Anti-TDP-43 binding molecules

Abstract

Provided are TDP-43 binding molecules that specifically bind to phosphorylated TDP-43, together with nucleic acid molecules that code for the binding molecules.These binding molecules are useful for diagnostic and therapeutic applications, and can be included in suitable compositions and kits.They can be used in pairing assays, including the use of capture and detection antibody pairs.They can be used to monitor diseases associated with TDP-43, including testing candidate therapeutic agents.

Description

[Technical field]

[0001] The present invention relates to the field of transactivation response DNA binding protein (TDP-43 or TARDBP) having a molecular weight of 43 kDa. The present invention relates to molecules that bind to TDP-43 and related TARDBP gene products, in particular anti-TDP-43 antibodies or antigen-binding fragments or derivatives thereof and uses thereof. The present invention relates to a method for treating amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), Alzheimer's disease (AD), Down's syndrome (DS), Parkinson's disease (PD) and related disorders (including Parkinson's disease type dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)), limbic predominant aged TDP-43 encephalopathy (LATE), myofibrillar myopathy (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary myopathies, and the like. The present invention provides means and methods for diagnosing, preventing, ameliorating, and / or treating disorders and / or abnormalities associated with TDP-43 and its various isoforms, including, but not limited to, progressive lateral sclerosis (PLS), progressive muscular atrophy, and diseases of both sporadic and inherited origin, including genetic cases resulting from mutations or variant-associated risk alleles in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), and TMEM106B genes. The present invention provides novel high affinity antibodies and antibody derivatives thereof with unique sequences, structures, and stability for use as tools for the diagnosis, prevention, monitoring, amelioration, and / or treatment of TDP-43-associated disorders and / or abnormalities. The present invention also provides novel epitope-specific TDP-43 binding molecules that, alone or in combination, enable targeting or detection of previously inaccessible forms of TDP-43 in vivo or in human biological samples. [Background technology]

[0002] TDP-43 and its role in central nervous system proteinopathies Diseases characterized by pathological aggregation of proteins in the central nervous system (CNS) and peripheral organs (proteinopathies) are one of the leading causes of disability and mortality in the world. One of the proteins that undergoes pathological aggregation is the transactivation response DNA-binding protein (TARDBP or TDP-43), which has a molecular weight of 43 kDa.TDP-43 proteinopathies (caused by aggregated forms of TDP-43) are a common pathological condition affecting amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease (FTLD-MND), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), nonfluent / agrammatic primary progressive aphasia (Nonfluent / Agrammatic Primary Progressive Aphasia), and neurodegenerative disorders including neurodegenerative disorders including neurodegenerative disorders. Aphasia (naPPA), Alzheimer's disease (AD), Down's syndrome (DS), Familial British Dementia, Parkinson's disease (PD) and related disorders (including Parkinson's disease type dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)), Corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), Facial-Onset Sensory Motor Neuropathy (FMSA), These include, but are not limited to, myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), and progressive muscular atrophy (Lagier-Tourenne et al., Human Molecular Genetics, 2010, Vol. 19, Review Issue 1 R46-R64; de Boer et al., Journal of Neurology, Neurosurgery and Psychiatry 2020 Vol. 92, Issue 1, 86-95, Nelson et al., Journal of Neuropathology & Experimental Neurology 2020, Vol. 75, Issue 6, June 2016, Pages 482-498).These include diseases of both sporadic and inherited origin, including genetic examples resulting from mutations or variant-associated risk alleles in the progranulin (GRN), TARDBP, valosin-containing protein (VCP), angiogenin (ANG), huntingtin (HTT), ataxin 3 (ATXN3), desmin (DES) or myotilin (MYOT) genes.

[0003] In 2006, TDP-43 was identified as a protein that accumulates in most cases of frontotemporal lobar degeneration (FTLD) with tau-negative ubiquitin-positive inclusions (termed FTLD-TDP) and in most cases of amyotrophic lateral sclerosis (ALS) (Arai et al., Biochemical and Biophysical Research Communications 351 (2006) 602-611; Neumann et al., Science 314, (2006), 130-133).

[0004] Aggregated TDP-43 from patient brains displays many abnormal modifications including hyperphosphorylation, ubiquitination, acetylation, and proteolytic cleavage to C-terminal fragments (Arai et al., Biochemical and Biophysical Research Communications 351 (2006) 602-611; Neumann et al., Science 314, (2006), 130-133; Neumann et al., Acta Neuropathol. (2009) 117:137-149; Hasegawa et al., (2008) Annals of Neurology Vol 64 No 1, 60-70; Cohen et al., Nat Commun. 6:5845, 2015). Another property of TDP-43 pathology is the redistribution and accumulation of TDP-43 from the nucleus to the cytoplasm. The characteristic lesions of FTLD-TDP are neuronal and glial cytoplasmic inclusions (NCIs and GCIs, respectively) and degenerated neurites (DNs), which are immunoreactive for TDP-43, as well as ubiquitin and p62, but negative for other neurodegeneration-associated proteins. Differences in inclusion morphology and their tissue distribution are associated with specific mutations and / or clinical symptoms. Four types of TDP-43 lesions have been reported so far by histological classification (Mackenzie and Neumann, J. Neurochem. (2016) 138 (Suppl. 1), 54-70). FTLD-TDP type A cases are characterized by a large amount of short neurodegenerative processes (DNs) and small ovoid or semilunar NCIs, mainly in layer II of the neocortex (Fig. 2f in Mackenzie et al., 2016 J. Neurochem. 138 (Suppl. 1), 54-70). This condition usually presents clinically as either behavioral variant frontotemporal dementia (bvFTD) or primary progressive aphasia (nfvPPA) and is associated with mutations in progranulin (GRN).Type B cases show a moderate number of small or granular NCIs in both superficial and deep cortical layers with relatively few DNs and NIIs (neuronal intranuclear inclusions; Fig. 2g in Mackenzie et al., 2016 J. Neurochem. 138 (Suppl. 1), 54-70). Many cases presenting simultaneously with FTD and ALS symptoms have been found to show FTLD-TDP Type B pathology. Type C cases have abundant long serpentine neurites, especially in superficial cortical layers, with little or no NCIs (Fig. 2j in Mackenzie et al., 2016 J. Neurochem. 138 (Suppl. 1), 54-70). This pathology is seen especially in cases presenting with semantic variant primary progressive aphasia (svPPA). FTLD-TDP type D shows abundant lenticular neuronal intranuclear inclusions (NIIs) and short DNs in the neocortex with extremely rare NCIs (Fig. 2k in Mackenzie et al., 2016 J. Neurochem. 138 (Suppl. 1), 54-70). This lesion pattern is seen only in cases of VCP associated with inclusion body myositis (IBM).

[0005] Genetic forms of TDP-43 proteinopathy Thirty-eight negative dominant mutations in TARDBP have been identified in patients with sporadic and familial ALS, as well as in patients with inherited FTD, mostly located in sequences encoding the glycine-rich domain (Fig. 1 in Lagier-Tourenne and Cleveland, Cell 136, 2009, 1001-1004). ALS-associated TARDBP mutations render the protein more prone to aggregation (Ticozzi et al., CNS Neurol. Disord. Drug Targets. 2010, 9(3), 285-296.), linking TDP-43 aggregation to clinical disease symptoms.

[0006] TDP-43 in FTD Frontotemporal dementia (FTD) is a clinical term that includes a wide range of diseases based on the degeneration of the frontal and temporal lobes, a pathological feature called frontotemporal lobar degeneration (FTLD). FTD is the second most common case of early degenerative dementia in people under 65 years of age (Le Ber, Revue Neurologique 169 (2013) 811-819). FTD is manifested by several symptoms, including bvFTD, characterized by changes in personality and behavior; semantic dementia (SD) and progressive non-fluent aphasia (PNFA), characterized by changes in language function; and corticobasal syndrome (CBS), progressive supranuclear palsy syndrome and motor neuron disease (FTD-MND), characterized by motor dysfunction. The clinical diagnosis of these conditions is complex and a final conclusion can only be made by postmortem histopathological analysis to detect aggregated proteins and identify the affected brain regions. From a pathological point of view, among the protein inclusions, approximately 45% of cases show pathological accumulation of misfolded tau, 45% of cases show pathological TDP-43, and a smaller population shows aggregations of fusion with sarcoma (FUS) protein and other proteins.

[0007] TDP-43 in ALS Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by early loss of upper and lower motor neurons. ALS progression follows disease progression from 1–5 years from diagnosis to death, marked by fatal motor paralysis and respiratory failure. In most cases of sporadic ALS, the neuropathology is characterized by abnormal cytoplasmic accumulation of TDP-43 in neurons and glia of the primary motor cortex, brainstem motor nuclei, spinal cord, and associated white matter tracts. ALS with dementia is associated with accumulation of TDP-43 in the extramotor neocortex and hippocampus. The role of TDP-43 phosphorylation in ALS patients has been studied with the help of antibodies that specifically bind to phosphorylated TDP-43 in nuclear and cytoplasmic inclusions with amino acids S379, S403, S404, S409, and S410 as the main sites of TDP-43 phosphorylation (Hasegawa et al., Ann Neurol 2008; 64:60-70; Neumann et al., Acta Neuropathol (2009) 117:137-149).

[0008] TDP-43 in AD TDP-43 pathology occurs in up to 57% of brains of Alzheimer's disease patients (Josephs KA et al., Acta Neuropathol. 2014; 127(6): 811-824; Josephs KA et al., Acta Neuropathol. 2014; 127(3): 441-450; McAleese et al., Brain Pathol. 2017 Jul; 27(4): 472-479). TDP-43 aggregation is associated with patient age and correlates with cognitive decline, memory loss, and medial temporal lobe atrophy in AD. TDP-43 in AD appears to represent a secondary or independent pathology that shares an overlapping brain distribution with amyloid beta and tau pathology in the medial temporal lobe. The AD-associated pathology TDP-43 follows a uniform pattern of progressive deposition reported by the so-called TDP-43 in AD (TAD) staging scheme: initially, TDP-43 deposition in the amygdala (stage I), followed by the hippocampus, limbic system, temporal lobes, and finally, the anterior striatum (stage V) (Josephs KA et al., Acta Neuropathol. 2014;127(6): 811-824; Josephs KA et al., Acta Neuropathol. 2014;127(3): 441-450).

[0009] Lesion propagation of aggregated TDP-43 Although the onset and initial symptoms of ALS and FTD vary significantly between patients, a common feature of disease progression is the spread of lesions from an initial localized area to many neurons. The intermittent worsening of symptoms may be explained by the progressive spread of TDP-43 lesions. TDP-43 lesions in the brains of ALS patients may spread in a four-step process, spreading transsynaptically via corticosubgrade axonal projections using anterograde axonal migration (Brettschneider et al., Ann Neurol. 2013 July; 74(1): 20-38.). Recent experimental evidence indicates that the proliferation of lesion proteins in neural tissues, amyloid beta, tau, alpha synuclein, and TDP-43, which arise by a prion-like mechanism (Hasegawa et al., 2017), show different initiation points and patterns of tissue distribution (Brettschneider J et al., Nature Rev. Neuroscience, 2015, 109). One aspect of these common propagation mechanisms is thought to be the intercellular spread of diseased protein aggregates. This process consists of release of aggregates from diseased cells, uptake by endogenous (or less affected) cells, followed by seeding of diseased protein conformations by templated conformational changes of intracellular proteins. In the case of TDP-43, sequestration of functional DTP-43 protein may be extreme enough to cause cellular defects (including loss-of-function mechanisms).

[0010] The cell-to-cell spread of TDP-43 has been studied at the molecular level in several in vitro models, where insoluble TDP-43 preparations derived from patient brains are able to induce intracellular aggregate formation in reporter cells (Nonaka et al., Cell Reports 4 (2013), 124-134; Feiler et al., 2015; Porta et al., Nat. Comm., 2018). Furthermore, it was shown that intracellular TDP-43 aggregates can be bound and released into exosomes before spreading to their neighboring cells (Nonaka et al., Cell Reports 4 (2013, 124-134)). Similarly, adenoviral-transduced TDP-43 expression leads to cytoplasmic aggregates that are phosphorylated, ubiquitous, and most importantly can act as seeds to initiate cell-to-cell spread (Ishii et al., PLoS ONE 12(6): e0179375, 2017). Patient-derived pathological TDP-43 can also induce widespread deposition of endogenous TDP-43 following intracerebral inoculation in transgenic and wild-type mice (Porta et al., Nat. Comm., 2018).

[0011] Different diagnostic strategies for neurodegenerative diseases including TDP-43 proteinopathies Diagnosis of FTD based on clinical symptoms is inadequate, especially in the early stages, as its clinical symptoms may overlap with other diseases. Therefore, the development of biochemical biomarkers that distinguish between different types of FTD pathology is an important health-related goal. The development of antibodies against different conformations of TDP-43 is an essential step to create more sensitive and specific diagnostic tools. In parallel with biochemical biomarkers, the development of imaging biomarkers may allow early and specific detection of pathology in TDP-43 proteinopathies. The ability to image TDP-43 deposits in the brain could be a major achievement for the diagnosis and drug development of TDP-43 proteinopathies. The use of cell-permeable antibody fragments may enable such detection.

[0012] The earliest event in neurodegenerative diseases is the appearance of an alternative conformation that renders the protein toxic (aggregation). Moreover, this aggregated conformation can self-propagate by recruiting endogenous normal proteins as misfolded conformations, a fundamental mechanism of observed propagation through diseased tissues.

[0013] Antibodies that allow differential targeting of specific isoforms or post-translational modifications of TFP-43 offer many advantages since they can distinguish between disease-associated and functional endogenous conformations of these proteins. These unique features offer the potential for improvements in diagnostic and therapeutic applications since such antibodies can distinguish previously inaccessible TDP-43 and TDP-43-derived targets. These features are therefore paramount for developing sensitive and specific diagnostics and therapeutics. Such high affinity and selective targeting of TDP-43 variants is particularly important for TDP-43 proteinopathies since TDP-43 aggregation can cause negative dominant effects on TDP-43 function and exacerbate disease when combined with inappropriate targeting of functional TDP-43.

[0014] Prevention and Treatment of TDP-43 Proteinopathy TDP-43 aggregation and lesion propagation are key features of ALS and FTD, fatal diseases for which no treatment is currently available. Slowing or preventing the progression of these lesions using TDP-43 binding molecules has the potential to prevent or treat ALS, FTD and the other TDP-43 proteinopathies described above.

[0015] Normal cell function and distribution of TDP-43 Transactivation response (TAR) DNA binding protein 43 kDa (TDP-43) is a 414 amino acid protein encoded by the TARDBP gene on chromosome 1p36.2 (also known as ALS10). Multiple TARDBP mRNAs are contained by differential splicing of six (or potentially seven) exons that code for a heterogeneous set of polypeptide isoforms with a shared amino acid sequence (D'Alton et al., RNA, 2015). In this application, TDP-43 refers to the human reference sequence (Q13148) and its isoforms, including polypeptides resulting from differential splicing, proteolytic fragments, and post-translationally modified polypeptides. TDP-43 belongs to the heterogeneous ribonucleoprotein (hnRNP) RNA-binding protein family (Wang et al., Trends in Molecular Medicine Vol.14 No.11, 2008, 479-485; Lagier-Tourenne et al., Human Molecular Genetics, 2010, Vol. 19, Review Issue 1 R46-R64). TDP-43 contains five functional domains (Figure 1 in Warraich et al., The International Journal of Biochemistry & Cell Biology 42 (2010) 1606-1609): two RNA recognition motifs (RRM1 and RRM2) with two highly conserved hexameric ribonucleoprotein 2 (RNP2) and octameric ribonucleoprotein 1 (RNP1) regions, a nuclear export signal (NES) and a nuclear localization signal (NLS) that allow transport of bound mRNAs between the nucleus and the cytoplasm, and a glycine-rich domain at the C-terminus that mediates protein-protein interactions). TDP-43 is involved in multiple aspects of RNA processing, including transcription, splicing, transport, and stabilization (Buratti and Baralle, FEBS Journal 277 (2010) 2268-2281).It is a highly conserved, ubiquitously expressed protein that shuttles intermittently between the nucleus and cytoplasm with tightly autoregulated expression. TDP-43 participates in multiple aspects of RNA processing, including transcription, splicing, transport, and stabilization, all of which are crucial for neuronal function. Thus, maintenance of TDP-43 function is essential to produce structurally correct neuronal gene products and to avoid the production of potentially harmful ones, including aggregation-prone forms of TDP-43 itself.

[0016] Intracellular clearance of TDP-43 and its aggregation-prone forms is achieved by several different degradation pathways, including the ubiquitin proteasome system (UPS), the autophagy-lysosome pathway (ALP) and chaperone-mediated autophagy (CMA), as shown by both in vitro cell culture and in vivo studies (Wang et al., 2010, Ormeno et al., 2020). The effectiveness of these intracellular mechanisms to clear TDP-43 is determined by differences in TDP-43 isoform production and post-translational modifications. Of particular note is that the load of aggregated TDP-43 already present in the cell has a significant negative effect on the clearance rate.

[0017] A possible role for TDP-43 in the pathology of neurodegenerative diseases has been reported with the accumulation of hyperphosphorylated TDP-43 protein inclusions shown in subtypes of frontotemporal dementia (FTD) and in the majority of cases of amyotrophic lateral sclerosis (ALS) (Arai et al., 2006; Neumann et al., 2006). In addition to FTD and ALS, further biochemical and immunohistochemical analyses have similarly shown phospho-TDP-43 as a major constituent of cytoplasmic ubiquitin immunoreactive lesions in the cerebral cortex and hippocampus in patients with motor neuron disease (MND), Alzheimer's disease (AD), dementia with Lewy bodies, Parkinson's disease (PD), progressive supranuclear palsy (PSP), Pick's disease, (PiD), multiple system atrophy (MSA), and Huntington's disease (HD) (Davidson et al., 2009). The pathology was observed in both glia and neurons where TDP-43 positive inclusions often at least partially co-localized with more characteristic inclusions seen in these diseases, such as tau, alpha-synuclein, beta-amyloid and polyglutamine expansions (Amador-Oriz et al., 2007, Nakashima-Yasuda et al., 2007, Higashi et al., 2007, Schwab et al., 2008, Uryu et al., 2008).

[0018] prior art Patent application WO2009 / 008529 discloses antibodies that specifically bind to abnormal aggregates of the TDP-43 protein.

[0019] Patent application WO2011005628A1 discloses an antibody that binds to TDP-43 and a method for assessing the absence or presence of a neurodegenerative disease in a subject, comprising characterizing TDP-43 in a tissue sample from the subject, wherein the tissue is cerebrospinal fluid.

[0020] Patent application WO2008 / 042190 discloses antibodies that bind to TDP-43 and a method for assessing the absence or presence of a neurodegenerative disease in a subject, comprising characterizing TDP-43 in a tissue sample from said subject.

[0021] Patent application WO2020 / 234473 discloses TDP-43 specific binding molecules, in particular anti-TDP-43 antibodies or antigen-binding fragments or derivatives thereof, and uses thereof and methods for diagnosing, preventing, ameliorating, and / or treating diseases, disorders and / or conditions associated with TDP-43 aggregates, including, but not limited to, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE), and limbic-predominant late-life TDP-43 encephalopathy (LATE). Summary of the Invention [Problem to be solved by the invention]

[0022] In view of the above, there is a need for TDP-43 binding molecules that selectively target specific TDP-43 isoforms and / or post-translationally modified forms of TDP-43 (i.e., phosphorylated forms) present in human tissues and biofluids. Such binding molecules can be used to detect, measure, or eliminate TDP-43 species in situ in neuronal cells or TDP-43 species stored or released in other tissues or biological fluids. Furthermore, they can be used as tools to assess or screen the activity of other TDP-43 binding molecules.

