Anti-TDP-43 binding molecules

Abstract

Provided are TDP-43 binding molecules that specifically bind to phosphorylated TDP-43, as well as nucleic acid molecules encoding the binding molecules. These binding molecules are useful in diagnostic and therapeutic applications, and can be included in suitable compositions and kits. They are useful in pairing assays involving the use of a capture antibody pair and a detection antibody pair. They are useful for monitoring diseases associated with TDP-43, including for testing candidate therapeutic agents.

Description

Technical Field

[0001] The present invention belongs to the field of transactivation response DNA binding protein (TDP-43 or TARDBP) with a molecular weight of 43kDa. 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 their uses. The present invention provides means and methods for diagnosing, preventing, alleviating and / or treating disorders and / or abnormalities associated with TDP-43 and its various isoforms, including but not limited to 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 syndrome (DS), Parkinson's disease (PD) and related disorders (including PD with Dementia (PDD), dementia with Lewy Bodies (DLB), multiple system atrophy (MSA)), limbic-predominant age-related TDP-43 encephalopathy (limbic-predominant age-related TDP-43encephalopathy, LATE), myofibrillar myopathy (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), primary lateral sclerosis (PLS), progressive muscular atrophy, and diseases with both sporadic and inherited origins (including genetic cases caused by mutations or variant-associated risk alleles of progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myoconstrictor protein (MYOT), TMEM106B genes). The present invention provides novel high-affinity antibodies and antibody derivatives with unique sequences, structures and stability, which are used as tools for diagnosing, preventing, monitoring, alleviating and / or treating TDP-43-related disorders and / or abnormalities. The present invention also provides novel epitope-specific TDP-43 binding molecules, which allow targeting and detection of previously inaccessible TDP-43 forms in vivo or in human biological samples, either alone or in combination. Background Art

[0002] TDP-43 and its role in central nervous system proteinopathies

[0003] Disorders 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 responsive DNA binding protein of 43 kDa (TARDBP or TDP-43). TDP-43 proteinopathies (caused by aggregated forms of TDP-43) include, but are not limited to, 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 (naPPA), Alzheimer's disease (AD), Down syndrome (DS), familial British dementia, Parkinson's disease (PD) and related disorders (including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), corticobasal degeneration (CBD), Niemann-Pick disease (Niemann-Pick disease), and schizophrenia. disease, NP, including type C NP), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget disease, polyglutamine diseases (e.g., Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease), hippocampal sclerosis with dementia, myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), primary lateral sclerosis (PLS), progressive muscular atrophy (Lagier-Tourenne et al.,Human Molecular Genetics,2010,Vol.19,Review Issue 1R46-R64;de Boer et al..Journal of Neurology,Neurosurgeryand Psychiatry 2020Vol.92,Issue 1,86–95;Nelson et al.,Journal of Neuropathology&Experimental Neurology 2020,Vol.75,Issue 6,June 2016,Pages482–498). These include diseases with both sporadic and inherited origins, including inherited cases caused by mutations or variant-associated risk alleles of the progranulin (GRN), TARDBP, valosin-containing protein (VCP), angiogenic protein (ANG), huntingtin (HTT), ataxia-inducing protein 3 (ATXN3), desmin (DES) or myotilin (MYOT) genes. .

[0004] In 2006, TDP-43 was identified as a protein that accumulates in the vast majority of cases of frontotemporal lobar degeneration (FTLD) with tau-negative, ubiquitin-positive inclusions (hereafter referred to as 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).

[0005] Aggregated TDP-43 from patient brains shows a number of abnormal modifications, including hyperphosphorylation, ubiquitination, acetylation, and C-terminal fragments cleaved by proteolysis (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 characteristic feature of TDP-43 pathological conditions is the redistribution and accumulation of TDP-43 from the nucleus to the cytoplasm. The hallmark lesions of FTLD-TDP are neuronal and glial cytoplasmic inclusions (NCIs and GCIs, respectively) and dystrophic neurites (DNs), which are immunoreactive for TDP-43, as well as ubiquitin and p62, but negative for other neurodegenerative disease-associated proteins. Differences in inclusion morphology and their tissue distribution are associated with specific mutations and / or clinical manifestations. To date, four types of TDP-43 pathology have been described by histological classification (Mackenzie and Neumann, J. Neurochem. (2016) 138 (Suppl 1), 54-70). FTLD-TDP type A cases are characterized by a large number of short dystrophic neurites (DNs) and compact oval or crescent-shaped NCIs, mainly in layer II of the neocortex (Mackenzie et al., 2016 J. Neurochem. 138 (Suppl 1), 54–70, Figure 2f). This pathological condition is usually clinically seen in the setting of behavioral variant frontotemporal dementia (bvFTD) or nonfluent / agrammatic variants of Primary Progressive Aphasia (nfvPPA) and is associated with mutations in progranulin (GRN). Type B cases show a moderate number of compact or granular NCIs in both superficial and deep cortical layers, with relatively few DNs and NIIs (neuronalintranuclear inclusions; Mackenzie et al., 2016 J. Neurochem. 138(Suppl. 1), 54–70, Figure 2 g). Most cases with concurrent FTD and ALS symptoms were found to have FTLD-TDP type B pathology. Type C cases have numerous long, tortuous neurites, primarily in the superficial cortical layers, with few or no NCIs (Mackenzie et al., 2016 J. Neurochem. 138(Suppl 1), 54–70, Figure 2 j). This pathology is particularly evident in cases of semantic variant primary progressive aphasia (svPPA). FTLD-TDP type D shows abundant lenticular neuronal intranuclear inclusions (NIIs) and short DNs in the neocortex, with only sparse NCIs (Mackenzie et al., 2016 J. Neurochem. 138(Suppl. 1), 54–70, Figure 2 k). This pathological pattern was only found in cases of VCP associated with inclusion body myositis (IBM).

[0006] Genetic forms of TDP-43 proteinopathy

[0007] Thirty-eight dominant negative mutations of TARDBP have been identified in patients with sporadic and familial ALS and patients with hereditary FTD, which are mainly located in sequences encoding glycine-rich domains (Lagier-Tourenne and Cleveland, Cell 136, 2009, 1001-1004, Figure 1). ALS-related TARDBP mutations make the protein more susceptible to aggregation (Ticozzi et al., CNS Neurol. Disord. Drug Targets. 2010, 9 (3), 285-296.), thereby linking TDP-43 aggregation to clinical disease manifestations.

[0008] TDP-43 in FTD

[0009] Frontotemporal dementia (FTD) is a clinical term that covers a wide range of diseases based on the degeneration of the frontal and temporal lobes, a pathological feature known as frontotemporal lobar degeneration (FTLD). FTD is the second most common cause of early degenerative dementia in the age group under 65 years old (Le Ber, Revue Neurologique 169 (2013) 811-819). FTD manifests itself in several syndromes, including bvFTD characterized by personality and behavioral changes; semantic dementia (SD) and progressive nonfluent aphasia (PNFA) characterized by changes in language function; corticobasal syndrome (CBS), progressive supranuclear palsy syndrome and motor neuron disease (FTD-MND) characterized by motor dysfunction. The clinical diagnosis of these syndromes is complex and the final conclusion can only be drawn by performing postmortem histopathological analysis to detect aggregated proteins and determine the affected brain areas. Regarding pathological protein inclusions, approximately 45% of cases showed pathological accumulation of misfolded Tau, 45% had pathological TDP-43 and a smaller subset had aggregates of fused in sarcoma (FUS) and other proteins.

[0010] TDP-43 in ALS

[0011] Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the premature loss of upper and lower motor neurons. The progression of ALS is characterized by fatal paralysis and respiratory failure, and its course is 1 to 5 years from diagnosis to death. In most sporadic ALS cases, the neuropathological condition is characterized by abnormal cytoplasmic accumulation of TDP-43 in neurons and glial cells of the primary motor cortex, brainstem motor nuclei, spinal cord and related white matter tracts. ALS with dementia involves the accumulation of TDP-43 in the extramotor neocortex and hippocampus. The role of TDP-43 phosphorylation in ALS patients has been explored with the help of antibodies that specifically bind to phosphorylated TDP-43 in nuclear and cytoplasmic inclusions, among which amino acids S379, S403, S404, S409, and S410 are 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).

[0012] TDP-43 in AD

[0013] TDP-43 pathology occurs in the brains of up to 57% of patients with Alzheimer's disease (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 the patient's age and is associated with cognitive decline, memory loss, and medial temporal atrophy in AD. It is shown that in AD, TDP-43 represents a second or independent pathology that shares overlapping brain distribution with amyloid-β and Tau pathology in the medial temporal lobe. AD-associated pathological TDP-43 follows a general progressive deposition pattern that has been described by the so-called TDP-43 in AD (TAD) staging scheme: TDP-43 is first deposited in the amygdala (stage I), then in the hippocampus, limbus, temporal and finally in the frontostriatum (stage V) (Josephs KA et al., Acta Neuropathol. 2014; 127(6):811-824; Josephs KA et al., Acta Neuropathol. 2014; 127(3):441–450).

[0014] Pathological spread of aggregated TDP-43

[0015] Although the onset and initial symptoms of ALS and FTD vary significantly between patients, a common feature of disease progression is the spread of pathology from the initial lesion area to most neurons. The continued deterioration of symptoms can be explained by the progressive spread of TDP-43 pathology. TDP-43 pathology in the brains of ALS patients has been shown to spread in a four-stage process and is thought to spread through synapses using anterograde axonal transport via axonal transmission from the cortex (Brettschneider et al., Ann Neurol. 2013 July; 74 (1): 20–38.). Recent experimental evidence suggests that the pathological protein spread of amyloid beta, tau, α-synuclein, and TDP-43 in neural tissue occurs through a shared prion-like mechanism (Hasegawa et al., 2017), but the starting point and topographical spread pattern are different (Brettschneider J et al., Nature Rev. Neuroscience, 2015, 109). One aspect of these shared propagation mechanisms is thought to be the cell-to-cell spread of pathological protein aggregates. This process consists of aggregate release from diseased cells, uptake by naive (less affected) cells, and subsequent seeding of pathological protein conformations through templated conformational changes of intracellular proteins. In the case of TDP-43, sequestration of functional TDP-43 protein may be extreme enough to cause cellular defects, including loss-of-function mechanisms.

[0016] TDP-43 intercellular spread has been studied at the molecular level in several in vitro models, where insoluble TDP-43 preparations from patient brains can induce intracellular aggregate formation in recipient cells (Nonaka et al., Cell Reports 4 (2013), 124–134; Feiler et al., 2015; Porta et al., Nat. Comm., 2018). In addition, it has been observed that intracellular TDP-43 aggregates can be released in conjunction with exosomes before spreading to subsequent cells (Nonaka et al., Cell Reports 4 (2013, 124–134)). Similarly, adenoviral transduction of TDP-43 expression leads to phosphorylated and ubiquitinated cytoplasmic aggregates that are more importantly able to act as seeds for initiating intercellular spread (Ishii et al., PLoS ONE 12 (6): e0179375, 2017). Patient-derived pathological TDP-43 can also lead to widespread deposition of endogenous TDP-43 after intracranial inoculation into transgenic and wild-type mice (Porta et al., Nat. Comm., 2018).

[0017] Differential diagnostic strategies for neurodegenerative diseases, including TDP-43 proteinopathies

[0018] Diagnosis of FTD based on clinical manifestations is inadequate because clinical manifestations can overlap with other diseases, especially in the early stages. Therefore, the development of biochemical biomarkers to distinguish different types of FTD pathological conditions is an important health-related goal. The development of antibodies against different conformations of TDP-43 will be an essential step in producing more sensitive and specific diagnostic tools. In parallel with biochemical biomarkers, the development of imaging biomarkers can enable early and specific detection of pathological conditions in TDP-43 protein diseases. The ability to image TDP-43 deposition in the brain can serve as a major achievement in the diagnosis and drug development of TDP-43 protein diseases. The use of cell-permeable antibody fragments can enable such detection.

[0019] The earliest event in neurodegenerative diseases is the acquisition of an alternative conformation that renders the protein toxic (aggregation). Furthermore, this aggregated conformation can self-propagate by recruiting endogenous normal proteins into the misfolded conformation, serving as the mechanistic basis for the observed spread through affected tissues.

[0020] Antibodies that allow differential targeting of specific isoforms or post-translational modifications of TDP-43 offer many advantages because they can distinguish between disease-associated and functional endogenous conformations of these proteins. These unique features offer the potential for improved diagnostic and therapeutic applications because such antibodies can distinguish between previously inaccessible TDP-43 and TDP-43-derived targets. Therefore, these features are critical for the development of sensitive and specific diagnostics and therapeutics. Such high affinity and selective targeting of TDP-43 subspecies are particularly important for TDP-43 proteinopathies because TDP-43 aggregation can lead to dominant negative effects on TDP-43 function, which can exacerbate the disease if combined with inadvertent targeting of functional TDP-43. Prevention and treatment of TDP-43 proteinopathies

[0021] TDP-43 aggregation and pathological spread are the main hallmarks of ALS and FTD, currently incurable and fatal diseases. Slowing or preventing these pathogenic processes using TDP-43 binding molecules has the potential to prevent or treat ALS, FTD and the other TDP-43 proteinopathies mentioned above.

[0022] Normal cellular function and distribution of TDP-43

[0023] Transactivation response (transactive response, TAR) DNA binding protein 43kDa (TDP-43) is a protein with 414 amino acids encoded by the TARDBP gene on chromosome 1p36.2 (also known as ALS10). Various TARDBPmRNAs contain differential splicing of six (or possibly seven) exons, which encode a heterogeneous collection of polypeptide isoforms with shared amino acid sequences (D'Alton et al., RNA, 2015). In this application, TDP-43 refers to the human reference sequence (Q13148) and its isoforms, including polypeptides produced by differential splicing, proteolytic fragments, and post-translationally modified polypeptides. TDP-43 belongs to the heterogeneous nuclear 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 1R46-R64). TDP-43 contains five functional domains (Warraich et al., The International Journal of Biochemistry & Cell Biology 42 (2010) 1606–1609, Figure 1): two RNA recognition motifs (RRM1 and RRM2), which have two highly conserved hexameric ribonucleoprotein 2 (RNP2) and octameric ribonucleoprotein 1 (RNP1) regions; nuclear export signal (NES) and nuclear localization signal (NLS), which enable it to shuttle between the nucleus and cytoplasm and transport bound mRNA; 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). TDP-43 is a highly conserved, ubiquitously expressed protein whose expression is strictly self-regulated, and it shuttles between the nucleus and the cytoplasm. TDP-43 is involved in multiple stages of RNA processing, including transcription, splicing, transport, and stabilization, all of which are essential for neuronal function. Therefore, maintaining TDP-43 function is essential for producing structurally correct neuronal gene products and avoiding the production of potentially harmful products, including aggregation-prone forms of TDP-43 itself.

[0024] The intracellular elimination of TDP-43 and its aggregation-prone forms is accomplished through several different degradation pathways, including the ubiquitin proteasome system (UPS), the autophagy-lysosomal pathway (ALP), and chaperone mediated autophagy (CMA), as shown in both in vitro cell culture and in vivo studies (Wang et al., 2010, Ormeno et al., 2020). The effectiveness of these intracellular mechanisms for eliminating TDP-43 is controlled by differences in the production and post-translational modifications of TDP-43 isoforms. Of particular note, the burden of aggregated TDP-43 already present in the cell has a significant negative effect on its elimination rate.

[0025] A possible role for TDP-43 in the pathology of neurodegenerative diseases has been reported, with accumulation of hyperphosphorylated TDP-43 protein inclusions shown in subtypes of frontotemporal degeneration (FTD) and in most cases of amyotrophic lateral sclerosis (ALS) (Arai et al., 2006; Neumann et al., 2006). In addition to FTD and ALS, additional biochemical and immunohistochemical analyses have also shown phosphorylated TDP-43 as a major component of cytoplasmic ubiquitin-immunoreactive lesions in the cerebral cortex and hippocampus of 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 patients with Huntington's disease (HD) (Davidson et al., 2009). This pathology has been observed in both glial cells and neurons, with TDP-43-positive inclusions often co-localizing (at least partially) with more characteristic inclusions found in these diseases, such as Tau, α-synuclein, β-amyloid, and expanded polyglutamine (Amador-Oriz et al., 2007, Nakashima-Yasuda et al., 2007, Higashi et al., 2007, Schwab et al., 2008, Uryu et al., 2008).

[0026] Prior art

[0027] Patent application WO2009 / 008529 discloses antibodies that specifically bind to abnormal aggregates of TDP-43 protein.

[0028] Patent application WO2011005628A1 discloses antibodies that bind to TDP-43 and a method for assessing the presence or absence of a neurodegenerative disease in a subject, comprising characterizing TDP-43 in a tissue sample of the subject, wherein the tissue is cerebrospinal fluid.

[0029] Patent application WO 2008 / 042190 discloses antibodies that bind to TDP-43 and a method of assessing the presence or absence of a neurodegenerative disease in a subject, comprising characterizing TDP-43 in a tissue sample from the subject.

[0030] Patent application WO2020 / 234473 discloses TDP-43-specific binding molecules, in particular anti-TDP-43 antibodies or antigen-binding fragments or derivatives thereof and their uses, as well as methods for diagnosing, preventing, alleviating and / or treating diseases, disorders and / or abnormalities associated with TDP-43 aggregates, wherein the diseases, disorders and / or abnormalities associated with TDP-43 aggregates include but are not limited to frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE) and limbic-dominant age-related TDP-43 encephalopathy (LATE). Summary of the invention

[0031] In view of the foregoing, 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 biological fluids. Such binding molecules can be used to detect, measure, or eliminate TDP-43 substances in neuronal cells in situ or TDP-43 substances stored or released into other tissues or biological fluids. In addition, they can be used as tools for evaluating or screening the activity of other TDP-43 binding molecules.

[0032] The development of sensitive and specific biofluid immunoassays using the TDP-43 binding molecules is an urgent task and will allow the differentiation of individuals or groups of individuals with pathological conditions in which TDP-43 proteinopathy plays a role in disease etiology or disease progression. Similar assays are also urgently needed for the evaluation of candidate therapeutic strategies that target TDP-43 or TDP-43-related pathways that can distinguish disease-related pathological processes from normal cellular functions. Given that TDP-43 proteinopathy is largely accompanied by a global loss of TDP-43 function, the ability to distinguish between health-promoting and pathological forms of TDP-43 is critical.

