of a bispecific anti-Aβ / TfR antibody results in low levels of drug-related adverse events. For example, in some embodiments, but not limited to, the level of drug-related adverse events can be reduced compared to aducanumab and / or lecanemab. In some embodiments, the drug-related adverse event is amyloid-related imaging abnormalities (ARIA). In some embodiments, the low level is less than 10% of the treated patients / animals.

[0033] Therefore, the present invention encompasses at least the following embodiments.

[0034] 1. A method for reducing amyloid levels in a subject with early-stage Alzheimer's disease, comprising administering a composition containing at least one anti-Aβ antibody in a therapeutically effective dose of 9 mg / kg or less than 9 mg / kg relative to the weight of the subject, once every four weeks.

[0035] 2. The at least one anti-Aβ antibody forms a binding site that specifically binds to the human Aβ protein, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) The method according to Embodiment 1, comprising a pair of antibody heavy chain variable domains and cogeneic antibody light chain variable domains.

[0036] 3. The method according to any one of Embodiments 1 to 2, wherein the at least one anti-Aβ antibody is a bispecific anti-Aβ / TfR antibody.

[0037] 4. The anti-Aβ / TfR antibody is It forms a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two pairs each of antibody heavy chain variable domains and congener antibody light chain variable domains, It forms a binding site that specifically binds to human TfR, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) A pair of antibody heavy chain variable domains and congener antibody light chain variable domains The method according to Embodiment 3, including the method described above.

[0038] 5. The method according to any one of Embodiments 1 to 4, wherein the at least one anti-Aβ antibody is trontinemab.

[0039] 6. A method for reducing amyloid levels in a subject with early-stage Alzheimer's disease, comprising the step of administering a composition comprising a therapeutically effective amount of the bispecific anti-Aβ / TfR antibody trontinemab.

[0040] 7. The method according to Embodiment 6, wherein the therapeutically effective amount of the bispecific anti-Aβ / TfR antibody trontinemab is 9 mg / kg or less relative to the weight of the subject.

[0041] 8. The method according to any one of Embodiments 6 to 7, wherein the therapeutically effective amount of the anti-Aβ antibody trontinemab is administered once every four weeks.

[0042] 9. A method for reducing amyloid levels in a subject having early-stage Alzheimer's disease, comprising the step of administering a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody, wherein the therapeutically effective amount results in fewer ARIA events than, preferably, aducanumab and / or lecanemab, compared to a monospecific anti-Aβ antibody.

[0043] 10. The at least one bispecific anti-Aβ / TfR antibody is i) Forms a binding site that specifically binds to human Aβ, and each of them, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, ii) Form a binding site that specifically binds to human TfR, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including The method according to Embodiment 9, including the method described in Embodiment 9.

[0044] 11. The method according to any one of Embodiments 9 to 10, wherein the at least one bispecific anti-Aβ / TfR antibody is trontinemab.

[0045] 12. The method according to any one of Embodiments 9 to 11, wherein the therapeutically effective amount of the at least one bispecific anti-Aβ / TfR antibody is 9 mg / kg or less relative to the weight of the subject.

[0046] 13. The method according to any one of Embodiments 9 to 12, wherein the therapeutically effective amount of the at least one bispecific anti-Aβ / TfR antibody is administered once every four weeks.

[0047] 14. The method according to any one of Embodiments 1 to 13, wherein at least one bispecific anti-Aβ / TfR antibody is administered intravenously.

[0048] 15. The method according to any one of Embodiments 1 to 14, wherein the subject having early-stage Alzheimer's disease has been diagnosed with mild, mild-to-prodromal, or prodromal Alzheimer's disease.

[0049] 16. The method according to any one of Embodiments 1 to 14, wherein the subject having early-stage Alzheimer's disease has been diagnosed with mild cognitive impairment due to Alzheimer's disease, moderate possibility of Alzheimer's disease, and / or has been diagnosed with mild Alzheimer's dementia.

[0050] 17. The method according to any one of Embodiments 1 to 16, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0051] 18. The method according to any one of Embodiments 1 to 17, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.6 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0052] 19. The method according to any one of Embodiments 1 to 18, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0053] 20. The method according to any one of Embodiments 1 to 19, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.8 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0054] 21. The method according to any one of Embodiments 1 to 20, wherein the composition comprises at least one anti-Aβ antibody in an amount of 2 mg / kg to 5 mg / kg relative to the weight of the subject.

[0055] 22. The method according to any one of Embodiments 1 to 21, wherein the composition comprises at least one anti-Aβ antibody in an amount of 3 mg / kg to 4 mg / kg relative to the weight of the subject.

[0056] 23. The method according to any one of Embodiments 1 to 17, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0057] 24. The method according to any one of Embodiments 1 to 17 and 23, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.6 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0058] 25. The method according to any one of Embodiments 1 to 17 and 23 to 24, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0059] 26. The method according to any one of Embodiments 1 to 25, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.8 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0060] 27. The method according to any one of Embodiments 1 to 26, wherein the composition comprises at least one anti-Aβ antibody in an amount of about 1.8 mg / kg, or about 1.9 mg / kg, or about 2.0 mg / kg, or about 2.1 mg / kg, or about 2.2 mg / kg, or about 2.3 mg / kg, or about 2.4 mg / kg, or about 2.5 mg / kg, or about 2.6 mg / kg, or about 2.7 mg / kg, or about 2.8 mg / kg, or about 2.9 mg / kg, or about 3.0 mg / kg, or about 3.1 mg / kg, or about 3.2 mg / kg, or about 3.3 mg / kg, or about 3.4 mg / kg, or about 3.5 mg / kg, or about 3.6 mg / kg, based on the weight of the subject.

[0061] 28. The method according to any one of Embodiments 1 to 26, wherein the composition comprises, for some doses, 1.2 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject, and thereafter the composition comprises a lower amount of the at least one anti-Aβ antibody in the range of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0062] 29. The method according to Embodiment 28, wherein the number of doses is 3 to 60.

[0063] 30. The method according to any one of Embodiments 1 to 29, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 20 centiloids compared to a placebo.

[0064] 31. The method according to any one of Embodiments 1 to 30, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 25 centiloids compared to a placebo.

[0065] 32. The method according to any one of Embodiments 1 to 31, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 60 centiloids compared to a placebo.

[0066] 33. The method according to any one of Embodiments 1 to 32, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 75 centiloids compared to a placebo.

[0067] 34. The method according to any one of Embodiments 1 to 33, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 80 centiloids compared to baseline.

[0068] 35. The method according to any one of Embodiments 1 to 34, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 85 centiloids compared to placebo.

[0069] 36. The method according to any one of Embodiments 1 to 35, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 90 centiloids compared to a placebo.

[0070] 37. The method according to any one of Embodiments 1 to 29, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 20 centiloids compared to baseline.

[0071] 38. The method according to any one of embodiments 1 to 29 and 37, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 25 centiloids compared to baseline.

[0072] 39. The method according to any one of embodiments 1 to 29 and 37 to 38, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 60 centiloids compared to baseline.

[0073] 40. The method according to any one of embodiments 1 to 29 and 37 to 39, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 75 centiloids compared to baseline.

[0074] 41. The method according to any one of embodiments 1 to 29 and 37 to 40, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 80 centiloids compared to baseline.

[0075] 42. The method according to any one of embodiments 1 to 29 and 37 to 41, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 85 centiloids compared to baseline.

[0076] 43. The method according to any one of embodiments 1 to 29 and 37 to 42, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 90 centiloids compared to baseline.

[0077] 44. The method according to any one of Embodiments 1 to 43, wherein the reduction in amyloid levels occurs after 18 months of administration of the composition.

[0078] 45. The method according to any one of Embodiments 1 to 44, wherein the reduction in amyloid levels occurs after 12 months of administration of the composition.

[0079] 46. ​​The method according to any one of Embodiments 1 to 45, wherein the reduction in amyloid levels occurs after 6 months of administration of the composition.

[0080] 47. The method according to any one of Embodiments 1 to 46, wherein the reduction in amyloid levels occurs after 3 months of administration of the composition.

[0081] 48. The method according to any one of Embodiments 1 to 47, wherein the administration results in a decrease in cerebrospinal fluid levels of Aβ1-42 protein fragments.

[0082] 49. The method according to any one of Embodiments 1 to 48, wherein the subject is simultaneously administered at least one Alzheimer's disease drug other than trontinemab.

[0083] 50. The method according to any one of Embodiments 1 to 48, wherein the subject is not simultaneously administered at least one Alzheimer's disease drug other than trontinemab.

[0084] 51. A method for converting an amyloid-positive subject with early Alzheimer's disease into an amyloid-negative subject, comprising the step of administering a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0085] 52. The method according to Embodiment 51, wherein, when the administration of the composition is determined by visual reading of amyloid PET images after 3 months of administration of the composition, at least 30% of the subjects are amyloid-negative, preferably 30-70% of the subjects are amyloid-negative when determined by visual reading of amyloid PET images after 3 months of administration (3 doses) of the composition.

[0086] 52a. The method according to any one of Embodiments 51 to 52, wherein the administration of the composition results in at least 30% of the subjects being amyloid-negative, preferably 30-70% of the subjects being amyloid-negative, when determined by visual reading of amyloid PET images after 6 months of administration of the composition (3 doses).

[0087] 52b. The method according to Embodiment 51, wherein administration of the antibody composition results in the determination that the subject is amyloid-negative by visual reading of an amyloid PET image after 3 months of administration of the antibody composition.

[0088] 52c. The method according to any one of Embodiments 51 and 52b, wherein administration of the antibody composition results in the determination that the subject is amyloid-negative by visual reading of an amyloid PET image after 4 to 6 months of administration of the antibody composition.

[0089] 52d. The method according to any one of Embodiments 51, 52b, or 52c, wherein administration of the antibody composition results in the determination that the subject is amyloid-negative by visual reading of an amyloid PET image after 3 to 6 months of administration of the antibody composition.

[0090] 53. The method according to any one of Embodiments 51 to 52, wherein the administration of the composition results in at least 50% of the subjects being amyloid-negative when determined by visual reading of amyloid PET images after 12 months of administration of the composition.

[0091] 54. The method according to any one of Embodiments 51 to 53, wherein the administration of the composition results in at least 70% of the subjects being amyloid-negative when determined by visual reading of amyloid PET images after 18 months of administration of the composition.

[0092] 55. The at least one bispecific anti-Aβ / TfR antibody, i) Forms a binding site that specifically binds to human Aβ protein, and each of them, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, ii) Form a binding site that specifically binds to human TfR, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including The method according to any one of embodiments 51 to 54, including the method described above.

[0093] 56. The method according to any one of Embodiments 51 to 55, wherein the at least one bispecific anti-Aβ / TfR antibody is trontinemab.

[0094] 57. The method according to any one of Embodiments 51 to 56, wherein the therapeutically effective amount of the at least one bispecific anti-Aβ / TfR antibody is 9 mg / kg or less relative to the weight of the subject.

[0095] 58. The method according to any one of Embodiments 51 to 57, wherein the therapeutically effective amount of the at least one bispecific anti-Aβ / TfR antibody is administered once every four weeks.

[0096] 59. The method according to any one of embodiments 51 to 58, wherein at least one bispecific anti-Aβ / TfR antibody is administered intravenously.

[0097] 60. The method according to any one of embodiments 51 to 59, wherein the subject having early-stage Alzheimer's disease has been diagnosed with mild or prodromal Alzheimer's disease.

[0098] 61. The method according to any one of Embodiments 51 to 59, wherein the subject having early-stage Alzheimer's disease has been diagnosed with mild cognitive impairment due to Alzheimer's disease, moderate possibility of cognitive impairment, and / or has been diagnosed with mild Alzheimer's dementia.

[0099] 62. The method according to any one of Embodiments 51 to 61, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0100] 63. The method according to any one of Embodiments 51 to 62, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.6 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0101] 64. The method according to any one of Embodiments 51 to 63, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0102] 65. The method according to any one of Embodiments 51 to 64, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.8 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0103] 66. The method according to any one of Embodiments 51 to 65, wherein the composition comprises at least one anti-Aβ antibody in an amount of 2 mg / kg to 5 mg / kg relative to the weight of the subject.

[0104] 67. The method according to any one of Embodiments 51 to 66, wherein the composition comprises at least one anti-Aβ antibody in an amount of 3 mg / kg to 4 mg / kg relative to the weight of the subject.

[0105] 68. The method according to any one of Embodiments 51 to 62, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0106] 69. The method according to any one of embodiments 51 to 62 and 68, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.6 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0107] 70. The method according to any one of embodiments 51 to 62 and 68 to 69, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0108] 71. The method according to any one of Embodiments 51 to 70, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.8 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0109] 72. The method according to any one of Embodiments 51 to 71, wherein the composition comprises at least one anti-Aβ antibody in an amount of about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, or about 3.6 mg / kg based on the weight of the subject.

[0110] 73. The method according to any one of Embodiments 51 to 72, wherein the composition comprises, for some doses, 1.2 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject, and thereafter the composition comprises 0.2 mg / kg to 3.6 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0111] 74. The method according to embodiment 73, wherein the number of doses is 3 to 60.

[0112] 75. The method according to any one of embodiments 51 to 74, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 75 centiloids compared to a placebo.

[0113] 76. The method according to any one of embodiments 51 to 75, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 80 centiloids compared to baseline.

[0114] 77. The method according to any one of embodiments 51 to 76, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 85 centiloids compared to a placebo.

[0115] 78. The method according to any one of embodiments 51 to 77, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 90 centiloids compared to placebo.

[0116] 79. The method according to any one of embodiments 51 to 74, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 75 centiloids compared to baseline.

[0117] 80. The method according to any one of embodiments 51 to 74 and 79, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 80 centiloids compared to baseline.

[0118] 81. The method according to any one of embodiments 51-74 and 79-80, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 85 centiloids compared to baseline.

[0119] 82. The method according to any one of embodiments 51-74 and 79-81, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 90 centiloids compared to baseline.

[0120] 83. The method according to any one of Embodiments 51 to 82, wherein the reduction in amyloid levels occurs after 18 months of administration of the composition.

[0121] 84. The method according to any one of Embodiments 51 to 83, wherein the reduction in amyloid levels occurs after 12 months of administration of the composition.

[0122] 85. The method according to any one of Embodiments 51 to 84, wherein the reduction in amyloid levels occurs after 6 months of administration of the composition.

[0123] 86. The method according to any one of Embodiments 51 to 85, wherein the reduction in amyloid levels occurs after 3 months of administration of the composition.

[0124] 87. The method according to any one of embodiments 51 to 86, wherein the administration results in a decrease in cerebrospinal fluid levels of Aβ1-42 protein fragments.

[0125] 88. The method according to any one of embodiments 51 to 87, wherein the subject is simultaneously administered at least one Alzheimer's disease drug other than trontinemab.

[0126] 89. The method according to any one of embodiments 51 to 88, wherein the subject is not simultaneously administered at least one Alzheimer's disease drug other than trontinemab.

[0127] 90. A method for treating a subject having early-stage Alzheimer's disease, comprising the step of administering a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody, wherein the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% compared to the severity of the same symptom in the same subject before treatment.

[0128] 91. The method according to Embodiment 90, wherein the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 25% compared to placebo, as determined by CDR-SB, or by at least 40% compared to placebo, as determined by PET imaging, after 18 months of administration of the composition.

[0129] 92. The method according to any one of Embodiments 90 to 91, wherein the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 60% compared to placebo as determined by CDR-SB, or by at least 75% compared to placebo as determined by PET imaging, after 18 months of administration of the composition.

[0130] 93. The method according to any one of embodiments 90 to 92, wherein the at least one symptom associated with Alzheimer's disease is selected from clinical exacerbation and brain amyloid levels.

[0131] 94. The at least one bispecific anti-Aβ / TfR antibody is i) Forms a binding site that specifically binds to human Aβ protein, and each of them, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, ii) Form a binding site that specifically binds to human TfR, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including The method according to any one of embodiments 90 to 93, including the method described above.

[0132] 95. The method according to any one of embodiments 90 to 94, wherein the at least one bispecific anti-Aβ / TfR antibody is trontinemab.

[0133] 96. The method according to any one of Embodiments 90 to 95, wherein the therapeutically effective amount of the at least one bispecific anti-Aβ / TfR antibody is 9 mg / kg or less relative to the weight of the subject.

[0134] 97. The method according to any one of embodiments 90 to 96, wherein the therapeutically effective amount of the at least one bispecific anti-Aβ / TfR antibody is administered once every four weeks.

[0135] 98. The method according to any one of embodiments 90 to 97, wherein at least one bispecific anti-Aβ / TfR antibody is administered intravenously.

[0136] 99. The method according to any one of embodiments 90 to 98, wherein the subject having early-stage Alzheimer's disease has been diagnosed with mild, mild-to-prodromal, or prodromal Alzheimer's disease.

[0137] 100. The method according to any one of embodiments 90 to 98, wherein the subject having early-stage Alzheimer's disease has been diagnosed with mild cognitive impairment due to Alzheimer's disease, moderate possibility, and / or has been diagnosed with mild Alzheimer's dementia.

[0138] 101. The method according to any one of Embodiments 90 to 100, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0139] 102. The method according to any one of Embodiments 90 to 101, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.6 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0140] 103. The method according to any one of Embodiments 90 to 102, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0141] 104. The method according to any one of Embodiments 90 to 103, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.8 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0142] 105. The method according to any one of Embodiments 90 to 104, wherein the composition comprises at least one anti-Aβ antibody in an amount of 2 mg / kg to 5 mg / kg relative to the weight of the subject.

[0143] 106. The method according to any one of Embodiments 90 to 105, wherein the composition comprises at least one anti-Aβ antibody in an amount of 3 mg / kg to 4 mg / kg relative to the weight of the subject.

[0144] 107. The method according to any one of Embodiments 90 to 101, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0145] 108. The method according to any one of embodiments 90 to 101 and 107, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.6 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0146] 109. The method according to any one of embodiments 90 to 101 and 107 to 108, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0147] 110. The method according to any one of Embodiments 90 to 109, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.8 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0148] 111. The method according to any one of Embodiments 90 to 110, wherein the composition comprises at least one anti-Aβ antibody in an amount of about 1.8 mg / kg, or about 1.9 mg / kg, or about 2.0 mg / kg, or about 2.1 mg / kg, or about 2.2 mg / kg, or about 2.3 mg / kg, or about 2.4 mg / kg, or about 2.5 mg / kg, or about 2.6 mg / kg, or about 2.7 mg / kg, or about 2.8 mg / kg, or about 2.9 mg / kg, or about 3.0 mg / kg, or about 3.1 mg / kg, or about 3.2 mg / kg, or about 3.3 mg / kg, or about 3.4 mg / kg, or about 3.5 mg / kg, or about 3.6 mg / kg, relative to the weight of the subject.

[0149] 112. The method according to any one of Embodiments 90 to 111, wherein the composition comprises, for some doses, 1.2 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject, and thereafter the composition comprises 0.2 mg / kg to 3.6 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0150] 113. The method according to embodiment 112, wherein the number of doses is 3 to 60.

[0151] 114. The method according to any one of embodiments 90 to 113, wherein the amyloid level of the subject is reduced by at least 20 centiloids compared to placebo, as determined by visual reading of an amyloid PET image.

[0152] 115. The method according to any one of embodiments 90 to 114, wherein the amyloid level of the subject is reduced by at least 25 centiloids compared to placebo, as determined by visual reading of an amyloid PET image.

[0153] 116. The method according to any one of embodiments 90 to 115, wherein the amyloid level of the subject is reduced by at least 60 centiloids compared to placebo, as determined by visual reading of an amyloid PET image.

[0154] 117. The method according to any one of embodiments 90 to 116, wherein the amyloid level of the subject is reduced by at least 75 centiloids compared to placebo, as determined by visual reading of an amyloid PET image.

[0155] 118. The method according to any one of embodiments 90 to 117, wherein the amyloid level of the subject is reduced by at least 80 centiloids compared to baseline, as determined by visual reading of an amyloid PET image.

[0156] 119. The method according to any one of embodiments 90 to 118, wherein the amyloid level of the subject is reduced by at least 85 centiloids compared to placebo, as determined by visual reading of an amyloid PET image.

[0157] 120. The method according to any one of embodiments 90 to 119, wherein the amyloid level of the subject is reduced by at least 90 centiloids compared to placebo, as determined by visual reading of an amyloid PET image.

[0158] 121. The method according to any one of embodiments 90 to 113, wherein the amyloid level of the subject is reduced by at least 20 centiloids compared to baseline, as determined by visual reading of an amyloid PET image.

[0159] 122. The method according to any one of embodiments 90-113 and 121, wherein the amyloid level of the subject is reduced by at least 25 centiloids compared to baseline, as determined by visual reading of an amyloid PET image.

[0160] 123. The method according to any one of embodiments 90-113 and 121-122, wherein the amyloid level of the subject is at least 60 centiloids lower than baseline, as determined by visual reading of an amyloid PET image.

[0161] 124. The method according to any one of embodiments 90-113 and 121-123, wherein the amyloid level of the subject is reduced by at least 75 centiloids compared to baseline, as determined by visual reading of an amyloid PET image.

[0162] 125. The method according to any one of embodiments 90-113 and 121-124, wherein the amyloid level of the subject is reduced by at least 80 centiloids compared to baseline, as determined by visual reading of an amyloid PET image.

[0163] 126. The method according to any one of embodiments 90-113 and 121-125, wherein the amyloid level of the subject is reduced by at least 85 centiloids compared to baseline, as determined by visual reading of an amyloid PET image.

[0164] 127. The method according to any one of embodiments 90-113 and 121-126, wherein the amyloid level of the subject is at least 90 centiloids lower than baseline, as determined by visual reading of an amyloid PET image.

[0165] 128. The method according to any one of Embodiments 90 to 127, wherein the decline occurs after 18 months of administration of the composition.

[0166] 129. The method according to any one of Embodiments 90 to 128, wherein the decline occurs after 12 months of administration of the composition.

[0167] 130. The method according to any one of Embodiments 90 to 129, wherein the decline occurs after 6 months of administration of the composition.

[0168] 131. The method according to any one of embodiments 90 to 130, wherein the administration results in a decrease in cerebrospinal fluid levels of Aβ1-42 protein fragments.

[0169] 132. The method according to any one of embodiments 90 to 131, wherein the subject is simultaneously administered at least one Alzheimer's disease drug other than trontinemab.

[0170] 133. The method according to any one of embodiments 90 to 131, wherein the subject is not simultaneously administered at least one Alzheimer's disease drug other than trontinemab.

[0171] 134. A method for treating a subject having early-stage Alzheimer's disease, comprising the step of administering a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody, wherein the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% compared to the severity of the same symptom in a subject receiving a placebo.

[0172] 135. The method according to Embodiment 134, wherein the severity of at least one symptom associated with Alzheimer's disease is determined by CDR-SB or PET.

[0173] 136. The method according to any one of Embodiments 134 to 135, wherein the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 25% compared to placebo as determined by CDR-SB, or by at least 40% compared to placebo as determined by PET imaging, after 18 months of administration of the composition.

[0174] 137. The method according to any one of Embodiments 134 to 137, wherein the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 60% compared to placebo as determined by CDR-SB, or by at least 75% compared to placebo as determined by PET imaging, after 18 months of administration of the composition.

[0175] 138. The method according to any one of embodiments 134 to 137, wherein the at least one symptom associated with Alzheimer's disease is selected from clinical exacerbation and brain amyloid levels.

[0176] 139. The at least one bispecific anti-Aβ / TfR antibody is i) Forms a binding site that specifically binds to human Aβ protein, and each of them, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, ii) Form a binding site that specifically binds to human TfR, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including The method according to any one of embodiments 134 to 138, including the method described above.

[0177] 140. The method according to any one of Embodiments 134 to 139, wherein the at least one bispecific anti-Aβ / TfR antibody is trontinemab.

[0178] 141. The method according to any one of Embodiments 134 to 140, wherein the therapeutically effective amount of the at least one bispecific anti-Aβ / TfR antibody is 9 mg / kg or less relative to the weight of the subject.

[0179] 142. The method according to any one of Embodiments 134 to 141, wherein the therapeutically effective amount of the at least one bispecific anti-Aβ / TfR antibody is administered once every four weeks.

[0180] 143. The method according to any one of embodiments 134 to 142, wherein at least one bispecific anti-Aβ / TfR antibody is administered intravenously.

[0181] 144. The method according to any one of embodiments 134 to 143, wherein the subject having early-stage Alzheimer's disease has been diagnosed with mild, mild-to-prodromal, or prodromal Alzheimer's disease.

[0182] 145. The method according to any one of Embodiments 134 to 144, wherein the subject having early-stage Alzheimer's disease has been diagnosed with mild cognitive impairment due to Alzheimer's disease, moderate possibility, and / or has been diagnosed with mild Alzheimer's dementia.

[0183] 146. The method according to any one of Embodiments 134 to 145, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0184] 147. The method according to any one of Embodiments 134 to 146, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.6 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0185] 148. The method according to any one of Embodiments 134 to 147, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0186] 149. The method according to any one of Embodiments 134 to 148, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.8 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0187] 150. The method according to any one of Embodiments 134 to 149, wherein the composition comprises at least one anti-Aβ antibody in an amount of 2 mg / kg to 5 mg / kg relative to the weight of the subject.

[0188] 151. The method according to any one of Embodiments 134 to 150, wherein the composition comprises at least one anti-Aβ antibody in an amount of 3 mg / kg to 4 mg / kg relative to the weight of the subject.

[0189] 152. The method according to any one of Embodiments 134 to 146, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0190] 153. The method according to any one of embodiments 134 to 146 and 152, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.6 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0191] 154. The method according to any one of embodiments 134 to 146 and 152 to 153, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0192] 155. The method according to any one of Embodiments 134 to 154, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.8 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0193] 156. The method according to any one of Embodiments 134 to 155, wherein the composition comprises at least one anti-Aβ antibody in an amount of about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, or about 3.6 mg / kg based on the weight of the subject.

[0194] 157. The method according to any one of Embodiments 134 to 156, wherein the composition comprises, for some doses, 1.2 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject, and thereafter the composition comprises 0.2 mg / kg to 3.6 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0195] 158. The method according to Embodiment 157, wherein the number of doses is 3 to 60.

[0196] 159. The method according to any one of embodiments 134 to 158, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 20 centiloids compared to placebo.

[0197] 160. The method according to any one of embodiments 134 to 159, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 25 centiloids compared to a placebo.

[0198] 161. The method according to any one of embodiments 134 to 160, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 60 centiloids compared to placebo.

[0199] 162. The method according to any one of embodiments 134 to 161, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 75 centiloids compared to placebo.

[0200] 163. The method according to any one of embodiments 134 to 162, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 80 centiloids compared to baseline.

[0201] 164. The method according to any one of embodiments 134 to 163, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 85 centiloids compared to placebo.

[0202] 165. The method according to any one of embodiments 134 to 164, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 90 centiloids compared to placebo.

[0203] 166. The method according to any one of embodiments 134 to 158, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is at least 20 centiloids lower than baseline.

[0204] 167. The method according to any one of embodiments 134-158 and 166, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 25 centiloids compared to baseline.

[0205] 168. The method according to any one of embodiments 134-158 and 166-167, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is at least 60 centiloids lower than baseline.

[0206] 169. The method according to any one of embodiments 134-158 and 166-168, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 75 centiloids compared to baseline.

[0207] 170. The method according to any one of embodiments 134-158 and 166-169, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 80 centiloids compared to baseline.

[0208] 171. The method according to any one of embodiments 134-158 and 166-170, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 85 centiloids compared to baseline.

[0209] 172. The method according to any one of embodiments 134-158 and 166-171, wherein the amyloid level, as determined by visual reading of an amyloid PET image, is reduced by at least 90 centiloids compared to baseline.

[0210] 173. The method according to any one of Embodiments 134 to 172, wherein the reduction in amyloid levels occurs after 18 months of administration of the composition.

[0211] 174. The method according to any one of Embodiments 134 to 173, wherein the reduction in amyloid levels occurs after 12 months of administration of the composition.

[0212] 175. The method according to any one of Embodiments 134 to 174, wherein the reduction in amyloid levels occurs after 6 months of administration of the composition.

[0213] 176. The method according to any one of embodiments 134 to 175, wherein the administration results in a decrease in cerebrospinal fluid levels of Aβ1-42 protein fragments.

[0214] 177. The method according to any one of embodiments 134 to 176, wherein the subject is simultaneously administered at least one Alzheimer's disease drug other than trontinemab.

[0215] 178. The method according to any one of embodiments 134 to 177, wherein the subject is not simultaneously administered at least one Alzheimer's disease drug other than trontinemab.

[0216] 179. A bispecific anti-Aβ / TfR antibody for use as a pharmaceutical in the treatment of Alzheimer's disease (in the target population).

[0217] 180. A bispecific anti-Aβ / TfR antibody for use in the treatment of Alzheimer's disease (in the target population).

[0218] 181. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179-180, wherein administration of the antibody results in at least 30% of the subjects being amyloid-negative, as determined by visual reading of amyloid PET images after 3 months of administration of the composition.

[0219] 182. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 181, wherein administration of the antibody results in at least 50% of the subjects being amyloid-negative when determined by visual reading of amyloid PET images after 12 months of administration of the composition.

[0220] 183. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 182, wherein, when the administration of the antibody is determined by visual reading of amyloid PET images after 18 months of administration of the composition, at least 70% of the subjects are amyloid-negative.