[0023] The development of sensitive and specific biofluid immunoassays using said TDP-43 binding molecules is an urgent task, allowing the differentiation of individuals or populations with pathologies in which TDP-43 proteinopathy plays a role in disease pathogenesis or disease progression.Similar assays are also urgently needed to evaluate candidate therapeutic strategies targeting TDP-43 or TDP-43-related pathways that can distinguish disease-related pathogenic processes from normal cellular functions.Given that TDP-43 proteinopathy is largely associated with a total loss of TDP-43 function, the ability to distinguish between health-promoting and pathological forms of TDP-43 is of paramount importance. [Means for solving the problem]

[0024] The present invention relates to a TDP-43 binding molecule. The TDP-43 binding molecule described herein binds to an epitope within amino acid residues 361-414 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of a non-human TDP-43. In one embodiment, the TDP-43 binding molecule binds to an epitope comprising at least one, two, three or four of phosphorylated amino acid residues pS403, pS404, pS409 and / or pS410 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of a non-human TDP-43. In another embodiment, the TDP-43 binding molecule binds to an epitope comprising at least one or two of phosphorylated amino acid residues pS375 and / or pS379 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of a non-human TDP-43. As used herein, phosphorylated serine residues are written as pS, and the amino acid residues are numbered according to the human TDP-43 amino acid sequence and are shown in SEQ ID NO: 1. In one embodiment, the TDP-43 binding molecule binds to an epitope comprising phosphorylated amino acid residues pS403 and / or pS404 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of non-human TDP-43. In another embodiment, the TDP-43 binding molecule binds to an epitope comprising phosphorylated amino acid residues pS409 and / or pS410 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of non-human TDP-43. In yet another embodiment, the TDP-43 binding molecule binds to an epitope comprising phosphorylated amino acid residues pS375 and / or pS379 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of non-human TDP-43. Regardless of the combination of one, two, three or four of the above-described features, the binding molecules of the invention, preferably antibodies or antigen-binding fragments thereof, may reduce the levels of TDP-43 in TDP-43-specific inclusion bodies and / or the levels of phosphorylated TDP-43 in vivo.

[0025] The TDP-43-binding molecule of the present invention is useful in drug screening assays.Thus, the present invention also provides the use of the TDP-43-binding molecule of the present invention in an assay or method for screening TDP-43-targeting drugs, for example, an assay or method for evaluating the efficacy of TDP-43-targeting drugs.

[0026] The invention is summarized in the following numbered embodiments. 1. 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; or b) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or c) 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: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or d) 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: 33, 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; or e) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or f) 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, 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: 55, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or g) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 77 A TDP-43-binding molecule that specifically binds to phosphorylated TDP-43.

[0027] 1'. 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; or b) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or c) 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: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or d) 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: 33, 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; or e) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or f) 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, 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: 55, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or g) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, 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: 76, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 77; or h) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 111, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 112, 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 A TDP-43-binding molecule that specifically binds to phosphorylated TDP-43.

[0028] 2. The TDP-43 binding molecule of embodiment 1, wherein any one of the binding molecules (a), (c), (f) or (g) binds to TDP-43-positive inclusions.

[0029] 3. The TDP-43-binding molecule according to embodiment 2, wherein the binding to TDP-43-positive inclusions is determined by immunohistochemistry.

[0030] 4. The TDP-43 binding molecule of any one of the preceding embodiments, which binds to an epitope comprising phosphorylated amino acid residues pS403, pS404, pS409 and / or pS410 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of a non-human TDP-43.

[0031] 4'. The TDP-43-binding molecule of any one of embodiments 1 to 3, which binds to an epitope comprising phosphorylated amino acid residues pS375, pS379, pS403, pS404, pS409 and / or pS410 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of a non-human TDP-43.

[0032] 5. A TDP-43 binding molecule according to any one of the preceding embodiments, which binds to an epitope comprising phosphorylated amino acid residues pS403 and / or pS404 of human TDP-43 (SEQ ID NO:1), or an equivalent epitope of a non-human TDP-43.

[0033] 6. The TDP-43-binding molecule according to embodiment 5, which binds to an epitope with a KD of 6.13 nM or less, preferably 5 nM or less, preferably 2 nM or less, and preferably wherein the epitope comprises or consists of GFNGGFG(pS)(pS)MDSKS (SEQ ID NO: 8), corresponding to amino acid positions 396 to 409 of SEQ ID NO: 1, and more preferably wherein the KD is measured by surface plasmon resonance.

[0034] 7. A TDP-43-binding molecule according to any one of embodiments 1 to 4, which binds to an epitope comprising phosphorylated amino acid residues pS409 and / or pS410 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope in a non-human TDP-43.

[0035] 8. The TDP-43-binding molecule according to embodiment 7, which binds to an epitope with a KD of 3.5 nM or less, preferably 2.5 nM or less, preferably 1.7 nM or less, and preferably wherein the epitope comprises or consists of FGSSMDSK(pS)(pS)GWG (SEQ ID NO: 9), corresponding to amino acid positions 401 to 413 of SEQ ID NO: 1, and more preferably wherein the KD is measured by surface plasmon resonance.

[0036] 8'. A TDP-43-binding molecule according to any one of embodiments 1 to 4, which binds to an epitope comprising phosphorylated amino acid residues pS375 and / or pS379 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope in a non-human TDP-43.

[0037] 8''. A TDP-43-binding molecule according to embodiment 8', which binds to an epitope with a KD of 21.5 nM or less, preferably wherein the epitope comprises or consists of GNNSY(pS)GSN(pS)GAAIG (SEQ ID NO: 5), corresponding to amino acid positions 370 to 384 of SEQ ID NO: 1, more preferably wherein the KD is measured by surface plasmon resonance.

[0038] 9. 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 b. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or c. 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: 16, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or d. 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: 33, 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; or e. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:51, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:52, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:53, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:55, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:57; or f. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or g. VH-CDR1 comprising the amino acid sequence of SEQ ID NO:51, VH-CDR2 comprising the amino acid sequence of SEQ ID NO:52, VH-CDR3 comprising the amino acid sequence of SEQ ID NO:53, VL-CDR1 comprising the amino acid sequence of SEQ ID NO:75, VL-CDR2 comprising the amino acid sequence of SEQ ID NO:76, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO:77; or h. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, 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 A TDP-43-binding molecule that preferably binds to phosphorylated TDP-43.

[0039] 9'. 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 b. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or c. 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: 16, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or d. 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: 33, 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; or e. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:51, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:52, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:53, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:55, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:57; or f. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or g. VH-CDR1 comprising the amino acid sequence of SEQ ID NO:51, VH-CDR2 comprising the amino acid sequence of SEQ ID NO:52, VH-CDR3 comprising the amino acid sequence of SEQ ID NO:53, VL-CDR1 comprising the amino acid sequence of SEQ ID NO:75, VL-CDR2 comprising the amino acid sequence of SEQ ID NO:76, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO:77; or h. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, 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; or i. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 111, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 112, 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. A TDP-43-binding molecule that preferably binds to phosphorylated TDP-43.

[0040] 10. 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 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: 16, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or c. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or d. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:51, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:52, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:53, 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:76, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:77; or e. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, 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 A TDP-43-binding molecule that binds to TDP-43-positive inclusions.

[0041] 11. A TDP-43 binding molecule comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, 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, and which binds to misfolded, aggregated TDP-43 and unaggregated physiological TDP-43.

[0042] 12. The TDP-43 binding molecule of embodiment 11, which binds to an epitope within amino acid residues 361 to 414 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope in a non-human TDP-43.

[0043] 13. The TDP-43-binding molecule of embodiment 11 or 12, which binds to human TDP-43 (SEQ ID NO: 1) with a KD of 0.39 nM or less, preferably wherein the KD is measured by surface plasmon resonance.

[0044] 14. a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or 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 or having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 14; or b. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:20 or having at least 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:20, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:24 or having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:24; or c. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or having at least 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 having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34; or d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or having 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 having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44; or e. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 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:50, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:54; or f. 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, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:64; or g. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 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:50, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:74; or h. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to 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 having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 84. 2. The TDP-43 binding molecule of any one of the preceding embodiments, comprising:

[0045] 14'. a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or 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 or having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 14; or b. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:20 or having at least 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:20, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:24 or having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:24; or c. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or having at least 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 having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34; or d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or having 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 having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44; or e. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 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:50, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:54; or f. 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, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:64; or g. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 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:50, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:74; or h. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to 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 having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 84; or i. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 110 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: 110, and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 114. 2. The TDP-43 binding molecule of any one of the preceding embodiments, comprising:

[0046] 15. The TDP-43 binding molecule according to any one of the preceding embodiments, which is an antibody or an antigen-binding fragment thereof.

[0047] 16. The TDP-43-binding molecule of any one of the preceding embodiments, which is an IgA, IgD, IgE, IgM, IgG1, IgG2, IgG2a, IgG2b, IgG3 or IgG4 antibody or antigen-binding fragment thereof.

[0048] 17. The TDP-43 binding molecule of any one of the preceding embodiments, which is an immunoconjugate.

[0049] 18. The TDP-43 binding molecule according to embodiment 17, wherein the immunoconjugate comprises paramagnetic beads.

[0050] 19. The TDP-43 binding molecule of embodiment 17, wherein the immunoconjugate comprises biotin.

[0051] 20. The TDP-43 binding molecule according to embodiment 17, wherein the immunoconjugate comprises a further therapeutic molecule.

[0052] 21. A TDP-43 binding molecule according to any one of the preceding embodiments for use in human or animal therapy and / or diagnosis.

[0053] 22. A TDP-43 binding molecule for use according to embodiment 21, which is a therapeutic or diagnostic tool.

[0054] 23. A TDP-43 binding molecule according to any one of embodiments 1 to 20 for research use, in particular as an analytical tool or reference molecule.

[0055] 24. A TDP-43 binding molecule according to any one of embodiments 1 to 20 for use in the prevention, alleviation, treatment and / or diagnosis of diseases, disorders and / or abnormalities associated with TDP-43.

[0056] 25. A TDP-43 binding molecule according to any one of embodiments 1 to 20 for use in the prevention, alleviation, treatment and / or diagnosis of a TDP-43 proteinopathy.

[0057] 26. A TDP-43 binding molecule for use according to embodiment 25, for use as a diagnostic tool for diagnosing or monitoring a TDP-43 proteinopathy.

[0058] 27. TDP-43 proteinopathy, a. Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), non-fluent / agrammatic variant primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down's syndrome (DS), familial British dementia, Parkinson's disease (PD) and related disorders (including Parkinson's disease type DDD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)), corticobasal degeneration (CBD), and Niemann-Pick disease a disease, disorder, and / or abnormality associated with TDP-43 aggregates selected from the group consisting of: facial onset sensorimotor neuropathy (FOSMN), limbic-predominant late-life TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (e.g., Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis dementia, myofibrillar myopathy (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), progressive muscular atrophy; or b. Diseases caused by mutations or variant-associated risk alleles in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), and ataxin 3 (ATXN3) genes 27. The TDP-43 binding molecule for use according to embodiment 25 or 26, wherein

[0059] 28. TDP-43 proteinopathy, a. a disease, disorder, and / or abnormality associated with TDP-43 aggregates selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), Alzheimer's disease (AD), Down's syndrome (DS), Parkinson's disease (PD) and related disorders (including Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), limbic-predominant late-life TDP-43 encephalopathy (LATE), myofibrillar myopathy (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), progressive muscular atrophy; or b. Diseases caused by mutations or variant-associated risk alleles in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), and TMEM106B genes 28. The TDP-43-binding molecule for use according to any one of embodiments 25 to 27, wherein

[0060] 29. A TDP-43 binding molecule for use according to any one of embodiments 25 to 28, wherein the disease, disorder and / or abnormality associated with TDP-43 or TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS).

[0061] 30. A TDP-43 binding molecule for use according to any one of embodiments 25 to 28, wherein the disease, disorder and / or abnormality associated with TDP-43 or TDP-43 proteinopathy is Alzheimer's disease (AD).

[0062] 31. A TDP-43 binding molecule for use according to any one of embodiments 25 to 28, wherein the disease, disorder and / or abnormality associated with TDP-43 or TDP-43 proteinopathy is frontotemporal dementia (FTD).

[0063] 32. The TDP-43 binding molecule for use according to embodiments 25 to 28, wherein the disease, disorder and / or abnormality associated with TDP-43 or TDP-43 proteinopathy is limbic-predominant late-life TDP-43 encephalopathy (LATE).

[0064] 33. A TDP-43 binding molecule for use according to any one of embodiments 25 to 28, wherein the disease, disorder and / or abnormality associated with TDP-43 or TDP-43 proteinopathy is frontotemporal lobar degeneration with motor neuron disease (FTLD-MND).

[0065] 34. A pharmaceutical composition comprising a TDP-43 binding molecule according to any one of embodiments 1 to 20, and a pharma- ceutically acceptable carrier and / or excipient.

[0066] 34'. A diagnostic composition comprising a TDP-43 binding molecule according to any one of embodiments 1 to 20, and an acceptable carrier and / or excipient.

[0067] 35. A nucleic acid molecule encoding a TDP-43-binding molecule according to any one of embodiments 1 to 20.

[0068] The nucleic acid of embodiment 35, comprising the nucleotide sequence set forth as SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:38, SEQ ID NO:39, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:79, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:118, or SEQ ID NO:119.

[0069] 36. A recombinant vector comprising the nucleic acid according to embodiment 35.

[0070] 37. A host cell comprising a nucleic acid according to embodiment 35 and / or a vector according to embodiment 36.

[0071] 38. A host cell expressing a TDP-43-binding molecule according to any one of embodiments 1 to 20.

[0072] 39. An expression vector comprising the nucleic acid molecule according to embodiment 35.

[0073] 40. A cell-free expression system comprising an expression vector according to embodiment 39.

[0074] 41. A method for producing a TDP-43 binding molecule, in particular an antibody or an antigen-binding fragment thereof, comprising: a. culturing a host cell according to embodiment 37 or 38 or a cell-free expression system according to embodiment 40 under suitable conditions for producing the binding molecule, in particular an antibody or an antigen-binding fragment thereof; and b. Isolating the binding molecules, particularly antibodies or antigen-binding fragments thereof. A method comprising:

[0075] 41'. A TDP-43 binding molecule according to any one of embodiments 1 to 20 for use in detecting and / or quantifying TDP-43 in a sample, wherein the sample is saliva, urine, nasal secretion, blood (including whole blood, plasma and serum, platelet-rich plasma, platelet cytosol fraction), a brain and / or CSF sample, a brain and / or ISF sample, more particularly a blood, brain, CSF and / or ISF sample.

[0076] 42'. A TDP-43-binding molecule according to any one of embodiments 1 to 20 for use in detecting and / or quantifying phosphorylated TDP-43 in a sample, wherein the sample is saliva, urine, nasal secretion, blood (including whole blood, plasma and serum, platelet-rich plasma, platelet cytosol fraction), a brain and / or CSF sample, a brain and / or ISF sample, more particularly a blood, brain, CSF and / or ISF sample.

[0077] 42. a. incubating the sample with a capture antibody and a detection antibody; b. incubating the mixture obtained in step a with a reagent suitable for detection by said detection antibody; c. Measuring the signal emitted by the detection antibody Including, Use of a TDP-43-binding molecule according to any one of embodiments 1 to 20 in a paired assay, in which the capture antibody is selected from the antibodies defined in any one of embodiments 1 to 20.

[0078] 43. Use of a TDP-43 binding molecule according to embodiment 42, wherein the detection antibody is selected from the antibodies defined in any one of embodiments 1 to 20.

[0079] 44. Use of a TDP-43 binding molecule according to embodiment 42 or 43, wherein the reagent is streptavidin-β-D-galactosidase.

[0080] 45. Use of a TDP-43 binding molecule according to any one of embodiments 42 to 44, wherein the capture antibody and / or the detection antibody binds to phosphorylated TDP-43, preferably specifically binds to phosphorylated TDP-43.

[0081] 46. ​​Use of a TDP-43 binding molecule according to any one of embodiments 42 to 44, wherein the capture antibody and / or the detection antibody binds to misfolded, aggregated TDP-43 and to non-aggregated physiological TDP-43.

[0082] 47. The capture antibody is i. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, 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; or ii. 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, 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; or iii. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 102, 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: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107. Use of a TDP-43 binding molecule according to any one of embodiments 42 to 46, comprising:

[0083] 48. The detection antibody is i. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, 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; or ii. 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, 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; or iii. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 102, 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: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107. Use of a TDP-43 binding molecule according to any one of embodiments 42 to 47, comprising:

[0084] 48'. The detection antibody is i. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, 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; or ii. 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, 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; or iii. 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, 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: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107; or iv. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or v. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57 Use of a TDP-43 binding molecule according to any one of embodiments 42 to 47, comprising:

[0085] 49. The detection antibody is a. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, 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 Including, The capture antibody is b. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 102, 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: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107 49. Use of a TDP-43 binding molecule according to embodiment 47 or 48, comprising:

[0086] 49'. The detection antibody is a. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27 Including, The capture antibody is b. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 91, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 92, 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 49. Use of a TDP-43 binding molecule according to embodiment 47 or 48, comprising:

[0087] 49''. Detection antibody, a. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27 Including, The capture antibody is b. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 102, 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: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107 49. Use of a TDP-43 binding molecule according to embodiment 47 or 48, comprising:

[0088] 49''.Detection antibody, a. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57 Including, The capture antibody is b. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 102, 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: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107 49. Use of a TDP-43 binding molecule according to embodiment 47 or 48, comprising:

[0089] 50. A method for quantifying phosphorylated TDP-43 in a sample, comprising contacting the sample with a TDP-43 binding molecule according to any one of embodiments 1 to 20.

[0090] 51. A method for quantification according to embodiment 50, wherein the sample is obtained from a subject.

[0091] 51'. The method of embodiment 51, wherein the sample is human blood, cerebrospinal fluid (CSF), interstitial fluid (ISF), saliva, nasal secretion, and / or urine, preferably blood, CSF or ISF.

[0092] 52. The method for quantification according to embodiment 50 or 51, further comprising comparing the TDP-43 level detected in the sample with a control.

[0093] 53. A method for quantification according to embodiment 52, wherein the control comprises phosphorylated TDP-43.

[0094] 54. A method for quantification according to embodiment 52 or 53, wherein the control is determined using a calibrator with a known amount of phosphorylated TDP-43.

[0095] 55. A method for quantifying phosphorylated TDP-43 in a sample obtained from a subject, comprising the use of a TDP-43 binding molecule according to any one of embodiments 42 to 49.

[0096] 55'. A method for monitoring a disease, disorder and / or condition associated with TDP-43 at two or more time points using a sample from a subject, comprising contacting the sample with a TDP-43 binding molecule according to any one of embodiments 1 to 20; a. higher levels of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates progression of a TDP-43-associated disease, disorder, and / or condition; or b. a lower level of TDP-43 and / or phosphorylated TDP-43 in a subsequent sample compared to one or more earlier samples indicates regression of a TDP-43-associated disease, disorder, and / or condition; or c. A method wherein no significant change in the levels of TDP-43 and / or phosphorylated TDP-43 in a subsequent sample compared to one or more earlier samples indicates a lack of progression of a TDP-43 associated disease, disorder and / or condition.

[0097] 55''. A method for monitoring a disease, disorder and / or condition associated with TDP-43 at two or more time points using a sample from a subject, comprising contacting the sample with a TDP-43 binding molecule according to any one of embodiments 1 to 20; a. higher levels of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates regression of a TDP-43-associated disease, disorder, and / or condition; or b. a lower level of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates progression of a TDP-43-associated disease, disorder, and / or condition; or c. A method wherein no significant change in the levels of TDP-43 and / or phosphorylated TDP-43 in a subsequent sample compared to one or more earlier samples indicates a lack of progression of a TDP-43 associated disease, disorder and / or condition.

[0098] 55''. The method of embodiment 55' or 55'', performed at multiple time points on matched samples between treatment and placebo groups to monitor the effectiveness of the candidate therapy over time.

[0099] 56. A kit for diagnosing a disease, disorder and / or abnormality associated with TDP-43, or a TDP-43 proteinopathy, or for use in a method according to any one of claims 50 to 55, comprising a TDP-43 binding molecule according to any one of embodiments 1 to 20.

[0100] 57. A kit according to embodiment 56, comprising a TDP-43-binding molecule according to any one of embodiments 1 to 20 as a capture antibody and a different TDP-43-binding molecule according to any one of embodiments 1 to 20 as a detection antibody.

[0101] 58. The kit according to embodiment 57, further comprising magnetic particles to which the capture antibody is bound or capable of being bound.

[0102] 59. The kit according to embodiment 57 or 58, wherein the detection antibody is directly or indirectly labeled.

[0103] 60. The kit according to any one of embodiments 57 to 59, further comprising a container containing a TDP-43 binding molecule.

[0104] To avoid confusion, where reference is made to multiple embodiments, it is intended that references to equivalent primary (') embodiments are also encompassed (e.g., a reference to embodiment 1 encompasses 1 and 1').

