Antitmem106b antibodies and methods of use thereof

Abstract

The present disclosure relates generally to compositions comprising antibodies (e.g., monoclonal antibodies, antibody fragments, etc.) that specifically bind to a TMEM106B polypeptide (e.g., mammalian TMEM106B or human TMEM106B), and the use of such compositions in preventing, reducing risk, or treating an individual in need thereof.

Description

[0001] This application is a divisional application of an invention patent application with an application date of December 21, 2018, application number 201880090231.2, and invention name “Anti-TMEM106B antibodies and methods of use thereof”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 612,098, filed December 29, 2017, which is hereby incorporated by reference in its entirety.

[0004] Submission of sequence listing as ASCII text file

[0005] The following content submitted as an ASCII text file is incorporated herein by reference in its entirety: Computer Readable Form (CRF) of the Sequence Listing (File Name: 735022002040SEQLIST.TXT, Record Date: December 19, 2018, Size: 169KB). Technical Field

[0006] The present disclosure relates to anti-TMEM106B antibodies and therapeutic uses of such antibodies. Background Art

[0007] Transmembrane protein 106B (TMEM106B) is a type 2 single-pass transmembrane glycoprotein that is primarily found in the membranes of late endosomes and lysosomes. (See, e.g., Lang et al., 2012, J Biol Chem, 287: 19355-19365; Chen-Plotkin et al., 2012, J Neurosci, 32: 11213-11227; Brady et al., 2013, Human Molecular Genetics, 22: 685-695.) TMEM106B is widely expressed in human tissues, and its expression in neurons, glial cells, and endothelial and perivascular cells in the brain is particularly noteworthy. TMEM106B is highly conserved in mammals, with human proteins sharing 99% sequence identity with cynomolgus monkey variants and 97% sequence identity with murine orthologs.

[0008] TMEM106B has a cytoplasmic domain predicted to be in the range of (human TMEM106B; SEQ ID NO: 1) amino acid residues 1-92, a transmembrane domain predicted to be in the range of amino acid residues 96-117, and a luminal domain predicted to be in the range of amino acid residues 118-274. Five sequence motifs of post-translational N-glycosylation sites (NXT / S) span its luminal domain. Simple glycans are added to three asparagine residues (N145, N151, and N164) and are not critical for TMEM106B positioning. Complex glycans are added to most C-terminal motifs at N183 and N256; The loss of complex glycans on N183 impairs the forward transport of TMEM106B to endosomes / lysosomes and causes endoplasmic reticulum retention. In addition, N256 complex glycosylation is necessary for proper TMEM106B sorting. (See, e.g., Nicholson and Rademakers, 2016, Acta Neuropathol, 132:639-651.)

[0009] The function of TMEM106B has not been fully characterized. Recent reports have shown the role of TMEM106B in dendritic branching, morphogenesis, and maintenance by inhibiting lysosomal transport along dendrites. (See, for example, Brady et al., 2013, Human Molecular Genetics, 126: 696-698; Schwenk et al., 2014, EMBO J, 33: 450-467; Clayton et al., 2018, Brain 141 (12): 3428-3442.)

[0010] TMEM106B has been shown to interact with a variety of proteins including, but not limited to, progranulin (GRN), other TMEM106 protein family members such as TMEM106A and TMEM106C, clathrin heavy chain (CLTC), μ1 subunit of adipocyte protein 2 (AP2M1), charged multivesicular protein 2b (CHMP2B), microtubule-associated protein 6 (MAP6), lysosomal-associated membrane protein 1 (LAMP1), and vacuolar-ATPase subunit accessory protein 1 (v-ATPase Ap1).

[0011] TMEM106B is genetically associated with a variety of disorders and diseases, especially neurodegenerative disorders. Such disorders include, but are not limited to, conditions characterized by the presence of pathological TDP-43 inclusions (i.e., TDP-43 proteinopathy; transactivation response DNA binding protein 43), frontotemporal lobar degeneration (FTLD), FTLD with TDP-43 inclusions (FTLD-TDP) (including FTLD-TDP caused by progranulin (GRN) or C90rf72 mutations), TDP-43 proteinopathy, Alzheimer's disease. Lewy body dementia (LBD), hippocampal sclerosis (HpScl), aging hippocampal sclerosis (HS-aging), hypomyelination leukodystrophy, and cognitive impairment in various disorders (such as amyotrophic lateral sclerosis (ALS)). TMEM106B is also associated with metastasis in non-small cell lung cancer (Kundu et al., 2016; Nature Commun. 2018; 9:2731, Cancer Research, Proceedings of the 107 th Annual Meeting of the American Association for Cancer Research, Abstract No. 688). TMEM106B is also associated with chronic traumatic encephalopathy (CTE)-associated neuropathology and dementia in CTE patients, including changes in AT8tau deposition, CD68 cell density, and PSD-95 concentrations (Cherry et al., 2018, Acta Neuropathol Commun. 6: 115).

[0012] Therefore, there is a need for therapies that target TMEM106B (including therapeutic antibodies that specifically bind to TMEM106B) and / or therapies that can inhibit the activity of TMEM106B (such as by reducing TMEM106B protein levels or function or by blocking or reducing the binding of TMEM106B to one or more of its ligands or binding partners, or otherwise modulating the effective concentration of one or more of its ligands or binding partners) to treat various diseases, disorders and conditions associated with TMEM106B activity.

[0013] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. Summary of the invention

[0014] The present disclosure generally relates to anti-TMEM106B antibodies and methods of using such antibodies. The methods provided herein can be used to prevent neurodegenerative diseases, disorders or conditions, reduce the risk of neurodegenerative diseases, disorders or conditions, or treat individuals with neurodegenerative diseases, disorders or conditions. In some embodiments, the present invention provides a method for preventing a disease, disorder or injury, reducing the risk of a disease, disorder or injury, or treating an individual with a disease, disorder or injury, wherein the disease, disorder or injury is selected from the group consisting of: a neurodegenerative disease, a disorder characterized by the presence of TDP-43 inclusions, a TDP-43 proteinopathy, inflammatory cell debris or protein aggregates, abnormal circulating bone marrow cells, unhealthy aging, frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), FTD with progranulin mutations, FTD with C90rf72 mutations, frontotemporal lobar degeneration with TDP-43 inclusions, hippocampal sclerosis (HpScl) , hippocampal sclerosis with aging (HS-aging), Alzheimer's disease, dementia with Lewy bodies, cognitive impairment, age-related cognitive impairment, age-related brain atrophy, age-related traits (including but not limited to inflammation), neuronal loss and cognitive deficits (such as cognitive deficits in the absence of known brain diseases, including cognitive deficits in the frontal cerebral cortex of elderly individuals, cognitive deficits in amyotrophic lateral sclerosis, cognitive deficits in chronic traumatic encephalopathy (CTE)), diseases, disorders and conditions associated with overexpression or increased activity of TMEM106B, hypomyelination disorders, cancer and metastasis, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0015] Thus, certain aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-TMEM106B antibody, wherein the anti-TMEM106B antibody has a property selected from the group consisting of reducing cellular levels of TMEM106B, reducing intracellular levels of TMEM106B, inhibiting or reducing the interaction of TMEM106B with one or more of its ligands or binding proteins, and any combination thereof.

[0016] In certain embodiments that can be combined with any one of the foregoing embodiments, the antibody reduces the cell surface level of TMEM106B, reduces the intracellular level of TMEM106B, reduces the total level of TMEM106B, reduces the intracellular level of TMEM106B, reduces the lysosomal level of TMEM106B, or any combination thereof. In certain embodiments that can be combined with any one of the foregoing embodiments, anti-TMEM106B antibodies induce TMEM106B degradation, TMEM106B cutting, TMEM106B internalization, TMEM106B downregulation, or any combination thereof. In certain embodiments that can be combined with any one of the foregoing embodiments, anti-TMEM106B antibodies reduce the cell level of TMEM106B in vivo. In certain embodiments that can be combined with any one of the foregoing embodiments, anti-TMEM106B antibodies reduce the cell level of TMEM106B in the brain. In certain embodiments that can be combined with any one of the foregoing embodiments, anti-TMEM106B antibodies reduce the cell level of TMEM106B in one or more peripheral organs. In certain embodiments that can be combined with any of the preceding embodiments, anti-TMEM106B antibodies reduce the cellular level of TMEM106B in the brain, one or more peripheral organs, or any combination thereof. In certain embodiments that can be combined with any of the preceding embodiments, anti-TMEM106B antibodies reduce the cellular level of TMEM106B in microglia. In certain embodiments that can be combined with any of the preceding embodiments, anti-TMEM106B antibodies reduce the cellular level of TMEM106B in neurons.

[0017] In certain embodiments that may be combined with any of the preceding embodiments, the anti-TMEM106B antibody inhibits or reduces one or more interactions between TMEM106B and progranulin, other TMEM106 protein family members (such as TMEM106B and TMEM106C), clathrin heavy chain (CLTC), μ1 subunit of adipocyte protein 2 (AP2M1), CHMP2B, microtubule-associated protein 6 (MAP6), lysosomal-associated membrane protein 1 (LAMP1), vacuolar-ATPase subunit accessory protein 1, or any protein or polypeptide that regulates the function of TMEM106B.

[0018] In certain embodiments that can be combined with any one of the preceding embodiments, the anti-TMEM106B antibodies of the present disclosure bind to discontinuous TMEM106B epitopes. In certain embodiments that can be combined with any one of the preceding embodiments, the discontinuous TMEM106B epitopes comprise two or more peptides, three or more peptides, four or more peptides, five or more peptides, six or more peptides, seven or more peptides, eight or more peptides, nine or more peptides, or 10 or more peptides. In certain embodiments that may be combined with any of the preceding embodiments, each peptide comprises five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, or 30 or more amino acid residues of the amino acid sequence of SEQ ID NO: 1, the amino acid sequence of SEQ ID NO: 2, or the amino acid sequence of SEQ ID NO: 315; or corresponds to the amino acid sequence of SEQ ID NO: 1, the amino acid sequence of SEQ ID NO: 2, or the amino acid sequence of SEQ ID NO: 315. In some embodiments, the present invention comprises five or more, six or more, seven or more, eight or more, nine or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, or 30 or more amino acid residues on a mammalian TMEM106B protein having the amino acid sequence of NO:315.

[0019] In certain embodiments that may be combined with any of the preceding embodiments, the anti-TMEM106B antibodies of the present disclosure bind to a conformational epitope of TMEM106B.

[0020] In certain embodiments that may be combined with any of the preceding embodiments, the anti-TMEM106B antibodies of the present disclosure compete for binding to TMEM106B with one or more reference anti-TMEM106B antibodies selected from the group consisting of TM-1, TM-17, TM-22, TM-23, TM-26, and TM-27, and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-TMEM106B antibodies of the present disclosure compete for binding to TMEM106B with one or more reference anti-TMEM106B antibodies selected from the group consisting of TM-2, TM-3, TM-5, TM-7, TM-9, TM-10, TM-11, TM-12, TM-13, TM-18, TM-19, TM-21, TM-25, TM-28, TM-29, TM-32, TM-35, TM-37, TM-39, TM-42, TM-45, TM-48, and TM-53, and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-TMEM106B antibodies of the present disclosure compete with one or more reference anti-TMEM106B antibodies for binding to TMEM106B selected from the group consisting of TM-4, TM-6, TM-8, TM-14, TM-15, TM-16, TM-20, TM-31, TM-33, TM-34, TM-36, TM-41, TM-44, TM-46, TM-47, TM-49, TM-50, TM-51, TM-52, and any combination thereof. In some embodiments, the reference anti-TMEM106B antibody comprises a V H and V L : TM-4, TM-6, TM-8, TM-14, TM-15, TM-16, TM-20, TM-31, TM-33, TM-34, TM-36, TM-41, TM-44, TM-46, TM-47, TM-49, TM-50, TM-51, TM-52 and any combination thereof.

[0021] Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-TMEM106B antibody, wherein the anti-TMEM106B antibody comprises at least one, two, three, four, five, or six HVRs of an antibody selected from the group consisting of: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-5 0. TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM -37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53. In some embodiments, the anti-TMEM106B antibody comprises six HVRs of an antibody selected from the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-53, TM-54, TM-55 3. TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38 , TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53.

[0022] Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-TMEM106B antibody that binds to substantially the same TMEM106B epitope as a reference anti-TMEM106B antibody, the anti-TMEM106B antibody comprising six HVRs of an antibody selected from the group consisting of: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35 18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, and TM-53. In some embodiments, the reference anti-TMEM106B antibody comprises a V H and V L (For example, as shown in Table 4B below): TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-1 3. TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, T M-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM- 40. TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53.

[0023] Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) anti-TMEM106B antibody that binds to one or more amino acids within amino acid residues 59-73, 80-90, 5-19, 59-69, 52-62, 64-74, 151-165, 185-195, 139-149, 248-258, 156-161, 202-207, 219-233, 126-140, 185-195, 260-274, 202-212, 151-161, 223-233, 143-153, 223-228, 133-145, and / or 198-212 of human TMEM106B (SEQ ID NO: 1).

[0024] In some embodiments of the present disclosure, anti-TMEM106B antibodies bind to one or more amino acids within amino acid residues 151-165 and / or 185-195. In some embodiments of the present disclosure, anti-TMEM106B antibodies bind to one or more amino acids within amino acid residues 59-73, 80-90, 139-149 and / or 248-258 of human TMEM106B (SEQ ID NO: 1). In some embodiments, anti-TMEM106B antibodies bind to one or more amino acids within amino acid residues 5-19, 156-161, 202-207 and / or 219-233 of human TMEM106B (SEQ ID NO: 1). In some embodiments, anti-TMEM106B antibodies bind to one or more amino acids within amino acid residues 126-140, 185-195 and / or 260-274 of human TMEM106B (SEQ ID NO: 1). In some embodiments, the anti-TMEM106B antibody binds to one or more amino acids within amino acid residues 202-212 of human TMEM106B (SEQ ID NO: 1). In some embodiments, the anti-TMEM106B antibody binds to one or more amino acids within amino acid residues 151-161 and / or 223-233 of human TMEM106B (SEQ ID NO: 1). In some embodiments, the anti-TMEM106B antibody binds to one or more amino acids within amino acid residues 59-69, 143-153 and / or 223-228 of human TMEM106B (SEQ ID NO: 1). In some embodiments, the anti-TMEM106B antibody binds to one or more amino acids within amino acid residues 133-145 and / or 198-212 of human TMEM106B (SEQ ID NO: 1). In some embodiments, the anti-TMEM106B antibody binds to one or more amino acids within amino acid residues 52-62, 64-75, and / or 223-228 of human TMEM106B (SEQ ID NO: 1).

[0025] Other aspects of the present disclosure relate to an isolated anti-TMEM106B antibody that binds to the amino acid sequence NITNNNYYSVEVENI (SEQ ID NO: 324), TIIGPLDMKQI (SEQ ID NO: 325), VTCPTCQGTGRIPRG (SEQ ID NO: 326), (ALIPYSDQRLR (SEQ ID NO: 327), (KRTIYLNITNT (SEQ ID NO: 328), YQYVDCGRNTT (SEQ ID NO: 329), (LSHLPLHSSKEDAYD (SEQ ID NO: 332), (NYYSVE (SEQ ID NO: 334), (VIAEEM (SEQ ID NO: 335), (IKVHNIVLMMQVTVT; SEQ ID NO: 336), (IGVKSAYVSYDVQKR; SEQ ID NO: 337), (QLGQSEYLNVLQPQQ (SEQ ID NO: NO: 338), (VIAEEMSYMYD (SEQ ID NO: 340), (NITNNNYYSVE (SEQ ID NO: 341), (NIVLMMQVTV (SEQ ID NO: 342), (VTCPTCQGTGR (SEQ ID NO: 343), (YLNITNTLNIT (SEQ ID NO: 344), (NIVLMM (SEQ ID NO: 345), (VSYDVQKRTIYLN (SEQ ID NO: 346), (TVPTVIAEEMSYMYD (SEQ ID NO: 347), (EFTGRDSVTCP (SEQ ID NO: 348) and / or (CQGTGRIPRGQE (SEQ ID NO: 349)).

[0026] In certain embodiments that can be combined with any of the foregoing embodiments, the anti-TMEM106B antibody further inhibits the interaction between TMEM106B and its ligands, signaling proteins, or binding proteins by: a) reducing the effective level of TMEM106B available for interaction with one or more ligands or binding proteins; b); blocking one or more of the sites on TMEM106B required for interaction with one or more ligands or binding proteins; c) preventing one or more post-translational events on TMEM106B required for interaction with one or more ligands or binding proteins and / or correction of TMEM106B processing and / or subcellular localization; d) inducing degradation of TMEM106B; e) changing the conformation of TMEM106B, or both of them. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-TMEM106B antibody specifically binds to human TMEM106B, mouse TMEM106B, cynomolgus monkey TMEM106B, or a combination thereof. In certain embodiments that can be combined with any one of the foregoing embodiments, the anti-TMEM106B antibody is a human antibody, a humanized antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody or a chimeric antibody. In certain embodiments that can be combined with any one of the foregoing embodiments, the anti-TMEM106B antibody is a bispecific antibody that recognizes a first antigen and a second antigen. In certain embodiments that can be combined with any one of the foregoing embodiments, the first antigen is TMEM106B, and the second antigen is an antigen that is conducive to transport across the blood-brain barrier. In certain embodiments that may be combined with any of the preceding embodiments, the second antigen is selected from the group consisting of: TMEM106B, transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, llama single domain antibody, TMEM 30 (A), protein transduction domain, TAT, Syn-B, transmembrane peptide, polyarginine peptide, angiopep, basic immunoglobulin (basigin), Glut1 and CD98hc and ANG1005.

[0027] In certain embodiments that may be combined with any of the preceding embodiments, the anti-TMEM106B antibodies of the present disclosure increase the expression of TGFβ.

[0028] In some embodiments that can be combined with any one of the foregoing embodiments, the antibody is a monoclonal antibody. In some embodiments that can be combined with any one of the foregoing embodiments, the antibody belongs to IgG class, IgM class or IgA class. In some embodiments, the antibody belongs to IgG class and has IgG1, IgG2 or IgG4 isotype. In certain embodiments that can be combined with any one of the foregoing embodiments, anti-TMEM106B antibodies are antibody fragments that are bound to the epitope of the amino acid residues on the human TMEM106B or mammal TMEM106B protein. In certain embodiments that can be combined with any one of the foregoing embodiments, the fragment is Fab, Fab', Fab'-SH, F(ab')2, Fv or scFv fragment. In some embodiments that can be combined with any one of the foregoing embodiments, the antibody is a humanized antibody or a chimeric antibody.

[0029] Other aspects of the present disclosure relate to a separated nucleic acid comprising a nucleic acid sequence encoding an anti-TMEM106B antibody of any one of the aforementioned embodiments. Other aspects of the present disclosure relate to a vector comprising a nucleic acid of any one of the aforementioned embodiments. Other aspects of the present disclosure relate to a separated host cell, the host cell comprising a vector of any one of the aforementioned embodiments. Other aspects of the present disclosure relate to a method for producing an anti-TMEM106B antibody, the method comprising culturing a host cell of any one of the aforementioned embodiments, thereby producing an anti-TMEM106B antibody. In certain embodiments, the method further comprises recovering the anti-TMEM106B antibody produced by the host cell. Other aspects of the present disclosure relate to a separated anti-TMEM106B antibody produced by the method of any one of the aforementioned embodiments. Other aspects of the present disclosure relate to a pharmaceutical composition comprising an anti-TMEM106B antibody of any one of the aforementioned embodiments and a pharmaceutically acceptable carrier.

[0030] Other aspects of the present disclosure relate to a method of preventing, reducing the risk of, or treating a subject having a disease, disorder, or injury selected from the group consisting of frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, non-traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, adverse symptoms of normal aging, dementia, mixed dementia, Creutzfeldt- Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, Lewy body dementia, multiple system atrophy, degenerative disc disease, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disease, sarcoidosis, diseases of aging, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, inflammatory disease, arthritis, multiple sclerosis, metabolic disorders, obesity, insulin resistance, type 2 diabetes, tissue or vascular damage, injury, inflammatory cell debris or protein aggregates, abnormal circulating bone marrow cells, unhealthy aging, age-related cognitive impairment, age-related brain atrophy, age-related traits (including but not limited to inflammation), neuronal loss and cognitive deficits (such as cognitive deficits in the absence of known brain diseases, including cognitive deficits in the frontal cerebral cortex of elderly individuals and one or more adverse symptoms of normal aging), the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody of any one of the preceding embodiments to an individual.Other aspects of the present disclosure relate to an anti-TMEM106B antibody of any of the preceding embodiments for use in preventing, reducing the risk of, or treating a subject having a disease, disorder, or injury selected from the group consisting of frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, adverse symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, Multiple system atrophy, degenerative disc disease, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglia degeneration, acute disseminated encephalomyelitis, granulomatous disease, sarcoidosis, diseases of aging, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, inflammatory disease, arthritis, multiple sclerosis, metabolic disorders, obesity, insulin resistance, type 2 diabetes, tissue or vascular damage, injury, inflammatory cell debris or protein aggregates, abnormal circulating bone marrow cells, unhealthy aging, age-related cognitive impairment, age-related brain atrophy, age-related traits (including but not limited to inflammation), neuronal loss and cognitive deficits (such as cognitive deficits in the absence of known brain diseases, including cognitive deficits in the frontal lobe cerebral cortex of elderly individuals and one or more adverse symptoms of normal aging). Other aspects of the present disclosure relate to an anti-TMEM106B antibody of any one of the aforementioned embodiments for preventing or reducing metastasis. Other aspects of the present disclosure relate to an anti-TMEM106B antibody of any of the preceding embodiments for use in preventing cancer, reducing the risk of cancer, or treating an individual with cancer.

[0031] Other aspects of the present disclosure relate to the use of an anti-TMEM106B antibody of any of the foregoing embodiments for the manufacture of a medicament for preventing, reducing the risk of, or treating a subject having a disease, disorder, or injury selected from the group consisting of frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, non-traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, adverse symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, Lewy dementia, multiple system atrophy, degenerative disc disease, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglia degeneration, acute disseminated encephalomyelitis, granulomatous diseases, sarcoidosis, diseases of aging, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infections, sepsis, eye infections, systemic infections, inflammatory diseases, arthritis, multiple sclerosis, metabolic disorders, obesity, insulin resistance, type 2 diabetes, tissue or vascular damage, injury, inflammatory cell debris or protein aggregates, abnormalities of circulating myeloid cells, unhealthy aging, age-related cognitive impairment, age-related brain atrophy, age-related traits (including but not limited to inflammation), neuronal loss and cognitive deficits (such as cognitive deficits in the absence of known brain diseases, including cognitive deficits in the frontal cerebral cortex of elderly individuals and one or more adverse symptoms of normal aging). Other aspects of the present disclosure relate to a method of preventing, reducing the risk of, or treating a subject having a disease, disorder, or injury selected from the group consisting of frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, dementia, stroke, Parkinson's disease, acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis, and osteoarthritis, comprising administering to the subject a therapeutically effective amount of an anti-TMEM106B antibody of any one of the preceding embodiments.Other aspects of the present disclosure relate to an anti-TMEM106B antibody of any of the preceding embodiments for preventing a disease, disorder or injury, reducing the risk of a disease, disorder or injury, or treating an individual with a disease, disorder or injury, wherein the disease, disorder or injury is selected from the group consisting of frontotemporal dementia, progressive supranuclear palsy, Alzheimer's disease, vascular dementia, epileptic seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, dementia, stroke, Parkinson's disease, acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis, and osteoarthritis. Other aspects of the present disclosure relate to the use of an anti-TMEM106B antibody of any of the preceding embodiments for the manufacture of a medicament for preventing a disease, disorder or injury, reducing the risk of a disease, disorder or injury, or treating an individual with a disease, disorder or injury, wherein the disease, disorder or injury is selected from the group consisting of frontotemporal dementia, progressive supranuclear palsy. Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, amyotrophic lateral sclerosis, traumatic brain injury, spinal cord injury, dementia, stroke, Parkinson's disease, acute disseminated encephalomyelitis, retinal degeneration, age-related macular degeneration, glaucoma, multiple sclerosis, septic shock, bacterial infection, arthritis and osteoarthritis.

[0032] In certain embodiments that may be combined with any of the preceding embodiments, the anti-TMEM106B antibody comprises two or more anti-TMEM106B antibodies.

[0033] It should be understood that one, some or all of the properties of the various embodiments described herein can be combined to form other embodiments of the present invention. These and other aspects of the present invention will be apparent to those skilled in the art. These and other embodiments of the present invention are further described by the following specific embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Listed are data showing the percentage of downregulation (DR) of TMEM106B in A549 cells following addition of various anti-TMEM106B antibodies of the present disclosure.

[0035] Figure 2 Listed are data showing the percent downregulation of TMEM106B in A549 cells following addition of various anti-TMEM106B antibodies of the present disclosure. DETAILED DESCRIPTION

[0036] The present disclosure relates to anti-TMEM106B antibodies (eg, monoclonal antibodies); and methods of making and using such antibodies; pharmaceutical compositions comprising such antibodies; nucleic acids encoding such antibodies; and host cells comprising nucleic acids encoding such antibodies.

[0037] The techniques and procedures described or referenced herein are well understood and generally adapted by those skilled in the art using conventional methods, such as widely used methods such as those described in Sambrook et al. Molecular Cloning: A Laboratory Manual 3rd ed. (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FM Ausubel et al., eds., (2003); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000).

