New molecules for diagnosis

Abstract

The present invention relates to novel amyloid - β (Aβ) - binding molecules, in particular Aβ antibodies or antigen - binding fragments thereof and / or their uses. The provided molecules can also be used to determine the predisposition to amyloid - β - related diseases, disorders or conditions, monitor the residual impairment of a disease or condition, or predict the responsiveness of a patient suffering from such a disease or condition to treatment with a specific drug. Accordingly, the present invention relates to novel molecules useful for diagnosing amyloid - β - related diseases, disorders or conditions. A sandwich immunoassay can be based on capturing and detecting an amyloid - β - binding antibody or an antigen - binding fragment thereof, wherein one or the other of the capturing or detecting antibody or antigen - binding fragment shows no cross - reactivity with soluble amyloid precursor protein (APP). Another amyloid - β - binding antibody or antigen - binding fragment can show cross - reactivity with soluble amyloid precursor protein (APP) without compromising the specificity of the assay for soluble APP.

Description

Technical Field

[0001] The present invention relates to novel amyloid-β (aβ, Abeta, Aβ) binding molecules, and in particular to aβ antibodies or antigen-binding fragments thereof and / or their uses. The provided molecules can also be used to determine a predisposition to an amyloid-β related disease, disorder or condition, monitor a disease, disorder or condition, or predict the responsiveness of a patient suffering from such a disease, disorder or condition to treatment with a particular drug. Accordingly, the present invention relates to novel molecules useful for diagnosing and / or treating amyloid-β related diseases, disorders or conditions. Background Art

[0002] Alzheimer's disease (AD) is the most common cause of dementia in the elderly, affecting an estimated 15 million people worldwide, 40% of whom are over 85 years old. The disease is characterized by the progressive loss of memory, language and motor skills, leading to complete incapacity and ultimately death in the patient. AD has a large and devastating impact on those who suffer from the disease, as well as their family, friends and caregivers.

[0003] Today, treatment focuses on controlling the symptoms of AD and its various stages. Currently available AD treatment options can help delay the worsening of AD symptoms for a limited period of time. However, there is no evidence that these drugs have any effect on the underlying progression of the disease. AD is currently incurable, and thus early AD treatment is necessary. In the absence of available disease-modifying treatment options, the need for good biomarkers for early diagnosis is as important as ever. The single most prominent and early biochemical feature of AD is the formation of extracellular amyloid-β (Aβ) plaques in the brain (Calderon-Garciduenas & Duyckaerts, 2017), which mainly contain Aβ in the 42-amino acid form. Aβ plaques are formed by Aβ peptides 39 to 43 amino acids in length (generated by the cleavage of amyloid precursor protein (APP)), which are in a random coil conformation in their native non-pathological form. During the transition to the pathological state, they mainly transform into a β-sheet secondary structure and spontaneously aggregate into insoluble deposits. Even though the exact role of Aβ in the development of AD is still controversial, it is widely accepted that soluble Aβ oligomers damage synaptic structure and function, and that the smallest synaptotoxic species are dimers or small soluble polymers, while neither Aβ monomers nor plaque cores significantly alter neuronal viability or synaptic plasticity (Shankar et al., 2008).

[0004] Down syndrome (DS), also known as trisomy 21, is one of the most common causes of intellectual disability, affecting 1 in 800 newborns. The disorder most commonly involves a triple dose of chromosome 21 (Belichenko, 2016). Subjects with DS have characteristic facial features, defects in the immune and endocrine systems, and delays in cognitive development. A key feature of adult subjects with DS is their increased risk of developing clinical symptoms similar to Alzheimer's disease (AD), which is characterized by the decline of specific cognitive domains that suggest a dementia diagnosis. Almost all subjects with DS older than 40 years exhibit neuropathological changes similar to AD in the form of senile plaque formation and neurofibrillary tangles (Head, 2012). It is generally accepted that the neuropathology of AD-like cognitive decline involves β-amyloid (Aβ) peptide deposition and subsequent plaque formation, neurofibrillary tangles, vascular damage, neuroinflammation, and ultimately neuronal cell death. The gene for amyloid precursor protein (APP), which encodes the precursor protein for Aβ, is located on chromosome 21. In subjects with DS, all or at least a portion of chromosome 21 is present in three copies. This therefore results in three copies of the gene encoding APP, leading to the production of excessive Aβ. Increased Aβ protein production has been shown to be associated with AD-like symptoms in subjects with DS as well as in the general population in which AD develops (Head, 2012). These findings ultimately suggest that lifelong overexpression of wild-type APP leads to cognitive decline in subjects with DS in a manner similar to the amyloid cascade hypothesis used to describe subjects with AD. Down syndrome-associated Alzheimer's disease is characterized by the presence of the neuropathological features of Alzheimer's disease (including in particular the accumulation of cerebral amyloid plaques and neurofibrillary tangles), which can lead to the emergence of clinical symptoms such as cognitive decline and functional impairment when the brain lesions are fully developed.

[0005] Amyloid-β related diseases, disorders or conditions are neurological disorders such as Alzheimer's disease (AD). Other examples of amyloid-β related diseases, disorders or conditions according to the present invention include mild cognitive impairment (MCI), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease (PD), Parkinson's Disease with Dementia (PDD), dementia with Lewy bodies, ALS (amyotrophic lateral sclerosis), adult onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, myotonic dystrophy, and liver dysfunction or failure. Many of these conditions are characterized by or associated with a loss of cognitive memory ability. Thus, conditions according to the present invention that are characterized by or associated with a loss of cognitive memory ability include AD, mild cognitive impairment (MCI), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Parkinson's Disease with Dementia (PDD), dementia with Lewy bodies, ALS (amyotrophic lateral sclerosis), myotonic dystrophy, liver dysfunction or failure, and inclusion body myositis (IBM).

[0006] Currently, there are no clinically validated biomarkers of patient samples (e.g., blood, cerebrospinal fluid, urine, etc.) available for specifically diagnosing, stratifying or monitoring the progression or regression of amyloid-β related diseases, disorders or conditions in an object. Most AD biomarker studies have focused on quantitative changes in Tau and Aβ proteins in cerebrospinal fluid from AD patients and modifications of these protein levels, where Aβ levels show earlier changes (Buchhave et al., 2012). For the field of AD biomarkers and diagnosis, there is a great need for Aβ antibodies that can be engineered and optimized for a given biomarker use and specific diagnostic technology platform.

[0007] Early diagnosis of Alzheimer's disease (AD) and other conditions in which Aβ plays a role in pathology and / or Aβ levels are altered in vulnerable body tissues as a marker of disease progression is crucial for early intervention. The progression of biochemical changes in AD is slow and a relatively long time elapses before the first clinical signs of the disease are visible. An even longer time elapses before a reliable diagnosis of AD can be made and distinguished from other forms of dementia (Knopman et al., 2001). In cases where neurodegeneration may begin 20 years or more before a reliable clinical diagnosis of symptoms, the symptoms of mild cognitive impairment (MCI) may be noted, suggesting that AD is in the prodromal phase (Britt et al., 2011). Although MCI is characteristic of the prodromal phase of AD, it has a highly variable natural history, with fluctuations in cognitive status over time making it an unreliable predictor of the progression to clinical diagnosis of AD (Gauthier et al., 2006). Alterations in biomarkers used as surrogates for disease progression in vulnerable tissues are thought to occur early during the preclinical prodromal phase of AD (Rob et al., 2017). Herein, antibodies generated for use in the determination of Aβ biomarkers for the early diagnosis and / or treatment of amyloid-β related diseases, disorders or conditions are described. SUMMARY OF THE INVENTION

[0008] One object of the present invention is to provide binding molecules, in particular amyloid-β antibodies or antigen-binding fragments thereof, which can be used for uses related to amyloid-β related diseases, disorders or conditions, such as for example diagnosis. The binding molecules of the present invention, in particular amyloid-β antibodies or antigen-binding fragments thereof, can selectively bind or capture any amyloid-β peptide or substance in solution, in particular in a body fluid or a buffer solution. Unexpectedly, it has been found that the amyloid-β antibodies or antigen-binding fragments thereof of the present invention can also selectively bind or capture any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance, and / or have no cross-reactivity with soluble amyloid precursor protein (APP), in particular with soluble APP generated by α-secretase cleavage (referred to herein as "soluble APPα" or "sAPPα"). The reference to selective binding or selective capture means that the binding molecule does not significantly bind to any other substance present in the solution (such as a body fluid) other than amyloid-β, regardless of the conformational state. This can apply to both in vitro and in vivo backgrounds. As described herein, selectivity is important for effective performance in a variety of diagnostic applications. Thus, in some preferred embodiments, the binding molecules of the present invention do not significantly bind to other protein substances found in plasma, which include apolipoproteins, immunoglobulins, albumin, fibrinogen, etc. In other words, when binding or capturing in a plasma sample, the binding molecules of the present invention are specific for amyloid-β, regardless of the conformational state. The degree of binding of the binding molecules of the present invention, in particular amyloid-β antibodies or antigen-binding fragments thereof, to unrelated non-amyloid-β proteins can be less than about 10% of the binding of the antibody to amyloid-β, as measured for example by radioimmunoassay (RIA). When reference is made to "no cross-reactivity" with sAPPα, it is intended to mean that the binding molecule does not have appreciable binding to sAPPα. This can be measured, for example, by comparing the binding to sAPPα with the binding to Aβ1-42. When normalized against Aβ1-42 binding, the level of binding to sAPPα can be less than 10% of the binding to Aβ1-42, preferably less than 5% or more preferably less than 3%. Such a comparison can be carried out by ELISA, for example indirect ELISA. Reference Figure 8Suitable assays are described in Example 3. These antibodies are particularly useful in the present invention, especially as capture antibodies and / or detection antibodies in the form of a sandwich immunoassay. The terms "capture" and "detection" are terms in the art. The capture antibody binds to and captures the antigen, usually by binding to a solid surface (to which the capture antibody is attached). The detection antibody also binds to the antigen, usually to a non-overlapping epitope, since the capture antibody and the detection antibody bind simultaneously. The detection antibody generates a signal for the assay. Detection can be direct (e.g., by a directly labeled antibody, such as an enzyme or a fluorescent label) or indirect (e.g., using a secondary antibody that is subsequently labeled). It has been found that if one of the capture antibody or the detection antibody is an antibody that is non-cross-reactive with sAPPα, the sandwich immunoassay will generally be specific and will not give a signal against sAPPα, even if the other antibody reacts with sAPPα. Specific antibodies that show no cross-reactivity with sAPPα are shown in Table 1 (last column, "-" indicates no binding). In some aspects of the present invention, antibodies that are non-cross-reactive with sAPPα are used as both the capture antibody and the detection antibody. Such an assay provides sensitive detection of Aβ without detecting sAPPα (i.e., also has good specificity).

[0009] Thus, some binding molecules of the present invention may show low cross-reactivity with sAPPα. It is usefully used in combination with the binding molecules of the present invention that show no cross-reactivity. Similarly, low cross-reactivity can be measured, for example, by comparing the binding to sAPPα and the binding to Aβ1-42. When normalized against Aβ1-42 binding, the level of binding to sAPPα can be greater than 10% to 60% of the binding to Aβ1-42, for example, about 50%. Such a comparison can be performed by ELISA, for example, indirect ELISA. Reference Figure 8 Suitable assays of this type of the present invention are described in Example 3. The results for the tested antibodies of the present invention are shown in Table 1. It has been determined that binding molecules that have a low level of cross-reactivity with sAPPα can be particularly advantageous when used in combination with binding molecules that are non-cross-reactive with sAPPα. Thus, according to the present invention, a combination of a binding molecule that has a low level of cross-reactivity with sAPPα and a binding molecule that is non-cross-reactive with sAPPα can be used for a sandwich immunoassay. In particular, the binding molecule that has a low level of cross-reactivity with sAPPα can be used as the capture antibody or the detection antibody, and the binding molecule that is non-cross-reactive with sAPPα can be used as the detection antibody or the capture antibody. Reference Figure 8 Suitable assays of this type of the present invention are described in Example 3. Thus, for example, the antibody ACI-31-25B1-Ab2 can be used as the capture antibody and ACI-24-41F12-Ab2 as the detection antibody.

[0010] Some binding molecules of the present invention may exhibit high cross-reactivity with sAPPα. Similarly, this can be measured, for example, by comparing the binding to sAPPα with the binding to Aβ1-42. When normalized against Aβ1-42 binding, the level of binding to sAPPα can be greater than 60% of the binding to Aβ1-42, such as 70% to 90%, such as about 80%. Such a comparison can be performed by ELISA, such as indirect ELISA. Reference Figure 8 A suitable assay is described in Example 3. The results for the antibodies of the present invention tested are shown in Table 1. Binding molecules with a high level of cross-reactivity with sAPPα can be used in combination with binding molecules without cross-reactivity with sAPPα. Thus, according to the present invention, a combination of a binding molecule with a high level of cross-reactivity with sAPPα and a binding molecule without cross-reactivity with sAPPα can be used for a sandwich immunoassay, which provides high sensitivity for Aβ and does not detect soluble APPα (i.e., high specificity). In such an assay, the selectivity is provided by the binding molecules of the present invention that do not cross-react with sAPPα. In particular, a binding molecule with a high level of cross-reactivity with sAPPα can be used as a capture antibody or a detection antibody, and a binding molecule without cross-reactivity with sAPPα can be used as a detection antibody or a capture antibody. Antibodies of the present invention with high cross-reactivity with sAPPα include ACI-8037-103H5-Ab2 and ACI-8037-109F4-Ab1. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 1; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. Thus, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17.

[0011] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37.

[0012] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 43; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 45; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 46; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 47. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 43; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 45; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 46; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 47.

[0013] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 65; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 65; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17.

[0014] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 73; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 73; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17.

[0015] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87.

[0016] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 91; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 92; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 93; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 91; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 92; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 93; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97.

[0017] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 102; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 103; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 105; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 106; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 102; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 103; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 105; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 106; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107.

[0018] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 111; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 112; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 113; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 117. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 111; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 112; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 113; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 117.

[0019] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 121; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 122; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 123; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 125; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 126; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 127. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 121; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 122; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 123; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 125; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 126; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 127.

[0020] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 131; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 132; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 133; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 135; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 137. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 131; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 132; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 133; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 135; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 137.

[0021] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 142; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 133; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 137. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 142; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 133; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 137.

[0022] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 151; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 153; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 155; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 151; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 153; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 155; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 161; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 162; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 163; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 165; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 166; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 167. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 161; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 162; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 163; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 165; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 166; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 167.

[0023] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 171; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 172; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 173; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 175; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 171; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 172; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 173; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 175; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157.

[0024] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 181; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 182; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 183; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 187. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 181; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 182; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 183; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 187.

[0025] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 181; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 182; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 183; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 195; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 196; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 197. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 181; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 182; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 183; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 195; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 196; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 197.

[0026] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14.

[0027] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34.

[0028] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44.

[0029] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 60 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 60 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64.

[0030] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 70 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 74. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 70 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 74.

[0031] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84.

[0032] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 90 and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 94. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 90 and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 94.

[0033] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 100 and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 104. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 100 and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 104.

[0034] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 110 and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 114. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 110 and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 114.

[0035] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 120 and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 124. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 120 and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 124.

[0036] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 130 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 134. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 130 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 134.

[0037] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 140 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 144. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 140 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 144.

[0038] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154.

[0039] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 160 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 164. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 160 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 164.

[0040] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 170 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 174. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 170 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 174.

[0041] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 180 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 184. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 180 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 184.

[0042] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 180 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 194. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 180 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 194.

[0043] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14.

[0044] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34.

[0045] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or a heavy chain variable region (VH) having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 40; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44 or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or a heavy chain variable region (VH) having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 40; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44 or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44.

[0046] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 60 or a heavy-chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 60; and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 64 or a light-chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 64. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 60 or a heavy-chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 60; and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 64 or a light-chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 64.

[0047] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 70 or a heavy-chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 70; and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 74 or a light-chain variable region (VL) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 74. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 70 or a heavy-chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 70; and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 74 or a light-chain variable region (VL) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 74.

[0048] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 80; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 80; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84.

[0049] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 90 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 90; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 94 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 94. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 90 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 90; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 94 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 94.

[0050] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 100 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 100; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 104. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 100 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 100; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 104.

[0051] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 110 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 110; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 114 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 114. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 110 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 110; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 114 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 114.

[0052] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 120 or a heavy chain variable region (VH) having at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 120; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 124 or a light chain variable region (VL) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 124. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 120 or a heavy chain variable region (VH) having at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 120; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 124 or a light chain variable region (VL) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 124.

[0053] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 130 or a heavy-chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 130; and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 134. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 130 or a heavy-chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 130; and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 134.

[0054] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 140 or a heavy-chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 140; and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 144. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 140 or a heavy-chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 140; and a light-chain variable region (VL) comprising the sequence of SEQ ID NO: 144.

[0055] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 150; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154 or a light chain variable region (VL) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 154. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 150; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154 or a light chain variable region (VL) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 154.

[0056] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 160 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 160; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 164 or a light chain variable region (VL) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 164. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 160 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 160; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 164 or a light chain variable region (VL) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 164.

[0057] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 170 or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 170; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 174. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 170 or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 170; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 174.

[0058] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 180 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 180; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 184. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 180 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 180; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 184.

[0059] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 180 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 180; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 194. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 180 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 180; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 194.

[0060] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 10. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 10.

[0061] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30.

[0062] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or a heavy chain variable region (VH) having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 40. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or a heavy chain variable region (VH) having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 40.

[0063] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 60 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 60. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 60 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 60.

[0064] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 70 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 70. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 70 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 70.

[0065] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 80. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 80.

[0066] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 90 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 90. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 90 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 90.

[0067] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 100 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 100. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 100 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 100.

[0068] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 110 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 110. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 110 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 110.

[0069] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 120 or a heavy-chain variable region (VH) having at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 120. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 120 or a heavy-chain variable region (VH) having at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 120.

[0070] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 130 or a heavy-chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 130. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 130 or a heavy-chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 130.

[0071] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 140 or a heavy-chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 140. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy-chain variable region (VH) comprising the sequence of SEQ ID NO: 140 or a heavy-chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 140.

[0072] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 150. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 150.

[0073] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 160 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 160. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 160 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 160.

[0074] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 170 or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 170. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 170 or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 170.

[0075] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 180 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 180. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 180 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 180.

[0076] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14.

[0077] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34.

[0078] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44 or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44 or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44.

[0079] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 64. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 64.

[0080] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 74 or a light chain variable region (VL) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 74. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 74 or a light chain variable region (VL) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 74.

[0081] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84.

[0082] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 94 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 94. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 94 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 94.

[0083] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 104. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 104.

[0084] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 114 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 114. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 114 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 114.

[0085] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 124 or a light chain variable region (VL) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 124. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 124 or a light chain variable region (VL) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO: 124.

[0086] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 134. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 134.

[0087] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 144. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a light chain variable region (VL) comprising the sequence of SEQ ID NO: 144.

[0088] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154 or a light chain variable region (VL) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 154. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154 or a light chain variable region (VL) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 154.

[0089] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises a light chain variable region (VL) comprising the sequence of SEQ ID NO: 164 or a light chain variable region (VL) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 164. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises a light chain variable region (VL) comprising the sequence of SEQ ID NO: 164 or a light chain variable region (VL) having at least 99% sequence identity to the amino acid sequence of SEQ ID NO: 164.

[0090] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises a light chain variable region (VL) comprising the sequence of SEQ ID NO: 174. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises a light chain variable region (VL) comprising the sequence of SEQ ID NO: 174.

[0091] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises a light chain variable region (VL) comprising the sequence of SEQ ID NO: 184. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises a light chain variable region (VL) comprising the sequence of SEQ ID NO: 184.

[0092] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises a light chain variable region (VL) comprising the sequence of SEQ ID NO: 194. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises a light chain variable region (VL) comprising the sequence of SEQ ID NO: 194.

[0093] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13.

[0094] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33.

[0095] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 43. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 43.

[0096] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63.

[0097] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 73. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 73.

[0098] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83.

[0099] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 91; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 92; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 93. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 91; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 92; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 93.

[0100] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 102; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 103. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 102; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 103.

[0101] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 111; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 112; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 113. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 111; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 112; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 113.

[0102] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 121; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 122; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 123. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 121; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 122; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 123.

[0103] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 131; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 132; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 133. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 131; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 132; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 133.

[0104] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 142; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 133. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 142; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 133.

[0105] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 151; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 153. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 151; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 153.

[0106] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 161; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 162; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 163. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 161; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 162; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 163.

[0107] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 171; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 172; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 173. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 171; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 172; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 173.

[0108] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 181; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 182; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 183. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 181; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 182; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 183.

[0109] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17.

[0110] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37.

[0111] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 45; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 46; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 47. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 45; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 46; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 47.

[0112] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 65; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 65; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17.

[0113] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17.

[0114] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87.

[0115] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97.

[0116] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 105; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 106; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 105; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 106; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107.

[0117] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 117. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 117.

[0118] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 125; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 126; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 127. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 125; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 126; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 127.

[0119] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 135; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 137. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 135; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 137.

[0120] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 137. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 137.

[0121] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 155; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 155; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157.

[0122] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 175; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 175; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157.

[0123] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 187. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 187.

[0124] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 195; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 196; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 197. Accordingly, the present invention also provides an amyloid-β binding molecule, particularly an amyloid-β antibody or an antigen-binding fragment thereof, which comprises: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 195; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 196; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 197.

[0125] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 27. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 38. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 48. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 50. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 56. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 58.

[0126] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 25. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 49. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 57. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 59.

[0127] In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 20 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 22 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 24 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 25. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 27 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 38 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 39. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 48 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 49. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 50 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 56 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 57. In some embodiments, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, comprises: a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 58 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 59.

