Therapeutic Uses of Bispecific Anti-Aβ / TfR Antibodies

Abstract

To provide therapeutic antibodies for the treatment of neurological diseases, especially Alzheimer's Disease.SOLUTION: The present invention provides a bispecific antibody specifically binding to human Aβ protein and human transferrin receptor (bispecific anti-Aβ / TfR antibody) as well as the use of such bispecific antibodies as a medicament in the treatment of Alzheimer's Disease, including the step where the bispecific antibody is administered intravenously at a dose of 0.2 mg / kg to 7.2 mg / kg once every four weeks.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] The WHO estimates that over 55 million people worldwide are living with dementia, with 10 million new cases diagnosed each year (World Health Organization (2023)). The total number of people with dementia is estimated to reach 78 million in 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, with a global prevalence of 5%-8% in people aged 60 years and older.

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

[0004] Alzheimer's disease (AD) is clinically characterized by progressive impairment of cognitive abilities, resulting in functional decline and gradual loss of independence (Mesterton, J., et al., Curr. Alzheimer's Res. 7 (2010) 358-367). There is significant interindividual 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, subtle impairments in memory, language, and visuospatial function can be observed. As AD progresses, patients become progressively impaired not only cognitively but also in activities of daily living, significantly increasing the burden on caregivers. The median survival time after a diagnosis of AD depends on the patient's age at diagnosis and ranges 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 six years after a diagnosis of AD (Helzner, EP, et al., Neurol. 71 (2008) 1489-1495).

[0005] Due to its increasing prevalence, human burden, long duration and high cost of treatment, AD is expected to remain a major public health problem.

[0006] The neuropathological hallmark of AD is extracellular amyloid plaques, made up of insoluble amyloid beta (Aβ) protein and intraneuronal neurofibrillary tangles composed of hyperphosphorylated tau filaments (Bloom, G.S., JAMA Neurol. 71 (2014) 505-508). Although the pathogenesis of AD is not fully understood, current research suggests that Aβ protein processing and deposition play a key role in the cascade of biological events involved in the development of pathological Aβ proteins, which are presumed to be the primary cause of memory decline and cognitive deterioration in the early stages of AD. Emerging evidence from several independent amyloid-clearing mAbs has identified a relationship between Aβ plaque reduction and cognitive improvement (see, e.g., Selkoe, D.J. and Hardy, J., EMBO Molec. Med. 8 (2016) 595-608; Kulic, L., et al., presented at the AD / PD 2021 virtual conference). The Aβ protein is derived from the proteolytic processing of the amyloid-β precursor protein (APP). This protein exists in two major 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 AD and triggers a cascade of downstream events that result in synaptic dysfunction, inflammation, neurodegeneration, and clinical symptoms (Selkoe, DJ and Hardy, J., EMBO Mol.). Consequently, therapeutics targeting this process, specifically the Aβ protein, have the potential to significantly alter disease progression.

[0007] Unfortunately, binding to the Aβ protein, i.e., the therapeutic target, is associated with adverse events. More specifically, recently approved standard monoclonal anti-Aβ antibodies demonstrate effective amyloid reduction within only 1.5 years of treatment and a modest progression delay of 27–35%, with an ARIA rate of 13–25%. 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 (AMBs) as disease-modifying therapies for Alzheimer's disease have strengthened confidence in the development of anti-Alzheimer's disease therapies. However, current treatments still face the dilemma of serious adverse reactions and limited efficacy (Int. J. Nanomed. 18(2023)7825-7845).

[0009] The current opinion in the art is that rapid and efficient clearance of aggregated forms of Aβ protein is a prerequisite for achieving significant clinical efficacy. Summary of the Invention

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

[0011] The present invention is based, at least in part, 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 in amyloid PET centiloid 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 doses given: 2.8).

[0012] Thus, it has been discovered that rapid amyloid plaque (Aβ protein plaque) clearance can be achieved at surprisingly and significantly lower dose levels than with standard, typical anti-Aβ monoclonal antibodies using the transferrin receptor-based (TfR-based) trontinemab Brainshuttle™ approach. 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, together with its structural and functional equivalents, may be the best amyloid-lowering treatment for this disease, with superior efficacy, safety, and convenience compared to standard antibodies, by slowing the rate of disease progression, for example, by at least half, and with a relatively low risk of ARIA. For example, one aspect of the present invention relates to a bispecific antibody that specifically binds to human Aβ protein and human transferrin receptor (bispecific anti-Aβ / TfR antibody) for use as a pharmaceutical 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.

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

[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 the 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. Thus, in one embodiment, administration of the antibody composition results in the subjects being 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. Thus, in one embodiment, administration of the antibody composition results in the subjects being 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 an 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. Thus, in certain embodiments, administration of the antibody composition results in 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.

[0018] In one embodiment, the bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to the human Aβ protein fragment Aβ1-42; Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3); and two copies of a first pair of an antibody heavy chain variable domain and a cognate antibody light chain variable domain comprising: ii) forming a binding site that specifically binds to human transferrin receptor 1; Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising Includes:

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

[0020] In certain embodiments, the treatment is treatment of a subject who has been diagnosed with mild Alzheimer's disease.

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

[0022] In certain embodiments, the treatment is treatment of a subject who has been diagnosed with prodromal Alzheimer's disease.

[0023] In one embodiment, administration of the bispecific anti-Aβ / TfR antibody reduces amyloid levels from amyloid-positive to amyloid-negative within 12 weeks as determined by PET imaging. PET imaging, in one embodiment, is performed using florbetapir or florbetaben. In one embodiment, administration is performed once every four weeks (Q4W). In one embodiment, administration is intravenous. In one embodiment, rapid amyloid plaque clearance with trontinumab is achieved at a significantly lower dose level than with typical anti-amyloid monoclonal antibodies. In one embodiment, the typical anti-amyloid antibody is aducanumab or / and lecanemab.

[0024] In one embodiment, 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, in one embodiment, is performed using florbetapir or florbetaben. In one embodiment, administration is performed once every four weeks (Q4W). In one embodiment, administration is intravenous. In one embodiment, rapid amyloid plaque clearance is achieved at a significantly lower dose level than typical anti-amyloid monoclonal antibodies. In one embodiment, a typical anti-amyloid antibody is aducanumab or / and lecanemab.

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

[0026] In one embodiment, administration of the bispecific anti-Aβ / TfR antibody reduces amyloid levels within three months of initiating administration of the antibody.

[0027] In certain embodiments, no additional Alzheimer's disease medications other than trontinemab are administered.

[0028] In one embodiment, the bispecific anti-Aβ / TfR antibody is administered at a dose 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, the Aβ is human Aβ protein fragment 1-42 and the transferrin receptor is human transfer receptor 1.

[0031] In one embodiment, the bispecific anti-Aβ / TfR antibody continues to be administered at a lower dose of 0.2 mg / kg to 3.6 mg / kg of the subject's weight after several doses have been administered, in one embodiment, the number of doses is 3 to 60.

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

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

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

[0035] 2. The at least one anti-Aβ antibody forms a binding site that specifically binds to human Aβ protein; Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3); and a cognate antibody light chain variable domain comprising:

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

[0037] 4. The anti-Aβ / TfR antibody is Forms a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3); and two pairs of antibody heavy chain variable domains and cognate antibody light chain variable domains, each comprising: Forms a binding site that specifically binds to human TfR, Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising 4. The method of embodiment 3, comprising:

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

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

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

[0041] 8. The method of any one of embodiments 6-7, 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 with early stage Alzheimer's disease, comprising administering a therapeutically effective amount of a composition comprising at least one bispecific anti-Aβ / TfR antibody, wherein the therapeutically effective amount results in a lower number of ARIA events compared to a monospecific anti-Aβ antibody, preferably aducanumab or / and lecanemab.

[0043] 10. The at least one bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to human Aβ, Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3); and two copies of a first pair of an antibody heavy chain variable domain and a cognate antibody light chain variable domain comprising: ii) forming a binding site that specifically binds to human TfR; Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising 10. The method of embodiment 9, comprising:

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

[0045] 12. The method of 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 of any one of embodiments 9 to 12, wherein said therapeutically effective amount of said at least one bispecific anti-Aβ / TfR antibody is administered once every four weeks.

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

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

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

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

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

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

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

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

[0055] 22. The method of any one of embodiments 1 to 21, 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.

[0056] 23. The method of any one of embodiments 1 to 17, wherein 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.

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

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

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

[0060] 27. The method of any one of embodiments 1-26, wherein the composition comprises 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 of the at least one anti-Aβ antibody relative to the weight of the subject.

[0061] 28. The method of any one of embodiments 1 to 26, wherein the composition comprises, for some administrations, 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 of embodiment 28, wherein the number of administrations is 3 to 60.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0077] 44. The method of any one of embodiments 1-43, wherein the reduction in amyloid levels is after 18 months of administration of the composition.

[0078] 45. The method of any one of embodiments 1-44, wherein the reduction in amyloid levels is after 12 months of administration of the composition.

[0079] 46. ​​The method of any one of embodiments 1-45, wherein the reduction in amyloid levels is after 6 months of administration of the composition.

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

[0081] 48. The method of any one of embodiments 1-47, wherein said administering results in a decrease in cerebrospinal fluid levels of Aβ1-42 protein fragments.

[0082] 49. The method of any one of embodiments 1-48, wherein the subject is concurrently administered at least one Alzheimer's disease medication other than trontinemab.

[0083] 50. The method of any one of embodiments 1-48, wherein the subject is not concurrently administered at least one Alzheimer's disease medication other than trontinemab.

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

[0085] 52. The method of embodiment 51, wherein 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 3 months of administration of the composition, preferably 30-70% of the subjects being amyloid negative as determined by visual reading of amyloid PET images after 3 months of administration (3 doses) of the composition.

[0086] 52a. The method of any one of embodiments 51-52, wherein 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 6 months of administration of the composition, preferably 30-70% of the subjects being amyloid negative as determined by visual reading of amyloid PET images after 6 months of administration (3 doses) of the composition.

[0087] 52b. The method of embodiment 51, wherein administering the antibody composition results in the subject being determined to be amyloid negative by visual reading of amyloid PET images after 3 months of administration of the antibody composition.

[0088] 52c. The method of any one of embodiments 51 and 52b, wherein administering the antibody composition results in the subject being determined to be amyloid negative by visual reading of amyloid PET images after 4 to 6 months of administration of the antibody composition.

[0089] 52d. The method of any one of embodiments 51, 52b, or 52c, wherein administration of the antibody composition results in the subject being determined to be amyloid negative by visual reading of amyloid PET images after 3 to 6 months of administration of the antibody composition.

[0090] 53. The method of any one of embodiments 51-52, wherein administering the composition 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.

[0091] 54. The method of any one of embodiments 51-53, wherein 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 18 months of administration of the composition.

[0092] 55. The at least one bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3); and two copies of a first pair of an antibody heavy chain variable domain and a cognate antibody light chain variable domain comprising: ii) forming a binding site that specifically binds to human TfR; Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising 55. The method of any one of embodiments 51 to 54, comprising:

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

[0094] 57. The method of 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 of 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 of any one of embodiments 51 to 58, wherein the at least one bispecific anti-Aβ / TfR antibody is administered intravenously.

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

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

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

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

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

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

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

[0104] 67. The method of any one of embodiments 51 to 66, 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.

[0105] 68. The method of any one of embodiments 51 to 62, wherein 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.

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

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

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

[0109] 72. The method of any one of embodiments 51-71, wherein the composition comprises 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 of the at least one anti-Aβ antibody relative to the weight of the subject.

[0110] 73. The method of any one of embodiments 51 to 72, wherein the composition comprises, for some administrations, 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 administrations is 3 to 60.

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

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

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

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

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

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

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

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

[0120] 83. The method of any one of embodiments 51-82, wherein the reduction in amyloid levels is after 18 months of administration of the composition.

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

[0122] 85. The method of any one of embodiments 51-84, wherein the reduction in amyloid levels is after 6 months of administration of the composition.

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

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

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

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

[0127] 90. A method of treating a subject with early stage Alzheimer's disease, comprising administering a therapeutically effective amount of a composition comprising 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 of 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 of any one of embodiments 90-91, 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 of any one of embodiments 90-92, wherein the at least one symptom associated with Alzheimer's disease is selected from clinical deterioration and cerebral amyloid levels.

[0131] 94. The at least one bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3); and two copies of a first pair of an antibody heavy chain variable domain and a cognate antibody light chain variable domain comprising: ii) forming a binding site that specifically binds to human TfR; Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising 94. The method of any one of embodiments 90 to 93, comprising:

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

[0133] 96. The method of 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 of any one of embodiments 90-96, 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 of any one of embodiments 90 to 97, wherein the at least one bispecific anti-Aβ / TfR antibody is administered intravenously.

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

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

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

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

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

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

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

[0143] 106. The method of any one of embodiments 90 to 105, 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.

[0144] 107. The method of any one of embodiments 90 to 101, wherein 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.

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

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

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

[0148] 111. The method of any one of embodiments 90-110, wherein the composition comprises 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 of the at least one anti-Aβ antibody relative to the weight of the subject.

[0149] 112. The method of any one of embodiments 90 to 111, wherein the composition comprises, for some administrations, 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 administrations is 3 to 60.

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

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

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

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

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

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

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

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

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

[0160] 123. The method of any one of embodiments 90-113 and 121-122, wherein the subject's amyloid level is reduced by at least 60 centiloids compared to baseline as determined by visual reading of amyloid PET images.

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

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

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

[0164] 127. The method of any one of embodiments 90-113 and 121-126, wherein the subject's amyloid level is reduced by at least 90 centiloids compared to baseline as determined by visual reading of amyloid PET images.

[0165] 128. The method of any one of embodiments 90-127, wherein the reduction is after 18 months of administration of the composition.

[0166] 129. The method of any one of embodiments 90-128, wherein the reduction is after 12 months of administration of the composition.

[0167] 130. The method of any one of embodiments 90-129, wherein the reduction is after 6 months of administration of the composition.

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

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

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

[0171] 134. A method of treating a subject with early stage Alzheimer's disease, comprising administering a therapeutically effective amount of a composition comprising 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 of 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 of any one of embodiments 134-135, 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 of 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 of any one of embodiments 134-137, wherein the at least one symptom associated with Alzheimer's disease is selected from clinical deterioration and cerebral amyloid levels.

[0176] 139. The at least one bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3); and two copies of a first pair of an antibody heavy chain variable domain and a cognate antibody light chain variable domain comprising: ii) forming a binding site that specifically binds to human TfR; Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising The method of any one of embodiments 134 to 138, comprising:

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

[0178] 141. The method of 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 the at least one bispecific anti-Aβ / TfR antibody is administered intravenously.

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

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

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

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

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

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

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

[0188] 151. The method of any one of embodiments 134 to 150, 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.

[0189] 152. The method of any one of embodiments 134 to 146, wherein 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.

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

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

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

[0193] 156. The method of any one of embodiments 134-155, wherein the composition comprises 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 of the at least one anti-Aβ antibody relative to the weight of the subject.

[0194] 157. The method of any one of embodiments 134 to 156, wherein the composition comprises, for some administrations, 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 administrations is 3 to 60.

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

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

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

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

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

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

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

[0203] 166. The method of any one of embodiments 134-158, wherein the amyloid level is reduced by at least 20 centiloids compared to baseline as determined by visual reading of amyloid PET images.

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

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

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

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

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

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

[0210] 173. The method of any one of embodiments 134-172, wherein the reduction in amyloid levels is after 18 months of administration of the composition.

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

[0212] 175. The method of any one of embodiments 134-174, wherein the reduction in amyloid levels is after 6 months of administration of the composition.

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

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

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

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

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

[0218] 181. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 180, wherein administration of the antibody results in at least 30% of 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 as 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 administration 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.

[0221] 184. The bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3); and two copies of a first pair of an antibody heavy chain variable domain and a cognate antibody light chain variable domain comprising: ii) forming a binding site that specifically binds to human TfR; Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising 184. The bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 183, comprising:

[0222] 185. The bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 184, wherein said 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 amount.

[0224] 187. The 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. The 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. The bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 188, wherein the antibody is administered intravenously.

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

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

[0229] 192. The bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 191, wherein said treatment is treatment of a subject with early Alzheimer's disease who has been diagnosed with mild cognitive impairment due to Alzheimer's disease, a moderate probability of Alzheimer's disease, and / or who has been diagnosed with mild Alzheimer's disease dementia.

[0230] 193. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 192, wherein the composition comprises 0.2 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody 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 0.6 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody 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 1.2 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody 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 1.8 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody 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 2 mg / kg to 5 mg / kg of the at least one anti-Aβ antibody 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 0.2 mg / kg to 3.6 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

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

[0238] 201. The bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 193 and 199 to 201, wherein the composition comprises 1.2 mg / kg to 3.6 mg / kg of the at least one anti-Aβ antibody 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 1.8 mg / kg to 3.6 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0240] 203. The bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 202, wherein the composition comprises 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 of the at least one anti-Aβ antibody relative to the weight of the subject.

[0241] 204. The bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 203, wherein the composition comprises, for some administrations, 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. The bispecific anti-Aβ / TfR antibody for use according to embodiment 204, wherein the number of administrations is between 3 and 60.

[0243] 206. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 205, wherein administration of the antibody reduces amyloid levels by at least 75 centiloids relative to placebo, as determined by visual reading of amyloid PET images.

[0244] 207. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 206, wherein administration of said antibody reduces amyloid levels by at least 80 centiloids relative to baseline as determined by visual reading of amyloid PET images.