[0033] The present invention relates to TDP-43 binding molecules. The TDP-43 binding molecules described herein bind to an epitope within amino acid residues 361 to 414 of human TDP-43 (SEQ ID NO: 1) or bind to an equivalent epitope in 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 the phosphorylated amino acid residues pS403, pS404, pS409 and / or pS410 of human TDP-43 (SEQ ID NO: 1), or binds to an equivalent epitope in non-human TDP-43. In another embodiment, the TDP-43 binding molecule binds to an epitope comprising at least one or two of the phosphorylated amino acid residues pS375 and / or pS379 of human TDP-43 (SEQ ID NO: 1), or binds to an equivalent epitope in non-human TDP-43. As used herein, phosphorylated serine residues are described as pS, wherein the amino acid residues are numbered according to the human TDP-43 amino acid sequence 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 binds to an equivalent epitope in 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 binds to an equivalent epitope in non-human TDP-43. In 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 binds to an equivalent epitope in non-human TDP-43. Regardless of the combination of one, two, three or four of the above listed characteristics, the binding molecules of the invention, preferably antibodies or antigen-binding fragments thereof, can reduce the level of TDP-43 in TDP-43-specific inclusion bodies and / or phosphorylated TDP-43 in vivo.

[0034] The TDP-43 binding molecules of the present invention can be used in drug screening assays. Therefore, the present invention also provides the use of the TDP-43 binding molecules of the present invention in an assay or method for screening TDP-43 targeted drugs, such as in an assay or method for evaluating the efficacy of TDP-43 targeted drugs.

[0035] The invention is summarized in the following numbered embodiments:

[0036] 1. A TDP-43 binding molecule that specifically binds to phosphorylated TDP-43, wherein the binding molecule comprises:

[0037] 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

[0038] 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

[0039] 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

[0040] 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

[0041] 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

[0042] 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

[0043] 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.

[0044] 1'. A TDP-43 binding molecule that specifically binds to phosphorylated TDP-43, wherein the binding molecule comprises:

[0045] 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

[0046] 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

[0047] 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

[0048] 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

[0049] 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

[0050] 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

[0051] 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

[0052] 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, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 113, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 117.

[0053] 2. The TDP-43 binding molecule of embodiment 1, wherein the binding molecule according to any one of (a), (c), (f) or (g) binds to TDP-43 positive inclusion bodies.

[0054] 3. The TDP-43 binding molecule of embodiment 2, wherein binding to TDP-43 positive inclusion bodies is determined by immunohistochemistry.

[0055] 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 to an equivalent epitope in non-human TDP-43.

[0056] 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 binds to an equivalent epitope in non-human TDP-43.

[0057] 5. The TDP-43 binding molecule of 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 to an equivalent epitope in non-human TDP-43.

[0058] 6. The TDP-43 binding molecule of embodiment 5, which binds to an epitope with a KD of 13 nM or less, preferably 5 nM or less, preferably 2 nM or less, preferably wherein the epitope comprises or consists of GFNGGFG(pS)(pS)MDSKS (SEQ ID NO:8) corresponding to amino acids 396 to 409 of SEQ ID NO:1, more preferably wherein the KD is measured by surface plasmon resonance.

[0059] 7. The TDP-43 binding molecule of 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 binds to an equivalent epitope in non-human TDP-43.

[0060] 8. The TDP-43 binding molecule of embodiment 7, which binds to the epitope with a KD of 3.5 nM or less, preferably 2.5 nM or less, preferably 1.7 nM or less, preferably wherein the epitope comprises or consists of FGSSMDSK(pS)(pS)GWG (SEQ ID NO:9) corresponding to amino acids 401 to 413 of SEQ ID NO:1, more preferably wherein the KD is measured by surface plasmon resonance.

[0061] 8'. The TDP-43 binding molecule of 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 binds to an equivalent epitope in non-human TDP-43.

[0062] 8". The TDP-43 binding molecule of embodiment 8', wherein the TDP-43 binding molecule binds to the 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 acids 370 to 384 of SEQ ID NO:1, more preferably wherein the KD is measured by surface plasmon resonance.

[0063] 9. A TDP-43 binding molecule, preferably one that binds to phosphorylated TDP-43, the TDP-43 binding molecule comprising:

[0064] 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

[0065] 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

[0066] 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

[0067] 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

[0068] 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

[0069] 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

[0070] 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

[0071] h. 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.

[0072] 9'. A TDP-43 binding molecule, preferably one that binds to phosphorylated TDP-43, the TDP-43 binding molecule comprising:

[0073] 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

[0074] 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

[0075] 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

[0076] 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

[0077] 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

[0078] 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

[0079] 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

[0080] h. 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

[0081] i. 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, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 113, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 117.

[0082] 10. A TDP-43 binding molecule that binds to TDP-43-positive endosomes, wherein the binding molecule comprises:

[0083] 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

[0084] b. a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 31, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 32, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 33, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 37; or

[0085] c. 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

[0086] 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

[0087] e. 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.

[0088] 11. A TDP-43 binding molecule that binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43, wherein the TDP-43 binding molecule comprises 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.

[0089] 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 to an equivalent epitope in non-human TDP-43.

[0090] 13. The TDP-43 binding molecule of any one of embodiments 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.

[0091] 14. The TDP-43 binding molecule of any one of the preceding embodiments, comprising:

[0092] a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10, or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14, or 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

[0093] b. a heavy chain variable region (VH) comprising 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) comprising 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

[0094] c. a heavy chain variable region (VH) comprising 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) comprising 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

[0095] d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40, or a heavy chain variable region (VH) having 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 40; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44, or a light chain variable region (VL) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 44; or

[0096] 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

[0097] 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 with the amino acid sequence of SEQ ID NO: 60; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64; or

[0098] 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

[0099] h. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:80, or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:80; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:84, or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:84.

[0100] 14'. The TDP-43 binding molecule of any one of the preceding embodiments, comprising:

[0101] a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10, or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14, or 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

[0102] b. a heavy chain variable region (VH) comprising 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) comprising 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

[0103] c. a heavy chain variable region (VH) comprising 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) comprising 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

[0104] d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40, or a heavy chain variable region (VH) having 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 40; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44, or a light chain variable region (VL) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 44; or

[0105] 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

[0106] 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 with the amino acid sequence of SEQ ID NO: 60; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64; or

[0107] 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

[0108] h. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80, or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 80; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84, or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 84; or

[0109] 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.

[0110] 15. The TDP-43 binding molecule of any preceding embodiment, which is an antibody or an antigen-binding fragment thereof.

[0111] 16. The TDP-43 binding molecule of any of the preceding embodiments, which is an IgA, IgD, IgE, IgM, IgG1, IgG2, IgG2a, IgG2b, IgG3 or IgG4 antibody, or an antigen-binding fragment thereof.

[0112] 17. The TDP-43 binding molecule of any one of the preceding embodiments, wherein the binding molecule is an immunoconjugate.

[0113] 18. The TDP-43 binding molecule of embodiment 17, wherein the immunoconjugate comprises paramagnetic beads.

[0114] 19. The TDP-43 binding molecule of embodiment 17, wherein the immunoconjugate comprises biotin.

[0115] 20. The TDP-43 binding molecule of embodiment 17, wherein the immunoconjugate comprises an additional therapeutic molecule.

[0116] 21. A TDP-43 binding molecule according to any one of the preceding embodiments for use in human or veterinary therapy and / or diagnosis.

[0117] 22. The TDP-43 binding molecule for use according to embodiment 21, wherein the TDP-43 binding molecule is a therapeutic tool or a diagnostic tool.

[0118] 23. The TDP-43 binding molecule of any one of embodiments 1 to 20 for use in research applications, in particular as an analytical tool or reference molecule.

[0119] 24. The TDP-43 binding molecule of any one of embodiments 1 to 20, for use in preventing, alleviating, treating and / or diagnosing a disease, disorder and / or abnormality associated with TDP-43.

[0120] 25. The TDP-43 binding molecule according to any one of embodiments 1 to 20, for use in preventing, alleviating, treating and / or diagnosing TDP-43 proteinopathy.

[0121] 26. The TDP-43 binding molecule for use according to embodiment 25, wherein the TDP-43 binding molecule is used as a diagnostic tool for diagnosing or monitoring TDP-43 proteinopathy.

[0122] 27. The TDP-43 binding molecule for use according to any one of embodiments 25 or 26, wherein the TDP-43 proteinopathy is any one of the following:

[0123] a. A disease, disorder and / or abnormality associated with TDP-43 aggregation selected from 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 syndrome (DS), familial English dementia, Parkinson's disease (PD) and related disorders (including PD dementia (PDD), dementia with Lewy bodies (DLB) , multiple system atrophy (MSA), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia, myofibrillar myopathies (such as inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), primary lateral sclerosis (PLS), progressive muscular atrophy; or

[0124] b. Diseases caused by mutations or variant-associated risk alleles in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), and ataxia-associated protein 3 (ATXN3) genes.

[0125] 28. The TDP-43 binding molecule for use according to any one of embodiments 25 to 27, wherein the TDP-43 proteinopathy is any one of the following:

[0126] a. a disease, disorder and / or abnormality associated with TDP-43 aggregates selected from 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 syndrome (DS), Parkinson's disease (PD) and related disorders (including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), limbic dominant age-related 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

[0127] b. Diseases caused by mutations or variant-associated risk alleles of the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), or TMEM106B genes.

[0128] 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 the TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS).

[0129] 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 the TDP-43 proteinopathy is Alzheimer's disease (AD).

[0130] 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 the TDP-43 proteinopathy is frontotemporal dementia (FTD).

[0131] 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 the TDP-43 proteinopathy is limbic dominant age-related TDP-43 encephalopathy (LATE).

[0132] 33. The 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 the TDP-43 proteinopathy is frontotemporal lobar degeneration with motor neuron disease FTLD-MND.

[0133] 34. A pharmaceutical composition comprising the TDP-43 binding molecule of any one of embodiments 1 to 20 and a pharmaceutically acceptable carrier and / or excipient.

[0134] 34'. A diagnostic composition comprising the TDP-43 binding molecule of any one of embodiments 1 to 20 and an acceptable carrier and / or excipient.

[0135] 35. A nucleic acid molecule encoding the TDP-43 binding molecule of any one of embodiments 1 to 20.

[0136] 35'. The nucleic acid described in embodiment 35 comprises the nucleotide sequence shown below: 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, SEQID NO:88, SEQ ID NO:89, SEQ ID NO:118 or SEQ ID NO:119.

[0137] 36. A recombinant vector comprising the nucleic acid described in embodiment 35.

[0138] 37. A host cell comprising the nucleic acid of embodiment 35 and / or the vector of embodiment 36.

[0139] 38. A host cell expressing the TDP-43 binding molecule according to any one of embodiments 1 to 20.

[0140] 39. An expression vector comprising the nucleic acid molecule of embodiment 35.

[0141] 40. A cell-free expression system, comprising the expression vector of embodiment 39.

[0142] 41. A method for producing a TDP-43 binding molecule, in particular an antibody or an antigen-binding fragment thereof, the method comprising the steps of:

[0143] a. culturing the host cell of embodiment 37 or 38 or the cell-free expression system of embodiment 40 under conditions suitable for producing the binding molecule, in particular the antibody or antigen-binding fragment thereof; and

[0144] b. isolating the binding molecule, in particular the antibody or antigen-binding fragment thereof.

[0145] 41′. The TDP-43 binding molecule of any one of embodiments 1 to 20, for detecting and / or quantifying TDP-43 in a sample, wherein the sample is saliva, urine, nasal secretions, blood (including whole blood, plasma and serum, platelets rich plasma, platelets cytosol fraction), brain and / or CSF sample, brain and / or ISF sample, more particularly blood, brain, CSF and / or ISF sample.

[0146] 42'. The TDP-43 binding molecule of any one of embodiments 1 to 20, for detecting and / or quantifying phosphorylated TDP-43 in a sample, wherein the sample is saliva, urine, nasal secretions, blood (including whole blood, plasma and serum, platelet-rich plasma, platelet cytosol fraction), brain and / or CSF sample, brain and / or ISF sample, more particularly blood, brain, CSF and / or ISF sample.

[0147] 42. Use of the TDP-43 binding molecule of any one of embodiments 1 to 20 in a pairing assay, the pairing assay comprising the steps of:

[0148] a. Incubating the sample with the capture antibody and the detection antibody;

[0149] b. incubating the mixture obtained in step a with a reagent suitable for detection by the detection antibody;

[0150] c. measuring the signal emitted by the detection antibody;

[0151] Wherein the capture antibody is selected from the antibodies as defined in any one of embodiments 1 to 20.

[0152] 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.

[0153] 44. The use of a TDP-43 binding molecule according to embodiment 42 or 43, wherein the agent is streptavidin-β-D-galactosidase.

[0154] 45. Use of a TDP-43 binding molecule according to any one of embodiments 42 to 44, wherein the capture antibody and / or detection antibody binds to phosphorylated TDP-43, preferably specifically binds to phosphorylated TDP-43.

[0155] 46. ​​Use of a TDP-43 binding molecule according to any one of embodiments 42 to 44, wherein the capture antibody and / or detection antibody binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43.

[0156] 47. The use of a TDP-43 binding molecule according to any one of embodiments 42 to 46, wherein the capture antibody comprises:

[0157] 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

[0158] 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

[0159] 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.

[0160] 48. The use of a TDP-43 binding molecule according to embodiments 42 to 47, wherein the detection antibody comprises:

[0161] 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

[0162] 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

[0163] 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.

[0164] 48'. Use of the TDP-43 binding molecule of embodiments 42 to 47, wherein the detection antibody comprises:

[0165] 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

[0166] 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

[0167] 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

[0168] 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

[0169] v. 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.

[0170] 49. The use of a TDP-43 binding molecule according to embodiment 47 or 48, wherein the detection antibody comprises:

[0171] a. 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;

[0172] And the capture antibody comprises:

[0173] b. 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.

[0174] 49'. Use of the TDP-43 binding molecule of embodiment 47 or 48, wherein the detection antibody comprises:

[0175] a. 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;

[0176] And the capture antibody comprises:

[0177] b. 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.

[0178] 49". Use of the TDP-43 binding molecule of embodiment 47 or 48, wherein the detection antibody comprises:

[0179] a. 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;

[0180] And the capture antibody comprises:

[0181] b. 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.

[0182] 49"'. Use of the TDP-43 binding molecule of embodiment 47 or 48, wherein the detection antibody comprises:

[0183] a. 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;

[0184] And the capture antibody comprises:

[0185] b. 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.

[0186] 50. A method for quantifying phosphorylated TDP-43 in a sample, the method comprising contacting the sample with a TDP-43 binding molecule according to any one of embodiments 1 to 20.

[0187] 51. The quantitative method of embodiment 50, wherein the sample is obtained from a subject.

[0188] 51'. The method described in embodiment 51, wherein the sample is human blood, cerebrospinal fluid (CSF), interstitial fluid (ISF), saliva, nasal secretions and / or urine, preferably blood, CSF or ISF.

[0189] 52. The quantification method of embodiment 50 or 51, further comprising comparing the TDP-43 level detected from the sample with a control.

[0190] 53. The quantitative method of embodiment 52, wherein the control comprises phosphorylated TDP-43.

[0191] 54. The quantification method of embodiment 52 or 53, wherein the control is determined using a known amount of a calibrator for phosphorylated TDP-43.

[0192] 55. A method of quantifying phosphorylated TDP-43 in a sample obtained from a subject, the method comprising using the TDP-43 binding molecule of any one of embodiments 42 to 49.

[0193] 55'. A method of 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, wherein;

[0194] a. a higher level of TDP-43 and / or phosphorylated 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

[0195] b. a lower level of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates regression of a disease, disorder, and / or condition associated with TDP-43; or

[0196] c. The absence of a significant change in the level of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates that the disease, disorder and / or condition associated with TDP-43 has not progressed.

[0197] 55". A method of 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, wherein;

[0198] a. a higher level of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates regression of a disease, disorder, and / or condition associated with TDP-43; or

[0199] b. lower levels of TDP-43 and / or phosphorylated 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

[0200] c. The absence of a significant change in the level of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates that the disease, disorder and / or condition associated with TDP-43 has not progressed.

[0201] 55"'. The method of embodiment 55' or 55" is performed at multiple time points in matched samples between treatment and placebo groups to monitor the effectiveness of the candidate treatment over a defined period of time.

[0202] 56. A kit for diagnosing a disease, disorder and / or abnormality associated with TDP-43, or a TDP-43 proteinopathy, or for use in the method of any one of claims 50 to 55, comprising a TDP-43 binding molecule according to any one of embodiments 1 to 20.

[0203] 57. The kit of 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.

[0204] 58. The kit of embodiment 57, wherein the kit further comprises magnetic particles, and the capture antibody is connected to the magnetic particles or can be connected to the magnetic particles.

[0205] 59. The kit of embodiment 57 or 58, wherein the detection antibody is directly or indirectly labeled.

[0206] 60. The kit of any one of embodiments 57 to 59, further comprising a container comprising the TDP-43 binding molecule.

[0207] For the avoidance of doubt, where a numbered embodiment is referred to, this is intended to also encompass reference to the corresponding prime (') embodiment (eg reference to embodiment 1 encompasses 1 and 1').

[0208] In some embodiments, the present invention encompasses binding molecules, in particular antibodies and antigen-binding fragments thereof as described herein, which specifically bind to phosphorylated TDP-43, and the use of these binding molecules for diagnosing, preventing, alleviating and / or treating diseases, disorders and / or abnormalities associated with TDP-43 aggregates, or TDP-43 proteinopathies, including but not limited to 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), nonfluent / agrammatic primary progressive aphasia (naPPA), Alzheimer disease (AD), Down syndrome (DS), familial British dementia, Parkinson disease (PD) and related conditions (including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia, myofibrillar myopathy ( For example, inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), primary lateral sclerosis (PLS), progressive muscular atrophy, diseases caused by mutations or variant-associated risk alleles of the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), and ataxia-inducing protein 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 (particularly associated with TDP-43 aggregates), or TDP-43 proteinopathy is directed against 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 syndrome (DS), Parkinson's disease (PD) and related disorders (including PD dementia (PDD), Lewy body dementia (DLB), multiple system atrophy (MS A)), limbic dominant age-related 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, and diseases of both sporadic and inherited origin (including genetic cases caused by mutations or variant-associated risk alleles of progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B genes). More preferably, the use is for amyotrophic lateral sclerosis (ALS). More preferably, the use is for frontotemporal dementia (FTD). More preferably, the use is for limbic dominant age-related TDP-43 encephalopathy (LATE). More preferably, the use is for Alzheimer's disease (AD). More preferably, the use is for frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD).