[0038] I. Definitions

[0039] Unless otherwise indicated, the terms "TMEM106B" or "TMEM106B polypeptide" are used interchangeably herein and refer to any native TMEM106B from any vertebrate source, including mammals, such as primates (e.g., humans and cynomolgus monkeys) and rodents (e.g., mice and rats). In some embodiments, the term encompasses both wild-type sequences and naturally occurring variant sequences (e.g., splice variants or allelic variants). In some embodiments, the term encompasses "full-length," unprocessed TMEM106B and any form of TMEM106B produced by processing in cells. In some embodiments, TMEM106B is human TMEM106B. In some embodiments, the amino acid sequence of an exemplary TMEM106B is Uniprot Accession No.: Q9NUM4 as of June 27, 2006. In some embodiments, the amino acid sequence of an exemplary human TMEM106B is SEQ ID NO: 1.

[0040] The terms "anti-TMEM106B antibody", "antibody that binds to TMEM106B", and "antibody that specifically binds to TMEM106B" refer to antibodies that can bind to TMEM106B with sufficient affinity, the affinity being sufficient to allow the antibody to be used as a diagnostic and / or therapeutic agent targeting TMEM106B. In one embodiment, the degree of binding of the anti-TMEM106B antibody to an unrelated, non-TMEM106B polypeptide is less than about 10% of the binding of the antibody to TMEM106B, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody that binds to TMEM106B has a dissociation constant (KD) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10 -8 M or smaller, e.g. 10 -8 M to 10 -13 M, for example 10 -9 M to 10 -13 M). In certain embodiments, an anti-TMEM106B antibody binds to an epitope of TMEM106B that is conserved between TMEM106B of different species.

[0041] With respect to the binding of an antibody to a target molecule, the term "specifically binds" to a specific polypeptide or an epitope on a specific polypeptide target or "specifically binds to" a specific polypeptide or an epitope on a specific polypeptide target or "has specificity" for a specific polypeptide or an epitope on a specific polypeptide target means binding that is measurably different from non-specific interactions. Specific binding can be measured, for example, by measuring the binding of a molecule compared to the binding of a control molecule. For example, specific binding can be measured by competition with a control molecule similar to the target (e.g., an excess of unlabeled target). In this case, if the binding of the labeled target to the probe is competitively inhibited by an excess of unlabeled target, specific binding is indicated. As used herein, the term "specifically binds" to an epitope on a specific polypeptide or a specific polypeptide target or "specifically binds to" an epitope on a specific polypeptide or a specific polypeptide target or "has specificity" for a specific polypeptide or an epitope on a specific polypeptide target can be measured, for example, by measuring a KD of about 10 for the target. -4 M or smaller, 10 -5 M or smaller, 10 -6 M or smaller, 10 -7 M or smaller, 10 -8 M or smaller, 10 -9 M or smaller, 10 -10 M or smaller, 10 -11 M or smaller, 10 -12 M or smaller or KD in 10 -4 M to 10 -6 M or 10-6 M to 10 -10 M or 10 -7 M to 10 -9 M. As will be appreciated by those of skill, affinity and KD values ​​are inversely proportional. High affinity for an antigen is measured by a low KD value. In one embodiment, the term "specific binding" refers to the binding of a molecule to a specific polypeptide or epitope on a specific polypeptide without substantially binding to any other polypeptide or polypeptide epitope.

[0042] The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. The term "antibody" herein is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) (including those formed from at least two intact antibodies), and antibody fragments, so long as they exhibit the desired biological activity.

[0043] "Native antibodies" are usually heterotetrameric glycoproteins of about 150,000 daltons composed of two identical light ("L") chains and two identical heavy ("H") chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (V H ), followed by several constant domains. Each light chain has a variable domain at one end (V L ), with a constant domain at the other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the variable domain of the light chain is aligned with the variable domain of the heavy chain. It is believed that specific amino acid residues form an interface between the light chain and heavy chain variable domains.

[0044] For the structure and properties of different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th edition, Daniel P. Stites, Abba I. Terr, and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, p. 71 and Chapter 6.

[0045] Light chains from any vertebrate species can be classified into one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequence of the constant domain of the light chain. Immunoglobulins can be classified into different classes, or isotypes, based on the amino acid sequence of the constant domain of their heavy chains (CH). There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, which have heavy chains called alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The gamma and alpha classes can be further divided into subclasses (isotypes) based on relatively minor differences in CH sequence and function, for example humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and generally described in, for example, Abbas et al., Cellular and Molecular Immunology, 4th edition (WB Saunders Co., 2000).

[0046] The "variable region" or "variable domain" of an antibody (such as the anti-TMEM106B antibody of the present disclosure) refers to the amino terminal domain of the heavy chain or light chain of the antibody. The variable domains of the heavy chain and the light chain can be referred to as "V H ” and “V L These domains are generally the most variable parts of an antibody (relative to other antibodies of the same class) and contain the antigen-binding site.

[0047] The term "variable" refers to the fact that certain segments of the variable domains are widely different in sequence between antibodies (such as the anti-TMEM106B antibodies disclosed herein). The variable domain mediates antigen binding and defines the specificity of a particular antibody to its specific antigen. However, variability is not evenly distributed throughout the variable domain. On the contrary, in the light chain and heavy chain variable domains, variability is concentrated in three segments called hypervariable regions (HVRs). The more highly conserved parts of the variable domains are called framework regions (FRs). The variable domains of natural heavy and light chains each include four FR regions, most of which adopt a β-folded configuration and are connected by three HVRs, which form a loop connecting a β-folded structure (forming a part of a β-folded structure in some cases). The HVRs in each chain are kept together in close proximity by the FR region, and together with the HVRs of the other chain, contribute to the formation of the antigen-binding site of the antibody (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0048] As used herein, the term "monoclonal antibody" refers to an antibody (such as the monoclonal anti-TMEM106B antibody of the present disclosure) obtained from a group of substantially homogeneous antibodies, i.e., each individual antibody constituting the antibody group, except for the possible naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation, etc.) that may be present in small amounts, other aspects are the same. Monoclonal antibodies have a high degree of specificity (for a single antigenic site). Compared with polyclonal antibody preparations that generally include different antibodies for different determinants (epitopes), each monoclonal antibody is directed to a single determinant on the antigen. In addition to specificity, the advantage of monoclonal antibodies is that they are synthesized by hybridoma culture and are not contaminated by other immunoglobulins. The modifier "monoclonal" represents the antibody characteristics obtained from a substantially homogeneous antibody group, and should not be interpreted as requiring the antibody to be produced by any particular method. For example, the monoclonal antibody used according to the present invention can be prepared by a variety of techniques, including, for example, hybridoma methods, recombinant DNA methods, and techniques for producing human or human-like antibodies in animals, wherein the animal has part or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences.

[0049] The terms "full-length antibody", "complete antibody" or "complete antibody" are used interchangeably and refer to antibodies (such as anti-TMEM106B antibodies of the present disclosure) in substantially complete form compared to antibody fragments. Specifically, complete antibodies include those having heavy chains and light chains comprising an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or their amino acid sequence variants. In some cases, a complete antibody may have one or more effector functions.

[0050] "Antibody fragment" refers to a molecule other than an intact antibody, which comprises a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (see U.S. Pat. No. 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062 (1995)); single-chain antibody molecules formed from antibody fragments and multispecific antibodies.

[0051] Papain digestion of antibodies (such as the anti-TMEM106B antibodies of the present disclosure) produces two identical antigen-binding fragments called "Fab" fragments and a residual "Fc" fragment (a name reflecting the ability to crystallize readily). The Fab fragment consists of the entire light chain and the variable region domain (V H ) and the first constant domain of a heavy chain (C H 1) Composition. Each Fab fragment is monovalent with respect to antigen binding, i.e., has a single antigen binding site. Pepsin treatment of an antibody produces a single large F(ab')2 fragment that roughly corresponds to two disulfide-linked Fab fragments with different antigen binding activities and is still able to cross-link antigen. Fab' fragments differ from Fab fragments in that the C H The carboxyl terminus of the constant domain has several additional residues, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine ​​residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced in the form of Fab' fragment pairs that had hinge cysteines between the Fab' fragments. Other chemical conjugates of antibody fragments are also known.

[0052] The Fc fragment comprises the carboxyl terminal portions of two heavy chains held together by disulfide bonds.The effector functions of an antibody are determined by the sequence of the Fc region, which is also recognized by Fc receptors (FcR) present on certain types of cells.

[0053] The "functional fragment" of an antibody (such as the anti-TMEM106B antibody of the present disclosure) comprises a portion of an intact antibody, generally including the antigen binding or variable region of the intact antibody, or the Fc region of an antibody that retains or has modified FcR binding ability. Examples of antibody fragments include linear antibodies, single-chain antibody molecules, and multispecific antibodies formed by antibody fragments.

[0054] The term "double body" refers to the use of V H Domain and V L Small antibody fragments prepared by constructing sFv fragments (see the preceding paragraph) with short linkers (about 5-10 residues) between the domains to allow interchain, but not intrachain, pairing of the variable domains, thereby generating bivalent fragments, i.e., fragments with two antigen-binding sites. Bispecific diabodies are heterodimers of two "cross-linked" sFv fragments, in which the V domains of the two antibodies are linked together. H Domain and V L Domains are present on different polypeptide chains.

[0055] As used herein, "chimeric antibody" refers to an antibody (immunoglobulin) (such as the chimeric anti-TMEM106B antibody of the present disclosure) in which a portion of the heavy chain and / or light chain is identical or homologous to a corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of one or more chains is identical or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, as long as they exhibit the desired biological activity. The chimeric antibodies of interest herein include Antibodies, wherein the antigen binding region of the antibody is derived from, for example, an antibody generated by immunizing a macaque with an antigen of interest. As used herein, "humanized antibody" is used as a subset of "chimeric antibody".

[0056] A "humanized" form of a non-human (e.g., murine) antibody (such as a humanized form of an anti-TMEM106B antibody disclosed herein) is a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, usually two variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to the HVRs of non-human antibodies, and all or substantially all of the FRs correspond to the FRs of human antibodies. A humanized antibody may optionally include at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody (e.g., a non-human antibody) refers to an antibody that has undergone humanization.

[0057] "Human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by humans (such as the anti-TMEM106B antibody of the present disclosure) and / or has been prepared using any one of the techniques for preparing human antibodies as disclosed herein. This definition of human antibody explicitly excludes humanized antibodies comprising non-human antigen binding residues. Human antibodies can be produced using a variety of techniques known in the art (including phage display libraries and yeast display libraries). Human antibodies can be prepared by administering antigens to transgenic animals, and produced via human B cell hybridoma technology, the transgenic animals have been modified to produce such antibodies in response to antigenic challenges, but the endogenous loci of the transgenic animals have been disabled (e.g., immunized xenomice).

[0058] As used herein, the term "hypervariable region", "HVR" or "HV" refers to regions of an antibody variable domain (such as the variable domains of the anti-TMEM106B antibodies of the present disclosure) whose sequences are hypervariable and / or form structurally defined loops. Typically, an antibody comprises six HVRs; H There are three (H1, H2, H3), and V L There are three of them (L1, L2, L3). In natural antibodies, H3 and L3 show the most diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies. Naturally occurring camelid antibodies composed only of heavy chains are functional and stable in the absence of light chains.

[0059] Many HVR descriptions are in use and are included in this article. In some embodiments, HVR can be a Kabat complementary determining region (CDR) based on sequence variability, and is the most commonly used (Kabat et al., supra). In some embodiments, HVR can be a Chothia CDR. And Chothia refers to the position of the structural loop (Chothia and Lesk J. Mol. Biol. 196: 901-917 (1987)). In some embodiments, HVR can be an AbM HVR. AbM HVR represents a compromise between Kabat CDR and Chothia structural loops, and is used by the AbM antibody modeling software of Oxford Molecular. In some embodiments, HVR can be a "contact" HVR. "Contact" HVR is based on the analysis of available complex crystal structures. The residues from each of these HVRs are annotated as follows.

[0060]

[0061]

[0062] An HVR may comprise an "extended HVR" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in VL and 26-35 (H1), 50-65 or 49-65 (preferred embodiments) (H2), and 93-102, 94-102, or 95-102 (H3) in VH. For each of these extended HVR definitions, the variable domain residues are numbered according to Kabat et al. (supra).

[0063] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0064] As used herein, an "acceptor human framework" is a V sequence comprising a human immunoglobulin framework or a human consensus framework. L or V H The acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may comprise pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. If pre-existing amino acid changes are present in VH, preferably those changes occur only in three, two, or one of the 71H, 73H, and 78H positions; for example, the amino acid residues at those positions may be 71A, 73T, and / or 78A. In one embodiment, the VL acceptor human framework is identical in sequence to the V L The human immunoglobulin framework sequence or the human consensus framework sequence is identical.

[0065] The "human consensus framework" is a L or V H The framework sequences are selected to represent the most common amino acid residues. L or V H The sequence is selected from a subset of variable domain sequences. Generally, the subset of sequences is the subset described by Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include: for V L , the subgroup may be subgroup κI, κII, κIII or κIV as described by Kabat et al. (supra). H, the subgroup may be subgroup I, subgroup II or subgroup III as described by Kabat et al. (supra).

[0066] "Amino acid modification" at a specified position of, for example, an anti-TMEM106B antibody of the present disclosure refers to the replacement or deletion of a specific residue, or the insertion of at least one amino acid residue adjacent to the specified residue. Insertion of an "adjacent" specified residue means insertion within one to two residues of the specified residue. Insertion can be at the N-terminus or C-terminus of the specified residue. The preferred amino acid modification herein is replacement.

[0067] "Affinity matured" antibodies (such as affinity matured anti-TMEM106B antibodies disclosed herein) are antibodies that have one or more changes in one or more HVRs of the antibody, thereby causing an improvement in the affinity of the antibody for the antigen compared to a parent antibody that does not have one or more of those changes. In one embodiment, the affinity matured antibody has a nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are produced by procedures known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describe affinity matured antibodies by V H Domain and V L Affinity maturation by domain shuffling. Random mutagenesis of HVR and / or framework residues is described, for example, in Barbas et al., Proc Nat. Acad. Sci. USA 91:3809-3813 (1994); Schier et al., Gene 169:147-155 (1995); Yelton et al., J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins et al., J. Mol. Biol. 226:889-896 (1992).

[0068] "Fv" is the smallest antibody fragment containing complete antigen recognition and binding sites. The fragment consists of a dimer of a heavy chain and a light chain variable region domain that are tightly and non-covalently associated. Six hypervariable loops (3 loops each from H and L chains) are produced by the folding of these two domains, which contribute to the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three HVRs specific for an antigen) has the ability to recognize and bind antigens, although the affinity is less than the entire binding site.

[0069] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment comprising the VH and VL antibody domains linked to a single polypeptide chain. Preferably, the sFv polypeptide also comprises a VH and V L A polypeptide linker between the domains that enables the sFv to form the desired structure for antigen binding.

[0070] Antibody "effector functions" refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype.

[0071] The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain, including a native sequence Fc region and a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain may vary, the human IgG heavy chain Fc region is generally defined as a sequence segment from the amino acid residue at position Cys226 or at position Pro230 to their carboxyl termini. The C-terminal lysine (residue 447 according to the EU numbering system) in the Fc region can be removed, for example, during the production or purification of the antibody or by recombinant engineering of the nucleic acid encoding the heavy chain of the antibody. Therefore, the composition of the complete antibody can include antibody groups in which all K447 residues are removed, antibody groups in which K447 residues are not removed, and antibody groups with and without a mixture of antibodies with K447 residues. The native sequence Fc region suitable for antibodies of the present disclosure includes human IgG1, IgG2, IgG3, and IgG4.

[0072] A "native sequence Fc region" comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes); native sequence human IgG2 Fc regions; native sequence human IgG3 Fc regions; and native sequence human IgG4 Fc regions, and naturally occurring variants thereof.

[0073] A "variant Fc region" comprises an amino acid sequence that differs from a native sequence Fc region by virtue of at least one amino acid modification (preferably one or more amino acid substitutions). Preferably, the variant Fc region has at least one amino acid substitution in the native sequence Fc region or in the Fc region of a parent polypeptide, such as about one to about ten amino acid substitutions, and preferably about one to about five amino acid substitutions, compared to the native sequence Fc region or the Fc region of a parent polypeptide. The variant Fc region herein preferably has at least about 80% homology with the native sequence Fc region and / or with the Fc region of a parent polypeptide, most preferably at least about 90% homology with them, more preferably at least about 95% homology.

[0074] "Fc receptor" or "FcR" describes a receptor that is bound to the Fc region of an antibody. Preferred FcRs are native sequence human FcRs. In addition, preferred FcRs are FcRs that bind to IgG antibodies (gamma receptors), and include receptors of FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternative splicing forms of these receptors, FcγRII receptors include FcγRIIA ("activating receptors") and FcγRIIB ("inhibitory receptors"), which have similar amino acid sequences, the main difference of which is their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. Inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif ("ITIM") in its cytoplasmic domain. Other FcRs (including those identified in the future) are also encompassed in the term "FcR" herein. FcR can also increase the serum half-life of antibodies.

[0075] As used herein, "percentage (%) of amino acid sequence identity" and "homology" with respect to peptide, polypeptide or antibody sequences refer to the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps (if necessary) to achieve the maximum percentage of sequence identity, and without considering any conservative substitutions as part of the sequence identity. Alignment for determining percentage of amino acid sequence identity can be achieved in a variety of ways within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN. TM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms known in the art needed to achieve maximal alignment over the full length of the sequences being compared.

[0076] When used in the context of antibodies that compete for the same epitope (e.g., neutralizing antibodies), the term "competition" means competition between antibodies as determined by an assay in which the antibody being tested prevents or inhibits (e.g., reduces) specific binding of a reference molecule (e.g., a ligand or a reference antibody) to a common antigen (e.g., TMEM106B or a fragment thereof). Various types of competitive binding assays can be used to determine whether an antibody competes with another antibody, for example: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, e.g., Stahli et al., 1983, Methods in Enzymology 9:242-253); solid phase direct biotin-avidin EIA (see, e.g., Kirkland et al., 1986, J. Immunol. 137:3614-3619), solid phase direct label assay, solid phase direct label sandwich assay (see, e.g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Laboratory Press, 1996). Press); solid phase direct labeling RIA using 1-125 labeling (see, for example, Morel et al., 1988, Molec. Immunol. 25: 7-15); solid phase direct biotin-avidin EIA (see, for example, Cheung et al., 1990, Virology 176: 546-552); and direct labeling RIA (Moldenhauer et al., 1990, Scand. J. Immunol. 32: 77-82). Typically, this assay involves the use of purified antigens bound to a solid surface or cells carrying any of these unlabeled test antibodies and labeled reference antibodies. Competitive inhibition is measured by determining the amount of labeling bound to a solid surface or cells in the presence of the test antibody. Typically, the test antibody is present in excess. Antibodies identified by competition assays (competing antibodies) include antibodies that bind to the same epitope as the reference antibody and antibodies that bind to adjacent epitopes that are close enough to the epitope bound by the reference antibody to cause steric hindrance. Additional details about methods for determining competitive binding are provided below and in the Examples herein. Typically, when a competing antibody is present in excess, it will inhibit (e.g., reduce) specific binding of a reference antibody to a common antigen by at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97.5%, and / or nearly 100%.

[0077] As used herein, the "interaction" between a TMEM106B polypeptide and a second polypeptide encompasses but is not limited to protein-protein interactions, physical interactions, chemical interactions, binding, covalent binding, and ionic binding. As used herein, when an antibody destroys, reduces, or completely eliminates the interaction between two polypeptides, the antibody "inhibits" the "interaction" between two polypeptides. When an antibody to a polypeptide is bound to one of the two polypeptides, an antibody to a polypeptide of the present disclosure "inhibits" the "interaction" between the two polypeptides. In some embodiments, the interaction can be inhibited by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97.5% and / or almost 100%.

[0078] The term "epitope" includes any determinant that can be bound by an antibody. An epitope is a region of an antigen that is bound by an antibody targeting an antigen, and when the antigen is a polypeptide, includes specific amino acids that directly contact the antibody. Most commonly, the epitope is located on a polypeptide, but in some cases, it may be located on other types of molecules (such as nucleic acids). An epitope determinant may include chemically active surface groups of a molecule, such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and may have specific three-dimensional structural features and / or specific charge characteristics. Typically, antibodies that are specific for a particular target antigen will preferentially recognize epitopes on a target antigen in a complex mixture of polypeptides and / or macromolecules.

[0079] An "agonistic" antibody or "activating" antibody is an antibody that induces (eg, increases) one or more activities or functions of the antigen after the antibody binds to the antigen.

[0080] An "antagonist" antibody or "blocking" antibody or "inhibitory" antibody is an antibody that reduces, inhibits and / or eliminates (e.g., reduces) the binding of an antigen to one or more ligands after the antibody binds to the antigen, and / or reduces, inhibits and / or eliminates (e.g., reduces) one or more activities or functions of the antigen after the antibody binds to the antigen. In some embodiments, an antagonist, blocking or inhibitory antibody substantially or completely inhibits the binding of an antigen to one or more ligands and / or one or more activities or functions of the antigen.

[0081] "Isolated" antibodies (such as isolated anti-TMEM106B antibodies of the present disclosure) are antibodies that have been identified, separated and / or recovered from components of the production environment of the antibody (e.g., natural or recombinant). Preferably, the isolated antibody is independent of all other contaminating components of the production environment of the antibody. Contaminating components of the production environment of the antibody, such as those produced from recombinant transfected cells, are substances that usually interfere with the research, diagnosis or therapeutic use of the antibody, and may include enzymes, hormones and other proteins or non-protein solutes. In preferred embodiments, the antibody will be purified to: (1) greater than 95% by weight of the antibody as determined by, for example, the Lowry method, in some embodiments, greater than 99% by weight; (2) as determined by using a spinning cup sequencer to a degree sufficient to obtain at least 15 N-terminal residues or internal amino acid sequences, or (3) homogeneity determined by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or preferably silver staining. Because at least one component of the natural environment of the antibody will not be present, the isolated antibody includes the in situ antibody within the recombinant T cell. Ordinarily, however, isolated polypeptide or antibody will be prepared by at least one purification step.

[0082] The "isolated" nucleic acid molecule encoding an antibody (such as an anti-TMEM106B antibody of the present disclosure) is a nucleic acid molecule identified and separated from at least one contaminating nucleic acid molecule, which is generally related to the environment in which the isolated nucleic acid molecule is produced. Preferably, the isolated nucleic acid is independent of all components associated with the production environment. The form of the isolated nucleic acid molecule encoding the polypeptide and antibody herein is different from the form or background in which the nucleic acid molecule exists in nature. Therefore, the isolated nucleic acid molecule is different from the nucleic acid encoding the polypeptide and antibody naturally present in the cell herein.

[0083] As used herein, the term "vector" is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid connected. One type of vector is a "plasmid", which refers to a circular double-stranded DNA, to which additional DNA segments can be connected. Another type of vector is a bacteriophage vector. Another type of vector is a viral vector, in which additional DNA segments can be connected to a viral genome. Some vectors can replicate autonomously in the host cells they introduce (e.g., bacterial vectors and additional mammalian vectors with bacterial replication origins). Other vectors (e.g., non-additional mammalian vectors) can be integrated into the genome of the host cell when introduced into the host cell, thereby replicating with the host genome. In addition, some vectors can guide the expression of genes operably connected to them. These vectors are referred to herein as "recombinant expression vectors", or simply as "expression vectors". Typically, useful expression vectors in recombinant DNA technology are typically in the form of plasmids. In this specification, "plasmid" and "vector" can be used interchangeably because plasmids are the most commonly used vector forms.

[0084] "Polynucleotide" or "nucleic acid" as used interchangeably herein refers to a polymer of nucleotides of any length, and includes DNA and RNA. The nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction.

[0085] "Host cell" includes a single cell or cell culture that can be or has been a recipient of a vector for incorporating a polynucleotide insert. Host cells include the progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. Host cells include cells transfected in vivo with one or more polynucleotides of the invention.

[0086] As used herein, "carrier" includes pharmaceutically acceptable carriers, excipients, or stabilizers that are non-toxic to exposed cells or mammals at the dosages and concentrations employed.

[0087] As used herein, the term "preventing" includes providing prevention against the occurrence or recurrence of a particular disease, disorder or condition in an individual. An individual may be predisposed to, susceptible to, or at risk of a particular disease, disorder or condition, but has not yet been diagnosed as having the disease, disorder or condition.

[0088] As used herein, an individual who is "at risk" of developing a particular disease, disorder, or condition may or may not have detectable symptoms of the disease or disease, and may or may not display detectable symptoms of the disease or disease prior to the treatment methods described herein. As known in the art, "at risk" means that an individual has one or more risk factors, which are measurable parameters associated with the development of a particular disease, disorder, or condition. An individual who has one or more of these risk factors has a higher probability of developing a particular disease, disorder, or condition than an individual who does not have one or more of these risk factors.

[0089] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of the individual being treated during the course of clinical pathology. Desired therapeutic effects include reduced progression rate, amelioration or alleviation of pathological conditions, and alleviation or improvement of the prognosis of a particular disease, disorder, or condition. For example, an individual is successfully "treated" if one or more symptoms associated with a particular disease, disorder, or condition are alleviated or eliminated.