[0221] 184. The bispecific anti-Aβ / TfR antibody is i) Forms a binding site that specifically binds to human Aβ protein, and each of them, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, ii) Form a binding site that specifically binds to human TfR, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including A bispecific anti-Aβ / TfR antibody for use as described in any one of embodiments 179 to 183, including a bispecific anti-Aβ / TfR antibody.

[0222] 185. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 184, wherein the bispecific anti-Aβ / TfR antibody is trontinemab.

[0223] 186. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 185, wherein the antibody is administered in a therapeutically effective dose.

[0224] 187. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 186, wherein the antibody is administered at a dose of 9 mg / kg or less (relative to the weight of the subject).

[0225] 188. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 187, wherein the antibody is administered once every four weeks.

[0226] 189. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 188, wherein the antibody is administered intravenously.

[0227] 190. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 189, wherein the treatment is for a subject having early-stage Alzheimer's disease.

[0228] 191. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 190, wherein the treatment is for a subject diagnosed with mild, mild-to-prodromal, or prodromal Alzheimer's disease.

[0229] 192. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 191, wherein the treatment is for a subject having early-stage Alzheimer's disease diagnosed with mild cognitive impairment, moderate possibility of Alzheimer's disease, and / or mild Alzheimer's dementia.

[0230] 193. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 192, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0231] 194. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 193, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.6 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0232] 195. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 194, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0233] 196. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 195, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.8 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0234] 197. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 196, wherein the composition comprises at least one anti-Aβ antibody in an amount of 2 mg / kg to 5 mg / kg relative to the weight of the subject.

[0235] 198. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 197, wherein the composition comprises 3 mg / kg to 4 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0236] 199. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 193, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0237] 200. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 193 and 199, wherein the composition comprises at least one anti-Aβ antibody in an amount of 0.6 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0238] 201. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179-193 and 199-201, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0239] 202. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 201, wherein the composition comprises at least one anti-Aβ antibody in an amount of 1.8 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0240] 203. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 202, wherein the composition comprises at least one anti-Aβ antibody in an amount of about 1.8 mg / kg or about 1.9 mg / kg or about 2.0 mg / kg or about 2.1 mg / kg or about 2.2 mg / kg or about 2.3 mg / kg or about 2.4 mg / kg or about 2.5 mg / kg or about 2.6 mg / kg or about 2.7 mg / kg or about 2.8 mg / kg or about 2.9 mg / kg or about 3.0 mg / kg or about 3.1 mg / kg or about 3.2 mg / kg or about 3.3 mg / kg or about 3.4 mg / kg or about 3.5 mg / kg or about 3.6 mg / kg based on the weight of the subject.

[0241] 204. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 203, wherein the composition comprises, for several doses, 1.2 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject, and thereafter the composition comprises 0.2 mg / kg to 3.6 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0242] 205. A bispecific anti-Aβ / TfR antibody for use as described in Embodiment 204, wherein the number of doses is 3 to 60.

[0243] 206. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 205, which reduces amyloid levels by at least 75 centroids compared to placebo when the administration of the antibody is determined by visual reading of an amyloid PET image.

[0244] 207. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 206, which reduces amyloid levels by at least 80 centiloids relative to baseline when the administration of the antibody is determined by visual reading of an amyloid PET image.

[0245] 208. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 207, which reduces amyloid levels by at least 85 centiloids compared to placebo, when the administration of the antibody is determined by visual reading of an amyloid PET image.

[0246] 209. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 208, which reduces amyloid levels by at least 90 centiloids compared to placebo, when the administration of the antibody is determined by visual reading of an amyloid PET image.

[0247] 210. A bispecific anti-Aβ / TfR antibody for use according to any one of Embodiments 179 to 205, which reduces amyloid levels by at least 75 centiloids relative to baseline when the administration of the antibody is determined by visual reading of an amyloid PET image.

[0248] 211. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179-205 and 210, which reduces amyloid levels by at least 80 centiloids relative to baseline when the administration of the antibody is determined by visual reading of an amyloid PET image.

[0249] 212. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179-205 and 210-211, which reduces amyloid levels by at least 85 centiloids relative to baseline when the administration of the antibody is determined by visual reading of an amyloid PET image.

[0250] 213. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179-205 and 210-212, which reduces amyloid levels by at least 90 centroids relative to baseline when the administration of the antibody is determined by visual reading of an amyloid PET image.

[0251] 214. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 213, wherein administration of the antibody reduces amyloid levels within 18 months after the start of administration of the antibody.

[0252] 215. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 214, wherein administration of the antibody reduces amyloid levels within 12 months after the start of administration of the antibody.

[0253] 216. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 215, wherein administration of the antibody reduces amyloid levels within six months after the start of administration of the antibody.

[0254] 217. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 216, wherein administration of the antibody reduces amyloid levels within three months after the start of administration of the antibody.

[0255] 218. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 217, wherein administration of the antibody results in a decrease in cerebrospinal fluid levels of Aβ1-42 protein fragments.

[0256] 219. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 218, wherein at least one Alzheimer's disease drug other than trontinemab is administered.

[0257] 220. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 219, in which no further Alzheimer's disease drugs other than trontinemab are administered.

[0258] 221. Use of bispecific anti-Aβ / TfR antibodies for the treatment of Alzheimer's disease.

[0259] 222. Use of bispecific anti-Aβ / TfR antibodies in methods for treating Alzheimer's disease.

[0260] 223. The use according to any one of Embodiments 221 to 222, wherein the use of the antibody results in at least 30% of the subjects being amyloid-negative, as determined by visual reading of amyloid PET images after a 3-month administration of the composition.

[0261] 224. The use according to any one of Embodiments 221 to 223, wherein the use of the antibody results in at least 50% of the subjects being amyloid-negative, as determined by visual reading of amyloid PET images after 12 months of administration of the composition.

[0262] 225. The use according to any one of Embodiments 221 to 224, wherein the use of the antibody results in at least 70% of the subjects being amyloid-negative, as determined by visual reading of amyloid PET images after 18 months of administration of the composition.

[0263] 226. The bispecific anti-Aβ / TfR antibody is i) Forms a binding site that specifically binds to human Aβ protein, and each of them, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, ii) Form a binding site that specifically binds to human TfR, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including Uses as described in any one of embodiments 221 to 225, including the use described in any one of embodiments 221 to 225.

[0264] 227. The use according to any one of Embodiments 221 to 226, wherein the bispecific anti-Aβ / TfR antibody is trontinemab.

[0265] 228. The use according to any one of embodiments 221 to 227, wherein the antibody is used / administered in a therapeutically effective amount.

[0266] 229. The use according to any one of Embodiments 221 to 228, wherein the antibody is used / administered at a dose of 9 mg / kg or less (relative to the weight of the subject).

[0267] 230. The use according to any one of Embodiments 221 to 229, wherein the antibody is used / administered once every four weeks.

[0268] 231. The use according to any one of embodiments 221 to 230, wherein the antibody is used / administered intravenously.

[0269] 232. The use according to any one of embodiments 221 to 231, wherein the treatment is for a subject having early-stage Alzheimer's disease.

[0270] 233. The use according to any one of embodiments 221 to 232, wherein the treatment is the treatment of a subject diagnosed with mild, mild to prodromal, or prodromal Alzheimer's disease.

[0271] 234. Use according to any one of embodiments 221 to 233, wherein the treatment is for a subject having early Alzheimer's disease diagnosed with mild cognitive impairment due to Alzheimer's disease, having a moderate likelihood, and / or diagnosed with mild Alzheimer's dementia.

[0272] 235. Use according to any one of embodiments 221 to 234, wherein the composition comprises from 0.2 mg / kg to 7.2 mg / kg of said at least one anti-Aβ antibody, based on the weight of the subject.

[0273] 236. Use according to any one of embodiments 221 to 235, wherein the composition comprises from 0.6 mg / kg to 7.2 mg / kg of said at least one anti-Aβ antibody, based on the weight of the subject.

[0274] 237. Use according to any one of embodiments 221 to 236, wherein the composition comprises from 1.2 mg / kg to 7.2 mg / kg of said at least one anti-Aβ antibody, based on the weight of the subject.

[0275] 238. Use according to any one of embodiments 221 to 237, wherein the composition comprises from 1.8 mg / kg to 7.2 mg / kg of said at least one anti-Aβ antibody, based on the weight of the subject.

[0276] 239. Use according to any one of embodiments 221 to 238, wherein the composition comprises from 2 mg / kg to 5 mg / kg of said at least one anti-Aβ antibody, based on the weight of the subject.

[0277] 240. Use according to any one of embodiments 221 to 239, wherein the composition comprises from 3 mg / kg to 4 mg / kg of said at least one anti-Aβ antibody, based on the weight of the subject.

[0278] 241. Use according to any one of embodiments 221 to 235, wherein the composition comprises from 0.2 mg / kg to 3.6 mg / kg of said at least one anti-Aβ antibody, based on the weight of the subject.

[0279] 242. The use according to any one of embodiments 221 to 235 and 241, wherein the composition contains at least one anti-Aβ antibody in an amount of 0.6 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0280] 243. The use according to any one of embodiments 221 to 235 and 241 to 242, wherein the composition contains at least one anti-Aβ antibody in an amount of 1.2 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0281] 244. The use according to any one of Embodiments 221 to 243, wherein the composition contains at least one anti-Aβ antibody in an amount of 1.8 mg / kg to 3.6 mg / kg relative to the weight of the subject.

[0282] 245. Use according to any one of Embodiments 221 to 244, wherein the composition contains at least one anti-Aβ antibody in an amount of about 1.8 mg / kg or about 1.9 mg / kg or about 2.0 mg / kg or about 2.1 mg / kg or about 2.2 mg / kg or about 2.3 mg / kg or about 2.4 mg / kg or about 2.5 mg / kg or about 2.6 mg / kg or about 2.7 mg / kg or about 2.8 mg / kg or about 2.9 mg / kg or about 3.0 mg / kg or about 3.1 mg / kg or about 3.2 mg / kg or about 3.3 mg / kg or about 3.4 mg / kg or about 3.5 mg / kg or about 3.6 mg / kg based on the weight of the subject.

[0283] 246. The use according to any one of Embodiments 221 to 245, wherein the composition comprises, for some doses, 1.2 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject, and thereafter the composition comprises 0.2 mg / kg to 3.6 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0284] 247. The use according to embodiment 246, wherein the number of doses is 3 to 60.

[0285] 248. The use according to any one of Embodiments 221 to 247, wherein the use / administration of the antibody reduces amyloid levels by at least 75 centiloids compared to placebo, when the use / administration of the antibody is determined by visual reading of an amyloid PET image.

[0286] 249. The use according to any one of Embodiments 221 to 248, wherein the use / administration of the antibody reduces the amyloid level by at least 80 centiloids relative to baseline, when the use / administration of the antibody is determined by visual reading of an amyloid PET image.

[0287] 250. The use according to any one of Embodiments 221 to 249, wherein the use / administration of the antibody reduces amyloid levels by at least 85 centiloids compared to placebo, when the use / administration of the antibody is determined by visual reading of an amyloid PET image.

[0288] 251. The use according to any one of Embodiments 221 to 250, wherein the use / administration of the antibody reduces amyloid levels by at least 90 centiloids compared to placebo, when the use / administration of the antibody is determined by visual reading of an amyloid PET image.

[0289] 252. The use according to any one of Embodiments 221 to 247, wherein the use / administration of the antibody reduces the amyloid level by at least 75 centiloids relative to baseline, when the use / administration of the antibody is determined by visual reading of an amyloid PET image.

[0290] 253. The use according to any one of embodiments 221-247 and 252, wherein the use / administration of the antibody reduces the amyloid level by at least 80 centiloids relative to baseline, when the use / administration of the antibody is determined by visual reading of an amyloid PET image.

[0291] The use / administration of the antibody according to any one of embodiments 221 to 247 and 252 to 253, when determined by visual reading of an amyloid PET image, causes the amyloid level to decrease by at least 85 centiloids relative to the baseline.

[0292] The use / administration of the antibody according to any one of embodiments 221 to 247 and 252 to 254, when determined by visual reading of an amyloid PET image, causes the amyloid level to decrease by at least 90 centiloids relative to the baseline.

[0293] The use / administration of the antibody according to any one of embodiments 221 to 255 decreases the amyloid level within 18 months after the start of the use / administration of the antibody.

[0294] The use / administration of the antibody according to any one of embodiments 221 to 256 decreases the amyloid level within 12 months after the start of the use / administration of the antibody.

[0295] The use / administration of the antibody according to any one of embodiments 221 to 257 decreases the amyloid level within 6 months after the start of the use / administration of the antibody.

[0296] The use / administration of the antibody according to any one of embodiments 221 to 257 decreases the amyloid level within 3 months after the start of the use / administration of the antibody.

[0297] The use / administration of the antibody according to any one of embodiments 221 to 259 results in a decrease in the cerebrospinal fluid level of the Aβ1-42 protein fragment.

[0298] At least one Alzheimer's disease drug other than trontinemab is used / administered, according to any one of embodiments 221 to 260.

[0299] 262. Use according to any one of embodiments 221 to 260, wherein no further Alzheimer's disease drugs other than trontinemab are used / administered.

[0300] 263. An antibody or use for the method or use according to any one of Embodiments 1 to 262, wherein the subject has white skin.

[0301] 264. An antibody or use for the method or use described in any one of Embodiments 1 to 262, wherein the subject is not of color.

[0302] 265. An antibody or use for the method or use according to any one of Embodiments 1 to 264, wherein the subject has a body weight of 60 kg to 70 kg.

[0303] 266. An antibody or use for the method or use according to any one of Embodiments 1 to 265, wherein the subject is an APOEε4-carrying individual. [Brief explanation of the drawing]

[0304] [Figure 1] Figure 1 shows a schematic diagram of the structure of trontinemab / RG6102. [Figure 2A] Figure 2A shows the results of brain (tissue) exposure to trontinemab in non-human primate hippocampi, comparing a single IV dose of 10 mg / kg trontinemab with a single IV dose of 20 mg / kg gantenerumab. [Figure 2B] Figure 2B shows the brain-to-plasma ratio achieved with trontinemab in the cortex, hippocampus, and striatum of non-human primates, compared to gantenerumab, as shown by the fold changes in Kp, Cmax, and AUC. [Figure 3] Figure 3 shows the progression of amyloid depletion in cohorts 1-3, as indicated by the average amyloid PET loading in Centiloid over 28 weeks. [Figure 4]Figure 4 shows the course of amyloid depletion in cohorts 1–3, as shown by the mean amyloid reduction from baseline in Centiloid over 28 weeks. [Figure 5] Figure 5 shows the progression of amyloid depletion in cohorts 1–4, indicated by the mean amyloid reduction from baseline in centroid over 12 and 28 weeks, respectively. [Figure 6] Figure 6 shows a comparison of the effects of trontinemab treatment in humans with other anti-Aβ treatment studies (GRADUATE I, GRADUATE II, CLARITY AD, TRAILBLAZER-ALZ-2), as shown by amyloid PET in Centroid over approximately 27 months. [Modes for carrying out the invention]

[0305] The subject matter of this disclosure relates to a method comprising the administration of a bispecific antibody that specifically binds to human Aβ protein and human transferrin receptor. In one embodiment, the method described herein comprises administering such a bispecific antibody at a lower dose and / or at a lower frequency compared to current anti-Aβ protein therapies known in the art. In one embodiment, despite being administered at such a lower dose and / or at a lower frequency, the method described herein achieves greater exposure to patient / animal brain tissue and / or a more efficient reduction of patient / animal Aβ protein plaques compared to current anti-Aβ protein therapies known in the art. In one embodiment, the method described herein results in a lower incidence of ARIA (amyloid-related imaging abnormalities) compared to current anti-Aβ protein therapies known in the art. The subject matter of this disclosure further provides compositions comprising such a bispecific antibody at such doses and / or configured for dosing at such frequencies to carry out such a method.

[0306] One aspect of the present invention is a method for reducing amyloid levels in a subject having mild or prodromal Alzheimer's disease, comprising the step of intravenously administering a composition of the bispecific anti-Aβ / TfR antibody trontinemab / RG6102 once every four weeks at a dose ranging from 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0307] One aspect of the present invention is a method for reducing amyloid levels in a subject having mild or prodromal Alzheimer's disease, comprising the step of intravenously administering a composition of the bispecific anti-Aβ / TfR antibody trontinemab / RG6102 once every four weeks at a dose ranging from 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject.

[0308] One aspect of the present invention is a method for reducing amyloid levels in a subject having mild or prodromal Alzheimer's disease, comprising the step of intravenously administering a composition of the bispecific anti-Aβ / TfR antibody trontinemab / RG6102 once every four weeks at a dose ranging from 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject, wherein the administered dose results in fewer ARIA events compared to a monospecific anti-Aβ antibody. In one embodiment of this aspect, the monospecific anti-Aβ antibody is administered at a dose of 10 mg / kg.

[0309] One aspect of the present invention is a method for converting amyloid-positive subjects having mild or moderate Alzheimer's disease into amyloid-negative subjects, comprising the step of intravenously administering a composition of the bispecific anti-Aβ / TfR antibody trontinemab / RG6102 once every four weeks at a dose ranging from 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subjects. In one preferred embodiment of this aspect, administration of the composition results in at least 30% of the subjects becoming amyloid-negative, as determined by visual reading of amyloid PET images after administration of a dose of 1.8 mg / kg for three months.

[0310] Amyloid positivity or amyloid negativity is determined in one embodiment by PET scan or visual reading of centiloids. In one embodiment, the threshold between amyloid negativity and amyloid positivity is 24.1 centiloids, i.e., amyloid negativity is less than 24.1 centiloids and amyloid positivity is 24.1 centiloids or more.

[0311] One aspect of the present invention is a method for treating a subject having mild or moderate Alzheimer's disease, comprising the step of intravenously administering a composition of the bispecific anti-Aβ / TfR antibody trontinemab / RG6102 once every four weeks at a dose ranging from 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject, wherein the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% compared to the severity of the same symptom in the same subject before treatment. In one preferred embodiment of this aspect, the at least one symptom associated with Alzheimer's disease is brain amyloid levels.

[0312] One aspect of the present invention is a method for treating a subject having early-stage Alzheimer's disease, comprising the step of intravenously administering a composition of the bispecific anti-Aβ / TfR antibody trontinemab / RG6102 once every four weeks at a dose ranging from 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject, wherein the severity of at least one symptom associated with Alzheimer's disease is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 95% compared to the severity of the same symptom in a subject receiving placebo. In one preferred embodiment of this aspect, the at least one symptom associated with Alzheimer's disease is brain amyloid levels.

[0313] One aspect of the present invention is a bispecific anti-Aβ / TfR antibody trontinemab / RG6102 for use as a pharmaceutical in the treatment of Alzheimer's disease, wherein the antibody is administered intravenously once every four weeks at a dose ranging from 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject. In one preferred embodiment of this aspect, administration of the composition results in at least 30% of the subjects being amyloid-negative, as determined by visual reading of amyloid PET images after administration of a dose of 1.8 mg / kg for three months.

[0314] One embodiment of the present invention is a bispecific anti-Aβ / TfR antibody for use in the treatment of Alzheimer's disease, wherein the antibody is administered intravenously once every four weeks at a dose ranging from 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject. In one preferred embodiment of this embodiment, administration of the composition results in at least 30% of the subjects being amyloid-negative, as determined by visual reading of amyloid PET images after administration of a dose of 1.8 mg / kg for three months. In one preferred embodiment of this embodiment, administration of the composition results in at least 70% of the subjects being amyloid-negative, as determined by visual reading of amyloid PET images after administration of a dose of 1.8 mg / kg for three to six months (3 to 6 doses).

[0315] One aspect of the present invention is the use of the bispecific anti-Aβ / TfR antibody trontinemab / RG6102 for the treatment of Alzheimer's disease, wherein the antibody is administered intravenously once every four weeks at a dose ranging from 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject. In one preferred embodiment of this aspect, administration of the composition results in at least 30% of the subjects being amyloid-negative, as determined by visual reading of amyloid PET images after administration of a dose of 1.8 mg / kg for three months. In one preferred embodiment of this aspect, administration of the composition results in at least 70% of the subjects being amyloid-negative, as determined by visual reading of amyloid PET images after administration of a dose of 1.8 mg / kg for three to six months (3 to 6 doses).

[0316] One aspect of the present invention relates to the use of the bispecific anti-Aβ / TfR antibody trontinemab / RG6102 in a method for treating Alzheimer's disease, wherein the antibody is administered intravenously once every four weeks at a dose ranging from 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject. In one preferred embodiment of this aspect, administration of the composition results in at least 30% of the subjects being amyloid-negative, as determined by visual reading of amyloid PET images after administration of a dose of 1.8 mg / kg for three months. In one preferred embodiment of this aspect, administration of the composition results in at least 70% of the subjects being amyloid-negative, as determined by visual reading of amyloid PET images after administration of a dose of 1.8 mg / kg for three to six months (3 to 6 doses).

[0317] In all aspects of the present invention and in one preferred embodiment, the dose is in the range of 1.8 mg / kg to 3.6 mg / kg of antibody relative to the weight of the subject.

[0318] In all aspects and one preferred embodiment of the present invention, amyloid levels are reduced by at least 20 centiloids from baseline, as determined by visual reading of amyloid PET images after 3 months / 3 doses.

[0319] In all aspects and one preferred embodiment of the present invention, amyloid levels are reduced by at least 25 centiloids from baseline, as determined by visual reading of amyloid PET images after 3 months / 3 doses.

[0320] In all aspects and one preferred embodiment of the present invention, amyloid levels are reduced by at least 60 centiloids from baseline, as determined by visual reading of amyloid PET images after 3 months / 3 doses.

[0321] While we do not wish to be bound by theory, it is anticipated that the initial removal of amyloid determined by PET is only the tip of the iceberg with respect to the administration of bispecific anti-Aβ / TfR antibodies disclosed herein, such as trontinemab. Since soluble oligomeric species are not measurable using PET, and removing insoluble amyloid does not remove the underlying factors that induce re-accumulation, the administration of bispecific anti-Aβ / TfR antibodies according to the present invention, such as trontinemab, encompasses the option of sustained suppression of amyloid rather than waiting for substantial lesions to re-accumulate.

[0322] In one embodiment, the present invention relates to a bispecific anti-Aβ / TfR antibody for use in the treatment of Alzheimer's disease, wherein the antibody is administered intravenously for an initial period at a dose ranging from 1.2 mg / kg to 7.2 mg / kg relative to the weight of the subject, and then a maintenance dose is administered thereafter. In one embodiment, the maintenance dose is a reduced dose compared to the dose administered during the initial period. For example, but not limited to, such a maintenance dose may be in the range of 1.8 mg / kg to 3.6 mg / kg of antibody relative to the weight of the subject. In one embodiment, the maintenance dose is 1.8 mg / kg of antibody relative to the weight of the subject. In one embodiment, the maintenance dose is 3.6 mg / kg of antibody relative to the weight of the subject.

[0323] Drug labeling, also known as prescription labeling, is the description, printing, or illustration on any drug or any container thereof, or attached to such drug. Drug labels strive to identify the drug content and to include specific instructions or warnings for administration, storage, and disposal. Labeling of approved drugs for healthcare providers provides important information about the drug, including: -Specific diseases and conditions that the drug is approved to treat. - How to use drugs to treat these specific diseases and symptoms. - Information regarding the risks of drugs. - Information that healthcare providers should discuss with patients before they take medication.

[0324] In the case of trontinemab, the label is likely to include the following information: Trontinemab is an antibody directed at amyloid-beta, indicated for the treatment of Alzheimer's disease. Treatment with trontinemab should be initiated in patients / animals with mild cognitive impairment or a mild cognitive stage of the disease, which is the population in which treatment was initiated in clinical trials. There is no safety or efficacy data regarding initiating treatment at an earlier or later stage of the disease than that studied.

[0325] Before starting treatment, confirm the presence of amyloid-beta lesions.

[0326] Obtain a recent baseline brain MRI before initiating treatment.

[0327] Obtain an MRI before the 5th, 7th, 9th, and 12th injections; if ARIA occurs as observed on X-ray, treatment recommendations will be based on the type, severity, and presence of the symptoms.

[0328] Dilution with 0.9% sodium chloride injection solution or USP is required before administration.

[0329] Administer as an intravenous infusion over approximately 1 hour via a terminal low-protein-binding 0.2 or 0.22 micron in-line filter.

[0330] In all aspects and preferred embodiments, the methods and compositions according to the present invention, comprising a bispecific anti-Aβ / TfR antibody or trontinemab, are for one or more of the following: - For the treatment of patients / animals with mild cognitive impairment or mild dementia of the disease, or for the treatment of patients / animals with mild, mild to moderate or moderate Alzheimer's disease; or / and - For the treatment of patients / animals in which the presence of amyloid-beta lesions has been confirmed before initiating treatment; or / and - For treatment of patients / animals for which a recent baseline brain MRI is available prior to initiating treatment; or / and -5th time or / and the 7th time or / and the 9th or / and the 12th For the treatment of patients / animals for which an MRI has been obtained before the first injection, if ARIA observed on radiographs occurs, the treatment recommendation shall be based on the type, severity and presence of the symptoms; or / or - For treatment, dilute the antibody solution with 0.9% sodium chloride injection, USP before administration; or / or - For the procedure, the antibody solution is administered as an intravenous infusion over approximately 1 hour via a terminal low-protein binding 0.2 or 0.22 micron in-line filter.

[0331] definition When used herein and in the appended claims, the singular forms “a,” “an,” and “the” include multiple referents unless the context makes otherwise obvious. Thus, for example, a reference to “a cell” includes multiple such cells and their equivalents known to those skilled in the art, and so on. Similarly, the terms “a” (or “an”), “one or more,” and “at least one” may also be used synonymously herein. It should also be noted that the terms “comprising,” “including,” and “having” may also be used synonymously.

[0332] The term "approximately" means a range of ±20% of the following number. In one embodiment, the term "approximately" means a range of ±10% of the following number. In one embodiment, the term "approximately" means a range of ±5% of the following number.

[0333] The term "comprising" also includes the term "consisting of."

[0334] The term "anti-(human) Aβ protein antibody" or "anti-Aβ antibody" refers to an antibody that can bind to human Aβ protein with sufficient affinity to be useful as a diagnostic and / or therapeutic agent in targeting the Aβ protein.

[0335] It should be noted that human Aβ protein has several naturally occurring forms, the human forms of which are called Aβ39, Aβ40, Aβ41, Aβ42, and Aβ43. The most prominent form, Aβ42, has the amino acid sequence of SEQ ID NO: 45. In Aβ41, Aβ40, and Aβ39, the C-terminal amino acids A, IA, and VIA are missing, respectively. In the Aβ43 form, an additional threonine residue is included in the C-terminus of SEQ ID NO: 45. In one preferred embodiment, the antibody according to the present invention specifically binds to a human Aβ protein having the amino acid sequence of SEQ ID NO: 45.

[0336] The "central nervous system" or "CNS" refers to the complex of nerve tissue that controls bodily functions, and includes the brain and spinal cord.

[0337] "Affinity" refers to the sum of all non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects the 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). Affinity can be measured by common methods known in the art, including those described herein.

[0338] The term “antibody-dependent cell-mediated cytotoxicity (ADCC)” refers to a function mediated by Fc receptor binding, and describes the lysis of target cells by the antibodies reported herein in the presence of effector cells. ADCC can be measured by treating a preparation of CD19-expressing erythrocytes (e.g., K562 cells expressing recombinant human CD19) with the antibodies according to the present invention in the presence of effector cells, such as PBMCs (peripheral blood mononuclear cells) immediately after isolation, or effector cells purified from a buffy coat, such as monocytes or NK (natural killer) cells. Target cells are labeled with 51Cr and then incubated with the antibodies. The labeled cells are incubated with effector cells, and the supernatant is analyzed for released 51Cr. A control is provided for incubation of target endothelial cells with effector cells, but without the antibodies. The ability of antibodies to induce the initial steps mediated by ADCC is investigated by measuring the binding of antibodies to Fcγ receptor-expressing cells, such as cells that recombinantly express FcγRI and / or FcγRIIA or NK cells (which essentially express FcγRIIIA).

[0339] The term "binding (to an antigen)" refers to the binding of an antibody to its congener antigen. Binding can be determined in an in vitro assay. In some embodiments, binding is determined in a binding assay in which the antibody is bound to a surface and the binding of the antigen to that antibody is measured by surface plasmon resonance (SPR), or vice versa. Binding affinity is defined by the terms ka (rate constant of antibody association from antibody / antigen complex), kd (dissociation constant), and KD (kd / ka). Thus, binding means a specific and detectable interaction between an antibody and its congener antigen, e.g., a binding affinity (KD) of 10E-4M or less. "Specifically binding" means a binding affinity (KD) of 10E-8M or less, 10E-13 to 10E-8M in some embodiments, and 10E-13 to 10E-9M in some embodiments.

