How to use anti-TREM2 antibodies

Abstract

The present disclosure is generally directed to the use of compositions comprising antibodies, e.g., monoclonal antibodies, chimeric antibodies, affinity matured antibodies, humanized antibodies, antibody fragments, etc., that specifically bind to one or more epitopes within a TREM2 protein, e.g., human TREM2, and improve and / or enhance functional characteristics, in treating and / or slowing the progression of disease or injury in individuals in need thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 313,215, filed February 23, 2022, which is incorporated herein by reference in its entirety.

[0002] Reference to Electronic Sequence Listing The contents of the electronic sequence listing (735022004140seqlist.xml; size: 219,983 bytes, and creation date: February 22, 2023) are incorporated herein by reference in their entirety.

[0003] The present disclosure relates to therapeutic uses of anti-TREM2 antibodies. [Background technology]

[0004] Alzheimer's disease (AD) is a degenerative brain disorder and the most common cause of dementia in the United States, affecting approximately 5.5 million Americans. Globally, 50 million people live with dementia, and this prevalence is predicted to triple by 2050. Among the top 10 causes of death in the United States, AD is the only leading cause of morbidity and mortality for which no adequate treatment exists to prevent, slow, or cure it (2017 Alzheimer's Association Report). Current treatments for AD, such as acetylcholinesterase inhibitors (e.g., donepezil) and N-methyl-D-aspartate (NMDA) receptor antagonists (e.g., memantine), demonstrate modest, transient benefits on cognitive and behavioral parameters in AD patients but do not slow or halt disease progression (Cummings (2004) N Engl J Med, 351:56-67).

[0005] Recent studies suggest that triggering receptor expressed on myeloid cells-2 (TREM2), an immunoglobulin-like receptor, may play an important role in AD. For example, heterozygous mutations in the TREM2 gene have been found to increase the risk of AD by up to threefold (Guerreiro et al. (2013) N Engl J Med 368:117-127; Jonsson et al. (2013) N Engl J Med 368:107-116) and increase the rate of brain volume atrophy (Rajagopalan et al. (2013) N Engl J Med 369:1565-1567). Even individuals without AD who have heterozygous TREM2 mutations exhibit cognitive impairment compared with individuals with two normal TREM2 alleles. In the context of AD pathology, TREM2 expression influences amyloid pathology, regulates neuritic dystrophy, tau hyperphosphorylation and aggregation, and influences synaptic and neuronal loss (Jay et al. (2017) Mol Neurodegener, 12(1):56). Additionally, TREM2 has been shown to play an important role in limiting the development of periplaque tau pathology (Leyns et al. (2019) Nat Neurosci, PMID:31235932). Recent mouse genetic model studies also strongly support the critical role of TREM2 in AD, with loss or insufficiency of TREM2 associated with increased pathology (Cheng-Hathaway et al (2018) Mol Neurodegener, 13(1):29; Wang et al (2015) Cell, 160:1061-1071; Wang et al (2016) J Exp Med, 213:667-675; Yuan et al (2016) Neuron, 90:724-739; Jay et al (2017) J Neurosci, 37:637-647).

[0006] TREM2 is primarily expressed on myeloid cells, including microglia (Colonna and Wang (2016) Nat Rev Neurosci, 17:201-207). Microglia are resident macrophages in the central nervous system that, when appropriately activated, are thought to play an important defensive role in Alzheimer's disease through their housekeeping functions, such as promoting the clearance of cellular debris via phagocytosis and secreting growth factors. TREM2 expression has been shown to regulate microglial chemotaxis and phagocytosis and enhance microglial survival, proliferation, and differentiation. In addition, TREM2 is known to be required for sustaining the trophic function of microglial cells in the aging brain, and animal studies have demonstrated overlap between aged microglial phenotypes and microglial molecular signatures, including the TREM2 pathway, found in models of AD (Krasemann et al. (2017) Immunity, 47(3):566-581). These findings suggest that activation of TREM2 may ameliorate AD pathology and lead to improved cognitive function through activation of the innate immune system.

[0007] Thus, there is a need in the art for new methods of treating AD and other neurodegenerative diseases through activation of the innate immune system (e.g., microglial cell activity), for example, using agonistic antibodies that target TREM2.

[0008] All references cited herein, including patents, patent applications, and publications, are incorporated herein by reference in their entirety. Summary of the Invention

[0009] The present disclosure is generally directed to methods of using compositions comprising antibodies, eg, monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind to human TREM2.

[0010] In one aspect, the present disclosure provides a method for treating or delaying the progression of a disease or injury in an individual, the method comprising administering an anti-TREM2 agonist antibody to the individual, the individual not being homozygous for the ApoE e4 allele.In some embodiments, the individual is not an ApoE e4 carrier.In some embodiments, the individual is heterozygous for the ApoE4 e4 allele.In some embodiments, the individual is not an ApoE e4 carrier, or the individual is heterozygous for the ApoE4 e4 carrier allele.

[0011] In some embodiments, the methods provided herein comprise intravenously administering to an individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg. In further embodiments, the methods provided herein comprise intravenously administering to an individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg, wherein the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein (i) HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 34), HVR-H2 comprises the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 35), HVR-H3 comprises the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 31), and HVR-L1 comprises the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 41); HVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO: 33), and HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32); or (ii) HVR-H1 comprises the amino acid sequence YAFSSWDMN (SEQ ID NO: 36), HVR-H2 comprises the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 37), HVR-H3 comprises the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 38), HVR-L1 comprises the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 39), HVR-L2 comprises the amino acid sequence KVSNRVS (SEQ ID NO: 40), and HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32).

[0012] In some embodiments, the methods provided herein include intravenously administering to an individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein (a) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence SYWIG (SEQ ID NO: 146) or SWIG (SEQ ID NO: 147), HVR-H2 comprising the amino acid sequence IIYPGDADARYSPSFQG (SEQ ID NO: 148), and HVR-H3 comprising the amino acid sequence RRQGIFGDALDF (SEQ ID NO: 149); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RASQSVSSNLA (SEQ ID NO: 150), HVR-L2 comprising the amino acid sequence GASTRAT (SEQ ID NO: 151), and HVR-L3 comprising the amino acid sequence L QDNNFPPT (SEQ ID NO: 152), or (b) the heavy chain variable region comprises the amino acid sequence EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDADARYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYFCARRRQGIFGDALDFWGQGTLVTVSS (SEQ ID NO: 153) and the light chain variable region comprises the amino acid sequence EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWFQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQPEDFAVYYCLQDNNFPPTFGQGTKVDIK (SEQ ID NO: 154).

[0013] In some embodiments, the methods provided herein include intravenously administering to an individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg, 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 the amino acid sequence GFTFTDFYMS (SEQ ID NO: 155), HVR-H2 comprising the amino acid sequence VIRNKANGYTAGYNPSVKG (SEQ ID NO: 156), and HVR-H3 comprising the amino acid sequence ARLTYGFDY (SEQ ID NO: 157); and the light chain variable region or the heavy chain variable region comprises an HVR-L1 comprising the amino acid sequence QSSKSLLHSTGKTYLN (SEQ ID NO: 158), an HVR-L2 comprising the amino acid sequence WMSTRAS (SEQ ID NO: 159), and an HVR-L3 comprising the amino acid sequence QQFLEYPFT (SEQ ID NO: 160), or the heavy chain variable region comprises an HVR-L1 comprising the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAGSGFTFTDFYMSWVRQAPGKGPEWLSVIRNKANGYTAGYNPSVKGRFTISRDNSKNTLYLQMNSLR AEDTAVYYCARLTYGFDYWGQGTLVTVSS (SEQ ID NO: 161), and the light chain variable region comprises the amino acid sequence DIVMTQTPLSLPVTPGEPASISCQSSKSLLHSTGKTYLNWYLQKPGQSPQLLIYWMSTRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQFLEYPFTFGQGTKVEIK (SEQ ID NO: 162), or the heavy chain variable region comprises the amino acid sequence GFTFTDFYMS (SEQ ID NO: 163). the light chain variable region comprises HVR-L1 comprising the amino acid sequence QSSKSLLHSTGKTYLN (SEQ ID NO: 166), HVR-L2 comprising the amino acid sequence WMSTRAS (SEQ ID NO: 167), and HVR-L3 comprising the amino acid sequence QQFLEYPFT (SEQ ID NO: 168); or the heavy chain variable region comprisesThe light chain variable region comprises the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFTDFYMSWVRQAPGKGLEWVSVIRNKANAYTAGYNPSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLTYGFDYWGQGTLVTVSS (SEQ ID NO: 169), and the light chain variable region comprises the amino acid sequence DIVMTQTPLSLPVTPGEPASISCQSSKSLLHSTGKTYLNWYLQKPGQSPQLLIYWMSTRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQFLEYPFTFGQGTKVEIK (SEQ ID NO: 170).

[0014] In some embodiments, the methods provided herein include intravenously administering to an individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein (a) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence DYNIH (SEQ ID NO: 173), HVR-H2 comprising the amino acid sequence YIYPKNGGTGYTQKFKS (SEQ ID NO: 174), and HVR-H3 comprising the amino acid sequence RTARASWFAF (SEQ ID NO: 175); and (b) the light chain variable region comprises HVR-L1 comprising the amino acid sequence KSSQSLLYSSNQKNYLA (SEQ ID NO: 176), HVR-L2 comprising the amino acid sequence WASTRES (SEQ ID NO: 177), and HVR-L3 comprising the amino acid sequence QQYYNYPFT (SEQ ID NO: 178). or (b) a heavy chain variable region comprising the amino acid sequence EVQLVQSGAEVKKPGESLKISCKGSGYTFTDYNIHWVRQMPGKGLEWMGYIYPKNGGTGYTQKFKSQVTISVDNSISTAYLQWSSLKASDTAMYYCARRTARASWFAFWGQGTLVTVSS (SEQ ID NO: 179) and a light chain variable region comprising the amino acid sequence DIVMTQSPATLSVSPGERATLSCKSSQSLLYSSNQKNYLAWYQQKPGQAPRVLIYWASTRESGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYYNYPFTFGQGTKLEIK (SEQ ID NO: 180).

[0015] In some embodiments, the methods provided herein include intravenously administering to an individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein (a) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence GYSITSDYAWN (SEQ ID NO: 50), HVR-H2 comprising the amino acid sequence YINYSGRTIYNPSLKS (SEQ ID NO: 51), and HVR-H3 comprising the amino acid sequence ARWNGNYGFAY ​​(SEQ ID NO: 52); and (b) the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQSLVHINGNTYLH (SEQ ID NO: 53), HVR-L2 comprising the amino acid sequence KVSNRFS (SEQ ID NO: 54), and HVR-L3 comprising the amino acid sequence SQTTHALF T (SEQ ID NO: 55), or (b) the heavy chain variable region comprises the amino acid sequence DVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQFPGNKLEWMGYINYSGRTIYNPSLKSRISITRDTSKNHFFLQLISVTTEDTATYYCARWNGNYGFAYWGQGTLVTVSA (SEQ ID NO: 56) and the light chain variable region comprises the amino acid sequence DWMTQNPLSLPVSLGDQASISCRSSQSLVHINGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQTTHALFTFGSGTKLEIK (SEQ ID NO: 57).

[0016] In some embodiments, the methods provided herein include intravenously administering to an individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein (a) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence GYTFTSY (SEQ ID NO: 58), HVR-H2 comprising the amino acid sequence IGRSDPTGGTNYNE (SEQ ID NO: 59), and HVR-H3 comprising the amino acid sequence VRTSGDY (SEQ ID NO: 60); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQSLVHNNGNTFLH (SEQ ID NO: 61), HVR-L2 comprising the amino acid sequence VSNRFS (SEQ ID NO: 62), and HVR-L3 comprising the amino acid sequence SQTTHVPPT (SEQ ID NO: 63); or (b) The heavy chain variable region comprises the amino acid sequence QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKQSPGRGLEWIGRSDPTTGGTNYNEKFKTKATLTVDKPSSTAYMQLSSLTSDDSAVYYCVRTSGTGDYWGQGTSLTVSSAKTTAPSVYPLAPVCGGTTGSSVT (SEQ ID NO: 64), and the light chain variable region comprises the amino acid sequence DVVMTQTPLSLPVSLGDQASISCRSSQSLVHNNGNTFLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQTTHVPPTFGGGTKLEIKRADAAPTVSIFPPSSEQLTSGGASVVCF (SEQ ID NO: 65).

[0017] In some embodiments, the methods provided herein include intravenously administering to an individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein (a) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence GFTFTDFY (SEQ ID NO: 66), HVR-H2 comprising the amino acid sequence IRNKANGYTT (SEQ ID NO: 67), and HVR-H3 comprising the amino acid sequence ARIGINNGGSLDYWG (SEQ ID NO: 68); and (b) the light chain variable region comprises HVR-L1 comprising the amino acid sequence QSLLYSENNQDY (SEQ ID NO: 69), HVR-L2 comprising the amino acid sequence GAS (SEQ ID NO: 70), and HVR-L3 comprising the amino acid sequence EQTYSYPYT (SEQ ID NO: 71). 3, or (b) the heavy chain variable region comprises the amino acid sequence EVKLLESGGGLVQPGGSMRLSCAASGFTFTDFYMNWIRQPAGKAPEWLGLIRNKANGYTTEYNPSVKGRFTISRDNTQNMLYLQMNTLR*EDTATYYCARIGINNGGSLDYWGQGVMVTVSS (SEQ ID NO: 72), where "*" represents any amino acid, and the light chain variable region comprises the amino acid sequence DILINQSPASLTVSAGEKVTMSCKSSQSLLYSENNQDYLAWYQQKPGQFPKLLIYGASNRHTGVPDRFTGSGSGTDFTLTISSVQAEDLADYYCEQTYSYPYTFGAGTKLELK (SEQ ID NO: 73).

[0018] In some embodiments, the dose is about 15 mg / kg to about 60 mg / kg. In some embodiments, the dose is about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, or about 60 mg / kg. In some embodiments, the anti-TREM2 antibody is administered at a dose of at least about 15 mg / kg approximately once every four weeks. In some embodiments, the anti-TREM2 antibody is administered at a dose of at least about 15 mg / kg approximately once every week. In some embodiments, the anti-TREM2 antibody is administered at a dose of about 15 mg / kg approximately once every four weeks. In some embodiments, the anti-TREM2 antibody is administered at a dose of about 20 mg / kg approximately once every four weeks. In some embodiments, the anti-TREM2 antibody is administered at a dose of about 25 mg / kg approximately once every four weeks. In some embodiments, the anti-TREM2 antibody is administered at a dose of about 30 mg / kg approximately once every four weeks. In some embodiments, the anti-TREM2 antibody is administered at a dose of about 35 mg / kg approximately once every four weeks. In some embodiments, the anti-TREM2 antibody is administered at a dose of about 40 mg / kg approximately once every four weeks. In some embodiments, the anti-TREM2 antibody is administered at a dose of about 45 mg / kg approximately once every four weeks. In some embodiments, the anti-TREM2 antibody is administered at a dose of about 50 mg / kg approximately once every four weeks. In some embodiments, the anti-TREM2 antibody is administered at a dose of about 55 mg / kg approximately once every four weeks. In some embodiments, the anti-TREM2 antibody is administered at a dose of about 60 mg / kg approximately once every four weeks.

[0019] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 34), HVR-H2 comprises the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 35), HVR-H3 comprises the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 31), HVR-L1 comprises the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 41), HVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO: 33), and HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 30.

[0020] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence YAFSSWDMN (SEQ ID NO: 36), HVR-H2 comprises the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 37), HVR-H3 comprises the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 38), HVR-L1 comprises the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 39), HVR-L2 comprises the amino acid sequence KVSNRVS (SEQ ID NO: 40), and HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 29.

[0021] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence SYWIG (SEQ ID NO: 146) or SWIG (SEQ ID NO: 147), HVR-H2 comprises the amino acid sequence IIYPGDADARYSPSFQG (SEQ ID NO: 148), HVR-H3 comprises the amino acid sequence RRQGIFGDALDF (SEQ ID NO: 149), HVR-L1 comprises the amino acid sequence RASQSVSSNLA (SEQ ID NO: 150), HVR-L2 comprises the amino acid sequence GASTRAT (SEQ ID NO: 151), and HVR-L3 comprises the amino acid sequence LQDNNFPPT (SEQ ID NO: 152). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 153 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 154.

[0022] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence GFTFTDFYMS (SEQ ID NO: 155), HVR-H2 comprises the amino acid sequence VIRNKANGYTAGYNPSVKG (SEQ ID NO: 156), HVR-H3 comprises the amino acid sequence ARLTYGFDY (SEQ ID NO: 157), HVR-L1 comprises the amino acid sequence QSSKSLLHSTGKTYLN (SEQ ID NO: 158), HVR-L2 comprises the amino acid sequence WMSTRAS (SEQ ID NO: 159), and HVR-L3 comprises the amino acid sequence QQFLEYPFT (SEQ ID NO: 160). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 161 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 162.

[0023] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence GFTFTDFYMS (SEQ ID NO: 163), HVR-H2 comprises the amino acid sequence VIRNKANAYTAGYNPSVKG (SEQ ID NO: 164), HVR-H3 comprises the amino acid sequence ARLTYGFDY (SEQ ID NO: 165), HVR-L1 comprises the amino acid sequence QSSKSLLHSTGKTYLN (SEQ ID NO: 166), HVR-L2 comprises the amino acid sequence WMSTRAS (SEQ ID NO: 167), and HVR-L3 comprises the amino acid sequence QQFLEYPFT (SEQ ID NO: 168). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 169 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 170.

[0024] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence DYNIH (SEQ ID NO: 173), HVR-H2 comprises the amino acid sequence YIYPKNGGTGYTQKFKS (SEQ ID NO: 174), HVR-H3 comprises the amino acid sequence RTARASWFAF (SEQ ID NO: 175), HVR-L1 comprises the amino acid sequence KSSQSLLYSSNQKNYLA (SEQ ID NO: 176), HVR-L2 comprises the amino acid sequence WASTRES (SEQ ID NO: 177), and HVR-L3 comprises the amino acid sequence QQYYNYPFT (SEQ ID NO: 178). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 179 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 180.

[0025] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence GYSITSDYAWN (SEQ ID NO:50), HVR-H2 comprises the amino acid sequence YINYSGRTIYNPSLKS (SEQ ID NO:51), HVR-H3 comprises the amino acid sequence ARWNGNYGFAY ​​(SEQ ID NO:52), HVR-L1 comprises the amino acid sequence RSSQSLVHINGNTYLH (SEQ ID NO:53), HVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO:54), and HVR-L3 comprises the amino acid sequence SQTTHALFT (SEQ ID NO:55). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57.

[0026] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence GYTFTSY (SEQ ID NO: 58), HVR-H2 comprises the amino acid sequence IGRSDPTGGTNYNE (SEQ ID NO: 59), HVR-H3 comprises the amino acid sequence VRTSGDY (SEQ ID NO: 60), HVR-L1 comprises the amino acid sequence RSSQSLVHNNGNTFLH (SEQ ID NO: 61), HVR-L2 comprises the amino acid sequence VSNRFS (SEQ ID NO: 62), and HVR-L3 comprises the amino acid sequence SQTTHVPPT (SEQ ID NO: 63). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 64 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 65.

[0027] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence GFTFTDFY (SEQ ID NO: 66), HVR-H2 comprises the amino acid sequence IRNKANGYTT (SEQ ID NO: 67), HVR-H3 comprises the amino acid sequence ARIGINNGGSLDYWG (SEQ ID NO: 68), HVR-L1 comprises the amino acid sequence QSLLYSENNQDY (SEQ ID NO: 69), HVR-L2 comprises the amino acid sequence GAS (SEQ ID NO: 70), and HVR-L3 comprises the amino acid sequence EQTYSYPYT (SEQ ID NO: 71). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 72 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 73.

[0028] In some embodiments, the antibody has a human IgG1 isotype.

[0029] In some embodiments, the antibody has a human IgG1 isotype and contains amino acid substitutions in the Fc region at residue positions P331S and E430G (residue numbering according to EU numbering).

[0030] In some embodiments, the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 43 and a light chain comprising the amino acid sequence of SEQ ID NO: 47; or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 44 and a light chain comprising the amino acid sequence of SEQ ID NO: 47.

[0031] In some embodiments, the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 45 and a light chain comprising the amino acid sequence of SEQ ID NO: 48, or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 and a light chain comprising the amino acid sequence of SEQ ID NO: 48.

[0032] In some embodiments, the antibody has a heavy chain comprising the following amino acid sequence: EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDADARYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYFCARRRQGIFGDALDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 171), and a light chain comprising the following amino acid sequence: EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWFQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQPEDFAVYYCLQDNNFPPTFGQGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 172).

[0033] In some embodiments, the disease or injury is selected from dementia, frontotemporal dementia, Alzheimer's disease, adrenoleukodystrophy (ALD), cerebral adrenoleukodystrophy (cALD), cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, demyelinating disorders, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), or a tauopathy.

[0034] In some embodiments, the disease or injury is Alzheimer's disease. In some embodiments, the individual has a Mini-Mental State Examination (MMSE) score of between about 16 and about 28 points before administration of the anti-TREM2 antibody. In some embodiments, the individual has a Clinical Dementia Rating-Global Score (CDR-GS) of 0.5, 1.0, or 2.0 before administration of the anti-TREM2 antibody. In some embodiments, the individual has a positive amyloid-PET scan before administration of the anti-TREM2 antibody. In some embodiments, the individual is receiving cholinesterase inhibitor and / or memantine treatment. In some embodiments, the individual has symptoms of Alzheimer's disease before administration of the anti-TREM2 antibody. In some embodiments, the symptoms are mild cognitive impairment and / or mild dementia. In some embodiments, the individual does not have symptoms of Alzheimer's disease before administration of the anti-TREM2 antibody.

[0035] In some embodiments, the individual is heterozygous or homozygous for a mutation in TREM2. In some embodiments, the individual comprises an amino acid substitution at residue position R47H, R62H, or both in the human TREM2 protein.

[0036] In some embodiments, the individual has a positive amyloid or tau blood test prior to administration of the anti-TREM2 antibody.

[0037] In some embodiments, administration of the anti-TREM2 antibody results in at least about a 30% decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid compared to the level of soluble TREM2 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in at least about a 40% decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid compared to the level of soluble TREM2 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, the decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid is present about two days after administration of the anti-TREM2 antibody. In some embodiments, the level of soluble TREM2 in the individual's cerebrospinal fluid is measured using an electrochemiluminescence assay in a sample of cerebrospinal fluid obtained from the individual.

[0038] In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of soluble CSF1R in the individual's cerebrospinal fluid of at least about 5% compared to the level of soluble CSF1R in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, the increase in the level of soluble CSF1R in the individual's cerebrospinal fluid is present about 2 days after administration of the anti-TREM2 antibody. In some embodiments, the level of soluble CSF1R in the individual's cerebrospinal fluid is measured using an ELISA assay in a sample of cerebrospinal fluid obtained from the individual.

[0039] In some embodiments, the methods provided herein also include measuring the level of soluble TREM2 in a blood, plasma, and / or cerebrospinal fluid sample from the individual before and after the individual receives one or more doses of an anti-TREM2 antibody. In some embodiments, the methods provided herein also include measuring the level of soluble CSF1R in a blood, plasma, and / or cerebrospinal fluid sample from the individual before and after the individual receives one or more doses of an anti-TREM2 antibody.

[0040] In some embodiments, the methods provided herein also include measuring the level of cerebral amyloid burden in the individual's brain before and after the individual is administered one or more doses of an anti-TREM2 antibody. In some embodiments, the level of cerebral amyloid burden in the individual's brain is measured using amyloid positron emission tomography. In some embodiments, the methods provided herein also include measuring the amount of tau in the individual's brain, assessed by measuring the level of tau in the individual's brain before and after the individual is administered one or more doses of an anti-TREM2 antibody. In some embodiments, the level of tau in the individual's brain is measured using tau positron emission tomography. In some embodiments, the methods provided herein also include measuring one or more brain abnormalities in the individual's brain before and after the individual is administered one or more doses of an anti-TREM2 antibody. In some embodiments, the one or more brain abnormalities are measured using magnetic resonance imaging. In some embodiments, the one or more brain abnormalities are brain volume. In some embodiments, the methods provided herein also include measuring the brain volume of the individual before and after the individual is administered one or more doses of an anti-TREM2 antibody. In some embodiments, the brain volume is measured using magnetic resonance imaging. In some embodiments, the brain volume is measured using volumetric magnetic resonance imaging.

[0041] In some embodiments, the methods provided herein also include detecting the presence of an alteration in one or more genes in an individual selected from APOE, TREM2, CD33, TMEM106b, or CLUSTERIN.

[0042] In some embodiments, the presence or absence of the ApoE e4 allele is detected in an individual. The ApoE gene is polymorphic with three major isoforms: ApoE-e2, ApoE-e3, and ApoE-e4. The ApoE-e3r isoform is rare. The isoforms differ from each other by amino acid substitutions at positions 130 (R130C; c.388 T>C; rs429358) and 176 (R176C; c.526 C>T; rs7412). ApoE alleles in an individual can be detected by performing SNP (single nucleotide polymorphism) genotyping assays at these two loci. In some embodiments, ApoE alleles in an individual are detected by real-time PCR. For example, the Covance ApoE genotyping assay can be used.

[0043] In some embodiments, the methods provided herein also include measuring the level of one or more biomarkers of neuroinflammation in blood, plasma, and / or cerebrospinal fluid samples from the individual before and after the individual receives one or more doses of an anti-TREM2 antibody.

[0044] In some embodiments, the methods provided herein also include measuring the level of one or more biomarkers of neurodegeneration in blood, plasma, and / or cerebrospinal fluid samples from the individual before and after the individual is administered one or more doses of an anti-TREM2 antibody.

[0045] In some embodiments, the one or more biomarkers of neurodegeneration is neurofilament light.

[0046] In some embodiments, the methods provided herein also include measuring the expression levels of TREM2, CSF1R, YKL40, IL-1RA, or osteopontin in blood, plasma, and / or cerebrospinal fluid samples from the individual before and after the individual receives one or more doses of an anti-TREM2 antibody. In some embodiments, the expression levels of TREM2, CSF1R, YKL40, IL-1RA, or osteopontin refer to mRNA expression levels. In some embodiments, the expression levels of TREM2, CSF1R, YKL40, IL-1RA, or osteopontin refer to protein expression levels. In some embodiments, the methods include measuring the protein expression levels of sTREM2 or sCSF1R in blood, plasma, and / or cerebrospinal fluid samples from the individual before and after the individual receives one or more doses of an anti-TREM2 antibody.

[0047] In some embodiments, the methods provided herein also include measuring the level of one or more biomarkers for Alzheimer's disease in a sample of cerebrospinal fluid from the individual before and after the individual is administered one or more doses of an anti-TREM2 antibody. In some embodiments, the methods provided herein also include measuring the level of one or more biomarkers for Alzheimer's disease in a sample of blood from the individual before and after the individual is administered one or more doses of an anti-TREM2 antibody. In some embodiments, the methods provided herein also include measuring the level of one or more biomarkers for Alzheimer's disease in a sample of plasma from the individual before and after the individual is administered one or more doses of an anti-TREM2 antibody. In some embodiments, the one or more biomarkers for Alzheimer's disease are selected from Aβ42, Aβ40, total tau, pTau, neurofilament light, or any combination thereof. In some embodiments, the one or more biomarkers for Alzheimer's disease are Aβ40, Aβ42, pTau, and / or total tau.