[0090] "Effective amount" refers to the amount that effectively achieves the desired treatment or prevention result at least at the necessary dosage and time period. The effective amount can be provided in one or more administrations. The effective amount herein can vary according to various factors, such as the disease state, age, sex and weight of the individual and the ability of the treatment to cause the desired response in the individual. The effective amount is also the amount in which the beneficial effect of the treatment exceeds any toxic or harmful effect of the treatment. For preventive use, the beneficial or desired results include such as eliminating or reducing risks, reducing severity or delaying the onset of the disease, including biochemical, histological and / or behavioral symptoms of the disease, complications of the disease, and intermediate pathological phenotypes that occur during the generation of the disease. For therapeutic use, the beneficial or desired results include such as reducing one or more symptoms caused by the disease, improving the quality of life of the disease patient, reducing the dosage of other drugs required for treating the disease, and enhancing the clinical results of the effect of another drug, such as via targeting, delaying the progression of the disease and / or prolonging the survival period. The effective amount of a drug, compound or pharmaceutical composition is sufficient to directly or indirectly achieve the amount of preventive or therapeutic treatment. As understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if it can achieve or has achieved the desired result in conjunction with one or more other agents.

[0091] For treatment, prevention, or risk reduction purposes, a "subject" refers to any animal classified as a mammal, including humans, domestic and farm animals, zoo animals, sports animals, or pets, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, minks, rats, cats, etc. In some embodiments, the subject is a human.

[0092] As used herein, administration "in conjunction" with another compound or composition includes simultaneous administration and / or administration at different times. Administration in conjunction also encompasses administration as a co-formulation or as a separate composition, including administration at different dosing frequencies or intervals, and using the same route of administration or different routes of administration. In some embodiments, administration in conjunction is administration as part of the same treatment regimen.

[0093] As used herein, the term "about" refers to the common error range for the corresponding value that is readily known to those skilled in the art. References herein to "about" a value or parameter include (and describe) embodiments involving that value or parameter per se.

[0094] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to an "antibody" refers to reference to one or more antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, and so forth.

[0095] As used herein, "TMEM106B" proteins of the present disclosure include, but are not limited to, mammalian TMEM106B proteins, human TMEM106B proteins, primate TMEM106B proteins, cynomolgus monkey TMEM106B proteins, mouse TMEM106B proteins, and rat TMEM106B proteins. In addition, anti-TMEM106B antibodies of the present disclosure can bind to epitopes within one or more of mammalian TMEM106B proteins, human TMEM106B proteins, primate TMEM106B, cynomolgus monkey TMEM106B proteins, mouse TMEM106B proteins, and rat TMEM106B proteins.

[0096] It should be understood that the aspects and embodiments of the present disclosure described herein include "comprising aspects and embodiments," "consisting of," and "consisting essentially of aspects and embodiments."

[0097] II. Anti-TMEM106B Antibody

[0098] Anti-TMEM106B antibodies are provided herein. The antibodies provided can be used, for example, for the diagnosis or treatment of TMEM106B-related diseases.

[0099] In one aspect, the present disclosure provides an isolated (e.g., monoclonal) antibody that is bound to an epitope within a TMEM106B protein of the present disclosure. TMEM106B proteins of the present disclosure include, but are not limited to, mammalian TMEM106B proteins, human TMEM106B proteins, mouse TMEM106B proteins, and cynomolgus monkey TMEM106B proteins.

[0100] Human TMEM106B is a 274 amino acid protein encoding a type 2 membrane glycoprotein. The amino acid sequence of human TMEM106B is shown in SEQ ID NO: 1: MGKSLSHLPLHSSKEDAYDGVTSENMRNGLVNSEVHNEDGRNGDVSQFPYVEFTGRDSVTCPTCQGTGRIPRGQENQLVALIPYSDQRLRPRRTKLYVMASVFVCLLLSGLAVFFLFPRSIDVKYIGVKSAYVSYDVQKRTIYLNITNTLNITNNNYYSVEVENITAQVQFSKTVIGKARLNNITIIGPLDMKQIDYTVPTVIAEEMSYMYDFCTLISIKVHNIVLMMQVTVTTTYFGHSEQISQERYQYVDCGRNTTYQLGQSEYLNVLQPQQ

[0101] In addition, the amino acid sequence of mouse TMEM106B is as SEQ ID NO:2 shows: GKSLSHLPLHSNKEDGYDGVTSTDNMRNGLVSSEVHNEDGRNGDVSQFPYVEFTGRDSVTCPTCQGTGRIPRGQENQLVALIPYSDQRLRPRRTKLYVMASVFVCLLLSGLAVFFLFPRSIEVKYIGVKSAYV SYDAEKRTIYLNITNTLNITNNNYYSVEVENITAQVQFSKTVIGKARLNNITNIGPLDMKQIDYTVPTVIAEEMSYMYDFCTLLSIKVHNIVLMMQVTVTTAYFGHSEQISQERYQYVDCGRNTTYQLAQSEYLNVLQPQQ

[0102] In addition, the amino acid sequence of cynomolgus monkey (cyno) TMEM106B is shown in SEQ ID NO: 315:

[0103] MGKSLSHLPLHSSKEDAYDGVTSENMRNGLVNSEVHNEDGRNGDVSQFPYVEFTGRDSVTRPTCQGTGRIPRGQENQLVALIPYSDQRLRPRRTKLYVMASVFVCLLLSGLAVFFLFPRSIDVKYIGVKSAYVSYDV QKRTIYLNITNTLNITNNNYYSVEVENITAQVQFAKTVIGKARLNNITHIGPLDMKQIDYTVPTVIAEEMSYMYDFCTLISIKVHNIVLMMQVTVTTTYFGHSEQISQERYQYVDCGRNTTYQLGQSEYLNVLQPQQ

[0104] In some embodiments, TMEM106B is expressed in cells. In some embodiments, TMEM106B is expressed in endosomes and / or lysosomes. In some embodiments, TMEM106B is expressed in late endosomes and / or late lysosomes. In some embodiments, TMEM106B is expressed on the surface of cells.

[0105] The TMEM106B protein of the present disclosure includes several domains, including but not limited to the N-terminal luminal domain (expected to be within the range of amino acid residues 11-274 of human TMEM106B; see SEQ ID NO: 1), the transmembrane domain (expected to be within the range of amino acid residues 96-117 of human TMEM106B) and the C-terminal domain (expected to be within the range of amino acid residues 1-92 of human TMEM106B). In addition, the TMEM106B protein of the present disclosure is expressed in many tissues and cells, including but not limited to the brain, neurons, glial cells, endothelial cells, pericytes, pericytes, etc.

[0106] TMEM106B binding partners

[0107] The TMEM106B proteins of the present disclosure may interact with (e.g., bind to) one or more ligands or binding proteins, including but not limited to progranulin (GRN), other TMEM106 protein family members (such as TMEM106B and TMEM106C), clathrin heavy chain (CLTC), μL subunit of adipocyte protein 2 (AP2M1), charged multivesicular protein 2b (CHMP2B), microtubule-associated protein 6 (MAP6), lysosomal-associated membrane protein 1 (LAMP1), and vacuolar-ATPase accessory protein 1. The anti-TMEM106B antibodies of the present disclosure affect the interaction of TMEM106B with its various ligands and binding partners.

[0108] Progranulin

[0109] TMEM106B has been shown to colocalize with progranulin in neuronal late endolysosomes, and TMEM106B overexpression increases the intracellular levels of progranulin (Chen-Plotkin et al., 2012, J Neurosci, 32: 11213-11227).

[0110] Progranulin is variously referred to as PGRN, pro-epithelialin, granulin-epithelialin precursor, PC (prostate cancer) cell-derived growth factor (PCDGF), and acrogranin. Progranulin is a 593 amino acid protein encoding a 68.5 kD secreted glycoprotein with 7.5 repeating units of a smaller granulin (epithelialin) motif (in the range of 6-25 kDa) that can be cleaved from the precursor PGRN by proteolysis. Examples of progranulin cleavage products include, but are not limited to, granulin A / epithelialin 1, granulin B, epithelialin 2, granulin C, granulin D, granulin E, granulin F, granulin G, and any other known peptide products derived from progranulin.

[0111] Progranulin is widely expressed and is associated with many events in non-neuronal cells, such as cell cycle regulation and cell motility, wound repair, inflammation, induction of growth factors such as vascular endothelial growth factor (VEGF), and tumorigenesis. Progranulin is also widely expressed in early neural development, but is restricted to specific neuronal populations such as cortical neurons, hippocampal pyramidal neurons, and Purkinje cells in late development.

[0112] Therefore, in some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit (e.g., block) or reduce the interaction between TMEM106B and progranulin. Alternatively, in some embodiments, the anti-TMEM106B antibodies of the present disclosure enhance or increase the interaction between TMEM106B and progranulin.

[0113] Other TMEM106 family members

[0114] TMEM106B protein has been shown to interact with other TMEM106 protein family members. For example, the N-terminus of TMEM106B has been shown to interact with its family member TMEM106C. (See Stagi et al., 2014, Mol Cell Neurosci, 61: 226-240.) The TMEM106B protein of the present disclosure binds to and changes the function and activity of TMEM106B. In addition, the TMEM106B protein binds to and changes the function and activity of TMEM106C.

[0115] Therefore, in some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit (e.g., block) or reduce the interaction between TMEM106B and other TMEM106 protein family members. In some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit (e.g., block) or reduce the interaction between TMEM106B and another TMEM106B polypeptide. In some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit (e.g., block) or reduce the interaction between TMEM106B and TMEM106C. Alternatively, in some embodiments, the anti-TMEM106B antibodies of the present disclosure enhance or increase the interaction between TMEM106B and other TMEM106 protein family members. In some embodiments, the anti-TMEM106B antibodies of the present disclosure enhance or increase the interaction between TMEM106B and another TMEM106B polypeptide. In some embodiments, the anti-TMEM106B antibodies of the present disclosure enhance or increase the interaction between TMEM106B and TMEM106C.

[0116] Clathrin heavy chain

[0117] The N-terminus of TMEM106B has been shown to interact with the endocytic adaptor protein clathrin heavy chain (CLTC). (See Stagi et al., 2014, Mol Cell Neurosci, 61:226-240.) The protein interaction and the endolysosomal localization of TMEM106B suggest that the TMEM106B cytoplasmic domain may be involved in the delivery of endocytic cargo to lysosomes.

[0118] Therefore, in some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit (e.g., block) or reduce the interaction between TMEM106B and CLTC. Alternatively, in some embodiments, the anti-TMEM106B antibodies of the present disclosure enhance or increase the interaction between TMEM106B and CLTC.

[0119] μL subunit of adipocyte protein 2

[0120] The N-terminus of TMEM106B has been shown to interact with the μ1 subunit of the endocytic adaptor protein adipocyte protein 2 (AP2M1). (See Stagi et al., 2014, Mol Cell Neurosci, 61:226-240.) The protein interaction together with the endolysosomal localization of TMEM106 suggests that the TMEM106B cytoplasmic domain may be involved in the delivery of endocytic cargo to lysosomes.

[0121] Thus, in some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit (e.g., block) or reduce the interaction between TMEM106B and the μ1 subunit of adipocyte protein 2 (AP2M1). Alternatively, in some embodiments, the anti-TMEM106B antibodies of the present disclosure enhance or increase the interaction between TMEM106B and the μ1 subunit of adipocyte protein 2 (AP2M1).

[0122] Charged polycystin 2b

[0123] TMEM106B has been shown to directly bind to charged multivesicular protein 2b (CHMP2B), which is a member of the endosomal sorting complex required for transport III (ESCRT-III) complex, which regulates endolysosomal protein transport and autophagic structure formation (Jun et al., 2015, Mol Brain, 8: 85). Therefore, in some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit (e.g., block) or reduce the interaction between TMEM106B and CHMP2B. Alternatively, in some embodiments, the anti-TMEM106B antibodies of the present disclosure enhance or increase the interaction between TMEM106B and CHMP2B.

[0124] Microtubule-associated protein 6

[0125] The C-terminus of microtubule-associated protein 6 (MAP6) directly binds to the N-terminus of TMEM106B (Schwenk et al., 2014, EMBO J, 33: 450-467). Similar to TMEM106B knockdown, MAP6 overexpression inhibits dendritic branching. MAP6 knockdown completely rescues the dendritic phenotype of TMEM106B knockdown, which supports the functional interaction between TMEM106B and MAP6. The TMEM106B / MAP6 interaction is shown to be crucial for regulating the dendritic transport of lysosomes, probably as a molecular disruption of retrograde transport. Lysosomal misdirection can promote neurodegeneration in patients with TMEM106B risk variants. The C-terminal repeat region of the neuron-rich splice variant of MAP6 preferentially binds to the cytoplasmic N-terminus of TMEM106B.

[0126] Therefore, in some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit (e.g., block) or reduce the interaction between TMEM106B and MAP6. Alternatively, in some embodiments, the anti-TMEM106B antibodies of the present disclosure enhance or increase the interaction between TMEM106B and MAP6.

[0127] Lysosomal associated membrane protein 1

[0128] TMEM106B colocalizes with LAMP1 in late endosome / lysosomal vesicles in cell bodies and dendrites, but colocalization does not occur in synaptic vesicles or early or recycling endosomes. (Stagi et al., 2014, Mol Cell Neurosci, 61: 226-240.) LAMP1 (lysosome-associated membrane protein 1) is a late endosome / lysosome marker. The reduction of TMEM106B increases the lysosomes (increased motility) of axonal transport, while the increase of TMEM106B inhibits this transport and produces large lysosomes. Therefore, in some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit (e.g., block) or reduce the interaction between TMEM106B and LAMP1. In some embodiments, the anti-TMEM106B antibodies of the present disclosure increase the lysosomes of axonal transport. In some embodiments, the anti-TMEM106B antibodies of the present disclosure increase the motility of lysosomes of axonal transport. Alternatively, in some embodiments, the anti-TMEM106B antibodies of the present disclosure enhance or increase the interaction between TMEM106B and LAMP1.

[0129] Vacuolar ATPase subunit accessory protein 1

[0130] TMEM106B has been shown to bind to the vacuolar-ATPase subunit accessory protein 1 (v-ATPase API) through its lumen (C-terminal) domain (Klein et al., 2017, Neuron, 95: 281-296). V-ATPase is responsible for lysosomal acidification; regulation of its function (such as by stabilization of a multi-unit protein complex) will affect lysosomal function. Therefore, in some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit (e.g., block) or reduce the interaction between TMEM106B and the vacuolar-ATPase subunit accessory protein 1. Alternatively, in some embodiments, the anti-TMEM106B antibodies of the present disclosure enhance or increase the interaction between TMEM106B and the vacuolar-ATPase subunit accessory protein 1.

[0131] Also provided herein is a method for screening anti-TMEM106B antibodies that bind to TMEM106B and block the interaction between TMEM106B and one or more TMEM106B ligands or binding partners (e.g., progranulin, other TMEM106 family members (i.e., TMEM106A, TMTM106C), clathrin heavy chain, μ1 subunit of adipocyte protein 2, CHMP2B, microtubule-associated protein 6, lysosomal-associated membrane protein 1, and vacuolar-ATPase auxiliary protein 1). In some embodiments, a peptide library can be synthesized in which the TMEM106B protein is cut into continuous 15-mer and 25-mer peptides separated by one amino acid residue, and the peptide library is then spotted onto a filter membrane. The ability of the binding of the TMEM106B ligand or binding partner to interact with the TMEM106B peptide or multiple peptides in the presence or absence of anti-TMEM106B antibodies can then be tested by SPOT binding analysis (e.g., Frank, R and Overwin, H (1996) Methods. Mol. Biol. 66, 149-169; Reineke, U et al., (2002) J. Immunol. Methods 267, 13-26; and Andersen, OS et al., (2010) J, BIOLOGICAL CHEMISTRY 285, 12210-12222). In some embodiments, the cellulose support can be prepared as an N-modified cellulose-aminohydroxypropyl ether membrane, and all synthetic rounds begin with spot definition by 9-fluorenylmethoxycarbonylalanine-pentafluorophenyl ester (generating an alanine linker between the peptide and the membrane). For example, the automated linear synthesis performed by the stepwise addition of different amino acids is protected by 9-fluorenyl-methoxycarbonyl at the N-terminus, and the growing peptide chain is appropriately protected by the side chain. In some embodiments, the mode of deprotection, activation and coupling is continued until a 16-mer peptide is produced, thereby producing a uniformly distributed array of covalently anchored peptides and cellulose supports at the C-terminus, and the N-terminus is a free end (Scham, D et al., (2000) J. Comb. Chem. 2, 361-369). In some embodiments, the removal of the side protecting group can be performed in two steps. First, 90% trifluoroacetic acid (dissolved in dichloromethane, containing 3% triisobutylsilane and 2% H2O) can be used to treat the membrane; secondly, 60% trifluoroacetic acid (dissolved in dichloromethane, containing 3% triisobutylsilane and 2% H2O) can be used to treat the membrane. In order to remove trifluoroacetate, H2O, ethanol, Tris buffered saline and ethanol can be used to wash the membrane several times, and then the membrane is dried.Finally, before preparing the predetermined peptide library for ligand binding analysis, the membrane is blocked in a blocking buffer that is swollen in Tris-buffered saline (pH 8.0) and supplemented with 5% sucrose for 2 h. In some embodiments, for binding studies of cellulose-binding peptides, the membrane-bound library can be incubated with a combination of S peptides and polyhistidine-tagged ligands in the presence or absence of anti-TMEM106B antibodies, for example, overnight in a blocking buffer at 4 ° C, and then incubated a second time with 1 mg / ml HRP-conjugated S protein in a blocking buffer, but at room temperature for 3 h. Subsequently, the membrane can be washed with Tris-buffered saline (e.g., three times for 10 minutes), and then the UptiLight chemiluminescent substrate and Lumilmager instrument can be used for quantitative characterization of the bound ligand to provide spot signal intensity (Boehringer light units). Alternatively, detection of the bound ligand can be performed by an immunochemical assay, which is performed with an antibody to a histidine tag and an HRP-conjugated anti-mouse secondary antibody. Standard Western blotting procedures and dot detection can be used for incubation.

[0132] Also provided herein are methods for screening anti-TMEM106B antibodies that block the interaction (e.g., binding) of TMEM106B and one or more TMEM106B ligands or binding partners (e.g., progranulin, other TMEM106 family members (i.e., TMEM106A, TMEM106C), clathrin heavy chain, μl subunit of adipocyte protein 2, CHMP2B, microtubule-associated protein 6, lysosomal-associated membrane protein 1, and vacuolar-ATPase accessory protein 1).

[0133] In some embodiments, the interaction between TMEM106B and a TMEM106B ligand or binding partner (e.g., progranulin, other TMEM106 family members (i.e., TMEM106A, TMEM106C), clathrin heavy chain, μl subunit of adipocyte protein 2, CHMP2B, microtubule-associated protein 6, lysosomal-associated membrane protein 1, and vacuolar-ATPase accessory protein 1) can be characterized using surface plasmon resonance analysis (e.g., Skeldal et al., 2012 J Biol Chem., 287:43798; and Andersen et al., 201, J Biol Chem, 285, 12210-12222). In the presence or absence of blocking anti-TMEM106B antibodies, CaHBS can be used as a standard running buffer (10mM HEPES pH7.4, 140mM NaCl, 2mM CaCl2, 1mM EGTA and 0.005% Tween 20) on a Biacore2000 instrument (Biacore, Sweden) to carry out the determination of the direct binding of TMEM106B of TMEM106B ligand or binding partner to immobilized TMEM106B. In some embodiments, the NHS / EDC method can be used to activate the biosensor chip from Biacore (CM5), and then coated with TMEM106B to a protein density of 79fmol / mm2, and used for affinity measurement of binding partners. The preparation of the biosensor surface using pro-TMEM106B will be carried out according to the same procedure. After each cycle of the ligand binding experiment, the regeneration of the flow cell can be carried out by a single injection of two 10-μl regeneration buffer (10mM glycine-HCl pH4.0, 500mM NaCl, 20mM EDTA and 0.005% Tween 20) pulses and 0.001% SDS. The fitting of the sensorgram for affinity estimation can be carried out, for example, by using BIAevaluation 3.1 version. According to a similar scheme, the immobilization of HisS-NGFpro or HisS-BDNFpro can also be carried out on a CM5 biosensor chip using NHS / EDC coupling kit to obtain a similar surface density of immobilized protein (~ 300fmol / mm2). In the absence or presence of competitive TMEM106B antibodies, the biosensor chip immobilized with TMEM106B ligands or binding partners can also be used to check the combination of TMEM106B.

[0134] In some embodiments, the interaction between TMEM106B and TMEM106B ligands and binding partners (e.g., progranulin, other TMEM106 family members (i.e., TMEM106A, TMEM106C), clathrin heavy chain, μ1 subunit of adipocyte protein 2, CHMP2B, microtubule-associated protein 6, lysosomal-associated membrane protein 1, and vacuolar-ATPase auxiliary protein 1) can be characterized using sedimentation assays (e.g., Andersen et al., 2010, J Biol Chem, 285, 12210-12222). For example, the expressed intracellular or extracellular domain of TMEM106B can be incubated with a labeled TMEM106B ligand or binding partner in the absence or presence of a TMEM106B blocking antibody, and precipitated using 100 μl of glutathione (GSH)-agarose beads (Amersham Biosciences, catalog number 17-0756-01). The amount of receptor domain applied can be determined by precipitation using Talon beads as a control. Bound proteins can be separated by SDS-PAGE analysis and visualized by standard Western blot analysis using an anti-histidine antibody.

[0135] In some embodiments, the interactions between TMEM106B and TMEM106B ligands and binding partners (e.g., progranulin, other TMEM106 family members (i.e., TMEM106A, TMEM106C), clathrin heavy chain, μ1 subunit of adipocyte protein 2, CHMP2B, microtubule-associated protein 6, lysosomal-associated membrane protein 1, and vacuolar-ATPase accessory protein 1) can be characterized using cellulose binding protein (e.g., Andersen et al., 2010, J Biol Chem, 285, 12210-12222). For example, membrane-bound proteins can be incubated with S peptide and polyhistidine-tagged progranulin, other TMEM106 family members (i.e., TMEM106A, TMEM106C), clathrin heavy chain, μ1 subunit of adipocyte protein 2, CHMP2B, microtubule-associated protein 6, lysosome-associated membrane protein 1, vacuolar-ATPase auxiliary protein 1, or another TMEM106B ligand or binding partner; incubated overnight at 4 ° C in blocking buffer, and then incubated for a second time with 1 μg / ml HRP-conjugated S protein in blocking buffer, but at room temperature for 3 hours. Subsequently, the membrane can be washed three times for 10 minutes with Tris buffered saline, and then quantitative characterization of the bound ligand is performed using UptiLight chemiluminescent substrate and Lumilmager instrument to provide spot signal intensity (Boehringer (Boehringer) light unit). Alternatively, detection of the bound ligand can be performed by immunochemical assay, which is performed with an antibody to histidine tag and an anti-mouse secondary antibody conjugated to HRP. Incubations can be followed by standard Western blot analysis and spot detection.

[0136] In some embodiments, the interaction between TMEM106B and TMEM106B ligands and binding partners (e.g., progranulin, other TMEM106 family members (i.e., TMEM106A, TMEM106C), clathrin heavy chain, μ1 subunit of adipocyte protein 2, CHMP2B, microtubule-associated protein 6, lysosome-associated membrane protein 1, and vacuolar-ATPase auxiliary protein 1) can be characterized using a proximity ligation assay (e.g., Gustafsen et al., 2013 The Journal of Neuroscience, 33: 64-71). For example, a primary antibody against TMEM106B and an antibody against a binding partner can be used to perform a proximity ligation assay (PLA) (Duolink II) on cells expressing or exposed to TMEM106B and its ligands or binding partners, followed by incubation with a secondary antibody conjugated to an oligonucleotide, the secondary antibody hybridizing to a subsequently added ring-forming oligonucleotide, and initiating rolling circle amplification when the antigen is positioned near 40 nM. The amplified DNA can be visualized by adding complementary fluorescently labeled oligonucleotides.

[0137] In some embodiments, the interaction between TMEM106B and TMEM106B ligands and binding partners (e.g., progranulin, other TMEM106 family members (i.e., TMEM106A, TMEM106C), clathrin heavy chain, μl subunit of adipocyte protein 2, CHMP2B, microtubule-associated protein 6, lysosomal-associated membrane protein 1, and vacuolar-ATPase accessory protein 1) can be characterized using alkaline phosphatase-labeled ligands (e.g., Hu et al., 2005, J. Neurosci. 25, 5298-5304; Fournier et al., 2001, Nature 409, 341-346; Lauren et al., 2009, Nature 457, 1128-1132; and Hu et al., 2010, Neuron 68, 654-667). For example, alkaline phosphatase (AP)-labeled ligands can be prepared to assess binding to TMEM106B on transfected cells or primary neurons. In order to detect the binding of AP-labeled ligands to cells expressing TMEM106B, the culture can be washed with, for example, Hanks' balanced salt solution (HBH), which contains 20 mM HEPES sodium pH 7.05 and 1 mg / ml bovine serum albumin (BSA). Then, the plate can be incubated with AP-labeled ligands in the presence or absence of TMEM106B blocking antibodies, for example, incubated in HBH at 23° C. for 2 h. AP-bound ligands can be detected and quantified according to methods well known in the art.

