COMPOSITIONS FOR THE TREATMENT OF DISEASES OR CONDITIONS RELATED TO INFLAMASOMES

Abstract

The compositions and methods described herein include agents that inhibit inflammasome signaling in mammals, such as antibodies directed against inflammasome components used alone or in combination with inhibitors of extracellular vesicle uptake. Also described herein are compositions and methods of use for treating inflammasome-related diseases or conditions.

Description

DESCRIPTION OF THE ELECTRONICALLY SUBMITTED TEXT FILE

[0003] U1 contained in the sent text file: electronically with this document is incorporated herein by reference in its entirety: One copy. in computer-readable format of the Sequence Listing (file name: UMMf_01Qm02WQ_SeqList_S^ record date: Jul 3, 2013, file size - 13.5 kilcbytes), & FIELD 100041 The invention relates generally to the fields of immunology and medicine. More particularly, the invention relates to compositions and methods for modulating ASC (apoptosis-associated Speck-like protein containing a caspase-activating recruitment domain (CARD)) 1G activity and inflammatory activity absent in mslauoma 2 (AIM2) in the central nervous system (CNSj and / or lungs of a mammal as treatments to reduce inflammation in response to lesions or conditions that cause inflammation in the CNS and / or lungs. The invention also relates to monoclonal antibodies or fragments thereof that specifically bind to ASC, [0005J Severe traumatic brain injury (TBI) is a major public health problem and is a leading cause of mortality and morbidity worldwide (Suwr^ C,R, et al., (2009)* Trauriatic brain injury in Lhe United S.tat.en: a» epidemiology oyerview. Mt Sinai J Sed 7 6r105-110) . In addition to injury, directly to the brain, TBI can cause complications in other organs, including the lungs. Acute lung injury (ALI; 2) is a problem. Cardiopuloona is common after trauma and is associated with an in-hospital mortality rate of up to 40% (Rincón F. et al., (2012) . Impace oí acute lung injury and acute respiratocy distress syndrome after traumatic braiú 10 injury i ή·· the United States Neurosurgery 71, 79 5--8 03), Patients with TBI, in. In particular, they are suspected of developing ALI, with some studies reporting an incidence of up to 30% (Nicnlls, M,R., et alM(2014), Trama-tic brain. injury: / lungs in a RAGB, Sci Transí Med 6, 252fs234) . 55 Recent studies have shown that systemic inflammatory factors can cause lung dysfunction and lung injury after a TCE (Rincón ü et al., (2012) . Impact oí acute luhg injury and acute respirato.ry distress· syndrome after traumatic brain injury in the ünlted 2Q States, Heurosurgery 71, 795-802), but the precise molecular mechanism underlying TBI-induced lung injury is still clearly defined. |OTOT] A flood of secreted inflammatory mediators, including cytokines, chemokines, and damage-associated molecular patterns (DAMPs) released by injured cells, contribute to brain inflammation and affect distal organs such as the lungs (Nicolls, M. R, et al.f(2014).Traumatic brain injury: lungs in a ROE. Thirst Transí Med 8, 252fs234) . One of the DAMPs most studied is the high mobility group. box-1 (HMGB1), which may serve as an early mediator of inflammation in several pathogenic states, including TBI (Andersson ü. et al., (2011). Introductionf HMGB1 in inflammation and innate immunity. J Tntern Med 273, .236-30), A more recent study has. demonstrated that HMGB1 may be involved in the mechanism of lung dysfunction induced by TBI (duber et al., (2014). The H.MGB1-RAGE' axis mediales traumatic brain injury-induced pulmonary dysfunction in lung transplantation. Sel Transí Med € , 252r,al2 4) .. HMGB1 release can be regulated by the inflammasome, a multi-protein complex involved in easpase-Ί activation and 1L-1^ and TL-IS processing after TRX ( Lu et al (2012).Novel tole of PKR in inflammasoms activation and HMGB1 ralease, age 488, 670~€74).

[0007] Various explanations have been put forward to explain the pathological mechanisms of pulmonary complications: following ICE, including increased: vascular permeability leading to capillary leakage and infiltration of proteinaceous debris (Ware et al., (2000).The Acate Respiratory stress Syndrome.Mee England Journal of Medicine 3 42, 13 34-134 3). The -vesicles: mracellular. (EV) are membrane-contained vesicles that play a role in cell-to-cell communication (Ysnez-lo, M. et TQ al., , (2015) Biological! proper^ of extracellular wsiCXes and their physiological functions. J Extracell Yesicles 4, 2706$) and have been implicated to play a role in ALI development in an LPS-induced murine model. In addition..., it has:demgstra.do:that VE can: transupó^ bipactiyas cytokines. em. 11-1(5 and inflammasome proteins (Qu., Y. et al., (2007). Nonclassical II-1 beta secretion stimulated by E2X7 receptors is dependent on inflammasome activation and correiated with exosome release in murine macrophages, J ímanol 179 , 1913-192 5) (from River© Vauca^ 2Q J.P. et al., (2015). Excsome-mediated inflammation signaling after central nervous system injury. J Neurpchem), and may elicit an immune response and amplify inflammation through its delivery to neighboring and surrounding cells *However, it is unknown whether EV-mediated inflammasome serialization may contribute to the pathomechanism of EV-induced ALT. TBI. In addition, it is also unknown whether the pathological mechanisms® of ALI induced by ΤΒ.Ϊ are shared by Other conditions that produce lung inflammation. In addition, there is a shortage of drugs approved by the Federal Drug Administration (FDA) to treat lung inflammation. IWW1 Consequently, there is an urgent need not only to elucidate the pathological mechanisms of lung inflammation caused by TBI as well. as other conditions, but also the development of therapeutic compositions and their uses to treat and / or prevent lung inflammation. SYNTHESIS |W0$j In one aspect, provided herein is an mpnoclenal antibody or antibody fragment thereof that binds to an apoptosis-associated Spes-like protein containing a 20' caspase-activating recruitment (ASC) domain, wherein the antibody, or antibody fragment specifically binds to an ASC epitope, wherein the epitope comprises: o consists of the amino acid sequence Ί t of SEQ ID NO: 5 © S-IS, 10-15 or 15-20 amino acids of SEQ ID NO: 5.

[0010] In this respect, provided herein is a monoclonal antibody or antibody fragment thereof which specifically binds ASC, wherein the antibody or antibody fragment is. comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the amino acid sequence of the VH region comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NQ: 7 and HCDR3 d® SEQ-ID NO: 8, or a variant thereof having at least one amino acid substitution in HCQ.R1, HCDR2 and / or HCDR3> In some cases, the sequence of amino acids of the VH region comprises SEQ ID NO: Id, 19, 20, 21, 2.2- or an amino acid sequence that is at least 95%, M%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 18, 19, 20, 21 or 22. In some cases, the ASO is ASC protein In some cases, the antibody fragment is a Fab, an F(ab')2, a Fab', a scFv , a single domain antibody: or a single chain camelid antibody or a shark antibody. In some cases, the monoclonal antibody or antibody fragment thereof is human, human, or chimeric. In some cases, a description is provided here. isolated nucleic acid molecule encoding the mongclonal antibody or ®is®o andcudpQ fragment. In some cases, an expression vector comprising the nucleic acid molecule is provided herein. In some cases (here it is provided that the η α c1e ic acid molecule is operative and provides adequate regulatory sequences for the expression of the nucleic acid segment in a host cell, In some instances, a recombinant host cell comprising the expression vector is provided herein.In another aspect, a method of producing an antibody or antibody fragment that binds to specifically to ASC, the method comprises: culturing a recomdant host cell comprising the X5 expression vector under conditions in which: the nucleic acid molecule is expressed, thus producing the monoclonal antibody or the body fragment thereof that binds specifically to ASO In some cases, a pharmaceutical composition is provided herein comprising the monoclonal antibody or antibody fragment thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. Presently, a small amount is allowed to treat inflammation in a subject, the method comprises administering to the subject a therapeutically effective amount of the monoclonal antibody to the antibody fragment thereof, thereby treating inflammation in the subject. In some cases, administration of the monoclonal antibody to the antibody fragment thereof reduces the levels of at least one inflammatory cytokine. In some cases, the inflammation is an inflammasome-related inflammation. In some cases, inflammation related to inflammation is rg associated with central nervous system (CNS) lesion, an autoimmune, autoinflammatory, or neurodegenerative disease♦ In some cases, the SEC lesion was selected from the group consisting of lesion traumatic brain injury (ΤΒΪ), cerebrovascular accident and spinal cord injury; spinal In some cas®, the: disease, autoimmune or neurodegenerative is amictrophic lateral sclerosis lea: (ALS), .Aiaheimer's disease,. Parkinson's disease, muscular dystrophy (ΠΜ)< systemic lupus erythemp^ lupus nephritis, ur Lr iti.s rheumat o.i de, disease 2p Inflammatory bowel (eg, Crohn's disease and ulcerative colitis) or multiple sclerosis (MS). In some cases, the inflammation related to the inflammaaoma is associated with a metatheolytic disease or disorder... In some ΙΟ houses, the metabolic disease is síndro.me raet abulic, obesity,. Diabetes mellitus, diabetic nephropathy p diabetic kidney disease (DKD), insulin resistance, atherosclerosis, a lipid storage disorder,5 a glycogen storage disease, medium-range AA dehydrogenase deficiency, liver disease non-alcoholic fatty acid (eg, non-alcoholic steatohepatitis (NASH)) and gout. In some caeos, the autoinflammatory disease is the syndrome: jq perrodlpo associated with cryopdrd.ua (CAFS), CAPS can encompass. familial cold autoinflammatory syndrome (ECAS), Mocile~Wells syndrome (IMWS) and neonatal onset multisystem inflammatory disease (NOMID). In some cases, the administration of the antibody ο ο η o o 1 o n a 1 o é .1 fragment 15 of the antibody results in the inhibition of the activation of the inflammation in the subject. In some cases , administration of the monoeIonal antibody © the antibody fragment thereof results in a reduction of ASC activity in comparison with a Obhtrol, In some cases, the control is an untreated subject. In some cases, the administration is ihtala perebroveptricula^intrapciitoneAl, iniravehpsa or porinhcitolon. In some instances, herein provides a method of treating Multiple Sclerosis (MS) in a subject, the cpMpreneur to administer to the subject a therapeutically effective amount of the mnoclonal antibody or antibody fragment thereof, thereby treating the MS in the subject In some cases, administration of the monoclonal antibody or antibody fragment thereof reduces the levels of at least one inflammatory cytokine, In some cases administration of the monoclonal antibody or antibody fragment thereof results in the 1$ inhibition of luxlamasome activation in the subject. In some cases, administration of the monaclonal antibody or antibody fragment thereof results in a reduction in ASC activity compared to a control. In some cases, the control is a. untreated subject. In some. cases, the administration is intracerebroventricular, intraperitoneal, intravenous by inhalation.

[6011] In yet another aspect, provided herein is a monoclonal antibody q an antibody fragment of the same pg that specifically binds to ASC, wherein the antibody p the antibody fragment comprises a light chain (Vi) variable region and a variable region of heavy chain (VH), where the amino acid sequence of the VL region comprises WDR1 of SEQ' ID NQ: 12, LCDR2 of SEQ XD NQ: 13 and LCDR3 of SEQ ID NO: 14, or a variant thereof having at least one amino acid substitution at 1CDR1, LCDO and / or LCDR3. In some cases, the amino acid sequence of § region VI comprises SEQ ID NO: 2 3, 29, 30, 31, O a. amino acid sequence that is at least 95%, 96%, 97%, 98%, or: 99% identical to the amino acid sequence of SEQ ID NO: 28, 23, 38, or 31, In some cases, ASC is ASC protein human. In some cases, the antibody fragment: is a X0 Fab, a F{ab') 2, a Fabr, a 'scFv, a single domain antibody, a diabody or a single chain c-amelid antibody. In some cases, the mchoclonal antibody or antibody fragment thereof is human, humanized, or chimeric. In some ca.»§, here is provided a.. X5 isolated nucleic acid-0 molecule encoding the monoclonal antibody or antibody fragment thereof. In some cases, an expression rheoton comprising the nddleic acid molecule is provided herein. In some cases, the nucleic acid molecule is provided herein to be operatively linked to appropriate regulatory sequences for expression of the nucleic acid segment in a host cell. In some cases, a host cell is provided herein. raeambinaate host comprising ©1 expression vector.. In another aspect, this document provides a method for producing an antibody © an antibody fragment that specifically binds to ASC, the method comprises: culturing a reeotototo host cell comprising the expression window in conditions in which the nucleic acid molecule is expressed, thus producing the monoclonal antibody or the antibody fragment thereof that specifically binds to ΑΕΕ. In some instances, there is provided herein a pharmaceutical composition comprising the monaclonal antibody or antibody fragment thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some instances, a method of treating inflammation in a subject is provided herein, the method comprising administering to the subject a therapeutically effective amount, of the "lonoclonal" antibody or antibody fragment^ thereof, thereby treating the inflammation in the subject. In some cases, administration of the monoclonal antibody or the do q antibody fragment thereof reduces the levels of at least one inflammatory cytokine. In some cases, the inflammation is an inflammation related to the inflammasoxua.. In. some cases, the Inflammation, related to the inflammasome, is associated with lesion of the central nervous system (CHS), a mutoimmune disease. autoinf lamatcria or neurodegenerative. In some cases, the CNS lesion was selected from the group consisting of traumatic brain injury {TBI}, accident ce f abrevasa^ and spinal cord injury (SCI). In some cases, the autoimmune or neurodegenerative disease is amyotrophic lateral eseleresis (ALS), Alzheimer's disease, Parkinson's disease, muscular dystrophy <DM), systemic lupus erythematosus ^0, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease ( eg, Crohn's disease and ulcerative colitis) or multiple sclerosis (MS)» In some cases, inflammation related to inflammation is associated with a metabolic disease or disorder. In some X5 cases, the metabolic disease is metabolic syndrome, obesity, diabetes mellitus, diabetic nephropathy or diabetic kidney disease (DKDj, insulin resistance, atherosclerosis, lipid storage disorder, glycogen storage disease, glycogen storage -medium chain coenzi® A dehydrogenase, nonalcoholic fatty liver disease (for example, nonalcoholic steatohepatitis (KASH)) and gout» In some cases autoinflammatory disease is cryopyrin-associated periodic syndrome (CAPS), CAPS may include familial cold autoinflammatory syndrome (FCASQ, Muctle-Wells syndrome (NWS') and neonatal death inflammatory disease iNOMID) In ​​some cases, either administration of the monoclonal antibody or antibody fragment of the same day resulting in inhibition of inflammasorna activation in the subject.In some cases, administration of the wonxxncn-í antibody or antibody fragment thereof results in ana χρ reduced activity, of ASE in comparison. with a controller. In some, qagos, the control is an untreated subject. In some cases, administration is intracerebroven^ intraperitoneal intravenous© by inhalation. .In. In some cases, a method is used to treat multiple sclerosis (MS) in a subject, the method comprises administering to the subject a therapeutically effective amount of the monclonal antibody or antibody fragment thereof, thereby treating the EM in the subject. In some cases, administration of the gg mondeIonal antibody or antibody fragment thereof: reduces levels of at least inflammatory oxytokine. In some cases, administration of the monoclonal antibody or antibody fragment thereof results in inhibition of inflammaplasma activation in the subject. In some cases, administration of the monoclonal antibody or antibody fragment thereof results in reduced ASO activity compared to a control. In some cases, the control is a subject: untreated. In some cases, administration is intracerebroventricular, intraperitoneal, intravenous or post inhalation.