[0128] The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 41; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 42; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 43; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 45; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 46; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 47. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 65; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17.The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise amino acid changes in the CDR sequences contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 73; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise amino acid changes in the CDR sequences contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise amino acid changes in the CDR sequences contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 91; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 92; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 93; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise amino acid changes in the CDR sequences contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 102; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 103; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 105; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 106; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107.The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided in the following: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 111; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 112; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 113; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 117. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided in the following: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 121; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 122; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 123; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 125; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 126; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 127. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided in the following: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 131; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 132; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 133; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 135; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 137. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided in the following: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 141; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 142; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 133; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 137.The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 151; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 153; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 155; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 161; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 162; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 163; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 165; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 166; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 167. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 171; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 172; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 173; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 175; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157. The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise an amino acid change in a CDR sequence contained therein and compared to the CDR sequences provided below: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 181; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 182; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 183; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 187.The binding molecule, antibody or antigen-binding fragment thereof may additionally or alternatively comprise amino acid changes in the CDR sequences contained therein and as compared to the CDR sequences provided in the following: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 181; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 182; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 183; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 195; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 196; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 197. In particular, the CDR sequences contained in the binding molecule, antibody or antigen-binding fragment thereof may comprise one, two or three amino acid changes relative to the CDR sequences provided herein. "Amino acid change" may relate to a mutation, deletion or addition of an amino acid. It may also relate to a chemical alteration of an amino acid, such as the formation of a non-natural amino acid.

[0129] Amino acid sequence variants of the binding molecules provided herein, particularly antibodies or antigen-binding fragments thereof, are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of an antibody. Amino acid sequence variants of an antibody can be prepared by introducing suitable modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions and / or insertions and / or substitutions of residues within the amino acid sequence of the antibody. Any combination of deletions, insertions and substitutions can be made to arrive at the final construct, provided that the final construct has the desired characteristics, such as antigen binding.

[0130] In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Target sites for replacement mutagenesis include the CDRs and the framework regions (FRs). Conservative substitutions are shown under the heading "preferred substitutions" in Table A. More significant changes are provided under the heading "exemplary substitutions" in Table A and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into the target antibody and the products screened for the desired activity, such as retained / improved antigen binding or improved selectivity.

[0131] Table A

[0132]

[0133]

[0134] Amino acids can be grouped according to common side chain properties:

[0135] (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile;

[0136] (2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln;

[0137] (3) Acidic: Asp, Glu;

[0138] (4) Basic: His, Lys, Arg;

[0139] (5) Residues affecting chain orientation: Gly, Pro;

[0140] (6) Aromatic: Trp, Tyr, Phe.

[0141] Non-conservative substitutions would require replacing a member of one of these categories with a member of another category.

[0142] One type of replacement variant involves replacing one or more hypervariable region residues of a parental antibody (e.g., a humanized or human antibody). Typically, the resulting variant selected for further study will have improved (e.g., enhanced) (e.g., increased affinity, reduced immunogenicity) and / or will substantially retain certain biological properties of the parental antibody in certain biological properties. An exemplary replacement variant is an affinity matured antibody, which can be conveniently generated, for example, using phage display-based affinity maturation techniques. Briefly, one or more CDR residues are mutated, the variant antibodies are displayed on phage and screened for a particular biological activity, e.g., binding affinity).

[0143] Changes (e.g., substitutions) can be made in the CDRs, for example, to improve antibody affinity. Such changes can be made in CDR "hot spots", i.e., residues encoded by codons that mutate at high frequency during somatic maturation (see, e.g., Chowdhury, Methods Mol.Biol. 207:179-196 (2008)), and / or in SDRs (a-CDRs), and the binding affinity of the resulting variant VH or VL is tested. Affinity maturation by construction of a secondary library and reselection from the secondary library has been described, for example, in Hoogenboom et al., in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable gene selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants having the desired affinity. Another method for introducing diversity involves CDR-directed methods, in which several CDR residues (e.g., 4 to 6 residues at a time) are randomized. CDR residues involved in antigen binding can be specifically identified, for example, using alanine-scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are typically targeted.

[0144] In certain embodiments, substitutions, insertions, or deletions can occur in one or more CDRs, provided that such changes do not substantially reduce the ability of the antibody to bind antigen. For example, conservative changes (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity can be made in the CDRs. Such changes can be outside of CDR "hot spots" or SDRs. In certain embodiments of the variant VH and VL sequences provided above, each CDR is unaltered or contains no more than one, two, or three amino acid substitutions.

[0145] An available method for identifying targetable mutagenic residues or regions of an antibody is called "alanine scanning mutagenesis", as described by Cunningham and Wells (1989) Science, 244: 1081-1085. In this method, residues or groups of target residues (e.g., charged residues such as Arg, Asp, His, Lys, and Glu) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction between the antibody and the antigen is affected. Additional substitutions can be introduced at the amino acid positions to show functional sensitivity to the initial substitution. Alternatively or additionally, the crystal structure of the antigen-antibody complex is used to identify the contact points between the antibody and the antigen. Such contact residues and neighboring residues can be targeted or eliminated as candidates for substitution. Variants can be screened to determine whether they possess the desired properties.

[0146] Amino acid sequence insertions include fusions of polypeptides ranging in length from one residue to polypeptides containing one hundred or more residues at the amino terminus and / or carboxyl terminus, as well as in-sequence insertions of single or multiple amino acid residues. Some examples of terminal insertions include antibodies having an N-terminal methionyl residue. Other insertion-type variants of antibody molecules include fusions of the N or C terminus of the antibody with an enzyme or other label (e.g., HRP or AP) or a polypeptide that increases the serum half-life of the antibody.

[0147] Within the scope of the present invention, amyloid-β can have the sequence of aβ1-43 (SEQ ID NO: 3), aβ1-42 (SEQ ID NO: 1), aβ1-41 (SEQ ID NO: 4), aβ1-40 (SEQ ID NO: 5), or aβ1-39 (SEQ ID NO: 6) or a fragment thereof.

[0148] The term "amyloid-beta peptide or species" refers to amyloid-beta generated by cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase activities. Thus, "amyloid-beta peptide or species" refers to amyloid-beta generated via the amyloidogenic pathway. However, the term is also intended to cover synthetically produced peptides. Those peptides will have the same amino acid sequence but are not produced by processes occurring in vivo. Methods of peptide synthesis are well known in the art and commercially available. Amyloid-beta peptide or species may predominantly comprise amyloid-beta 1-42 (Aβ1-42) or amyloid-beta 1-43 (Aβ1-43) and their (shorter) fragments. Amyloid-beta peptide or species may incorporate post-translational modifications (PTMs), which include but are not limited to phosphorylation (e.g., phosphorylation of serine at amino acid residue 8 of amyloid-beta (pS8-Aβ)), glycosylation, oligomerization, and / or proteolytic cleavage. Synthetic processes may be used to add some PTMs. This may involve, for example, native components used in an in vitro environment, such as kinases. Amyloid-beta peptide or species may include (but are not limited to) the following amyloid-beta peptides: Aβ1-38, Aβ1-39, Aβ1-40, pS8-Aβ1-40, Aβ1-42, pS8-Aβ1-42, and Aβ1-43 and their (shorter) fragments. Aβ peptide fragments will contain epitopes recognized by binding molecules. Amyloid-beta peptide or species may adopt different conformational states, such as monomers, oligomers, or fibrillar structures.

[0149] Amyloid precursor protein (APP) is an integral membrane protein that is proteolytically processed to generate multiple peptide fragments, some of which are released and present in samples of body fluids (which may be referred to herein as "biological fluids"). The most prominent APP peptide fragments found in biological fluids include peptides (Aβ1-43, Aβ1-42, Aβ1-41, Aβ1-40, and Aβ1-39) released by beta- and gamma-secretase activities of the amyloidogenic pathway in the Aβ family. Another APP cleavage product found in biological fluids is soluble APPα (sAPPα), which is released by alpha-secretase of the non-amyloidogenic pathway. A binding molecule of the present invention that has no cross-reactivity with sAPPα, when used in combination, for example, when paired with a second Aβ antibody in a sandwich assay, advantageously does not detect sAPPα.

[0150] Thus, the binding molecules of the present invention, particularly antibodies or antigen-binding fragments thereof, can selectively bind or capture any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance, and have no cross-reactivity with soluble APPα. Some binding molecules of the present invention, particularly antibodies or antigen-binding fragments thereof, can selectively bind or capture any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance, and have low cross-reactivity with soluble APPα. Some binding molecules of the present invention may show higher cross-reactivity with sAPPα. Binding molecules showing no cross-reactivity, low cross-reactivity or high cross-reactivity with soluble APPα can be combined for use in a sandwich immunoassay, provided that one of the binding molecules of the present invention shows no cross-reactivity with sAPPα. In this case, the assay shows a specific signal for the overall pairing against Aβ and no signal against sAPPα. Preferably, the solution is a body fluid as described herein or a buffer solution. More preferably, the solution is a body fluid. Body fluid samples are defined as saliva, urine, nasal secretions, blood, brain and / or CSF, brain and / or ISF, more particularly blood, brain and / or CSF or brain and / or ISF. For example, a blood sample can be whole blood, serum or plasma sample, but preferably a plasma sample.

[0151] The binding molecules of the present invention, particularly antibodies or antigen-binding fragments thereof, bind to epitopes within the amino acid sequence of SEQ ID NO: 1. SEQ ID NO: 1 is the amino acid sequence of human Aβ1-42. It should be understood that equivalent binding regions exist in non-human Aβ. Thus, for example, the mouse Aβ1-42 amino acid sequence is 93% (39 / 42 residues) identical to the human sequence. The present invention encompasses binding molecules, particularly antibodies or antigen-binding fragments thereof, that bind to regions / peptides in non-human Aβ, particularly mouse Aβ, that are equivalent to those specified above with reference to SEQ ID NO: 1. The Aβ1-42 amino acid sequence is identical between mouse and rat. In certain embodiments, the binding molecules of the present invention, particularly antibodies or antigen-binding fragments thereof, bind to epitopes within amino acid residues 1 to 8 of SEQ ID NO: 1 (SEQ ID NO: 2). In certain embodiments, the binding molecules of the present invention, particularly antibodies or antigen-binding fragments, bind to epitopes within amino acid residues 1 to 8 (SEQ ID NO: 2), 1 to 5 (SEQ ID NO: 7), 17 to 23 (SEQ ID NO: 9), 22 to 35 (SEQ ID NO: 29), or 26 to 34 (SEQ ID NO: 8) of SEQ ID NO: 1. In some embodiments, amino acids 1 and 2 of Aβ1-42 are essential for binding to an antibody, particularly antibody ACI-24-41F12-Ab2 and related ones as described herein (e.g., by common CDRs and / or VH / VL sequences) (see SEQ ID Nos 10 to 25 and related embodiments). Without wishing to be bound by theory, it is believed that this antibody binds to an epitope that is inaccessible in soluble APPα. Soluble APPα contains amino acids 1 to 5 and 1 to 8 of Aβ1-42, but this antibody does not bind to sAPPα with high affinity.

[0152] In certain embodiments, the dissociation constant (KD) of the binding molecules of the present invention and as provided herein, particularly antibodies or antigen-binding fragments thereof, is ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or less, e.g., 10 -8 M to 10 -13 M, e.g., 10 -9 M to 10 -13M), particularly with respect to binding to aβ1-42. In some embodiments, provided are binding molecules that bind to human amyloid-β, particularly antibodies or antigen-binding fragments thereof, wherein the binding molecule, particularly the antibody or antigen-binding fragment thereof, binds to aβ with a KD of less than 100 nM, less than 10 nM, less than 1 nM, less than 200 pM, or less than 100 pM. In the present invention, it is preferred to use ELISA to determine the KD, such as described in Example 3 provided herein.

[0153] As used herein, the terms “binding molecule,” “amyloid-β antibody,” “anti-amyloid-β antibody,” “aβ antibody,” or simply “antibody” refer to a binding molecule, and more particularly an antibody that is capable of binding to Aβ monomers and / or soluble Aβ oligomers with sufficient affinity such that the binding molecule, antibody, or antigen-binding fragment thereof can be used as a diagnostic agent and / or therapeutic agent targeting amyloid-β. In one embodiment, the binding molecule of the present invention, particularly the amyloid-β antibody or antigen-binding fragment thereof, binds to an unrelated non-amyloid-β protein to an extent less than about 10% of the binding of the antibody to amyloid-β, as measured, for example, by radioimmunoassay (RIA).

[0154] In general, the term “antibody” is used herein in the broadest sense and encompasses a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific, bispecific antibodies), fully human antibodies, and antibody fragments, so long as they exhibit the desired antigen-binding activity. Antibodies within the present invention may also be chimeric antibodies, recombinant antibodies, antigen-binding fragments of recombinant antibodies, humanized antibodies, or antibodies displayed on the surface of a phage or on the surface of a chimeric antigen receptor (CAR) T cell.

[0155] An “antigen-binding fragment” of an antibody refers to a molecule that is different from the intact antibody and contains a portion of the intact antibody and binds to the antigen to which the intact antibody binds. Some examples of antibody fragments include but are not limited to Fv, Fab, Fab’, Fab’-SH, F(ab’)2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

[0156] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., each antibody comprising the population is identical except for possible minor variations that may occur naturally. A monoclonal antibody is highly specific, being directed against a single antigenic site. The modifier "monoclonal" indicates the character of the antibody as being from a substantially homogeneous population of antibodies and is not to be construed as requiring that the antibody be made by any particular method. Monoclonal antibodies according to the invention may be prepared by the hybridoma method described by Kohler, Nature 256(1975), 495.

[0157] Thus, in the context of the present invention, the term "antibody" refers to an entire immunoglobulin molecule as well as a portion of such an immunoglobulin molecule (i.e., "its antigen-binding fragment"). Further, as described above, the term refers to modified and / or altered antibody molecules. The term also refers to recombinantly or synthetically produced / synthesized antibodies. The term also refers to intact antibodies and antibody fragments thereof, such as isolated light and heavy chains, Fab, Fv, Fab', Fab'-SH, F(ab')2. The term antibody also includes, but is not limited to, fully human antibodies, chimeric antibodies, humanized antibodies, CDR-grafted antibodies, and antibody constructs such as single-chain Fv (scFv) or antibody fusion proteins.

[0158] The term "CDR" as used herein refers to "complementary determining region", which is well known in the art. CDRs are part of immunoglobulins, which determine the specificity of the molecule and contact specific ligands. CDRs are the most variable parts of the molecule and contribute to the diversity of these molecules. There are three CDR regions in each V domain: CDR1, CDR2, and CDR3. VH-CDR or CDR-H describes the CDR regions of the variable heavy chain, and VL-CDR or CDR-L refers to the CDR regions of the variable light chain. VH means variable heavy chain and VL means variable light chain. The CDR regions of the Ig source region can be determined as described in Kabat, "Sequences of Proteins of Immunological Interest", 5th ed., NIH Publication no. 91-3242, U.S. Department of Health and Human Services (1991); Chothia J., Mol. Biol. 196 (1987), 901-917 or Chothia, Nature 342 (1989), 877-883. The CDR sequences provided herein are defined according to Kabat. However, those skilled in the art will understand that the present invention is intended to cover binding molecules in which the CDR sequences are defined according to any useful identification / numbering scheme.For example, the following numbering schemes can be adopted to define CDR: Chothia (Canonical structures for the hypervariable regions of immunoglobulins. Chothia C, Lesk AM. J Mol Biol. 1987 Aug 20;196(4):901-17), IMGT (IMGT, the international ImMunoGeneTics database. Giudicelli V, Chaume D, Bodmer J, Müller W, Busin C, Marsh S, Bontrop R, Marc L, Malik A, Lefranc MP. Nucleic Acids Res. 1997 Jan 1;25(1):206-11 and Unique database numbering system for immunogenetic analysis. Lefranc MP. Immunol Today. 1997 Nov;18(11):509), MacCallum (MacCallum RM, Martin AC, Thornton JM, J Mol Biol. 1996 Oct 11;262(5):732-45) and Martin (Abhinandan KR, Martin ACR. Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains. Mol Immunol. (2008) 45:3832-9. 10.1016 / j.molimm.2008.05.022).

[0159] The "Fc" region contains two heavy chain fragments that contain the CH2 and CH3 domains of the antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.

[0160] The "Fv region" contains the variable regions from both the heavy and light chains, but lacks the constant regions.

[0161] An "antibody that binds to an epitope in a protein-defined region" is an antibody that requires the presence of one or more amino acids in that region to bind to the protein.

[0162] In certain embodiments, one or more amino acid modifications can be introduced into the Fc region of an antibody provided herein to generate an Fc region variant. The Fc region variant can comprise a murine Fc region sequence that is an antibody isotype or class (e.g., IgG1, IgG2a, IgG2b, or IgG2c) that contains amino acid modifications (e.g., substitutions) at one or more amino acid positions. The Fc region variant can comprise a human Fc region sequence (antibody isotype or class, e.g., human IgM, IgG1, IgG2, IgG3, or IgG4 Fc region) that contains amino acid modifications (e.g., substitutions) at one or more amino acid positions. An antibody isotype or class refers to the type of constant domain, region, or sequence contained in its heavy chain. There are five main antibody classes: IgA, IgD, IgE, IgG, and IgM, and several of these can also be divided into subclasses or isotypes, such as IgA1, IgA2, IgG1, IgG2, IgG2a (for murine only), IgG2b (for murine only), IgG2c (for murine only), IgG3, and IgG4. The heavy chain constant domains corresponding to the different classes of immunoglobulins are designated α, δ, ε, γ, and μ, respectively. The antibody light chain constant domain, region, or sequence can be one of two main classes, κ or λ. When the light chain class is not specified, it is assumed to be the more common κ light chain. In some embodiments, the antibody or antigen-binding fragment thereof of the invention comprises a murine IgG2a or chimeric (mouse / human) IgG1 isotype.

[0163] In some embodiments, the antibodies or antigen-binding fragments thereof of the present invention can be recombinantly produced. In some embodiments, (isolated) nucleic acids are provided, wherein the (isolated) nucleic acids encode a binding molecule of the present invention, particularly an antibody or an antigen-binding fragment thereof. As used herein, the term "nucleic acid" refers to a nucleic acid molecule. In some embodiments, a host cell or a cell-free expression system is provided, wherein the host cell or the cell-free expression system comprises the (isolated) nucleic acid encoding a binding molecule of the present invention, particularly an antibody or an antigen-binding fragment thereof. In some embodiments, a host cell is transfected with a vector comprising the (isolated) nucleic acid encoding a binding molecule of the present invention, particularly an antibody or an antigen-binding fragment thereof. In some embodiments, a host cell is transfected with a vector comprising the (isolated) nucleic acids encoding the heavy chain (HC) and the light chain (LC) of a binding molecule of the present invention, particularly an antibody or an antigen-binding fragment thereof. In some embodiments, a host cell is transfected with a) a first vector comprising the (isolated) nucleic acid encoding the heavy chain (HC) of a binding molecule of the present invention, particularly an antibody or an antigen-binding fragment thereof, and b) a second vector comprising the (isolated) nucleic acid encoding the light chain (LC) of a binding molecule of the present invention, particularly an antibody or an antigen-binding fragment thereof. In some embodiments, the host cell can be, but is not limited to, Chinese Hamster Ovary (CHO) cells. Suitable host cells can be cells of prokaryotes, yeast, or higher eukaryotes, particularly mammalian cells.Some examples of available mammalian host cell lines are monkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); human embryonic kidney line (293 or subcloned 293 cells for growth in suspension culture, Graham et al., J. Gen. Virol. 36:59 (1977)); baby hamster kidney cell (BHK, ATCC CCL 10); Chinese hamster ovary cell / -DHFR (CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); mouse Sertoli cell (TM4, Mather, Biol. Reprod. 23:243-251 (1980)); mouse myeloma cells SP2 / 0-AG14 (ATCC CRL 1581; ATCC CRL8287) or NS0 (HPA culture deposit number 85110503); monkey kidney cell (CV1 ATCC CCL 70); African green monkey kidney cell (VERO-76, ATCC CRL-1587); human cervical cancer cell (HELA, ATCC CCL 2); dog kidney cell (MDCK, ATCC CCL34); Buffalo rat hepatocyte (BRL 3A, ATCC CRL 1442); human lung cell (W138, ATCC CCL 75); human hepatocyte (Hep G2, HB 8065); mouse mammary tumor (MMT 060562, ATCC CCL51); TRI cell (Mather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982)); MRC 5 cell; FS4 cell; and human liver cancer cell line (HepG2), as well as DSM’s PERC-6 cell line. Expression vectors suitable for each of these host cells are also well known in the art. The term "host cell" generally refers to a cultured cell line. Thus, whole humans into which an expression vector encoding an antigen-binding polypeptide according to the present invention has been introduced are expressly excluded from the definition of "host cell". Cell-free expression systems can be based on cell lysates or extracts, such as the use of CHO cell lysates (Stech, M., Nikolaeva, O., Thoring, L. et al. Cell-free synthesis of functional antibodies using a coupled in vitro transcription-translation system based on CHO cell lysates. Sci Rep 7, 12030 (2017)).

[0164] In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid encodes a binding molecule of the invention as provided herein, particularly an antibody or an antigen-binding fragment thereof. In some embodiments, there is provided a host cell, wherein the host cell comprises an (isolated) nucleic acid encoding a binding molecule of the invention as provided herein, particularly an antibody or an antigen-binding fragment thereof. In some embodiments, a method of producing a binding molecule of the invention as provided herein, particularly an antibody or an antigen-binding fragment thereof, comprises culturing a host cell or a cell-free expression system under conditions suitable for producing the binding molecule, particularly an antibody or an antigen-binding fragment thereof. In some embodiments, a method for producing an (isolated) binding molecule of the invention as provided herein, particularly an antibody or an antigen-binding fragment thereof, comprises the steps of: a) culturing a host cell or a cell-free expression system under conditions suitable for producing the binding molecule, particularly an antibody or an antigen-binding fragment thereof, and b) recovering the binding molecule, particularly an antibody or an antigen-binding fragment thereof. Recovery of the binding molecule, particularly an antibody or an antigen-binding fragment thereof, can be carried out by any suitable means as would be understood by a person skilled in the art. Recovery can include purification to a desired purity level. Recovery can include isolating the antibody from the culture. Recovery can involve, for example, the use of chromatography. Such production methods can be scaled up and can thus enable large-scale production of the binding molecules of the invention. There is also provided a binding molecule produced according to the method, which can be considered an isolated binding molecule.