[0105] In one embodiment, the present invention relates to the binding molecules of the present invention, in particular antibodies and antigen-binding fragments thereof, as described herein, which specifically bind to phosphorylated TDP-43, and to the therapeutic use of such antibodies and antigen-binding fragments thereof in patients with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), non-fluent / Agrammatic primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down's syndrome (DS), Familial British dementia, Parkinson's disease (PD) and related disorders (including Parkinson's disease type dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)), Corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), Facial onset sensorimotor neuropathy (FOSMN), Limbic-dominant senile TDP-43 encephalopathy (LATE), Chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (e.g., Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis dementia, myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), progressive muscular atrophy, progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein The present invention encompasses the use of these binding molecules to diagnose, prevent, ameliorate, and / or treat diseases, disorders, and / or conditions associated with TDP-43 aggregates, or TDP-43 proteinopathies, including, but not limited to, diseases caused by mutations or variant-associated risk alleles in the VCP, angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), and ataxin 3 (ATXN3) genes.Preferably, the use of these binding molecules for diagnosing, preventing, alleviating, and / or treating diseases, disorders, and / or abnormalities associated with TDP-43, in particular associated with TDP-43 aggregates, or TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), Alzheimer's disease (AD), Down's syndrome (DS), Parkinson's disease (PD) and related diseases (PDD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and related disorders, including ... The present invention relates to diseases of both sporadic and genetic origin, including myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), progressive muscular atrophy, and genetic cases resulting from mutations or variant-associated risk alleles of progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B genes. More preferably, the use relates to amyotrophic lateral sclerosis (ALS). More preferably, the use relates to frontotemporal dementia (FTD). More preferably, said use relates to limbic-dominant late-life TDP-43 encephalopathy (LATE). More preferably, said use relates to Alzheimer's disease (AD). More preferably, said use relates to frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD).

[0106] In another embodiment, the TDP-43 binding molecule of the invention, in particular the anti-TDP-43 antibody or antigen-binding fragment thereof (described herein as specific for TDP-43), upon contacting with a sample, is capable of detecting a variety of conditions including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), non-fluent / agrammatic primary progressive aphasia, Alzheimer's disease (AD), Down's syndrome (DS), Familial British Dementia, Parkinson's disease (PD) and related disorders (including Parkinson's disease type D dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), facial onset sensorimotor neuropathy (FOSMN), limbic-predominant senile TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (e.g., Hansch et al., 2011). Dermatitis (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease), hippocampal sclerosis dementia, myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), progressive muscular atrophy, or other conditions that may be associated with amyloidosis, such as progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT) Detect, diagnose, and / or monitor diseases, disorders and / or abnormalities associated with TDP-43, particularly associated with aggregated or aggregation-prone forms of TDP-43 (differentiated from normal functional TDP-43), in suspected TDP-43 or other proteinopathies, particularly including, but not limited to, TDP-43-associated proteinopathies, including diseases caused by mutations or variant associated risk alleles in the ataxin 3 (ATXN3) gene, and differentiation of these to non-TDP-43-associated clinical phenocopies.

[0107] In one embodiment, the present invention encompasses the binding molecules of the present invention, particularly antibodies or antigen-binding fragments thereof, described herein, that specifically bind to phosphorylated TDP-43, and the use of these binding molecules, particularly these antibodies, to detect the presence of specific phosphorylated TDP-43-derived species in a sample. Thus, the TDP-43 binding molecules of the present invention, such as the anti-TDP43 antibodies described herein, can be used, inter alia, to screen clinical samples, particularly human blood, cerebrospinal fluid (CSF), interstitial fluid (ISF), saliva, nasal secretions and / or urine, to confirm the presence of TDP-43 in the sample, for example by using an ELISA-based assay or a surface-compatible assay. Tissue samples may be used in some circumstances, such as brain tissue samples. The methods and compositions of the present invention are also applied to diagnose pre-symptomatic disease and / or monitor disease progression and / or treatment effects.In certain embodiments, an antibody specific for TDP-43 (e.g., a full-length antibody or a TDP-43-binding fragment or derivative of the antibody) is contacted with a sample (e.g., blood, cerebrospinal fluid (CSF), interstitial fluid (ISF), saliva, nasal secretion, urine, or brain tissue) to identify amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), non-fluent / agrammatic variant primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down's syndrome (DS), familial British dementia, Parkinson's disease (PD), or a combination of these disorders. ) and its related diseases (including Parkinson Disease Dementia (PDD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)), Corticobasal Degeneration (CBD), Niemann-Pick Disease (NP, including type C of NP), Facial Onset Sensorimotor Neuropathy (FOSMN), Limbic Predominant Late-onset TDP-43 Encephalopathy (LATE), Chronic Traumatic Encephalopathy, Perry Syndrome, Paget's Disease, Polyglutamine Diseases (e.g., Huntington's Disease (HD) and Spinocerebellar Ataxia Type 3 (SCA3, also known as Machado-Joseph Disease)), Hippocampal Sclerosis Dementia, Myofibrillar Myopathies (e.g., Inclusion Body Myositis, Inclusion Body Myopathy, Oculopharyngeal Muscular Dystrophy (with Rimmed Vacuoles)), Primary Lateral Sclerosis (PLS), Progressive Muscle Atrophy. In one embodiment, an antibody specific for TDP-43 (e.g., a full-length antibody or a TDP-43-binding fragment or derivative of the antibody) is contacted with a sample (e.g., blood, cerebrospinal fluid (CSF), interstitial fluid (ISF), saliva, nasal secretion, urine, or brain tissue) to detect, diagnose, and / or monitor a disease caused by a mutation or variant-associated risk allele in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxin 3 (ATXN3) gene.

[0108] The TDP-43 binding molecules of the present invention can be used to detect and / or quantify TDP-43, preferably phosphorylated TDP-43, in a suitable sample. The sample can be a cell-free sample, such as blood, CSF, ISF, saliva, nasal secretion or urine. In a preferred embodiment, the cell-free sample can be blood, CSF or ISF. "Blood" includes whole blood and derivative samples, such as serum and plasma. "Plasma" includes derivative samples, such as platelets. "Platelets" includes derivative samples, such as platelet cytosol fraction. The sample can be a cell sample, such as tissue, preferably brain tissue. The appropriate TDP-43 species is quantified or detected. In one embodiment, soluble TDP-43 or phospho-TDP-43 is quantified or detected in a cell-free sample (e.g., detection of TDP-43 in human plasma in Example 8). In one embodiment, soluble TDP-43 or phospho-TDP-43 is quantified or detected in acellular samples (e.g., detection of TDP-43 in platelet fractions derived from human plasma in Example 9). In another embodiment, TDP-43 inclusions are quantified or detected in cell samples, preferably brain tissue (e.g., detection of phospho-TDP-43 inclusions in Example 7).

[0109] The TDP-43 binding molecules of the present invention can be used to quantify phosphorylated TDP-43 in suitable samples, particularly clinical samples, such as blood, CSF, ISF, saliva, nasal secretions or urine. Many suitable immunoassay methods are known. Thus, such methods (e.g., ELISA, MSD (Meso Scale Discovery), HTRF (Homogeneous Time Resolved Fluorescence), SIMOA® and AlphaLISA, etc.) can be performed for diagnosis. The binding molecules of the present invention have phosphosite-specific high affinity binding to human TDP-43 lesions in brain tissue and are herein shown to be useful in highly sensitive immunoassays. The method for quantifying phosphorylated TDP-43 in suitable samples using the binding molecules of the present invention can also be used to select a treatment (for further treatment of the subject). Thus, individualized treatment methods are envisaged. Samples may be taken before and after treatment with such methods.

[0110] In one embodiment, the TDP-43 binding molecule of the present invention is used in a pairing assay, which comprises the steps of: incubating a sample with a capture antibody comprising the TDP-43 binding molecule described herein conjugated to paramagnetic beads, and a detection antibody comprising the TDP-43 binding molecule described herein conjugated to biotin; incubating the resulting solution with a reagent suitable for detection by the detection antibody, such as streptavidin-β-D-galactosidase; and measuring the signal emitted by the detection antibody. In one embodiment, the capture antibody or detection antibody is a TDP-43 binding molecule that binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43. In one embodiment, the capture antibody or detection antibody specifically binds to phosphorylated TDP-43. In one embodiment, the capture antibody binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43, and the detection antibody specifically binds to phosphorylated TDP-43. In another embodiment, the detection antibody binds to misfolded, aggregated TDP-43 and non-aggregated physiological TDP-43, and the capture antibody specifically binds to phosphorylated TDP-43.

[0111] In another embodiment, the present invention provides a method for preventing, alleviating, and / or treating a disease, disorder, and / or disorder associated with TDP-43, particularly TDP-43 aggregates, or a TDP-43 proteinopathy. According to one embodiment, the method of the present invention comprises administering to a subject an effective concentration of a binding molecule of the present invention specific for TDP-43, particularly an antibody (e.g., a full-length antibody or a TDP-43-binding fragment or derivative of the antibody) described herein. In another embodiment, the present invention provides a method for preventing, alleviating, and / or treating a TDP-43 proteinopathy. According to one embodiment, the binding molecules of the invention described herein, particularly antibodies or antigen-binding fragments thereof, specific for phosphorylated TDP-43, are administered to treat, ameliorate, and / or prevent amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant aged TDP-43 encephalopathy (LATE), Alzheimer's disease (AD), frontotemporal lobar degeneration with motor neuron disease FTLD-MND. In another embodiment, the binding molecules of the invention described herein, particularly antibodies or antigen-binding fragments thereof, specific for phosphorylated TDP-43, are administered to prevent, ameliorate, and / or treat a neurodegenerative disease selected from amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant aged TDP-43 encephalopathy (LATE), Alzheimer's disease (AD), frontotemporal lobar degeneration with motor neuron disease FTLD-MND.

[0112] In another embodiment, the binding molecules of the invention described herein, in particular the antibodies or antigen-binding fragments thereof, specific for TDP-43 are used to treat amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), behavioral variant of frontotemporal dementia (bvFTD), semantic variant of primary progressive aphasia (svPPA), non-fluent / agrammatic variant of primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down's syndrome (DS), familial British dementia, Parkinson's disease (PD) and related disorders (PDD, dementia with Lewy bodies (DLB), multiple system atrophy ( In one embodiment, the therapeutic agent is administered to prevent, ameliorate, and / or treat a disease selected from the group consisting of myofibrillar myopathy (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including type C of NP), facial onset sensorimotor neuropathy (FOSMN), limbic-predominant senile TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (e.g., Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis dementia, myofibrillar myopathy (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), and progressive muscular atrophy. In another embodiment, the binding molecules of the invention described herein, particularly antibodies or antigen-binding fragments thereof, specific for TDP-43 are administered to prevent, alleviate, and / or treat a disease caused by mutations or variant-associated risk alleles in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxin 3 (ATXN3) genes. [Brief description of the drawings]

[0113] [Figure 1A]Immunoassay pairing antibodies ACI-7071-4665-B5-R3B-Ab2 and ACI-7071-809F12-Ab1-rec2 for measuring human TDP-43 in plasma samples from healthy controls and FTLD-TDP patients using SIMOA® assay technology. (A) Calibration curves using human TDP-43 were run on separate days to establish a limit of detection (LOD) of 0.021 pM and a LLOQ of 0.09 pM. (B) TDP-43 was measured in human plasma from healthy controls and FTLD-TDP (semantic dementia, C9ORF72 or GRN) patients. [Figure 1B] Same as above. [Diagram 2] FIG. 1 is a graphical representation of TDP-43 protein levels measured in platelet-poor and platelet-rich plasma, and in the soluble and insoluble fractions of platelet-rich plasma, as measured by immunoassay pairing antibodies ACI-7071-4665-B5-R3B-Ab2 and ACI-7071-809F12-Ab1-rec2 using SIMOA® assay technology. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0114] DETAILED DESCRIPTION OF EMBODIMENTS OF THE PRESENTINVENTION

[0115] definition Transactivation response (TAR) DNA binding protein 43 kDa (referred to herein as TDP-43) is a 414 amino acid protein encoded by the TARDBP gene on chromosome 1p36.2 (also known as ALS10). Multiple TARDBP mRNAs are contained by differential splicing of six (or potentially seven) exons that code for a heterogeneous set of polypeptide isoforms with a shared amino acid sequence (d'Alton et al., RNA). TDP-43 belongs to the heterogeneous ribonucleoprotein (hnRNP) RNA binding protein family (Wang et al., Trends in Molecular Medicine Vol.14 No.11, 2008, 479-485; Lagier-Tourenne et al., Human Molecular Genetics, 2010, Vol. 19, Review Issue 1 R46-R64). TDP-43 contains five functional domains (Figure 1 in Warraich et al., The International Journal of Biochemistry & Cell Biology 42 (2010) 1606-1609): two RNA recognition motifs (RRM1 and RRM2) with two highly conserved hexameric ribonucleoprotein 2 (RNP2) and octameric ribonucleoprotein 1 (RNP1) regions, a nuclear export signal (NES) and a nuclear localization signal (NLS) that allow transport of bound mRNAs between the nucleus and the cytoplasm, and a glycine-rich domain at the C-terminus that mediates protein-protein interactions). TDP-43 is involved in multiple aspects of RNA processing, including transcription, splicing, transport, and stabilization (Buratti and Baralle, FEBS Journal 277 (2010) 2268-2281). It is a highly conserved, ubiquitously expressed protein that shuttles between the nucleus and cytoplasm with tightly autoregulated expression.

[0116] In this application, TDP-43 refers to the human reference sequence (Q13148) and its isoforms, including proteolytic fragments and post-translationally modified polypeptides that retain the epitope bound by the binding molecule. Human TDP-43 has the following sequence: MSEYIRVTEDENDEPIEIPSEDDGTVLLSTVTAQFPGACGLRYRNPVSQCMRGVRLVEGILHAPDAGWGNLVYVVNYPKDNKRKMDETDASSAVKVKRAVQKTSD LIVLGLPWKTTEQDLKEYFSTFGEVLMVQVKKDLKTGHSKGFGFVRFTEYETQVKVMSQRHMIDGRWCDCKLPNSKQSQDEPLRSRKVFVGRCTEDMTEDELREFF SQYGDVMDVFIPKPFRAFAFVTFADDQIAQSLCGEDLIIKGISVHISNAEPKHNSNRQLERSGRFGGNPGGFGNQGGFGNSRGGGAGLGNNQGSNMGGGMNFGAFSINPAMMAAAQAALQSSWGMMGMLASQQNQSGPSGNNQNQGNMQREPNQAFGSGNNSYSGSNSGAAIGWGSASNAGSGSGFNGGFGSSMDSKSSGWGM (SEQ ID NO: 1).

[0117] As used herein, an "antigen-binding molecule" is a molecule capable of specifically or selectively binding to an antigen, particularly TDP-43. The binding molecule may include or be an antibody or a fragment thereof. An anti-TDP-43 binding molecule is a molecule that binds to the TDP-43 protein at an epitope-specific recognition site, such as an anti-TDP-43 antibody or a fragment thereof. That is, the antigen-binding molecule of the present invention binds to an epitope within the amino acid sequence of SEQ ID NO:1. The antigen-binding molecules provided herein, particularly antibodies or antigen-binding fragments thereof, recognize full-length TDP-43. Other anti-TDP-43 binding molecules may also include multivalent molecules, multispecific molecules (e.g., bispecific antibodies), fusion molecules, aptamers, avimers, or other naturally occurring or recombinantly produced molecules. Exemplary antigen-binding molecules useful in the present invention include antibody-like molecules. Antibody-like molecules are molecules that can exhibit a function by binding to a target molecule (see, for example, Current Opinion in Biotechnology 2006, 17:653-658; Current Opinion in Biotechnology 2007, 18:1-10; Current Opinion in Structural Biology 1997, 7:463-469; Protein Science 2006, 15:14-27), and include, for example, DARPins (WO2002 / 020565), affibodies (WO1995 / 001937), avimers (WO2004 / 044011; WO2005 / 040229), adnectins (WO2002 / 032925), and fynomers (WO2013 / 135588).

[0118] As used herein, the terms "anti-TDP-43 antibody" and "antibody that binds to TDP-43" or simply "antibody" refer to an antibody that can bind to TDP-43 with sufficient affinity so that the antibody is useful as a diagnostic and / or therapeutic agent targeting TDP-43. In general, the term "antibody" is used herein in its broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific or biparatopic antibodies), fully human antibodies, and antibody fragments (limited to those that exhibit the desired antigen-binding activity). Antibodies within the present invention can also be chimeric antibodies, recombinant antibodies, antigen-binding fragments of recombinant antibodies, antibodies, or antibodies displayed on the surface of a phage or on the surface of a chimeric antigen receptor (CAR) T cell.

[0119] An "antigen-binding fragment" of an antibody or a "functional fragment thereof" refers to a molecule other than an intact or full-length antibody that contains a portion of an intact or full-length antibody and binds (completely or partially) to an antigen to which the intact or full-length antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2 formed from antibody fragments; bispecific antibodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies. Antigen-binding fragments may also be referred to as "functional fragments" because they retain the binding function of the original antibody from which they are derived.

[0120] An "antibody that binds to an epitope" within a defined region of a protein is an antibody that requires the presence of one or more amino acids within the region in order to bind to said protein.

[0121] In one embodiment, an "antibody that binds to an epitope" within a defined region of a protein is identified by mutational analysis in which amino acids of the protein are mutated and the binding of the antibody to the resulting altered protein (e.g., the altered protein (containing the epitope)) is determined until it is at least 20% of the binding to the unaltered protein. In one embodiment, an "antibody that binds to an epitope" within a defined region of a protein is identified by mutational analysis in which amino acids of the protein are mutated and the binding of the antibody to the resulting altered protein (e.g., the altered protein (containing the epitope)) is determined until it is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the binding to the unaltered protein. In one embodiment, the binding of the antibody is determined by FACS, WB, or by a suitable binding assay (e.g., ELISA).

[0122] The term "bind" as used in the context of the present invention defines the binding (interaction) of at least two "antigen interaction sites" with each other. The term "antigen interaction site" defines according to the present invention a part of the antibody or antigen-binding fragment of the present invention, which exhibits the ability to specifically interact with a polypeptide motif, i.e. a specific antigen or a specific group of antigens of TDP-43. Said binding / interaction is also understood to define "specific recognition". The term "specifically recognize" means according to the present invention that said antibody is capable of specifically interacting and / or binding to at least two amino acids of TDP-43 as defined herein, in particular to interact and / or bind to at least two amino acids within amino acid residues 361 to 414 of human TDP-43 (SEQ ID NO: 1).

[0123] The term "pan-TDP-43 antibody" refers to an antibody that binds to misfolded, aggregated TDP-43 and non-aggregated physiological TDP-43, including monomeric TDP-43, oligomeric TDP-43, post-translationally modified TDP-43 (e.g., phosphorylation, ubiquitination, acetylation, sumoylation, and / or methylation), aggregated TDP-43, and truncated TDP-43.

[0124] The terms "specific interaction," "specific binding," and "specific binding," as used interchangeably according to the present invention, mean that the antibodies or antigen-binding fragments thereof of the present invention do not or do not substantially cross-react with (poly)peptides of similar structure. Thus, a TDP-43 binding molecule of the present invention that specifically binds to phosphorylated TDP-43 at one or more phosphorylated residues does not or does not substantially cross-react with TDP-43 that is not phosphorylated at those one or more residues. Thus, in certain embodiments of the invention, the antibody or antigen-binding fragment thereof specifically binds / interacts with the structure of TDP-43 formed by a specific phosphorylated amino acid sequence within the amino acid residues of human TDP-43 (SEQ ID NO: 1), more specifically binds / interacts with the structure of TDP-43 formed by a specific amino acid sequence within the phosphorylated amino acid residues pS403, pS404, pS409 or pS410 of human TDP-43 (SEQ ID NO: 1), and even more specifically binds / interacts with binding to at least one or two phosphoserines selected from the group consisting of pS403, pS404, pS409, pS410 of human TDP-43 (SEQ ID NO: 1). In such embodiments, the antibody or antigen-binding fragment thereof does not or does not substantially cross-react with non-phosphorylated S403, S404, S409 or S410 of human TDP-43 (SEQ ID NO: 1).

[0125] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof specifically binds / interacts with the structure of TDP-43 formed by a specific phosphorylated amino acid sequence within the amino acid residues of human TDP-43 (SEQ ID NO: 1), more specifically binds / interacts with the structure of TDP-43 formed by a specific amino acid sequence within the phosphorylated amino acid residues pS375 or pS379 of human TDP-43 (SEQ ID NO: 1), and even more specifically binds / interacts with binding to at least one phosphoserine selected from the group consisting of pS375 or pS379 of human TDP-43 (SEQ ID NO: 1).In such an embodiment, the antibody or antigen-binding fragment thereof does not or does not substantially cross-react with the non-phosphorylated S375 or S379 of human TDP-43 (SEQ ID NO: 1).

[0126] In certain embodiments, the TDP-43 binding molecule binds to both misfolded, aggregated TDP-43 and non-aggregated physiological TDP-43, including monomeric TDP-43, oligomeric TDP-43, post-translationally modified TDP-43 (e.g., phosphorylation, ubiquitination, acetylation, sumoylation, and / or methylation), aggregated TDP-43, and truncated TDP-43. In certain embodiments of the present invention, the antibody or antigen-binding fragment thereof specifically binds / interacts with the structure of TDP-43 formed by a specific amino acid sequence within amino acid residues 361-375 of human TDP-43 (SEQ ID NO: 1).