[0012] In yet another aspect, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds ASO, wherein the antibody or antibody fragment comprises a heavy chain (VH) variable region. and a light chain variable region (VE), where the amino acid sequence of region VE 15 comprises HCDR1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 7 and HCDR3 gives SEQ ID NO: 8, or a variant thereof having at least one amino acid substitution in HODR1, HCDR2 and / or HCDR3; and where the amino acid sequence of the VL region comprises 1CDR1 of ó-EQ ID KG12zX.CDR2 of SEQ ID NO: 13 and 21) LCDR3 of SEQ ID NO: 14, or a variant of the system that has at least one substitution of amino acid in LCDR1, LCDR2 and / or LCDR3 „ In some cases:, the amino acid sequence of the VH region comprises SEQ ID NO: 1S:, 19, 20, 21, 2 2 r an amino acid sequence that is at least 95%, 96%, 97%, 98 % or - 99% identical to the sequence. amino acids of SEQ ID NO: 18, 19, 20, 21 or 22; and wherein J.a amino acid sequence gives the VL region comprising SEQ ID NO: 28, 29, 30, 31, or a .5 amino acid sequence that. is at least 5%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 28, 29, 30, or 31. In some cases, the amino acid sequence of the VH region comprises SEQ ID NOo 18, or an amino acid sequence that is at least 95%, 96%, 97%, 98% 1q or 99% identical to the amino acid sequence of SEQ ID NO: 18; and wherein the amino acid sequence of the VL region comprises SEQ ID 30: 2 8 or An amino acid sequence that is at least 95%, 96%, 97% > 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 28. In some cases, the amino acid sequence of the region. VH comprises SEQ ID NG: 18, or an amino acid sequence that is at least 95%, 95%, 971, .93% or: 99% identical to the amino acid sequence of SEQ ID NO: 18; and wherein the amino acid sequence of the VL region comprises SEQ' ID SD: 29 or a pg amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID K.Q: 29. In some cases, the amino acid sequence of the VH region comprises SEQ ID NO: 18., or a sequence that is at least: 96% 97% 98% or 99% identical to the amino acid sequence from SEQ ID NO;: 18; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 30 or an amino acid sequence that a® is at least 95%, W%, 97%, 98% § or 99% identical to the amino acid sequence of SEQ: ID NO: 30< In some cases, the amino acid sequence of the VE region comprises SEQ ID NO; 18, or an amino acid sequence that is at least 95% 96%, 97% 98% or 99% identical to the amino acid sequence of SEQ ID NQ: 1% and where the amino acid sequence of Region VI comprises SEQ ID NO: 31 or an amino acid sequence that is at least 95% 96% 97% 98% or 99% identical to the amino acid sequence of SEQ ID NO: 31. In some cases, the amino acid sequence of the region VH understands the SEQ ID NO: 19, or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 19; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 28 or an amino acid sequence that is at least 95%, 96% 97%, 98% or 99% gg identical to the amino acid sequence of SEQ ID NO: 28 In some cases, the amino acid sequence of the VH region comprises SEQ ID NO: 19, or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NQ: 19; and where the amino acid sequence of the VL region. comprises SEQ ID NO: 29 or an amino acid sequence that is at least 9 59, 96%, 97%z 98% or 99% identical to the amino acid sequence of SEQ ID NO* 29. In some cases, the amino acid sequence of the VH region comprises SEQ ID NO: 19, or an amino acid sequence that is at least 95%, 95%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 19.; and where the amino acid sequence of region VI comprises 1st SEQ ID NO; 30 or an amino acid sequence that is at least 95%, 90, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 30. In some cases, the amino acid sequence of the VH region comprises SEQ ID NO; 19, or- a 5-amino acid sequence that is ai wws 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 19; and where the amino acid sequence of region VI comprises SEQ ID NQ: 31 or an amino acid sequence that is at least 95%, 96%, 97%, 98% c<99% identical to the 2Q amino acid sequence of SEQ ID NO; 31. In some cases, the amino acid sequence of the VH region comprises SEQ ID NO: 20¿ or an amino acid sequence that is at least 95%, 95%, 97%, 98% © 99% identical to the sequence amino acids of SEQ ID NO: 20; and where the sequence of amino acids gives the rule VE coincides with SEQ I> W 28 or a sequence of arain or icids that is less than 95%, 96%, 97, 98% or 99% identical to that amino acid sequence.® give SEQ ID NO: 28. In some cases, the amino acid sequence of the VH region comprises SEQ ID NO: 2 0, or An amino acid sequence that is at least 95%, 96%, 97<, 98%, or 99% identical to the sequence of amino acids of. SEQ ID SO: 20; and wherein the amino acid sequence of region vi and g comprises SEQ ID DC: 29 or uses amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID DO: 29. In some cases, the amino acid sequence of the VK region comprises SEQ ID KQ: 20, or an amino acid sequence that is at least 95%, gp 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NQ: 20.; and wherein the amino acid sequence of the VL region comprises SEQ TD MQ: 3Ό or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ DO ID: 30. yp In some cases, the amino acid sequence of the VM region comprises SEQ ID NO: 20, or an amino acid sequence that is at least 9 5%, 9 6%, 97%, 98%, or 9 9% identical to the gene. of amino acids from SEQ ID DQ: 20; and where the sequence gives: amino acids of the VL region comprises SEQ IB so: 31 or an amino acid sequence that is at least 95:%, 9 6%, 97'%, 98% or 9 9% identical to sequence Xa of amino acids of SEQ ID NGc 31, In some cases, the sequence of and amino acids of the W region comprises SEQ ID NO: 21, or an amino acid sequence that is. at least 95%, 9Si, 97%, 90 or 99% identical to the amino acid sequence of SEQ ID NO: 21; and where the amino acid sequence of the. VL region comprises SEQ ID NO: 28 o. a sequence of amino acids XQ that is at least 95%, 96%, 97%, 98%, or 9:9% identical, to the amino acid sequence of SEQ ID NO: 28. In some: cases, the amino acid sequence of the VH region comprises SEQ ID NO: 21, I heard an amino acid sequence that is at least 95%, 96%, 97%, &S%, or 99% identical to the jg: amino acid sequence of SEQ ID NO: 21; and wherein the amino acid sequence of the VL< region comprises: SEQ ID NO.: 29 or an amino acid sequence: which is. ^1 least 9:5%:79:6%, 97%, or 99% identical to the amino acid sequence of SEQ TD NO: 29.,:In some cases, the -amino acid sequence of the 'VH region comprises the SEQ TD NO: 21, or an amino acid sequence that is at least 9.5%, 9:6%, 97%, 9.8%, or 99%: identical to the amino acid sequence of 9EQ ID NO: 21; and where: the amino acid sequence of the. VL region buy SEQ ID NO: 30 or more amino acid sequence: that: is at least 95%, 96%, 97%; 98% .q 99% identical to the amino acid sequence of SEQ ID SO: 30. In some cases, the amino acid sequence: of the VH region comprises SEQ ID NO: 21, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 21; and where the amino acid sequence of the VL region comprises SEQ ID NO: 31 or an amino acid sequence that is at least 951, 96%, 97%, 98% ig or 99% identical to the amino acid sequence of SEQ ID NO: 31. In some cases, the amino acid sequence of the VH region comprises SEQ ID NO: 22, or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to that of amino acid sequence of SEQ ID NO: 22; and wherein the amino acid sequence of the VL region comprises SEQ ID DO: 28 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or '99% identical to the amino acid sequence of SEQ ID NO: 28. In some cases, the amino acid sequence of the V.H region comprises SEQ ID 2Q DO: 22, or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID WO-t 22; and in. where the amino acid sequence of the rtn_^í VL comprises the- SEQ ID NO: 29 or an amino acid sequence that is at least 95%, 9 6%> 97%, 99% or 99% identical to the amino acid sequence of SEQ ID NO: 29. In some cases, the amino acid sequence of the VH region comprises SEQ ID NO: 22, or an amino acid sequence that is at least 951, 96%, 975, 9§1, or 99% identical to . the amino acid sequence of SEQ TD N d 22; and wherein the amino acid sequence of the Vi region comprises SEQ TD NG: 30 or an amino acid sequence that is at least 9 5%, 96%, 97%, 98% or 99% identical to. the amino acid sequence of SEQ ID NO: 30. In some cases, the amino acid sequence of the VH region comprises SEQ ID NO: 22, or an amino acid sequence that is at least 9 5 9, 96%, 97% , 98% or 99% identical to the amino acid sequence of SEJ 19 NO: 22; and where the; amino acid sequence, of the VD region comprises :SE.Q ID NO: 3.1 or an amino acid sequence, which, is at least 95%, 96%, 97%, 98% or 99%. identical to the amino acid sequence of SEQ ID NO: 31. In some cases, the ASC is a human ASO protein. In some qasss, the antibody fragment is a Rafe·,· an F(abf}2, a FabS, a scFv, a 2Q single-domain antibody, a diabody, or a single-chain camelid antibody* In some cases, the mono!nal antibody or antibody fragment thereof is human, humanized, or chimeric* In some cases, a single domain molecule is provided here isolated nucleic acid, encoding the monoclonal antibody or the antibody fragment thereof. In some cases, an expression vector is provided herein comprising the nucleic acid molecule-, En. some cases. / here .it is provided that the nucleic acid molecule is operatively linked to regulatory sequences suitable for expression of the nucleic acid segment in a host cell., In some cases, a cell is provided herein: recombinant host comprising the expression vector. In another aspect, provided herein is a method of producing an antibody or antibody fragment that specifically binds to ASCs, the method comprising culturing a recombinant host cell comprising the expression vector under conditions under which it is expressed. the nucleic acid molecule; thus producing the monoclonal antibody or the antibody fragment thereof - which specifically binds to ASC. In some cases, a pharmaceutical composition is provided herein 2Q comprises the antibody- monoclone1 or antibody fragment thereof / and a pharmaceutically acceptable carrier, diluent, or excipient. In some cases, it (presently documented) provides a method: to treat inflammation in a subject, The method comprises administering to the subject a therapeutically effective amount of the monoclonal antibody or antibody fragment thereof, thereby treating inflammation in the subject In some cases, administration of the monoclonal antibody or antibody fragment it reduces levels of at least one inflammatory cytokine.In some cases, the inflammation is an inflammasome-related inflammation.In some cases, the inflammasome-related inflammation is associated with central nervous system (CNS) lesion, a autoimmne, autoinflammatory, or neurodegenerative disease... In some cases, CNS injury was selected from the group consisting of traumatic brain injury (TBI), stroke, and spinal cord injury (SCI), In. In some cases, the autoimmune or neurodegenerative disease is amyotrophic lateral sclerosis (ALS), Alcheimer's disease, Farkinson's disease, muscular dystrophy (DM), systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, 2Q inflammatory bowel disease (for example, Crohn's and ulcerative colitis) or multiple sclerosis (ΕΝ). In some cases, inflammasome-related inflammation is associated with urm ©nfcrmodsc or me disorder. t abol i cc. in 0(00070 cases, the metabolic disease is metabolic syndrome, obesity, diabetes raellitus, diabetic nephropathy or diabetic kidney disease (PKD), insulin resistance, atherosclerosis, a lipid storage disorder, r a glycogen storage disease, medium-chain acid-enzyme A dehydrogenase deficiency, non-alcoholic fatty liver disease (eg, non-alcoholic steate hepatitis (NASH) ), and gout In some cases, the autoinflammatory disease is the syndrome Cryopyrin-associated periodic X0 (CAPS), CAPS may encompass familial cold autoinflammatory syndrome (FCASJ), Muckle-Wells syndrome (MWS) and neonatal-onset maltisystemic inflammatory disease (ΝΟΗΣΕ). In some cases, administration of the antibody - monoclonal antibody fragment: thereof results in inhibition of inflammasome activation in the subject In some cases, administration of the monoclonal antibody or antibody fragment thereof results in a reduction give ASC activity compared to a control.In some cases, the control is an untreated subject-, In some cases, administration is intracerebroventricular, intraperitoneal, intravenous, or by inhalation.In some cases, given here A method of treating multiple sclerosis (MS) in a subject, the method comprises administering to the subject a therapeutically effective amount of the monoclonal antibody or the antibody fragment thereof, thereby treating the MS in the subject. subject. In some cases, administration of the monochthonal antibody or antibody fragment thereof reduces levels of inflammatory cytokines. In some cases, administration of the monoclonal antibody or antibody fragment thereof results in the inhibition of inflamma soma activation in the subject. In some cases, administration of the monoclonal antibody or antibody fragment thereof results in a reduction in: ASC activity compared to a control. In some cases, the control is an untreated subject. In some cases,. administration is intracerebroventricular, intraperitoneal, intravenous or by inhalation.:, BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The EIG. 1A-1N illustrate inflammasome activation in Cóu / BLE mouse lung and cartilage tissue after TBI. FIG 1A shows a representative immunoblot of caspaactive arenel, ASC, IL-18, ΙΕ-β, HMGB1 and AIM2 after ΤΒΪ. Caspase-1 active <FIG IB), ASC (FIG XC), IL~18 (EX®.. ID), 1», X (FIG IF) and IIβ, (FIG 1G), are significantly elevated in cortical tissue at 4 and 24 h after TBI. Data are presented as: medial. / - SEM, ****p < 9.001, **·*ρ <0.01, **p <0.01, *p <0.0 5 compared to the simulation. N 4-5 per group ·. The Fig:. 1H shows a representative immunoblot: active caspose-1, ASC, II-18, XL-p, HMGS1 and AI®2 in lung tissue. I, i, K·, 1, Μ, N) Active Caspase-i !0 (FIG iI), ASG (FIE. U), 11-18. (FIG 1K), HMGB1 (FXG..1A):, AI®' 2 (.FTG. 1M) and IA~{3 (FIA..IP) are significantly elevated in lung tissue 4 and 24 h after PCT . The data is present as mediae / ~ SEM. p 4~5 p:prgroup, <0.901, ***p <0.01, *#p;<0.01, *p and p <0.05 compared to sham. 10014] FIG 2A-2C illustrates the expression of inflamma.cma: proteins in m-type alveolar epithelial cells. FIG 2Ά shows ΑΙΜ2, the FXG. 2B shows active Caspase-1 and FIG 2.G' shows ASC immunoreactivity apxagntos in 20: lung tissue after CCI (1.24 M compared with mice: confocal images of AIM2, casp.ase-1 and A.S;C (green) and type-IX epithelial cells (protein C s u r f a c t an t. β, red).

[0015] FIG 3A~3E illustrates that ΤΒΪ increases the expression of nuclear HMGB1 and eitaplás^ in the lung of mice. FIG 3A shows a representative immunoblot of nuclear HMGB1 after TBL, FIG 3B shows that La 5: Nuclear EMGBl is significantly elevated in 4-h wounded animals compared to sham. FIG 3C shows a representative immunoblot of cytoplasmic HMGB1 after TBI. FIG ID shows that cytoplasmic HMGB1 is significantly elevated in 4 hour lesioned animals compared to mock. Data are presented as mean 47- SEM; *p < 1.05 compared to sham. N “4·-5 per group. FIG 3:E shows that HHGB1 immunoresults were increased in lung tissue after COI compared to sham mice».Coarse images of HMGB1 and TI-type epithelial cells {surfactant protein C, red).

[0016] FIG 4A-4G illustrates the formation of p i reptosomes in the lungs of mice 4 hours after TBI, FIG 4Ά shows that IBI. induces the formation of ABC scales in the lung tissue, indicating the formation of the pyroptosome, an oligomerization of ASC nuclei that leads to caspase-1 activation and pyroptosis. The E.I.G. 4 E m u es c r η η η ¿5 .i. η nu n o t r a i i s f e r e n u i a r e p r e s e u t a t .1 v a y 1 a FIG 4C shows the quantifi cation of' gasdermiha. Gasdermin-D is significantly elevated in lung tissue after TBI. Data are presented as mean / - SEM. E-4-5 per group, "p < 0.01 compared g to sham:" {0017] FIG 5A-5B illustrates that TBI induces alveolar morphological changes and acute lung injury in mice. FIG 5Ά shows H&E staining of lung sections from sham and lesioned animals at 4 and 2 4 hours. The 1Q sections; show evidence of neutrophil infiltration •arrowheads), changes in the morphology of the alveolar capillary membranes (asterisk, *} , interstitial edema (short arrows), and evidence of thickening of the interstitium: and the alveolar septum (pound, |) * FIG, IB 15 shows that the Acute Lung Injury score is significantly increased in injured animals compared to sham at 4 and 14 hours.Data are presented as mean+. / -·SEH» N - 4-5 per group, *p < 0.05 compared to sham.

[0018] FIG 6 illustrates the expression of QD.81 in EV derived from serum of control and TBI-lesioned raen. Representative immunoblot of CD81 in EV derived from mock control serum and TBI-injured mice. [0019| FIG 7A-7G illustrates the adoptive transfer of EVs from animals with cuspase-I inducing TBI and ASC in the lungs of non-lesipnate mice. FIG Fig. 7A illustrates a representative immunoblot that. sample. that caspase-1 (Fig. 7B% ASC (Fig. 7C% IL-18 (Fig. 7D), AIM2 (Fig. 7E% HMGB.1 (Fig. 7F)) are elevated in the lungs of animals receiving EV isolated 131 mice compared to VE of sham animals Data are presented ©ornómedla+7-SEM *p < 3.05 compared to sham N ~ 3 per group VE of TBI mice induced alveolar morphologic changes (reduced alveolar size) and inflammatory cell® infiltration as determined by staining, with H&E (FIG 7G) The ALI score is significantly increased in EVs delivered by injured mice compared to uninjured mice (FIG 7G ) „ Data are presented as mean / - SEM; **p < 0.01., *p < 0.05 compared to group: uninjured. [0(1201 FIG 8.A-8F illustrates enoxaparin treatment (3 mg / kg) and IC 100 (5 mg / kg) reduce inflammasome expression in the lungs of animals given 3dml illustrated EV from lesioned mice.FIG 8A illustrates a representative immunoblot showing that caspase-1 (FIG BB) , ASC (FIG 8G% IL-1> (FIG BD) , AIM2 (FIG, OU LMGB1 (FIG 8 F} are reduced in the lungs of animals that were treated with euosparin and IC 100 compared to control animals untreated positive. Dates are presented as msdia-r / - SEM; ****p<0.001, ***p<0.01, **p<0.01, *p<0.03 compared to sham. N = 4 per group, 100211 FIG, 9A-9E illustrates treatment with enchaparin (3 mg / kg) and IC 100 (5 mg / kg) reduces the ALI score in the lungs of animals which. 10 injured mice were given EV. FIG 5A-9D H&E staining of lung sections from saline (FIG, 9$), untreated (FIG 9BJ, enoxaparin (FIG 9G) and IC 100 Unti-Á&C; FIG, 9P; lungs from EV-treated mice Sections show evidence of neutrophil infiltration, changes in alveolar capillary membrane morphology, interstitial edema, and evidence of thickening of the interstitium and alveolar septum.FIG 9E illustrates that acute lung injury scoring is significantly reduced in enoxaparin-treated animals, CI 10 0 compared to untreated animals.Data are presented as mean d / - SEM, N - 4 per group, ****p < 0.ID., *p <0.05.