[0340] "Effector function" refers to the biological activity resulting from the Fc region of an antibody, which varies depending on the antibody class. Examples of antibody effector functions include: C1q binding and complement-dependent cell-mediated cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, downregulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

[0341] Fc receptor-binding-dependent effector function can be mediated by the interaction between the Fc region of an antibody and the Fc receptor (FcR), a specialized cell surface receptor on hematopoietic cells. Fc receptors belong to the immunoglobulin superfamily and have been shown to mediate both the phagocytosis of antibody-coated pathogens by immune complexes via antibody-dependent cell-mediated cytotoxicity (ADCC) and the lysis of corresponding antibody-coated red blood cells and various other cellular targets (e.g., tumor cells) (see, e.g., Van de Winkel, J. Gand Anderson, CL, J. Leukoc. Biol. 49 (1991) 511-524). FcRs are defined by their specificity for immunoglobulin isotypes: the Fc receptor for IgG antibodies is called FcγR. Fc receptor binding is described, for example, in Ravetch, J.V. and Kinet, JP, Annu. Rev. Immunol. 9 (1991) 457-492; Capel, P.J., et al., Immunomethods 4 (1994) 25-34; de Haas, M., et al., J. Lab. Clin. Med. 126 (1995) 330-341; and Gessner, J.E., et al., Ann. Hematol. 76 (1998) 231-248.

[0342] Cross-linking of the Fc region of IgG antibodies with receptors (FcγRs) induces a wide variety of effector functions, including phagocytosis, antibody-dependent cell-mediated cytotoxicity, release of inflammatory mediators, and regulation of immune complex elimination and antibody production. In humans, three classes of FcγRs are characterized as follows: -FcγRI(CD64) binds monomeric IgG with high affinity and is expressed on macrophages, monocytes, neutrophils, and eosinophils. Modification of the Fc region IgG at at least one of the amino acid residues E233-G236, P238, D265, N297, A327, and P329 (numbered according to Kabat's EU index) reduces binding to FcγRI. IgG2 residues at positions 233-236, substituted with IgG1 and IgG4, reduced FcγRI binding by 103-fold and eliminated the human monocyte response to antibody-sensitized erythrocytes (Armour, KL, et al., Eur. J. Immunol. 29(1999) 2613-2624). -FcγRII(CD32) binds complexed IgG with moderate to low affinity and is widely expressed. This receptor can be divided into two subtypes: FcγRIIA and FcγRIIB. FcγRIIA is found in many cells involved in killing (e.g., macrophages, monocytes, neutrophils) and appears to be able to activate the killing process. FcγRIIB appears to play a role in the inhibitory process and is found in B cells, macrophages, as well as mast cells and eosinophils. On B cells, FcγRIIB appears to have the function of further suppressing immunoglobulin production and isotype switching to, for example, the IgE class. On macrophages, FcγRIIB acts to inhibit phagocytosis mediated by FcγRIIA. On eosinophils and mast cells, the B form may assist in suppressing the activation of these cells through the binding of IgE to its distinct receptor. Reduced binding to FcγRIIA is observed, for example, in antibodies containing an IgG Fc region with mutations in at least one of the following amino acid residues: E233-G236, P238, D265, N297, A327, P329, D270, Q295, A327, R292, and K414 (numbered according to Kabat's EU index). -FcγRIII(CD16) binds IgG with moderate to low affinity and exists in two types. FcγRIIIA is found on NK cells, macrophages, eosinophils, and some monocytes and T cells and mediates ADCC. FcγRIIIB is highly expressed on neutrophils. Reduced binding to FcγRIIIA is observed, for example, with antibodies containing an IgG Fc region with mutations in at least one of the following amino acid residues: E233-G236, P238, D265, N297, A327, P329, D270, Q295, A327, S239, E269, E293, Y296, V303, A327, K338 and D376 (numbered according to Kabat's EU index).

[0343] The mapping of the binding site for the Fc receptor on human IgG1, the aforementioned mutation sites, and methods for measuring binding to FcγRI and FcγRIIA are described in Shields, RL, et al., J. Biol. Chem. 276 (2001) 6591-6604.

[0344] The "effective dose" of an active substance, such as a pharmaceutical preparation, refers to the amount that is effective in terms of the dosage and duration required to achieve the desired therapeutic or preventive outcome.

[0345] As used herein, the term “Fc receptor” refers to an activating receptor characterized by the presence of a cytoplasmic ITAM sequence associated with this receptor (see, for example, Ravetch, JV and Bolland, S., Annu. Rev. Immunol. 19(2001) 275-290). Such receptors are FcγRI, FcγRIIA, and FcγRIIIA. The term “absence of FcγR binding” means that, at an antibody concentration of 10 μg / ml, the binding of the antibody to NK cells is less than 10% of the binding observed for the anti-OX40L antibody LC.001 reported in International Publication No. 2006 / 029879.

[0346] IgG4 exhibits reduced FcR binding, while antibodies of other IgG subclasses show strong binding. However, Pro238, Asp265, Asp270, Asn297 (loss of Fc carbohydrate), Pro329, as well as 234, 235, 236 and 237, Ile253, Ser254, Lys288, Thr307, Gln311, Asn434 and His435 are residues that, when modified, also reduce FcR binding (Shields, R. Let al., J. Biol. Chem. 276 (2001) 6591-6604; Lund, J. et al., FASEB J. 9 (1995) 115-119; Morgan, A. et al., Immunology 86 (1995) 319-324; and European Patent No. 0307434). In one embodiment, the antibody according to the present invention is of the IgG1 or IgG2 subclass and includes mutants PVA236, GLPSS331, L234A / L235A, or P329G / L234A / L235A. In one embodiment, the antibody reported herein is of the IgG4 subclass and includes mutant L235E. In one embodiment, the antibody according to the present invention further includes mutant S228P.

[0347] The "framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The variable domain FR generally consists of four FR domains: FR1, FR2, FR3, and FR4. Therefore, the HVR and FR sequences generally appear in the following order in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0348] A “humanized” antibody refers to a chimeric antibody containing amino acid residues derived from a non-human HVR and amino acid residues derived from a human FR. In one embodiment, the humanized antibody contains substantially all of at least one, typically two, variable domains, where all or substantially all of the HVR (e.g., CDR) corresponds to the HVR (e.g., CDR) of the non-human antibody, and all or substantially all of the FR corresponds to the FR of the human antibody. The humanized antibody may optionally contain at least a portion of the antibody constant region derived from a human antibody. The “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0349] The terms “hypervariable region” or “HVR,” as used herein, refer to each region of an antibody variable domain that contains amino acid residue stretches whose sequences are hypervariable (“complementarity-determining region” or “CDR”) and / or form structurally defined loops (“hypervariable loop”) and / or contain residues that contact an antigen (“antigen contact region”). Generally, an antibody contains a total of six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3).

[0350] HVR is (a) Hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia, C. and Lesk, AM, J. Mol. Biol. 196 (1987) 901-917); (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242). (c) Antigen contact sites formed at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al., J.Mol.Biol.262:732-745 (1996)); and (d) A combination of (a), (b), and / or (c) containing HVR amino acid residues 46-56(L2), 47-56(L2), 48-56(L2), 49-56(L2), 26-35(H1), 26-35b(H1), 49-65(H2), 93-102(H3), and 94-102(H3). Includes.

[0351] Unless otherwise specified, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein in accordance with Kabat et al. (cited above).

[0352] A “humanized” antibody refers to a chimeric antibody containing amino acid residues derived from a non-human HVR and amino acid residues derived from a human FR. In one embodiment, the humanized antibody contains substantially all of at least one, typically two, variable domains, where all or substantially all of the HVR (e.g., CDR) corresponds to the HVR (e.g., CDR) of the non-human antibody, and all or substantially all of the FR corresponds to the FR of the human antibody. The humanized antibody may optionally contain at least a portion of the antibody constant region derived from a human antibody. The “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0353] "Isolated" antibodies are those separated from components of their natural environment. In some embodiments, antibodies are purified to a purity of over 95% or over 99%, as determined by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., size exclusion chromatography, ion exchange, or reversed-phase HPLC). For an overview of methods for evaluating antibody purity, see, for example, Flatman, S. et al., J. Chrom. B 848 (2007) 79-87.

[0354] "Isolated" nucleic acids refer to nucleic acid molecules that have been separated from components in their natural environment.

[0355] "Isolated nucleic acids encoding anti-human Aβ protein antibodies" refers to one or more nucleic acid molecules encoding the heavy and light chains (or fragments thereof) of an antibody, including such nucleic acid molecules in a single plasmid or in separate plasmids.

[0356] The “individual” or “subject” is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a human.

[0357] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies; that is, except for possible variant antibodies, which are generally present in small amounts and may contain naturally occurring mutations or arise during the production of a monoclonal antibody preparation, the individual antibodies constituting that population are identical and / or bind to the same epitope. In contrast to polyclonal antibody preparations, which typically contain different antibodies against different determinants (epitopes), each monoclonal antibody in a monoclonal antibody preparation is against a single determinant on an antigen. Therefore, the modifier “monoclonal” indicates the characteristic of an antibody obtained from a substantially homogeneous population of antibodies and should not be interpreted as requiring the production of the antibody by any particular method. For example, monoclonal antibodies according to the present invention may be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of a human immunoglobulin locus, such methods, and other exemplary methods for producing monoclonal antibodies, are described herein.

[0358] The term “package insert” is used to refer to instructions that are typically included in the market packaging of therapeutic products and that contain information about indications, usage, dosage, administration, combination therapy, contraindications and / or warnings relating to the use of such therapeutic products.

[0359] The term "pharmaceutical preparation" refers to a preparation that is in a form that enables the biological activity of the active ingredient contained therein, such as a therapeutic antibody, and that does not contain any additional ingredients that would be unacceptably toxic to the target population to which the preparation is to be administered.

[0360] A "pharmaceutically acceptable carrier" refers to a component in a pharmaceutical preparation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, additives, stabilizers, or preservatives.

[0361] As used herein, the term “treatment” (and its grammatical variations, e.g., “to treat” or “to treat”) refers to a clinical intervention in an attempt to alter the natural course of the individual being treated, and may be performed for preventive purposes or during the course of a clinical lesion. Desired effects of treatment include, but are not limited to, preventing the onset or recurrence of the disease, alleviating symptoms, reducing the direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or alleviating the disease state, and achieving remission or improving prognosis. For example, but not limited to, such treatment may include interventions to mitigate clinical exacerbation in a subject with a disease associated with amyloid accumulation, e.g., Alzheimer's disease. In some embodiments, such treatment may include converting an amyloid-positive subject to an amyloid-negative subject. In some embodiments, such treatment may include interventions to reduce the severity of at least one symptom associated with a disease associated with amyloid accumulation, e.g., Alzheimer's disease, in a subject. In some embodiments, the antibodies of the present invention are used to delay or prevent the onset of the disease or to slow the progression of the disease.

[0362] As used in this application, the term "valency" refers to the presence of a specified number of binding sites within the (antibody) molecule. Therefore, the terms "bivalent," "tetravalent," and "hexavalent" refer to the presence of two, four, and six binding sites, respectively, within the (antibody) molecule.

[0363] The term "variable region" or "variable domain" refers to a domain in the heavy or light chain of an antibody that is involved in the antibody's binding to its antigen. The variable domains of the heavy and light chains of an antibody (VH and VL, respectively) generally have a similar structure, with each domain containing four framework regions (FRs) and three hypervariable regions (HVRs) (see, for example, Kindt, T.Jet al., Kuby Immunology, 6th ed., WH Freeman and Co., NY (2007), page 91). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a particular antigen can be isolated using the VH or VL domain from the antibody that binds that antigen, respectively, to screen for a library of complementary VL or VH domains. For example, see Portolano, S et al., J.Immunol. 150 (1993) 880-887; Clackson, T et al., Nature 352 (1991) 624-628). (Homogenetic pairs of antibody heavy chain variable domains and antibody light chains)

[0364] Where ranges of values ​​are enumerated herein, the boundaries and each value and subrange within those ranges are intended to be included. For example, "2 mg / kg to 6 mg / kg" is intended to include, for example, 2.0 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.5 mg / kg, 4 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.5 mg / kg, 6 mg / kg, 2.5 mg / kg to 3 mg / kg, 2.5 mg / kg to 4.5 mg / kg, 3 mg / kg to 4.5 mg / kg, 4.5 mg / kg to 6 mg / kg, 2.5 mg / kg to 4 mg / kg, etc.

[0365] As used herein, “early AD” or “early Alzheimer’s disease” refers to a range of AD severities from mild cognitive impairment to moderate possibility to mild Alzheimer’s dementia. Subjects with early AD include subjects with mild Alzheimer’s dementia. In one embodiment, subjects with early AD have a Minimal Mental State Examination (MMSA) score of 22–30 and a Clinical Dementia Scale (CDR) total range of 0.5–1.0.

[0366] As used herein, subjects with “mild Alzheimer’s disease dementia” are those who meet the National Institute on Aging and Alzheimer’s Association (NIA-AA) core clinical criteria for possible Alzheimer’s disease dementia, as defined in “McKhann, GM et al.,” “The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease,” “Alzheimer Dement. 7(2011) 263-269.” This specification also includes subjects with a CDR score of 0.5–1.0 and a memory box score of 0.5 or higher at screening and baseline.

[0367] As used herein, “MMSE” refers to the Mini-Mental State Examination, a cognitive measurement commonly used for screening purposes but also frequently measured over the long term in AD clinical trials. It has a 30-point scale where higher scores indicate less impairment and lower scores indicate more impairment. As used herein, seven items measuring orientation to time and place, encoding, memory retrieval, attention, language, and drawing were assessed. (Folstein, MF, et al., J. Psychiatr. Res. 12 (1975) 189-198).

[0368] As used herein, “CDR-SB” refers to the Clinical Dementia Scale-Box Sum. The CDR is a clinical scale that represents impairment of performance on a 5-point scale for each of six functional categories, including memory, orientation, judgment, and problem-solving; community issues; home and hobbies; and personal care. (Berg, L. et al., Ann. Neurol. 23(1988) 477-484.) The scores obtained for the degree of impairment for each of the six functional categories are combined into one comprehensive score (ranging from 0 to 3) of the dementia CDR score. The box sum provides a further measure of change, with each category having a maximum score of 3, and the total score being the sum of the category scores, giving a possible total score of 0 to 18, with higher scores indicating a more severe impairment. The total score can be used as a clinical measure of the severity of dementia.

[0369] As used herein, whether an initial AD subject is “amyloid-positive” or “amyloid-negative” is determined based on whether the patient / animal has a positive amyloid load, as indicated by a long-term PET assessment of amyloid imaging agent uptake into the brain. In some embodiments, a qualitative visual reading of a PET scan is used to determine amyloid-positive and amyloid-negative by classifying the subject as having either “normal” or “abnormal” uptake based on the PET image pattern. The person performing the reading is trained and certified to recognize brain PET images with abnormal or normal uptake patterns, or amyloid detection is performed through a semi-quantitative or quantitative approach.

[0370] As used herein, the term “prevent” means obtaining a beneficial or desired outcome, including but not limited to a preventive benefit. For a preventive benefit, a composition may be administered to subjects at risk of developing Alzheimer’s disease, subjects having one or more preclinical symptoms of Alzheimer’s disease but no clinical symptoms, or subjects reporting one or more physiological symptoms of Alzheimer’s disease, even if they have not been clinically diagnosed with Alzheimer’s disease. As used herein, “prevention” may further include a therapeutic benefit, meaning the eradication or improvement of one or more of the underlying symptoms being treated or associated physiological symptoms.

[0371] As used herein, the terms “Serious Adverse Event” or “SAE” mean an event that is (1) fatal; (2) life-threatening; (3) requires hospitalization or extension of an existing hospitalization for a hospitalized patient; (4) results in permanent or significant physical disability / incapacity; and / or (5) a birth defect / defect observed after administration of any of the compositions described herein.

[0372] The severity of serious adverse events can be assessed based on a uniform scale used in this art. For example, the severity of a serious adverse event in question may be evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). A description of the various CTCAE adverse event grades is provided below: - Grade 1: Mild; asymptomatic or mildly symptomatic; clinical or diagnostic findings only; no intervention required. - Grade 2: Moderate; requiring minimal, local, or non-invasive intervention; age-appropriate limitations in instrumental activities of daily living. - Grade 3: Severe or medically significant, but not immediately life-threatening; requires hospitalization or extended hospital stay; incapacitated; limitations in daily living activities. - Grade 4: Life-threatening consequences requiring emergency intervention. - Grade 5: Death related to an adverse event.

[0373] As used herein, the term “centiloid” refers to the centiloid scale unit as defined in Klunk, WE, et al., Alz. Dement. 11 (2015) 1-15. Because there was considerable variability in the exact numbers reported as quantitative outcome determinations for tracer retention, standardization of quantitative amyloid imaging determinations by scaling the results of each specific analytical method or tracer to a scale of 0-100 is fixed using young controls (under 45 years of age) and typical Alzheimer's disease patients.

[0374] Therefore, the centroid scale is a standardized PET-based amyloid loading measurement that homogenizes amyloid loading measurements across tracers and sites (see, for example, Villain, N., et al., Rev. Neuro. 178 (2022) 1011-1030; Klunk, WE, et al., Alz. Dement. 11 (2015) 1-15; Navitsky, M., et al. Alz. Dement. 14 (2018) 1565-1571).

[0375] 0 represents the mean value in "highly confident" amyloid-negative subjects (i.e., younger subjects), and 100 represents the mean value in "typical" AD patients with dementia (Klunk, WE, et al., Alz. Dement. 11(2015) 1-15). The usual cutoff for defining "amyloid-positive" and "amyloid-negative" individuals is approximately 10-25 centiloids (de Souza, GS, et al., Mol. Imag. Biol. 24(2021) 394-403). Case reports of autopsy data from patients under aducanumab confirm this clearance, so this clearance measured by amyloid PET is not an artifact related to the antibody itself (Plowey, ED, et al., Acta Neuropathol. 144(2022) 143-153).

[0376] For example, if the amyloid plaque level assessed by PET drops to less than 25 centroids, this indicates the removal of the amyloid plaques under the pathological cutoff value.

[0377] Some authors suggest that reducing the amyloid load to below 20 centiloids is necessary to achieve significant cognitive benefits, and that there may be a delay of several months between amyloid removal and clinical effects (Karran, E. and De Strooper, B., Nat. Rev. Drug. Discov. 21(2022) 306-318).

[0378] As used herein, the term "PET" refers to amyloid positron emission tomography. Briefly, a standardized centroid approach using "ADNI-like" cortical regions and a whole cerebellar reference region was used to determine the amyloid load. This resulted in a single, comprehensive measure of amyloid load for each participant at each time period.

[0379] The determined overall decline is considered an appropriate measure for comparison with other molecules present or present in the clinical setting.

[0380] More specifically, participants were scanned with either florbetapil (brand name Amyvid) or florbetaben (brand name Neuraceq) using imaging protocols consistent with FDA and EU labels. Amyloid loading was quantified by the centroid method (e.g., Klunk, WE, et al., Alz. Dement. 11(2015) 1-15).

[0381] To be included in this study, participants needed to have a minimum of 50 centroids (CL) to confirm amyloid lesions and a sufficiently high loading to demonstrate a possible treatment effect with trontinemab. (Note that 100 CL represents the mean of a typical AD group, 0 CL is the mean of a healthy control without amyloid, and 24 CL is considered the threshold for detectable amyloid that distinguishes none / sparse from moderate / high frequency plaques (see, e.g., Navitsky, M., et al., Alzheimer's Dement. 14(2018) 1565-1571). Navitsky et al. provided conversion of florbetapir SUVr values ​​to the centroid scale, following the guidelines of Klunk et al.

[0382] Florbetapir was developed under the trade name Amyvid. Florbetapir was approved by the FDA in 2012. Florbetapir has a longer half-life and similar selectivity to the PIB compound (N-methyl-[11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole) and is thought to have a similar binding pattern to PIBs with high affinity for Aβ plaques (Anand, K. and Sabbagh, M., Neurotherap. 14(2017) 54-61).

[0383] More specifically, Amyvid is a radiodiagnostic for positron emission tomography (PET) imaging of the brain to estimate the density of beta-amyloid senile plaques in adult patients with cognitive impairment being evaluated for Alzheimer's disease (AD) and other causes of cognitive decline. A negative Amyvid scan indicates that senile plaques are sparse or absent and is not consistent with a neuropathological diagnosis of AD at the time of imaging acquisition, and a negative scan result reduces the likelihood that the patient's cognitive impairment is attributable to AD. A positive Amyvid scan indicates moderate to high frequency of amyloid senile plaques, and neuropathological examination indicates that this amount of amyloid plaques is present in AD patients but can also be present in patients with other types of neurological symptoms and in older adults with normal cognition.

[0384] Generally, the dosage and administration are as follows: - The recommended dose of Amyvid is 370 MBq (10 mCi), with a maximum mass dose of 50 μg, administered as a single intravenous bolus in a total volume of 10 mL or less. Follow the injection procedure with an intravenous flush of 0.9% sterile sodium chloride. - Obtain a 10-minute PET image starting approximately 30-50 minutes after intravenous injection (the patient must lie supine, with the head positioned so that the brain, including the cerebellum, is centered in the PET scanner's field of view). -Image interpretation: - The purpose of Amyvid image interpretation is to provide an estimate of brain β-amyloid plaque density. - The images should be displayed transversely to the body axis, with access to the sagittal and coronal planes as needed. When examining the images, include all transverse slices of the brain using a grayscale scale where the maximum intensity of the scale is set to the maximum intensity of all brain pixels. First, locate the brain slice with the highest level of image contrast (highest radioactivity signal for Amyvid uptake) and adjust the contrast appropriately. Begin image interpretation by sequentially viewing slices from the bottom to the top of the brain. Periodically refer to sagittal and coronal image displays as needed to more clearly define radioactivity uptake and ensure that the entire brain is displayed. - Image interpretation is based on the distribution of radioactive signals within the brain. Images are designated as positive or negative by comparing radioactivity in cortical gray matter with radioactivity in adjacent white matter. This decision occurs only in the cerebral cortex; signal uptake in the cerebellum does not contribute to scan interpretation (for example, a positive scan may show retained cerebellar gray-white contrast even if cortical gray-white contrast is lost). - Negative scans show more radioactivity in white matter than in gray matter, creating a clear gray-white contrast. - Positive scans typically indicate cortical regions with a clear reduction or loss of gray-white contrast. These scans have one or more regions with increased cortical gray matter signaling that results in reduced (or absent) gray-white contrast. Specifically, positive scans have one of the following: -a) Two or more brain regions (each larger than a single cortical gyrus) where reduced gray-white contrast is present or absent. This is the most common appearance of a positive scan; or -b) One or more areas in the gray matter where the radioactivity is high and clearly exceeds that of the adjacent white matter.

[0385] Piramal Imaging developed florbetabene under the trade name Neuraceq. This compound is an 18F-labeled polyethylene glycol stilbene derivative that showed high specificity for Aβ in vitro without binding to tau, frontotemporal dementia tissue, or DLB tissue (Anand, K. and Sabbagh, M., Neurotherap. 14(2017) 54-61).

[0386] Richards, D. and Sabbagh, MN. reported on florbetaben for PET imaging of β-amyloid plaques in the brain (Neurol.Ther.3(2014)79-88). More specifically, they reported investigating PET scan reads at the control level (whole brain) to determine the sensitivity and specificity of florbetaben in this context. Results from visual assessment using methods applicable to clinical routines were compared with neuropathological assessment of the absence / presence of β-amyloid plaques according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. Image analysis from the initial 31 deceased subjects and 10 young, healthy volunteers considered β-amyloid-negative yielded 100% sensitivity (95% CI 80.5–100.0%), 91.67% specificity (95% CI 80.6–100.0%), and near-perfect agreement between readers [estimated inter-rater reliability (j) = 0.870]. These results were subsequently confirmed in a larger cohort of subjects and used for approval in the EU and US. Furthermore, since a sufficiently large number of amyloid-negative subjects became available for analysis, the addition of young, healthy volunteers was no longer required.

[0387] More specifically, Neuraceq® is a radiodiagnostic agent adapted for positron emission tomography (PET) imaging of the brain to estimate the density of beta-amyloid senile plaques in adult patients with cognitive impairment being evaluated for Alzheimer's disease (AD) and other causes of cognitive decline. A negative Neuraceq scan indicates that senile plaques are sparse or absent and is not consistent with a neuropathological diagnosis of AD at the time of imaging acquisition, and a negative scan result reduces the likelihood that the patient's cognitive impairment is attributable to AD. A positive Neuraceq scan indicates moderate to high frequency of amyloid senile plaques, and neuropathological examination indicates that this amount of amyloid plaques is present in AD patients, but can also be present in patients with other types of neurological symptoms and in older adults with normal cognition.

[0388] Generally, the dosage and administration are as follows: The recommended dose of Neuraceq is 300 MBq (8.1 mCi), with a maximum mass dose of 30 mcg, administered as a single slow intravenous bolus (6 seconds / mL) in a total volume of up to 10 mL. - Start 45–130 minutes after Neuraceq injection and acquire PET images over 15–20 minutes (the patient must remain in a supine position, with the head positioned so that the brain, including the cerebellum, is centered in the PET scanner's field of view). -Image interpretation: The purpose of Neuraceq image interpretation is to estimate the density of β-amyloid senile plaques in the brain's gray matter. - PET images should be displayed transversely to the body axis using grayscale or inverse grayscale. Sagittal and coronal planes may be used for additional directional purposes. CT or MR images may be useful for anatomical reference purposes. However, visual assessment should be performed using the axial plane according to the recommended reading method. - Image interpretation is performed by visually comparing activity in cortical gray matter with activity in adjacent white matter. To assist the reader in locating, regions shown in the PET image that "anatomically" correspond to white matter structures (e.g., cerebellar white matter or splenium) should be identified. Images should be systematically observed and assessed by scrolling through the cerebellum, lateral temporal and frontal lobes, posterior cingulate cortex / precuneus, and parietal lobe. For a gray matter cortical region to be assessed as showing "tracer uptake," a large portion of the slices from each region must be affected. - For each patient, PET imaging assessment is classified as either "beta-amyloid positive" or "beta-amyloid negative." This decision is based on the assessment of tracer uptake in the gray matter of the following four brain regions: temporal lobe, frontal lobe, posterior cingulate cortex / precuneus, and parietal lobe, according to the following assessment rules. -β-amyloid negative- In all four brain regions, tracer uptake (i.e., signal intensity) in gray matter is lower than in white matter (no β-amyloid deposition). -β-amyloid positive- A smaller area of ​​tracer uptake equal to or greater than that present in the white matter ("moderate" β-amyloid deposition) that involves a large portion of a slice within at least one of the four brain regions and extends beyond the white matter margin to the perilateral cortical margin, or a dense area of ​​tracer uptake equal to or greater than that present in the white matter that extends beyond the white matter margin to the perilateral cortical margin and involves an entire region including a large portion of a slice within at least one of the four brain regions ("marked" β-amyloid deposition). There is no known clinical or histopathological correlation to distinguish between "moderate" β-amyloid deposition and "marked" β-amyloid deposition.

[0389] As used herein, the term "ARIA" means amyloid-related imaging abnormalities. Amyloid-related imaging abnormalities (ARIA) are magnetic resonance imaging (MRI) abnormalities that represent leakage of bodily fluids or blood into the pia mater and / or parenchyma of the brain. ARIA-E (E for edema or effusion) represents vasogenic edema and / or sulcal effusion, most commonly seen in axial T2 FLAIR series, and ARIA-H (H for hemosiderin [iron] deposition) represents microhemorrhages or superficial iron deposition, most commonly seen in iron-sensitive series such as gradient echo T2* or susceptibility-weighted imaging series (Sperling, RA, et al., Alzheimers Dement. 7 (2011) 367-385; Hampel, H., et al., Brain 146 (2023) 4414-4424).

[0390] ARIA has been reported using antibodies that can reduce Aβ aggregates, leading to the understanding that ARIA is a class effect of these agents (Salloway, S., et al., Neurol. 73 (2009) 2061-2070; Ostrowitzki, S., et al., Alz. Res. Ther. 9 (2017) 95). ARIA primarily occurs in association with anti-amyloid immunotherapy, but can also occur spontaneously in people with Alzheimer's disease or in association with other cerebrovascular and neurological symptoms. The majority of patients / animals experiencing ARIA are asymptomatic. The most common symptoms may include headache, confusion, dizziness, nausea, and visual disturbances. These symptoms typically resolve after discontinuation of anti-amyloid therapy (Sperling, R., et al., Lancet Neurol. 11 (2012) 241-249; Sevigny, J., et al., Nature 537 (2016) 50-56; Ostrowitzki et al. 2017; Greenberg, SM, et al. Nat. Rev. Neurol. 16 (2020) 30-42; Salloway, S., et al., JAMA Neurol. 79 (2022) 13-21).

[0391] The pathophysiological mechanisms of ARIA are not fully understood, but they are thought to reflect increased transport of parenchymal amyloid-beta (Aβ) into the perivascular space and / or a temporary increase in vascular permeability due to leakage of vessels after clearance of vascular Aβ. In normal vascular structures, smooth muscle cells are regularly distributed, but in Alzheimer's disease patients, the accumulation of Aβ lesions disrupts the distribution of smooth muscle cells. After anti-amyloid therapy, vessels may become more susceptible to ARIA, resulting in leakage of proteinaceous fluids and / or red blood cells into the vessel wall and surrounding tissue. With Aβ clearance and restoration of vascular structural integrity, the risk of ARIA may decrease (Sperling et al. 2012, see above; Barakos, J., et al., J. Prev. Alz. Dis. 9 (2022) 211-220).