[0127] Inclusions refer to a variety of intracellular non-living substances that are not bound by membranes. Inclusions may contain nutrient storage / deutoplasmic substances, secretory products, and pigment granules. "TDP-43 positive inclusions" or "positively stained inclusions" refer to pathological deposits of TDP-43 that carry disease-specific post-translational modifications, such as phosphorylation, ubiquitination, sumoylation, and acetylation. TDP-43 pathological deposits may contain full-length and / or specific truncated forms of the protein.

[0128] The TDP-43 binding molecule described herein binds to TDP-43 positive inclusions, particularly TDP-43 positive inclusions that contain, consist of, or consist essentially of phosphorylated TDP-43. The TDP-43 positive inclusions can be cytoplasmic inclusions. For a detailed description of the staining assay that can be used for TDP-43 positive inclusions, see Example 7.

[0129] The cross-reactivity of a panel of antigen-binding molecules, in particular antibodies or antigen-binding fragments thereof, under study, can be tested by evaluating the binding of said panel of antibodies or antigen-binding fragments thereof under typical conditions (see, for example, Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, (1988), and Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, (1999)) to the (poly)peptide of interest as well as to many more or less closely related (structurally and / or functionally) (poly)peptides. Only those constructs (i.e., antibodies, antigen-binding fragments thereof, etc.) that bind to a particular structure of TDP-43 as defined herein, e.g., a specific epitope or (poly)peptide / protein of TDP-43 as defined herein, but do not or do not substantially bind to any other epitope or (poly)peptide of the same TDP-43, are selected for further experiments by the methods provided herein as being specific for the epitope or (poly)peptide / protein of interest. These methods may include, inter alia, binding, blocking and competition experiments with structurally and / or functionally closely related molecules, including FACS analysis, surface plasmon resonance (SPR, e.g., BIACORE®), analytical ultracentrifugation, isothermal titration calorimetry, fluorescence anisotropy, fluorescence spectroscopy, or radiolabeled ligand binding assays.

[0130] Thus, specificity can be experimentally tested by methods known in the art and described herein, including but not limited to Western blot, ELISA-, RIA-, ECL-, IRMA tests, and peptide scans.

[0131] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., each antibody comprising the population is identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific for a single antigenic site. Monoclonal antibodies are advantageous in that they may be synthesized by a hybridoma culture substantially free of other immunoglobulins. The term "monoclonal" indicates the character of the antibody as a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. As described above, monoclonal antibodies for use in accordance with the present invention may be made by the hybridoma method described in Kohler, Nature 256 (1975), 495.

[0132] The term "polyclonal antibody" as used herein refers to an antibody produced between or in the presence of one or more other non-identical antibodies. Generally, polyclonal antibodies are produced from B lymphocytes in the presence of several other B lymphocytes that produced non-identical antibodies. Usually, polyclonal antibodies are obtained directly from immunized animals.

[0133] The term "fully human antibody" as used herein refers to an antibody that contains only human immunoglobulin protein sequences. A fully human antibody may contain mouse glycan if it is produced in a mouse, mouse cell, or a hybridoma derived from a mouse cell. Similarly, a "mouse antibody" or a "murine antibody" refers to an antibody that contains only mouse / murine immunoglobulin protein sequences. Alternatively, a "fully human antibody" may contain rat glycan if it is produced in a rat, rat cell, or a hybridoma derived from a rat cell. Similarly, the term "rat antibody" refers to an antibody that contains only rat immunoglobulin sequences. Fully human antibodies may also be generated, for example, by phage display, a widely used screening technique that allows the generation and screening of fully human antibodies. Phage antibodies may also be used in the context of the present invention. Phage display methods are described, for example, in US5403484, US5969108, and US5885793. Another technique that allows the development of fully human antibodies involves a modification of the murine hybridoma technology. Mice have been bred to contain human immunoglobulin loci in place of their own mouse genes (see, eg, US5877397).

[0134] The term "chimeric antibody" refers to an antibody comprising a variable region of the present invention fused or chimerized to an antibody region (e.g., constant region) derived from another human or non-human species (e.g., mouse, horse, rabbit, dog, cow, chicken).

[0135] The term "antibody" also relates to recombinant human antibodies, xenoantibodies, and heterohybrid antibodies. The term "recombinant (human) antibody" includes all human sequence antibodies prepared, expressed, generated, or isolated by recombinant methods, such as antibodies isolated from animals transgenic for human immunoglobulin genes (e.g., mice); antibodies expressed using recombinant expression vectors transfected into host cells, antibodies isolated from recombinant combinatorial human antibody libraries, or antibodies prepared, expressed, generated, or isolated by any other technique involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions (if present) derived from human germline immunoglobulin sequences. However, such antibodies can be subjected to in vitro mutagenesis (or, in the case of animals transgenic for human Ig sequences, in vivo somatic mutagenesis) whereby the amino acid sequences of the VH and VL regions of the recombinant antibodies are derived from and related to human germline VH and VL sequences, but are sequences that may not naturally occur within the human antibody germline repertoire in vivo.

[0136] A "heterologous antibody" is defined with respect to the transgenic non-human organism producing such an antibody. The term refers to an antibody that has an amino acid sequence found in, or encodes a nucleic acid sequence corresponding to, an organism that is not a transgenic non-human animal, generally an organism derived from a species other than the species of the transgenic non-human animal.

[0137] The term "heterohybrid antibody" refers to an antibody that has light and heavy chains derived from different organisms. For example, an antibody that has a human heavy chain bound to a mouse light chain is a heterohybrid antibody. Examples of heterohybrid antibodies include chimeric and humanized antibodies.

[0138] "Humanized" forms of non-human (e.g., mouse or rabbit) antibodies are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (e.g., Fv, Fab, Fab', F(ab')2, or other antigen-binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin. Often, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementarity determining region (CDR) of the recipient are replaced by residues from a CDR (donor antibody) of a non-human species, such as mouse, rat, or rabbit, that has the desired specificity, affinity, and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may contain residues that are found neither in the recipient antibody nor in the introduced CDR or framework sequences. These modifications are made to further improve and optimize antibody function. Generally, the humanized antibody will contain substantially all of at least one, typically two, variable regions, with all or substantially all of the CDR regions corresponding to those of a non-human immunoglobulin and all or substantially all of the FR regions being those of a human immunoglobulin consensus sequence. The humanized antibody may also contain at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature 321 (1986), 522-525; Reichmann Nature 332 (1998), 323-327 and Presta Curr Op Struct Biol 2 (1992), 593-596.

[0139] A common method for antibody humanization involves CDR grafting, in which functional antigen-binding sites from a non-human donor antibody are grafted onto a human acceptor antibody. CDR grafting methods are known in the art and are described, for example, in US5225539, US5693761, and US6407213. Another related method is the generation of humanized antibodies from transgenic animals that have been genetically engineered to contain one or more humanized immunoglobulin loci that can undergo gene rearrangement and gene conversion (see, for example, US7129084).

[0140] Thus, in the context of the present invention, the term "antibody" relates to whole immunoglobulin molecules as well as to parts of such immunoglobulin molecules (i.e. "antigen-binding fragments thereof"). Furthermore, the term relates to modified and / or converted antibody molecules as described above. The term also relates to recombinantly or synthetically produced / synthesized antibodies. The term also relates to intact antibodies as well as antibody fragments thereof (e.g. separated 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 Fvs (scFv) or antibody fusion proteins.

[0141] A "single-chain Fv" or "scFv" antibody fragment is, in the context of the present invention, a VFv antibody fragment. H and V L Generally, the scFv polypeptide has V domains that enable the scFv to form the desired structure for antigen binding. H and V LFurther included are polypeptide linkers between the domains. Techniques describing the production of single chain antibodies are disclosed, for example, in Pluckthun in The Pharmacology of Monoclonal Antibodies, Rosenburg and Moore eds. Springer-Verlag, NY (1994), 269-315.

[0142] As used herein, a "Fab fragment" refers to a fragment that contains one light chain and one C H Fab molecules are composed of the variable region of one heavy chain and the variable region of one heavy chain. The heavy chain of a Fab molecule cannot form disulfide bonds with another heavy chain molecule.

[0143] The "Fc" region is the C region of an antibody. H 2 and C H The two heavy chain fragments contain two or more disulfide bonds and a C3 region. H It is held together by three domains of hydrophobic interactions.

[0144] A "Fab' fragment" is a fragment that contains one light chain and one V H Area and C H The C(ab')2 fragment comprises a portion of one heavy chain containing the C(ab')2 domain, and further comprises two Fab' fragments that allow interchain disulfide bonds to form between the two heavy chains to form an F(ab')2 molecule. H 1 and C H Includes the area between the two areas.

[0145] A "F(ab')2 fragment" is a fragment that contains two light chains, as well as C H 1 and C H It contains two heavy chains with a portion of the constant region between them, and an interchain disulfide bond is formed between the two heavy chains, so that an F(ab')2 fragment is composed of two Fab' fragments linked by disulfide bonds between the two heavy chains.

[0146] The "Fv region" comprises the variable regions from both the heavy and light chains, but lacks the constant regions.

[0147] The humanized antibodies, humanized antibody constructs, humanized antibody fragments, humanized antibody derivatives (all Ig derived) used according to the invention, or their corresponding immunoglobulin chains, can be further modified using conventional techniques known in the art, for example, by amino acid deletion, insertion, substitution, addition, and / or recombination, and / or any other modification known in the art, either alone or in combination. Methods for introducing such modifications in the DNA sequence underlying the amino acid sequence of the immunoglobulin chain are well known to those skilled in the art; see, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual; Cold Spring Harbor Laboratory Press, 2002; nd edition (1989) and 3 rd See, for example, the 'Ig-derived regions', ... nd edition (1989) and 3 rdedition (2001); Gerhardt et al., Methods for General and Molecular Bacteriology ASM Press (1994); Lefkovits, Immunology Methods Manual: The Comprehensive Sourcebook of Techniques; Academic Press (1997); Golemis, Protein-Protein Interactions: A Molecular Cloning Manual Cold Spring Harbor Laboratory Press (2002)).

[0148] The term "CDR" as used herein relates to "complementarity determining region" as it is well known in the art. CDRs are the parts of immunoglobulins that determine the specificity of the molecule and contact a particular ligand. 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 region (CDR1, CDR2, and CDR3). CDR-H represents the CDR region of the variable heavy chain and CDR-L relates to the CDR region of the variable light chain. VH means variable heavy chain and VL means variable light chain. The CDR regions of Ig-derived regions are described in Kabat "Sequences of Proteins of Immunological Interest", 5 thedit. NIH Publication no. 91-3242 US Department of Health and Human Services (1991). The CDR sequences provided herein are defined by Kabat. However, it will be understood by those skilled in the art that the present invention is intended to encompass binding molecules in which the CDR sequences are defined by any useful identification / numbering method. For example, 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, Muller 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) numbering methods may be used to define the CDRs.

[0149] Thus, in the context of the present invention, the antibody molecules described herein above are selected from the group consisting of full length antibodies (immunoglobulins, e.g., IgG1, IgG2, IgA1, IgA2, IgG3, IgG4, IgA, IgM, IgD, or IgE), F(ab)-, Fab'-SH-, Fv-, Fab'-, F(ab')2 fragments, chimeric antibodies, CDR-grafted antibodies, fully human antibodies, bivalent antibody constructs, antibody fusion proteins, synthetic antibodies, bivalent single chain antibodies, trivalent single chain antibodies, and multivalent single chain antibodies.

[0150] "Humanization methods" are well known in the art and have been described in particular for antibody molecules, e.g., Ig-derived molecules. The term "humanized" refers to a humanized form of a non-human (e.g., murine) antibody or fragment thereof (e.g., Fv, Fab, Fab', F(ab'), scFvs, or other antigen-binding subsequences of antibodies) that contains some portion of sequence derived from the non-human antibody. Humanized antibodies include human immunoglobulins in which residues from the complementarity determining regions (CDRs) of a human immunoglobulin are replaced by residues from the CDRs of a non-human species (e.g., mouse, rat, or rabbit) that have the desired binding specificity, affinity, and capacity. Generally, the humanized antibody will contain substantially all of at least one, and generally two, variable regions, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are of human immunoglobulin consensus sequence. A humanized antibody may optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin; see, inter alia, Jones et al., Nature 321 (1986), 522-525, Presta, Curr. Op. Struct. Biol. 2 (1992), 593-596. Methods for humanizing non-human antibodies are well known in the art. In general, a humanized antibody has one or more amino acids introduced into it from a source where the non-human still maintains the original binding activity of the antibody. Methods for humanizing antibodies / antibody molecules are described in more detail in Jones et al., Nature 321 (1986), 522-525; Reichmann et al., Nature 332 (1988), 323-327; and Verhoeyen et al., Science 239 (1988), 1534-1536.Specific examples of humanized antibodies, such as antibodies against EpCAM, are known in the art (see, e.g., LoBuglio, Proceedings of the American Society of Clinical Oncology Abstract (1997), 1562 and Khor, Proceedings of the American Society of Clinical Oncology Abstract (1997), 847).

[0151] Thus, in the context of the present invention, there is provided an antibody molecule or an antigen-binding fragment thereof which can be successfully used in a pharmaceutical composition.

[0152] The specificity of the antibody or antigen-binding fragment of the present invention can be expressed not only by the form of the amino acid sequence of the antibody or antigen-binding fragment defined above, but also by the epitope to which the antibody can bind. Thus, in one embodiment, the present invention relates to an anti-TDP-43 antibody or an antigen-binding fragment thereof, particularly an anti-phosphorylated TDP-43 antibody or an antigen-binding fragment thereof, which recognizes the same epitope as the antibody of the present invention.

[0153] It can be understood by the skilled artisan that the epitope may be contained in the TDP-43 protein, but also in its degradation products, or may be a chemically synthesized peptide. The amino acid positions are only indicated to indicate the position of the corresponding amino acid sequence in the sequence of the (full-length human) TDP-43 protein (SEQ ID NO: 1). The present invention encompasses all peptides that contain the epitope. The peptide may be part of a polypeptide of 100 or more amino acids in length, or may be a small peptide of 100 or less, preferably 50 or less, more preferably 25 or less amino acids, even more preferably 16 or less amino acids. The amino acids of such peptides may be natural or unnatural amino acids (e.g. beta amino acids, gamma amino acids, D-amino acids) or a combination thereof. Furthermore, the present invention may encompass each retro-inverso peptide of the epitope. The peptide may be unbound or bound. It may be, for example, attached to a small molecule (e.g., a drug or a fluorophore), a high molecular weight polymer (e.g., polyethylene glycol (PEG), polyethyleneimine (PEI), hydroxypropyl methacrylate (HPMA), etc.), or to a protein, fatty acid, sugar moiety, or may be inserted into a membrane.

[0154] To test whether the antibody of interest and the antibody of the present invention recognize the same epitope, the following competition experiment can be performed: Vero cells infected with 3 MOI (multiplicity of infection) are incubated for 1 hour after 20 hours with various concentrations of the antibody of interest as a competitor. In the second incubation step, the antibody of the present invention is applied at a fixed concentration of 100 nM and its binding is detected by flow cytometry using a fluorescently labeled antibody against the constant region of the antibody of the present invention. Binding that occurs inversely proportional to the concentration of the antibody of interest is an indication that both antibodies recognize the same epitope. However, many other assays that can be used are known in the art.

[0155] The present invention also relates to the generation of specific antibodies against endogenous and recombinant polypeptides of phosphorylated TDP-43. The generation is based, for example, on the immunization of animals (e.g., mice). However, other animals for the generation of antibodies / antisera are also included within the present invention. For example, monoclonal and polyclonal antibodies can be generated by rabbits, mice, goats, donkeys, etc. A polynucleotide encoding a selected polypeptide corresponding to TDP-43 can be subcloned into a suitable vector, and said recombinant polypeptide is expressed in an organism capable of expression, e.g., bacteria. Thus, the expressed recombinant protein can be injected intraperitoneally into mice, and the resulting specific antibodies can be obtained, for example, from mouse serum provided by intracardiac blood puncture. The present invention also contemplates the generation of specific antibodies against endogenous and recombinant polypeptides by using DNA vaccination methods as illustrated in the described examples. DNA vaccination methods are well known in the art and include gene gun or jet injection and liposome-mediated delivery by intramuscular or subcutaneous injection. Thus, a polypeptide or protein or epitope of phosphorylated TDP-43, in particular the epitope of the antibody provided herein, can be obtained by directly immunizing an animal by direct intramuscular injection of a vector expressing a desired polypeptide or protein or epitope of phosphorylated TDP-43, in particular the epitope of the antibody of the present invention present within amino acid residues 361-414 of human TDP-43 (SEQ ID NO: 1), more specifically an epitope that binds / interacts with the structure of TDP-43 formed by the specific amino acid sequence of phosphorylated amino acid residues pS403, pS404, pS409, pS410 of human TDP-43 (SEQ ID NO: 1).

[0156] The amount of specific antibody obtained can be quantified using ELISA, also described herein below. Further methods for the production of antibodies are well known in the art, see, for example, Harlow and Lane, "Antibodies, A Laboratory Manual", CSH Press, Cold Spring Harbor, 1988.

[0157] Thus, under certain assay conditions, a particular antibody and corresponding epitope of TDP-43 will bind to each other and not to significant amounts of other components present in the sample. Specific binding to a target analyte under such conditions may require a binding moiety that is selected for its properties for the particular target analyte. A variety of immunoassay methods may be used to select antibodies that react specifically with a particular antigen. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies that have specific immunoreactivity with an analyte. See Shepherd and Dean (2000), Monoclonal Antibodies: A Practical Approach, Oxford University Press and / or Howard and Bethell for a description of immunoassay methods and conditions that can be used to determine specific immunoreactivity. Typically, a specific or selective reaction is at least twice the background signal due to noise, and more typically 10-100 times or more higher than background. Those skilled in the art are in a position to provide and create specific binding molecules for novel polypeptides. For certain binding assays one can easily use to avoid unwanted cross-reactivity; for example, polyclonal antibodies can be easily purified and selected by known methods (see Shepherd and Dean, loc. Cit.).

[0158] The "class" of an antibody refers to the type of constant region or constant region carried by its heavy chain. There are five main antibody classes (IgA, IgD, IgE, IgG, and IgM), and some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions that correspond to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0159] In some embodiments, amino acid sequence variants of the antibodies provided herein are included. For example, it may be desired to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of the antibody can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions from, and / or insertions into, and / or substitutions of residues within the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be made in the final construct, so long as the final construct has the desired characteristics, e.g., antigen binding.

[0160] In some embodiments, antibody variants are provided that have one or more amino acid substitutions. Interesting sites for substitution mutagenesis include CDRs and FRs. Conservative substitutions are shown in Table 1 under the heading of "preferred substitutions". More changes are provided in Table 1 under the heading of "exemplary substitutions" and are further described below with respect to amino acid side chain classes. Amino acid substitutions can be introduced into the antibody of interest, and the product can be screened for the desired activity, for example, maintaining / improving antigen binding, reducing immunogenicity, or improving ADCC or CDC.

[0161] Table 1 [Table 1]

[0162] Amino acids can be grouped according to common side chain properties: (1) Hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basic: His, Lys, Arg; (5) Residues that affect chain orientation: Gly, Pro; (6) Aromaticity: Trp, Tyr, Phe.

[0163] Non-conservative substitutions involve changing a member of one of these classes for another class.

[0164] One type of substitutional variant involves substituting one or more hypervariable region residues of a parent antibody (e.g., humanized or human antibodies). Generally, the resulting variant selected for further study has an alteration (e.g., improvement) in certain biological properties (e.g., higher affinity, lower immunogenicity) compared to the parent antibody and / or has substantially retained certain biological properties of the parent antibody. A typical substitutional variant is an affinity matured antibody, which can be conveniently generated, for example, using phage display-based affinity maturation techniques (e.g., techniques described herein). Briefly, one or more CDR residues are mutated and the mutant antibody is displayed on phage and screened for a particular biological activity (e.g., binding affinity).

[0165] Alterations (e.g., substitutions) may be made in the CDRs, for example, to improve the affinity of the antibody. Such alterations may be made in CDR "hot spots", i.e., residues encoded by codons that are frequently mutated during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or in the SDRs (a-CDRs), with the resulting mutant VH or VL tested for binding affinity. Affinity maturation by construction and reselection from secondary libraries is described, for example, in Hoogenboom et al., Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001).). In certain embodiments of affinity maturation, diversity is introduced into the variable genes 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 generated. The library is then screened to identify any antibody variants with the desired affinity. Another method for introducing diversity involves the CDR designation method, in which several CDR residues (e.g., 4-6 residues at a time) are randomized. The CDR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 are often specifically targeted.