[0245] 208. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 207, wherein administration of said antibody reduces amyloid levels by at least 85 centiloids relative to placebo, as determined by visual reading of amyloid PET images.

[0246] 209. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 208, wherein administration of said antibody reduces amyloid levels by at least 90 centiloids relative to placebo, as determined by visual reading of amyloid PET images.

[0247] 210. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179 to 205, wherein administration of said antibody reduces amyloid levels by at least 75 centiloids relative to baseline, as determined by visual reading of amyloid PET images.

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

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

[0250] 213. A bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179-205 and 210-212, wherein administration of said antibody reduces amyloid levels by at least 90 centiloids relative to baseline, as determined by visual reading of amyloid PET images.

[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 initiation 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 6 months after initiation 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 3 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 said antibody results in a reduction in cerebrospinal fluid levels of Aβ1-42 protein fragments.

[0256] 219. The 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. The bispecific anti-Aβ / TfR antibody for use according to any one of embodiments 179-219, in which no further Alzheimer's disease medication other than trontinemab is administered.

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

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

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

[0261] 224. The use of 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 of 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) forming a binding site that specifically binds to human Aβ protein, Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 5 (LCDR1), SEQ ID NO: 6 (LCDR2), and SEQ ID NO: 7 (LCDR3); and two copies of a first pair of an antibody heavy chain variable domain and a cognate antibody light chain variable domain comprising: ii) forming a binding site that specifically binds to human TfR; Three heavy chain complementarity determining regions (HCDRs) comprising 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) containing the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising The use according to any one of embodiments 221 to 225, comprising:

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

[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 treatment of a subject with early stage Alzheimer's disease.

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

[0271] 234. The use according to any one of embodiments 221 to 233, wherein the treatment is treatment of a subject with early Alzheimer's disease who has been diagnosed with mild cognitive impairment due to Alzheimer's disease, a moderate probability of Alzheimer's disease, and / or who has been diagnosed with mild Alzheimer's disease dementia.

[0272] 235. The use according to any one of embodiments 221 to 234, wherein the composition comprises 0.2 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0273] 236. The use according to any one of embodiments 221 to 235, wherein the composition comprises 0.6 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0274] 237. The use according to any one of embodiments 221 to 236, wherein the composition comprises 1.2 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0275] 238. The use according to any one of embodiments 221 to 237, wherein the composition comprises 1.8 mg / kg to 7.2 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0276] 239. The use according to any one of embodiments 221 to 238, wherein the composition comprises 2 mg / kg to 5 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

[0277] 240. The use according to any one of embodiments 221 to 239, 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.

[0278] 241. The use according to any one of embodiments 221 to 235, wherein 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.

[0279] 242. The use according to any one of embodiments 221 to 235 and 241, wherein the composition comprises 0.6 mg / kg to 3.6 mg / kg of the at least one anti-Aβ antibody 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 comprises 1.2 mg / kg to 3.6 mg / kg of the at least one anti-Aβ antibody relative to the weight of the subject.

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

[0282] 245. The use of any one of embodiments 221 to 244, wherein the composition comprises 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 of the at least one anti-Aβ antibody relative to the weight of the subject.

[0283] 246. The use of any one of embodiments 221 to 245, wherein the composition comprises, for some administrations, 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 administrations is 3 to 60.

[0285] 248. The use according to any one of embodiments 221 to 247, wherein the use / administration of said antibody reduces amyloid levels by at least 75 centiloids relative to placebo, as determined by visual reading of amyloid PET images.

[0286] 249. The use according to any one of embodiments 221 to 248, wherein the use / administration of said antibody reduces amyloid levels by at least 80 centiloids relative to baseline as determined by visual reading of amyloid PET images.

[0287] 250. The use according to any one of embodiments 221 to 249, wherein the use / administration of said antibody reduces amyloid levels by at least 85 centiloids relative to placebo, as determined by visual reading of amyloid PET images.

[0288] 251. The use according to any one of embodiments 221 to 250, wherein the use / administration of said antibody reduces amyloid levels by at least 90 centiloids relative to placebo, as determined by visual reading of amyloid PET images.

[0289] 252. The use according to any one of embodiments 221 to 247, wherein the use / administration of said antibody reduces amyloid levels by at least 75 centiloids relative to baseline as determined by visual reading of amyloid PET images.

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

[0291] 254. The use according to any one of embodiments 221-247 and 252-253, wherein the use / administration of said antibody reduces amyloid levels by at least 85 centiloids relative to baseline as determined by visual reading of amyloid PET images.

[0292] 255. The use according to any one of embodiments 221-247 and 252-254, wherein the use / administration of said antibody reduces amyloid levels by at least 90 centiloids relative to baseline as determined by visual reading of amyloid PET images.

[0293] 256. The use according to any one of embodiments 221 to 255, wherein the use / administration of the antibody reduces amyloid levels within 18 months after the start of the use / administration of the antibody.

[0294] 257. The use according to any one of embodiments 221 to 256, wherein the use / administration of the antibody reduces amyloid levels within 12 months after the start of the use / administration of the antibody.

[0295] 258. The use according to any one of embodiments 221 to 257, wherein the use / administration of the antibody reduces amyloid levels within 6 months after the start of the use / administration of the antibody.

[0296] 259. The use according to any one of embodiments 221 to 257, wherein the use / administration of the antibody reduces amyloid levels within 3 months after the start of the use / administration of the antibody.

[0297] 260. The use according to any one of embodiments 221-259, wherein the use / administration of said antibody results in a reduction of cerebrospinal fluid levels of Aβ1-42 protein fragments.

[0298] 261. The use according to any one of embodiments 221-260, wherein at least one Alzheimer's disease drug other than trontinemab is used / administered.

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

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

[0301] 264. The antibody for use or (of) the method according to any one of embodiments 1 to 262, wherein the subject is not a person of color.

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

[0303] 266. The antibody for use or (of) the method according to any one of embodiments 1 to 265, wherein the subject is an APOEε4 carrier. [Brief explanation of the drawings]

[0304] [Figure 1] FIG. 1 shows a schematic representation of the structure of trontinemab / RG6102. [Figure 2A] FIG. 2A shows the results of brain (tissue) exposure to trontinemab in the non-human primate hippocampus comparing a single IV dose of 10 mg / kg trontinemab followed by gantenerumab with a single IV dose of 20 mg / kg gantenerumab. [Figure 2B] FIG. 2B shows the brain-to-plasma ratios achieved with trontinemab compared to gantenerumab in the cortex, hippocampus, and striatum of non-human primates, shown as fold changes in Kp, Cmax, and AUC. [Figure 3] Figure 3 shows the course of amyloid depletion in cohorts 1–3, shown as mean amyloid PET burden in centimeters over 28 weeks. [Figure 4]Figure 4 shows the course of amyloid depletion in cohorts 1-3, shown as the mean amyloid reduction from baseline in centimeters over 28 weeks. [Figure 5] Figure 5 shows the course of amyloid depletion in cohorts 1-4, shown as the mean amyloid reduction from baseline in centimeters over 12 and 28 weeks, respectively. [Figure 6] Figure 6 shows a comparison of trontinemab treatment effects in humans with other anti-Aβ treatment studies (GRADUATE I, GRADUATE II, CLARITY AD, TRAILBLAZER-ALZ-2), as shown by amyloid PET in the centroid over approximately 27 months. DETAILED DESCRIPTION OF THE INVENTION

[0305] The presently disclosed subject matter relates to methods comprising administering a bispecific antibody that specifically binds to human Aβ protein and human transferrin receptor. In certain embodiments, the methods described herein comprise administering such bispecific antibodies at a lower dosage and / or less frequently than current anti-Aβ protein therapies known in the art. In certain embodiments, the methods described herein achieve greater exposure to the patient's brain tissue and / or more efficient reduction of Aβ protein plaques in the patient compared to current anti-Aβ protein therapies known in the art, despite being administered at such lower dosage and / or less frequently. In certain embodiments, the methods described herein result in a lower incidence of ARIA (amyloid-related imaging abnormalities) compared to current anti-Aβ protein therapies known in the art. The presently disclosed subject matter further provides compositions comprising such bispecific antibodies at such dosages and / or configured for such frequent dosing for performing such methods.

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

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

[0308] One aspect of the invention is a method of reducing amyloid levels in a subject with mild or prodromal Alzheimer's disease, comprising administering intravenously once every four weeks a bispecific anti-Aβ / TfR antibody composition of trontinemab / RG6102 at a dose ranging from 1.2 mg / kg to 7.2 mg / kg of the subject's body weight, 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 of converting an amyloid-positive subject with mild or moderate Alzheimer's disease to an amyloid-negative subject, comprising administering intravenously 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 of the subject's weight. 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 three months of administration of the 1.8 mg / kg dose.

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

[0311] One aspect of the present invention is a method of treating a subject with mild or moderate Alzheimer's disease, comprising administering intravenously a composition of the bispecific anti-Aβ / TfR antibody trontinumab / RG6102 at a dose ranging from 1.2 mg / kg to 7.2 mg / kg of the subject's body weight once every four weeks, 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% relative to the severity of the same symptom in the same subject prior to treatment. In one preferred embodiment of this aspect, the at least one symptom associated with Alzheimer's disease is cerebral amyloid levels.

[0312] One aspect of the present invention is a method of treating a subject with early-stage Alzheimer's disease, comprising administering intravenously a composition of the bispecific anti-Aβ / TfR antibody trontinemab / RG6102 at a dose ranging from 1.2 mg / kg to 7.2 mg / kg of the subject's body weight once every four weeks, 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% relative to the severity of the same symptom in a subject receiving a placebo. In one preferred embodiment of this aspect, the at least one symptom associated with Alzheimer's disease is cerebral amyloid levels.

[0313] One aspect according to the present invention is the bispecific anti-Aβ / TfR antibody trontinumab / 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 of the subject's weight. In one preferred embodiment of this aspect, administration of the composition results in at least 30% of subjects being amyloid negative as determined by visual reading of amyloid PET images after three months of administration of a 1.8 mg / kg dose.

[0314] One aspect 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 of the subject's weight. In a preferred embodiment of this aspect, administration of the composition results in at least 30% of subjects being amyloid-negative as determined by visual reading of amyloid PET images after three months of administration of a 1.8 mg / kg dose. In a preferred embodiment of this aspect, administration of the composition results in at least 70% of subjects being amyloid-negative as determined by visual reading of amyloid PET images after three to six months of administration (three to six doses) of a 1.8 mg / kg dose.

[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 of the subject's weight. In a preferred embodiment of this aspect, administration of the composition results in at least 30% of subjects being amyloid-negative as determined by visual reading of amyloid PET images after three months of administration of a 1.8 mg / kg dose. In a preferred embodiment of this aspect, administration of the composition results in at least 70% of subjects being amyloid-negative as determined by visual reading of amyloid PET images after three to six months of administration (three to six doses) of a 1.8 mg / kg dose.

[0316] One aspect of the present invention is 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 of the subject's weight. In a preferred embodiment of this aspect, administration of the composition results in at least 30% of subjects being amyloid-negative as determined by visual reading of amyloid PET images after three months of administration of a 1.8 mg / kg dose. In a preferred embodiment of this aspect, administration of the composition results in at least 70% of subjects being amyloid-negative as determined by visual reading of amyloid PET images after three to six months of administration (three to six doses) of a 1.8 mg / kg dose.

[0317] In one preferred embodiment of all aspects and embodiments of the invention, the dose ranges from 1.8 mg / kg to 3.6 mg / kg of antibody relative to the weight of the subject.

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

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

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

[0321] Without wishing to be bound by theory, it is anticipated that the initial clearance of amyloid as determined by PET is only the "tip of the iceberg" with respect to the administration of a bispecific anti-Aβ / TfR antibody, such as, for example, trontinemab, as disclosed herein. Because soluble oligomeric species are not measurable using PET and clearing insoluble amyloid does not remove the underlying inducers of reaccumulation, administration of a bispecific anti-Aβ / TfR antibody, such as, for example, trontinemab, in accordance with the present invention, encompasses the option of sustained suppression of amyloid, rather than waiting until substantial lesions have accumulated again.

[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 at a dose ranging from 1.2 mg / kg to 7.2 mg / kg of the subject's weight for an initial period, followed by a maintenance dose. In one embodiment, the maintenance dose is a reduced dose compared to the dose administered during the initial period. For example, without limitation, such a maintenance dose can be in the range of 1.8 mg / kg to 3.6 mg / kg of the subject's weight. In one embodiment, the maintenance dose is 1.8 mg / kg of the antibody relative to the subject's weight. In one embodiment, the maintenance dose is 3.6 mg / kg of the antibody relative to the subject's weight.

[0323] Drug labeling, also known as prescription labeling, is writing, printing, or drawing on or attached to any drug or any of its containers. Drug labels strive to identify the drug contents and to provide specific instructions or warnings for administration, storage, and disposal. Approved drug labeling for healthcare providers provides important information about the drug, including: -The specific diseases and conditions that the drug is approved to treat. -Methods of using drugs to treat these specific diseases and conditions. -Information about drug risks. -Information that healthcare providers should discuss with patients before they take the medication.

[0324] In the case of trontinemab, the label would include the following information: trontinemab is an antibody directed against amyloid beta indicated for the treatment of Alzheimer's disease. Treatment with trontinemab should be initiated in patients with mild cognitive impairment or the mild dementia stage of the disease, the population in which treatment was initiated in clinical trials. There is no safety or efficacy data regarding initiating treatment at earlier or later stages of the disease than those tested.

[0325] Confirm the presence of amyloid-beta pathology before initiating treatment.

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

[0327] Obtain an MRI before the 5th, 7th, 9th, and 12th infusions; if radiographically visible ARIA occurs, treatment recommendations will be based on the type, severity, and presence of symptoms.

[0328] Dilution with 0.9% Sodium Chloride Injection, USP is required prior to administration.

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

[0330] In preferred embodiments of all aspects and embodiments, the methods and compositions according to the invention comprising a bispecific anti-Aβ / TfR antibody or trontinumab are for one or more of the following: - for the treatment of patients with mild cognitive impairment or the mild dementia stage of the disease, or for the treatment of patients with mild, mild-moderate or moderate Alzheimer's disease; or / and - For the treatment of patients / animals with confirmed presence of amyloid-beta pathology prior to initiating treatment; or / and - For treatment in patients / animals who have a recent baseline brain MRI obtained prior to starting treatment; or / and -5th time or / and the seventh time Or / and 9th or / and 12th For treatment of patients in whom an MRI was obtained prior to the second infusion, if radiographically observed ARIA occurs, treatment recommendations will be based on the type, severity, and presence of symptoms; or / and For treatment, diluting the antibody solution with 0.9% Sodium Chloride Injection, USP prior to administration; or / and For treatment, the antibody solution is administered as an intravenous infusion over approximately 1 hour through a terminated low protein binding 0.2 or 0.22 micron in-line filter.

[0331] definition It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to "a cell" includes a plurality of such cells and equivalents thereof known to those skilled in the art, and so forth. Similarly, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein. It should also be noted that the terms "comprising," "including," and "having" can be used interchangeably.

[0332] The term "about" refers to a range of ±20% of the preceding numerical value. In one embodiment, the term "about" refers to a range of ±10% of the preceding numerical value. In one embodiment, the term "about" refers to a range of ±5% of the preceding numerical value.

[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 human Aβ protein with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting Aβ protein.

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

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

[0337] "Affinity" refers to the strength of the sum of all noncovalent 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, which reflects a 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 cellular cytotoxicity (ADCC)" refers to the lysis of target cells by the antibodies reported herein in the presence of effector cells, a function mediated by Fc receptor binding. ADCC can be measured by treating a preparation of CD19-expressing red blood cells (e.g., K562 cells expressing recombinant human CD19) with an antibody according to the present invention in the presence of effector cells, such as freshly isolated PBMCs (peripheral blood mononuclear cells) or purified effector cells from buffy coats, such as monocytes or NK (natural killer) cells. Target cells are labeled with 51Cr and then incubated with the antibody. The labeled cells are incubated with effector cells, and the supernatant is analyzed for released 51Cr. Controls include incubation of target endothelial cells with effector cells but without antibody. The ability of antibodies to trigger early steps in mediating ADCC is investigated by measuring antibody binding to cells expressing Fcγ receptors, such as recombinantly expressed FcγRI and / or FcγRIIA or NK cells (which constitutively express FcγRIIIA).

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

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

[0341] Fc receptor binding-dependent effector functions can be brought about by the interaction of the Fc region of an antibody with Fc receptors (FcRs), specialized cell surface receptors on hematopoietic cells. Fc receptors belong to the immunoglobulin superfamily and have been shown to mediate both the removal of antibody-coated pathogens by phagocytosis of 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. G. and Anderson, C. L., J. Leukoc. Biol. 49 (1991) 511-524). FcRs are defined by their specificity for immunoglobulin isotypes: Fc receptors for IgG antibodies are called FcγRs. Fc receptor binding is described, for example, in Ravetch, JV and Kinet, JP, Annu. Rev. Immunol. 9 (1991) 457-492; Capel, PJ, et al., Immunomethods 4 (1994) 25-34; de Haas, M., et al., J. Lab. Clin. Med. 126 (1995) 330-341; and Gessner, JE, et al., Ann. Hematol. 76 (1998) 231-248.