[0165] As used herein, the term “isolated” means a molecule that has been separated and / or recovered from its natural environment, such as a nucleic acid or an antibody. In the present invention, the molecule is preferably chemically synthesized or synthesized in a cell system different from the cell of its natural source and is thus “isolated” from its naturally associated components. The molecule can be separated from its natural environment, for example, by purification or produced by technical processes including, but not limited to, gene synthesis, polymerase chain reaction (PCR), vector purification, and protein (antibody) purification. Such a molecule can particularly be a nucleic acid, such as a DNA-, RNA-, or cDNA-sequence, or a peptide, an antibody, or a protein.

[0166] The present invention is not limited to the isolated antibody or isolated nucleic acid as defined above, but also relates to the antibody or nucleic acid itself regardless of its source.

[0167] This also applies to the peptides, nucleic acids, DNA, RNA, and / or cDNA sequences provided by the present invention, which are covered in isolated form (as defined above) or in any other form. Different techniques known in the art can be used, including (but not limited to) SDS-polyacrylamide gel electrophoresis (SDS-PAGE), column chromatography, filtration, isoelectric focusing, dialysis, recrystallization, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, and immunoprecipitation to purify, isolate, or separate the binding molecules of the present invention, particularly antibodies or their antigen-binding fragments or derivatives, from inside the cell or from outside the cell (e.g., the culture medium).

[0168] In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 18 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 19 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 52 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 53 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 54 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 55 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 68 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 69 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 78 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 79 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 88 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 89 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 98 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 99 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 108 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 109 encoding an aβ antibody or an antigen-binding fragment thereof.In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 118 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 119 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 128 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 129 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 138 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 139 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 148 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 149 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 158 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 159 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 168 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 169 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 178 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 179 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 188 encoding an aβ antibody or an antigen-binding fragment thereof. In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 189 encoding an aβ antibody or an antigen-binding fragment thereof.In some embodiments, there is provided an (isolated) nucleic acid, wherein the (isolated) nucleic acid comprises SEQ ID NO: 199 encoding an aβ antibody or an antigen-binding fragment thereof.

[0169] In some embodiments, there is provided a diagnostic composition comprising a binding molecule (of the invention and as provided herein), particularly an antibody or an antigen-binding fragment thereof, and an acceptable carrier and / or excipient. For example, the binding molecule, particularly an antibody or an antigen-binding fragment thereof, can be combined, as appropriate, with an acceptable carrier or medium (such as sterile water or saline solution, vegetable oil, emulsifying agent, suspending agent, surfactant, stabilizer, flavoring agent, excipient, vehicle, preservative, and binder), and formulated into a diagnostic preparation. The preferred diagnostic composition of the invention is compatible with a body fluid used as a test sample. Thus, the diagnostic composition can be used directly with a body fluid sample without further processing of the body fluid sample. For cell and / or tissue applications, the diagnostic composition can be formulated, in some embodiments, the same or differently, to facilitate use with such samples.

[0170] In some embodiments, there is provided a diagnostic composition comprising at least two amyloid-β binding antibodies or antigen-binding fragments thereof of the invention and an acceptable carrier and / or excipient.

[0171] In some embodiments, there is provided a diagnostic composition comprising:

[0172] a. a first amyloid-β binding antibody or an antigen-binding fragment thereof that selectively binds to any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance, and

[0173] b. a second amyloid-β binding antibody or an antigen-binding fragment thereof that selectively binds to any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance,

[0174] wherein at least one or both of the first and second antibodies exhibit no cross-reactivity with soluble amyloid precursor protein (APP), particularly soluble APPα.

[0175] One or both of the antibodies can be an antibody of the invention. Either antibody can be used as a capture antibody. Thus, it can be provided for attachment or conjugation to a solid support. The other antibody can be used as a detection antibody. Thus, it can be conjugated with a suitable label. Conjugated antibodies are described herein, and that description applies mutatis mutandis.

[0176] In some embodiments, both the first and second antibodies show no cross-reactivity with soluble amyloid precursor protein (APP), particularly with soluble APPα. In other embodiments, at least one of the first and second antibodies or antigen-binding fragments thereof shows cross-reactivity with soluble amyloid precursor protein (APP). The cross-reactivity can be low or high. The other antibody or antigen-binding fragment shows no cross-reactivity with soluble amyloid precursor protein (APP). In some embodiments, diagnostic compositions are provided that comprise at least two amyloid-β binding antibodies or antigen-binding fragments thereof and an acceptable carrier and / or excipient, wherein the amyloid-β binding antibody or antigen-binding fragment is selected from:

[0177] a) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and / or

[0178] b) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; and / or

[0179] c) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 151; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 153; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 155; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157.

[0180] In some specific embodiments, diagnostic compositions are provided that comprise a) and b) above or a) and c) above.

[0181] In a more preferred embodiment, a diagnostic composition is provided that comprises at least two amyloid-β binding antibodies or antigen-binding fragments thereof, and an acceptable carrier and / or excipient, wherein the amyloid-β binding antibody or antigen-binding fragment is selected from:

[0182] a) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; and

[0183] b) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37.

[0184] In some embodiments, a diagnostic composition is provided that comprises at least two amyloid-β binding antibodies or antigen-binding fragments thereof, and an acceptable carrier and / or excipient, wherein the amyloid-β binding antibody or antigen-binding fragment is selected from:

[0185] a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14; and / or

[0186] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34; and / or

[0187] c) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154.

[0188] In some specific embodiments, a diagnostic composition comprising a) and b) above or a) and c) above is provided.

[0189] In a more preferred embodiment, there is provided a diagnostic composition comprising at least two amyloid-β binding antibodies or antigen-binding fragments thereof, and an acceptable carrier and / or excipient, wherein the amyloid-β binding antibody or antigen-binding fragment is selected from:

[0190] a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14; and

[0191] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34.

[0192] In some embodiments, there is provided a diagnostic composition comprising at least two amyloid-β binding antibodies or antigen-binding fragments thereof, and an acceptable carrier and / or excipient, wherein the amyloid-β binding antibody or antigen-binding fragment is selected from:

[0193] a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14; and / or

[0194] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 30; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 34; and / or

[0195] c) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 150; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 154.

[0196] In some specific embodiments, a diagnostic composition comprising the above a) and b) or the above a) and c) is provided.

[0197] In some embodiments, a diagnostic composition is provided that comprises at least two amyloid-β binding antibodies or antigen-binding fragments thereof and an acceptable carrier and / or excipient, wherein the amyloid-β binding antibody or antigen-binding fragment is selected from:

[0198] a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14; and

[0199] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34.

[0200] In some embodiments, a diagnostic composition is provided that comprises at least one amyloid-β binding antibody or antigen-binding fragment thereof of the present invention in combination with at least one amyloid-β antibody known in the art and an acceptable carrier and / or excipient, particularly an antibody or antigen-binding fragment thereof that shows no cross-reactivity with soluble amyloid precursor protein (APP). In some embodiments, the amyloid-β antibody known in the art is a commercially available aβ binding antibody. In some embodiments, the antibodies are selected from: NAB228 (Invitrogen), 6E10 (Covance), 2C8 (Invitrogen), 4G8 (Chemicon), W0-2 (Merck), and DE2 (Chemicon). Such antibodies can be used as capture antibodies, and the antibodies of the present invention can be used as detection antibodies (or vice versa).

[0201] In some embodiments, provided are conjugated binding molecules, particularly antibodies or antigen-binding fragments thereof, comprising: a binding molecule as described herein, particularly an antibody or antigen-binding fragment thereof, and a conjugate molecule. The conjugates of the invention may be referred to as immunoconjugates. Any suitable conjugate molecule may be used according to the invention. Some suitable examples include, but are not limited to: enzymes (e.g., alkaline phosphatase or horseradish peroxidase), avidin, streptavidin, biotin, protein A / G, magnetic beads, fluorophores, radioisotopes (i.e., radiolabeled conjugates), nucleic acid molecules, detectable labels, therapeutic agents, toxins, and blood-brain barrier penetrating moieties. Conjugation methods are well known in the art, and several techniques for conjugating antibodies to labels or other molecules are commercially available. Conjugation is typically through amino acid residues (e.g., lysine, histidine, or cysteine) contained within the binding molecules of the invention. They may rely on methods such as the NHS (N-succinimidyl) ester method, the isothiocyanate method, the carbodiimide method, and the periodate method. Conjugation may be achieved, for example, by generating a fusion protein. This is suitable in the case of conjugating a binding molecule to another protein molecule. Thus, suitable genetic constructs may be formed that allow for the expression of a fusion of the binding molecule of the invention with a label or other molecule. Conjugation may be through a suitable linker moiety to ensure proper spatial separation of the antibody from the conjugate molecule (e.g., detectable label). However, a linker may not be required in all cases.

[0202] In some embodiments, provided are diagnostic compositions comprising a purified binding molecule as described herein, particularly an antibody or antigen-binding fragment thereof, and an acceptable carrier and / or excipient.

[0203] The binding molecules of the invention, particularly amyloid-β binding antibodies or antigen-binding fragments thereof, have many uses. They may be used for research purposes, particularly as analytical tools or reference molecules. They may be used to detect amyloid-β aggregates, including plaques, in vitro or in vivo. The binding molecules may be used to stain amyloid-β aggregates. For example, the binding molecules may be used for histochemical detection in postmortem brain tissue. The binding molecules are typically labeled and may be directly or indirectly labeled as discussed herein. Such uses may be carried out on any suitable animal, particularly a mammal. Preferred subjects are humans and mice.

[0204] In some embodiments, methods for diagnosing an amyloid-β related disease, disorder or condition are provided, such as Alzheimer's disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease (PD), Parkinson's disease dementia (PDD), dementia with Lewy bodies, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, myotonic dystrophy, and liver dysfunction or failure. The method comprises administering to a subject a binding molecule of the invention, particularly an antibody or an antigen-binding fragment thereof, or a diagnostic composition of the invention. More particularly, in some embodiments, methods for diagnosing an amyloid-β related disease, disorder or condition are provided, wherein the amyloid-β related disease, disorder or condition is selected from Alzheimer's disease (AD), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cerebral amyloid angiopathy (CAA), myotonic dystrophy, and dementia with Lewy bodies. The subject is typically a mammalian subject, preferably a human. For in vivo methods, the binding molecule is typically labeled with a suitable label for visualization purposes.

[0205] In certain embodiments, the binding molecules of the invention and as provided herein, particularly antibodies or antigen-binding fragments thereof, can be used to detect the presence of Aβ in a biological sample. In certain embodiments, the binding molecules of the invention and as provided herein, particularly antibodies or antigen-binding fragments thereof, can be used to detect the presence of Aβ in a bodily fluid sample. The term "bodily fluid sample" includes samples derived from bodily fluids by further processing such as concentration, centrifugation, and addition of additional substances (such as buffers and preservatives). In some specific embodiments, the binding molecules of the invention as provided herein, particularly antibodies or antigen-binding fragments thereof, can be used to detect the presence of pathological Aβ in a biological sample. The term "detect" as used herein encompasses quantitative and / or qualitative detection. Biological samples are typically obtained from mammals, particularly humans. Biological samples are typically clinical samples from a subject suspected of having or being screened for an amyloid-β related disease, disorder, or condition according to any of the methods described herein. Obtaining a sample does not form an essential step of the methods of the invention, and thus the methods of the invention can start with samples that have already been isolated. Obtaining a sample can be performed according to any suitable technique determined by the sample under discussion. In certain embodiments, biological samples include cells, tissues, and / or bodily fluids (such as nasal secretions, urine, blood, etc.) from a subject. Some examples of suitable biological samples include cerebrospinal fluid (CSF), interstitial fluid (ISF), cells or tissues of the brain (such as cerebral cortex or hippocampus). Some examples of suitable bodily fluids include cerebrospinal fluid (CSF), interstitial fluid (ISF), blood (including whole blood and derivatives such as serum and plasma), urine, and nasal secretions. In some embodiments, the biological sample is cerebrospinal fluid (CSF) or blood. In some embodiments, the biological sample is plasma.

[0206] In certain embodiments, methods are provided for detecting Aβ in a biological sample, wherein the method comprises contacting the biological sample with a binding molecule of the invention as provided herein, particularly an Aβ antibody or an antigen-binding fragment thereof, under conditions that permit binding of the binding molecule, particularly the Aβ antibody or an antigen-binding fragment thereof, to Aβ, and detecting whether a complex is formed between the binding molecule, particularly the Aβ antibody or an antigen-binding fragment thereof, and Aβ. If formation of the complex is detected, it can be determined that the sample contains Aβ. In the absence of complex formation or if complex formation is below a predetermined threshold, it can be determined that the sample does not contain Aβ. Such methods can be in vitro or in vivo methods. Additionally, the complex formed between the binding molecule, Aβ antibody or an antigen-binding fragment thereof and Aβ in the test biological sample can be compared to the complex formed in a control biological sample (e.g., a biological sample from one or more healthy subjects). The amount of the complex formed between the binding molecule, Aβ antibody or an antigen-binding fragment thereof and Aβ in the test biological sample can also be quantified and compared to the amount of the complex formed in a control biological sample (e.g., a biological sample from one or more healthy subjects) or the average amount of the complex known to be formed in healthy subjects.

[0207] In certain embodiments, the binding molecules of the invention and as provided herein, particularly antibodies or antigen-binding fragments thereof, can be used to detect the presence of Aβ in a biological sample. In some specific embodiments, the binding molecules of the invention and as provided herein, particularly antibodies or antigen-binding fragments thereof, can be used in immunoassays (including but not limited to ELISA, MSD (Meso Scale Discovery Inc., USA), Luminex (Luminex Corp., USA), Alphalisa (PerkinElmer, Inc., USA), Gyrolab (Gyros Protein Technologies AB, Sweden), Simoa (Quanterix Corp., USA), Gyros TM(Given et al., 2012), Singulex Erenna (EMD Millipore, Corp., USA), iR-SENSE / Immuno-InfraRed assay (Nabers et al, 2016), MITOMI (Piraino et al, 2016), immunoprecipitation combined with liquid chromatography mass spectrometry (IP LC-MS / MS; Shimadzu, Germany), surface plasmon resonance (Surface plasmon resonance, SPR; Cytiva Europe, Switzerland), atomic force microscope (Atomic force microscope, AFM) (Kiio and Park, 2020) or any other assay technique or kit that relies on antibodies for target immunocapture and / or detection). Thus, binding molecules, particularly antibodies or antigen-binding fragments thereof, can be used to validate / screen assays for binding molecules, aβ or aβ fragments, aβ antibodies or antigen-binding fragments thereof. The binding molecules of the present invention, particularly antibodies or antigen-binding fragments thereof, can be used as detection tools and / or positive controls because they bind to all aβ species in the sample in a selective manner. In one embodiment, at least two amyloid-β antibodies or antigen-binding fragments thereof can be used as assay reagents, positive controls, biomarker detection reagents, and / or calibrators for the immunoassays listed above. In one embodiment, at least two amyloid-β antibodies or antigen-binding fragments thereof can be used in an immunoassay, preferably a sandwich assay (ELISA) that results in a sandwich pairing of antibodies, wherein preferably the antibodies are selected from ACI-24-41F12-Ab3, ACI-31-25B1-Ab2, and ACI-8041-5A2D4-Ab1, and even more preferably the antibodies are ACI-24-41F12-Ab3 and ACI-31-25B1-Ab2. In one embodiment, the at least two amyloid-β antibodies or antigen-binding fragments thereof can be used in a sandwich assay (ELISA) that results in a sandwich pairing of antibodies, wherein one antibody or antigen-binding fragment thereof is used to capture the target (including but not limited to aβ), preferably ACI-31-25B1-Ab2, and wherein the other antibody or antigen-binding fragment thereof is used to detect the captured target, preferably ACI-24-41F12-Ab3, and more preferably ACI-24-41F12-Ab3 conjugated to a detectable label.

[0208] The present invention relates to a method for detecting amyloid-β in a sample obtained from a subject, the method comprising:

[0209] a. Capturing amyloid-β with an amyloid-β binding antibody or an antigen-binding fragment thereof, which selectively binds to any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance, and

[0210] b. Detecting the captured amyloid-β with an amyloid-β binding antibody or an antigen-binding fragment thereof, which selectively binds to any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance

[0211] wherein at least one or both of the capturing (a) and detecting (b) antibodies or antigen-binding fragments thereof show no cross-reactivity with soluble amyloid precursor protein (APP), particularly no cross-reactivity with soluble APPα. One or both of the capturing antibody and the detecting antibody can be the antibodies of the present invention. The capturing antibody can be provided for attachment or conjugation to a solid support. The detecting antibody can be conjugated with a suitable label. Conjugated antibodies are described herein, and this description applies with necessary modifications.

[0212] In some embodiments, both the capturing antibody and the detecting antibody show no cross-reactivity with soluble amyloid precursor protein (APP), particularly no cross-reactivity with soluble APPα. In other embodiments, one of the capturing antibody and the detecting antibody or antigen-binding fragment thereof shows cross-reactivity with soluble amyloid precursor protein (APP). The cross-reactivity can be low or high. The other antibody or antigen-binding fragment shows no cross-reactivity with soluble amyloid precursor protein (APP).

[0213] In some embodiments, the capturing antibody or antigen-binding fragment is immobilized on the surface of a solid support, such as the surface of a well (e.g., a well in a microtiter plate). In some embodiments, the detecting antibody or antigen-binding fragment is labeled with a detectable label.

[0214] In some embodiments, an amyloid-β binding antibody or antigen-binding fragment for capture or detection (preferably detection) comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, an amyloid-β binding antibody or antigen-binding fragment for capture or detection (preferably detection) comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14. In some embodiments, an amyloid-β binding antibody or antigen-binding fragment for capture or detection (preferably detection) comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14.

[0215] In some embodiments, an amyloid-β binding antibody or antigen-binding fragment for capture or detection (preferably capture) comprises:

[0216] a. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or

[0217] b. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 151; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 153; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 155; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157.

[0218] Preferred amyloid-β binding antibodies or antigen-binding fragments for capture comprise a) above.

[0219] In some embodiments, amyloid-β binding antibodies or antigen-binding fragments for capture or detection (preferably capture) comprise:

[0220] a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34; or

[0221] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154.

[0222] In some embodiments, amyloid-β binding antibodies or antigen-binding fragments for capture or detection (preferably capture) comprise:

[0223] a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 30; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 34; and / or

[0224] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 150; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 154.

[0225] The present invention also relates to a method for detecting amyloid-β in a sample obtained from a subject, the method comprising:

[0226] a. capturing amyloid-β with an amyloid-β binding antibody or an antigen-binding fragment thereof, the amyloid-β binding antibody or an antigen-binding fragment thereof selectively binding to any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance, and showing no cross-reactivity with soluble amyloid precursor protein (APP), in particular having high cross-reactivity with soluble APPα; and

[0227] b. Detect the captured amyloid-β with an amyloid-β binding antibody or an antigen-binding fragment thereof, which selectively binds to any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance, and exhibits (low or high) cross-reactivity with soluble amyloid precursor protein (APP), especially no cross-reactivity with soluble APPα.

[0228] In some embodiments, the capture antibody or antigen-binding fragment is immobilized on the surface of a solid support, such as the surface of a well (e.g., a well in a microplate). In some embodiments, the capture antibody and / or the detection antibody or antigen-binding fragment has a high affinity for aβ. In some embodiments, the detection antibody or antigen-binding fragment is labeled with a detectable label. In some embodiments, the captured amyloid-β binding antibody or antigen-binding fragment comprises:

[0229] a. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or

[0230] b. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 151; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152; VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 153; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 155; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157.

[0231] The preferred captured amyloid-β binding antibody or antigen-binding fragment comprises a) above.

[0232] In some embodiments, the captured amyloid-β binding antibody or antigen-binding fragment comprises:

[0233] a) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34; or

[0234] b) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154.

[0235] In some embodiments, the amyloid-β binding antibody or antigen-binding fragment comprises:

[0236] a) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 30; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 34; and / or a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 150; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 154. In some embodiments, the amyloid-β binding antibody or antigen-binding fragment for detection comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the amyloid-β binding antibody or antigen-binding fragment for detection comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14. In some embodiments, the amyloid-β binding antibody or antigen-binding fragment for detection comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14.

[0237] In some embodiments, the present invention includes a method for detecting amyloid-β in a sample obtained from a subject, the method comprising the steps of capturing amyloid-β with a first amyloid-β binding antibody or a fragment thereof, and detecting the captured amyloid-β in the sample with a second amyloid-β binding antibody or a fragment thereof, wherein each amyloid-β binding antibody or antigen-binding fragment thereof is independently selected from: ACI-24-41F12-Ab3, ACI-31-25B1-Ab2, and ACI-8041-5A2D4-Ab1, preferably the antibodies are ACI-24-41F12-Ab3 and ACI-31-25B1-Ab2, and more preferably ACI-24-41F12-Ab3 conjugated to a detectable label. In another embodiment of the present invention, the step of capturing amyloid-β is performed with a first amyloid-β binding antibody or a fragment thereof selected from: ACI-24-41F12-Ab3, ACI-31-25B1-Ab2, and ACI-8041-5A2D4-Ab1, preferably the antibodies are ACI-24-41F12-Ab3 and ACI-31-25B1-Ab2, and more preferably ACI-31-25B1-Ab2. In another embodiment of the present invention, the step of detecting the captured amyloid-β is performed with a second amyloid-β binding antibody or a fragment thereof conjugated to a detectable label and selected from: ACI-24-41F12-Ab3, ACI-31-25B1-Ab2, and ACI-8041-5A2D4-Ab1, preferably the antibodies are ACI-24-41F12-Ab3 and ACI-31-25B1-Ab2, and more preferably ACI-24-41F12-Ab3. In some embodiments, the step of detecting the captured amyloid-β in the sample is performed with a second amyloid-β binding antibody or a fragment thereof, wherein each amyloid-β binding antibody or antigen-binding fragment thereof is conjugated to a detectable label known in the art.