[0138] In certain embodiments that can be combined with any of the foregoing embodiments, the anti-TMEM106B antibody further inhibits the interaction between TMEM106B and its ligands, signaling proteins, or binding proteins by: a) reducing the effective level of TMEM106B available for interaction with one or more ligands or binding proteins; b); blocking one or more of the sites on TMEM106B required for interaction with one or more ligands or binding proteins; c) preventing one or more post-translational events on TMEM106B required for interaction with one or more ligands or binding proteins and / or correction of TMEM106B processing and / or subcellular localization; d) inducing degradation of TMEM106B; e) changing the conformation of TMEM106B, or both of them. In certain embodiments that can be combined with any of the foregoing embodiments, the anti-TMEM106B antibody specifically binds to human TMEM106B, mouse TMEM106B, cynomolgus monkey TMEM106B, or a combination thereof. In certain embodiments that can be combined with any one of the foregoing embodiments, the anti-TMEM106B antibody is a human antibody, a humanized antibody, a bispecific antibody, a monoclonal antibody, a multivalent antibody, a conjugated antibody or a chimeric antibody. In certain embodiments that can be combined with any one of the foregoing embodiments, the anti-TMEM106B antibody is a bispecific antibody that recognizes a first antigen and a second antigen. In certain embodiments that can be combined with any one of the foregoing embodiments, the first antigen is TMEM106B, and the second antigen is an antigen that is conducive to transport across the blood-brain barrier. In certain embodiments that may be combined with any of the preceding embodiments, the second antigen is selected from the group consisting of: TMEM106B, transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, llama single domain antibody, TMEM 30 (A), protein transduction domain, TAT, Syn-B, transmembrane peptide, polyarginine peptide, angiopep, basic immunoglobulin (basigin), Glut1 and CD98hc and ANG1005.

[0139] TMEM106B proteolysis

[0140] TMEM106B undergoes intramembrane proteolysis and is processed into an N-terminal fragment (NTF) containing a transmembrane and intracellular domain; the processing is lysosomal protease dependent. (Brady et al., 2014, J Biol Chem, 289: 19670-19680) GxGD aspartyl protease SPPL2A (and SPPL2B to a lesser extent) has been shown to be responsible for the intramembrane cleavage event. In addition, it is reported that one or more uncharacterized lysosomal proteases and SPPL2A cut TMEM106B at approximately the 127th and 106th amino acids of the N-terminus, respectively, to produce two TMEM106B NTFs (Brady et al., 2014, supra); however, the exact cleavage site has not yet been determined. Overexpression of TMEM106B leads to the appearance of NTF 17 (1-127) and NTF 13 (1-106), which may be mediated by caspase activity.

[0141] Therefore, in some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit the proteolysis of TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit the intramembrane proteolysis of TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit the proteolysis of TMEM106B, thereby preventing TMEM106B from being cut into N-terminal fragments. In some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit the GxGD aspartyl protease SPPL2A cutting of TMEM106B. In other embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit the GxGD aspartyl protease SPPL2B cutting of TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure inhibit the caspase-mediated cutting of TMEM106B.

[0142] TMEM106B as a disease target

[0143] TMEM106B is associated with a variety of diseases, disorders and symptoms. Frontotemporal lobar degeneration (FTLD) (or frontotemporal dementia (FTD)) is the third most common neurodegenerative disease after Alzheimer's disease and Parkinson's disease, accounting for 20% of senile dementia cases. (See, for example, Rademakers et al., 2012, Nat Rev Neurol, 8: 423-434). The condition is caused by progressive deterioration of the frontal lobe of the brain. Over time, degeneration can progress to the temporal lobe. Clinical manifestations are varied, with symptoms including dementia, behavioral changes, and speech impairment. (See, e.g., Cruts & Van Broeckhoven, 2008, Trends Genet. 24: 186-194; Neary et al., 1998, Neurology 51: 1546-1554; Ratnavalli et al., 2002, Neurology 58: 1615-1621.) Other symptoms of upper or lower motor neuron disease are common, suggesting partial overlap with amyotrophic lateral sclerosis (ALS). Most FTLD cases show neuronal cytoplasmic aggregates of the nuclear DNA / RNA binding protein TDP-43 (Neumann et al., 2006, Science, 314: 130-133) and pathogenic mutations in TARDBP, a gene encoding TDP-43 that is rare and a major cause of ALS (Sreedharan et al., 2008, Science, 319: 1668-1672). Familial forms of FTLD with TDP-43 pathology are primarily due to hexanucleotide repeat expansions in C9orf72 (DeJesus-Hemandez et al., 2011; Renton et al., 2011) and dominant loss-of-function mutations in growth factor progranulin (GRN) (Cruts et al., 2006, Curr Alzheimer Res, 3:485-491). While the identification of mutations associated with rare familial forms of the disease has provided greater insight into the pathogenesis of FTLD, the etiology of the more common sporadic cases has been more elusive and complicated by the variability of clinical and neuropathological presentations.

[0144] Most cases of FTD are inherited in an autosomal dominant manner, but even in a family, symptoms can range from FTD with behavioral disorders to primary progressive aphasia to cortical-basal ganglia degeneration. Like most neurodegenerative diseases, FTD is characterized by the pathological presence of specific protein aggregates in the diseased brain. In the past, the first description of FTD recognized the presence of intraneural accumulation of hyperphosphorylated Tau protein in neurofibrillary tangles or Pick bodies. The identification of mutations in genes encoding tau proteins in several families supports the causal role of microtubule-associated protein tau (Hutton, M. et al., Nature 393: 702-705 (1998)). However, most FTD brains do not show accumulation of hyperphosphorylated Tau, but do show immunoreactivity to ubiquitin (Ub) and TAR DNA binding protein 43 (TDP-43) (Neumann et al., 2007, Arch. Neurol. 64: 1388-1394). The majority of these FTD cases with Ub inclusions (FTD-U) were shown to harbor mutations in the progranulin gene.

[0145] Single nucleotide polymorphisms (SNPs) identified on chromosome 7 revealed that the first genetic risk factor for FTLD-TDP was a SNP in the genomic region encoding TMEM106B. (Van Deerlin et al., 2010, Nat Genetics, 42:234-239.)

[0146] Initial studies evaluating TMEM106B SNPs as disease risk factors in FTLD-TDP were conducted before the discovery of the C9orf72 repeat expansion in 2012. Since that discovery, two independent groups have found that TMEM106B SNPs are also associated with the risk of developing FTLD and / or ALS caused by C9orf72 mutations. (See Gallagher et al., 2014, Acta Neuropathol, 127:407-418; van Blitterswijk et al., 2014, Acta Neuropath, 127:397-406.) In these C9orf72 mutant cohorts, individuals carrying the minor allele of the TMEM106B SNP [rs1990622 and / or rs3173615] were significantly reduced in frequency in LD with rs1990622, but not as significantly as in the cohort of GRN mutation carriers. Further analysis of C9orf72 repeat expansion carriers in each group based on the main disease manifestations of FTLD, FTLD-ALS or ALS showed that TMEM106B SNP specifically defends against the development of FTLD, but not against the development of ALS, and C9orf72 expansion carriers (homozygous for the protective TMEM106B allele) have less TDP-43 burden in the brain compared with risk allele carriers. These findings are consistent with early examinations of TMEM106B SNPs in clinical cohorts of ALS patients, in which TMEM106B SNP rs 1990622 and rs 1020004 were not associated with disease risk, but were significantly associated with cognitive function in ALS patients, and individuals homozygous for the rs 1990622 minor allele had better cognitive behavior than individuals heterozygous or homozygous for the major risk allele (Vass et al., 2011, Acta Neuropathol, 121: 373-380).

[0147] Neurodegenerative disease markers such as TDP-43 aggregates are not FTLD specific and have been observed in other neurodegenerative diseases including Alzheimer's disease (AD), Lewy body dementia (LBD), and hippocampal sclerosis (HpScl) (Amador-Ortiz et al., 2007, Ann Neurol, 61:435-445; Zarow et al., 2008, Curr Neurol Neurosci Rep, 8:363-370), even in apparently healthy individuals, albeit to a limited extent (see, e.g., Yu et al., 2015, Neurology, 84:927-934). In the absence of a clinical neurological diagnosis, TMEM106B risk variants are associated with TDP-43 neuropathology. Similarly, it is found that in AD patients, it affects the pathological manifestations of AD with protective TMEM106B haplotypes that are less related to TDP-43 pathology (Rutherford et al., 2012, Neurology, 79: 717-718). Hippocampal sclerosis is also a common pathological sign of Alzheimer's patients (including FTLD-TDP and AD), usually co-existing with TDP-43 pathology. It is found that in AD patients, TMEM106B genotype is related to primary hippocampal sclerosis (Aoki et al., 2015, Acta Neuropathol, 129: 53-64) and hippocampal sclerosis pathology, which makes TMEM106B the strongest genetic index of AD-HpScl and HpScl known so far (Murray et al., 2014, Acta Neuropathol, 128: 411-421). Together, these studies suggest that the TMEM106B SNP is a risk factor for the development and severity of TDP-43 proteinopathy in non-FTLD diseases such as AD and HpScl.

[0148] A genomic study of more than 1500 human brain autopsy samples identified the common variant of TMEM106B as the main genome-wide determinant of the biological aging rate of the human brain: According to the gene expression profile, there are 2 risk alleles at the locus of the TMEM106B gene, which makes individuals show -12 years older than their actual age (Rhinn and Abeliovich, 2017, Cell Syst, 4: 404-415). In individuals without known neurological diseases and individuals with neurodegenerative diseases (such as Alzheimer's disease), this effect of TMEM106B risk allele can be observed. With regard to the brain and life (cortex rather than cerebellum, especially over 65 years old), the role of TMEM106B in aging shows high selectivity. This effect is independently confirmed in another cohort, where carriers of protective TMEM106B haplotypes show a reduction in age-related cognitive decline (Rhinn and Abeliovich, 2017, supra). For a certain amount of brain pathology, TMEM106B protective haplotypes were shown to be associated with better cognitive behavior, confirming the effect on cognitive behavior (White et al., 2017, PLoS Med, 14: e1002287). These results strengthen the pleiotropic role of TMEM106B in aging other than neurodegenerative diseases.

[0149] Evidence suggests that TMEM106B variants increase the risk of FTLD-TDP by increasing TMEM106B mRNA and protein expression levels. Increased TMEM106B leads to a decrease in the average number of late endosomes / lysosomes per cell, loss of lysosomal acidification, and impaired lysosomal degradation.

[0150] Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) is a fatal neurogenetic disease with no available treatment. Impaired production or secretion of progranulin due to mutations in the progranulin gene (GRN) is a common cause of FTLD-TDP. As discussed above, TMEM106B is associated with genome-wide associations with FTLD-TDP with and without GRN mutations. Increased expression of TMEM106B, which models the disease, leads to enlargement and reduced acidification of endolysosomes, as well as defective mannose-6-phosphate receptor trafficking. Endogenous neuronal TMEM106B colocalizes with progranulin in late lysosomes, and TMEM106B overexpression increases the intracellular levels of progranulin. (Chen-Plotkin et al., 2012, J Neurosci, 32: 11213-11227.) In some embodiments, the present disclosure provides methods for preventing FTLD-TDP, reducing the risk of FTLD-TDP, or treating FTLD-TDP by administering a therapeutically effective amount of an anti-TMEM-160B antibody of the present disclosure to an individual in need thereof. In some embodiments, the present disclosure provides methods

[0151] FTLD is considered a disease with a common pathological background of amyotrophic lateral sclerosis (ALS). ALS is an incurable motor neuron degenerative disease characterized by the loss of both upper and lower motor neurons. Approximately 15% of FTLD patients develop motor neuron disease, and more than 15% of ALS patients have cognitive and behavioral deficits. An important pathological hallmark of FTLD and ALS is cytoplasmic transactivation response DNA binding protein-43 (TDP-43) inclusions. TDP-43 is the main component of inclusions in ~50^% of FTLD patients (subtype FTLD-TDP) and most ALS patients. Genome-wide association studies and cohort studies have identified three SNPs (re1990622, rs6966915 and rs1020004) in the TMEM106B gene region as genetic risk modifiers for FTLD-TDP. The risk association is more prominent in FTLD-TDP cases with GRN and C9ORF72 mutations. Using a cell-based model, overexpression of TMEM106B induces cell death, enhances oxidative stress-induced cytotoxicity, and causes cleavage of TDP-43, suggesting that upregulation of TMEM106B increases the risk of FTLD by directly causing neurotoxicity. (Suzuki and Matsuoka, 2016, J Biol Chem, 291: 21448-21460.) In addition, TMEM106B is involved in the development of cognitive impairment in ALS (Vass et al., 2011, Acta Neuropathol, 121: 373-380).

[0152] Hippocampal sclerosis of senescence (HS-senescence) is a common, high-morbidity-associated neurodegenerative disease of the elderly that is diagnosed neuropathologically when neuronal loss and astrocytosis are observed in the hippocampal formations and is not thought to be due to Alzheimer's-type plaques and tangles. It has a clinical course similar to Alzheimer's disease. HS-senescence is distinguished from other hippocampal sclerosis disorders by the presence of TDP-43 pathology and the absence of severe symptoms or clinical signs of frontotemporal dementia. HS-senescence is associated with SNP rs1990622 (TMEM106b) and other SNPs and polymorphisms in TMEM106b, ABCC9 (not associated with FTLD), and GRN. (Nelson et al., 2015, J Neuropathol Exp Neurol, 74:75-84.) In some embodiments, the present disclosure provides methods for preventing, reducing the risk of, or treating hippocampal sclerosis of aging by administering a therapeutically effective amount of an anti-TMEM-160B antibody of the present disclosure to an individual in need thereof.

[0153] The recent murine gene knockout of TMEM106B (Klein et al. 2017, Neuron 95, 281-296) shows the effect of TMEM106B in the granulin pathway. Specifically, the gene knockout of TMEM106B protein can rescue some pathogenic phenotypes associated with GRN knockout in mouse models, including partial rescue of lysosomal protein levels, rescue of behavioral changes (such as hyperactivity and inhibition release). As reported in other studies, TMEM106B gene knockout itself has good tolerance in mice. In addition, this work shows the possible mechanism of action of TMEM106B by showing direct interaction (by co-immunoprecipitation) with v-ATPase subunit AP1. The v-ATPase complex plays an important role in reducing the pH of lysosomes to trigger protein degradation and recycling. Thus, its interaction with TMEM106B could lead to some of the lysosomal phenotypes associated with TMEM106B overexpression, and conversely, blocking this interaction (or simply reducing the level of TMEM106B present) could ameliorate this phenotype.

[0154] Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that has been diagnosed pathologically in individuals with a history of repeated head impacts. TMEM106B has been shown to be an important factor in CTE progression, especially CTE-related neuropathology and dementia. Specifically, carriers of the minor (G) allele at SNP rs3173615 (T185S coding mutation) show reduced levels of neuropathology, including reduced levels of AT8-positive p-tau, reduced density of CD68-positive cells, and increased levels of PSD-95 (a postsynaptic marker commonly used to study synaptic loss). The G-allele is also associated with a 60% reduction in the risk of dementia before death. In both cases, the effects of the G-allele are additive, and the GG genotype is the most protective. The TMEM106B genotype has no effect on the risk of the disease; on the contrary, the effect is observed in the severity of disease progression.

[0155] Microglia are the main innate immune cells of the central nervous system (CNS). Microglia exist in a static or activated state according to the inflammatory environment, which is different in healthy CNS and various disease states. TGFβ is an important factor in the development and function of microglia, and is necessary for the maintenance of microglia-specific homeostatic gene markers. TGFβ signal transduction and inhibition of TGFβ pathways are common features of microglia isolated from neurodegenerative disease models. In addition, TGFβ has been described as having a key function in the prevention of microglia / macrophage-mediated CNS pathology and neurodegeneration (Butovsky and Weiner, 2018, Nature, 19: 622-635; Lund et al., 2018, Nature Immunol, 19: 425-441). Therefore, therapies that directly or indirectly increase TGFβ expression, signaling and / or function will provide beneficial effects in the treatment of neurodegenerative diseases and disorders, including amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis, Parkinson's disease, autism spectrum disorders, dementia, etc. In some embodiments, the anti-TMEM106B antibodies of the present disclosure are effective in increasing TGFβ levels in cells.

[0156] Dementia is a non-specific syndrome (i.e., a group of signs and symptoms) that manifests as a severe loss of the overall cognitive ability of previously unimpaired people, beyond the expected range of normal aging. Due to unique overall brain damage, dementia can be static. Alternatively, dementia can be progressive, causing long-term depression due to physical injury or disease. Although dementia is more common in the elderly population, it can also occur before the age of 65. The cognitive areas affected by dementia include but are not limited to memory, attention span, language and problem solving. Typically, symptoms must exist for at least six months before an individual is diagnosed with dementia.

[0157] Exemplary forms of dementia include, but are not limited to, frontotemporal dementia, Alzheimer's disease, vascular dementia, semantic dementia, and dementia with Lewy bodies.

[0158] Without wishing to be bound by theory, it is believed that administration of an anti-TMEM106B antibody of the present disclosure may prevent, reduce the risk of, and / or treat dementia.

[0159] Alzheimer's disease (AD) is the most common form of dementia. The disease has no cure, worsens as it progresses, and ultimately leads to death. In most cases, AD is diagnosed in people over the age of 65. However, the less prevalent early-onset Alzheimer's disease can appear earlier.

[0160] Common symptoms of Alzheimer's disease include behavioral symptoms, such as difficulty recalling recent events; cognitive symptoms, confusion, irritability and aggression, mood swings, language impairment, and long-term memory loss. As the disease progresses, physical function is lost, eventually leading to death. Alzheimer's disease develops for an unknown and variable time before it fully manifests, and can progress for years without being diagnosed.

[0161] Amyotrophic lateral sclerosis (ALS) or motor neuron disease or Lou Gehrig's disease, used interchangeably, refers to a debilitating disease of varying etiology characterized by rapidly progressive weakness, muscle wasting and fasciculations, muscle spasms, difficulty speaking (dysarthria), swallowing (dysphagia), and breathing (dyspnea).

[0162] TMEM106B is also related to hypomyelinated leukodystrophy. (Simons et al., 2017, Brain.) Hypomyelinated leukodystrophy is a group of heterogeneous diseases, and clinical manifestations include early-onset nystagmus, ataxia and spasticity. The hypomyelination of the brain of four patients with hypomyelinated leukodystrophy showed the same dominant mutation (Aps252Asn) in TMEM106B, which shows that TMEM106B is related to hypomyelination disorders, probably due to the role played by TMEM106B in lysosomal function. Therefore, in some embodiments, the present disclosure provides a method for treating hypomyelination disorders in individuals in need, the method comprising applying a therapeutically effective amount of an anti-TMEM106B antibody of the present disclosure to an individual. In some embodiments, the present disclosure provides a method for treating hypomyelinated leukodystrophy in individuals in need, the method comprising applying a therapeutically effective amount of an anti-TMEM106B antibody of the present disclosure to an individual.

[0163] The methods provided herein can be used to prevent neurodegenerative diseases, disorders or conditions, reduce the risk of neurodegenerative diseases, disorders or conditions, or treat individuals suffering from neurodegenerative diseases, disorders or conditions. In some embodiments, the invention provides a method for preventing neurodegenerative diseases, reducing the risk of neurodegenerative diseases, or treating individuals suffering from neurodegenerative diseases, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0164] In some embodiments, the invention provides a method for preventing, reducing the risk of, or treating a subject having a disease, disorder, condition, or injury characterized by the presence of TDP-43 inclusion bodies, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to a subject in need thereof.

[0165] In some embodiments, the present invention provides a method for preventing, reducing the risk of, or treating an individual with a TDP-43 proteinopathy, comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0166] In some embodiments, the invention provides a method for preventing, reducing the risk of, or treating a subject suffering from a disease, disorder, condition, or injury characterized by the presence of inflammatory cell debris or protein aggregates, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to a subject in need thereof.

[0167] In some embodiments, the invention provides a method for preventing, reducing the risk of, or treating a subject having a disease, disorder, condition, or injury characterized by the presence of abnormal circulating myeloid cells, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to a subject in need thereof.

[0168] In some embodiments, the invention provides a method for preventing, reducing the risk of, or treating an individual suffering from unhealthy aging, comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0169] In some embodiments, the present invention provides a method for preventing, reducing the risk of, or treating an individual with frontotemporal lobar degeneration (FTLD), comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0170] In some embodiments, the present invention provides a method for preventing, reducing the risk of, or treating an individual with frontotemporal dementia (FTD), comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0171] In some embodiments, the invention provides a method for preventing, reducing the risk of, or treating an individual with frontotemporal dementia with a progranulin mutation, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0172] In some embodiments, the present invention provides a method for preventing, reducing the risk of, or treating an individual with frontotemporal dementia with a C90rf72 mutation, comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0173] In some embodiments, the present invention provides a method for preventing, reducing the risk of, or treating an individual with frontotemporal lobar degeneration with TDP-43 inclusions, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0174] In some embodiments, the present invention provides a method for preventing, reducing the risk of, or treating an individual with hippocampal sclerosis (HpScl), comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0175] In some embodiments, the present invention provides a method for preventing hippocampal sclerosis of senescence (HS-senescence), reducing the risk of hippocampal sclerosis of senescence, or treating an individual with hippocampal sclerosis of senescence, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0176] In some embodiments, the invention provides a method for preventing Alzheimer's disease, reducing the risk of Alzheimer's disease, or treating an individual with Alzheimer's disease, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0177] In some embodiments, the invention provides a method for preventing, reducing the risk of, or treating an individual with Lewy body dementia, comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0178] In some embodiments, the invention provides a method for preventing, reducing the risk of, or treating an individual with cognitive impairment, comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0179] In some embodiments, the present invention provides a method for preventing, reducing the risk of, or treating an individual with age-related cognitive impairment, comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0180] In some embodiments, the invention provides a method for preventing, reducing the risk of, or treating an individual with CTE-related cognitive impairment, comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0181] In some embodiments, the present invention provides a method for preventing, reducing the risk of, or treating an individual with age-related brain atrophy, comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0182] In some embodiments, the present invention provides a method for preventing, reducing the risk of, or treating an individual with age-related traits, including but not limited to inflammation, neuronal loss, and cognitive deficits (such as cognitive deficits in the absence of known brain diseases, including cognitive deficits in the frontal cerebral cortex of elderly individuals), comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0183] In some embodiments, the present invention provides a method for preventing, reducing the risk of, or treating an individual with amyotrophic lateral sclerosis-related cognitive impairment, comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0184] In some embodiments, the present invention provides a method for preventing a disease, disorder or condition associated with overexpression or increased activity of TMEM106B, reducing the risk of such diseases, disorders or conditions, or treating an individual suffering from such diseases, disorders or conditions, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0185] In some embodiments, the invention provides a method for preventing, reducing the risk of, or treating an individual with a hypomyelination disorder, comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0186] In some embodiments, the present invention provides a method for reducing or inhibiting metastasis in an individual in need thereof, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to the individual in need thereof.

[0187] In some embodiments, the present invention provides a method for preventing cancer, reducing the risk of cancer, or treating an individual suffering from cancer, comprising administering a therapeutically effective amount of an anti-TMEM106B antibody to an individual in need thereof.

[0188] A. Exemplary Antibodies and Certain Other Antibody Embodiments

[0189] In some embodiments, provided herein are anti-TMEM106B antibodies comprising at least one, two, three, four, five, or six HVRs selected from the group consisting of: (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, and 35, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO: NO:3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35; (b) HVR-H2, which comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35; NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of: SEQ ID NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78. NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78;(c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, and 120, or an amino acid sequence that is at least about 95% homologous to an amino acid sequence selected from the group consisting of SEQ ID NO:79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, and 120. NO:79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120; (d) HVR-L1, which comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120; NO:121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159 and 160, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of: SEQ ID NO:121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159 and 160 NO:121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 14 0, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159 and 160;(e) HVR-L2, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, and 185, or an amino acid sequence that is at least about 95% homologous to an amino acid sequence selected from the group consisting of SEQ ID NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, and 185. NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185; and (f) HVR-L3, which comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185; NO:186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, and 224, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of: SEQ ID NO:186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215 NO:186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223 and 224. ;

[0190] In some embodiments, provided herein is an anti-TMEM106B antibody comprising at least one, two, three, four, five or six HVRs selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 3; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 79; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 121; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 186; (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 37; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 80; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:5; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:123; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:163; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:188; (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:6; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:39; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: NO:82; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:124; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:164; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:189; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:7; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:40; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:83; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:125;(e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:165; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:190; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:8; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:41; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:84; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:126; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:166; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:191; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:9; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:42; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: NO:85; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:127; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:167; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:192; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:10; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:43; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:86; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:128; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:168; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:193; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:11; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:43; NO:44; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:87; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:123; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:169; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:188; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:12; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:45; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:88; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:129;(e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:170; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:194; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:13; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:46; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:89; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:130; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:171; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:195; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:14; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:47; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: NO:90; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:131; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:170; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:196; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:15; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:48; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:91; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:132; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:172; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:197; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:3; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:48; NO:49; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:92; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:133; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:173; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:198; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:16; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:50; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:93; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:134;(e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:172; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:199; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:17; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:51; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:94; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:135; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:174; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:200; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:18; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:52; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: NO:95; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:133; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:173; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:198; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:6; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:53; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:96; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:136; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:175; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:201; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:14; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO: NO:54; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:97; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:137; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:176; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:202; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:17; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:51; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:94; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:135;(e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:174; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:200; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:19; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:55; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:98; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:138; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:169; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:203; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:20; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:56; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: NO:99; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:139; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:161; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:204; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:3; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:57; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:100; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:140; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:177; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:205; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:13; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:57; NO:46; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:89; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:141; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:171; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:206; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:11; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:58; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:101; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:138;(e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:169; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:207; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:3; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:57; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:100; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:140; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:177; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:205; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:3; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:59; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: NO:102; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:142; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:178; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:208; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:9; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:60; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:103; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:143; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:167; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:192; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:21; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO: NO:61; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:104; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:144; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:169; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:209; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:22; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:62; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:105; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:145;(e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:161; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:210; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:12; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:63; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:106; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:128; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:179; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:211; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:14; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:64; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: NO:107; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:146; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:161; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:202; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:23; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:65; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:108; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:147; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:180; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:212; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:24; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO: NO:66; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:109; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:148; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:162; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:213; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:25; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:67; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:110; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:149;(e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:161; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:196; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:26; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:68; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:111; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:150; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:181; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:214; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:27; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:69; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: NO:112; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:151; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:181; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:215; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:28; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:70; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:113; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:152; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:182; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:216; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:29; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO: NO:71; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:111; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:153; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:181; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:214; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:30; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:72; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:114; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:152;(e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:182; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:217; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:31; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:73; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:115; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:154; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:183; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:218; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:32; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:74; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: NO:116; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:155; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:182; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:219; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:33; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:75; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:117; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:156; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:161; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:220; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:34; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO: NO:76; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:118; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:157; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:184; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:221; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:32; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:74; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:116; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:158;(e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:185; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:222; (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:35; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:77; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO:119; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:159; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:182; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:223; and (a) HVR-H1, which comprises the amino acid sequence of SEQ ID NO:29; (b) HVR-H2, which comprises the amino acid sequence of SEQ ID NO:78; (c) HVR-H3, which comprises the amino acid sequence of SEQ ID NO: NO:120; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:160; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:183; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:224. ;

[0191] In some embodiments, provided herein is an anti-TMEM106B antibody comprising at least one, at least two, or all three V selected from the following: HHVR sequences: (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO: NO:3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35; (b) HVR-H2, which comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35; NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78;and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, and 120, or an amino acid sequence that is at least about 95% homologous to an amino acid sequence selected from the group consisting of SEQ ID NO: NO:79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 1 02, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120. ;

[0192] In some embodiments, provided herein is an anti-TMEM106B antibody comprising at least one, at least two, or all three V selected from the following: LHVR sequences: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, and 160, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO: NO:121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159 and 160; (b) HVR-L2, which comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155 NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, and 185, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, and 185;and (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, and 224, or an amino acid sequence that is at least about 95% homologous to an amino acid sequence selected from the group consisting of SEQ ID NO: 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, NO:186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223 and 224. ;

[0193] In some embodiments, provided herein is an anti-TMEM106B antibody comprising (a) V H A domain comprising at least one, at least two or all three V selected from the following HHVR sequences: (i) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO: NO:3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35, (ii) HVR-H2, which comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, and (iii) HVR-H3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, and NO:79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 1 02, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120,or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO:79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, and 120, and (b) V, L A domain comprising at least one, at least two or all three V selected from the following LHVR sequences: (i) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, and 160, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO: NO:121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159 and 160, (ii) HVR-L2, which comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of: SEQ ID NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185 NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185, and (iii) HVR-L3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185. NO:186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223 and 224,or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO: 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, and 224.