[0022] FIG 10A-10F iksLu el s un i ni al. r o de EV derived from serum of 1BI patients resulting in ό increased expression of inflamma soma protein in lung endothelial cells. 1, ASC, AIM2, HMGB1 in FMVEC after incubation with TBIEV and control-EV for 4 hours. FIG, 1OB-1OE shows quantification of Western blots, n - 3 filters per group, n = 6 patients, t-test, ****p. <0.091, ***p 1Ó **p -<0:,QÍ, *ρ 10.03. FIG 1Ó shows the: Immunoassay highlights of significant increase in TL-Ιβ expression using simple olex assay Ella n ~ 3 filters per group, n — 6 patients, t-test, ****p < 0 -.001, *tp:< p ,01., sp Q5„ (»«231 FIG,. 11A-I1C illustrates that administration of TBIEV to lung endotolial cells increases active caspase-1 immunoreactivity and cell death, FIG, 11A shows the - Caspase-1 FLIGA colocalization and PI staining and PMVEC incubated with TBT-EV for 4 hours. 11G shows the analysis, from the LED to fluorescent plates34 of PMVEC incubated with TBI and control-EV for 4 hours, n - 6, ***p eff g ef

[0024] FIG 13A-12E illustrates that treatment with a humanized anti-ASC monoclonal antibody (ie, IC 100) 5 improves functional outcome in EAE, FIG 12A shows the clinical course of HOG35-55-induced EAE in C57BL / 6 mice treated with carrier or increasing doses of IC 100. Administration of IC 100 (10, 30 and 45 mg / kg ip every 4 days) was started on day 8, before the mice showed 10 signs of paralysis. Results are expressed as clinical score: daily mean, i SEM of 9-10 mice / group. The 30 and 45 mg / kg curves are significantly different from the carrier curve; ** p < 0.001 Fenn test “Wít.h^ FIG, 12B: imu.es tra a comparison of the 15 maximum clinical scores (highest disease score achieved by a mouse) between groups; Fe £ Ofe.5, Student's t-test. FIG, 13C shows a comparison of the Cumulative Disease Index (GDI) between groups. The.Oi is equal to Xa sum of all fe scores, gg from day of onset for each animal and is a measure of EAE severity; *p E 0.05, Student's t-test. the ig. 12D ..shows a comparison of the onset day between the groups, EX onset day is considered the day on which a mouse showed the first symptoms of EAE. FIG 12E shows a comparison of the peak day of illness between groups. The highest sickness day is the day on which a racen reached the highest sickness score. Onset day 5 is considered the day a mouse showed the first symptoms of EAE. [OT25] FIG 1?·7>-1?Β insanity that treatment with IC 100 reduces the infiltration of peripheral immune cells into the spinal cord or he beat after ΕΆΕ. SúaStíOW pdr cíWméttla of flow of the pcbl asiotes Q®. leukocytes infiltrating the spinal cord (FIG 1M) or present in the spleen (FIG 13B) at 35 dpi after EAE. Results are expressed as average 1 SEM of 5 mice / group, *p <pf05f **p <0.001, Student's t-test.

[0026] FIG 14 illustrates that treatment with IC 100 reduces microglia in the spinal cord after ERE. Quantification by flow cytometry of total initial and MHCU+ activated microglia in the spinal cord at 35 dpi after EAE. Results are expressed as average i SEM of 5 mice / group, *p < 0.05, tudont t-test.

[0027] FIG 15 illustrates the concentration of IC 10 0 in tissues. IC 100 concentrations in pg / ml in brain, spinal cord, liver and based on control catches and IG 100 treated mice at 10, .30 and 45 mg / kg at 35 dpi after EO. These data are shown as mean ± ÁEM. N ~ 2~1O / rats per group.

[0028] The ELG. 16; illustrates that the IQ 100 is captured in ASC in unstimulated THP-1 cells and uptake is increased by inflammasome activation. [00291 FIG, 17 illustrates that IC 100 prevented the release of XL1-beta from THP-1 cells. [00301 FIG 18 shows confocal images of spinal cord neurons illustrating that an anti-ASC antibody (XC 1001) penetrates spinal cord neurons.

[0031] FIG 1S illustrates a comparison of antibody binding of three different antibodies against. human ASC to different species,

[0032] FIG 20 illustrates the induction of the inflammasome per nicotine (500 nM) in human nucleus pulposus cells and treated with three different antibodies against human ASC (H1, H2, H3) and two against mouse ASC (Mi, M2). , H1 was if more effective in preventing I.Libeta release / inflammasome activation.

[0033] The. FIG 21 illustrates raw BLI kinetic analysis data for monoelonal anti-ASC antibodies. (0034j FIG 22 illustrates a comparison of the kinetics of three different antibodies against human ASO. DETAILED DESCRIPTION DAAIOClONÉS ' (0035] Unless otherwise defined, all technical terms used in this document have the same meaning; as understood: · commonly a technical expert to which this invention pertains. (0030] Section references used in this document are for organizational purposes only: and should not be construed as limiting the purpose described. All documents, © part of documents, cited in this document, including, but not limited to, patents , patent applications, articles,< free and treated, are expressly incorporated herein by reference in their entirety for any purpose.In the event that one or more of the documents incorporated © parts of: documents: define a term · that contradicts the definition of that term in the application, the definition that appears in puta: application shall prevail.However, mention, of any reference, article, publication, patent, patent publication and patent application cited in this document does not it is, and should not be taken as recency, or any form of suggestion, that it constitutes valid prior art or forms part of common general knowledge in any country in the world. ÍWH The ended a OR a refers to one or more of that entity, that is, it can refer to several referents. As such, the terms one or one, one © more, and at least one are used interchangeably herein. In addition, the reference to an element in the indefinite article nú or una does not exclude the possibility that more than one of the elements is present, unless the context clearly requires that there be one and only one of the elements.

[0038] Unless the context otherwise requires, a. throughout the present specification and claims, the word. comprises and variations thereof, such as, comprises, and comprises are to be construed in an open, inclusive sense as including, but not limited to. It should be understood that the use of the alternative: (for example, or) means one, both or any combination of the alternatives. As used herein, the terms approximately and consisting essentially of mean + / - 20% of the indicated range, value, or structure, unless otherwise indicated.

[0030] Reference throughout this specification to an embodiment or embodiment means that a joint feature, structure, or characteristic described in connection with the embodiment may be included in al aews an embodiment of Therefore, occurrences of the phrases in one embodiment or in one embodiment in various spots throughout this specification may not necessarily be present. refer all: to. same embodiment. It is appreciated that certain features of the disclosure, which, for clarity, are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various disclosure features, which, for brevity, are described in the. context..© of a single embodiment, they can also be .separated q in malquier qufó.pgmbw^ adequate.

[0040] Throughout this description, various aspects of the methods and compositions provided herein may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as inflexibly limiting the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. For example, the description of a range as 1 to 6 should be considered to have subranges specifically described as 1 to 3, 1 to 4, 1 to 0, 2 to 4, 2 to 6, 3 to 0. , etc., as well as individual numbers within that range, for example, 1, -2, 3-, 4, 5 and 6. This applies regardless of the width of the range. [mu] As used herein, protein and polypeptideα,'' are used synonymously to mean any peptide-linked amino acid chain, regardless of length or post-translational metabolism, eg, glinosylation or phosphorylation. IW42J As used in this document, the term "antibody" refers generally and broadly to immunoglobulin (ig) molecules and immunologically active portions or fragments of immunoglobulin molecules, ie, molecules that contain a site. union -a Φ-Φ is specifically nnne- Cinmunor^^ with) an antigen (eg, ASE, NLRB1, ΆΙΜ2, etc.), The antibodies provided herein can be polyclonal antibodies, monoclonal antibodies tmAh), 5 chimeric antibodies, humanized antibodies , anti-idiotypic (anti-Id) antibodies against antibodies that can be labeled in soluble c-bound form, as well as active fragments, regions or derivatives thereof. Antibodies for use in the present ,1a may be chimeric^.·, humanized 1Ú -or human.

[0043] Eor "specifically binds" or "immunoreactive" is understood to mean that the antibody reacts with one or more antigenic determinants of the desired antigen and does not react with other polypeptides. In certain embodiments, an antibody is said to specifically bind to an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules. The term antibody refers: broadly to a molecule of innu :..,u ι-Φ :lina (1φ , pg that generally comprises four polypeptide chains, two heavy chains (H) and two light chains (Lj, or any functional fragment , mutant, variant, or derivative thereof, which retains the essential target-binding characteristics of an Ipi molecule. Such mutant, variant, or derivative antibody formats are known in the art. -ASO and anti-NLRP1 of the present invention are capable of binding to portions of ASC and OH, respectively, which interfere with caspase^i activation. [00441 As used herein, the term "humanized antibody" refers to an antibody in which minute portions of a non-human antibody are introduced into Ip an antibody' that would otherwise be human. [00451 As used herein, the term "human antibody" refers to an antibody wherein substantially each part of the protein is substantially non-immunogenic in humans, with only- σ minor sequence variations. [00461 In a full length antibody, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region 20 comprises three domains, CH1, Cü2 and Cü3. Each light chain comprises a variable region: light chain (abbreviated herein as LCVR or VL) and a light hip constant region. The light chain constant region comprises a domain, CL. The VH and VL regi nes can be further subdivided into regions of hypervariability, called determinant regions of oomplemen larity. (CDEj , interspersed with regions that are more conserved, termed .5 framework (FR) regions, Each VH and VL is composed of three CDRs and four FRs, arranged from amine-terminus to carbomi-terminus in the following order: FRL, CDR1, FR2, CDR2, FR3, CDR3, FR4, The immunoglob^ molecules can be of any type (eg, IgG, IqE, IgM, IgD, IgA, and IgY) eg and class (eg, ñ;GL LgG:2 , IgG3, LgG4, IgAl, and IgAG) or subclass IgG, IgD, and IgE antibodies generally contain two identical heavy chains and two identical light chains and two antigen-combining domains, each composed of a variable region of the same chain. heavy (VH) and a variable region of light (VL) chain IgA antibodies are generally composed of two monomers, each monomer consisting of two heavy chains and two light chains (like IgG, IgD, and IgE antibodies); Either way, the IgA molecule has four domains of 2nd binding to the antigen, each one of them, again composed of a VH and a d. Certain IgA antibodies are monomeric in that they are composed of two heavy chains and two light chains. Secreted IgM antibodies are generally composed of five monomers, each monomer composed of two heavy ® chains and two ligara ® chains (such as IgG and IgE antibodies); thus, the IgM molecule has ten antigen-binding domains, yield ρησ composed § again of a VH and a VL < There is also a cell surface form of XgM and this has a two-heavy-chain structure / two light chains similar to IgG, IgD and IgE antibodies.

[0047] The term tet^eδ©,,or antigen-binding portion' or antigen-binding site or binding domain'·' or binding region, as used herein , can refer to the domain, region, portion, or site: of a protein, polypeptide, cligopeptide, or peptide or antibody or antibody-derived binding domain that retains the ability to specifically bind to an auriger (for example, .ASC protein). > Exemplary binding domains include variable regions of single-chain antibodies (eg, domain antibodies: siv, scEv, soFab), fusion proteins that coMpp-end an antibody portion (eg, a domain of antibody), ect©receptor and ligand® domains (for example, Cyt-ocines, guimioquiñás} . Fm a form of real 1 Pation, the fusion protein comprises one or more CDR(s). In another form©| of embodiment, the fusion protein comprises ODR H3 (VH CDR3) and / or CDR 13 (VI CDR3)> For purposes of this invention, a fusion protein contains one or more antibodies and an additional amino acid sequence such as For example, a heterologous sequence or a hamalegous sequence from another region, attached to the N or € end of the antibody· or antibody fragment thereof... Heteralegous sequences. Examples include, but are not limited to, a: Míwta* such: as a FLA> tag or a 1q Sois tag or an enzyme or- a pelipeptide that increases the half-life of the antibody in the blood. Tags are well known in the art. The additional amino acid sequence; which may include amino- and / or carboxyl-terminal fusions, may vary in length from one residue to 15 polypeptides containing one hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues [00481 Generally, an antigen-binding site may be formed by l.ps immunoglobulin domains of the 2nd variable region of the heavy chain (VH) and of the variable region of the chain: light (VL), with the antigen-binding interface formed by six loops of surface polypeptides, called complementarity determining regions (CDRs). There are three CDRs each in VH (HCDR1, HCDR2, HCDR3) and VL (LCbR1, LCpO, together with framework regions (FR). In certain embodiments, the binding domain comprises or consists of an antigen binding site. 5 (eg, comprising one variable heavy chain sequence and one variable light chain sequence or three light chain complementary determining regions (CDRs) and three heavy chain CDRs of an antibody placed in framework regions (FRs) (for example, human RFs that XQ optionally comprise one or more amino acid substitutions).

[0049] The term CDR or CDR region can mean the hypervariable regions of the immunoglobulin heavy or light chains as defined by Kabat et al., 1991 xó iKabat, EA et al ♦, (1991) Sequences of Froteins of Immunological Interast, Sth Edition. US Department of Health and Human Services, Public Service, NIH, Washington), and subsequent editions. An antibody, typically contains. 3 C.DR of posed chain and 3 CDR of light chain.

[0050] It has been shown that the antigen-binding function of an antibody can be performed by full length fragments of an antibody. The fimes of .realization of antibodies and fragments of ant. ibodies can also be bispecific, trispecific, dual specific, or multispecific formats; specifically bind to two or more different antigens. Examples of binding fragments included in it end ''antigen-binding fragment'* d^ ur ínl λΈβ / ρ·? include: (i) a Lab fragment consisting of VL, VH, CL and CH1 domains (feard, ES et al., (1989) Natura 341, 544-54E); (ii) an Fd fragment consisting of the ·. VH and t:Hl (MoCafferty et al,, (1990) Saturé, 348, 552-554); (iii) an Fe fragment consisting of several VL and VH domains of a single antibody (Holt et al., (2003) Trenos in Biotechnology 21, 4.34 -00); (fe) a fragment: dAb (Ward, ES et al,, Nature 341, 544-540 (1989), McCafferty et. al., (1990) Nature, 348, 552-554, Holt et al., (2' 003) Trends in Biotechnology 21, 484-490], consisting of a VH or VL domain; (v) isolated CDH regions.; (vi) Ffab'jSr fragments a bivalent fragment comprising two linked Fab (vil) Fv fragments of single-chain (scEv) molecules, in which a VH domain and a VL domain are linked by a peptide linker that prevents the two domains from associating to form an antigen-binding site (Sird et al., (1988 ) Science, 242, 423-426, Huston et al., (1988) PNAS USA, 85, 5879-5883).The invention also encompasses a Fab# fragment.In addition, although the two domains of the FvrVL and Vil fragment are encoded ppr separate genes, they can be joined, using rsuombinant methods, by a synthetic linker that allows them to be made as a single protein chain in which: the VL and VH regions pair up to form molecules: .monovalent (known as single-chain Fv (seh 'h Such monocatenaric antibodies are also intended to be included within the term ^antigano-binding fragment of an antibody. In certain embodiments of the invention, scFv molecules may be incorporated into a fusion protein. In some embodiments, the invention includes a single chain camelid antibody; (vil!) Fv single-chain bispecific cimers (PCT / OS921099S5) and (ix) diabodies', 15 multivalent or multispecific fragments constructed by i.Sxvn muca Hv Lliger, P. (1993) et al., Proc. nati. Acad Sai. OSA 90 6444-6448). Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single gg polypeptide chain, but which use a linker that is too short to allow matching between the two 1st-chain domains, thus forces the domains to pair with complemented domains from another chain and creating two antigen-binding sites (see, for example, Holiiger, B., et al. (199.3) Proa:, bati. Acad. Scí. USA 90: 6444-6448; Fcijak, RJ, et al. {1994} Structure 2: 1121-1123).. Such antibody binding fragments are § known in the art (Kentcrmann and Dubel eds., Ardboáy Enginecring (2Q01) Springex-Vérlag. New York. '7 9 0 pp.} In some aspects, the invention includes a single domain antibody In general, the term "antibody" when used herein: encompasses an antibody fragment. An antibody fragment generally retains the anion properties to the antigen of an antibody - of 1 ©:ng i t u d c omp 1 e t a . (M5I] Fv, scEy, or .diabody molecules can be stabilized by incorporating disulfide bonds that span the VH and VL domains (Reiter, T. et al., Matute Blotaoh, 14, 1239-1245, 1996} Minibodies can also be prepared that comprise a scFv linked to a CH3 domain (Hu, 8. et al., (1996) Cancer Res., 56, 3:055-3061). Lab', which differs from the Fab fragments by the addition of some residues at the carbyl end of the domain: CAI of La cadéné: heavy, including one or more steins from the hinge region of the antibody, and Fab'~SH , which is a Fab' fragment, where the cystaine residue(s) of the dcm' us constants bear a free thiol group. [0052J W, when used herein, can refer to the minimal fragment of an antibody that retains both the "antigen recognition" and antigen-binding sites. Fab when used. in this document it can refer to a fragment of an antibody comprising the constant-domain of the light chain and the CH.1 domain of the heavy chain. The term mAb refers to a. monkey ig antibody the © n al,