[0048] In some embodiments, the methods provided herein also include measuring the level of one or more biomarkers of microglial cell function in a sample of cerebrospinal fluid from the individual before and after the individual is administered one or more doses of an anti-TREM2 antibody. In some embodiments, the methods provided herein also include measuring the level of one or more biomarkers of microglial cell function in a sample of blood from the individual before and after the individual is administered one or more doses of an anti-TREM2 antibody. In some embodiments, the methods provided herein also include measuring the level of one or more biomarkers of microglial cell function in a sample of plasma from the individual before and after the individual is administered one or more doses of an anti-TREM2 antibody. In some embodiments, the one or more biomarkers of microglial cell function are CSF1R, IL1RN, YKL40, and / or osteopontin.

[0049] In some embodiments, the methods provided herein also include determining the score of one or more clinical assessments of the individual before and after the individual is administered one or more doses of the anti-TREM2 antibody, wherein the one or more clinical assessments are selected from a Mini-Mental State Examination (MMSE) score, a Clinical Dementia Rating-Global Score (CDR-GS), a Clinical Dementia Rating Sum of Boxes (CDR-SB), or a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

[0050] In some embodiments, the methods provided herein also include performing a tau or amyloid positron emission tomography (PET) imaging assessment in the individual before and after the individual receives one or more doses of an anti-TREM2 antibody.

[0051] In some embodiments, the disease or injury is Alzheimer's disease, and the Alzheimer's disease is early Alzheimer's disease. In some embodiments, the individual has cerebral amyloidosis prior to administration of the anti-TREM2 antibody, and the cerebral amyloidosis is assessed in a cerebrospinal fluid sample obtained from the individual or by positron emission tomography (PET). In some embodiments, the individual has a Mini-Mental State Examination (MMSE) score of at least about 22 points prior to administration of the anti-TREM2 antibody. In some embodiments, the individual has a Clinical Dementia Rating-Global Score (CDR-GS) of about 0.5 to about 1.0 prior to administration of the anti-TREM2 antibody. In some embodiments, the individual has a Repeatable Battery for the Assessment of Neuropsychological Status on the Delayed Memory Index (RBANS DMI) score of 85 or less prior to administration of the anti-TREM2 antibody. In some embodiments, the individual has a positive amyloid or tau blood test prior to administration of the anti-TREM2 antibody.In some embodiments, the methods provided herein also include determining the score of one or more clinical assessments of the individual before and after the individual is administered one or more doses of the anti-TREM2 antibody, where the one or more clinical assessments are selected from the Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Alzheimer's Disease Assessment Scale-Cognitive Subscale-13 (ADAS-Cog13), Alzheimer's Disease Cooperative Study-Activities of Daily Living adapted to Mild Cognitive Impairment (ADCS-ADL-MCI), and Alzheimer's Disease Composite Score (ADCOMS). In some embodiments, the methods provided herein also include measuring the level of one or more biomarkers for Alzheimer's disease, including but not limited to any of the biomarkers described herein, before and after the individual is administered one or more doses of an anti-TREM2 antibody, where the one or more biomarkers for Alzheimer's disease are measured by magnetic resonance imaging (MRI) or in a sample of blood, plasma, or cerebrospinal fluid obtained from the individual. In some embodiments, the methods provided herein also include performing tau or positron emission tomography (PET) imaging assessments on the individual before and after the individual receives one or more doses of an anti-TREM2 antibody. In some embodiments, the methods provided herein also include performing one or more speech assessments on the individual before and after the individual is administered one or more doses of an anti-TREM2 antibody.

[0052] In some embodiments, the methods provided herein also include evaluating the individual for amyloid-related imaging abnormalities (ARIA), vasogenic cerebral edema, new cerebral microbleeds, or uveitis. In some embodiments, the ARIA is amyloid-related imaging abnormalities edema (ARIA-E) and / or amyloid-related imaging abnormalities hemosiderin (ARIA-H). ARIA is typically evaluated using magnetic resonance imaging (MRI).

[0053] Magnetic resonance imaging (MRI) abnormalities in patients with Alzheimer's disease (AD) were first observed in immunotherapy trials of bapineuzumab, a monoclonal antibody therapy against beta-amyloid (Black, Ronald S et al., (2010). Alzheimer's disease and associated disorders vol. 24, 2:198-203). These abnormalities, visualized on T2-weighted / fluid-attenuated inversion recovery (FLAIR) sequences of MRI, were initially termed "angioedema" (VE) (Ostrowitzki, Susanne et al., (2012). Archives of neurology vol. 69, 2:198-207; Sperling, Reisa et al., (2012). The Lancet. Neurology vol. 11, 3:241-9). Identification of additional patients with a spectrum of imaging changes led to the umbrella term amyloid-associated imaging abnormalities (ARIA). ARIA includes abnormalities detected by FLAIR sequences, including angioedema and sulcal effusion (ARIA-E), and abnormalities detectable by MRI sequences (T2 or T2*), such as gradient-refocused echo (GRE) sequences, including microhemorrhages (mH) and hemosiderosis (ARIA-H). ARIA-E and ARIA-H frequently coexist and appear to represent a spectrum of imaging abnormalities. Although initially observed in immunotherapy trials using bapineuzumab, ARIA-E and ARIA-H have been associated with patients treated with other amyloid-modifying drugs (Sperling, Reisa A et al., (2011). Alzheimer's & Dementia: The Journal of the Alzheimer's Association, vol. 7, 4:367-85). ARIA-E occurs due to an increase in extracellular fluid volume caused by increased permeability of brain capillary endothelial cells to serum proteins.ARIA-E manifests as increased magnetic resonance signal intensity on FLAIR sequences in the parietal, occipital, and frontal lobes, as well as in the cerebellum and brainstem, in the parenchyma and / or lemniscus (Sperling, Reisa A et al., (2011). Alzheimer's & Dementia: The Journal of the Alzheimer's Association, vol. 7, 4: 367-85). On the other hand, ARIA-H manifests as focal, very hypointense lesions within the brain parenchyma, detected on MRI sequences (T2 or T2*), such as gradient-refocused echo (GRE) sequences. The microhemorrhages (mH) in ARIA-H are small deposits of iron in the tissue in the form of hemosiderin. These arise due to leakage of blood from blood vessels adjacent to the tissue parenchyma. Another type of hemorrhagic lesion included in ARIA-H is intracerebral microhemorrhage (CMH), or microbleeds. These lesions are generally associated with vascular beta-amyloid associated with AD, cerebral amyloid angiopathy (CAA), or Aβ-modifying therapy. The presence of CMH at baseline can predict future CMH and clinical outcomes in the general population and AD (Joseph-Mathurin M., et al., (2012). Neurology Mar, 96(12)). It has been speculated that direct clearance of amyloid from the vessel wall may compromise vascular integrity and lead to ARIA. Alternatively, amyloid-associated endothelial dysfunction may lead to increased vascular permeability (Sperling, Reisa A et al., (2011). Alzheimer's & dementia: the journal of the Alzheimer's Association vol. 7, 4:367-85).

[0054] Vasogenic cerebral edema occurs as a result of blood-brain barrier (BBB) ​​disruption, resulting in extravasation of fluid and intravascular proteins into the parenchyma. Fluid accumulates extracellularly, increasing brain volume. Brain injuries, including brain trauma, ischemic stroke, subarachnoid hemorrhage, traumatic brain injury, subdural hematoma, epidural hematoma, or intracerebral hematoma, and hemorrhage, can cause reversible or irreversible disruption of the blood-brain barrier, damaging vascular endothelial cells and resulting in the excessive release of vascular permeability factors and cytokines, leading to increased permeability (Michinaga S. et al., (2015). Int. J. Mol. Sci. May;16(5)9949-9975). Vasogenic cerebral edema can be assessed by MRI and CT imaging (Raslan A et al., (2007). Neurosurg Focus May 15;22(5):E12).

[0055] The eye shares many neural and vascular similarities with the brain and therefore provides a direct window into brain pathology (Lim J. K. Het. al., (2016) Front. Neurosci. vol. 10). Uveitis is inflammation of the eye and can result from infection, trauma, autoimmune disease, or inflammatory disorders. Depending on the location of inflammation, uveitis can be anterior uveitis (front of the eye), intermediate uveitis (behind the lens), posterior uveitis (back of the eye), or panuveitis (from anterior to posterior). Causes of uveitis include multiple sclerosis, psoriasis, lupus, and AIDS. Symptoms include redness, pain, and vision loss. Uveitis can be detected by blood tests, skin tests, MRI, CT scans, and X-rays.

[0056] In some embodiments of the methods provided herein, (a) the dose is about 15 mg / kg and the terminal half-life of the antibody in the plasma of the individual is about 8.63 days; (b) the dose is about 30 mg / kg and the terminal half-life of the antibody in the plasma of the individual is about 7.44 days; (c) the dose is about 45 mg / kg and the terminal half-life of the antibody in the plasma of the individual is about 8.40 days; or (d) the dose is about 60 mg / kg and the terminal half-life of the antibody in the plasma of the individual is about 9.93 days.

[0057] In some embodiments of the methods provided herein, the method further comprises performing an amyloid or tau blood test on a sample obtained from the individual before and after the individual is administered one or more doses of the anti-TREM2 antibody. [Brief explanation of the drawings]

[0058] [Figure 1]

[0023] Figure 1 shows a diagram of the Phase 1 study described in Example 1 evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AT.1FM when administered as a single ascending dose in healthy participants and as multiple doses in participants with mild to moderate AD. SAD = single ascending dose; MD = multiple dose. Arrows indicate administration of AT.1FM at the indicated dose. The ratio of participants receiving active drug (AT.1FM) to those receiving placebo is shown for each cohort (active drug:placebo). An asterisk (*) indicates that a lumbar puncture was performed to obtain a cerebrospinal fluid (CSF) baseline sample (SAD cohorts F, G, H, I, K, and N; MD cohorts J, L, and M). A plus sign (+) indicates an open-label cohort. [Figure 2]

[0023] Figure 1 shows safety results from the SAD phase of the Phase 1 study described in Examples 1 and 2. TEAE = treatment-emergent adverse event; SAE = serious adverse event; "disc." = discontinuation. An asterisk (*) indicates an adverse event not related to study treatment. [Figure 3A] 1 shows the results of an experiment evaluating the effect of AT.1FM on levels of soluble TREM2 (sTREM2) and soluble CSF1R (sCSF1R) in the cerebrospinal fluid (CSF) of participants in the SAD phase of the study described in Examples 1 and 2. The percent change in levels of sTREM2 in CSF two days after administration of the indicated dose of AT.1FM or placebo is shown compared to baseline sTREM2 levels in CSF. [Figure 3B]1 shows the results of an experiment evaluating the effect of AT.1FM on levels of soluble TREM2 (sTREM2) and soluble CSF1R (sCSF1R) in the cerebrospinal fluid (CSF) of participants in the SAD phase of the study described in Examples 1 and 2. The percent change in levels of sCSF1R in CSF two days after administration of the indicated dose of AT.1FM or placebo is shown compared to baseline sCSF1R levels in CSF. [Figure 4] 1 shows the levels of sTREM2 in the CSF of healthy human volunteers administered AT.1FM or placebo. The percent change from baseline (mean ± standard deviation) in sTREM2 levels in CSF is shown on days 2 (D2) and 12 (D12) after administration of the indicated doses of AT.1FM or placebo. [Figure 5] 1 shows the levels of soluble CSF1R (sCSF1R) in the CSF of healthy human volunteers administered AT.1FM or placebo. The percent change from baseline (mean ± standard deviation) in sCSF1R levels in the CSF is shown on days 2 (D2) and 12 (D12) after administration of the indicated doses of AT.1FM or placebo. [Figure 6] 1 shows the levels of YKL40 in the CSF of healthy human volunteers administered AT.1FM or placebo. The percent change from baseline (mean ± standard deviation) in YKL40 levels in CSF is shown on days 2 and 12 after administration of the indicated doses of AT.1FM or placebo. [Figure 7] 1 shows the levels of IL-1RA in the CSF of healthy human volunteers administered AT.1FM or placebo. The percent change from baseline (mean ± standard deviation) in IL-1RA levels in CSF is shown on days 2 and 12 after administration of the indicated doses of AT.1FM or placebo. [Figure 8]1 shows osteopontin (OPN) levels in the CSF of healthy human volunteers administered AT.1FM or placebo. The percent change from baseline (mean ± standard deviation) in OPN levels in the CSF is shown on days 2 and 12 after administration of the indicated doses of AT.1FM or placebo. [Figure 9] 1 shows the concentration of AT.1FM in the CSF of healthy human volunteers. The concentration of AT.1FM in the CSF (ng / mL; mean + standard deviation) is shown on days 2 and 12 after administration of the indicated doses of AT.1FM. [Figure 10A] Figure 1 shows TREM2 protein concentrations in the frontal cortex and hippocampus of non-human primates treated with AT.1FM or control. Non-human primates were intravenously administered control or AT.1FM at the indicated doses once weekly for a total of five doses. TREM2 protein concentrations (mean ± standard error of the mean) in the frontal cortex 48 hours after the fifth dose of AT.1FM or control are shown. Measurements were normalized to tissue protein concentration (N = 6 per dose group, *, p < 0.05; ***, p < 0.001; ****, p < 0.0001 by one-way ANOVA). [Figure 10B] Figure 1 shows TREM2 protein concentrations in the frontal cortex and hippocampus of non-human primates treated with AT.1FM or control. Non-human primates were intravenously administered control or AT.1FM at the indicated doses once weekly for a total of five doses. TREM2 protein concentrations (mean ± standard error of the mean) in the hippocampus 48 hours after the fifth dose of AT.1FM or control are shown. Measurements were normalized to tissue protein concentration (N = 6 per dose group, *, p < 0.05; ***, p < 0.001; ****, p < 0.0001 by one-way ANOVA). [Figure 11]1 shows the levels of sTREM2 in the CSF of non-human primates administered AT.1FM or control once weekly for three weeks. The levels of sTREM2 in the CSF (percent of baseline; mean ± standard error of the mean) are shown at the indicated time points (hours) after the first administration of control or AT.1FM. The arrow indicates the time of administration of control or AT.1FM. [Figure 12] Figure 1 shows osteopontin levels in the CSF of non-human primates administered AT.1FM or control once a month for two months for a total of three doses (N=5 per group). CSF osteopontin levels (percent of baseline; mean ± standard error of the mean) are shown at the indicated time points (hours) after the first dose of control or AT.1FM. Arrows indicate the time of administration of control or AT.1FM at 250 mg / kg. The gray dashed line indicates baseline (pre-dose) levels of osteopontin. [Figure 13] Figure 1 shows CSF1R protein concentrations in the frontal cortex and hippocampus of non-human primates administered AT.1F or control. Non-human primates were intravenously administered 80 mg / kg of control or AT.1F once a week for a total of five doses (N=5 per group). CSF1R protein concentrations (ng CSF1R protein / mg total protein) are shown in the frontal cortex (left panel) and hippocampus (right panel) 48 hours after the fifth dose of AT.1F or control. DETAILED DESCRIPTION OF THE INVENTION

[0059] Provided herein are methods for treating or delaying the progression of diseases, disorders, or injuries by administering a TREM2 agonist.Such diseases or injuries include dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, adrenoleukodystrophy (ALD), cerebral adrenoleukodystrophy (cALD), cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, demyelinating disorders, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), and tauopathy.In some embodiments, the individual treated according to the methods provided herein is not homozygous for the ApoE e4 allele.In some embodiments, the individual is not an ApoE e4 carrier, or the individual is heterozygous for the ApoE4 e4 carrier allele. Agonists of TREM2 include anti-TREM2 antibodies that induce or increase one or more TREM2 activities and / or enhance one or more activities induced by binding of one or more ligands to TREM2. For example, an agonist anti-TREM2 antibody can decrease soluble TREM2, induce spleen tyrosine kinase (Syk) phosphorylation, induce TREM2 binding to DAP12, induce DAP12 phosphorylation, increase proliferation, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells (microglial cells), or increase the activity and / or expression of TREM2-dependent genes.

[0060] definition As used herein, the term "preventing" includes providing prophylaxis against the occurrence or recurrence of a particular disease, disorder, or condition, including delaying the onset of a particular disease, disorder, or condition in individuals who may be susceptible to, predisposed to, or at risk of developing such disease, disorder, or condition, but who have not yet been diagnosed with the disease, disorder, or condition.

[0061] As used herein, an individual "at risk" of developing a particular disease, disorder, or condition may or may not have detectable disease or disease symptoms, and may or may not exhibit detectable disease or disease symptoms, prior to the treatment methods described herein. "At risk" indicates that an individual has one or more risk factors, which are measurable parameters that correlate with the development of a particular disease, disorder, or condition, as known in the art. Individuals who have one or more of these risk factors have a higher probability of developing a particular disease, disorder, or condition than individuals who do not have one or more of these risk factors.

[0062] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of a treated individual's clinical pathology. Desirable therapeutic effects include reducing the rate of progression, ameliorating or alleviating morbidity, and remission or improved prognosis of a particular disease, disorder, or condition. An individual is successfully "treated," for example, if one or more symptoms associated with a particular disease, disorder, or condition are alleviated or eliminated.

[0063] An "effective amount" refers to at least an amount that is effective, at dosages and for periods of time necessary to achieve the desired therapeutic or prophylactic result. An effective amount can be provided in one or more administrations. The effective amount herein can vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the treatment to induce a desired response in the individual. An effective amount is also one in which the therapeutic beneficial effects outweigh any toxic or adverse effects of the treatment. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, reducing the severity, or delaying the onset of disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes observed during the course of disease development. For therapeutic use, beneficial or desired results include clinical results, such as reducing one or more symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other drugs required to treat the disease, enhancing the effect of another drug, for example, delaying disease progression, and / or prolonging survival. An effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to achieve preventive or therapeutic treatment directly or indirectly.As understood in clinical situations, the effective amount of a drug, compound or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound or pharmaceutical composition.Therefore, "effective amount" can be determined in light of the administration of one or more therapeutic agents, and a single agent can be considered to be given in an effective amount when it can or does achieve the desired result in conjunction with one or more other agents.

[0064] An "individual" for purposes of treating, preventing, or reducing risk refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. In some embodiments, the individual is a human.

[0065] As used herein, administration "in conjunction with" another compound or composition includes simultaneous administration and / or administration at different times. Administering in conjunction also encompasses administration as a co-formulation or as separate compositions, including at different dosing frequencies or intervals, and using the same or different routes of administration.

[0066] The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. The term "antibody" is used herein in the broadest sense and specifically includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0067] The basic four-chain antibody unit is a heterotetrameric glycoprotein consisting of two identical light (L) chains and two identical heavy (H) chains. H and V L pairing together to form a single antigen-binding site. For the structure and properties of different antibody classes, see, e.g., Basic and Clinical Immunology, 8th Ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6.

[0068] Light chains from any vertebrate species can be assigned to one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequence of their constant domains. Depending on the amino acid sequence of their heavy chain constant domains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, which have heavy chains designated alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The gamma and alpha classes are 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 are described generally in, for example, Abbas et al., Cellular and Molecular Immunology, 4th ed. (WB Saunders Co., 2000).

[0069] "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 among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain contains at one end a variable domain (V) followed by a number of constant domains. H Each light chain has a variable domain (V L ) at its other end, with the light-chain constant domain aligned with the first heavy-chain constant domain and the light-chain variable domain aligned with the heavy-chain variable domain. Particular amino acid residues are believed to form an interface between the light-chain variable domain and the heavy-chain variable domain.

[0070] An "isolated" antibody, such as an isolated anti-TREM2 antibody of the present disclosure, is an antibody that has been identified, separated, and / or recovered from a component of its production environment (e.g., natural or recombinant). Preferably, the isolated polypeptide is free from association with substantially all other contaminating components from the production environment. Contaminating components from the production environment, such as those arising from recombinantly engineered cells, are typically materials that would interfere with research, diagnostic, or therapeutic uses for the antibody and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide will be purified (1) to greater than 95% by weight, and in some embodiments, greater than 99% by weight, of the antibody, e.g., as determined by the Lowry method; (2) to at least 15 residues from the N-terminus, or sufficient to obtain internal amino acid sequence by use of a spinning cup sequencer; or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver staining.

[0071] The "variable region" or "variable domain" of an antibody, such as the anti-TREM2 antibody of the present disclosure, refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy and light chains, respectively, are referred to as "V H " and "V L These domains are generally the most variable parts of an antibody (compared to other antibodies of the same class) and contain the antigen-binding sites.

[0072] The term "variable" refers to the fact that certain segments of variable domains differ extensively in sequence among antibodies, such as the anti-TREM2 antibodies of the present disclosure. Variable domains mediate antigen binding and define the specificity of a particular antibody for a particular antigen. However, variability is not uniformly distributed throughout the span of the variable domains. Instead, variability is concentrated in three segments called hypervariable regions (HVRs) in both the light-chain and heavy-chain variable domains. The more conserved portions of variable domains are called framework regions (FRs). Naturally occurring heavy and light-chain variable domains each contain four FR regions connected by three HVRs that primarily adopt a beta-sheet configuration and form loops that connect, and in some cases form part of, the beta-sheet structure. The HVRs of each chain are held in close proximity by the FR regions and, together with the HVRs of the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institutes 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.

[0073] As used herein, the term "monoclonal antibody" refers to an antibody, such as a monoclonal anti-TREM2 antibody of the present disclosure, obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible natural mutations and / or post-translational modifications (e.g., isomerization, amidation, etc.) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they may be synthesized by hybridoma culture, substantially uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as obtained from a substantially homogeneous population of antibodies and should not be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies used in accordance with the present invention can be produced using, for example, hybridoma techniques (e.g., Kohler and Milstein, Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA techniques (see, for example, U.S. Pat. No. 4,816,567), phage display techniques (e.g., Clackson et al., Nature, 352:624-628 (1991); Marks et al. al.,J.Mol.Biol.222:581-597(1992);Sidhu et al.,J.Mol.Biol.338(2):299-310(2004);Lee et al.,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Nat'l Acad.Sci.USA 101(34):12467-472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004)), yeast display technology (e.g., WO2009 / 036379A2; WO2010105256; WO2012009568; and Xu et al., Protein Eng. Des. Sel., 26(10):663-70 (2013)), and techniques for producing human or human-like antibodies in animals that have some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (e.g., WO1998 / 24893; WO1996 / 34096; WO1996 / 33735; WO1991 / 10741; Jakobovits et al. al.,Proc.Nat'l Acad.Sci.USA 90:2551(1993);Jakobovits et al.,Nature 362:255-258(1993);Bruggemann et al.,Year in Immunol. 7:33 (1993); U.S. Patent No. 5,545,807; U.S. Patent No. 5,545,806; U.S. Patent No. 5,569,825; U.S. Patent No. 5,625,126; U.S. Patent No. 5,633,425; 10:779-783(1992);Lonberg et al.,Nature 368:856-859(1994);Morrison,Nature 368:812-813 (1994); Fishwild et al., Nature Biotechnol. 14:845-851 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol. 13:65-93 (1995)).

[0074] The terms "full length antibody," "intact antibody," or "complete antibody" are used interchangeably to refer to an antibody, such as an anti-TREM2 antibody of the present disclosure, in a substantially intact form, as opposed to an antibody fragment. Specifically, a complete antibody includes an antibody having a heavy chain and a light chain, including an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, an intact antibody may have one or more effector functions.

[0075] An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding and / or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (see Example 2 of U.S. Pat. No. 5,641,870; Zapata et al., Protein Eng. 8(10):1057-1062 (1995)); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0076] Papain digestion of antibodies, such as the anti-TREM2 antibodies of the present disclosure, produces two identical antigen-binding fragments called "Fab" fragments, and a residual "Fc" fragment (a name reflecting its ability to crystallize readily). The Fab fragment contains the variable region domains of the heavy chains (V H ) and the first constant domain of one heavy chain (C H Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment, roughly corresponding to two disulfide-linked Fab fragments that are capable of binding and cross-linking antigen. The Fab' fragment contains one or more cysteines from the antibody hinge region. HF(ab')2 antibody fragments differ from Fab fragments by having several additional residues at the carboxy terminus of one domain. Fab'-SH is the designation used herein for Fab' in which the cysteine ​​residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments can be produced as pairs of Fab' fragments that have hinge cysteines between them. Other chemical linkages of antibody fragments are also known.

[0077] The Fc fragment contains the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of an antibody are determined by the sequences in the Fc region that are recognized by Fc receptors (FcRs) found on certain types of cells.

[0078] An "Fv" is the minimum antibody fragment that contains a complete antigen-recognition and antigen-binding site. This fragment consists of a dimer of one heavy-chain and one light-chain variable region domain in tight, non-covalent association. The folding of these two domains leaves six hypervariable loops (three loops from each H and L chain) that contribute amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, a single variable domain (or half of an Fv containing only three HVRs specific for an antigen) can still recognize and bind to antigen, albeit with lower affinity than the entire binding site.

[0079] A "single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment comprising the VH and VL antibody domains linked in a single polypeptide chain. Preferably, the sFv polypeptide contains a VH domain that enables the sFv to form the desired structure for antigen binding. H Domain and V LThe sFv further comprises a polypeptide linker between the domains, which enables the sFv to form the desired structure for antigen binding. For a review of sFvs, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-VerLAG-3, New York, pp. 269-315 (1994).

[0080] A "functional fragment" of an antibody, such as an anti-TREM2 antibody of the present disclosure, includes a portion of the intact antibody that generally includes the antigen-binding or variable region of the intact antibody or the Fc region of the antibody that retains or modifies FcR binding ability.

[0081] The term "diabody" refers to a V diabody in which inter-chain, rather than intra-chain, pairing of variable domains is achieved, thereby resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. H Domains and V L Diabodies refer to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10 residues) between the domains. Diabodies are described in more detail, for example, in EP 404,097, WO 93 / 11161, and Hollinger et al., Proc. Nat'l Acad. Sci. USA 90:6444-48 (1993).

[0082] As used herein, a "chimeric antibody" refers to an antibody, such as a chimeric anti-TREM2 antibody of the present disclosure, in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, so long as the desired biological activity is exhibited (U.S. Patent No. 4,816,567; Morrison et al., Proc. Nat'l Acad. Sci. USA, 81:6851-55 (1984)). Chimeric antibodies include antibodies in which the variable regions of the antibody are derived from a murine antibody and the constant regions are derived from a human antibody. As used herein, a "humanized antibody" is a subset of a "chimeric antibody."

[0083] "Humanized" forms of non-human (e.g., murine) antibodies, such as humanized forms of the anti-TREM2 antibodies of the present disclosure, are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from an HVR of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and / or capacity. In some instances, FR residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or the donor antibody. These modifications may be made to further refine antibody performance, such as binding affinity. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of non-human immunoglobulin sequences and all or substantially all of the FR regions are those of human immunoglobulin sequences. However, the FR region may contain one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FR is typically no more than six in the H chain and no more than three in the L chain. Humanized antibodies will optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, e.g., Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Patent Nos. 6,982,321 and 7,087,409.