[0194] In some embodiments, provided herein is an anti-TMEM106B antibody comprising (a) V HA domain comprising (i) an HVR-H1 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, and 35, or an amino acid sequence that is at least about 95% homologous to an amino acid sequence selected from the group consisting of: SEQ ID NO: NO:3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35, (ii) HVR-H2, which comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, and (iii) HVR-H3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, and NO:79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 1 02, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120,or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO:79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, and 120, and (b) V, LA domain comprising (i) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, and 160, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO: NO:121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159 and 160, (ii) HVR-L2, which comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185, or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of: SEQ ID NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185 NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185, and (iii) HVR-L3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185. NO:186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223 and 224,or an amino acid sequence having at least about 95% homology to an amino acid sequence selected from the group consisting of SEQ ID NO: 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, and 224.

[0195] In another aspect, the anti-TMEM106B antibody comprises a heavy chain variable domain (V H ) sequence, the heavy chain variable domain sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, and 268. In certain embodiments, V is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from the group consisting of HThe sequences contain substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence: SEQ ID NO: 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267 and 268, but the anti-TMEM106B antibodies comprising the sequence retain the ability to bind to TMEM106B. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted and / or deleted in SEQ ID NO: 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267 or 268. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in SEQ ID NO: 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267 or 268. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the HVRs (i.e., in the FRs). Optionally, the anti-TMEM106B antibody comprises a V sequence of SEQ ID NO: 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, or 268. H In a specific embodiment, V Hcomprising one, two or three HVRs selected from the group consisting of: (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35, (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, and NO:79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 1 02, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120.

[0196] In another aspect, an anti-TMEM106B antibody is provided, wherein the antibody comprises a light chain variable domain (V L ), said light chain variable domain having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to an amino acid sequence selected from the group consisting of: SEQ ID NO: 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, and 314. In certain embodiments, V is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to an amino acid sequence selected from the group consisting of LThe sequences contain substitutions (e.g., conservative substitutions), insertions or deletions relative to the reference sequence: SEQ ID NO: 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313 and 314, but the anti-TMEM106B antibodies comprising the sequences retain the ability to bind to TMEM106B. In some embodiments, a total of 1 to 10 amino acids are substituted, inserted and / or deleted in SEQ ID NO: 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313 or 314. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in SEQ ID NO: 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313 or 314. In certain embodiments, the substitutions, insertions or deletions occur in regions outside of the HVRs (i.e., in the FRs). Optionally, the anti-TMEM106B antibody comprises a V sequence of SEQ ID NO: 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, or 314. LIn a specific embodiment, V L 154, 155, 156, 157, 158, 159, and 160, (b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO: 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, and 160, NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185, and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185. NO:186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223 and 224.

[0197] In some embodiments, an anti-TMEM106B antibody is provided, wherein the antibody comprises a V as in any of the embodiments provided above. H and V in any of the embodiments provided above L In some embodiments, provided herein are anti-TMEM106B antibodies, wherein the antibody comprises V as in any of the embodiments provided above. H and V in any of the embodiments provided above L In one embodiment, the antibody comprises V in SEQ ID NO: 225-268 and SEQ ID NO: 269-314, respectively. H and V L sequences, including post-translational modifications of those sequences.

[0198] In some embodiments, provided herein are anti-TMEM106B antibodies comprising a heavy chain variable domain (V H) and the light chain variable domain (V L ), where V H and V L Selected from the group consisting of: V comprising the amino acid sequence of SEQ ID NO: 225 H and V comprising the amino acid sequence of SEQ ID NO: 269 L ; V comprising the amino acid sequence of SEQ ID NO: 226 H and V comprising the amino acid sequence of SEQ ID NO: 270 L ; V comprising the amino acid sequence of SEQ ID NO: 227 H and V comprising the amino acid sequence of SEQ ID NO: 271 L ; V comprising the amino acid sequence of SEQ ID NO: 228 H and V comprising the amino acid sequence of SEQ ID NO: 272 L ; V comprising the amino acid sequence of SEQ ID NO: 229 H and V comprising the amino acid sequence of SEQ ID NO: 273 L ; V comprising the amino acid sequence of SEQ ID NO: 230 H and V comprising the amino acid sequence of SEQ ID NO: 274 L ; V comprising the amino acid sequence of SEQ ID NO: 231 H and V comprising the amino acid sequence of SEQ ID NO: 275 L ; V comprising the amino acid sequence of SEQ ID NO: 232 H and V comprising the amino acid sequence of SEQ ID NO: 276 L ; V comprising the amino acid sequence of SEQ ID NO: 233 H and V comprising the amino acid sequence of SEQ ID NO: 277 L ; V comprising the amino acid sequence of SEQ ID NO: 234 H and V comprising the amino acid sequence of SEQ ID NO: 278 L ; V comprising the amino acid sequence of SEQ ID NO: 235 H and V comprising the amino acid sequence of SEQ ID NO: 279 L ; V comprising the amino acid sequence of SEQ ID NO: 236 H and V comprising the amino acid sequence of SEQ ID NO: 280 L ; V comprising the amino acid sequence of SEQ ID NO: 237 Hand V comprising the amino acid sequence of SEQ ID NO: 281 L ; V comprising the amino acid sequence of SEQ ID NO: 238 H and V comprising the amino acid sequence of SEQ ID NO: 282 L ; V comprising the amino acid sequence of SEQ ID NO: 239 H and V comprising the amino acid sequence of SEQ ID NO: 283 L ; V comprising the amino acid sequence of SEQ ID NO: 240 H and V comprising the amino acid sequence of SEQ ID NO: 284 L ; V comprising the amino acid sequence of SEQ ID NO: 241 H and V comprising the amino acid sequence of SEQ ID NO: 285 L ; V comprising the amino acid sequence of SEQ ID NO: 242 H and V comprising the amino acid sequence of SEQ ID NO: 286 L ; V comprising the amino acid sequence of SEQ ID NO: 243 H and V comprising the amino acid sequence of SEQ ID NO: 287 L ; V comprising the amino acid sequence of SEQ ID NO: 240 H and V comprising the amino acid sequence of SEQ ID NO: 288 L ; V comprising the amino acid sequence of SEQ ID NO: 244 H and V comprising the amino acid sequence of SEQ ID NO: 289 L ; V comprising the amino acid sequence of SEQ ID NO: 245 H and V comprising the amino acid sequence of SEQ ID NO: 290 L ; V comprising the amino acid sequence of SEQ ID NO: 246 H and V comprising the amino acid sequence of SEQ ID NO: 291 L ; V comprising the amino acid sequence of SEQ ID NO: 235 H and V comprising the amino acid sequence of SEQ ID NO: 292 L ; V comprising the amino acid sequence of SEQ ID NO: 247 H and V comprising the amino acid sequence of SEQ ID NO: 293 L ; V comprising the amino acid sequence of SEQ ID NO: 248 H and V comprising the amino acid sequence of SEQ ID NO: 294 L; V comprising the amino acid sequence of SEQ ID NO: 249 H and V comprising the amino acid sequence of SEQ ID NO: 295 L ; V comprising the amino acid sequence of SEQ ID NO: 250 H and V comprising the amino acid sequence of SEQ ID NO: 296 L ; V comprising the amino acid sequence of SEQ ID NO: 251 H and a V comprising the amino acid sequence of SEQ ID NO: 297 L ; V comprising the amino acid sequence of SEQ ID NO: 252 H and V comprising the amino acid sequence of SEQ ID NO: 298 L ; V comprising the amino acid sequence of SEQ ID NO: 253 H and V comprising the amino acid sequence of SEQ ID NO: 299 L ; V comprising the amino acid sequence of SEQ ID NO: 254 H and V comprising the amino acid sequence of SEQ ID NO: 300 L ; V comprising the amino acid sequence of SEQ ID NO: 255 H and V comprising the amino acid sequence of SEQ ID NO: 301 L ; V comprising the amino acid sequence of SEQ ID NO: 256 H and V comprising the amino acid sequence of SEQ ID NO: 302 L ; V comprising the amino acid sequence of SEQ ID NO: 257 H and V comprising the amino acid sequence of SEQ ID NO: 303 L ; V comprising the amino acid sequence of SEQ ID NO: 258 H and V comprising the amino acid sequence of SEQ ID NO: 304 L ; V comprising the amino acid sequence of SEQ ID NO: 259 H and V comprising the amino acid sequence of SEQ ID NO: 305 L ; V comprising the amino acid sequence of SEQ ID NO: 260 H and V comprising the amino acid sequence of SEQ ID NO: 306 L ; V comprising the amino acid sequence of SEQ ID NO: 261 H and V comprising the amino acid sequence of SEQ ID NO: 307 L ; V comprising the amino acid sequence of SEQ ID NO: 262 Hand V comprising the amino acid sequence of SEQ ID NO: 308 L ; V comprising the amino acid sequence of SEQ ID NO: 263 H and V comprising the amino acid sequence of SEQ ID NO: 309 L ; V comprising the amino acid sequence of SEQ ID NO: 264 H and V comprising the amino acid sequence of SEQ ID NO: 310 L ; V comprising the amino acid sequence of SEQ ID NO: 265 H and V comprising the amino acid sequence of SEQ ID NO:311 L ; V comprising the amino acid sequence of SEQ ID NO: 266 H and V comprising the amino acid sequence of SEQ ID NO:312 L ; V comprising the amino acid sequence of SEQ ID NO: 267 H and V comprising the amino acid sequence of SEQ ID NO: 313 L ; and V comprising the amino acid sequence of SEQ ID NO: 268 H and V comprising the amino acid sequence of SEQ ID NO: 314 L .

[0199] In some embodiments, the anti-TMEM106B antibodies of the present disclosure competitively inhibit the binding of at least one antibody selected from the group consisting of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45 TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53. In some embodiments, when the anti-TMEM106B antibodies of the present disclosure reduce binding to TMEM106B of one or more selected from TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-53, TM-54, TM-55 17. TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30 , TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, T When the binding of the anti-TMEM106B antibody to TMEM106B is within the range of about 50% to 100%, the anti-TMEM106B antibody is combined with one or more selected from TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-53, and any combination thereof M-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-2 2. TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35,Antibodies to TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53, and any combination thereof, compete for binding to TMEM106B. In some embodiments, when the anti-TMEM106B antibodies of the present disclosure reduce binding to TMEM106B of one or more selected from TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45 TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53, and any combination thereof, bind to TMEM106B by at least 50%, at least 50% and at least 50% of the antibody. 5%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100%, the anti-TMEM106B antibody is combined with one or more selected from TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53 and any combination thereof compete for binding to TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure reduce one or more selected from TM-1, TM-2,TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM -18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-3 2. TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53 and any combination thereof bind to TMEM106B. 100% means that the anti-TMEM106B antibody is substantially completely One or more total blocking agents are selected from TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53, and any combination thereof, bind to TMEM106B. In some embodiments, an anti-TMEM106B antibody and one or more selected from TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23 , TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36 , TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49,The antibodies of TM-50, TM-51, TM-52, and TM-53, and any combination thereof, are present in amounts corresponding to a 10:1 ratio, a 9:1 ratio, an 8:1 ratio, a 7:1 ratio, a 6:1 ratio, a 5:1 ratio, a 4:1 ratio, a 3:1 ratio, a 2:1 ratio, a 1:1 ratio, a 0.75:1 ratio, a 0.5:1 ratio, a 0.25:1 ratio, a 0.1:1 ratio, a 0.075:1 ratio, a 0.050:1 ratio, a 0.025:1 ratio, a 0.01:1 ratio, a 0.0075:1 ratio, a 0.0050:1 ratio, a 0.002 5:1 ratio, 0.001: ratio, 0.00075:1 ratio, 0.00050:1 ratio, 0.00025:1 ratio, 0.0001: ratio, 1:10 ratio, 1:9 ratio, 1:8 ratio, 1:7 ratio, 1:6 ratio, 1:5 ratio, 1:4 ratio, 1:3 ratio, 1:2 ratio, 1:0.75 ratio, 1:0.5 ratio, 1:0.25 ratio, 1:0.1 ratio, 1:0.075 ratio, 1:0.050 ratio, 1:0.025 ratio, 1:0.01 ratio, 1:0.0075 ratio, 1:0.00 50 ratio, 1:0.0025 ratio, 1:0.001 ratio, 1:0.00075 ratio, 1:0.00050 ratio, 1:0.00025 ratio or 1:0.0001 ratio of anti-TMEM106B antibody and one or more selected from TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM- 47, TM-48, TM-49, TM-50, TM-51, TM-52, and TM-53, and any combination thereof. In some embodiments, with one or more selected from TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28,In some embodiments, the anti-TMEM106B antibody is present in an excess amount ranging from about 1.5-fold to 100-fold, or greater than 100-fold, compared to the amount of antibodies against TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, and TM-53, and any combination thereof. In some embodiments, with one or more selected from TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-53, TM-54, TM-55, TM-56, TM-57, TM-58, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65 The anti-TMEM106B antibody is present in about a 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, or 100-fold excess compared to the amount of the antibody of TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, and TM-53, and any combination thereof.

[0200] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to an epitope of human TMEM106B that is distinct from at least one of TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-53, TM-54, TM-55, TM-56, TM-57, TM-58, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65 5. The TMEM106B epitopes bound by the antibodies of TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53 are identical or overlapping. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to at least one selected from TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-53, TM-54, TM-55, TM-56, TM-57, TM-58, TM-59, TM-60, TM-61, TM-62, TM-63, TM-64, TM-65 Detailed exemplary methods for mapping the epitope to which the antibody binds are provided in Morris (1996) "Epitope Mapping Protocols", in Methods in Molecular Biology, Vol. 66 (Humana Press, Totowa, NJ).

[0201] In some embodiments, the anti-TMEM106B antibodies of the present disclosure compete with one or more antibodies selected from TM-1, TM-17, TM-22, TM-23, TM-26 and TM-27 and any combination thereof for binding to TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure compete with one or more antibodies selected from TM-2, TM-3, TM-5, TM-7, TM-9, TM-10, TM-11, TM-12, TM-13, TM-18, TM-19, TM-21, TM-25, TM-28, TM-29, TM-32, TM-35, TM-37, TM-39, TM-42, TM-45, TM-48 and TM-53 and any combination thereof for binding to TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure compete with one or more antibodies selected from TM-4, TM-6, TM-8, TM-14, TM-15, TM-16, TM-20, TM-31, TM-33, TM-34, TM-36, TM-41, TM-44, TM-46, TM-47, TM-49, TM-50, TM-51, TM-52, and any combination thereof for binding to TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure compete with one or more antibodies selected from TM-1, TM-2, TM-3, TM-7, TM-12, TM-13, TM-23, TM-24, TM-29, TM-30, TM-51, and any combination thereof for binding to TMEM106B.

[0202] In some embodiments, the anti-TMEM106B antibodies of the present disclosure competitively inhibit the binding of at least one antibody selected from TM-1, TM-17, TM-22, TM-23, TM-26 and TM-27 and any combination thereof to TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure competitively inhibit the binding of at least one antibody selected from TM-2, TM-3, TM-5, TM-7, TM-9, TM-10, TM-11, TM-12, TM-13, TM-18, TM-19, TM-21, TM-25, TM-28, TM-29, TM-32, TM-35, TM-37, TM-39, TM-42, TM-45, TM-48 and TM-53 and any combination thereof to TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure competitively inhibit the binding of at least one antibody selected from TM-4, TM-6, TM-8, TM-14, TM-15, TM-16, TM-20, TM-31, TM-33, TM-34, TM-36, TM-41, TM-44, TM-46, TM-47, TM-49, TM-50, TM-51, TM-52, and any combination thereof to TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure competitively inhibit the binding of at least one antibody selected from TM-1, TM-2, TM-3, TM-7, TM-12, TM-13, TM-23, TM-24, TM-29, TM-30, TM-51, and any combination thereof to TMEM106B.

[0203] In some embodiments, the anti-TMEM106B antibodies of the present disclosure have an epitope on TMEM106B that is identical or overlapping with at least one antibody selected from TM-1, TM-17, TM-22, TM-23, TM-26, and TM-27, and any combination thereof that binds to TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure have an epitope on TMEM106B that is identical or overlapping with at least one antibody selected from TM-2, TM-3, TM-5, TM-7, TM-9, TM-10, TM-11, TM-12, TM-13, TM-18, TM-19, TM-21, TM-25, TM-28, TM-29, TM-32, TM-35, TM-37, TM-39, TM-42, TM-45, TM-48, and TM-53, and any combination thereof that binds to TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure have an epitope on TMEM106B that is identical or overlapping with at least one antibody selected from TM-4, TM-6, TM-8, TM-14, TM-15, TM-16, TM-20, TM-31, TM-33, TM-34, TM-36, TM-41, TM-44, TM-46, TM-47, TM-49, TM-50, TM-51, TM-52, and any combination thereof that binds to TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure have an epitope on TMEM106B that is identical or overlapping with at least one antibody selected from TM-1, TM-2, TM-3, TM-7, TM-12, TM-13, TM-23, TM-24, TM-29, TM-30, TM-51, and any combination thereof that binds to TMEM106B.

[0204] Any suitable competition assay or TMEM106B binding assay known in the art (such as BIAcore analysis, ELISA assay or flow cytometry) can be used to determine whether the anti-TMEM106B antibody binds to one or more selected from TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52, TM-53, TM-54, TM-55 TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53, and any combination thereof, compete for binding to (or competitively inhibit such binding of) TMEM106B. In an exemplary competitive assay, immobilized TMEM106B or cells expressing TMEM106B on the cell surface are incubated in a solution comprising a first labeled antibody (e.g., human or non-human primate) that is bound to TMEM106B and a second unlabeled antibody, the ability of the second unlabeled antibody to compete with the first antibody for binding to TMEM106B is tested. The second antibody may be present in a hybridoma supernatant. As a control, immobilized TMEM106B or cells expressing TMEM106B are incubated in a solution comprising a first labeled antibody, but not comprising a second unlabeled antibody. After incubation under conditions that allow the first antibody to bind to TMEM106B, excess unbound antibodies are removed, and the amount of the label associated with immobilized TMEM106B or cells expressing TMEM106B is measured. If the amount of label associated with immobilized TMEM106B or cells expressing TMEM106B in the test sample is substantially reduced relative to the control sample, it indicates that the second antibody is competing with the first antibody for binding to TMEM106B. See, Harlow and Lane (1988) Antibodies: A Laboratory Manual Chapter 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

[0205] Also provided herein is an anti-TMEM106B antibody that competitively inhibits the binding of an anti-TMEM106B antibody and / or competes with the binding of an anti-TMEM106B antibody, wherein the anti-TMEM106B antibody comprises (a) V H A domain comprising (i) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, and 35, (ii) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, and (iii) HVR-H3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, and NO: 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120, and (b) V LA domain comprising (i) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, and 160, (ii) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1 NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185, and (iii) HVR-L3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185. NO: 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223 and 224. In some embodiments, the antibody comprises V in SEQ ID NO: 225-268 and SEQ ID NO: 269-314, respectively. H and V L sequence.

[0206] Provided herein are anti-TMEM106B antibodies that bind to an epitope of human TMEM106B that is identical to or overlaps with an epitope bound by an anti-TMEM106B antibody, the anti-TMEM106B antibody comprising: (a) V HA domain comprising (i) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, and 35, (ii) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, and (iii) HVR-H3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 and 78, and NO: 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120, and (b) V LA domain comprising (i) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, and 160, (ii) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1 NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185, and (iii) HVR-L3 comprising an amino acid sequence selected from the group consisting of: SEQ ID NO:161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184 and 185. NO: 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223 and 224. In some embodiments, the antibody comprises V in SEQ ID NO: 225-268 and SEQ ID NO: 269-314, respectively. H and V L In some embodiments, the epitope of human TMEM106B is the same as the epitope bound by the anti-TMEM106B antibody.

[0207] The anti-TMEM106B antibodies of the present disclosure can bind to various regions of TMEM106B, including various regions of human TMEM106B. Such regions of TMEM106B include the cytoplasmic domain of TMEM106B or the luminal domain of TMEM106B.

[0208] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more regions or domains of TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more regions or domains of human TMEM106B.

[0209] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to the cytoplasmic and / or luminal domains of TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 59-73, 80-90, 15-24, 33-40, 5-19, 30-40, 34-40, 59-69, 52-62, 64-74, 151-165, 185-195, 139-149, 248-258, 156-161, 202-207, 219-233, 126-140, 185-195, 260-274, 202-212, 151-161, 223-233, 143-153, 223-228, 133-145, and / or 198-212 of human TMEM106B (SEQ ID NO: 1).

[0210] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 151-165 and / or 185-195 of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 151-165 (NITNNNYYSVEVENI; SEQ ID NO: 324). In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues T>S of human TMEM106B is a risk allele 185-195 (TIIGPLDMKQI; SEQ ID NO: 325). In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to a non-contiguous epitope formed by one or more amino acids within amino acid residues 151-165 (NITNNNYYSVEVENI; SEQ ID NO: 324) and one or more amino acids within amino acid residues 185-195 (TIIGPLDMKQI; SEQ ID NO: 325) of human TMEM106B.

[0211] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 59-73, 80-90 cytoplasmic, 139-149 and / or 248-258 of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 59-73 (VTCPTCQGTGRIPRG; SEQ ID NO: 326) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 80-90 (ALIPYSDQRLR; SEQ ID NO: 327) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 139-149 (KRTIYLNITNT; SEQ ID NO: 328) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 248-258 (YQYVDCGRNTT: 329) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 59-73 (VTCPTCQGTGRIPRG; SEQ ID NO: 326), one or more amino acids within amino acid residues 80-90 (ALIPYSDQRLR; SEQ ID NO: 327), one or more amino acids within amino acid residues 139-149 (KRTIYLNITNT; SEQ ID NO: 328), and one or more amino acids within amino acid residues 248-258 (YQYVDCGRNTT: 329).

[0212] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 15-24 and / or 33-40 of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 15-24 (EDAYDGVTSE; SEQ ID NO: 330) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 33-40 (SEVHNEDG; SEQ ID NO: 331) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 15-24 (EDAYDGVTSE; SEQ ID NO: 330) and one or more amino acids within amino acid residues 33-40 (SEVHNEDG; SEQ ID NO: 331) of human TMEM106B.

[0213] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 5-19, 30-40, 156-161, 202-207 and / or 219-233 of human TMEM106B. In some embodiments, the anti-TME M106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 5-19 (LSHLPLHSS KEDAYD; SEQ ID NO: 332) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 30-40 (SEVHNEDG; SEQ ID NO: 333) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 156-161 (NYYSVE; SEQ ID NO: 334) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 202-207 (VIAEEM; SEQ ID NO: 335) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 219-233 (IKVHNIVLMMQVTVT; SEQ ID NO: 336) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 5-19 (LSHLPLHSSKEDAYD; SEQ ID NO: 332), 30-40 (SEVHNEDG; SEQ ID NO: 333), 156-161 (NYYSVE; SEQ ID NO: 334), 202-207 (VIAEEM; SEQ ID NO: 335), and 219-233 (IKV HNIVLMMQVTVT; SEQ ID NO: 336) of human TMEM 106B.