[0238] Accordingly, the present invention provides a method for detecting amyloid-β in a sample obtained from a subject, the method comprising contacting the sample with a binding molecule of the present invention, particularly an antibody or an antigen-binding fragment, and detecting the binding of the antibody or its antigen-binding fragment to detect amyloid-β in the sample. Similarly, the present invention provides a method for quantifying amyloid-β in a sample obtained from a subject, the method comprising contacting the sample with a binding molecule of the present invention, particularly an antibody or an antigen-binding fragment, and quantifying based on the binding of the binding molecule to amyloid-β. The method may comprise comparing the level of amyloid-β in the sample with the level of amyloid-β in one or more control samples. The level in the control sample represents a known level relative to which the level in the test sample can be determined. Thus, the control sample is not necessarily tested simultaneously with the quantification method. However, in some embodiments, the reference level is determined in parallel with the test sample. For example, quantitative ELISA, ELISA, MSD (Meso Scale Discovery Inc., USA), Luminex (Luminex Corp., USA), Alphalisa (PerkinElmer, Inc., USA), Gyrolab (Gyros Protein Technologies AB, Sweden), Simoa (Quanterix Corp., USA), Gyros TM (Given et al., 2012), Singulex Erenna (EMD Millipore, Corp., USA), iR-SENSE / Immuno-InfraRed assay (Naberset al, 2016), MITOMI (Piraino et al, 2016), immunoprecipitation combined with liquid chromatography mass spectrometry (IP LC-MS / MS; Shimadzu, Germany), surface plasmon resonance (SPR; Cytiva Europe, Switzerland), atomic force microscopy (AFM) (Kiio and Park, 2020). A standard curve can be generated to allow quantification based on a dilution series (serial dilution) of aβ. The diagnostic compositions of the present invention can be used in such methods. The sandwich immunoassays described herein incorporating suitable capture antibodies and detection antibodies or their antigen-binding fragments can be used in the method for quantifying amyloid-β in a sample obtained from a subject.

[0239] The present invention also provides methods for diagnosing diseases, disorders, and / or conditions associated with amyloid-β, which include contacting a sample with a binding molecule of the present invention, particularly an antibody or antigen-binding fragment, and comparing the level of amyloid-β in the sample with the level of amyloid-β in one or more control samples. A higher level of amyloid-β in the sample, compared to the control level based on healthy subjects, indicates a disease, disorder, and / or condition associated with amyloid-β. Additionally or alternatively, a similar or higher level of amyloid-β in the sample, compared to a diseased control (i.e., one or more samples from a subject suffering from a disease, disorder, and / or condition associated with amyloid-β), indicates a disease, disorder, and / or condition associated with amyloid-β. The diagnostic compositions of the present invention can be used in such methods. The sandwich immunoassays described herein incorporating suitable capture antibodies and detection antibodies or their antigen-binding fragments can be used in the methods for diagnosing diseases, disorders, and / or conditions associated with amyloid-β.

[0240] The binding molecules of the present invention can also be used in classification methods, for example, to indicate the relative stage of a disease, disorder, and / or condition associated with amyloid-β. Accordingly, the present invention also provides methods for classifying a disease, disorder, and / or condition associated with amyloid-β, which include: contacting a sample from a subject with a binding molecule of the present invention, particularly an antibody or antigen-binding fragment, and comparing the level of amyloid-β in the sample with the level of amyloid-β in one or more control samples in order to classify the disease. A series of controls representing different disease classes can be used to classify the sample. The test sample can be classified based on the best match with the control samples. A higher level of amyloid-β in the sample, compared to the control level based on healthy subjects, indicates a disease, disorder, and / or condition associated with amyloid-β. A similar or higher level of amyloid-β in the sample, compared to a diseased control at a certain disease stage, indicates that stage of a disease, disorder, and / or condition associated with amyloid-β. Such methods can be carried out with respect to subjects known to be suffering from a disease, disorder, and / or condition associated with amyloid-β and / or with respect to subjects not yet known to be suffering from a disease, disorder, and / or condition associated with amyloid-β. The diagnostic compositions of the present invention can be used in such methods. The sandwich immunoassays described herein incorporating suitable capture antibodies and detection antibodies or their antigen-binding fragments can be used in the classification methods of the present invention.

[0241] The present invention also provides methods for monitoring an amyloid-β related disease, disorder, and / or condition at two or more time points using a sample from a subject, the methods comprising: contacting the sample with a binding molecule of the present invention, particularly an antibody or antigen-binding fragment, and comparing the amyloid-β levels in the sample, wherein a higher amyloid-β level in a later sample as compared to one or more earlier samples indicates progression of an amyloid-β related disease, disorder, and / or condition. Similarly, the present invention provides methods for monitoring an amyloid-β related disease, disorder, and / or condition at two or more time points using a sample from a subject, the methods comprising: contacting the sample with a binding molecule of the present invention, particularly an antibody or antigen-binding fragment, and comparing the amyloid-β levels in the sample, wherein a lower amyloid-β level in a later sample as compared to one or more earlier samples indicates regression of an amyloid-β related disease, disorder, and / or condition. These methods also allow monitoring for lack of disease progression, wherein there is no significant change in the amyloid-β level in a later sample as compared to one or more earlier samples. Such methods are typically carried out with respect to a subject known to have an amyloid-β related disease, disorder, and / or condition. The diagnostic compositions of the present invention can be used in such methods. The sandwich immunoassays described herein incorporating suitable capture antibodies and detection antibodies or their antigen-binding fragments can be used in the monitoring methods of the present invention.

[0242] Monitoring methods can be used to determine whether a particular treatment is successful or, conversely. Thus, the present invention also provides methods for monitoring amyloid-β-related diseases, disorders, and / or conditions using a sample from a subject at two or more time points, the method comprising contacting the sample with a binding molecule of the present invention, particularly an antibody or antigen-binding fragment, wherein a lower amyloid-β level in a later sample compared to one or more earlier samples indicates successful treatment of an amyloid-β-related disease, disorder, and / or condition. The treatment can be any suitable candidate therapeutic agent, such as an antibody or small molecule therapeutic agent. These methods also allow monitoring for lack of disease progression, wherein there is no significant change in the amyloid-β level in a later sample compared to one or more earlier samples. In some cases, this can also be considered successful treatment. Indeed, a decrease in the rate of increase of the aβ level between samples compared to the rate of increase before treatment can also be considered indicative of successful treatment. Such methods are typically carried out with respect to a subject known to have an amyloid-β-related disease, disorder, and / or condition. When the treatment does not provide a decrease in the rate of increase of the aβ level between samples compared to the rate of increase before treatment, it can be determined that treatment has not been successful. The diagnostic compositions of the present invention can be used in such methods. The sandwich immunoassays described herein incorporating a suitable capture antibody and a detection antibody or antigen-binding fragment thereof can be used in the methods of the present invention for monitoring treatment.

[0243] The binding molecules of the present invention can also be used to assist in treatment selection. Accordingly, the present invention provides a method for selecting a treatment for treating an amyloid-β related disease, disorder, and / or condition, the method comprising contacting a sample obtained before and after treatment with a binding molecule of the present invention, particularly an antibody or an antigen-binding fragment, wherein a lower amyloid-β level in the sample obtained after treatment as compared to the sample obtained before treatment indicates successful treatment of the amyloid-β related disease, disorder, and / or condition, and thus the treatment is selected for administration. The treatment can be any suitable candidate therapeutic agent, such as an antibody or a small molecule therapeutic agent. A treatment that arrests disease progression can also be selected, wherein there is no significant change in the amyloid-β level in a later sample as compared to one or more earlier samples. In some cases, this can also be considered successful treatment. Indeed, a decrease in the rate of increase of the aβ level between samples as compared to the rate of increase before treatment can also be considered to indicate successful treatment and thus result in the selection of a particular treatment. Such methods are typically carried out with respect to a subject known to have an amyloid-β related disease, disorder, and / or condition. When treatment does not provide a decrease in the rate of increase of the aβ level between samples as compared to the rate of increase before treatment, unsuccessful treatment can be determined. Such a treatment is not selected for administration. Alternatively, a higher amyloid-β level in the sample obtained after treatment as compared to the sample obtained before treatment can indicate unsuccessful treatment of the amyloid-β related disease, disorder, and / or condition, and thus the treatment is not selected for administration. The diagnostic compositions of the present invention can be used in such methods. The sandwich immunoassays described herein incorporating a suitable capture antibody and a detection antibody or an antigen-binding fragment thereof can be used in the treatment selection method of the present invention (as applied to an individual subject).

[0244] The methods of the invention can also be used to determine whether a particular treatment is successful or not in the context of a larger controlled study (e.g., a clinical trial). Thus, these methods are typically applied to a group of treated subjects that is compared to a group of subjects treated without the treatment. In such a context, a control sample treated without the treatment can also be used for comparison purposes (placebo group). Accordingly, the invention also provides a method for evaluating a candidate treatment for an amyloid-β related disease, disorder, and / or condition, the method comprising, after treating one or more subjects, contacting a sample from one or more treated subjects with a binding molecule of the invention, particularly an antibody or antigen-binding fragment, wherein a lower amyloid-β level in the sample as compared to the level in a corresponding sample from a subject treated without the treatment indicates successful treatment of the amyloid-β related disease, disorder, and / or condition. The method is typically carried out with respect to a plurality (i.e., at least two) of treated subjects and a plurality of control subjects. The sizes of the treatment group and the control group can be the same or different. In some embodiments, each can comprise 3 or more, 4 or more, 5 or more, 10 or more, 20 or more, 50 or more subjects. The treatment can be any suitable candidate therapeutic agent, such as a biotherapeutic agent, particularly an antibody, a vaccine, or a small molecule therapeutic agent. The method can be carried out at multiple time points in matched samples between the treatment group and the placebo group to monitor the effectiveness of the candidate treatment over a defined period of time. An initial pre-treatment sample is typically also obtained. Thus, the method can comprise contacting samples from one or more treated subjects and one or more subjects treated without the treatment with a binding molecule of the invention, particularly an antibody or antigen-binding fragment, before the treatment is carried out, to determine the baseline level of amyloid-β. "Before the treatment is carried out" means before the treatment or placebo is administered to the group of subjects. Accordingly, the binding molecules of the invention can also be used to assist in the evaluation of candidate treatments in the context of a clinical trial. Candidate treatments that provide successful treatment can be selected and ultimately approved for marketing. The diagnostic compositions of the invention can be used in such methods. The sandwich immunoassays described herein incorporating a suitable capture antibody and a detection antibody or antigen-binding fragment thereof can be used in the treatment selection methods of the invention (as applied to a clinical trial).

[0245] According to all relevant methods, amyloid-β related diseases, disorders, and / or conditions can be selected from the following: Alzheimer's disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Parkinson's disease dementia (PDD), dementia with Lewy bodies, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, myotonic dystrophy, and liver dysfunction or failure. In some specific embodiments, the amyloid-β related disease, disorder, or condition is Alzheimer's disease (AD), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cerebral amyloid angiopathy (CAA), myotonic dystrophy, or dementia with Lewy bodies.

[0246] Suitable samples for use with a variety of methods are typically biological samples as discussed herein, particularly body fluids. Suitable immunoassay formats are known to those skilled in the art and include, but are not limited to, ELISA, MSD (Meso Scale Discovery Inc., USA), Luminex (Luminex Corp., USA), Alphalisa (PerkinElmer, Inc., USA), Gyrolab (Gyros Protein Technologies AB, Sweden), Simoa (Quanterix Corp., USA), Gyros TM (Given et al., 2012), Singulex Erenna (EMD Millipore, Corp., USA), iR-SENSE / Immuno-InfraRed assay (Nabers et al, 2016), MITOMI (Piraino et al, 2016), immunoprecipitation combined with liquid chromatography mass spectrometry (IP LC-MS / MS; Shimadzu, Germany), surface plasmon resonance (SPR; Cytiva Europe, Switzerland), atomic force microscopy (AFM) (Kiio and Park, 2020).

[0247] In some embodiments, the binding molecule, aβ antibody, or antigen-binding fragment thereof of the present invention is part of a diagnostic kit comprising such a binding molecule, aβ antibody, or antigen-binding fragment thereof. Such a kit may contain all the necessary components for performing the methods and / or assays provided herein, such as buffers, detectable dyes, laboratory equipment, reaction vessels, instructions, etc. The binding molecule, particularly an antibody or antigen-binding fragment thereof, may be conjugated to a label or other molecule as discussed herein. Depending on the requirements of each respective assay technique, they may be labeled or expressed with a dye or tag (such as a fluorophore or fluorescent dye), or conjugated to an enzyme or solid support (such as an assay chip). In another embodiment, the binding molecule, particularly an antibody or antigen-binding fragment thereof of the present invention, may be conjugated to a radioisotope (i.e., a radioactive conjugate), a nucleic acid molecule, a detectable label, a therapeutic agent, a toxin, or a blood-brain barrier penetrating moiety to form an immunoconjugate. The kit may be used to perform any method of the present invention and may thus incorporate any suitable components required to perform those methods, including reagents. The present invention also relates to a kit comprising an aβ antibody or antigen-binding fragment thereof of the present invention. The kit generally contains the aβ antibody or antigen-binding fragment thereof of the present invention in a suitable container. The aβ antibody or antigen-binding fragment thereof may be provided in the form of a diagnostic composition ready for use, or it may be provided in a kit with suitable reagents (such as a saline solution) for reconstituting the product. The kit may be provided with instructions for use. Thus, the discussion of the methods of the present invention applies with the necessary modifications. Kits for performing the sandwich immunoassays of the present invention are also provided. They incorporate suitable capture antibodies and detection antibodies or antigen-binding fragments thereof. Thus, the present invention relates to a kit for detecting amyloid-β in a sample obtained from a subject, the kit comprising:

[0248] a. a capture amyloid-β binding antibody or antigen-binding fragment thereof that selectively binds to any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance; and

[0249] b. a detection amyloid-β binding antibody or antigen-binding fragment thereof that selectively binds to any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance,

[0250] wherein at least one of the capture and detection antibodies or antigen-binding fragments thereof exhibits no cross-reactivity with soluble amyloid precursor protein (APP), particularly soluble APPα.

[0251] One or both of the antibodies may be the antibodies of the present invention.

[0252] In some embodiments, a capture antibody or antigen-binding fragment is immobilized on the surface of a solid support, such as the surface of a well (e.g., a well in a microtiter plate), or a solid support and / or means for immobilizing the capture antibody or antigen-binding fragment on the solid support are provided to provide the capture antibody or antigen-binding fragment. In some embodiments, a detection antibody or antigen-binding fragment is labeled with a detectable label, or a label and means for directly or indirectly conjugating the antibody to the label are provided to provide the detection antibody or antigen-binding fragment.

[0253] In some embodiments, both the capture antibody and the detection antibody show no cross-reactivity with soluble amyloid precursor protein (APP), particularly soluble APPα. In other embodiments, one of the capture antibody and the detection antibody or its antigen-binding fragment shows cross-reactivity with soluble amyloid precursor protein (APP). The cross-reactivity can be low or high. The other antibody or its antigen-binding fragment (the capture antibody or the detection antibody) shows no cross-reactivity with soluble amyloid precursor protein (APP).

[0254] In some embodiments, a capture or detection (preferably detection) amyloid-β-binding antibody or antigen-binding fragment comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, a capture or detection (preferably detection) amyloid-β-binding antibody or antigen-binding fragment comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14. In some embodiments, a capture or detection (preferably detection) amyloid-β-binding antibody or antigen-binding fragment comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14.

[0255] In some embodiments, a capture or detection (preferably capture) amyloid-β-binding antibody or antigen-binding fragment comprises:

[0256] a. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or

[0257] b. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 151; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152; VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 153; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 155; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157.

[0258] The preferred amyloid-β binding capture antibody or antigen-binding fragment comprises a) above.

[0259] In some embodiments, the amyloid-β binding capture or detection (preferably capture) antibody or antigen-binding fragment comprises:

[0260] a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34; or

[0261] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154.

[0262] In some embodiments, the amyloid-β binding capture or detection (preferably capture) antibody or antigen-binding fragment comprises:

[0263] a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34; and / or

[0264] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 150; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154 or a light chain variable region (VL) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 154.

[0265] The present invention also relates to a kit for detecting amyloid-β in a sample obtained from a subject, the kit comprising:

[0266] a. A capture amyloid-β binding antibody or an antigen-binding fragment thereof that selectively binds to any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance, and shows no cross-reactivity with soluble amyloid precursor protein (APP), particularly high cross-reactivity with soluble APPα; and

[0267] b. A detection amyloid-β binding antibody or an antigen-binding fragment thereof that selectively binds to any amyloid-β peptide or substance in solution, regardless of the conformational state of the amyloid-β peptide or substance, and shows cross-reactivity (low or high) with soluble amyloid precursor protein (APP), particularly no cross-reactivity with soluble APPα.

[0268] In some embodiments, the capture antibody or antigen-binding fragment is immobilized on the surface of a solid support, such as the surface of a well (e.g., a well in a microtiter plate), or the capture antibody or antigen-binding fragment is provided with a solid support and / or means for immobilizing the capture antibody or antigen-binding fragment on the solid support. In some embodiments, the detection antibody or antigen-binding fragment has a high affinity for aβ. In some embodiments, the detection antibody or antigen-binding fragment is labeled with a detectable label, or the detection antibody or antigen-binding fragment is provided with a label and means for directly or indirectly conjugating the antibody to the label. In some embodiments, the capture amyloid-β binding antibody or antigen-binding fragment comprises:

[0269] a. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or

[0270] b. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 151; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 152; VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 153; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 155; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 156; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 157.

[0271] The preferred amyloid-β binding capture antibody or antigen-binding fragment comprises a) above.

[0272] In some embodiments, the amyloid-β binding capture antibody or antigen-binding fragment comprises:

[0273] a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34; or

[0274] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154.

[0275] In some embodiments, the amyloid-β binding capture antibody or antigen-binding fragment comprises:

[0276] a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34; and / or

[0277] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 150; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 154 or a light chain variable region (VL) having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 154.

[0278] In some embodiments, the amyloid-β binding antibody or antigen-binding fragment thereof comprises: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments, the amyloid-β binding antibody or antigen-binding fragment thereof comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14. In some embodiments, the amyloid-β binding antibody or antigen-binding fragment thereof comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14.

[0279] The present invention can also be defined in the following numbered clauses:

[0280] 1. An antibody or antigen-binding fragment thereof, comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, wherein the antibody or antigen-binding fragment thereof binds to amyloid-β.

[0281] 2. The antibody or antigen-binding fragment thereof as described in clause 1, wherein the antibody or antigen-binding fragment binds to amino acid residues 1 to 8 (SEQ ID NO: 2) of human amyloid-β SEQ ID NO: 1.

[0282] 3. The antibody or antigen-binding fragment thereof as described in clauses 1 to 2, wherein the antibody comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10.

[0283] 4. The antibody or antigen-binding fragment thereof as described in any one of the preceding clauses, wherein the antibody comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14.

[0284] 5. The antibody or antigen-binding fragment thereof as described in any one of the preceding clauses, wherein the antibody comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14.

[0285] 6. The antibody or antigen-binding fragment thereof as described in any one of the preceding clauses, wherein the antibody comprises: a heavy chain (HC) comprising the amino sequence of SEQ ID NO: 20 and a light chain (LC) comprising the amino sequence of SEQ ID NO: 21.

[0286] 7. The antibody or antigen-binding fragment thereof as described in any one of the preceding clauses, wherein the antibody comprises: a heavy chain (HC) comprising the amino sequence of SEQ ID NO: 22 and a light chain (LC) comprising the amino sequence of SEQ ID NO: 23.

[0287] 8. The antibody or antigen-binding fragment thereof as described in any one of the preceding clauses, wherein the antibody comprises: a heavy chain (HC) comprising the amino sequence of SEQ ID NO: 24 and a light chain (LC) comprising the amino sequence of SEQ ID NO: 25.

[0288] 9. The antibody or antigen-binding fragment thereof as described in any one of the preceding clauses, wherein the antibody or antigen-binding fragment is for diagnosing amyloid-β related diseases or disorders in a subject.

[0289] 10. An antibody or antigen-binding fragment thereof as described in any of the preceding clauses, said antibody or antigen-binding fragment thereof being used for detecting amyloid-β in a sample.

[0290] 11. An antibody or antigen-binding fragment thereof as described in any of the preceding clauses, said antibody or antigen-binding fragment thereof being used for detecting amyloid-β in a sample, wherein the sample is a saliva, urine, blood, brain, and / or CSF sample, more particularly a blood and / or CSF sample.

[0291] 12. An antibody or antigen-binding fragment thereof as described in any of the preceding clauses, said antibody or antigen-binding fragment thereof being used for diagnosing amyloid-β-related diseases or disorders, wherein the amyloid-β-related diseases or disorders are selected from Alzheimer's disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, dementia with Lewy bodies, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, and optic neuritis.

[0292] 13. An antibody or antigen-binding fragment thereof as described in any of the preceding clauses, said antibody or antigen-binding fragment thereof being used for diagnosing amyloid-β-related diseases or disorders, wherein the amyloid-β-related diseases or disorders are Alzheimer's disease (AD), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cerebral amyloid angiopathy (CAA), myotonic dystrophy, and dementia with Lewy bodies.

[0293] 14. An antibody or antigen-binding fragment thereof as described in any of the preceding clauses, said antibody or antigen-binding fragment thereof being used for diagnosing amyloid-β-related diseases or disorders, wherein the amyloid-β-related diseases or disorders are Alzheimer's disease (AD).

[0294] 15. An antibody or antigen-binding fragment thereof as described in any of clauses 1 to 13, said antibody or antigen-binding fragment thereof being used for diagnosing amyloid-β-related diseases or disorders, wherein the amyloid-β-related diseases or disorders are Down syndrome.