[0084] A "human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody, such as the anti-TREM2 antibody of the present disclosure, generated using any of the techniques for generating human antibodies disclosed herein or otherwise known in the art. This definition of human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991) can also be used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xenomouse, that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous gene loci have been disabled (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584, regarding XENOMOUSE™ technology). See also, e.g., Li et al., Proc. Nat'l Acad. Sci. USA, 103:3557-3562 (2006), regarding human antibodies generated by human B cell hybridoma technology. Alternatively, for human antibodies, see also, e.g., WO2009 / 036379A2, WO2010105256, WO2012009568, and Xu et al., Protein Eng. Des. Sel., 26(10):663-70(2013).

[0085] The term "hypervariable region" or "HVR," as used herein, refers to the region of an antibody variable domain, such as an anti-TREM2 antibody of the present disclosure, that is hypervariable in sequence and / or forms structurally defined loops. Generally, antibodies contain six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). In natural antibodies, H3 and L3 represent the most diversity of the six HVRs, and H3 in particular is thought to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003). In fact, naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993) and Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0086] Multiple HVR delineations are in use and are encompassed herein. In some embodiments, HVRs may be Kabat complementarity-determining regions (CDRs), which are based on sequence variability and are the most commonly used (Kabat et al., supra). In some embodiments, HVRs may be Chothia CDRs. Chothia instead refers to the location of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). In some embodiments, HVRs may be AbM HVRs. AbM HVRs represent a compromise between Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. In some embodiments, HVRs may be "contact" HVRs. "Contact" HVRs are based on analysis of available complex crystal structures. Residues from each of these HVRs are shown below. [Table 1]

[0087] HVRs may also include "extended HVRs" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) of the VL, and 26-35 (H1), 50-65 or 49-65 (preferred embodiment) (H2), and 93-102, 94-102, or 95-102 (H3) of the VH. The variable domain residues are numbered according to Kabat et al., supra, for each of these extended HVR definitions.

[0088] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0089] The phrases "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat," and variations thereof, refer to the numbering system used in the heavy or light chain variable domains of the antibody compilations in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, the FRs or HVRs of the variable domain. For example, a heavy chain variable domain may include a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The Kabat numbering of residues for a given antibody may be determined by aligning the regions of homology of the antibody's sequence with the "standard" Kabat-numbered sequence.

[0090] The Kabat numbering system is generally used when referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The terms "EU numbering system," "EU numbering," or "EU index" are generally used when referring to residues in the immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). "Kabat's EU index" refers to the residue numbering of the human IgG1 EU antibody. References to residue numbers in the variable domain of an antibody refer to residue numbering according to the Kabat numbering system. References to residue numbers in the constant region of an antibody refer to residue numbering according to the EU numbering system (see, e.g., U.S. Patent Application Publication No. 2010-280227).

[0091] As used herein, an "acceptor human framework" is a framework comprising the amino acid sequence of a VL or VH framework derived from a human immunoglobulin framework or a human consensus framework. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence or may contain 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. When pre-existing amino acid changes are present in the VH, preferably, these changes occur at only three, two, or one of positions 71H, 73H, and 78H; for example, the amino acid residues at these positions may be 71A, 73T, and / or 78A. In one embodiment, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.

[0092] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). For VL, the subgroup may be, for example, subgroup kappa I, kappa II, kappa III, or kappa IV, as in Kabat et al., supra. Additionally, for VH, the subgroup may be, for example, subgroup I, subgroup II, or subgroup III, as in Kabat et al., supra.

[0093] For example, an "amino acid modification" at a particular position of an anti-TREM2 antibody of the present disclosure refers to a substitution or deletion of the particular residue, or an insertion of at least one amino acid residue adjacent to the particular residue. An insertion "adjacent to" a particular residue refers to an insertion within one to two residues thereof. The insertion may be at the N-terminus or C-terminus of the particular residue. A preferred amino acid modification herein is a substitution.

[0094] An "affinity matured" antibody, such as the affinity matured anti-TREM2 antibody of the present disclosure, is an antibody with one or more modifications in one or more HVRs thereof that result in an improvement in the affinity of the antibody for antigen compared to a parent antibody lacking those modification(s). In one embodiment, the affinity matured antibody has nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies can be produced by procedures known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of HVR and / or framework residues has been described, for example, by 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).

[0095] As used herein, the terms "specifically bind" or "specifically recognize" refer to a measurable and reproducible binding interaction between a target and an antibody, such as, for example, between an anti-TREM2 antibody and TREM2, that determines the presence of the target within a heterogeneous population of molecules, such as biological molecules. For example, an antibody, such as the anti-TREM2 antibody of the present disclosure, that specifically binds to a target or epitope of a target is an antibody that binds preferentially to this target or epitope, e.g., with higher affinity or antibody avidity, than it binds to other unrelated targets or epitopes. For example, it is understood that an antibody that specifically binds to a first target may or may not specifically bind to a second target. Thus, "specific binding" does not necessarily require (although it can include) exclusive binding. An antibody that specifically binds to a target has at least about 10 3 M -1 Or 104 M -1 , depending on the time, about 10 5 M -1 Or 10 6 M -1 , in other cases, about 10 6 M -1 Or 10 7 M -1 , about 10 8 M -1 ~10 9 M -1 , or 10 10 M -1 ~10 11 M -1 The binding constant may be greater than or equal to 100 kJ / min. Various immunoassay formats can be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies specifically immunoreactive with a protein. For descriptions of immunoassay formats and conditions that can be used to determine specific immunoreactivity, see, for example, Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York, or Vashist and Luong (2018) Handbook of Immunoassay Technologies, Approaches, Performances, and Applications, Academic Press.

[0096] As used herein, an antibody "inhibits the interaction" between two proteins when the antibody disrupts, reduces, or completely eliminates the interaction between the two proteins by binding to one of the two proteins.

[0097] An "agonist" antibody is an antibody that induces (eg, increases) one or more activities or functions of a target upon binding to the target.

[0098] An "antagonist" or "blocking" antibody is an antibody that reduces or eliminates (e.g., decreases) antigen binding to one or more binding partners after the antibody binds to the antigen and / or reduces or eliminates (e.g., decreases) one or more activities or functions of the antigen after the antibody binds to the antigen. In some embodiments, an antagonist or blocking antibody substantially or completely inhibits antigen binding to one or more binding partners and / or one or more activities or functions of the antigen.

[0099] 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.

[0100] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226 or Pro230 to its carboxyl-terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) may be removed, for example, during antibody production and purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, intact antibody compositions may include antibody populations in which all K447 residues have been removed, antibody populations in which the K447 residue has not been removed, and antibody populations having a mixture of antibodies with and without the K447 residue. Native-sequence Fc regions suitable for use in the antibodies of the present disclosure include human IgG1, IgG2, IgG3, and IgG4.

[0101] A "native-sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native-sequence human Fc regions include native-sequence human IgG1 Fc regions (non-A allotypes and A allotypes), native-sequence human IgG2 Fc regions, native-sequence human IgG3 Fc regions, and native-sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0102] A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to the native-sequence Fc region, e.g., about one to about ten amino acid substitutions, preferably about one to about five amino acid substitutions in the native-sequence Fc region. The variant Fc region herein will preferably be at least about 80% homologous to the native-sequence Fc region, most preferably at least about 90% homologous thereto, and more preferably at least about 95% homologous thereto.

[0103] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Furthermore, a preferred FcR is one that binds IgG antibodies (gamma receptors) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptors") and FcγRIIB ("inhibiting receptors"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif ("ITIM") in its cytoplasmic domain. (See, e.g., M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs are encompassed by the term "FcR" herein. FcRs can also increase the serum half-life of antibodies.

[0104] In vivo FcR binding and serum half-life of human FcR high-affinity binding polypeptides can be assayed, for example, in transgenic mice or transgenic human cell lines expressing human FcR, or in primates to which polypeptides having variant Fc regions are administered. WO 2004 / 42072 (Presta) describes antibody variants with improved or diminished binding to FcR. See also, e.g., Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).

[0105] As used herein, "percent 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 those in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways within the skill of those in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for alignment comparisons, including any algorithms known in the art necessary to achieve maximal alignment over the full length of the sequences being compared.

[0106] For example, an "isolated" nucleic acid molecule encoding an antibody, such as the anti-TREM2 antibody of the present disclosure, is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule that is normally associated with the environment in which it is produced. Preferably, an isolated nucleic acid is free from association with substantially all components associated with the production environment. Isolated nucleic acid molecules encoding the polypeptides and antibodies herein are distinguished from nucleic acids that naturally occur in a cell.

[0107] As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA into which additional DNA segments can be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, into which additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" or simply, "expression vectors." In general, expression vectors useful in recombinant DNA techniques are often in the form of plasmids. As used herein, "plasmid" and "vector" may be used interchangeably, as the plasmid is the most commonly used form of vector.

[0108] "Polynucleotide" or "nucleic acid," as used interchangeably herein, refers to a polymer of nucleotides of any length, including DNA and RNA. The nucleotides can 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. A polynucleotide can also contain modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. The sequence of nucleotides can also be interrupted by non-nucleotide components. A polynucleotide can also contain modification(s) that are performed after synthesis, such as conjugation to a label. Other types of modifications include, for example, "caps"; substitution of one or more of the naturally occurring nucleotides with analogs; and internucleotide modifications such as those with uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those containing intercalators (e.g., acridine, psoralens, etc.), those containing chelators (e.g., metals, radioactive metals, boron, metal oxides, etc.), those containing alkylators, those with modified linkages (e.g., alpha-anomeric nucleic acids, etc.), and unmodified forms of the polynucleotide(s). Additionally, any of the hydroxyl groups normally present on the sugars may be replaced with, for example, phosphonate groups, phosphate groups, protected with standard protecting groups, or activated to prepare further linkages to additional nucleotides, or conjugated to a solid or semi-solid support. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of 1 to 20 carbon atoms. Other hydroxyls can also be derivatized to standard protecting groups.Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars commonly known in the art, including, for example, 2'-O-methylribose, 2'-O-allylribose, 2'-fluororibose, or 2'-azidoribose; carbocyclic sugar analogs; α-anomeric sugars; epimeric sugars such as arabinose, xylose, or lyxose; pyranose sugars; furanose sugars; sedoheptulose; acyclic analogs; and basic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), (O)NR2 ("amidate"), P(O)R, P(O)OR', CO, or CH2 ("formacetal"), where each R or R' is independently H or substituted or unsubstituted alkyl (1-20C), optionally containing an ether (-O-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl, or aralkyl. Not all linkages within a polynucleotide need be identical. The foregoing applies to all polynucleotides referred to herein, including RNA and DNA.

[0109] A "host cell" includes, for example, an individual cell or cell culture that may contain a vector(s) or other exogenous nucleic acid that introduces a polynucleotide insert(s). In some embodiments, the vector or other exogenous nucleic acid is introduced into the genome of the host cell. A host cell includes the progeny of a single host cell, and the progeny may not necessarily be completely identical (morphologically or in terms of genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells that have been transfected in vivo with a polynucleotide(s) of the invention.

[0110] As used herein, "carrier" refers to a pharmaceutically acceptable carrier, excipient, or stabilizer that is nontoxic to cells or mammals exposed thereto at the dosages and concentrations employed. Often, physiologically acceptable carriers are pH-buffered aqueous solutions. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and / or nonionic surfactants, such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

[0111] The terms "TREM2," "TREM2 protein," or "TREM2 polypeptide" are used interchangeably herein to refer to any native TREM2 from any mammalian source, including primates (e.g., humans and cynomolgus monkeys) and rodents (e.g., mice and rats), unless otherwise indicated. 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 TREM2," as well as any form of TREM2 that results from processing in cells (e.g., soluble TREM2). In some embodiments, the TREM2 is human TREM2. In some embodiments, the amino acid sequence of an exemplary human TREM2 is SEQ ID NO: 1.

[0112] The term "about" as used herein refers to a normal range of error for the respective value, readily known to one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to that value or parameter itself.

[0113] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, reference to an "antibody" is a reference to one antibody to many antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, and so forth.

[0114] It is understood that the aspects and embodiments of the present disclosure described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0115] overview The present disclosure relates to methods of treating or delaying the progression of a disease, disorder, or injury by administering a TREM2 agonist. TREM2 agonists include anti-TREM2 antibodies that induce or increase one or more TREM2 activities and / or enhance one or more activities induced by binding of one or more ligands to TREM2. For example, agonist anti-TREM2 antibodies can decrease soluble TREM2, induce spleen tyrosine kinase (Syk) phosphorylation, induce TREM2 binding to DAP12, induce DAP12 phosphorylation, increase proliferation, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells (microglial cells), or increase the activity and / or expression of TREM2-dependent genes. Without wishing to be bound by theory, it is believed that agonizing TREM2 (e.g., by administering an anti-TREM2 antibody of the present disclosure) to promote or increase microglial cell activity in an individual may result in amelioration of the pathology and / or one or more symptoms of dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, adrenoleukodystrophy (ALD), cerebral adrenoleukodystrophy (cALD), cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, demyelinating disorders, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), or a tauopathy. Thus, as described below, the methods of the present disclosure fulfill a need in the art for identifying methods of treating patients by agonizing anti-TREM2 antibodies.

[0116] Analysis of the terminal half-life of the disclosed anti-TREM2 antibodies in the plasma of healthy individuals showed that, at the doses tested, the anti-TREM2 antibodies unexpectedly exhibited a short terminal half-life compared to other antibodies of a similar class (Ovacik, M and Lin, L, (2018) Clin Transl Sci 11, 540-552) (see, e.g., Example 4). The relatively short terminal half-life of the anti-TREM2 antibodies suggested that the antibodies may not have sufficiently robust therapeutic efficacy.

[0117] Advantageously, intravenous administration of a single dose of anti-TREM2 antibody (see, e.g., Example 1) resulted in a decrease in the level of soluble TREM2 (e.g., a decrease of at least about 10%) and an increase in the level of soluble CSF1R (e.g., an increase of at least about 5%) in the cerebrospinal fluid of healthy individuals (see, e.g., Examples 2-3). These results demonstrated that the anti-TREM2 antibody binds to its target (i.e., TREM2) in individuals. Additional analysis of the anti-TREM2 antibody in the cerebrospinal fluid of healthy individuals showed that the antibody was present in the cerebrospinal fluid 12 days after administration of the antibody at the tested dose (see, e.g., Example 5). Furthermore, measurement of biomarkers of microglial cell activation unexpectedly revealed that administration of the anti-TREM2 antibody resulted in an increase in the levels of soluble CSF1R, YKL40a, IL-1RA, and osteopontin in the CSF of healthy individuals administered the anti-TREM2 antibody (see, e.g., Example 3). These results suggested that anti-TREM2 antibodies promote the activation of microglial cells after target engagement.

[0118] Thus, although anti-TREM2 antibodies exhibit relatively short half-lives and therefore cannot be predicted to have sufficiently robust therapeutic efficacy, they unexpectedly exhibited relatively long-lasting pharmacodynamic (PD) effects (e.g., decreased levels of soluble TREM2 in cerebrospinal fluid and increased levels of soluble CSF1R, YKL40a, IL-1RA, and osteopontin) that were present in some cases up to 12 days after administration of the antibody (see, e.g., Examples 2-3).

[0119] Advantageously, administration of multiple doses of anti-TREM2 antibodies to non-human primates also reduced levels of soluble TREM2 in the hippocampus and frontal cortex (see, e.g., Example 6) and in cerebrospinal fluid (see, e.g., Example 7). In addition, biomarkers of microglial cell activity (e.g., osteopontin and CSF1R) were also increased in the cerebrospinal fluid (see, e.g., Example 8), hippocampus, and frontal cortex (see, e.g., Example 8) of non-human primates administered multiple doses of anti-TREM2 antibodies.

[0120] Furthermore, as discussed in Example 9, an increased risk of amyloid-related imaging abnormalities (ARIA) was observed in ApoE e4 / e4 homozygous patients treated with anti-TREM2 antibodies. Thus, the methods provided herein exclude APOE e4 / e4 homozygotes to mitigate safety risks associated with ARIA.

[0121] Thus, the methods provided herein advantageously allow for safe and relatively infrequent administration of the anti-TREM2 antibodies of the present disclosure, which is particularly advantageous for patients with neurodegenerative diseases, such as Alzheimer's disease, which typically affect patients for long periods of time and therefore require regular treatment over many years. Because intravenous administration of therapeutic drugs cannot be performed at home, patients must travel to an infusion center, which is a burden for both patients and caregivers. Finally, the memory loss, mood swings, aggression, and other behavioral symptoms of these diseases make patient compliance difficult.

[0122] All references cited herein, including patents, patent applications, and publications, are incorporated herein by reference in their entirety.

[0123] Treatment method The present disclosure provides a method of treating and / or delaying the progression of a disease or injury in an individual, the method comprising administering to an individual in need thereof, the individual being not homozygous for the ApoE e4 allele, an antibody that binds to a TREM2 protein, wherein the antibody is an agonist. In some embodiments, the individual is not an ApoE e4 carrier. In some embodiments, the individual is heterozygous for the ApoE4 e4 allele. In some embodiments, the individual is not an ApoE e4 carrier or the individual is heterozygous for the ApoE4 e4 allele. The apolipoprotein E (ApoE) gene has three major isoforms: e4, e3, and e2. The e4 allele increases the risk of developing AD, e3 is the most common isoform, and e2 is protective against AD (Saunders AM et. al., (1993). Neurology; 43:1467-1472; Corder E Het. al., (1994). Nature Genetics vol. 7 June).

[0124] A significant genetic factor associated with sporadic or non-familial AD is the APOE gene. Apolipoprotein E (APOE) is a multifunctional protein that plays a central role in lipid metabolism. Three major human isoforms, apoE2, apoE3, and apoE4, are encoded by distinct alleles (2, 3, and 4) and are known to regulate lipid metabolism and redistribution. Due to multiple isoforms, individuals can be homozygous (E2 / E2, E3 / E3, or E4 / E4) or heterozygous (E2 / E3, E2 / E4, E3 / E4) for ApoE alleles. Unlike the most commonly occurring isoform, apoE3, apoE4 is associated with an increased risk of developing AD and other neurodegenerative disorders (Huang, Yadong et al., (2006). Neurology vol. 66, 2 Suppl 1:S79-85; Raber, Jacob et al., (2004). Neurobiology of Aging vol. 25, 5:641-50). Clinical and epidemiological data have revealed that 50% of AD cases are associated with the APO ε4 allele (Raber, Jacob et al., (2004). Neurobiology of Aging vol. 25, 5:641-50). Carriers of the APOE ε4 allele (E2 / E4, E3 / E4, or E4 / E4) are at increased risk for AD and other age-related cognitive disorders. Although the underlying mechanisms are not fully understood, a genetic component is strongly implicated in the progression of AD. Research shows that the APOE ε2 and APOE ε4 alleles have opposite effects on the rate of cognitive decline compared to the most common APOE ε3 / ε3 genotype (Qian J. et. al, (2021). Neurology May, 96(19)). APOE ε4 carriers had significantly faster declines in all cognitive domains tested (memory, attention, executive function, and language) compared to APOE ε3 / ε3 carriers. Compared to the APOE ε3 allele, the APOE ε2 allele was found to protect against cognitive decline, whereas the APOE ε4 allele was found to promote cognitive decline beyond the known neuropathological effects of AD.The presence of the apolipoprotein ε4 allele also correlates with the development of ARIA-E. Apolipoprotein ε4 carriers are associated with higher vascular amyloid burden than Apo ε4 non-carriers (Greenberg, SM et al., (1995). Annals of neurology vol. 38, 2:254-9).

[0125] As disclosed herein, the anti-TREM2 antibodies of the disclosure can be used to treat and / or slow the progression of dementia, frontotemporal dementia, Alzheimer's disease, adrenoleukodystrophy (ALD), cerebral adrenoleukodystrophy (cALD), cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, demyelinating disorders, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), or a tauopathy disease.For example, Neumann, H et al., (2007) J Neuroimmunol 184:92-99; Takahashi, K et al., (2005) J Exp Med 201:647-657; Takahashi, K et al., (2007) PLoS Med 4:e124; Hsieh, CL et al., (2009) J Neurochem 109:1144-1156;Malm,TM et al,Neurotherapeutics.2014 Nov 18;Paloneva,J et al.,(2002)Am J Hum Genet 71:656-662;Paloneva,J et al.,(2003)J Exp Med 198:669-675;Guerreiro,RJ et al.,(2013) JAMA Neurol 70:78-84;Guerreiro,RJ et al.,(2012)Arch Neurol:1-7;Guerreiro,R et al.,(2013)N Engl J Med 368:117-127;Jonsson,T et al.,(2013)N Engl J Med 368:107-116;Neumann,H et al. al.,(2013)N Engl J Med 368:182-184;Wang Y,et al.,(2015)Cell 160(6):1061-71;Cady,J et al.,(2014)JAMA Neurol.71:449-452;Cooper-Knock,J et al.,(2017)Acta Neuropathol.Commun.5:23;Cantoni, C et As described in [End Page 111] al., (2015) Acta Neuropathol. 129:429-447; Ren, M, et al., (2018) Exp. Neurol. 302:205-213; and Vuono, R et al., (2020) Mov Disord 35:401-408, TREM2 activity is implicated in such diseases, disorders, and conditions.

[0126] In some embodiments, the treatment methods provided herein comprise administering to an individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg, wherein the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein (i) HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 34), HVR-H2 comprises the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 35), HVR-H3 comprises the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 31), and HVR-L1 comprises the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 41), and HVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO: 33), and HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32); or (ii) HVR-H1 comprises the amino acid sequence YAFSSWDMN (SEQ ID NO: 36), HVR-H2 comprises the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 37), HVR-H3 comprises the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 38), HVR-L1 comprises the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 39), HVR-L2 comprises the amino acid sequence KVSNRVS (SEQ ID NO: 40), and HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32).

[0127] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 34), HVR-H2 comprises the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 35), HVR-H3 comprises the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 31), HVR-L1 comprises the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 41), HVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO: 33), and HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 30.

[0128] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence YAFSSWDMN (SEQ ID NO: 36), HVR-H2 comprises the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 37), HVR-H3 comprises the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 38), HVR-L1 comprises the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 39), HVR-L2 comprises the amino acid sequence KVSNRVS (SEQ ID NO: 40), and HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 29.

[0129] In some embodiments, the antibody comprises a heavy chain variable region and a light chain variable region, wherein (a) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence SYWIG (SEQ ID NO: 146) or SWIG (SEQ ID NO: 147), HVR-H2 comprising the amino acid sequence IIYPGDADARYSPSFQG (SEQ ID NO: 148), and HVR-H3 comprising the amino acid sequence RRQGIFGDALDF (SEQ ID NO: 149); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RASQSVSSNLA (SEQ ID NO: 150), HVR-L2 comprising the amino acid sequence GASTRAT (SEQ ID NO: 151), and HVR-L3 comprising the amino acid sequence LQDNNFPPT (SEQ ID NO: 152); or or (b) the heavy chain variable region comprises the amino acid sequence EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDADARYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYFCARRRQGIFGDALDFWGQGTLVTVSS (SEQ ID NO: 153) and the light chain variable region comprises the amino acid sequence EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWFQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQPEDFAVYYCLQDNNFPPTFGQGTKVDIK (SEQ ID NO: 154).

[0130] In some embodiments, the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence GFTFTDFYMS (SEQ ID NO: 155), HVR-H2 comprising the amino acid sequence VIRNKANGYTAGYNPSVKG (SEQ ID NO: 156), and HVR-H3 comprising the amino acid sequence ARLTYGFDY (SEQ ID NO: 157); and the light chain variable region comprises HVR-L1 comprising the amino acid sequence QSSKSLLHSTGKTYLN (SEQ ID NO: 158), HVR-L2 comprising the amino acid sequence WMSTRAS (SEQ ID NO: 159), and HVR-L3 comprising the amino acid sequence GGGGGGGGGGGGGGGG (SEQ ID NO: 160). or HVR-L3 comprising the amino acid sequence QQFLEYPFT (SEQ ID NO: 160), or wherein the heavy chain variable region comprises the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAGSGFTFTDFYMSWVRQAPGKGPEWLSVIRNKANGYTAGYNPSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLTYGFDYWGQGTLVTVSS (SEQ ID NO: 161), and the light chain variable region comprises the amino acid sequence DIVMTQTPLSLPVTPGEPASISCQSSKSLLHSTGKTYLNWYLQKP or the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence GFTFTDFYMS (SEQ ID NO: 163), HVR-H2 comprising the amino acid sequence VIRNKANAYTAGYNPSVKG (SEQ ID NO: 164), and HVR-H3 comprising the amino acid sequence ARLTYGFDY (SEQ ID NO: 165); and the light chain variable region comprises the amino acid sequence QSSKSLLHSTGKTYLN (SEQ ID NO: 166). HVR-L1 comprising the amino acid sequence WMSTRAS (SEQ ID NO: 167), and HVR-L3 comprising the amino acid sequence QQFLEYPFT (SEQ ID NO: 168), or the heavy chain variable region comprises the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFTDFYMSWVRQAPGKGLEWVSVIRNKANAYTAGYNPSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLTYGFDYWGQGTLVTVSS (SEQ ID NO: 169), and the light chain variable region comprisesContains the amino acid sequence DIVMTQTPLSLPVTPGEPASISCQSSKSLLHSTGKTYLNWYLQKPGQSPQLLIYWMSTRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQFLEYPFTFGQGTKVEIK (SEQ ID NO: 170).

[0131] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence GYSITSDYAWN (SEQ ID NO:50), HVR-H2 comprises the amino acid sequence YINYSGRTIYNPSLKS (SEQ ID NO:51), HVR-H3 comprises the amino acid sequence ARWNGNYGFAY ​​(SEQ ID NO:52), HVR-L1 comprises the amino acid sequence RSSQSLVHINGNTYLH (SEQ ID NO:53), HVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO:54), and HVR-L3 comprises the amino acid sequence SQTTHALFT (SEQ ID NO:55). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57.

[0132] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence GYTFTSY (SEQ ID NO: 58), HVR-H2 comprises the amino acid sequence IGRSDPTGGTNYNE (SEQ ID NO: 59), HVR-H3 comprises the amino acid sequence VRTSGDY (SEQ ID NO: 60), HVR-L1 comprises the amino acid sequence RSSQSLVHNNGNTFLH (SEQ ID NO: 61), HVR-L2 comprises the amino acid sequence VSNRFS (SEQ ID NO: 62), and HVR-L3 comprises the amino acid sequence SQTTHVPPT (SEQ ID NO: 63). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 64 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 65.

[0133] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence GFTFTDFY (SEQ ID NO: 66), HVR-H2 comprises the amino acid sequence IRNKANGYTT (SEQ ID NO: 67), HVR-H3 comprises the amino acid sequence ARIGINNGGSLDYWG (SEQ ID NO: 68), HVR-L1 comprises the amino acid sequence QSLLYSENNQDY (SEQ ID NO: 69), HVR-L2 comprises the amino acid sequence GAS (SEQ ID NO: 70), and HVR-L3 comprises the amino acid sequence EQTYSYPYT (SEQ ID NO: 71). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 72 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 73.

[0134] In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence DYNIH (SEQ ID NO: 173), HVR-H2 comprises the amino acid sequence YIYPKNGGTGYTQKFKS (SEQ ID NO: 174), HVR-H3 comprises the amino acid sequence RTARASWFAF (SEQ ID NO: 175), HVR-L1 comprises the amino acid sequence KSSQSLLYSSNQKNYLA (SEQ ID NO: 176), HVR-L2 comprises the amino acid sequence WASTRES (SEQ ID NO: 177), and HVR-L3 comprises the amino acid sequence QQYYNYPFT (SEQ ID NO: 178). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 179 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 180.