[0214] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 126-140, 185-195, and / or 260-274 of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 126-140 (IGVKSAYVSYDVQKR; SEQ ID NO: 337) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues T185S risk allele 185-195 (TIIGPLDMKQI; SEQ ID NO: 325) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 260-274 (QLGQSEYLNVLQPQ Q; SEQ ID NO: 338) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 126-140 (IGVKSAYVSYDVQKR; SEQ ID NO: 337), 185-195 (TIIGPL DMKQI; SEQ ID NO: 325), and 260-274 (QLGQ SEYLNVLQPQ Q; SEQ ID NO: 338) of human TMEM106B.

[0215] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 34-40 and / or 202-212 of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 34-40 (EVHNEDG; SEQ ID NO: 339) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 202-212 (VIAEEMSYMYD; SEQ ID NO: 340) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 34-40 (EVHNEDG; SEQ ID NO: 339) and 202-212 (VIAEEMSYMYD; SEQ ID NO: 340) of human TMEM106B.

[0216] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 151-161 and / or 223-233 of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 151-161 (NITNNNYYSVE; SEQ ID NO: 341) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 223-233 (NIVLMMQ VTV; SEQ ID NO: 342) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 151-161 (NITNNNYYSVE; SEQID NO: 341) and 223-233 (NIVLMMQV TV; SEQ ID NO: 342) of human TMEM106B.

[0217] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 59-69, 143-153 and / or 223-228 of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 59-69 (VTCPTCQGTGR; SEQ ID NO: 343) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 143-153 (YLNITNTLNIT; SEQ ID NO: 344) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 223-228 (NIVLMM; SEQ ID NO: 345) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 59-69 (VTCPTCQGTGR; SEQ ID NO: 343), 143-153 (YLNITNTLNIT; SEQ ID NO: 344), and 223-228 (NIVLMM; SEQ ID NO: 345) of human TMEM106B.

[0218] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 133-145 and / or 198-212 of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 133-145 of human TMEM106B (V SYD V QKRTIYLN; SEQ ID NO: 346). In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 198-212 of human TMEM106B (TVPTVIAEEMSYMYD; SEQ ID NO: 347). In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 133-145 (VSYDVQKRTIYLN; SEQ ID NO: 346) and 198-212 (TVPTVIAEEMSYMYD; SEQ ID NO: 347) of human TMEM106B.

[0219] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 52-62, 64-75, and / or 223-228 of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 52-62 (EFTGRDSVTCP; SEQ ID NO: 348) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 64-75 (CQGTGRIPRGQE; SEQ ID NO: 349) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 223-228 (NIVLMM; SEQ ID NO: 345) of human TMEM106B. In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more amino acids within amino acid residues 52-62 (EFTGRDSVTCP; SEQ ID NO: 348), 64-75 (CQGTGRIPRGQE; SEQ ID NO: 349), and 223-228 (NIVLMM; SEQ ID NO: 345) of human TMEM106B.

[0220] In some embodiments, the anti-TMEM106B antibodies of the present disclosure bind to one or more epitopes within human TMEM106B selected from the group consisting of amino acid residues NITNNNYYSVEVENI (SEQ ID NO: 324), TIIGPLDMKQI (SEQ ID NO: 325), VTCPTCQGTGRIPRG (SEQ ID NO: 326), ALIPYSDQRLR (SEQ ID NO: 327), KRTIYLNITNT (SEQ ID NO: 328), YQYVDCGRNTT (SEQ ID NO: 329), EDAYDGVTSE (SEQ ID NO: 330), SEVHNEDG (SEQ ID NO: 331), LSHLPLHSSKEDAYD (SEQ ID NO: 332), LVNSEVHNEDG (SEQ ID NO: 333), NYYSVE (SEQ ID NO: 334), VIAEEM (SEQ ID NO: 335), IKVHNIVLMMQVTVT (SEQ ID NO: 336), NO:336), IGVKSAYVSYDVQKR (SEQ ID NO:337), QLGQSEYLNVLQPQQ (SEQ ID NO:338), EVHNEDG (SEQ ID NO:339), VIAEEMSYMYD (SEQ ID NO:340), NITNNNYYSVE (SEQ ID NO:341), NIVLMMQVTVT (SEQ ID NO:342), VTCPTCQGTGR (SEQ ID NO:343), YLNITNTLNIT (SEQ ID NO:344), NIVLMM (SEQ ID NO:345), VSYDVQKRTIYLN (SEQ ID NO:346), TVPTVIAEEMSYMYD (SEQ ID NO:347), EFTGRDSVTCP (SEQ ID NO:348) and CQGTGRIPRGQE (SEQ ID NO:349).

[0221] In some embodiments, the anti-TMEM106B antibody according to any of the above embodiments is a monoclonal antibody, including humanized antibodies and / or human antibodies. In some embodiments, the anti-TMEM106B antibody is an antibody fragment, such as Fv, Fab, Fab', scFv, diabody or F(ab')2 fragment. In some embodiments, the anti-TMEM106B antibody is a substantially full-length antibody, such as an IgG1 antibody, an IgG2a antibody, or other antibody classes or isotypes as defined herein.

[0222] In some embodiments, an anti-TMEM106B antibody according to any of the above embodiments may include, alone or in combination, any of the features described in Sections 1-7 below:

[0223] (1) Anti-TMEM106B antibody binding affinity

[0224] In some embodiments of any of the antibodies provided herein, the antibody has a dissociation constant (Kd) of <1 μM, <100 nM, <10 nM, <1 nM, <0.1 nM, <0.01 nM, or <0.001 nM (e.g., 10 -8 M or smaller, e.g. 10 -8 M to 10 - 13 M, for example 10 -9 M to 10 -13 M). The dissociation constant can be determined by any analytical technique, including any biochemical or biophysical technique, such as ELISA, surface plasmon resonance (SPR), biolayer interferometry (see, e.g., by ForteBio's Octet system), isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), circular dichroism (CD), stopped-flow analysis, and colorimetric or fluorescent protein melting analysis. In one embodiment, Kd is measured by a radiolabeled antigen binding assay (RIA). In a certain embodiment, an RIA is performed with a Fab version of the antibody of interest and its antigen, e.g., as described in Chen et al. J. Mol. Biol. 293:865-881 (1999). In some embodiments, Kd is measured using a BIACORE surface plasmon resonance assay, such as an assay performed by a BIACORE-2000 or BIACORE-3000 (BIAcore, Inc., Piscataway, NJ) at 25°C with immobilized antigen CM5 at ~10 response units (RU). In some embodiments, Kd is determined using a monovalent antibody (e.g., Fab) or a full-length antibody. D In some embodiments, a monovalent form of the full-length antibody is used to determine K D .

[0225] In some embodiments, the anti-TMEM106B antibodies of the present disclosure may have nanomolar or even picomolar affinity for TMEM106B. In some embodiments, the dissociation constant (Kd) of the antibody is from about 0.1 nM to about 500 nM. For example, the Kd of the antibody binding to human TMEM106B is from about 500 nM, about 400 nM, about 300 nM, about 200 nM, about 100 nM, about 75 nM, about 50 nM, about 25 nM, about 10 nM, about 9 nM, about 8 nM, about 7 nM, about 6 nM, about 5 nM, about 4 nM, about 3 nM, about 2 nM, about 1 nM or about 1 nM to about 0.1 nM.

[0226] (2) Antibody fragments

[0227] In some embodiments of any of the antibodies provided herein, the antibody is an antibody fragment. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, F(ab')2, Fv and scFv fragments and other fragments described below. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, for example, WO 93 / 16185; and U.S. Patent Nos. 5571894 and 5587458. For a discussion of Fab and F(ab')2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No. 5869046.

[0228] Diabodies are antibody fragments with two antigen binding sites, which can be bivalent or bispecific. See, e.g., EP404097; WO 1993 / 01161; Hudson et al. Nat. Med. 9:129-134 (2003). Tribodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003). Single-domain antibodies are antibody fragments that contain all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (see, e.g., U.S. Pat. No. 6,248,516).

[0229] As described herein, antibody fragments can be prepared by a variety of techniques, including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells (eg, E. coli or bacteriophage).

[0230] (3) Chimeric and humanized antibodies

[0231] In some embodiments of any one of the antibodies provided herein, the antibody is a chimeric antibody. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567. In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate (such as a monkey)) and a human constant region. In another example, a chimeric antibody is a "class switching" antibody, in which the class or subclass has been changed from the class or subclass of the parent antibody. Chimeric antibodies include their antigen binding fragments.

[0232] In some embodiments of any one of the antibodies provided herein, the antibody is a humanized antibody. Generally, non-human antibodies are humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibodies. In certain embodiments, humanized antibodies are substantially non-immunogenic in humans. In certain embodiments, the affinity of humanized antibodies to targets is substantially the same as that of antibodies from another species from which humanized antibodies are derived. See, for example, U.S. Patent Nos. 5530101, 5693761; 5693762; and 5585089. In certain embodiments, the amino acids of antibody variable domains that can be modified without reducing the natural affinity of the antigen-binding domain and reducing immunogenicity are identified. See, for example, U.S. Patent Nos. 5766886 and 5869619. In general, humanized antibodies include one or more variable domains, wherein HVR (or portions thereof) are derived from non-human antibodies, and FR (or portions thereof) are derived from human antibody sequences. Humanized antibodies will optionally also include at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (eg, the antibody from which the HVR residues are derived), for example, to restore or improve antibody specificity or affinity.

[0233] Humanized antibodies and methods for making them are reviewed, for example, in Almagro et al. Front. Biosci. 13: 1619-1633 (2008), and further described, for example, in U.S. Pat. Nos. 5821337, 7527791, 6982321, and 7087409. Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using a "best fit" approach (see, for example, Sims et al., J. Immunol. 151: 2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular light chain variable region or heavy chain variable region subset (see, for example, Carter et al., Proc. Natl. Acad. Sci. USA, 89: 4285 (1992); and Presta et al., J. Immunol., 151: 2623 (1993). 993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272: 10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271: 22611-22618 (1996)).

[0234] (4) Human antibodies

[0235] In some embodiments of any of the antibodies provided herein, the antibody is a human antibody. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk et al., Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg Curr. Opin. Immunol. 20: 450-459 (2008).

[0236] Human antibodies can be prepared by applying an immunogen to a transgenic animal, which has been modified to produce complete human antibodies or complete antibodies with human variable regions in response to antigenic challenges. The mouse strains that are defective in mouse antibody production can be engineered with large fragments of human Ig loci, in the expectation that such mice can produce human antibodies in the absence of mouse antibodies. Human Ig large fragments can retain larger variable gene diversity and appropriate regulation of antibody production and expression. By utilizing the antibody diversification and selection mechanism of mice and the lack of immune tolerance of human proteins, the human antibody library replicated in these mouse strains can produce high-affinity fully human antibodies for any antigen of interest (including human antigens). Using hybridoma technology, antigen-specific human monoclonal antibodies with desired specificity can be produced and selected. Some exemplary methods are described in U.S. Patent No. 5545807, EP 546073 and EP546073. See also, for example, description of XENOMOUSE TM US Patent Nos. 6075181 and 6150584 for the technology; description US Patent No. 5770429 for technology; description KM US Patent No. 7041870, and describes The human variable regions of intact antibodies produced by such animals can also be further modified, for example, by combining with different human constant regions.

[0237] Human antibodies can also be prepared by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for producing human monoclonal antibodies have been described. (See, for example, Kozbor. J. Immunol. 133: 3001 (1984) and Boemer et al., J. Immunol. 147: 86 (1991)). Human antibodies produced via human B cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 1 03: 3557-3562 (2006). Additional methods include, for example, those described in U.S. Pat. No. 7189826 (describing the production of monoclonal human IgM antibodies from hybridoma cell lines). Human hybridoma technology (trioma technology) is also described in Vollmers et al., Histology and Histopathology 20 (3): 927-937 (2005) and Vollmers et al., Methods and Findings in Experimental and Clinical Pharmacology 27 (3): 185-91 (2005). Human antibodies can also be produced by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences can then be combined with desired human constant domains. The technology for selecting human antibodies from antibody libraries is described below.

[0238] In some embodiments of any of the antibodies provided herein, the antibody is a human antibody isolated by in vitro methods and / or screening of combinatorial libraries (to obtain antibodies with one or more desired activities). Suitable examples include, but are not limited to, phage display (CAT, Morphosys, Dyax, Biosite / Medarex, Xoma, Symphogen, Alexion (formerly Proliferon), Affimed), ribosome display (CAT), yeast display (Adimab), and the like. In certain phage display methods, VH and VL gene libraries are cloned separately by polymerase chain reaction (PCR), and random recombination is performed in phage libraries, and then antigen-binding phages can be screened, as described in Winter et al., Ann. Rev. Immunol. 12: 433-455 (1994). For example, many methods for generating phage display libraries and screening antibodies with desired binding characteristics from such libraries are known in the art. See also Sidhu et al., J. Mol. Biol. 338(2):299-310, 2004; Lee et al., J. Mol. Biol. 340(5):1073-1093, 2004; Fellouse Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(-2):1 19-132 (2004). Phages usually display antibody fragments as single-chain Fv (scFv) fragments or as Fab fragments. Libraries of immune origin provide high-affinity antibodies to the immunogen without the need to construct hybridomas. Alternatively, the initial library can be cloned (e.g., from humans) to provide antibodies from a single source for a wide range of non-self-antigens and self-antigens without any immunization, as described by Griffiths et al., EMBO J. 12: 725-734 (1993). Finally, the initial library can also be prepared synthetically by cloning unrearranged V gene segments from stem cells using PCR primers containing random sequences to encode highly variable HVR3 regions and achieve rearrangement in vitro, as described by Hoogenboom et al., J. Mol. Biol., 227: 381-388, 1992. Patent disclosures describing human antibody phage libraries include, for example, U.S. Patent No. 5750373 and U.S. Patent Publication Nos. 2007 / 0292936 and 2009 / 0002360. Antibodies isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.

[0239] (5) Constant region including Fc region

[0240] In some embodiments of any one of the antibodies provided herein, the antibody comprises an Fc. In some embodiments, the Fc is a human IgG1, IgG2, IgG3 and / or IgG4 isotype. In some embodiments, the antibody belongs to the IgG class, the IgM class or the IgA class.

[0241] In certain embodiments of any one of the antibodies provided herein, the antibody has an IgG2 isotype. In some embodiments, the antibody contains a human IgG2 constant region. In some embodiments, the human IgG2 constant region comprises an Fc region. In some embodiments, the antibody induces one or more TMEM106B activities or is unrelated to the binding of Fc receptors. In some embodiments, the antibody binds to inhibitory Fc receptors. In certain embodiments, the inhibitory Fc receptor is an inhibitory Fc-gamma receptor IIB (FcγIIB).

[0242] In certain embodiments of any of the antibodies provided herein, the antibody has an IgG1 isotype. In some embodiments, the antibody contains a mouse IgG1 constant region. In some embodiments, the antibody contains a human IgG1 constant region. In some embodiments, the human IgG1 constant region comprises an Fc region. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is an inhibitory Fc-gamma receptor IIB (FcγIIB).

[0243] In certain embodiments of any one of the antibodies provided herein, the antibody has an IgG4 isotype. In some embodiments, the antibody contains a human IgG4 constant region. In some embodiments, the human IgG4 constant region comprises an Fc region. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is an inhibitory Fc-gamma receptor IIB (FcγIIB).

[0244] In certain embodiments of any one of the antibodies provided herein, the antibody has a hybrid IgG2 / 4 isotype. In some embodiments, the antibody comprises an amino acid sequence comprising amino acids 118-260 according to the EU numbering of human IgG2 and amino acids 261-447 according to the EU numbering of human IgG4 (WO 1997 / 11971; WO 2007 / 106585).

[0245] In some embodiments, the Fc region increases clustering but does not activate complement compared to a corresponding antibody comprising an Fc region (not comprising amino acid substitutions). In some embodiments, the antibody induces one or more activities of a target to which the antibody specifically binds. In some embodiments, the antibody binds to TMEM106B.

[0246] Modification of the anti-TMEM106B antibody disclosed herein to modify effector function and / or increase the serum half-life of the antibody is also desirable. For example, the Fc receptor binding site on the constant region can be modified or mutated to remove or reduce the binding affinity to certain Fc receptors (such as FcγRI, FcγRII and / or FcγRIII), thereby reducing antibody-dependent cell-mediated cytotoxicity. In some embodiments, the effector function is weakened by removing the N-glycosylation of the Fc region of the antibody (for example, in the CH2 domain of IgG). In some embodiments, the effector function is weakened by modifying regions such as 233-236, 297 and / or 327-331 of human IgG, such as WO 99 / 58572 and Armour et al., Molecular Immunology 40: 585-593 (2003); Reddy et al., J. Immunology 164: 1925-1933 (2000) described. In other embodiments, modification of the anti-TMEM106B antibodies of the present disclosure to modify effector functions, thereby increasing selectivity for detection of ITIM-containing FcgRIIb (CD32b) without activating humoral responses, increasing clustering of TMEM106B antibodies on neighboring cells, including antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis, is also desired.

[0247] For example, to increase the serum half-life of an antibody, a salvage receptor binding epitope can be incorporated into an antibody (particularly an antibody fragment) as described in U.S. Pat. No. 5,739,277. As used herein, the term "salvage receptor binding epitope" refers to an epitope of the Fc region of an IgG molecule (e.g., IgG1, IgG2, IgG3, or IgG4) that is responsible for increasing the in vivo serum half-life of the IgG molecule. Other amino acid sequence modifications.

[0248] (6) Multispecific Antibodies

[0249] A multispecific antibody is an antibody with binding specificity to at least two different epitopes, the epitopes being included in those epitopes on the same or another polypeptide (e.g., one or more TMEM106B polypeptides disclosed herein). In some embodiments, a multispecific antibody may be a bispecific antibody. In some embodiments, a multispecific antibody may be a trispecific antibody. In some embodiments, a multispecific antibody may be a tetraspecific antibody. Such antibodies may be derived from full-length antibodies or antibody fragments (e.g., F(ab')2 bispecific antibodies). In some embodiments, a multispecific antibody comprises a first antigen binding region that is bound to a first site on TMEM106B, and comprises a second antigen binding region that is bound to a second site on TMEM106B. In a certain embodiment, a multispecific antibody comprises a first antigen binding region that is bound to TMEM106B and a second antigen binding region that is bound to a second polypeptide.

[0250] Provided herein are multispecific antibodies comprising a first antigen-binding region and a second antigen-binding region, wherein the first antigen-binding region comprises six HVRs of an antibody described herein, binds to TMEM106B, and the second antigen-binding region binds to a second polypeptide. In some embodiments, the first antigen-binding region comprises V H or V L .

[0251] In some embodiments of any of the multispecific antibodies, the second polypeptide is: a) an antigen that facilitates transport across the blood-brain barrier; (b) an antigen that facilitates transport across the blood-brain barrier, the antigen selected from: transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM 197, llama single domain antibody, TMEM 30 (A), protein transduction domain, TAT, Syn-B, penetrant peptide, polyarginine peptide, vascular peptide and ANG1005; (c) a pathogenic protein selected from amyloid β, oligomeric amyloid β, amyloid β plaques, amyloid precursor protein or fragments thereof, τ, IAPP, α-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxia, ataxia 1, ataxia 2, ataxia 3, ataxia 7, ataxia 8, ataxia 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, β2 microglobulin, gelsolin, corneal epithelial protein, cystatin, immune Globulin light chain AL, S-IBM protein, repeat-associated non-ATG (RAN) translation product, dipeptide repeat (DPR) peptide, glycine-alanine (GA) repeat peptide, glycine-proline (GP) repeat peptide, glycine-arginine (GR) repeat peptide, proline-alanine (PA) repeat peptide, ubiquitin and proline-arginine (PR) repeat peptide; (d) ligands and / or proteins expressed on immune cells, wherein the ligands and / or proteins are selected from: CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA-4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG-3 and phosphatidylserine; and / or (e) proteins, lipids, polysaccharides or glycolipids expressed on one or more tumor cells and any combination thereof.

[0252] Many antigens that facilitate transport across the blood-brain barrier are known in the art (see, e.g., Gabathuler R. Neurobiol. Dis. 37: 48-57 (2010)). Such second antigens include, but are not limited to, transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor (including CRM197 (a non-toxic mutant of diphtheria toxin)), llama single domain antibodies (such as TMEM30 (A) (Flippase)), protein transduction domains (such as TAT), Syn-B or transmembrane peptides, polyarginine or generally positively charged peptides, vascular peptides (such as ANG1005) (see, e.g., Gabathuler, 2010) and other cell surface proteins enriched on blood-brain barrier endothelial cells (see, e.g., Daneman et al., PLoS One 5 (10): e13741 (2010)).

[0253] The multivalent antibody may recognize the TMEM106B antigen, as well as, but not limited to, additional antigens, Aβ peptide antigens, or α-synuclein antigens, or tau protein antigens, or TDP-43 protein antigens, or prion protein antigens, or huntingtin protein antigens, or RAN, translation product antigens (including dipeptide repeats (DPR peptides) composed of glycine-alanine (GA), glycine-proline (GP), glycine-arginine (GR), proline-alanine (PA), or proline-arginine (PR), insulin receptor, insulin-like growth factor receptor. Transferrin receptor or any other antigen that facilitates antibody transfer across the blood-brain barrier. In some embodiments, the second polypeptide is transferrin. In some embodiments, the second polypeptide is tau. In some embodiments, the second polypeptide is Aβ. In some embodiments, the second polypeptide is TREM2. In some embodiments, the second polypeptide is α-synuclein.

[0254] The multivalent antibody contains at least one polypeptide chain (and preferably two polypeptide chains), wherein one or more polypeptide chains comprise two or more variable domains. For example, one or more polypeptide chains may comprise VD1-(X1) n -VD2-(X2) n -Fc, wherein VD1 is the first variable domain, VD2 is the second variable domain, Fc is a polypeptide chain of the Fc region, X1 and X2 represent amino acids or polypeptides, and n is 0 or 1. Similarly, one or more polypeptide chains may include V H -C H 1-Flexible joint-V H -C H 1-Fc region chain; or V H -CH 1-V H -C H 1-Fc region chain. The multivalent antibody herein preferably further comprises at least two (and preferably four) light chain variable domain polypeptides. The multivalent antibody herein may, for example, comprise about two to about eight light chain variable domain polypeptides. The light chain variable domain polypeptides contemplated herein comprise a light chain variable domain and optionally further comprise a CL domain.

[0255] Techniques for preparing multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein and Cuello Nature 305:537 (1983), WO 93 / 08829 and Traunecker et al., EMBO J. 10:3655 (1991)), and "knob-in-hole" engineering (see, e.g., U.S. Pat. No. 5,731,168). See also WO 2013 / 026833 (CrossMab). Multispecific antibodies can also be prepared by the following techniques: engineering electrostatic steering effects for preparing antibody Fc heterodimer molecules (WO 2009 / 089004A1); cross-linking two or more antibodies (see, e.g., U.S. Pat. No. 4,676,980); using leucine; using "diabody" technology to prepare bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993)); and using single-chain Fv (scFv) dimers (see, e.g., Gruber et al., J. Immunol. 152:5368 (1994)); and preparing trispecific antibodies as described, e.g., by Tutt et al., J. Immunol. 147:60 (1991).

[0256] Also included herein are engineered antibodies with three or more functional antigen binding sites, including "octopus antibodies" (see, e.g., US2006 / 0025576). Antibodies herein also include "dual-acting FAbs" or "DAFs" that contain antigen binding sites that bind to multiple TMEM106B (see, e.g., US2008 / 0069820).

[0257] (7) Antibody variants

[0258] In some embodiments of any of the antibodies provided herein, amino acid sequence variants of the antibodies are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibodies.

[0259] (i) Substitution, insertion and deletion variants

[0260] In some embodiments of any one of the antibodies provided herein, antibody variants with one or more amino acid substitutions are provided. The amino acid sequence variants of the antibody can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions and / or insertions and / or substitutions of residues within the amino acid sequence of the antibody.

[0261] Table A: Amino Acid Substitutions

[0262]

[0263]

[0264] Substantial modification of the biological properties of the antibody is achieved by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of ​​substitution (e.g., a sheet or helical conformation), (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. Naturally occurring residues are divided into several groups based on common side chain properties:

[0265] (1) Hydrophobicity: norleucine, Met, Ala, Val, Leu, Ile;

[0266] (2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln;

[0267] (3) Acidic: Asp, Glu;

[0268] (4) Basic: His, Lys, Arg;

[0269] (5) Residues that affect chain orientation: Gly, Pro; and

[0270] (6) Aromatic: Trp, Tyr, Phe.

[0271] For example, non-conservative substitutions may involve replacing a member of one of these classes with a member of another class. For example, such substituted residues may be introduced into regions of human antibodies that are homologous to non-human antibodies, or into non-homologous regions of the molecule.

[0272] According to certain embodiments, when changing the polypeptide or antibody described herein, the hydropathic index of the amino acid can be considered. According to the hydrophobicity and charge characteristics of the amino acid, each amino acid has been assigned a hydropathic index. They are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine / cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (-0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamic acid (-3.5); glutamine (-3.5); aspartic acid (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).

[0273] The importance of the hydropathic amino acid index in conferring a biological function to a protein interaction is understood in the art. Kyte et al., J. Mol. Biol., 157: 105-131 (1982). It is known that certain amino acids can replace other amino acids with similar hydropathic indexes or scores and still retain similar biological activity. When making changes based on the hydropathic index, in certain embodiments, replacement of amino acids with hydropathic indices within ± 2 is included. In certain embodiments, those amino acids within ± 1 are included, and in certain embodiments, those amino acids within ± 0.5 are included.