[0392] Trontinemabu / RG6102 Troncinemab is, a) A full-length antibody comprising two pairs each of full-length antibody light chains and full-length antibody heavy chains, wherein the binding sites formed by each pair of full-length heavy chains and full-length light chains specifically bind to a first antigen, b) comprising one additional Fab fragment, the additional Fab fragment being fused to the C-terminus of one heavy chain of a full-length antibody, and the binding site of the additional Fab fragment specifically binding to a second antigen, Each full-length antibody light chain contains the amino acid residue arginine at position 123 of the constant light chain domain (CL) (instead of the glutamate residue in the wild type; E123R mutation) and the amino acid residue lysine at position 124 (instead of the glutamine residue in the wild type; Q124K mutation) (numbered by Kabat), Each full-length antibody heavy chain contains a glutamic acid residue at position 147 (instead of the wild-type lysine residue; K147E mutation) and a glutamic acid residue at position 213 (instead of the wild-type lysine amino acid residue; K213E mutation) of the first constant heavy chain domain (CH1) (numbered according to the Kabat EU index), The additional Fab fragment that specifically binds to the second antigen includes a domain crossover such that the constant light chain domain (CL) and constant heavy chain domain 1 (CH1) are interchangeable with each other. The first antigen is human Aβ protein, and the second antigen is human transferrin receptor. It is a bispecific antibody.

[0393] More specifically, in one preferred embodiment, trontinemab is a bispecific antibody comprising a (full-length) light chain having the amino acid sequence of SEQ ID NO: 17, a (full-length) heavy chain having the amino acid sequence of SEQ ID NO: 18, a (full-length) light chain having the amino acid sequence of SEQ ID NO: 19, and an antibody Fab fragment having the amino acid sequence of SEQ ID NO: 20 (SEQ ID NO: 21, which includes SEQ ID NO: 18 + linker + SEQ ID NO: 20).

[0394] Sequence ID 17 is the amino acid sequence DIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGVPARFSGSGSGTDFTLTISSLEPEDFATYYCLQIYNMPITFGQGTKVEIKRTVAAPSVFIFPPSDRKLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC It has, Sequence ID 18 is the amino acid sequence QVELVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAINASGTRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGKGNTHKPYGYVRYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPK SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG It has, Sequence ID 19 is the amino acid sequence AIQLTQSPSSLSASVGDRVTITCRASQSISSYLAWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNYASSNVDNTFGGGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC has

[0395] Sequence ID 20 is the amino acid sequence QSMQESGPGLVKPSQTLSLTCTVSGFSLSSYAMSWIRQHPGKGLEWIGYIWSGGSTDYASWAKSRVTISKTSTTVSLKLSSVTAADTAVYYCARRYGTSYPDYGDASGFDPWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC has

[0396] Sequence ID 21 is the amino acid sequence QVELVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAINASGTRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGKGNTHKPYGYVRYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGGSGGGGSGGGGSQSMQESGPGLVKPSQTLSLTCTVSGFSLSSYAMSWIRQHPGKGLEWIGYIWSG GSTDYASWAKSRVTISKTSTTVSLKLSSVTAADTAVYYCARRYGTSYPDYGDASGFDPWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC It holds.

[0397] AβVH (Sequence ID 04), CDR is underlined: QVELVESGGG LVQPGGSLRL SCAAS GFTFS SYAMS WVRQA PGKGLEWVS A INASGTRTYY ADSVKG RFTI SRDNSKNTLY LQMNSLRAED TAVYYCAR GK GNTHKPYGYV RYFDV WGQGT LVTVSS CDR-H1 (Sequence ID 01): GFTFSSYAMS CDR-H2 (Sequence ID 02): AINASGTRTY YADSVKG CDR-H3 (Sequence ID 03): GKGNTHKPYG YVRYFDV AβVL (Sequence ID 08), CDR is underlined: DIVLTQSPAT LSLSPGERAT LSC RASQSVS SSYLA WYQQK PGQAPRLLIY GASSRAT GVP ARFSGSGSGT DFTLTISSLE PEDFATYYC L QIYNMPIT FG QGTKVEIK CDR-L1 (Sequence ID 05): RASQSVSSSY LA CDR-L2 (Sequence ID 06): GASSRAT CDR-L3 (Sequence ID 07): LQIYNMPIT TfRVH (Sequence ID 12), CDR is underlined: QSMQESGPGL VKPSQTLSLT CTVSGFSLS S YAMS WIRQHP GKGLEWIG YI WSGGSTDYAS WAKS RVTISK TSTTVSLKLS SVTAADTAVY YCAR RYGTSY PDYGDASGFD P WGQGTLVTV SS CDR-H1 (Sequence ID 09): SYAMS CDR-H2 (Sequence ID 10): YIWSGGSTDY ASWAKS CDR-H3 (Sequence ID 11): RYGTSYPDYG DASGFDP TfRVL (sequence number 16), CDR is underlined: AIQLTQSPSS LSASVGDRVT ITC RASQSIS SYLA WYQQKP GKAPKLLIY R ASTLAS GVPS RFSGSGSGTD FTLTISSLQP EDFATYYC QQ NYASSNVDNT FGGGTKVEIK CDR-L1 (Sequence ID 13: RASQSISSYL A) CDR-L2 (Sequence ID 14): RASTLAS CDR-L3 (Sequence ID 15): QQNYASSNVD NT

[0398] Troncinemab can be characterized as follows: Immunoglobulin [G1-VH-C kappa_V kappa-CH1]_[G1_ kappa] with domain crossover, anti-[Homo sapiens APP (amyloid β, A4 precursor protein) Aβ, structural epitopes 1-40 / 42)] and anti-[Homo sapiens TFRC (transferrin receptor, p90, CD71)] humanized monoclonal antibodies, bispecific; fusion chain G1-VH-C kappa bispecific, anti-APP Aβ and anti-TFRC (1-702) [γ1 heavy chain anti-APP] Aβ(1-455) humanized [VH(Homo sapiens IGHV3-23*04 (92.9%)-(IGHD)-IGHJ4*01 (93.3%), CDR-IMGT[8.8.19](26-33.51-58.97-115))(1-126)-Homo sapiens IGH1*01,G1m17,1,G1v32 CH3 W22(CH1 K26>E(156), K119>E(222), K120(223)(127-224), Hinge1-15(225-239), CH2(240-349), CH3 S10>C(363), D12(365), L14(367), T22>W(375)(350-454), CHS K2>del(455))(127-455)]-18 Margose Glycyl-Ceryl-Tris(Tetraglycyl-Ceryl) Linker(456-473)-VH-C Kappa Chain Anti-TFRC(474-702) Humanized [VH(Homo sapiens IGHV4-31*02(76.0%)-(IGHD)-IGHJ5*02(100%), CDR-IMGT[8.7.19](498-505.523-529.566-584))(474-595)-Alanyl-Ceryl(596-597)-C-KAPPA(Homo sapiens IGKC*01(100%), Km3 A45.1(641), V101(679)(598-702)], (229-215')-Kappa light chain anti-APP Aβ(1'-215') humanized [V-KAPPA(Homo sapiens IGKV3D-7*01(89.6%)-IGKJ1*01(100%), CDR-IMGT[7.3.9](27-33.51-53.90-98))(1'-108')-Homo sapiens IGKC*01(100%), Km3 A45.Disulfide with 1(154), V101(192), E12>R(124), Q13>K(125)(109'-215'), (702-215")-V-Kappa-CH1 chain antiTFRC(1")-215") humanized [V-KAPPA(Homo sapiens IGKV1-13*02(94.4%)-IGKJ4*01(100%), CDR-IMGT[6.3.12](27-32.50-52.89-100))(1")-110")-Diceryl(111")-112")-CH1-Hinge(Homo sapiens IGHG1*01 CH1-h,G1m17(CH1 Disulfide with K120(209)(113””-210””), hinge 1-5(211””-215””))(113””-215””)], γ1 heavy chain anti-APP Aβ(1”-456”) humanized [VH(Homo sapiens IGHV3-23*04(92.9%)-(IGHD)-IGHJ4*01(93.3%), CDR-IMGT[8.8.19](26-33.51-58.97-115))(1”-126”)-Homo sapiens IGHG1*01, G1m17,1, G1v33 CH3 S22,A24,V86(CH1 K26>E(156), K119>E(222), K120(223)(127”-224”), Hinge 1-15(225”-239”), CH2(240”-349”), CH3 Y5>C(358), D12(365), L14(367), T22>S(375), L24>A(377), Y86>V(416)(350”-454”), CHS(455”-456”)(127”-456”)), (229”-215”')-Kappa light chain anti-APP Aβ(1"'-215"') humanized [V-KAPPA(Homo sapiens IGKV3D-7*01(89.6%)-IGKJ1*01(100%), CDR-IMGT[7.3.9](27-33.51-53.90-98))(1"'-108"')-Homo sapiens IGKC*01(100%), Km3 A45.1(154), V101(192)E12>R(124), Q13>K(125)(109"'-215"')] disulfide, dimer (235-235":238-238":363-358")-trisdisulfide, produced in Chinese hamster ovary (CHO) cells, glycoform α. [ka] [ka]

[0399] Trontinemab targets fibrillary Aβ protein as well as amyloid plaques and oligomers, meaning that trontinemab is generally suitable for both plaque removal and prevention of re-accumulation, as well as oligomer neutralization.

[0400] Comparison of anti-Aβ monoclonal antibodies Zhao et al. (Int.J.Nanomed.18(2023)7825-7845) summarized the clinical advances of anti-Aβ antibodies as follows: Aducanumab -Target residues 3-7 in the N-terminus of Aβ protein; - It exhibits low monovalent affinity, but shows strong binding activity to epitope-rich aggregates, allowing aducanumab to selectively bind to Aβ protein oligomeric aggregates or fibrillary aggregates; this binding activates microglia; - Phase III efficacy trials: EMERGE (NCT02484547) and ENGAGE (NCT02477800); High-dose aducanumab met its primary endpoint in the EMERGE trial, but low-dose aducanumab did not show a significant benefit compared to the placebo group; the ENGAGE trial did not meet its primary endpoint. - Approximately one-third of participants treated with aducanumab developed amyloid-related imaging abnormalities (ARIA), of which one-quarter were symptomatic and 3% were severe; ARIA-E (angiogenic edema) and ARIA-H (microbleeds and hemosiderin deposition) were commonly observed in patients receiving a dose of 10 mg / kg, with incidences of 19.1% and 35%, respectively; APOEε4 carriers had a higher incidence compared to non-carriers; Recanemab - It selectively binds to soluble Aβ protein aggregates (including oligomers and protofibrils), binding approximately 1000 times more than Aβ protein monomers and 10-15 times more than insoluble fibrils; - Phase III CLARITY AD trial (NCT03887455); intravenous recanemab at a dose of 10 mg / kg every two weeks; clinical worsening was assessed using CDR-SB as the primary endpoint, and the recanemab group showed a substantial reduction in clinical worsening; ARIA-H and ARIA-E findings - Despite its moderate therapeutic effect, recanemab failed to demonstrate a clinically significant benefit in patients with clinically apparent or prodromal dementia; -New evidence from the Phase 2 Recanemab Study shows that fluid biomarkers reappear after discontinuation of treatment with conventional amyloid-depleting monoclonal antibodies; plasma Aβ42 / 40 ratio begins to decrease again, and plasma p-tau181 begins to increase; these biomarkers precede slow re-accumulation of amyloid PET / brain amyloid; the observation of biomarkers was associated with clinical deterioration as measured via CDR-SB, ADCOMS, and ADAS-cog; the rate of clinical progression after discontinuation of treatment was similar in participants treated with recanemab and those treated with placebo; - Prescription information for lecanemab marketed as Leqembi instructs administration of 10 mg / kg of lecanemab every two weeks as a one-hour intravenous infusion, recommends increased clinical vigilance for amyloid-related imaging abnormalities ("ARIA") during the first 14 weeks of treatment with Leqembi, and includes a warning section describing the increased risk of ARIA in apolipoprotein Eε4 ("ApoE4") homozygotes compared to heterozygotes and non-carriers; Donanema - Specifically targets the pyroglutamine-oxidized form (N3pG-Aβ) of Aβ protein aggregated in amyloid plaques; - Phase III trial, TRAILBLAZER-ALZ2 (NCT04437511); duration 72 weeks; donanemab administered every 4 weeks; donanemab was reported to be associated with the development of ARIA, with approximately 40% of participants in the donanemab group experiencing ARIA, of which approximately 26.1% presented with symptomatic ARIA (symptomatic ARIA-E was observed in only 0.8% of participants given placebo); Remternetag -Specifically targets N3pG-Aβ; ABBV-916 - Recognizes N3pG-Aβ aggregated in amyloid plaques; ACU193 - Aβ protein oligomer-selective antibody; -A Phase I clinical trial (NCT04931459) showed a significant reduction in amyloid plaque levels detectable by brain amyloid PET scans after 6–12 weeks in patients receiving higher doses of ACU193; 10.4% of patients experienced ARIA-E, of which 2.1% were symptomatic.

[0401] In a clinical setting, binding of anti-AβmAbs to amyloid plaques is associated with a higher incidence of ARIA. [Table 1] TIFF2026065045000004.tif181170 [Table 2]

[0402] Amyloid reduction and clinical efficacy Recent efforts have focused on targeting amyloid as the most promising therapeutic target (Graham, WV, et al., Annu. Rev. Med. 68 (2017) 413-430) (Bachurin, SO, et al., Med. Res. Rev. 37 (2017) 1186-1225). These therapies are based on the amyloid hypothesis, which assumes that Aβ accumulation is the primary factor driving Aβ pathogenesis (Selkoe, DJ, Neuron. 6 (1991) 487-498; Hardy, J. and Selkoe, DJ, Science 297 (2002) 353-356; Selkoe and Hardy 2016, cited above). Several monoclonal anti-Aβ antibodies, including aducanumab, lecanemab, donanemab, and gantenerumab, have been shown to bind to the Aβ protein, promote its clearance, and reduce both Aβ aggregate deposition and markers of neurodegeneration in CSF in a clinical setting (Salloway et al. 2009, cited above; Ostrowitzki, S., et al., Arch. Neurol. 69 (2012) 198-207; Sevigny et al. 2016, cited above; Klein, G., et al., J. Prev. Alz. Dis. 8 (2021) 3-6; Klein, G., et al., Alz. Res. Ther. 11 (2019) 101; Bateman, RJ, et al., N. Engl. J. Med. 389 (2023) 1862-1876; Small, S. Swanson,LW,Cold Spring Harb.Symp.Quant.Biol.83(2018)193-200;Budd Haeberlein,S.,et al.J.Prev.Alz.Dis.9(2022)197-210;Bateman AAT-AD / PD 2020;Ostrowitzki et al 2017, supra;Bateman AAT-AD / PD 2020).

[0403] Furthermore, a Phase II trial using donanemab, an amyloid plaque-targeting therapy, met its primary efficacy endpoint, demonstrating a significant reduction in amyloid plaques along with a localized decrease in tau loading, as revealed by amyloid and tau PET imaging after 76 weeks of treatment.

[0404] A large-scale Phase II trial with recanemab demonstrated significant amyloid reduction at maximum dose and dose-dependent clinical benefits on various cognitive measures, further supporting the potential association between dose-dependent amyloid removal and clinical efficacy (Swanson et al. 2018, cited above). This was confirmed in the large-scale Phase III trial with recanemab (CLARITY AD), which met its primary endpoint. Recanemab was shown to reduce CDR-SB scores more efficiently than placebo at 18 months. This trial also met all secondary endpoints, demonstrating the efficacy of recanemab in early-stage AD (Van Dyck et al., NEJM 388(2022)9-21).

[0405] Therefore, targeting amyloid deposits is one of the most promising approaches for treating AD. Numerous preclinical evidence suggests that targeting Aβ aggregates with Aβ vaccination or passive immunization with anti-Aβ antibodies in transgenic models of AD resulted in reduced amyloidosis and improved cognitive function (Bard, F., et al. Nat. Med. 6(2000) 916-919; Janus, C., et al. Biochim. Biophys. Acta 1502(2000) 63-75). Clinical results obtained with four antibodies—gantenerumab, lecanemab, aducanumab, and donanemab—support a potential link between amyloid removal and clinical efficacy. In a Phase I trial of aducanumab in early-stage AD patients, a slowing of clinical progression was associated with a time- and dose-related reduction in deposited amyloid, as seen on brain amyloid PET imaging (Sevigny et al. 2016, cited above). Similarly, a recent publication (McDade, E., et al., Alz. Res. Ther. 14(2022) 191) showed a significant correlation between the level of amyloid removal achieved by different doses of recanemab and progression on various clinical measures.

[0406] Clinically, anti-amyloid antibodies have demonstrated a significant effect in preventing clinical worsening due to their rapid removal of amyloid plaques and a high proportion of participants achieving amyloid-negative levels at the end of the double-blind treatment period. For example, lecanemab was able to bring 81% of participants below the criterion amyloid-positive threshold of 30 centiloids after 18 months of treatment. Overall, a mean amyloid PET level of 22.99 centiloids was achieved in the lecanemab group after 18 months of treatment (van Dyck, CH, et al., N.Eng.J.Med. 388(2023)9-21). Donanemab achieved similar results, with 72% of participants below the amyloid-positive threshold of 24.1 centiloids after 18 months (Eli Lilly and Company 2023), and, like lecanemab, met its primary clinical endpoint in Phase II. Two important Phase II trials using gantenerumab, GRADUATE I and GRADUATE II, did not meet their primary endpoints. However, the scale of amyloid plaque reduction was smaller than expected and predicted based on data from open-label long-term administration (OLE) trials from two historical Phase III trials of gantenerumab (ScarletRoAD and MargueriteRoAD), ScarletRoAD and MargueriteRoAD, which demonstrated robust and sustained Aβ plaque reduction in OLE comparable to levels achieved by other amyloid-reducing antibodies.

[0407] Based on these results, rapidly lowering amyloid levels below the positive threshold appears to be a necessary feature to achieve clinical efficacy (Karran, E. and De Strooper, B., Nat. Rev. Drug. Discov. 21(2022) 306-318). The degree and rate of amyloid plaque removal by anti-amyloid antibodies depend on both dose and exposure. Due to their large size, only about 0.1%–0.2% of peripherally administered antibodies cross the intact blood-brain barrier (Poduslo, JF, et al., Proc. Natl. Acad. Sci. USA 91(1994) 5705-5709; Yu, Y. and Watts, R.J., Neurotherap. 10(2013) 459-472).

[0408] Furthermore, the incidence of ARIA, ARIA-E, or ARIA-H was significantly increased by high-clearance anti-amyloid immunotherapy (Villain, N. et al., Rev. Neuro. 178 (2022) 1011-1030).

[0409] Shcherbinin et al. (JAMA Neurology 79(2022)1015-1024) reported that complete amyloid clearance at 24 weeks was associated with a more pronounced deceleration of tau lesions (Tau PET) at 76 weeks, as found in a Phase II clinical trial of donanemab.

[0410] A meta-analysis of clinical trial data for aducanumab, donanemab, and lecanemab by Villain, N. et al. (Rev. Neuro. 178 (2022) 1011-1030) supported the claim that these clinical trial data alone were sufficient to convincingly demonstrate the clinical benefit in mitigating clinical progression in patients with Alzheimer's disease, and that they demonstrated the significant overall effect of high-clearance anti-amyloid immunotherapy on CDR-SB and ADAS-Cog progression, rather than MMSE progression. Therefore, it provides an opportunity to confirm trends regarding the clinical efficacy of high-clearance anti-amyloid immunotherapy and to estimate the magnitude of the clinical effect of high-clearance anti-amyloid immunotherapy (Liu, KY and Howard, R., Nat. Rev. Neuro. 17 (2021) 715-722; Liu, KY, et al., Lancet Psychiatry 8 (2021) 1013-1016).

[0411] Therapeutic effective dose of at least one bispecific anti-Aβ / TfR antibody The method of the present invention involves administering a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody to a target. As used herein, the term “therapeutically effective amount” means an amount of the compound or pharmaceutical composition sufficient to produce the desired therapeutic effect.

[0412] Those skilled in the art will understand that the therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody administered to a subject may depend on many factors, including pharmacodynamic characteristics, route of administration, frequency of treatment, and the health, age, and weight of the subject to be treated, and that the appropriate dose can be determined for each subject using the information disclosed herein.

[0413] In some embodiments, the therapeutically effective dose is a dose selected to improve and / or maintain efficacy, as well as to improve at least one of safety and tolerability. In some embodiments, the therapeutically effective dose is selected to reduce at least one side effect, as well as to improve and / or maintain efficacy at the same time.

[0414] In one embodiment, at least one bispecific anti-Aβ / TfR antibody is administered to the subject at a dose of 1 mg / kg to 9 mg / kg, 1 mg / kg to 8 mg / kg, 1 mg / kg to 7.2 mg / kg, 1 mg / kg to 6.5 mg / kg, 1 mg / kg to 6 mg / kg, 1 mg / kg to 5.5 mg / kg, 1 mg / kg to 4 mg / kg, 1 mg / kg to 3.9 mg / kg, 1 mg / kg to 3.8 mg / kg, 1 mg / kg to 3.7 mg / kg, or 1 mg / kg to 3.6 mg / kg relative to the subject's body weight.

[0415] In one embodiment, at least one bispecific anti-Aβ / TfR antibody is administered to the subject at a dose of 1.2 mg / kg to 9 mg / kg, 1.2 mg / kg to 8 mg / kg, 1.2 mg / kg to 7.2 mg / kg, 1.2 mg / kg to 6.5 mg / kg, 1.2 mg / kg to 6 mg / kg, 1.2 mg / kg to 5.5 mg / kg, 1.2 mg / kg to 4 mg / kg, 1.2 mg / kg to 3.9 mg / kg, 1.2 mg / kg to 3.8 mg / kg, 1.2 mg / kg to 3.7 mg / kg, or 1.2 mg / kg to 3.6 mg / kg relative to the subject's body weight.

[0416] In one embodiment, at least one bispecific anti-Aβ / TfR antibody is administered to the subject at a dose of 1.5 mg / kg to 9 mg / kg, 1.5 mg / kg to 8 mg / kg, 1.5 mg / kg to 7.2 mg / kg, 1.5 mg / kg to 6.5 mg / kg, 1.5 mg / kg to 6 mg / kg, 1.5 mg / kg to 5.5 mg / kg, 1.5 mg / kg to 4 mg / kg, 1.5 mg / kg to 3.9 mg / kg, 1.5 mg / kg to 3.8 mg / kg, 1.5 mg / kg to 3.7 mg / kg, or 1.5 mg / kg to 3.6 mg / kg relative to the subject's body weight.

[0417] In one embodiment, at least one bispecific anti-Aβ / TfR antibody is administered to the subject at a dose of 1.8 mg / kg to 9 mg / kg, 1.8 mg / kg to 8 mg / kg, 1.8 mg / kg to 7.2 mg / kg, 1.8 mg / kg to 6.5 mg / kg, 1.8 mg / kg to 6 mg / kg, 1.8 mg / kg to 5.5 mg / kg, 1.8 mg / kg to 4 mg / kg, 1.8 mg / kg to 3.9 mg / kg, 1.8 mg / kg to 3.8 mg / kg, 1.8 mg / kg to 3.7 mg / kg, or 1.8 mg / kg to 3.6 mg / kg relative to the subject's body weight.

[0418] In one embodiment, at least one bispecific anti-Aβ / TfR antibody is administered to the subject at a dose of 2 mg / kg to 9 mg / kg, 2 mg / kg to 8 mg / kg, 2 mg / kg to 7.2 mg / kg, 2 mg / kg to 6.5 mg / kg, 2 mg / kg to 6 mg / kg, 2 mg / kg to 5.5 mg / kg, 2 mg / kg to 4 mg / kg, 2 mg / kg to 3.9 mg / kg, 2 mg / kg to 3.8 mg / kg, 2 mg / kg to 3.7 mg / kg, or 2 mg / kg to 3.6 mg / kg relative to the subject's body weight.

[0419] In one embodiment, at least one bispecific anti-Aβ / TfR antibody is administered to the subject at a dose of 2.2 mg / kg to 9 mg / kg, 2.2 mg / kg to 8 mg / kg, 2.2 mg / kg to 7.2 mg / kg, 2.2 mg / kg to 6.5 mg / kg, 2.2 mg / kg to 6 mg / kg, 2.2 mg / kg to 5.5 mg / kg, 2.2 mg / kg to 4 mg / kg, 2.2 mg / kg to 3.9 mg / kg, 2.2 mg / kg to 3.8 mg / kg, 2.2 mg / kg to 3.7 mg / kg, or 2.2 mg / kg to 3.6 mg / kg relative to the subject's body weight.

[0420] In one embodiment, at least one bispecific anti-Aβ / TfR antibody is administered to the subject at a dose of 2.4 mg / kg to 9 mg / kg, 2.4 mg / kg to 8 mg / kg, 2.4 mg / kg to 7.2 mg / kg, 2.4 mg / kg to 6.5 mg / kg, 2.4 mg / kg to 6 mg / kg, 2.4 mg / kg to 5.5 mg / kg, 2.4 mg / kg to 4 mg / kg, 2.4 mg / kg to 3.9 mg / kg, 2.4 mg / kg to 3.8 mg / kg, 2.4 mg / kg to 3.7 mg / kg, or 2.4 mg / kg to 3.6 mg / kg relative to the subject's body weight.

[0421] In one embodiment, at least one bispecific anti-Aβ / TfR antibody is administered to the subject at a dose of 2.6 mg / kg to 9 mg / kg, 2.6 mg / kg to 8 mg / kg, 2.6 mg / kg to 7.2 mg / kg, 2.6 mg / kg to 6.5 mg / kg, 2.6 mg / kg to 6 mg / kg, 2.6 mg / kg to 5.5 mg / kg, 2.6 mg / kg to 4 mg / kg, 2.6 mg / kg to 3.9 mg / kg, 2.6 mg / kg to 3.8 mg / kg, 2.6 mg / kg to 3.7 mg / kg, or 2.6 mg / kg to 3.6 mg / kg relative to the subject's body weight.

[0422] In one embodiment, at least one bispecific anti-Aβ / TfR antibody is administered to the subject at a dose of 2.8 mg / kg to 9 mg / kg, 2.8 mg / kg to 8 mg / kg, 2.8 mg / kg to 7.2 mg / kg, 2.8 mg / kg to 6.5 mg / kg, 2.8 mg / kg to 6 mg / kg, 2.8 mg / kg to 5.5 mg / kg, 2.8 mg / kg to 4 mg / kg, 2.8 mg / kg to 3.9 mg / kg, 2.8 mg / kg to 3.8 mg / kg, 2.8 mg / kg to 3.7 mg / kg, or 2.8 mg / kg to 3.6 mg / kg relative to the subject's body weight.

[0423] In one embodiment, at least one bispecific anti-Aβ / TfR antibody is administered to the subject at a dose of 3 mg / kg to 9 mg / kg, 3 mg / kg to 8 mg / kg, 3 mg / kg to 7.2 mg / kg, 3 mg / kg to 6.5 mg / kg, 3 mg / kg to 6 mg / kg, 3 mg / kg to 5.5 mg / kg, 3 mg / kg to 4 mg / kg, 3 mg / kg to 3.9 mg / kg, 3 mg / kg to 3.8 mg / kg, 3 mg / kg to 3.7 mg / kg, or 3 mg / kg to 3.6 mg / kg relative to the subject's body weight.

[0424] In one embodiment, relative to the subject's body weight, the dosage is 1 mg / kg to 9 mg / kg, 1.2 mg / kg to 9 mg / kg, 1.4 mg / kg to 9 mg / kg, 1.8 mg / kg to 9 mg / kg, 1.9 mg / kg to 9 mg / kg, 2 mg / kg to 9 mg / kg, 2.1 mg / kg to 9 mg / kg, 2.2 mg / kg to 9 mg / kg, 2.3 mg / kg to 9 mg / kg, 2.4 mg / kg to 9 mg / kg, 2.5 mg / kg to 9 mg / kg, 2.6 mg / kg to 9 mg / kg, 2.7 mg / kg to 9 mg / kg, 2.8 mg / kg to 9 mg / kg, 2.9 mg / kg to 9 mg / kg, 3 mg / kg to 9 mg / kg, 3.1 mg / kg to 9 mg / kg, and 3.2 mg At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: 1 / kg~9mg / kg, 3.3mg / kg~9mg / kg, 3.4mg / kg~9mg / kg, 3.5mg / kg~9mg / kg, 3.6mg / kg~9mg / kg, 3.7mg / kg~9mg / kg, 3.8mg / kg~9mg / kg, 3.9mg / kg~9mg / kg, 4mg / kg~9mg / kg, 4.5mg / kg~9mg / kg, 5mg / kg~9mg / kg, 5.5mg / kg~9mg / kg, 6mg / kg~9mg / kg, 6.5mg / kg~9mg / kg, 7mg / kg~9mg / kg, 7.2mg / kg~9mg / kg, or 8mg / kg~9mg / kg.