[0053] The 'Fe region' or 'Fe domain' refers to a polypeptide sequence corresponding to or derived from the portion of a source antibody that is responsible for binding to body receptors. cells and IS; Clq component of the complement. Fe stands for 'crystalline fragment' - the fragment of an antibody that will readily form a protein crystal. The various protein fragments, originally described by protein digestion, may define the general structure of an immunoglobulin protein. As originally defined in the Mblipgrafxa, the Fe fragment consists of the disulfide-linked heavy chain hinge regions, CH2 and GH3 domains. More recently, however; the term has been applied to a single chain consisting of CH3, CH2, and at least a portion of the hinge sufficient to form a desulfurized dimer linked to a second such chain. For a review of the structure and function of immunoglobulins, see Rutnam, The Plasma Proteins, Vol. V (Academy Press, TNC, 1987), pp. 49-140,' and Padlan, Mol, Immunbl. 31:169217, 19 94. As used herein, the term Fe includes variants of naturally occurring sequences. In one embodiment Xq, the antibodies or antibody fragments derived therefrom provided in. This document (for example, monoelonal anti-ASC antibodies or antibody fragments thereof) have a modified Fe region or domain. In some cases, the modified X5 region or Fe domain may confer greater thermal stability to the resulting antibody or antibody fragment derived therefrom. increased thermal stability: may result in increased serum half-life. The Fd region or domain may be modified as described in US 2016.0193295, the meaning of which is incorporated herein by reference. As described in US2016019329S, the Fd region or domain may be modified to possess a deletion of one α plus cysteine ​​residues in the hinge region and substitution with a snlfhydrylp-containing residue of one q„ plus aminopdcl due to the CK3 interface. In another embodiment, the Fe region or domain of antibodies or antibody fragments derived from them The same proposed herein (for example, the anti-ASC monoclonal antibodies or antibody fragments thereof) can be stabilized by modifying the Fe region to possess intra-domain disulfide bonds as described in Wozniak-Knopp G: , Sta'dlmann J, Aüker F (2912) Etabilization of the Fe Fragment oí Human IqGl by Engineered Intredomain Disulfide Bonds. PLoS ONE 7(1): ©30083, the contents of which are incorporated herein by reference x In yet another way: of embodiment, the antibodies have modified Fe regions as described in WO 99 / 5857 2 > which is incorporated herein as reference. In still other embodiments, the Fo region or domain may be modified as described in US9574010, the contents of which are incorporated herein by reference. !00S4| By the terms apoptosis-associated Speck-like protein containing a caspose-activating recruitment domain (CAED) and- -'ASCW is meant an expression product of an ASC gene or isotherms thereof, or a protein sharing at least 65% , 7 5% 80% 8 5% 9C% 95% 96% 97% 98% or 99% amino acid sequence identity cor ASC (for example, S%O373§0 (£9%%%% H:%%&183 %9ΟΡΖ3~2) or Q9ULS3“3 in humans, NP 075747 in mouse or p N%75S825 (BAC4375^j ​​% rats) and shows a functional activity of ASC A functional activity of a protein ss any activity associated with the physiological function of The funcionaXe® activities of ASC include, for example, the recruitment of .proteins for Xa JO activation of caspasal and initiation of cell death. [BG55| By the term ASC gene p ASC nucleic acid is meant a nucleic acid sequence encoding native ASC, gecomic sequences a. paítir of which the ASC cDNA and / or sialic variants can be transcribed and 15 homologues of the above. The terms encompass %catanaxed DNA, single-stranded DNA, and RNA. [0656| As used herein, the term inflammasome means a multi-protein complex (eg, at least two proteins) that activates cuspase ~ 20 1. Furthermore, the term inflammasome can refer to a multi-protein complex that activates cuspase activity. easpasa~% which, in their view, regulates the processing and activation of IL-1% XL-18 and ΙΊ,-3% See Arenó et al. 2008; Li et he. 2008; and Maxtinon et al. 2002, each of which is incorporated by reference in its entirety. The terms NLRR1 inflammasome, NALP1 inflammasome, NLRP2 inflammasome, NALP2 inflammasome, §NLRP3 irflamasome, NALP3 inflammasome, NLBda^ inflammasome, i.nf lamasoma I£AF or inflamaseme ATM2 / Z mean a protein complex of at least caspase-1 and an adapter protein, eg, ASC. For example, the terms inflammasome NLRP1 and inflammasome:NALP1 can mean a multiprotein complex containing NLRP1, ASC, casposaI, caspase-II, XIAP, and pannexin-1 for caspaseal activation and interlaukin-ΐβ processing. i.interleukin-18 and interleukin- 33. The terms NLRP2 inflammasome and NALP2 / ' inflamaseme can mean a multi-tiprotel^co-complex containing MLRP2 (also known as NALP2), ASO and easpasa-1, while that the terms NLRP1'1' inflammasome and NALF3“ inflammasome may mean a multiprotein complex containing NLRP3 (also known as NALP3), ASQ. and the terms 20 NLRC4 inflammasome and IPAFW inflammasome can mean a. multiprotein complex containing NLRC4 (also known as IPAF), ASC and caspase-1. Furthermore, the term Inflammascma AXM2 can mean a multi-protein complex comprising AIN12, ASC and caspase-1.,

[0057] As used herein, the phrase sequence identity* means the percentage of identical .5 subunits at corresponding positions in two sequences (eg, nucleic acid sequences, amino acid sequences) when the two sequences align. to maximize the pairing of subunits, that is, taking into account the gaps, and the Insertions; Sequence identity rg: can be measured using count analysis software (eg, sequence analysis software package from Acoelrys CGC, San Diego, CA).

[0058] The phrases "therapeutically effective amount" and "effective dose" refer to an amount sufficient to produce a therapeutically (eg, clinically) desirable result; the exact nature of the result will vary depending on the nature of the disorder being treated. For example, when the disorder to be treated is a WE, the result may be an improvement in motor skills and locomotor function, a decrease in spinal cord injury, etc. The compositions described in this document can be administered one or three times a day to two or more times a week. The skilled killer will appreciate that certain chemicals may influence the dosage and time required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, previous treatments, general health, and / or the age of the subject, and other diseases present. In addition, treatment of a subject with a therapeutically effective amount of the compositions of the invention may include a single treatment or a series of t. r at am lenses,.: ¡0059] As used in this document, . The term treatment is defined as the application:c administration of a therapeutic agent described in this document, or identified by a method described in this document, to a patient, e the application or administration of the therapeutic agent to an isolated tissue or line cell phone of a patient..., who has a disease, a symptom of a disease or a pre-opposition to a disease, with the purpose of curing, healing, alleviating, alleviating, altering, remedying, improving or affecting the disease# the symptoms of disease , or predisposition to disease.

[0060] The terms patient, subject and individual are used interchangeably herein and mean a mammalian subject to be treated. In one embodiment, the mammalian patient is a human. In some cases, the methods of the invention find use in experimental animals, in api i cao; veterinary sciences and in the development of animal models for diseases, including, but not limited to, rodents, including mice, rats, and hamsters, as well as primates.

[0061] As used interchangeably herein, Absent in melanoma 2 and ATM2'·' can mean an expression product of an AIM:2 gene or isoforms; or a protein that shares at least 65%:, 7 5%, 8 0%, 8 5%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with ΑΪΜ2 {for example, accession number(s) NX 0148:82, 0004824, 0016858337, XPQQ52 4567 3, AÁB81613, BAF34731, AAH1094Q) and shows functional ATM? activity. (00621 Cone uses d rrc3e;> protein 1 containing domains. NAQHT, LRR and 9íDf?, Ñ'ALEl and NLRP1 mean an expression product of a gene or isoforms of NALPl or NLRP1; or a protein that shares at least 65%, 751, 89%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with NALP1 (eg, number of acoceó) AAH51787, NP 90102:8:2:23, NP_127500, W_127499, NP_127497, 0055737). y shows an aut i v ity f one i a1 of NALP1.

[0063] Com© is used interchangeably herein, NAL92 and NLPP2 mean an expression product of a gene or isotherms of NALP.2 or NLRP2; or a protein that shares at least 651, 75%, 80%, 85%,. 96%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity to NALP2 (eg, accession numbers NP 001167552, NP 001167553, W_001167554 © NP_060322) and shows functional NALP2 activity. [0064.] As used interchangeably herein, NALP3 and NLRP3 mean an expression product of a gene or isotherms of NALP3 or NLRP3; p a protein that shares at least 65%, 75%, 86%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with NALP3 (e.g., numbers of access NP 001073289, NP_001120933, NPJJ01120934, Hp 012 30062, NP_00488€, NPJ99632, XP_011542350, ^0168 55670, XPJ)I6855$71, XPJH685S672 or XP,016855673) and shows functional NALP3 activity,

[0065] As used interchangeably herein, NLRC4 and iPAF signifjc^u an expression product of a gene. or isoforms from NLRC4 or IPAF; or a protein that shares at least 65%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with NLRC4 (for example, numbers of access NP 001Á86087, ΝΡΌΟΊΙΒΟΟΟΕfo SP__0<7Q32; and shows a functional activity of N L RC 4. [OO] The terms cerebrovascular accident' and ischemic cerebrovascular accident' refer to when blood flow is interrupted. part of the brain or spinal cord 1.

[0067] By traumatic CNS injury is meant any insult to the CNS by an external mechanical force, possibly leading to permanent or temporary alterations of CNS function.

[0008] Methods involving conventional molecular biology techniques are described in this document. Such techniques are generally known in the art and are described in detail in methodology treatises such as molecular cloning; Laboratory Manual, 3* ed.. Val. 1-3, ed. Sgmbrpak et al., Cold Spring Harbor Laboratory Press, Cald Spring Herbar, New Eck, 2001; and Current Protocols in Molecular Biolegy, ed. Ausubel et al., Gceene Publishing and Wiley-IntersaiéncA,. New York, 1292 Icon regular updates i . Immunology techniques are generally known in the art and have been described in detail in methodology treatises such as the Advanoes in Immunology, vplume 33, ed. Default ut W·. Alt, Acadamip Press. Burlington, ΜΑ, 2007; Mahing and Using Antibodies; A Practice Handbook, eds. Gary 0. Hgward and Matthew R. Kaser, ,CRC .Press, Boca Raton, FL, 2QM; Medical Immunology, ed., edited: by Gabriel Virella, reports Healthcare Press, London, England, § 2007; and Harlow and Lene ANTXBODXES: A Laboratory Manual,. Coló Spring .Harbor Labora dory Freos, Cold Spring Harbor, H¥, 198 8 . [00691 Although similar, or equivalent compositions and methods to those described may be used: in this document 1.0 in the practice or testing of the present invention, suitable compositions and methods are described below. All publications, patent applications and patents mentioned in this document are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, shall prevail. The particular embodiments discussed below are illustrative and are not intended to be limiting. OVERVIEW

[0070] Herein: provided are monoclinal antibodies or antibody fragments thereof that specifically bind to the apoptotic-associated Spec-like protein that. contains a casposa activator recruitment domain .(ASC), Monoclonal antibodies or Κλοτλ utos u< os os ρι.'ΛΛί mus? u-'p u r.icrivnu -¾ uu antigenic fragment of ASC that comprises, consists of, or consists essentially of an amino acid sequence of SEQ: ID NO. 5 < In addition to this embodiment, the invention contemplates the. use of tonoclonaic antibodies or antibody fragments thereof in a method of treating inflammation in a subject. The inflammation may be X0 an innate immune inflammation. The inflammation may be an inflammation related to the inflammasonsa. In one embodiment, the monocalonal antibodies or antibody fragments thereof provided herein can be used in a method of reducing inflammation in a mammal as described in US 8,685,400. the contents of which are incorporated herein by reference in their entirety. The inflammation may be in the lungs and / or in the central nervous system (CNS). Inflammation in the lungs and / or the CNS may be the result of injury20 (eg, traumatic brain injury, TBI) or spinal cord injury (SCI) or CNS disease, condition, or affliction or affecting the CNS As provided herein, the disease, condition, or affliction of the CNS or that to the CNS can be a stroke, cardiovascular accident, autoimmune diseases and / or CNS diseases, including Leu Gehrig's amicotrophic lateral sclerosis (ALS), multiple sclerosis (MS)f 5. CNS immune dysfunction, muscle breakdown, muscular dystrophy (DM), Maheimer's disease (AD), Parkinson's disease (PD), The use of the monclonal antibody © antibody fragment thereof in a method of treating inflammation may reduce infection in the CNS and / or lungs of the patient. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the monoclonal antibody to the antibody fragment derived therefrom is used to treat MS by administering the monoclonal antibody to the antibody fragment derived therefrom to a patient suffering from or suspected of suffering from MS. The antibody, monelone! The antibody fragment thereof of this embodiment may be present in a composition such as, for example, a 2Q pharmaceutical composition as provided herein. In some cases, the monoclonal antibody or fragment thereof is used in combination with one or more other agents in the treatment methods provided herein. The other agents can be any agent provided. herein (eg, EV uptake inhibitors) and / or antibodies or antibody fragments directed against, other components of the inflamase (eg, IL-18, caspase-1, NALP1, ΑΣΜ2, oto.)♦

[0071] The. The invention also encompasses antibodies, monoclonals, or antibody fragments thereof that specifically bind to ASC, where the antibody or antibody fragment comprises a heavy chain variable region (VHj) and a light chain variable region (VE), where the VH region The amino acid sequence comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 and HCDR3 of SEQ ID NO: 8, or a variant thereof having at least one amino acid substitution in HCDR1, WDRÍ and / or HCDR3 In addition to this form of reprimand, the invention contemplates the Use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation, in a subject... The inflammation may be an innate immune inflammation. Inflammation may be an inflammation related, to the inflamma soma, In and g one embodiment, the monoclonal antibodies or fragmentps do antibodies, of> Jas ais ® »» provided herein can be used in a method of reducing inflammation in a mammal as described in the document US 8. ύο5,4üU (the contents of which are incorporated herein by reference in their entirety. Inflammation may be in the lungs and / or CNS. Inflammation in the lungs and / or CNS may be the result of injury ( for example, traumatic brain injury (TBI or spinal cord injury (SCI)) or disease, condition, or affliction of the CNS or affecting the SBC.Case is provided herein, the disease, condition, or affliction of the CNS c that Affects the CNS can be a -cerebrovascular accident, as well as autoimmune diseases and / or CNS diseases, including Leu Gehrig's amycerotic lateral sclerosis (ALS),- multiple sclerosis (MS),- logical dysfunction of the CNS, muscle degradation , muscular dystrophy (DM), Alzheimer's disease (AD), Parkinson's disease (PD). X5 The use of a Monoclonal body or antibody fragment thereof in a method of treating inflammation can reduce inflammation in the CNS and / or lungs of the patient. The use of the mcnoclonal antibody c antibody fragment of the same mcd in a method for tr^tsx the ir.i limation can reduce innate immune inflammation or re-lam with the inflammasome in the patient. The reduction can be compared to a control (eg, untreated patient and 7th patient before treatment). In one embodiment, the monastic anticnerpp or the antibody fragment derived therefrom is used to treat a lesion of the central nervous system (SN0) and / or a neurodegenerative, autoimmune, autoinflammatory, or metabolic disease. CNS lesion I know. You can select from the group consisting of Traumatic Brain Injury (TBI), Stroke, and Spinal Cord Injury {SCI>. autoimmune or neurodegenerative disease can be selected from amyotrophic lateral sclerosis (ΕΒΆ), Alzheimer's disease, Parkinson's disease (PD), muscular dystrophy < DM), systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease (eg, Croan's and ulcerative colitis) and multiple sclerosis (jMS, In one embodiment 1.5, the menoclonal antibody or antibody fragment derived therefrom is used to treat ΈΜ by administering the monoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of suffering from MS In one embodiment, the monoclonal antibody 2Q or antibody fragment derived therefrom is used to treat PD by administering the monoclonal antibody to the antibody fragment derived therefrom to a patient suffering from have or are suspected of having PS. In one embodiment, the moneolonal antibody or antibody fragment derived therefrom is used to treat lupus nephritis by administering the microclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of suffering from lupus nephritis. . Metabolic disease can be selected from syndrame metaphoileus, obesity, diabetes, diabetic nephropathy or diabetic kidney disease (DKD), insulin resistance, atherosclerosis, a storage disorder: jg of lipidoSf a disease by almaenamien Lo of glycogen, acll-eoenzyme A dehydrogenase medium chain deficiency, nonalcoholic fatty liver disease (eg, nonalcoholic steatohepatitis (NASH)), and gout. In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat diabetic nephropathy by administering the monoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of suffering from diabetic nephropathy. In one embodiment, the monoclonal 2-antibody or antibody fragment derived therefrom is used. to treat .NASH by administering the monoclonal antibody. p antibody fragment derived therefrom to a patient suffering from or suspected of suffering from NASH, t disease 6Ί autocinfiamatory may be cryopyrin-associated periodic syndrome (CAPS). CAPS may encompass cold autoinflammatory syndrome (ACES), Muckle-Wlis syndrome (WS), and inflammatory disease. and mu 111 s 1 neonatal onset systemic {RGMID). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat CAPS by administering the monoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of having CAPS. The monodonal antibody or antibody fragment thereof in this form. The embodiment may be present in a composition such as, for example, a pharmaceutical composition as provided herein. In some cases, the monoclonal antibody or fragment thereof is used in combination with one or more other agents. in the treatment methods provided here. The other agents can be any agent provided herein (eg, E-uptake inhibitors) and / or antibodies or antibody fragments directed against other components of the inflammation (eg, 1L~18, caspase-1, NALP1 , AIM2, etc.).