[0342] Cross-linking of receptors (FcγRs) to the Fc region of IgG antibodies triggers a wide variety of effector functions, including phagocytosis, antibody-dependent cellular cytotoxicity, and release of inflammatory mediators, as well as clearance of immune complexes and control of antibody production. In humans, three classes of FcγRs have been characterized: FcγRI (CD64) binds monomeric IgG with high affinity and is expressed on macrophages, monocytes, neutrophils, and eosinophils. Modification of the Fc region of IgG at at least one of the amino acid residues E233-G236, P238, D265, N297, A327, and P329 (numbering according to the EU index of Kabat) reduces binding to FcγRI. Substitution of IgG2 residues 233-236 into IgG1 and IgG4 reduced binding to FcγRI 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 on 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 inhibitory processes and is found on B cells, macrophages, as well as mast cells and eosinophils. On B cells, FcγRIIB appears to function in further suppressing immunoglobulin production and isotype switching, for example, to the IgE class. On macrophages, FcγRIIB acts to inhibit phagocytosis mediated by FcγRIIA. On eosinophils and mast cells, the B form may help suppress the activation of these cells through the binding of IgE to its distinct receptor. Reduced binding to FcγRIIA is seen, for example, in antibodies comprising an IgG Fc region with a mutation in at least one of amino acid residues E233 to G236, P238, D265, N297, A327, P329, D270, Q295, A327, R292, and K414 (numbering according to the EU index of Kabat). FcγRIII (CD16) binds IgG with moderate to low affinity and exists as 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 a mutation at 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 (numbering according to the EU index of Kabat).

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

[0344] An "effective amount" of an agent, eg, a pharmaceutical formulation, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic or prophylactic result.

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

[0346] IgG4 exhibits reduced FcR binding, whereas antibodies of other IgG subclasses exhibit strong binding. However, Pro238, Asp265, Asp270, Asn297 (loss of Fc carbohydrate), Pro329, and residues 234, 235, 236, and 237 Ile253, Ser254, Lys288, Thr307, Gln311, Asn434, and His435 are residues that, when altered, also reduce FcR binding (Shields, RR et 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 invention is of the IgG1 or IgG2 subclass and comprises the mutations PVA236, GLPSS331, L234A / L235A or P329G / L234A / L235A. In one embodiment, the antibody reported herein is of the IgG4 subclass and comprises the mutation L235E. In one embodiment, the antibody according to the invention further comprises the mutation S228P.

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

[0348] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to the HVRs (e.g., CDRs) of a non-human antibody and all or substantially all of the FRs correspond to the FRs of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0349] The term "hypervariable region" or "HVR," as used herein, refers to each of the regions of an antibody variable domain that comprise stretches of amino acid residues that are hypervariable in sequence ("complementarity determining regions" or "CDRs") and / or form structurally defined loops ("hypervariable loops") and / or contain residues that contact the antigen ("antigen contacts"). Generally, antibodies contain 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, A. M., 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, E.A. 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 contacts occurring 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), including 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 indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al. (supra).

[0352] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to the HVRs (e.g., CDRs) of a non-human antibody and all or substantially all of the FRs correspond to the FRs of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0353] An "isolated" antibody is an antibody that has been separated from the components of its natural environment. In some embodiments, the antibody is purified to greater than 95% or greater than 99% purity, as determined, for example, by electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., size exclusion chromatography or ion exchange or reverse-phase HPLC) analytical methods. For a review of methods for assessing antibody purity, see, for example, Flatman, S. et al., J. Chrom. B 848 (2007) 79-87.

[0354] An "isolated" nucleic acid refers to a nucleic acid molecule that is separated from a component of its natural environment.

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

[0356] An "individual" or "subject" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, 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 certain embodiments, the individual or subject is human.

[0357] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and / or bind the same epitope, except for possible, typically minor, variant antibodies that contain, for example, naturally occurring mutations or that arise during production of the monoclonal antibody preparation. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies according to the present invention can 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 the human immunoglobulin loci; such methods, as well as other exemplary methods for producing monoclonal antibodies, are described herein.

[0358] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products that contain information about the indications, usage, dosage, administration, concomitant therapy, contraindications and / or warnings for use of such therapeutic product.

[0359] The term "pharmaceutical formulation" refers to a preparation of the active ingredient contained therein, e.g., a therapeutic antibody, in a form that allows the biological activity to be effective, and that does not contain additional ingredients that are unacceptably toxic to the subject to whom the formulation will be administered.

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

[0361] As used herein, the term "treatment" (and grammatical variants thereof, e.g., "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual being treated and can be performed for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing the direct or indirect pathological consequences of disease, preventing metastasis, slowing the rate of disease progression, ameliorating or mitigating the disease state, and achieving remission or improving prognosis. For example, but not limited to, such treatment can include intervention to reduce clinical deterioration in a subject with a disease associated with amyloid accumulation, e.g., Alzheimer's disease. In certain embodiments, such treatment can include converting an amyloid-positive subject to an amyloid-negative subject. In certain embodiments, such treatment can include intervention 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 certain embodiments, antibodies of the invention are used to delay or prevent disease onset or to slow disease progression.

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

[0363] The term "variable region" or "variable domain" refers to the domain of an antibody's heavy or light chain that is involved in binding the antibody to its antigen. The variable domains of an antibody's heavy and light chains (VH and VL, respectively) generally have a similar structure, with each domain containing four framework regions (FR) and three hypervariable regions (HVR) (see, for example, Kindt, TJ et al., Kuby Immunology, 6th ed., W.H. 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 a specific antigen can be isolated by using a VH or VL domain from an antibody that binds that antigen to screen a library of complementary VL or VH domains, respectively. See, for example, Portolano, S. et al., J. Immunol. 150 (1993) 880-887; Clackson, T. et al., Nature 352 (1991) 624-628).

[0364] When a range of values ​​is recited herein, it is intended to encompass the limits and each value and subrange within the range. For example, "2 mg / kg to 6 mg / kg" is intended to encompass, 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 continuum of AD severity ranging from mild cognitive impairment due to AD - moderate probability to mild Alzheimer's disease dementia. Subjects with early AD include those with mild Alzheimer's disease dementia. In one embodiment, subjects with early AD have a Minimal Mental State Examination (MMSA) score of 22-30 and a CDR (Clinical Dementia Scale) composite range of 0.5-1.0.

[0366] As used herein, a subject with "mild Alzheimer's disease dementia" is one who meets the National Institute on Aging and Alzheimer's Association (NIA-AA) core clinical criteria for possible Alzheimer's disease dementia 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." Also included herein are subjects who have a CDR score of 0.5-1.0 and a memory box score of 0.5 or greater at screening and baseline.

[0367] As used herein, "MMSE" refers to the Mini-Mental State Examination, a cognitive measurement instrument that is generally used for screening purposes but is often measured longitudinally in AD clinical trials, and has a 30-point scale where higher scores indicate less impairment and lower scores indicate more impairment.As used herein, seven items are assessed to measure time and place orientation, memorization, memory recall, attention, language and drawing.(Folstein, MF, et al., J.Psychiatr.Res.12(1975)189-198).

[0368] As used herein, "CDR-SB" refers to the Clinical Dementia Scale-Sum of Boxes. The CDR is a clinical scale that represents impairments in performance on a five-point scale for each of six functional categories, including memory, orientation, judgment, and problem-solving, community problems, home and hobbies, and personal care. (Berg, L. et al., Ann. Neurol. 23 (1988) 477-484.) The impairment ratings obtained for each of the six functional categories are combined into a single global score (ranging from 0 to 3) for the Dementia CDR score. The sum of the box scores provides an additional measure of change, with each category having a maximum score of 3 points. The total score is the sum of the category scores, resulting in a possible total score of 0 to 18, with higher scores indicating more severe impairment. The total score can be used as a clinical measure of dementia severity.

[0369] As used herein, whether an early stage AD subject is "amyloid positive" or "amyloid negative" is determined based on whether the patient / animal has a positive amyloid burden as shown by longitudinal PET assessment of amyloid imaging agent uptake in the brain. In some embodiments, a qualitative visual reading of PET scans is used to determine amyloid positivity and amyloid negativity by classifying subjects as having either "normal" or "abnormal" uptake based on PET image patterns. The reader is trained and certified to recognize brain PET images with abnormal or normal patterns of uptake, or amyloid detection is performed through a semi-quantitative or quantitative approach.

[0370] As used herein, the term "prevent" refers to obtaining beneficial or desired results, including but not limited to preventive benefits.For preventive benefits, the composition can be administered to a subject at risk of developing Alzheimer's disease, to a subject who has one or more preclinical symptoms of Alzheimer's disease but does not have clinical symptoms, or to a subject who reports 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" can also include therapeutic benefits, and therapeutic benefits refer to the eradication or improvement of one or more physiological symptoms of the underlying condition being treated or related thereto.

[0371] As used herein, the term "serious adverse event" or "SAE" means an event that (1) results in death; (2) is life-threatening; (3) requires inpatient hospitalization or extension of an existing hospitalization; (4) results in permanent or significant disability / incapacity; and / or (5) is a congenital anomaly / birth defect observed after administration of a composition described herein.

[0372] The severity of serious adverse events can be assessed based on a uniform scale used in the art.For example, the severity of serious adverse events of a subject can be evaluated according to the "Common Terminology Criteria for Adverse Events" or "CTCAE" of the National Cancer Institute.The following is a description of various CTCAE adverse event grades: Grade 1: Mild; asymptomatic or mildly symptomatic; clinical or diagnostic findings only; no intervention required. - Grade 2: Moderate; minimal, local, or non-invasive intervention required; age-appropriate limitations in instrumental activities of daily living. Grade 3: Severe or medically significant, but not immediately life-threatening; requiring hospitalization or prolonged hospitalization; disabling; limiting self-care activities of daily living - Grade 4: Life-threatening consequences requiring urgent intervention. -Grade 5: Death related to an adverse event.

[0373] As used herein, the term "centiloid" refers to a unit on the centiloid scale described in Klunk, W.E., et al., Alzheimer's Disease. 11 (2015) 1-15. Because there was considerable variability in the exact numbers reported as quantitative outcome measures of tracer retention, standardization of quantitative amyloid imaging measures by scaling the results of each specific analytical method or tracer to a scale of 0 to 100 was established for young controls (age 45 or younger) and typical Alzheimer's disease patients.

[0374] Thus, the centiloid scale is a standardized PET-based amyloid burden measurement that homogenizes amyloid burden measurements across tracers and sites (see, e.g., 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 is the mean value in "high probability" amyloid-negative subjects (i.e., young subjects), and 100 is 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). This clearance measured by amyloid PET is not an artifact related to the antibody itself, as case reports of autopsy data from patients receiving aducanumab confirm this clearance (Plowey, ED, et al., Acta Neuropathol. 144 (2022) 143-153).

[0376] For example, if amyloid plaque levels assessed by PET decrease to below 25 centiloids, this indicates clearance of amyloid plaques below the pathological cutoff.

[0377] Some authors believe that amyloid burden must be reduced to below 20 centiloids to provide significant cognitive benefit, and that there is a lag time of several months between amyloid clearance and clinical response (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, to determine amyloid burden, a standardized centroid approach was used, using "ADNI-like" cortical area and the whole cerebellum reference area. This resulted in a single comprehensive measure of amyloid burden for each participant in each period.

[0379] The determined overall reduction is considered to be a suitable measure for comparison with other molecules that have been or are in the clinic.

[0380] Specifically, participants were scanned using either florbetapir (Amyvid) or florbetaben (Neuraceq) using imaging protocols consistent with FDA and EU labeling. Amyloid burden was quantified by the centrifugal method (e.g., Klunk, WE, et al., Alzheimer's Disease. 11 (2015) 1-15).

[0381] To be included in the study, participants had to have a minimum centiloid (CL) of 50 to confirm amyloid pathology and a sufficiently high loading dose to demonstrate a possible treatment effect with trontinemab. (Note that 100 CL represents the mean for typical AD, 0 CL is the mean for amyloid-free healthy controls, 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 a conversion of florbetapir SUVr values ​​to the centiloid scale following the guidelines of Klunk et al.

[0382] Florbetapir, developed under the trade name Amyvid, was approved by the FDA in 2012. It 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 PIB, with high affinity for Aβ plaques (Anand, K. and Sabbagh, M., Neurotherap. 14 (2017) 54-61).

[0383] More specifically, Amyvid is a radioactive diagnostic agent for positron emission tomography (PET) imaging of the brain to estimate β-amyloid neuritic plaque density in cognitively impaired adult patients being evaluated for Alzheimer's disease (AD) and other causes of cognitive decline. A negative Amyvid scan indicates sparse or absent neuritic plaques, which is inconsistent with a neuropathological diagnosis of AD at the time of image acquisition. A negative scan result reduces the likelihood that the patient's cognitive impairment is attributable to AD. A positive Amyvid scan indicates moderate to frequent amyloid neuritic plaques, and neuropathological examination indicates that this amount of amyloid neuritic plaques is present in AD patients but may also be present in patients with other types of neurological conditions and elderly people with normal cognition.

[0384] In general, dosage and administration are as follows: The recommended dose of Amyvid is 370 MBq (10 mCi), a maximum 50 μg mass dose, administered as a single intravenous bolus in a total volume of 10 mL or less. Follow the injection with an intravenous flush of 0.9% sterile sodium chloride. Obtain 10-minute PET images starting approximately 30-50 minutes after intravenous injection (the patient should be supine, with the head positioned to place the brain, including the cerebellum, in the center of the PET scanner's field of view). -Image interpretation: The goal of -Amyvid image interpretation is to provide an estimate of cerebral β-amyloid neuritic plaque density. Images should be viewed transaxially, with sagittal and coronal views accessible as needed. When reviewing images, include all transaxial slices of the brain using a black-and-white scale with the maximum intensity of the scale set to the maximum intensity of all brain pixels. First, locate the brain slice with the highest level of image contrast (highest radioactive signal relative to Amyvid uptake) and adjust the contrast appropriately. Begin image interpretation by viewing sequential slices from bottom to top of the brain. Periodically refer to sagittal and coronal image views as needed to more clearly define radioactive uptake and ensure the entire brain is visible. Image interpretation is based on the distribution of radioactive signal within the brain. Images are designated as positive or negative by comparing radioactivity in the cortical gray matter with that in the adjacent white matter. This determination is made only in the cerebral cortex; signal uptake in the cerebellum does not contribute to scan interpretation (e.g., a positive scan may show preserved cerebellar gray-white contrast even when cortical gray-white contrast is lost). -Negative scans show more radioactivity in white matter than in gray matter, producing a clear gray-white contrast. - Positive scans typically show cortical areas with a reduction or loss of distinct gray-white contrast. These scans have one or more areas with increased cortical gray matter signal resulting in reduced (or absent) gray-white contrast. Specifically, positive scans have any of the following: a) Two or more brain regions (each larger than a single cortical gyrus) with reduced or absent gray-white contrast, which is the most common appearance of a positive scan; or b) One or more areas of intense gray matter activity that clearly exceeds the activity in the adjacent white matter.

[0385] Piramal Imaging has developed florbetaben under the trade name Neuraceq, an 18F-labeled polyethylene glycol stilbene derivative that has shown 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 beta-amyloid plaques in the brain (Neurol. Ther. 3 (2014) 79-88). More specifically, they investigated PET scan readings at the subject level (whole brain) to determine the sensitivity and specificity of florbetaben in this setting. Results from visual assessment using methods applicable to clinical routine were compared with neuropathological assessment of the absence / presence of beta-amyloid plaques according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. Analysis of images from the initial 31 deceased subjects and 10 young, healthy volunteers considered beta-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 interrater 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, because a sufficiently large number of amyloid-negative subjects were available for analysis, the addition of young, healthy volunteers was no longer required.

[0387] More specifically, Neuraceq™ is a radioactive diagnostic agent indicated for positron emission tomography (PET) imaging of the brain to estimate β-amyloid neuritic plaque density in cognitively impaired adult patients being evaluated for Alzheimer's disease (AD) and other causes of cognitive decline. A negative Neuraceq scan indicates sparse or absent neuritic plaques and is inconsistent with a neuropathological diagnosis of AD at the time of image acquisition; a negative scan result reduces the likelihood that the patient's cognitive impairment is attributable to AD. A positive Neuraceq scan indicates moderate to frequent amyloid neuritic plaques; neuropathological examination indicates that this amount of amyloid neuritic plaques is present in AD patients, but may also be present in patients with other types of neurological conditions and elderly people with normal cognition.

[0388] In general, dosage and administration are as follows: -The recommended dose of Neuraceq is 300 MBq (8.1 mCi), maximum 30 mcg mass dose, administered as a single slow intravenous bolus (6 seconds / mL) in a maximum total volume of 10 mL. PET images are acquired over 15-20 minutes, beginning 45-130 minutes after Neuraceq injection. (The patient must remain supine, with the head positioned to place the brain, including the cerebellum, in the center of the PET scanner's field of view.) -Image interpretation: The purpose of Neuraceq image interpretation is to estimate β-amyloid neuritic plaque density within the brain's gray matter. PET images should be displayed in the transaxial orientation using grayscale or inverse grayscale. Sagittal and coronal planes may be used for additional orientation 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 the cortical gray matter with activity in the adjacent white matter. To assist the reader in identifying locations, regions displayed in the PET images that "anatomically" correspond to white matter structures (e.g., cerebellar white matter or ampulla) should be identified. Images should be viewed and assessed systematically, starting with the cerebellum and scrolling through the 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 proportion of slices from the respective region must be affected. For each patient, the PET imaging assessment will be classified as either "β-amyloid positive" or "β-amyloid negative." This determination will be based on assessment of tracer uptake in the gray matter of four brain regions: temporal lobe, frontal lobe, posterior cingulate cortex / precuneus, and parietal lobe, according to the following rules for assessment: - β-amyloid negative - tracer uptake (i.e., signal intensity) in the gray matter is lower than in the white matter in all four brain regions (no β-amyloid deposits) - β-amyloid positive - a smaller area of ​​tracer uptake equal to or higher than that present in the white matter, involving a majority of slices in at least one of four brain regions and extending beyond the white matter rim to the outer cortical periphery ("moderate" β-amyloid deposits), or a large, confluent area of ​​tracer uptake equal to or higher than that present in the white matter, extending beyond the white matter rim to the outer cortical periphery and involving the entire region including a majority of slices in at least one of four brain regions ("prominent" β-amyloid deposits). There are no known clinical or histopathological correlates that distinguish "moderate" from "prominent" β-amyloid deposits.