[0135] In some embodiments, the antibody has a human IgG1 isotype. In some embodiments, the antibody has a human IgG1 isotype and contains amino acid substitutions in the Fc region at residue positions P331S and E430G (residue numbering according to EU numbering).

[0136] In some embodiments, the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 43 and a light chain comprising the amino acid sequence of SEQ ID NO: 47; or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 44 and a light chain comprising the amino acid sequence of SEQ ID NO: 47.

[0137] In some embodiments, the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 45 and a light chain comprising the amino acid sequence of SEQ ID NO: 48, or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 and a light chain comprising the amino acid sequence of SEQ ID NO: 48.

[0138] In some embodiments, the antibody has a heavy chain comprising the following amino acid sequence: EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDADARYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYFCARRRQGIFGDALDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 171), and a light chain comprising the following amino acid sequence: EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWFQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQPEDFAVYYCLQDNNFPPTFGQGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 172).

[0139] Without wishing to be bound by theory, it is believed that agonizing TREM2 (e.g., by administering an anti-TREM2 antibody of the present disclosure) to promote or increase microglial cell activity in an individual may result in amelioration of the pathology and / or one or more symptoms of dementia, frontotemporal dementia, Alzheimer's disease, adrenoleukodystrophy (ALD), cerebral adrenoleukodystrophy (cALD), cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, demyelinating disorders, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), or a tauopathy.

[0140] Dementia Dementia is a nonspecific syndrome (i.e., a set of signs and symptoms) that manifests as a significant loss of overall cognitive ability in a previously unimpaired person beyond that which would be expected from normal aging. Dementia may be static as a result of a unique global brain injury. Alternatively, dementia may be progressive, resulting in long-term decline due to physical injury or disease. Dementia is much more common in the elderly population, but it can also develop before the age of 65. Cognitive domains affected by dementia include, but are not limited to, memory, sustained attention, language, and problem-solving. Generally, symptoms must be present for at least six months before an individual is diagnosed with dementia.

[0141] Exemplary forms of dementia include, but are not limited to, frontotemporal dementia, Alzheimer's disease, vascular dementia, semantic dementia, and dementia with Lewy bodies.

[0142] Without wishing to be bound by theory, it is believed that administering an anti-TREM2 antibody of the present disclosure can treat and / or slow the progression of dementia. In some embodiments, administering an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with dementia. In some embodiments, administering an anti-TREM2 antibody of the present disclosure can promote or increase microglial cell activity in an individual with dementia, for example, compared to baseline.

[0143] frontotemporal dementia Frontotemporal dementia (FTD) is a condition resulting from progressive degeneration of the frontal lobes of the brain. Over time, degeneration can progress to the temporal lobes. Second only to Alzheimer's disease (AD) in prevalence, FTD accounts for 20% of presenile dementia cases. Clinical features of FTD include memory deficits, behavioral abnormalities, personality changes, and language impairment (Cruts, M. & Van Broeckhoven, C., Trends Genet. 24:186-194 (2008); Neary, D., et al., Neurology 51:1546-1554 (1998); Ratnavalli, E., Brayne, C., Dawson, K. & Hodges, JR, Neurology 58:1615-1621 (2002)).

[0144] A significant proportion of FTD cases are inherited in an autosomal dominant manner, but even within a single family, symptoms can range from FTD with behavioral disturbances to primary progressive aphasia to corticobasal ganglionic degeneration. Like most neurodegenerative diseases, FTD can be characterized by the pathological presence of specific protein aggregates in affected brains. Historically, the first description of FTD recognized the presence of intraneuronal accumulations of hyperphosphorylated Tau protein in neurofibrillary tangles, or Pick bodies. The causal role of the microtubule-associated protein Tau has been supported by the identification of mutations in the gene encoding the Tau protein in several families (Hutton, M., et al., Nature 393:702-705 (1998)). However, the majority of FTD brains do not show accumulation of abnormally phosphorylated Tau, but rather show immunoreactivity for ubiquitin (Ub) and the TAR DNA-binding protein (TDP43) (Neumann, M., et al., Arch. Neurol. 64:1388-1394 (2007)).

[0145] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure can treat and / or delay the progression of FTD. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure can promote microglial cell activity, for example, compared to baseline, in an individual with FTD. In some embodiments, administration of an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with FTD.

[0146] In some embodiments, treating and / or delaying FTD progression is determined by change from baseline in a neurocognitive and / or functional test or assessment (i.e., a clinical outcome assessment). Non-limiting examples of neurocognitive and functional tests that can be used to assess treating and / or delaying FTD progression include the Frontotemporal Dementia Clinical Rating Scale (FCRS), the Frontotemporal Dementia Rating Scale (FRS), the Clinical Global Impression-Improvement (CGI-I) assessment, the Neuropsychiatric Inventory (NPI) assessment, the Color Trails Test (CTT) Part 2, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Delis-Kaplan Executive Function System Color-Word Interference Test, the Interpersonal Reactivity Index, the Winterlight Lab Speech Assessment (WLA), and the Summerlight Lab Speech Assessment (SLA). In some embodiments, treating and / or delaying FTD progression is determined by change from baseline in one neurocognitive and / or functional test or assessment. In some embodiments, treating and / or delaying FTD progression is determined by change from baseline in more than one neurocognitive and / or functional test or assessment (e.g., 2, 3, 4, 5, 6, 7, 8, 9 or more neurocognitive and / or functional tests or assessments).

[0147] In some embodiments, the treatment and / or delay of FTD progression is determined by changes from baseline in global and / or regional brain volume, white matter hyperintensity volume, cerebral blood flow, diffusion anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity, and / or functional brain activity. In certain embodiments, cerebral blood flow is measured by arterial spin labeling MRI. In certain embodiments, radial diffusivity is measured by diffusion tensor imaging. In certain embodiments, functional brain activity is measured by functional MRI.

[0148] In some embodiments, treating and / or delaying FTD progression is determined by a change from baseline in markers of neurodegeneration in whole blood, plasma, and CSF. Markers of neurodegeneration may include, but are not limited to, neurofilament-light chain [Nfl], Tau, and / or pTau. In some embodiments, treating and / or delaying FTD progression is determined by a change from baseline in markers of lysosomal function. Markers of lysosomal function may be, but are not limited to, cathepsins. In some embodiments, treating and / or delaying FTD progression is determined by a change from baseline in markers of microglial cell activity. Markers of microglial cell activity may be, but are not limited to, interleukin-6, sCSF1R, YKL40 (CHI3L1), IL-1RA (IL1RN), and osteopontin (SPP1). In some embodiments, treating and / or delaying FTD progression is determined by a change from baseline in messenger ribonucleic acid (mRNA) expression in peripheral cells. In some embodiments, treating and / or delaying FTD progression is determined by a change from baseline in an analyte relevant to FTD disease biology and / or response to an anti-TREM2 antibody.

[0149] In some embodiments, treating and / or delaying FTD progression is determined by changes from baseline in neuroinflammation and / or microglial cell activation. Neuroinflammation and / or microglial cell activation can be measured by any known method in the art. In certain embodiments, neuroinflammation and / or microglial cell activation can be measured using Translocator Protein-Positron Emission (TSPO-PET) imaging. In certain embodiments, [ 18 [F]PBR06 and / or [C]PBR28 PET are used as radiotracers in TSPO-PET imaging. In certain embodiments, [ 18 [F]PBR06 is used as a radiotracer in TSPO-PET imaging. In certain embodiments, [11C]PBR28 PET is used as a radiotracer in TSPO-PET imaging.

[0150] In some embodiments, the individual is heterozygous for a mutation in GRN (Granulin gene). In some embodiments, the mutation in GRN is a loss-of-function mutation. In some embodiments, the individual is heterozygous for a C9orf72 hexanucleotide repeat expansion. In some embodiments, the individual exhibits symptoms of FTD. In some embodiments, the individual does not exhibit symptoms of FTD.

[0151] In some embodiments, an individual exhibits symptoms of FTD if they meet the diagnostic criteria for possible behavioral FTD (bvFTD) or probable bvFTD or primary progressive aphasia (PPA). In some embodiments, an individual has one or more of the behavioral / cognitive symptoms required for a diagnosis of possible bvFTD (Rascovsky et al., (2011) Brain 134(9):2456-2477). In some embodiments, an individual has mild symptomatology (e.g., mild cognitive impairment, mild behavioral disorder) that does not significantly affect activities of daily living. In certain embodiments, an individual has bvFTD or PPa with concomitant motor neuron disease. In some embodiments, the individual has mild FTD severity as defined by a Clinical Dementia Rating Scale (CDR) global score of 1 or less and box scores of 1 or less in both the Language domain and the Behavior, Comportment, and Personality domains of the Frontotemporal Dementia Clinical Rating Scale (FCRS).

[0152] Alzheimer's disease Alzheimer's disease (AD) is the most common form of dementia. There is no cure for the disease, and it worsens as it progresses, eventually leading to death. In most cases, AD is diagnosed in people over the age of 65. However, early-onset Alzheimer's disease, which is less common, can develop much earlier.

[0153] Common symptoms of Alzheimer's disease include difficulty remembering recent events; cognitive symptoms, confusion, irritability and aggression, mood swings, impairments with language, and behavioral signs such as long-term memory loss. As the disease progresses, bodily functions are lost and ultimately death occurs. Alzheimer's disease develops for an unknown and indeterminate period before becoming fully apparent and can proceed undiagnosed for years.

[0154] Studies have shown that Triggering Receptor Expressed on Myeloid cells-2 (TREM2), an immunoglobulin-like receptor, may play an important role in AD. For example, heterozygous mutations in the TREM2 gene have been found to increase the risk of AD by up to threefold (Guerreiro et al. (2013) N Engl J Med 368:117-127; Jonsson et al. (2013) N Engl J Med 368:107-116) and increase the rate of brain volume atrophy (Rajagopalan et al. (2013) N Engl J Med 369:1565-1567). Recent mouse genetic model studies also strongly support the essential role of TREM2 in AD, with loss or insufficiency of TREM2 associated with increased pathology (Cheng-Hathaway et al. (2018) Mol Neurodegener, 13(1):29; Wang et al. (2015) Cell, 160:1061-1071; Wang et al. (2016) J Exp Med, 213:667-675; Yuan et al. (2016) Neuron, 90:724-739; Jay et al. (2017) J Neurosci, 37:637-647). TREM2 expression has been shown to enhance microglial cell survival, proliferation, and differentiation, regulate microglial chemotaxis and phagocytosis, and is required for maintaining microglial trophic function in the aging brain. Additionally, animal studies have revealed overlap between aging microglial cell phenotypes and microglial cell molecular signatures found in models of AD, including the TREM2 pathway (Krasemann et al (2017) Immunity, 47(3):566-581).

[0155] Thus, without wishing to be bound by theory, it is believed that activation of TREM2 (e.g., using the agonist anti-TREM2 antibodies provided herein) may ameliorate AD pathology and lead to improved cognitive function by increasing microglial cell activity. In some embodiments, administering an anti-TREM2 antibody of the present disclosure promotes or increases microglial cell activity in an individual with AD, e.g., compared to baseline. In some embodiments, administering an anti-TREM2 antibody of the present disclosure can treat and / or slow the progression of Alzheimer's disease. In some embodiments, administering an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with AD.

[0156] In some embodiments of the methods of treatment provided herein, the disease or injury is Alzheimer's disease. In some embodiments, the individual has a clinical diagnosis of probable Alzheimer's disease dementia based on the National Institute on Aging Alzheimer's Association criteria. In some embodiments, the individual has a Mini-Mental State Examination (MMSE) score of 16 to 28 points (e.g., any of 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 points). In some embodiments, the individual has a Clinical Dementia Rating-global Score (CDR-GS) of 0.5, 1.0, or 2.0. In some embodiments, the individual has a positive amyloid positron emission tomography (PET) scan. In some embodiments, a positive amyloid-PET scan is 18The presence of one or more TREM2 mutations in an individual is determined by a qualitative readout using F-Florbeta PET / computed tomography (CT) imaging. In some embodiments, the individual is taking or receiving a cholinesterase inhibitor, e.g., for the treatment of Alzheimer's disease. In some embodiments, the individual is taking or receiving memantine therapy, e.g., for the treatment of Alzheimer's disease. In some embodiments, the individual comprises an amino acid substitution at residue position R47H in the human TREM2 protein. In some embodiments, the individual comprises an amino acid substitution at residue position R62H in the human TREM2 protein. In some embodiments, the individual comprises amino acid substitutions at residue positions R47H and R62H in the human TREM2 protein. In some embodiments, the presence of one or more TREM2 mutations in an individual is determined using any method known in the art, such as sequencing (e.g., whole genome sequencing, targeted sequencing, next-generation sequencing, or Sanger sequencing) or polymerase chain reaction (e.g., PCR or qPCR). In some embodiments, the individual has or exhibits one or more symptoms of Alzheimer's disease. In some embodiments, the individual does not have or exhibit symptoms of Alzheimer's disease.

[0157] In some embodiments, treating and / or delaying Alzheimer's disease is determined by a change from baseline in the level of one or more biomarkers of microglial cell activity in the individual, e.g., in the individual's cerebrospinal fluid or blood. Biomarkers of microglial cell activity include, but are not limited to, sCSF1R, sTREM2, YKL40 (CHI3L1), IL-1RA (IL1RN), and osteopontin (SPP1).

[0158] In certain embodiments, the treatment and / or delay of Alzheimer's disease is determined by a change from baseline in one or more symptoms of Alzheimer's disease.

[0159] In certain embodiments, treatment and / or delay of Alzheimer's disease is determined using one or more clinical assessment tools, such as the Mini-Mental State Examination (MMSE), the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Clinical Dementia Rating (CDR), the Clinical Dementia Rating-Global Score (CDR-GS), and the Clinical Dementia Rating Sum of Boxes (CDR-SB). In some embodiments, administration of an antibody of the disclosure results in an improvement in the score on one or more clinical assessments compared to before administration of the anti-TREM2 antibody.

[0160] In certain embodiments, the treatment and / or delay of Alzheimer's disease is determined by a change from baseline in one or more biomarkers of Alzheimer's disease in the individual's cerebrospinal fluid, such as sTREM2, sCSF1R, Abeta, Tau, p-Tau, neurofilament light chain, neurogranin, and YKL40.

[0161] In certain embodiments, the treatment and / or delay of Alzheimer's disease is determined by a change from baseline in one or more biomarkers of Alzheimer's disease in the individual's blood, such as sTREM2, sCSF1R, a biomarker of neuroinflammation (e.g., IL-6, SPP1, IFI2712A or TOP2A), and expression levels (e.g., mRNA levels) of TREM2 and CSF1R.

[0162] In certain embodiments, the treatment and / or delay of Alzheimer's disease is determined by a change from baseline in one or more brain abnormalities, such as cerebral vasogenic edema, superficial siderosis of the central nervous system, and cerebral micro- or macrohemorrhages. In certain embodiments, the one or more brain abnormalities are measured using any method known in the art, such as magnetic resonance imaging.

[0163] In certain embodiments, the treatment and / or delay of Alzheimer's disease is determined by a change from baseline in the level of brain amyloid burden, hi certain embodiments, the level of brain amyloid burden is determined using any method known in the art, such as amyloid positron emission tomography.

[0164] In some embodiments of the methods of treatment provided herein, the disease or injury is Alzheimer's disease, and the Alzheimer's disease is early Alzheimer's disease. In some embodiments, early Alzheimer's disease refers to Alzheimer's disease based on the Alzheimer's disease continuum as defined by the 2018 National Institute on Aging and Alzheimer's Association (NIA-AA) Research Framework (Jack et al., Alzheimers Dement (2018) 14(4):535-562), which includes evidence of cerebral amyloidosis (A+) and clinical severity consistent with Stage 2, 3, or early Stage 4. In some embodiments, an individual with early Alzheimer's disease has a Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1, a Mini-Mental State Examination (MMSE) score of about 22 to about 30 points (e.g., about any of 22, 23, 24, 25, 26, 27, 28, 29, or 30 points), and a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score on the Delayed Memory Index (DMI) of about 85 points or less (e.g., an RBANS DMI score of about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, or about 40).In some embodiments, early Alzheimer's disease refers to disease having clinical severity consistent with early Alzheimer's disease as defined by the European Medicines Agency (European Medicines Agency: CPMP / EWP / 553 / 95 Rev. 2. Guideline on the clinical investigation of medicines for the treatment of Alzheimer's disease 2018, available at: www[dot]ema.europa[dot]eu / en / documents / scientific-guideline / guideline-clinical-investigation-medicines-treatment-alzheimers-disease-revision-2_en.pdf, August 2020) or by the U.S. Food and Drug Administration (Food and Drug Administration Center for Drug Evaluation and Research. Guidance for industry: Early Alzheimer's Disease: Developing Drugs for Treatment (FDA Maryland), 2018).

[0165] In some embodiments, early Alzheimer's disease is diagnosed using one or more clinical assessment tools, such as the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating-Global Score (CDR-GS), or the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) with Delayed Memory Index (DMI). In some embodiments, early Alzheimer's disease is diagnosed based on the presence of cerebral amyloidosis. Cerebral amyloidosis can be assessed using any method known in the art, such as by cerebrospinal fluid assessment or positron emission tomography (PET).

[0166] In some embodiments, the individual treated according to the methods provided herein has a diagnosis of early Alzheimer's disease. In some embodiments, the diagnosis of early Alzheimer's disease includes evidence of cerebral amyloidosis as determined by CSF or PET evaluation. In some embodiments, the individual has evidence of cerebral amyloidosis as determined by a positive amyloid or tau blood test before administration of the anti-TREM2 antibody. In some embodiments, the individual has a positive amyloid or tau blood test before administration of the anti-TREM2 antibody. In some embodiments, the amyloid or blood test is a PrecivityAD™-Aβ blood test, or a test for phosphorylated tau 217 (p-tau217), a test for phosphorylated tau 181 (p-tau181), a test for neurofilament light, or a test for the Aβ42 / 40 ratio. In some embodiments, the amyloid or tau blood test is an immunoassay-based test for the Aβ42 / 40 ratio (see, e.g., Yamashita et al., Alzheimer's Association International Conference (2019) 15(7S), part 29, P4-548). In some embodiments, the amyloid or tau blood test is a mass spectrometry-based test for the Aβ42 / 40 ratio (see, e.g., Schindler et al., Neurology (2019) 93(17)). In some embodiments, the amyloid or tau blood test is an immunoassay-based test for p-tau217 (see, e.g., Palmqvist et al., JAMA (2020) 324(8):772-781).

[0167] In some embodiments, the amyloid or tau blood test is the PrecivityAD™-Aβ blood test. The PrecivityAD™-Aβ blood test is based on mass spectrometry assessment of blood proteins that indicate the probability of amyloid deposition in the brain as measured by an amyloid PET scan. The test incorporates the Aβ42 / 40 ratio, ApoE genotype, and the individual's age into a statistical algorithm to estimate an Amyloid Probability Score (APS). In some embodiments, the individual has evidence of cerebral amyloidosis as determined by a positive PrecivityAD™-Aβ blood test, e.g., the individual has a high APS (www.c2ndiagnostics.com / products / home). See, e.g., Schindler et al., Neurology (2019) 93(17): e1647-e1659. In some embodiments, the individual has evidence of cerebral amyloidosis as determined by intermediate APS and confirmation of cerebral amyloidosis by amyloid PET or CSF pTau / Aβ42 ratio. In some embodiments, the individual does not have low APS. In some embodiments, the individual has evidence of cerebral amyloidosis as determined by an amyloid PET scan. In some embodiments, the individual has evidence of cerebral amyloidosis as determined by CSF testing. In some embodiments, the individual has evidence of cerebral amyloidosis as determined by the presence of amyloid beta (Aβ) pathology. In some embodiments, the presence of amyloid beta (Aβ) pathology is assessed by a positive PrecivityAD™-Aβ blood test, e.g., the individual has a high Amyloid Probability Score (APS). In some embodiments, the presence of amyloid beta (Aβ) pathology is assessed by an amyloid PET scan. In some embodiments, the presence of amyloid beta (Aβ) pathology is assessed by CSF testing. In some embodiments, the individual has evidence of cerebral amyloidosis as determined by the presence of amyloid pathology. In some embodiments, the presence of amyloid pathology is assessed by an amyloid PET scan.In some embodiments, the presence of amyloid pathology is assessed by measuring the CSF phosphorylated tau (pTau) / amyloid beta (1-42) (Aβ42) ratio. In some embodiments, the individual has evidence of cerebral amyloidosis, for example, as determined by a positive historical amyloid PET scan collected within 24 months prior to the start of treatment with the methods of the present disclosure. In some embodiments, the individual has evidence of Alzheimer's disease amyloid pathology, as determined by a positive amyloid PET scan and / or a CSF pTau / Aβ42 ratio of greater than 0.024. Any suitable method known in the art, such as an immunoassay, for example, the Roche Elecsys assay, can be used to measure the CSF pTau / Aβ42 ratio. In some embodiments, the individual has early Alzheimer's disease with a clinical severity consistent with Stage 2, 3, or early Stage 4 as defined in the 2018 NIA-AA Research Framework (Jack et al., Alzheimers Dement (2018) 14(4):535-562), also described in the 2018 NIA-AA Research Framework as mild cognitive impairment and mild dementia. In some embodiments, the individual has a Mini-Mental State Examination (MMSE) score of at least about 22 points (e.g., about any of 22, 23, 24, 25, 26, 27, 28, 29, or 30 points). In some embodiments, the individual has early Alzheimer's disease with mild symptomatology as defined by a Mini-Mental State Examination (MMSE) score of at least about 22 points (e.g., about any of 22, 23, 24, 25, 26, 27, 28, 29, or 30 points). In some embodiments, the individual has a Clinical Dementia Rating-Global Score (CDR-GS) of about 0.5 to about 1.0.In some embodiments, the individual has a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score with a Delayed Memory Index (DMI) of about 85 or less (e.g., an RBANS DMI score of any of about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, or about 40). In some embodiments, the individual has a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) score with a Delayed Memory Index (DMI) that is about one standard deviation below population-based normative data. In some embodiments, the individual exhibits amnestic deficit as assessed by the Delayed Memory Index (DMI) of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). In some embodiments, the individual has evidence of episodic memory impairment as defined by an RBANS score with a DMI of about 85 or less (e.g., an RBANS DMI score of any of about 85, about 80, about 75, about 70, about 65, about 60, about 55, about 50, about 45, or about 40). In some embodiments, the individual does not have frontotemporal dementia (FTD), Parkinson's disease, dementia with Lewy bodies, Huntington's disease, or vascular dementia. In some embodiments, the individual does not have a condition other than Alzheimer's disease that has the potential to affect cognition. Examples of conditions that may affect cognition include, but are not limited to, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, Parkinson's disease, corticobasal degeneration, Creutzfeldt-Jakob disease, progressive supranuclear palsy, frontotemporal degeneration, Huntington's disease, normal pressure hydrocephalus, hypoxic disorders, seizure disorders, static encephalopathy, closed brain injury, and developmental disorders. In some embodiments, the individual does not have uncontrolled hypertension, diabetes, or thyroid disease.In some embodiments, the individual does not have significant cardiac disease, cardiovascular disease or disorder, liver disease or disorder, or kidney disease or disorder. In some embodiments, the individual does not have evidence of clinically significant brain disease other than Alzheimer's disease. In some embodiments, the individual is not receiving anticoagulant therapy. In some embodiments, the individual does not have a history or presence of vascular disease that may affect cognitive function, such as clinically significant carotid artery, vertebral stenosis, or plaque; aortic aneurysm; intracranial aneurysm; major hemorrhage; or cerebral arteriovenous malformation. In some embodiments, the individual does not have a history or presence of clinical stroke within the past two years prior to treatment with the methods of the present disclosure. In some embodiments, the individual does not have a history or presence of an acute event consistent with a transient ischemic attack within the past 180 days prior to treatment with the methods of the present disclosure. In some embodiments, the individual does not have the presence of any cortical stroke on MRI. In some embodiments, the individual does not have a history of severe, clinically significant (e.g., persistent neurological deficit or structural brain damage) CNS trauma (e.g., cerebral contusion). In some embodiments, the individual does not have a history or presence of intracranial tumors, e.g., gliomas, except for benign brain tumors that do not cause cognitive symptoms. In some embodiments, the individual does not have a presence of an infection that affects brain function. In some embodiments, the individual does not have a history of an infection that results in neurological sequelae. Examples of such infections include, but are not limited to, human immunodeficiency virus, syphilis, neuroborreliosis, and viral or bacterial meningitis / encephalitis. In some embodiments, the individual does not have or has not had an acute illness that requires or has required intravenous antibiotics within the past 30 days prior to treatment with the disclosed methods. In some embodiments, the individual does not have a history or presence of a systemic autoimmune disorder that may be responsible for a progressive neurological disease with associated cognitive impairment. Examples of such autoimmune disorders include, but are not limited to, multiple sclerosis, lupus erythematosus, antiphospholipid syndrome, and Behcet's disease. In some embodiments, the individual does not have a history or presence of uveitis, a chronic inflammatory or degenerative condition of the eye, an existing ocular infection, any ongoing ocular disorder (e.g., degenerative, cataract, or diabetic retinopathy) requiring medical intervention, injectable pharmaceutical therapy (e.g., ranibizumab or aflibercept for macular degeneration). In some embodiments, the individual does not have any history of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder. In some embodiments, the individual is not at risk for suicide. In some embodiments, the individual does not have a history of alcohol and / or moderate to severe substance use disorder (per Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) within the past two years prior to treatment with the methods of the present disclosure. In some embodiments, the individual has more than two lacunar infarcts, 3 In some embodiments, the individual does not have MRI evidence of any regional infarction or white matter hyperintense lesions greater than 100% on a FLAIR sequence corresponding to a total Fazekas score of 3. In some embodiments, the individual does not have the presence of more than 5 microhemorrhages and / or areas of leptomeningeal hemosiderosis on MRI. In some embodiments, the individual does not have significant cerebrovascular pathology as assessed by MRI. In some embodiments, the individual is not positive for hepatitis B surface antigen, total hepatitis B core antibody, or HIV-1 or -2 antibody or antigen. In some embodiments, the individual does not have a history of central nervous system spirochete infection (e.g., syphilis, borreliosis, or Lyme disease). In some embodiments, the individual is positive for hepatitis C virus antibody and negative for hepatitis C ribonucleic acid (RNA). In some embodiments, the individual does not have active or latent tuberculosis disease. In some embodiments, the individual does not have a chronic active immune disorder requiring systemic immunosuppressive therapy within one year prior to treatment with the methods of the present disclosure. In some embodiments, the individual has a hemoglobin level of less than 10 g / dL, a hemoglobin level of less than 1000 / mm 3 Absolute neutrophil count of greater than 150,000 / mm 3In some embodiments, the individual does not have bone marrow dysfunction based on a platelet count of less than 0.05 mg / kg. In some embodiments, the individual does not have abnormal thyroid-stimulating hormone (TSH) levels. In some embodiments, the individual does not have folate or vitamin B12 levels so low that a deficiency could contribute to cognitive impairment. In some embodiments, the individual does not have a hemoglobin A1c greater than 8% or poorly controlled diabetes (including hypoglycemic events). In some embodiments, the individual is not taking an ongoing regimen of medication known to impair consciousness or cognition. In some embodiments, the individual has not been treated with medication for Parkinson's disease or any other neurodegenerative disorder within one year prior to treatment with the methods of the present disclosure, except for treatment for Alzheimer's disease. In some embodiments, if a medication is being taken by the individual for a non-neurodegenerative disorder, e.g., restless legs disorder, the individual may be taking a medication used to treat a neurodegenerative disorder, e.g., pramipexole. In some embodiments, the individual has not taken a typical antipsychotic or neuroleptic drug within 180 days prior to treatment with the methods of the present disclosure, except for short-term treatment for non-psychiatric indications (e.g., vomiting). In some embodiments, the individual has not taken an atypical antipsychotic drug, except for intermittent short-term use (e.g., less than one week). In some embodiments, the individual has not taken an anticoagulant within 90 days prior to treatment with the methods of the present disclosure. In some embodiments, the individual has not received systemic immunosuppressive therapy. In some embodiments, the individual has not used opiates or opioids, including long-acting opioid medications, for long periods of time within 90 days prior to treatment with the methods of the present disclosure. In some embodiments, the individual has not taken stimulants (e.g., amphetamines, methylphenidate preparations, or modafinil) within 30 days prior to treatment with the methods of the present disclosure. In some embodiments, the individual has not used benzodiazepines, barbiturates, or hypnotics for long periods of time beginning more than 90 days prior to treatment with the methods of the present disclosure.