[0166] In some embodiments, substitution, insertion, or deletion can occur within one or its CDRs, as long as such changes do not substantially reduce the antibody's ability to bind to antigen.For example, conservative changes (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity can be made in CDRs.Such changes can be outside the CDR "hot spots" or SDRs.In some embodiments of the mutant VH and VL sequences provided above, each CDR is not changed or contains no more than one, two, or three amino acid substitutions.

[0167] A method useful for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis" as described in Cunningham and Wells (1989) Science, 244: 1081-1085. In this method, a residue or group 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 of the antibody with the antigen is affected. Further substitutions can be introduced into amino acid positions that show functional sensitivity to the initial substitution. Alternatively, or in addition, a crystal structure of an antigen-antibody complex is used to identify contact points between the antibody and the antigen. Residues adjacent to such contacting residues can be targeted as candidates for substitution or eliminated. The mutants can be screened to see if they have the desired properties.

[0168] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion includes an antibody with an N-terminal methionine residue. Other insertional variants of antibody molecules include the fusion to the N- or C-terminus of the antibody of an enzyme (e.g., ADEPT) or a polypeptide which increases the serum half-life of the antibody.

[0169] In certain embodiments, the antibodies provided herein are altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence to create or remove one or more glycosylation sites.

[0170] If the antibody comprises an Fc region, the sugar chains attached thereto may be altered. Endogenous antibodies produced by mammalian cells typically comprise biantennary oligosaccharides that are generally attached by N-terminal linkage to Asn297 in the CH2 region of the Fc region. See, for example, Wright et al., TIBTECH 15:26-32 (1997). The oligosaccharides may include various sugar chains, such as mannose, N-acetylglucosamine (GlcNAc), galactose, and sialic acid, as well as fucose attached to GlcNAc in the "stem" of the biantennary oligosaccharide structure. In certain embodiments, modifications of the oligosaccharides in the antibodies of the present invention may be made to create antibody variants with certain improved properties.

[0171] In one embodiment, antibody variants are provided that have a glycan structure that lacks fucose attached (directly or indirectly) to the Fc region. For example, the amount of fucose in such antibodies can be 1%-80%, 1%-65%, 5%-65%, or 20%-40%. The amount of fucose is determined by calculating the average amount of fucose in the glycan at Asn297 relative to the sum of all glycan structures (e.g., complex, hybrid and high mannose structures) attached to Asn297 as measured by MALDI-TOF mass spectrometry, e.g., as described in WO2008 / 077546. Asn297 refers to an asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues; see Edelman, GM et al., Proc. Natl. Acad. USA, 63, 78-85 (1969)), although Asn297 can also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence changes in the antibody. Such fucosylation variants can have improved ADCC function. See, e.g., US Patent Publication Nos. US2003 / 0157108 (Presta, L.); US2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of "defucosylated" or "fucose-deficient" antibody variants in the literature include US2003 / 0157108; WO2000 / 61739; WO2001 / 29246; US2003 / 0115614; US2002 / 0164328; US2004 / 0093621; US2004 / 0132140. ;US2004 / 0110704;US2004 / 0110282;US2004 / 0109865;WO2003 / 085119;WO2003 / 084570;WO2005 / 035586;WO2005 / 035778;W02005 / 053742;W02002 / 031140;Okazaki et al., J. Mol. Biol. 336:1239-1249 (2004);Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614 (2004).Examples of cell lines capable of producing defucosylated antibodies include Lec 13 CHO cells, which lack protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application No. 2003 / 0157108Al (Presta, L); and WO2004 / 056312Al (Adams et al.), especially Example 11), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Bioteeh. Bioeng. 87: 614 (2004); Kanda, Y. et al., Bioteehnol. Bioeng., 94(4):680-688 (2006); and WO2003 / 085107).

[0172] Further provided are antibody variants having bisected oligosaccharides, for example, where the biantennary oligosaccharides attached to the Fc region of the antibody are bisected by GlcNAc. Such antibody variants may exhibit reduced fucosylation and / or improved ADCC function. Examples of such antibody variants are described, for example, in WO2003 / 011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and US2005 / 0123546 (Umana et al.). Also provided are antibody variants having at least one galactose residue in the oligosaccharides attached to the Fc region. Such antibody variants may exhibit improved CDC function. Such antibody variants are described, for example, in WO1997 / 30087 (Patel et al.); WO1998 / 58964 (Raju, S.); and WO1999 / 22764 (Raju, S.).

[0173] In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby creating a variant of the Fc region. The variant Fc region may comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) containing an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0174] In certain embodiments, the present invention contemplates antibody variants that have some, but not all, effector functions, making them desirable candidates for applications where in vivo antibody half-life is important, but certain effector functions (e.g., complement activation and ADCC) are unnecessary or harmful. In vitro and / or in vivo cytotoxicity assays can be performed to confirm the reduction / loss of CDC and / or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to confirm that the antibody lacks FcγR binding (which may result in the lack of ADCC activity) but retains FcRn binding ability. NK cells, the primary cells for mediating ADCC, express only FcγRIII, while monocytes and microglia express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991). Non-limiting examples of in vitro assays to assess ADCC activity of a molecule of interest are described in U.S. Patent No. 5,500,362 (see, e.g., Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) and Hellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985);5,821,337 (see, Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)).

[0175] Alternatively, non-radioactive assay methods may be used (e.g., ACTI® Non-Radioactive Cytotoxicity Assay for Flow Cytometry (Cell Technology, Inc., Mountain View, Calif.); and CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega, Madison, Wis.). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC), and natural killer (NK) cells.

[0176] Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model, such as those disclosed in Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998).

[0177] C1q binding assays can also be performed to confirm that the antibody cannot bind to Clq and therefore lacks CDC activity.See, for example, Clq and C3c binding ELISA in WO2006 / 029879 and WO2005 / 100402.CDC assays can also be performed to assess complement activation (see, for example, Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996); Cragg, MS et al., Blood 101:1045-1052 (2003); and Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). FcRn binding and in vivo clearance / half-life measurements can also be made using methods known in the art (see, e.g., Petkova, SB et al., Int'l. Immunol. 18(12):1759-1769 (2006)).

[0178] Antibodies with reduced effector function include those with substitutions of one or more of residues 234, 235, 238, 265, 269, 270, 297, 327 and 329 of the Fc region (U.S. Pat. No. 6,737,056). Certain antibody variants with improved or reduced binding to FcRs have been described (see, e.g., U.S. Pat. No. 6,737,056; WO2004 / 056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001)). Such Fc mutations include Fc mutations with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc mutation (with substitutions of residues 265 and 297 to alanine) (U.S. Patent No. 7,332,581), or the so-called "DANG" Fc mutation with substitutions of residue 265 to alanine and 297 to glycine. Alternatively, antibodies with reduced effector function include antibodies with substitutions of one or more of residues 234, 235, and 329 of the Fc region (the so-called "PG-LALA" Fc mutation (with substitutions of residues 234 and 235 to alanine and 329 to glycine)) (Lo, M. et al., Journal of Biochemistry, 292, 3900-3908). Other known mutations at positions 234, 235 and 321 can be used, namely TM mutations, including the mutations L234F / L235E / P331S in the CH2 domain (Oganesyan et al. Acta Cryst. D64, 700-704. (2008)). Antibodies derived from the human IgG4 isotype contain the mutations S228P / L235E to stabilize the hinge and reduce FgR binding (Schlothauer et al, PEDS, 29 (10):457-466).

[0179] Other Fc variants include those having a substitution of one or more of the following residues in the Fc region: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434, e.g., a substitution of residue 434 in the Fc region (U.S. Patent No. 7,371,826). For other examples of variants in the Fc region, see also Duncan & Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821.

[0180] In one embodiment, the Fc region is mutated to increase affinity to FcRn at pH 6.0, thereby increasing the antibody half-life. Antibodies with increased affinity to FcRn include those with substitutions of one or more of residues 252, 253, 254, 256, 428, 434 of the Fc region, including the so-called YTE mutations with substitutions M252Y / S254T / T256E (Dall'Acqua et al, J Immunol. 169:5171-5180 (2002)) or LS mutations M428L / N434S (Zalevsky et al, Nat Biotechnol. 28(2): 157-159 (2010)).

[0181] In certain embodiments, it may be desirable to create cysteine ​​modified antibodies, e.g., "thioMAbs" in which one or more residues of an antibody are replaced with cysteine ​​residues. In certain embodiments, the replacement of residues occurs at accessible sites of the antibody. By replacing these residues with cysteine, reactive thiol groups are placed at accessible sites of the antibody, which may be used to conjugate the antibody to other moieties (e.g., drug moieties or linker drug moieties) to create immunoconjugates, as further described herein. In certain embodiments, any one or more of the following residues may be replaced with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine ​​modified antibodies may be created, for example, as described in U.S. Pat. No. 7,521,541.

[0182] In certain embodiments, the antibodies provided herein may be further modified to include additional non-protein moieties that are known and readily available in the art. Moieties suitable for derivatization of antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly 1,3-dioxolane, poly 1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymer, polypropylene oxide / ethylene oxide copolymer, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may be useful in manufacturing due to its stability in water. The polymers may be of any molecular weight and may be branched or unbranched. The number of polymers attached to an antibody can vary, and when more than one polymer is attached, they can be the same or different molecules. In general, the number and / or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular property or function of the antibody to be improved, whether the antibody derivative will be used therapeutically under particular conditions, etc.

[0183] In another embodiment, a conjugate of an antibody and a non-protein moiety is provided that can be selectively heated by exposure to radiation. In one embodiment, the non-protein moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation can be of any wavelength, including but not limited to, wavelengths that are not harmful to normal cells, but heat the non-protein moiety to a temperature that kills cells in close proximity to the antibody-non-protein moiety.

[0184] The antibodies may be produced using recombinant methods and compositions, for example, as described in U.S. Pat. No. 4,816,567. In one embodiment, an isolated nucleic acid is provided that encodes an anti-phosphorylated TDP-43 antibody described herein. Such a nucleic acid may encode an amino acid sequence comprising the VL and / or an amino acid sequence comprising the VH of the antibody (e.g., the light and / or heavy chains of the antibody). In a further embodiment, one or more vectors (e.g., expression vectors) comprising such a nucleic acid are provided. In a further embodiment, a host cell comprising such a nucleic acid is provided. In one such embodiment, the host cell comprises (e.g., is transformed with) (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody, or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is a eukaryotic cell, for example, a Chinese hamster ovary (CHO) cell or a lymphoid cell (e.g., YO, NSO, Sp20). In one embodiment, a method for producing an anti-phosphorylated TDP-43 antibody is provided, comprising culturing a host cell comprising nucleic acid encoding said antibody, as provided above, under conditions suitable for expression of said antibody, and, optionally, recovering said antibody from said host cell (or host cell culture medium).

[0185] For recombinant production of the TDP-43 antibody of the present invention, for example, nucleic acid encoding the antibody as described above is isolated and inserted into one or more vectors for further cloning and / or expression in a host cell or cell-free expression system. Such nucleic acid can be easily isolated and sequenced using conventional methods (e.g., by using oligonucleotide probes capable of specifically binding to genes encoding the heavy and light chains of the antibody).

[0186] Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic or eukaryotic cells as described herein. For example, antibodies may be produced in bacteria, particularly when glycosylation and Fc effector functions are not required. For expression of antibody fragments and polypeptides in bacteria, see, for example, U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Val. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes the expression of antibody fragments in E. coli.) After expression, the antibody can be isolated from the bacterial cell paste in a soluble fraction and further purified.

[0187] In addition to prokaryotes, eukaryotic microbes, such as filamentous fungi or yeast, are suitable cloning or expression hosts for antibody-encoding vectors, including fungal and yeast strains whose glycosylation pathways have been "humanized" resulting in the production of antibodies with partial or full human glycosylation patterns. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215 (2006).

[0188] Suitable host cells for the expression of glycosylated antibodies are also derived from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plants and insect cells. In particular, many baculovirus strains have been identified that can be used in combination with insect cells for transfection of Spodoptera frugiperda cells.

[0189] Plant cell cultures can be used as hosts. See, for example, U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (which describe the PLANTIBODIES® technology for producing antibodies in transgenic plants).

[0190] Vertebrate cells may also be used as hosts, for example mammalian cell lines used for growth in suspension may be useful. Other examples of useful mammalian host cell lines include macaque kidney CV1 lines transformed with SV40 (COS-7); human embryonic kidney lines (293 or 293 cells described in Graham et al., J. Gen Viral. 36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (e.g., TM4 cells described in Mather, Biol. Reprod. 23:243-251 (1980)); macaque kidney cells (CV1); African green monkey kidney cells (VER0-76); human cervical carcinoma cells (HeLa); canine kidney cells (MDCK; buffalo rat hepatocytes (BRL3A); human lung cells (W138); human liver cells (HepG2); mouse mammary tumor (MMT060562); e.g., Mather et al., Annals N. Y Aead. Sei. 383:44-68 (1982); MRC5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells (including DHFR CHO cells) (Urlaub et al., Proc. Natl. Acad. Cii. USA 77:4216 (1980)); and myeloma cell lines, e.g., YO, NSO, and Sp2 / 0. For a review of certain mammalian host cell lines suitable for antibody production, see, e.g., Yazaki and Wu, Methods in Molecular Biology, Val. 248 (BKC Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

[0191] There are several art-known approaches to deliver molecules across the blood-brain barrier (BBB), including, for example, altering the route of administration, disrupting the BBB and altering its permeability, nanoparticle delivery, Trojan horse approaches, receptor-mediated transport, and cell and gene therapy.

[0192] Altered routes of administration can be achieved by direct injection into the brain (see, e.g., Papanastassiou et al., Gene Therapy 9: 398-406(2002)), implantation of a delivery device into the brain (see, e.g., Gillet et al., Nature Med. 9: 589-595 (2003); and Gliadel Wafers®, Guildford Pharmaceutical), and intranasal administration, which bypasses the BBB (Mittal et al., Drug Deliv.21(2):75-86. (2014)).

[0193] Methods of barrier disruption include, but are not limited to, ultrasound (see, e.g., U.S. Patent Publication No. 2002 / 0038086), osmotic pressure (e.g., by administration of hyperosmolar mannitol (Neuwelt, EA, Implication of the Blood-Brain Barrier and its Manipulation, Vols 1 & 2, Plenum Press, NY (1989))), permeabilization with bradykinin or permeabilizer A-7 (see, e.g., U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206 and 5,686,416).

[0194] Methods for altering BBB permeability include, but are not limited to, increasing the permeability of the blood-brain barrier using glucocorticoid blockers (see, e.g., U.S. Patent Application Publication Nos. 2002 / 0065259, 2003 / 0162695, and 2005 / 0124533), activating potassium channels (see, e.g., U.S. Patent Application Publication No. 2005 / 0089473), and inhibiting ABC drug transporters (see, e.g., U.S. Patent Application Publication No. 2003 / 0073713).

[0195] Trojan horse delivery methods for delivering antibodies or antibody fragments thereof across the blood-brain barrier include, but are not limited to, cationization of the antibody (see, e.g., U.S. Pat. No. 5,004,697) and the use of cell-penetrating peptides such as the Tat peptide to enter the CNS (see, e.g., Dietz et al., J. Neurochem. 104:757-765 (2008)).

[0196] Nanoparticle delivery methods for delivering an antibody or antibody fragment thereof across the blood-brain barrier include, but are not limited to, encapsulating the antibody or antigen-binding fragment thereof in a liposome or extracellular vesicle, such as, but not limited to, an exosome that is bound to the antibody or antigen-binding fragment, or a peptide that binds to a receptor on the vascular endothelium of the blood-brain barrier (see, e.g., US Patent Application Publication No. 20020025313), and coating the antibody or antigen-binding fragment thereof with low density lipoprotein particles (see, e.g., US Patent Application Publication No. 20040204354) or apolipoprotein E (see, e.g., US Patent Application Publication No. 20040131692).

[0197] The antibodies of the invention may be further modified to enhance blood-brain barrier crossing.

[0198] The antibody or antigen-binding fragment of the present invention can be fused to a polypeptide that binds to a blood-brain barrier receptor. BBB receptors include, but are not limited to, transferrin receptor, insulin receptor, or low density lipoprotein receptor. The polypeptide can be a peptide, a receptor ligand, a single domain antibody (VHH), scFv, or a Fab fragment.

[0199] The antibody of the present invention can also be delivered as a corresponding nucleic acid encoding the antibody. Such a nucleic acid molecule can be part of a viral vector for targeted delivery to the blood-brain barrier, or any other cell type in the CNS. A non-limiting example is a viral vector comprising a nucleic acid molecule encoding the antibody of the present invention for targeted delivery to endothelial cells of the BBB, pericytes or astrocytes of the BBB. In certain embodiments, the endothelial cells of the BBB, pericytes or astrocytes of the BBB express and secrete the antibody in the brain parenchyma. The viral vector can be a recombinant adeno-associated viral vector (rAAV) selected from any AAV serotype known in the art, including but not limited to AAV1-AAV12, capable of expressing the antibody or antibody fragment or antibody derivative intracellularly or in the brain parenchyma.

[0200] Cell therapy methods for delivering the antibodies or antibody fragments or antibody derivatives of the invention across the blood-brain barrier include, but are not limited to, using the homing ability of endothelial progenitor cells (EPCs) transfected ex vivo with vectors to overcome the strong sieving activity of the blood-brain barrier and the secretion and delivery of antibodies or antibody fragments to the brain by these cells (see, e.g., Heller and al., J Cell Mol Med. 00:1-7 (2020)), or the use of polymeric cell transplantation devices loaded with genetically modified cells to secrete antibodies or antibody fragments (see, e.g., Marroquin Belaunzaran et al. PloS ONE 6(4): e18268 (2011)).

[0201] Pharmaceutically acceptable carriers, diluents, adjuvants and excipients are well known in the pharmaceutical technical field and are described, for example, in Remington's Pharmaceutical Sciences, 15 th or 18 thEd. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy 19 th Ed.(Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3 rd Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc, 1999); Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12 th Ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); Fiedler's “Lexikon der Hilfstoffe” 5 th Ed., Edition Cantor Verlag Aulendorf 2002; “The Handbook of Pharmaceutical Excipients”, 4 th Ed., American Pharmaceuticals Association, 2003; and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are incorporated herein by reference.

[0202] Carriers, diluents, adjuvants and pharmaceutical excipients can be selected having regard to the intended route of administration and standard pharmaceutical practice. The compounds must be acceptable in the sense of not being harmful to the recipient.