[0389] As used herein, the term "ARIA" refers to amyloid-related imaging abnormalities. Amyloid-related imaging abnormalities (ARIA) are magnetic resonance imaging (MRI) abnormalities that represent fluid or blood leakage into the pia mater and / or parenchyma in the brain. ARIA-E (E for edema or effusion) refers to vasogenic edema and / or sulcal effusion, most commonly seen on axial T2 FLAIR sequences, and ARIA-H (H for hemosiderin [iron] deposition) refers to microbleeds or superficial siderosis, most commonly seen on iron-sensitive sequences such as gradient-echo T2* or susceptibility-weighted imaging sequences (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 capable of reducing 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 who experience 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 drugs (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 transiently increased vascular permeability due to vascular leakage after clearance of vascular Aβ. In normal vasculature, smooth muscle cells are regularly distributed, but in Alzheimer's disease patients, the accumulation of Aβ pathology disrupts smooth muscle cell distribution. Following anti-amyloid treatment, blood vessels may become more susceptible to ARIA, resulting in leakage of proteinaceous fluid and / or red blood cells into the vessel wall and surrounding tissue. With Aβ clearance and restoration of vascular integrity, the risk of ARIA may decrease (Sperling et al. 2012, supra; Barakos, J., et al., J. Prev. Alz. Dis. 9 (2022) 211-220).

[0392] Trontinemab / RG6102 Trontinemab is a) a full-length antibody comprising two pairs of full-length antibody light chains and two pairs of full-length antibody heavy chains, wherein the binding site formed by each pair of full-length heavy chains and full-length light chains specifically binds to a first antigen; b) one additional Fab fragment, wherein the additional Fab fragment is fused to the C-terminus of one heavy chain of the full-length antibody, and the binding site of the additional Fab fragment specifically binds to a second antigen; each of the full-length antibody light chains comprises an amino acid residue arginine at position 123 (instead of the wild-type glutamic acid residue; E123R mutation) and an amino acid residue lysine at position 124 (instead of the wild-type glutamine residue; Q124K mutation) of the constant light domain (CL) (numbering according to Kabat); each of the full-length antibody heavy chains comprises 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) in the first constant heavy chain domain (CH1) (numbering according to the Kabat EU index); an additional Fab fragment that specifically binds to a second antigen, comprising a domain crossover such that the constant light chain domain (CL) and the constant heavy chain domain 1 (CH1) are substituted for each other; The first antigen is human Aβ protein and the second antigen is human transferrin receptor; It is a bispecific antibody.

[0393] More particularly, 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 comprising the amino acid sequence of SEQ ID NO: 20 (SEQ ID NO: 21, which comprises SEQ ID NO: 18 + linker + SEQ ID NO: 20).

[0394] SEQ ID NO: 17 is the amino acid sequence DIVLTQSPATLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGVPARFSGSGSGTDFTLTISSLEPEDFATYYCLQIYNMPITFGQGTKVEIKRTVAAPSVFIFPPSDRKLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC and SEQ ID NO: 18 is the amino acid sequence QVELVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAINASGTRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGKGNTHKPYGYVRYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPK SCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPI EKTISKAKGQPREPQVCTLPPSRDELTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLVSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG and SEQ ID NO: 19 is the amino acid sequence AIQLTQSPSSLSASVGDRVTITCRASQSISSYLAWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQNYASSNVDNTFGGGTKVEIKSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC have

[0395] SEQ ID NO: 20 is the amino acid sequence QSMQESGPGLVKPSQTLSLTCTVSGFSLSSYAMSWIRQHPGKGLEWIGYIWSGGSTDYASWAKSRVTISKTSTTVSLKLSSVTAADTAVYYCARRYGTSYPDYGDASGFDPWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC have

[0396] SEQ ID NO: 21 is the amino acid sequence QVELVESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAINASGTRTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGKGNTHKPYGYVRYFDVWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVEDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDEKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPCRDELTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGSGGGGSGGGGSGGGGSQSMQESGPGLVKPSQTLSLTCTVSGFSLSSYAMSWIRQHPGKGLEWIGYIWSG GSTDYASWAKSRVTISKTSTTVSLKLSSVTAADTAVYYCARRYGTSYPDYGDASGFDPWGQGTLVTVSSASVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC It has.

[0397] AβVH (SEQ ID NO: 04), CDRs are underlined: QVELVESGGG LVQPGGSLRL SCAAS GFTFS SYAMS WVRQA PGKGLEWVS A INASGTRTYY ADSVKG RFTI SRDNSKNTLY LQMNSLRAED TAVYYCAR GK GNTHKPYGYV RYFDV WGQGT LVTVSS CDR-H1 (SEQ ID NO: 01): GFTFSSYAMS CDR-H2 (SEQ ID NO: 02): AINASGTRTY YADSVKG CDR-H3 (SEQ ID NO: 03): GKGNTHKPYG YVRYFDV AβVL (SEQ ID NO: 08), CDRs are underlined: DIVLTQSPAT LSLSPGERAT LSC RASQSVS SSYLA WYQQK PGQAPRLLIY GASSRAT GVP ARFSGSGSGT DFTLTISSLE PEDFATYYC L QIYNMPIT FG QGTKVEIK CDR-L1 (SEQ ID NO: 05): RASQSVSSSY LA CDR-L2 (SEQ ID NO: 06): GASSRAT CDR-L3 (SEQ ID NO: 07): LQIYNMPIT TfRVH (SEQ ID NO: 12), CDRs are underlined: QSMQESGPGL VKPSQTLSLT CTVSGFSLS S YAMS WIRQHP GKGLEWIG YI WSGGSTDYAS WAKS RVTISK TSTTVSLKLS SVTAADTAVY YCAR RYGTSY PDYGDASGFD P WGQGTLVTV SS CDR-H1 (SEQ ID NO: 09): SYAMS CDR-H2 (SEQ ID NO: 10): YIWSGGSTDY ASWAKS CDR-H3 (SEQ ID NO: 11): RYGTSYPDYG DASGFDP TfRVL (SEQ ID NO: 16), CDRs are underlined: AIQLTQSPSS LSASVGDRVT ITC RASQSIS SYLA WYQQKP GKAPKLLIY R ASTLAS GVPS RFSGSGSGTD FTLTISSLQP EDFATYYC QQ NYASSNVDNT FGGGTKVEIK CDR-L1 (SEQ ID NO: 13: RASQSISSYL A CDR-L2 (SEQ ID NO: 14): RASTLAS CDR-L3 (SEQ ID NO: 15): QQNYASSNVD NT

[0398] Trontinemab is characterized as follows: Immunoglobulin with domain crossover [G1-VH-Ckappa_Vkappa-CH1]_[G1_kappa], anti-[Homo sapiens APP (amyloid beta, A4 precursor protein) Aβ, conformational epitope 1-40 / 42)] and anti-[Homo sapiens TFRC (transferrin receptor, p90, CD71)] humanized monoclonal antibody, bispecific; fusion chain G1-VH-Ckappa 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 IGHG1*01,G1m17,1,G1v32 CH3 W22 (CH1 K26>E(156), K119>E(222), K120(223)(127-224), hinge 1-15(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 diglycyl-seryl-tris(tetraglycyl-seryl) 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-seryl(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 A45.1(154), V101(192), E12>R(124), Q13>K(125)(109'-215')] with disulfide (702-215"")-V kappa-CH1 chain anti-TFRC(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"")-diseryl(111""-112"")-CH1-hinge(Homo sapiens IGHG1*01 CH1-h, G1m17(CH1 K120(209)(113""-210""), Hinge 1-5(211""-215""))(113""-215"")] disulfide with 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")-tris disulfide, produced in Chinese hamster ovary (CHO) cells, glycoform α. [ka] [ka]

[0399] Trontinemab also targets fibrillar Aβ protein as well as amyloid plaques and oligomers, which means that it is generally suitable for both clearing plaques and preventing their re-accumulation, as well as neutralizing oligomers.

[0400] Comparison of anti-Aβ monoclonal antibodies Zhao et al. (Int. J. Nanomed. 18 (2023) 7825-7845) summarized the clinical progress of anti-Aβ antibodies as follows: Aducanumab -Target residues 3–7 in the N-terminus of the Aβ protein; - Low monovalent affinity but strong avidity for epitope-rich aggregates, allowing aducanumab to selectively bind to Aβ protein oligomeric or fibrillar aggregates; this binding activates microglia; -Phase III efficacy trials: EMERGE (NCT02484547) and ENGAGE (NCT02477800); high-dose aducanumab in the EMERGE trial met its primary endpoint, while low-dose aducanumab did not demonstrate significant benefit compared with 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 (vasogenic edema) and ARIA-H (microhemorrhages and hemosiderin deposits) were commonly observed in patients receiving the 10 mg / kg dose, with an incidence of 19.1% and 35%, respectively; APOE ε4 carriers had a higher incidence compared to non-carriers; Lecanemab -Selectively binds to soluble Aβ protein aggregates (including oligomers and protofibrils), approximately 1000 times more than Aβ protein monomers and 10-15 times more than insoluble fibrils; -Phase III CLARITY AD trial (NCT03887455); intravenous lecanemab at a dose of 10 mg / kg every 2 weeks; Clinical deterioration was assessed using the CDR-SB as the primary endpoint, and the lecanemab group demonstrated a substantial reduction in clinical deterioration; ARIA-H and ARIA-E findings - Despite its modest therapeutic effect, lecanemab failed to demonstrate clinically significant benefit in patients with clinically overt or prodromal dementia; -New evidence from the phase 2 lecanemab study shows that fluid biomarkers reappear after stopping 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 the slow reaccumulation of amyloid PET / cerebral amyloid; biomarker observations were associated with clinical worsening measured via CDR-SB, ADCOMS, and ADAS-cog; the rate of clinical progression after stopping treatment was similar in participants treated with lecanemab and placebo; -The prescribing information for lecanemab, marketed as Leqembi, directs administration of 10 mg / kg lecanemab as a 1-hour intravenous infusion once every 2 weeks and includes a warning box that recommends increased clinical vigilance for amyloid-related imaging abnormalities ("ARIA") during the first 14 weeks of treatment with Leqembi and describes the increased risk of ARIA in apolipoprotein E ε4 ("ApoE4") homozygotes compared with heterozygotes and non-carriers; Donanemab -specifically targets the pyroglutamylated form of Aβ protein (N3pG-Aβ) aggregated in amyloid plaques; -Phase III trial, TRAILBLAZER-ALZ2 (NCT04437511); 72-week duration; treatment with donanemab every 4 weeks; donanemab has been reported to be associated with the occurrence of ARIA, with approximately 40% of participants in the donanemab group experiencing ARIA, of which approximately 26.1% exhibited symptomatic ARIA (symptomatic ARIA-E was observed in only 0.8% of participants given placebo); Lemterne Tag -N3pG - specifically targets Aβ; ABBV-916 -Recognizes N3pG-Aβ aggregated in amyloid plaques; ACU193 -Aβ protein oligomer-selective antibodies; A Phase I clinical trial (NCT04931459) showed a significant reduction in amyloid plaque levels detectable by brain amyloid PET scans after 6 to 12 weeks in patients receiving higher doses of ACU193; 10.4% of patients experienced ARIA-E, of which 2.1% were symptomatic.

[0401] In the clinical setting, binding of anti-Aβ mAbs to amyloid plaques is associated with a higher incidence of ARIA. [Table 1] TIFF0007802859000004.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 postulates that Aβ accumulation is the primary driver of Aβ pathogenesis (Selkoe, DJ, Neuron. 6 (1991) 487-498; Hardy, J. and Selkoe, DJ, Science 297 (2002) 353-356; Selkoe and Hardy 2016, supra). Several monoclonal anti-Aβ antibodies, including aducanumab, lecanemab, donanemab, and gantenerumab, have been shown to bind to Aβ protein, promote its clearance, and reduce both Aβ aggregate deposition and markers of neurodegeneration in the CSF in clinical settings (Salloway et al. 2009, supra; Ostrowitzki, S., et al., Arch. Neurol. 69 (2012) 198-207; Sevigny et al. 2016, supra; 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, SA and 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 with the amyloid plaque-targeting therapy donanemab met its primary efficacy endpoint, demonstrating a significant reduction in amyloid plaques along with a regional reduction in tau burden as revealed by amyloid and tau PET imaging after 76 weeks of treatment.

[0404] The potential link between dose-dependent amyloid clearance and clinical efficacy is further supported by the results of a large-scale Phase II trial with lecanemab, which demonstrated significant amyloid reduction at the highest dose and dose-dependent clinical benefit on various measures of cognition (Swanson et al. 2018, supra). This was confirmed in a large-scale Phase III trial with lecanemab (CLARITY AD), which met its primary endpoint. Lecanemab was found to more effectively reduce CDR-SB scores compared with placebo at 18 months. This trial also met all secondary endpoints, demonstrating the efficacy of lecanemab in early AD (Van Dyck et al., NEJM 388(2022)9-21).

[0405] Therefore, targeting amyloid deposits is one of the most promising approaches for the treatment of AD. Numerous preclinical evidence suggests that targeting Aβ aggregates in transgenic AD models with vaccination against Aβ or passive immunization with anti-Aβ antibodies has 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 the potential link between amyloid clearance and clinical efficacy. In a phase I trial of aducanumab in patients with early-stage AD, a slowing of clinical deterioration was associated with a time- and dose-related reduction in deposited amyloid, as seen by cerebral amyloid PET imaging (Sevigny et al. 2016, supra). Similarly, a recent publication (McDade, E., et al., Alz. Res. Ther. 14 (2022) 191) demonstrated a significant correlation between the level of amyloid clearance achieved with different doses of aducanumab and progression on various clinical measures.

[0406] Clinically, significant efficacy in preventing clinical deterioration has been demonstrated by anti-amyloid antibodies that rapidly clear amyloid plaques and a high proportion of participants achieving amyloid negativity at the end of the double-blind treatment period. For example, lecanemab was able to bring 81% of participants below the baseline amyloid positivity threshold of 30 centimeters after 18 months of treatment. Overall, a mean amyloid PET level of 22.99 centimeters 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 positivity threshold of 24.1 centimeters after 18 months (Eli Lilly and Company 2023), and like lecanemab, met its primary clinical endpoint in Phase II. Two pivotal Phase II trials with gantenerumab, GRADUATE I and GRADUATE II, did not meet their primary endpoints. However, the magnitude of amyloid plaque clearance was less than expected and predicted based on open-label, long-term administration (OLE) data from two historic Phase III trials of gantenerumab (ScarletRoAD and MargueriteRoAD), which demonstrated robust and sustained Aβ plaque reduction in the OLE comparable to levels achieved by other amyloid-lowering antibodies.

[0407] Based on these results, rapidly reducing amyloid levels below the positive threshold appears to be a necessary feature for achieving clinical efficacy (Karran, E. and De Strooper, B., Nat. Rev. Drug. Discov. 21 (2022) 306-318). The extent and speed of amyloid plaque clearance by anti-amyloid antibodies is both dose- and exposure-dependent. Due to their large size, only approximately 0.1% to 0.2% of peripherally administered antibodies cross an intact BBB (Poduslo, JF, et al., Proc. Natl. Acad. Sci. USA 91 (1994) 5705-5709; Yu, YJ, and Watts, RJ, Neurotherap. 10 (2013) 459-472).

[0408] Furthermore, the incidence of either 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 accompanied by a more pronounced slowing of tau pathology (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 assertion that these clinical trial data alone were sufficient to convincingly demonstrate clinical benefit in reducing clinical deterioration in patients with Alzheimer's disease, demonstrating a significant overall effect of high-clearance anti-amyloid immunotherapy on progression of CDR-SB and ADAS-Cog, but not on progression of MMSE. This provides an opportunity to confirm trends regarding the clinical efficacy of high-clearance anti-amyloid immunotherapy and estimate the magnitude of its clinical benefit (Liu, K.Y. and Howard, R., Nat. Rev. Neurol. 17 (2021) 715-722; Liu, K.Y., et al., Lancet Psychiatry 8 (2021) 1013-1016).

[0411] A therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody The methods of the present invention include administering to a subject a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. As used herein, the term "therapeutically effective amount" refers to the amount of a compound or pharmaceutical composition sufficient to produce a desired therapeutic effect.

[0412] Those skilled in the art will understand that the therapeutically effective amount 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 will be able to determine the appropriate amount for each subject using the information disclosed herein.

[0413] In certain embodiments, a therapeutically effective amount is a dose selected to improve efficacy and / or maintain efficacy, and improve at least one of safety and tolerability. In some embodiments, a therapeutically effective amount is selected to reduce at least one side effect, and simultaneously improve efficacy and / or maintain efficacy.