[0072] In some embodiments, the invention provides mnoclenal antibodies or fragments. of antibodies thereof that specifically bind to ASC, wherein the antibody or antibody fragment comprises a light chain variable region (VL) and a heavy chain variable region (VH) wherein the amino acid sequence of the VL region comprises LCDF1 of SEQ. ID NO: 12, LCDR2 from SEQ Ib NO: 13 and LQDR3 from SEQ III NO: 14, or a variant thereof having at least one lp aminoacM substitution in LCER1, LCDR2 and fe LOOR3. In addition to this embodiment, the invention contemplates the use of the moboclonal antibody or antibody fragment thereof in a method of treating inflammation in a subject. The inflammation may be an .inflammation .immune lunette. The i η ~ 1 am i in may be an inflammasome-related inflammation. In one embodiment, the monoclonal antibodies or antibody fragments thereof provided herein can be used in a method of reducing inflammation in a mammal as described in the document US 8,685,400, the contents of which are incorporated herein by reference in their entirety. Inflammation may be in the lungs and / or in the SSC, Inflammation in the lungs and / or the. CNS can be the result®, of a leifm (for example, traumatic brain injury (TBI) or spinal cord injury (SCI)): or disease, condition or affliction of CSF or affecting the CNS. As provided herein, the disease, condition, or affliction of the CNS or affecting the CNI may be stroke, as well as autoimmune diseases and / or CNS diseases, including Lou's amyotrophic lateral sclerosis (ALS). Gehrig, multiple sclerosis (MS), CNS immune dysfunction, muscle breakdown, muscular dystrophy (MD), 1Q Alzheimer's disease^ (AD), Parkinscn disease (EPI . The use of the monoclonal antibody or antibody fragment thereof in a method of treating the. inflammation can reduce inflammation in the y / p lungs of the patient. The use of the mcnoclonal antibody or antibody fragment X5 thereof in a method of treating inflammation can reduce innate or rslscionads immune inflammation. the i ni lamas orna in the patient. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the monoclonal antibody and the antibody fragment derived therefrom is used to treat a central nervous system (CNS) lesion and / or an autoinflammatory, metapolytic, asthoimmune disease. BNC injury can be from the group consisting of traumatic brain injury (TBI), stroke and spinal cord injury (ECI), Au:tdinimmune b neurode.generat.iva disease can be selected from sclerosis amyotrophic lateral (ALS), alrheimer's disease, Parkin's disease & cn PSC), dystrophy: muscular (DM), systemic lupus erythematosus, lupus nephritis, arthritis. rheumatoid, inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis), and multiple sclerosis (HD). In one embodiment, the monclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the moneo lona! or the antibody fragment: derived therefrom to a patient suffering from or suspected of having MS* In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat PD by administering the mcnoclonal antibody or the antibody fragment derived therefrom to a patient suffering from or suspected of suffering from PD. In a. In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat epic nephnhs 1 by administering the monoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of suffering from lupus nephritis. Metabolic disease can be selected from metabolic syndrome, obesity, diabetes mellitus, diabetic nephropathy to diabetic kidney disease (DKDj, insulin resistance, atherosclerosis, a tombstone storage disorder, a glycogen storage disease, acyl-coenzyme deficiency A medium chain dehydrogenase, nonalcoholic fatty liver disease (eg, nonalcoholic steatohepatitis (NASH)), and gout In one embodiment, the mondeIdnal antibody or antibody fragment derived thereof is used to treat ne The monoclonal antibody or antibody fragment derived therefrom was administered to a patient suffering from or suspected of having diabetic nephropathy by a diabetic repeat patient.In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is Is? rr.xiiXítnnj? the manoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of suffering from CASd. autoinflammatory disease may be oriopyrin-associated periodic syndrome (CAPS). CAPS may encompass familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multiple inflammatory disease (NOMIB). In one embodiment, the monoclonal antipuergO: or antibody fragment derived thereof is used to treat CAPS by administering the monoclonal antibody or antibody fragment derived therefrom, to a patient suffering from suspected CAts. The antibody mono.noclo.ua 1 or antibody fragment thereof in this way. r ea liration may be present in a tai w® composition, for example:, pharmaceutical re edmpocuci&n as provided herein., In some cases, the antibody: mgnooion ©: fragmented from it: ge; use gg in combination with one or more of the other agents in the 1 treatment methods provided here. ©.other agents may be any agent provided in. present (for example, inhibitors of the uptake of 'El) and / or antiquar^ or fragments of antibodies directed against other comenórítes of the inflammason a (for example m p 1 o, I l -18, cas p a s -1, NALPÍ, ALO, etc,}. (0.073'1 EP other embodiments Xa invention, also 20 provides monoelonal antibodies or antibody fragments thereof that specifically bind to. ASI, wherein the antibody or antibody fragment comprises a heavy chain variable region ( VH) and a light chain (VL) variable region, wherein the amino acid sequence of the VH region comprises HQDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7 and HCDR3 of SEQ ID NO: 8, or a variant: thereof, having at least one § amino acid substitution in HCDR1, 'GDR2 and / or HCHR3;: and where the artinoacid sequence of the VL region comprises LCDR1 of SEQ: id NQ; 12, LCDR2 of SEQ ID Mi: 13 and LCDR3 of SEQ ID NO: 1% or a variant thereof having at least one amino acid substitution in LCDR1, LCDR2 and / or LCDR3. In addition to this embodiment, the invention contemplates the use of the mononational antibody and antibody fragment thereof in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The inflammation may be an inflammasome-related inflammation. In one embodiment, the monoclonal antibodies or antibody fragments thereof provided herein can be used in a method of reducing inflammation in a mammal as described in US 8,685,400, the contents of which - are incorporated Here are 20 references in their entirety. The inflammation may be in the lungs and / or in the CNS. Inflammation in the lungs and / or CNS may be the result of injury (for example, traumatic brain injury (ΤΒΪ) or spinal cord injury ÍSEI) ) or disease, condition or affliction of the 'SMC or affecting the CNS. As provided herein, the CNS disease, condition, or affliction affecting the KSK may be stroke, as well as anti-immune diseases and / or CHS diseases, including Lou's amyotrophleic lateral sclerosis (ALS). Sehrig, multiple sclerosis (MS), ECS immune dysfunction, muscle breakdown, muscular dystrophy (MD), Alzheimer's disease (AD), Parkinson's disease (PD). 1Q The use of the monoclonal antibody or- antibody fragment thereof in a method for te to tac id inflammation can reduce inflammation in the 3NC and / or lungs of the. patient. Use of the monoclipnal antibody or antibody fragment thereof (in a method of treating inflammation may reduce inflammasome-related innate immune © inflammation in the patient. The reduction may be compared to a control (eg. Non-treated patient bound and / or patient prior to treatment) In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat central nervous system (CNS) lesion and / or autoimmune disease. , autoinflammatory, metabolic or neurodegenerative CNS injury may be selected •from the group that in traumatic brain injury (TBI) ,. stroke and spinal cord injury (SCI), autoimmune or neurodegenerative disease can be selected from amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Farkinson's disease (EB), muscular dystrophy (DN), systemic lupus erythematosus, nephritis. lupus, rheumatoid arthritis, inflammatory bowel disease (for example, Crohn's disease and ulcerative colitis), and multiple sclerosis (MIE). In one ig embodiment, the monoclonal antibody or the antibody fragment derived therefrom is used to treat MS by administering: the. Menoclonal antibody and antibody fragment derived therefrom to a patient suffering from or suspected of having MS. In one embodiment, the aonoclonal antibody or antibody fragment derived therefrom is used to treat £P by administering the . monoclonal antibody or the antibody fragment derived therefrom to a patient suffering from or suspected of suffering from PD>. In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat lupus nephritis by administering the monoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of suffering from ion nephritis. The metabolic disease can be selected from metabolic syndrome, obesity, diabetes mellitus, diabetic kidney disease or disease: diabetic kidney disease (tD'KD), insulin resistance, atherosclerosis, a lipid storage disorder, a glycogen storage disease, glycogen deficiency, In one embodiment, the monoclonal antibody or the antibody fragment derived thereof is used To treat diabetic nephropathy, administering the monoalone antibody or antibody fragment derived therefrom, to a patient suffering from or suspected of having diabetic nephropathy. In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat NASH by administering the monoclonal antibody or antibody fragment derived therefrom to: a patient suffering from or suspected of having NASH. The autoinflammatory disease may be a periodic syndrome -associated with 2Q cryopyrin (CAPS), CAPS may encompass familial cold autoinflammatory syndrome (FCAS), Furniture-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NQMID). In a. embodiment^ the monoelena1 antibody or antibody fragment derived therefrom is used to treat CAPS by administering the meneelena1 antibody or antibody fragment derived therefrom to a patient suffering from or suspected of having CAPS. The moneelona1 antibody or antibody fragment thereof of this embodiment may be present in a composition such as, for example, a pharmaceutical composition as provided herein. In some cases, the vq manclonal antibody or fragment thereof is used in combination with one or -more of the other agents in lop methods: d$ treatment provided upii. Xps other agents can be any agent provided herein (eg, EV uptake inhibitors) and / or antibodies or antibody fragments directed to other components of the inflammasome (eg, IL-18, caspase-1, NALP1, AIM-2, etc.).

[0074] Provided herein are compositions and methods for reducing immune inflammation. 20: Innate or related to the inflammasome. In some cases, inflammation related to whether iaflamomasome is found in the CNS of a mammal that has been subjected to is affected by a condition that. It produces or causes an innate inflammation or inflammation related to the inf'l amaroma. In some cases, inflammation-related inflammation is found in a mammal (for example, a human) that has or is suspected of being affected by a condition that is associated with, results in, or causes innate or related inflammation. with it inflammaeoma. The condition that causes an innate or related immune infXamaqion. with inflammaeoma can be a lesion of the CNS, a disease trust or non auto i. inmu η. or , auto in f .1 ama .orlo, 1q neurodegenerative and / or metabolic» CNS injury can be selected from the group consisting of traumatic brain injury (TBI), brain accident, and spinal cord injury (SCI)♦ Autoimmune disease or neurodeqenarativa can be 1 s c c i o n a r s e. an t r e s c 1 e r o s i s amyotrophic lateral disease (ALE), .Alzhelmer's .disease, Parkinson's disease (PD), muscular dystrophy (DM), systemic ο lupus erythema, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease (for example, Crohn's disease and culi.ti.®: ulcerative), and multiple sclerosis (JMS, ... Metabolic disease can be selected from metabolic syndrome, obesity, diabetes mellitus, diabetic nephropathy or diabetic kidney disease (DKD), insulin resistance, athorosolerasis, a lipid storage disorder, a glideen storage disease, medium chain aeyl-caenzyme A doshydrogenase deficiency, liver disease non-alcoholic fatty (eg, cold alcoholic steatohepatitis (NASH)) and gofa Autoinflammatory disease may be Eriopyrin-associated periodic syndrome (CAPS) CAPS may encompass familial cold autoinflammatory syndrome (FCAS), Muckle syndrome, and Wells disease (MWS) and newborn-onset multisystem inflammatory disease (NGMID). The compositions: and methods described herein may include antibodies: or active fragments thereof as provided: herein that specifically bind to at least one component (eg, ASC) of a mammalian inflamaseme and / d compounds that: modulate (eg, inhibit or reduce) the extracellular vesicle (üV) uptake and use as- treatments for CNS inflammation oh a mammal. Examples of afeepipnes: that can cause inflammation in the CNS include CNS injury (eg , Spinal Cord Injury^ (SCI), Traumatic Brain Injury pg ¢11:1) © accident .car abrevase a neurodegenerative disease, a. Suttoimmune disease (eg, MS), asthma, chronic obstructive pulmonary disease (COPD), fibrosis: puffy, interstitial lung disease or acute respiratory distress syndrome. Campasicion can be administered in a therapeutically effective amount. A therapeutically effective amount can be a dose as provided in this document. The agent may be an inhibitor of extracellular vesicle uptake (EVj and / or an antibody or a fragmentc:active: 'of the meme as I know it provides in this document that binds to a component of an inflammasome to a combination of the The composition can be administered by any suitable route, for example, by inhalation, intravenously, intraperitoneally or intracerebroventricularly The composition can further include at least one carrier that is pharmaceutically acceptable: 5 b le.

[0075] Herein documents provide guidelines and methods for treating multiple sclerosis (MS) in a subject suffering from or suspected of having MS. The methods for treating MS provided herein may involve the administration of a composition (eg, a pharmaceutical composition) comprising an agent (eg, XC1OE) to the subject suffering from or suspected of suffering from MS. Multiple sclerosis (MS) is an autoimmune disease that affects the brain and spinal cord Subject may present with clinical symptoms consistent with MS Subject may be diagnosed with any type of ΈΜ known in the art MS It can be recurrent recurrent MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) or progressive relapsing MS (PEmS). The diagnosis of MS can be determined or can have been determined using any method known in the art. In one embodiment, the subject has been diagnosed as having Ed using the methods detailed in OS 62 / 560,963, filed September 20, 2017, the contents of which are incorporated herein by reference in their entirety. The agent: can be a standard treatment known in the art for MS, an inhibitor of EV uptake (for example, any inhibitor: of uptake: give EV from Table 1), an antibody or antibody fragment thereof as provided herein that binds to a component of an inflammasome (for example, an anti-ASC monoclonal antibody or an antibody fragment thereof such as, for example, IC 100; or any combination thereof. The composition i:n can be administered by any suitable route, for example, by inhalation, intravenously, intraperitoneally, or intracerebroventricularly. The composition may also include at least one pharmaceutically acceptable carrier or diluent. Standard treatment of Care may be selected from therapies aimed at modifying disease outcome, relapse control, symptom control, or any combination of 5. Therapies directed at disease outcome modification may be selected from beta-interiorenes, glatiramer acetate, fingolimod , terifiunomida, tell me you Lf urna rato, mi tapant roña, ore 1 i zumab, al em t uwsab, d a o1i zumab y nata1i z uma b.

[0076] In e 1 p r es ents do increases provide compositions and methods for treating Piesen's disease (PD) in a subject suffering from or suspected of suffering from ÜP. The methods of treating PD provided in this document may involve the administration of a medicine (eg, a pharmaceutical composition) comprising an agent (eg, IC ICO) to individuals who have or are suspected of having PD. Eartinscc disease (EPi) is a pxgpressive disorder of the nervous system that affects movement due to the gradual degradation and / or death of nerve cells in the brain of a mammal (for example, a living being). human) suffering from PD PD can occur and / or progress through five stages i.e. stages 1 to 5) and the fields of interest and methods provided herein can be used to treat an individual suffering from or suspected that. He suffers in any of the five stages. The diagnosis of EF may be or may have been determined using any method known in the art. In one embodiment, the subject has been diagnosed as having ER using the methods detailed in WO 2013 / 060516, filed September 20, 2018, the contents of which are incorporated herein by reference in their entirety. The agent may be a standard treatment known in. the. technique for PD, an EV uptake inhibitor (eg, any EV uptake inhibitor from Table 1), an antibody or antibody fragment thereof as provided herein that binds to a component of an inflammasome (eg, an antibody: anti-ASC monoclenal or an antibody fragment thereof such as, eg, IC 100) or any combination thereof. The composition can be administered by any suitable route, for example, by inhalation, intravenously, or intraperitoneally. intragerehroventricular, The composition may further include at least one pharmaceutically acceptable carrier or diluent. Standard treatment can be selected from carbldopa (Lodusyn}, combination. da e v o d o p® o arbí d o p a ~ 1 é ve dopa, Du o p a, a g a n i s t as d®. i a dopamine, MAC B inhibitors, 1¾ catechol inhibitors ;O-methyltransferase (CQMT), an icosphainanthadine and deep brain stimulation.Dopamine agonists can be selected from among pramipexole (Mirapex), ropinirole (Requlp) and rotigotine (Neuprc). MAC B can be selected from selsgiline (Eldepryl, Eelapar), rasagiline (Azilect) and safinamide (Xadago) Inhibitors, de-COWT can be selected from Entacapone (Comtan) and Tolcapone (Tasmar). select between benztropine (Qogentin) or trihexyphenidyl.

[0077] Provided herein are compositions and methods for treating Alzheimer's disease (AD) in a subject suffering from or suspected of suffering from AD. The methods of treating AD provided herein may involve the administration of an {eg, a pharmaceutical composition} comprising an agent (eg, IC 10.0) to the subject suffering from or suspected of suffering from AD. 20 Alzheimer's disease (AD) is a progressive disorder of the nervous system that causes brain cells to degenerate and die in people with AD and progresses from mild cognitive impairment (MCI) to total memory loss even if you change in personality and behavior. The diagnosis of AD can be or may have been determined using any method known in the art. In one embodiment, the subject has been diagnosed as having AD using the methods detailed in WQ 2Q19 / 060S16, filed September 20, 2018, the contents of which are incorporated herein by reference in their entirety. being a standard treatment known in the art for AD, uri ig ds EV uptake inhibitor (for example, craLguier EV uptake inhibitor from Table 1), an antibody or antibody fragment thereof as provided herein document that binds to a μη component of an inflammasome (eg, an antipe ASE monoclonal antibody or an antibody fragment thereof such a bed, eg, IC 100} or any combination thereof. The composition can be administered by any route eg, by inhalation, intravenously, intraperitoneally, or iul. (Namenda) . Cholinesterase inhibitors can be. select among dpnepezil (Aricept), galantamlna {RazadyneJ and rivastigmine (Exelonj . Provided herein are compositions and methods for treating rheumatoid arthritis (RA) in a subject having or suspected of having RA. The methods for treating RA provided in this document may involve the administration of a composition (for example, "rafaxra-A'ptica composition") comprising an agent (for example, XC 100) to the subject suffering from or suspected of having RA Rheumatoid arthritis (RAj) is a chronic autoimmune inflammatory disorder that can cause damage to an individual's joints, as well as the skin, eyes, lungs, heart, and blood vessels. of RA can be or may have been determined using any method known in the art.In one embodiment, the subject has been diagnosed as having RA using the methods detailed by me in WO 2019 / 060516, filed September 20 2018, the contents of which are incorporated herein by reference in their entirety. The agent may be a standard of care treatment known in the art for RA, an EV uptake inhibitor (for example, any EV uptake inhibitor from Table 1), an antibody or antibody fragment of the same titer. It is known herein that binds to a component of an inflamed soma (for example, a known anti-ASC antibody or an antibody fragment thereof such as, for example, IC 100) or any combination of the The composition may be administered by any suitable route, for example, by inhalation, intravenously, intraperitoneally, or intracerebraventricularly, The composition may further include at least one pharmaceutically acceptable carrier or diluent. Selected from non-steroidal anti-inflammatory drugs (ΑΙΝΕ), steroids (eg, Prednisone), disease-modifying antirheumatic drugs (DMARDs), and biologics, MINs may include ibuprofen (Advil, Motrin IB), and naproxen sodium (Aleve). DMARPs can include methotrexate (Trexall, Qtrexup, others), leflunomide (Brava), hydroxychloroquine (Elaquenil), and sulfasalazine {Azulfidine). Biologic agents may include abatdcept (Órencia), adalireumab' (Humiraj, arakinra 2Q (Klneret), parieítinib (plumiant), certolizumab (Címcla), etanercept (Enbre.l), golimumab (Simponi ), inflieimab (Remi cade), rituximab {Rituxan.), serilumab ÍKevzara), toeiliaumab (Actemra) and tofacitinib ( xeljanzj.