[0209] In another embodiment, a TDP-43 binding molecule, in particular an anti-TDP-43 antibody or antigen-binding fragment thereof of the invention (specific for TDP-43 as described herein) is contacted with a sample to detect, diagnose and / or monitor diseases, disorders and / or abnormalities associated with TDP-43, in particular aggregated or aggregation-prone forms of TDP-43 (different from normal functional TDP-43) in suspected TDP-43 or other proteinopathies (in particular including TDP-43-related proteinopathies), including but not limited to amyotrophic lateral sclerosis, Alzheimer's disease (AD), Down syndrome (DS), familial English dementia, Parkinson's disease (PD) and related conditions (including PD dementia (PDD), dementia with Lewy bodies (DLB), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), nonfluent / agrammatic primary progressive aphasia (naPPA), ), multiple system atrophy (MSA), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia, myofibrillar myopathies (such as inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), primary lateral sclerosis (PLS), progressive muscular atrophy, or diseases caused by mutations or variant-associated risk alleles in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiopoietin (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), or ataxia-inducing protein 3 (ATXN3) genes; and how these differ from non-TDP-43 related clinical manifestations.

[0210] In one embodiment, the present invention encompasses binding molecules, in particular antibodies of the present invention as described herein or antigen-binding fragments thereof, which specifically bind to phosphorylated TDP-43, and the use of these binding molecules (in particular these antibodies) for detecting the presence of substances derived from specific phosphorylated TDP-43 in a sample. Thus, the TDP-43 binding molecules of the present invention, such as the anti-TDP43 antibodies described herein, can be particularly used to screen clinical samples, in particular human blood, cerebrospinal fluid (CSF), interstitial fluid (ISF), saliva, nasal secretions and / or urine for the presence of TDP-43 in the sample, for example by using an ELISA-based assay or a surface adapted assay. In some cases, tissue samples, such as brain tissue samples, can be used. The methods and compositions of the present invention also have applications in diagnosing presymptomatic diseases and / or monitoring disease progression and / or therapeutic efficacy. According to some 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 secretions, urine, or brain tissue) to detect 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 syndrome (DS), familial English dementia dementia, Parkinson's disease (PD) and related disorders (including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including type C NP), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia, myofibrillar myopathies (such as inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), primary lateral sclerosis (PLS), progressive muscular 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 secretions, urine or brain tissue) to detect, diagnose and / or monitor a disease caused by a mutation or variant-associated risk allele of a progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxin 3 (ATXN3) gene.

[0211] The TDP-43 binding molecules of the present invention can be used to detect and / or quantify TDP-43 in a suitable sample, preferably phosphorylated TDP-43. The sample can be a cell-free sample, such as blood, CSF, ISF, saliva, nasal secretions or urine. In a preferred embodiment, the cell-free sample can be blood, CSF or ISF. "Blood" includes whole blood and derived samples, such as serum and plasma. "Plasma" includes derived samples, such as platelets. "Platelets" include derived samples, such as platelet cytosol fractions. The sample can be a cell sample, such as a tissue, preferably brain tissue. Suitable TDP-43 substances are quantified or detected. In one embodiment, soluble TDP-43 or phosphorylated TDP-43 is quantified or detected in a cell-free sample (e.g., TDP-43 from human plasma is detected in Example 8). In one embodiment, soluble TDP-43 or phosphorylated TDP-43 is quantified or detected in a cell-free sample (e.g., TDP-43 from a platelet fraction derived from human plasma is detected in Example 9). In another embodiment, TDP-43 inclusions are quantified or detected in a cell sample (preferably brain tissue) (eg, phosphorylated TDP-43 inclusions are detected in Example 7).

[0212] 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 formats are known. Therefore, the method (e.g., ELISA, MSD (Meso Scale Discovery), HTRF (Homogeneous Time Resolved Fluorescence), and AlphaLISA) can be implemented for diagnostic purposes. It is shown herein that the binding molecules of the invention have phosphorylation site specificity, high affinity, binding to human TDP-43 pathological conditions in brain tissue, and utility in high sensitivity immunoassays. Methods of quantifying phosphorylated TDP-43 in suitable samples using the binding molecules of the invention can also be used to select treatments (additional treatments for a subject). Thus, personalized treatment methods are contemplated. Samples can be obtained before or after treatment according to such methods.

[0213] In some embodiments, the TDP-43 binding molecules of the present invention are used in a paired assay, which comprises the following steps: incubating a sample with a capture antibody and a detection antibody, wherein the capture antibody comprises a TDP-43 binding molecule described herein conjugated to paramagnetic beads, and the detection antibody comprises a TDP-43 binding molecule described herein conjugated to biotin; incubating the obtained solution with a reagent suitable for detection by the detection antibody (e.g., streptavidin-β-D-galactosidase); measuring the signal emitted by the detection antibody. In some embodiments, the capture antibody or the detection antibody is a TDP-43 binding molecule that binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43. In some embodiments, the capture antibody or the 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.

[0214] In other embodiments, the present invention provides a method for preventing, alleviating and / or treating a disease, disorder and / or abnormality associated with TDP-43 (particularly associated with 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 as described herein, particularly an antibody of the present invention that is specific to TDP-43 (e.g., a full-length antibody or a TDP-43 binding fragment or derivative of the antibody). In another embodiment, the present invention provides a method for preventing, alleviating and / or treating a TDP-43 proteinopathy. According to some embodiments, a binding molecule, particularly an antibody or antigen-binding fragment thereof as described herein that is specific to phosphorylated TDP-43, is administered to treat, alleviate and / or prevent amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic dominant age-related TDP-43 encephalopathy (LATE), Alzheimer's disease (AD), frontotemporal lobar degeneration with motor neuron disease FTLD-MND. In another embodiment, the binding molecules, in particular the antibodies or antigen-binding fragments thereof described herein that are specific for phosphorylated TDP-43, are administered to prevent, alleviate and / or treat a neurodegenerative disease selected from the group consisting of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic-dominant age-related TDP-43 encephalopathy (LATE), Alzheimer's disease (AD), frontotemporal lobar degeneration with motor neuron disease FTLD-MND.

[0215] In another embodiment, the binding molecules, in particular the antibodies or antigen-binding fragments thereof described herein that are specific for TDP-43, are administered to prevent, alleviate and / or treat a disease 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), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), non-fluent / agrammatic primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down syndrome (DS), familial British dementia, Parkinson's disease (PD) and related disorders ( Including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including type C NP), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia, myofibrillar myopathy (such as inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), primary lateral sclerosis (PLS), and progressive muscular atrophy. In another embodiment, a binding molecule, in particular an antibody or antigen-binding fragment thereof described herein that is specific for TDP-43, is administered to prevent, alleviate and / or treat a disease caused by a mutation or variant-associated risk allele of the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxia protein 3 (ATXN3) genes. DETAILED DESCRIPTION

[0216] definition

[0217] Transactivation response (TAR) DNA binding protein 43kDa (referred to herein as TDP-43) is a protein with 414 amino acids encoded by the TARDBP gene on chromosome 1p36.2 (also known as ALS10). Various TARDBP mRNAs include differential splicing of six (or possibly seven) exons, which encode heterogeneous sets of polypeptide isoforms with shared amino acid sequences (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.14No.11, 2008, 479-485; Lagier-Tourenne et al., Human Molecular Genetics, 2010, Vol.19, Review Issue 1R46-R64). TDP-43 contains five functional domains (Warraich et al., The International Journal of Biochemistry & Cell Biology 42 (2010) 1606-1609, Figure 1): two RNA recognition motifs (RRM1 and RRM2), which have two highly conserved hexameric ribonucleoprotein 2 (RNP2) and octameric ribonucleoprotein 1 (RNP1) regions; nuclear export signal (NES) and nuclear localization signal (NLS), which enable it to shuttle between the nucleus and cytoplasm and transport bound mRNA; 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). TDP-43 is a highly conserved, ubiquitously expressed protein whose expression is strictly self-regulated, and it shuttles between the nucleus and the cytoplasm.

[0218] In this application, TDP-43 refers to the human reference sequence (Q13148) and its isoforms, including post-translationally modified polypeptides and proteolytic fragments that retain the epitope that binds to the binding molecule. Human TDP-43 has the following sequence:

[0219]

[0220] As used herein, "antigen binding molecules" are any molecules that can specifically or selectively bind to an antigen, particularly TDP-43. The binding molecule may include or may be an antibody or a fragment thereof. An anti-TDP-43 binding molecule is a molecule that binds to a TDP-43 protein at a specific recognition site (epitope), such as an anti-TDP-43 antibody or a fragment thereof. That is, the antigen binding molecules of the present invention bind to an epitope within the amino acid sequence of SEQ ID NO: 1. The antigen binding molecules (particularly antibodies or antigen binding fragments thereof) provided herein recognize full-length TDP-43. Other anti-TDP-43 binding molecules may also include multivalent molecules, multispecific molecules (e.g., diabodies), fusion molecules, aptamers, avidomers, 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 functions by binding to target molecules (see, e.g., 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, DARPin (WO 2002 / 020565), Affibody (WO 1995 / 001937), Affibody (WO 2004 / 044011; WO 2005 / 040229), Adnectin (WO 2002 / 032925) and fynomer (WO 2013 / 135588).

[0221] As used herein, the terms "anti-TDP-43 antibody" and "antibody that binds to TDP-43" or simply "antibody" refer to an antibody that is capable of binding to TDP-43 with sufficient affinity so that the antibody can be used as a diagnostic and / or therapeutic agent targeting TDP-43. Generally, the term "antibody" as used herein is used in the broadest sense and covers a variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies or biparatopic antibodies), fully human antibodies, and antibody fragments, as long as they exhibit the desired antigen binding activity. The antibody in the present invention can also be a chimeric antibody, a recombinant antibody, an antigen-binding fragment of a recombinant antibody, an antibody, or an antibody displayed on the surface of a phage or displayed on the surface of a chimeric antigen receptor (CAR) T cell.

[0222] An "antigen-binding fragment" or "functional fragment thereof" of an antibody refers to a molecule that contains a portion of an intact or full-length antibody and binds (completely or partially) to an antigen that binds to the intact or full-length antibody, which is different from the intact or full-length antibody. Some examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments. 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.

[0223] 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 that region in order to bind to the protein.

[0224] In certain embodiments, "antibodies that bind to epitopes within defined regions of proteins" are identified by mutation analysis, wherein the amino acids of a protein are mutated, and the binding of the antibody to the resulting altered protein (e.g., an altered protein comprising the epitope) is determined to be at least 20% of the binding to the unaltered protein. In some embodiments, "antibodies that bind to epitopes within defined regions of proteins" are identified by mutation analysis, wherein the amino acids of a protein are mutated, and the binding of the antibody to the resulting altered protein (e.g., an altered protein comprising the epitope) is determined to be 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 certain embodiments, the binding of the antibody is determined by FACS, WB, or by a suitable binding assay (e.g., ELISA).

[0225] The term "binding to..." as used in the context of the present invention defines the binding (interaction) of at least two "antigen interaction sites" to each other. According to the present invention, the term "antigen interaction site" defines a motif of a polypeptide, i.e. a part of an antibody or antigen binding fragment of the present invention, which shows the ability to specifically interact with a specific antigen or a specific group of antigens of TDP-43. The binding / interaction should also be understood as defining "specific recognition". According to the present invention, the term "specific recognition" means that the antibody is able to specifically interact and / or bind to at least two amino acids of TDP-43 as defined herein, in particular to interact / bind to at least two amino acids within amino acid residues 361 to 414 of human TDP-43 (SEQ ID NO: 1).

[0226] 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., phosphorylated, ubiquitinated, acetylated, para-ubiquitinated and / or methylated), aggregated TDP-43, and truncated TDP-43.

[0227] The terms "specific interaction", "specific binding" and "specifically binds" 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 having similar structures. 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 these one or more residues. Thus, in some embodiments of the present invention, the antibodies or antigen-binding fragments thereof of the present invention specifically bind to / interact with a TDP-43 structure formed by a specific phosphorylated amino acid sequence within the amino acid residues of human TDP-43 (SEQ ID NO: 1), more particularly bind to / interact with a TDP-43 structure 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), even more particularly bind to / interact with at least one or two phosphorylated serines selected from pS403, pS404, pS409 or pS410 of human TDP-43 (SEQ ID NO: 1). In such embodiments, the antibodies or antigen-binding fragments thereof of the present invention do not or do not substantially cross-react with non-phosphorylated S403, S404, S409 or S410 of human TDP-43 (SEQ ID NO: 1).

[0228] In some embodiments of the present invention, the antibodies or antigen-binding fragments thereof of the present invention specifically bind to / interact with a TDP-43 structure formed by a specific phosphorylated amino acid sequence within the amino acid residues of human TDP-43 (SEQ ID NO: 1), more particularly bind to / interact with a TDP-43 structure 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 particularly bind to / interact with at least one phosphorylated serine selected from pS375 or pS379 of human TDP-43 (SEQ ID NO: 1). In such embodiments, the antibodies or antigen-binding fragments thereof of the present invention do not or do not substantially cross-react with non-phosphorylated S375 or S379 of human TDP-43 (SEQ ID NO: 1).

[0229] In some 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., phosphorylated, ubiquitinated, acetylated, ubiquitinated and / or methylated), aggregated TDP-43, and truncated TDP-43. In some embodiments of the present invention, the antibody or antigen-binding fragment thereof of the present invention specifically binds to / interacts with a TDP-43 structure formed by a specific amino acid sequence within amino acid residues 361 to 375 of human TDP-43 (SEQ ID NO: 1).

[0230] Inclusion bodies refer to a variety of intracellular non-living substances that are not membrane-bound. Inclusion bodies may contain stored nutrients / deutoplasmic substances, secretory products, and pigment granules. "TDP-43 positive inclusion bodies" or "positively stained inclusion bodies" refer to pathogenic deposits of TDP-43 that carry disease-specific post-translational modifications (e.g., phosphorylation, ubiquitination, ubiquitination, and acetylation). TDP-43 pathogenic deposits may contain the full length and / or specific truncated forms of the protein.

[0231] The TDP-43 binding molecules described herein bind to TDP-43 positive inclusion bodies, particularly to TDP-43 positive inclusion bodies that contain, consist of or consist essentially of phosphorylated TDP-43. The TDP-43 positive inclusion bodies may be cytoplasmic inclusion bodies. For a detailed description of staining assays that can be used for TDP-43 positive inclusion bodies, reference may be made to Example 7.

[0232] The cross-reactivity of the set of antigen-binding molecules, in particular antibodies or antigen-binding fragments thereof, under investigation can be tested, for example, by evaluating the binding of said set of antibodies or antigen-binding fragments thereof to the (poly)peptide of interest and to a number of more or less closely related (poly)peptides (structurally and / or functionally) under conventional 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)). Only those constructs (i.e. antibodies, antigen-binding fragments thereof, etc.) that bind to certain TDP-43 structures as defined herein, e.g. a specific epitope or (poly)peptide / protein of TDP-43 as defined herein, but not or not substantially to any other epitope or (poly)peptide of the same TDP-43 are considered specific for the epitope or (poly)peptide / protein of interest and are selected for further investigation according to the methods provided herein. These methods may include, among other things, binding studies, blocking and competition studies with structurally and / or functionally closely related molecules. These binding studies may also include FACS analysis, surface plasmon resonance (SPR, e.g., using BIACORE TM ), analytical ultracentrifugation, isothermal titration calorimetry, fluorescence anisotropy, fluorescence spectroscopy, or by radiolabeled ligand binding assays.

[0233] Therefore, specificity can be determined experimentally by methods known in the art and as described herein. Such methods include, but are not limited to, Western blots, ELISA-, RIA-, ECL-, IRMA-tests and peptide scanning.

[0234] The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous antibody population, i.e., the individual antibodies constituting the population are identical except for possible naturally occurring mutations that may be present in small amounts. Monoclonal antibodies are highly specific and are directed against a single antigenic site. The advantage of monoclonal antibodies is that they can be synthesized by hybridoma cultures and are substantially free from contamination by other immunoglobulins. The term "monoclonal" indicates the characteristics of the antibody in a substantially homogeneous antibody population, and should not be interpreted as requiring the antibody to be produced by any particular method. As described above, the monoclonal antibodies used according to the present invention can be prepared by the hybridoma method described by Kohler, Nature 256 (1975), 495.

[0235] The term "polyclonal antibody" as used herein refers to an antibody produced among or in the presence of one or more other different antibodies. Generally, polyclonal antibodies are produced by B lymphocytes in the presence of several other B lymphocytes that produce different antibodies. Typically, polyclonal antibodies are obtained directly from immunized animals.

[0236] The term "fully human antibody" as used herein refers to an antibody comprising only human immunoglobulin protein sequences. If produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell, a fully human antibody may include a mouse sugar chain. Similarly, a "mouse antibody" or "rat antibody" refers to an antibody comprising only a mouse / rat immunoglobulin protein sequence. Alternatively, if produced in a rat, in a rat cell, or in a hybridoma derived from a rat cell, a "fully human antibody" may include a rat sugar chain. Similarly, the term "rat antibody" refers to an antibody comprising only a rat immunoglobulin sequence. Fully human antibodies can also be produced, for example, by phage display, which is a widely used screening technique that can produce and screen fully human antibodies. Phage antibodies can also be used in the context of the present invention. Phage display methods are described in, for example, US 5,403,484, US 5,969,108, and US 5,885,793. Additional techniques that can develop fully human antibodies involve modifications to mouse hybridoma technology. Mice are transgenic to contain human immunoglobulin loci in exchange for their own mouse genes (see, e.g., US 5,877,397).