[0414] In certain embodiments, a subject is administered 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 of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.

[0415] In certain embodiments, a subject is administered 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 of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.

[0416] In certain embodiments, a subject is administered 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 of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.

[0417] In certain embodiments, a subject is administered 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 of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.

[0418] In certain embodiments, a subject is administered 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 of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.

[0419] In certain embodiments, a subject is administered 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 of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.

[0420] In certain embodiments, a subject is administered 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 of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.

[0421] In certain embodiments, a subject is administered 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 of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.

[0422] In certain embodiments, a subject is administered 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 of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.

[0423] In certain embodiments, a subject is administered 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 of at least one bispecific anti-Aβ / TfR antibody relative to the subject's body weight.

[0424] In one embodiment, the dose 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, 3.2 mg / kg to 9 mg / kg, or

[0032] In some embodiments, the subject is administered 4 mg / kg to 9 mg / kg, 3.3 mg / kg to 9 mg / kg, 3.4 mg / kg to 9 mg / kg, 3.5 mg / kg to 9 mg / kg, 3.6 mg / kg to 9 mg / kg, 3.7 mg / kg to 9 mg / kg, 3.8 mg / kg to 9 mg / kg, 3.9 mg / kg to 9 mg / kg, 4 mg / kg to 9 mg / kg, 4.5 mg / kg to 9 mg / kg, 5 mg / kg to 9 mg / kg, 5.5 mg / kg to 9 mg / kg, 6 mg / kg to 9 mg / kg, 6.5 mg / kg to 9 mg / kg, 7 mg / kg to 9 mg / kg, 7.2 mg / kg to 9 mg / kg, or 8 mg / kg to 9 mg / kg of at least one bispecific anti-Aβ / TfR antibody.

[0425] In one embodiment, the dose is 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 to 7.2 mg / kg, or 3.1 mg / kg to 7.2 mg / kg.

[0032] In some embodiments, a dose of at least one bispecific anti-Aβ / TfR antibody is administered to the subject.

[0426] In one embodiment, the doses may be 1 mg / kg to 6.5 mg / kg, 1.2 mg / kg to 6.5 mg / kg, 1.4 mg / kg to 6.5 mg / kg, 1.8 mg / kg to 6.5 mg / kg, 1.9 mg / kg to 6.5 mg / kg, 2 mg / kg to 6.5 mg / kg, 2.1 mg / kg to 6.5 mg / kg, 2.2 mg / kg to 6.5 mg / kg, 2.3 mg / kg to 6.5 mg / kg, 2.4 mg / kg to 6.5 mg / kg, 2.5 mg / kg to 6.5 mg / kg, 2.6 mg / kg to 6.5 mg / kg, 2.7 mg / kg to 6.5 mg / kg, 2.8 mg / kg to 6.5 mg / kg, 2.9 mg / kg to 6.5 mg / kg, 3 mg / kg, or 5 mg / kg, based on the subject's body weight.

[0023] In some embodiments, a dose of at least one bispecific anti-Aβ / TfR antibody is administered to the subject.

[0427] In one embodiment, the dose is 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, or 2.9 mg / kg to 6 mg / kg, based on the subject's body weight. g, 3 mg / kg to 6 mg / kg, 3.1 mg / kg to 6 mg / kg, 3.2 mg / kg to 6 mg / kg, 3.3 mg / kg to 6 mg / kg, 3.4 mg / kg to 6 mg / kg, 3.5 mg / kg to 6 mg / kg, 3.6 mg / kg to 6 mg / kg, 3.7 mg / kg to 6 mg / kg, 3.8 mg / kg to 6 mg / kg, 3.9 mg / kg to 6 mg / kg, 4 mg / kg to 6 mg / kg, 4.5 mg / kg to 6 mg / kg, 5 mg / kg to 6 mg / kg, or 5.5 mg / kg to 6 mg / kg of at least one bispecific anti-Aβ / TfR antibody is administered to the subject.

[0428] In one embodiment, the dose is 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, 2.9 mg / kg to 5.5 mg / kg, or 3.0 mg / kg to 3.5 mg / kg.

[0023] In one embodiment, a dose of at least one bispecific anti-Aβ / TfR antibody is administered to the subject. The dose may range from 3 mg / kg to 5.5 mg / kg, 3 mg / kg to 5.5 mg / kg, 3.1 mg / kg to 5.5 mg / kg, 3.2 mg / kg to 5.5 mg / kg, 3.3 mg / kg to 5.5 mg / kg, 3.4 mg / kg to 5.5 mg / kg, 3.5 mg / kg to 5.5 mg / kg, 3.6 mg / kg to 5.5 mg / kg, 3.7 mg / kg to 5.5 mg / kg, 3.8 mg / kg to 5.5 mg / kg, 3.9 mg / kg to 5.5 mg / kg, 4 mg / kg to 5.5 mg / kg, 4.5 mg / kg to 5.5 mg / kg, or 5 mg / kg to 5.5 mg / kg of the at least one bispecific anti-Aβ / TfR antibody is administered to the subject.

[0429] In one embodiment, the dose is 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

[0023] In some embodiments, the subject is administered 2.9 mg / kg to 5 mg / kg, 3 mg / kg to 5 mg / kg, 3.1 mg / kg to 5 mg / kg, 3.2 mg / kg to 5 mg / kg, 3.3 mg / kg to 5 mg / kg, 3.4 mg / kg to 5 mg / kg, 3.5 mg / kg to 5 mg / kg, 3.6 mg / kg to 5 mg / kg, 3.7 mg / kg to 5 mg / kg, 3.8 mg / kg to 5 mg / kg, 3.9 mg / kg to 5 mg / kg, 4 mg / kg to 5 mg / kg, or 4.5 mg / kg to 5 mg / kg of at least one bispecific anti-Aβ / TfR antibody.

[0430] In one embodiment, the dose 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, 2.8 mg / kg to 4.6 mg

[0023] In one embodiment, the subject is administered at least one bispecific anti-Aβ / TfR antibody at a dose of 2.9 mg / kg to 4.6 mg / kg, 3 mg / kg to 4.6 mg / kg, 3.1 mg / kg to 4.6 mg / kg, 3.2 mg / kg to 4.6 mg / kg, 3.3 mg / kg to 4.6 mg / kg, 3.4 mg / kg to 4.6 mg / kg, 3.5 mg / kg to 4.6 mg / kg, 3.6 mg / kg to 4.6 mg / kg, 3.7 mg / kg to 4.6 mg / kg, 3.8 mg / kg to 4.6 mg / kg, 3.9 mg / kg to 4.6 mg / kg, 4 mg / kg to 4.6 mg / kg, or 4.5 mg / kg to 4.6 mg / kg.

[0431] In one embodiment, the dose is 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, 2.8 mg

[0033] In some embodiments, the subject is administered at least one bispecific anti-Aβ / TfR antibody at a dose of 2.9 mg / kg to 4.2 mg / kg, 3 mg / kg to 4.2 mg / kg, 3.1 mg / kg to 4.2 mg / kg, 3.2 mg / kg to 4.2 mg / kg, 3.3 mg / kg to 4.2 mg / kg, 3.4 mg / kg to 4.2 mg / kg, 3.5 mg / kg to 4.2 mg / kg, 3.6 mg / kg to 4.2 mg / kg, 3.7 mg / kg to 4.2 mg / kg, 3.8 mg / kg to 4.2 mg / kg, 3.9 mg / kg to 4.2 mg / kg, or 4 mg / kg to 4.2 mg / kg.

[0432] In one embodiment, the dose is 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, or

[0023] In some embodiments, the subject is administered 2.7 mg / kg to 3.8 mg / kg, 2.8 mg / kg to 3.8 mg / kg, 2.9 mg / kg to 3.8 mg / kg, 3 mg / kg to 3.8 mg / kg, 3.1 mg / kg to 3.8 mg / kg, 3.2 mg / kg to 3.8 mg / kg, 3.3 mg / kg to 3.8 mg / kg, 3.4 mg / kg to 3.8 mg / kg, 3.5 mg / kg to 3.8 mg / kg, 3.6 mg / kg to 3.8 mg / kg, or 3.7 mg / kg to 3.8 mg / kg of at least one bispecific anti-Aβ / TfR antibody.

[0433] In one embodiment, the dose is 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, 2.5 mg / kg to 3.6 mg / kg, or 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, or 3.5 mg / kg to 3.6 mg / kg of at least one bispecific anti-Aβ / TfR antibody is administered to the subject.

[0434] In one embodiment, the dose is 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, 3.1 mg / kg to 4.2 mg / kg, or 4.2 mg / kg, based on the subject's body weight. 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

[0033] In some embodiments, 2.2 mg / kg to 3.1 mg / kg, 2.2 mg / kg to 3 mg / kg, 2.2 mg / kg to 2.9 mg / kg, 2.2 mg / kg to 2.8 mg / kg, 2.2 mg / kg to 2.7 mg / kg, 2.2 mg / kg to 2.6 mg / kg, 2.2 mg / kg to 2.5 mg / kg, 2.2 mg / kg to 2.4 mg / kg, or 2.2 mg / kg to 2.3 mg / kg of at least one bispecific anti-Aβ / TfR antibody is administered to the subject.

[0435] In one embodiment, the dose is 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, or 5 mg / kg, based on the subject's body weight. 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

[0033] In some embodiments, 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 of at least one bispecific anti-Aβ / TfR antibody is administered to the subject.

[0436] In one embodiment, the doses may be 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 ...

[0032] In one embodiment, the subject is administered 1.2 mg / kg to 2.6 mg / kg, 1.2 mg / kg to 2.5 mg / kg, 1.2 mg / kg to 2.4 mg / kg, 1.2 mg / kg to 2.3 mg / kg, 1.2 mg / kg to 2.2 mg / kg, 1.2 mg / kg to 2.1 mg / kg, 1.2 mg / kg to 2 mg / kg, 1.2 mg / kg to 1.9 mg / kg, 1.2 mg / kg to 1.8 mg / kg, 1.3 mg / kg to 2.6 mg / kg, 1.4 mg / kg to 2.5 mg / kg, 1.5 mg / kg to 2.4 mg / kg, 1.6 mg / kg to 2.3 mg / kg, 1.7 mg / kg to 2.2 mg / kg, or 1.8 mg / kg to 2.1 mg / kg of at least one bispecific anti-Aβ / TfR antibody.

[0437] In one embodiment, the dose is 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, 3 mg / kg, or 4.2 mg / kg, based on the subject's body weight. 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

[0033] In some embodiments, 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 of at least one bispecific anti-Aβ / TfR antibody is administered to the subject.

[0438] In one embodiment, the dose is 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, or 3.5 mg / kg to 3.6 mg / kg relative to the subject's body weight. g, 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 of at least one bispecific anti-Aβ / TfR antibody is administered to the subject.

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

[0440] In certain embodiments, for some administrations, the dose may be 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, or 2.8 mg / kg to 7.2 mg / kg. / 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 is administered to the subject at 0.2 mg / kg to 7.2 mg / kg, 5 mg / kg to 7.2 mg / kg, 5.5 mg / kg to 7.2 mg / kg, 6 mg / kg to 7.2 mg / kg, 6.5 mg / kg to 7.2 mg / kg, or 7 mg / kg to 7.2 mg / kg, and after said several administrations, the dose is increased to 0.2 mg / kg to 3.6 mg / kg, 0.3 mg / kg to 3.6 mg / kg, 0.4 mg / kg to 3.6 mg / kg, 0.5 mg / kg to 3.6 mg / kg, 0.6 mg / kg to 3.6 mg / kg, 0.8 mg / kg to 3.6 mg / kg, 0.9 mg / kg to 3.6 mg / kg, 10 mg / kg to 10.6 mg / kg, 11 mg / kg to 11.6 mg / kg, 12 mg / kg to 12.6 mg / kg, 13 mg / kg to 13.6 mg / kg, 14 mg / kg to 14.6 mg / kg, 15 mg / kg to 15.6 mg / kg, 16 mg / kg to 16.6 mg / kg, 17 mg / kg to 17.6 mg / kg, 18 mg / kg to 18.6 mg / kg, 19 mg / kg to 19.6 mg / kg, 20 mg / kg to 20.6 mg / kg, 21 mg / kg to 21.6 mg / kg, 22 mg / kg to 22.6 mg / kg, 23 mg / kg to 23.6 mg / kg, 24 mg / kg to 24.6 mg / kg, 25 mg / kg to 25.6 mg / kg, 26 mg / kg to 26.6 mg / kg, 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 second, smaller dose of at least one bispecific anti-Aβ / TfR antibody of 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 certain embodiments, the number of administrations is 3 to 60. In certain embodiments, the number of administrations is 3, 6, 12, 18, 24, 36, 48, or 60.

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

[0443] Dosing regimen for at least one bispecific anti-Aβ / TfR antibody The method of the present invention comprises administering to a subject a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. Those skilled in the art will understand that any therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody can be administered once or multiple times according to one or more dosing regimens. Those skilled in the art will be able to determine the appropriate dosing regimen for each subject depending on several factors, including pharmacodynamic characteristics, route of administration, dosage, and the health, age, and weight of the subject to be treated, and 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 third day, once a week, once every two weeks (“biweekly”), once every four weeks (“every four week period”), 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, once every sixteen weeks, once every sixteen weeks, once every eighteen ... In some embodiments, a composition comprising at least one bispecific anti-Aβ / TfR antibody is administered once every four months, once every 18 weeks, once every 20 weeks, once every five months, once every 22 weeks, once every 24 weeks, once every six months, once every seven months, once every eight months, once every nine months, once every 10 months, once every 11 months, once every 12 months, once every 13 months, once every 14 months, once every 15 months, once every 16 months, once every 17 months, or once every 18 months. In some embodiments, a composition comprising at least one bispecific anti-Aβ / TfR antibody is administered daily, every other day, every third day, once weekly, once every two weeks ("biweekly"), once every four weeks ("four-week intervals"), or once monthly. In some embodiments, a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody is administered once every two weeks or once every four weeks. In some embodiments, a composition comprising 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 comprising 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 comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody is administered once a month.

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

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

[0447] In some embodiments, a composition comprising at least one bispecific anti-Aβ / TfR antibody is administered to a subject at a dose of 1.8-7.2 mg / kg of the subject's body weight once every four weeks. In one preferred embodiment, a composition comprising at least one bispecific anti-Aβ / TfR antibody is administered to a subject at a dose of 2.6-3.6 mg / kg of the subject's body weight 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] Compositions Comprising at Least One Bispecific Anti-Aβ / TfR Antibody In some embodiments, at least one bispecific anti-Aβ / TfR antibody is included in a composition. In some embodiments, the composition consists of 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 the present disclosure may be in the form of a solution, a lyophilized product, and / or any other suitable form deemed appropriate by those skilled in the art.The administration route of the compositions of the present disclosure may be any suitable route, including intravenous administration and subcutaneous administration.In some embodiments, the compositions are formulated as a sterile, non-pyrogenic liquid for intravenous administration.In some embodiments, the compositions are saline solutions.

[0451] Formulations for anti-Aβ antibodies are known in the art, for example, as disclosed in WO 2008 / 071394, WO 2013 / 131866, CN 115227813, JP 2014 / 001232, WO 2009 / 017467, and WO 2006 / 083689.

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

[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; - about 0.001% to about 1% (w / v) of at least one surfactant; about 1 mM to about 100 mM buffer; optionally, from about 10 mM to about 500 mM of a stabilizer and / or from about 5 mM to about 500 mM of a tonicity agent, - Formulated in a stable formulation containing at a pH of about 4.0 to about 7.0.

[0454] In certain embodiments, the formulation is a liquid formulation.

[0455] In a preferred embodiment, the liquid formulation comprises: 1) - about 1 to about 200 mg / mL of an anti-Aβ antibody; approximately 0.04% polysorbate 20 (w / v), about 20 mM L-histidine, about 250 mM sucrose, at a pH of about 5.5, or 2) approximately 37.5 mg / mL of an anti-Aβ antibody; approximately 0.02% polysorbate 20 (w / v), about 10 mM L-histidine, about 125 mM sucrose, at a pH of about 5.5, or 3) approximately 37.5 mg / mL of an anti-Aβ antibody; approximately 0.01% polysorbate 20 (w / v), about 10 mM L-histidine, about 125 mM sucrose, - at a pH value of approximately 5.5, or 4) approximately 7.5 mg / mL of an anti-Aβ antibody; approximately 0.04% polysorbate 20 (w / v), about 20 mM L-histidine, about 250 mM sucrose, - at a pH value of approximately 5.5, or 5) approximately 7.5 mg / mL of an anti-Aβ antibody; approximately 0.02% polysorbate 20 (w / v), about 10 mM L-histidine, about 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), about 10 mM L-histidine, about 125 mM trehalose, - at a pH value of approximately 5.5, or 7) approximately 37.5 mg / mL of an anti-Aβ antibody; approximately 0.01% polysorbate 20 (w / v), about 10 mM L-histidine, about 125 mM trehalose, - at a pH value of approximately 5.5, or 8) approximately 75 mg / mL of an anti-Aβ antibody, approximately 0.02% polysorbate 20 (w / v), about 20 mM L-histidine, about 250 mM trehalose, - at a pH value of approximately 5.5, or 9) approximately 75 mg / mL of an anti-Aβ antibody, approximately 0.02% polysorbate 20 (w / v), about 20 mM L-histidine, about 250 mM mannitol, - at a pH value of approximately 5.5, or 10) approximately 75 mg / mL of an anti-Aβ antibody, approximately 0.02% polysorbate 20 (w / v), about 20 mM L-histidine, about 140 mM sodium chloride, - at a pH value of approximately 5.5, or 11) approximately 150 mg / mL of an anti-Aβ antibody, -0.02% polysorbate 20 (w / v), about 20 mM L-histidine, about 250 mM trehalose, - at a pH value of approximately 5.5, or 12) approximately 150 mg / mL of an anti-Aβ antibody, approximately 0.02% polysorbate 20 (w / v), about 20 mM L-histidine, about 250 mM mannitol, - at a pH value of approximately 5.5, or 13) approximately 150 mg / mL of an anti-Aβ antibody, approximately 0.02% polysorbate 20 (w / v), about 20 mM L-histidine, about 140 mM sodium chloride, - at a pH value of approximately 5.5, or 14) approximately 10 mg / mL of an anti-Aβ antibody, approximately 0.01% polysorbate 20 (w / v), about 20 mM L-histidine, about 140 mM sodium chloride, -Contains at a pH value of approximately 5.5. In a preferred embodiment, the liquid formulation comprises: -about 1 mg / mL to about 200 mg / mL of an anti-Aβ antibody; about 0.01% to about 0.1% poloxamer (w / v), about 5 mM to about 50 mM of a buffering agent; about 100 mM to about 300 mM of a stabilizer, -Includes pH values ​​in the range of pH 4.5 to pH 7.0, inclusive.