[0168] In certain embodiments, treatment and / or delay of early Alzheimer's disease is determined using one or more clinical assessment tools, such as the Clinical Dementia Rating (CDR), Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Alzheimer's Disease Assessment Scale-Cognitive Subscale-13 (ADAS-Cog13), Alzheimer's Disease Cooperative Study-Activities of Daily Living adapted to Mild Cognitive Impairment (ADCS-ADL-MCI), Alzheimer's Disease Composite Score (ADCOMS), or Winterlight Labs Speech Assessment (WLSA). In some embodiments, administration of an antibody of the disclosure results in an improvement in the score on one or more clinical assessments compared to before administration of the anti-TREM2 antibody. In certain embodiments, treatment and / or delay of early Alzheimer's disease is assessed based on the percent change in score on one or more clinical assessment tools, such as, for example, CDR-SB, MMSE, RBANS, ADAS-Cog13, ADCS-ADL-MCI, ADCOMS, or WLSA, compared to before administration of the anti-TREM2 antibody.In certain embodiments, treatment and / or delay of early Alzheimer's disease is assessed based on the rate of change in scores on one or more clinical assessment tools, such as CDR-SB, MMSE, RBANS, ADAS-Cog13, ADCS-ADL-MCI, ADCOMS, or WLSA, i.e., based on a comparison of scores on one or more clinical assessment tools obtained before administration of an anti-TREM2 antibody with corresponding scores on one or more clinical assessment tools obtained after the individual has been administered one or more doses of an anti-TREM2 antibody; or based on a comparison of two or more scores on one or more clinical assessment tools obtained during the course of treatment with an anti-TREM2 antibody according to the methods of the disclosure. In certain embodiments, the treatment and / or delay of early Alzheimer's disease is determined by a change from baseline in one or more biomarkers of Alzheimer's disease in the individual's cerebrospinal fluid, such as soluble TREM2 (sTREM2) and other CSF biomarkers associated with Alzheimer's disease (e.g., Aβ42, Aβ40, total tau, pTau, or NfL) or microglial cell function (e.g., CSF1R, IL1RN, YKL40, and osteopontin). In certain embodiments, the treatment and / or delay of early Alzheimer's disease is determined by a change from baseline in one or more biomarkers of Alzheimer's disease in the individual's blood, such as soluble TREM2 (sTREM2) in plasma, plasma biomarkers associated with Alzheimer's disease (e.g., Aβ42, Aβ40, total tau, pTau, NfL), or TREM2 RNA expression. In certain embodiments, the treatment and / or delay of early Alzheimer's disease is determined by a change from baseline in one or more biomarkers of microglial cell function in the individual's plasma or cerebrospinal fluid, such as CSF1R, IL1RN, osteopontin, or YKL40. In certain embodiments, the treatment and / or delay of early Alzheimer's disease is determined by a change from baseline in one or more biomarkers of neurodegeneration in the individual's plasma or cerebrospinal fluid, such as NfL. In certain embodiments, the treatment and / or delay of early Alzheimer's disease is determined by a change from baseline in brain volume as assessed, for example, by volumetric MRI.In certain embodiments, the treatment and / or delay of early Alzheimer's disease is achieved by administering, for example, [. 18 [F]MK-6240 Tau-PET radiotracer is used, e.g., as determined by the change from baseline in brain pathological tau burden as assessed by Tau-PET. In certain embodiments, the treatment and / or delay of early Alzheimer's disease is determined by, e.g., [F]MK-6240 Tau-PET radiotracer. 18 F]Florbetaben (Neuraceq), [ 18 F] florbetapir (Amyvid), or [ 18 In certain embodiments, the treatment and / or delay of early Alzheimer's disease is determined by the change from baseline in cerebral amyloid burden as assessed, for example, by longitudinal amyloid-PET using [F]flutametamol (Vizamyl) as a radioactive tracer. 18 F]Florbetaben (Neuraceq), [ 18 F] florbetapir (Amyvid), or [ 18 Magnetic resonance imaging (MRI), such as amyloid PET imaging using [F]flutametamol (Vizamyl) as a radiotracer (e.g., longitudinal amyloid PET), or e.g., [ 18 The treatment and / or delay of early Alzheimer's disease is determined by a change from baseline in one or more biomarkers of Alzheimer's disease as assessed by Tau-PET imaging using the [F]MK-6240 Tau-PET radiotracer. In certain embodiments, the treatment and / or delay of early Alzheimer's disease is determined by tau and / or amyloid positron emission tomography (PET) imaging. In certain embodiments, the treatment and / or delay of early Alzheimer's disease is determined by a change from baseline in an individual's speech, for example, using the Winterlight Labs Speech Assessment (WLSA).

[0169] In certain embodiments, the methods of the present disclosure include performing a genomic assessment to determine whether an individual is an APOE e4 carrier or non-carrier and / or whether they have one or more of a TREM2 variant, a CD33 variant, a TMEM106b variant, or a CLUSTERIN variant. In certain embodiments, the methods of the present disclosure include performing an amyloid or tau blood test on a sample obtained from the individual (e.g., an individual with early Alzheimer's disease) before treatment with the methods of the present disclosure. In certain embodiments, the methods of the present disclosure include determining that the individual (e.g., an individual with early Alzheimer's disease) has a positive amyloid or tau blood test before treatment with the methods of the present disclosure. In certain embodiments, the methods of the present disclosure include performing an amyloid or tau blood test on a sample obtained from the individual before and after the individual is administered one or more doses of an anti-TREM2 antibody. In some embodiments, the amyloid or blood test is the PrecivityAD™-Aβ blood test, or a test for phosphorylated tau 217 (p-tau217), a test for phosphorylated tau 181 (p-tau181), a test for neurofilament light, or a test for the Aβ42 / 40 ratio. In some embodiments, the amyloid or tau blood test is an immunoassay-based test for the Aβ42 / 40 ratio (see, e.g., Yamashita et al., Alzheimer's Association International Conference (2019) 15(7S), part 29, P4-548). In some embodiments, the amyloid or tau blood test is a mass spectrometry-based test for the Aβ42 / 40 ratio (see, e.g., Schindler et al., Neurology (2019) 93(17)). In some embodiments, the amyloid or tau blood test is an immunoassay-based test for p-tau217 (see, e.g., Palmqvist et al., JAMA (2020) 324(8):772-781).

[0170] Nasu-Hakora disease Nasu-Hakola disease (NHD), sometimes alternatively referred to as lipomembranous polycystic osseous dysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare genetic leukodystrophy characterized by progressive presenile dementia with recurrent fractures due to multicystic bone cysts in the lower and upper extremities. The course of NHD disease is generally divided into four stages: the latent stage, the osteopathic stage, the early neuropathic stage, and the late neuropathic stage. After normal development in early childhood (latent stage), NHD begins to manifest in adolescence or young adulthood (typical age of onset: 20–30 years) with pain in the hands, wrists, ankles, and feet. Patients then begin to suffer from recurrent fractures due to multicystic bone lesions and osteoporotic lesions in the extremities (osseous stage). In the third or fourth decade of life (early neurological stage), patients exhibit significant personality changes characteristic of frontal lobe syndrome (e.g., euphoria, difficulty concentrating, impaired judgment, and social inhibition). Patients also typically suffer from progressive memory loss. Epileptic seizures are also frequently observed. Finally (late neurological stage), patients progress to severe dementia, are unable to speak or move, and die, usually by the age of 50.

[0171] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure can treat and / or delay Nasu-Hakola disease (NHD). In some embodiments, administration of an anti-TREM2 antibody can promote or increase microglial cell activity in an individual with NHD, for example, compared to baseline. In some embodiments, administration of an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with NHD.

[0172] Adrenoleukodystrophy (ALD) and cerebral adrenoleukodystrophy (cALD) Adrenoleukodystrophy (ALD) is a rare, X-linked, fatal neurodegenerative disease. Patients with ALD have mutations in the ABCD1 gene, which encodes the peroxisomal ATP-binding cassette transporter. The disease is characterized by a reduced ability to degrade very long-chain fatty acids (VLCFAs), such as hexacosanoic acid, leading to their accumulation in the brain, adrenal tissue, and plasma (Moser, Hugo W et al., (2005). Jama 294.24:3131-3134). ALD manifests as a rapidly progressive form of inflammatory demyelination, leading to progressive neurological decline, a vegetative state, and death within 2–3 years. Blood-brain barrier damage, leading to leukocyte migration into the brain, is involved in its progression (Moser, Hugo W et al., (2005). Jama 294.24:3131-3134). The most severe neurological manifestation of ALD is cerebral adrenoleukodystrophy (cALD), in which progressive inflammatory demyelination coincides with blood-brain barrier dysfunction, increased MMP9 expression, and alterations in endothelial tight junction proteins and adhesion molecules (Musolino, Patricia L et al., (2015). Brain: a journal of neurology vol. 138, Pt 11:3206-20).

[0173] In some embodiments, ALD and cALD can be treated and / or delayed by administering an anti-TREM2 antibody of the present disclosure. In some embodiments, administering an anti-TREM2 antibody can promote or increase microglial activity in an individual with ALD or cALD, for example, compared to baseline. In some embodiments, administering an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with ALD or cALD.

[0174] Amyotrophic lateral sclerosis (ALS) As used herein, amyotrophic lateral sclerosis (ALS), or motor neuron disease, or Lou Gehrig's disease, are used interchangeably and refer to a debilitating disease with various etiologies characterized by rapidly progressive weakness, muscle atrophy and fasciculations, muscle spasticity, difficulty speaking (dysarthria), difficulty swallowing (dysphagia), and difficulty breathing (dyspnea).

[0175] Progranulin plays a role in ALS (Schymick, JC et al., (2007) J Neurol Neurosurg Psychiatry.; 78:754-6) and has been shown to prevent damage caused by ALS-causing proteins such as TDP-43 (Laird, AS et al., (2010). PLoS ONE 5:e13368). It has also been demonstrated that pro-NGF induces p75-mediated death of oligodendrocytes and corticospinal neurons after spinal cord injury (Beatty et al., Neuron (2002), 36, pp. 375-386; Giehl et al., Proc. Natl. Acad. Sci USA (2004), 101, pp. 6226-30).

[0176] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure can treat and / or delay ALS. In some embodiments, administration of an anti-TREM2 antibody can promote or increase microglial cell activity in an individual with ALS, for example, compared to baseline. In some embodiments, administration of an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with ALS.

[0177] In some embodiments, treating and / or slowing ALS progression is determined by changes from baseline in brain atrophy, brain connectivity, brain free water, and / or brain inflammation. Any method known in the art can be used to measure brain atrophy, brain connectivity, brain free water, and / or brain inflammation, including, but not limited to, MRI. In certain embodiments, brain atrophy is measured using structural MRI. In certain embodiments, brain free water and / or brain inflammation is measured using diffusion tensor imaging (DTI). In some embodiments, treating and / or slowing ALS progression is determined by changes from baseline in one or more markers of neurodegeneration, one or more markers of glial activity, progranulin, and / or one or more markers of TDP-43 pathology.

[0178] Parkinson's disease Parkinson's disease (PD), sometimes called idiopathic or primary Parkinson's syndrome, hypokinetic rigidity syndrome (HRS), or paralysis agitans, is a neurodegenerative brain disorder that affects motor system control. The gradual death of dopamine-producing cells in the brain leads to the primary symptoms of Parkinson's disease. Parkinson's disease is often diagnosed in people over the age of 50. Parkinson's disease is idiopathic (has no known cause) in most people. However, genetic factors also play a role in this disease.

[0179] Symptoms of Parkinson's disease include, but are not limited to, tremors in the hands, arms, legs, jaw, and face; muscle rigidity of the limbs and trunk; slowness of movement (bradykinesia), as well as posture; difficulty walking; neuropsychiatric disturbances, changes in speech or behavior, depression, anxiety, pain, psychosis, dementia, hallucinations, and sleep disorders.

[0180] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure can treat and / or delay PD. In some embodiments, administration of an anti-TREM2 antibody can promote or increase microglial cell activity in an individual with PD, for example, compared to baseline. In some embodiments, administration of an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with PD.

[0181] Huntington's disease Huntington's disease (HD) is an inherited neurodegenerative disorder caused by autosomal dominant mutations in the huntingtin gene (HTT). Expansion of a cytokine-adenine-guanine (CAG) triplet repeat within the huntingtin gene leads to the production of a mutant huntingtin protein (Htt) encoded by the gene. This mutant huntingtin protein (mHtt) is toxic and causes neuronal death. Symptoms of Huntington's disease can appear at any age but most commonly appear between the ages of 35 and 44.

[0182] Symptoms of Huntington's disease include, but are not limited to, impaired motor control, seizures, irregular movements (chorea), abnormal eye movements, problems with balance, seizures, difficulty chewing, difficulty swallowing, cognitive impairment, changes in speech, memory problems, difficulty thinking, insomnia, fatigue, dementia, personality changes, depression, anxiety, and obsessive-compulsive behaviors.

[0183] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure can treat and / or delay HD. In some embodiments, administration of an anti-TREM2 antibody can promote or increase microglial cell activity in an individual with HD, for example, compared to baseline. In some embodiments, administration of an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with HD.

[0184] Tauopathy Tauopathies, or tauopathies, are a group of neurodegenerative diseases caused by the aggregation of the microtubule-associated protein tau in the brain. Alzheimer's disease (AD) is the most well-known tauopathic disease and involves the accumulation of tau protein in neurons in an insoluble form as insoluble neurofibrillary tangles (NFTs). Other tauopathy diseases and disorders include progressive supranuclear palsy, dementia pugilistica (chronic traumatic encephalopathy), frontotemporal dementia, and chromosome 17-linked parkinsonism, Ritiko-Bodig disease (Parkinsonism-dementia complex of Guam), neurofibrillary tangle senile dementia, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous cerebral sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Pick's disease, corticobasal degeneration, argyrophilic grain disease (AGD), Huntington's disease, frontotemporal dementia, and frontotemporal lobar degeneration.

[0185] In some embodiments, administering an anti-TREM2 antibody of the present disclosure can treat and / or delay a tauopathy disease. In some embodiments, administering an anti-TREM2 antibody can promote or increase microglial cell activity, for example, compared to baseline, in an individual with a tauopathy disease. In some embodiments, administering an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with a tauopathy disease.

[0186] Multiple sclerosis Multiple sclerosis (MS) can also be called disseminated sclerosis or disseminated encephalomyelitis. MS is an inflammatory disease in which the fatty myelin sheath surrounding the axons in the brain and spinal cord is damaged, resulting in demyelination and scarring and a wide range of signs and symptoms. MS affects the ability of nerve cells in the brain and spinal cord to communicate effectively with each other. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are contained within an insulating substance called myelin. In MS, the body's immune system attacks and damages the myelin. When myelin is lost, axons can no longer conduct signals effectively. MS onset usually occurs in young adults and is more common in women.

[0187] Symptoms of MS include, but are not limited to, altered sensations such as decreased sensitivity or tingling, pins and needles or numbness such as hypoesthesia and dysesthesia, muscle weakness, clonus, muscle spasms, difficulty moving, coordination and balance disorders such as ataxia, difficulty speaking such as dysarthria or difficulty swallowing such as dysphagia, visual disturbances such as nystagmus, optic neuritis including flashing lights and diplopia, fatigue, acute or chronic pain, and bladder-rectum disorders, varying degrees of cognitive impairment, emotional symptoms of depression or anxious mood, Uhthoff phenomenon, which is a worsening of existing symptoms due to exposure to temperatures higher than normal ambient temperature, and Lhermitte sign, which is an electrical sensation down the back when bending the neck.

[0188] In some embodiments, administering an anti-TREM2 antibody of the present disclosure can treat and / or delay MS. In some embodiments, administering an anti-TREM2 antibody can promote or increase microglial cell activity in an individual with MS, for example, compared to baseline. In some embodiments, administering an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with MS.

[0189] Traumatic brain injury and spinal cord injury Traumatic brain injury (TBI) may also be known as intracranial injury. Traumatic brain injury occurs when an external force traumatically damages the brain. Traumatic brain injury can be classified based on severity, mechanism (closed or penetrating head injury), or other characteristics (e.g., occurring in a specific location or over a widespread area).

[0190] In some embodiments, TBI can be treated by administering an anti-TREM2 antibody of the present disclosure. In some embodiments, administering an anti-TREM2 antibody can promote or increase microglial cell activity in an individual with TBI, for example, compared to baseline. In some embodiments, administering an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with TBI.

[0191] Spinal cord injury (SCI) includes any damage to the spinal cord that results from trauma rather than disease. Depending on where the spinal cord and nerve roots are damaged, symptoms can vary widely, from pain to paralysis to urinary incontinence. Spinal cord injuries are described at various levels, from an "incomplete" injury, which can range from having no effect on the patient, to a "complete" injury, which means total loss of function.

[0192] In some embodiments, SCI can be treated by administering an anti-TREM2 antibody of the present disclosure. In some embodiments, administering an anti-TREM2 antibody can promote or increase microglial cell activity in an individual with SCI, for example, compared to baseline. In some embodiments, administering an anti-TREM2 antibody can induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with SCI.

[0193] Adult-onset leukoencephalopathy (ALSP) and childhood-onset leukoencephalopathy with axonal spheroids and pigmented glia Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and childhood-onset leukoencephalopathy are rare and fatal neurological disorders that alter the "white matter" of the central nervous system in affected individuals (Freeman et al. (2009) "Adult onset leukodystrophy with neuroaxonal spheroids: Clinical, neuroimaging, and neuropathologic observations." Brain Pathol. 19(1):39-47. PMID:18422757; Rademakers et al. (2011) "Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids." Nat Genet. 44(2):200-205. PMID:22197934; Oosterhof et al. (2019) "Homozygous mutations in CSF1R Causes a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia.” Am J Hum Genet. 104(5):936-947. PMID:30982608). ALSP was previously considered to be two separate conditions: hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and familial pigmented orthochromatic leukoencephalopathy (POLD). However, given that patients with both HDLS and POLD may have pigmented glial cells and spheroids, HDLS and POLD have been deemed part of the same spectrum of disorders encompassed by ALSP (Nicholson et al. (2013) “CSF1R mutations link POLD and HDLS as a single disease entity.” Neurology 80(11):1033-1040. PMID:23408870).In some embodiments, ALSP or childhood-onset leukoencephalopathy can be treated by administering an anti-TREM2 antibody of the present disclosure.

[0194] Clinical evaluation In some embodiments of the methods of treatment provided herein, the methods include determining the score of one or more clinical assessments of the individual before and after the individual receives one or more doses of an anti-TREM2 antibody. In some embodiments, the clinical assessment is selected from a Mini-Mental State Examination (MMSE) score, a Clinical Dementia Rating-Global Score (CDR-GS), a Clinical Dementia Rating Sum of Boxes (CDR-SB), or a Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). In some embodiments, administration of an antibody of the disclosure results in an improvement in one or more clinical assessment scores compared to before administration of the anti-TREM2 antibody, e.g., compared to the score on one or more clinical assessments about 42 days to less than 1 day before administration of the anti-TREM2 antibody (e.g., any of 42 days, 41 days, 40 days, 39 days, 38 days, 37 days, 36 days, 35 days, 34 days, 33 days, 32 days, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less than 1 day).

[0195] Pharmaceutical Dosage The antibodies (and any additional therapeutic agents) provided herein can be administered by any suitable means, including parenteral, intrapulmonary, intranasal, intralesional, intracerebrospinal, intracranial, intrathecal, intrasynovial, intrathecal, oral, topical, or inhalation routes. Parenteral infusions include intravenous, intraarterial, intraarticular, intraperitoneal, or subcutaneous administration, either intramuscularly, as a bolus, or by continuous infusion over a period of time. In some embodiments, administration is intravenous. In some embodiments, administration is subcutaneous. Dosing can be by any suitable route, for example, by injection, such as intravenous or subcutaneous injection, depending in part on whether administration is brief or chronic. Various dosing schedules are contemplated herein, including, but not limited to, single or multiple doses at various time points, bolus administration, and pulse infusion.

[0196] The antibodies provided herein are formulated, dispensed, and administered in a manner consistent with good medical practice. Factors to consider in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the scheduling of administration, and other factors known to physicians. The antibodies need not be formulated with one or more agents currently used to prevent or treat the disorder of interest, but are optionally formulated with them. The effective amount of such other agents depends on the amount of antibody present in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used in the same dosages using the routes of administration as described herein, or at about 1-99% of the dosages described herein, or at any dosage and by any route empirically / clinically determined to be appropriate.

[0197] The dosage of a particular anti-TREM2 antibody may be empirically determined in an individual receiving one or more administrations of the anti-TREM2 antibody. The individual may be given gradually increasing doses of the anti-TREM2 antibody. To assess the effectiveness of an anti-TREM2 antibody, clinical symptoms of any disease, disorder, injury, or condition of the disclosure (e.g., dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, adrenoleukodystrophy (ALD), cerebral adrenoleukodystrophy (cALD), cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, demyelinating disorders, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), and tauopathy) can be monitored.

[0198] The appropriate dosage of the antibodies of the invention (when used alone or in combination with one or more other additional therapeutic agents) for the prevention or treatment of disease or injury will depend on the type of disease or injury being treated, the type of antibody, the severity and course of the disease or injury, whether the antibody is being administered for prophylactic or therapeutic purposes, previous treatments, the patient's clinical 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.

[0199] In some aspects, the methods of the present disclosure comprise intravenously administering to an individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg. In some embodiments, the dose is about 15 mg / kg to about 60 mg / kg. In some embodiments, the dose is about 15 mg / kg to about 50 mg / kg. In some embodiments, the dose is about 20 mg / kg to about 50 mg / kg. In some embodiments, the dose is about 20 mg / kg to about 60 mg / kg. In some embodiments, the dose is about 15 mg / kg to about 20 mg / kg. In some embodiments, the dose is about 45 mg / kg to about 50 mg / kg. In some embodiments, the dose is about 50 mg / kg to about 60 mg / kg. In some embodiments, the dose is about 20 mg / kg to about 30 mg / kg. In some embodiments, the dose is about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, or about 60 mg / kg.

[0200] In some embodiments, doses are administered intermittently, for example, approximately once every week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. In some embodiments, doses are administered q1w, q2w, q3w, q4w, q5w, q6w, q7w, or q8w.

[0201] In some embodiments, the dosing frequency is q1w or greater (i.e., the dose is administered once every week or less frequently). In some embodiments, the dosing frequency is q2w or greater (i.e., the dose is administered once every two weeks or less frequently). In some embodiments, the dosing frequency is q3w or greater (i.e., the dose is administered once every three weeks or less frequently). In some embodiments, the dosing frequency is q4w or greater (i.e., the dose is administered once every four weeks or less frequently). In some embodiments, the dosing frequency is q5w or greater (i.e., the dose is administered once every five weeks or less frequently). In some embodiments, the dosing frequency is q6w or greater (i.e., the dose is administered once every six weeks or less frequently). In some embodiments, the dosing frequency is q7w or greater (i.e., the dose is administered once every 7 weeks or less frequently). In some embodiments, the dosing frequency is q8w or greater (i.e., the dose is administered once every 8 weeks or less frequently). In some embodiments, the dosing frequency is once every 2 weeks. In some embodiments, the dosing frequency is once every 3 weeks. In some embodiments, the dosing frequency is once every 4 weeks. In some embodiments, the dosing frequency is once every 5 weeks. In some embodiments, the dosing frequency is once every 6 weeks.

[0202] In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of at least about 15 mg / kg once weekly. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 15 mg / kg once weekly. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 20 mg / kg once weekly. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 25 mg / kg once weekly. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 30 mg / kg once weekly. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 35 mg / kg once weekly. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 40 mg / kg once weekly. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 45 mg / kg once weekly. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 50 mg / kg once weekly. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 55 mg / kg once weekly. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 60 mg / kg once weekly.

[0203] In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of at least about 15 mg / kg once every two weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 15 mg / kg once every two weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 20 mg / kg once every two weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 25 mg / kg once every two weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 30 mg / kg once every two weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 35 mg / kg once every two weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 40 mg / kg once every two weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 45 mg / kg once every two weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 50 mg / kg once every two weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 55 mg / kg once every two weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 60 mg / kg once every two weeks.

[0204] In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of at least about 15 mg / kg once every three weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 15 mg / kg once every three weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 20 mg / kg once every three weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 25 mg / kg once every three weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 30 mg / kg once every three weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 35 mg / kg once every three weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 40 mg / kg once every three weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 45 mg / kg once every three weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 50 mg / kg once every three weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 55 mg / kg once every three weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 60 mg / kg once every three weeks.

[0205] In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of at least about 15 mg / kg once every four weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 15 mg / kg once every four weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 20 mg / kg once every four weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 25 mg / kg once every four weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 30 mg / kg once every four weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 35 mg / kg once every four weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 40 mg / kg once every four weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 45 mg / kg once every four weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 50 mg / kg once every four weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 55 mg / kg once every four weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 60 mg / kg once every four weeks.

[0206] In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of at least about 15 mg / kg once every five weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 15 mg / kg once every five weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 20 mg / kg once every five weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 25 mg / kg once every five weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 30 mg / kg once every five weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 35 mg / kg once every five weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 40 mg / kg once every five weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 45 mg / kg once every five weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 50 mg / kg once every five weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 55 mg / kg once every five weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 60 mg / kg once every five weeks.

[0207] In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of at least about 15 mg / kg once every six weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 15 mg / kg once every six weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 20 mg / kg once every six weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 25 mg / kg once every six weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 30 mg / kg once every six weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 35 mg / kg once every six weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 40 mg / kg once every six weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 45 mg / kg once every six weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 50 mg / kg once every six weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 55 mg / kg once every six weeks. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 60 mg / kg once every six weeks.