[0237] The term "chimeric antibody" refers to an antibody comprising a variable region of the invention fused to or chimerized with an antibody region (e.g., constant region) from another human or non-human species (e.g., mouse, horse, rabbit, dog, cow, chicken).

[0238] The term antibody also relates to recombinant human antibodies, heterologous antibodies and heterogeneous hybrid antibodies. The term "recombinant (human) antibody" includes all human sequence antibodies prepared, expressed, produced or separated by recombinant means, for example, antibodies separated from animals (e.g., mice) that are transgenic for human immunoglobulin genes, antibodies expressed using recombinant expression vectors transfected into host cells, antibodies separated from recombinant, combined human antibody libraries, or antibodies prepared, expressed, produced or separated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable regions and constant regions (if present) derived from human germline immunoglobulin sequences. However, such antibodies may be subjected to in vitro mutagenesis (or, when using animals that are transgenic for human Ig sequences, in vivo somatic mutagenesis is performed), and therefore the amino acid sequences of the VH and VL regions of the recombinant antibodies are such sequences: although they are derived from and related to human germline VH and VL sequences, they may not naturally exist in human antibody germline libraries in vivo.

[0239] "Heterologous antibody" is defined relative to the transgenic non-human organism that produces such an antibody. The term refers to an antibody having an amino acid sequence or encoding nucleic acid sequence that corresponds to those present in an organism that does not consist of the transgenic non-human animal, and typically is from a species other than the transgenic non-human animal species.

[0240] The term "heterologous hybrid antibody" refers to an antibody having light chains and heavy chains from different organisms. For example, an antibody having a human heavy chain associated with a mouse light chain is a heterologous hybrid antibody. Some examples of heterologous hybrid antibodies include chimeric antibodies and humanized antibodies.

[0241] The "humanized" form of non-human (e.g., mouse or rabbit) antibodies is a chimeric immunoglobulin, immunoglobulin chain, or fragment thereof (e.g., Fv, Fab, Fab', F(ab')2, or other antigen-binding subsequences of antibodies) containing a minimal sequence derived from a non-human immunoglobulin. Typically, a humanized antibody is a human immunoglobulin (acceptor antibody), wherein the residues from the complementary determining region (complementary determining region, CDR) of the acceptor are replaced by residues from the CDR of a non-human species (e.g., mouse, rat, or rabbit) (donor antibody) with desired specificity, affinity, and ability. In some cases, the Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. In addition, a humanized antibody may include residues that are neither present in the acceptor antibody nor in the CDR or framework sequence of the importation. These modifications are performed to further improve and optimize antibody performance. In general, a humanized antibody will comprise substantially all of at least one and usually two variable domains, wherein 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 those of a human immunoglobulin consensus sequence. A humanized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc), typically a constant region of a human immunoglobulin. For additional 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.

[0242] A popular method for antibody humanization involves CDR grafting, in which a functional antigen binding site from a non-human 'donor' antibody is grafted onto a human 'acceptor' antibody. CDR grafting methods are known in the art and are described, for example, in US 5,225,539, US 5,693,761, and US 6,407,213. Another related method is to produce humanized antibodies from transgenic animals that are genetically engineered to contain one or more humanized immunoglobulin loci capable of gene rearrangement and gene conversion (see, e.g., US 7,129,084).

[0243] Therefore, in the context of the present invention, the term "antibody" relates to complete immunoglobulin molecules as well as parts of such immunoglobulin molecules (i.e., "antigen-binding fragments thereof"). In addition, as described above, the term relates to modified and / or altered antibody molecules. The term also relates to recombinantly or synthetically produced / synthesized antibodies. The term also relates to complete antibodies and antibody fragments thereof, such as isolated light and heavy chains, Fab, Fv, Fab', Fab'-SH, F(ab')2. The term antibody also includes, but is not limited to, fully human antibodies, chimeric antibodies, humanized antibodies, CDR-grafted antibodies, and antibody constructs, such as single chain Fv (scFv) or antibody fusion proteins.

[0244] In the context of the present invention, a "single-chain Fv" or "scFv" antibody fragment has a V H and V L domains, wherein these domains are present in a single polypeptide chain. Typically, scFv polypeptides are also present in V H and V L A polypeptide linker is included between the domains which enables the scFv to form the desired antigen binding structure. Techniques for producing single chain antibodies are described, for example, in Plückthun in The Pharmacology of Monoclonal Antibodies, Rosenburg and Moore eds. Springer-Verlag, NY (1994), 269-315.

[0245] As used herein, a "Fab fragment" comprises a light chain and a heavy chain C H 1 and variable region. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0246] The "Fc" region contains two C H 2 and C H The two heavy chain fragments are linked by two or more disulfide bonds and by C H The 3 domains are held together by hydrophobic interactions.

[0247] A "Fab' fragment" comprises a light chain and a portion of a heavy chain, wherein the portion of the heavy chain comprises V H Domain and C H 1 domain and also contained in C H 1 and C H The region between the two Fab' domains allows for the formation of an interchain disulfide bond between the two heavy chains of the two Fab' fragments to form the F(ab')2 molecule.

[0248] A "F(ab')2 fragment" comprises two light chains and two heavy chains, wherein the heavy chains are contained in C H 1 and C H The F(ab')2 fragment consists of two Fab' fragments held together by the disulfide bonds between the two heavy chains.

[0249] The "Fv region" comprises the variable regions from both the heavy and light chains, but lacks the constant regions.

[0250] The humanized antibodies, humanized antibody constructs, humanized antibody fragments, humanized antibody derivatives (all of Ig origin) used according to the present invention, or their corresponding immunoglobulin chains can be further modified using conventional techniques known in the art, for example, by using amino acid deletions, insertions, substitutions, additions and / or recombination and / or any other modifications known in the art, alone or in combination. Methods for introducing such modifications in DNA sequences based on the amino acid sequences of immunoglobulin chains 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, 2nd edition (1989) and 3rd edition (2001). The term "domain of Ig origin" particularly relates to a (poly)peptide construct comprising at least one CDR. The fragments or derivatives of the domains of the listed Ig origin define the following (poly)peptides, which are part of the above antibody molecules and / or modified by chemical / biochemical or molecular biological methods. Corresponding methods are known in the art and are described, inter alia, in laboratory manuals (see, Sambrook et al., Molecular Cloning: A Laboratory Manual; Cold Spring Harbor Laboratory Press, 2nd edition (1989) and 3rd edition (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)).

[0251] The term "CDR" used herein refers to a "complementarity determining region", which is well known in the art. CDR is a part of an immunoglobulin that determines the specificity of the molecule and contacts a specific ligand. CDR is the most variable part of the molecule and contributes to the diversity of these molecules. There are three CDR regions in each V domain: CDR1, CDR2, and CDR3. CDR-H shows the CDR region of the variable heavy chain, while CDR-L refers to the CDR region of the variable light chain. VH means variable heavy chain, and VL means variable light chain. The CDR region of the Ig source region can be determined as described in Kabat "Sequences of Proteins of Immunological Interest", 5th edition. NIH publication no.91-3242 U.S. Department of Health and Human Services (1991). The CDR sequences provided herein are defined according to Kabat. However, the skilled person will understand that the present invention is intended to cover such binding molecules, wherein the CDR sequences are defined according to any available identification / numbering scheme.For example, the following numbering schemes can be used to define CDRs: Chothia (Canonical structures for the hypervariable regions of immunoglobulins. Chothia C, Lesk AM. J Mol Biol. 1987 Aug 20; 196(4):901-17), IMGT (IMGT, the international ImMunoGeneTics database. Giudicelli V, Chaume D, Bodmer J, Müller W, Busin C, Marsh S, Bontrop R, Marc L, Malik A, Lefranc MP. Nucleic Acids Res. 1997 Jan 1; 25(1):206-11 and Unique database numbering system for immunogenetic analysis. Lefranc MP. Immunol Today. 1997 Nov; 18(11):509), MacCallum (MacCallum RM, Martin AC, Thornton JM, J Mol Biol. 1996 Oct 11; 262(5):732-45) and Martin (Abhinandan KR, Martin ACR. Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains. Mol Immunol. (2008) 45:3832–9.10.1016 / j.molimm.2008.05.022).

[0252] Therefore, in the context of the present invention, the antibody molecules described herein above are selected from whole antibodies (immunoglobulins, such as 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.

[0253] "Humanization methods" are well known in the art, and are particularly described for antibody molecules, such as molecules in Ig sources. The term "humanization" refers to a humanized form of a non-human (e.g., mouse) antibody or its fragment (e.g., Fv, Fab, Fab', F(ab'), scFv or other antigen-binding portion sequences of an antibody) comprising some parts of a sequence derived from a non-human antibody. Humanized antibodies include human immunoglobulins, wherein residues from the complementary determining regions (CDRs) of human immunoglobulins are replaced by residues from CDRs of non-human species (e.g., mice, rats or rabbits) with desired binding specificity, affinity and ability. In general, humanized antibodies will include at least one, and typically substantially all of two variable domains, wherein all or substantially all of the CDR regions correspond to those of non-human immunoglobulins, and all or substantially all of the FR regions are those of human immunoglobulin consensus sequences. Optimally, the humanized antibody will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin; see, in particular, 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. Typically, a humanized antibody has one or more amino acids introduced therein from a non-human source, while retaining the original binding activity of the antibody. Methods for humanizing antibodies / antibody molecules are also described in 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. Some specific examples of humanized antibodies, such as antibodies against EpCAM, are known in the art (see, for example, 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).

[0254] Thus, in the context of the present invention, antibody molecules or antigen-binding fragments thereof are provided which can be successfully used in pharmaceutical compositions.

[0255] The specificity of the antibody or antigen-binding fragment of the present invention can be represented not only by the properties of the amino acid sequence of the antibody or antigen-binding fragment as defined above, but also by the epitope to which the antibody can bind. Therefore, in one embodiment, the present invention relates to an anti-TDP-43 antibody or antigen-binding fragment thereof, in particular an anti-phosphorylated TDP-43 antibody or antigen-binding fragment thereof, which recognizes the same epitope as the antibody of the present invention.

[0256] It will be appreciated by those skilled in the art that the epitope may be contained in the TDP-43 protein, but may also be contained in its degradation products or may be a chemically synthesized peptide. The amino acid position is indicated only to show 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 comprising the epitope. The peptide may be part of a polypeptide having a length of greater than 100 amino acids, or may be a small peptide of less than 100, preferably less than 50, more preferably less than 25 amino acids, and even more preferably less than 16 amino acids. The amino acids of such a peptide may be natural amino acids or non-natural amino acids (e.g., β-amino acids, γ-amino acids, D-amino acids) or a combination thereof. In addition, the present invention may encompass the corresponding retro-inverso peptide of the epitope. The peptide may be unbound or bound. It can be conjugated to, for example, small molecules (e.g., drugs or fluorophores), high molecular weight polymers (e.g., polyethylene glycol (PEG), polyethylene imine (PEI), hydroxypropylmethacrylate (HPMA), etc.) or proteins, fatty acids, sugar moieties or can be inserted into the membrane.

[0257] In order to test whether the antibody in question and the antibody of the present invention recognize the same epitope, the following competition study can be performed: Vero cells infected with 3 MOI (multiplicity of infection) are incubated for 1 hour with different concentrations of the antibody in question as a competitor after 20 hours. In the second incubation step, the antibody of the present invention is applied at a constant concentration of 100 nM, and its binding is detected by flow cytometry using a fluorescently labeled antibody to the constant domain of the antibody of the present invention. Binding in inverse proportion (inversely proportional) to the concentration of the antibody in question indicates that the two antibodies recognize the same epitope. However, many other assays known in the art can be used.

[0258] The present invention also relates to the production of specific antibodies against natural and recombinant polypeptides of phosphorylated TDP-43. The production is based on, for example, immunization of animals such as mice. However, other animals for producing antibodies / antisera are also contemplated in the present invention. For example, monoclonal antibodies and polyclonal antibodies can be produced by rabbits, mice, goats, donkeys, etc. The polynucleotide encoding the corresponding selected polypeptide of TDP-43 can be subcloned into a suitable vector, wherein the recombinant polypeptide is expressed in an organism capable of expression, such as in bacteria. Therefore, 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 production of specific antibodies against natural and recombinant polypeptides by using a DNA vaccine strategy as exemplified in the attached examples. DNA vaccine strategies are well known in the art and encompass liposome-mediated delivery, which is carried out by gene gun or jet injection as well as intramuscular or intradermal injection. Therefore, antibodies against polypeptides or proteins or epitopes of phosphorylated TDP-43 (particularly epitopes of the antibodies provided herein) can be obtained by directly immunizing animals by intramuscularly injecting a vector expressing the desired polypeptide or protein or epitope of phosphorylated TDP-43, particularly an epitope of the antibody of the present invention located within amino acid residues 361 to 414 of human TDP-43 (SEQ ID NO: 1), more particularly an epitope that binds to or interacts with the TDP-43 structure formed by a specific amino acid sequence within the phosphorylated amino acid residues pS403, pS404, pS409, pS410 of human TDP-43 (SEQ ID NO: 1).

[0259] The amount of specific antibody obtained can be quantified using ELISA, which is also described below. Additional methods for generating antibodies are well known in the art, see, for example, Harlow and Lane, "Antibodies, A Laboratory Manual", CSH Press, Cold Spring Harbor, 1988.

[0260] Thus, under specified assay conditions, a specific antibody binds to the corresponding epitope of TDP-43, but not to other components present in the sample in significant amounts. Specific binding to a target analyte under such conditions may require a binding moiety that is selected for its specificity for a specific target analyte. A variety of immunoassay formats can be used to select antibodies that specifically react with a specific antigen. For example, solid phase ELISA immunoassays are routinely used to select monoclonal antibodies that specifically immunoreact with an analyte. For a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity, see Shepherd and Dean (2000), Monoclonal Antibodies: A Practical Approach, Oxford University Press and / or Howard and Bethell. Generally speaking, a specific or selective reaction will be at least twice the background signal-to-noise ratio, and more typically more than 10 to 100 times greater than the background. Those skilled in the art are able to provide and generate specific binding molecules for new polypeptides. For specific binding assays, it is easy to avoid unwanted cross-reactivity, for example, polyclonal antibodies can be easily purified and selected by known methods (see Shepherd and Dean, loc. Cit.).

[0261] The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0262] In certain embodiments, the amino acid sequence variants of the antibodies provided herein are contemplated. For example, it is desirable to improve the binding affinity and / or other biological properties of the antibodies. The amino acid sequence variants of the antibodies can be prepared by introducing suitable modifications into the nucleotide sequence encoding the antibodies, or by peptide synthesis. Such modifications include, for example, the disappearance of residues in the antibody amino acid sequence and / or the insertion and / or its replacement therein. Any combination of disappearance, insertion and replacement can be performed to obtain the final construct, provided that the final construct has the desired characteristics, such as antigen binding.

[0263] In certain embodiments, antibody variants with one or more amino acid replacements are provided. The target site of replacement mutagenesis includes CDR and FR. Conservative replacements are shown in Table 1 under the heading of "preferred replacements". More replacement changes are provided in Table 1 under the heading of "exemplary replacements", and are further described as follows with reference to amino acid side chain categories. Amino acid replacements can be introduced into the target antibody, and the product can be screened for desired activity, for example, retained / improved antigen binding, reduced immunogenicity or improved ADCC or CDC.

[0264] Table 1

[0265] Amino acids can be grouped according to common side chain properties:

[0266] (1) Hydrophobicity: norleucine, Met, Ala, Val, Leu, Ile;

[0267] (2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln;

[0268] (3) Acidic: Asp, Glu;

[0269] (4) Basic: His, Lys, Arg;

[0270] (5) Residues that affect chain orientation: Gly, Pro;

[0271] (6) Aromatic: Trp, Tyr, Phe.

[0272] Non-conservative substitutions will entail exchanging a member of one of these classes for another class.

[0273] One type of substitution variant involves replacing one or more hypervariable region residues of a parent antibody (e.g., a humanized or human antibody). Typically, the resulting variant selected for further study will have improvements (e.g., improvements) in certain biological properties relative to the parent antibody (e.g., increased affinity, reduced immunogenicity); and / or will substantially retain certain biological properties of the parent antibody. An exemplary substitution variant is an affinity matured antibody, which can be conveniently produced, for example, using affinity maturation techniques based on phage display (e.g., those described herein). In short, one or more CDR residues are mutated and the variant antibody is displayed on a phage and screened for a specific biological activity (e.g., binding affinity).

[0274] Changes (e.g., substitutions) may be made in the CDRs, for example to improve antibody affinity. Such changes may be made in CDR "hot spots", residues encoded by codons that mutate at high frequencies during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207: 179-196 (2008)), and / or SDRs (a-CDRs), and the resulting variants VH or VL are tested for binding affinity. Affinity maturation by constructing a secondary library and reselecting from the secondary library has been described, for example, in Hoogenboom et al., in Methods in Molecular Biology 178: 1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001).). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain mixing, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method for introducing diversity involves a CDR-directed approach in which several CDR residues (e.g., 4 to 6 residues at a time) are randomized. CDR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. In particular, CDR-H3 and CDR-L3 are typically targeted.

[0275] In certain embodiments, substitutions, insertions or deletions may occur in one or more CDRs, as long as such changes do not substantially reduce the ability of the antibody to bind to antigen. For example, conservative changes (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in the CDRs. Such changes may be outside of CDR "hot spots" or SDRs. In certain embodiments of the variant VH and VL sequences provided above, each CDR is unchanged or contains no more than one, two or three amino acid substitutions.

[0276] The available method for identifying residues or regions of antibodies that can be targeted for mutagenesis is called "alanine scanning mutagenesis", as described by Cunningham and Wells (1989) Science, 244: 1081-1085. In this method, residues or target residue groups (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. Additional replacements can be introduced at amino acid positions that show functional sensitivity to the initial replacement. As an alternative or supplement, the crystal structure of the antigen-antibody complex is used to identify the contact points between the antibody and the antigen. Such contact residues and adjacent residues can be targeted or eliminated as candidates for replacement. Variants can be screened to determine whether they contain the desired properties.