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

[0458] In certain embodiments, 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 buffering agent has a concentration of about 10 mM to about 30 mM, hi one preferred embodiment, the buffering agent has a concentration of about 20 mM.

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

[0461] In certain embodiments, the stabilizer is selected from sugars and amino acids.

[0462] In certain embodiments, the stabilizer is selected from trehalose and arginine.

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

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

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

[0466] In certain embodiments, the buffering agent is at a concentration ranging from about 5 mM to about 100 mM, including about 5 mM and about 100 mM. In certain embodiments, the buffering agent is at a concentration ranging from about 30 mM to about 70 mM, including about 30 mM and about 70 mM. In one preferred embodiment, the buffering agent is at a concentration of about 50 mM.

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

[0468] In one embodiment, the pH value of the pharmaceutical composition ranges from about pH 4.5 to about pH 6.0, including about pH 4.5 and about pH 6.0. In one embodiment, the pH value of the pharmaceutical composition ranges from about pH 4.7 to about pH 5.5, including about pH 4.7 and about pH 5.5. In a 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 a preferred embodiment, the concentration of the anti-Aβ antibody is about 100 mg / mL or about 150 mg / mL.

[0470] In certain embodiments, the pharmaceutical composition further comprises a surfactant.

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

[0472] In one embodiment, the surfactant concentration ranges from about 0.01% to about 0.1% (w / v), including about 0.01% and about 0.1% (w / v). In one embodiment, the surfactant concentration ranges from about 0.02% to about 0.08% (w / v), including about 0.02% and about 0.08% (w / v). In a preferred embodiment, the surfactant concentration ranges from about 0.04% to 0.06% (w / v), including about 0.04% and about 0.06% (w / v).

[0473] In certain embodiments, the pharmaceutical composition further comprises a sugar.

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

[0475] In some embodiments, the pharmaceutical composition comprises the sugar at a concentration ranging from about 20 mg / mL to about 100 mg / mL, including about 20 mg / mL and about 100 mg / mL. In some embodiments, the pharmaceutical composition comprises the sugar at a concentration ranging from about 30 mg / mL to about 90 mg / mL, including about 30 mg / mL and about 90 mg / mL. In a preferred embodiment, the pharmaceutical composition comprises the sugar at a concentration of about 40 mg / mL, about 60 mg / mL, about 70 mg / mL, or about 80 mg / mL.

[0476] In certain embodiments, the pharmaceutical composition further comprises a chelating agent.

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

[0478] In certain embodiments, the chelating agent is at a concentration ranging from about 0.01 mg / mL to about 20 mg / mL, including about 0.01 mg / mL and about 20 mg / mL. In certain embodiments, the chelating agent is at a concentration ranging from about 0.1 mg / mL to about 1 mg / mL, including about 0.1 mg / mL and about 1 mg / mL. In one embodiment, the chelating agent is at a concentration of about 0.5 mg / mL.

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

[0480] In one embodiment, the antibody used in the invention is in a formulation comprising 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 in a formulation containing 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 an anti-Aβ antibody at a concentration ranging from about 17 mg / ml to about 23 mg / ml, including about 17 mg / ml and about 23 mg / ml; histidine at a concentration ranging from about 5 mM to about 15 mM, including about 5 mM and about 15 mM; mannitol in an amount ranging from about 2% w / v to about 6% w / v, including about 2% w / v and about 6% w / v; methionine at a concentration ranging from about 5 mM to about 15 mM, including about 5 mM and about 15 mM, and polysorbate in an amount ranging from 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 has 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 about 6.0.

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

[0490] Reduction of clinical deterioration One aspect of the present invention relates to a method of reducing clinical deterioration in a subject with early Alzheimer's disease, e.g., mild, mild-to-prodromal, or prodromal Alzheimer's disease. For example, and without limitation, such embodiments can comprise administering to the subject a therapeutically effective amount of a composition comprising at least one bispecific anti-Aβ / TfR antibody disclosed herein. In some embodiments, the subject with early Alzheimer's disease has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate probability and / or has been diagnosed with mild Alzheimer's disease dementia.

[0491] Any of the bispecific anti-Aβ / TfR antibodies disclosed herein, their therapeutically acceptable amounts, dosing regimens therefor, and compositions comprising them can be used in the methods of reducing clinical deterioration in a subject with early Alzheimer's disease according to the present invention. For example, in some embodiments, a composition comprising 1.8 mg / kg, 2.6 mg / kg, 3 mg / kg, 3.6 mg / kg, or 7.2 mg / kg of the subject's body weight of at least one bispecific anti-Aβ / TfR antibody, e.g., trontinemab, 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 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%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, 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%, 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 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%.In some embodiments, the attenuation of clinical deterioration is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months, and / or 60 months after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0492] In some embodiments, clinical deterioration is reduced by 20% to 60% relative to placebo as determined by CDR-SB. In some embodiments, clinical deterioration is reduced by 25% to 60% relative to placebo as determined by CDR-SB. In some embodiments, clinical deterioration is reduced by 25% to 50% relative to placebo as determined by CDR-SB. In some embodiments, clinical deterioration is reduced by at least 20% relative to placebo as determined by CDR-SB. In some embodiments, clinical deterioration is reduced by at least 30% relative to placebo as determined by CDR-SB. In some embodiments, clinical deterioration is reduced by at least 25%, e.g., at least 26% or at least 28%, as determined by CDR-SB. In some embodiments, clinical deterioration is reduced by at least 30%, e.g., at least 35% or at least 38%, as determined by CDR-SB. In some embodiments, the attenuation of clinical deterioration is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months, and / or 60 months after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0493] In some embodiments, clinical deterioration is reduced by at least 30% relative to placebo, e.g., at least 35% or at least 40%, as determined by CDR-SB after 6 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, clinical deterioration is reduced by at least 30% relative to placebo, e.g., at least 35% or at least 45%, as determined by CDR-SB after 12 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, clinical deterioration is reduced by at least 20% relative to placebo, e.g., at least 25%, as determined by CDR-SB after 18 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In one preferred embodiment, the composition comprises 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.

[0494] In some embodiments, clinical deterioration 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% relative to placebo as determined by CDR-SB, and the subject has been diagnosed with Mild Cognitive Impairment due to Alzheimer's Disease - Probable Moderate. In some embodiments, the reduction in clinical deterioration is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months, and / or 60 months after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

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

[0496] In some embodiments, clinical worsening 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%, at least 22%, at least 23%, at least 24%, at least 25%, at least 16% relative to placebo as determined by CDR-SB. In some embodiments, the reduction in clinical deterioration is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months, and / or 60 months after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

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

[0498] In some embodiments, clinical deterioration in subjects diagnosed with mild Alzheimer's disease dementia is reduced by at least 51% relative to placebo as determined by CDR-SB after 18 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the composition comprises 1.8 to 7.2 mg / kg of at least one bispecific anti-Aβ / TfR antibody, administered every 24 hours or once a month. In one preferred embodiment, the at least one bispecific anti-Aβ antibody is trontinemab.

[0499] In some embodiments, the attenuation of clinical deterioration 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 comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the attenuation of clinical deterioration is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months, and / or 60 months after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0500] In some embodiments, the reduction in clinical worsening is determined one month after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the reduction in clinical worsening is determined six months after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the reduction in clinical worsening is determined twelve months after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the reduction in clinical worsening is determined 18 months after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the reduction in clinical worsening is determined 24 months after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the reduction in clinical worsening is determined 60 months after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

[0501] In some embodiments, the reduction in clinical deterioration is determined after administration of a composition comprising a therapeutically effective amount of trontinemab.

[0502] In some embodiments, the reduction in clinical deterioration 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 comprising a therapeutically effective amount of trontinemab. In some embodiments, the reduction in clinical deterioration is determined 1 month after administration of a composition comprising a therapeutically effective amount of trontinemab. In some embodiments, the reduction in clinical deterioration is determined after 6 months of administration of a composition comprising a therapeutically effective amount of trontinemab. In some embodiments, the reduction in clinical deterioration is determined after 12 months of administration of a composition comprising a therapeutically effective amount of trontinemab. In some embodiments, the reduction in clinical deterioration is determined after 18 months of administration of a composition comprising a therapeutically effective amount of trontinemab. In some embodiments, the reduction in clinical deterioration is determined after 60 months of administration of a composition comprising a therapeutically effective amount of trontinemab. In some embodiments, the reduction in clinical deterioration is determined after 63 months of administration of a composition comprising a therapeutically effective amount of trontinemab.

[0503] Conversion of an amyloid-positive to amyloid-negative subject A further aspect according to 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 has early Alzheimer's disease, e.g., mild, mild-to-prodromal, or prodromal Alzheimer's disease, and has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate probability and / or mild Alzheimer's disease dementia.

[0504] Any of the bispecific anti-Aβ / TfR antibodies disclosed herein, their therapeutically acceptable amounts, dosing regimens therefor, and compositions comprising them can be used in methods for converting an amyloid-positive subject to an amyloid-negative subject. For example, in some embodiments, a composition comprising 1.8 mg / kg, 2.6 mg / kg, 3.8 mg / kg, or 7.2 mg / kg of at least one bispecific anti-Aβ / TfR antibody, e.g., trontinemab, based on 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, administration of the composition results in an amyloid PET image reduction of 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%, 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 the subjects convert from amyloid positive to amyloid negative.

[0506] In some embodiments, administration of the composition results in the conversion of 50% to 100%, e.g., 60% to 90%, of subjects from amyloid-positive to amyloid-negative, 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, as determined by visual reading of amyloid PET images, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. 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, as determined by visual reading of amyloid PET images, after 18 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the composition comprises 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.

[0507] In some embodiments, administration of the composition results in an improvement in amyloid PET activity of 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%, 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%, at least 81%, at least 82%, at least 83%, at least 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%, at least 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 In some embodiments, the method 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 the subjects being amyloid negative.

[0508] In some embodiments, clinical worsening 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%, 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%, 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%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least In some embodiments, the reduction in clinical deterioration is determined 1 month, 6 months, 12 months, 18 months, 24 months, 36 months, and / or 60 months after administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody.

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

[0510] In some embodiments, clinical deterioration in subjects not concurrently receiving at least one Alzheimer's disease medication is reduced by at least 45% relative to placebo as determined by CDR-SB after 18 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the composition comprises 1.8-7.2 mg / kg of at least one bispecific anti-Aβ / TfR antibody, 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] Reduced brain amyloid levels One aspect according to the present invention is a method of reducing brain amyloid levels in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising at least one bispecific anti-Aβ / TfR antibody according to the present invention and disclosed herein.

[0512] Those skilled in the art will understand that, in addition to subjects with Alzheimer's disease, Aβ protein plaque deposits are present in the brains of subjects with other neurodegenerative diseases and conditions, and therefore, the methods disclosed herein are beneficial for subjects with such neurodegenerative diseases and / or conditions. Such diseases and conditions are known to include, for example, Down's syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, and dementia with Lewy bodies. (See, e.g., 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 subject has early stage Alzheimer's disease.

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

[0515] In some embodiments, the subject has Alzheimer's disease, Down's syndrome, chronic traumatic encephalopathy, cerebral amyloid angiopathy, dementia with Lewy bodies, or another brain disease or condition involving soluble and / or insoluble Aβ aggregates containing Aβ peptide.

[0516] In some embodiments, the subject with early stage Alzheimer's disease has been diagnosed with mild cognitive impairment due to Alzheimer's disease - moderate probability and / or has been diagnosed with mild Alzheimer's disease dementia.

[0517] Any of the bispecific anti-Aβ / TfR antibodies disclosed herein, their therapeutically acceptable amounts, dosing regimens therefor, and compositions containing them can be used in methods for reducing brain amyloid levels in subjects with early, mild, or prodromal Alzheimer's disease. In one preferred embodiment, a composition containing 1.8 to 7.2 mg / kg of the subject's body weight, e.g., 1.8 mg / kg, 2.6 mg / kg, 3.8 mg / kg, or 7.2 mg / kg of at least one bispecific anti-Aβ / TfR antibody, e.g., trontinemab, 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, the 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 binding of a radioactive tracer to brain Aβ protein amyloid and visualized by positron emission tomography (PET). In some embodiments, the reduction in adjusted mean change from baseline is at least 40 centiloids (baseline to -40 centiloids), for example, at least 65 centiloids (baseline to -65 centiloids) or at least 90 centiloids (baseline to -90 centiloids) after 3 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the reduction in amyloid in the brain is determined by imaging using binding of a radioactive tracer to brain Aβ protein amyloid and visualized by PET. In some embodiments, the reduction in adjusted mean change from baseline is at least 50 centiloids (-50 centiloids from baseline), e.g., at least 55 centiloids (-55 centiloids from baseline) or at least 60 centiloids (-60 centiloids from baseline) after 12 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the reduction in adjusted mean change from baseline is at least 60 centiloids (-60 centiloids from baseline), e.g., at least 65 centiloids (-65 centiloids from baseline) or at least 70 centiloids (-70 centiloids from baseline) after 18 months of administration of a composition comprising a therapeutically effective amount 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 fragment relative to the level of cerebrospinal fluid Aβ1-42 protein fragment before said administration.In some embodiments, the method comprises increasing the level of Aβ1-42 protein fragments in cerebrospinal fluid 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%, 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 24%, at least 26%, 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%, 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 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%, at least 75%, at least 76%, resulting in a reduction in cerebrospinal fluid Aβ1-42 protein fragment levels by 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%.

[0521] In some embodiments, administration of a composition comprising at least one bispecific anti-Aβ / TfR antibody results in an improvement in amyloid PET levels of 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%, 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%, at least 81 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%, 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 resulting 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 the 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%, e.g., 80% to 100%, or 85% to 100% of subjects 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%, e.g., at least 80%, or at least 85% of subjects 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 subjects being amyloid negative, as determined by visual reading of amyloid PET images.

[0523] In some embodiments, after 3 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody, at least 30% of subjects are amyloid-negative as determined by visual reading of amyloid PET images. In some embodiments, after 6 months of administration of a composition comprising a therapeutically effective amount 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 subjects are amyloid-negative as determined by visual reading of amyloid PET images. In some embodiments, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody, at least 75%, e.g., at least 80%, or at least 85% of subjects are amyloid-negative as determined by visual reading of amyloid PET images. In some embodiments, after 18 months of administration of a composition comprising a therapeutically effective amount 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 comprises 1.8-7.2 mg / kg, e.g., 1.8 mg / kg, 2.6 mg / kg, 3.6 mg / kg, or 7.2 mg / kg, of at least one bispecific anti-Aβ / TfR antibody, 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 reduced brain amyloid level after administration relative 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%, or at least 22% of the brain amyloid level before said 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%, 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% reduction.

[0525] In some embodiments, the reduction in amyloid in the brain is determined by imaging using binding of a radioactive tracer to brain Aβ amyloid and visualized by PET. In some embodiments, the reduction in amyloid in the brain is determined by imaging using binding of a radioactive tracer to brain Aβ amyloid and visualized by PET. In some embodiments, the reduction in adjusted mean change from baseline is at least 40 centiloids (-40 centiloids from baseline), e.g., at least 65 centiloids (-65 centiloids from baseline) or at least 90 centiloids (-90 centiloids from baseline) after 3 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the adjusted mean change reduction from a subject's level before administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody is at least 50 centiloids (-50 centiloids from baseline), e.g., at least 55 centiloids (-55 centiloids from baseline) or at least 59 centiloids (-59 centiloids from baseline) after 12 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody. In some embodiments, the adjusted mean change reduction from a subject's level before administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody is at least 60 centiloids (-60 centiloids from baseline), e.g., at least 65 centiloids (-65 centiloids from baseline) or at least 70 centiloids (-70 centiloids from baseline) after 18 months of administration of a composition comprising 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 relative to cerebrospinal fluid Aβ1-42 protein fragment levels before administration.In some embodiments, the method comprises increasing the cerebrospinal fluid Aβ1-42 protein fragment level 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%, 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 24%, at least 26%, 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%, 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 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%, or at least 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%, or 100% reduction in cerebrospinal fluid Aβ1-42 protein fragment levels.