[0274] It is also understood in the art that similar amino acid substitutions can be made effectively on the basis of hydrophilicity, especially where the resulting biologically functional protein or peptide is intended for use in immunological embodiments, as is the case in the present case. In certain embodiments, the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of the protein's neighboring amino acids, correlates with the immunogenicity and antigenicity of the protein, i.e., the biological properties of the protein.

[0275] The following hydrophilicity values ​​have been assigned to these amino acid residues: arginine (+3.0); lysine (+3.0 ± 1); aspartic acid (+3.0 ± 1); glutamic acid (+3.0 ± 1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5 ± 1); alanine (-0.5); histidine (-0.5); cysteine ​​(-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5) and tryptophan (-3.4). When changes are made based on similar hydrophilicity values, in certain embodiments, substitutions of amino acids with hydrophilicity values ​​within ±2 are included, in certain embodiments, substitutions of those amino acids within +1 are included, and in certain embodiments, substitutions of those amino acids within ±0.5 are included. Epitopes can also be identified from the primary amino acid sequence based on hydrophilicity. These regions are also referred to as "epitope core regions."

[0276] In certain embodiments, substitutions, insertions or deletions may occur within one or more HVRs, as long as these changes do not substantially reduce the ability of the antibody to bind to antigens. For example, conservative changes (e.g., conservative substitutions provided herein) that do not substantially reduce binding affinity may be made in HVRs. Such changes may be, for example, outside the antigen contact residues in HVRs. In certain embodiments of the variant VH and VL sequences provided above, each HVR is unchanged, or contains no more than one, two or three amino acid substitutions.

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

[0278] Any cysteine ​​residues not involved in maintaining the proper conformation of the antibody may also be replaced, usually with serine, to improve the oxidative stability of the molecule and prevent abnormal cross-linking. Conversely, one or more cysteine ​​bonds may be added to the antibody to improve the stability of the antibody (especially where the antibody is an antibody fragment, such as an Fv fragment).

[0279] (ii) Glycosylation variants

[0280] In some embodiments of any one of the antibodies provided herein, the antibody is altered to increase or decrease the degree of glycosylation of the antibody. The addition or deletion of glycosylation sites of the antibody can be conveniently achieved by altering the amino acid sequence to create or remove one or more glycosylation sites.

[0281] Glycosylation of antibodies is usually N-connected or O-connected. N-connection refers to the attachment of the carbohydrate moiety to the side chain of asparagine residues. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine are recognition sequences for enzymatic attachment of the carbohydrate moiety to the side chain of asparagine, wherein X is any amino acid except proline. Therefore, any of these tripeptide sequences present in the polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of a sugar (i.e., one of N-acetylgalactosamine, galactose or xylose) to a hydroxyamino acid (most commonly serine or threonine, but 5-hydroxyproline or 5-hydroxylysine can also be used).

[0282] The addition of glycosylation sites to antibodies is conveniently achieved by altering the amino acid sequence so that the antibody contains one or more of the above-mentioned tripeptide sequences (for N-linked glycosylation sites). The sequence of the original antibody may also be altered by addition of one or more serine or threonine residues or by replacement of one or more serine or threonine residues (for O-linked glycosylation sites).

[0283] In the case where the antibody comprises the Fc district, the carbohydrate connected thereto can be changed. The natural antibody produced by mammalian cells generally comprises the biantennary oligosaccharide of side chain, and the oligosaccharide is generally connected to the Asn297 (according to Kabat numbering) of the CH2 domain in the Fc district by N-connection. Oligosaccharide can include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, and the fucose of the GlcNAc in the " stem " of the biantennary oligosaccharide structure. In some embodiments, the oligosaccharide in the antibody of the present invention can be modified to produce antibody variants with some improved properties.

[0284] In one embodiment, antibody variants are provided having a carbohydrate structure lacking fucose attached (directly or indirectly) to the Fc region.See, e.g., U.S. Patent Publication Nos. 2003 / 0157108 and 2004 / 0093621. Examples of disclosures involving "defucosylated" or "fucose-deficient" antibody variants include: US2003 / 0157108; US2003 / 0115614; US2002 / 0164328; US2004 / 0093621; US2004 / 0132140; US 2004 / 0110704; US2004 / 0110282; US2004 / 0109865; Okazaki et al., J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng. 87:614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Led 3 CHO cells deficient in protein fucosylation (Ripka et al., Arch. Biochem. Biophys. 249:533-545 (1986); US 2003 / 0157108), and knockout cell lines, such as α-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al., Biotech. Bioeng. 87:614 (2004) and Kanda et al., Biotechnol. Bioeng. 94(4):680-688 (2006)).

[0285] (iii) Modified constant region

[0286] In some embodiments of any of the antibodies provided herein, the antibody Fc is an antibody Fc isotype and / or modification. In some embodiments, the antibody Fc isotype and / or modification is capable of binding to an Fcγ receptor.

[0287] In some embodiments of any of the antibodies provided herein, the modified antibody Fc is an IgG1 modified Fc. In some embodiments, the IgG1 modified Fc comprises one or more modifications. For example, in some embodiments, the IgG1 modified Fc comprises one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments, the one or more amino acid substitutions are selected from N297A (Bolt S et al., (1993) Eur J Immunol 23:403-411), D265A (Shields et al., (2001) RJ Biol. Chem. 276, 6591-6604), L234A, L235A (Hutchins et al., (1995) Proc Natl Acad Sci USA, 92: 11980-11984; Alegre et al., (1994) Transplantation 57: 1537-1543.31; Xu et al., (2000) Cell Immunol, 200: 16-26), G237A (Alegre et al., (1994) Transplantation 57: 1537-1543.31; Xu et al., (2000) Cell Immunol, 200: 16-26). Immunol, 200: 16-26), C226S, C229S, E233P, L234V, L234F, L235E (McEarchem et al., (2007) Blood, 109: 1185-1192), P33 IS (Sazinsky et al., (2008) Proc Natl Acad Sci USA 2008, 105: 20167-20172), S267E, L328F, A330L, M252Y, S254T and / or T256E, wherein the amino acid positions are according to the EU numbering convention.

[0288] In some embodiments of any one of the Fc modified by IgG1, the Fc comprises an N297A mutation according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, the Fc comprises an D265A and N297A mutation according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, the Fc comprises an D270A mutation according to EU numbering. In some embodiments, the Fc modified by IgG1 comprises an L234A and L235A mutation according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, the Fc comprises an L234A and G237A mutation according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, the Fc comprises an L234A, L235A and G237A mutation according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, Fc includes one or more (including all mutations) of P238D, L328E, E233, G237D, H268D, P271G and A330R mutations according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, Fc includes one or more of S267E / L328F mutations according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, Fc includes one or more of P238D, L328E, E233D, G237D, H268D, P271G and A330R mutations according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, Fc includes one or more of P238D, L328E, G237D, H268D, P271G and A330R mutations according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, Fc comprises P238D, S267E, L328E, E233D, G237D, H268D, P271G and A330R mutations according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, Fc comprises P238D, S267E, L328E, G237D, H268D, P271G and A330R mutations according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, Fc comprises C226S, C229S, E233P, L234V and L235A mutations according to EU numbering. In some embodiments of any one of the Fc modified by IgG1, Fc comprises L234F, L235E and P331S mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc's, the Fc comprises S267E and L328F mutations according to EU numbering. In some embodiments of any of the IgG1 modified Fc's, the Fc comprises a S267E mutation according to EU numbering.In some embodiments of any of the IgG1 modified Fcs, the Fc comprises replacement of the constant heavy chain 1 (CH1) and hinge region with CH1 and replacement of the hinge region of IgG2 (amino acids 118-230 of IgG2 according to EU numbering) with a kappa light chain.

[0289] In some embodiments of any one of the Fc modified by IgG1, compared with the corresponding antibody with Fc region (not comprising two or more amino acid replacements), Fc comprises two or more amino acid replacements, and the amino acid replacement increases antibody clustering but does not activate complement. Therefore, in some embodiments of any one of the Fc modified by IgG1, the Fc modified by IgG1 is an antibody comprising Fc region, wherein the antibody is included in the amino acid replacement at position E430G and one or more amino acid replacements in the Fc region, and the residue position of the amino acid replacement is selected from: according to EU numbering L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S and any combination thereof. In some embodiments, the Fc modified by IgG1 comprises amino acid replacements at positions E430G, L243A, L235A and P331S according to EU numbering. In some embodiments, the Fc modified by IgG1 comprises amino acid replacements at positions E430G and P331S according to EU numbering. In some embodiments, the IgG1 modified Fc comprises amino acid replacements at positions E430G and K322A according to EU numbering. In some embodiments, the IgG1 modified Fc comprises amino acid replacements at positions E430G, A330S, and P331S according to EU numbering. In some embodiments, the IgG1 modified Fc comprises amino acid replacements at positions E430G, K322A, A330S, and P331S according to EU numbering. In some embodiments, the IgG1 modified Fc comprises amino acid replacements at positions E430G, K322A, and A330S according to EU numbering. In some embodiments, the IgG1 modified Fc comprises amino acid replacements at positions E430G, K322A, and P331S according to EU numbering.

[0290] In some embodiments of any of the IgG1 modified Fcs, the IgG1 modified Fc may further comprise an A330L mutation (Lazar et al., Proc Natl Acad Sci USA, 103:4005-4010 (2006)) according to the EU numbering convention, or one or more of L234F, L235E and / or P331S mutations (Sazinsky et al., Proc Natl Acad Sci USA, 105:20167-20172 (2008)) combined herein to eliminate complement activation. In some embodiments of any of the IgG1 modified Fcs, the IgG1 modified Fc may further comprise one or more of A330L, A330S, L234F, L235E and / or P331S according to EU numbering. In some embodiments of any of the IgG1 modified Fcs, the IgG1 modified Fc may further comprise one or more mutations to enhance antibody half-life in human serum (e.g., one or more (including all) of the M252Y, S254T, and T256E mutations according to the EU numbering convention). In some embodiments of any of the IgG1 modified Fcs, the IgG1 modified Fc may further comprise one or more of E430G, E430S, E430F, E430T, E345K, E345Q, E345R, E345Y, S440Y, and / or S440W according to EU numbering.

[0291] Other aspects of the present disclosure relate to antibodies with modified constant regions (i.e., Fc regions). If the antibody is engineered to eliminate FcgR binding, the antibody that activates the targeted receptor based on binding to the FcgR receptor can lose agonist activity (see, e.g., Wilson et al., Cancer Cell 19: 101-113 (2011); Armour et al., Immunology 40: 585-593 (2003); and White et al., Cancer Cell 27: 138-148 (2015)). Therefore, it is believed that when the antibody has an Fc domain (CH1 and hinge region) from a human IgG2 isotype or another type of Fc domain that can preferentially bind to inhibitory FcgRIIB r receptors or their variants, the anti-TMEM106B antibody of the present disclosure with the correct epitope specificity can activate the target antigen with minimal adverse reactions.

[0292] In some embodiments of any one of the antibodies provided herein, the modified antibody Fc is an IgG2 modified Fc. In some embodiments, the IgG2 modified Fc comprises one or more modifications. For example, in some embodiments, the IgG2 modified Fc comprises one or more amino acid replacements (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments of any of the IgG2 modified Fc, one or more amino acid substitutions are selected from V234A according to the EU numbering convention (Alegre et al., Transplantation 57: 1537-1543 (1994); Xu et al., Cell Immunol, 200: 16-26 (2000)); G237A (Cole et al., Transplantation, 68: 563-571 (1999)); H268Q, V309L, A330S, P331S (US 2007 / 0148167; Armour et al., Eur J Immunol 29: 2613-2624 (1999); Armour et al., The Haematology Journal 1 (Suppl. 1): 27 (2000); Armour et al., The Haematology Journal 1 (Suppl. 1): 28 (2000); Haematology Journal 1 (Suppl. 1): 27 (2000)), C219S and / or C220S (White et al., Cancer Cell 21, 138-148 (2015)); S267E, L328F (Chu et al., Mol Immunol, 45: 3926-3933 (2008)); and M252Y, S254T and / or T256E (according to EU numbering convention). In some embodiments of any of the IgG2 modified Fcs, the Fc comprises amino acid replacements at positions V234A and G237A according to EU numbering. In some embodiments of any of the IgG2 modified Fcs, the Fc comprises amino acid replacements at positions C219S or C220S according to EU numbering. In some embodiments of any of the IgG2 modified Fcs, the Fc comprises amino acid replacements at positions A330S and P331S according to EU numbering. In some embodiments of any of the IgG2 modified Fcs, the Fc comprises amino acid substitutions at positions S267E and L328F according to EU numbering.

[0293] In some embodiments of any of the IgG2 modified Fcs, the Fc comprises a C127S amino acid substitution according to the EU numbering convention (White et al., (2015) Cancer Cell 27, 138-148; Lightle et al., Protein Sci. 19: 753-762 (2010); and WO 2008 / 079246). In some embodiments of any of the IgG2 modified Fcs, the antibody has an IgG2 isotype having a kappa light chain constant domain comprising a C214S amino acid substitution according to the EU numbering convention (White et al., Cancer Cell 27: 138-148 (2015); Lightle et al., Protein Sci. 19: 753-762 (2010); and WO 2008 / 079246).

[0294] In some embodiments of any of the IgG2 modified Fcs, the Fc comprises a C220S amino acid substitution according to the EU numbering convention. In some embodiments of any of the IgG2 modified Fcs, the antibody has an IgG2 isotype having a kappa light chain constant domain comprising a C214S amino acid substitution according to the EU numbering convention.

[0295] In some embodiments of any of the IgG2 modified Fcs, the Fc comprises a C219S amino acid substitution according to the EU numbering convention. In some embodiments of any of the IgG2 modified Fcs, the antibody has an IgG2 isotype having a kappa light chain constant domain comprising a C214S amino acid substitution according to the EU numbering convention.

[0296] In some embodiments of any one of the IgG2 modified Fcs, the Fc comprises an IgG2 isotype heavy chain constant domain 1 (CH1) and a hinge region (White et al., Cancer Cell 27: 138-148 (2015)). In certain embodiments of any one of the IgG2 modified Fcs, the IgG2 isotype CH1 and hinge region comprise an amino acid sequence of 118-230 according to EU numbering. In some embodiments of any one of the IgG2 modified Fcs, the antibody Fc region comprises an S267E amino acid replacement, an L328F amino acid replacement, or both thereof, and / or an N297A or N297Q amino acid replacement according to the EU numbering convention.

[0297] In some embodiments of any of the IgG2 modified Fcs, the Fc further comprises one or more amino acid substitutions at positions E430G, E430S, E430F, E430T, E345K, E345Q, E345R, E345Y, S440Y, and S440W according to EU numbering. In some embodiments of any of the IgG2 modified Fcs, the Fc may further comprise one or more mutations to enhance antibody half-life in human serum (e.g., one or more (including all mutations) of M252Y, S254T, and T256E mutations according to EU numbering convention). In some embodiments of any of the IgG2 modified Fcs, the Fc may further comprise A330S and P331S.

[0298] In some embodiments of any of the IgG2 modified Fcs, the Fc is an IgG2 / 4 hybrid Fc. In some embodiments, the IgG2 / 4 hybrid Fc comprises IgG2 aa 118 to 260 and IgG4 aa 261 to 447. In some embodiments of any of the IgG2 modified Fcs, the Fc comprises one or more amino acid substitutions at positions H268Q, V309L, A330S, and P331S according to EU numbering.

[0299] In some embodiments of either of the IgG1 and / or IgG2 modified Fc, the Fc comprises one or more additional amino acid substitutions selected from A330L, L234F, L235E, or P331S according to EU numbering; and any combination thereof.

[0300] In certain embodiments of any one of the Fc modified by IgG1 and / or IgG2, the Fc comprises one or more amino acid replacements at residue positions selected from C127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, E345R, E430G, S440Y, and any combination thereof according to EU numbering. In some embodiments of any one of the Fc modified by IgG1 and / or IgG2, the Fc comprises amino acid replacements at positions E430G, L243A, L235A, and P331S according to EU numbering. In some embodiments of any one of the Fc modified by IgG1 and / or IgG2, the Fc comprises amino acid replacements at positions E430G and P331S according to EU numbering. In some embodiments of any one of the Fc modified by IgG1 and / or IgG2, the Fc comprises amino acid replacements at positions E430G and K322A according to EU numbering. In some embodiments of any one of the Fc modified by IgG1 and / or IgG2, the Fc comprises amino acid replacements at positions E430G, A330S and P331S according to EU numbering. In some embodiments of any one of the Fc modified by IgG1 and / or IgG2, the Fc comprises amino acid replacements at positions E430G, K322A, A330S and P331S according to EU numbering. In some embodiments of any one of the Fc modified by IgG1 and / or IgG2, the Fc comprises amino acid replacements at positions E430G, K322A and A330S according to EU numbering. In some embodiments of any one of the Fc modified by IgG1 and / or IgG2, the Fc comprises amino acid replacements at positions E430G, K322A and P331S according to EU numbering. In some embodiments of any of the IgG1 and / or IgG2 modified Fcs, the Fc comprises amino acid replacements at positions S267E and L328F according to EU numbering. In some embodiments of any of the IgG1 and / or IgG2 modified Fcs, the Fc comprises amino acid replacements at positions C127S according to EU numbering. In some embodiments of any of the IgG1 and / or IgG2 modified Fcs, the Fc comprises amino acid replacements at positions E345R, E430G, and S440Y according to EU numbering.

[0301] In some embodiments of any one of the antibodies provided herein, modified antibody Fc is an IgG4 modified Fc. In some embodiments, the IgG4 modified Fc includes one or more modifications. For example, in some embodiments, the IgG4 modified Fc includes one or more amino acid replacements (for example, relative to the wild-type Fc region of the same isotype). In some embodiments of any one of the IgG4 modified Fc, one or more amino acid replacements are selected from L235A, G237A, S229P, L236E (Reddy et al., J Immunol 164: 1925-1933 (2000)), S267E, E318A, L328F, M252Y, S254T and / or T256E according to EU numbering convention. In some embodiments of any one of the IgG4 modified Fc, Fc may additionally include L235A, G237A and E318A according to EU numbering convention. In some embodiments of any of the IgG4 modified Fcs, the Fc may further comprise S228P and L235E according to the EU numbering convention. In some embodiments of any of the IgG4 modified Fcs, the IgG4 modified Fc may further comprise S267E and L328F according to the EU numbering convention.

[0302] In some embodiments of any of the IgG4 modified Fcs, the IgG4 modified Fc comprises can be combined with an S228P mutation according to the EU numbering convention (Angal et al., Mol Immunol. 30: 105-108 (1993)) and / or with one or more mutations described in (Peters et al., J Biol Chem. 287(29): 24525-33 (2012)) to enhance antibody stability.

[0303] In some embodiments of any of the IgG4 modified Fcs, the IgG4 modified Fc may further comprise one or more mutations to enhance antibody half-life in human serum (e.g., one or more (including all) of the M252Y, S254T, and T256E mutations according to the EU numbering convention).

[0304] In some embodiments of any one of the Fc modified by IgG4, Fc includes L235E according to EU numbering. In certain embodiments of any one of the Fc modified by IgG4, Fc includes one or more amino acid replacements at residue positions selected from C127S, F234A, L235A, L235E, S267E, K322A, L328F, E345R, E430G, S440Y and any combination thereof according to EU numbering. In some embodiments of any one of the Fc modified by IgG4, Fc includes amino acid replacements at positions E430G, L243A, L235A and P331S according to EU numbering. In some embodiments of any one of the Fc modified by IgG4, Fc includes amino acid replacements at positions E430G and P331S according to EU numbering. In some embodiments of any one of the Fc modified by IgG4, Fc includes amino acid replacements at positions E430G and K322A according to EU numbering. In some embodiments of any of the IgG4 modified Fcs, the Fc comprises an amino acid replacement at position E430 according to EU numbering. In some embodiments of any of the IgG4 modified Fcs, the Fc region comprises an amino acid replacement at position E430G and K322A according to EU numbering. In some embodiments of any of the IgG4 modified Fcs, the Fc comprises an amino acid replacement at position S267E and L328F according to EU numbering. In some embodiments of any of the IgG4 modified Fcs, the Fc comprises an amino acid replacement at position C127S according to EU numbering. In some embodiments of any of the IgG4 modified Fcs, the Fc comprises an amino acid replacement at position E345R, E430G, and S440Y according to EU numbering.

[0305] (8) Other antibody modifications

[0306] In some embodiments of any one of the antibodies, the antibody is a derivative. The term "derivative" refers to a chemically modified molecule comprising an insertion, deletion or replacement of an amino acid (or nucleic acid). In certain embodiments, the derivative comprises a covalent modification, including but not limited to chemical bonding with a polymer, a lipid or other organic or inorganic moieties. In certain embodiments, the chemically modified antigen-binding proteins may have a longer circulation half-life than the antigen-binding proteins that are not chemically modified. In certain embodiments, the chemically modified antigen-binding proteins may have improved targeting capabilities for desired cells, tissues and / or organs. In some embodiments, the derivative antigen-binding proteins are covalently modified to include one or more water-soluble polymer attachments, including but not limited to polyethylene glycol, polyoxyethylene glycol or polypropylene glycol. See, for example, U.S. Patent Nos. 4640835, 4496689, 4301144, 4670417, 4791192 and 4179337. In certain embodiments, the derivative antigen binding protein comprises one or more polymers, including but not limited to monomethoxy-polyethylene glycol, dextran, cellulose, copolymers of ethylene glycol / propylene glycol, carboxymethyl cellulose, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers), poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, and mixtures of such polymers.

[0307] In certain embodiments, derivatives are covalently modified by polyethylene glycol (PEG) subunits. In certain embodiments, one or more water-soluble polymers are bonded at one or more specific positions of derivatives (e.g., at the amino terminal). In certain embodiments, one or more water-soluble polymers are randomly attached to one or more side chains of derivatives. In certain embodiments, PEG is used to improve the therapeutic ability of antigen-binding proteins. In certain embodiments, PEG is used to improve the therapeutic ability of humanized antibodies. Some such methods are discussed, for example, in U.S. Patent No. 6133426, which is incorporated by reference for any purpose.

[0308] Peptide analogs are commonly used as non-peptide drugs in the pharmaceutical industry, and their properties are similar to those of the template peptide. These types of non-peptide compounds are called "peptide mimetics or peptidomimetics". Fauchere, J. Adv. Drug Res., 15: 29 (1986); and Evans et al., J. Med. Chem., 30: 1229 (1987), which are incorporated herein by reference for any purpose. Such compounds are usually developed by means of computerized molecular modeling. Peptide mimetics that are structurally similar to peptides used for treatment can be used to produce similar therapeutic or preventive effects. Typically, mimetics are structurally similar to an exemplary polypeptide (i.e., a polypeptide having biochemical properties or pharmacological activity), such as a human antibody, but have one or more peptide bonds, which are optionally replaced by a bond selected from the following by methods well known in the art: -CH2NH-, -CH2S-, -CH2-CH2-, -CH-CH- (cis and trans), -COCH2-, -CH(OH)CH2-, and -CH2SO-. Systematic replacement of one or more amino acids of a consensus sequence with D-amino acids of the same type (e.g., D-lysine replaces L-lysine) can be used in certain embodiments to produce more stable peptides. In addition, constrained peptides comprising a consensus sequence or substantially identical consensus sequence variations can be produced by methods known in the art (Rizo and Gierasch Ann. Rev. Biochem., 61: 387 (1992), incorporated herein by reference for any purpose); for example, by adding internal cysteine ​​residues capable of forming intramolecular disulfide bridges that cyclize the peptide.

[0309] Drug conjugation involves coupling a biologically active cytotoxic (anticancer) payload or drug to an antibody that specifically targets a tumor marker (e.g., a polypeptide that is ideally present only in or on tumor cells). The antibodies track these proteins in vivo and attach themselves to the surface of cancer cells. The biochemical reaction between the antibody and the target protein (antigen) triggers a signal in the tumor cell, which then absorbs or internalizes the antibody along with the cytotoxin. After the ADC is internalized, the cytotoxic drug is released and kills the cancer. Due to this targeting, ideally, the drug has lower side effects and provides a wider therapeutic window than other chemotherapeutic agents. The technology of conjugating antibodies has been disclosed and is known in the art (see, for example, Jane de Lartigue QncLive July 5, 2012; ADC Review onantibody-drug conjugates; and Ducry et al. Bioconjugate Chemistry 21(1):5-13(2010).

[0310] III. Nucleic Acids, Vectors and Host Cells

[0311] The anti-TMEM106B antibodies of the present disclosure can be produced using recombinant methods and compositions, for example as described in U.S. Pat. No. 4,816,567. In some embodiments, an isolated nucleic acid having a nucleotide sequence encoding any of the anti-TMEM106B antibodies of the present disclosure is provided. Such nucleic acids may encode a V comprising a V L The amino acid sequence and / or comprising V H In some embodiments, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In some embodiments, host cells comprising such nucleic acids are also provided. In some embodiments, the host cell comprises (e.g., has been transduced with): (1) a vector comprising a nucleic acid encoding a V or V sequence of an antibody; L The amino acid sequence of the antibody V H (2) a first vector comprising a V encoding an antibody L A nucleic acid having an amino acid sequence of H In some embodiments, the host cell is a eukaryotic cell, such as a Chinese hamster ovary (CHO) cell or a lymphocyte (e.g., a Y0, NS0, Sp20 cell). The host cell of the present disclosure also includes, but is not limited to, isolated cells, cells cultured in vitro, and cells cultured in vitro.