[0277] Amino acid sequence insertions include amino-terminal and / or carboxyl-terminal fusions of polypeptides ranging from one residue to one hundred or more residues in length, and intrasequence insertions of single or multiple amino acid residues. Some examples of terminal insertions include antibodies with an N-terminal methionyl residue. Other insertion variants of antibody molecules include fusions of the N- or C-terminus of an antibody with an enzyme (e.g., for ADEPT) or a polypeptide that increases the serum half-life of the antibody.

[0278] In certain embodiments, the antibodies provided herein are altered to increase or decrease the extent to which the antibodies are glycosylated. The addition or deletion of glycosylation sites for antibodies can be conveniently achieved by altering the amino acid sequence so that one or more glycosylation sites are generated or removed.

[0279] When the antibody comprises an Fc region, the carbohydrates connected thereto may be altered. Natural antibodies produced by mammalian cells generally comprise a branched biantennary oligosaccharide that is generally connected to the Asn297 of the CH2 domain of the Fc region via an N bond. See, for example, Wright et al., TIBTECH 15:26-32 (1997). Oligosaccharides may include a variety of carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, and fucose connected to GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, the oligosaccharides in the antibodies of the present invention may be modified to produce antibody variants with certain improved properties.

[0280] In one embodiment, antibody variants having a carbohydrate structure lacking fucose connected to the Fc region (directly or indirectly) are provided. For example, the amount of fucose in such an antibody can be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose in the sugar chain of Asn297, relative to the sum of all sugar structures (e.g., complex, hybrid and high mannose structures) connected to Asn 297, as measured by MALDI-TOF mass spectrometry, for example as described in WO 2008 / 077546. Asn297 refers to the 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)); however, due to minor sequence variations in antibodies, Asn297 may also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. Such fucosylation variants may have improved ADCC function. See, e.g., U.S. Patent Publication Nos. US2003 / 0157108 (Presta, L.); US2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Some examples of publications related to "defucosylated" or "fucose-deficient" antibody variants include:

[0281] US 2003 / 0157108; WO 2000 / 61739; WO2001 / 29246; US 2003 / 0115614; US 2002 / 0164328; US2004 / 0093621; US2004 / 0132140; US2004 / 0110704; US 2004 / 0110282; US 2004 / 0109865; WO 2003 / 085119; WO 2003 / 084570; WO 2005 / 035586; WO 2005 / 035778; W02005 / 053742; W02002 / 031140; Okazaki et al., J. Mol. Biol. 336: 1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614 (2004).

[0282] Some examples of cell lines capable of producing defucosylated antibodies include protein fucosylation-deficient Lec13 CHO cells (Ripka et al., Arch. Biochem. Biophys. 249: 533-545 (1986); U.S. Patent Application No US2003 / 0157108 Al, Presta, L; and WO 2004 / 056312 Al, Adams et al., particularly in Example 11), and knockout cell lines, such as α-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).

[0283] Also provided are antibody variants with bisected oligosaccharides, for example, wherein the biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and / or improved ADCC function. Some examples of such antibody variants are described in, for example, WO 2003 / 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 oligosaccharide attached to the Fc region. Such antibody variants may have improved CDC function. Such antibody variants are described in, for example, WO 1997 / 30087 (Patel et al.); WO 1998 / 58964 (Raju, S.); and WO 1999 / 22764 (Raju, S.).

[0284] In certain embodiments, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. An Fc region variant may be included in a human Fc region sequence (e.g., human IgG1, IgG2, IgG3 or IgG4 Fc region) containing an amino acid modification (e.g., replacement) at one or more amino acid positions.

[0285] In certain embodiments, the present invention contemplates the following antibody variants, which have some but not all effector functions, making them desirable candidates for applications where the in vivo half-life of the antibody is important and 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 determine the reduction / depletion of CDC and / or ADCC activity. For example, Fc receptor (Fc receptor, FcR) binding assays can be performed to ensure that the antibody lacks FcγR binding (and therefore may lack ADCC activity) but retains FcRn binding ability. The main cell NK cells that mediate ADCC express only FcγRIII, while monocytes and microglia express FcγRI, FcγRII and FcγRIII. FcR expression on hematopoietic cells is summarized in Ravetch and Kinet, Annu. Rev. Immunol. 9: Table 3 on page 464 of 457-492 (1991). Some non-limiting examples of in vitro assays for assessing ADCC activity of a molecule of interest are described in U.S. Pat. Nos. 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)).

[0286] Alternatively, non-radioactive assays can be used (see, e.g., ACTI for flow cytometry). TM Nonradioactive cytotoxicity assay (Cell Technology, Inc. Mountain View, CA); and CytoTox Non-radioactive cytotoxicity assay (Promega, Madison, WI). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.

[0287] Alternatively or additionally, ADCC activity of the molecule of interest can be assessed in vivo, for example in an animal model such as that disclosed in Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). C1q binding assays can also be performed to determine that the antibody is unable to bind to C1q and therefore lacks CDC activity. See, for example, C1q and C3c binding ELISAs in WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, a CDC assay may be performed (see, e.g., 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 determination may also be performed using methods known in the art (see, e.g., Petkova, SB et al., Int'l. Immunol. 18 (12): 1759-1769 (2006)).

[0288] Antibodies with reduced effector function include those in which one or more of residues 234, 235, 238, 265, 269, 270, 297, 327, and 329 of the Fc region are replaced (U.S. Pat. No. 6,737,056). Certain antibody variants with improved or reduced binding to FcRs are described. (See, e.g., U.S. Pat. No. 6,737,056; WO 2004 / 056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001)). Such Fc mutants include Fc mutants with substitutions at two or more of the amino acids at positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc mutants in which the residues at positions 265 and 297 are substituted with alanine (U.S. Pat. No. 7,332,581), or the so-called "DANG" FC mutants in which the residue at position 265 is substituted with alanine and the residue at position 297 is substituted with glycine. Alternatively, antibodies with reduced effector function include antibodies in which one or more of the residues at positions 234, 235, and 329 in the Fc region are substituted, i.e., the so-called "PG-LALA" Fc mutants in which the residues at positions 234 and 235 are substituted with alanine and the residue at position 329 is substituted with glycine (Lo, M. et al., Journal of Biochemistry, 292, 3900-3908). Other known mutations at positions 234, 235 and 321, i.e. the so-called TM mutant comprising the mutations L234F / L235E / P331S in the CH2 domain, can be used (Oganesyan et al. Acta Cryst. D64, 700–704. (2008)). Antibodies from the human IgG4 isotype comprise the mutations S228P / L235E to stabilize the hinge and reduce FgR binding (Schlothauer et al, PEDS, 29(10): 457–466).

[0289] Other Fc variants include Fc variants with substitutions at one or more of the following Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, ​​413, 424, or 434; for example, an Fc variant with a substitution at residue 434 in the Fc region (U.S. Pat. No. 7,371,826). See also Duncan & Winter, Nature 322: 738-40 (1988); U.S. Pat. No. 5,648,260; U.S. Pat. No. 5,624,821.

[0290] In certain embodiments, the Fc region is mutated to increase its affinity for FcRn at pH 6.0 and thus extend the antibody half-life. Antibodies with enhanced affinity for FcRn include those in which one or more of the following Fc region residues are replaced: 252, 253, 254, 256, 428, 434; including the so-called YTE mutation (Dall'Acqua et al, J Immunol. 169: 5171-5180 (2002)) or the LS mutation M428L / N434S (Zalevsky et al, Nat Biotechnol. 28 (2): 157–159 (2010)).

[0291] In certain embodiments, it may be desirable to produce cysteine ​​engineered antibodies, such as "thioMAbs," in which one or more residues of an antibody are replaced by cysteine ​​residues. In some specific embodiments, the replaced residues occur at accessible sites of the antibody. By replacing these residues with cysteine, reactive sulfhydryl groups are thereby located at accessible sites of the antibody and can be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to produce immunoconjugates, as further described herein. In certain embodiments, any one or more of the following residues may be replaced by 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 ​​engineered antibodies may be produced as described, for example, in U.S. Patent No. 7,521,541.

[0292] In certain embodiments, the antibodies provided herein may also be modified to include additional non-proteinaceous moieties known in the art and readily available. Moieties suitable for antibody derivatization include, but are not limited to, water-soluble polymers. Some non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol / propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-triazine ... The invention relates to the invention of the invention to a poly(ethylene glycol) derivative of an antibody. The invention relates to a poly(ethylene glycol) derivative of an antibody. The invention relates to a poly(ethylene glycol) derivative of an antibody. The invention relates to a poly(ethylene glycol) derivative of an antibody. The invention relates to a poly(ethylene glycol) derivative of an antibody. The invention relates to a poly(ethylene glycol) derivative of an antibody. The invention relates to a poly(ethylene glycol) derivative of an antibody. The invention relates to a poly(ethylene glycol) derivative of an antibody. The invention relates to a poly(ethylene glycol) derivative of an antibody. The invention relates to a poly(ethylene glycol) derivative of an antibody. The invention relates to a poly(ethylene glycol) derivative of an antibody. The invention relates to a poly(ethylene glycol) derivative of an antibody.

[0293] In another embodiment, a conjugate of an antibody with a nonproteinaceous portion that can be selectively heated by exposure to radiation is provided. In one embodiment, the nonproteinaceous portion is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation can be of any wavelength, and includes but is not limited to a wavelength that does not damage normal cells but heats the nonproteinaceous portion to a temperature that kills cells adjacent to the antibody-nonproteinaceous portion.

[0294] The antibodies can 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 encoding an anti-phospho-TDP-43 antibody described herein is provided. Such a nucleic acid may encode an amino acid sequence comprising the VL of the antibody and / or an amino acid sequence comprising the VH of the antibody (e.g., the light chain and / or heavy chain of the antibody). In another embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In another embodiment, a host cell comprising such nucleic acids is provided. In one such embodiment, the host cell comprises the following (e.g., has been transformed with the following): (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 and a second vector, wherein the first vector comprises a nucleic acid encoding an amino acid sequence comprising the VL of the antibody, and the second vector comprises a nucleic acid encoding an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is eukaryotic, for example, a Chinese Hamster Ovary (CHO) cell or a lymphoid cell (e.g., YO, NSO, Sp20). In one embodiment, a method for preparing an anti-phosphorylated TDP-43 antibody is provided, wherein the method comprises: culturing a host cell comprising a nucleic acid encoding the antibody as provided above under conditions suitable for expressing the antibody; and optionally recovering the antibody from the host cell (or host cell culture medium).

[0295] For recombinant production of the TDP-43 antibodies of the invention, nucleic acids encoding the antibodies, such as those described above, are 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 acids can be easily isolated and sequenced using routine procedures (e.g., by using oligonucleotide probes that are capable of specifically binding to genes encoding the heavy and light chains of the antibodies).

[0296] Suitable host cells for cloning or expressing antibody encoding vectors include prokaryotic or eukaryotic cells described herein. For example, antibodies can 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 (BKCLo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, describing the expression of antibody fragments in Escherichia coli (E. coli.)). After expression, the antibodies in the soluble fraction can be separated from the bacterial cell paste and can be further purified.

[0297] In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast are also suitable cloning or expression hosts for antibody-encoding vectors, including fungi and yeast strains whose glycosylation pathways have been "humanized" to produce antibodies with partial or complete human glycosylation patterns. See Gerngross, Nat. Biotech. 22: 1409-1414 (2004); and Li et al., Nat. Biotech. 24: 210-215 (2006).

[0298] Suitable host cells for expressing glycosylated antibodies also come from multicellular organisms (invertebrates and vertebrates). Some examples of invertebrate cells include plant and insect cells. Many baculovirus strains have been identified that can be used in conjunction with insect cells, particularly for transfecting Spodoptera frugiperda cells.

[0299] Plant cell cultures can also be used as hosts. See, e.g., U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES for producing antibodies in transgenic plants). TM technology).

[0300] Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted for growth in suspension can be used. Other examples of useful mammalian host cell lines are macaque kidney CV1 line transformed by SV40 (COS-7); human embryonic kidney cell line (293 or 293 cells, as described, e.g., in Graham et al., J. Gen Viral. 36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (TM4 cells, as described, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); macaque kidney cells (CV1); African green macaque kidney cells (VER0-76); human cervical carcinoma cells (HeLa); canine kidney cells (MDCK); buffalo rat liver cells (BRL3A); human lung cells (W138); human hepatocytes (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., in Mather et al., Biol. Reprod. 23:243-251 (1980)). al., Annals NY Aead. Sei. 383: 44-68 (1982); MRC 5 cells; and FS4 cells. Other mammalian host cell lines that can be used 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, such as YO, NSO and Sp2 / 0. For a review of certain mammalian host cell lines suitable for antibody production, see, for example, Yazaki and Wu, Methods in Molecular Biology, Val. 248 (BKCLo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

[0301] There are several methods known in the art for delivering molecules across the blood brain barrier (BBB), such as alteration of the route of administration, disruption of the BBB and alteration of its permeability, nanoparticle delivery, Trojan horse approach, receptor-mediated transport, and cell and gene therapy.

[0302] Variation of the route 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 in the brain (see, e.g., Gillet al., Nature Med. 9:589-595 (2003); and Gliadel Wafers TM , Guildford Pharmaceutical), and intranasal administration bypassing the BBB (Mittal et al, Drug Deliv. 21(2):75-86. (2014)).

[0303] 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 hypertonic mannitol (Neuwelt, EA, Implication of the Blood-Brain Barrier and its Manipulation, Vols 1 & 2, Plenum Press, NY (1989)); permeabilization, by, e.g., bradykinin or permeabilizing agent A-7 (see, e.g., U.S. Patent Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416).

[0304] Methods for altering BBB permeability include, but are not limited to, using glucocorticoid blockers to increase the permeability of the blood-brain barrier (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).

[0305] Trojan horse delivery methods for delivering antibodies or antibody fragments thereof across the blood-brain barrier include, but are not limited to, cationizing the antibody (see, e.g., U.S. Pat. No. 5,004,697), and using cell penetrating peptides such as Tat peptides to gain access to the CNS (see, e.g., Dietz et al., J. Neurochem. 104:757-765 (2008)).

[0306] Nanoparticle delivery methods for delivering antibodies or antigen-binding fragments thereof across the blood-brain barrier include, but are not limited to, encapsulating the antibody or antigen-binding fragment thereof in liposomes or extracellular vesicles such as exosomes, wherein the liposomes or extracellular vesicles are coupled to antibodies or antigen-binding fragments or, as an alternative, peptides that bind to receptors on the vascular endothelium of the blood-brain barrier (see, e.g., U.S. Patent Application Publication No. 20020025313); and encapsulating the antibody or antigen-binding fragment thereof in low-density lipoprotein particles (see, e.g., U.S. Patent Application Publication No. 20040204354) or in apolipoprotein E (see, e.g., U.S. Patent Application Publication No. 20040131692).

[0307] The antibodies of the invention may be additionally modified to enhance blood-brain barrier penetration.

[0308] The antibodies or antigen-binding fragments thereof of the present invention can be fused with polypeptides that bind to blood-brain barrier receptors. BBB receptors include, but are not limited to, transferrin receptors, insulin receptors, or low-density lipoprotein receptors. The polypeptide can be a peptide, a receptor ligand, a single domain antibody (VHH), a scFv, or a Fab fragment.

[0309] The antibodies of the present invention can also be delivered as the corresponding nucleic acid encoding the antibodies. Such nucleic acid molecules can be part of a viral vector for targeted delivery to any other cell type in the blood-brain barrier or CNS. A non-limiting example is a viral vector comprising a nucleic acid molecule encoding an antibody of the present invention, which is used for targeted delivery to the endothelial cells of the BBB, pericytes of the BBB or astrocytes. In some embodiments, the endothelial cells of the BBB, pericytes of the BBB or astrocytes express antibodies and secrete antibodies into 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 to AAV12), so that antibodies or antibody fragments or antibody derivatives can be expressed intracellularly or expressed in the brain parenchyma.

[0310] Cell therapy methods for delivering antibodies, antibody fragments or antibody derivatives of the present invention across the blood-brain barrier include, but are not limited to: using the homing ability of endothelial progenitor cells (EPC) transfected ex vivo with a vector, and secreting antibodies or antibody fragments by these cells and delivering the antibodies or antibody fragments to the brain to overcome the powerful filtration activity of the blood-brain barrier (see, for example, Heller and al., J Cell Mol Med. 00: 1–7 (2020)); or using a polymer cell implant device loaded with genetically modified cells to secrete antibodies or antibody fragments (see, for example, Marroquin Belaunzaran et al. PloS ONE 6(4): e18268 (2011)).

[0311] Pharmaceutically acceptable carriers, diluents, adjuvants and excipients are well known in the pharmaceutical art and are described, for example, in the following:

[0312] Remington's Pharmaceutical Sciences, 15 th or 18 th Ed. (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 ofPharmaceutical 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 Nationa1 Formulary (United States Pharmacopeial Convention); Fiedler's "Lexikon der Hilfstoffe" 5 thEd., Edition Cantor VerlagAulendorf 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.

[0313] The choice of carriers, diluents, adjuvants and pharmaceutical excipients may be selected with regard to the intended route of administration and standard pharmaceutical practice. The compounds must be acceptable in the sense of not being deleterious to the recipients thereof.

[0314] An "effective amount" of a compound to be administered to a subject is a dose that is appropriate, according to sound medical judgment, to treat, prevent, or alleviate a disease, disorder, or abnormality. The specific dosage level and frequency may depend, for example, on a variety of factors, including: the activity of the particular compound used, the metabolic stability and duration of action of the compound, the mode and time of administration, the rate of excretion, and the 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 to be administered.

[0315] Some Inventive Embodiments of TDP-43 Binding Molecules

[0316] In some embodiments, a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, is provided comprising:

[0317] 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

[0318] 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

[0319] 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

[0320] 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

[0321] 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

[0322] 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

[0323] 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.

[0324] In some embodiments, a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, is provided comprising:

[0325] 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

[0326] 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

[0327] 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

[0328] 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

[0329] 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

[0330] 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

[0331] 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

[0332] 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

[0333] In some embodiments, a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, is provided comprising:

[0334] 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

[0335] 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

[0336] 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

[0337] 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

[0338] 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

[0339] 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

[0340] 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.