[0425] In one embodiment, with respect to the subject's body weight, the dosage ranges are 1 mg / kg to 7.2 mg / kg, 1.2 mg / kg to 7.2 mg / kg, 1.4 mg / kg to 7.2 mg / kg, 1.8 mg / kg to 7.2 mg / kg, 1.9 mg / kg to 7.2 mg / kg, 2 mg / kg to 7.2 mg / kg, 2.1 mg / kg to 7.2 mg / kg, 2.2 mg / kg to 7.2 mg / kg, 2.3 mg / kg to 7.2 mg / kg, 2.4 mg / kg to 7.2 mg / kg, 2.5 mg / kg to 7.2 mg / kg, 2.6 mg / kg to 7.2 mg / kg, 2.7 mg / kg to 7.2 mg / kg, 2.8 mg / kg to 7.2 mg / kg, 2.9 mg / kg to 7.2 mg / kg, 3 mg / kg to 7.2 mg / kg, 3.1 mg / kg At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: kg~7.2 mg / kg, 3.2 mg / kg~7.2 mg / kg, 3.3 mg / kg~7.2 mg / kg, 3.4 mg / kg~7.2 mg / kg, 3.5 mg / kg~7.2 mg / kg, 3.6 mg / kg~7.2 mg / kg, 3.7 mg / kg~7.2 mg / kg, 3.8 mg / kg~7.2 mg / kg, 3.9 mg / kg~7.2 mg / kg, 4 mg / kg~7.2 mg / kg, 4.5 mg / kg~7.2 mg / kg, 5 mg / kg~7.2 mg / kg, 5.5 mg / kg~7.2 mg / kg, 6 mg / kg~7.2 mg / kg, 6.5 mg / kg~7.2 mg / kg, or 7 mg / kg~7.2 mg / kg.

[0426] In one embodiment, relative to the body weight of the subject, the following ranges are used: 1 mg / kg~6.5 mg / kg, 1.2 mg / kg~6.5 mg / kg, 1.4 mg / kg~6.5 mg / kg, 1.8 mg / kg~6.5 mg / kg, 1.9 mg / kg~6.5 mg / kg, 2 mg / kg~6.5 mg / kg, 2.1 mg / kg~6.5 mg / kg, 2.2 mg / kg~6.5 mg / kg, 2.3 mg / kg~6.5 mg / kg, 2.4 mg / kg~6.5 mg / kg, 2.5 mg / kg~6.5 mg / kg, 2.6 mg / kg~6.5 mg / kg, 2.7 mg / kg~6.5 mg / kg, 2.8 mg / kg~6.5 mg / kg, 2.9 mg / kg~6.5 mg / kg, 3 mg / kg At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: g-6.5 mg / kg, 3.1 mg / kg-6.5 mg / kg, 3.2 mg / kg-6.5 mg / kg, 3.3 mg / kg-6.5 mg / kg, 3.4 mg / kg-6.5 mg / kg, 3.5 mg / kg-6.5 mg / kg, 3.6 mg / kg-6.5 mg / kg, 3.7 mg / kg-6.5 mg / kg, 3.8 mg / kg-6.5 mg / kg, 3.9 mg / kg-6.5 mg / kg, 4 mg / kg-6.5 mg / kg, 4.5 mg / kg-6.5 mg / kg, 5 mg / kg-6.5 mg / kg, 5.5 mg / kg-6.5 mg / kg, or 6 mg / kg-7.2 mg / kg.

[0427] In one embodiment, relative to the body weight of the subject, the amounts are 1 mg / kg to 6 mg / kg, 1.2 mg / kg to 6 mg / kg, 1.4 mg / kg to 6 mg / kg, 1.8 mg / kg to 6 mg / kg, 1.9 mg / kg to 6 mg / kg, 2 mg / kg to 6 mg / kg, 2.1 mg / kg to 6 mg / kg, 2.2 mg / kg to 6 mg / kg, 2.3 mg / kg to 6 mg / kg, 2.4 mg / kg to 6 mg / kg, 2.5 mg / kg to 6 mg / kg, 2.6 mg / kg to 6 mg / kg, 2.7 mg / kg to 6 mg / kg, 2.8 mg / kg to 6 mg / kg, and 2.9 mg / kg to 6 mg / kg. At least one bispecific anti-Aβ / TfR antibody is administered to the target population at doses of g, 3 mg / kg~6 mg / kg, 3.1 mg / kg~6 mg / kg, 3.2 mg / kg~6 mg / kg, 3.3 mg / kg~6 mg / kg, 3.4 mg / kg~6 mg / kg, 3.5 mg / kg~6 mg / kg, 3.6 mg / kg~6 mg / kg, 3.7 mg / kg~6 mg / kg, 3.8 mg / kg~6 mg / kg, 3.9 mg / kg~6 mg / kg, 4 mg / kg~6 mg / kg, 4.5 mg / kg~6 mg / kg, 5 mg / kg~6 mg / kg, or 5.5 mg / kg~6 mg / kg.

[0428] In one embodiment, relative to the body weight of the subject, the doses are 1 mg / kg to 5.5 mg / kg, 1.2 mg / kg to 5.5 mg / kg, 1.4 mg / kg to 5.5 mg / kg, 1.8 mg / kg to 5.5 mg / kg, 1.9 mg / kg to 5.5 mg / kg, 2 mg / kg to 5.5 mg / kg, 2.1 mg / kg to 5.5 mg / kg, 2.2 mg / kg to 5.5 mg / kg, 2.3 mg / kg to 5.5 mg / kg, 2.4 mg / kg to 5.5 mg / kg, 2.5 mg / kg to 5.5 mg / kg, 2.6 mg / kg to 5.5 mg / kg, 2.7 mg / kg to 5.5 mg / kg, 2.8 mg / kg to 5.5 mg / kg, and 2.9 mg / kg. At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: kg~5.5 mg / kg, 3 mg / kg~5.5 mg / kg, 3.1 mg / kg~5.5 mg / kg, 3.2 mg / kg~5.5 mg / kg, 3.3 mg / kg~5.5 mg / kg, 3.4 mg / kg~5.5 mg / kg, 3.5 mg / kg~5.5 mg / kg, 3.6 mg / kg~5.5 mg / kg, 3.7 mg / kg~5.5 mg / kg, 3.8 mg / kg~5.5 mg / kg, 3.9 mg / kg~5.5 mg / kg, 4 mg / kg~5.5 mg / kg, 4.5 mg / kg~5.5 mg / kg, or 5 mg / kg~5.5 mg / kg.

[0429] In one embodiment, relative to the body weight of the subject, the doses are 1 mg / kg to 5 mg / kg, 1.2 mg / kg to 5 mg / kg, 1.4 mg / kg to 5 mg / kg, 1.8 mg / kg to 5 mg / kg, 1.9 mg / kg to 5 mg / kg, 2 mg / kg to 5 mg / kg, 2.1 mg / kg to 5 mg / kg, 2.2 mg / kg to 5 mg / kg, 2.3 mg / kg to 5 mg / kg, 2.4 mg / kg to 5 mg / kg, 2.5 mg / kg to 5 mg / kg, 2.6 mg / kg to 5 mg / kg, 2.7 mg / kg to 5 mg / kg, 2.8 mg / kg to 5 mg / kg At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: kg, 2.9 mg / kg~5 mg / kg, 3 mg / kg~5 mg / kg, 3.1 mg / kg~5 mg / kg, 3.2 mg / kg~5 mg / kg, 3.3 mg / kg~5 mg / kg, 3.4 mg / kg~5 mg / kg, 3.5 mg / kg~5 mg / kg, 3.6 mg / kg~5 mg / kg, 3.7 mg / kg~5 mg / kg, 3.8 mg / kg~5 mg / kg, 3.9 mg / kg~5 mg / kg, 4 mg / kg~5 mg / kg, and 4.5 mg / kg~5 mg / kg.

[0430] In one embodiment, relative to the body weight of the subject, the dosage is 1 mg / kg to 4.6 mg / kg, 1.2 mg / kg to 4.6 mg / kg, 1.4 mg / kg to 4.6 mg / kg, 1.8 mg / kg to 4.6 mg / kg, 1.9 mg / kg to 4.6 mg / kg, 2 mg / kg to 4.6 mg / kg, 2.1 mg / kg to 4.6 mg / kg, 2.2 mg / kg to 4.6 mg / kg, 2.3 mg / kg to 4.6 mg / kg, 2.4 mg / kg to 4.6 mg / kg, 2.5 mg / kg to 4.6 mg / kg, 2.6 mg / kg to 4.6 mg / kg, 2.7 mg / kg to 4.6 mg / kg, and 2.8 mg / kg to 4.6 mg At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: / kg, 2.9mg / kg~4.6mg / kg, 3mg / kg~4.6mg / kg, 3.1mg / kg~4.6mg / kg, 3.2mg / kg~4.6mg / kg, 3.3mg / kg~4.6mg / kg, 3.4mg / kg~4.6mg / kg, 3.5mg / kg~4.6mg / kg, 3.6mg / kg~4.6mg / kg, 3.7mg / kg~4.6mg / kg, 3.8mg / kg~4.6mg / kg, 3.9mg / kg~4.6mg / kg, 4mg / kg~4.6mg / kg, and 4.5mg / kg~4.6mg / kg.

[0431] In one embodiment, relative to the body weight of the subject, the dosage ranges are 1 mg / kg to 4.2 mg / kg, 1.2 mg / kg to 4.2 mg / kg, 1.4 mg / kg to 4.2 mg / kg, 1.8 mg / kg to 4.2 mg / kg, 1.9 mg / kg to 4.2 mg / kg, 2 mg / kg to 4.2 mg / kg, 2.1 mg / kg to 4.2 mg / kg, 2.2 mg / kg to 4.2 mg / kg, 2.3 mg / kg to 4.2 mg / kg, 2.4 mg / kg to 4.2 mg / kg, 2.5 mg / kg to 4.2 mg / kg, 2.6 mg / kg to 4.2 mg / kg, 2.7 mg / kg to 4.2 mg / kg, and 2.8 mg. At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: 1 / kg~4.2mg / kg, 2.9mg / kg~4.2mg / kg, 3mg / kg~4.2mg / kg, 3.1mg / kg~4.2mg / kg, 3.2mg / kg~4.2mg / kg, 3.3mg / kg~4.2mg / kg, 3.4mg / kg~4.2mg / kg, 3.5mg / kg~4.2mg / kg, 3.6mg / kg~4.2mg / kg, 3.7mg / kg~4.2mg / kg, 3.8mg / kg~4.2mg / kg, 3.9mg / kg~4.2mg / kg, and 4mg / kg~4.2mg / kg.

[0432] In one embodiment, relative to the body weight of the subject, the doses are 1 mg / kg to 3.8 mg / kg, 1.2 mg / kg to 3.8 mg / kg, 1.4 mg / kg to 3.8 mg / kg, 1.8 mg / kg to 3.8 mg / kg, 1.9 mg / kg to 3.8 mg / kg, 2 mg / kg to 3.8 mg / kg, 2.1 mg / kg to 3.8 mg / kg, 2.2 mg / kg to 3.8 mg / kg, 2.3 mg / kg to 3.8 mg / kg, 2.4 mg / kg to 3.8 mg / kg, 2.5 mg / kg to 3.8 mg / kg, 2.6 mg / kg to 3.8 mg / kg At least one bispecific anti-Aβ / TfR antibody in the following concentrations: kg, 2.7 mg / kg~3.8 mg / kg, 2.8 mg / kg~3.8 mg / kg, 2.9 mg / kg~3.8 mg / kg, 3 mg / kg~3.8 mg / kg, 3.1 mg / kg~3.8 mg / kg, 3.2 mg / kg~3.8 mg / kg, 3.3 mg / kg~3.8 mg / kg, 3.4 mg / kg~3.8 mg / kg, 3.5 mg / kg~3.8 mg / kg, 3.6 mg / kg~3.8 mg / kg, and 3.7 mg / kg~3.8 mg / kg.

[0433] In one embodiment, relative to the body weight of the subject, the doses are 1 mg / kg to 3.6 mg / kg, 1.2 mg / kg to 3.6 mg / kg, 1.4 mg / kg to 3.6 mg / kg, 1.8 mg / kg to 3.6 mg / kg, 1.9 mg / kg to 3.6 mg / kg, 2 mg / kg to 3.6 mg / kg, 2.1 mg / kg to 3.6 mg / kg, 2.2 mg / kg to 3.6 mg / kg, 2.3 mg / kg to 3.6 mg / kg, 2.4 mg / kg to 3.6 mg / kg, and 2.5 mg / kg to 3.6 mg / kg. At least one bispecific anti-Aβ / TfR antibody is administered to the target population at doses of kg, 2.6 mg / kg to 3.6 mg / kg, 2.7 mg / kg to 3.6 mg / kg, 2.8 mg / kg to 3.6 mg / kg, 2.9 mg / kg to 3.6 mg / kg, 3 mg / kg to 3.6 mg / kg, 3.1 mg / kg to 3.6 mg / kg, 3.2 mg / kg to 3.6 mg / kg, 3.3 mg / kg to 3.6 mg / kg, 3.4 mg / kg to 3.6 mg / kg, and 3.5 mg / kg to 3.6 mg / kg.

[0434] In one embodiment, relative to the subject's body weight, the doses are 2.2 mg / kg to 4.2 mg / kg, 2.3 mg / kg to 4.2 mg / kg, 2.4 mg / kg to 4.2 mg / kg, 2.5 mg / kg to 4.2 mg / kg, 2.6 mg / kg to 4.2 mg / kg, 2.7 mg / kg to 4.2 mg / kg, 2.8 mg / kg to 4.2 mg / kg, 2.9 mg / kg to 4.2 mg / kg, 3 mg / kg to 4.2 mg / kg, and 3.1 mg / kg. kg~4.2mg / kg, 3.2mg / kg~4.2mg / kg, 3.3mg / kg~4.2mg / kg, 3.4mg / kg~4.2mg / kg, 3.5mg / kg~4.2mg / kg, 3.6mg / kg~4 .2mg / kg, 3.7mg / kg~4.2mg / kg, 3.8mg / kg~4.2mg / kg, 3.9mg / kg~4.2mg / kg, 4mg / kg~4.2mg / kg, 4.1mg / kg~4.2mg / k g, 2.2mg / kg~4.1mg / kg, 2.2mg / kg~4mg / kg, 2.2mg / kg~3.9mg / kg, 2.2mg / kg~3.8mg / kg, 2.2mg / kg~3.7mg / kg, 2.2 mg / kg~3.6mg / kg, 2.2mg / kg~3.5mg / kg, 2.2mg / kg~3.4mg / kg, 2.2mg / kg~3.3mg / kg, 2.2mg / kg~3.2mg / kg, 2.2mg / k At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: g-3.1 mg / kg, 2.2 mg / kg-3 mg / kg, 2.2 mg / kg-2.9 mg / kg, 2.2 mg / kg-2.8 mg / kg, 2.2 mg / kg-2.7 mg / kg, 2.2 mg / kg-2.6 mg / kg, 2.2 mg / kg-2.5 mg / kg, 2.2 mg / kg-2.4 mg / kg, or 2.2 mg / kg-2.3 mg / kg.

[0435] In one embodiment, relative to the subject's body weight, the doses are 2.2 mg / kg to 4.2 mg / kg, 2.3 mg / kg to 4.2 mg / kg, 2.4 mg / kg to 4.2 mg / kg, 2.5 mg / kg to 4.2 mg / kg, 2.6 mg / kg to 4.2 mg / kg, 2.7 mg / kg to 4.2 mg / kg, 2.8 mg / kg to 4.2 mg / kg, 2.9 mg / kg to 4.2 mg / kg, and 3 mg / kg. kg~4.2mg / kg, 3.1mg / kg~4.2mg / kg, 3.2mg / kg~4.2mg / kg, 3.3mg / kg~4.2mg / kg, 3.4mg / kg~4.2mg / kg, 3 .5mg / kg~4.2mg / kg, 3.6mg / kg~4.2mg / kg, 3.7mg / kg~4.2mg / kg, 3.8mg / kg~4.2mg / kg, 3.9mg / kg~4.2mg / kg, 4mg / kg~4.2mg / kg, 4.1mg / kg~4.2mg / kg, 2.6mg / kg~4.1mg / kg, 2.6mg / kg~4mg / kg, 2.6mg / kg~3.9mg / kg, 2.6mg / kg~3.8mg / kg, 2.6mg / kg~3.7mg / kg, 2.6mg / kg~3.6mg / kg, 2.6mg / kg~3.5mg / kg, 2.6mg / kg At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: g-3.4 mg / kg, 2.6 mg / kg-3.3 mg / kg, 2.6 mg / kg-3.2 mg / kg, 2.6 mg / kg-3.1 mg / kg, 2.6 mg / kg-3 mg / kg, 2.6 mg / kg-2.9 mg / kg, 2.6 mg / kg-2.8 mg / kg, or 2.6 mg / kg-2.7 mg / kg.

[0436] In one embodiment, relative to the subject's body weight, the amounts are 1.2 mg / kg to 4.2 mg / kg, 1.2 mg / kg to 4.1 mg / kg, 1.2 mg / kg to 4.0 mg / kg, 1.2 mg / kg to 3.9 mg / kg, 1.2 mg / kg to 3.8 mg / kg, 1.2 mg / kg to 3.7 mg / kg, 1.2 mg / kg to 3.6 mg / kg, 1.2 mg / kg to 3.5 mg / kg, 1.2 mg / kg to 3.4 mg / kg, 1.2 mg / kg to 3.3 mg / kg, 1.2 mg / kg to 3.1 mg / kg, 1.2 mg / kg to 3 mg / kg, 1.2 mg / kg to 2.9 mg / kg, 1.2 mg / kg to 2.8 mg / kg, 1.2 mg / kg to 2.7 mg / kg, and 1.2 mg At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: 1.6 mg / kg~2.6 mg / kg, 1.2 mg / kg~2.5 mg / kg, 1.2 mg / kg~2.4 mg / kg, 1.2 mg / kg~2.3 mg / kg, 1.2 mg / kg~2.2 mg / kg, 1.2 mg / kg~2.1 mg / kg, 1.2 mg / kg~2 mg / kg, 1.2 mg / kg~1.9 mg / kg, 1.2 mg / kg~1.8 mg / kg, 1.3 mg / kg~2.6 mg / kg, 1.4 mg / kg~2.5 mg / kg, 1.5 mg / kg~2.4 mg / kg, 1.6 mg / kg~2.3 mg / kg, 1.7 mg / kg~2.2 mg / kg, and 1.8 mg / kg~2.1 mg / kg.

[0437] In one embodiment, relative to the subject's body weight, the doses are 2.6 mg / kg to 4.2 mg / kg, 2.3 mg / kg to 4.2 mg / kg, 2.4 mg / kg to 4.2 mg / kg, 2.5 mg / kg to 4.2 mg / kg, 2.6 mg / kg to 4.2 mg / kg, 2.7 mg / kg to 4.2 mg / kg, 2.8 mg / kg to 4.2 mg / kg, 2.9 mg / kg to 4.2 mg / kg, and 3 mg / kg. kg~4.2mg / kg, 3.1mg / kg~4.2mg / kg, 3.2mg / kg~4.2mg / kg, 3.3mg / kg~4.2mg / kg, 3.4mg / kg~4.2mg / kg, 3 .5mg / kg~4.2mg / kg, 3.6mg / kg~4.2mg / kg, 3.7mg / kg~4.2mg / kg, 3.8mg / kg~4.2mg / kg, 3.9mg / kg~4.2mg / kg, 4mg / kg~4.2mg / kg, 4.1mg / kg~4.2mg / kg, 2.6mg / kg~4.1mg / kg, 2.6mg / kg~4mg / kg, 2.6mg / kg~3.9mg / kg, 2.6mg / kg~3.8mg / kg, 2.6mg / kg~3.7mg / kg, 2.6mg / kg~3.6mg / kg, 2.6mg / kg~3.5mg / kg, 2.6mg / kg At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: g-3.4 mg / kg, 2.6 mg / kg-3.3 mg / kg, 2.6 mg / kg-3.2 mg / kg, 2.6 mg / kg-3.1 mg / kg, 2.6 mg / kg-3 mg / kg, 2.6 mg / kg-2.9 mg / kg, 2.6 mg / kg-2.8 mg / kg, or 2.6 mg / kg-2.7 mg / kg.

[0438] In one embodiment, relative to the subject's body weight, the dosage ranges are 2.6 mg / kg to 3.6 mg / kg, 2.7 mg / kg to 3.6 mg / kg, 2.8 mg / kg to 3.6 mg / kg, 2.9 mg / kg to 3.6 mg / kg, 3 mg / kg to 3.6 mg / kg, 3.1 mg / kg to 3.6 mg / kg, 3.2 mg / kg to 3.6 mg / kg, 3.3 mg / kg to 3.6 mg / kg, 3.4 mg / kg to 3.6 mg / kg, and 3.5 mg / kg to 3.6 mg / kg. At least one bispecific anti-Aβ / TfR antibody in the following concentrations is administered: g, 2.6 mg / kg~3.5 mg / kg, 2.6 mg / kg~3.4 mg / kg, 2.6 mg / kg~3.3 mg / kg, 2.6 mg / kg~3.2 mg / kg, 2.6 mg / kg~3.1 mg / kg, 2.6 mg / kg~3 mg / kg, 2.6 mg / kg~2.9 mg / kg, 2.6 mg / kg~2.8 mg / kg, or 2.6 mg / kg~2.7 mg / kg.

[0439] In some embodiments, the subject is administered at a dose of 0.5 mg / kg of body weight of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the subject is administered at a dose of 1 mg / kg of body weight of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the subject is administered at a dose of 1.2 mg / kg of body weight of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the subject is administered at a dose of 1.8 mg / kg of body weight of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the subject is administered at a dose of 2 mg / kg of body weight of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the subject is administered at a dose of 2.6 mg / kg of body weight of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the subject is administered at a dose of 2.8 mg / kg of body weight of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the subject is administered at a dose of 3 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 3.2 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 3.4 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 3.6 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 4 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 4.5 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 5 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 5.5 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.In some embodiments, the subject is administered at a dose of 6 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 6.5 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 7 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 7.2 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 8 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight. In some embodiments, the subject is administered at a dose of 9 mg / kg of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.

[0440] In one embodiment, for several doses, the dosage relative to the subject's body weight was 1 mg / kg to 7.2 mg / kg, 1.2 mg / kg to 7.2 mg / kg, 1.4 mg / kg to 7.2 mg / kg, 1.8 mg / kg to 7.2 mg / kg, 1.9 mg / kg to 7.2 mg / kg, 2 mg / kg to 7.2 mg / kg, 2.1 mg / kg to 7.2 mg / kg, 2.2 mg / kg to 7.2 mg / kg, 2.3 mg / kg to 7.2 mg / kg, 2.4 mg / kg to 7.2 mg / kg, 2.5 mg / kg to 7.2 mg / kg, 2.6 mg / kg to 7.2 mg / kg, and 2.7 mg. / kg~7.2mg / kg, 2.8mg / kg~7.2mg / kg, 2.9mg / kg~7.2mg / kg, 3mg / kg~7.2mg / kg, 3.1mg / kg~7.2mg / kg, 3.2mg / kg~7.2mg / kg, 3.3mg / kg~7.2mg / kg, 3.4mg / kg~7.2mg / kg, 3.5mg / kg~7.2mg / kg, 3.6mg / kg~7.2mg / kg, 3.7mg / kg~7.2mg / kg, 3.8mg / kg~7.2mg / kg, 3.9mg / kg~7.2mg / kg, 4mg / kg~7.2mg / kg, 4.5mg / A first dose of at least one bispecific anti-Aβ / TfR antibody in the following concentrations relative to the subject's body weight is administered: kg~7.2 mg / kg, 5 mg / kg~7.2 mg / kg, 5.5 mg / kg~7.2 mg / kg, 6 mg / kg~7.2 mg / kg, 6.5 mg / kg~7.2 mg / kg, or 7 mg / kg~7.2 mg / kg. After several of these administrations, the subject's body weight is further divided into concentrations of 0.2 mg / kg~3.6 mg / kg, 0.3 mg / kg~3.6 mg / kg, 0.4 mg / kg~3.6 mg / kg, 0.5 mg / kg~3.6 mg / kg, 0.6 mg / kg~3.6 mg / kg, and 0. 7mg / kg~3.6mg / kg, 0.8mg / kg~3.6mg / kg, 0.9mg / kg~3.6mg / kg, 1.0mg / kg~1.1mg / kg, 1.2mg / kg~3.6mg / kg, 1.3mg / kg~3.6mg / kg, 1.4mg / kg~3.6mg / kg, 1 .5mg / kg~3.6mg / kg, 1.6mg / kg~3.6mg / kg, 1.7mg / kg~3.6mg / kg, 1.8mg / kg~3.6mg / kg, 1.9mg / kg~3.6mg / kg, 2mg / kg~3.6mg / kg, 2.1mg / kg~3.6mg / kg, 2.2mg / kg~3.6mg / kg, 2.3mg / kg~3.6mg / kg, 2.4mg / kg~3.6mg / kg, 2.5mg / kg~3.6mg / kg, 2.6mg / kg~3.6mg / kg, 2.7mg / kg~3.6mg / kg, 2.8mg / k g~3.6mg / kg, 2.9mg / kg~3.6mg / kg, 3mg / kg~3.6mg / kg, 3.1mg / kg~3.6mg / kg, 3.2mg / kg~3.6mg / kg, 3.3mg / kg~3.6mg / kg, 3.4mg / kg~3.6mg / Administration is continued with a lower second dose of at least one bispecific anti-Aβ / TfR antibody in the following ranges: kg, 3.5 mg / kg to 3.6 mg / kg, 2.6 mg / kg to 3.5 mg / kg, 2.6 mg / kg to 3.4 mg / kg, 2.6 mg / kg to 3.3 mg / kg, 2.6 mg / kg to 3.2 mg / kg, 2.6 mg / kg to 3.1 mg / kg, 2.6 mg / kg to 3 mg / kg, 2.6 mg / kg to 2.9 mg / kg, 2.6 mg / kg to 2.8 mg / kg, or 2.6 mg / kg to 2.7 mg / kg.

[0441] In one embodiment, the number of doses is 3 to 60. In another embodiment, the number of doses is 3, 6, 12, 18, 24, 36, 48, or 60.

[0442] In one preferred embodiment, at least one bispecific anti-Aβ / TfR antibody is trontinemab (RG6102).

[0443] Dosage regimens for at least one bispecific anti-Aβ / TfR antibody The method of the present invention involves administering a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody to a subject. Those skilled in the art will understand that any therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody may be administered once or multiple times according to one or more dosing regimens. Those skilled in the art will be able to determine an appropriate dosing regimen for each subject, depending on several factors including pharmacodynamic characteristics, route of administration, dose, and the health, age, and weight of the subject to be treated, as well as using the information disclosed herein.

[0444] In some embodiments, a composition comprising at least one bispecific anti-Aβ / TfR antibody is administered daily, every other day, every three days, once a week, every two weeks ("every other week"), every four weeks ("every four weeks"), once a month, once every six weeks, once every eight weeks, once every two months, once every ten weeks, once every twelve weeks, once every three months, once every fourteen weeks, and every sixteen weeks. The drug is administered once, every four months, every 18 weeks, every 20 weeks, every five months, every 22 weeks, every 24 weeks, every six months, every seven months, every eight months, every nine months, every ten months, every eleven months, every twelve months, every thirteen months, every fourteen months, every fifteen months, every sixteen months, every seventeen months, or every eighteen months. In some embodiments, a composition containing at least one bispecific anti-Aβ / TfR antibody is administered daily, every other day, every three days, once a week, every two weeks ("every other week"), every four weeks ("every four weeks"), or once a month. In some embodiments, a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody is administered every two weeks or every four weeks. In some embodiments, a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody is administered once every two weeks. In one preferred embodiment, a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody is administered once every four weeks. In a further preferred embodiment, a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody is administered once a month.

[0445] In some embodiments, a composition containing a therapeutically effective dose of trontinemab is administered once a week. In some embodiments, a composition containing a therapeutically effective dose of trontinemab is administered once every two weeks. In some embodiments, a composition containing a therapeutically effective dose of trontinemab is administered once every three weeks. In one preferred embodiment, a composition containing a therapeutically effective dose of trontinemab is administered once every four weeks. In a further preferred embodiment, a composition containing a therapeutically effective dose of trontinemab is administered once a month.

[0446] In some embodiments, a composition containing at least one bispecific anti-Aβ / TfR antibody at a dose of 1.8 mg / kg, 2.6 mg / kg, 3 mg / kg, 3.6 mg / kg, or 7.2 mg / kg relative to the subject's body weight is administered to the subject once a week. In some embodiments, a composition containing at least one bispecific anti-Aβ / TfR antibody at a dose of 1.8 mg / kg, 2.6 mg / kg, 3 mg / kg, 3.6 mg / kg, or 7.2 mg / kg relative to the subject's body weight is administered to the subject once every two weeks. In some embodiments, a composition containing at least one bispecific anti-Aβ / TfR antibody at a dose of 1.8 mg / kg, 2.6 mg / kg, 3 mg / kg, 3.6 mg / kg, or 7.2 mg / kg relative to the subject's body weight is administered to the subject once every three weeks. In one preferred embodiment, a composition containing at least one bispecific anti-Aβ / TfR antibody at a dose of 1.8 mg / kg, 2.6 mg / kg, 3 mg / kg, 3.6 mg / kg, or 7.2 mg / kg relative to the subject's body weight is administered to the subject once every four weeks. In a further preferred embodiment, a composition containing at least one bispecific anti-Aβ / TfR antibody at a dose of 1.8 mg / kg, 2.6 mg / kg, 3 mg / kg, 3.6 mg / kg, or 7.2 mg / kg relative to the subject's body weight is administered to the subject once a month.