[0295] 16. A diagnostic composition comprising an isolated antibody or antigen-binding fragment thereof as described in any of the preceding clauses and an acceptable carrier and / or excipient.

[0296] 17. An isolated nucleic acid encoding an antibody as described in any of clauses 1 to 15.

[0297] 18. A nucleic acid comprising the nucleotide sequence provided in SEQ ID NO: 18 or SEQ ID NO: 19.

[0298] 19. A recombinant vector comprising the nucleic acid described in clause 17 or 18.

[0299] 20. A host cell comprising the nucleic acid described in clause 17 or 18 and / or the vector described in clause 19.

[0300] 21. An isolated host cell that expresses the antibody or antigen-binding fragment described in any one of clauses 1 to 15.

[0301] 22. A method for producing an isolated binding molecule, particularly an antibody, comprising the steps of: a) culturing the host cell described in clause 20 or 21 under conditions suitable for producing the antibody or its antigen-binding fragment, and b) isolating the antibody or its antigen-binding fragment.

[0302] The present invention can also be defined in the following numbered clauses:

[0303] 1. An amyloid-β binding antibody or its antigen-binding fragment, comprising:

[0304] a) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12; VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; or

[0305] b) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32; VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33; VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 36; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or

[0306] c) A VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 42; a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 43; a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 45; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 46; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 47.

[0307] 2. The amyloid-β binding antibody or antigen-binding fragment thereof according to clause 1, wherein the antibody or antigen-binding fragment thereof comprises:

[0308] a) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; or

[0309] b) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 30; or

[0310] c) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or a heavy chain variable region (VH) having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 40.

[0311] 3. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of the preceding clauses, wherein the antibody or antigen-binding fragment thereof comprises:

[0312] a) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14; or

[0313] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34; or

[0314] c) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or a heavy chain variable region (VH) having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 40; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44 or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44.

[0315] 4. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of the preceding clauses, wherein the antibody or antigen-binding fragment thereof comprises:

[0316] a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14; or

[0317] b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34; or

[0318] c) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44.

[0319] 5. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of the preceding clauses, wherein the antibody comprises:

[0320] a) a heavy chain (HC) comprising the amino sequence of SEQ ID NO: 20 and a light chain (LC) comprising the amino sequence of SEQ ID NO: 21; or

[0321] b) a heavy chain (HC) comprising the amino sequence of SEQ ID NO: 22 and a light chain (LC) comprising the amino sequence of SEQ ID NO: 23; or

[0322] c) A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 24 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 25; or

[0323] d) A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 27 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 28; or

[0324] e) A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 38 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 39; or

[0325] f) A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 48 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 49; or

[0326] g) A heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 50 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 51.

[0327] 6. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of the preceding clauses, wherein the antibody or antigen-binding fragment thereof binds to an epitope within amino acid residues 1 to 5 (SEQ ID NO: 7), 1 to 8 (SEQ ID NO: 2), 22 to 35 (SEQ ID NO: 29), or 26 to 34 (SEQ ID NO: 8) of SEQ ID NO: 1 or to an equivalent epitope in non-human amyloid-β.

[0328] 7. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of the preceding clauses, wherein the antibody or antigen-binding fragment thereof is a murine antibody, a chimeric antibody, a humanized antibody, or a human antibody or an antigen-binding fragment thereof.

[0329] 8. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of the preceding clauses, wherein the antibody or antigen-binding fragment thereof is an IgM, IgG1, IgG2, IgG2a, IgG2b, IgG3, or IgG4 antibody or an antigen-binding fragment thereof.

[0330] 9. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of the preceding clauses, wherein the antibody or antigen-binding fragment thereof is conjugated to another molecule, particularly a detectable label.

[0331] 10. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of the preceding clauses, wherein the antibody or antigen-binding fragment thereof is used for diagnosing amyloid-β related diseases, disorders, or conditions in a subject.

[0332] 11. The amyloid-β binding antibody or antigen-binding fragment thereof as described in any one of the preceding clauses, wherein the antibody or antigen-binding fragment thereof is used for detecting amyloid-β in a biological sample.

[0333] 12. The amyloid-β binding antibody or antigen-binding fragment thereof as described in clause 11, wherein the biological sample is a body fluid sample or a buffer solution.

[0334] 13. The amyloid-β binding antibody or antigen-binding fragment thereof as described in any one of clauses 1 to 12, wherein the antibody or antigen-binding fragment thereof is used for detecting amyloid-β in a body fluid sample, and wherein the body fluid sample is saliva, urine, nasal secretion, blood (including whole blood, plasma and serum, preferably plasma), brain and / or CSF sample, brain and / or ISF sample, and more particularly blood, brain, CSF and / or ISF sample.

[0335] 14. The amyloid-β binding antibody or antigen-binding fragment thereof as described in any one of the preceding clauses, wherein the antibody or antigen-binding fragment thereof is used for diagnosing amyloid-β related diseases, disorders or conditions, and wherein the amyloid-β related diseases, disorders or conditions are selected from Alzheimer's disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Parkinson's disease dementia (PDD), dementia with Lewy bodies, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, myotonic dystrophy and liver dysfunction or failure.

[0336] 15. The amyloid-β binding antibody or antigen-binding fragment thereof as described in any one of the preceding clauses, wherein the antibody or antigen-binding fragment thereof is used for diagnosing amyloid-β related diseases, disorders or conditions, and wherein the amyloid-β related diseases, disorders or conditions are Alzheimer's disease (AD), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cerebral amyloid angiopathy (CAA), myotonic dystrophy or dementia with Lewy bodies.

[0337] 16. The amyloid-β binding antibody or antigen-binding fragment thereof as described in any one of the preceding clauses, wherein the antibody or antigen-binding fragment thereof is used for diagnosing amyloid-β related diseases, disorders or conditions, and wherein the amyloid-β related diseases, disorders or conditions are Alzheimer's disease (AD).

[0338] 17. An amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of clauses 1 to 15, wherein the antibody or antigen-binding fragment thereof is used for diagnosing an amyloid-β related disease, disorder or condition, and wherein the amyloid-β related disease, disorder or condition is Down syndrome (DS).

[0339] 18. An amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of clauses 1 to 15, wherein the antibody or antigen-binding fragment thereof is used for diagnosing an amyloid-β related disease, disorder or condition, and wherein the amyloid-β related disease, disorder or condition is Alzheimer's disease associated with Down syndrome.

[0340] 19. A method for detecting amyloid-β in a sample obtained from a subject, the method comprising contacting the sample with an amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of the preceding clauses, and detecting the binding of the antibody or antigen-binding fragment thereof to detect amyloid-β in the sample.

[0341] 20. A method for quantifying amyloid-β in a sample obtained from a subject, the method comprising contacting the sample with an amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of clauses 1 to 18, and quantifying amyloid-β in the sample based on the level of binding of the antibody or antigen-binding fragment thereof to amyloid-β.

[0342] 21. A method for diagnosing a disease, disorder and / or condition associated with amyloid-β, which comprises performing the method according to clause 19 or 20, wherein a higher level of amyloid-β in the sample, compared to a control level based on healthy subjects, indicates a disease, disorder and / or condition associated with amyloid-β.

[0343] 22. A method for diagnosing a disease, disorder and / or condition associated with amyloid-β, which comprises performing the method according to clause 19 or 20, wherein a similar or higher level of amyloid-β in the sample, compared to a diseased control level, indicates a disease, disorder and / or condition associated with amyloid-β.

[0344] 23. A method for classifying a disease, disorder and / or condition associated with amyloid-β, which comprises:

[0345] a. performing the method according to clause 21 and / or 22,

[0346] b. classifying the disease, disorder and / or condition associated with amyloid-β.

[0347] 24. A method for monitoring an amyloid-β related disease, disorder, and / or condition at two or more time points using a sample from a subject, the method comprising contacting the sample with an amyloid-β binding antibody or an antigen-binding fragment thereof as described in any one of clauses 1 to 18, wherein:

[0348] a. Higher amyloid-β levels in a later sample as compared to one or more earlier samples indicate progression of an amyloid-β related disease, disorder, and / or condition;

[0349] b. Lower amyloid-β levels in a later sample as compared to one or more earlier samples indicate regression of an amyloid-β related disease, disorder, and / or condition; and / or

[0350] c. No significant change in amyloid-β levels in a later sample as compared to one or more earlier samples indicates lack of progression of an amyloid-β related disease, disorder, and / or condition.

[0351] 25. A method for selecting a treatment for treating an amyloid-β related disease, disorder, and / or condition, the method comprising contacting samples obtained before and after treatment with the treatment with an amyloid-β binding antibody or an antigen-binding fragment thereof as described in any one of clauses 1 to 18, wherein:

[0352] a. Lower amyloid-β levels in a sample obtained after treatment as compared to a sample obtained before treatment indicate successful treatment of an amyloid-β related disease, disorder, and / or condition, and thus the treatment is selected for administration;

[0353] b. No significant change in amyloid-β levels in a sample obtained after treatment as compared to a sample obtained before treatment indicate successful treatment of an amyloid-β related disease, disorder, and / or condition, and thus the treatment is selected for administration;

[0354] c. A decrease in the rate of increase in amyloid-β levels between samples obtained during treatment as compared to a sample obtained before treatment indicate successful treatment of an amyloid-β related disease, disorder, and / or condition, and thus the treatment is selected for administration;

[0355] d. Higher amyloid-β levels in a sample obtained after treatment as compared to a sample obtained before treatment indicate unsuccessful treatment of an amyloid-β related disease, disorder, and / or condition, and thus the treatment is not selected for administration; or

[0356] e. An increase rate of amyloid-β levels between samples obtained during treatment that has not decreased as compared to samples obtained before treatment indicates that a disease, disorder, and / or condition associated with amyloid-β has not been successfully treated, and thus the treatment is not selected for administration.

[0357] 26. A method for evaluating a candidate treatment for a disease, disorder, and / or condition associated with amyloid-β, the method comprising, after treating one or more subjects, contacting a sample from one or more treated subjects with an antibody or antigen-binding fragment as described in any one of clauses 1 to 18, wherein a lower amyloid-β level in the sample as compared to the level in a corresponding sample from a subject not treated with the treatment indicates successful treatment of a disease, disorder, and / or condition associated with amyloid-β.

[0358] 27. The method of clause 26, which is performed at multiple time points in matched samples between a treatment group and a placebo group to monitor the effectiveness of the candidate treatment over a defined period of time.

[0359] 28. The method of clause 26 or 27, which comprises contacting samples from the one or more treated subjects and the one or more subjects not treated with the treatment with an antibody or antigen-binding fragment as described in any one of clauses 1 to 18 before treatment with the treatment or placebo, respectively, to determine a baseline level of amyloid-β.

[0360] 29. The method according to any one of clauses 19 to 28, wherein the disease, disorder, and / or condition associated with amyloid-β is selected from Alzheimer's disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Parkinson's disease dementia (PDD), Lewy body dementia, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, myotonic dystrophy, and liver dysfunction or failure.

[0361] 30. The method of clause 29, wherein the amyloid-β-related disease, disorder, or condition is Alzheimer's disease (AD), Down syndrome (DS), Down syndrome-related Alzheimer's disease, cerebral amyloid angiopathy (CAA), myotonic dystrophy, or Lewy body dementia.

[0362] 31. The method of clause 29 or 30, wherein the amyloid-β-related disease, disorder, or condition is Alzheimer's disease (AD).

[0363] 32. The method according to clause 29 or 30, wherein the amyloid-β related disease, disorder or condition is Down syndrome (DS).

[0364] 33. A diagnostic composition comprising an amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of clauses 1 to 18, and an acceptable carrier and / or excipient.

[0365] 34. A nucleic acid encoding an amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of clauses 1 to 18.

[0366] 35. A nucleic acid comprising a nucleotide sequence provided in SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54 or SEQ ID NO: 55. [[ID=·11]]

[0367] 36. A recombinant vector comprising the nucleic acid according to clause 34 or 35.

[0368] 37. A host cell comprising the nucleic acid according to clause 34 or 35 and / or the vector according to clause 36.

[0369] 38. An isolated host cell expressing an amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of clauses 1 to 18.

[0370] 39. A method for producing an amyloid-β binding antibody or an antigen-binding fragment thereof, comprising the steps of:

[0371] a. Culturing the host cell according to clause 37 or 38 under conditions suitable for producing the amyloid-β binding antibody or an antigen-binding fragment thereof, and

[0372] b. Recovering the amyloid-β binding antibody or an antigen-binding fragment thereof.

[0373] 40. A kit for diagnosing a disease, disorder or condition related to amyloid-β, or a kit for the method according to any one of clauses 19 to 32, comprising an amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of clauses 1 to 18.

[0374] 41. An amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of clauses 1 to 18, said antibody or antigen-binding fragment for research use, particularly as an analytical tool or reference molecule.

[0375] 42. An amyloid-β binding antibody or an antigen-binding fragment thereof as described in any one of clauses 1 to 18, said antibody or antigen-binding fragment thereof being for detecting amyloid-β aggregates, including plaques, in vitro or in vivo.

[0376] 43. An amyloid-β binding antibody or an antigen-binding fragment thereof for the application described in clause 42, said antibody or antigen-binding fragment thereof being for histochemical detection in brain tissue.

[0377] Description of Drawings and Tables

[0378] Figure 1 . ACI-24-41F12-Ab3 (murine IgG2a isotype) binds to Aβ1-42 with a Kd of 66 pM. No binding to BSA protein was observed. Data are represented as O.D. and shown as the mean ± SD of individual assay replicates.

[0379] Figure 2 . Antibody ACI-31-25B1-Ab2 (murine IgG2a isotype) binds to Aβ1-42 with a Kd of 41 pM. No binding to BSA protein was observed. Data are represented as O.D.

[0380] Figure 3 . Antibody ACI-31-30C11-Ab1 (murine IgG2a isotype) binds to Aβ1-42 with a Kd of 196 pM. No binding to BSA protein was observed. Data are represented as O.D.

[0381] Figure 4 . Antibody ACI-31-25B1-Ab2 (murine IgG2a isotype) captures soluble Aβ1-42 with a Kd of 312 pM. Data are represented as O.D.

[0382] Figure 5 . Antibody ACI-8041-1F11B5-Ab1 (murine IgG2a isotype) captures soluble Aβ1-42 with a Kd of 343 pM. Data are represented as O.D.

[0383] Figure 6 . Antibody ACI-8041-9D7E1-Ab1 (murine IgG2a isotype) captures soluble Aβ1-42 with a Kd of 1.1 nM. Data are represented as O.D.

[0384] Figure 7 . Antibody ACI-8041-10H3B11-Ab1 (murine IgG2a isotype) captures soluble Aβ1-42 with a Kd of 2.6 nM. Data are represented as O.D.

[0385] Figure 8.A) Indirect ELISA that compared the binding of the individual antibodies ACI-24-41F12-Ab3 (murine IgG2a isotype) and ACI-31-25B1-Ab2 (murine IgG2a / λ isotype) to sAPPα (normalized relative to Aβ1-42 binding). Scrambled Aβ1-42 was used as a control, which showed no binding. Antibody ACI-24-41F12-Ab3 showed binding to sAPPα, while no binding was observed for antibody ACI-31-25B1-Ab2. B) A sandwich pair of antibodies ACI-24-41F12-Ab3 (detection) and ACI-31-25B1-Ab2 (capture) detected soluble Aβ1-42 with a Kd of 9.7 nM, with a higher selectivity for Aβ1-42 than for scrambled Aβ1-42 or sAPPα. Data are represented as O.D. or % of Aβ1-42 binding.

[0386] Table 1. Aβ1-42 binding regions and epitopes, and interactions with sAPPα.

[0387] Table 2. Nucleotide sequences of the heavy chain variable domain and the light chain variable domain (VH and VL).

[0388] Table 3. Amino acid sequences of the heavy chain variable domain and the light chain variable domain (VH and VL).

[0389] Table 4. Amino acid sequences of the heavy chain (HC) and light chain (LC) variable and constant regions.

[0390] Table 5. Amino acid sequences of the heavy chain (HC) and light chain (LC) constant regions.

[0391] The invention is further described with reference to the following non-limiting examples:

[0392] Methods

[0393] Example 1. Antibody production

[0394] 1.1. Preparation of an aβ liposome vaccine composition

[0395] Prepare liposome-based antigen constructs according to the protocol disclosed in WO2012 / 055933. Use liposome vaccines with tetra-palmitoylated human Aβ1-15 peptide as the antigen to generate antibodies ACI-24-41F12-Ab2 (murine IgG2b) and ACI-24-41F12-Ab3 (murine IgG2a isotype and chimeric mouse / human IgG1 isotype), or use liposome vaccines with tetra-palmitoylated human Aβ22-35 peptide as the antigen to generate ACI-31-25B1-Ab2 (murine IgG2b / λ, murine IgG2a / λ and chimeric mouse / human IgG1 isotype) and ACI-31-30C11-Ab1 (murine IgG2b), or use liposome vaccines with tetra-palmitoylated human Aβ1-23 peptide as the antigen to generate ACI-8037-103H5-Ab2 (murine IgG2a) and ACI-8037-109F4-Ab1 (murine IgG2a), or use liposome vaccines with tetra-palmitoylated human Aβ5-23 peptide as the antigen to generate ACI-8039-306H5-Ab1 (murine IgG2a), ACI-8039-307F7-Ab2 (murine IgG2a) and ACI-8039-309D9-Ab2 (murine IgG2a), or use liposome vaccines with tetra-palmitoylated human Aβ10-29 peptide as the antigen to generate ACI-8041-1F11B5-Ab1 (murine IgG2a), ACI-8041-2B9H5-Ab1 (murine IgG2a), ACI-8041-3G11B3-Ab1 (murine IgG2a), ACI-8041-4G6D2-Ab1 (murine IgG2a), ACI-8041-5A2D4-Ab1 (murine IgG2a), ACI-8041-5A6H9-Ab1 (murine IgG2a), ACI-8041-6C3C4-Ab1 (murine IgG2a), ACI-8041-9D7E1-Ab1 (murine IgG2a) and ACI-8041-10H3B11-Ab1 (murine IgG2a). Mice (C57BL / 6, 9 weeks old, female) are injected subcutaneously (s.c.) three times with the vaccine, with a two-week interval between each immunization (on days 0, 14 and 28). Blood samples are collected and plasma is prepared 7 days before the first immunization and 7 days after each immunization (on days 7, 21 and 35). After the last bleeding, mice are selected based on vaccine response, and splenocytes are used for fusion with murine myeloma cells 65 days after the start of the study. Hybridomas that bind to the target are selected, subcloned to obtain monoclonal antibodies, and then ranked for target-binding characteristics to select hybridoma clones for sequencing and recombinant antibody production.The following data describe the properties of ACI-24-41F12-Ab2, a hybridoma-derived murine IgG2b / κ antibody, and recombinant murine IgG2a / κ antibody (hereinafter referred to as ACI-24-41F12-Ab3 (IgG2a isotype)) and recombinant chimeric mouse / human IgG1 isotype (hereinafter referred to as ACI-24-41F12-Ab3 (hIgG1 isotype)) which have the same variable heavy (VH) chain sequence, variable light (VL) chain sequence, and binding properties as the ACI-24-41F12-Ab2 antibody (data not shown). The following data also describe ACI-31-25B1-Ab2 in the murine IgG2a / λ form, and some properties of ACI-31-30C11-Ab1, ACI-8037-103H5-Ab2, ACI-8037-109F4-Ab1, ACI-8039-306H5-Ab1, ACI-8039-307F7-Ab2, ACI-8039-309D9-Ab2, ACI-8041-1F11B5-Ab1, ACI-8041-2B9H5-Ab1, ACI-8041-3G11B3-Ab1, ACI-8041-4G6D2-Ab1, ACI-8041-5A2D4-Ab1, ACI-8041-5A6H9-Ab1, ACI-8041-6C3C4-Ab1, ACI-8041-9D7E1-Ab1, and ACI-8041-10H3B11-Ab1 which have murine IgG2a isotype constant region heavy chain and K constant region light chain (Table 5).

[0396] Example 2. Preparation of Aβ1-42 for Assays

[0397] The Aβ1-42 lyophilized powder (Bachem) was reconstituted to 1 mM in hexafluoroisopropanol (HFIP, Sigma). The peptide solution was sonicated for 15 minutes at room temperature, stirred overnight, and aliquots were prepared into non-siliconized microcentrifuge tubes. The HFIP was then evaporated under a stream of argon. The resulting peptide film was dried in vacuo for 10 minutes and stored at -80 °C until use. Alternatively, for target capture in solution, a biotinylated form of the Aβ1-42 peptide was used. This was prepared in a similar manner as described above.

[0398] Example 3. Target Binding

[0399] Antibody target binding was evaluated by enzyme - linked immunosorbent assay (ELISA). Briefly, Nunc MaxiSorp 96 - well plates (Nunc) were coated at 4 °C with 50 μL of 10 μg / mL Aβ1 - 42 or bovine serum albumin (BSA, Sigma) diluted in PBS for 18 hours. In selected assays, additionally the coated wells as described above were included with the full - length sAPPα fragment (Sigma) at 4 μg / mL (0.04 μM). The plates were then washed 4 times with 300 μL of PBS containing 0.05% Tween 20 (Millipore). To block non - specific binding to the plate, a freshly prepared PBS solution containing 0.05% Tween 20 and 1% BSA was added to each well (100 μL / well), and the plates were incubated at 37 °C for 1 hour. The primary antibody was diluted to 100 nM in PBS containing 1% BSA and 0.05% Tween 20, followed by 3 - fold serial dilutions in duplicate. The solution was added to the plates at 50 μL / well and incubated at 37 °C for 1 hour. Subsequently, the plates were washed 4 times with 300 μL of PBS containing 0.05% Tween 20. Then the plates were incubated with horseradish peroxidase (HRP) - conjugated goat anti - mouse secondary IgG (Abcam) at 37 °C for 1 hour. After the final wash step (washed 4 times with 300 μL of PBS containing 0.05% Tween 20), the plates were incubated with 3,3’,5,5’ - tetramethylbenzidine (TMB) substrate (BD Biosciences), and the reaction was terminated with the stop solution (Sigma). Finally, the optical density (O.D.) was read at an absorption wavelength of 450 nm using a Tecan Infinite plate reader. The measurements were expressed as the mean O.D. ± standard deviation (S.D.) of 1 mean from repeated runs.