[0341] In some embodiments, a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, is provided comprising:

[0342] 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

[0343] 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

[0344] 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

[0345] 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

[0346] 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

[0347] 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

[0348] 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

[0349] h) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 117.

[0350] In some embodiments, a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, is provided comprising:

[0351] a) a heavy chain variable region (VH), comprising:

[0352] 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

[0353] 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

[0354] 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

[0355] 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

[0356] v. 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

[0357] vi. 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

[0358] vii. 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; and

[0359] b) a light chain variable region (VL), comprising:

[0360] 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

[0361] 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

[0362] 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

[0363] 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

[0364] v. 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

[0365] vi. 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

[0366] vii. 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.

[0367] In some embodiments, a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, is provided comprising:

[0368] a) a heavy chain variable region (VH), comprising:

[0369] 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

[0370] 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

[0371] 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

[0372] 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

[0373] v. 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

[0374] vi. 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

[0375] vii. 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

[0376] viii. 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; and

[0377] b) a light chain variable region (VL), comprising:

[0378] 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

[0379] 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

[0380] 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

[0381] 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

[0382] v. 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

[0383] vi. 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

[0384] vii. 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

[0385] viii. A VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115; a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116; and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 117.

[0386] In some embodiments, there is provided a TDP-43 binding molecule, in particular a TDP-43 antibody or antigen-fragment thereof, comprising:

[0387] a) a heavy chain variable region (VH), comprising:

[0388] 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 with 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 with 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 with SEQ ID NO: 13; or

[0389] 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

[0390] 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 with 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 with 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 with SEQ ID NO:33; or

[0391] 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 with 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 with 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 with SEQ ID NO:33; or

[0392] 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

[0393] 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

[0394] 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

[0395] b) a light chain variable region (VL), comprising:

[0396] 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

[0397] 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

[0398] 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

[0399] 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

[0400] 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

[0401] 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

[0402] 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.

[0403] In some embodiments, a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, is provided comprising:

[0404] a) a heavy chain variable region (VH), comprising:

[0405] 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 with 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 with 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 with SEQ ID NO: 13; or

[0406] 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

[0407] 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 with 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 with 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 with SEQ ID NO:33; or

[0408] 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 with 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 with 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 with SEQ ID NO:33; or

[0409] 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

[0410] 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

[0411] 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

[0412] 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 with 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 with 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 with SEQ ID NO: 113; and

[0413] b) a light chain variable region (VL), comprising:

[0414] 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

[0415] 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

[0416] 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

[0417] 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

[0418] 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

[0419] 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

[0420] 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

[0421] viii. a 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 with SEQ ID NO: 115; a 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 with SEQ ID NO: 116; and a 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 with SEQ ID NO: 117.

[0422] Similarly, in some embodiments, there is provided a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0423] a) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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 the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15 or a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 16 NO:15 has a VL-CDR1 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 with the amino acid sequence of SEQ ID NO:16 or a VL-CDR2 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:16, and a VL-CDR3 with the amino acid sequence of SEQ ID NO:17 or a VL-CDR3 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:17; or

[0424] b) a heavy chain variable region (VH) and a light chain variable region (VL), the 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; the light chain variable region (VL) comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, or a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 26. NO:25 has a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having an amino acid sequence of SEQ ID NO:26 or a VL-CDR2 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:26, and a VL-CDR3 having an amino acid sequence of SEQ ID NO:27 or a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:27; or

[0425] c) a heavy chain variable region (VH) and a light chain variable region (VL), the 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; the light chain variable region (VL) comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35, or a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 36. NO:35 has a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having the amino acid sequence of SEQ ID NO:16 or a VL-CDR2 having an amino acid sequence that has 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 a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:37; or

[0426] d) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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 the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 45, or a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 46. NO:45 having a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having an amino acid sequence of SEQ ID NO:46 or a VL-CDR2 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:46, and a VL-CDR3 having an amino acid sequence of SEQ ID NO:47 or a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:47; or

[0427] e) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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 the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, or a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 56. NO:55 has a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having the amino acid sequence of SEQ ID NO:26 or a VL-CDR2 having an amino acid sequence that has 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 a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:57; or

[0428] f) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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 the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, or a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 56. NO:55 has a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having the amino acid sequence of SEQ ID NO:26 or a VL-CDR2 having an amino acid sequence that has 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 a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:57; or

[0429] g) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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 the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, or a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 76. NO:75 having a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having an amino acid sequence of SEQ ID NO:76 or a VL-CDR2 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:76, and a VL-CDR3 having an amino acid sequence of SEQ ID NO:77 or a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:77; or

[0430] h) a heavy chain variable region (VH) and a light chain variable region (VL), the 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; the light chain variable region (VL) comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85, or a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 86. NO:85 has a VL-CDR1 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 with the amino acid sequence of SEQ ID NO:16 or a VL-CDR2 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:16, and a VL-CDR3 with the amino acid sequence of SEQ ID NO:87 or a VL-CDR3 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:87.

[0431] Similarly, in some embodiments, there is provided a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0432] a) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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 the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15 or a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 16 NO:15 has a VL-CDR1 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 with the amino acid sequence of SEQ ID NO:16 or a VL-CDR2 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:16, and a VL-CDR3 with the amino acid sequence of SEQ ID NO:17 or a VL-CDR3 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:17; or

[0433] b) a heavy chain variable region (VH) and a light chain variable region (VL), the 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; the light chain variable region (VL) comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 25, or a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 26. NO:25 has a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having an amino acid sequence of SEQ ID NO:26 or a VL-CDR2 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:26, and a VL-CDR3 having an amino acid sequence of SEQ ID NO:27 or a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:27; or

[0434] c) a heavy chain variable region (VH) and a light chain variable region (VL), the 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; the light chain variable region (VL) comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 35, or a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 36. NO:35 has a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having the amino acid sequence of SEQ ID NO:16 or a VL-CDR2 having an amino acid sequence that has 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 a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:37; or

[0435] d) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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 the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 45, or a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 46. NO:45 having a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having an amino acid sequence of SEQ ID NO:46 or a VL-CDR2 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:46, and a VL-CDR3 having an amino acid sequence of SEQ ID NO:47 or a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:47; or

[0436] e) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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 the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, or a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 56. NO:55 has a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having the amino acid sequence of SEQ ID NO:26 or a VL-CDR2 having an amino acid sequence that has 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 a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:57; or

[0437] f) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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 the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 55, or a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 56. NO:55 has a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having the amino acid sequence of SEQ ID NO:26 or a VL-CDR2 having an amino acid sequence that has 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 a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:57; or

[0438] g) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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 the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 75, or a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 76. NO:75 having a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having an amino acid sequence of SEQ ID NO:76 or a VL-CDR2 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:76, and a VL-CDR3 having an amino acid sequence of SEQ ID NO:77 or a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:77; or

[0439] h) a heavy chain variable region (VH) and a light chain variable region (VL), the 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; the light chain variable region (VL) comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85, or a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 86. NO:85 having a VL-CDR1 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 having an amino acid sequence of SEQ ID NO:16 or a VL-CDR2 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:16, and a VL-CDR3 having an amino acid sequence of SEQ ID NO:87 or a VL-CDR3 having an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:87; or

[0440] i) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) comprising 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; the light chain variable region (VL) comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115 or a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 116 NO:115 has a VL-CDR1 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity, a VL-CDR2 with the amino acid sequence of SEQ ID NO:116 or a VL-CDR2 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:116, and a VL-CDR3 with the amino acid sequence of SEQ ID NO:117 or a VL-CDR3 with an amino acid sequence that has at least 80%, 90%, 95% or 100% sequence identity to SEQ ID NO:117.

[0441] Similarly, in some embodiments, there is provided a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0442] a) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; or

[0443] b) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) 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, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23; the light chain variable region (VL) comprising 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

[0444] c) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) comprising 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; the light chain variable region (VL) comprising 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

[0445] d) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) comprising 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; the light chain variable region (VL) comprising 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

[0446] e) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) comprising 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; the light chain variable region (VL) comprising 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

[0447] f) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) 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, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63; the light chain variable region (VL) comprising 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

[0448] g) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) comprising 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; the light chain variable region (VL) comprising 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

[0449] h) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) 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, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO:83; the light chain variable region (VL) comprising 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.

[0450] Similarly, in some embodiments, there is provided a TDP-43 binding molecule, particularly a TDP-43 antibody or antigen-binding fragment thereof, comprising:

[0451] a) a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 11, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 13; and the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 15, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 17; or

[0452] b) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) 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, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 23; the light chain variable region (VL) comprising 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

[0453] c) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) comprising 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; the light chain variable region (VL) comprising 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

[0454] d) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) comprising 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; the light chain variable region (VL) comprising 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

[0455] e) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) comprising 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; the light chain variable region (VL) comprising 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

[0456] f) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) 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, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 63; the light chain variable region (VL) comprising 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

[0457] g) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) comprising 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; the light chain variable region (VL) comprising 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

[0458] h) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) 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, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 83; the light chain variable region (VL) comprising 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

[0459] i) a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) comprising 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; the light chain variable region (VL) comprising a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 117.

[0460] In another embodiment, the TDP-43 antibody comprises a heavy chain variable domain (VH) selected from the group consisting of SEQ ID NO: 10, 20, 30, 40, 50, 60 and 80, including post-translational modifications of the sequence. In a specific embodiment, the heavy chain variable domain (VH) comprises at least one, two or three CDRs selected from the group consisting of: (a) a VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 11, 21, 31, 41, 51, 61 and 81; (b) a VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 12, 22, 32, 42, 52, 62 and 82; (c) a VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 13, 23, 33, 53, 63 and 83.

[0461] In another embodiment, the TDP-43 antibody comprises a heavy chain variable domain (VH) selected from the group consisting of SEQ ID NO: 10, 20, 30, 40, 50, 60, 80 and 110, including post-translational modifications of the sequence. In a specific embodiment, the heavy chain variable domain (VH) comprises at least one, two or three CDRs selected from the group consisting of: (a) a VH-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 11, 21, 31, 41, 51, 61, 81 and 111; (b) a VH-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 12, 22, 32, 42, 52, 62, 82 and 112; (c) a VH-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 13, 23, 33, 53, 63, 83 and 113.

[0462] In another embodiment, the TDP-43 antibody comprises a light chain variable domain (VL) selected from the group consisting of SEQ ID NO: 14, 24, 34, 44, 54 and 84, including post-translational modifications of the sequence. In a specific embodiment, the light chain variable domain (VL) comprises at least one, two or three CDRs selected from the group consisting of: (a) a VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 15, 25, 35, 45, 55, 75 and 85; (b) a VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 16, 26, 46 and 76; (c) a VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 17, 27, 37, 47, 57, 77 and 87.

[0463] In another embodiment, the TDP-43 antibody comprises a light chain variable domain (VL) selected from the group consisting of SEQ ID NO: 14, 24, 34, 44, 54, 64, 74, 84 and 114, including post-translational modifications of the sequence. In a specific embodiment, the light chain variable domain (VL) comprises at least one, two or three CDRs selected from the group consisting of: (a) a VL-CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 15, 25, 35, 45, 55, 75, 85 and 115; (b) a VL-CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 16, 26, 46, 76 and 116; (c) a VL-CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 17, 27, 37, 47, 57, 77, 87 and 117.

[0464] In some embodiments, the TDP-43 antibody comprises:

[0465] a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; or

[0466] b. a heavy chain variable region (VH) comprising 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 to the amino acid sequence of SEQ ID NO: 20; or

[0467] c. a heavy chain variable region (VH) comprising 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; or

[0468] d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 40; or

[0469] 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 with the amino acid sequence of SEQ ID NO: 50; or

[0470] 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 with the amino acid sequence of SEQ ID NO: 60; or

[0471] g. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80, or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 80.

[0472] In some embodiments, the TDP-43 antibody comprises:

[0473] a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10 or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; or

[0474] b. a heavy chain variable region (VH) comprising 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 to the amino acid sequence of SEQ ID NO: 20; or

[0475] c. a heavy chain variable region (VH) comprising 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; or

[0476] d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 40; or

[0477] 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 with the amino acid sequence of SEQ ID NO: 50; or

[0478] 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 with the amino acid sequence of SEQ ID NO: 60; or

[0479] g. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80, or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 80; or

[0480] h. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 110, or a heavy chain variable region (VH) having at least 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 110.

[0481] In some embodiments, the TDP-43 antibody comprises:

[0482] a. a light chain variable region (VL) comprising 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

[0483] b. a light chain variable region (VL) comprising 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

[0484] c. a light chain variable region (VL) comprising 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

[0485] d. a light chain variable region (VL) comprising 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 the amino acid sequence of SEQ ID NO: 44; or

[0486] e. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 54; or

[0487] f. a light chain variable region (VL) comprising the sequence of SEQ ID NO:84, or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:84.

[0488] In some embodiments, the TDP-43 binding molecule, in particular a TDP-43 antibody or antigen-binding fragment comprises:

[0489] a) a heavy chain variable region (VH) selected from the group consisting of:

[0490] i. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10, or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; or

[0491] ii. a heavy chain variable region (VH) comprising 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 to the amino acid sequence of SEQ ID NO: 20; or

[0492] iii. a heavy chain variable region (VH) comprising 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; or

[0493] iv. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 40; or

[0494] v. 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 with the amino acid sequence of SEQ ID NO: 50; or

[0495] vi. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 60 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 60; or

[0496] vii. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80, or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 80; and

[0497] b) a light chain variable region (VL) selected from the group consisting of:

[0498] i. a light chain variable region (VL) comprising 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

[0499] ii. a light chain variable region (VL) comprising 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

[0500] iii. a light chain variable region (VL) comprising 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

[0501] iv. a light chain variable region (VL) comprising 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 the amino acid sequence of SEQ ID NO: 44; or

[0502] v. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 54; or

[0503] vi. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64; or

[0504] vii. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 74; or

[0505] viii. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84, or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 84.

[0506] In some embodiments, the TDP-43 binding molecule, in particular a TDP-43 antibody or antigen-binding fragment comprises:

[0507] a) a heavy chain variable region (VH) selected from the group consisting of:

[0508] i. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10, or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; or

[0509] ii. a heavy chain variable region (VH) comprising 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 to the amino acid sequence of SEQ ID NO: 20; or

[0510] iii. a heavy chain variable region (VH) comprising 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; or

[0511] iv. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 40; or

[0512] v. 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 with the amino acid sequence of SEQ ID NO: 50; or

[0513] vi. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 60 or a heavy chain variable region (VH) having at least 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 60; or

[0514] vii. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80, or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 80; or

[0515] viii. 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 with the amino acid sequence of SEQ ID NO: 110; and

[0516] b) a light chain variable region (VL) selected from the group consisting of:

[0517] i. a light chain variable region (VL) comprising 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

[0518] ii. a light chain variable region (VL) comprising 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

[0519] iii. a light chain variable region (VL) comprising 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

[0520] iv. a light chain variable region (VL) comprising 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 the amino acid sequence of SEQ ID NO: 44; or

[0521] v. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 54; or

[0522] vi. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64; or

[0523] vii. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 74; or

[0524] viii. a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84 or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 84; or

[0525] ix. a light chain variable region (VL) comprising the sequence of SEQ ID NO:114.

[0526] In some embodiments, the TDP-43 binding molecule, in particular a TDP-43 antibody or antigen-binding fragment thereof comprises:

[0527] a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10, or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14, or 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

[0528] b. a heavy chain variable region (VH) comprising 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) comprising 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

[0529] c. a heavy chain variable region (VH) comprising 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) comprising 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

[0530] d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40, or a heavy chain variable region (VH) having 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 40; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44, or a light chain variable region (VL) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 44; or

[0531] 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

[0532] 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 with the amino acid sequence of SEQ ID NO: 60; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64; or

[0533] 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

[0534] h. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO:80, or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:80; and a light chain variable region (VL) comprising the sequence of SEQ ID NO:84, or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO:84.

[0535] In some embodiments, the TDP-43 binding molecule, in particular a TDP-43 antibody or antigen-binding fragment thereof comprises:

[0536] a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10, or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14, or 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

[0537] b. a heavy chain variable region (VH) comprising 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) comprising 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

[0538] c. a heavy chain variable region (VH) comprising 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) comprising 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

[0539] d. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 40, or a heavy chain variable region (VH) having 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 40; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44, or a light chain variable region (VL) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 44; or

[0540] 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

[0541] 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 with the amino acid sequence of SEQ ID NO: 60; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64; or

[0542] 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

[0543] h. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 80, or a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 80; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84, or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 84; or

[0544] 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.

[0545] In some embodiments, the TDP-43 antibody comprises:

[0546] a. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 14; or

[0547] b. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 20 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 24; or

[0548] c. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 30 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 34; or

[0549] d. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 40 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 44; or

[0550] 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

[0551] f. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 60 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 64; or

[0552] g. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 50 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 74; or

[0553] 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.

[0554] In some embodiments, the TDP-43 antibody comprises:

[0555] a. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 14; or

[0556] b. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 20 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 24; or

[0557] c. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 30 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 34; or

[0558] d. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 40 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 44; or

[0559] 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

[0560] f. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 60 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 64; or

[0561] g. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 50 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 74; or

[0562] 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

[0563] 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.

[0564] In a preferred embodiment, the TDP-43 antibody comprises:

[0565] a. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 10 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 14; or

[0566] b. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 20 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 24; or

[0567] c. a heavy chain variable region (VH) containing the sequence of SEQ ID NO: 30 and a light chain variable region (VL) containing the sequence of SEQ ID NO: 34; or

[0568] 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.

[0569] In some embodiments, the invention relates to a TDP-43 binding molecule selected from the group consisting of ACI-8071-943.12A8-Abl, ACI-8071-943.7H9-Abl, ACI-8071-943.7D3-Abl, ACI-8071-943.2E6-Abl, ACI-8072-946.8H6-Abl, ACI-8072-946.4G5-Abl, ACI-8072-946.9D6-Abl, ACI-7071-4665-B5-R3B-Ab2. Preferably, the TDP-43 binding molecule is selected from ACI-8071-943.12A8-Abl, ACI-8071-943.7H9-Abl, ACI-8071-943.7D3-Abl, ACI-8072-946.4G5-Abl. In particular, ACI-8071-943.12A8-Abl and ACI-8071-943.7D3-Abl can be used as therapeutic antibodies. ACI-8071-943.7H9-Abl and ACI-8072-946.4G5-Abl can be used as diagnostic / detection antibodies, for example in paired assays.