[0203] The "effective amount" of a compound administered to a subject is a dose that is suitable for treating, preventing, or alleviating a disease, disorder, or disorder according to sound medical judgment. The specific dose level and frequency of administration may depend on a variety of factors, including, for example, the activity of the specific compound used, the metabolic stability and duration of action of the compound, the mode and time of administration, excretion rate, and drug combination. Patient-specific factors, such as age, weight, general health, sex, diet, and the severity of a particular condition, may also affect the amount administered. Embodiments of the invention of TDP-43 binding molecules

[0204] In one embodiment, 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, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; or b) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23; or c) 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; or d) 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: 33; or e) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53; or f) 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; or g) VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83 The present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0205] In one embodiment, 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, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; or b) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23; or c) 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; or d) 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: 33; or e) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53; or f) 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; or g) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83; or h) 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; or The present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0206] In one embodiment, a) 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; or b) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or c) 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: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or d) 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; or e) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or f) 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: 76, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 77; or g) 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 present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0207] In one embodiment, a) 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; or b) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or c) 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: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or d) 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; or e) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or f) 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: 76, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 77; or g) 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; or h) 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 present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0208] In one embodiment, a) a heavy chain variable region (VH) comprising: i. 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; or ii. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23; or iii. 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; or iv. 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: 33; or v. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53; or vi. 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; or vii. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83; and b) a light chain variable region (VL) comprising: i. 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; or ii. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or iii. 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: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or iv. 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; or v. VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or vi. VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 77; or vii. 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 present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0209] In one embodiment, a) a heavy chain variable region (VH) comprising: i. 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; or ii. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23; or iii. 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; or iv. 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: 33; or v. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53; or vi. 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; or vii. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83; or viii. 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; and b) a light chain variable region (VL) comprising: i. 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; or ii. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or iii. 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: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or iv. 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; or v. VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or vi. VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 77; or vii. 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; or viii. 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 present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0210] In one embodiment, a) a heavy chain variable region (VH) comprising: i. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 11, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 12, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 13; or ii. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 22, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 23; or iii. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 31, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 32, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 33; or iv. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 41, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 41, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 42, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 42, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 33; or v. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:51, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:51, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:52, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:52, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:53, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:53; or vi. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 61, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 62, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 63; or vii. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 81, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 82, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 83; and b) a light chain variable region (VL) comprising: i. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 15, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 17; or ii. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 27; or iii. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 35, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 37; or iv. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 45, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 45, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 46, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 46, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 47, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 47; or v. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:55, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:55, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:57, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:57; or vi. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 75, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 76, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 77, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 77; or vii. VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 85; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 87. The present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0211] In one embodiment, a) a heavy chain variable region (VH) comprising: i. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 11, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 12, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 13; or ii. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 22, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 23; or iii. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 31, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 32, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 33; or iv. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 41, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 41, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 42, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 42, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 33; or v. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:51, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:51, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:52, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:52, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:53, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:53; or vi. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 61, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 62, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 63; or vii. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 81, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 82, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 83; or viii. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 111, or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 111, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 112, or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 112, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 113, or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 113; and b) a light chain variable region (VL) comprising: i. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 15, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 17; or ii. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 27; or iii. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 35, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 37; or iv. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 45, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 45, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 46, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 46, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 47, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 47; or v. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:55, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:55, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:57, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:57; or vi. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 75, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 76, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 77, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 77; or vii. a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 85, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 87; or viii. VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115, or a VL-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 115; VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116, or a VL-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 116; and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 117, or a VL-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 117. The present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0212] Similarly, in one embodiment, a) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 12; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 13; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 15 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 15, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 17; or b) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 23; and a light chain variable region (VL) comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 27; or c) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 31; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 32; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 33; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 35, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 37 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 37; or d) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 41 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 42 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 33; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 45 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 45, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 46 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 46, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 47 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 47; or e) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 51; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 52; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 53; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 55 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 55, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 26, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 57; or f) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 61; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 62; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 63; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 55 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 55, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 26, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 57; or g) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 51; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 52; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 53; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 75, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 76, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 77 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 77; or h) a heavy chain variable region (VH) comprising: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 81; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 82; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 83; and a light chain variable region (VL) comprising VL-CDR1 having the amino acid sequence of SEQ ID NO: 85 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 85, VL-CDR2 having the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16, and VL-CDR3 having the amino acid sequence of SEQ ID NO: 87 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 87. The present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0213] Similarly, in one embodiment, a) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 11; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 12; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 13; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 15 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 15, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 17 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 17; or b) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 21; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 22; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 23; and a light chain variable region (VL) comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 27; or c) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 31; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 32; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 33; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 35 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 35, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 37 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 37; or d) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 41 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 41; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 42 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 42; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 33; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 45 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 45, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 46 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 46, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 47 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 47; or e) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 51; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 52; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 53; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 55 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 55, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 26, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 57; or f) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 61; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 62; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 63; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 55 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 55, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 26 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 26, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 57; or g) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 51; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 52; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 53; and a light chain variable region (VL) comprising a VL-CDR1 having the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 75, a VL-CDR2 having the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 76, and a VL-CDR3 having the amino acid sequence of SEQ ID NO: 77 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 77; or h) a heavy chain variable region (VH) comprising: a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81 or a VH-CDR1 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 81; a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82 or a VH-CDR2 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 82; and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83 or a VH-CDR3 comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 83; and a light chain variable region (VL) comprising: a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 85; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 16; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 87; i) a heavy chain variable region (VH) comprising: VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 111 or comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 111; VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 112 or comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 112; and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 113 or comprising an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 113; and a light chain variable region (VL) comprising VL-CDR1 having the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 115, VL-CDR2 having the amino acid sequence of SEQ ID NO: 116 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 116, and VL-CDR3 having the amino acid sequence of SEQ ID NO: 117 or an amino acid sequence having at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO: 117. The present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0214] Similarly, in one embodiment, a) a heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising 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 b) a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or c) a heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or d) a heavy chain variable region (VH) comprising 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: 33, and a light chain variable region (VL) comprising 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; or e) a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or f) a heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or g) a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 77; or h) a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83, and a light chain variable region (VL) comprising 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 present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0215] Similarly, in one embodiment, a) a heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising 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 b) a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or c) a heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or d) a heavy chain variable region (VH) comprising 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: 33, and a light chain variable region (VL) comprising 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; or e) a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or f) a heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57; or g) a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 51, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 52, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 53, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 76, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 77; or h) a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83, and a light chain variable region (VL) comprising 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; or i) a heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising 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 present invention provides a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0216] In another embodiment, the TDP-43 antibody comprises a heavy chain variable domain (VH) selected from SEQ ID NO: 10, 20, 30, 40, 50, 60 and 80 (including post-translational modifications of these sequences). In a particular embodiment, the heavy chain variable domain (VH) comprises at least one, two or three CDRs selected from: (a) a VH-CDR1 comprising an amino acid sequence selected from SEQ ID NO: 11, 21, 31, 41, 51, 61 and 81; (b) a VH-CDR2 comprising an amino acid sequence selected from SEQ ID NO: 12, 22, 32, 42, 52, 62 and 82; (c) a VH-CDR3 comprising an amino acid sequence selected from SEQ ID NO: 13, 23, 33, 53, 63 and 83.

[0217] In another embodiment, the TDP-43 antibody comprises a heavy chain variable domain (VH) selected from SEQ ID NO: 10, 20, 30, 40, 50, 60, 80 and 110 (including post-translational modifications of these sequences). In a particular embodiment, the heavy chain variable domain (VH) comprises at least one, two or three CDRs selected from (a) VH-CDR1 comprising an amino acid sequence selected from SEQ ID NO: 11, 21, 31, 41, 51, 61, 81 and 111, (b) VH-CDR2 comprising an amino acid sequence selected from SEQ ID NO: 12, 22, 32, 42, 52, 62, 82 and 112, (c) VH-CDR3 comprising an amino acid sequence selected from SEQ ID NO: 13, 23, 33, 53, 63, 83 and 113.

[0218] In another embodiment, the TDP-43 antibody comprises a light chain variable domain (VL) selected from SEQ ID NOs: 14, 24, 34, 44, 54 and 84 (including post-translational modifications of these sequences). In a particular embodiment, the light chain variable domain (VL) comprises at least one, two or three CDRs selected from: (a) VL-CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 15, 25, 35, 45, 55, 75 and 85; (b) VL-CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 16, 26, 46 and 76; (c) VL-CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 17, 27, 37, 47, 57, 77 and 87.

[0219] In another embodiment, the TDP-43 antibody comprises a light chain variable domain (VL) selected from SEQ ID NOs: 14, 24, 34, 44, 54, 64, 74, 84 and 114 (including post-translational modifications of these sequences). In a particular embodiment, the light chain variable domain (VL) comprises at least one, two or three CDRs selected from (a) VL-CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 15, 25, 35, 45, 55, 75, 85 and 115, (b) VL-CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 16, 26, 46, 76 and 116, (c) VL-CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 17, 27, 37, 47, 57, 77, 87 and 117.

[0220] In one embodiment, the TDP-43 antibody is a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 10; or b. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:20 or having at least 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:20; or c. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30; or d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 40; or e. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 or having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:50; or f. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:60 or having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:60; or g. A heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 80. Includes.

[0221] In one embodiment, the TDP-43 antibody is a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 10; or b. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:20 or having at least 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:20; or c. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30; or d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 40; or e. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 or having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:50; or f. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:60 or having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:60; or g. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 80; or h. A heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 110 or having at least 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 110. Includes.

[0222] In one embodiment, the TDP-43 antibody is a. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14 or having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 14; or b. a light chain variable region (VL) comprising the sequence of SEQ ID NO:24 or having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:24; or c. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34; or d. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44; or e. a light chain variable region (VL) comprising the sequence of SEQ ID NO:54; or f. A light chain variable region (VL) comprising the sequence of SEQ ID NO: 84 or having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 84. Includes.

[0223] In certain embodiments, the TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, a) i. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 10; or ii. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:20 or having at least 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:20; or iii. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30; or iv. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 40; or v. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 or having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:50; or vi. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 60 or having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 60; or vii. A heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 80. A heavy chain variable region (VH) selected from: b) i. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14 or having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 14; or ii. a light chain variable region (VL) comprising the sequence of SEQ ID NO:24 or having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:24; or iii. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34; or iv. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44; or v. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 54; or vi. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64; or vii. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 74; or viii. A light chain variable region (VL) comprising the sequence of SEQ ID NO: 84 or having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 84. and a light chain variable region (VL) selected from:

[0224] In certain embodiments, the TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, a) i. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 10; or ii. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:20 or having at least 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:20; or iii. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 30; or iv. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 40; or v. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 or having at least 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:50; or vi. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 60 or having at least 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 60; or vii. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 80; or viii. A heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 110 or having at least 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 110. A heavy chain variable region (VH) selected from: b) i. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14 or having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 14; or ii. a light chain variable region (VL) comprising the sequence of SEQ ID NO:24 or having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:24; or iii. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 34 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34; or iv. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44; or v. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 54; or vi. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64; or vii. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 74; or viii. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84 or having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 84; or ix. Light chain variable region (VL) comprising the sequence of SEQ ID NO: 114 and a light chain variable region (VL) selected from:

[0225] In certain embodiments, the TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or 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 or having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 14; or b. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:20 or having at least 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:20, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:24 or having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:24; or c. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or having at least 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 having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34; or d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or having 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 having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44; or e. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 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:50, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:54; or f. 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, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:64; or g. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 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:50, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:74; or h. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to 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 having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 84. Includes.

[0226] In certain embodiments, the TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or 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 or having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 14; or b. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:20 or having at least 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:20, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:24 or having at least 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO:24; or c. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 30 or having at least 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 having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 34; or d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or having 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 having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 44; or e. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 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:50, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:54; or f. 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, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:64; or g. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 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:50, and a light chain variable region (VL) comprising the sequence of SEQ ID NO:74; or h. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80 or having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity to 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 having at least 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 84; or i. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 110 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: 110, and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 114. Includes.

[0227] In one embodiment, the TDP-43 antibody is 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: 20 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 24; or c. 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 d. 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; or e. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 50 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 54; or f. 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 g. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:74; or h. 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 Includes.

[0228] In one embodiment, the TDP-43 antibody is 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: 20 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 24; or c. 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 d. 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; or e. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 50 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 54; or f. 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 g. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:50 and a light chain variable region (VL) comprising the sequence of SEQ ID NO:74; or h. 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 i. 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 Includes.

[0229] In a preferred embodiment, the TDP-43 antibody is 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: 20 and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 24; or c. 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 d. 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 Includes.

[0230] In certain embodiments, the invention relates to a TDP-43 binding molecule selected from ACI-8071-943.12A8-Ab1, ACI-8071-943.7H9-Ab1, ACI-8071-943.7D3-Ab1, ACI-8071-943.2E6-Ab1, ACI-8072-946.8H6-Ab1, ACI-8072-946.4G5-Ab1, ACI-8072-946.9D6-Ab1, ACI-7071-4665-B5-R3B-Ab2. Preferably, the TDP-43 binding molecule is selected from ACI-8071-943.12A8-Ab1, ACI-8071-943.7H9-Ab1, ACI-8071-943.7D3-Ab1, ACI-8072-946.4G5-Ab1. Specifically, ACI-8071-943.12A8-Ab1 and ACI-8071-943.7D3-Ab1 can be useful as therapeutic antibodies. ACI-8071-943.7H9-Ab1 and ACI-8072-946.4G5-Ab1 can be useful as diagnostic / detection antibodies, for example, in pairing assays.

[0231] In certain embodiments, the present invention relates to a TDP-43 binding molecule selected from ACI-8071-943.12A8-Ab1, ACI-8071-943.7H9-Ab1, ACI-8071-943.7D3-Ab1, ACI-8071-943.2E6-Ab1, ACI-8072-946.8H6-Ab1, ACI-8072-946.4G5-Ab1, ACI-8072-946.9D6-Ab1, ACI-7071-4665-B5-R3B-Ab2, ACI-8070-942.30D12-Ab1. In certain embodiments, preferably ACI-7071-4665-B5-R3B-Ab2, ACI-7071-809F12-Ab1-rec2, ACI-8072-946.4G5-Ab1 and ACI-8071-943.7H9-Ab1 may be useful as diagnostic / detection antibodies, for example in pairing assays.

[0232] In one embodiment, an (isolated) nucleic acid is provided, said (isolated) nucleic acid encoding a TDP-43 binding molecule described herein, in particular a TDP-43 antibody or an antigen-binding fragment thereof.

[0233] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 18 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0234] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 19 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0235] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 28 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0236] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 29 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0237] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 38 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0238] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 39 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0239] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 48 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0240] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 49 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0241] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 58 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0242] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO:59 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0243] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 68 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0244] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO:69 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0245] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 79 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0246] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 88 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0247] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 89 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0248] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 118 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0249] In some embodiments, an (isolated) nucleic acid is provided, said (isolated) nucleic acid comprising SEQ ID NO: 119 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0250] Compositions and methods The present invention also relates to a pharmaceutical composition comprising the TDP-43 binding molecule of the present invention described herein, in particular an antibody or antigen-binding fragment thereof, and a pharma- ceutically acceptable carrier agent and / or excipient and / or diluent.

[0251] In certain embodiments, a pharmaceutical composition is provided comprising an (isolated) antibody described herein and a pharma- ceutical acceptable carrier.

[0252] In certain embodiments, conjugated binding molecules, particularly antibodies or antigen-binding fragments thereof, are provided, including the binding molecules described herein, particularly antibodies or antigen-binding fragments thereof, and conjugated molecules. The conjugates of the present invention may be referred to as immunoconjugates. Any suitable conjugated molecule may be used in accordance with the present invention. 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., radioconjugates), paramagnetic beads, nucleic acid molecules, detectable labels, therapeutic agents, toxins, and blood-brain barrier-crossing moieties. In one embodiment of the present invention, the immunoconjugate comprises paramagnetic beads (capture antibodies). In another embodiment of the present invention, the immunoconjugate comprises biotin (detection antibodies). 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 via an amino acid residue (e.g., lysine, histidine or cysteine) contained in the binding molecule of the present invention. These may rely on methods such as the NHS (succinimidyl) ester method, the isothiocyanate method, the carbodiimide method and the periodate method. Conjugation may be achieved, for example, by creating a fusion protein. This is appropriate since the binding molecule is conjugated with another protein molecule. Thus, a suitable genetic construct may be formed that allows the expression of a fusion of the binding molecule of the present invention with a label or other molecule. Conjugation may be via a suitable linker moiety to ensure a suitable spatial separation between the antibody and the conjugated molecule, e.g., a detectable label. However, a linker is not necessary in all cases. In some embodiments, the TDP-43 binding molecule of the present invention is conjugated to a detectable label.

[0253] The present invention also relates to immunoconjugates comprising the TDP-43 binding molecules provided herein conjugated to one or more therapeutic agents, e.g., chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins (of bacterial, fungal, plant, or animal origin), or fragments thereof), radioisotopes (i.e., radioconjugates), blood-brain barrier penetrating moieties, or detectable labels. There are various techniques to improve drug delivery across the blood-brain barrier (BBB), as discussed herein (this discussion applies mutatis mutandis). Non-invasive techniques include the so-called "Trojan horse approach," in which a conjugated molecule delivers the binding molecule of the present invention by mediating binding and transport to the BBB receptor. Suitable molecules may include endogenous ligands or antibodies, particularly monoclonal antibodies that bind to specific epitopes of the BBB receptor.

[0254] The present invention further includes the use of the antibodies of the present invention in paired assays, such as immunoassays or ELISAs, for detecting or quantifying phosphorylated TDP-43 in human samples. For a detailed description of preferred paired assays that can be used, reference can be made to Example 8. Such assays include incubation of a sample with at least two different TDP-43 binding molecules of the present invention. The two different TDP-43 binding molecules of the present invention do not compete with each other for binding to TDP-43 and bind to different epitopes. One binding molecule is typically a capture antibody, which is used to immobilize TDP-43, and the other binding molecule is a detection antibody, which binds to the immobilized TDP-43 and provides a signal in the assay directly (by labeling the antibody) or indirectly (via a downstream signal generation system, which may include a secondary antibody that may, for example, enzymatically amplify the signal and bind to the detection antibody). In a preferred embodiment, the assay may be a quantitative assay that can provide a quantitative readout.

[0255] In one embodiment, the assay comprises: a. incubating the sample with a capture antibody, which can be a TDP-43 binding molecule of the present invention conjugated to paramagnetic beads; b) adding a detection antibody to the solution, the detection antibody being a labeled TDP-43 binding molecule of the present invention, e.g., an antibody of the present invention conjugated to biotin; c. adding an optionally labeled substrate for the TDP-43 binding molecule, e.g., streptavidin-β-D-galactosidase; d. optionally washing the plate using a magnetic microplate washer; e. Reading the signal emitted by the labeled TDP-43 binding molecule. Includes.

[0256] In one embodiment, the capture antibody is an immunoconjugate or a TDP-43 binding molecule as described herein, particularly an antibody or an antigen-binding fragment thereof, conjugated to paramagnetic beads.In a preferred embodiment, the capture antibody specifically binds to phosphorylated TDP-43.In another preferred embodiment, the capture antibody of the present invention binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43.

[0257] In a preferred embodiment, the capture antibody is a. a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83, and a light chain variable region (VL) comprising 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; or b. a heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising 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; or c. A heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 105, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107. The TDP-43-binding molecule is selected from the group of TDP-43-binding molecules comprising:

[0258] In a more preferred embodiment, the capture antibody comprises a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83, and a light chain variable region (VL) comprising 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 present invention relates to a TDP-43 binding molecule comprising:

[0259] In a preferred embodiment, the detection antibody specifically binds to phosphorylated TDP-43. In another preferred embodiment, the detection antibody of the present invention binds to misfolded, aggregated TDP-43 and non-aggregated physiological TDP-43.

[0260] In a preferred embodiment, the capture antibody specifically binds to phosphorylated TDP-43. In another preferred embodiment, the capture antibody of the present invention binds to misfolded, aggregated TDP-43 and non-aggregated physiological TDP-43.

[0261] In a preferred embodiment, the detection antibody is a. a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83, and a light chain variable region (VL) comprising 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; or b. a heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising 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; or c. a heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 105, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107; or d. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 22, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 27; or e. VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 61, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 62, VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63, VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57 The TDP-43-binding molecule is selected from the group of TDP-43-binding molecules comprising:

[0262] In a preferred embodiment, the detection antibody is a. a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83, and a light chain variable region (VL) comprising 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; or b. a heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising 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; or c. A heavy chain variable region (VH) comprising 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, and a light chain variable region (VL) comprising VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 105, VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107. The TDP-43-binding molecule is selected from the group of TDP-43-binding molecules comprising:

[0263] In a more preferred embodiment, the detection antibody comprises a heavy chain variable region (VH) comprising VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, and VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83, and a light chain variable region (VL) comprising 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 present invention relates to a TDP-43 binding molecule comprising:

[0264] In one embodiment of the present invention, the capture antibody specifically binds to phosphorylated TDP-43, and the detection antibody specifically binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43. In another embodiment of the present invention, the detection antibody specifically binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43, and the capture antibody specifically binds to phosphorylated TDP-43. In one embodiment, the capture antibody and the detection antibody have different epitopes.

[0265] In one embodiment, the detection antibody comprises a TDP-43 binding molecule comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 81, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 82, 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, and the capture antibody comprises a TDP-43 binding molecule comprising 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, 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: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107. In further embodiments, a paired assay for detecting or quantifying TDP-43 with defined capture and detection antibodies may provide a lower limit of quantification of 0.02 pM and / or a lower limit of detection of 0.09 pM.

[0266] In one embodiment, the detection antibody comprises a TDP-43 binding molecule comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27, and the capture antibody comprises a TDP-43 binding molecule comprising 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, 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. In further embodiments, a paired assay detecting or quantifying phosphorylated TDP-43 with defined capture and detection antibodies may provide a lower limit of quantification of 0.13 pM and / or a lower limit of detection of 0.5 pM.

[0267] In one embodiment, the detection antibody comprises a TDP-43 binding molecule comprising a VH-CDR1 comprising the amino acid sequence of SEQ ID NO:21, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO:22, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:23, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO:25, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO:26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:27, and the capture antibody comprises a TDP-43 binding molecule comprising 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, 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:26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:107. In further embodiments, a paired assay detecting or quantifying phosphorylated TDP-43 with defined capture and detection antibodies may provide a lower limit of quantification of 0.17 pM and / or a lower limit of detection of 0.61 pM.

[0268] In one embodiment, the detection antibody comprises a TDP-43 binding molecule comprising 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, 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: 55, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 57, and the capture antibody comprises a TDP-43 binding molecule comprising 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, 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: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107. In further embodiments, a paired assay detecting or quantifying phosphorylated TDP-43 with defined capture and detection antibodies may provide a lower limit of quantification of 0.02 pM and / or a lower limit of detection of 0.8 pM.