[0400] The ELISA assay was used to evaluate the binding of antibodies ACI - 24 - 41F12 - Ab3 (recombinant murine IgG2a isotype, also designated ACI - 24 - 41F12 - Ab3 - recl), antibody ACI - 31 - 25B1 - Ab2 (murine IgG2a / λ isotype) and antibody ACI - 31 - 30C11 - Ab1 (murine IgG2a isotype) to Aβ1 - 42. Antibody ACI - 24 - 41F12 - Ab3 bound to Aβ1 - 42 with a Kd of 66 pM, and no cross - reactivity to BSA was observed at the same protein concentration ( Figure 1 ). The assay was repeated at least four independent times with comparable results. Antibody ACI - 31 - 25B1 - Ab2 bound to Aβ1 - 42 with a Kd of 41 pM ( Figure 2), and the antibody ACI-31-30C11-Ab1 binds to Aβ1-42 with a Kd of 196 pM ( Figure 3 ), and shows no cross-reactivity with BSA.

[0401] The binding of antibodies ACI-31-25B1-Ab2, ACI-8041-1F11B5-Ab1, ACI-8041-9D7E1-Ab1, and ACI-8041-10H3B11-Ab1 to Aβ1-42 in solution was further evaluated using a target capture assay by ELISA as an indication of soluble target capture in biological fluids. Briefly, Nunc MaxiSorp 96-well plates (Nunc) were coated with 50 μL of 5 μg / mL goat anti-mouse IgG, Fc-γ fragment-specific antibody (Jackson Immune Research) diluted in carbonate-bicarbonate buffer at 4 °C for 18 h. The plates were then washed 4 times with 300 μL of PBS containing 0.05% Tween 20 (Millipore). To block non-specific binding to the plates, freshly prepared PBS solution containing 0.05% Tween 20 and 1% BSA was added to each well (100 μL / well), and the plates were incubated at 37 °C for 1 h. The primary antibodies were diluted to 5 μg / mL (33.3 nM) in PBS containing 1% BSA and 0.05% Tween 20, 50 μL / well was added to each well, and the plates were incubated at 37 °C for 1 h. Subsequently, the plates were washed four times with 300 μL of PBS containing 0.05% Tween 20. Human Aβ1-42 biotinylated at the peptide C-terminus was diluted to 10 μg / mL (2.2 μM) in PBS containing 1% BSA and 0.05% Tween 20, followed by three-fold serial dilutions, 50 μL was added to each well and the plates were incubated at 37 °C for 1 h. After washing four times with 300 μL of PBS containing 0.05% Tween 20, the plates were incubated with 50 μL / well of streptavidin-HRP (R&D systems) diluted 1:200 in PBS containing 1% BSA and 0.05% Tween 20 at ambient temperature for 45 min. The plates were washed again four times with 300 μL of PBS containing 0.05% Tween 20 and then incubated with 50 or 100 μL / well of 3,3',5,5'-tetramethylbenzidine (TMB) enzyme substrate (BD Biosciences) at ambient temperature for 20 or 30 min. The reaction was terminated with 1.2 M HCl (Sigma) solution. Finally, the optical density (O.D.) was read at an absorption wavelength of 450 nm using a Tecan Infinite plate reader. The measurements are expressed as O.D.. The antibody ACI-31-25B1-Ab2 captures Aβ1-42 in solution with a Kd of 312 pM ( Figure 4), the antibody ACI-8041-1F11B5-Ab1 captured Aβ1-42 in solution with a Kd of 343 pM Figure 5 ), the antibody ACI-8041-9D7E1-Ab1 captured Aβ1-42 in solution with a Kd of 1.1 nM Figure 6 ), and the antibody ACI-8041-10H3B11-Ab1 captured Aβ1-42 in solution with a Kd of 2.6 nM Figure 7 ). The antibodies ACI-24-41F12-Ab3, ACI-31-30C11-Ab1, ACI-8037-103H5-Ab2, ACI-8037-109F4-Ab1, ACI-8039-306H5-Ab1, ACI-8039-307F7-Ab2, ACI-8039-309D9-Ab2, ACI-8041-2B9H5-Ab1, ACI-8041-3G11B3-Ab1, ACI-8041-4G6D2-Ab1, ACI-8041-5A2D4-Ab1, ACI-8041-5A6H9-Ab1, and ACI-8041-6C3C4-Ab1 also captured Aβ1-42 in solution (data not shown).

[0402] In addition, the selected antibodies were assayed using a paired or sandwich ELISA to verify the binding and selectivity for Aβ1-42. Briefly, Nunc MaxiSorp 96-well plates (Nunc) were coated with 50 μL of 5 μg / mL capture antibody diluted in carbonate-bicarbonate buffer at 4 °C for 18 h. The plates were then washed and blocked as described in the previous paragraph. Subsequently, the analyte proteins were diluted to 666 nM (for Aβ1-42 (Bachem) and random Aβ1-42 (Anaspec)) or 165 nM (for sAPPα (Sigma)) in PBS containing 1% BSA and 0.05% Tween 20, followed by 3-fold serial dilutions and 50 μL was added to each well. The plates were incubated at 37 °C for 2 h and then washed as before, and then incubated at 37 °C with 50 μL / well of biotinylated detection antibody diluted to 2 μg / mL in PBS containing 1% BSA and 0.05% Tween 20 for 1 h. The subsequent steps were the same as described in the previous paragraph for Aβ1-42 target capture, except that the incubation with TMB was carried out for only 30 min at 100 μL / well.

[0403] Aβ1-42 in solution was detected using the selected antibodies in a sandwich ELISA run with a Kd range of 100 pM. Figure 8Figure 0 shows the results of an example of a sandwich ELISA using the antibody ACI-24-41F12-Ab3, an N-terminal Aβ1-42 binder that cross-reacts with sAPPα, and an intermediate domain binder that does not bind sAPPα. This demonstrates that the assay is more selective for soluble Aβ1-42 than sAPPα, and the Kd for soluble Aβ1-42 is 9.7 nM( Figure 8 B). The sandwich pair of antibody ACI-24-41F12-Ab3 (detection) and ACI-31-25B1-Ab2 (capture) detected soluble Aβ1-42. Additionally, when using a random Aβ1-42 composed of all 42 identical amino acids present in the human Aβ1-42 peptide as the assay analyte, the complete lack of signal further confirmed the selectivity for soluble Aβ1-42.

[0404] Example 4. Epitope Mapping

[0405] Epitope mapping of ACI-24-41F12-Ab2, ACI-31-25B1-Ab2, and ACI-31-30C11-Ab1 was performed by ELISA using a peptide library spanning the amino acid sequence of Aβ1-42, which consisted of 33 overlapping biotinylated peptides, each with 8, 9, or 10 residues (Mimotopes Ltd., Melbourne, Australia). Biotinylated Aβ1-42 (Bachem) was used as a control peptide. The epitope mapping ELISA was performed according to the manufacturer's instructions. Briefly, streptavidin-coated plates (Nunc) were blocked with 0.1% BSA in PBS at 4 °C on an orbital shaker at 50 rpm for 18 h. After washing with PBS containing 0.05% Tween 20, the plates were coated with each peptide from the library diluted to a final concentration of 10 μM in 0.1% BSA containing 0.1% sodium azide in PBS for 1 h at ambient temperature. After washing, the plates were incubated with 1 μg / mL of ACI-24-41F12-Ab2, ACI-31-25B1-Ab2, or ACI-31-30C11-Ab1 diluted in 2% BSA containing 0.1% sodium azide in PBS for 1 h at ambient temperature. The plates were washed again and incubated with goat anti-mouse IgG conjugated to alkaline phosphatase (Jackson Immune Research) for 1 h at ambient temperature. After the final wash, the plates were incubated with the phosphatase substrate (pNPP, Sigma) for 2 h, and the absorbance was read at 405 nm using a plate reader (Tecan).

[0406] To determine the epitopes of ACI-24-41F12-Ab2 and ACI-31-25B1-Ab2 on Aβ1-42, binding of the antibodies to 33 overlapping 8-, 9- or 10-mer peptides covering the entire Aβ1-42 sequence was analyzed by ELISA using streptavidin plates and biotinylated peptides at the termini (Table 1). In cases where the epitope was not localized, the binding region was determined using the same assay as above but with target peptides corresponding to different vaccine antigen sequences used for antibody production. Binding to full-length Aβ1-42 was used as a positive control. The epitope of ACI-24-41F12-Ab2 was localized to the N-terminal region and identified as within residues 1 to 8 of the Aβ1-42 peptide sequence (more precisely within amino acid residues 1 to 5, where amino acids 1 and 2 of Aβ1-42 are required for antibody binding). The epitope of ACI-31-25B1-Ab2 was localized to the middle domain region and identified as within residues 22 to 35 of the Aβ1-42 peptide sequence, more precisely within amino acid residues 26 to 34 (Table 1). For ACI-8037-103H5-Ab2 and ACI-8037-109F4-Ab1, the Aβ1-42 binding region is Aβ1-5; for ACI-8039-306H5-Ab1, ACI-8039-307F7-Ab2, ACI-8039-309D9-Ab2, ACI-8041-1F11B5-Ab1, ACI-8041-2B9H5-Ab1, ACI-8041-3G11B3-Ab1, ACI-8041-4G6D2-Ab1, ACI-8041-5A2D4-Ab1, ACI-8041-5A6H9-Ab1, ACI-8041-6C3C4-Ab1, ACI-8041-9D7E1-Ab1, ACI-8041-10H3B11-Ab1, the Aβ1-42 binding region is Aβ17-23; and for ACI-31-30C11-Ab1, the Aβ1-42 binding region is Aβ22-35. Cross-reactivity with sAPPα sharing the same amino acid sequence as human Aβ1-42 in residues 1 to 16 is additionally shown in Table 1. Cross-reactivity was determined for antibodies ACI-24-41F12-Ab2, ACI-8037-103H5-Ab2 and ACI-8037-109F4-Ab1.Cross-reactivity was not determined for the antibodies ACI-31-25B1-Ab2, ACI-31-30C11-Ab1, ACI-8039-306H5-Ab1, ACI-8039-307F7-Ab2, ACI-8039-309D9-Ab2, ACI-8041-1F11B5-Ab1, ACI-8041-2B9H5-Ab1, ACI-8041-3G11B3-Ab1, ACI-8041-4G6D2-Ab1, ACI-8041-5A2D4-Ab1, ACI-8041-5A6H9-Ab1, ACI-8041-6C3C4-Ab1, ACI-8041-9D7E1-Ab1, and ACI-8041-10H3B11-Ab1.

[0407] Table 1. Aβ1-42 binding regions and epitopes, and interaction with sAPPα:

[0408]

[0409]

[0410] ND: Not determined, -: Not bound, +: Low binding, +++: High binding

[0411] Example 5. Sequencing of Antibody Variable Region Genes

[0412] Harvest mouse hybridoma cells and lyse them using a guanidine salt-containing lysis buffer that inactivates RNase. Then eliminate genomic DNA by adding DNase-free RNase to the sample. After cell disruption and genomic DNA elimination, purify the RNA using a silica-based affinity column with multiple washes and elute it from the column using RNase-free water. Once the RNA is extracted, measure its purity and concentration by spectrophotometry. Evaluate the integrity of the RNA on a denaturing agarose gel and reverse transcribe the RNA into cDNA using reverse transcriptase (RT). Before adding the reaction mixture, heat the RNA to 70 °C for 10 minutes to disrupt the RNA secondary structure. Use the RT product directly for PCR amplification. For high-fidelity PCR amplification of the cDNA, independently mix each variable region primer corresponding to different gene families encoding antibodies with constant primers used separately for the variable heavy chain domain (VH) and variable light chain domain (VL). Initially, use a degenerate primer pool (12 for VH and 12 for VL), and depending on the results, use a second pool to obtain the PCR product. After the PCR reaction, analyze the product by gel electrophoresis on a 2% agarose gel stained with ethidium bromide. The PCR products of VL and VH are purified separately on the agarose gel using tris-acetate-EDTA (TAE). Then sequence the purified fragments excised from the gel using the dye terminator sequencing method. Use the same primers as those used for PCR for the sequencing reaction. Sequence in both directions to provide overlaps at both ends. Analyze the sequencing data through the Ig Blast / Kabat database. The nucleotide sequences of VH and VL are shown in Table 2. The protein sequences of VH and VL and their complementary determining regions (CDRs) are shown in Table 3. The protein sequences of the HC and LC of mouse IgG2b, mouse IgG2a, and mouse / human chimeric IgG1 are shown in Table 4.

[0413] Table 2. Nucleotide sequences of the variable heavy chain domain and variable light chain domain (VH and VL)

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421] Table 3. Amino acid sequences of the heavy chain variable domain and the light chain variable domain (VH and VL)

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432] Table 4. Amino acid sequences of the variable and constant regions of the heavy chain (HC) and the light chain (LC)

[0433]

[0434]

[0435]

[0436]

[0437]

[0438] Table 5. Amino acid sequences of the murine IgG2a / κ isotype constant regions of the heavy chain (HC) and the light chain (LC).

[0439]

[0440] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For all purposes related to this invention, all publications and patents specifically mentioned herein are incorporated by reference in their entirety.

[0441] The scope of the present invention is not limited by some of the specific embodiments described herein. In fact, through the foregoing description and the accompanying drawings, various modifications of the present invention other than those described herein will become apparent to those skilled in the art. Such modifications are intended to fall within the scope of the appended claims. In addition, all aspects and embodiments of the present invention described herein are considered to be widely applicable and combinable with any and all other consistent embodiments, including those appropriately obtained from other aspects of the present invention (including those in isolation).

[0442] References

[0443] Belichenko PV, Madani R, Rey-Bellet L, et al, An Anti--β-Amyloid Vaccine for Treating Cognitive Deficits in a Mouse Model of Down Syndrome. PLOS ONE. 2016;11(3):e0152471.

[0444] Britt, W.G., 3rd, Hansen, A.M., Bhaskerrao, S., Larsen, J.P., Petersen, F., Dickson, A.....Kirseh, W.M. (2011). Mild cognitive impairment: prodromaal Alzheimer′s disease or something else? J Alzheimers Dis, 27(3), 543-551. doi:10.3233 / JAD-2011-110740

[0445] Buchhave, P., Minthon, L., Zetterberg.H., Wallin, A,K., Blennow, K., & Hansson, O. (2012)Cerebrospinal fluid leyes of beta-amyloid 1-42, but not of tau, are carefully changed already 5 to 10 years before the onset of Alzheimer dementia.Arch Gen Psychiaty, 69(1), 98-106. doi:10.1001 / archgenpsychiatry.2011.155

[0446] Calderon-Garciduenas, A.L., & Duyckaerts, C. (2017). Alzheimer disease. Handb Clin Neurol, 145, 325 - 337. doi:10.1016 / B978-0-12-802395-2.00023-7

[0447] Gauthier, S., Reisbeig, B., Zaudig, M., Petersen, R.C., Ritchie, K., Broich, K.,... International Psychogeriatric Association Expert Conference on mild cognitive, i. (2006). Mild cognitive impairment. Lancet, 367(9518), 1262 - 1270, doi:10.1016 / S0140-6736(06)68542-5

[0448] Given, A.M., Whalen, P.M., O′Brien, P.J and Ray, C.A. (2012). Development and validation of an alpha fetoprotein immunoassay using Gyros technology. J Pham Biomed Anal., 64 - 65:8 - 15. doi:10.1016 / j.jpba.2012.02.001

[0449] Graham et al., J. Gen. Virol. 36:59 (1977)

[0450] Head E, Powell D, Gold B.T, Schmitt F.A. Alzheimer′s Disease in Down Syndrome. European journal of neurodegenerative disease. 2012;1(3):353 - 364.

[0451] Knopman, D, S., DeKosky, S.T., Cummings, J, L., Chui, H., Corey-Bloom, J., Relkin, N.,...Stevens, J.C. (2001). Practice parameter:diagnosis of dementia(an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology, 56(9), 1143-1153. doi:10.1212 / wnl.56.9.1143

[0452] Kiio and Soyeun Park. Nano-scientifc Application of Atomic Force Microscopy in Pathology:from Molecules to Tissues. International Journal of Medical Sciences(2020);17(7):844-858. doi:10.7150 / ijms.41805

[0453] Mather. Biol. Reprod. 23:243-251(1980)

[0454] Mather et al., Annals N.Y. Acad. Sci. 383:44-68(1982)

[0455] Nabers A, Ollesch J, Schartner J, C, Genius J, Hauβmann U, Klafki H, Wiltfang J, Gerwert K. J. An infrared sensor analysing label-free the secondary structure of the Abeta peptide in presence of complex fluids. Biophotonics. 2016 Mar;9(3):22434. doi:10.1002 / jbio.201400145. Epub 2015 Mar 23. PMID:25808829

[0456] Piraino F, Volpetti F, Watson C, Maerkl SJ. A Digital-Analog Microfluidic Platform for Patient-Centric Multiplexed Biomarker Diagnostics of Ultra-low Volume Samples. ACS Nano. 2016 Jan 26;10(1):1699-710. doi:10.1021 / acsnano.5b07939. Epub 2016 Jan 12. PMID:26741022

[0457] Robb, C, Udeh-Momoh, C., Wagenpfeil, S., Schope, J., Alexopoulos, P.,... Perneczky, R., & Alzheimer's Disease Neuroimaging, I. (2017). Biomarkers and Functional Decline in Prodromal Alzheimer's Disease. J Alzheimers Dis, 58(1), 69-78. doi:10.3233 / JAD-161162

[0458] Shankar, G.M., Li, S., Mehta, T.H., Garcia-Munoz, A., Shepardson, N.E., Smith, I.,... Selkoe, D.J. (2008). Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med, 14(8), 837-842. doi:10.1038 / nm1782

[0459] Stech, M., Nikolaeva, O., Thoring, L., et al. Cell-free synthesis of functional antibodies using a coupled in vitro transcription-translation system based on CHO cell lysates. Sci Rep 7, 12030(2017)