[0570] In some embodiments, the invention relates to a TDP-43 binding molecule selected from the group consisting of ACI-8071-943.12A8-Abl, ACI-8071-943.7H9-Abl, ACI-8071-943.7D3-Abl, ACI-8071-943.2E6-Abl, ACI-8072-946.8H6-Abl, ACI-8072-946.4G5-Abl, ACI-8072-946.9D6-Abl, ACI-7071-4665-B5-R3B-Ab2, ACI-8070-942.30D12-Abl. In some embodiments, preferably, ACI-7071-4665-B5-R3B-Ab2, ACI-7071-809F12-Abl-rec2, ACI-8072-946.4G5-Abl and ACI-8071-943.7H9-Abl can be used as diagnostic / detection antibodies, for example in paired assays.

[0571] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid encodes a TDP-43 binding molecule as described herein, in particular a TDP-43 antibody and fragments thereof.

[0572] In some embodiments, a (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 18 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0573] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 19 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0574] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 28 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0575] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 29 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0576] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 38 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0577] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 39 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0578] In some embodiments, a (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 48 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0579] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 49 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0580] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 58 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0581] In some embodiments, a (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 59 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0582] In some embodiments, a (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 68 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0583] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 69 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0584] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 79 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0585] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 88 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0586] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 89 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0587] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 118 encoding the heavy chain variable region (VH) of an anti-TPD-43 antibody.

[0588] In some embodiments, an (isolated) nucleic acid is provided, wherein the (isolated) nucleic acid comprises SEQ ID NO: 119 encoding the light chain variable region (VL) of an anti-TPD-43 antibody.

[0589] Compositions and methods

[0590] The present invention also relates to a pharmaceutical composition comprising a TDP-43 binding molecule of the present invention as described herein, in particular an antibody or an antigen-binding fragment thereof, and a pharmaceutically acceptable carrier and / or excipient and / or diluent.

[0591] In some embodiments, a pharmaceutical composition is provided, comprising an (isolated) antibody described herein and a pharmaceutically acceptable carrier.

[0592] In some embodiments, there is provided a binding molecule comprising the following conjugation, particularly an antibody or its antigen binding fragment: a binding molecule as described herein, particularly an antibody or its antigen binding fragment, and a conjugated molecule. The conjugate of the present invention may be referred to as an immunoconjugate. Any suitable conjugated molecule may be used according to the present invention. Some suitable examples include, but are not limited to, enzymes (e.g., alkaline phosphatase or horseradish peroxidase), avidin, streptavidin, biotin, protein A / G, magnetic beads, fluorophores, radioisotopes (i.e., radioconjugates), paramagnetic beads, nucleic acid molecules, detectable labels, therapeutic agents, toxins, and blood-brain barrier penetrating 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, and conjugation is usually by amino acid residues (e.g., lysine, histidine, or cysteine) contained in the binding molecules of the present invention. They may rely on methods such as the NHS (succinimidyl) ester method, the isothiocyanate method, the carbodiimide method, and the periodate method. Conjugation can be achieved, for example, by producing a fusion protein. This is appropriate in the case of a binding molecule conjugated to another protein molecule. Thus, a suitable genetic construct can be formed that allows the expression of a fusion of the binding molecule of the invention with a marker or other molecule. Conjugation may be through a suitable linker moiety to ensure appropriate spatial separation of the antibody and the conjugated molecule (e.g., a detectable label). However, a linker is not required in all cases. In some embodiments, the TDP-43 binding molecule of the invention is linked to a detectable label.

[0593] The present invention also relates to immunoconjugates comprising a TDP-43 binding molecule provided herein conjugated to one or more therapeutic agents, such as: a chemotherapeutic agent or drug, a growth inhibitory agent, a toxin (e.g., a protein toxin of bacterial, fungal, plant or animal origin, an enzymatically active toxin, or a fragment thereof), a radioactive isotope (i.e., a radioconjugate), a blood-brain barrier penetrating moiety, or a detectable label. There are a variety of techniques for improving drug delivery across the blood-brain barrier (BBB) ​​as discussed herein, and this discussion applies mutatis mutandis. Non-invasive techniques include the so-called "Trojan horse approach," in which the conjugated molecule delivers the binding molecule of the invention by binding to a BBB receptor and mediating transport. Suitable molecules may comprise endogenous ligands or antibodies, particularly monoclonal antibodies, that bind to specific epitopes on BBB receptors.

[0594] The present invention also includes the use of the antibodies of the present invention in paired assays (e.g., 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 an assay comprises incubating 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; they 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 for the assay directly (in the case where the antibody is labeled) or indirectly (through a downstream signal generation system, which can amplify the signal (e.g., enzymatically amplify the signal) and can involve a secondary antibody that binds to the detection antibody). In some preferred embodiments, the assay can be a digital assay that can provide a quantitative readout.

[0595] In one embodiment, the determining comprises the following steps:

[0596] a. incubating the sample with a capture antibody, which may be a TDP-43 binding molecule of the present invention conjugated to paramagnetic beads;

[0597] b. adding a detection antibody to the solution of a), wherein the detection antibody may be a labeled TDP-43 binding molecule of the present invention, such as an antibody of the present invention conjugated to biotin;

[0598] c. optionally adding a substrate for the labeled TDP-43 binding molecule, such as streptavidin-β-D-galactosidase;

[0599] d. Optionally washing the plate using a magnetic microplate washer;

[0600] e. Read the signal emitted by the labeled TDP-43 binding molecule.

[0601] In one embodiment, the capture antibody is an immunoconjugate or TDP-43 binding molecule, in particular an antibody or antigen-binding fragment thereof as described herein 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 invention binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43.

[0602] In a preferred embodiment, the capture antibody is a TDP-43 binding molecule selected from the group of TDP-43 binding molecules comprising:

[0603] a. a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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; and the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87; or

[0604] b. a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 91, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 92, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 93; and the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97; or

[0605] c. a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) 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, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 103; the light chain variable region (VL) comprising 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.

[0606] In a more preferred embodiment, the capture antibody comprises a TDP-43 binding molecule comprising a heavy chain variable region (VH) 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, and a VH-CDR3 comprising the amino acid sequence of 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, 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.

[0607] 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.

[0608] In a preferred embodiment, the capture antibody specifically binds to phosphorylated TDP-43. In another preferred embodiment, the capture antibody of the invention binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43.

[0609] In a preferred embodiment, the detection antibody is a TDP-43 binding molecule selected from the group of TDP-43 binding molecules comprising:

[0610] a. a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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; and the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87; or

[0611] b. a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 91, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 92, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 93; and the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97; or

[0612] c. a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 101, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 102, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 103; and the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 105, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 26, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 107; or

[0613] 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

[0614] e. 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.

[0615] In a preferred embodiment, the detection antibody is a TDP-43 binding molecule selected from the group of TDP-43 binding molecules comprising:

[0616] a. a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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; and the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87; or

[0617] b. a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 91, a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 92, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 93; and the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 95, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 96, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 97; or

[0618] c. a heavy chain variable region (VH) and a light chain variable region (VL), the heavy chain variable region (VH) 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, and a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 103; the light chain variable region (VL) comprising 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.

[0619] In a more preferred embodiment, the detection antibody comprises a TDP-43 binding molecule comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region (VH) comprises 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; and the light chain variable region (VL) comprises a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 85, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 16, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 87.

[0620] In one embodiment of the invention, the capture antibody specifically binds to phosphorylated TDP-43, and the detection antibody binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43. In another embodiment of the invention, 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. In one embodiment, the capture antibody and the detection antibody have different epitopes.

[0621] 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:106, The VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 26 and the VL-CDR3 comprises the amino acid sequence of SEQ ID NO: 107. In another embodiment, a paired assay for detecting or quantifying TDP-43 using defined capture and detection antibodies can provide a lower limit of quantification of 0.02 pM and / or a lower limit of detection of 0.09 pM.

[0622] 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: VL-CDR3 of the amino acid sequence of ID NO: 97. In another embodiment, a paired assay for detecting or quantifying phosphorylated TDP-43 using defined capture and detection antibodies can provide a lower limit of quantification of 0.13 pM and / or a lower limit of detection of 0.5 pM.

[0623] 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: 106 The VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 26 and the VL-CDR3 comprises the amino acid sequence of SEQ ID NO: 107. In another embodiment, a paired assay for detecting or quantifying phosphorylated TDP-43 using the defined capture and detection antibodies can provide a lower limit of quantification of 0.17 pM and / or a lower limit of detection of 0.61 pM.

[0624] 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: The VL-CDR2 comprises the amino acid sequence of SEQ ID NO: 26 and the VL-CDR3 comprises the amino acid sequence of SEQ ID NO: 107. In another embodiment, a paired assay for detecting or quantifying phosphorylated TDP-43 using the defined capture and detection antibodies can provide a lower limit of quantification of 0.02 pM and / or a lower limit of detection of 0.8 pM.

[0625] In some embodiments, an immunoconjugate is provided, wherein the immunoconjugate comprises an (isolated) antibody described herein and a therapeutic agent. In some embodiments, a labeled antibody is provided, comprising an antibody described herein and a detectable label.

[0626] In some 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.

[0627] In some embodiments, the TDP-43 binding molecule or an immunoconjugate comprising the same is present as a composition comprising the TDP-43 binding molecule.

[0628] In some embodiments, the TDP-43 binding molecule is part of a pharmaceutical composition comprising the TDP-43 binding molecule or an immunoconjugate wherein 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 pharmaceutically acceptable carrier and / or excipient and / or diluent.

[0629] In some 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.

[0630] In some 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 a composition comprising the TDP-43 binding molecule.

[0631] Also provided are kits comprising the binding molecules of the invention. In particular, such kits can be used for diagnostic applications. Thus, kits for diagnosing diseases, disorders and / or abnormalities associated with TDP-43, in particular associated with TDP-43 aggregates, or TDP-43 proteinopathy, or for the methods of the invention are provided, comprising the TDP-43 binding molecules of the invention. Such kits may contain all the necessary components for performing the methods provided herein. Typically, each component is stored separately in a single integral package. Suitable additional components included in the kit are, for example, buffers, detectable dyes, laboratory equipment, reaction vessels, instructions, and the like. The instructions for use may be customized for the specific method in which the kit is to be used. Also provided are suitably labeled TDP-43 binding molecules of the invention, which may be included in such kits.

[0632] In some embodiments, the TDP-43 binding molecules are used in immunodiagnostic methods for diagnosing TDP-43 proteinopathies. In some embodiments, the TDP-43 binding molecules are used as a diagnostic tool in combination with therapeutic TDP-43 molecules.

[0633] In some embodiments, a 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 a TDP-43 binding molecule is administered to a subject in need thereof, or is used to diagnose, prevent, alleviate or treat a disease, disorder and / or abnormality associated with TDP-43 (particularly associated with TDP-43 aggregates), or a TDP-43 proteinopathy, including but not limited to 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 syndrome ( DS), Parkinson's disease (PD) and related conditions (including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), limbic-dominant age-related 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 caused by mutations or variant-associated risk alleles in progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B genes.

[0634] In some embodiments, a 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 a TDP-43 binding molecule is administered to a subject in need thereof, or used in a method for diagnosing or monitoring a disease, disorder and / or abnormality associated with TDP-43 (particularly associated with TDP-43 aggregates), or a TDP-43 proteinopathy, wherein the disease, disorder and / or abnormality associated with TDP-43 (particularly associated with TDP-43 aggregates) is The abnormality or TDP-43 proteinopathy is 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), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), nonfluent / agrammatic primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down syndrome (DS), familial British dementia, Parkinson's disease (PD) and related conditions (including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia , myofibrillar myopathies (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), diseases with both sporadic and inherited origins (including inherited cases caused by mutations or variant-associated risk alleles of progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxia-inducing protein 3 (ATXN3) genes).

[0635] In another embodiment, the present invention relates to any method for detecting, diagnosing or monitoring a disease, disorder and / or abnormality associated with TDP-43, in particular associated with TDP-43 aggregates, or a TDP-43 proteinopathy, wherein the disease, disorder and / or abnormality associated with TDP-43, in particular associated with TDP-43 aggregates, or a TDP-43 proteinopathy is 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 syndrome (DS), familial British dementia, Parkinson's disease (PD) and related disorders (including PD dementia (PDD), Lewy body dementia (DLB), multiple system atrophy (MSA)) , corticobasal degeneration (CBD), Niemann-Pick disease (NP, including type C NP), facial-onset sensorimotor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia, myofibrillar myopathies (such as inclusion body myositis, Inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), diseases with both sporadic and inherited origins (including inherited cases caused by mutations or variant-associated risk alleles in the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxia-inducing protein 3 (ATXN3) genes).

[0636] Preferably, the disease, disorder and / or abnormality associated with TDP-43 (particularly associated with TDP-43 aggregates), or TDP-43 proteinopathy is selected from 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 syndrome (DS), Parkinson's disease (PD) and related disorders (including PD dementia (PDD), Lewy body dementia (DLB), multiple system atrophy (MSA) ), limbic dominant age-related TDP-43 encephalopathy (LATE), myofibrillar myopathy (e.g., inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), and diseases with both sporadic and inherited origins (including genetic cases caused by mutations or variant-associated risk alleles of progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myoconstrictor protein (MYOT), TMEM106B genes). More preferably, the disease, disorder and / or abnormality associated with TDP-43 (particularly associated with TDP-43 aggregates), or TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic dominant age-related TDP-43 encephalopathy (LATE), Alzheimer's disease (AD), frontotemporal lobar degeneration with motor neuron disease FTLD-MND (also known as ALS-FTD).

[0637] The present invention also provides 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, the method comprising contacting the sample with a binding molecule, particularly an antibody or antigen-binding fragment of the present invention, and comparing the level of TDP-43 in the sample, wherein;

[0638] a. a change in the level of TDP-43 in a later sample compared to one or more earlier samples is indicative of a change in a disease, disorder and / or condition associated with TDP-43; or

[0639] b. The absence of a significant change in TDP-43 levels in a later sample compared to one or more earlier samples indicates that the disease, disorder and / or condition associated with TDP-43 has not changed.

[0640] The present invention also provides 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, the method comprising contacting the sample with a binding molecule, particularly an antibody or antigen-binding fragment of the present invention, and comparing the level of phosphorylated TDP-43 in the sample, wherein;

[0641] a. a change in the level of phosphorylated TDP-43 in a later sample compared to one or more earlier samples is indicative of a change in a disease, disorder and / or condition associated with TDP-43; or

[0642] b. The absence of a significant change in the level of phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates that the disease, disorder and / or condition associated with TDP-43 has not changed.

[0643] The present invention also provides 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, the method comprising contacting the sample with a binding molecule, particularly an antibody or antigen-binding fragment of the present invention, and comparing the level of TDP-43 in the sample, wherein:

[0644] a. a higher 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;

[0645] b. a lower level of TDP-43 in a later sample compared to one or more earlier samples indicates regression of a disease, disorder, and / or condition associated with TDP-43; or

[0646] c. The absence of a significant change in TDP-43 levels in a later sample compared to one or more earlier samples indicates that the disease, disorder, and / or condition associated with TDP-43 has not progressed.

[0647] Alternatively, the present invention also provides 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, the method comprising contacting the sample with a binding molecule, particularly an antibody or antigen-binding fragment of the present invention, and comparing the level of TDP-43 in the sample, wherein:

[0648] a. a higher level of TDP-43 in a later sample compared to one or more earlier samples indicates regression of a disease, disorder and / or condition associated with TDP-43; or

[0649] b. lower levels 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

[0650] c. The absence of a significant change in TDP-43 levels in a later sample compared to one or more earlier samples indicates that the disease, disorder, and / or condition associated with TDP-43 has not progressed.

[0651] The present invention also provides 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, the method comprising contacting the sample with a binding molecule, particularly an antibody or antigen-binding fragment of the present invention, and comparing the level of phosphorylated TDP-43 in the sample, wherein:

[0652] a. a higher level of phosphorylated 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;

[0653] b. a lower level of phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates regression of a disease, disorder, and / or condition associated with TDP-43; or

[0654] c. The absence of a significant change in the level of phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates that the disease, disorder and / or condition associated with TDP-43 has not progressed.

[0655] Alternatively, the present invention also provides 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, the method comprising contacting the sample with a binding molecule, particularly an antibody or antigen-binding fragment of the present invention, and comparing the level of phosphorylated TDP-43 in the sample, wherein:

[0656] a. a higher level of phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates regression of a disease, disorder and / or condition associated with TDP-43;

[0657] b. lower levels of phosphorylated TDP-43 in later samples compared to one or more earlier samples indicates progression of a disease, disorder and / or condition associated with TDP-43; or

[0658] c. The absence of a significant change in the level of phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates that the disease, disorder and / or condition associated with TDP-43 has not progressed.

[0659] Such methods are typically performed on subjects known to have a disease, disorder, and / or condition associated with TDP-43, and can be performed at multiple time points in matched samples between treatment and placebo groups to monitor the effectiveness of the candidate treatment over a defined period of time. The diagnostic compositions of the invention can be used in such methods. Paired immunoassays described herein incorporating appropriate capture antibodies and detection antibodies or antigen-binding fragments thereof can be used in the monitoring methods of the invention.

[0660] In some embodiments, the TDP-43 binding molecule is used in a method for quantifying phosphorylated TDP-43 in a sample, the method comprising contacting the sample with a TDP-43 binding molecule of the invention, comparing the TDP-43 level detected from the sample with a control, the control optionally being determined using a known amount of a calibrator for phosphorylated TDP-43. In one embodiment of the invention, the quantification method is based on a paired analysis as described herein.

[0661] In one embodiment, the quantitative method comprises the following steps:

[0662] a. incubating the sample with a capture antibody and a detection antibody as described herein;

[0663] b. incubating the mixture obtained in step a with a reagent suitable for detection by the detection antibody;

[0664] c. measuring the signal emitted by the detection antibody;

[0665] d. Comparing the level of TDP-43 detected from the sample to a control, optionally determined using a known amount of a calibrator for phosphorylated TDP-43.