[0447] In some embodiments, a composition containing at least one bispecific anti-Aβ / TfR antibody at a dose of 1.8 to 7.2 mg / kg relative to the subject's body weight is administered to the subject once every four weeks. In one preferred embodiment, a composition containing at least one bispecific anti-Aβ / TfR antibody at a dose of 2.6 to 3.6 mg / kg relative to the subject's body weight is administered to the subject once every four weeks or once a month.

[0448] In some embodiments, a composition containing 1.8 to 7.2 mg / kg of trontinemab relative to the subject's body weight is administered to the subject once every four weeks. In one preferred embodiment, a composition containing 2.6 to 3.6 mg / kg of trontinemab relative to the subject's body weight is administered to the subject once every four weeks or once a month.

[0449] A composition comprising at least one bispecific anti-Aβ / TfR antibody. In some embodiments, at least one bispecific anti-Aβ / TfR antibody is included in the composition. In some embodiments, the composition comprises at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the composition comprises at least one bispecific anti-Aβ / TfR antibody and further comprises at least one additional component. The at least one additional component may be selected from physiologically acceptable additives suitable for use in humans.

[0450] The compositions of this disclosure may be in the form of solutions, lyophilized products, and / or any other suitable form deemed appropriate by those skilled in the art. The routes of administration of the compositions of this disclosure may be any suitable route, including intravenous and subcutaneous administration. In some embodiments, the compositions are formulated as sterile, non-pyrogenic liquids for intravenous administration. In some embodiments, the compositions are physiological saline solutions.

[0451] Formulations for anti-Aβ antibodies are known in the art, for example, as disclosed in International Publication No. 2008 / 071394, International Publication No. 2013 / 131866, Chinese Patent No. 115227813, Japanese Patent Application Publication No. 2014 / 001232, International Publication No. 2009 / 017467 and International Publication No. 2006 / 083689.

[0452] In general, anti-Aβ antibodies used in accordance with the present invention can be formulated into any formulation suitable for intravenous administration. For example, but not limited to, formulations known for other antibodies, particularly other anti-Aβ antibodies, can be used.

[0453] In one embodiment, the anti-Aβ antibody used in accordance with the present invention is - Anti-Aβ antibodies (w / v) from about 1 to about 250 mg / mL; - Approximately 0.001% to 1% of at least one surfactant (w / v); - Approximately 1 mM to 100 mM buffering material; -Optionally, approximately 10 mM to approximately 500 mM of stabilizer and / or approximately 5 mM to approximately 500 mM of isotonic agent, It is formulated as a stable preparation containing a pH of approximately 4.0 to 7.0.

[0454] In one embodiment, the formulation is a liquid formulation.

[0455] In one preferred embodiment, the liquid formulation is 1) -Anti-Aβ antibodies of approximately 1 to 200 mg / mL, - Approximately 0.04% polysorbate 20 (w / v), -Approximately 20 mM L-histidine, -Approximately 250 mM sucrose, -At a pH of approximately 5.5, or 2) - Approximately 37.5 mg / mL of anti-Aβ antibody, - Approximately 0.02% polysorbate 20 (w / v), -Approximately 10 mM L-histidine, -Approximately 125 mM sucrose, -At a pH of approximately 5.5, or 3) - Approximately 37.5 mg / mL of anti-Aβ antibody, - Approximately 0.01% polysorbate 20 (w / v), -Approximately 10 mM L-histidine, -Approximately 125 mM sucrose, -At a pH value of approximately 5.5, or 4) - Approximately 7.5 mg / mL of anti-Aβ antibody, - Approximately 0.04% polysorbate 20 (w / v), -Approximately 20 mM L-histidine, -Approximately 250 mM sucrose, -At a pH value of approximately 5.5, or 5) - Approximately 7.5 mg / mL of anti-Aβ antibody, - Approximately 0.02% polysorbate 20 (w / v), -Approximately 10 mM L-histidine, -Approximately 125 mM sucrose, -At a pH value of approximately 5.5, or 6) -About 37.5mg / mL anti-Aβ antibody, - Approximately 0.02% polysorbate 20 (w / v), -Approximately 10 mM L-histidine, -Approximately 125 mM trehalose, -At a pH value of approximately 5.5, or 7) - Approximately 37.5 mg / mL of anti-Aβ antibody, - Approximately 0.01% polysorbate 20 (w / v), -Approximately 10 mM L-histidine, -Approximately 125 mM trehalose, -At a pH value of approximately 5.5, or 8) - Approximately 75 mg / mL of anti-Aβ antibody, - Approximately 0.02% polysorbate 20 (w / v), -Approximately 20 mM L-histidine, -Approximately 250 mM trehalose, -At a pH value of approximately 5.5, or 9) - Approximately 75 mg / mL of anti-Aβ antibody, - Approximately 0.02% polysorbate 20 (w / v), -Approximately 20 mM L-histidine, -Approximately 250 mM mannitol, -At a pH value of approximately 5.5, or 10) - Approximately 75 mg / mL of anti-Aβ antibody, - Approximately 0.02% polysorbate 20 (w / v), -Approximately 20 mM L-histidine, - Approximately 140 mM sodium chloride, -At a pH value of approximately 5.5, or 11) - Approximately 150 mg / mL of anti-Aβ antibody, -0.02% polysorbate 20 (w / v), -Approximately 20 mM L-histidine, -Approximately 250 mM trehalose, -At a pH value of approximately 5.5, or 12) - Approximately 150 mg / mL of anti-Aβ antibody, - Approximately 0.02% polysorbate 20 (w / v), -Approximately 20 mM L-histidine, -Approximately 250 mM mannitol, -At a pH value of approximately 5.5, or 13) - Approximately 150 mg / mL of anti-Aβ antibody, - Approximately 0.02% polysorbate 20 (w / v), -Approximately 20 mM L-histidine, - Approximately 140 mM sodium chloride, -At a pH value of approximately 5.5, or 14) - Approximately 10 mg / mL of anti-Aβ antibody, - Approximately 0.01% polysorbate 20 (w / v), -Approximately 20 mM L-histidine, - Approximately 140 mM sodium chloride, It contains a pH value of approximately 5.5. In one preferred embodiment, the liquid formulation is -Anti-Aβ antibodies ranging from approximately 1 mg / mL to approximately 200 mg / mL, -Approximately 0.01% to approximately 0.1% poloxamer (w / v), - Approximately 5mM to 50mM of cushioning material, - Approximately 100 mM to 300 mM stabilizer, -Includes pH values ​​in the range of pH 4.5 to pH 7.0, including pH 4.5 and pH 7.0.

[0456] In one embodiment, the antibody has a concentration of about 100 mg / ml to about 200 mg / ml, preferably about 150 mg / ml.

[0457] In one embodiment, poloxamer is present at a concentration of 0.02% to 0.06%, preferably about 0.04%. In one preferred embodiment, poloxamer is poloxamer 188.

[0458] In one embodiment, the buffer is a sodium acetate buffer or a histidine buffer. In one preferred embodiment, the buffer is a histidine / histidine-HCl buffer.

[0459] In one embodiment, the buffer has a concentration of about 10 mM to about 30 mM. In one preferred embodiment, the buffer has a concentration of about 20 mM.

[0460] In one embodiment, the formulation has a pH value in the range of pH 5 to pH 6, including pH 5 and pH 6. In one preferred embodiment, the pH of the formulation is 5.5.

[0461] In one embodiment, the stabilizer is selected from sugars and amino acids.

[0462] In one embodiment, the stabilizer is selected from trehalose and arginine.

[0463] In one embodiment, the stabilizer is trehalose, having a concentration of about 150 mM to about 250 mM. In one preferred embodiment, the stabilizer is trehalose, having a concentration of about 200 mM.

[0464] In one embodiment, the stabilizer is toarginine, having a concentration of about 100 mM to about 150 mM. In one preferred embodiment, the stabilizer is arginine, having a concentration of about 135 mM.

[0465] In one embodiment, the antibody used in the present invention is contained in a pharmaceutical composition comprising an anti-Aβ antibody and a buffer, wherein the buffer is a histidine salt buffer or an acetate buffer.

[0466] In one embodiment, the buffer has a concentration in the range of about 5 mM to about 100 mM, including about 5 mM and about 100 mM. In another embodiment, the buffer has a concentration in the range of about 30 mM to about 70 mM, including about 30 mM and about 70 mM. In one preferred embodiment, the buffer has a concentration of about 50 mM.

[0467] In one preferred embodiment, the buffer is a histidine acetate buffer or a sodium acetate buffer.

[0468] In one embodiment, the pH value of the pharmaceutical composition is in the range of about pH 4.5 to about pH 6.0, including about pH 4.5 and about pH 6.0. In another embodiment, the pH value of the pharmaceutical composition is in the range of about pH 4.7 to about pH 5.5, including about pH 4.7 and about pH 5.5. In one preferred embodiment, the pH value of the pharmaceutical composition is about pH 5.0 or about pH 5.5.

[0469] In one embodiment, the concentration of the anti-Aβ antibody is about 60 mg / mL to about 200 mg / mL. In another embodiment, the concentration of the anti-Aβ antibody is about 90 mg / mL to about 150 mg / mL. In one preferred embodiment, the concentration of the anti-Aβ antibody is about 100 mg / mL or about 150 mg / mL.

[0470] In one embodiment, the pharmaceutical composition further comprises a surfactant.

[0471] In one embodiment, the surfactant is a polysorbate. In one preferred embodiment, the surfactant is polysorbate 80 or polysorbate 20.

[0472] In one embodiment, the concentration of the surfactant is in the range of about 0.01% to about 0.1% (w / v), including about 0.01% and about 0.1% (w / v). In another embodiment, the concentration of the surfactant is in the range of about 0.02% to about 0.08% (w / v), including about 0.02% and about 0.08% (w / v). In one preferred embodiment, the concentration of the surfactant is in the range of about 0.04% to 0.06% (w / v), including about 0.04% and 0.06% (w / v).

[0473] In one embodiment, the pharmaceutical composition further comprises a sugar.

[0474] In one embodiment, the pharmaceutical composition comprises sucrose or trehalose. In one preferred embodiment, the pharmaceutical composition comprises sucrose.

[0475] In one embodiment, the pharmaceutical composition contains sugar in a concentration range of about 20 mg / mL to about 100 mg / mL, including about 20 mg / mL and about 100 mg / mL. In another embodiment, the pharmaceutical composition contains sugar in a concentration range of about 30 mg / mL to about 90 mg / mL, including about 30 mg / mL and about 90 mg / mL. In one preferred embodiment, the pharmaceutical composition contains sugar in a concentration of about 40 mg / mL, or about 60 mg / mL, or about 70 mg / mL, or about 80 mg / mL.

[0476] In one embodiment, the pharmaceutical composition further comprises a chelating agent.

[0477] In one embodiment, the chelating agent is ethylenediaminetetraacetic acid (EDTA) disodium salt.

[0478] In one embodiment, the chelating agent has a concentration in the range of approximately 0.01 mg / mL to approximately 20 mg / mL, including approximately 0.01 mg / mL and approximately 20 mg / mL. In another embodiment, the chelating agent has a concentration in the range of approximately 0.1 mg / mL to approximately 1 mg / mL, including approximately 0.1 mg / mL and approximately 1 mg / mL. In yet another embodiment, the chelating agent has a concentration of approximately 0.5 mg / mL.

[0479] In one embodiment, the pharmaceutical composition comprises the following components: (i) (a) Anti-Aβ antibody of about 90 mg / mL to about 150 mg / mL, (b) Polysorbate at approximately 0.2 mg / mL to approximately 0.8 mg / mL (c) Sucrose in a concentration of approximately 30 mg / mL to 90 mg / mL (d) Histidine salt buffer or acetate buffer in a concentration of approximately 30 mM to 70 mM; The pH of the pharmaceutical composition is approximately 4.7 to approximately 5.5; or (ii) (a) Anti-Aβ antibody of about 90 mg / mL to about 150 mg / mL, (b) Polysorbate at approximately 0.2 mg / mL to approximately 0.8 mg / mL (c) Sucrose in a concentration of approximately 30 mg / mL to 90 mg / mL (d) Histidine salt buffer or acetate buffer in a concentration of approximately 30 mM to 70 mM; (e) Disodium ethylenediaminetetraacetic acid in a concentration of approximately 0.1 mg / mL to approximately 1 mg / mL; The pH of the pharmaceutical composition is approximately 4.7 to 5.5. (iii) (a) Approximately 100 mg / mL of anti-Aβ antibody, (b) Polysorbate 80 at approximately 0.4 mg / mL, (c) Sucrose at approximately 40 mg / mL, (d) Approximately 50 mM histidine acetate buffer; The pH of the pharmaceutical composition is approximately 5.0; (iv) (a) Approximately 100 mg / mL of anti-Aβ antibody, (b) Polysorbate 80 at approximately 0.6 mg / mL, (c) Sucrose at approximately 60 mg / mL, (d) Approximately 50 mM sodium acetate buffer; The pH of the pharmaceutical composition is approximately 5.0; (v) (a) Approximately 150 mg / mL of anti-Aβ antibody, (b) Polysorbate 80 at approximately 0.6 mg / mL, (c) Sucrose at approximately 60 mg / mL, (d) Approximately 50 mM sodium acetate buffer; The pH of the pharmaceutical composition is approximately 5.0; (vi) (a) Approximately 100 mg / mL of anti-Aβ antibody, (b) Approximately 0.6 mg / mL polysorbate 80, (c) Approximately 70 mg / mL sucrose, (d) Approximately 50 mM sodium acetate buffer, (e) Approximately 0.5 mg / mL ethylenediaminetetraacetate disodium salt; The pH of the pharmaceutical composition is approximately 5.5.

[0480] In one embodiment, the antibody used in the present invention is in a formulation containing about 10 mg of anti-Aβ antibody in about 10 mM histidine, about 10 mM methionine, about 4% mannitol, and about 0.005% (w / v) polysorbate 80 at a pH of about 6.0.

[0481] In one embodiment, the antibody used in the present invention is contained in a formulation comprising about 10 mg to about 250 mg of anti-Aβ antibody, about 4% mannitol or about 150 mM NaCl, about 5 mM to about 10 mM histidine, and about 10 mM methionine.

[0482] In one embodiment, the antibody used in the present invention comprises anti-Aβ antibody in a concentration in the range of about 17 mg / ml to about 23 mg / ml, including about 17 mg / ml and about 23 mg / ml; histidine in a concentration in the range of about 5 mM to about 15 mM, including about 5 mM and about 15 mM; mannitol in an amount in the range of about 2% w / v to about 6% w / v, including about 2% w / v and about 6% w / v; methionine in a concentration in the range of about 5 mM to about 15 mM, including about 5 mM and about 15 mM; and polysorbate in an amount in the range of about 0.001% w / v to about 0.01% w / v, including about 0.001% w / v and about 0.01% w / v, wherein the formulation is in a formulation having a pH of 5.5 to 6.5.

[0483] In one preferred embodiment, the antibody is present at a concentration of about 20 mg / ml.

[0484] In one preferred embodiment, histidine is present at a concentration of about 10 mM.

[0485] In one preferred embodiment, mannitol is present in an amount of about 4% w / v.

[0486] In one preferred embodiment, methionine is present at a concentration of about 10 mM.

[0487] In one preferred embodiment, the polysorbate is present in an amount of 0.005% w / v.

[0488] In one preferred embodiment, the pH is approximately 6.0.

[0489] In one preferred embodiment, histidine is L-histidine, mannitol is D-mannitol, methionine is L-methionine, and polysorbate is polysorbate-80.

[0490] Reduction of clinical deterioration One aspect of the present invention relates to a method for mitigating clinical exacerbation in subjects having early-stage Alzheimer's disease, such as mild, mild-to-prodromal, or prodromal Alzheimer's disease. For example, but not limited to, such embodiments may include administering to the subject a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody disclosed herein. In some embodiments, subjects having early-stage Alzheimer's disease have been diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease and / or have been diagnosed with mild Alzheimer's dementia.

[0491] Any of the bispecific anti-Aβ / TfR antibodies disclosed herein, the therapeutically acceptable doses thereof, the dosing regimens therefor, and the compositions comprising them may be used in methods for mitigating clinical progression in subjects with early-stage Alzheimer's disease according to the present invention. For example, in some embodiments, a composition comprising at least one bispecific anti-Aβ / TfR antibody, such as trontinemab, at a dose of 1.8 mg / kg, 2.6 mg / kg, 3 mg / kg, 3.6 mg / kg, or 7.2 mg / kg relative to the subject's body weight is administered to the subject once a week, once every two weeks, once every three weeks, once every four weeks, or once a month. In some embodiments, clinical worsening, as determined by CDR-SB, was at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, and less than 20%. At least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, or at least 60% reduction.In some embodiments, the reduction of the above-mentioned clinical exacerbation is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months and / or 60 months after administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0492] In some embodiments, clinical worsening is reduced by 20% to 60% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical worsening is reduced by 25% to 60% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical worsening is reduced by 25% to 50% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical worsening is reduced by at least 20% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical worsening is reduced by at least 30% compared to placebo, as determined by the CDR-SB. In some embodiments, clinical worsening is reduced by at least 25%, for example, at least 26% or at least 28%, as determined by the CDR-SB. In some embodiments, clinical worsening is reduced by at least 30%, for example, at least 35% or at least 38%, as determined by the CDR-SB. In some embodiments, the reduction of the above-mentioned clinical exacerbation is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months and / or 60 months after administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0493] In some embodiments, clinical exacerbation is reduced by at least 30%, e.g., at least 35%, or at least 40%, compared to placebo, when determined by CDR-SB after 6 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, clinical exacerbation is reduced by at least 30%, e.g., at least 35%, or at least 45%, compared to placebo, when determined by CDR-SB after 12 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, clinical exacerbation is reduced by at least 20%, e.g., at least 25%, compared to placebo, when determined by CDR-SB after 18 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In one preferred embodiment, the composition contains 1.8 to 7.2 mg / kg of at least one bispecific anti-Aβ / TfR antibody and is administered once every 4 weeks or once a month. In one preferred embodiment, at least one bispecific anti-Aβ / TfR antibody is trontinemab.

[0494] In some embodiments, clinical exacerbation is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, or at least 14% compared to placebo, as determined by CDR-SB, and the subjects are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction of clinical exacerbation described above is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months and / or 60 months after administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0495] In some embodiments, clinical exacerbation is reduced by 10%–20% compared to placebo, as determined by CDR-SB, and subjects are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, clinical exacerbation is reduced by at least 5%, e.g., at least 10%, at least 12%, or at least 14%, compared to placebo, as determined by CDR-SB, and subjects are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease. In some embodiments, the reduction in clinical exacerbation described above is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months, and / or 60 months after administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0496] In some embodiments, clinical worsening, as determined by the CDR-SB, was at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, and less than 20%. All patients are reduced by 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, or at least 51%, and the patients are diagnosed with mild Alzheimer's disease dementia. In some embodiments, the reduction of the above clinical worsening is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months and / or 60 months after administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0497] In some embodiments, clinical worsening is reduced by 40% to 60% compared to placebo, as determined by CDR-SB, and the subjects are diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 45%, e.g., at least 48%, at least 50%, or at least 51%, compared to placebo, as determined by CDR-SB, and the subjects are diagnosed with mild Alzheimer's disease dementia. In some embodiments, clinical worsening is reduced by at least 51% compared to placebo, as determined by CDR-SB, and the subjects are diagnosed with mild Alzheimer's disease dementia. In some embodiments, the reduction in clinical worsening described above is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months, and / or 60 months after administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0498] In some embodiments, clinical exacerbation in subjects diagnosed with mild Alzheimer's disease dementia is reduced by at least 51% compared to placebo, as determined by CDR-SB after 18 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the composition contains 1.8 to 7.2 mg / kg of at least one bispecific anti-Aβ / TfR antibody and is administered once every 2-4 days or once a month. In one preferred embodiment, the at least one bispecific anti-Aβ antibody is trontinemab.

[0499] In some embodiments, the reduction in clinical exacerbation is determined 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 36 months, 42 months, 48 ​​months, 54 months, 60 months, 63 months, 66 months and / or 72 months after administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the reduction in clinical exacerbation is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months and / or 60 months after administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0500] In some embodiments, a reduction in clinical exacerbation is determined one month after administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, a reduction in clinical exacerbation is determined after six months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, a reduction in clinical exacerbation is determined after twelve months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, a reduction in clinical exacerbation is determined after eighteen months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, a reduction in clinical exacerbation is determined after twenty-four months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, a reduction in clinical exacerbation is determined after sixty months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody.

[0501] In some embodiments, the reduction in clinical exacerbation is determined after administration of a composition containing a therapeutically effective dose of trontinemab.

[0502] In some embodiments, the reduction in clinical worsening is determined 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 30 months, 36 months, 42 months, 48 ​​months, 54 months, 60 months, 63 months, 66 months and / or 72 months after administration of the composition containing a therapeutically effective dose of trontinemab. In some embodiments, the reduction in clinical worsening is determined 1 month after administration of the composition containing a therapeutically effective dose of trontinemab. In some embodiments, a reduction in clinical exacerbation is determined after 6 months of administration of a composition containing a therapeutically effective dose of trontinemab. In some embodiments, a reduction in clinical exacerbation is determined after 12 months of administration of a composition containing a therapeutically effective dose of trontinemab. In some embodiments, a reduction in clinical exacerbation is determined after 18 months of administration of a composition containing a therapeutically effective dose of trontinemab. In some embodiments, a reduction in clinical exacerbation is determined after 60 months of administration of a composition containing a therapeutically effective dose of trontinemab. In some embodiments, a reduction in clinical exacerbation is determined after 63 months of administration of a composition containing a therapeutically effective dose of trontinemab.

[0503] Transition from amyloid-positive to amyloid-negative target A further aspect of the present invention is a method for converting an amyloid-positive subject to an amyloid-negative subject. In some embodiments, the method comprises administering to the subject a composition comprising at least one bispecific anti-Aβ / TfR antibody disclosed herein. In some embodiments, the subject having early-stage Alzheimer's disease, e.g., mild, mild-to-prodromal, or prodromal Alzheimer's disease, has been diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease, and / or has been diagnosed with mild Alzheimer's dementia.

[0504] Any of the bispecific anti-Aβ / TfR antibodies disclosed herein, the therapeutically acceptable doses thereof, the dosing regimens therefor, and the compositions comprising them may be used in methods for converting amyloid-positive subjects to amyloid-negative subjects. For example, in some embodiments, a composition comprising at least one bispecific anti-Aβ / TfR antibody, such as trontinemab, at a dose of 1.8 mg / kg, 2.6 mg / kg, 3.8 mg / kg, or 7.2 mg / kg relative to the subject's body weight is administered to the subject once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.

[0505] In some embodiments, when the dosage of the composition is determined by visual reading of amyloid PET images, the amounts are at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, and at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, or at least 81% of subjects are converted from amyloid-positive to amyloid-negative.

[0506] In some embodiments, administration of the composition results in a conversion from amyloid-positive to amyloid-negative in 50% to 100%, e.g., 60% to 90%, of subjects, as determined by visual reading of amyloid PET images. In some embodiments, administration of the composition results in at least 55%, e.g., at least 60% or at least 65%, of subjects becoming amyloid-negative after 12 months of administration of the composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody, as determined by visual reading of amyloid PET images. In some embodiments, administration of the composition results in at least 70%, e.g., at least 75% or at least 80%, of subjects becoming amyloid-negative after 18 months of administration of the composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody, as determined by visual reading of amyloid PET images. In some embodiments, the composition contains 1.8 to 7.2 mg / kg of at least one bispecific anti-Aβ / TfR antibody and is administered once every four weeks or once a month. In one preferred embodiment, at least one bispecific anti-Aβ / TfR antibody is trontinemab.

[0507] In some embodiments, the dosage of the composition, when determined by visual reading of amyloid PET images, is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, and at least 2 2%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, and 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, and less This results in at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of subjects being amyloid-negative.

[0508] In some embodiments, clinical worsening, as determined by the CDR-SB, was at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, and at least The clinical worsening is reduced by 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, or at least 45%, and the subject is not simultaneously administered at least one Alzheimer's disease drug. In some embodiments, the reduction of the clinical worsening described above is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months and / or 60 months after administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0509] In some embodiments, clinical worsening is reduced by at least 35%, e.g., at least 40%, at least 42%, or at least 45% compared to placebo, as determined by CDR-SB, and the subject is not simultaneously administered at least one Alzheimer's disease drug. In some embodiments, clinical worsening is reduced by at least 45% compared to placebo, as determined by CDR-SB, and the subject is not simultaneously administered at least one Alzheimer's disease drug. In some embodiments, the reduction in clinical worsening described above is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months, and / or 60 months after administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0510] In some embodiments, clinical progression in subjects not concurrently receiving at least one Alzheimer's disease drug is reduced by at least 45% compared to placebo, as determined by CDR-SB after 18 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the composition contains 1.8 to 7.2 mg / kg of at least one bispecific anti-Aβ / TfR antibody and is administered once every four weeks or once a month. In one preferred embodiment, the at least one bispecific anti-Aβ / TfR antibody is trontinemab.

[0511] Decreased brain amyloid levels One aspect of the present invention is a method for reducing brain amyloid levels in a subject requiring a reduction in brain amyloid levels, comprising the step of administering a composition comprising a therapeutically effective amount of the present invention and at least one bispecific anti-Aβ / TfR antibody disclosed herein.

[0512] Those skilled in the art will understand that, in addition to subjects with Alzheimer's disease, Aβ protein plaques are present in the brains of subjects with other neurodegenerative diseases and conditions, and therefore the methods disclosed herein are beneficial to subjects with such neurodegenerative diseases and / or conditions. Such diseases and conditions are known to include, for example, Down syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, and Lewy body dementia. (See, for example, Catafau et al., "Amyloid PET imaging: applications beyond Alzheimer's disease," Clin. Transl. Imaging 3(1):39-55 (2015); and Banerjee, G. et al., "The increasing impact of cerebral amyloid angiopathy: essential new insights for clinical practice," J. Neurol. Neurosurg. Psychiatry 88:982-994 (2017).)

[0513] In some embodiments, the subjects have early-stage Alzheimer's disease.

[0514] In one preferred embodiment, the subject has mild, mild to prodromal, or prodromal Alzheimer's disease.

[0515] In some embodiments, the subjects have Alzheimer's disease, Down syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, Lewy body dementia, or other brain diseases or conditions involving soluble and / or insoluble Aβ aggregates containing Aβ peptides.

[0516] In some embodiments, subjects with early-stage Alzheimer's disease are diagnosed with mild to moderate cognitive impairment due to Alzheimer's disease and / or with mild Alzheimer's dementia.

[0517] Any of the bispecific anti-Aβ / TfR antibodies disclosed herein, the therapeutically acceptable doses thereof, the dosing regimens therefor, and compositions comprising them may be used in methods to reduce cerebral amyloid levels in subjects having early, mild, or prodromal Alzheimer's disease. In one preferred embodiment, a composition comprising at least one bispecific anti-Aβ / TfR antibody, such as trontinemab, in an amount of 1.8 to 7.2 mg / kg relative to the subject's body weight, for example, 1.8 mg / kg, 2.6 mg / kg, 3.8 mg / kg, or 7.2 mg / kg, is administered to the subject once a week, once every two weeks, once every three weeks, once every four weeks, or once a month.

[0518] In one preferred embodiment, at least one bispecific anti-Aβ / TfR antibody is trontinemab.

[0519] In some embodiments, the reduction in amyloid in the brain is determined by imaging using the binding of a radiotracer to brain Aβ protein amyloid and visualized by positron emission tomography (PET). In some embodiments, the adjusted mean change reduction from baseline is at least 40 centoids (-40 centoids from baseline), e.g., at least 65 centoids (-65 centoids from baseline) or at least 90 centoids (-90 centoids from baseline) after 3 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the reduction in amyloid in the brain is determined by imaging using the binding of a radiotracer to brain Aβ protein amyloid and visualized by PET. In some embodiments, the adjusted mean change reduction from baseline is at least 50 centroids (-50 centroids from baseline), e.g., at least 55 centroids (-55 centroids from baseline) or at least 60 centroids (-60 centroids from baseline) after 12 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the adjusted mean change reduction from baseline is at least 60 centroids (-60 centroids from baseline), e.g., at least 65 centroids (-65 centroids from baseline) or at least 70 centroids (-70 centroids from baseline) after 18 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody.

[0520] In some embodiments, the method results in a reduced level of cerebrospinal fluid Aβ1-42 protein fragments compared to the pre-administration level.In some embodiments, the method involves adding at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, and less than 1% of the cerebrospinal fluid Aβ1-42 protein fragment levels prior to administration. At least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, small At least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, This results in a decrease of at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of cerebrospinal fluid Aβ1-42 protein fragment levels.

[0521] In some embodiments, when the administration of a composition comprising at least one bispecific anti-Aβ / TfR antibody is determined by visual reading of an amyloid PET image, the amounts are at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, and at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, small At least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least This results in 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of subjects being amyloid-negative.