[0208] In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of at least about 15 mg / kg once every 7 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 15 mg / kg once every 7 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 20 mg / kg once every 7 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 25 mg / kg once every 7 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 30 mg / kg once every 7 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 35 mg / kg once every 7 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 40 mg / kg once every 7 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 45 mg / kg once every 7 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 50 mg / kg once every seven weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 55 mg / kg once every seven weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 60 mg / kg once every seven weeks.

[0209] In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of at least about 15 mg / kg once every 8 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 15 mg / kg once every 8 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 20 mg / kg once every 8 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 25 mg / kg once every 8 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 30 mg / kg once every 8 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 35 mg / kg once every 8 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 40 mg / kg once every 8 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 45 mg / kg once every 8 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 50 mg / kg once every 8 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 55 mg / kg once every 8 weeks. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 60 mg / kg once every 8 weeks.

[0210] In certain embodiments, each dose of the anti-TREM2 antibody is administered intravenously to an individual over about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of at least about 15 mg / kg over about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 15 mg / kg over about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 20 mg / kg over about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 25 mg / kg over about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 30 mg / kg over about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 35 mg / kg over about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 40 mg / kg over 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 45 mg / kg over about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 50 mg / kg over about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 55 mg / kg over about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 60 mg / kg over about 60 minutes.

[0211] In certain embodiments, each dose of the anti-TREM2 antibody is administered intravenously to an individual over at least about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of at least about 15 mg / kg over at least about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of at least about 15 mg / kg over at least about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 20 mg / kg over at least about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 25 mg / kg over at least about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 30 mg / kg over at least about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 35 mg / kg over at least about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to an individual at a dose of about 40 mg / kg over at least about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 45 mg / kg over at least about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 50 mg / kg over at least about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 55 mg / kg over at least about 60 minutes. In some embodiments, the anti-TREM2 antibody is administered to the individual at a dose of about 60 mg / kg over at least about 60 minutes.

[0212] In certain embodiments, at least 1 dose, at least 2 doses, at least 3 doses, at least 4 doses, at least 5 doses, at least 6 doses, at least 7 doses, at least 8 doses, at least 9 doses, at least 10 doses, at least 11 doses, at least 12 doses, at least 13 doses, at least 14 doses, at least 15 doses, at least 16 doses, at least 17 doses, at least 18 doses, at least 19 doses, or at least 20 doses of an anti-TREM2 antibody are administered intravenously to an individual.

[0213] In some embodiments, the individual is incubated for at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 11 weeks, at least about 12 weeks, at least about 13 weeks, at least about 14 weeks, at least about 15 weeks, at least about 16 weeks, at least about 17 weeks, at least about 18 weeks, at least about 19 weeks, at least about 20 weeks, at least about 21 weeks, at least about 22 weeks, at least about 23 weeks, at least about 24 weeks, at least about 25 weeks, at least about 26 weeks, at least about 27 weeks, at least about 28 weeks, at least about 29 weeks, at least about 30 weeks, at least about 31 weeks, at least about 32 weeks, at least about 33 weeks, at least about 34 weeks, at least about 35 weeks, at least about 36 weeks, at least about 37 weeks, at least about 38 weeks, at least about 39 weeks, at least about 40 weeks, at least about 41 weeks, at least about 42 weeks, at least about 43 weeks, at least about 44 weeks, at least about 45 weeks, at least about 46 weeks, at least about 47 weeks, at least about 48 weeks, at least about 49 weeks, at least about 50 weeks, at least about 51 weeks, at least about 52 weeks, at least about 53 weeks, at least about 54 weeks, at least about 55 weeks, at least about 56 weeks, at least about 57 weeks, at least about 58 weeks, at least about 59 weeks, at least about 60 weeks, at least about 61 weeks, at least about 62 weeks, at least about 63 weeks, at least about 64 weeks weeks, at least about 28 weeks, at least about 29 weeks, at least about 30 weeks, at least about 31 weeks, at least about 32 weeks, at least about 33 weeks, at least about 34 weeks, at least about 35 weeks, at least about 36 weeks, at least about 37 weeks, at least about 38 weeks, at least about 39 weeks, at least about 40 weeks, at least about 41 weeks, at least about 42 weeks, at least about 43 weeks, at least about 44 weeks, at least about 45 weeks, at least about 46 weeks, at least about 47 weeks, at least about 48 weeks, at least about 49 weeks, at least about 50 weeks, at least about 51 weeks, or at least about 52 weeks in length.

[0214] In some embodiments, the individual is treated with steroids for up to 4 weeks, up to 5 weeks, up to 6 weeks, up to 7 weeks, up to 8 weeks, up to 9 weeks, up to 10 weeks, up to 11 weeks, up to 12 weeks, up to 13 weeks, up to 14 weeks, up to 15 weeks, up to 16 weeks, up to 17 weeks, up to 18 weeks, up to 19 weeks, up to 20 weeks, up to 21 weeks, up to 22 weeks, up to 23 weeks, up to 24 weeks, up to 25 weeks, up to 26 weeks, up to 27 weeks, up to 28 weeks, up to Treatment is for a treatment period of 29 weeks, up to 30 weeks, up to 31 weeks, up to 32 weeks, up to 33 weeks, up to 34 weeks, up to 35 weeks, up to 36 weeks, up to 37 weeks, up to 38 weeks, up to 39 weeks, up to 40 weeks, up to 41 weeks, up to 42 weeks, up to 43 weeks, up to 44 weeks, up to 45 weeks, up to 46 weeks, up to 47 weeks, up to 48 weeks, up to 49 weeks, up to 50 weeks, up to 51 weeks, or up to 52 weeks in length.

[0215] In some embodiments, the anti-TREM2 antibody is administered on the first day of the treatment period and every week thereafter. In some embodiments, the anti-TREM2 antibody is administered on the first day of the treatment period and every two weeks thereafter. In some embodiments, the anti-TREM2 antibody is administered on the first day of the treatment period and every three weeks thereafter. In some embodiments, the anti-TREM2 antibody is administered on the first day of the treatment period and every four weeks thereafter. In some embodiments, the anti-TREM2 antibody is administered on the first day of the treatment period and every five weeks thereafter. In some embodiments, the anti-TREM2 antibody is administered on the first day of the treatment period and every six weeks thereafter. In some embodiments, the anti-TREM2 antibody is administered on the first day of the treatment period and every seven weeks thereafter. In some embodiments, the anti-TREM2 antibody is administered on the first day of the treatment period and every eight weeks thereafter.

[0216] An initial, larger loading dose, followed by one or more smaller doses may be administered. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.

[0217] Soluble TREM2 levels As used herein, "soluble TREM2" or "sTREM2" refers to any form of TREM2 that results from processing, e.g., cleavage, of the TREM2 protein, resulting in a soluble, processed form of TREM2, e.g., as described herein in the "TREM2 Protein" section.

[0218] In some aspects, the methods of the disclosure comprise intravenously administering an anti-TREM2 antibody to an individual, wherein administering the anti-TREM2 antibody to the individual results in a decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid compared to the level of soluble TREM2 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administering the anti-TREM2 antibody to the individual results in a decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid by at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100%, compared to the level of soluble TREM2 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administering an anti-TREM2 antibody to an individual results in at least about a 30% decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid compared to the level of soluble TREM2 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administering an anti-TREM2 antibody to an individual results in at least about a 40% decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid compared to the level of soluble TREM2 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administering an anti-TREM2 antibody to an individual results in at least about a 50% decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid compared to the level of soluble TREM2 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administering an anti-TREM2 antibody to an individual results in at least about a 60% decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid compared to the level of soluble TREM2 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody.

[0219] In some embodiments, a decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid compared to the level of soluble TREM2 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present from about 2 to about 12 days (e.g., any of days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) after administration of the antibody. In some embodiments, a decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid compared to the level of soluble TREM2 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present for at least about 2 days after administration of the antibody. In some embodiments, a decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid compared to the level of soluble TREM2 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present for at least about 12 days after administration of the antibody. In some embodiments, a decrease in the level of soluble TREM2 in the cerebrospinal fluid of the individual is present about day 2 after administration of the anti-TREM2 antibody compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the antibody. In some embodiments, a decrease in the level of soluble TREM2 in the cerebrospinal fluid of the individual is present about day 12 after administration of the antibody compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.

[0220] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in a reduction in the level of soluble TREM2 in the cerebrospinal fluid of at least about 30% of individuals on day 2 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in a reduction in the level of soluble TREM2 in the cerebrospinal fluid of at least about 40% of individuals on day 2 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in a reduction in the level of soluble TREM2 in the cerebrospinal fluid of at least about 30% of individuals on day 2 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in a reduction in the level of soluble TREM2 in the cerebrospinal fluid of at least about 40% of individuals on day 2 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 45 mg / kg results in a reduction in the level of soluble TREM2 in the cerebrospinal fluid of at least about 50% of individuals on day 2 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 60 mg / kg results in a reduction in the level of soluble TREM2 in the cerebrospinal fluid of at least about 55% of individuals on day 2 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.

[0221] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in a decrease in the level of soluble TREM2 in the cerebrospinal fluid of at least about 30% of individuals on day 12 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in a decrease in the level of soluble TREM2 in the cerebrospinal fluid of at least about 40% of individuals on day 12 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in a decrease in the level of soluble TREM2 in the cerebrospinal fluid of at least about 30% of individuals on day 12 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in a decrease in the level of soluble TREM2 in the cerebrospinal fluid of at least about 40% of individuals on day 12 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 45 mg / kg results in a decrease in the level of soluble TREM2 in the cerebrospinal fluid of at least about 30% of individuals on day 12 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 45 mg / kg results in a decrease in the level of soluble TREM2 in the cerebrospinal fluid of at least about 40% of individuals on day 12 after administration of the antibody, compared to the level of soluble TREM2 in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 60 mg / kg results in a reduction in the level of soluble TREM2 in the cerebrospinal fluid of an individual by at least about 40% 12 days after administration of the antibody compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 60 mg / kg results in a reduction in the level of soluble TREM2 in the cerebrospinal fluid of an individual by at least about 50% on day 12 after administration of the antibody compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.

[0222] In some embodiments, the level of soluble TREM2 in the individual's cerebrospinal fluid is compared to the level of soluble TREM2 in the individual's cerebrospinal fluid about 42 days to less than 1 day (e.g., any of 42 days, 41 days, 40 days, 39 days, 38 days, 37 days, 36 days, 35 days, 34 days, 33 days, 32 days, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less than 1 day) prior to administration of the anti-TREM2 antibody. In some embodiments, the level of soluble TREM2 in the individual's cerebrospinal fluid is compared to the level of soluble TREM2 in the individual's cerebrospinal fluid at least about 4 days prior to administration of the anti-TREM2 antibody.

[0223] The level of sTREM2 in an individual's cerebrospinal fluid can be measured using any method known in the art, such as ELISA, immunoassay, immunoblot, and mass spectrometry.

[0224] In certain embodiments, the level of sTREM2 in an individual's cerebrospinal fluid is measured by immunoassay using electrochemiluminescence methodology. For example, in some embodiments, an anti-human TREM2 antibody is diluted in coating buffer and immobilized on a 96-well microtiter sample plate. After blocking and washing the plate, endogenous quality control and test samples are diluted in assay buffer, dispensed onto the sample plate, and incubated. A second anti-human TREM2 antibody that binds to a different epitope than the first antibody is then added as a capture antibody. The plate is then washed, and sulfo-tagged streptavidin is added and incubated, followed by the addition of MSD Read Buffer T. The concentration of sTREM2 (i.e., the level of sTREM2) is determined on a standard curve obtained by relative light units versus concentration. The calibration curve is plotted as 1 / y 2 A four-parameter curve fit with weighting is used to generate the range qualified by this method in human CSF from 0.400 ng / mL to 50.0 ng / mL.

[0225] Soluble CSF1R levels As used herein, "soluble CSF1R" or "sCSF1R" refers to any form of CSF1R that results from processing, e.g., cleavage, of the CSF1R protein, resulting in a soluble, processed form of CSF1R, e.g., as described herein in Example 2.

[0226] In some aspects, the methods of the present disclosure include intravenously administering an anti-TREM2 antibody to an individual, wherein administering the anti-TREM2 antibody to the individual results in an increase in the level of soluble CSF1R in the cerebrospinal fluid of the individual compared to the level of soluble CSF1R in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of soluble CSF1R in the individual's cerebrospinal fluid of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 100%, compared to the level of soluble CSF1R in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of soluble CSF1R in the individual's cerebrospinal fluid of at least about 5%, compared to the level of soluble CSF1R in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of soluble CSF1R in the individual's cerebrospinal fluid by at least about 10% compared to the level of soluble CSF1R in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of soluble CSF1R in the individual's cerebrospinal fluid by at least about 15% compared to the level of soluble CSF1R in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of soluble CSF1R in the individual's cerebrospinal fluid by at least about 20% compared to the level of soluble CSF1R in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of soluble CSF1R in the individual's cerebrospinal fluid by at least about 25% compared to the level of soluble CSF1R in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody.

[0227] In some embodiments, an elevated level of soluble CSF1R in the individual's cerebrospinal fluid compared to the level of soluble CSF1R in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present from about 2 to about 12 days (e.g., any of days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) after administration of the antibody. In some embodiments, an elevated level of soluble CSF1R in the individual's cerebrospinal fluid compared to the level of soluble CSF1R in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present for at least about 2 days after administration of the antibody. In some embodiments, an elevated level of soluble CSF1R in the individual's cerebrospinal fluid compared to the level of soluble CSF1R in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present for at least about 12 days after administration of the antibody. In some embodiments, an elevated level of soluble CSF1R in the cerebrospinal fluid of the individual is present about day 2 after administration of the anti-TREM2 antibody compared to the level of soluble CSF1R in the cerebrospinal fluid of the individual before administration of the antibody. In some embodiments, an elevated level of soluble CSF1R in the cerebrospinal fluid of the individual is present about day 12 after administration of the anti-TREM2 antibody compared to the level of soluble CSF1R in the cerebrospinal fluid of the individual before administration of the antibody.

[0228] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in an increase in the level of soluble CSF1R in the cerebrospinal fluid of at least about 5% of individuals on day 2 after administration of the antibody, compared to the level of soluble CSF1R in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in an increase in the level of soluble CSF1R in the cerebrospinal fluid of at least about 10% of individuals on day 2 after administration of the antibody, compared to the level of soluble CSF1R in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 45 mg / kg results in an increase in the level of soluble CSF1R in the cerebrospinal fluid of at least about 15% of individuals on day 2 after administration of the antibody, compared to the level of soluble CSF1R in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 60 mg / kg results in an increase in the level of soluble CSF1R in the cerebrospinal fluid of at least about 25% of individuals on day 2 after administration of the antibody, compared to the level of soluble CSF1R in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody.

[0229] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in an increase in the level of soluble CSF1R in the cerebrospinal fluid of at least about 5% of individuals on day 12 after administration of the antibody, compared to the level of soluble CSF1R in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in an increase in the level of soluble CSF1R in the cerebrospinal fluid of at least about 10% of individuals on day 12 after administration of the antibody, compared to the level of soluble CSF1R in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 45 mg / kg results in an increase in the level of soluble CSF1R in the cerebrospinal fluid of at least about 1% of individuals on day 12 after administration of the antibody, compared to the level of soluble CSF1R in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 60 mg / kg results in an increase in the level of soluble CSF1R in the cerebrospinal fluid of at least about 10% of individuals 12 days after administration of the antibody compared to the level of soluble CSF1R in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody.

[0230] In some embodiments, the level of soluble CSF1R in the individual's cerebrospinal fluid is compared to the level of soluble CSF1R in the individual's cerebrospinal fluid about 42 days to less than 1 day (e.g., any of 42 days, 41 days, 40 days, 39 days, 38 days, 37 days, 36 days, 35 days, 34 days, 33 days, 32 days, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less than 1 day) prior to administration of the anti-TREM2 antibody. In some embodiments, the level of soluble CSF1R in the individual's cerebrospinal fluid is compared to the level of soluble CSF1R in the individual's cerebrospinal fluid at least about 4 days prior to administration of the anti-TREM2 antibody.

[0231] The level of sCSF1R in an individual's cerebrospinal fluid can be measured using any method known in the art, such as ELISA (e.g., an ELISA assay from R&D Systems), immunoassay, immunoblot, and mass spectrometry. In certain embodiments, the level of sCSF1R in an individual's cerebrospinal fluid is measured with an ELISA assay from R&D Systems, which has a qualification range of 125 pg / mL to 4000 pg / mL in 100% human CSF.

[0232] YKL40 level In some aspects, the methods of the present disclosure include intravenously administering an anti-TREM2 antibody to an individual, wherein administration of the anti-TREM2 antibody to the individual results in an increase in the level of YKL40 in the cerebrospinal fluid of the individual compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of YKL40 in the individual's cerebrospinal fluid of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, or at least about 200% compared to the level of YKL40 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody results in an increase in the level of YKL40 in the individual's cerebrospinal fluid by at least about 5% compared to the level of YKL40 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody results in an increase in the level of YKL40 in the individual's cerebrospinal fluid by at least about 10% compared to the level of YKL40 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody results in an increase in the level of YKL40 in the individual's cerebrospinal fluid by at least about 15% compared to the level of YKL40 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody results in an increase in the level of YKL40 in the individual's cerebrospinal fluid by at least about 20% compared to the level of YKL40 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of YKL40 in the cerebrospinal fluid of the individual by at least about 25% compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.In some embodiments, administration of an anti-TREM2 antibody results in an increase in the level of YKL40 in the individual's cerebrospinal fluid by at least about 30% compared to the level of YKL40 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody results in an increase in the level of YKL40 in the individual's cerebrospinal fluid by at least about 40% compared to the level of YKL40 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody results in an increase in the level of YKL40 in the individual's cerebrospinal fluid by at least about 50% compared to the level of YKL40 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody results in an increase in the level of YKL40 in the individual's cerebrospinal fluid by at least about 60% compared to the level of YKL40 in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody results in an increase in the level of YKL40 in the cerebrospinal fluid of the individual by at least about 70% compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody results in an increase in the level of YKL40 in the cerebrospinal fluid of the individual by at least about 80% compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody results in an increase in the level of YKL40 in the cerebrospinal fluid of the individual by at least about 90% compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.

[0233] In some embodiments, an elevated level of YKL40 in the cerebrospinal fluid of the individual compared to the level of YKL40 in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody is present from about 2 to about 12 days (e.g., any of days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) after administration of the antibody. In some embodiments, an elevated level of YKL40 in the cerebrospinal fluid of the individual compared to the level of YKL40 in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody is present for at least about 2 days after administration of the antibody. In some embodiments, an elevated level of YKL40 in the cerebrospinal fluid of the individual compared to the level of YKL40 in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody is present for at least about 12 days after administration of the antibody. In some embodiments, an elevated level of YKL40 in the cerebrospinal fluid of the individual is present about day 2 after administration of the anti-TREM2 antibody compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the antibody. In some embodiments, an elevated level of YKL40 in the cerebrospinal fluid of the individual is present about day 12 after administration of the anti-TREM2 antibody compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the antibody.

[0234] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in an increase in the level of YKL40 in the cerebrospinal fluid of at least about 1% of individuals on day 2 after administration of the antibody, compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in an increase in the level of YKL40 in the cerebrospinal fluid of at least about 10% of individuals on day 2 after administration of the antibody, compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 45 mg / kg results in an increase in the level of YKL40 in the cerebrospinal fluid of at least about 25% of individuals on day 2 after administration of the antibody, compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 60 mg / kg results in an increase in the level of YKL40 in the cerebrospinal fluid of at least about 75% of individuals on day 2 after administration of the antibody, compared to the level of YKL40 in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody.

[0235] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in an increase in the level of YKL40 in the cerebrospinal fluid of at least about 1% of individuals on day 12 after administration of the antibody, compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in an increase in the level of YKL40 in the cerebrospinal fluid of at least about 1% of individuals on day 12 after administration of the antibody, compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 45 mg / kg results in an increase in the level of YKL40 in the cerebrospinal fluid of at least about 1% of individuals on day 12 after administration of the antibody, compared to the level of YKL40 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 60 mg / kg results in an increase in the level of YKL40 in the cerebrospinal fluid of at least about 5% of individuals 12 days after administration of the antibody compared to the level of YKL40 in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody.

[0236] In some embodiments, the level of YKL40 in the individual's cerebrospinal fluid is compared to the level of YKL40 in the individual's cerebrospinal fluid about 42 days to less than 1 day (e.g., 42 days, 41 days, 40 days, 39 days, 38 days, 37 days, 36 days, 35 days, 34 days, 33 days, 32 days, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less than 1 day) prior to administration of the anti-TREM2 antibody. In some embodiments, the level of YKL40 in the individual's cerebrospinal fluid is compared to the level of YKL40 in the individual's cerebrospinal fluid at least about 4 days prior to administration of the anti-TREM2 antibody.

[0237] The level of YKL40 in an individual's cerebrospinal fluid can be measured using any method known in the art, such as ELISA, immunoassay, immunoblot, mass spectrometry, etc. In one particular embodiment, the level of YKL40 in an individual's cerebrospinal fluid is measured using an immunoassay from Roche.

[0238] IL-1RA levels In some aspects, the methods of the disclosure include intravenously administering an anti-TREM2 antibody to an individual, wherein administering the anti-TREM2 antibody to the individual results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administering the anti-TREM2 antibody increases the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 110%, at least about 120%, at least about 130%, at least about 140%, at least about 150%, at least about 160%, or at least about 170% of the IL-1RA level in the cerebrospinal fluid of the individual, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 10% compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 25% compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody, hi some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 50% compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 75%, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 100%, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 125%, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 150%, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 175%, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 200%, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 250%, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 300%, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.

[0239] In some embodiments, an increase in the level of IL-1RA in the individual's cerebrospinal fluid compared to the level of IL-1RA in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present from about 2 to about 12 days (e.g., any of days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) after administration of the antibody. In some embodiments, an increase in the level of IL-1RA in the individual's cerebrospinal fluid compared to the level of IL-1RA in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present for at least about 2 days after administration of the antibody. In some embodiments, an increase in the level of IL-1RA in the individual's cerebrospinal fluid compared to the level of IL-1RA in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present for at least about 12 days after administration of the antibody. In some embodiments, an increase in the level of IL-1RA in the individual's cerebrospinal fluid compared to the level of IL-1RA in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present about 2 days after administration of the antibody. In some embodiments, an increase in the level of IL-1RA in the cerebrospinal fluid of the individual is present about 12 days after administration of the anti-TREM2 antibody compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the antibody.

[0240] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in an increase in the level of IL-1RA in the cerebrospinal fluid of an individual by at least about 50% on day 2 after administration of the antibody, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in an increase in the level of IL-1RA in the cerebrospinal fluid of an individual by at least about 300% on day 2 after administration of the antibody, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 45 mg / kg results in an increase in the level of IL-1RA in the cerebrospinal fluid of an individual by at least about 125% on day 2 after administration of the antibody, compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 60 mg / kg results in an increase in the level of IL-1RA in the cerebrospinal fluid of the individual by at least about 125% on day 2 after administration of the antibody compared to the level of IL-1RA in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.

[0241] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in an increase in the level of IL-1RA in the cerebrospinal fluid of at least about 10% of individuals on day 12 after administration of the antibody, compared to the level of IL-1RA in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in an increase in the level of IL-1RA in the cerebrospinal fluid of at least about 175% of individuals on day 12 after administration of the antibody, compared to the level of IL-1RA in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 45 mg / kg results in an increase in the level of IL-1RA in the cerebrospinal fluid of at least about 25% of individuals on day 12 after administration of the antibody, compared to the level of IL-1RA in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 60 mg / kg results in an increase in the level of IL-1RA in the cerebrospinal fluid of at least about 25% of individuals 12 days after administration of the antibody compared to the level of IL-1RA in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody.

[0242] In some embodiments, the level of IL-1RA in the individual's cerebrospinal fluid is compared to the level of IL-1RA in the individual's cerebrospinal fluid about 42 days to less than 1 day (e.g., any of 42 days, 41 days, 40 days, 39 days, 38 days, 37 days, 36 days, 35 days, 34 days, 33 days, 32 days, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less than 1 day) prior to administration of the anti-TREM2 antibody. In some embodiments, the level of IL-1RA in the individual's cerebrospinal fluid is compared to the level of IL-1RA in the individual's cerebrospinal fluid at least about 4 days prior to administration of the anti-TREM2 antibody.

[0243] The level of IL-1RA in an individual's cerebrospinal fluid can be measured using any method known in the art, such as ELISA, immunoassay, immunoblot, and mass spectrometry, hi certain embodiments, the level of IL-1RA in an individual's cerebrospinal fluid is measured using an ECL immunoassay using the Meso Scale Discovery system.

[0244] Osteopontin levels In some aspects, the methods of the disclosure include intravenously administering an anti-TREM2 antibody to an individual, wherein administering the anti-TREM2 antibody to the individual results in an increase in the level of osteopontin in the cerebrospinal fluid of the individual compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the cerebrospinal fluid of the individual by any of at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 100%, at least about 105%, at least about 110%, at least about 115%, at least about 120%, at least about 125%, at least about 150%, at least about 175%, or at least about 200%, compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the individual's cerebrospinal fluid by at least about 25% compared to the level of osteopontin in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the individual's cerebrospinal fluid by at least about 30% compared to the level of osteopontin in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the individual's cerebrospinal fluid by at least about 40% compared to the level of osteopontin in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the individual's cerebrospinal fluid by at least about 50% compared to the level of osteopontin in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody.In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the individual's cerebrospinal fluid by at least about 60% compared to the level of osteopontin in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the individual's cerebrospinal fluid by at least about 70% compared to the level of osteopontin in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the individual's cerebrospinal fluid by at least about 80% compared to the level of osteopontin in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the individual's cerebrospinal fluid by at least about 90% compared to the level of osteopontin in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the cerebrospinal fluid of the individual by at least about 100% compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the cerebrospinal fluid of the individual by at least about 110% compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in an increase in the level of osteopontin in the cerebrospinal fluid of the individual by at least about 120% compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.

[0245] In some embodiments, an increase in the level of osteopontin in the individual's cerebrospinal fluid compared to the level of osteopontin in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present from about 2 days to about 12 days (e.g., any of days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12) after administration of the antibody. In some embodiments, an increase in the level of osteopontin in the individual's cerebrospinal fluid compared to the level of osteopontin in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present for at least about 2 days after administration of the antibody. In some embodiments, an increase in the level of osteopontin in the individual's cerebrospinal fluid compared to the level of osteopontin in the individual's cerebrospinal fluid before administration of the anti-TREM2 antibody is present for at least about 12 days after administration of the antibody. In some embodiments, an elevated level of osteopontin in the cerebrospinal fluid of the individual is present about day 2 after administration of the anti-TREM2 antibody compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the antibody. In some embodiments, an elevated level of osteopontin in the cerebrospinal fluid of the individual is present about day 12 after administration of the anti-TREM2 antibody compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the antibody.

[0246] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in an increase in the level of osteopontin in the cerebrospinal fluid of at least about 35% of individuals on day 2 after administration of the antibody, compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in an increase in the level of osteopontin in the cerebrospinal fluid of at least about 60% of individuals on day 2 after administration of the antibody, compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 45 mg / kg results in an increase in the level of osteopontin in the cerebrospinal fluid of at least about 30% of individuals on day 2 after administration of the antibody, compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 60 mg / kg results in an increase in the level of osteopontin in the cerebrospinal fluid of at least about 100% of individuals on day 2 after administration of the antibody, compared to the level of osteopontin in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody.