[0312] Provided is a method for preparing an anti-TMEM106B antibody of the present disclosure. In some embodiments, the method includes culturing a host cell of the present disclosure comprising a nucleic acid encoding an anti-TMEM106B antibody under conditions suitable for antibody expression. In some embodiments, the antibody is subsequently recovered from the host cell (or host cell culture medium).

[0313] For the recombinant production of anti-TMEM106B antibodies of the present disclosure, nucleic acid encoding anti-TMEM106B antibodies is separated and inserted into one or more vectors to further clone and / or express in a host cell. Such nucleic acid can be easily separated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that can specifically bind to the heavy chain and light chain of the encoding antibody).

[0314] The nucleic acid sequence comprising any one of the anti-TMEM106B antibodies of the present disclosure, or the fragment of cell surface expression as described herein or the suitable vector of their polypeptide (including antibody) includes but is not limited to cloning vector and expression vector. Suitable cloning vector can be constructed according to standard techniques, or can be selected from a large number of cloning vectors available in the art. Although the selected cloning vector can be changed according to the host cell desired to be used, useful cloning vectors generally have self-replication ability, can have a single target of a specific restriction endonuclease, and / or can carry the gene of a marker, which can be used to select a clone comprising a vector. Suitable examples include plasmids and bacterial viruses, such as pUC18, pUC19, Bluescript (e.g., pBS SK+) and derivatives thereof, mpl8, mpl9, pBR322, pMB9, ColE1, pCR1, RP4, phage DNA and shuttle vectors (such as pSA3 and pAT28). These and many other cloning vectors can be obtained from commercial suppliers (such as BioRad, Strategene and Invitrogen).

[0315] Suitable host cells for cloning or expressing antibody encoding vectors include prokaryotic or eukaryotic cells. For example, anti-TMEM106B antibodies disclosed herein can be produced in bacteria, especially when glycosylation and Fc effector functions are not required. About the expression of antibody fragments and polypeptides in bacteria (for example, U.S. Patent Nos. 5648237, 5789199 and 5840523). After expression, antibodies can be separated from bacterial cell cytoplasm with soluble fractions, and can be further purified.

[0316] In addition to prokaryotes, eukaryotic microbes (such as filamentous fungi or yeast) are suitable cloning or expression hosts for antibody-encoding vectors, including fungal and yeast strains whose glycosylation pathways have been "humanized" to produce antibodies with partial or full human glycosylation patterns (e.g., Gemgross Nat. Biotech. 22: 1409-1414 (2004); and Li et al., Nat. Biotech. 24: 210-215 (2006)).

[0317] Suitable host cells for expressing glycosylated antibodies can also be derived from multicellular organisms (invertebrates and vertebrates). 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 transfection of Spodoptera frugiperda cells. Plant cell cultures can also be used as hosts (e.g., U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429, which describe PLANTIBODIES for producing antibodies in transgenic plants). TM technology).

[0318] Vertebrate cells can also be used as hosts. For example, mammalian cell lines suitable for growth in suspension can be useful. Other examples of useful mammalian host cell lines are monkey kidney CV1 lines (COS-7) transformed by SV40; human embryonic kidney cell lines (293 or 293 cells, such as Graham et al. J. Gen Virol. 36: 59 (1977) described); baby hamster kidney cells (BHK); mouse Sertoli cells (TM4 cells, such as Mather, Biol. Reprod. 23: 243-251 (1980) described); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical cancer cells (HELA); canine kidney cells (MDCK); Buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells, as described, for example, in Mather et al. Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other useful mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines, such as Y0, NS0, 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, Vol. 248 (BKCLo ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

[0319] IV. Pharmaceutical Compositions / Formulations

[0320] Provided herein are pharmaceutical compositions and / or pharmaceutical formulations comprising an anti-TMEM106B antibody of the present disclosure and a pharmaceutically acceptable carrier.

[0321] In some embodiments, the pharmaceutically acceptable carrier is preferably non-toxic to the recipient at the dosage and concentration adopted. The antibodies described herein can be formulated as solid, semi-solid, liquid or gaseous preparations. Examples of such preparations include, but are not limited to, tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols. Depending on the desired preparation, a pharmaceutically acceptable carrier may include a pharmaceutically acceptable non-toxic carrier of a diluent, which is a vehicle commonly used to prepare a pharmaceutical composition for animal or human administration. In certain embodiments, the pharmaceutical composition may include a formulation material for changing, maintaining or maintaining, for example, pH, osmotic pressure volume molar concentration, viscosity, transparency, color, isotonicity, odor, sterility, stability, dissolution or release rate, adsorption or penetration of the composition.

[0322] In certain embodiments, pharmaceutically acceptable carriers include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine or lysine); antimicrobial agents; antioxidants (such as ascorbic acid, sodium sulfite or sodium bisulfite); buffers (such as borates, bicarbonates, Tris-HCl, citrates, phosphates or other organic acids); bulking agents (such as mannitol or glycine); chelating agents (such as ethylenediaminetetraacetic acid (EDTA)); complexing agents (such as caffeine, polyvinylpyrrolidone, β-cyclodextrin or hydroxypropyl-β-cyclodextrin); bulking agents; monosaccharides; disaccharides; and other carbohydrates (such as glucose, mannose or dextrin); proteins (such as serum albumin, gelatin or immunoglobulins); colorants, flavorings and diluents; emulsifiers; hydrophilic polymers (such as polyvinylpyrrolidone); low molecular weight the polypeptide; a salt-forming counterion (such as sodium); a preservative (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenylethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid or hydrogen peroxide); a solvent (such as glycerol, propylene glycol or polyethylene glycol); a sugar alcohol (such as mannitol or sorbitol); a suspending agent; a surfactant or wetting agent (such as pluronics, PEG, sorbitan esters, polysorbates (such as polysorbate 20, polysorbate 80), triton, trishydroxymethylaminomethane, lecithin, cholesterol, tyloxapol); a stability enhancer (such as sucrose or sorbitol); a tonicity enhancer (such as an alkali metal halide, preferably sodium chloride or potassium chloride, mannitol, sorbitol); a delivery vehicle; a diluent; an excipient and / or a pharmaceutical adjuvant. Additional examples of formulations suitable for various types of administration can be found in Remington: The Science and Practice of Pharmacy, Pharmaceutical Press 22nd edition (2013). For a brief review of drug delivery methods, see Langer, Science 249: 1527-1533 (1990).

[0323] Suitable preparations for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending agents, solubilizers, thickening agents, stabilizers and preservatives.

[0324] The formulation can be optimized for retention and stability in the brain or central nervous system. When the agent is administered into the cranial cavity, it is desirable to retain the agent in the cavity and not diffuse or cross the blood-brain barrier. Stabilization techniques include cross-linking, polymerizing or connecting to groups such as polyethylene glycol, polyacrylamide, neutral protein carriers, etc. to achieve an increase in molecular weight.

[0325] Other strategies for increasing retention include embedding antibodies, such as anti-TMEM106B antibodies of the present disclosure, in biodegradable or bioerodible implants. The release rate of the therapeutic agent is controlled by the transport rate through the polymer matrix and the biodegradation of the implant. The implant can be a particle, a sheet, a patch, a plaque, a fiber, a microcapsule, etc., and can have any size or shape compatible with the selected insertion site. The biodegradable polymer composition that can be used can be an organic ester or ether, which will produce physiologically acceptable degradation products (including monomers) when degraded. Anhydrides, amides, orthoesters, etc. can be used alone or in combination with other monomers. The polymer will be a condensation polymer. The polymer can be cross-linked or non-cross-linked. Of particular concern are polymers, homopolymers or copolymers of hydroxy aliphatic carboxylic acids and polysaccharides. Among the polyesters of interest, polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone and combinations thereof are included. The polysaccharides of interest are calcium alginate and functionalized cellulose, especially carboxymethyl cellulose esters, which are characterized by being water insoluble, having a molecular weight of about 5 kD to 500 kD, etc. Biodegradable hydrogels can also be used in the implants of the subject invention. Hydrogels are generally copolymer materials, which are characterized by being able to absorb liquids.

[0326] V. Therapeutic Uses

[0327] As disclosed herein, the anti-TMEM106B antibodies of the present disclosure can be used to prevent various diseases, disorders and conditions, reduce the risk of various diseases, disorders and conditions, or treat various diseases, disorders and conditions. In some embodiments, the anti-TMEM106B antibodies of the present disclosure can effectively prevent the following diseases, disorders and conditions, reduce the risk of the following diseases, disorders and conditions, or treat the following diseases, disorders and conditions: frontotemporal lobar degeneration, frontotemporal lobar dementia, frontotemporal lobar dementia with progranulin mutation, frontotemporal lobar dementia with C90rf72 mutation, frontotemporal lobar degeneration with TDP-43 inclusions, TDP-43 proteinopathy, hippocampal sclerosis (HpScl), hippocampal sclerosis of aging (HS-aging), cognitive impairment associated with various disorders (including but not limited to cognitive impairment in amyotrophic lateral sclerosis), cognitive impairment associated with chronic traumatic encephalopathy and hypomyelination disorders (including but not limited to hypomyelinating leukodystrophy).

[0328] Other aspects of the present disclosure relate to a method of preventing, reducing the risk of, or treating a subject having a disease, disorder, or injury selected from the group consisting of frontotemporal dementia, Alzheimer's disease, vascular dementia, seizures, retinal dystrophy, non-traumatic brain injury, spinal cord injury, long-term depression, atherosclerotic vascular disease, adverse symptoms of normal aging, dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, malaria, idiopathic Tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, Lewy body dementia, multiple system atrophy, degenerative disc disease, Shy-Drager syndrome, progressive supranuclear palsy, cortical basal ganglia degeneration, acute disseminated encephalomyelitis, granulomatous disease, sarcoidosis, diseases of aging, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, inflammatory disease, arthritis, multiple sclerosis, metabolic disorder, obesity, insulin resistance, type 2 diabetes, tissue or vascular damage, injury and one or more adverse symptoms of normal aging, the method comprising administering a therapeutically effective amount of an anti-TMEM106B antibody of any one of the preceding embodiments to an individual.

[0329] In some embodiments, the anti-TMEM106B antibodies of the present disclosure can reduce TDP-43 inclusions in the brain, reduce the decline in cognitive and behavioral functions, and improve cognitive and behavioral functions.

[0330] In some embodiments, the subject or individual is a mammal. Mammals include, but are not limited to, livestock (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates (such as monkeys)), rabbits, and rodents (e.g., mice and rats). In some embodiments, the subject or individual is a human.

[0331] Antibodies provided herein (and any other therapeutic agent) can be administered by any suitable means, including parenteral, intrapulmonary, intranasal, intralesional administration, intracerebral spinal, intracranial, intraspinal, intrasynovial, intrathecal, oral, topical or inhalation routes. Parenteral infusion includes intramuscular, intravenous administration with bolus or continuous infusion for a period of time, intraarterial, intraarticular, intraperitoneal or subcutaneous administration. In some embodiments, administration is intravenous administration. In some embodiments, administration is subcutaneous administration. Administration can be by any suitable route, for example, by injection, such as intravenous or subcutaneous injection, which depends in part on whether administration is short-lived or long-term. Various dosing schedules are contemplated herein, including but not limited to single administration or multiple administrations at various time points, push administration and pulse infusion.

[0332] The antibodies provided herein will be formulated, administered and used in a manner consistent with good medical practice. Factors considered in this context include the specific illness treated, the specific mammal treated, the clinical condition of the individual patient, the cause of the illness, the delivery site of the medicament, the method of administration, the administration schedule, and other factors known to practitioners. The antibody is not required but optionally formulated with one or more medicaments currently used to prevent or treat the illness in question. The effective amount of such other medicaments depends on the amount of the antibody present in the preparation, the type of illness or treatment, and other factors discussed above. These medicaments are generally used in the same dose as described herein and by the administration route as described herein, or with about 1% to 99% of the dosage as described herein, or with any dosage determined to be appropriate empirically / clinically and by any approach determined to be appropriate empirically / clinically.

[0333] For the prevention or treatment of disease, the appropriate dosage of the antibodies of the invention (when used alone or in combination with one or more other therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's medical history and response to the antibody, and the judgment of the attending physician. The antibody is suitably administered to the patient at one time or over a series of treatments.

[0334] Depending on the type and severity of the disease, an antibody of about 1 μg / kg to 15 mg / kg (e.g., 0.1 mg / kg-10 mg / kg) can be used as an initial candidate dose for administration to a patient, whether, for example, by one or more separate administrations, or by continuous infusion. According to the factors mentioned above, a typical daily dose can be in the range of about 1 μg / kg to 100 mg / kg or more. For repeated administrations of several days or longer, according to the condition, treatment should generally continue until the desired inhibition of disease symptoms occurs. An exemplary dose of an antibody will be in the range of about 0.05 mg / kg to about 10 mg / kg. Therefore, one or more doses (or any combination thereof) of about 0.5 mg / kg, 2.0 mg / kg, 4.0 mg / kg or 10 mg / kg can be administered to a patient. These doses can be intermittent, for example, administered weekly or every three weeks (e.g., so that the patient receives about two doses to about twenty doses, or, for example, about six doses of antibody). In certain embodiments, the dosing frequency is three times a day, twice a day, once a day, every other day, once a week, once every two weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, or once a month, once every two months, once every three months, or longer. An initial higher loading dose may be administered, followed by one or more lower doses. However, other dosage regimens may also be available. The progress of the therapy may be easily monitored by conventional techniques and assays.

[0335] VI. Diagnostic Uses

[0336] In some embodiments of any of the antibodies, any of the anti-TMEM106B antibodies provided herein can be used to detect the presence of TMEM106B in a sample or individual. As used herein, the term "detection" encompasses quantitative or qualitative detection. Provided herein is a method for using the antibodies of the present disclosure for diagnostic purposes (such as detection of TMEM106B in an individual or tissue sample derived from an individual). In some embodiments, the individual is human. In some embodiments, the tissue sample is blood, brain, cerebrospinal fluid, etc.

[0337] The detection method may involve quantification of antigen-binding antibodies. Antibody detection in biological samples may be performed by any method known in the art, including immunofluorescence microscopy, immunocytochemistry, immunohistochemistry, ELISA, FACS analysis, immunoprecipitation, or micropositron emission tomography. In certain embodiments, for example, using 18F The antibody is radiolabeled and subsequently detected by micropositron emission tomography analysis. Antibody binding in patients can also be quantified by non-invasive techniques such as positron emission tomography (PET), X-ray computed tomography, single photon emission computed tomography (SPECT), computed tomography (CT), and computed axial tomography (CAT).

[0338] VII. Products

[0339] Provided herein are articles (e.g., kits) comprising anti-TMEM106B antibodies described herein. Articles may include one or more containers comprising antibodies described herein. The container may have any suitable packaging, including but not limited to vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), etc. The container may be a unit dose, bulk packaging (e.g., multi-dose packaging) or a subunit dose.

[0340] In some embodiments, the kit may additionally include a second reagent. In some embodiments, the second reagent is a pharmaceutically acceptable buffer or diluent, including but not limited to such as antibacterial water for injection (BWFI), phosphate buffered saline, Ringer's solution and glucose solution. In some embodiments, the second reagent is a pharmaceutically active agent.

[0341] In some embodiments of any one of the products, the product also includes instructions for use according to the method of the present disclosure. Instructions generally include information about the dosage, dosing schedule and route of administration for the intended treatment. In some embodiments, these instructions include administering the separated antibody of the present disclosure (e.g., anti-TMEM106B antibody described herein) to prevent disease, illness or injury, reduce the risk of disease, illness or injury, or treat the description of an individual with disease, illness or injury according to any method of the present disclosure, the disease, illness or injury is selected from frontotemporal lobar degeneration, frontotemporal lobar dementia, frontotemporal lobar dementia with progranulin mutation, frontotemporal lobar dementia with C9orf72 mutation, frontotemporal lobar degeneration with TDP-43 inclusions, TDP-43 proteinopathy, hippocampal sclerosis (HpScl), aging hippocampal sclerosis (HS-aging), cognitive impairment associated with various disorders (including but not limited to cognitive impairment in amyotrophic lateral sclerosis) and hypomyelination disorders (including but not limited to hypomyelination leukodystrophy). In some embodiments, the instructions include instructions for use of the anti-TMEM106B antibody and a second agent (eg, a second pharmaceutically active agent).

[0342] The present disclosure will be more fully understood with reference to the following examples. However, they should not be construed as limiting the scope of the present disclosure. All references throughout the present disclosure are hereby expressly incorporated by reference.

[0343] Example

[0344] Example 1: TMEM106B is a risk factor in various neurodegenerative disorders

[0345] In order to find the genetic risk factors for FTLD, a genome-wide association study (GWAS) was performed on 2509 control subjects and 515 subjects with pathologically confirmed FTLD-TDP, some of which contained GRN mutations (vanDeerlin et al., 2010, Nat Genetics, 42: 234-239). The GWAS found 3 SNPs in the 68kb region on chromosome 7p21.3, which were associated with the occurrence of FTLD-TDP with genome-wide significance (rs6966915, rs102004 and upper marker SNP rs1990622; p value range = 5.00 × 10-11 to 1.08 × 10-11). The three significantly associated SNPs were in the same linkage disequilibrium (LD) block with nine other nominally associated SNPs, and all spanned the locus of the TMEM106B gene. In this case, the minor allele of each significant SNP in the control cohort was greatly underrepresented in FTLD-TDP patients (32.1 vs. 43.6% in controls for the rs1990622 minor C allele; p value = 1.08 × 10-11), suggesting that individuals expressing the minor TMEM106B allele are less likely to develop the disease [odds ratio (OR) = 0.61 for the rs1990622 minor allele]. After stratifying the initial GWAS cohort according to GRN mutation status, the associations for the first three SNPs remained significant in both groups, but were greatest in people with GRN-associated FTLD-TDP in GRN carriers (rs 1990622 p value = 1.34 × 10-9; OR 0.34) compared with non-GRN carriers (rs1990622 p value = 6.90 × 10-7; OR 0.68). These SNPs confer the greatest risk in patients who also carry GRN mutations, suggesting that there is a functional interaction between TMEM106B and GRN. The genetic association of TMEM106B variants with FTLD-TDP has been replicated with high confidence (Cruchaga et al., 2011; Finch et al., 2011; Van der Zee et al., 2011). In addition to increasing the risk of FTLD, the major allele at rs1990622 also reduces the age of onset of FTLD. (See, for example, Finch et al., 2011, Neurology, 76: 467-474; Cruchaga et al., 2011, Arch Neurol.)

[0346] Initial studies evaluating TMEM106B SNPs as disease risk factors in FTLD-TDP were conducted before the discovery of the C9orf72 repeat expansion in 2012. Two independent groups found that TMEM106B SNPs were also associated with the risk of developing FTLD and / or ALS caused by C9orf72 mutations. (See Gallagher et al., 2014, Acta Neuropathol, 127:407-418; van Blitterswijk et al., 2014, Acta Neuropath, 127:397-406.) In these C9orf72 mutant cohorts, individuals carrying the minor alleles of the TMEM106B SNP [rs1990622 and / or rs3173615] were significantly reduced in frequency in LD with rs1990622, but not as significantly as in the cohort of GRN mutation carriers. Interestingly, analysis of C9orf72 repeat expansion carriers in each group based on the main disease manifestation of FTLD, FTLD-ALS or ALS showed that TMEM106B SNP specifically defends against the development of FTLD, but not against the development of ALS, and C9orf72 expansion carriers (homozygous for the protective TMEM106B allele) have less TDP-43 burden in the brain compared with risk allele carriers. These findings are consistent with early examinations of TMEM106B SNPs in clinical cohorts of ALS patients, in which TMEM106B SNP rs 1990622 and rs 1020004 were not associated with disease risk, but were significantly associated with cognitive function in ALS patients, and individuals homozygous for the rs 1990622 minor allele had better cognitive behavior than individuals heterozygous or homozygous for the major risk allele (Vass et al., 2011, Acta Neuropathol, 121: 373-380).

[0347] Neurodegenerative disease markers such as TDP-43 aggregates are not FTLD specific and have been observed in other neurodegenerative diseases including Alzheimer's disease (AD), Lewy body dementia (LBD), and hippocampal sclerosis (HpScl) (Amador-Ortiz et al., 2007, Ann Neurol, 61:435-445; Zarow et al., 2008, Curr Neurol Neurosci Rep, 8:363-370), even in apparently healthy individuals, albeit to a limited extent (see, e.g., Yu et al., 2015, Neurology, 84:927-934). In the absence of a clinical neurological diagnosis, TMEM106B risk variants are associated with TDP-43 neuropathology. Similarly, it is found that in AD patients, it affects the pathological manifestations of AD with protective TMEM106B haplotypes that are less related to TDP-43 pathology (Rutherford et al., 2012, Neurology, 79: 717-718). Hippocampal sclerosis is also a common pathological sign of Alzheimer's patients (including FTLD-TDP and AD), usually co-existing with TDP-43 pathology. It is found that in AD patients, TMEM106B genotype is related to primary hippocampal sclerosis (Aoki et al., 2015, Acta Neuropathol, 129: 53-64) and hippocampal sclerosis pathology, which makes TMEM106B the strongest genetic index of AD-HpScl and HpScl known so far (Murray et al., 2014, Acta Neuropathol, 128: 411-421). Together, these studies suggest that the TMEM106B SNP is a risk factor for the development and severity of TDP-43 proteinopathy in non-FTLD disorders such as AD and HpScl.

[0348] A genomic study of more than 1500 human brain autopsy samples identified the common variant of TMEM106B as the main genome-wide determinant of the biological aging rate of the human brain: According to the gene expression profile, the presence of 2 risk alleles at the locus of the TMEM106B gene makes individuals show ~12 years older than (Rhinn and Abeliovich, 2017, Cell Syst, 4: 404-415). In individuals without known neurological diseases and individuals with neurodegenerative diseases (such as Alzheimer's disease), this effect of TMEM106B risk alleles can be observed. With respect to the brain and life (cortex rather than cerebellum, especially over 65 years old), the role of TMEM106B in aging shows high selectivity. This effect is independently confirmed in another cohort, where carriers of protective TMEM106B haplo...

Claims

1. An isolated antibody that binds to human TMEM106B, wherein the antibody reduces the cell surface level of TMEM106B or reduces the intracellular level of TMEM106B.

2. An isolated antibody that binds to human TMEM106B, wherein the antibody binds to the amino acid sequence of human TMEM106B: NITNNNYYSVEVENI (SEQ ID NO: 324), TIIGPLDMKQI (SEQ ID NO: 325), VTCPTCQGTGRIPRG (SEQ ID NO: 326), (ALIPYSDQRLR (SEQ ID NO: 327), (KRTIYLNITNT (SEQ ID NO: 328), YQYVDCGRNTT (SEQ ID NO: 329), (LSHLPLHSSKEDAYD (SEQ ID NO: 332), (NYYSVE (SEQ ID NO: 334), (VIAEEM (SEQ ID NO: 335), (IKVHNIVLMMQVTVT; SEQ ID NO: 336), (IGVKSAYVSYDVQKR; SEQ ID NO: 337), (QLGQSEYLNVLQPQQ (SEQ ID NO: NO: 338), (VIAEEMSYMYD (SEQ ID NO: 340), (NITNNNYYSVE (SEQ ID NO: 341), (NIVLMMQVTV (SEQ ID NO: 342), (VTCPTCQGTGR (SEQ ID NO: 343), (YLNITNTLNIT (SEQ ID NO: 344), (NIVLMM (SEQ ID NO: 345), (VSYDVQKRTIYLN (SEQ ID NO: 346), (TVPTVIAEEMSYMYD (SEQ ID NO: 347), (EFTGRDSVTCP (SEQ ID NO: 348), or (CQGTGRIPRGQE (SEQ ID NO: 349)).

3. An isolated anti-TMEM106B antibody, wherein the anti-TMEM106B antibody comprises at least one, two, three, four, five or six HVRs of an antibody selected from the group consisting of: TM-1, TM-2, TM-3, TM-4, TM-5, TM-6, TM-7, TM-8, TM-9, TM-10, TM-11, TM-12, TM-13, TM-14, TM-15, TM-16, TM-17, TM-18, TM-19, TM-20, TM-21, TM-22, TM-23, TM-24, TM-25, TM-26, TM-27, TM-28, TM-29, TM-30, TM-31, TM-32, TM-33, TM-34, TM-35, TM-36, TM-37, TM-38, TM-39, TM-40, TM-41, TM-42, TM-43, TM-44, TM-45, TM-46, TM-47, TM-48, TM-49, TM-50, TM-51, TM-52 and TM-53.

4. An isolated antibody that binds to human TMEM106B, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-35; HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 36-78; and HVR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 79-120; and Wherein the light chain variable region comprises: HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 121-160; HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 161-185; and HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 186-224.

5. The antibody of any one of claims 1-4, wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 225-268.

6. The antibody of any one of claims 1-5, wherein the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 269-314.

7. An isolated antibody that binds to human TMEM106B, wherein the antibody competes with one or more of the antibodies of any one of claims 1-6 for binding to human TMEM106B.

8. An isolated antibody that binds to human TMEM106B, wherein the antibody binds to a TMEM106B epitope that is substantially the same as or overlaps with the antibody of any one of claims 1-7.

9. The antibody of any one of claims 1-8, wherein the antibody reduces or inhibits the interaction or binding of TMEM106B and at least one TMEM106B ligand or binding partner.

10. The antibody of claim 9, wherein the TMEM106B ligand or binding partner is selected from the group consisting of progranulin, TMEM106A, TMTM106C, clathrin heavy chain, μl subunit of adipocyte protein 2, CHMP2B, microtubule-associated protein 6, lysosomal-associated membrane protein 1, and vacuolar-ATPase accessory protein 1.

Images