[0522] In some embodiments, administration of a composition comprising at least one bispecific anti-Aβ / TfR antibody results in 75% to 100% of the subject, e.g., 80% to 100% or 85% to 100%, being amyloid-negative, as determined by visual reading of amyloid PET images. In some embodiments, administration of a composition comprising at least one bispecific anti-Aβ / TfR antibody results in at least 75% of the subject, e.g., at least 80% or at least 85%, being amyloid-negative, as determined by visual reading of amyloid PET images. In some embodiments, administration of a composition comprising at least one bispecific anti-Aβ / TfR antibody results in 100% of the subject being amyloid-negative, as determined by visual reading of amyloid PET images.

[0523] In some embodiments, after 3 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody, at least 30% of the subjects are amyloid-negative, as determined by visual reading of amyloid PET images. In some embodiments, after 6 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody, at least 30%, e.g., at least 40%, at least 50%, at least 60%, or at least 70% of the subjects are amyloid-negative, as determined by visual reading of amyloid PET images. In some embodiments, after 12 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody, at least 75%, e.g., at least 80%, or at least 85% of the subjects are amyloid-negative, as determined by visual reading of amyloid PET images. In some embodiments, after 18 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody, at least 75%, e.g., at least 80%, at least 85%, at least 90%, or at least 95% of subjects are amyloid-negative, as determined by visual reading of amyloid PET images. In some embodiments, the composition contains at least one bispecific anti-Aβ / TfR antibody in a dose of 1.8 to 7.2 mg / kg, e.g., 1.8 mg / kg, 2.6 mg / kg, 3.6 mg / kg, or 7.2 mg / kg, and is administered once every four weeks or once a month. In one preferred embodiment, the at least one bispecific anti-Aβ / TfR antibody is trontinemab.

[0524] In some embodiments, the method results in a brain amyloid level after administration compared to the brain amyloid level before administration. In some embodiments, the brain amyloid level is at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, and at least 22% compared to the brain amyloid level before administration. , at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, At least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, small It will decrease by at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%.

[0525] In some embodiments, the reduction in amyloid in the brain is determined by imaging using the binding of a radiotracer to Aβ amyloid in the brain and visualized by PET. In some embodiments, the reduction in amyloid in the brain is determined by imaging using the binding of a radiotracer to Aβ amyloid in the brain and visualized by PET. In some embodiments, the adjusted mean change reduction from baseline is at least 40 centoids (-40 centoids from baseline), e.g., at least 65 centoids (-65 centoids from baseline) or at least 90 centoids (-90 centoids from baseline) after 3 months of administration of a composition comprising a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the adjusted mean change reduction from the subject's level before administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody is at least 50 centoids (-50 centoids from baseline), e.g., at least 55 centoids (-55 centoids from baseline) or at least 59 centoids (-59 centoids from baseline) after 12 months of administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the adjusted mean change reduction from the subject's level before administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody is at least 60 centoids (-60 centoids from baseline), e.g., at least 65 centoids (-65 centoids from baseline) or at least 70 centoids (-70 centoids from baseline) after 18 months of administration of a composition containing a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0526] In some embodiments, the method results in reduced cerebrospinal fluid Aβ1-42 protein fragment levels compared to pre-administration levels.In some embodiments, the method involves at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, and less than 1% of the cerebrospinal fluid Aβ1-42 protein fragment levels prior to administration. 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, and less At least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, small This results in a decrease of at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of cerebrospinal fluid Aβ1-42 protein fragment levels.

[0527] In some embodiments, administration of a composition containing at least one bispecific anti-Aβ / TfR antibody results in a brain amyloid level reduction of -0.20 to -0.60, for example, -0.20 to -0.40, relative to the brain amyloid level before administration of the composition containing at least one bispecific anti-Aβ / TfR antibody, as determined by visual reading of amyloid PET images. In some embodiments, administration of a composition containing at least one bispecific anti-Aβ / TfR antibody results in a brain amyloid level reduction of at least -0.25, relative to the brain amyloid level before administration of the composition containing at least one bispecific anti-Aβ / TfR antibody, as determined by visual reading of amyloid PET images. In some embodiments, administration of a composition containing at least one bispecific anti-Aβ / TfR antibody results in a brain amyloid level reduction of at least -0.30, relative to the brain amyloid level before administration of the composition containing at least one bispecific anti-Aβ / TfR antibody, as determined by visual reading of amyloid PET images. In some embodiments, administration of a composition comprising at least one bispecific anti-Aβ / TfR antibody results in a brain amyloid level reduction of at least -0.60 compared to the brain amyloid level before administration of the composition comprising at least one bispecific anti-Aβ / TfR antibody, as determined by visual reading of amyloid PET images.

[0528] In some embodiments, when the administration of a composition comprising at least one bispecific anti-Aβ / TfR antibody is determined by visual reading of an amyloid PET image, the amounts are at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, and at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, small At least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least This results in 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% of subjects being amyloid-negative.

[0529] In some embodiments, administration of a composition comprising at least one bispecific anti-Aβ / TfR antibody results in 75% to 100% of the subject, e.g., 80% to 100% or 85% to 100%, being amyloid-negative, as determined by visual reading of amyloid PET images. In some embodiments, administration of a composition comprising at least one bispecific anti-Aβ / TfR antibody results in at least 75% of the subject, e.g., at least 80% or at least 85%, being amyloid-negative, as determined by visual reading of amyloid PET images. In some embodiments, administration of a composition comprising at least one bispecific anti-Aβ / TfR antibody results in 100% of the subject being amyloid-negative, as determined by visual reading of amyloid PET images.

[0530] In some embodiments, after 12 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody, at least 75%, e.g., at least 80%, or at least 85% of the subjects are amyloid-negative, as determined by visual reading of amyloid PET images. In some embodiments, after 18 months of administration of a composition containing a therapeutically effective dose of at least one bispecific anti-Aβ / TfR antibody, at least 75%, e.g., at least 80%, at least 85%, at least 90%, or at least 95% of the subjects are amyloid-negative, as determined by visual reading of amyloid PET images. In some embodiments, the composition contains at least one bispecific anti-Aβ / TfR antibody in a dose of 1.8 to 7.2 mg / kg, e.g., 1.8 mg / kg, 2.6 mg / kg, 3.6 mg / kg, or 7.2 mg / kg, and is administered once every four weeks or once a month. In one preferred embodiment, the at least one bispecific anti-Aβ / TfR antibody is trontinemab.

[0531] clinical results A major obstacle in the development of novel anti-Aβ monoclonal antibody (mAb) therapies is delivery to the brain across the blood-brain barrier (BBB). Due to the large size of mAbs, only a small percentage (approximately 0.1%–0.2%) of peripherally administered antibodies reach the brain. Monoclonal antibodies appear to enter the brain passively, for example, via the choroid plexus, and then slowly distribute to different brain regions.

[0532] Gantenerumab, an anti-amyloid monoclonal antibody, has been evaluated in several clinical trials. In the SCarlet RoAD clinical trial (ClinicalTrials.gov identifier: NCT10224106; conversion from a phase 2 / 3 trial of gantenerumab in prodromal AD to open-label long-term administration and rollover to the Open RoAD open-label trial; prodromal AD, CDR 0.5), gantenerumab was administered subcutaneously every four weeks (Q4W) at a final dose of 1,200 mg. In the Marguerite RoAD clinical trial (ClinicalTrials.gov identifier: NCT02051608; conversion from a phase 3 trial of gantenerumab in mild AD to open-label long-term administration and rollover to the Open RoAD open-label trial; mild AD, CDR 1.0), gantenerumab was administered subcutaneously every four weeks (Q4W) at a final dose of 1,200 mg. In the GRADUATE I and II Phase 3 trials (ClinicalTrials.gov identifier: NCT03444870 and NCT03443973; two international, collaborative, parallel, multicenter, randomized, double-blind, placebo-controlled trials of gantenerumab in patients with early-stage AD (prodromal or MCI-AD to mild AD)) and the post-GRADUATE trial (ClinicalTrials.gov identifier: NCT04374253; an open-label, long-term administration trial), gantenerumab was administered subcutaneously every other week (Q2W) at a final dose of 510 mg. In the GRADUATION Phase 2 trial (ClinicalTrials.gov identifier: NCT04592341; a multicenter, open-label, single-arm trial), gantenerumab was administered subcutaneously once a week (Q1W) at a final dose of 255 mg. In the SKYLINE Phase 3 trial (ClinicalTrials.gov identifier: NCT05256134; a randomized, double-blind, placebo-controlled secondary prevention trial of gantenerumab in participants at risk of AD or in the earliest stages of AD), gantenerumab was administered subcutaneously at a 1-month dose of 1,020 mg, with flexible administration (Q1W or Q2W). (See, for example, Bateman, RJ, et al., Alzheimer's Res. Ther. 14(2022) 178.)

[0533] Brainshuttle® (BrS) is a technology developed to increase the penetration of large molecules, such as antibodies, into the brain. Access to large molecules into the brain is restricted by the blood-brain barrier (BBB), a gatekeeper between the blood and brain tissue that carefully filters which molecules can enter the brain. By using a specific antibody format, antibodies are created that can cross the blood-brain barrier by binding to one of the protein receptors located on their surface, namely human transferrin receptor 1 (TfR1, CD71). The so-called "Brainshuttle®" technology enables the delivery of all types of therapeutic molecules into the brain, regardless of the molecule's inherent ability to cross the blood-brain barrier.

[0534] Trontinemab (also known as RG6102 or RO7126209; see also proposed INN List 127, Cas 2568868-35-7, USAN KL-203, FDA UNII N0GBZ1GWC2) is a BrS antibody employing a specific "2+1" design. More specifically, trontinemab is a bispecific antibody consisting of a variant of the anti-amyloid monoclonal antibody gantenerumab, a bivalent monospecific y-shaped fully human monoclonal antibody targeting amyloid-beta protein, and an additional domain-exchanged Fab (anti-TfR1Fab) conjugated to one C-terminus of the heavy chain of the gantenerumab variant, which specifically binds to human transferrin receptor 1 (see International Publication 2017 / 055540 expressly incorporated herein by reference).

[0535] The structure of trontinemab is shown in Figure 1.

[0536] Trontinemab was developed for the treatment of Alzheimer's disease. When administered intravenously, trontinemab circulates in the bloodstream and binds to transferrin receptors present on endothelial cells that make up the blood-brain barrier. This leads to its active endocytosis, transport across the blood-brain barrier, and release into the brain parenchyma.

[0537] Preclinical studies have been conducted using a “mouse version” of trontinemab, in which a gantenerumab mutant is fused to a single Fab that binds to the mouse transferrin receptor. In AD mouse models, a substantial increase in brain concentration was observed (Niewoehner, J., et al., Neuron 8(2014) 49-60). Up to 40 times more BrS antibodies entered the brain and bound to amyloid plaques compared to standard Y-shaped IgG antibodies. Trontinemab stimulated plaque clearance by immune cells at lower doses compared to the parent antibody gantenerumab. Simultaneously, no immune response was initiated against endothelial cells or other cells expressing the transferrin receptor.

[0538] A surrogate trontinemab (BrS-mAb31) that cross-reacts with mouse TfR1 and its surrogate counterpart molecule (mAb31) were used for the mouse in vivo evaluation of trontinemab. The BrS-mAb31 surrogate binds to an epitope similar to trontinemab in the apical domain on TfR1, outside the binding interface between TfR1 and transferrin (Tf). The mouse surrogate for the BrS construct consisted of a single Fab of a rat antibody specific to mouse TfR1, fused to the C-terminal Fc region of mAb31, a human IgG1 antibody (a preclinical version of gantenerumab) specific to Aβ fibrillaries and oligomers. Using a monovalent binding mode to TfR1, this BrS-mAb31 was shown to enhance plaque decoration in a mouse model of AD compared to the parent antibody (Niewoehner et al., 2014, see above).

[0539] In a transgenic amyloidosis mouse model, BrS-mAb31 showed lower plasma exposure than its non-BrS analog, mAb31, which was thought to be due to target-mediated pharmacokinetics via peripheral TfR binding. In a 4-month treatment study using weekly doses, BrS-mAb31 showed approximately 12-fold higher brain exposure than mAb31 7 days after the last injection. Furthermore, BrS-mAb31 resulted in a significantly greater reduction in Aβ protein amyloid plaques in the cortex and hippocampus compared to vehicle controls and equimolar low-dose mAb31, even though the plasma exposure of the BrS construct was thus lower. In vitro studies demonstrated that the effector function of BrS-mAb31 is masked peripherally, primarily due to its sterically hindrance-induced inverted TfR binding mode, thereby reducing the likelihood of first infusion reactions.

[0540] It must be noted that there are no established and available animal models for AD in non-human primates (NHPs).

[0541] We were able to achieve substantially higher brain exposure through shuttle-based chemotradition using trontinemab (Kulic, L., et al., presented at AD / PD2021, virtual conference).

[0542] A single IV dose of 10 mg / kg of trontinemab was used compared to a single IV dose of 20 mg / kg of gantenerumab, resulting in 6 to 42 times higher brain (tissue) exposure in non-human primates, particularly in the deep brain region, compared to gantenerumab alone. This is shown in Figure 2A and the table below. [Table 3]

[0543] The brain-to-plasma ratio in different brain regions ranged from 0.46% to 0.78%, which corresponds to a 6 to 17 times higher area under the steady-state brain region concentration-time curve (AUC) compared to gantenerumab (see Figure 2B).

[0544] However, it remained unclear whether Brainshuttle™ technology could achieve faster amyloid plaque clearance and broader, more uniform brain penetration in humans compared to antibodies that do not use active TfR1 receptor-mediated transcellular transport across the blood-brain barrier.

[0545] In the first human trial of trontinemab in healthy human volunteers (Phase Ia, single-dose escalation dose (SAD)), doses from 0.1 mg / kg to 7.2 mg / kg were tested (0.1 mg / kg and 0.4 mg / kg: four active substances and two placebos, respectively; 1.2 mg / kg, 3.6 mg / kg and 7.2 mg / kg: six active substances and two placebos, respectively). The results are summarized below.

[0546] A dose-proportional increase in plasma pharmacokinetics (PK) was observed with trontinemab. Furthermore, an eightfold increase in the CSF / plasma ratio was observed compared to conventional IgG mAbs (0.5–1.2% vs. 0.1–0.2%). Trontinemab doses of 0.1–3.6 mg / kg were generally well-tolerated. All observed adverse events (AEs) were classified as either Grade 1 or Grade 2 in severity and resolved. No Grade 3, 4, or 5 AEs were observed. The most frequent AEs considered to be related to the study procedure were acute fluid-associated reactions, headache, and nausea. No serious AEs (including fatal outcomes) were reported up to the maximum study dose level of 7.2 mg / kg.

[0547] The second human trial of trontinemab (Phase Ib / IIa, multiple dose escalation (MAD); NCT04639050, BP42155, EudraCT2020-002477-98) was conducted in participants with prodromal or mild to moderate Alzheimer's disease (AD). This was a randomized, international, multicenter, double-blind, placebo-controlled, parallel-group trial with an alternating parallel-group design, in which four initial series cohorts were planned.

[0548] Doses of 0.2 mg / kg, 0.6 mg / kg, 1.8 mg / kg, and 3.6 mg / kg were tested (each dose cohort included up to 120 participants, with at least 8 participants receiving the active substance and at least 2 participants receiving a placebo).

[0549] This trial consisted of a continuous screening period (up to 12 weeks, including a 1-week baseline period), a double-blind treatment period (28 weeks), and a safety follow-up period (28 weeks). The trial used an alternating parallel-group design and assigned participants to four planned serial dose cohorts (selected dose levels: 0.2 mg / kg (Cohort 1), 0.6 mg / kg (Cohort 2), 1.8 mg / kg (Cohort 3), and 3.6 mg / kg (Cohort 4)).

[0550] Trontinemab was administered intravenously once every four weeks for 28 weeks (primary endpoint; total of 7 doses), and the safety follow-up period was 28 weeks.

[0551] Participants had to meet the following criteria: - Age: 50 to 85 years old (adult, elderly adult); - Mild to moderate AD dementia (meeting the National Institute on Aging-Alzheimer's Association [NIA-AA] core clinical criteria for high-probability AD dementia) or prodromal AD (meeting the NIA-AA diagnostic criteria and guidelines for mild cognitive impairment due to AD); - A Mini-Mental State Examination (MMSE) score of 18 to 28 within 84 days prior to baseline; - Within 84 days prior to baseline, a Clinical Dementia Scale-Total Score (CDR-GS) of 0.5, 1, or 2; - Positive amyloid PET scan (cutoff: >50 centroid units) within 12 months prior to baseline.

[0552] Each cohort was administered sentinel therapy. Amyloid plaque load was assessed by florbetapir and florbetaben PET imaging at screening, day 78 (cohorts 3 and 4 only), and day 196. An interim analysis of amyloid PET results was performed before increasing to the maximum dose level of 3.6 mg / kg (cohort 4).

[0553] In participants, brain amyloid load was determined by amyloid positron emission tomography (PET) at baseline (week 0), week 12 (cohorts 3+4), and week 28 (cohorts 1-4). Trontinemab concentrations in plasma (up to 32 weeks) and cerebrospinal fluid (CSF) (baseline and week 25) were also determined.

[0554] Furthermore, CDR and MMSE (baseline, 28-week, and 40-week) were determined to evaluate clinical efficacy.

[0555] To assess cerebral perfusion, changes from baseline were determined using PET and ASL-MRI (arterial spin-labeled magnetic resonance imaging). In blood and CSF changes from baseline, the following would / were determined as biomarkers, among others: Aβ1-42 protein fragments (amyloid β peptides 1-42; SEQ ID NO: 45), tTau (total tau protein), pTau (phosphorylated tau protein), neurogranin, NfL (neurofilament light protein), and sTREM2 (soluble trigger receptor 2 expressed on myeloid cells) (blood: baseline, weeks 11, 24, 25, and 26; CSF: baseline, week 25).

[0556] Currently, the following has been discovered: - The safety and amyloid PET interim analyses were based on a data snapshot as of January 18, 2023. Safety results included blinded data from a total of 44 participants who received either trontinemab or placebo. The majority of adverse events (AEs) were mild (grade 1) or moderate (grade 2) in severity. Consistent with previous results from a phase 1a single-dose escalation trial of trontinemab, infusion-related reactions (IRRs) were the most common AEs to occur under treatment. All IRRs were mild or moderate in severity. -Intermediate amyloid PET results included data from 36 participants (11 men, 25 women) enrolled in cohorts 1–3 who underwent at least one post-baseline amyloid PET scan. Significant dose-dependent amyloid plaque reduction was observed across all three analyzed dose levels. In cohort 3 (1.8 mg / kg), strong amyloid plaque reduction and amyloid PET negativity (cutoff: <24 centiloids) were already recorded in several participants at day 78. Trontinemab administered at a dose of -1.8 mg / kg results in amyloid reduction three times faster and more extensively than other standard monoclonal antibodies, which have superior safety and a low ARIA risk. This is expected to lead to superior clinical efficacy. - Reaching (or falling below) the amyloid-negative threshold appears to lead to clinical benefits. For example, a 70% amyloid-negative rate after 28 weeks of treatment with medication every four weeks can result in a 44% CDR-SB RR (relative reduction in total box total of the Clinical Dementia Scale) at 18 months compared to placebo, while a 90% amyloid-negative rate after 28 weeks of treatment with medication every four weeks can result in a CDR-SB RR of 50% or more compared to placebo at 18 months (Scelsi et al., CTAD 2023). [Table 4]

[0557] Participants in different trial cohorts had the following characteristics: [Table 5]

[0558] The multi-dose pharmacodynamics of trontinemab, showing the mean change from baseline in amyloid PET centiloids based on nominal hospital visits, are as follows: For participants in active treatment, the mean change from baseline determined 28 days after administration of dose 7 was -20.2 centiloids in the 0.2 mg / kg cohort (a decrease of 20.2 centiloids from baseline; range: -49.4 to -0.7) and -27.6 centiloids in the 0.6 mg / kg cohort (a decrease of 27.6 centiloids from baseline; range: -52 The mean number of doses given was 6.6 and 6.2, respectively. The cohort receiving 1.8 mg / kg showed a more significant mean change from baseline, based on data at the time of the data snapshot. The mean change from baseline, determined 22 days after administration of nominal dose 3, was -65.3 centroids in the 1.8 mg / kg cohort (after a mean number of doses given: 2.8) (a decrease of 65.3 centroids from baseline; range: -102.8 to -42.6). [Table 6]

[0559] Thus, surprisingly, it was found that rapid amyloid plaque clearance could be achieved at significantly lower dose levels than when using typical anti-amyloid monoclonal antibodies.

[0560] These results demonstrate that trontinemab rapidly reduces amyloid plaque load in a dose-dependent manner. In most patients, amyloid plaque load decreases to levels comparable to those of people without Alzheimer's disease, and within a short timeframe.

[0561] More specifically, a monthly intravenous dose of 1.8 mg / kg was found to result in a rapid and significant amyloid reduction of 84 centiloids (-84 centiloids from baseline) after 7 months. This was faster than with standard anti-Aβ monoclonal antibodies, and 72% of participants were below the Aβ protein positivity threshold (24.1 CL) at week 28.

[0562] More specifically, a monthly intravenous dose of 3.6 mg / kg was found to result in a rapid and significant amyloid reduction of 91 centroids (-91 centroids from baseline) after 3 months (n=8). This was approximately 6 times faster than with standard anti-Aβ monoclonal antibodies, with 6 / 8 (63%) participants below the Aβ protein positivity threshold (24.1 CL) at week 12.

[0563] These data confirm the significantly improved safety and tolerability profile of trontinemab compared to standard anti-Aβ monoclonal antibodies. However, acute fluid-related reactions (IRRs) remain the most prominent adverse event (7 / 15; 46.7%), accompanied by common symptoms of chills, fever, and headache, and can be mitigated by appropriate premedication, in one embodiment, with corticosteroid premedication or acetaminophen / NSAID and dexamethasone premedication. NSAID = nonsteroidal anti-inflammatory drug.

[0564] None of the participants in Cohort 4 had previously shown ARIA-E (the overall ARIA-E rate in this study was 2 / 59, and all cases were radiographically mild and reversible). Transient mild anemia was observed in five participants in Cohort 3 and one participant in Cohort 4. A trend toward decreased mean hemoglobin levels and decreased red blood cell counts was recorded in all treatment groups (including placebo), suggesting that frequent blood sampling may have significantly contributed to the anemia phenotype.

[0565] Therefore, in one embodiment, trontinemab has a total ARIA-E rate of less than 13% and a symptomatic ARIA-E rate of less than 3% in the treated subjects. This low ARIA-E rate results in a shorter ARIA-E risk period due to faster amyloid removal.

[0566] In one embodiment, trontinemab is administered without dose setting. While not bound by this theory, it is thought that this rapid amyloid plaque clearance by trontinemab could be achieved by using a TfR1-based Brainshuttle™ approach.

[0567] It was revealed that 4 out of 11 participants (36%) had levels below the 24.1 centiroid amyloid-positive threshold by week 11. By week 28, 6 out of 8 participants (75%) had already fallen below the 24.1 centiroid amyloid-positive threshold, and 5 out of 8 participants (63%) had fallen below the 11 centiroid threshold.

[0568] In contrast, participants given doses of 0.2 mg / kg and 0.6 mg / kg had mean amyloid levels of 74 and 56 centiloids, respectively, at week 28. No participants in the 0.2 mg / kg group were below the amyloid-positive threshold of 24.1 centiloids, and only one participant in the 0.6 mg / kg group was below the amyloid-positive threshold of 24.1 centiloids. [Table 7]

[0569] The results for cohorts 1-3 are visualized in Figures 3 (mean amyloid PET load in Centroid) and 4 (mean amyloid reduction from baseline in Centroid). This trial was randomized (4:1) with more than 10 participants per group (active:placebo). All participants were Caucasian and weighed between 60kg and 70kg. The prevalence of APOEε4 was 71% with a 0.2mg / kg dose, 43% with a 0.6mg / kg dose, and 63% with a 1.8mg / kg dose.

[0570] Results, including those for Cohort 4 at 12 weeks, are visualized in Figure 5 (mean amyloid reduction from baseline in centroid). This trial was randomized (4:1) with more than 10 participants per group (active:placebo). With the exception of one participant in Cohort 4, all participants were Caucasian and weighed between 68 kg and 72.5 kg. The prevalence of APOEε4 was approximately 71% with a 0.2 mg / kg dose, approximately 43% with a 0.6 mg / kg dose, approximately 63% with a 1.8 mg / kg dose, and approximately 67% with a 3.6 mg / kg dose.

[0571] At doses of 1.8 mg / kg and 3.6 mg / kg, it was possible to achieve a reduction of at least 60 centroids to over 90 centroids after 12 weeks, and at least 80 centroids to over 90 centroids after 28 weeks.

[0572] The table below shows the results obtained with trontinemab, along with the results for other anti-Aβ antibodies. It should be noted that amyloid PET loading is expressed in centroids, which may vary between trials. However, even if the absolute change was comparable to the GRADUATE trial, CLARITY-AD (recanemab) allowed for a faster crossing of the amyloid-positive threshold due to its lower baseline level. [Table 8]

[0573] It must be clearly noted that one-third of the patients were already PET-negative 12 weeks (4-week dosing; Q4W) after administration of trontinemab at doses of 1.8 mg / kg or 3.6 mg / kg.

[0574] The following incidents occurred during testing up to October 23, 2023. [Table 9]

[0575] In a cohort of 12 participants (3 receiving placebo, 9 receiving medication), only two cases of ARIA have occurred so far in the 1.8 mg / kg dose group (one case of amyloid-related imaging abnormality - edema (ARIA-E), mild, resolved within one week without medication; one case of amyloid-related imaging abnormality - hemosiderin deposition (ARIA-H), asymptomatic).

[0576] Aβ protein mottling correlates with cumulative dose, and therefore, TfR1 transport across the blood-brain barrier is not blunted by multiple doses.

[0577] The ARIA event data, along with the number of participants experiencing each listed event, is shown in the table below. [Table 10]

[0578] Trontinemab is a novel Brainshuttle® bispecific anti-TfR / Aβ antibody that crosses the blood-brain barrier via active TfR1-mediated transcellular transport at the capillary level. In individuals with AD, trontinemab demonstrated rapid and robust amyloid plaque reduction at lower doses than known for conventional non-Brainshuttle® standard IgG antibodies and at surprisingly low doses than expected (i.e., already at 1.8 mg / kg).

[0579] Preliminary results show a significant reduction already at a dose of 1.8 mg / kg, with a further acceleration of amyloid plaque reduction at 3.6 mg / kg and amyloid-negative results in the majority of participants after 12 weeks of treatment.

[0580] The lower, more persistently low incidence of ARIA (no ARIA-E / ARIA-H at 3.6 mg / kg) and the overall favorable safety and tolerability profile compared to those previously known in the art for anti-Aβ antibodies demonstrate the improved characteristics of trontinemab (Figure 6).

[0581] Therefore, trontinemab provides anti-amyloid immunotherapy by inducing high clearance of amyloid load, as measured by positron emission tomography, in the brains of early-stage AD patients, as evidenced by biomarkers.

[0582] The rate of amyloid clearance observed in patients receiving anti-amyloid therapy (measured by amyloid PET) has been established to be associated with a significant slowdown in cognitive deterioration on several cognitive measures, ultimately in a dose-dependent manner.

[0583] Therefore, trontinemab may be a disease-modifying agent that delays neurodegeneration and neuronal cell death by acting on the pathological mechanisms of Alzheimer's disease, thereby inhibiting the progression of clinical symptoms, i.e., demonstrating a relationship between changes in clinical symptoms and changes in biomarkers. Therefore, trontinemab may help slow the progression of mild cognitive impairment and mild dementia in Alzheimer's disease with an improved safety profile. Therefore, an indication for trontinemab may be to slow the progression of mild cognitive impairment and mild dementia in Alzheimer's disease. ***

[0584] In addition to the various embodiments described and claimed, the subject matter of this disclosure also covers other embodiments having other combinations of the features disclosed and claimed herein. Accordingly, specific features presented herein may be combined with each other in other ways within the scope of the subject matter of this disclosure, such that the subject matter of this disclosure includes any preferred combination of the features disclosed herein. The foregoing descriptions of specific embodiments of the subject matter of this disclosure are provided for illustrative and explanatory purposes only. They are not intended to be exhaustive or to limit the subject matter of this disclosure to the embodiments disclosed.

[0585] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have meanings generally understood by those skilled in the art. Furthermore, unless otherwise required by context, singular terms shall include plural forms, and plural terms shall include singular forms.

[0586] As used herein, the amino acid positions of all constant regions and domains of the heavy and light chains are numbered according to the Kabat numbering system described in Kabat, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991), and are referred to herein as "Kabat numbering". Specifically, the Kabat numbering system (see pp. 647-660) from Kabat, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) is used for the light chain constant domains CL of kappa and lambda isotypes, and the Kabat EU index numbering system (see pp. 661-723) is used for the heavy chain constant domains (CH1, hinge, CH2, and CH3, in this case further clarified by the reference to "Kabat EU index numbering" herein).

[0587] The “knob-into-hole” dimerization module and its use in antibody manipulation are described in Carter P.; Ridgway JBB; Presta LG: Immunotechnology, Volume 2, Number 1, February 1996, pp. 73-73(1).

[0588] General information regarding the nucleotide sequences of the light and heavy chains of human immunoglobulins is given in Kabat, EA, et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991).