[0247] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 15 mg / kg results in an increase in the level of osteopontin in the cerebrospinal fluid of at least about 20% of individuals on day 12 after administration of the antibody, compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 30 mg / kg results in an increase in the level of osteopontin in the cerebrospinal fluid of at least about 35% of individuals on day 12 after administration of the antibody, compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 45 mg / kg results in an increase in the level of osteopontin in the cerebrospinal fluid of at least about 1% of individuals on day 12 after administration of the antibody, compared to the level of osteopontin in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure at a dose of about 60 mg / kg results in an increase in the level of osteopontin in the cerebrospinal fluid of at least about 50% of individuals 12 days after administration of the antibody, compared to the level of osteopontin in the cerebrospinal fluid of the individuals before administration of the anti-TREM2 antibody.

[0248] In some embodiments, the level of osteopontin in the individual's cerebrospinal fluid is compared to the level of osteopontin in the individual's cerebrospinal fluid about 42 days to less than 1 day (e.g., any of 42 days, 41 days, 40 days, 39 days, 38 days, 37 days, 36 days, 35 days, 34 days, 33 days, 32 days, 31 days, 30 days, 29 days, 28 days, 27 days, 26 days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days, 17 days, 16 days, 15 days, 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, or less than 1 day) prior to administration of the anti-TREM2 antibody. In some embodiments, the level of osteopontin in the individual's cerebrospinal fluid is compared to the level of osteopontin in the individual's cerebrospinal fluid at least about 4 days prior to administration of the anti-TREM2 antibody.

[0249] The level of osteopontin in an individual's cerebrospinal fluid can be measured using any method known in the art, such as ELISA, immunoassay, immunoblotting, and mass spectrometry. In certain embodiments, the level of osteopontin in an individual's cerebrospinal fluid is measured using an ECL immunoassay using the Meso Scale Discovery system.

[0250] Pharmacokinetics of anti-TREM2 antibodies In some embodiments, the terminal half-life of an anti-TREM2 antibody of the present disclosure in the blood (e.g., plasma) is approximately 5 days, approximately 6 days, approximately 7 days, approximately 8 days, approximately 9 days, or approximately 10 days. In some embodiments, the half-life of an anti-TREM2 antibody in the blood (e.g., plasma) is approximately 7 days. In some embodiments, the terminal half-life of an anti-TREM2 antibody in the blood (e.g., plasma) is approximately 8 days. In some embodiments, the terminal half-life of an anti-TREM2 antibody in the blood (e.g., plasma) is approximately 9 days. In some embodiments, the terminal half-life of an anti-TREM2 antibody in the blood (e.g., plasma) is approximately 10 days. In some embodiments, the dose of the anti-TREM2 antibody is about 15 mg / kg, and the terminal half-life of the antibody in the individual's plasma is about 8.63 days. In some embodiments, the dose of the anti-TREM2 antibody is about 30 mg / kg, and the terminal half-life of the antibody in the individual's plasma is about 7.44 days. In some embodiments, the dose of the anti-TREM2 antibody is about 45 mg / kg and the terminal half-life of the antibody in the plasma of an individual is about 8.40 days, hi some embodiments, the dose of the anti-TREM2 antibody is about 60 mg / kg and the terminal half-life of the antibody in the plasma of an individual is about 9.93 days.

[0251] The terminal half-life of an anti-TREM2 antibody of the present disclosure in an individual's blood (e.g., plasma) is determined using any method known in the art, such as immunoassay, immunoblot, and mass spectrometry. In certain embodiments, the terminal half-life of an anti-TREM2 antibody of the present disclosure in an individual's blood (e.g., plasma) is determined using an ELISA assay.

[0252] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to an individual results in the presence of the anti-TREM2 antibody in the cerebrospinal fluid of the individual. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to an individual results in the presence of at least about 10 ng / ml, at least about 25 ng / ml, at least about 50 ng / ml, at least about 75 ng / ml, at least about 100 ng / ml, at least about 125 ng / ml, at least about 150 ng / ml, at least about 175 ng / ml, at least about 200 ng / ml, at least about 225 ng / ml, at least about 250 ng / ml, at least about 275 ng / ml, at least about 300 ng / ml, at least about 325 ng / ml, at least about 350 ng / ml, at least about 375 ng / ml, at least about 400 ng / ml, at least about 425 ng / ml, at least about 450 ng / ml, at least about 475 ng / ml, at least about 500 ng / ml, at least about 100 ng / ml, at least about 125 ng / ml, at least about 150 ng / ml, at least about 175 ng / ml, at least about 200 ng / ml, at least about 225 ng / ml, at least about 250 ng / ml, at least about 275 ng / ml, at least about 300 ng / ml, at least about 325 ng / ml, at least about 350 ng / ml, at least about 375 ng / ml, at least about 400 ng / ml, at least about 425 ng / ml, at least about 450 ng / ml, at least about 475 ng / ml, at ng / ml, at least about 525ng / ml, at least about 550ng / ml, at least about 575ng / ml, at least about 600ng / ml, at least about 625ng / ml, at least about 650ng / ml, at least about 675ng / ml, at least about 700ng / ml, at least about 725ng / ml, at least about 750ng / ml, at least about 775ng / ml, at least about 800ng / ml, at least about 850ng / ml, at least about 900ng / ml, at least about 950ng / ml, at least about 1000ng / ml, at least about 1050ng / ml, at least about 1100ng / ml, at least about 1150ng / ml, at least about 1200ng / ml, at least about 1250ng / ml, or at least about 1300ng / ml. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to an individual results in a concentration of the anti-TREM2 antibody in the individual's cerebrospinal fluid of about 10 ng / ml to about 750 ng / ml.In some embodiments, an anti-TREM2 antibody of the present disclosure is present in the cerebrospinal fluid of an individual for at least about 2 days, at least about 3 days, at least about 4 days, at least about 5 days, at least about 6 days, at least about 7 days, at least about 8 days, at least about 9 days, at least about 10 days, at least about 11 days, or at least about 12 days after administration of the antibody. In some embodiments, an anti-TREM2 antibody of the present disclosure is present in the cerebrospinal fluid of an individual for at least about 2 days after administration of the antibody. In some embodiments, an anti-TREM2 antibody of the present disclosure is present in the cerebrospinal fluid of an individual for at least about 12 days after administration of the antibody.

[0253] In some embodiments, administering an anti-TREM2 antibody of the present disclosure to an individual at a dose of about 15 mg / kg results in a concentration of the anti-TREM2 antibody in the individual's cerebrospinal fluid of at least about 100 ng / ml two days after administration of the anti-TREM2 antibody. In some embodiments, administering an anti-TREM2 antibody of the present disclosure to an individual at a dose of about 30 mg / kg results in a concentration of the anti-TREM2 antibody in the individual's cerebrospinal fluid of at least about 250 ng / ml two days after administration of the anti-TREM2 antibody. In some embodiments, administering an anti-TREM2 antibody of the present disclosure to an individual at a dose of about 45 mg / kg results in a concentration of the anti-TREM2 antibody in the individual's cerebrospinal fluid of at least about 400 ng / ml two days after administration of the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to an individual at a dose of about 60 mg / kg results in a concentration of the anti-TREM2 antibody in the individual's cerebrospinal fluid of at least about 600 ng / ml two days after administration of the anti-TREM2 antibody.

[0254] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to an individual at a dose of about 15 mg / kg results in a concentration of the anti-TREM2 antibody in the individual's cerebrospinal fluid of at least about 50 ng / ml 12 days after administration of the anti-TREM2 antibody.

[0255] In some embodiments, administering an anti-TREM2 antibody of the present disclosure to an individual at a dose of about 30 mg / kg results in a concentration of the anti-TREM2 antibody in the cerebrospinal fluid of the individual at 12 days after administration of the anti-TREM2 antibody of at least about 125 ng / ml. In some embodiments, administering an anti-TREM2 antibody of the present disclosure to an individual at a dose of about 45 mg / kg results in a concentration of the anti-TREM2 antibody in the cerebrospinal fluid of the individual at 12 days after administration of the anti-TREM2 antibody of at least about 200 ng / ml. In some embodiments, administering an anti-TREM2 antibody of the present disclosure to an individual at a dose of about 60 mg / kg results in a concentration of the anti-TREM2 antibody in the cerebrospinal fluid of the individual at 12 days after administration of the anti-TREM2 antibody of at least about 300 ng / ml.

[0256] Anti-TREM2 antibodies of the present disclosure can be measured in an individual's CSF using any method known in the art, such as immunoassays, immunoblots, and mass spectrometry, hi certain embodiments, anti-TREM2 antibodies of the present disclosure are measured in an individual's CSF using an ELISA assay.

[0257] Diagnostic Use The isolated antibodies of the present disclosure (e.g., the anti-TREM2 antibodies described herein) also have diagnostic utility. Accordingly, the present disclosure provides methods of using the antibodies of the present disclosure, or functional fragments thereof, for diagnostic purposes, such as detecting TREM2 protein in an individual or a tissue sample derived from an individual.

[0258] In some embodiments, the individual is a human. In some embodiments, the individual is a human patient suffering from or at risk of developing a disease, disorder, or injury of the present disclosure. In some embodiments, the diagnostic method comprises detecting TREM2 protein in a biological sample, such as a biopsy specimen, tissue, or cell. An isolated antibody of the present disclosure (e.g., an anti-TREM2 antibody described herein) is contacted with the biological sample, and antigen-binding antibodies are detected. For example, a biopsy specimen may be stained with an anti-TREM2 antibody described herein to detect and / or quantify disease-associated cells. The detection method may include quantification of antigen-binding antibodies. Antibody detection in a biological sample 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, the antibody is, for example, 18 The antibody is radiolabeled with F and subsequently detected using micropositron emission tomography. Antibody binding may also be quantified in individuals 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).

[0259] In other embodiments, isolated antibodies of the present disclosure (e.g., anti-TREM2 antibodies described herein) can be used to, for example, detect and / or quantitate microglial cells in brain specimens taken from preclinical disease models (e.g., non-human disease models). Thus, isolated antibodies of the present disclosure (e.g., anti-TREM2 antibodies described herein) can be useful in assessing therapeutic response following treatment in models for nervous system diseases or injuries, such as dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, adrenoleukodystrophy (ALD), cerebral adrenoleukodystrophy (cALD), cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, demyelinating disorders, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), and tauopathy, compared to controls.

[0260] TREM2 protein The present disclosure provides a method of treating, preventing, or reducing the risk in an individual of having a disease or injury, comprising administering to the individual an antibody that binds to the TREM2 protein, wherein the antibody is an agonist.

[0261] Triggering receptor expressed on myeloid cells 2 (TREM2) is variously referred to as TREM-2, TREM2a, TREM2b, TREM2c, triggering receptor expressed on myeloid cells-2a, and triggering receptor expressed on monocytes 2. TREM2 is a 230-amino acid membrane protein. TREM2 is an immunoglobulin-like receptor expressed primarily on myeloid cells, including, but not limited to, macrophages, dendritic cells, monocytes, dermal Langerhans cells, Kupffer cells, osteoclasts, and microglia. In some embodiments, TREM2 forms a receptor signaling complex with DAP12. In some embodiments, TREM2 phosphorylates and signals through DAP12 (an ITAM domain adaptor protein). In some embodiments, TREM2 signaling leads to downstream activation of PI3K or other intracellular signals. On myeloid cells, Toll-like receptor (TLR) signaling is important for activating TREM2 activity, for example, in the context of infection responses. TLRs, such as those expressed on macrophages and dendritic cells, also play a key role in pathological inflammatory responses.

[0262] TREM2 proteins of the present disclosure include, but are not limited to, the human TREM2 protein (Uniprot accession number Q9NZC2, SEQ ID NO: 1), and non-human mammalian TREM2 proteins, such as the mouse TREM2 protein (Uniprot accession number Q99NH8, SEQ ID NO: 2), the rat TREM2 protein (Uniprot accession number D3ZZ89, SEQ ID NO: 3), the rhesus monkey TREM2 protein (Uniprot accession number F6QVF2, SEQ ID NO: 4), the cynomolgus monkey TREM2 protein (NCBI accession number XP_015304909.1, SEQ ID NO: 5), the horse TREM2 protein (Uniprot accession number F7D6L0, SEQ ID NO: 6), the pig TREM2 protein (Uniprot accession number H2EZZ3, SEQ ID NO: 7), and the dog TREM2 protein (Uniprot accession number E2RP46, SEQ ID NO: 8). As used herein, "TREM2 protein" refers to both wild-type and naturally occurring variant sequences. In some embodiments, the agonist anti-TREM2 antibodies of the present disclosure bind to a wild-type TREM2 protein, a naturally occurring variant of a TREM2 protein, or a disease variant of a TREM2 protein.

[0263] In some embodiments, an example of a human TREM2 amino acid sequence is shown below as SEQ ID NO: 1: [ka]

[0264] In some embodiments, human TREM2 is a preprotein that includes a signal peptide. In some embodiments, human TREM2 is a mature protein. In some embodiments, the mature TREM2 protein does not include a signal peptide. In some embodiments, the mature TREM2 protein is expressed on a cell. In some embodiments, the TREM2 protein contains a signal peptide located at amino acid residues 1-18 of human TREM2 (SEQ ID NO: 1), an extracellular immunoglobulin-like variable (IgV) domain located at amino acid residues 29-112 of human TREM2 (SEQ ID NO: 1), an additional extracellular sequence located at amino acid residues 113-174 of human TREM2 (SEQ ID NO: 1), a transmembrane domain located at amino acid residues 175-195 of human TREM2 (SEQ ID NO: 1), and an intracellular domain located at amino acid residues 196-230 of human TREM2 (SEQ ID NO: 1). The TREM2 cleavage site was identified as occurring C-terminal to histidine 157 (see WO2018 / 015573), and cleavage at that site leads to shedding of the relevant portion of the TREM2 extracellular domain, detectable as an increase in soluble TREM2 (sTREM2) corresponding to that portion of TREM2.

[0265] The transmembrane domain of human TREM2 contains a lysine at amino acid residue 186 that can interact with an aspartate in DAP12, a key adaptor protein that transduces signaling from TREM2, TREM1, and other related IgV family members.

[0266] Certain aspects of the present disclosure relate to methods of treating a disease or injury in an individual, the method comprising administering to the individual an anti-TREM2 antibody of the present disclosure by the methods provided herein. In some embodiments, the individual is heterozygous or homozygous for a mutation in TREM2 (e.g., in a human TREM2 gene). The mutation may be of any type, including, for example, a missense mutation, an indel, or a mutation that produces a truncated protein product. In some embodiments, the individual has a R47H TREM2 mutation. In some embodiments, the individual has a R62H TREM2 mutation. In some embodiments, the individual has R47H and R62H TREM2 mutations. In certain embodiments, the individual comprises one or more amino acid substitutions in a human TREM2 protein. In certain embodiments, the individual comprises an amino acid substitution at residue position R47H, R62H, or both in a human TREM2 protein. In certain embodiments, the individual comprises an amino acid substitution at residue position R47H in a human TREM2 protein. In certain embodiments, the individual comprises an amino acid substitution at residue position R62H in the human TREM2 protein. In certain embodiments, the individual comprises amino acid substitutions at residue positions R47H and R62H in the human TREM2 protein. In certain embodiments, the mutation in the TREM2 gene or amino acid substitution in the TREM2 protein results in reduced function of TREM2 in the affected individual, for example, compared to a TREM2 protein determined to have "wild-type" function or function determined to be within the normal range. In certain embodiments, the individual comprises at least one copy of a functional TREM2 gene. Any method known in the art, such as targeted sequencing, whole genome sequencing, and polymerase chain reaction (e.g., qPCR), can be used to determine whether an individual has a mutation in the TREM2 gene or in the TREM2 protein.

[0267] Anti-TREM2 antibody Certain aspects of the present disclosure relate to antibodies (e.g., monoclonal antibodies) that bind to TREM2 protein, where the anti-TREM2 antibody is an agonist. In some embodiments, the antibodies of the present disclosure bind to mature TREM2 protein. In some embodiments, the antibodies of the present disclosure bind to mature TREM2 protein, where the mature TREM2 protein is expressed on a cell. In some embodiments, the antibodies of the present disclosure bind to TREM2 protein expressed on one or more human cells selected from human dendritic cells, human macrophages, human monocytes, human osteoclasts, human dermal Langerhans cells, human Kupffer cells, human microglia, and any combination thereof. In some embodiments, the antibodies of the present disclosure bind to TREM2 protein expressed on one or more human microglial cells.

[0268] Anti-TREM2 antibodies that induce and / or enhance ligand-induced activity In some embodiments, the anti-TREM2 antibodies of the present disclosure are agonistic antibodies that induce or increase one or more TREM2 activities, ie, the antibodies induce or increase one or more activities of TREM2 after binding to a TREM2 protein expressed on a cell.

[0269] In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to the TREM2 protein without competing with, inhibiting, or otherwise blocking one or more TREM2 ligands from binding to the TREM2 protein. Examples of TREM2 ligands include, but are not limited to, TREM2 ligands expressed by E. coli cells, apoptotic cells, nucleic acids, anionic lipids, APOE, APOE2, APOE3, APOE4, anionic APOE, anionic APOE2, anionic APOE3, anionic APOE4, lipidated APOE, lipidated APOE2, lipidated APOE3, lipidated APOE4, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine, sulfatides, phosphatidylcholine, sphingomyelin, membrane phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid beta peptide. Thus, in certain embodiments, the one or more TREM2 ligands include E. coli cells, apoptotic cells, nucleic acids, anionic lipids, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine (PS), sulfatides, phosphatidylcholine, sphingomyelin (SM), phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid beta peptides.

[0270] The anti-TREM2 antibodies used in the methods of the present disclosure are agonistic antibodies. In some embodiments, antibodies of the present disclosure that bind to the TREM2 protein may include agonistic antibodies that bind to TREM2 through their epitope specificity and activate one or more TREM2 activities. In some embodiments, such antibodies may bind to a ligand-binding site on TREM2 and mimic the action of one or more TREM2 ligands, or may stimulate TREM2 to transduce a signal by binding to one or more domains that are not the ligand-binding site. In some embodiments, the antibody does not compete with or otherwise block ligand binding to TREM2. In some embodiments, the antibody acts additively or synergistically with one or more TREM2 ligands to activate and / or enhance more than one TREM2 activity, as described below.

[0271] Agonist anti-TREM2 antibodies of the present disclosure may exhibit the ability to bind to TREM2 without blocking the simultaneous binding of one or more TREM2 ligands. Anti-TREM2 antibodies of the present disclosure may further exhibit additive and / or synergistic functional interactions with one or more TREM2 ligands. Thus, in some embodiments, the maximal activity of TREM2 when bound to an anti-TREM2 antibody of the present disclosure in combination with one or more TREM2 ligands of the present disclosure may be higher (e.g., enhanced) than the maximal activity of TREM2 when exposed to a saturating concentration of the ligand alone or to a saturating concentration of the antibody alone. Furthermore, the activity of TREM2 at a given concentration of TREM2 ligand may be higher (e.g., enhanced) in the presence of the antibody.

[0272] Thus, in some embodiments, anti-TREM2 antibodies of the present disclosure have an additive effect with one or more TREM2 ligands, enhancing one or more TREM2 activities when bound to a TREM2 protein. In some embodiments, anti-TREM2 antibodies of the present disclosure synergize with one or more TREM2 ligands to enhance one or more TREM2 activities. In some embodiments, anti-TREM2 antibodies of the present disclosure increase the potency of one or more TREM2 ligands to induce one or more TREM2 activities compared to the potency of the one or more TREM2 ligands to induce one or more TREM2 activities in the absence of the antibody. In some embodiments, anti-TREM2 antibodies of the present disclosure enhance one or more TREM2 activities in the absence of cell surface clustering of TREM2. In some embodiments, anti-TREM2 antibodies of the present disclosure enhance one or more TREM2 activities by inducing or maintaining cell surface clustering of TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure are clustered by one or more Fc-gamma receptors expressed on one or more immune cells, including, but not limited to, B cells and microglial cells. In some embodiments, enhancement of one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein is measured in primary cells or in cell lines, including, but not limited to, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts, dermal Langerhans cells, and Kupffer cells.

[0273] In certain embodiments, anti-TREM2 antibodies of the present disclosure that enhance one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein induce at least a 2-fold, at least a 3-fold, at least a 4-fold, at least a 5-fold, at least a 6-fold, at least a 7-fold, at least a 8-fold, at least a 9-fold, at least a 10-fold, at least a 11-fold, at least a 12-fold, at least a 13-fold, at least a 14-fold, at least a 15-fold, at least a 16-fold, at least a 17-fold, at least a 18-fold, at least a 19-fold, at least a 20-fold or more increase in one or more TREM2 activities compared to the level of one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein in the absence of the anti-TREM2 antibody.

[0274] In some embodiments, TREM2 activities that may be induced and / or enhanced by an anti-TREM2 antibody of the present disclosure and / or one or more TREM2 ligands of the present disclosure include, but are not limited to, TREM2 binding to DAP12; DAP12 phosphorylation; activation of Syk kinase; modulation of one or more pro-inflammatory mediators selected from IFN-β, IL-1α, IL-1β, TNF-α, YM-1, IL-6, IL-8, CRP, CD86, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, Rorc, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, GM-CSF, CSF-1, MHC-II, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23 (optionally). the modulation occurs in one or more cells selected from macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells; recruitment of Syk, ZAP70, or both to the DAP12 / TREM2 complex; increased activity of one or more TREM2-dependent genes (optionally, the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor); increased survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; CD83, CD86 These include modulating the expression of one or more stimulatory molecules selected from MHC class II, CD40, and any combination thereof (optionally, CD40 is expressed on dendritic cells, monocytes, macrophages, or any combination thereof, and optionally, the dendritic cells comprise bone marrow-derived dendritic cells); increasing memory, and reducing cognitive impairment. In some embodiments, the anti-TREM2 antibodies of the present disclosure increase memory and / or reduce cognitive impairment when administered to an individual.

[0275] In some embodiments, the agonist anti-TREM2 antibodies of the present disclosure induce or increase one or more TREM2 activities selected from TREM2 binding to DAP12, DAP12 phosphorylation, activation of Syk kinase, recruitment of Syk to the DAP12 / TREM2 complex, increased activity of one or more TREM2-dependent genes, or any combination thereof. In some embodiments, the one or more TREM2-dependent genes include the nuclear factor of activated T cells (NFAT) transcription factor.

[0276] Syk phosphorylation In some embodiments, the anti-TREM2 antibodies of the present disclosure may induce spleen tyrosine kinase (Syk) phosphorylation after binding to TREM2 protein expressed in cells.

[0277] Spleen tyrosine kinase (Syk) is an intracellular signaling molecule that functions downstream of TREM2 by phosphorylating several substrates, thereby promoting the formation of signaling complexes that lead to cell activation and inflammatory processes.

[0278] In some embodiments, the ability of agonistic TREM2 antibodies to induce Syk activation is determined by culturing mouse macrophages and measuring the phosphorylation state of Syk protein in cell extracts. In some embodiments, bone marrow-derived macrophages (BMDMs) from wild-type (WT) mice, TREM2 knockout (KO) mice, and mice lacking expression of a functional Fc receptor common gamma chain gene (FcgR KO; REF: Takai T 1994. Cell 76(3):519-29) are starved in 1% serum RPMI for 4 hours, then removed from tissue culture dishes with PBS-EDTA, washed with PBS, and counted. In some embodiments, cells are coated with full-length TREM2 antibodies or control antibodies for 15 minutes on ice. In some embodiments, after washing with cold PBS, cells are incubated at 37°C in the presence of goat anti-human IgG for the indicated time periods. In some embodiments, after stimulation, cells are lysed with lysis buffer (1% v / v NP-40%, 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM EDTA, 1.5 mM MgCl, 10% glycerol, and protease and phosphatase inhibitors), followed by centrifugation at 16,000 g for 10 minutes at 4°C to remove insoluble material. In some embodiments, the lysate is then immunoprecipitated with an anti-Syk antibody (N-19 for BMDM or 4D10 for human DC, Santa Cruz Biotechnology). In some embodiments, the deposited proteins are fractionated by SDS-PAGE, transferred to a PVDF membrane, and probed with an anti-phosphotyrosine antibody (4G10, Millipore). In some embodiments, immunoblots are reprobed with anti-Syk antibody (for BMDM, Abcam) or anti-Syk (for human DC, Novus Biological) to confirm proper immunodeposition of all substrates. In some embodiments, visualization is performed with an enhanced chemiluminescence (ECL) system (GE healthcare) as described (e.g., Peng et al., (2010) Sci Signal., 3(122):ra38).

[0279] DAP12 binding and phosphorylation In some embodiments, the anti-TREM2 antibodies of the present disclosure may induce TREM2 binding to DAP12. In other embodiments, the anti-TREM2 antibodies of the present disclosure may induce DAP12 phosphorylation after binding to TREM2 protein expressed on cells. In other embodiments, TREM2-mediated DAP12 phosphorylation is induced by one or more SRC family tyrosine kinases. Examples of Src family tyrosine kinases include, but are not limited to, Src, Syk, Yes, Fyn, Fgr, Lck, Hck, Blk, Lyn, and Frk.

[0280] DAP12 is variously referred to as TYRO protein tyrosine kinase binding protein, TYROBP, KARAP, and PLOSL. DAP12 is a transmembrane signaling protein containing an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. In certain embodiments, anti-TREM2 antibodies can induce DAP12 phosphorylation at the ITAM motif. Any method known in the art for determining protein phosphorylation, such as DAP12 phosphorylation, may be used.

[0281] In some embodiments, DAP12 is phosphorylated by an SRC family kinase, resulting in the recruitment and activation of Syk kinase, ZAP70 kinase, or both, to the DAP12 / TREM2 complex.

[0282] In some embodiments, the ability of TREM2 antibodies to induce DAP12 activation is determined by culturing mouse macrophages and measuring the phosphorylation state of DAP12 protein in cell extracts. In some embodiments, mouse wild-type (WT) bone marrow-derived macrophages (BMDMs) and TREM2 knockout (KO) BMDMs are starved in 1% serum RPMI for 4 hours before stimulation with the antibody. In some embodiments, 15×10 6Cells are incubated with full-length TREM2 antibody or control antibody on ice for 15 minutes. In some embodiments, cells are washed and incubated in the presence of goat anti-human IgG at 37°C for the indicated time periods. In some embodiments, after stimulation, cells are lysed with lysis buffer (1% v / v n-dodecyl-β-D-maltoside, 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM EDTA, 1.5 mM MgCl2, 10% glycerol, and protease and phosphatase inhibitors) followed by centrifugation at 16,000g for 10 minutes at 4°C to remove insoluble material. In some embodiments, cell lysates are immunoprecipitated with a secondary TREM2 antibody (R&D Systems). In some embodiments, deposited proteins are fractionated by SDS-PAGE, transferred to a PVDF membrane, and probed with an anti-phosphotyrosine Ab (4G10, Millipore). In some embodiments, the membranes are stripped and reprobed with anti-DAP12 antibody (Cells Signaling, D7G1X). In some embodiments, each cell lysate used for TREM2 immunoprecipitation contains equal amounts of protein as indicated by a control antibody (anti-Actin, Santa Cruz).