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

[0528] In some embodiments, administration of a composition comprising at least one bispecific anti-Aβ / TfR antibody results in an improvement in amyloid PET levels of 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%, 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%, at least 81 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%, 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 resulting 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 the 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%, e.g., 80% to 100%, or 85% to 100% of subjects 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%, e.g., at least 80%, or at least 85% of subjects 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 subjects being amyloid negative, as determined by visual reading of amyloid PET images.

[0530] In some embodiments, after 12 months of administration of a composition comprising a therapeutically effective amount of at least one bispecific anti-Aβ / TfR antibody, at least 75%, e.g., at least 80%, or at least 85% of subjects are amyloid-negative, as determined by visual reading of amyloid PET images. In some embodiments, after 18 months of administration of a composition comprising a therapeutically effective amount 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 comprises 1.8-7.2 mg / kg, e.g., 1.8 mg / kg, 2.6 mg / kg, 3.6 mg / kg, or 7.2 mg / kg, of at least one bispecific anti-Aβ / TfR antibody, 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 key obstacle in the development of novel anti-Aβ monoclonal antibody (mAb) therapies is their 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 reaches the brain. Monoclonal antibodies appear to enter the brain passively, e.g., via the choroid plexus, and distribute slowly 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 of a phase 2 / 3 gantenerumab trial in prodromal AD to open-label long-term treatment and rollover to the Open RoAD open-label trial; prodromal AD, CDR 0.5), gantenerumab was administered subcutaneously once every 4 weeks (Q4W) at a final dose of 1,200 mg. In the Marguerite RoAD clinical trial (ClinicalTrials.gov identifier: NCT02051608; conversion of a phase 3 gantenerumab trial in mild AD to open-label long-term treatment and rollover to the Open RoAD open-label trial; mild AD, CDR 1.0), gantenerumab was administered subcutaneously once every 4 weeks (Q4W) at a final dose of 1,200 mg. In the GRADUATE I and II phase 3 trials (ClinicalTrials.gov identifiers: NCT03444870 and NCT03443973; two international, parallel, multicenter, randomized, double-blind, placebo-controlled trials of gantenerumab in patients with early AD (prodromal or mild CI-AD to mild AD)) and GRADUATE AFTER (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 weekly (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 for or in the earliest stages of AD), gantenerumab was administered subcutaneously at a monthly dose of 1,020 mg, flexibly (Q1W or Q2W). (See, e.g., 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 of large molecules to the brain is restricted by the blood-brain barrier (BBB), a gatekeeper between the blood and brain tissue that carefully screens which molecules can enter the brain. Using specific antibody formats, antibodies have been created that can cross the BBB by binding to one of the protein receptors located on its 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 BBB.

[0534] Trontinemab (also known as RG6102 or RO7126209; see also proposed INN List127, Cas2568868-35-7, USAN KL-203, and FDA UNII N0GBZ1GWC2) is a BrS antibody employing a unique "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-swapped Fab (anti-TfR1 Fab) that specifically binds to human transferrin receptor 1, conjugated to the C-terminus of one of the heavy chains of the gantenerumab variant (see WO 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. It is administered intravenously and, while circulating in the bloodstream, binds to the transferrin receptor present on the 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 gantenerumab variants are fused to a single Fab that binds to the mouse transferrin receptor. In AD mouse models, substantial increases in brain concentrations could be 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 with standard Y-shaped IgG antibodies. trontinemab stimulated plaque clearance by immune cells at lower doses than the parent antibody, gantenerumab. At the same time, it did not initiate an immune response against endothelial cells or other cells expressing the transferrin receptor.

[0538] A surrogate trontinemab (BrS-mAb31) and its surrogate counterpart (mAb31), which cross-react with mouse TfR1, were used for the in vivo evaluation of trontinemab in mice. The BrS-mAb31 surrogate binds to a similar epitope as trontinemab in the apical domain of TfR1, outside the binding interface between TfR1 and transferrin (Tf). The mouse surrogate of the BrS construct consisted of a single Fab fragment of a rat antibody specific for mouse TfR1 fused to the C-terminal Fc region of mAb31, a human IgG1 antibody (the preclinical version of gantenerumab) specific for Aβ fibrils and oligomers. Using a monovalent binding mode to TfR1, 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 exhibited lower plasma exposure than the non-BrS analog, mAb31, which was attributed to target-mediated drug disposition through peripheral TfR binding. In a 4-month treatment study using weekly dosing, BrS-mAb31 exhibited approximately 12-fold higher brain exposure than mAb31 7 days after the last injection. Furthermore, BrS-mAb31 resulted in significantly greater reductions in Aβ protein amyloid plaques in the cortex and hippocampus compared with 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 hidden in the periphery, primarily due to its inverted TfR binding mode due to steric hindrance, thereby reducing the likelihood of acute infusion reactions.

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

[0541] Using trontinumab, substantially higher brain exposure could be achieved through shuttling (Kulic, L., et al. Presented at the AD / PD2021 virtual conference).

[0542] Using a single IV dose of 10 mg / kg trontinemab versus a single IV dose of 20 mg / kg gantenerumab, we were able to achieve 6-42 fold higher brain (tissue) exposure in non-human primates, particularly in deep brain regions, compared to gantenerumab, as shown in Figure 2A and the table below. [Table 3]

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

[0544] However, the question remained whether using Brainshuttle™ technology would enable more widespread and uniform brain penetration with faster amyloid plaque clearance in humans compared to antibodies that do not use active TfR1 receptor-mediated transcytosis through the blood-brain barrier.

[0545] In the first-in-human trial of trontinemab in healthy human volunteers (Phase Ia, Single Ascending 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. Additionally, an 8-fold 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 intensity and resolved. No Grade 3, 4, or 5 AEs were observed. The most common AEs considered related to study treatment were acute infusion-related reactions, headache, and nausea. No serious AEs (including fatal outcomes) were reported up to the maximum dose level tested, 7.2 mg / kg.

[0547] The second human trial of trontinemab (Phase Ib / IIa, multiple ascending dose (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 study using an interleaved, parallel-group design with four initial sequential cohorts.

[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 at least eight participants receiving the active substance and at least two participants receiving placebo, up to a maximum of 120 participants).

[0549] The study 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 study used an interleaved parallel-group design and assigned participants to four planned sequential 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 will be administered intravenously once every 4 weeks for 28 weeks (primary endpoint; 7 doses in total), with a safety follow-up period of 28 weeks.

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

[0552] Each cohort received sentinel dosing. Amyloid plaque burden 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 escalation to the maximum dose level of 3.6 mg / kg (cohort 4).

[0553] Participants were assessed for cerebral amyloid burden by amyloid positron emission tomography (PET) at baseline (week 0), week 12 (cohorts 3+4), and week 28 (cohorts 1-4). Plasma (up to 32 weeks) and cerebrospinal fluid (CSF) concentrations (baseline, week 25) were also determined.

[0554] Additionally, CDR and MMSE (baseline, week 28 and week 40) were determined to assess clinical efficacy.

[0555] To assess cerebral perfusion, changes from baseline in PET and ASL-MRI (arterial spin-labeling magnetic resonance imaging) were determined. Blood and CSF changes from baseline included Aβ1-42 protein fragment (amyloid beta peptide 1-42; SEQ ID NO: 45), tTau (total tau protein), pTau (phosphorylated tau protein), neurogranin, NfL (neurofilament light protein), and sTREM2 (soluble triggering receptor 2 expressed on myeloid cells) as biomarkers (blood: baseline, weeks 11, 24, 25, and 26; CSF: baseline, week 25).

[0556] Currently, the following has been found: The interim analysis of safety and amyloid PET was based on a data snapshot as of January 18, 2023. Safety results included blinded data from a total of 44 participants who received 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-ascending-dose study of trontinemab, acute infusion-related reactions (IRRs) were the most common treatment-emergent AEs. All IRRs were mild or moderate in severity. Interim 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), robust amyloid plaque reduction and amyloid PET negativity (cutoff: <24 centimeters) were noted already at day 78 in several participants. Administered at a dose of -1.8 mg / kg, trontinumab produces three times faster and more extensive amyloid reduction than other standard monoclonal antibodies with an excellent safety profile and low risk of ARIA, which is expected to translate into superior clinical efficacy. - Reaching (or falling below) the amyloid-negative threshold appears to translate into clinical benefit; for example, a 70% amyloid-negative rate after 28 weeks of treatment with 4-weekly dosing would result in a 44% CDR-SB RR (Clinical Dementia Scale Box Sum Relative Reduction) at 18 months compared to placebo, whereas a 90% amyloid-negative rate after 28 weeks of treatment with 4-weekly dosing would result in a 50% or greater CDR-SB RR at 18 months compared to placebo (Scelsi et al., CTAD 2023). [Table 4]

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

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

[0559] Thus, it has surprisingly been found that rapid amyloid plaque clearance can be achieved at dose levels significantly lower than with typical anti-amyloid monoclonal antibodies.

[0560] These results show that trontinemab rapidly reduces amyloid plaque burden in a dose-dependent manner, and in the majority of patients, amyloid plaque burden is reduced to levels comparable to those in people without AD in a short time.

[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, faster than with a standard anti-Aβ monoclonal antibody, with 72% of participants below the Aβ protein positivity threshold (24.1 cl) at 28 weeks.

[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 centiloids (-91 centiloids from baseline) after 3 months (n=8), approximately 6 times faster than with a standard anti-Aβ monoclonal antibody, with 6 / 8 (63%) participants falling below the Aβ protein positivity threshold (24.1 cl) at week 12.

[0563] The data confirmed the significantly improved safety and tolerability profile of trontinemab compared to standard anti-Aβ monoclonal antibodies. Acute infusion-related reactions (IRR) remained the most prominent side effect (7 / 15; 46.7%), with the common symptoms of chills, fever, and headache, which can be mitigated by appropriate premedication, in one embodiment with corticosteroids or acetaminophen / NSAID and dexamethasone. NSAID = nonsteroidal anti-inflammatory drug.

[0564] None of the Cohort 4 participants ever showed 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. Decreased mean hemoglobin levels and trends toward decreased red blood cell counts were recorded in all treatment groups (including placebo), suggesting that frequent blood sampling may have significantly contributed to the anemic phenotype.

[0565] Thus, in one embodiment, trontinemab has an overall ARIA-E rate of less than 13% of treated subjects and a symptomatic ARIA-E rate of 3% or less of treated subjects. This low ARIA-E rate results in a shorter ARIA-E risk period due to faster amyloid clearance.

[0566] In one embodiment, trontinemab is administered without titration. Without being bound by this theory, it is believed that this rapid amyloid plaque clearance by trontinemab may be achieved by using a TfR1-based Brainshuttle™ approach.

[0567] Four of 11 participants (36%) were found to be below the amyloid positivity threshold of 24.1 centimeters at week 11. Already at week 28, six of eight participants (75%) were below the amyloid positivity threshold of 24.1 centimeters, and five of eight participants (63%) were below 11 centimeters.

[0568] In contrast, participants given the 0.2 mg / kg and 0.6 mg / kg doses had mean amyloid levels of 74 and 56 centimeters, respectively, at week 28, with no participants in the 0.2 mg / kg group and only one participant in the 0.6 mg / kg group falling below the amyloid positivity threshold of 24.1 centimeters. [Table 7]

[0569] Results for cohorts 1–3 are visualized in Figures 3 (mean amyloid PET burden in centimeters) and 4 (mean amyloid reduction from baseline in centimeters). The study was randomized (4:1) with 10 or more participants per group (active:placebo). All participants were Caucasian and weighed 60–70 kg. APOE ε4 carrier status was 71% for the 0.2 mg / kg dose, 43% for the 0.6 mg / kg dose, and 63% for the 1.8 mg / kg dose.

[0570] Results, including those for Cohort 4 after 12 weeks, are visualized in Figure 5 (mean amyloid reduction from baseline in centimeters). The study was randomized (4:1) with 10 or more participants per group (active:placebo). All participants, except for one in Cohort 4, were Caucasian and weighed between 68 kg and 72.5 kg. APOE ε4 carrier status was approximately 71% for the 0.2 mg / kg dose, approximately 43% for the 0.6 mg / kg dose, approximately 63% for the 1.8 mg / kg dose, and approximately 67% for the 3.6 mg / kg dose.

[0571] It can be seen that at doses of 1.8 mg / kg and 3.6 mg / kg, a decrease of at least 60 centimeters to over 90 centimeters was achieved after 12 weeks, and a decrease of at least 80 centimeters to over 90 centimeters after 28 weeks.

[0572] In the table below, the results obtained with trontinemab are shown together with those of other anti-Aβ antibodies. It should be noted that amyloid PET load is expressed in centiroids, which may vary between studies. However, even though the absolute change was comparable to that in the GRADUATE study, the lower baseline levels in CLARITY-AD (lecanemab) allowed the amyloid positivity threshold to be crossed more quickly. [Table 8]

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

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

[0575] Only two cases of ARIA have occurred to date in the 1.8 mg / kg cohort in 12 participants (3 placebo, 9 medication): one amyloid-related imaging abnormality - edema (ARIA-E), mild, resolved within 1 week without medication; and one amyloid-related imaging abnormality - hemosiderin deposition (ARIA-H), asymptomatic.

[0576] Aβ protein plaque decoration correlates with cumulative dose, and thus TfR1 transport across the BBB is not blunted by multiple dosing.

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

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

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

[0580] The sustained low incidence of ARIA (no ARIA-E / ARIA-H to date at 3.6 mg / kg) lower than known in the art for anti-Aβ antibodies and the overall favorable safety and tolerability profile demonstrate the improved properties of trontinemab (Figure 6).

[0581] Thus, trontinemab offers an anti-amyloid immunotherapy by inducing a high clearance of amyloid burden, as measured by positron emission tomography, in the brains of patients with biomarker-proven early-stage AD.

[0582] It has been established that the rate of amyloid clearance (measured by amyloid PET) observed in patients under anti-amyloid treatment is ultimately associated with a significant slowing of cognitive deterioration on several cognitive measures in a dose-dependent manner.

[0583] Therefore, trontinemab may / is a disease-modifying drug that slows 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 / is useful for slowing the progression of mild cognitive impairment and mild dementia due to Alzheimer's disease with an improved safety profile. Therefore, the indication for trontinemab may / is to slow the progression of mild cognitive impairment and mild dementia due to Alzheimer's disease. ***

[0584] In addition to the various embodiments depicted and claimed, the presently disclosed subject matter is directed to other embodiments having other combinations of the features disclosed and claimed herein. Thus, the specific features presented herein can be combined with each other in other ways within the scope of the presently disclosed subject matter, such that the presently disclosed subject matter includes any suitable combination of the features disclosed herein. The foregoing descriptions of specific embodiments of the presently disclosed subject matter have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the presently disclosed subject matter to the disclosed embodiments.

[0585] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

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

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

[0588] General information relating to the nucleotide sequences of human immunoglobulin light and heavy chains 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 practicing the present invention are described, for example, in Ausubel, F. M. (ed.), Current Protocols in Molecular Biology, Volumes I to III (1997); Glover, N. D. and Hames, B. D. ed., DNA Cloning: A Practical Approach, Volumes I and II (1985), Oxford University Press; Freshney, R. I. (ed.), Animal Cell Culture—a practical approach, IRL Press Limited (1986); Watson, J. D. et al., Recombinant DNA, Second Edition, CHSL Press (1992); Winnacker, E. L., From Genes to Clones, NY, VCH Publishers (1987); Celis, J., ed., Cell Biology, Second Edition, Academic Press (1998); Freshney, R. I., Culture of Animal Cells: A Manual of Basic Technique, second edition, Alan R. Liss, Inc., NY (1987).

[0590] The use of recombinant DNA technology makes it possible to produce derivatives of nucleic acids. Such derivatives can be modified at individual or several nucleotide positions, for example, by substitution, alteration, replacement, deletion or insertion. Modification or derivatization can be carried out, for example, by site-directed mutagenesis. Such modifications can be easily carried out 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; Hames, B.D., and Higgins, S.G., Nucleic acid hybridization - a practical approach (1985) IRL Press, Oxford, England).

[0591] All documents cited herein are expressly incorporated by reference. [Example]

[0592] Example 1: Phase Ia study In the first-in-human trial of trontinemab in healthy human volunteers (Phase Ia, Single Ascending 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. Additionally, an 8-fold 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 intensity and resolved. No Grade 3, 4, or 5 AEs were observed. The most common AEs considered related to study treatment were acute infusion-related reactions, headache, and nausea. No serious AEs (including fatal outcomes) were reported up to the maximum dose level tested, 7.2 mg / kg.

[0594] Example 2: Phase Ib / IIa study The second human trial of trontinemab (Phase Ib / IIa, multiple ascending dose (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 study using an interleaved, parallel-group design with four initial sequential cohorts.

[0595] Doses of 0.2 mg / kg, 0.6 mg / kg, 1.8 mg / kg, and 3.6 mg / kg will be tested (each dose cohort will include at least 8 participants receiving the active substance and at least 2 participants receiving the placebo, up to a maximum of 120 participants).

[0596] The study 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 study used an interleaved parallel-group design and assigned participants to four planned sequential 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 will be administered intravenously once every 4 weeks for 28 weeks (primary endpoint; 7 doses in total), with a safety follow-up period of 28 weeks.