[0460] Urlaub et al., Proc. Natl. Acad. Sci. USA 77: 4216 (1980) Sequence Listing <110> AC Immune SA <120> New Molecules for Diagnosis <130> AC2561 PCT <160> 199 <170> BiSSAP 1.3.6 <210> 1 <211> 42 <212> PRT <213> Mammalia <220> <223> Aβ1-42 <400> 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1 5 10 15 Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile 20 25 30 Gly Leu Met Val Gly Gly Val Val Ile Ala 35 40 <210> 2 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Binding Epitope <400> 2 Asp Ala Glu Phe Arg His Asp Ser 1 5 <210> 3 <211> 43 <212> PRT <213> Mammalia <220> <223> Aβ1-43 <400> 3 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1 5 10 15 Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile 20 25 30 Gly Leu Met Val Gly Gly Val Val Ile Ala Thr 35 40 <210> 4 <211> 41 <212> PRT <213> Mammal <220> <223> Aβ1-41 <400> 4 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1 5 10 15 Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile 20 25 30 Gly Leu Met Val Gly Gly Val Val Ile 35 40 <210> 5 <211> 40 <212> PRT <213> Mammal <220> <223> Aβ1-40 <400> 5 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1 5 10 15 Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile 20 25 30 Gly Leu Met Val Gly Gly Val Val 35 40 <210> 6 <211> 39 <212> PRT <213> Mammal <220> <223> Aβ1-39 <400> 6 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His Gln Lys 1 5 10 15 Leu Val Phe Phe Ala Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile 20 25 30 Gly Leu Met Val Gly Gly Val 35 <210> 7 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> Binding Epitope <400> 7 Asp Ala Glu Phe Arg 1 5 <210> 8 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> Binding Epitope <400> 8 Ser Asn Lys Gly Ala Ile Ile Gly Leu 1 5 <210> 9 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> Binding epitope <400> 9 Leu Val Phe Phe Ala Glu Asp 1 5 <210> 10 <211> 121 <212> PRT <213> Artificial sequence <220> <223> VH <400> 10 Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Ser Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val 65 70 75 80 Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Arg Arg Asn Gly Tyr Asp Gly Gly Phe Ala Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ala 115 120 <210> 11 <211> 7 <212> PRT <213> Artificial sequence <220> <223> VH CDR1 <400> 11 Thr Ser Gly Met Gly Val Ser 1 5 <210> 12 <211> 16 <212> PRT <213> Artificial sequence <220> <223> VH-CDR2 <400> 12 His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 13 <211> 11 <212> PRT <213> Artificial sequence <220> <223> VH-CDR3 <400> 13 Arg Arg Asn Gly Tyr Asp Gly Gly Phe Ala Tyr 1 5 10 <210> 14 <211> 112 <212> PRT <213> Artificial sequence <220> <223> VL <400> 14 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 <210> 15 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> VL-CDR1 <400> 15 Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu Glu 1 5 10 15 <210> 16 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> VL-CDR2 <400> 16 Lys Val Ser Asn Arg Phe Ser 1 5 <210> 17 <211> 9 <212> PRT <213> Artificial sequence <220> <223> VL-CDR3 <400> 17 Phe Gln Gly Ser His Val Pro Leu Thr 1 5 <210> 18 <211> 363 <212> DNA <213> Artificial sequence <220> <223> VH <400> 18 caggttactc tgaaagagtc tggccctggg atattgcagt cctcccagac cctcagtctg 60 acttgttctt tctctgggtt ttcactgagc acttctggta tgggtgtgag ctggattcgt 120 cagccttcag gaaagggtct ggagtggctg gcacacattt actgggatga tgacaagcgc 180 tataacccat ccctgaagag ccggctcaca atctccaagg atacctccag aaaccaggta 240 ttcctcaaga tcaccagtgt ggacactgca gatactgcca catactactg tgctcgaagg 300 aggaatggtt acgacggggg gtttgcttac tggggccaag ggactctggt cactgtctct 360 gca 363 <210> 19 <211> 336 <212> DNA <213> Artificial sequence <220> <223> VL <400> 19 gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 gatgttttga tgacccaaac tccactctcc ctgcctgtca gtcttggaga tcaagcctcc 60 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120 atctcttgca gatctagtca gagcattgta catagtaatg gaaacaccta tttagaatgg 120 tacctgcaga aaccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180 tacctgcaga aaccaggcca gtctccaaag ctcctgatct acaaagtttc caaccgattt 180 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240 tctggggtcc cagacaggtt cagtggcagt ggatcaggga cagatttcac actcaagatc 240 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttccg 300 agcagagtgg aggctgagga tctgggagtt tattactgct ttcaaggttc acatgttccg 300 ctcacgttcg gtgctgggac caagctggag ctgaaa 336 ctcacgttcg gtgctgggac caagctggag ctgaaa 336 <210> 20<210> 20 <211> 457<211> 457 <212> PRT<212> PRT <213> Artificial Sequence<213> Artificial Sequence <220><220> <223> ACI-24-41F12-Ab2 (IgG2b variant) HC <223> ACI-24-41F12-Ab2 (IgG2b variant) HC <400> 20 <400> 20 Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Ser Ser Gln Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Ser Ser Gln 1 5 10 15 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 20 25 30 Gly Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu Gly Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu 35 40 45 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val 65 70 75 80 Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Arg Arg Asn Gly Tyr Asp Gly Gly Phe Ala Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Pro Pro Ser 115 120 125 Val Tyr Pro Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser Ser Val 130 135 140 Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Ser Val Thr Val 145 150 155 160 Thr Trp Asn Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe Pro Ala 165 170 175 Leu Leu Gln Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr Val Pro 180 185 190 Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Ser Val Ala His Pro 195 200 205 Ala Ser Ser Thr Thr Val Asp Lys Lys Leu Glu Pro Ser Gly Pro Ile 210 215 220 Ser Thr Ile Asn Pro Cys Pro Pro Cys Lys Glu Cys His Lys Cys Pro 225 230 235 240 Ala Pro Asn Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Asn 245 250 255 Ile Lys Asp Val Leu Met Ile Ser Leu Thr Pro Lys Val Thr Cys Val 260 265 270 Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe 275 280 285 Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg Glu 290 295 300 Asp Tyr Asn Ser Thr Ile Arg Val Val Ser Thr Leu Pro Ile Gln His 305 310 315 320 Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys 325 330 335 Asp Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys Gly Leu 340 345 350 Val Arg Ala Pro Gln Val Tyr Ile Leu Pro Pro Pro Ala Glu Gln Leu 355 360 365 Ser Arg Lys Asp Val Ser Leu Thr Cys Leu Val Val Gly Phe Asn Pro 370 375 380 Gly Asp Ile Ser Val Glu Trp Thr Ser Asn Gly His Thr Glu Glu Asn 385 390 395 400 Tyr Lys Asp Thr Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Ile 405 410 415 Tyr Ser Lys Leu Asn Met Lys Thr Ser Lys Trp Glu Lys Thr Asp Ser 420 425 430 Phe Ser Cys Asn Val Arg His Glu Gly Leu Lys Asn Tyr Tyr Leu Lys 435 440 445 Lys Thr Ile Ser Arg Ser Pro Gly Lys 450 455 <210> 21 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> ACI-24-41F12-Ab2 (IgG2b variant) LC <400> 21 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu 115 120 125 Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe 130 135 140 Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg 145 150 155 160 Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu 180 185 190 Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser 195 200 205 Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215 <210> 22 <211> 451 <212> PRT <213> Artificial sequence <220> <223> ACI-24-41F12-Ab3 (IgG2a variant) HC <400> 22 Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Ser Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser 50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val 65 70 75 80 Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Arg Arg Asn Gly Tyr Asp Gly Gly Phe Ala Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ala Ala Lys Thr Thr Ala Pro Ser 115 120 125 Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val 130 135 140 Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu 145 150 155 160 Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr 180 185 190 Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro 195 200 205 Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr 210 215 220 Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met 245 250 255 Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu 260 265 270 Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val 275 280 285 His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu 290 295 300 Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly 305 310 315 320 Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile 325 330 335 Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val 340 345 350 Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr 355 360 365 Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu 370 375 380 Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val 405 410 415 Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val 420 425 430 His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg Thr 435 440 445 Pro Gly Lys 450 <210> 23 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> ACI-24-41F12-Ab3 (IgG2a variant) LC <400> 23 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 Arg Ala Asp Ala Ala Pro Thr Val Ser Ile Phe Pro Pro Ser Ser Glu 115 120 125 Gln Leu Thr Ser Gly Gly Ala Ser Val Val Cys Phe Leu Asn Asn Phe 130 135 140 Tyr Pro Lys Asp Ile Asn Val Lys Trp Lys Ile Asp Gly Ser Glu Arg 145 150 155 160 Gln Asn Gly Val Leu Asn Ser Trp Thr Asp Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Met Ser Ser Thr Leu Thr Leu Thr Lys Asp Glu Tyr Glu 180 185 190 Arg His Asn Ser Tyr Thr Cys Glu Ala Thr His Lys Thr Ser Thr Ser 195 200 205 Pro Ile Val Lys Ser Phe Asn Arg Asn Glu Cys 210 215 <210> 24 <211> 451 <212> PRT <213> Artificial Sequence <220> <223> ACI-24-41F12-Ab3 (hIgG1 variant) HC <400> 24 Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Ile Leu Gln Ser Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ser Phe Ser Gly Phe Ser Leu Ser Thr Ser 20 25 30 Gly Met Gly Val Ser Trp Ile Arg Gln Pro Ser Gly Lys Gly Leu Glu 35 40 45 Trp Leu Ala His Ile Tyr Trp Asp Asp Asp Lys Arg Tyr Asn Pro Ser ]>50 55 60 Leu Lys Ser Arg Leu Thr Ile Ser Lys Asp Thr Ser Arg Asn Gln Val 65 70 75 80 Phe Leu Lys Ile Thr Ser Val Asp Thr Ala Asp Thr Ala Thr Tyr Tyr 85 90 95 Cys Ala Arg Arg Arg Asn Gly Tyr Asp Gly Gly Phe Ala Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ala Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 25 <211> 219 <212> PRT <213> Artificial Sequence <220> <223> ACI-24-41F12-Ab3 (hIgG1 variant) LC <400> 25 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu Glu Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 110 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 115 120 125 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe 130 135 140 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 145 150 155 160 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 165 170 175 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 180 185 190 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 195 200 205 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 26 <400> 26 000 <210> 27 <211> 458 <212> PRT <213> Artificial Sequence <220> <223> ACI-31-25B1-Ab2 (murine IgG2b with λ LC) HC <400> 27 Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Ser Thr Tyr 20 25 30 Gly Met Ser Trpe Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Ser Gly Arg Ser Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Asn Ser Asn Asn Gln Arg Asp Tyr Tyr Ala Met Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Pro Pro 115 120 125 Ser Val Tyr Pro Leu Ala Pro Gly Cys Gly Asp Thr Thr Gly Ser Ser 130 135 140 Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Ser Val Thr 145 150 155 160 Val Thr Trp Asn Ser Gly Ser Leu Ser Ser Ser Val His Thr Phe Pro 165 170 175 Ala Leu Leu Gln Ser Gly Leu Tyr Thr Met Ser Ser Ser Val Thr Val 180 185 190 Pro Ser Ser Thr Trp Pro Ser Gln Thr Val Thr Cys Ser Val Ala His 195 200 205 Pro Ala Ser Ser Thr Thr Val Asp Lys Lys Leu Glu Pro Ser Gly Pro 210 215 220 Ile Ser Thr Ile Asn Pro Cys Pro Pro Cys Lys Glu Cys His Lys Cys 225 230 235 240 Pro Ala Pro Asn Leu Glu Gly Gly Pro Ser Val Phe Ile Phe Pro Pro 245 250 255 Asn Ile Lys Asp Val Leu Met Ile Ser Leu Thr Pro Lys Val Thr Cys 260 265 270 Val Val Val Asp Val Ser Glu Asp Asp Pro Asp Val Gln Ile Ser Trp 275 280 285 Phe Val Asn Asn Val Glu Val His Thr Ala Gln Thr Gln Thr His Arg 290 295 300 Glu Asp Tyr Asn Ser Thr Ile Arg Val Val Ser Thr Leu Pro Ile Gln 305 310 315 320 His Gln Asp Trp Met Ser Gly Lys Glu Phe Lys Cys Lys Val Asn Asn 325 330 335 Lys Asp Leu Pro Ser Pro Ile Glu Arg Thr Ile Ser Lys Ile Lys Gly 340 345 350 Leu Val Arg Ala Pro Gln Val Tyr Ile Leu Pro Pro Pro Ala Glu Gln 355 360 365 Leu Ser Arg Lys Asp Val Ser Leu Thr Cys Leu Val Val Gly Phe Asn 370 375 380 Pro Gly Asp Ile Ser Val Glu Trp Thr Ser Asn Gly His Thr Glu Glu 385 390 395 400 Asn Tyr Lys Asp Thr Ala Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe 405 410 415 Ile Tyr Ser Lys Leu Asn Met Lys Thr Ser Lys Trp Glu Lys Thr Asp 420 425 430 Ser Phe Ser Cys Asn Val Arg His Glu Gly Leu Lys Asn Tyr Tyr Leu 435 440 445 Lys Lys Thr Ile Ser Arg Ser Pro Gly Lys 450 455 <210> 28 <211> 221 <212> PRT <213> Artificial Sequence <220> <223> ACI-31-25B1-Ab2 (murine IgG2b with λ LC) LC <400> 28 Gln Leu Val Leu Thr Gln Ser Ser Ser Ala Ser Phe Ser Leu Gly Ala 1 5 10 15 Ser Ala Lys Leu Thr Cys Thr Leu Ser Ser Gln His Ile Thr Tyr Thr 20 25 30 Ile Glu Trp Tyr Gln Gln Gln Pro Leu Lys Pro Pro Lys Tyr Val Met 35 40 45 Val Leu Glu Lys Asp Gly Ser His Ser Thr Gly Asp Gly Ile Pro Asp 50 55 60 Arg Phe Ser Gly Ser Ser Ser Gly Ala Asp Arg Tyr Leu Ser Ile Ser 65 70 75 80 Asn Ile Gln Pro Glu Asp Glu Ala Val Tyr Ile Cys Gly Val Gly Asp 85 90 95 Ala Ile Lys Glu Gln Phe Val Tyr Val Phe Gly Gly Gly Thr Lys Val 100 105 110 Thr Val Leu Gly Gln Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro 115 120 125 Pro Ser Ser Glu Glu Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr 130 135 140 Ile Thr Asp Phe Tyr Pro Gly Val Val Thr Val Asp Trp Lys Val Asp 145 150 155 160 Gly Thr Pro Val Thr Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln 165 170 175 Ser Asn Asn Lys Tyr Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg 180 185 190 Ala Trp Glu Arg His Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly 195 200 205 His Thr Val Glu Lys Ser Leu Ser Arg Ala Asp Cys Ser 210 215 220 <210> 29 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Binding epitope <400> 29 Glu Asp Val Gly Ser Asn Lys Gly Ala Ile Ile Gly Leu Met 1 5 10 <210> 30 <211> 122 <212> PRT <213> Artificial sequence <220> <223> ACI-31-25B-1-Ab2 HCVR <400> 30 Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Ser Thr Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Ser Gly Arg Ser Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Asn Ser Asn Asn Gln Arg Asp Tyr Tyr Ala Met Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 31 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> ACI-31-25B1-Ab2 VH-CDR1 <400> 31 Thr Tyr Gly Met Ser 1 5 <210> 32 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> ACI-31-25B1-Ab2 VH-CDR2 <400> 32 Thr Ile Ser Ser Gly Arg Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 33 <211> 13 <212> PRT <213> Artificial Sequence <220> <223> ACI-31-25B1-Ab2 VH-CDR3 <400> 33 Asn Ser Asn Asn Gln Arg Asp Tyr Tyr Ala Met Asp Tyr 1 5 10 <210> 34 <211> 115 <212> PRT <213> Artificial Sequence <220> <223> ACI-31-25B1-Ab2 LCVR <400> 34 Gln Leu Val Leu Thr Gln Ser Ser Ser Ala Ser Phe Ser Leu Gly Ala 1 5 10 15 Ser Ala Lys Leu Thr Cys Thr Leu Ser Ser Gln His Ile Thr Tyr Thr 20 25 30 Ile Glu Trp Tyr Gln Gln Gln Pro Leu Lys Pro Pro Lys Tyr Val Met 35 40 45 Val Leu Glu Lys Asp Gly Ser His Ser Thr Gly Asp Gly Ile Pro Asp 50 55 60 Arg Phe Ser Gly Ser Ser Ser Gly Ala Asp Arg Tyr Leu Ser Ile Ser 65 70 75 80 Asn Ile Gln Pro Glu Asp Glu Ala Val Tyr Ile Cys Gly Val Gly Asp 85 90 95 Ala Ile Lys Glu Gln Phe Val Tyr Val Phe Gly Gly Gly Thr Lys Val 100 105 110 Thr Val Leu 115 <210> 35 <211> 12 <212> PRT <213> Artificial sequence <220> <223> ACI-31-25B1-Ab2 VL-CDR1 <400> 35 Thr Leu Ser Ser Gln His Ile Thr Tyr Thr Ile Glu 1 5 10 <210> 36 <211> 7 <212> PRT <213> Artificial sequence <220> <223> ACI-31-25B1-Ab2 VL-CDR2 <400> 36 Gly Ser His Ser Thr Gly Asp 1 5 <210> 37 <211> 13 <212> PRT <213> Artificial sequence <220> <223> ACI-31-25B1-Ab2 VL-CDR3 <400> 37 Gly Val Gly Asp Ala Ile Lys Glu Gln Phe Val Tyr Val 1 5 10 <210> 38 <211> 452 <212> PRT <213> Artificial sequence <220> <223> ACI-31-25B1-Ab2 (murine IgG2a with λ LC) HC <400> 38 Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Arg Phe Thr Phe Ser Thr Tyr 20 25 30 Gly Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Ser Gly Arg Ser Tyr Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg Asn Ser Asn Asn Gln Arg Asp Tyr Tyr Ala Met Asp Tyr Trp 100 105 110 Gly Gln Gly Thr Ser Val Thr Val Ser Ser Ala Lys Thr Thr Ala Pro 115 120 125 Ser Val Tyr Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser 130 135 140 Val Thr Leu Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr 145 150 155 160 Leu Thr Trp Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro 165 170 175 Ala Val Leu Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val 180 185 190 Thr Ser Ser Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His 195 200 205 Pro Ala Ser Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro 210 215 220 Thr Ile Lys Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu 225 230 235 240 Gly Gly Pro Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu 245 250 255 Met Ile Ser Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser 260 265 270 Glu Asp Asp Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu 275 280 285 Val His Thr Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr 290 295 300 Leu Arg Val Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser 305 310 315 320 Gly Lys Glu Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro 325 330 335 Ile Glu Arg Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln 340 345 350 Val Tyr Val Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val 355 360 365 Thr Leu Thr Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val 370 375 380 Glu Trp Thr Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu 385 390 395 400 Pro Val Leu Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg 405 410 415 Val Glu Lys Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val 420 425 430 Val His Glu Gly Leu His Asn His His Thr Thr Lys Ser Phe Ser Arg 435 440 445 Thr Pro Gly Lys 450 <210> 39 <211> 221 <212> PRT <213> Artificial Sequence <220> <223> ACI-31-25B1-Ab2 (murine IgG2a with λ LC) LC <400> 39 Gln Leu Val Leu Thr Gln Ser Ser Ser Ala Ser Phe Ser Leu Gly Ala 1 5 10 15 Ser Ala Lys Leu Thr Cys Thr Leu Ser Ser Gln His Ile Thr Tyr Thr 20 25 30 Ile Glu Trp Tyr Gln Gln Gln Pro Leu Lys Pro Pro Lys Tyr Val Met 35 40 45 Val Leu Glu Lys Asp Gly Ser His Ser Thr Gly Asp Gly Ile Pro Asp 50 55 60 Arg Phe Ser Gly Ser Ser Ser Gly Ala Asp Arg Tyr Leu Ser Ile Ser 65 70 75 80 Asn Ile Gln Pro Glu Asp Glu Ala Val Tyr Ile Cys Gly Val Gly Asp 85 90 95 Ala Ile Lys Glu Gln Phe Val Tyr Val Phe Gly Gly Gly Thr Lys Val 100 105 110 Thr Val Leu Gly Gln Pro Lys Ser Ser Pro Ser Val Thr Leu Phe Pro 115 120 125 Pro Ser Ser Glu Glu Leu Glu Thr Asn Lys Ala Thr Leu Val Cys Thr 130 135 140 Ile Thr Asp Phe Tyr Pro Gly Val Val Thr Val Asp Trp Lys Val Asp 145 150 155 160 Gly Thr Pro Val Thr Gln Gly Met Glu Thr Thr Gln Pro Ser Lys Gln 165 170 175 Ser Asn Asn Lys Tyr Met Ala Ser Ser Tyr Leu Thr Leu Thr Ala Arg 180 185 190 Ala Trp Glu Arg His Ser Ser Tyr Ser Cys Gln Val Thr His Glu Gly 195 200 205 His Thr Val Glu Lys Ser Leu Ser Arg Ala Asp Cys Ser 210 215 220 <210> 40 <211> 117 <212> PRT <213> 人工序列 <220> <223> ACI-31-30C11-Ab1 HCVR <400> 40 Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Ser Ser 20 25 30 Trp Leu Asn Trp Val Lys Gln Arg Pro Gly Glu Gly Leu Glu Trp Ile 35 40 45 Gly Arg Ile Tyr Pro Gly Asp Gly Asp Ile Asn Tyr Asn Gly Lys Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys 85 90 95 Thr Lys Arg Gly Arg Tyr Ala Leu Asp Tyr Trp Gly Gln Gly Thr Ser 100 105 110 Val Thr Val Ser Ser 115 <210> 41 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> ACI-31-30C11-Ab1 VH-CDR1 <400> 41 Ser Ser Trp Leu Asn 1 5 <210> 42 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> ACI-31-30C11-Ab1 VH-CDR2 <400> 42 Arg Ile Tyr Pro Gly Asp Gly Asp Ile Asn Tyr Asn Gly Lys Phe Lys 1 5 10 15 Gly <210> 43 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> ACI-31-30C11-Ab1 VH-CDR3 <400> 43 Arg Gly Arg Tyr Ala Leu Asp Tyr 1 5 <210> 44 <211> 111 <212> PRT <213> Artificial Sequence <220...

Claims

1. An amyloid-β binding antibody or an antigen-binding fragment thereof, comprising: a) A VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:11; a VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:12; a VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:13; a VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:15; a VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:16; and a VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:17; or b) A VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:31; a VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:32; a VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:33; a VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:35; a VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:36; and a VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:37; or c) A VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:61; a VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:62; a VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:63; a VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:65; a VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:16; and a VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:17; or d) A VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:11; a VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:12; a VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:73; a VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:75; a VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:16; and a VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:17; or e) A VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:61; a VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:62; a VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:83; a VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:85; a VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:16; and a VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:87; or f) VH - CDR1 consisting of the amino acid sequence of SEQ ID NO:91; VH - CDR2 consisting of the amino acid sequence of SEQ ID NO:92; VH - CDR3 consisting of the amino acid sequence of SEQ ID NO:93; VL - CDR1 consisting of the amino acid sequence of SEQ ID NO:95; VL - CDR2 consisting of the amino acid sequence of SEQ ID NO:96; and VL - CDR3 consisting of the amino acid sequence of SEQ ID NO:97; or g) VH - CDR1 consisting of the amino acid sequence of SEQ ID NO:101; VH - CDR2 consisting of the amino acid sequence of SEQ ID NO:102; VH - CDR3 consisting of the amino acid sequence of SEQ ID NO:103; VL - CDR1 consisting of the amino acid sequence of SEQ ID NO:105; VL - CDR2 consisting of the amino acid sequence of SEQ ID NO:106; and VL - CDR3 consisting of the amino acid sequence of SEQ ID NO:107; or h) VH - CDR1 consisting of the amino acid sequence of SEQ ID NO:111; VH - CDR2 consisting of the amino acid sequence of SEQ ID NO:112; VH - CDR3 consisting of the amino acid sequence of SEQ ID NO:113; VL - CDR1 consisting of the amino acid sequence of SEQ ID NO:115; VL - CDR2 consisting of the amino acid sequence of SEQ ID NO:116; and VL - CDR3 consisting of the amino acid sequence of SEQ ID NO:117; or i) VH - CDR1 consisting of the amino acid sequence of SEQ ID NO:121; VH - CDR2 consisting of the amino acid sequence of SEQ ID NO:122; VH - CDR3 consisting of the amino acid sequence of SEQ ID NO:123; VL - CDR1 consisting of the amino acid sequence of SEQ ID NO:125; VL - CDR2 consisting of the amino acid sequence of SEQ ID NO:126; and VL - CDR3 consisting of the amino acid sequence of SEQ ID NO:127; or j) VH - CDR1 consisting of the amino acid sequence of SEQ ID NO:131; VH - CDR2 consisting of the amino acid sequence of SEQ ID NO:132; VH - CDR3 consisting of the amino acid sequence of SEQ ID NO:133; VL - CDR1 consisting of the amino acid sequence of SEQ ID NO:135; VL - CDR2 consisting of the amino acid sequence of SEQ ID NO:16; and VL - CDR3 consisting of the amino acid sequence of SEQ ID NO:137; or k) VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:141; VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:142; VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:133; VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:15; VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:16; and VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:137; or l) VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:151; VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:152; VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:153; VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:155; VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:156; and VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:157; or m) VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:161; VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:162; VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:163; VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:165; VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:166; and VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:167; or n) VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:171; VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:172; VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:173; VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:175; VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:156; and VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:157; or o) VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:181; VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:182; VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:183; VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:95; VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:96; and VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:187; or p) A VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:181; a VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:182; a VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:183; a VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:195; a VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:196; and a VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:

197.

2. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises: a) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO:10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:10; or b) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO:30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:30; or c) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO:60 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:60; or d) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO:70 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:70; or e) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO:80 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO:80; or f) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO:90 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:90; or g) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO:100 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO:100; or h) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO:110 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:110; or i) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO:120 or a heavy chain variable region (VH) having at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:120; or j) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:130 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:130; or k) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:140 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:140; or l) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:150 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:150; or m) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:160 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:160; or n) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:170 or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:170; or o) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:180 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:

180.

3. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises: a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:14; or b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:30 or a heavy chain variable region (VH) having at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:30; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:34 or a light chain variable region (VL) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:34; or c) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:60 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:60; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:64 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:64; or d) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:70 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:70, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:74 or a light chain variable region (VL) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO:74; or a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:80 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO:80, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:84; or e) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:90 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:90; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:94 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:94; or f) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:100 or a heavy chain variable region (VH) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO:100; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:104; or g) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:110 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:110; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:114 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:114; or h) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:120 or a heavy chain variable region (VH) having at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:120; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:124 or a light chain variable region (VL) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO:124; or i) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:130 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:130; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:134; or j) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:140 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:140; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:144; or k) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:150 or a heavy chain variable region (VH) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:150; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:154 or a light chain variable region (VL) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:154; or l) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:160 or a heavy chain variable region (VH) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:160; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:164 or a light chain variable region (VL) having at least 99% sequence identity with the amino acid sequence of SEQ ID NO:164; or m) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:170 or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:170; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:174; or n) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:180 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:180; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:184; or o) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:180 or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:180; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:

194.

4. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises: a) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:14; or b) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:30 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:34; or c) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:60 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:64; or d) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:70 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:74; or e) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:80 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:84; or f) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:90 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:94; or g) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:100 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:104; or h) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:110 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:114; or i) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:120 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:124; or j) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:130 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:134; or k) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:140 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:144; or l) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:150 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:154; or m) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:160 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:164; or n) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:170 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:174; or o) a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:180 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:184; or p) A heavy chain variable region (VH) comprising the sequence of SEQ ID NO:180 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:

194.

5. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody comprises: a) A heavy chain (HC) comprising the amino sequence of SEQ ID NO:20 and a light chain (LC) comprising the amino sequence of SEQ ID NO:21; or b) A heavy chain (HC) comprising the amino sequence of SEQ ID NO:22 and a light chain (LC) comprising the amino sequence of SEQ ID NO:23; or c) A heavy chain (HC) comprising the amino sequence of SEQ ID NO:24 and a light chain (LC) comprising the amino sequence of SEQ ID NO:25; or d) A heavy chain (HC) comprising the amino sequence of SEQ ID NO:27 and a light chain (LC) comprising the amino sequence of SEQ ID NO:28; or e) A heavy chain (HC) comprising the amino sequence of SEQ ID NO:38 and a light chain (LC) comprising the amino sequence of SEQ ID NO:39; or f) A heavy chain (HC) comprising the amino sequence of SEQ ID NO:58 and a light chain (LC) comprising the amino sequence of SEQ ID NO:

59.

6. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment selectively binds or captures any amyloid-β peptide in solution, regardless of the conformational state of the amyloid-β peptide.

7. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment binds to an epitope within amino acid residues 1 to 5 (SEQ ID NO:7), 1 to 8 (SEQ ID NO:2), 17 to 23 (SEQ ID NO:9), 22 to 35 (SEQ ID NO:29), or 26 to 34 (SEQ ID NO:8) of SEQ ID NO:1 or to an equivalent epitope in non-human amyloid-β.

8. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment is a murine antibody, a chimeric antibody, a humanized antibody, or a human antibody or an antigen-binding fragment thereof.

9. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment is an IgM, IgG1, IgG2, IgG2a, IgG2b, IgG3, or IgG4 antibody or an antigen-binding fragment thereof.

10. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment is conjugated to a detectable label.

11. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, wherein the antibody or antigen-binding fragment thereof is used for diagnosing amyloid-β related diseases, disorders or conditions in a subject.

12. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, wherein the antibody or antigen-binding fragment thereof is used for detecting amyloid-β in a biological sample.

13. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 12, wherein the biological sample is a body fluid sample or a buffer solution.

14. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, wherein the antibody or antigen-binding fragment thereof is used for detecting amyloid-β in a body fluid sample, and the body fluid sample is saliva, urine, nasal secretion, blood, CSF sample or ISF sample.

15. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 14, wherein the body fluid sample is a blood, CSF or ISF sample.

16. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 15, wherein the blood sample is a whole blood, serum or plasma sample.

17. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, wherein the antibody or antigen-binding fragment thereof is used for diagnosing amyloid-β related diseases, disorders or conditions, and the amyloid-β related diseases, disorders or conditions are selected from: Alzheimer's disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Parkinson's disease dementia (PDD), dementia with Lewy bodies, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, myotonic dystrophy and liver dysfunction or failure.

18. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, wherein the antibody or antigen-binding fragment thereof is used for diagnosing amyloid-β related diseases, disorders or conditions, and the amyloid-β related diseases, disorders or conditions are Alzheimer's disease (AD), Down syndrome (DS), cerebral amyloid angiopathy (CAA), myotonic dystrophy or dementia with Lewy bodies.

19. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, wherein the antibody or antigen-binding fragment thereof is used for diagnosing amyloid-β related diseases, disorders or conditions, and the amyloid-β related diseases, disorders or conditions are Alzheimer's disease (AD).

20. The amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, wherein the antibody or antigen-binding fragment thereof is for diagnosing amyloid-β related diseases, disorders or conditions, and wherein the amyloid-β related diseases, disorders or conditions are Down syndrome (DS).

21. The amyloid-β binding antibody or antigen-binding fragment thereof according to claim 17, wherein Alzheimer's disease (AD) is Down syndrome-related Alzheimer's disease.

22. Use of the amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 21 in the preparation of a kit for a method of detecting amyloid-β in a sample obtained from a subject, the method comprising contacting the sample with the amyloid-β binding antibody or antigen-binding fragment thereof, and detecting the binding of the antibody or antigen-binding fragment thereof to detect amyloid-β in the sample.

23. Use of the amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 21 in the preparation of a kit for a method of quantifying amyloid-β in a sample obtained from a subject, the method comprising contacting the sample with the amyloid-β binding antibody or antigen-binding fragment thereof, and quantifying amyloid-β in the sample based on the level of binding of the antibody or antigen-binding fragment thereof to amyloid-β.

24. Use of the amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 21 in the preparation of a kit for diagnosing diseases, disorders and / or conditions related to amyloid-β, the diagnosis comprising performing the method according to claim 22 or 23, wherein a higher level of amyloid-β in the sample, compared to a control level based on healthy subjects, indicates a disease, disorder and / or condition related to amyloid-β, and wherein the diseases, disorders or conditions related to amyloid-β are selected from: Alzheimer's disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Parkinson's disease dementia (PDD), dementia with Lewy bodies, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, myotonic dystrophy and liver dysfunction or failure.

25. The use according to claim 24, wherein Alzheimer's disease is Down syndrome-related Alzheimer's disease.

26. Use of an amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of claims 1 to 21 in the preparation of a kit for diagnosing a disease, disorder, and / or condition associated with amyloid-β, said diagnosis comprising performing the method according to claim 22 or 23, wherein an amyloid-β level in the sample that is similar to or higher than a diseased control level indicates a disease, disorder, and / or condition associated with amyloid-β, wherein the disease, disorder, or condition associated with amyloid-β is selected from: Alzheimer's disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Parkinson's disease dementia (PDD), dementia with Lewy bodies, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, myotonic dystrophy, and liver dysfunction or failure.

27. Use according to claim 26, wherein the Alzheimer's disease is Down syndrome-related Alzheimer's disease.

28. Use of an amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of claims 1 to 21 in the preparation of a kit for classifying a disease, disorder, and / or condition associated with amyloid-β, said classification comprising: a. performing the method according to claim 24 and / or 26; b. classifying the disease, disorder, and / or condition associated with amyloid-β.

29. Use of an amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of claims 1 to 21 in the preparation of a kit for monitoring a disease, disorder, and / or condition associated with amyloid-β using a sample from a subject at two or more time points, said monitoring comprising contacting the sample with the amyloid-β binding antibody or an antigen-binding fragment thereof, wherein: a. a higher amyloid-β level in a later sample compared to one or more earlier samples indicates progression of a disease, disorder, and / or condition associated with amyloid-β; b. a lower amyloid-β level in a later sample compared to one or more earlier samples indicates regression of a disease, disorder, and / or condition associated with amyloid-β; and / or c. a non-significant change in the amyloid-β level in a later sample compared to one or more earlier samples indicates lack of progression of a disease, disorder, and / or condition associated with amyloid-β; Wherein the amyloid-β related diseases, disorders or conditions are selected from: Alzheimer's disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Parkinson's disease dementia (PDD), Lewy body dementia, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, myotonic dystrophy, and liver dysfunction or failure.

30. The use according to claim 29, wherein the Alzheimer's disease is Down syndrome-related Alzheimer's disease.

31. Use of an amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of claims 1 to 21 in the preparation of a kit for selecting a treatment for treating an amyloid-β related disease, disorder and / or condition, said selection comprising contacting samples taken before and after treatment with the amyloid-β binding antibody or an antigen-binding fragment thereof, wherein: a. A lower amyloid-β level in a sample taken after treatment as compared to a sample taken before treatment indicates successful treatment of an amyloid-β related disease, disorder and / or condition, and thus the treatment is selected for administration; b. An amyloid-β level that does not change significantly in a sample taken after treatment as compared to a sample taken before treatment indicates successful treatment of an amyloid-β related disease, disorder and / or condition, and thus the treatment is selected for administration; c. A decrease in the rate of increase in amyloid-β levels between samples taken during treatment as compared to a sample taken before treatment indicates successful treatment of an amyloid-β related disease, disorder and / or condition, and thus the treatment is selected for administration; d. A higher amyloid-β level in a sample taken after treatment as compared to a sample taken before treatment indicates unsuccessful treatment of an amyloid-β related disease, disorder and / or condition, and thus the treatment is not selected for administration; or e. A lack of decrease in the rate of increase in amyloid-β levels between samples taken during treatment as compared to a sample taken before treatment indicates unsuccessful treatment of an amyloid-β related disease, disorder and / or condition, and thus the treatment is not selected for administration; The amyloid-β related diseases, disorders or conditions are selected from: Alzheimer's disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Parkinson's disease dementia (PDD), dementia with Lewy bodies, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, myotonic dystrophy, and liver dysfunction or failure.

32. The use according to claim 31, wherein the Alzheimer's disease is Down syndrome-related Alzheimer's disease.

33. Use of the amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 21 in the preparation of a kit for evaluating a candidate treatment for amyloid-β related diseases, disorders and / or conditions, said use comprising, after treating one or more subjects, contacting a sample from one or more treated subjects with the antibody or antigen-binding fragment thereof, wherein a lower amyloid-β level in the sample, compared to the level in a corresponding sample from a subject not treated with said treatment, indicates successful treatment of an amyloid-β related disease, disorder and / or condition, wherein the amyloid-β related diseases, disorders or conditions are selected from: Alzheimer's disease (AD), mild cognitive impairment (MCI), Down syndrome (DS), cardiac amyloidosis, cerebral amyloid angiopathy (CAA), multiple sclerosis, Parkinson's disease, Parkinson's disease dementia (PDD), dementia with Lewy bodies, ALS (amyotrophic lateral sclerosis), adult-onset diabetes, inclusion body myositis (IBM), ocular amyloidosis, glaucoma, macular degeneration, lattice dystrophy, optic neuritis, myotonic dystrophy, and liver dysfunction or failure.

34. The use according to claim 33, wherein the Alzheimer's disease is Down syndrome-related Alzheimer's disease.

35. The use according to claim 33, which is carried out at multiple time points in matched samples between a treatment group and a placebo group to monitor the effectiveness of the candidate treatment over a defined period of time.

36. The use according to claim 33 or 35, which comprises contacting samples from the one or more treated subjects and the subjects not treated with said treatment with the antibody or antigen-binding fragment according to any one of claims 1 to 21 before treatment with the treatment or placebo respectively, to determine the baseline level of amyloid-β.

37. A diagnostic composition comprising the amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 21 and an acceptable carrier and / or excipient.

38. A nucleic acid encoding the amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 21.

39. The nucleic acid according to claim 38, which comprises the nucleotide sequence provided in SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:78, SEQ ID NO:79, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:128, SEQ ID NO:129, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:158, SEQ ID NO:159, SEQ ID NO:168, SEQ ID NO:169, SEQ ID NO:178, SEQ ID NO:179, SEQ ID NO:188, SEQ ID NO:189 or SEQ ID NO:

199.

40. A recombinant vector, which comprises the nucleic acid according to claim 38 or 39.

41. A host cell, which comprises the nucleic acid according to claim 38 or 39 and / or the recombinant vector according to claim 40.

42. A method for producing an amyloid-β binding antibody or an antigen-binding fragment thereof, which comprises the following steps: a. culturing the host cell according to claim 41 under conditions suitable for producing the amyloid-β binding antibody or the antigen-binding fragment thereof, and b. recovering the amyloid-β binding antibody or the antigen-binding fragment thereof.

43. A kit for diagnosing a disease, disorder or condition associated with amyloid-β, or a kit for use according to any one of claims 22 to 36, which comprises the amyloid-β binding antibody or the antigen-binding fragment thereof according to any one of claims 1 to 21 and a container.

44. The amyloid-β binding antibody or the antigen-binding fragment thereof according to any one of claims 1 to 10, which is used as an analytical tool or a reference molecule for research purposes.

45. The amyloid-β binding antibody or the antigen-binding fragment thereof according to any one of claims 1 to 10, which is used for detecting amyloid-β aggregates, including plaques, in vitro or in vivo.

46. The amyloid-β binding antibody or the antigen-binding fragment thereof according to claim 45, which is used for histochemical detection in brain tissue.

47. A diagnostic composition comprising at least two amyloid-β binding antibodies or antigen-binding fragments thereof according to any one of claims 1 to 21, and an acceptable carrier and / or excipient.

48. The diagnostic composition according to claim 47, wherein the two amyloid-β binding antibodies or antigen-binding fragments selectively bind or capture any amyloid-β peptide in solution, regardless of the conformational state of the amyloid-β peptide, and wherein at least one of the two amyloid-β binding antibodies or antigen-binding fragments does not exhibit any cross-reactivity with soluble APPα.

49. A diagnostic composition comprising two amyloid-β binding antibodies or antigen-binding fragments, and an acceptable carrier and / or excipient, the two amyloid-β binding antibodies or antigen-binding fragments comprising: a first amyloid-β binding antibody or antigen-binding fragment thereof, which is an amyloid-β binding antibody or antigen-binding fragment thereof according to any one of claims 1 to 21; and a second amyloid-β binding antibody or antigen-binding fragment thereof, which is not an antibody according to any one of claims 1 to 21.

50. A diagnostic composition comprising at least two amyloid-β binding antibodies or antigen-binding fragments thereof according to claim 48 or 49, and an acceptable carrier and / or excipient, wherein at least one or both of the amyloid-β binding antibodies or antigen-binding fragments are selected from: a) VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:11; VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:12; VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:13; VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:15; VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:16; and VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:17; and / or b) VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:31; VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:32; VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:33; VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:35; VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:36; and VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:37; and / or c) VH-CDR1 consisting of the amino acid sequence of SEQ ID NO:151; VH-CDR2 consisting of the amino acid sequence of SEQ ID NO:152; VH-CDR3 consisting of the amino acid sequence of SEQ ID NO:153; VL-CDR1 consisting of the amino acid sequence of SEQ ID NO:155; VL-CDR2 consisting of the amino acid sequence of SEQ ID NO:156; and VL-CDR3 consisting of the amino acid sequence of SEQ ID NO:

157.

51. Use of an amyloid-β binding antibody or an antigen-binding fragment thereof in the preparation of a kit for detecting amyloid-β in a sample obtained from a subject, said use comprising the step of capturing amyloid-β with a first amyloid-β binding antibody or a fragment thereof, and the step of detecting the captured amyloid-β in the sample with a second amyloid-β binding antibody or a fragment thereof, wherein: a) each amyloid-β binding antibody or an antigen-binding fragment thereof is selected from the antibodies or antigen-binding fragments according to any one of claims 1 to 21, or b) one amyloid-β binding antibody or an antigen-binding fragment thereof according to any one of claims 1 to 21, and the other antibody is an amyloid-β binding antibody or an antigen-binding fragment thereof different from the antibody according to any one of claims 1 to 21.

52. Use of an amyloid-β binding antibody or an antigen-binding fragment thereof in the preparation of a kit for detecting amyloid-β in a sample obtained from a subject, said use comprising the step of capturing amyloid-β with a first amyloid-β binding antibody or a fragment thereof, and the step of detecting the captured amyloid-β in the sample with a second amyloid-β binding antibody or a fragment thereof, wherein the first and second amyloid-β binding antibodies or antigen-binding fragments thereof are selected from any one of claims 1 to 21, and wherein at least one of the first and second antibodies or antigen-binding fragments does not show any cross-reactivity with soluble APPα.

53. A diagnostic composition, comprising: a. A first amyloid-β binding antibody or an antigen-binding fragment thereof, which selectively binds to any amyloid-β peptide in solution, regardless of the conformational state of the amyloid-β peptide, and b. A second amyloid-β binding antibody or an antigen-binding fragment thereof, which selectively binds to any amyloid-β peptide in solution, regardless of the conformational state of the amyloid-β peptide, wherein at least one or both of the first and second antibodies do not show cross-reactivity with soluble APPα.

54. The diagnostic composition according to claim 53, wherein at least one of the first and second antibodies or antigen-binding fragments thereof that exhibit no cross-reactivity with soluble APPα is an antibody or antigen-binding fragment thereof according to any one of claims 1 to 21.

55. The diagnostic composition according to claim 54, wherein the antibody or antigen-binding fragment thereof that exhibits no cross-reactivity with soluble APPα comprises: i. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34; or ii. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 150 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:

154.

56. The diagnostic composition according to any one of claims 53 to 55, wherein one of the first and second antibodies or antigen-binding fragments thereof exhibits cross-reactivity with soluble amyloid precursor protein (APP).

57. The diagnostic composition according to claim 56, wherein the antibody or antigen-binding fragment thereof that exhibits cross-reactivity with soluble amyloid precursor protein (APP) is an antibody or antigen-binding fragment thereof according to any one of claims 1 to 21.

58. The diagnostic composition according to claim 57, wherein the antibody or antigen-binding fragment thereof that exhibits cross-reactivity with soluble amyloid precursor protein (APP) comprises: a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:

14.

59. Use of an amyloid-β binding antibody or antigen-binding fragment thereof in the preparation of a kit for detecting amyloid-β in a sample obtained from a subject, the use comprising: a. capturing amyloid-β with an amyloid-β binding antibody or antigen-binding fragment thereof that selectively binds to any amyloid-β peptide in solution, regardless of the conformational state of the amyloid-β peptide, and b. detecting the captured amyloid-β with an amyloid-β binding antibody or antigen-binding fragment thereof that selectively binds to any amyloid-β peptide in solution, regardless of the conformational state of the amyloid-β peptide, and exhibits no cross-reactivity, low cross-reactivity, or high cross-reactivity with soluble APPα, wherein at least one or both of the capturing and detecting antibodies or antigen-binding fragments thereof exhibit no cross-reactivity with soluble APPα.

60. The use according to claim 59, wherein at least one of the capturing and detecting antibodies or antigen-binding fragments thereof that exhibit no cross-reactivity with soluble APPα is an antibody or antigen-binding fragment thereof according to any one of claims 1 to 21.

61. Use according to claim 59 or 60, wherein one of the capture and detection antibodies or antigen-binding fragments thereof shows cross-reactivity with soluble amyloid precursor protein (APP).

62. Use according to claim 61, wherein the antibody or antigen-binding fragment thereof showing cross-reactivity with soluble amyloid precursor protein (APP) is the antibody or antigen-binding fragment thereof according to any one of claims 1 to 21.

63. A kit for detecting amyloid-β in a sample obtained from a subject, the kit comprising: a. A capture amyloid-β-binding antibody or antigen-binding fragment thereof that selectively binds to any amyloid-β peptide in solution, regardless of the conformational state of the amyloid-β peptide; and b. A detection amyloid-β-binding antibody or antigen-binding fragment thereof that selectively binds to any amyloid-β peptide in solution, regardless of the conformational state of the amyloid-β peptide; wherein at least one of the capture and detection antibodies or antigen-binding fragments thereof shows no cross-reactivity with soluble APPα.

64. The kit according to claim 63, wherein at least one of the capture and detection antibodies or antigen-binding fragments thereof showing no cross-reactivity with soluble APPα is the antibody or antigen-binding fragment thereof according to any one of claims 1 to 21.

65. The kit according to claim 63 or 64, wherein one of the capture and detection antibodies or antigen-binding fragments thereof shows cross-reactivity with soluble amyloid precursor protein (APP).

66. The kit according to claim 65, wherein the antibody or antigen-binding fragment thereof showing cross-reactivity with soluble amyloid precursor protein (APP) is the antibody or antigen-binding fragment thereof according to any one of claims 1 to 21.

67. Use according to claim 23, wherein the sample is saliva, urine, nasal secretion, blood, CSF sample, brain and / or ISF sample.

68. The kit according to claim 63, wherein the sample is saliva, urine, nasal secretion, blood, CSF sample, brain and / or ISF sample.

69. The diagnostic composition according to claim 47, further comprising a sample, wherein the sample is saliva, urine, nasal secretion, blood, CSF sample, brain and / or ISF sample.

70. The diagnostic composition according to claim 53, further comprising a sample, wherein the sample is saliva, urine, nasal secretion, blood, CSF sample, brain and / or ISF sample.

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