[0079] Compositions and methods for treating: nephritis are provided herein. pencil in a subject suffering from or suspected of suffering from lupine nephritis. Methods of treating nephritis 1 typlea provided a 5. This document may involve administration of a composition (eg, a pharmaceutical composition) comprising an agent (eg, IC 10U) to the subject suffering from or suspected of suffering from lupine nephritis. Lupus nephritis is a type of kidney inflammation that is often a 1Q- common complication of. systemic lupus erythemates often referred to simply as lupus. Lupus nephritis is an autoimmune disease in which lupus autoantibodies affect the structures of an individual's kidneys, which can lead to kidney inflammation, as well as henaturia, proteinuria, high blood pressure, impaired kidney function, or even failure. renal. The diagnosis of lupus nephritis can be or may have been made using any method known in the art. In one embodiment, the subject has been diagnosed as having lupus nephritis using the methods detailed in WO 2019 / 060516, filed September 10, 2019, the contents of which are incorporated herein by reference in their entirety... The agent may be an art-known treatment for lupus nephritis, an EV uptake inhibitor (eg, any EV uptake inhibitor from Table i), an antibody or antibody fragment thereof as provided herein that binds to a component of an inflammation (for example, an anti-ASC monoclonal antibody or an antibody fragment thereof such as, for example, LC 100). or any combination thereof. The composition can be administered by any suitable route, | (eg, by inhalation, by: intravenous, intraperitoneal, or intracerebroventricular route. The composition may further include at least one pharmaceutically acceptable carrier or diluent. Standard of care treatment for lupus nephritis may: include medications 5 to control blood pressure and / or a special diet low in protein and salt In addition, the standard treatment for: lupus nephritis may, be treatments for lupus such as, for example, non-steroidal anti-inflammatory drugs,, * : d E), medleame ή to s anti pa1udi no s, q cortioosteroids (for example, prednisene; methylprsdnisolana), immunosuppressants: or biological agents. Examples of ΑΪΝΕ may include naproxenc sodium (Aleve) and ibuprofec (Adyil, Motxin IE, others). A. An example of an antimalarial drug may be hydroxyoloroquine (Plaqueni1). Examples of immunosuppressants may include azathioprine (Imuran, Wsan), mycofepolute mol ethyl (CéllCepM and methotrexate coca11), Examples of biologics: may include belimumab Oenlysta) or rituximab (Bituxan).

[0080] Compositions and methods are provided herein ®1: for treating non-alcoholic steatohepatitis (NASH) in a Subject suffering from or suspected to have 30' NASH. The methods of treating NASH provided herein may involve the administration of a composition, (eg, a pharmaceutical composition) comprising an agent (eg, IC 100) to the subject suffering from or suspected of suffering from NASH. NASH is a type of non-alcoholic fatty liver disease (NA-.FLD), NAFLó is a generic term for a variety of liver conditions that affect people who drink little or no alcohol. The main feature of NAFLD is too much fat stored in liver cells and is marked by 2Q inflammation of the liver, which can progress to. scars' and irreversible damage. This damage can be similar to that caused by excessive alcohol consumption. In its most severe form, nonalcoholic steatohepatitis can progress to cirrhosis and liver failure. The diagnosis of NASH can be or may have been determined using any method known in the art. In a form of confirmation, the subject has been diagnosed as having NASH using the § methods detailed in document NO 2019 / 060516, filed September 20, 1616, the contents of which are incorporated herein by reference in their entirety. The agent may be a standard treatment known in the art for NASH, an EV uptake inhibitor (for example, any EV uptake inhibitor from Table 1), an antibody or antibody fragment thereof as provided in herein that binds to a component of an inflammasome (for example, an anti-ASC nmodo^l. antibody or an antibody fragment thereof such as, for example, XC 100} or any combination thereof® The composition may be administered by any suitable route, for example, by inhalation, intravenously, intraperitoneally, or intracerebroventricularly The composition may further include mena® a carrier or 2p di Luyen pharmaceutically acceptable tea·. Standard treatment for ΕΗΝΆ may include lifestyle changes, such as losing weight, increasing exercise, avoiding medications that damage the liver, lowering cholesterol, and / or controlling diabetes. (00811 Provided herein are compositions and methods for treating diabetic nephropathy in a subject suffering from or suspected of having diabetic nephropathy... Methods of treating diabetic nephropathy provided herein may involve the administration of a composition (eg, a pharmaceutical composition) comprising an agent (eg, IC IOS) to the subject suffering from or suspected of suffering from diabetic nephropathy Diabetic nephropathy is a serious kidney-related complication of type diabetes I and type 2 diabetes which may also be referred to as diabetic kidney disease WÓ), The diagnosis of DKD may or may have been determined using any method known in the art. In one embodiment, it has been designed that the subject has: W ubilitando los métodos l éet allied · .in document WG 2W.9 / 0 (é^ presented on September 20, 2018, whose content will 2L incorporates herein by reference in its entirety, The agent can be a treatment- ©standard known: in the art for DEL, an inhibitor of EV uptake (for example, any inhibitor of EV uptake of the Table 1), a. antibody or antibody fragment thereof as provided herein documented that binds to a component of an infiamasome (eg, an anti-asc monoclonal antibody or antibody fragment thereof: such as, eg, IC 100) or any combination of them. The composition may be administered by any suitable route, for example, by inhalation, intravenously, intraperitoneally, or intracerebroventricularly. The composition may further include at least one pharmaceutically acceptable diluent carrier. The standard of care treatment, for the. diabetic nephropathy may include lifestyle changes, colossing weight, increasing exercise, lowering cholesterol, controlling protein in the urine, promoting bone health, controlling high blood pressure, controlling diabetes, dialysis kidney or transplant

[0082] Provided herein are compositions and methods for treating inflammatory bowel disease (Eli) in a subject - suffering from or suspected of having Eli. The methods for treating Eli provided herein may involve the administration of a composition (eg, w pharmaceutical composition) comprising an agent (eg, IC 100) to the subject suffering from or suspected of suffering from Eli, ΕΊΙ is a general term used to describe disorders involving inflammation chronic digestive tract: of an individual. Sil can include ulcerative colitis and Crohn's disease. Ulcerative colitis is prolonged inflammation and sores (ulcers) in the innermost lining of the large intestine (colon) and rectum, while Croan's disease is characterized by inflammation of the lining of the digestive tract, often extending deeply into the affected tissues. The diagnosis of IBD can be or may have been determined using any method known in the art. In a way of. In accomplishment, the subject has been diagnosed as having Eli using the methods detailed in WQ 2019 / 060516, filed September 20, 2018, the contents of which are incorporated herein by reference in their entirety ίό. The agent can be a treatment: known standard in the. technique for Eli, an EV uptake inhibitor (eg, any EV uptake inhibitor from Table 1), an antibody or antibody fragment: thereof as provided herein that binds to a component of an inflammasome (eg, an anti-ASe mcnoclonal antibody or an antibody fragment thereof such as, eg, TC 100) or any combination thereof. The composition can be administered by any suitable route, for example, by inhalation, intravenously, intraperitoneally or intrauerebroyentrieu^ The Pompos^ may further include at least one pharmaceutically acceptable carrier or diluent. Standard treatment for Eli may include anti-infant medications, immune system suppressants, antibiotics, antidiarrheal medications, pain relievers, iron supplements, and calcium and vitamin Θ supplements. Antibiotics may include ciprpf loxain. (Cipra) and metronidanol (Flagyl). Examples of immunological drugs may include azathioprine (ézasan, Imuranj, mercaptopurine (Purinethol, Purixan), cyclosporine (Sangrad, deoral, Sandimmune), and methotrepate Cfrexalljz Other examples of immunosuppressants may include biologic tumor necrosis factor (TNF) alpha inhibitors such as, for example, infliximab (Hemicade), adalimumab (Hamiba), golimumab (Simponi), natalizumab (Tysdbri), vedoi^ gg (Entyvio), and ustekinumab. (Stelara) .. Anti-inflamma tories may include oorticosteroids and aminosalin compounds, such as mesalamine (Asacol HE, Delzlcoi), balsalazide (Calaza!), and olsalazine (Dipentum),

[0083] Provided herein are compounds and methods for treating cryopyrin-associated periodic syndrome (CAPS) in a subject suffering from or suspected of having CAPS. The methods for treating CAPS § provided herein may involve administration of a composition (eg, a Pharmaceutical Composition) comprising an agent (eg, IC 100) to the subject suffering from or suspected of having CAPS. The syndrome had a period. i cos associados aoriopyrina (CAPS), also called associated autoinflammatory syndrome· a. criopin tin., consist of three autoimmune diseases related to a defect in the same gene (ie, NLRP3): neon-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome (MWS)) and familial cold autoinflammatory syndrome (FCAS). NOMID is characterized by fever with inflammation in multiple organs. Early symptoms of NOMID may include a non-itchy, hive-like rash; inflammation of the membrane that: surrounds the brain, causing 20 headache, blindness or hearing loss; bulging appearance of the eyes; and episodes of vomiting. After one year of age, half of children with NOMID may develop joint pain and swelling. MWS is characterized by symptoms: which come and go, such as a skin rash, red eyes, joint pain, and severe headaches with vomiting. Episodes last between one and three days. Hearing loss, which may be complete, often occurs in adolescence. FEAS I know catacteriia for fever, chills, nausea, thirst as well: rheumatism, headache and pain in the joints. SI diagnosis of CAPS can be or may have been determined using any method known in the art. In an ig form of realiza o ion, it is given diagnosed that the subject. has CAPS using the methods detailed in WO 2019 / 06Q516, filed September 20, 2018, the contents of which are incorporated herein by reference in their entirety. The agent can be a standard treatment known in the art for CAPS, an EV uptake inhibitor (for example, any EV uptake inhibitor of the Table 1) , an .antibody or antibody fragment du.1 itself cloned in this documents that binds to a component of an inflammation (for example, a monoclonal anti-ASC antibody. to an antibody fragment of the same as, for example, IC ISO) or any card i nation thereof. The composition may be administered by any suitable route, for example, by inhalation, intravenously, intraperitoneally or intracerebrally. The composition may further include at least one pharmaceutically acceptable carrier or diluent. Standard-of-care treatment for CAES may include biologic agents that target interleukin-1, as well as physical therapy, splints to treat joint deformities, and nonsteroidal anti-inflammatory drugs, corticosteroids, or methotrexate to reduce symptoms. .

[0084] Provided herein are 0 compositions and methods for reducing 1® inflammation in the lungs of a mammal that has undergone or is affected by a condition that results in or causes lung inflammation. The fields and methods described in this document may include antibodies or active fragments of 15· the same· as provided in the. present document {.eg. Id ISO) that specifically bind to at least one component [pW example, ASCj of an in.flama®pma. mammalian and / or compounds that modulate (for example, inhibit or reduce) the uptake of extracellular vesicles iEV) and are used: 2Q as treatments for lung inflammation in a: mamíi ero,

[0085] In the present decumerit methods are described to reduce the inflWacicn in the skins of a ferocious mammal: that gg has a condition that results in and / or causes an inflammatory response in the lungs. In one embodiment, the method of treating inflammation in the lungs of a mammal comprises administering to the mammal a composition comprising an agent (eg, TC 100) that inhibits inflammasome signaling. The mammal can be a patient or subject as provided herein. Examples of conditions. that can cause inflammation in the lungs include damage to the central nervous system (CNS) (for example, spinal cord injury (SCI), traumatic brain injury (TBI), or stroke), neurodegenerative disease, anti-immune disease (eg, MS), asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, interstitial lung disease, or acute respiratory distress syndrome. The composition can be administered in a therapeutically effective amount. The therapeutically effective amount may be one dose, if p>c. . e_> 0.00 v__ a ' <. ,s,jr 2Q inhibitor of extracellular vesicle (EV) uptake, an antibody or an active fragment thereof as provided herein that binds to a component of an inflammasome or a combination thereof. The composition 100 can be administered by any suitable route, for example, by inhalation, by intraperitoneal or intracerebral intravenous route. The composition may also include at least one pharmaceutically acceptable carrier or diluent,

[0086] Provided herein are compositions and methods for reducing inflammation in the kidneys of a mammal' which has been subjected to is affected by a giving condition. does not result in or cause inflammation of the kidney. The compositions: and methods described herein may include antibodies or active fragments thereof as provided herein (for example # IC 100} that specifically bind to at least one component (eg, ASO) of a mammalian inflammasome and / or compounds that modulate (eg, inhibit or reduce) the uptake of extracellular vesicles (EVj and are used as treatments for '« 'í in.K..h in a mammal,

[0087] The present document describes methods of reducing inflammation in the kidneys of a mammal having a condition that results in and / or causes an inflammatory response: in the kidneys. In one embodiment, the method of treating inflammation in the kidneys of a mammal comprises administering to the mammal a 101 composition that: an agent (eg, IG 100) that inhibits inflammasome signaling. The mammal can be a patient or subject as provided herein. Examples of conditions that can cause inflammation in the kidneys include lupus nephritis. The composition can be administered in a therapeutically effective amount. The therapeutically effective amount may be a dose as provided herein. The agent may be an inhibitor of vmcula® "xiwellulares LEV") uptake, üb antibody: or: an active formulation thereof as provided sr. herein that binds to a component of an inflammable or a combination thereof. The composition may be administered by a suitable route, for example, by inhalation, via Intravenous, intraperitoneal, or intracerebroventricular Ί5. The composition may further include at least one pharmaceutically acceptable carrier or diluent.

[0688] In one embodiment, administration of an agent (eg, Antibody p antibody fragment derived therefrom (eg, IC 10C; alone or in combination, eg, with an inhibitor of uptake of EV) in the methods provided in this document may result in a reduction in the level of activity 102 and / or expression of an aompanent©· of a mammalian inflamme in the CNS, kidneys or lungs of the subject. The reduction may be in cells of the lung, such as type II alveolar cells. The reduction may be compared to a central tumor. The control can be "subject before administration of the agent" The control can be the activity and Zd the level of expression of the component(s) of the inflammasome in a subject to whom the agent was not administered, In a As an embodiment, administration of the agent results in the reduction of caspase-1 activation in the subject's SN€ or NSS cells. In one embodiment, administration of the agent results in: reduction of naspase-1 activation in at least the lungs or the. lung cells j§ of the subject. In one embodiment, administration of the agent results in the reduction of the suppression level: one or more. components of the inflammasome (eg, ASC, AXM2, NALpl, NALP2, NALF2, NALF3, or NLBC4) in at least La" CNS cells or the subject's CNS. In one embodiment, administration of the agent results in the reduced expression level of one or more inflammasome components (for example, ASG, AIM2ZNALP1, 103 NALE2, NMJ2, NALP3 or NLRC4) in at least the lungs or lung cells of the subject.

[0089] In. In another embodiment, administration of the agent (eg, antibody or antibody fragment derived therefrom alone: ​​or in combination, eg, with an inhibitor of EV uptake) may result in a reduction or elimination of acute lung injury (ALI). In one embodiment, the reduction in ALX is evidenced by reduced infiltration of 1Q neutrophils into the alveolar and / or interstitial space, reduced or absent alveolar septal thickening, or a combination thereof. The reduction can be compared to a control. Ε.Ί control may be ALp in the subject prior to administration of the agent. The control may be ALX in a subject suffering from ALT who is unknown to be administered the agent.

[0090] In yet another embodiment, administration of the agent (eg, antibody: o-fra.gmenh^ or antibody derived therefrom (eg, IC lOüj alone or in combination, eg, with an inhibitor of the Pyroptosis is a proinflammatory form of cell death that involves activation of caspase-1. 104 be triggered by caspaseal-mediated cleavage of gasdermin D (GSDMD). In one embodiment, reduction of pyroptosis is evidenced by reduction or lack of cleavage of GSDMD in the lungs or lung cells (eg, alveolar cells). type II) of the subject. Reduction or elimination of pyro«c if.s can be compared with a control. Reduction or lack of cleavage of GSDMD can be compared with a control. Control can be the level of pyroptosis in the subject before 0 from agent management. The control may be the level of pyroptosis in a subject suffering from pyroptosis to whom the agent is not administered.