[0589] Useful methods and techniques for carrying out the present invention are described, for example, in Ausubel, FM (ed.), Current Protocols in Molecular Biology, Volumes I to III (1997); Glover, N. and Hames, B. ed., DNA Cloning: A Practical Approach, Volumes I and II (1985), Oxford University Press; Freshney, RI (ed.), Animal Cell Culture - a practical approach, IRL Press Limited (1986); Watson, J. Det al., Recombinant DNA, Second Edition, CHSL Press (1992); Winnacker, EL, From Genes to Clones; NY, VCH Publishers (1987); Celis, J., ed., Cell Biology, Second Edition, Academic Press (1998); Freshney, RI, Culture of Animal Cells: A Manual of Basic Technique, second edition, Alan R. Liss, Inc., NY (1987).

[0590] Recombinant DNA technology enables the creation of nucleic acid derivatives. Such derivatives can be modified at individual or several nucleotide positions, for example, by substitution, alteration, exchange, deletion, or insertion. Modification or derivatization can be carried out, for example, by site-directed mutagenesis. Such modifications can be easily performed by those skilled in the art (see, for example, Sambrook, J., et al., Molecular Cloning: A Laboratory Manual (1999), Cold Spring Harbor Laboratory Press, New York, USA; and Hames, BD, and Higgins, SG, Nucleic Acid Hybridization - A Practical Approach (1985), IRL Press, Oxford, England).

[0591] All references cited herein are expressly incorporated herein by reference. [Examples]

[0592] Example 1: Phase Ia Test In the first human trial of trontinemab in healthy human volunteers (Phase Ia, single-dose escalation dose (SAD)), doses from 0.1 mg / kg to 7.2 mg / kg were tested (0.1 mg / kg and 0.4 mg / kg: four active substances and two placebos, respectively; 1.2 mg / kg, 3.6 mg / kg and 7.2 mg / kg: six active substances and two placebos, respectively). The results are summarized below.

[0593] A dose-proportional increase in plasma pharmacokinetics (PK) was observed with trontinemab. Furthermore, an eightfold increase in the CSF / plasma ratio was observed compared to conventional IgG mAbs (0.5–1.2% vs. 0.1–0.2%). Trontinemab doses of 0.1–3.6 mg / kg were generally well-tolerated. All observed adverse events (AEs) were classified as either Grade 1 or Grade 2 in severity and resolved. No Grade 3, 4, or 5 AEs were observed. The most frequent AEs considered to be related to the study procedure were acute fluid-associated reactions, headache, and nausea. No serious AEs (including fatal outcomes) were reported up to the maximum study dose level of 7.2 mg / kg.

[0594] Example 2: Phase Ib / IIa Test The second human trial of trontinemab (Phase Ib / IIa, multiple dose escalation (MAD); NCT04639050, BP42155, EudraCT2020-002477-98) will be conducted in participants with prodromal or mild to moderate Alzheimer's disease (AD). This is a randomized, international, multicenter, double-blind, placebo-controlled, parallel-group trial with an alternating parallel-group design, with four initial series cohorts planned.

[0595] The study will test doses of 0.2 mg / kg, 0.6 mg / kg, 1.8 mg / kg, and 3.6 mg / kg (each dose cohort will include up to 120 participants, with at least 8 participants receiving the active substance and at least 2 participants receiving a placebo).

[0596] This trial consisted of a continuous screening period (up to 12 weeks, including a 1-week baseline period), a double-blind treatment period (28 weeks), and a safety follow-up period (28 weeks). The trial used an alternating parallel-group design and assigned participants to four planned serial dose cohorts (selected dose levels: 0.2 mg / kg (Cohort 1), 0.6 mg / kg (Cohort 2), 1.8 mg / kg (Cohort 3), and 3.6 mg / kg (Cohort 4)).

[0597] Trontinemab was administered intravenously once every four weeks for 28 weeks (primary endpoint; total of 7 doses), and the safety follow-up period was 28 weeks.

[0598] Participants had to meet the following criteria: - Age: 50 to 85 years old (adult, elderly adult); - Mild to moderate AD dementia (meeting the National Institute on Aging-Alzheimer's Association [NIA-AA] core clinical criteria for high-probability AD dementia) or prodromal AD (meeting the NIA-AA diagnostic criteria and guidelines for mild cognitive impairment due to AD); - A Mini-Mental State Examination (MMSE) score of 18 to 28 within 84 days prior to baseline; - Within 84 days prior to baseline, a Clinical Dementia Scale-Total Score (CDR-GS) of 0.5, 1, or 2; - Positive amyloid PET scan (cutoff: >50 centroid units) within 12 months prior to baseline.

[0599] Each cohort was administered sentinel therapy. Amyloid plaque load was assessed by florbetapir and florbetaben PET imaging at screening, day 78 (cohorts 3 and 4 only), and day 196. An interim analysis of amyloid PET results was performed before increasing to the maximum dose level of 3.6 mg / kg (cohort 4).

[0600] In participants, brain amyloid load was determined by amyloid positron emission tomography (PET) at baseline (week 0), week 12 (cohorts 3+4), and week 28 (cohorts 1-4). Trontinemab concentrations in plasma (up to 32 weeks) and cerebrospinal fluid (CSF) (baseline and week 25) were also determined.

[0601] Furthermore, CDR and MMSE (baseline, 28-week, and 40-week) were determined to evaluate clinical efficacy.

[0602] To assess cerebral perfusion, changes from baseline were determined using PET and ASL-MRI (arterial spin-labeled magnetic resonance imaging). In blood and CSF changes from baseline, the following would / were determined as biomarkers, among others: Aβ1-42 protein fragments (amyloid β peptides 1-42; SEQ ID NO: 45), tTau (total tau protein), pTau (phosphorylated tau protein), neurogranin, NfL (neurofilament light protein), and sTREM2 (soluble trigger receptor 2 expressed on myeloid cells) (blood: baseline, weeks 11, 24, 25, and 26; CSF: baseline, week 25).

[0603] Currently, the following has been discovered: - The safety and amyloid PET interim analyses were based on a data snapshot as of January 18, 2023. Safety results included blinded data from a total of 44 participants who received either trontinemab or placebo. The majority of adverse events (AEs) were mild (grade 1) or moderate (grade 2) in severity. Consistent with previous results from a phase 1a single-dose escalation trial of trontinemab, acute fluid-related reactions (IRRs) were the most common treatment-induced AE. All IRRs were mild or moderate in severity. -Intermediate amyloid PET results included data from 36 participants (11 men, 25 women) enrolled in cohorts 1–3 who underwent at least one post-baseline amyloid PET scan. Significant dose-dependent amyloid plaque reduction was observed across all three analyzed dose levels. In cohort 3 (1.8 mg / kg), strong amyloid plaque reduction and amyloid PET negativity (cutoff: <24 centiloids) were already recorded in several participants at day 78. Trontinemab administered at a dose of -1.8 mg / kg results in amyloid reduction three times faster and more extensively than other standard monoclonal antibodies, which have superior safety and a low ARIA risk. This is expected to lead to superior clinical efficacy. - Reaching (or falling below) the amyloid-negative threshold appears to lead to clinical benefits. For example, a 70% amyloid-negative rate after 28 weeks of treatment with medication every four weeks can result in a 44% CDR-SB RR (relative reduction in total box total of the Clinical Dementia Scale) at 18 months compared to placebo, while a 90% amyloid-negative rate after 28 weeks of treatment with medication every four weeks can result in a CDR-SB RR of 50% or more compared to placebo at 18 months (Scelsi et al., CTAD 2023). [Table 11]

[0604] Participants in different trial cohorts had the following characteristics: [Table 12]

[0605] The multi-dose pharmacodynamics of trontinemab, showing the mean change from baseline in amyloid PET centiloids based on nominal hospital visits, are as follows: For participants in active treatment, the mean change from baseline determined 28 days after administration of dose 7 was -20.2 centiloids in the 0.2 mg / kg cohort (a decrease of 20.2 centiloids from baseline; range: -49.4 to -0.7) and -27.6 centiloids in the 0.6 mg / kg cohort (a decrease of 27.6 centiloids from baseline; range: -52 The mean number of doses given was 6.6 and 6.2, respectively. The cohort receiving 1.8 mg / kg showed a more significant mean change from baseline, based on data at the time of the data snapshot. The mean change from baseline, determined 22 days after administration of nominal dose 3, was -65.3 centroids in the 1.8 mg / kg cohort (after a mean number of doses given: 2.8) (a decrease of 65.3 centroids from baseline; range: -102.8 to -42.6). [Table 13]

[0606] Thus, surprisingly, it was found that rapid amyloid plaque clearance could be achieved at significantly lower dose levels than when using typical anti-amyloid monoclonal antibodies.

[0607] These results demonstrate that trontinemab rapidly reduces amyloid plaque load in a dose-dependent manner. In most patients, amyloid plaque load decreases to levels comparable to those of people without Alzheimer's disease, and within a short timeframe.

[0608] More specifically, a monthly intravenous dose of 1.8 mg / kg was found to result in a rapid and significant amyloid reduction of 84 centiloids (-84 centiloids from baseline) after 7 months. This was faster than with standard anti-Aβ monoclonal antibodies, and 72% of participants were below the Aβ protein positivity threshold (24.1 CL) at week 28.

[0609] More specifically, a monthly intravenous dose of 3.6 mg / kg was found to result in a rapid and significant amyloid reduction of 91 centroids (-91 centroids from baseline) after 3 months (n=8). This was approximately 6 times faster than with standard anti-Aβ monoclonal antibodies, with 6 / 8 (63%) participants below the Aβ protein positivity threshold (24.1 CL) at week 12.

[0610] These data confirm the significantly improved safety and tolerability profile of trontinemab compared to standard anti-Aβ monoclonal antibodies. However, acute fluid-related reactions (IRRs) remain the most prominent adverse event (7 / 15; 46.7%), accompanied by common symptoms of chills, fever, and headache, and can be mitigated by appropriate premedication, in one embodiment, with corticosteroid premedication or acetaminophen / NSAID and dexamethasone premedication. NSAID = nonsteroidal anti-inflammatory drug.

[0611] None of the participants in Cohort 4 had previously shown ARIA-E (the overall ARIA-E rate in this study was 2 / 59, and all cases were radiographically mild and reversible). Transient mild anemia was observed in five participants in Cohort 3 and one participant in Cohort 4. A trend toward decreased mean hemoglobin levels and decreased red blood cell counts was recorded in all treatment groups (including placebo), suggesting that frequent blood sampling may have significantly contributed to the anemia phenotype.

[0612] Therefore, in one embodiment, trontinemab has a total ARIA-E rate of less than 13% and a symptomatic ARIA-E rate of less than 3% in the treated subjects. This low ARIA-E rate results in a shorter ARIA-E risk period due to faster amyloid removal.

[0613] It was revealed that 4 out of 11 participants (36%) had levels below the 24.1 centroid amyloid-positive threshold at week 11. By week 28, 6 out of 8 participants (75%) had levels below the 24.1 centroid amyloid-positive threshold, and 5 out of 8 participants (63%) had levels below 11 centroids. In contrast, participants given doses of 0.2 mg / kg and 0.6 mg / kg had mean amyloid levels of 74 and 56 centroids, respectively, at week 28. No participants in the 0.2 mg / kg group had levels below the 24.1 centroid amyloid-positive threshold, and only one participant in the 0.6 mg / kg group had levels below the 24.1 centroid amyloid-positive threshold. [Table 14]

[0614] The results for cohorts 1-3 are visualized in Figures 3 (mean amyloid PET load in Centroid) and 4 (mean amyloid reduction from baseline in Centroid). This trial was randomized (4:1) with more than 10 participants per group (active:placebo). All participants were Caucasian and weighed between 60kg and 70kg. The prevalence of APOEε4 was 71% with a 0.2mg / kg dose, 43% with a 0.6mg / kg dose, and 63% with a 1.8mg / kg dose.

[0615] Results, including those for Cohort 4 at 12 weeks, are visualized in Figure 5 (mean amyloid reduction from baseline in centroid). This trial was randomized (4:1) with more than 10 participants per group (active:placebo). With the exception of one participant in Cohort 4, all participants were Caucasian and weighed between 68 kg and 72.5 kg. The prevalence of APOEε4 was approximately 71% with a 0.2 mg / kg dose, approximately 43% with a 0.6 mg / kg dose, approximately 63% with a 1.8 mg / kg dose, and approximately 67% with a 3.6 mg / kg dose.

[0616] At doses of 1.8 mg / kg and 3.6 mg / kg, it was possible to achieve a reduction of at least 60 centroids to over 90 centroids after 12 weeks, and at least 80 centroids to over 90 centroids after 28 weeks.

[0617] The following table and Figure 6 show the results obtained with trontinemab, along with the results for other anti-Aβ antibodies. It should be noted that amyloid PET loading is expressed in centiloids, which may vary between trials. However, even if the absolute change was comparable to the GRADUATE trial, CLARITY-AD (recanemab) allowed for a faster crossing of the amyloid-positive threshold due to its lower baseline level. [Table 15]

[0618] It must be clearly noted that one-third of the patients were already PET-negative 12 weeks (4-week dosing; Q4W) after administration of trontinemab at doses of 1.8 mg / kg or 3.6 mg / kg.

[0619] The following incidents occurred during testing up to October 23, 2023. [Table 16]

[0620] In a cohort of 12 participants (3 receiving placebo, 9 receiving medication), only two cases of ARIA have occurred so far in the 1.8 mg / kg dose group (one case of amyloid-related imaging abnormality - edema (ARIA-E), mild, resolved within one week without medication; one case of amyloid-related imaging abnormality - hemosiderin deposition (ARIA-H), asymptomatic).

[0621] Aβ protein mottling correlates with cumulative dose, and therefore, TfR1 transport across the blood-brain barrier is not blunted by multiple doses.

[0622] The ARIA event data, along with the number of participants experiencing each listed event, is shown in the table below. [Table 17]

Claims

1. A bispecific antibody (bispecific anti-Aβ / TfR antibody) that specifically binds to human Aβ protein and human transferrin receptor for use as a pharmaceutical in the treatment of Alzheimer's disease, wherein the antibody is administered intravenously once every four weeks at a dose of 0.2 mg / kg to 7.2 mg / kg.

2. A bispecific anti-Aβ / TfR antibody for use in the treatment of Alzheimer's disease, wherein the antibody is administered intravenously once every four weeks at a dose of 0.2 mg / kg to 7.2 mg / kg.

3. A bispecific anti-Aβ / TfR antibody for use according to any one of claims 1 to 2, wherein the administration of the antibody results in at least 30% of the subjects being amyloid-negative when determined by visual reading of amyloid PET images after 3 months of administration of the composition.

4. The aforementioned bispecific anti-Aβ / TfR antibody i) Form a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, ii) Form a binding site that specifically binds to the human transferrin receptor, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including A bispecific anti-Aβ / TfR antibody for use according to any one of claims 1 to 3, comprising:

5. A bispecific anti-Aβ / TfR antibody for use according to any one of claims 1 to 4, wherein the bispecific anti-Aβ / TfR antibody is trontinemab.

6. A bispecific anti-Aβ / TfR antibody for use according to any one of claims 1 to 5, wherein the treatment is for a subject diagnosed with mild or prodromal Alzheimer's disease.

7. A bispecific anti-Aβ / TfR antibody for use according to any one of claims 1 to 6, wherein the antibody is administered in a dose of 1.8 mg / kg to 7.2 mg / kg.

8. A bispecific anti-Aβ / TfR antibody for use according to any one of claims 1 to 7, wherein the antibody is administered in a dose of 1.8 mg / kg to 3.6 mg / kg.

9. A bispecific anti-Aβ / TfR antibody for use according to any one of claims 1 to 8, which reduces amyloid levels by at least 40 centiloids compared to placebo when the administration of the antibody is determined by visual reading of an amyloid PET scan.

10. A bispecific anti-Aβ / TfR antibody for use according to any one of claims 1 to 9, wherein administration of the antibody reduces amyloid levels within three months after the start of administration of the antibody.

11. A bispecific anti-Aβ / TfR antibody for use according to any one of claims 1 to 10, wherein no further Alzheimer's disease drugs other than trontinemab are administered.

12. A bispecific anti-Aβ / TfR antibody for use according to any one of claims 1 to 11, wherein Aβ is human Aβ protein fragment 1 to 42 and the transferrin receptor is human transfer receptor 1.

13. A bispecific anti-Aβ / TfR antibody for use according to any one of claims 1 to 12, wherein at least one anti-Aβ antibody is continued to be administered at a lower dose of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject after several doses of the aforementioned dose.

14. A bispecific anti-Aβ / TfR antibody for use according to claim 13, wherein the number of doses is 12 to 36.

15. A method for reducing amyloid levels in a subject, the method comprising administering a composition comprising a bispecific antibody (bispecific anti-Aβ / TfR antibody) that specifically binds to human Aβ protein and human transferrin receptor, wherein the composition is administered intravenously once every four weeks at a dose of 0.2 mg / kg to 7.2 mg / kg.

16. The method according to claim 15, wherein the administration of the composition results in the subject being amyloid-negative when determined by visual reading of an amyloid PET image.

17. The method according to claim 16, wherein the determination of amyloid negativity is made after administration of the composition for three months.

18. The aforementioned bispecific anti-Aβ / TfR antibody iii) Forms a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, iv) Forms a binding site that specifically binds to the human transferrin receptor, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including The method according to any one of claims 15 to 17, including the method described in any one of claims 15 to 17.

19. The method according to any one of claims 15 to 18, wherein the bispecific anti-Aβ / TfR antibody is trontinemab.

20. The method according to any one of claims 15 to 19, wherein the subject is diagnosed with mild or prodromal Alzheimer's disease.

21. The method according to any one of claims 15 to 20, wherein the composition is administered in a dose of 1.8 mg / kg to 7.2 mg / kg.

22. The method according to any one of claims 15 to 21, wherein the composition is administered in a dose of 1.8 mg / kg to 3.6 mg / kg.

23. The method according to any one of claims 15 to 22, wherein the administration of the composition reduces the amyloid level of the subject by at least 40 centiloids when the administration is determined by visual reading of an amyloid PET scan.

24. The method according to any one of claims 15 to 23, wherein the administration of the composition reduces the amyloid level of the subject by at least 60 centiloids when the administration is determined by visual reading of an amyloid PET scan.

25. The method according to any one of claims 15 to 24, wherein administration of the composition reduces the amyloid level of the target within three months after the start of administration of the composition.

26. The method according to any one of claims 19 to 25, wherein no further Alzheimer's disease drugs other than trontinemab are administered to the subject.

27. The method according to any one of claims 15 to 26, wherein Aβ is human Aβ protein fragments 1 to 42 and the transferrin receptor is human transfer receptor 1.

28. The method according to any one of claims 15 to 27, wherein the composition is administered in a lower dose of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject after several doses of the composition.

29. The method according to claim 28, wherein the number of doses is 12 to 36.

30. The method according to any one of claims 15 to 29, wherein the subject does not exhibit amyloid-related imaging abnormality-edema (ARIA-E) or amyloid-related imaging abnormality-hemosiderin deposition (ARIA-H).

31. The method according to any one of claims 15 to 30, wherein administration of the composition reduces the severity of at least one symptom associated with Alzheimer's disease in a subject.

32. The method according to claim 31, wherein the symptoms associated with Alzheimer's disease are determined by CDR-SB, CDR-GS, MMSE, ADCOMS and / or PET.

33. The method according to claim 31, wherein the at least one symptom associated with Alzheimer's disease is selected from clinical exacerbation and brain amyloid levels.

34. The method according to claim 33, wherein the clinical deterioration of the subject is evaluated using CDR-SB, CDR-GS, MMSE, ADCOMS and / or ADAS-cog.

35. The method according to any one of claims 15 to 34, wherein the CSF / plasma ratio of the antibody in the subject is 0.5% to 1.2%.

36. A method for reducing the severity of at least one symptom associated with Alzheimer's disease in a subject, wherein the severity of the at least one symptom is reduced compared to the severity of the same symptom in the same subject before treatment, the method comprising administering a composition comprising a bispecific antibody (bispecific anti-Aβ / TfR antibody) that specifically binds to human Aβ protein and human transferrin receptor, the antibody being administered intravenously once every four weeks at a dose of 0.2 mg / kg to 7.2 mg / kg.

37. The method according to claim 36, wherein administration of the composition reduces the amyloid level of the target.

38. The method according to any one of claims 36 to 37, wherein the administration of the composition results in the subject being amyloid-negative when determined by visual reading of an amyloid PET image.

39. The method according to claim 38, wherein the determination of amyloid negativity is made after administration of the composition for three months.

40. The aforementioned bispecific anti-Aβ / TfR antibody i) Form a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, ii) Form a binding site that specifically binds to the human transferrin receptor, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including The method according to any one of claims 36 to 39, including the method described in any one of claims 36 to 39.

41. The method according to any one of claims 36 to 40, wherein the bispecific anti-Aβ / TfR antibody is trontinemab.

42. The method according to any one of claims 36 to 41, wherein the subject is diagnosed with mild or prodromal Alzheimer's disease.

43. The method according to any one of claims 36 to 42, wherein the composition is administered in a dose of 1.8 mg / kg to 7.2 mg / kg.

44. The method according to any one of claims 36 to 43, wherein the composition is administered in a dose of 1.8 mg / kg to 3.6 mg / kg.

45. The method according to any one of claims 36 to 44, wherein the administration of the composition reduces the amyloid level of the subject by at least 40 centiloids when the administration is determined by visual reading of an amyloid PET scan.

46. The method according to claim 45, wherein the administration of the composition reduces the amyloid level of the subject by at least 60 centiloids when determined by visual reading of an amyloid PET scan.

47. The method according to any one of claims 36 to 46, wherein administration of the composition reduces the amyloid level of the target within three months after the start of administration of the composition.

48. The method according to any one of claims 41 to 47, wherein no further Alzheimer's disease drugs other than trontinemab are administered to the subject.

49. The method according to any one of claims 36 to 48, wherein Aβ is human Aβ protein fragments 1 to 42 and the transferrin receptor is human transfer receptor 1.

50. The method according to any one of claims 36 to 49, wherein the composition is administered in a lower dose of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject after several doses of the composition.

51. The method according to claim 50, wherein the number of doses is 12 to 36.

52. The method according to any one of claims 36 to 51, wherein the subject does not exhibit amyloid-related imaging abnormality-edema (ARIA-E) or amyloid-related imaging abnormality-hemosiderin deposition (ARIA-H).

53. The method according to any one of claims 36 to 52, wherein the symptoms associated with Alzheimer's disease are determined by CDR-SB, CDR-GS, MMSE, ADCOMS and / or PET.

54. The method according to any one of claims 36 to 53, wherein the at least one symptom associated with Alzheimer's disease is selected from clinical exacerbation and brain amyloid levels.

55. The method according to any one of claims 36 to 54, wherein the CSF / plasma ratio of the antibody in the subject is 0.5% to 1.2%.

56. A method for reducing clinical deterioration in a subject, comprising administering a composition comprising a bispecific antibody (bispecific anti-Aβ / TfR antibody) that specifically binds to human Aβ protein and human transferrin receptor, wherein the antibody is administered intravenously once every four weeks at a dose of 0.2 mg / kg to 7.2 mg / kg.

57. The method according to claim 56, wherein administration of the composition reduces the amyloid level of the target.

58. The method according to any one of claims 56 to 57, wherein the administration of the composition results in the subject being amyloid-negative when determined by visual reading of an amyloid PET image.

59. The method according to claim 58, wherein the determination of amyloid negativity is made after administration of the composition for three months.

60. The aforementioned bispecific anti-Aβ / TfR antibody i) Form a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, ii) Form a binding site that specifically binds to the human transferrin receptor, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including The method according to any one of claims 56 to 59, including the method described in any one of claims 56 to 59.

61. The method according to claim 60, wherein the bispecific anti-Aβ / TfR antibody is trontinemab.

62. The method according to any one of claims 56 to 61, wherein the subject is diagnosed with mild or prodromal Alzheimer's disease.

63. The method according to any one of claims 56 to 62, wherein the composition is administered in a dose of 1.8 mg / kg to 7.2 mg / kg.

64. The method according to any one of claims 56 to 63, wherein the composition is administered in a dose of 1.8 mg / kg to 3.6 mg / kg.

65. The method according to any one of claims 56 to 64, wherein the administration of the composition reduces the amyloid level of the subject by at least 40 centiloids when the administration is determined by visual reading of an amyloid PET scan.

66. The method according to claim 65, wherein the administration of the composition reduces the amyloid level of the subject by at least 60 centiloids when the administration is determined by visual reading of an amyloid PET scan.

67. The method according to any one of claims 56 to 66, wherein administration of the composition reduces the amyloid level of the target within three months after the start of administration of the composition.

68. The method according to any one of claims 61 to 67, wherein no further Alzheimer's disease drugs other than trontinemab are administered to the subject.

69. The method according to any one of claims 56 to 68, wherein Aβ is human Aβ protein fragments 1 to 42 and the transferrin receptor is human transfer receptor 1.

70. The method according to any one of claims 56 to 69, wherein the composition is administered in a lower dose of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject after several doses of the composition.

71. The method according to claim 70, wherein the number of doses is 12 to 36.

72. The method according to any one of claims 56 to 71, wherein the subject does not exhibit amyloid-related imaging abnormality-edema (ARIA-E) or amyloid-related imaging abnormality-hemosiderin deposition (ARIA-H).

73. The method according to any one of claims 56 to 72, wherein the clinical deterioration of the subject is evaluated using CDR-SB, CDR-GS, MMSE, ADCOMS and / or ADAS-cog.

74. The method according to any one of claims 56 to 73, wherein the CSF / plasma ratio of the antibody in the subject is 0.5% to 1.2%.

75. A method for exposing target brain tissue to an antibody, the method comprising administering a composition comprising a bispecific antibody (bispecific anti-Aβ / TfR antibody) that specifically binds to human Aβ protein and human transferrin receptor, wherein the antibody is administered intravenously once every four weeks at a dose of 0.2 mg / kg to 7.2 mg / kg, and the CSF / plasma ratio of the antibody in the target is 0.5% to 1.2%.

76. The method according to claim 75, wherein administration of the composition reduces the amyloid level of the target.

77. The method according to any one of claims 75 to 76, wherein the administration of the composition results in the subject being amyloid-negative when determined by visual reading of an amyloid PET image.

78. The method according to claim 77, wherein the determination of amyloid negativity is made after administration of the composition for three months.

79. The aforementioned bispecific anti-Aβ / TfR antibody i) Form a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3) Two copies of the first pair of antibody heavy chain variable domains and congener antibody light chain variable domains, ii) Form a binding site that specifically binds to the human transferrin receptor, Three heavy chain complementarity-determining regions (HCDRs) containing the amino acid sequences of SEQ ID NO: 9 (HCDR1), SEQ ID NO: 10 (HCDR2), and SEQ ID NO: 11 (HCDR3), Three light chain complementarity-determining regions (LCDRs) including the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3) One copy of a second pair of antibody heavy chain variable domains and congener antibody light chain variable domains, including The method according to any one of claims 75 to 78, including the method described in any one of claims 75 to 78.

80. The method according to claim 79, wherein the bispecific anti-Aβ / TfR antibody is trontinemab.

81. The method according to any one of claims 75 to 79, wherein the subject is diagnosed with mild or prodromal Alzheimer's disease.

82. The method according to any one of claims 75 to 80, wherein the composition is administered in a dose of 1.8 mg / kg to 7.2 mg / kg.

83. The method according to any one of claims 75 to 81, wherein the composition is administered in a dose of 1.8 mg / kg to 3.6 mg / kg.

84. The method according to any one of claims 75 to 83, wherein the administration of the composition reduces the amyloid level of the target by at least 40 centiloids when determined by visual reading of an amyloid PET scan.

85. The method according to claim 84, wherein the administration of the composition reduces the amyloid level of the target by at least 60 centiloids when determined by visual reading of an amyloid PET scan.

86. The method according to any one of claims 75 to 85, wherein the administration of the composition reduces the amyloid level of the target within three months after the start of the administration of the composition.

87. The method according to any one of claims 80 to 86, wherein no further Alzheimer's disease drugs other than trontinemab are administered to the subject.

88. The method according to any one of claims 75 to 87, wherein Aβ is human Aβ protein fragments 1 to 42 and the transferrin receptor is human transfer receptor 1.

89. The method according to any one of claims 75 to 88, wherein the composition is administered in a lower dose of 0.2 mg / kg to 3.6 mg / kg relative to the weight of the subject after several doses of the composition.

90. The method according to claim 89, wherein the number of doses is 12 to 36.

91. The method according to any one of claims 75 to 90, wherein the subject does not exhibit amyloid-related imaging abnormalities - edema (ARIA-E) or amyloid-related imaging abnormalities - hemosiderin deposition (ARIA-H).

92. The method according to any one of claims 75 to 91, wherein administration of the composition reduces the severity of at least one symptom associated with Alzheimer's disease in a subject.

93. The method according to claim 92, wherein the symptoms associated with Alzheimer's disease are determined by CDR-SB, CDR-GS, MMSE, ADCOMS and / or PET.

94. The method according to claim 92, wherein the at least one symptom associated with Alzheimer's disease is selected from clinical exacerbation and brain amyloid levels.

95. The method according to claim 94, wherein the clinical deterioration of the subject is evaluated using CDR-SB, CDR-GS, MMSE, ADCOMS and / or ADAS-cog.

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