[0269] In certain embodiments, an immunoconjugate is provided, said immunoconjugate comprising an (isolated) antibody described herein and a therapeutic agent. In certain embodiments, a labeled antibody is provided, comprising an antibody described herein and a detectable label.

[0270] In certain embodiments, the TDP-43 binding molecule is part of an immunoconjugate in which the TDP-43 binding molecule is covalently linked to another suitable therapeutic agent.

[0271] In certain embodiments, the TDP-43 binding molecule or an immunoconjugate comprising the same is present as a composition comprising the TDP-43 binding molecule.

[0272] In certain embodiments, the TDP-43 binding molecule is part of a pharmaceutical composition comprising the TDP-43 binding molecule or an immunoconjugate (in which the TDP-43 binding molecule is covalently linked to another suitable therapeutic agent), or a composition comprising the TDP-43 binding molecule in combination with a pharma- ceutically acceptable carrier and / or excipient and / or diluent.

[0273] In certain embodiments, the TDP-43 binding molecule is part of a diagnostic composition comprising the TDP-43 binding molecule and an acceptable carrier and / or excipient and / or diluent.

[0274] In certain embodiments, the TDP-43-binding molecule is part of a detection and / or diagnostic kit comprising the TDP-43-binding molecule or an immunoconjugate (in which the TDP-43-binding molecule is covalently linked to another suitable therapeutic agent), or comprising a composition comprising the TDP-43-binding molecule.

[0275] Kits comprising the binding molecules of the present invention are also provided. In particular, such kits may be used for diagnostic applications. Thus, kits for the diagnosis of diseases, disorders and / or disorders associated with TDP-43, particularly TDP-43 aggregates, or TDP-43 proteinopathies, or kits for use in the methods of the present invention comprising the TDP-43 binding molecules of the present invention are provided. Such kits may include all components necessary to carry out the methods provided herein. Typically, each component is stored separately in one overall package. Suitable additional components to be included in the kit are, for example, buffers, detectable dyes, laboratory equipment, reaction vessels, instructions, etc. The instructions may be tailored to the particular method in which the kit is used. Appropriately labeled TDP-43 binding molecules of the present invention are also provided, which may be included in such kits.

[0276] In certain embodiments, the TDP-43 binding molecule is used in an immunodiagnostic method for the diagnosis of a TDP-43 proteinopathy. In certain embodiments, the TDP-43 binding molecule is used as a diagnostic tool in combination with a therapeutic TDP-43 molecule.

[0277] In certain embodiments, the TDP-43-binding molecule or immunoconjugate (wherein said TDP-43-binding molecule is covalently linked to another suitable therapeutic agent) or composition comprising the TDP-43-binding molecule is administered to a subject in need thereof or to a therapeutic agent for the treatment of amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), Alzheimer's disease (AD), Down's syndrome (DS), Parkinson's disease (PD) and related disorders, including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), limbic-predominant late-life TDP-43 encephalopathy (LATE) ), myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), progressive muscular atrophy, and diseases resulting from mutations or variant-associated risk alleles in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B genes, or TDP-43 proteinopathies.

[0278] In certain embodiments, the TDP-43 binding molecule or immunoconjugate (wherein said TDP-43 binding molecule is covalently linked to another suitable therapeutic agent) or composition comprising the TDP-43 binding molecule is administered to a subject in need thereof or to a subject with a disease such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), behavioral variant frontotemporal dementia (bvFTD), conscious dementia, or dementia with ... Primary progressive aphasia with taste variant (svPPA), non-fluent / agrammatic primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down's syndrome (DS), familial British dementia, Parkinson's disease (PD) and related disorders (including Parkinson's disease type dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), facial onset sensorimotor neuropathy (FOSMN), limbic dominant senile dementia (LDD), and other conditions. Late-stage TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (e.g., Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis dementia, myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin In one embodiment, the present invention relates to a method for diagnosing or monitoring a disease, disorder, and / or abnormality associated with TDP-43, particularly a disease, disorder, and / or abnormality associated with TDP-43 aggregates, or a TDP-43 proteinopathy, selected from the group consisting of diseases of both sporadic and hereditary origin, including genetic cases resulting from mutations or variant-associated risk alleles in the TDP-43 (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxin 3 (ATXN3) genes.

[0279] In other embodiments, the present invention relates to a method for treating amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), behavioral variant of frontotemporal dementia (bvFTD), semantic subtype of primary progressive aphasia (svPPA), non-fluent / agrammatic primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down's syndrome (DS), Familial British Dementia, Parkinson's Disease (PD) and related disorders (including Parkinson's Disease Dementia (PDD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA)), Corticobasal Degeneration (CBD), Niemann-Pick Disease (NP, including NP type C), Facial Onset Sensorimotor Neuropathy (FOSMN), Limbic Predominant Elderly TDP-43 Encephalopathy (LATE), Chronic Traumatic Encephalopathy, Perry Syndrome, Paget's Disease, Polyglutamine The present invention relates to any method for detecting, diagnosing, or monitoring a disease, disorder, and / or abnormality associated with TDP-43, particularly TDP-43 aggregates, or a TDP-43 proteinopathy, which are diseases of both sporadic and inherited origin, including genetic cases resulting from mutations or variant-associated risk alleles in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxin 3 (ATXN3) genes.

[0280] Preferably, the disease, disorder, and / or abnormality associated with TDP-43, in particular associated with TDP-43 aggregates, or TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), Alzheimer's disease (AD), Down's syndrome (DS), Parkinson's disease (PD) and related diseases, including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA). ), limbic predominant senile TDP-43 encephalopathy (LATE), myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), as well as genetic cases resulting from mutations or variant-associated risk alleles in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), and TMEM106B genes. More preferably, the disease, disorder and / or abnormality associated with TDP-43, in particular associated with TDP-43 aggregates, or TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant senile TDP-43 encephalopathy (LATE), Alzheimer's disease (AD), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD).

[0281] The present invention also relates to a method for monitoring a disease, disorder, and / or condition associated with TDP-43 at two or more time points using a sample from a subject, comprising contacting the sample with a binding molecule of the invention, in particular an antibody or antigen-binding fragment thereof, and comparing the levels of TDP-43 in the samples; a. a change in the level of TDP-43 in a subsequent sample compared to one or more earlier samples indicates an alteration in a disease, disorder, and / or condition associated with TDP-43; or b. The method provides a method in which no significant change in the level of TDP-43 in a subsequent sample compared to one or more earlier samples indicates a lack of alteration of a disease, disorder, and / or condition associated with TDP-43.

[0282] The present invention relates to a method for monitoring a disease, disorder, and / or condition associated with TDP-43 at two or more time points using a sample from a subject, comprising contacting the sample with a binding molecule of the invention, in particular an antibody or antigen-binding fragment thereof, and comparing the levels of phosphorylated TDP-43 in the samples; a. a change in the level of phosphorylated TDP-43 in a subsequent sample compared to one or more earlier samples indicates an alteration in a TDP-43-associated disease, disorder, and / or condition; or b. The method provides a method in which no significant change in the level of phosphorylated TDP-43 in a subsequent sample compared to one or more earlier samples indicates a lack of alteration of a disease, disorder, and / or condition associated with TDP-43.

[0283] The present invention also relates to a method for monitoring a disease, disorder, and / or condition associated with TDP-43 at two or more time points using a sample from a subject, comprising contacting the sample with a binding molecule of the invention, in particular an antibody or antigen-binding fragment thereof, and comparing the levels of TDP-43 in the samples; a. a higher level of TDP-43 in a later sample compared to one or more earlier samples indicates progression of a TDP-43 associated disease, disorder, and / or condition; b. a lower level of TDP-43 in a later sample compared to one or more earlier samples indicates regression of a TDP-43-associated disease, disorder, and / or condition; or c. The method provides a method in which no significant change in the level of TDP-43 in a subsequent sample compared to one or more earlier samples indicates a lack of progression of a disease, disorder, and / or condition associated with TDP-43.

[0284] Alternatively, the present invention also relates to a method for monitoring a disease, disorder, and / or condition associated with TDP-43 at two or more time points using a sample from a subject, comprising contacting the sample with a binding molecule of the present invention, in particular an antibody or antigen-binding fragment thereof, and comparing the levels of TDP-43 in the samples; a. a higher level of TDP-43 in a later sample compared to one or more earlier samples indicates regression of a TDP-43-associated disease, disorder, and / or condition; b. a lower level of TDP-43 in a later sample compared to one or more earlier samples indicates progression of a disease, disorder, and / or condition associated with TDP-43; or c. The method provides a method in which no significant change in the level of TDP-43 in a subsequent sample compared to one or more earlier samples indicates a lack of progression of a disease, disorder, and / or condition associated with TDP-43.

[0285] The present invention also relates to a method for monitoring a disease, disorder, and / or condition associated with TDP-43 at two or more time points using a sample from a subject, comprising contacting the sample with a binding molecule of the invention, in particular an antibody or antigen-binding fragment thereof, and comparing the levels of phosphorylated TDP-43 in the samples; a. a higher level of phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates progression of a TDP-43 associated disease, disorder, and / or condition; b. a lower level of phosphorylated TDP-43 in the subsequent sample compared to one or more earlier samples indicates regression of a TDP-43-associated disease, disorder, and / or condition; or c. The method provides a method in which no significant change in the level of phosphorylated TDP-43 in a subsequent sample compared to one or more earlier samples indicates a lack of progression of a disease, disorder, and / or condition associated with TDP-43.

[0286] Alternatively, the present invention also relates to a method for monitoring a disease, disorder, and / or condition associated with TDP-43 at two or more time points using a sample from a subject, comprising contacting the sample with a binding molecule of the present invention, in particular an antibody or antigen-binding fragment thereof, and comparing the levels of phosphorylated TDP-43 in the samples; a. a higher level of phosphorylated TDP-43 in the later sample compared to one or more earlier samples indicates regression of a TDP-43-associated disease, disorder, and / or condition; b. a lower level of phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates progression of a TDP-43-associated disease, disorder, and / or condition; or c. The method provides a method in which no significant change in the level of phosphorylated TDP-43 in a subsequent sample compared to one or more earlier samples indicates a lack of progression of a disease, disorder, and / or condition associated with TDP-43.

[0287] Such methods are typically performed on subjects known to have a disease, disorder, and / or condition associated with TDP-43, and may be performed at multiple time points on matched samples between treatment and placebo groups to monitor the effectiveness of candidate therapies over time.The diagnostic compositions of the present invention may be used in such methods.The paired immunoassays described herein incorporating suitable capture and detection antibodies or antigen-binding fragments thereof may be used in the monitoring methods of the present invention.

[0288] In one embodiment, the TDP-43 binding molecule is used in a method for quantifying phosphorylated TDP-43 in a sample, comprising contacting the sample with the TDP-43 binding molecule of the present invention and comparing the TDP-43 level detected in the sample with a control (which may be determined using a calibrator with a known amount of phosphorylated TDP-43).In one embodiment of the present invention, the method for quantifying is based on the pairing assay described herein.

[0289] In one embodiment, the method for quantification comprises: a. incubating the sample with a capture antibody and a detection antibody described herein; b. incubating the mixture obtained in step a with a reagent suitable for detection by the detection antibody; c. measuring the signal emitted by the detection antibody; d. Comparing the level of TDP-43 detected in the sample to a control (which may be determined using a calibrator with a known amount of phosphorylated TDP-43). Includes.

[0290] A calibrator can be a peptide, protein, or compound used as a standard or reference material of known concentration to allow quantification of analyte levels in a patient. In one embodiment of the present invention, the calibrator is a peptide that comprises, consists of, or consists essentially of an epitope of a capture antibody and an epitope of a detection antibody. In a preferred embodiment, the calibrator is selected from the group consisting of full-length TDP-43 (SEQ ID NO: 1), peptide 28 (SEQ ID NO: 7 linked to SEQ ID NO: 8 via a trioxatridecan-succinamic acid linker), and peptide 29 (SEQ ID NO: 7 linked to SEQ ID NO: 9 via a trioxatridecan-succinamic acid linker).

[0291] In one embodiment of the present invention, the calibrant is a peptide that comprises, consists of, or consists essentially of an epitope of a capture antibody and an epitope of a detection antibody. In a preferred embodiment, the calibrant is selected from the group consisting of full-length TDP-43 (SEQ ID NO: 1), peptide 11 (SEQ ID NO: 4 linked to SEQ ID NO: 5 via a trioxatridecane-succinamic acid linker), and peptide 23 (SEQ ID NO: 6 linked to SEQ ID NO: 5 via a trioxatridecane-succinamic acid linker).

[0292] In certain embodiments, the TDP-43 binding molecule is capable of detecting and / or detecting a variety of diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), non-fluent / agrammatic variant primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down's syndrome (DS), familial British dementia, Parkinson's disease (PD) and related diseases (PDD, Leishman's disease, Parkinson ... and in methods for detecting dementia with Bea bodies (DLB), multiple system atrophy (MSA), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including type C of NP), facial onset sensorimotor neuropathy (FOSMN), limbic-predominant late-life TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (e.g., Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis dementia, myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), and progressive muscular atrophy.

[0293] In certain embodiments, the TDP-43 binding molecule is used in a method to detect a disease caused by a mutation or variant-associated risk allele in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxin 3 (ATXN3) gene by contacting a sample (e.g., blood, cerebrospinal fluid, interstitial fluid (ISF), or brain tissue) with a TDP-43 binding molecule of the invention. In certain embodiments, the TDP-43-binding molecule is used in a method for detecting amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant senile TDP-43 encephalopathy (LATE), Alzheimer's disease (AD), or frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) by contacting a TDP-43-binding molecule of the invention with a sample (e.g., blood, cerebrospinal fluid, interstitial fluid (ISF), or brain tissue).

[0294] In certain embodiments, the TDP-43 binding molecule is capable of detecting and treating amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), non-fluent / agrammatic variant primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down's syndrome (DS), familial British dementia, Parkinson's disease (PD) and related disorders (PDD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA) and related disorders) by contacting a TDP-43 molecule of the invention with a sample (e.g., blood, cerebrospinal fluid, interstitial fluid (ISF), or brain tissue). inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles), primary lateral sclerosis (PLS), and progressive muscular atrophy. In certain embodiments, the TDP-43 binding molecule is used in a method to detect a disease caused by a mutation or variant-associated risk allele in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxin 3 (ATXN3) gene by contacting a sample (e.g., blood, cerebrospinal fluid, interstitial fluid (ISF), or brain tissue) with a TDP-43 binding molecule of the invention.

[0295] In certain embodiments, the TDP-43-binding molecule or immunoconjugate (wherein said TDP-43-binding molecule is covalently linked to another suitable therapeutic agent) or composition comprising the TDP-43-binding molecule is administered to a subject in need thereof or to treat a disease, disorder, and / or abnormality associated with TDP-43, in particular associated with TDP-43 aggregates, or a TDP-43 proteinopathy, or a disease, disorder, and / or abnormality associated with TDP-43, in particular associated with TDP-43 aggregates, or a disease, disorder, and / or abnormality associated with TDP-43 proteinopathy, in particular a disease, disorder, and / or abnormality associated with TDP-43 aggregates, in particular a disease, disorder, and / or abnormality associated with TDP-43 proteinopathy ... Dementia of the cerebral cortex, Parkinson's disease (PD) and related disorders (including Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), facial onset sensorimotor neuropathy (FOSMN), limbic-predominant senile TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, and Papillon syndrome. It is used to prevent, reduce, or treat: Streptococcus epidermidis, polyglutamine diseases (e.g., Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis dementia, myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), progressive muscular atrophy. In certain embodiments, the TDP-43 binding molecule or an immunoconjugate (wherein said TDP-43 binding molecule is covalently linked to another suitable therapeutic agent) or a composition comprising the TDP-43 binding molecule is administered to a subject in need thereof or used to prevent, ameliorate, or treat a disease caused by a mutation or variant-associated risk allele in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), or ataxin 3 (ATXN3) gene.

[0296] In certain embodiments, the TDP-43 binding molecule or immunoconjugate (wherein said TDP-43 binding molecule is covalently linked to another suitable therapeutic agent) or composition comprising the TDP-43 binding molecule is administered to a subject in need thereof or to a therapeutic agent for the treatment of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic grain disease), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), non-fluent / agrammatic variant primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down's syndrome (DS), familial British dementia, Parkinson's disease (PD) and related disorders (PD-type and / or pulmonary circulation disorders (PMS), including primary degeneration (PDD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including type C of NP), facial onset sensorimotor neuropathy (FOSMN), limbic-predominant senile TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (e.g., Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis dementia, myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, and oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), and progressive muscular atrophy. In one embodiment, the TDP-43 binding molecule or immunoconjugate (wherein said TDP-43 binding molecule is covalently linked to another suitable therapeutic agent) or composition comprising the TDP-43 binding molecule is administered to a subject in need thereof or used to treat a disease caused by a mutation or variant-associated risk allele in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxin 3 (ATXN3) gene. Preferably, said disease treatment helps preserve or increase mental awareness and / or reduces the level of TDP-43 aggregates in the brain.

[0297] In certain embodiments, the TDP-43-binding molecule or immunoconjugate (wherein said TDP-43-binding molecule is covalently linked to another suitable therapeutic agent) or composition comprising the TDP-43-binding molecule is administered to a subject in need thereof or used to manufacture a medicament for treating a disease, disorder, and / or abnormality associated with TDP-43, in particular associated with TDP-43 aggregates, as defined by the present invention, or a TDP-43 proteinopathy, or amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant senile TDP-43 encephalopathy (LATE), Alzheimer's disease (AD), frontotemporal lobar degeneration with motor neuron disease FTLD-MND.

[0298] Pharmaceutical formulations of the anti-TDP-43 antibodies (preferred types of TDP-43 binding molecules) or immunoconjugates described herein can be prepared by combining such antibodies or immunoconjugates (having the desired purity) with, optionally, one or more pharma- ceutical acceptable carriers and / or excipients and / or diluents (see Remington's Pharmaceutical Sciences 16). thedition, Osol, A. Ed. (1980)). Typically, the antibody or fragment thereof is prepared as a lyophilized formulation or as an aqueous solution. Pharmaceutically acceptable carriers are generally non-toxic to recipients at the dosages and concentrations employed, and include, but are not limited to, buffers (e.g., phosphate, citric acid, and other organic acids); antioxidants (including ascorbic acid and methionine); preservatives (e.g., octadecyldimethylbenzyl ammonium chloride); chloride); hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl alcohol or benzyl alcohol; alkyl parabens (e.g., methylparaben or propylparaben); catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol; low molecular weight (about 10 residues or less) polypeptides; proteins (e.g., serum albumin, gelatin, or immunoglobulins); hydrophilic polymers (e.g., polyvinylpyrrolidone); amino acids (e.g., glycine, glutamine, asparagine, histidine, arginine, or lysine); monosaccharides, disaccharides, and other sugars (including glucose, mannose, or dextrin); chelating agents (e.g., EDTA); sugars (e.g., sucrose, mannitol, trehalose, or sorbitol); salt-forming counterions (e.g., sodium); metal complexes (e.g., Zn protein complexes); and / or non-ionic surfactants (e.g., polyethylene glycol (PEG)). Exemplary pharma- ceutically acceptable carriers described herein further include interstitial drug dispersants, such as soluble neutral active hyaluronidase glycoproteins (sHASEGPs), such as human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in U.S. Patent Publication Nos. 2005 / 0260186 and 2006 / 0104968.In one embodiment, the sHASEGP is combined with one or more additional glycosaminoglycanases (e.g., chondroitinases). Pharmaceutically acceptable excipients that can be used to formulate the composition include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances (e.g., sodium carboxymethylcellulose), polyethylene glycol, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol, and lanolin. The diluent can be a buffer solution. These may include salts selected from the group consisting of phosphate, acetate, citrate, succinate and tartrate, and / or the buffer comprises histidine, glycine, TRIS glycine, Tris, or mixtures thereof. It is further envisaged in the context of the present invention that the diluent is a buffer selected from the group consisting of potassium phosphate, acetic acid / sodium acetate, citric acid / sodium citrate, succinic acid / sodium succinate, tartaric acid / sodium tartrate, and histidine / histidine HCl, or mixtures thereof.

[0299] Exemplary lyophilized antibody or immunoconjugate formulations are described in U.S. Patent No. 6,267,958. Aqueous antibody or immunoconjugate formulations include those described in U.S. Patent No. 6,171,586 and WO2006 / 044908, the latter formulations including a histidine acetate buffer.

[0300] The formulations described herein may also contain more than one active ingredient as necessary for the particular indication to be treated, preferably those with complementary activities that do not produce deleterious effects on each other.