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

[0599] Each cohort received sentinel dosing. Amyloid plaque burden 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 escalation to the maximum dose level of 3.6 mg / kg (cohort 4).

[0600] Participants were assessed for cerebral amyloid burden by amyloid positron emission tomography (PET) at baseline (week 0), week 12 (cohorts 3+4), and week 28 (cohorts 1-4). Plasma (up to 32 weeks) and cerebrospinal fluid (CSF) concentrations (baseline, week 25) were also determined.

[0601] Additionally, CDR and MMSE (baseline, week 28 and week 40) were determined to assess clinical efficacy.

[0602] To assess cerebral perfusion, changes from baseline in PET and ASL-MRI (arterial spin-labeling magnetic resonance imaging) were determined. Blood and CSF changes from baseline included Aβ1-42 protein fragment (amyloid beta peptide 1-42; SEQ ID NO: 45), tTau (total tau protein), pTau (phosphorylated tau protein), neurogranin, NfL (neurofilament light protein), and sTREM2 (soluble triggering receptor 2 expressed on myeloid cells) as biomarkers (blood: baseline, weeks 11, 24, 25, and 26; CSF: baseline, week 25).

[0603] Currently, the following has been found: The interim analysis of safety and amyloid PET was based on a data snapshot as of January 18, 2023. Safety results included blinded data from a total of 44 participants who received 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-ascending-dose study of trontinemab, acute infusion-related reactions (IRRs) were the most common treatment-emergent AE. All IRRs were mild or moderate in severity. Interim 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), robust amyloid plaque reduction and amyloid PET negativity (cutoff: <24 centimeters) were noted already at day 78 in several participants. Administered at a dose of -1.8 mg / kg, trontinumab produces three times faster and more extensive amyloid reduction than other standard monoclonal antibodies with an excellent safety profile and low risk of ARIA, which is expected to translate into superior clinical efficacy. - Reaching (or falling below) the amyloid-negative threshold appears to translate into clinical benefit; for example, a 70% amyloid-negative rate after 28 weeks of treatment with 4-weekly dosing would result in a 44% CDR-SB RR (Clinical Dementia Scale Box Sum Relative Reduction) at 18 months compared to placebo, whereas a 90% amyloid-negative rate after 28 weeks of treatment with 4-weekly dosing would result in a 50% or greater CDR-SB RR at 18 months compared to placebo (Scelsi et al., CTAD 2023). [Table 11]

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

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

[0606] Thus, it has surprisingly been found that rapid amyloid plaque clearance can be achieved at dose levels significantly lower than with typical anti-amyloid monoclonal antibodies.

[0607] These results show that trontinemab rapidly reduces amyloid plaque burden in a dose-dependent manner, and in the majority of patients, amyloid plaque burden is reduced to levels comparable to those in people without AD in a short time.

[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, faster than with a standard anti-Aβ monoclonal antibody, with 72% of participants below the Aβ protein positivity threshold (24.1 cl) at 28 weeks.

[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 centiloids (-91 centiloids from baseline) after 3 months (n=8), approximately 6 times faster than with a standard anti-Aβ monoclonal antibody, with 6 / 8 (63%) participants falling below the Aβ protein positivity threshold (24.1 cl) at week 12.

[0610] The data confirmed the significantly improved safety and tolerability profile of trontinemab compared to standard anti-Aβ monoclonal antibodies. Acute infusion-related reactions (IRR) remained the most prominent side effect (7 / 15; 46.7%), with the common symptoms of chills, fever, and headache, which can be mitigated by appropriate premedication, in one embodiment with corticosteroids or acetaminophen / NSAID and dexamethasone. NSAID = nonsteroidal anti-inflammatory drug.

[0611] None of the Cohort 4 participants ever showed 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. Decreased mean hemoglobin levels and trends toward decreased red blood cell counts were recorded in all treatment groups (including placebo), suggesting that frequent blood sampling may have significantly contributed to the anemic phenotype.

[0612] Thus, in one embodiment, trontinemab has an overall ARIA-E rate of less than 13% of treated subjects and a symptomatic ARIA-E rate of 3% or less of treated subjects. This low ARIA-E rate results in a shorter ARIA-E risk period due to faster amyloid clearance.

[0613] Four of 11 participants (36%) were found to be below the amyloid positivity threshold of 24.1 centimeters at week 11. Already at week 28, six of eight participants (75%) were below the amyloid positivity threshold of 24.1 centimeters, and five of eight participants (63%) were below 11 centimeters. In contrast, participants given the 0.2 mg / kg and 0.6 mg / kg doses had mean amyloid levels of 74 and 56 centimeters, respectively, at week 28; no participants in the 0.2 mg / kg group were below the amyloid positivity threshold of 24.1 centimeters, and only one participant in the 0.6 mg / kg group was below the amyloid positivity threshold of 24.1 centimeters. [Table 14]

[0614] Results for cohorts 1–3 are visualized in Figures 3 (mean amyloid PET burden in centimeters) and 4 (mean amyloid reduction from baseline in centimeters). The study was randomized (4:1) with 10 or more participants per group (active:placebo). All participants were Caucasian and weighed 60–70 kg. APOE ε4 carrier status was 71% for the 0.2 mg / kg dose, 43% for the 0.6 mg / kg dose, and 63% for the 1.8 mg / kg dose.

[0615] Results, including those for Cohort 4 after 12 weeks, are visualized in Figure 5 (mean amyloid reduction from baseline in centimeters). The study was randomized (4:1) with 10 or more participants per group (active:placebo). All participants, except for one in Cohort 4, were Caucasian and weighed between 68 kg and 72.5 kg. APOE ε4 carrier status was approximately 71% for the 0.2 mg / kg dose, approximately 43% for the 0.6 mg / kg dose, approximately 63% for the 1.8 mg / kg dose, and approximately 67% for the 3.6 mg / kg dose.

[0616] It can be seen that at doses of 1.8 mg / kg and 3.6 mg / kg, a decrease of at least 60 centimeters to over 90 centimeters was achieved after 12 weeks, and a decrease of at least 80 centimeters to over 90 centimeters after 28 weeks.

[0617] The results obtained with trontinemab are shown in the table below and in Figure 6, along with those for other anti-Aβ antibodies. It should be noted that amyloid PET loads are expressed in centimeters, which may vary between studies. However, even though absolute changes were comparable to those in the GRADUATE study, the lower baseline levels in CLARITY-AD (lecanemab) allowed for a faster crossing of the amyloid positivity threshold. [Table 15]

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

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

[0620] Only two cases of ARIA have occurred to date in the 1.8 mg / kg cohort in 12 participants (3 placebo, 9 medication): one amyloid-related imaging abnormality - edema (ARIA-E), mild, resolved within 1 week without medication; and one amyloid-related imaging abnormality - hemosiderin deposition (ARIA-H), asymptomatic.

[0621] Aβ protein plaque decoration correlates with cumulative dose, and thus TfR1 transport across the BBB is not blunted by multiple dosing.

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

Claims

1. 1. A pharmaceutical composition comprising a bispecific antibody that specifically binds to human Aβ protein and human transferrin receptor (bispecific anti-Aβ / TfR antibody) for the treatment of Alzheimer's disease in a subject, the bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to human Aβ protein; three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO:5 (LCDR1), SEQ ID NO:6 (LCDR2), and SEQ ID NO:7 (LCDR3); and two copies of a first pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising: ii) forming a binding site that specifically binds to the human transferrin receptor; Three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domain and cognate antibody light chain variable domain comprising Including, wherein the antibody is administered intravenously at a dose of 3.6 mg / kg of subject body weight once every four weeks. Pharmaceutical compositions.

2. 10. The pharmaceutical composition of claim 1, wherein administration of the pharmaceutical 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 of the pharmaceutical composition.

3. 2. The pharmaceutical composition of claim 1, wherein the bispecific anti-Aβ / TfR antibody is trontinumab.

4. 10. The pharmaceutical composition of claim 1, wherein the subject has been diagnosed with mild or prodromal Alzheimer's disease.

5. 4. The pharmaceutical composition of claim 3, wherein the subject has been diagnosed with mild or prodromal Alzheimer's disease.

6. 10. The pharmaceutical composition of claim 1, wherein administration of said pharmaceutical composition reduces amyloid levels by at least 40 centiloids relative to placebo as determined by visual reading of an amyloid PET.

7. 4. The pharmaceutical composition of claim 3, wherein administration of said pharmaceutical composition reduces amyloid levels by at least 40 centiloids relative to placebo as determined by visual reading of an amyloid PET.

8. 6. The pharmaceutical composition of claim 5, wherein administration of said pharmaceutical composition reduces amyloid levels by at least 40 centiloids relative to placebo as determined by visual reading of an amyloid PET.

9. 10. The pharmaceutical composition of claim 1, wherein administration of the pharmaceutical composition reduces amyloid levels within three months of initiating administration of the pharmaceutical composition.

10. 4. The pharmaceutical composition of claim 3, wherein administration of the pharmaceutical composition reduces amyloid levels within three months of initiation of administration.

11. 6. The pharmaceutical composition of claim 5, wherein administration of the pharmaceutical composition reduces amyloid levels within three months of initiation of administration.

12. 10. The pharmaceutical composition of claim 1, wherein no additional Alzheimer's disease medication other than trontinemab is administered.

13. 2. The pharmaceutical composition according to claim 1, wherein Aβ is human Aβ protein fragment 1-42 and the transferrin receptor is human transferrin receptor 1.

14. 4. The pharmaceutical composition according to claim 3, wherein Aβ is human Aβ protein fragment 1-42 and the transferrin receptor is human transferrin receptor 1.

15. 6. The pharmaceutical composition according to claim 5, wherein Aβ is human Aβ protein fragment 1-42 and the transferrin receptor is human transferrin receptor 1.

16. 12. The pharmaceutical composition according to claim 11, wherein Aβ is human Aβ protein fragment 1-42 and the transferrin receptor is human transferrin receptor 1.

17. 13. The pharmaceutical composition according to claim 12, wherein Aβ is human Aβ protein fragment 1-42 and the transferrin receptor is human transferrin receptor 1.

18. 10. The pharmaceutical composition of claim 1, wherein the subject does not exhibit amyloid-related imaging abnormalities - edema (ARIA-E) or amyloid-related imaging abnormalities - hemosiderin deposition (ARIA-H) after administration of the pharmaceutical composition.

19. 10. The pharmaceutical composition of claim 1, wherein administration of the pharmaceutical composition reduces the severity of at least one symptom associated with Alzheimer's disease in a subject.

20. 20. The pharmaceutical composition of claim 19, wherein the symptoms associated with Alzheimer's disease are determined by CDR-SB, CDR-GS, MMSE, ADCOMS and / or PET.

21. 20. The pharmaceutical composition of claim 19, wherein the at least one symptom associated with Alzheimer's disease is selected from clinical deterioration and cerebral amyloid levels.

22. 22. The pharmaceutical composition of claim 21, wherein the subject's clinical deterioration is assessed using CDR-SB, CDR-GS, MMSE, ADCOMS and / or ADAS-cog.

23. 2. The pharmaceutical composition of claim 1, wherein the CSF / plasma ratio of said antibody in said subject is 0.5% to 1.2%.

24. A pharmaceutical composition for administering an antibody to brain tissue of a subject, the composition comprising a bispecific antibody that specifically binds to human Aβ protein and human transferrin receptor (bispecific anti-Aβ / TfR antibody). the bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to human Aβ protein; three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO:5 (LCDR1), SEQ ID NO:6 (LCDR2), and SEQ ID NO:7 (LCDR3); and two copies of a first pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising: ii) forming a binding site that specifically binds to the human transferrin receptor; Three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domain and cognate antibody light chain variable domain comprising Including, wherein the antibody is administered intravenously once every four weeks at a dose of 3.6 mg / kg of body weight of the subject, and the CSF / plasma ratio of the antibody in the subject is between 0.5% and 1.2%. Pharmaceutical compositions.

25. 25. The pharmaceutical composition of claim 24, wherein administration of the pharmaceutical composition reduces amyloid levels in the subject.

26. 25. The pharmaceutical composition of claim 24, wherein administration of the pharmaceutical composition results in the subject being amyloid negative as determined by visual reading of amyloid PET images.

27. 27. The pharmaceutical composition of claim 26, wherein the amyloid-negative determination is made after three months of administration of the pharmaceutical composition.

28. 25. The pharmaceutical composition of claim 24, wherein the bispecific anti-Aβ / TfR antibody is trontinemab.

29. 25. The pharmaceutical composition of claim 24, wherein the subject has been diagnosed with mild or prodromal Alzheimer's disease.

30. 25. The pharmaceutical composition of claim 24, wherein administration of said pharmaceutical composition reduces amyloid levels in said subject by at least 40 centiloids as determined by visual reading of an amyloid PET.

31. 25. The pharmaceutical composition of claim 24, wherein administration of said pharmaceutical composition reduces amyloid levels in said subject by at least 60 centiloids as determined by visual reading of an amyloid PET.

32. 25. The pharmaceutical composition of claim 24, wherein administration of the pharmaceutical composition reduces amyloid levels in the subject within three months of initiating administration of the pharmaceutical composition.

33. 29. The pharmaceutical composition of claim 28, wherein no additional Alzheimer's disease medication other than trontinemab is administered to the subject.

34. 25. The pharmaceutical composition of claim 24, wherein Aβ is human Aβ protein fragment 1-42 and the transferrin receptor is human transferrin receptor 1.

35. 25. The pharmaceutical composition of claim 24, wherein the subject does not exhibit amyloid-related imaging abnormalities - edema (ARIA-E) or amyloid-related imaging abnormalities - hemosiderin deposition (ARIA-H) after administration of the pharmaceutical composition.

36. 36. The pharmaceutical composition of any one of claims 24 to 35, wherein administration of the pharmaceutical composition reduces the severity of at least one symptom associated with Alzheimer's disease in a subject.

37. 37. The pharmaceutical composition of claim 36, wherein the symptoms associated with Alzheimer's disease are determined by CDR-SB, CDR-GS, MMSE, ADCOMS and / or PET.

38. 37. The pharmaceutical composition of claim 36, wherein the at least one symptom associated with Alzheimer's disease is selected from clinical deterioration and brain amyloid levels.

39. 39. The pharmaceutical composition of claim 38, wherein the subject's clinical deterioration is assessed using CDR-SB, CDR-GS, MMSE, ADCOMS and / or ADAS-cog.

40. 1. Use of a bispecific antibody that specifically binds human Aβ protein and human transferrin receptor (bispecific anti-Aβ / TfR antibody) in the manufacture of a medicament for the treatment of Alzheimer's disease in a subject, comprising: the bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to human Aβ protein; three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO:5 (LCDR1), SEQ ID NO:6 (LCDR2), and SEQ ID NO:7 (LCDR3); and two copies of a first pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising: ii) forming a binding site that specifically binds to the human transferrin receptor; Three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domain and cognate antibody light chain variable domain comprising Including, wherein the medicament is administered intravenously once every four weeks at a dose of 3.6 mg / kg of antibody per subject's body weight. use.

41. 1. Use of a bispecific antibody that specifically binds to human Aβ protein and human transferrin receptor (bispecific anti-Aβ / TfR antibody) in the manufacture of a medicament for reducing amyloid levels in a subject, comprising: the bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to human Aβ protein; three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO:5 (LCDR1), SEQ ID NO:6 (LCDR2), and SEQ ID NO:7 (LCDR3); and two copies of a first pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising: ii) forming a binding site that specifically binds to the human transferrin receptor; Three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domain and cognate antibody light chain variable domain comprising Including, wherein the medicament is administered intravenously once every four weeks at a dose of 3.6 mg / kg of antibody per subject's body weight. use.

42. Use of a bispecific antibody that specifically binds to human Aβ protein and human transferrin receptor (bispecific anti-Aβ / TfR antibody) in the manufacture of a medicament for reducing clinical deterioration in a subject with early stage Alzheimer's disease, comprising: the bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to human Aβ protein; three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO:5 (LCDR1), SEQ ID NO:6 (LCDR2), and SEQ ID NO:7 (LCDR3); and two copies of a first pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising: ii) forming a binding site that specifically binds to the human transferrin receptor; Three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domain and cognate antibody light chain variable domain comprising Including, wherein the medicament is administered intravenously to the subject at a dose of 3.6 mg / kg of antibody per subject's body weight once every four weeks. use.

43. 1. Use of a bispecific antibody that specifically binds to human Aβ protein and human transferrin receptor (bispecific anti-Aβ / TfR antibody) in the manufacture of a medicament for administering the antibody to brain tissue of a subject, comprising: the bispecific anti-Aβ / TfR antibody i) forming a binding site that specifically binds to human Aβ protein; three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO:5 (LCDR1), SEQ ID NO:6 (LCDR2), and SEQ ID NO:7 (LCDR3); and two copies of a first pair of antibody heavy chain variable domains and cognate antibody light chain variable domains comprising: ii) forming a binding site that specifically binds to the human transferrin receptor; Three heavy chain complementarity determining regions (HCDRs) comprising 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) comprising the amino acid sequences of SEQ ID NO: 13 (LCDR1), SEQ ID NO: 14 (LCDR2), and SEQ ID NO: 15 (LCDR3); and one copy of a second pair of antibody heavy chain variable domain and cognate antibody light chain variable domain comprising Including, wherein the medicament is administered intravenously once every four weeks at a dose of 3.6 mg / kg of antibody per subject's body weight; the CSF / plasma ratio of said antibody in said subject is between 0.5% and 1.2%; use.

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