[0091] The success of or response to a method of treatment provided herein (eg, Treatment of lesions of the SNG, autoimmune, autoinflammatory, neurodegenerative, or metabolic diseases (eg, ME, PD, lupus nephritis, NAS:d , ΕΌ, CAPS, inflammation of the gut).(Eli); AD, rheumatoid arthritis), innate or inflammation-related immune inflammation, CNS inflammation, and. / q lung inflammation) can be monitored by measuring levels of at least an inflammasome protein. Accordingly, in some embodiments, treatment methods 105 in this document- further comprise measuring the level of at least one inflammasome protein, in a biological master obtained from the subject after treatment, preparing a signature of the treatment humnmom protein associated with a positive response to treatment. , wherein the treatment protein signature comprises a reduced level of at least One inflammatory protein, and the. identification of subjects exhibiting the presence of the treatment protein signature as positively responding to treatment. A reduction in the level, abundance, or concentration of one or more inflammasome proteins (eg, ASC, IL-18, or caspase-1) is indicative of the efficacy of treatment in the subject. The one or more inflammasome proteins cm. measurements in the sample obtained after treatment may be the same or different from the proteins of the. inflamaseme measurements on a sample obtained before treatment. Inflammasome protein levels can also be used to "titrate" the dose or frequency of treatment < Inflammatory protein levels can be determined using the methods and techniques provided herein or as found in the document OS 62 / 560,963, filed, September 20, 2017. 106

[0092] In a form of re-alligation, the agent to be administered in the. method of treatments provided herein is an EV uptake inhibitor. The EV uptake inhibitor can be a compound, antisense § RNA, siRNA, peptide, antibody or an active fragment thereof as provided herein or a combination thereof. The compound or peptide may be one or more compounds selected from heparin, u-dir luoramethylornithine (DFMOj, enoxaparin, 10 asialafetuin, human receptor associated protein (RAF), RGD peptide (Arg-Gy-A&p), citccalasin D, cytoealasin B, Ethylenediaminetetraaoetic acid (EDTA), Latruncu1in A, Latrunculin B, NSC2376B, Dynaso.ru, C lo rp roma ain, 5- ÍN~ Ethyl-N^isopropyl) amilorxide (EIRA), Amiloride, Bafilomidine IB A Monensin and Gloroquine, Annexin-V, N2940Qmannin, Methyl-gcyclodextrin ( MgCD), filipina, simvastatin, fumonisin B1 and N-but ildeoxino jirimicin hydrochloride, UG126 or a proton pump inhibitor. The r<V uptake inhibitory antibody or an active fragment of the. same as eg provided herein may be one or more antibodies or active fragments thereof directed against protein targets listed in Table 1. a composition for treating and / or reducing inflammation in the CNS or lungs 107 of a mammal using an EV uptake inhibitor may further include at least uh. pharmaceutically acceptable carrier or diluent.

[0093] Table 1. Exemplary targets and corresponding antibodies for use in capitating blockade of MS. Gene Symbol Gene Name Example Antibodies1c ICAM-1 Intercellular Adhesion Molecule i Invitrogen Antibody 1CAM-1 (Life Technologies, 07-5403); ób 5 4 (TP AM~T) anti i criar po manee l on a 1 (R'g, 5) , e B i o a c 1 e n e LÍA-i Antigeno asociado© a la función 1 ihfoc.it lea 1 Abblotee Antibody LEA- 1 (Abblat ^ 2 A0 9 O ) ; Developmental Studies Hybridoma Bank Antibody LFA-l {Developmental Studies Hybridoma Bank, MBM24) 108 Gene symbol Gene name A π t. i c υ a rpo s of e j a m p 1 o O®-® Membrane protein: from: T cells 4 Antibody B i ote g e n d T1MDÁ (8:1010000:0, 354004); lifeSpan B i o s c 1 e n c e s O» antibody (1 if e s p a n 8ioscienoto 1G~B1<13) MFG-E8 Fat globules factor § protein of 1 edi® · “Etc Λ. π t i α u e r p o MB L I n t e r n a t i ona 1 NIEGE 8 (MIL, MáS-Mr Santa Crut niege® Antibody (Santa Gruz, sz-8ü29;; MBA International MFGE8 Antibody (MBA, 1SA2-:G:í0) DC~STGN Molecule from: specific intercellular adhesion of dendritic cells3-No integrin grip Antibody Invi tragan DG SIGN N ​​(é B i o s c i e n o e, e B - h2Q9, 17-.:2099-41) ; Aptioue rpo BB Bies cienes PC SIGN (BD, 109 110 Gene Symbol Gene Name Example Antibodies from Bb Bioseienoes (BD Ph a-mi ng e n, 55 537 0) ITGAL In t ©g r i n a subunit a If a L TS1 / 22.1.1. 13.3; «17 / 4.4,1!.9 ITGAM Integrin alpha M subunit Monoclgnal antibody CPl,lb fVIMl 2) í Olías 91 and BD Bioseienees CD1Ib aútibody (Bb Eharmingen, ÍCRF44; 555385) ITGAX In t eg r1na s ubuπ i ty alpha X Anti-integrin antibody «X, clone N418' (MAB13 9 9 Z); Anti cu © r pe BD Biosciences CDllc (BD Sioselenco, B-ly6; 560363) CU 4 4 c 1 us t o r of differentiation 44 Anti-merpo Invitrogen CD4 4 (eBiosc.ience.< VFF - 7; «Al-82392 ); Invitrogen CD4 4 antibody (eBíoscience, IM7; Gene Symbol Gene Name Example Antibodies Wi-lSSiiSj ; Invitrogen C544 Antibody (eBiosolence, 5F12; MA5~12394); Antibody: BD Bioscíences CB44 (BD Uso i encae, 513.; 550 9 99 OR 550988) XTGA3 Integrin alpha 3 subunit Antibody integrin alfas of EMB My Hippar o (My Hypothesis, P1B5; MAE1952Z © ΜΑΒΙ952P) ITGA4 Alpha 4 subunit of in t cg rin Antibody Bio X Cell ITGA4 (BioXoell, PS / 2) (BEO071-5MG); BD Brosdienoes ITGA4 Antibody (BD Biosciences, 581892); Antibody i BD Biescienceo ITGA4 (BD, 3401763; Antibody EM© Mlllipore XTGA4 '112 Gene Symbol Gene Name Example Antibodies (Millipore, P4C2; »B195 5) IWAV Xntegrin subunit alpha V / 1 n t l z -j o r p o d e inte g r o n ¿a Abcam alpha v (AbcaM abΊ0 6 ) r An t1 Aboam alpha v integrin body (Abcamr ab782§9); Abe^m alpha v integr.in antibody (AbcaMr ablSS'dl ) ; Anti-integrin alpha y body from Invitrogen (TBerme Fisher Scientlfic, 27217E:S, »1-91.091; Integrin alpha v antibody from R & D Systems (R & D 3: ys t eme, M A S 2 5 2 8J ITGB3 Integrin subunit beta 3 A o t i. cu a r p o d e n t e g r i r. a beta3 from Abeam (Abcam, ab78289); 113 Gene Symbol Gene Name Example Antibodies Abnova integrin beta3 1 Abnova, WO, :MAB7>^ SELL S ele o tin a L Antibody BioLegend G 0:6 21 {B id1e ge nd, 394©©AI; BidLegend CD62L Antibody (Hiolegend, 304810) cwi CD81 Molecule BD B i o s cian c e s G D 81 Antibody (BD P h a rmi n geη, 555675); R and D S y s t e is s CD81 antibody {R & D S y s t e m s, MAB4615) LRP1 LDL binder related re 1 protein Invi trog e n body an11 LRP1 (Life Technologies, 37-76 0 0) ; Invitrogen LRP1 ant i c u ® (The rmo Fisher, MA1-27198) vascular cell adhesion molecule 1 Invitrogen h VCAM-l ant i c u ® (Caltag, IGIIBI; 114 gene symbol Gene name Example antibodies MAS-1é42$); Antibody Immun.ot sch ant i~VCAM-1 CTd 51 Molecule CD151 {Ra ph blood group) Antibody BO Bioscendes CD151 (Becton Oickinson, 55 6 05 6); Ant ic u o rρo Epitemios CD151 (Epitomica, 5901-1) |0094| In one embodiment, the agent to be administered is an antibody or an active fragment thereof as provided herein directed against a component of a mammalian inflammasome or an antigen or epitope derived therefrom. In another form In embodiment, the agent to be administered is an antisense or AWip RNA directed against a component of a mammalian inflammasome. The inflammable component may be a component of any inflamma-soma known in the art, such as, for example, the inflamma Soma NAPL1, NALP2? NALP3, NLRC4 © AIM2. In a way. In a typical embodiment, the antibody specifically binds to ASC or an antigen or epitope derived from US he. However, an anti5.body can be used against any other component of a mammalian inflammasome (for example, the NALP1, NALP2, NALP3, NLRCá or AIM2 inflammasome),

[0095] An antibody as described herein may be a monoclonal or pal iclonal antibody. or active fragments of my name. Said antibodies c active fragments1 can be chimeric, human: ·© humanized: as described in the present document.

[0096] If any suitable antibody can be used, an active fragment thereof such as: is provided herein that specifically binds to ASC, for example, an antibody that inhibits ASE activity in the CNS (for example, SMC cells) or lung cells (eg, Type II alveolar cells) from the subject. In one embodiment, the antibody specifically binds to an amino acid sequence that has at least 8-5% sequence identity to the amino acid sequence SEQ ID NQ: 1 or SEQ ID DO: 2. In another embodiment, the antibody or seismic fragment binds to an amino acid sequence that is at least 85%, 8-6%, 87%, 88%, 89 %, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99i or 100% sequence identity to the amino acid sequence KKEKLKLhSVPLREGiGRIPR (SEQ ID NO: 5). in another way of 116 further embodiment, the antibody or fragment thereof binds to an amino acid sequence ΚΚΕΚΙΚΙΧηΥΜΕΘ^^ (SEQ IB Wi 51 © 1 / 3, 4, Pf7, 3, 9, 13, 11, :12, 13> 1K, 15, X6y 17, 18, 19 or 20 amino acids of SEQ ID EO: 5. In yet another embodiment, the antibody or fragment thereof binds 2-5, .5-10, 10~15 or 15-20 amino acids from SEQ ID 50c 5. In some embodiments, an ASE epitope. (for example, epitope with the amino acid SEQ ID NG: fj bound by an antibody or antibody fragment is continuous. In 2Q' some: forre / of embodiment, an ASC epitope (eg, epitope with amino acid SEQ ID 501 5) bound by an antibody or antibody fragment is discontinuous. In some cases, the mcnoclonal antibody or antibody fragment thereof prepocloned herein inhibits or reduces ASC activity.

[0097] As used herein, the term "epitope" includes any protein determinant capable of specifically binding to an immunoglobulin or immunoglobulin fragment. Epitepic determinants usually consist of chemically active surface groupings of molecules such as amino acid or sugar side chains and usually have specific three-dimensional structural characteristics as well as characteristics of 117 specific cargo, The term epitope also refers to a unit of structure conventionally linked by an immunoglobulin heavy chain variable region (VH) and a pair of light chain variable regions (VIO). A .5 epitope can define the site of - minimal binding for an antibody and therefore represent the specificity target of an antibody,

[0098] Similarly, in another embodiment, the inflamma soma is NALP1 inflamma, and the at least one component is MALM (ie, NLRP1) ♦ In this embodiment, the antibody or a fragment active ingredient thereof as provided herein specifically binds to an amino acid sequence having at least §5f sequence identity to the amino acid sequence SEQ ID Wi 3 or SEQ ID NO: d.

[0099] In yet another embodiment, the agent is one or more inhibitors of uptake: of EV in combination with one or more antibodies or active fragments thereof as provided herein that bind to a component of 20 : an inflammasome. The Ev uptake inhibitor can be any EV uptake inhibitor as provided herein. The antibody that binds to a component of an mf lamas ota can be any 118 antibody which binds to any component: of the infi aneacma bed is provided herein. In one embodiment, the agent administered to a subject suffering from CNS or lung inflammation comprises tin Pepatin (eg, enoxaparin) in combination with an antibody that binds to a component of the AIM2 inflammamas (eg, ASC). ,

[00100] In one embodiment, the method comprises: providing a therapeutically effective amount of a composition: including an antibody or an active fragment thereof as provided herein that specifically binds to at least one component (for eg, ASC) from an inflammasome, mammalian (eg, Inflamascma AIM2); and administering the composition to the mammal afflicted with inflammation of the SNd or lungs or MS, wherein administration of the composition to the mammal results in a reduction of caspaseal activation in the SKC or lungs of the mammal. In another embodiment, the method comprises providing an amount 2Q therapeutically effective of a composition that includes an antibody that binds especially to: al has a component (eg, ASC) of a mammalian inflammasome (eg, inflamma som AIM2); and manage the Π9 composition to the mammal afflicted with NLS or lung inflammation or MS, wherein administration of the composition to the mammal results in reduced levels of one or more components of the inflamase (eg, ASC). In yet another embodiment, the method comprises: providing a therapeutically effective amount of a composition that includes an antibody that specifically binds to at least one component (eg, AEG) of a mammalian inflammasome (eg, AIM2 ig inflammasome). and administering the composition to the mammal afflicted with INC or lung inflammation or MS, wherein administration of the composition to the mammal results in a reduction in ALI The CNS or lung inflammation may be the result of injury of the CNS (for Í5 example, SCI or TBI), asthma, chronic obstructive pulmonary disorder (COPD), a neurodegenerative disease or a m u n o i m u n e c o i i i s disease η υ; i c o n n e n t e i n f 1 a m a t o r . i o. In one embodiment, the lung inflammation is caused by a CNS lesion, such as TBI or SCI. 1001011 In one embodiment, the methods provided herein further involve detecting a level of activity of one or more components of a mammalian inflammasome in a sample from a subject. 120 suspected of suffering from iaflamaclon of the SBC or of the lungs or EM. The method for detecting the level or activity involves measuring the level of at least one inflammatory protein (eg, ASC or A1M2) in the sample obtained from the subject; determining the presence or absence of an elevated activity level of said at least one inflammatory protein (eg, ASC or AIH2). The level or activity of said at least one inflammatory soma protein can be enhanced relative to the level of said at least one soma inflammatory protein. in a control sample. The level or activity of said at least one inflammasome protein in the protein signature can be enhanced relative to a predetermined reference value or range of reference values, the: a' .minus: a ., protein. of the. inflames soma Í5 may be a leucin-rich nucleotide-binding pyrin repeat domain containing protein 1 (NLRP1), NLRP2, NLRP3# NLRC4, Alto, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASO ), oaspase- 1,- or combinations thereof. The sample may be cerebrospinal fluid (CSF), saliva, blood, serum, plasma, urine, or a lung aspirate. 121 Antiquated that bind specifically to ai mechas up component of A mammalian flamemasome 100102] The methods described in this document: to reduce inflammation in the CNS and / or lungs of a mammal include compositions that include, an antibody or an active fragment thereof: as provided herein that specifically binds to at least one component {for example, ASC, ΆΤΜ2) of a mammalian inflammas-ama (eg, he inflammasorna ΆΤΜ2). A composition for treating and / or reducing inflammation in the CNS and / or lungs of a mammal may further include at least one pharmaceutically acceptable carrier or diluent. Exemplary antibodies directed against components of a mammalian inflabasema for use in the methods herein may be those found in "1 USSOóáOO, the contents of which are incorporated herein by reference in their entirety. Also provided herein are exemplary onoclonal antibodies or antibody fragments, such as, for example, the monoclonal antibody or antibody fragment comprising a VH region such that the amino acid sequence of the VH region. comprises HCDRi of SEQ ID NO: 6, 122 HCDA2 gives SEQ ID NO: 7 and HCDR3 gives SEQ ID NO: 8, and a Vi tal region. than the amino acid sequence of the. VL region comprises LCDR1 of SEQ ID NO: 12, LCDR2 of SEQ ID NO: 13 and LCmS of SEQ ID NO: 14.

[00103] In upa: embodiment, a composition for treating and / or reducing inflammation in the lungs of a mammal includes an antibody or an active fragment thereof as provided herein which is specifically binds to a domain or portion thereof of a mammalian ASO protein such as a human, mouse, or rat ASO protein. Any <bc^dc can be used, and several are available with omex c Examples of 11~ ASC antibodies for use in the present methods may be those found in OS8685400, the contents of which are incorporated herein by reference in their entirety. Examples of commercially available anti-ASC ¿<ur:bodies for use in the methods provided herein include, but are not limited to, 04-147 Anti~ASC, antibody 2Q mouse monoclcnal clone 2EI-7 from Mi 11iporeSigma, ΆΒ3 607 Anti-ASC antibody from Millipore Sigma, orbl94 021 Anti-ASC from Biorbyt, 13-0331313-50 Anti-ASC from LifeSpan Biosciences, AF3805 Anti-ASC from R & D Systems, NBÍl-78§77 Anti-ASC de 123 Novus Biologicals, 500-4Q1-Y67 Anti-ASC from Rookland Imwn©ehem^ DOS 6-3 Anti-ASC from MBL InternadAL177 anti-ASC from Adipogen, anti-ASC monoclonal antibody (clone O.9.3E9) , anti-ASC antibody (F~9) from < Santa Grúa g Bioteehnology, áhti-ASC antibody (B-3) from Santa Cruz Bdotechncl^ ASC polyclonal antibody - ADI-9P5-173 In so Life Sciences, or Al 51 Anti-Human ASC - Leincc Technologies;. The human ASC protein may have accession number OJ)3739CA2 (WQLE3- ^ NP~&50183 (Q9üLZ3--2í or Q9U:.Z3-3. The rat ASC protein may have accession number NP_ 758825- (BAC43754H The mouse ASC protein may have accession number W_0 7 57 47»3, In one embodiment / the antibody binds to a FWIN- domain EAADBAP1N(PYp) c a portion or fragment thereof of a mammalian ASC protein (eg, human, mouse, or rat ASC).In this embodiment, an antibody as described therein is presented. document specifically binds to an amino acid sequence that has at least 65% (eg, 65, 70g 75, 30, 85%) sequence identity with a human, mouse, or rat PEE domain or fragment thereof. In one embodiment, the antibody binds to a C-terminal caspase recruitment domain (CAED) or a portion or fragment thereof of a caspase ASC protein. 124 mammalian (eg, human, mouse, or rat ASC), in this form of. embodiment, an antibody^ as described herein specifically binds to a sequence of nmine acids that is at least 65% (eg, 65, 70j 75, 80, §W; sequence identity with a human, mouse or rat CARD domain or fragment thereof. ASC. In yet another embodiment, the antibody: binds to a fibroid portion or fragment of a wmlferb ASC pxotein sequence (eg, human, mouse, or rat AEG) located between the PIO and CARO domains . In another embodiment, a composition for treating and / or reducing Infima in he OG and / or LóA Ge a maOferó includes an antibody that specifically binds to a region of rat ASC, for example, the amino acid sequence ALRQTQFÍLVTD (SEQ ID EO: 1) (ie, rat ASO residues 178-193, accession number üAC43d4). In this embodiment, an antibody as described herein specifically binds to an amino acid sequence that has at least 65% (eg, 65, 70, 75, gg . 80, 85%} sequence identity with the amino acid sequence AERQTQ.PÍLVTDLEQS (SEQ Ib DO: 1) from rat ASC In another embodiment, a composition for treating and / or reducing inflammation in the CNS and / or lungs of a 125 mammal includes an antibody that binds. specific to a region of human ASC, for example, the amino acid sequence RESQSÍLVEÜLERS (SEQ ID NO: 2)1 In another embodiment, a composition for treating and / or remediating inflammation in the CNS and / or Mammalian lungs includes an antibody that specifically binds to a region of human ASE, eg, the amino acid sequence KKFKLKLLSVb'LREGVGF I . SEQ ΓΡ R f : 5; that is, residues 2141 of ASC 'huaía:ñ.a) g 5-10, 10-15: or 15-2 0 amino acids of SEQ and g PE NO: 5. In one embodiment, an antibody that binds to an ASC domain or fragment thereof described herein inhibits ASC activity in lung cells, eg, type II alveolar cells of a mammal. In another embodiment, an antibody that binds to an ASO domain or fragment thereof as described herein (for example, anti-ASC manclonal antibody to antibody fragments thereof reported herein) inhibits ASC activity in the ASO domain. CNS of a mammal suffering from or suspected of suffering from a SBC lesion or gg disorder. Examples of CNS lesions or disorders may include TBI, SCI, cerebrovascular accident, Leu Gehrig's amyotrophic lateral sclerosis (ALS), sclerosis; multiple (MS), immunological dysfunction rupture 126 CNS muscle, muscular dystrophy (W), Elrheimer's disease (AD), Parkinson's disease (PD).