[0283] Proliferation, survival and function of TREM2-expressing cells In some embodiments, the anti-TREM2 antibodies of the present disclosure may increase the proliferation, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells (microglia) after binding to TREM2 protein expressed in the cells. In some embodiments, the anti-TREM2 antibodies of the present disclosure do not inhibit the growth (e.g., proliferation and / or survival) of one or more innate immune cells.

[0284] In some embodiments, the anti-TREM2 antibodies of the present disclosure may increase the proliferation, survival, and / or function of microglial cells (microglia) after binding to the TREM2 protein expressed in the cells. Microglial cells are a type of glial cell that are resident macrophages in the brain and spinal cord, and therefore act as the first and primary form of active immune defense in the central nervous system (CNS). Microglial cells comprise 20% of the total glial cell population in the brain. Microglial cells constantly remove plaques, damaged neurons, and infectious agents from the CNS. The brain and spinal cord are considered "immune-privileged" organs, separated from the rest of the body by a series of endothelial cells known as the blood-brain barrier, which prevents most infections from reaching vulnerable neural tissue. When infectious agents are introduced directly into the brain or cross the blood-brain barrier, microglial cells must respond quickly to reduce inflammation and destroy them before they can damage sensitive neural tissue. Unable to utilize antibodies from the rest of the body (few antibodies are small enough to cross the blood-brain barrier), microglia must be able to recognize foreign particles, engulf them, and act as antigen-presenting cells to activate T cells. Because this process must occur rapidly to prevent potentially fatal damage, microglial cells are extremely sensitive to even minor pathological changes in the CNS. They achieve this sensitivity in part by possessing unique potassium channels that respond to even small changes in extracellular potassium.

[0285] As used herein, macrophages of the present disclosure include, but are not limited to, M1 macrophages, activated M1 macrophages, and M2 macrophages. As used herein, microglial cells of the present disclosure include, but are not limited to, M1 microglial cells, activated M1 microglial cells, and M2 microglial cells.

[0286] In some embodiments, the anti-TREM2 antibodies of the present disclosure may increase the expression of CD83 and / or CD86 on dendritic cells, monocytes, and / or macrophages.

[0287] As used herein, proliferation rate, survival, and / or function of macrophages, dendritic cells, monocytes, and / or microglia can include increased expression when the proliferation rate, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or microglia in a subject treated with an anti-TREM2 antibody of the disclosure is greater than the proliferation rate, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or microglia in a corresponding subject not treated with an anti-TREM2 antibody. In some embodiments, the anti-TREM2 antibodies of the disclosure may enhance the proliferation rate, survival, and / or function of a subject's dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or microglia by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 10 ... The increase may be 0%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%.In other embodiments, the anti-TREM2 antibodies of the disclosure may enhance or decrease the proliferation rate, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or microglia in a subject by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, or less, as compared to the proliferation rate, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or microglia in a corresponding subject not treated with the anti-TREM2 antibody. The increase may be at least 2.1 fold, at least 2.15 fold, at least 2.2 fold, at least 2.25 fold, at least 2.3 fold, at least 2.35 fold, at least 2.4 fold, at least 2.45 fold, at least 2.5 fold, at least 2.55 fold, at least 3.0 fold, at least 3.5 fold, at least 4.0 fold, at least 4.5 fold, at least 5.0 fold, at least 5.5 fold, at least 6.0 fold, at least 6.5 fold, at least 7.0 fold, at least 7.5 fold, at least 8.0 fold, at least 8.5 fold, at least 9.0 fold, at least 9.5 fold, or at least 10 fold.

[0288] In some embodiments, to assess the ability of anti-TREM2 antibodies to induce or enhance cell survival in vitro, FcgRI, FcgRIII, and FceRI receptors (Fcgr1KO mice, REF: Takai T, Li M, Sylvestre D, Clynes R, Ravetch J. (1994). Cell, 76:519-529) are cultured in the presence of plate-bound anti-TREM2 antibodies to determine cell viability when cells are cultured under suboptimal growth conditions. In some embodiments, murine bone marrow progenitor cells from FcgR1 KO mice (Taconic, Model 584) are obtained by flushing tibial and femoral bone marrow cells with cold PBS. In some embodiments, after one wash with PBS, red blood cells are lysed using ACK lysis buffer (Lonza), washed twice with PBS, and 0.5 × 10 6Macrophages were generated by suspending 2.5 × 10 cells / ml in complete RPMI medium (10% FCS, Pen / Strep, Gln, neAA) with the indicated amount of M-CSF (Peprotech). In some embodiments, to analyze cell viability of bone marrow-derived macrophages, cells were prepared as above and 2.5 × 10 4 Cells are plated in 96-well plates at 200 □l / well with a suboptimal amount of M-CSF (10 ng / ml) in non-tissue culture treated plates for 2 days. In some embodiments, cells are then quantified using a ToxGlo™ kit (Promega), and luminescence is determined as a measure of cell viability. In some embodiments, all experiments are performed in the presence or absence of anti-TREM2 antibodies or isotype control antibodies.

[0289] TREM2-dependent gene expression In some embodiments, the anti-TREM2 antibodies of the present disclosure may increase the activity and / or expression of TREM2-dependent genes, such as one or more transcription factors of the nuclear factor of activated T cells (NFAT) family of transcription factors.

[0290] In some embodiments, the ability of soluble full-length anti-TREM2 antibodies to activate mouse or human TREM2-dependent genes is assessed using a luciferase reporter gene under the control of the NFAT (nuclear factor of activated T cells) promoter. In some embodiments, the mouse thymic lymphoma T lymphocyte-derived cell line BW5147.G.1.4 (ATCC® TIB48™) is infected with mouse TREM2 and DAP12 and with Cignal Lenti NFAT-luciferase virus (Qiagen). Alternatively, in some embodiments, the BW5147.G.1.4 cell line is infected with human TREM2 / DAP12 fusion protein and with Cignal Lenti NFAT-luciferase virus (Qiagen). In some embodiments, PMA (0.05 μg / ml) and ionomycin (0.25 μM) are added together as a positive control for signal transduction. In some embodiments, cells are incubated with soluble anti-TREM2 and isotype control antibodies for 6 hours, and luciferase activity is measured by adding OneGlo reagent (Promega) to each well and incubating for 3 minutes at room temperature on a plate shaker. In some embodiments, luciferase signals are measured using a BioTek plate reader. In some embodiments, cells exhibit sustained TREM2-dependent signaling, either due to the presence of endogenous ligands that result in TREM2 signaling, or due to spontaneous receptor aggregation.

[0291] In some embodiments, the enhancement of one or more TREM2 activities induced by the binding of one or more TREM2 ligands to the TREM2 protein is measured, for example, using an in vitro cell assay. In some embodiments, the increase in one or more TREM2 activities can be measured by any suitable in vitro cell-based assay or suitable in vivo model described herein or known in the art, for example, by using a luciferase-based reporter assay to measure TREM2-dependent gene expression, by using Western blot analysis to measure the increase in TREM2-induced phosphorylation of downstream signaling partners such as Syk, or by using flow cytometry such as fluorescence-activated cell sorting (FACS) to measure changes in cell surface levels of markers of TREM2 activation. To measure the interaction (e.g., binding) between TREM2 and one or more TREM2 ligands, any in vitro cell-based assay or suitable in vivo model described herein or known in the art can be used.

[0292] In some embodiments, increases in one or more TREM2 activities are measured by in vitro cell-based assays. To assess the ability of anti-TREM2 antibodies to enhance cell survival in vitro, FcgRI, FcgRIII, and FceRI receptors (Fcgr1KO mice, REF: Takai T, Li M, Sylvestre D, Clynes R, Ravetch J. (1994). Cell, 76:519-529) are cultured in the presence of plate-bound anti-TREM2 antibodies, and cell viability is determined when the cells are cultured under suboptimal growth conditions. In some embodiments, murine bone marrow progenitor cells from FcgR1KO mice (Taconic, Model 584) are obtained by flushing tibial and femoral bone marrow cells with cold PBS. In some embodiments, after one wash with PBS, red blood cells are lysed using ACK lysis buffer (Lonza), washed twice with PBS, and 0.5×10 6Macrophages were generated by suspending 2.5 × 10 cells / ml in complete RPMI medium (10% FCS, Pen / Strep, Gln, neAA) with the indicated amount of M-CSF (Peprotech). In some embodiments, to analyze cell viability of bone marrow-derived macrophages, cells were prepared as above and 2.5 × 10 4 Cells are plated in 96-well plates at 200 ...

Claims

1. 23. A method of treating or slowing the progression of a disease or injury in an individual, said individual being not homozygous for the ApoE e4 allele, comprising administering to said individual an anti-TREM2 agonist antibody.

2. The method of claim 1 , wherein the individual is not an ApoE e4 carrier.

3. The method of claim 1 , wherein the individual is heterozygous for the ApoE4 e4 allele.

4. The method of claim 1, wherein the individual is not an ApoE e4 carrier or the individual is heterozygous for the ApoE4 e4 allele.

5. The method of any one of claims 1 to 4, comprising administering to the individual the anti-TREM2 antibody intravenously at a dose of at least about 15 mg / kg.

6. administering to the individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg intravenously, wherein the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3; and (i) the HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 34), the HVR-H2 comprises the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 35), the HVR-H3 comprises the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 31), the HVR-L1 comprises the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 41), the HVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO: 33), and the HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32); or (ii) The method of any one of claims 1 to 4, wherein the HVR-H1 comprises the amino acid sequence YAFSSDWMN (SEQ ID NO: 36), the HVR-H2 comprises the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 37), the HVR-H3 comprises the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 38), the HVR-L1 comprises the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 39), the HVR-L2 comprises the amino acid sequence KVSNRVS (SEQ ID NO: 40), and the HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32).

7. administering to the individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg intravenously, the antibody comprising a heavy chain variable region and a light chain variable region; (a) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence SYWIG (SEQ ID NO: 146) or SWIG (SEQ ID NO: 147), HVR-H2 comprising the amino acid sequence IIPGDADARYSPSFQG (SEQ ID NO: 148), HVR-H3 comprising the amino acid sequence RRQGIFGDALDF (SEQ ID NO: 149), and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RASQSVSSNLA (SEQ ID NO: 150), HVR-L2 comprising the amino acid sequence GASTRAT (SEQ ID NO: 151), and HVR-L3 comprising the amino acid sequence LQDNNFPPT (SEQ ID NO: 152); or (b) the heavy chain variable region comprises the amino acid sequence EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDADARYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYFCARRRQGIFGDALDFWGQGTLVTVSS (SEQ ID NO: 153); 5. The method of any one of claims 1 to 4, wherein the light chain variable region comprises the amino acid sequence EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWFQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQPEDFAVYYCLQDNNFPPTFGQGTKVDIK (SEQ ID NO: 154).

8. administering to the individual an anti-TREM2 antibody at a dose of at least about 15 mg / kg intravenously, the antibody comprising a heavy chain variable region and a light chain variable region; (a) the heavy chain variable region comprises an HVR-H1 comprising the amino acid sequence GFTFTDFYMS (SEQ ID NO: 155), an HVR-H2 comprising the amino acid sequence VIRNKANGYTAGYNPSVKG (SEQ ID NO: 156), an HVR-H3 comprising the amino acid sequence ARLTYGFDY (SEQ ID NO: 157), and the light chain variable region comprises an HVR-L1 comprising the amino acid sequence QSSKSLLHSTGKTYLN (SEQ ID NO: 158), an HVR-L2 comprising the amino acid sequence WMSTRAS (SEQ ID NO: 159), and an HVR-L3 comprising the amino acid sequence QQFLEYPFT (SEQ ID NO: 160); or (b) the heavy chain variable region has the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAGSGFTFTFFYMSWVRQAPGKGPEWLSVIRNKANGYTAGYNPSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLTYGFDYWGQGTLVTVSS (SEQ ID NO: 161). wherein the light chain variable region comprises the amino acid sequence DIVMTQTPLSLPVTPGEPASISCQSSKSLLHSTGKTYLNWYLQKPGQSPQLLIYWMSTRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQFLEYPFTFGQGTKVEIK (SEQ ID NO: 162); or (c) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence GFTFTDFYMS (SEQ ID NO: 163), HVR-H2 comprising the amino acid sequence VIRNKANAYTAGYNPSVKG (SEQ ID NO: 164), HVR-H3 comprising the amino acid sequence ARLTYGFDY (SEQ ID NO: 165), and the light chain variable region comprises HVR-L1 comprising the amino acid sequence QSSKSLLHSTGKTYLN (SEQ ID NO: 166), HVR-L2 comprising the amino acid sequence WMSTRAS (SEQ ID NO: 167), and HVR-L3 comprising the amino acid sequence QQFLEYPFT (SEQ ID NO: 168); or (d) the heavy chain variable region comprises the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFTFFYMSWVRQAPGKGLEWVSVIRNKANAYTAGYNPSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLTYGFDYWGQGTLVTVSS (SEQ ID NO: 169), and the light chain variable region comprises the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFFTDFYMSWVRQAPGKGLEWVSVIRNKANAYTAGYNPSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARLTYGFDYWGQGTLVTVSS (SEQ ID NO: 169). The method of any one of claims 1 to 4, wherein the variable region comprises the amino acid sequence DIVMTQTPLSLPVTPGEPASISCQSSKSLLHSTGKTYLNWYLQKPGQSPQLLIYWMSTRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQFLEYPFTFGQGTKVEIK (SEQ ID NO: 170).

9. The method of any one of claims 5 to 8, wherein the dose is from about 15 mg / kg to about 60 mg / kg.

10. 10. The method of any one of claims 5-9, wherein the dose is about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, or about 60 mg / kg.

11. The method of any one of claims 5 to 10, wherein the anti-TREM2 antibody is administered approximately once every four weeks at a dose of at least about 15 mg / kg.

12. The method of any one of claims 5 to 10, wherein the anti-TREM2 antibody is administered approximately once weekly at a dose of at least about 15 mg / kg.

13. The method of any one of claims 5 to 11, wherein the anti-TREM2 antibody is administered approximately once every four weeks at a dose of about 15 mg / kg.

14. The method of any one of claims 5 to 11, wherein the anti-TREM2 antibody is administered approximately once every four weeks at a dose of about 20 mg / kg.

15. The method of any one of claims 5 to 11, wherein the anti-TREM2 antibody is administered approximately once every four weeks at a dose of about 25 mg / kg.

16. The method of any one of claims 5 to 11, wherein the anti-TREM2 antibody is administered approximately once every four weeks at a dose of about 30 mg / kg.

17. The method of any one of claims 5 to 11, wherein the anti-TREM2 antibody is administered approximately once every four weeks at a dose of about 35 mg / kg.

18. The method of any one of claims 5 to 11, wherein the anti-TREM2 antibody is administered approximately once every four weeks at a dose of about 40 mg / kg.

19. The method of any one of claims 5 to 11, wherein the anti-TREM2 antibody is administered approximately once every four weeks at a dose of about 45 mg / kg.

20. The method of any one of claims 5 to 11, wherein the anti-TREM2 antibody is administered approximately once every four weeks at a dose of about 50 mg / kg.

21. The method of any one of claims 5 to 11, wherein the anti-TREM2 antibody is administered approximately once every four weeks at a dose of about 55 mg / kg.

22. The method of any one of claims 5 to 11, wherein the anti-TREM2 antibody is administered approximately once every four weeks at a dose of about 60 mg / kg.

23. The antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein the HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 34), the HVR-H2 comprises the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 35), and the HVR-H3 comprises the amino acid sequence 23. The method of any one of claims 1 to 6 and 9 to 22, wherein the HVR-L1 comprises the sequence ARLLRNQPGESYAMDY (SEQ ID NO: 31), the HVR-L1 comprises the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 41), the HVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO: 33), and the HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32).

24. The method of any one of claims 1 to 6 and 9 to 23, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

30.

25. The antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein the HVR-H1 comprises the amino acid sequence YAFSSDWMN (SEQ ID NO: 36), the HVR-H2 comprises the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 37), and the HVR-H3 comprises the amino acid sequence 23. The method of any one of claims 1 to 6 and 9 to 22, wherein the HVR-L1 comprises the sequence ARLLRNKPGESYAMDY (SEQ ID NO: 38), the HVR-L1 comprises the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 39), the HVR-L2 comprises the amino acid sequence KVSNRVS (SEQ ID NO: 40), and the HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32).

26. 26. The method of any one of claims 1 to 6, 9 to 22, and 25, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

29.

27. The method of any one of claims 1 to 26, wherein the antibody has a human IgG1 isotype.

28. 28. The method of any one of claims 1 to 27, wherein the antibody has a human IgG1 isotype and comprises amino acid substitutions in the Fc region at residue positions P331S and E430G, the numbering of the residues being according to EU numbering.

29. The antibody, a. a heavy chain comprising the amino acid sequence of SEQ ID NO: 43, and a light chain comprising the amino acid sequence of SEQ ID NO: 47; or b. The method of any one of claims 1-6, 9-24, and 27-28, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:44, and a light chain comprising the amino acid sequence of SEQ ID NO:

47.

30. The antibody, a. a heavy chain comprising the amino acid sequence of SEQ ID NO: 45, and a light chain comprising the amino acid sequence of SEQ ID NO: 48; or b. The method of any one of claims 1-6, 9-22, and 25-27, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:46, and a light chain comprising the amino acid sequence of SEQ ID NO:

48.

31. The antibody, A heavy chain comprising the amino acid sequence: EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIYPGDADARYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYFCARRRQGIFGDALDFWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSC DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 171), and b. The method of any one of claims 1-5, 7, and 9-22, comprising a light chain comprising the amino acid sequence: EIVMTQSPATTLSVSPGERATLSCRASQSVSSNLAWFQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQPEDFAVYYCLQDNNFPPTFGQGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 172).

32. 32. The method of any one of claims 1 to 31, wherein the disease or injury is selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, adrenoleukodystrophy (ALD), cerebral adrenoleukodystrophy (cALD), cognitive impairment, memory loss, demyelinating disorders, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis (ALS), Huntington's disease, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), and tauopathy diseases.

33. The method of any one of claims 1 to 32, wherein the disease or injury is Alzheimer's disease.

34. 34. The method of claim 33, wherein the individual has a Mini-Mental State Examination (MMSE) score of between about 16 points and about 28 points prior to administration of the anti-TREM2 antibody.

35. The method of claim 33 or claim 34, wherein the individual has a Clinical Dementia Rating-Global Score (CDR-GS) of 0.5, 1.0, or 2.0 prior to administration of the anti-TREM2 antibody.

36. The method of any one of claims 33 to 35, wherein the individual has a positive amyloid-PET scan prior to administration of the anti-TREM2 antibody.

37. The method of any one of claims 33 to 36, wherein the individual is receiving a cholinesterase inhibitor and / or memantine therapy.

38. The method of any one of claims 33-37, wherein the individual has symptoms of Alzheimer's disease prior to administration of the anti-TREM2 antibody.

39. 39. The method of claim 38, wherein the condition is mild cognitive impairment and / or mild dementia.

40. The method of any one of claims 33-37, wherein the individual is free of symptoms of Alzheimer's disease prior to administration of the anti-TREM2 antibody.

41. The method of any one of claims 1 to 40, wherein the individual is heterozygous or homozygous for a mutation in TREM2.

42. 42. The method of any one of claims 1-41, wherein the individual comprises an amino acid substitution at residue position R47H, R62H, or both, in the human TREM2 protein.

43. The method of any one of claims 1-42, wherein the individual has a positive amyloid or tau blood test prior to administration of the anti-TREM2 antibody.

44. The method of any one of claims 1 to 43, wherein administration of the anti-TREM2 antibody results in at least about a 30% decrease in the level of soluble TREM2 in the cerebrospinal fluid of the individual compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.

45. The method of any one of claims 1 to 44, wherein administration of the anti-TREM2 antibody results in at least about a 40% reduction in the level of soluble TREM2 in the cerebrospinal fluid of the individual compared to the level of soluble TREM2 in the cerebrospinal fluid of the individual before administration of the anti-TREM2 antibody.

46. 46. ​​The method of claim 44 or claim 45, wherein the decrease in the level of soluble TREM2 in the individual's cerebrospinal fluid is present about 2 days after administration of the anti-TREM2 antibody.

47. 47. The method of any one of claims 44 to 46, wherein the level of soluble TREM2 in the individual's cerebrospinal fluid is measured in a sample of cerebrospinal fluid obtained from the individual using an electrochemiluminescence assay.

48. The method of any one of claims 1 to 47, wherein administration of the anti-TREM2 antibody results in an increase in the level of soluble CSF1R in the cerebrospinal fluid of the individual by at least about 5% compared to the level of soluble CSF1R in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody.

49. 49. The method of claim 48, wherein the elevated level of soluble CSF1R in the individual's cerebrospinal fluid is present about 2 days after administration of the anti-TREM2 antibody.

50. 50. The method of claim 48 or claim 49, wherein the level of soluble CSF1R in the cerebrospinal fluid of the individual is measured in a sample of cerebrospinal fluid obtained from the individual using an ELISA assay.

51. The method of any one of claims 1 to 50, further comprising measuring levels of soluble TREM2 in blood, plasma, and / or cerebrospinal fluid samples from the individual before and after the individual has been administered one or more doses of the anti-TREM2 antibody.

52. 52. The method of any one of claims 1-51, further comprising measuring the level of soluble CSF1R in blood, plasma, and / or cerebrospinal fluid samples from the individual before and after the individual has been administered one or more doses of the anti-TREM2 antibody.

53. 53. The method of any one of claims 1-52, further comprising measuring the level of cerebral amyloid burden in the brain of the individual before and after the individual has been administered one or more doses of the anti-TREM2 antibody.

54. 54. The method of claim 53, wherein the level of cerebral amyloid burden in the individual's brain is measured using amyloid positron emission tomography.

55. 55. The method of any one of claims 1-54, further comprising measuring one or more brain abnormalities in the brain of the individual before and after the individual is administered one or more doses of the anti-TREM2 antibody.

56. 56. The method of claim 55, wherein the one or more brain abnormalities are measured using magnetic resonance imaging.

57. 57. The method of claim 55 or claim 56, wherein the one or more brain abnormalities is brain volume.

58. 58. The method of any one of claims 1 to 57, further comprising detecting the presence of an alteration in one or more genes in said individual selected from the group consisting of APOE, TREM2, CD33, TMEM106b, and CLUSTERIN.

59. 59. The method of claim 58, wherein the presence or absence of the ApoE e4 allele is detected in the individual.

60. The method of any one of claims 1 to 59, further comprising measuring the level of one or more biomarkers of neurodegeneration in blood, plasma, and / or cerebrospinal fluid samples from the individual before and after the individual has been administered one or more doses of the anti-TREM2 antibody.

61. 61. The method of claim 60, wherein the one or more biomarkers of neurodegeneration is neurofilament light.

62. The method of any one of claims 1 to 61, further comprising measuring expression levels of TREM2, CSF1R, YKL40, IL-1RA, or osteopontin in blood, plasma, and / or cerebrospinal fluid samples from the individual before and after the individual has been administered one or more doses of the anti-TREM2 antibody.

63. The method of any one of claims 1 to 62, further comprising measuring the level of one or more biomarkers for Alzheimer's disease in blood, plasma, and / or cerebrospinal fluid samples from the individual before and after the individual has been administered one or more doses of the anti-TREM2 antibody.

64. 64. The method of claim 63, wherein the one or more biomarkers of Alzheimer's disease are Aβ40, Aβ42, pTau, and / or total tau.

65. 65. The method of any one of claims 1-64, further comprising determining the score of one or more clinical assessments of the individual before and after the individual is administered one or more doses of the anti-TREM2 antibody, wherein the one or more clinical assessments are selected from the group consisting of Mini-Mental State Examination (MMSE) score, Clinical Dementia Rating-Global Score (CDR-GS), Clinical Dementia Rating Sum of Boxes (CDR-SB), and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

66. 66. The method of any one of claims 1-65, further comprising performing tau or amyloid positron emission tomography (PET) imaging assessments in the individual before and after the individual is administered one or more doses of the anti-TREM2 antibody.

67. 67. The method of any one of claims 1 to 66, wherein the disease or injury is Alzheimer's disease, and the Alzheimer's disease is early Alzheimer's disease.

68. 68. The method of claim 67, wherein the individual has cerebral amyloidosis prior to administration of the anti-TREM2 antibody, and cerebral amyloidosis is assessed in a sample of cerebrospinal fluid obtained from the individual or by positron emission tomography (PET).

69. 69. The method of claim 67 or claim 68, wherein the individual has a Mini-Mental State Examination (MMSE) score of at least about 22 points prior to administration of the anti-TREM2 antibody.

70. 70. The method of any one of claims 67-69, wherein the individual has a Clinical Dementia Rating-Global Score (CDR-GS) of about 0.5 to about 1.0 prior to administration of the anti-TREM2 antibody.

71. 71. The method of any one of claims 67-70, wherein the individual has a Repeatable Battery for the Assessment of Neuropsychological Status on the Delayed Memory Index (RBANS DMI) score of 85 or less prior to administration of the anti-TREM2 antibody.

72. The method of any one of claims 67-71, wherein the individual has a positive amyloid or tau blood test prior to administration of the anti-TREM2 antibody.

73. The method further comprises determining a score on one or more clinical assessments of the individual before and after the individual is administered one or more doses of the anti-TREM2 antibody, the one or more clinical assessments being selected from the group consisting of Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Alzheimer's Disease Assessment Scale-Cognitive Subscale-13 (ADAS-Cog13 ...

73. The method of any one of claims 67-72, wherein the cognitive impairment score is selected from the group consisting of Cooperative Study-Activities of Daily Living adapted to Mild Cognitive Impairment (ADCS-ADL-MCI), and Alzheimer's Disease Composite Score (ADCOMS).

74. The method of any one of claims 67-73, further comprising measuring the level of one or more biomarkers for Alzheimer's disease before and after the individual is administered one or more doses of the anti-TREM2 antibody, wherein the one or more biomarkers for Alzheimer's disease are measured by magnetic resonance imaging (MRI) or in a sample of blood, plasma or cerebrospinal fluid obtained from the individual.

75. 75. The method of any one of claims 67-74, further comprising performing tau or amyloid positron emission tomography (PET) imaging assessments in the individual before and after the individual is administered one or more doses of the anti-TREM2 antibody.

76. 76. The method of any one of claims 67-75, further comprising performing one or more speech assessments in the individual before and after the individual is administered one or more doses of the anti-TREM2 antibody.

77. 77. The method of any one of claims 1-76, further comprising evaluating the individual for amyloid-related imaging abnormalities (ARIA), vasogenic cerebral edema, new cerebral microbleeds, or uveitis.

78. 78. The method of claim 77, wherein the ARIA is amyloid-related imaging abnormality edema (ARIA-E) and / or amyloid-related imaging abnormality hemosiderin (ARIA-H).

79. 80. The method of any one of claims 1-13 and 23-78, wherein: (a) the dose is about 15 mg / kg and the terminal half-life of the antibody in the individual's plasma is about 8.63 days; (b) the dose is about 30 mg / kg and the terminal half-life of the antibody in the individual's plasma is about 7.44 days; (c) the dose is about 45 mg / kg and the terminal half-life of the antibody in the individual's plasma is about 8.40 days; or (d) the dose is about 60 mg / kg and the terminal half-life of the antibody in the individual's plasma is about 9.93 days.

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