[0666] The calibrator can be a peptide, protein or compound that is used as a standard or reference material of known concentration to allow quantification of the analyte level in the patient. In one embodiment of the 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 full-length TDP-43 (SEQ ID NO: 1), peptide 28 (SEQ ID NO: 7 is connected to SEQ ID NO: 8 via a trioxatridecan-succinamic acid linker) and peptide 29 (SEQ ID NO: 7 is connected to SEQ ID NO: 9 via a trioxatridecan-succinamic acid linker).

[0667] In one embodiment of the invention, the calibrator is a peptide comprising, consisting of, or consisting 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 11 (SEQ ID NO: 4 connected to SEQ ID NO: 5 via a trioxatridecane-succinamic acid linker), and peptide 23 (SEQ ID NO: 6 connected to SEQ ID NO: 5 via a trioxatridecane-succinamic acid linker).

[0668] In some embodiments, the TDP-43 binding molecules are used in methods wherein a TDP-43 binding molecule of the invention is contacted with a sample (e.g., blood, cerebrospinal fluid, interstitial fluid (ISF), or brain tissue) to detect 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), nonfluent / agrammatic primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down syndrome (DS), familial British dementia, Parkinson's disease (PD), and related diseases. Dementia (including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including type C NP), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia, myofibrillar myopathies (such as inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), primary lateral sclerosis (PLS), progressive muscular atrophy.

[0669] In some embodiments, the TDP-43 binding molecules are used in such methods, wherein the TDP-43 binding molecules of the invention are contacted with a sample (e.g., blood, cerebrospinal fluid, interstitial fluid (ISF) or brain tissue) to detect diseases caused by mutations or variant-associated risk alleles of progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxia protein 3 (ATXN3) genes. In some embodiments, the TDP-43 binding molecules are used in such methods, wherein the TDP-43 binding molecules of the invention are contacted with a sample (e.g., blood, cerebrospinal fluid, interstitial fluid (ISF) or brain tissue) to detect amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), limbic dominant age-related TDP-43 encephalopathy (LATE), Alzheimer's disease (AD), frontotemporal lobar degeneration with motor neuron disease FTLD-MND.

[0670] In some embodiments, the TDP-43 binding molecules are used in such methods, wherein the TDP-43 binding molecules of the invention are contacted with a sample (e.g., blood, cerebrospinal fluid, interstitial fluid (ISF), or brain tissue) to detect a disease, disorder, or abnormality associated with TDP-43 aggregates selected from 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), nonfluent / agrammatic primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down syndrome (DS), familial English dementia , Parkinson's disease (PD) and related disorders (including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including type C NP), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia, myofibrillar myopathies (such as inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), primary lateral sclerosis (PLS), progressive muscular atrophy. In some embodiments, the TDP-43 binding molecules are used in such methods, wherein the TDP-43 binding molecules of the invention are contacted with a sample (e.g., blood, cerebrospinal fluid, interstitial fluid (ISF) or brain tissue) to detect a disease caused by a mutation or variant-associated risk allele of the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), ataxia protein 3 (ATXN3) gene.

[0671] In some embodiments, a 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 a TDP-43 binding molecule is administered to a subject in need thereof, or is used to prevent, alleviate or treat a disease, disorder and / or abnormality associated with TDP-43 (particularly associated with TDP-43 aggregates), or a TDP-43 proteinopathy, or 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 Dementia (AD), Down syndrome (DS), familial British dementia, Parkinson's disease (PD) and related conditions (including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia, myofibrillar myopathies (such as inclusion body myositis, inclusion body myopathy, oculopharyngeal muscular dystrophy with rimmed vacuoles), primary lateral sclerosis (PLS), progressive muscular atrophy. In some embodiments, a 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 a TDP-43 binding molecule is administered to a subject in need thereof, or is used to prevent, alleviate or treat a disease caused by a mutation or variant-associated risk allele of a gene encoding progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), or ataxin 3 (ATXN3).

[0672] In some embodiments, a 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 a TDP-43 binding molecule is administered to a subject in need thereof, or is used to treat a disease 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), behavioral variant frontotemporal dementia (bvFTD), semantic variant primary progressive aphasia (svPPA), non-fluent / agrammatic primary progressive aphasia (naPPA), Alzheimer's disease (AD), Down syndrome (DS), familial British dementia, Parkinson's disease (PD) and related disorders (including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia, myofibrillar myopathies (such as inclusion body myositis, inclusion bo...

Claims

1. A TDP-43 binding molecule that specifically binds to phosphorylated TDP-43, wherein the binding molecule comprises: 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) 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, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 113, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:

117.

2. The TDP-43 binding molecule of claim 1, wherein the binding molecule according to any one of (a), (c), (f) or (g) binds to TDP-43 positive inclusion bodies.

3. The TDP-43 binding molecule of claim 2, wherein binding to TDP-43 positive inclusion bodies is determined by immunohistochemistry.

4. The TDP-43 binding molecule of any of the preceding claims, 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 to an equivalent epitope in non-human TDP-43.

5. The TDP-43 binding molecule of any one of the preceding claims, which binds to an epitope of human TDP-43 (SEQ ID NO: 1) comprising phosphorylated amino acid residues pS403 and / or pS404, or to an equivalent epitope in non-human TDP-43.

6. The TDP-43 binding molecule of claim 5, which binds to the epitope with a KD of 13 nM or less, preferably 5 nM or less, preferably 2 nM or less, preferably wherein the epitope comprises or consists of GFNGGFG(pS)(pS)MDSKS (SEQ ID NO: 8) corresponding to amino acids 396 to 409 of SEQ ID NO: 1, more preferably wherein the KD is measured by surface plasmon resonance.

7. The TDP-43 binding molecule of any one of claims 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 binds to an equivalent epitope in non-human TDP-43.

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

9. The TDP-43 binding molecule of any one of claims 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 binds to an equivalent epitope in non-human TDP-43.

10. The TDP-43 binding molecule of claim 9, which binds to the 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 acids 370 to 384 of SEQ ID NO:1, more preferably wherein the KD is measured by surface plasmon resonance.

11. A TDP-43 binding molecule, preferably one that binds to phosphorylated TDP-43, the TDP-43 binding molecule comprising: 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. 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 i. 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, a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 113, a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 115, a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 116, and a VL-CDR3 comprising the amino acid sequence of SEQ ID NO:

117.

12. A TDP-43 binding molecule that binds to TDP-43-positive endosomes, wherein the binding molecule comprises: 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: 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 c. 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 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. 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.

13. A TDP-43 binding molecule that binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43, wherein the TDP-43 binding molecule comprises 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.

14. The TDP-43 binding molecule of claim 13, which binds to an epitope within amino acid residues 361 to 414 of human TDP-43 (SEQ ID NO: 1) or to an equivalent epitope in non-human TDP-43.

15. The TDP-43 binding molecule of any one of claims 13 or 14, 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.

16. The TDP-43 binding molecule of any preceding claim, comprising: a. a heavy chain variable region (VH) comprising the sequence of SEQ ID NO: 10, or a heavy chain variable region (VH) having at least 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 14, or 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) comprising 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) comprising 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) comprising 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) comprising 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) comprising the sequence of SEQ ID NO: 40, or a heavy chain variable region (VH) having 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 40; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 44, or a light chain variable region (VL) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with 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 with the amino acid sequence of SEQ ID NO: 60; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 64; or 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 a heavy chain variable region (VH) having at least 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 80; and a light chain variable region (VL) comprising the sequence of SEQ ID NO: 84, or a light chain variable region (VL) having at least 97%, 98% or 99% sequence identity with 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.

17. The TDP-43 binding molecule of any preceding claim, which is an antibody or an antigen-binding fragment thereof.

18. The TDP-43 binding molecule of any of the preceding claims, which is an IgA, IgD, IgE, IgM, IgGl, IgG2, IgG2a, IgG2b, IgG3 or IgG4 antibody, or an antigen-binding fragment thereof.

19. The TDP-43 binding molecule of any of the preceding claims, wherein the binding molecule is an immunoconjugate.

20. The TDP-43 binding molecule of claim 19, wherein the immunoconjugate comprises paramagnetic beads.

21. The TDP-43 binding molecule of claim 19, wherein the immunoconjugate comprises biotin.

22. The TDP-43 binding molecule of claim 19, wherein the immunoconjugate comprises an additional therapeutic molecule.

23. A TDP-43 binding molecule as claimed in any preceding claim for use in human or veterinary therapy and / or diagnosis.

24. The TDP-43 binding molecule for use according to claim 23, wherein the TDP-43 binding molecule is a therapeutic tool or a diagnostic tool.

25. The TDP-43 binding molecule of any one of claims 1 to 22 for use in research applications, in particular as an analytical tool or reference molecule.

26. The TDP-43 binding molecule of any one of claims 1 to 22, for use in preventing, alleviating, treating and / or diagnosing a disease, disorder and / or abnormality associated with TDP-43.

27. The TDP-43 binding molecule according to any one of claims 1 to 22, for use in preventing, alleviating, treating and / or diagnosing TDP-43 proteinopathy.

28. The TDP-43 binding molecule for use according to claim 27, wherein the TDP-43 binding molecule is used as a diagnostic tool for diagnosing or monitoring TDP-43 proteinopathy.

29. The TDP-43 binding molecule for use according to claim 27 or 28, wherein the TDP-43 proteinopathy is any one of the following: a. A disease, disorder and / or abnormality associated with TDP-43 aggregation selected from 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 syndrome (DS), familial English dementia, Parkinson's disease (PD) and related disorders (including PD dementia (PDD), dementia with Lewy bodies (DLB) , multiple system atrophy (MSA), corticobasal degeneration (CBD), Niemann-Pick disease (NP, including NP type C), facial-onset sensory motor neuronopathy (FOSMN), limbic-dominant age-related TDP-43 encephalopathy (LATE), chronic traumatic encephalopathy, Perry syndrome, Paget's disease, polyglutamine diseases (such as Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3, also known as Machado-Joseph disease)), hippocampal sclerosis with dementia, myofibrillar myopathies (such as 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), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), TMEM106B, huntingtin (HTT), and ataxia-associated protein 3 (ATXN3) genes.

30. The TDP-43 binding molecule for use according to any one of claims 27 to 29, wherein the TDP-43 proteinopathy is any one of the following: a. a disease, disorder and / or abnormality associated with TDP-43 aggregates selected from 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 syndrome (DS), Parkinson's disease (PD) and related disorders (including PD dementia (PDD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA)), limbic dominant age-related 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 of the progranulin (GRN), TARDBP, C9ORF72, valosin-containing protein (VCP), angiogenic protein (ANG), desmin (DES), myotilin (MYOT), or TMEM106B genes.

31. A TDP-43 binding molecule for use according to any one of claims 27 to 30, wherein the disease, disorder and / or abnormality associated with TDP-43, or the TDP-43 proteinopathy is amyotrophic lateral sclerosis (ALS).

32. A TDP-43 binding molecule for use according to any one of claims 27 to 30, wherein the disease, disorder and / or abnormality associated with TDP-43, or the TDP-43 proteinopathy is Alzheimer's disease (AD).

33. A TDP-43 binding molecule for use according to any one of claims 27 to 30, wherein the disease, disorder and / or abnormality associated with TDP-43, or the TDP-43 proteinopathy is frontotemporal dementia (FTD).

34. The TDP-43 binding molecule for use according to claims 27 to 30, wherein the disease, disorder and / or abnormality associated with TDP-43, or the TDP-43 proteinopathy is Limbic Predominant Age-related TDP-43 Encephalopathy (LATE).

35. The TDP-43 binding molecule for use according to any one of claims 27 to 30, wherein the disease, disorder and / or abnormality associated with TDP-43, or the TDP-43 proteinopathy is frontotemporal lobar degeneration with motor neuron disease FTLD-MND.

36. A pharmaceutical composition comprising the TDP-43 binding molecule of any one of claims 1 to 22 and a pharmaceutically acceptable carrier and / or excipient.

37. A diagnostic composition comprising a TDP-43 binding molecule according to any one of claims 1 to 22 and an acceptable carrier and / or excipient.

38. A nucleic acid molecule encoding the TDP-43 binding molecule of any one of claims 1 to 22.

39. The nucleic acid molecule of claim 38, comprising the nucleotide sequence of 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.

40. A recombinant vector comprising the nucleic acid of claim 38 or 39.

41. A host cell comprising the nucleic acid of claim 38 or 39 and / or the vector of claim 40.

42. A host cell expressing a TDP-43 binding molecule according to any one of claims 1 to 22.

43. An expression vector comprising the nucleic acid molecule of claim 38 or 39.

44. A cell-free expression system comprising the expression vector of claim 43.

45. A method for producing a TDP-43 binding molecule, in particular an antibody or an antigen-binding fragment thereof, the method comprising the steps of: a. culturing the host cell according to claim 41 or 42 or the cell-free expression system according to claim 44 under conditions suitable for producing the binding molecule, in particular the antibody or antigen-binding fragment thereof; and b. isolating the binding molecule, in particular the antibody or antigen-binding fragment thereof.

46. ​​The TDP-43 binding molecule of any one of claims 1 to 22, for use in detecting and / or quantifying TDP-43 in a sample, wherein the sample is saliva, urine, nasal secretions, blood (including whole blood, plasma and serum, platelet-rich plasma, platelet cytosol fraction), brain and / or CSF sample, brain and / or ISF sample, more particularly blood, brain, CSF and / or ISF sample.

47. The TDP-43 binding molecule of any one of claims 1 to 22, for use in detecting and / or quantifying phosphorylated TDP-43 in a sample, wherein the sample is saliva, urine, nasal secretions, blood (including whole blood, plasma and serum, platelet-rich plasma, platelet cytosol fraction), brain and / or CSF sample, brain and / or ISF sample, more particularly blood, brain, CSF and / or ISF sample.

48. Use of the TDP-43 binding molecule of any one of claims 1 to 22 in a pairing assay, the pairing assay comprising the steps of: a. Incubating the sample with the capture antibody and the detection antibody; 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; Wherein the capture antibody is selected from the group consisting of antibodies as defined in any one of claims 1 to 22.

49. Use of a TDP-43 binding molecule according to claim 48, wherein the detection antibody is selected from the antibodies defined in any one of claims 1 to 22.

50. The use of a TDP-43 binding molecule according to claim 48 or 49, wherein the agent is streptavidin-β-D-galactosidase.

51. Use of a TDP-43 binding molecule according to any one of claims 48 to 50, wherein the capture antibody and / or detection antibody binds to phosphorylated TDP-43, preferably specifically binds to phosphorylated TDP-43.

52. Use of a TDP-43 binding molecule according to any one of claims 48 to 50, wherein the capture antibody and / or detection antibody binds to misfolded aggregated TDP-43 and non-aggregated physiological TDP-43.

53. The use of a TDP-43 binding molecule according to any one of claims 48 to 52, wherein the capture antibody comprises: 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.

54. The use of a TDP-43 binding molecule according to any one of claims 48 to 53, wherein the detection antibody comprises: 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. 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.

55. The use of a TDP-43 binding molecule according to claim 53 or 54, wherein the detection antibody comprises: a. 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: b. 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.

56. The use of the TDP-43 binding molecule of claim 53 or 54, wherein the detection antibody comprises: a. 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: b. 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.

57. The use of the TDP-43 binding molecule of claim 53 or 54, wherein the detection antibody comprises: a. 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: b. 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.

58. The use of the TDP-43 binding molecule of claim 53 or 54, wherein the detection antibody comprises: a. 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: b. 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.

59. A method for quantifying phosphorylated TDP-43 in a sample, the method comprising contacting the sample with a TDP-43 binding molecule according to any one of claims 1 to 22.

60. The quantification method of claim 59, wherein the sample is obtained from a subject.

61. The method of claim 60, wherein the sample is human blood, cerebrospinal fluid (CSF), interstitial fluid (ISF), saliva, nasal secretions and / or urine, preferably blood, CSF or ISF.

62. The quantification method of any one of claims 59 to 61, further comprising comparing the level of TDP-43 detected from the sample to a control.

63. The quantification method of claim 62, wherein the control comprises phosphorylated TDP-43.

64. The quantification method of claim 62 or 63, wherein the control is determined using a known amount of a calibrator for phosphorylated TDP-43.

65. A method for quantifying phosphorylated TDP-43 in a sample obtained from a subject, the method comprising using the TDP-43 binding molecule of any one of claims 48 to 58.

66. A method of 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 of any one of claims 1 to 22, wherein; a. a change in the level of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples is indicative of a change in a disease, disorder and / or condition associated with TDP-43; or b. The absence of a significant change in the level of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates that the disease, disorder and / or condition associated with TDP-43 has not changed.

67. A method of 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 of any one of claims 1 to 22, wherein; a. a higher level of TDP-43 and / or phosphorylated 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 b. a lower level of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates regression of a disease, disorder, and / or condition associated with TDP-43; or c. The absence of a significant change in the level of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates that the disease, disorder and / or condition associated with TDP-43 has not progressed.

68. A method of 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 of any one of claims 1 to 22, wherein; a. a higher level of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates regression of a disease, disorder, and / or condition associated with TDP-43; or b. lower levels of TDP-43 and / or phosphorylated 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 absence of a significant change in the level of TDP-43 and / or phosphorylated TDP-43 in a later sample compared to one or more earlier samples indicates that the disease, disorder and / or condition associated with TDP-43 has not progressed.

69. The method of any one of claims 66 to 68, performed at multiple time points in matched samples between treatment and placebo groups to monitor the effectiveness of the candidate treatment over a defined period of time.

70. A kit for diagnosing a disease, disorder and / or abnormality associated with TDP-43 or a TDP-43 proteinopathy, or for use in the method of any one of claims 59 to 69, comprising a TDP-43 binding molecule according to any one of claims 1 to 22.

71. The kit of claim 70, comprising a TDP-43 binding molecule according to any one of claims 1 to 22 as a capture antibody and a different TDP-43 binding molecule according to any one of claims 1 to 22 as a detection antibody.

72. The kit of claim 71, wherein the kit further comprises magnetic particles, the capture antibody being attached to the magnetic particles or being attachable to the magnetic particles.

73. The kit of claim 71 or 72, wherein the detection antibody is directly or indirectly labeled.

74. The kit of any one of claims 71 to 73, further comprising a container comprising the TDP-43 binding molecule.

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