[0301] The active ingredient may be encapsulated in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions, for example in microcapsules prepared by coacervation techniques or interfacial polymerization, e.g., hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively. Such techniques are described in Remington's Pharmaceutical Sciences 16 th edition, Osol, A. Ed. (1980).

[0302] Sustained release preparations may also be prepared.Suitable examples of sustained release preparations include semi-permeable matrices of solid hydrophobic polymers containing the antibody or immunoconjugate, which matrices are in the form of shaped articles, such as films or microcapsules.The preparations used for in vivo administration are generally sterile.Sterilization can be easily achieved, for example, by filtration through a sterile filtration membrane.

[0303] Any of the antigen-binding molecules, anti-TDP-43 antibodies, or immunoconjugates provided herein may be used in a method, such as a diagnostic method or a therapeutic method. The TDP-43-binding molecules of the present invention may be used in a therapeutic method, or may be used to prepare a medicament for use in a therapeutic method, or may be used to treat a disease defined by the present invention.

[0304] In another embodiment, an anti-TDP-43 antibody (preferred type of TDP-43 binding molecule) or immunoconjugate is provided for use as a medicament.In a further embodiment, an anti-phosphorylated TDP-43 antibody (preferred type of TDP-43 binding molecule) or immunoconjugate is provided for use in a method of treatment.In one embodiment, an anti-TDP-43 antibody (preferred type of TDP-43 binding molecule) or immunoconjugate is provided for use in the prevention, diagnosis, and / or treatment of TDP-43 proteinopathy. In a preferred embodiment of the invention, an anti-TDP-43 antibody (a preferred type of TDP-43 binding molecule) or immunoconjugate is provided for use in the prevention, diagnosis, and / or treatment of TDP-43-related, in particular TDP-43 aggregate-related, diseases, disorders and / or disorders, or TDP-43 proteinopathies, including, but not limited to, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-predominant late-life TDP-43 encephalopathy (LATE), Alzheimer's disease (AD), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD).

[0305] In a further aspect, the present invention provides the use of an anti-TDP-43 antibody (a preferred type of TDP-43 binding molecule) or immunoconjugate in the manufacture or preparation of a medicament. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent (e.g., those described below).

[0306] A "subject" or "individual" according to any of the embodiments may be an animal, a mammal, preferably a human.

[0307] In a further aspect, the present invention provides a pharmaceutical formulation comprising any of the anti-TDP-43 antibodies (preferred types of TDP-43 binding molecules) or immunoconjugates provided herein, for example, for use in any of the methods of treatment. In one embodiment, the pharmaceutical formulation comprises any of the anti-TDP-43 antibodies (preferred types of TDP-43 binding molecules) or immunoconjugates provided herein and a pharma- ceutically acceptable carrier and / or excipient and / or diluent (as described elsewhere herein). In another embodiment, the pharmaceutical formulation comprises any of the anti-TDP-43 antibodies (preferred types of TDP-43 binding molecules) or immunoconjugates provided herein and at least one additional therapeutic agent (e.g., as described below).

[0308] The antibody or immunoconjugate of the present invention can be used alone or in combination with other agents in therapy. For example, the antibody (preferred type of TDP-43 binding molecule) or immunoconjugate of the present invention can be co-administered with at least one additional therapeutic agent that targets alpha-synuclein, BACE1, tau, beta-amyloid, TDP-43 or neuroinflammatory proteins.

[0309] Such combination therapy as described above includes combined administration (two or more therapeutic agents in the same or separate formulations) and separate administration, in which case the administration of the antibody (preferred type of TDP-43-binding molecule) or immunoconjugate of the present invention can be performed before, simultaneously with, and / or after the administration of the further therapeutic agent and / or adjuvant. The antibody (preferred type of TDP-43-binding molecule of the present invention) or immunoconjugate of the present invention can also be used in combination with radiation therapy.

[0310] The antibody (preferred type of TDP-43 binding molecule) or immunoconjugate (and additional therapeutic agent) of the present invention can be administered by any suitable method, including parenteral, intrapulmonary, and intranasal, and optionally topical, intralesional, intrauterine, or intravesical administration. Parenteral inhalation includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Dosing can be by any suitable route, for example, injection, such as intravenous or subcutaneous injection, depending in part on whether the dosing is short-term or chronic. Various dosing schedules are contemplated herein, including, but not limited to, single or multiple administrations at various times, bolus administration, and pulse infusion.

[0311] The antibody (preferred type of TDP-43 binding molecule) or immunoconjugate of the present invention may be formulated, dosed and administered in a manner consistent with appropriate medical practice. Factors to consider in this context include the particular disease, disorder and / or disorder associated with TDP-43, particularly TDP-43 aggregates, or TDP-43 proteinopathy being treated, the particular mammalian animal being treated, the clinical condition of each subject, the etiology of the disease, disorder and / or disorder associated with TDP-43, particularly TDP-43 aggregates, or TDP-43 proteinopathy, the site of delivery of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners. The antibody or immunoconjugate does not require, but may be formulated accordingly with, one or more agents currently used to prevent or treat the disease, disorder and / or disorder associated with TDP-43, particularly TDP-43 aggregates, or TDP-43 proteinopathy in question. The effective amount of such other agents will depend on the amount of antibody or immunoconjugate present in the formulation, the disease, disorder and / or condition associated with TDP-43, particularly TDP-43 aggregates, or TDP-43 proteinopathy, or the type of treatment, and other factors described above. These will generally be used in the same dosages and by any route of administration as described herein, or about 1-99% of the dosages described herein, or any dosage and by any route as empirically / clinically determined to be appropriate.

[0312] In the prevention or treatment of a disease, the appropriate dose of the antibody (preferred type of TDP-43 binding molecule) or immunoconjugate of the present invention (when used alone or in combination with one or more other additional therapeutic agents) depends on the type of disease to be treated, the type of antibody or immunoconjugate, the severity and course of the disease, whether the antibody or immunoconjugate is administered for prophylactic or therapeutic purposes, previous treatment history, the subject's medical history and responsiveness to the antibody or immunoconjugate, and the judgment of the therapist. The antibody (preferred type of TDP-43 binding molecule) or immunoconjugate is suitably administered to the subject at one time or over a series of treatment periods. Depending on the type and seve...

Claims

1. A TDP-43 binding molecule that specifically binds to phosphorylated TDP-43 and is an antibody or an antigen-binding fragment thereof, wherein the binding molecule a) VH-CDR1 containing the amino acid sequence of SEQ ID NO: 11, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 12, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 13, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 15, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 16, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 17; or b) VH-CDR1 containing the amino acid sequence of SEQ ID NO: 21, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 22, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 23, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 25, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 27; or c) VH-CDR1 containing the amino acid sequence of SEQ ID NO: 31, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 32, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 33, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 35, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 16, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 37; or d) VH-CDR1 containing the amino acid sequence of SEQ ID NO: 41, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 42, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 33, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 45, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 46, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 47; or e) VH-CDR1 containing the amino acid sequence of SEQ ID NO: 51, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 52, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 53, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 55, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 57; or f) VH-CDR1 containing the amino acid sequence of SEQ ID NO: 61, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 62, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 63, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 55, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 57; or g) VH-CDR1 containing the amino acid sequence of SEQ ID NO: 51, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 52, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 53, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 75, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 76, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 77; or h) VH-CDR1 containing the amino acid sequence of SEQ ID NO: 111, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 112, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 113, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 115, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 116, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 117 A TDP-43 binding molecule containing this molecule.

2. The TDP-43 binding molecule according to claim 1, wherein one of the binding molecules (a), (c), (f), or (g) binds to a TDP-43 positive inclusion body, and optionally, the binding to the TDP-43 positive inclusion body is determined by immunohistochemistry.

3. a. An epitope comprising the phosphorylated amino acid residues pS375, pS379, pS403, pS404, pS409 and / or pS410 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of non-human TDP-43; b. An epitope comprising the phosphorylated amino acid residues pS403 and / or pS404 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of non-human TDP-43, optionally wherein the TDP-43 binding molecule binds to the epitope at a KD of 13 nM or less, preferably 5 nM or less, preferably 2 nM or less, preferably the epitope comprises or consists of GFNGGFG(pS)(pS)MDSKS (SEQ ID NO: 8) corresponding to amino acid positions 396-409 of SEQ ID NO: 1, more preferably the KD is measured by surface plasmon resonance; c. An epitope comprising the phosphorylated amino acid residues pS409 and / or pS410 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of non-human TDP-43, optionally wherein the TDP-43 binding molecule binds to the epitope at a KD of 3.5 nM or less, preferably 2.5 nM or less, preferably 1.7 nM or less, preferably the epitope comprises or consists of FGSSMDSK(pS)(pS)GWG (SEQ ID NO: 9) corresponding to amino acid positions 401-413 of SEQ ID NO: 1, more preferably the KD is measured by surface plasmon resonance; or d. An epitope comprising the phosphorylated amino acid residues pS375 and / or pS379 of human TDP-43 (SEQ ID NO: 1), or an equivalent epitope of non-human TDP-43, optionally wherein the TDP-43 binding molecule binds to the epitope with a KD of 21.5 nM or less, preferably comprising or consisting of GNNSY(pS)GSN(pS)GAAIG (SEQ ID NO: 5) corresponding to amino acid positions 370-384 of SEQ ID NO: 1, more preferably the KD is measured by surface plasmon resonance. A TDP-43 binding molecule according to claim 1, which binds to [the specified molecule].

4. a. A heavy chain variable region (VH) containing 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) containing the sequence of SEQ ID NO: 14 or a light chain variable region (VL) having at least 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 14; or b. A heavy chain variable region (VH) containing the sequence of SEQ ID NO: 20 or a heavy chain variable region (VH) having at least 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 20, and a light chain variable region (VL) containing the sequence of SEQ ID NO: 24 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: 24; or c. A heavy chain variable region (VH) containing the sequence of SEQ ID NO: 30 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: 30, and a light chain variable region (VL) containing the sequence of SEQ ID NO: 34 or a light chain variable region (VL) having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 34; or d. A heavy chain variable region (VH) containing the sequence of SEQ ID NO: 40 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity with respect to the amino acid sequence of SEQ ID NO: 40, and a light chain variable region (VL) containing the sequence of SEQ ID NO: 44 or a light chain variable region (VL) having at least 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the amino acid sequence of SEQ ID NO: 44; or e. A heavy chain variable region (VH) containing the sequence of SEQ ID NO: 50, or a heavy chain variable region (VH) having at least 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the amino acid sequence of SEQ ID NO: 50, and a light chain variable region (VL) containing the sequence of SEQ ID NO: 54; or f. A heavy chain variable region (VH) containing 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) containing the sequence of SEQ ID NO: 64; or g. A heavy chain variable region (VH) containing the sequence of SEQ ID NO: 50, or a heavy chain variable region (VH) having at least 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the amino acid sequence of SEQ ID NO: 50, and a light chain variable region (VL) containing the sequence of SEQ ID NO: 74; or h. A heavy chain variable region (VH) containing the sequence of SEQ ID NO: 110 or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with respect to the amino acid sequence of SEQ ID NO: 110, and a light chain variable region (VL) containing the sequence of SEQ ID NO:

114. A TDP-43 binding molecule according to claim 1, comprising:

5. The TDP-43 binding molecule according to claim 1, which is an IgA, IgD, IgE, IgM, IgG1, IgG2, IgG2a, IgG2b, IgG3, or IgG4 antibody or its antigen-binding fragment.

6. The TDP-43 binding molecule according to claim 1, which is a humanized antibody or its antigen-binding fragment.

7. The binding molecule is an immunoconjugate, and optionally the immunoconjugate is a. Including paramagnetic beads; b. Contains biotin; or c. Including further therapeutic molecules, The TDP-43 binding molecule according to claim 1.

8. A pharmaceutical composition comprising a TDP-43 conjugated molecule according to any one of claims 1 to 7 for use in the treatment and / or diagnosis of a human or animal, wherein the TDP-43 conjugated molecule is optionally a therapeutic or diagnostic tool.

9. A TDP-43 conjugated molecule according to any one of claims 1 to 7, particularly for research use as an analytical tool or reference molecule.

10. A pharmaceutical composition comprising a TDP-43 conjugated molecule according to any one of claims 1 to 7, for use in the prevention, alleviation, treatment and / or diagnosis of diseases, disorders and / or abnormalities related to TDP-43.

11. A pharmaceutical composition comprising a TDP-43 binding molecule according to any one of claims 1 to 7, for use in the prevention, mitigation, treatment and / or diagnosis of TDP-43 proteinosis.

12. The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is used as a diagnostic tool for diagnosing or monitoring TDP-43 proteinosis.

13. The aforementioned TDP-43 proteinosis, a. Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic granulosis), frontotemporal dementia with motor neuron disease FTLD-MND (also known as ALS-FTD), behavioral disorder frontotemporal dementia (bvFTD), semantic subtype primary progressive aphasia (svPPA), non-fluent / agrammatic primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down syndrome (DS), familial dementia, Parkinson's disease (PD) and related disorders ( This includes dementia peritoneal (PD) type (PDD), Lewy body dementia (DLB), multiple system atrophy (MSA), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), facial sensorimotor neuropathy (FOSMN), limbic-dominant senile TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (e.g., Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3), Machado-Joseph disease, and Diseases, disorders and / or abnormalities associated with TDP-43 aggregates selected from the group consisting of (even if publicly known), hippocampal sclerosis dementia, myofibrillary myopathy (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal myofascial dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), progressive muscular atrophy, preferably amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD, including argyrophilic granule disease), frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) Alzheimer's disease (AD), Down syndrome (DS), Parkinson's disease (PD) and related disorders (including PD dementia (PDD), Lewy body dementia (DLB), and multiple system atrophy (MSA)), limbic-dominant senile TDP-43 encephalopathy (LATE), myofibril myopathy (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy (with rimmed vacuoles)), primary lateral sclerosis (PLS), progressive muscular atrophy; or b. Diseases caused by mutations or mutant-associated risk alleles of the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), and ataxin 3 (ATXN3) genes, preferably diseases caused by mutations or mutant-associated risk alleles of the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenin (ANG), desmin (DES), myotilin (MYOT), and TMEM106B genes. The pharmaceutical composition according to claim 11, which is any of the following.

14. Diseases, disorders, and / or abnormalities related to TDP-43, or TDP-43 proteinosis, a. Amyotrophic lateral sclerosis (ALS); b. Alzheimer's disease (AD); c. Frontotemporal lobe dementia (FTD); d. Limbic-dominant senile TDP-43 encephalopathy (LATE); or e. Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) The pharmaceutical composition according to claim 13.

15. A pharmaceutical composition comprising a TDP-43 binding molecule according to any one of claims 1 to 7, and a pharmaceutically acceptable carrier and / or excipient.

16. A diagnostic composition comprising a TDP-43 binding molecule according to any one of claims 1 to 7, and an acceptable carrier and / or excipient.

17. A nucleic acid molecule that encodes a TDP-43 binding molecule according to any one of claims 1 to 7, or comprises a nucleotide sequence according to SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 79, SEQ ID NO: 118, or SEQ ID NO:

119.

18. A recombinant vector or expression vector comprising the nucleic acid described in claim 17.

19. A host cell comprising a nucleic acid encoding the TDP-43 binding molecule described in Claim 1 and / or a vector comprising a nucleic acid encoding the TDP-43 binding molecule described in Claim 1, or a host cell expressing the TDP-43 binding molecule described in Claim 1.

20. A cell-free expression system comprising an expression vector containing a nucleic acid encoding the TDP-43 binding molecule described in Claim 1.

21. A method for producing a TDP-43 binding molecule which is an antibody or an antigen-binding fragment thereof, a. A step of culturing the host cells described in claim 19 or the cell-free expression system described in claim 20 under conditions suitable for generating the antibody or its antigen-binding fragment; and b. The step of isolating the antibody or its antigen-binding fragment. Methods that include...

22. A TDP-43 binding molecule according to any one of claims 1 to 7, for use in the detection and / or quantification of phosphorylated TDP-43 in a sample, wherein the sample is saliva, urine, nasal secretions, blood (including whole blood, plasma and serum, platelet-enriched plasma, platelet cytosol fraction), brain and / or CSF sample, brain and / or ISF sample, more specifically, blood, brain, CSF and / or ISF sample.

23. a. A step of incubating the sample with the capture antibody and the detection antibody; b. A step of incubating the mixture obtained in step a with a reagent suitable for detection by the detection antibody; c. A step of measuring the signal released by the detection antibody. Use of a TDP-43 conjugating molecule according to any one of claims 1 to 7 in a pair formation assay, wherein optionally the detection antibody is selected from the antibodies defined in any one of claims 1 to 7, and further optionally the reagent is streptavidin-β-D-galactosidase.

24. The aforementioned capture antibody i. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 81, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 82, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 83, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 85, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 16, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 87; or ii. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 91, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 92, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 93, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 95, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 96, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 97; or iii. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 101, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 102, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 103, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 105, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 107 The use according to claim 23, including the use described in claim 23.

25. The detected antibody is i. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 81, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 82, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 83, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 85, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 16, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 87; or ii. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 91, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 92, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 93, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 95, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 96, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 97; or iii. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 101, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 102, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 103, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 105, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 107; or iv. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 21, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 22, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 23, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 25, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 27; or v. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 61, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 62, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 63, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 55, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 57 The use according to claim 23, including the use described in claim 23.

26. The detected antibody is a. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 21, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 22, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 23, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 25, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 27 Includes, The aforementioned capture antibody b. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 91, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 92, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 93, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 95, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 96, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 97 including; or The detected antibody is a. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 21, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 22, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 23, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 25, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 27 Includes, The aforementioned capture antibody b. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 101, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 102, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 103, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 105, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 107 including; or The detected antibody is a. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 61, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 62, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 63, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 55, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 57 Includes, The aforementioned capture antibody b. VH-CDR1 containing the amino acid sequence of SEQ ID NO: 101, VH-CDR2 containing the amino acid sequence of SEQ ID NO: 102, VH-CDR3 containing the amino acid sequence of SEQ ID NO: 103, VL-CDR1 containing the amino acid sequence of SEQ ID NO: 105, VL-CDR2 containing the amino acid sequence of SEQ ID NO: 26, and VL-CDR3 containing the amino acid sequence of SEQ ID NO: 107 The use according to claim 23, including the use described in claim 23.

27. A method for quantifying phosphorylated TDP-43 in a sample, comprising contacting the sample with the TDP-43 binding molecule described in claim 1.

28. The method according to claim 27, wherein the sample is human blood, cerebrospinal fluid (CSF), interstitial fluid (ISF), saliva, nasal secretions and / or urine, preferably blood, CSF or ISF, and optionally the method comprises comparing the TDP-43 level detected from the sample with a control, optionally the control comprising phosphorylated TDP-43, and further optionally the control being determined using a known amount of calibration substance in phosphorylated TDP-43.

29. A method for monitoring TDP-43-related diseases, disorders and / or conditions at two or more time points using a sample from a subject, comprising contacting the sample with a TDP-43-binding molecule as described in claim 1, a. A change in the level of phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates a change in disease, disorder, and / or condition related to TDP-43; or b. No significant change in the level of phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates the absence of a change in disease, disorder, and / or condition related to TDP-43; or c. Higher levels of phosphorylated TDP-43 in later samples compared to one or more earlier samples indicate progression of a disease, disorder, and / or condition associated with TDP-43; or d. Lower levels of phosphorylated TDP-43 in later samples compared to one or more earlier samples indicate regression of TDP-43-related diseases, disorders and / or conditions; or e. No significant change in the level of phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates the absence of progression of TDP-43-related disease, disorder, and / or condition; or f. Higher levels of phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicate regression of TDP-43-related diseases, disorders, and / or conditions; or g. Lower levels of phosphorylated TDP-43 in later samples compared to one or more earlier samples indicate progression of TDP-43-related diseases, disorders, and / or conditions. method.

30. The method according to claim 29, wherein the effectiveness of the candidate therapy over a period of time is monitored by performing the procedure on corresponding samples at multiple time points between the treatment group and the placebo group.

31. A kit for diagnosing diseases, disorders and / or abnormalities related to TDP-43, or TDP-43 proteinosis, comprising a TDP-43 binding molecule according to any one of claims 1 to 7.

32. A kit for use in the method of any one of claims 27 to 30, comprising the TDP-43 conjugating molecule described in claim 1, optionally comprising the TDP-43 conjugating molecule described in claim 1 as a capture antibody and a different TDP-43 conjugating molecule described in claim 1 as a detection antibody, optionally further comprising magnetic particles to which the capture antibody is bound or capable of being bound, optionally the detection antibody is directly or indirectly labeled, optionally further comprising a container containing the TDP-43 conjugating molecule.

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