[00104] In certain embodiments, the invention provides antibodies and antibody fragments that specifically bind to and comprise ASCs. or more sequences: of amino acids shown in . Table 2. Also provided herein are isolated nucleic acid molecules encoding the monomeric antibodies or autobody fragments thereof comprising the nucleic acid sequences shown in Table 2. In some cases, the expression vectors comprising the nucleic acid molecules from Table 2. The expression vector may comprise heavy chain or light chain constant regions. An example of a heavy chain and light chain expression vector system for use in the compositions and methods provided herein is the pANT antitope expression vector system for lgG4 kappa light chain and past (S241P). The heavy or light chain nucleic acid molecule can be operatively linked to appropriate regulatory sequences for expression of the nucleic acid segments in a host cell. 127

[00105] Table Variable heavy and variable light (Kappa) chain sequences of anti-ASC antibody or antibody fragments thereof of the invention Sequence of a^ CSR1 heavy chain (H) j TSGMGVS (SEQ ID NO: 6) i Heavy chain CDR1 nucleic acid sequence (8) ¡ACTAGTGGAATGGGTGTGAGC {SEQ ID NO: 9) Heavy chain (H) CDR2 amino acid sequence ÜIYW'DDDKRYNPSLKS (SEQ ID NO: 7) SequenciTdel°^^ s , CDR2 „ d^ cade^ CACATTTATTGGGAfGATGATAAGCGCTACAACCCATCTCTGAAGAGC (SEQ ID nd: 1Q) CSR3 Heavy Chain (H) Amino Acid Sequence • SWMWi CWS O} CDR3 Heavy Chain (H) Nucleic Acid Sequence | AGCACCCGCATCGTGGCCAACGCCATGGACTAC (SEQ ID NO: 11) | CDR1 Light Chain (Kappa) i (L) Amino Acid Sequence IKASQSVD¥DGbSYMN ¡SEQ IDEA: 12} tCDR1 light chain (Kappa) nucleic acid sequence (L) IAAGGGGAGECAGAGTGTTGACTAoGACGGCGACAGTTACATGAAT (SEQ ID NO: ( Light chain (Kappa) amino acid sequence 128 Γαϊ i AMBLE S IBNQ: s Sequence of light chain CDR2 (Kappa) nucleic acids (X4 § · ( milQ .1 jJ S · ©' ; 1% 1Sequence of light chain CDR3 (Kappa) amino acids 1 <*o QQSNEDPYT (EEQ TD NQ:. 14) 1 CDR3 light (Kappa) chain nucleic acid sequence (1 CAGOΑΛΤCEA 1 MGAGGACCCTTACACE (SEQ IB NQ: 17 ? j Variable heavy chain (VH) amino acid sequence 1 QVTLKESGPG ILQPSQTLSLTQSFSGFSLSTS GMGV^W.i RQP SGKGLEWE AHI WDD DKRYWGLO ALTISKESTY NQVISTY CAR STPXVMAi 4DYBGQG TSVTVSS (S EQ ID NO: 18) j Variable heavy chain nucleic acid sequence (VH) 1 CAGGTC GGC AAAAAAC rx Variable Heavy Chain (VH) Amino Acid Sequence 2 kes 129 WW (SEQ ID NO: 19) Variable Heavy Chain Nucleic Acid Sequence i 11 (VH) 2 CAGGTCACCTTGAAGGAGTCTGGTCCTGCQCTGGTGAAACCDAGACAGACCCTCACG CTGACCTGCAGCTTCTCTGGGTTQTCAGT'CAGGACTAGTGGAATGGGTGTGÁGCÍGG ATCCGTCAGCCCGCCGGAAAGGTTGCATG GGATGAT GATAAGOQCTACAACCCATCTCTGAAGAGCACGGTCACCATOTCCAAGGACAtoTGI aaaaaccaggtggtccttacaatgaccaacatggaccütgíggacacagccacatat TCCTGTGCACGGAGOACCCCATCGTGGCCAACGCCATGGACTACTGGGGCCAAGGA ACCCTGGTCACCGTCTCCTCA (SEQ 10 NO: 24) ) 3 qvtlkesgpalvkptqtltltcsfsgfslstsgmgvswirqpagkglewlahiywdd DKRS X rST KSAETI SKDSgKNQ VVLT WNMDPVDTAT YYCAÁST PITAN AMDY WQG: TLVTVSS (SEQ ID NO: 20} Variable Heavy Chain (VH) Nucleic Acid Sequence 3 CAGGGTCGATGTCGCTGATGGATGGATGCTGCT AACCCAGACAGACCCTCACG G-C C Ato G'—- ' - GCG ” .GTi'to -.'ACCAG7 AGtoGA? to toGTGm 7 ... ATCCGTCAGCCCGCCGGAAAGGGCCTGGAGTGGCTTGCACACATTTATTGGGATGAT GATAAGCGCTACAACCCATCTCTGAAGAGGAGGCTCACCATTCCAAGGACAGCTCC AAAAACCAGGTGGTCCTTACAATGACCAACATGGACCCTGTGGACACAGCGTCGCATAGTGACTTGTCGCATG AACGC'CATGGACTAGTGGGGCCAAGGA ACGCTGGTCAGGGTCTGCTCA. (SEQ. ID NO: 29) 130 j of variable heavy chain (VH) amino acids 4 QVTLK.ESaPALVKPTgTLTLTCTFSGFSW^ DKRYEPSLKGRLTISKFTSW^ TLVTPSS ID WU useful variable-heavy chain (VH) nucleic acids 4 C A G G T C AC C T T G A A G G A G T C T G G G T C C T G C C C T G G T GA A AC C C A C A C A G A C C C T C A C G CTGAGCTGCACCTTCTCTGGGTTCTCACTCAGCACTAGTGGAATGGGTGTGAGCTGG ATCCGTC.AG:CCeGCGG-GAAAGGGGGTGGAGEGGCTTGCAGACAlTTATTGGGATGAT GATAAGCGCTACAACCCATGTCTGAAGAGCAGGQTCACCATCTCCAAGGACACCTCC I AOAAEEAGGTGGTGGTTAEAAlGACGAAeATWAeSEFGTGGAGAGA TACTGTGCACGGAGCACCCCCATCGTGGCCAACGCCATGGACTACTGGGGCCAAGGA (SEQ XF :^í -2:6) Chimeric Variable Heavy Chain (VH) Amino Acid Sequence (O) q V1I» K E SG p GIL QP SQ I11'31, T C S f S G E S A S E FG M G V S WIRQ. p S G K G u E W A A H x F W D P D K R Y N P SLR S R L TIS K D S S S N Q V F L KIT S V D T A D T A T Y S C A R S T PIV A N AM D Y W G Q G TSWVSS (SEQ ID W: 22) Variable heavy (VH) chimeric sequence (O) CAGGTTACTCTGAAAGAGTQTGGCCCTGGGATATTGCAGCCCFCCCAGACDCTCAGT QT G AG T T G X T €1T TDT DF G GGTTT X GAQEG AG-C AG.T TGT G G X A X GE G G ATTCGTCAGCGTTCAGGAAAGGGTGTGGAGTGGCTGGCACACAXTTACTGGGATGAT GACAAGüGCFATAAGCCATCCCTGAAGAGCCGGCTCA-GAATCTCCAAGGATTCCTCC 131 AGCAACeAGGTCTTCCTCAAGATCACCAGTGTGGACACWCAGAT^ TeeTGGGCTCGAAGTACTCCGATIGTAGCTAATGCTATGGACTACTGGGGTCAAGGA । IACCTCAGTCACCGTCTCCTCA (SEQ ID Λ: 27) | Amino acid sequence of the variable light chain Kappa (VL) 1 DlVLTQSPpSLAVSLGElWINCKASQSVWDGDSYMN^ [ LES GIF AR F S G S G S G T D FT L TI SSL Q E E DVAT1ICQQSNÉ D P YI FGQ G T KLEIK hsEQ ID NO: 28) ¡ Acid sequence nucle^ light chain chain i J GAGATGGTGGTGAC^GGAGTGTaOAGAGTOCGTGGSTGTGG'GGG-TGGGCGAGAGGGCC:: | ACCATCAAGTGCAAGGCCAGCCAGAGTGTTGAQTAGGACGGCGAGAGTTACATGAAT tggtácco' zékG gaa^ca.ggacagcctccgaAgctggt.catttacgccgoatctaac I áTGGAATCCGGCATeCGTGCGCGATTCAGTGGCAGCGGGIOTGGGACAGATTTCAGT |GTCACCATCAGCAGeGTGCAGGAGGAAGATGEGGGAACTTATTACTGTCAGCAATGT | AATGAGGACCCTTACACTTTTGGCCAGGGGACCAAGGTGGAGATCAAA (.SEQ ID Variable light chain ) chain amino acid sequence Kappa (VL)2 ΐ DlVLTaSRDSLAVSLGERATIÑCKASGSVWDGDSLHW^ | LESGILARESGSGSGTDFTLTISSLQPEW FGQGTKLE XK | (SEQ ID NO: 29) Light chain nucleic acid sequence 132 5 ία 15' 20 Kappa variable (VL) 2 GÁCATCGTGGTGACGCAGTCT.CCAGACTCCCTGGGTGTGTÜTCTGGGCGAGAGGGCÜ AüCATCAACTGCAAGGCCAGCCAGAGTGTTGACTACGACGGCGACAGTTACATGAAT TGGTAGCAGCAGAAAeCAGGACAGCCTCCTAAGCTGCGCATCTGATGCTGCGCATCTG GQCQGCOCGATTCAGTGGCAGCGGGTGTGGGAGAGATTTCACT CTCACCATCAGCAGCCTGCAGCCIGaAGATGTGGCAACTTATTACTGTCAGCAATCT AAOGAGGACCCTTAGACTTTTGGCCAGGGGACCAAGCTGGAGATGAAA (SEQ ID NO: 33) Variable Light Chain Amino Acid Sequence Kappa (VL) DISCO LG DISCO DIV R PD DIV DVL Q DIV DS1MWYQQ O GQ P PKLL11AA SN LESGIPARFSGSGSGTDFTLTXS.SLQPEDVA^^^ (SEQ ID NG: 30) Scouenoxa of Kappa variable light chain (VL) 3 nucleic acids GACAT CGT GAT GACCC AGICTCCAGACT CCCT GGGTGTGTC7 C1GGGCGAGAGGGCC ACCATCAAC'?GCAAGTGATAGGG ACAGTOACATGAAT TGGTACCAGCAGAAACCAGGACAGCCT'CCTAAGGTGGTCATTTACGGCGCATCTAAC CTGGAATQCGGCATC :CCTGCCCGÁTTGAGTGGCAG€GGGTCTGGGACAGATTTCA.CT CTCACCATCGIGCAGCCTGCAGCCTGAAGATG'TGGCAACTTATTACTGTCAGCAATCT AÁTGAGGAGG'CTTACACTTTTGGCCAGGGGACCAAGCTGGAGATCAAA (SEQ ID NO: 34) Variable Light (Kappa)O (VH) Chain Chimeric Amino Acid Sequence InVLTQslM LESGIrARFSGSGSGTDETLNIHWEEEmATYlCQQSNED^^ j (SEQ ID MO: 31) (Kappa) variable(VH) (0) I GACATTGTGCTGACCCAATCTCCAGCTTCTT'TGGC:TGT.GTCTCTAGGGCAGAGGGCC IACCATCTCCTGCAAGGCCAGCCAAAGTGTTGATTATGATGGTGATAGTTATATGAAC | TGGTACCAACAGAAACCAGGACAGGCAGCCAAACTCCTCATCTATGQTGCATCCAAT |eTAGAAiCTGGCATCCCAGCCAGGTTTÁGTGGCAGT'GGGTC'TGG § GT uAAΌATuGa 7)Co· I OI G.G AG;G AfeAGGAI GG1GuAACCIAl iΆ GIGTCAALAAAGT IAATGAGGAcCCGTACACGTTCGGAGGGGGGACCAAGCTGGAAA'TAAAA ( seq id I EO: 3 5 i [0OR106| In one embodiment, provided herein is a mcnoclonal antibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain (VH) variable region and a light chain to kappa chain (V'L) variable region, wherein the amino acid sequence of the VH region comprises SEQ ID PC: 1S, 19, 20, 21, 22, or an amino acid sequence that is at least 95 %, 96%, 97%, 98% or identical to the amino acid sequence of SEQ ID NO; 18, 19, 20, 21 or 22" In addition to this embodiment, the use: of the antibody is provided herein 134 KWioclonal © antibody fragment thereof in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The inflammation can be a inflammation related to inflammation. The inflammation may be in: the lungs and / or the CNS. Inflammation in the lungs and / or the CNS may be the result of injury {eg, traumatic brain injury {TBI) e.g. spinal cord injury (SCI)} or disease, condition or affliction of the CNS or that. affect the CNS. As provided herein, the disease, condition or affliction of or affecting NCD may be stroke, as well as autoimmune diseases and / or CNS diseases, including Lou Gehrig's amyotrophic lateral sclerosis (ALS). , p1e multiple serosis (MS), 1S NG immune dysfunction, muscle breakdown, muscular dystrophy (DM>, Alaheimer's disease (AD), Parkinson's disease (PD) . The use of monoclotal antibody or antibody fragment thereof in its method of exacerbating inflammation can reduce inflammation. inflammation in the CNS and / or lungs of the patient. The reduction can be compared to a center; (for example, patient not treated and / or patient before treatment). In one embodiment, the monoclonal antibody or the 135 antibody fragment derived therefrom is used to treat MS by administering the monoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of: suffering from. In some cases, the monoelonal antibody or antibody fragment thereof of this embodiment is present in a composition. The composition may be a pharmaceutical composition as provided herein. |βΜβ7| In a further embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain variable region ( VH) and a light chain or kappa (VI) chain variable region, wherein the 15 amino acid sequence of the VL region comprises SEQ ID NO: 28, 2 9, 30, 31, or an amino acid sequence that is at least least 95%, 96%, 9.7%, 98%, or 99% identical is the amino acid sequence of SF2Q ID NO: 28, 29, 30, or 31. In addition to this embodiment, the use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The inflammation may be an inflammasorna-related inflammation. The 136 inflammation may be in the lungs and / or CNS Inflammation in the lungs and / or CNS may be the result of an injury (for example, traumatic brain injury (TBI) or spinal cord injury ( SCl)j or 5 disease, condition or affliction of the SNG or that affects the CNS, As provided herein, the disease, condition or affliction of the CNS or affecting the CNS may be stroke, as well as autoimmune diseases and / or diseases including Lou Gehrig's amyotrophic lateral sclerosis (ALS). , multiple sclerosis (MS), CNS immune dysfunction, muscle breakdown, muscular dystrophy (DM), Alzheimer's disease fEA), Parkinaon disease (SE). The use of the monoclonal antibody or antibody fragment thereof in j5 in a method of treating inflammation can reduce inflammation in the CNS and / or lungs of the patient. Redceixri can be compared to a control (for example, untreated patient and / or patient before treatment)< In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat ΕΉ by administering the antibody monoclipnal or the antibody fragment derived therefrom to a patient who has or is suspected of having MS. In some cases, the 137 toonoclonal antibody or the antibody fragment thereof of this embodiment is present in a composition. The composition can be a pharmaceutical composition as provided herein, S

[00108] In a matter of fact, provided herein is a stonoclonal antibody or antibody fragment thereof that specifically binds to ASE, wherein the antibody or antibody fragment thereof comprises a variable region of heavy chain (VH) and a light chain or kappa chain (VL) variable region, where the amine sequence: from? the VE region comprises SEQ ID W j 18, 19, 20, 21, 22, or an amino acid sequence that is at least 95%, 98%, 97%, 98%, or 99% identical to that amino acid sequence of SEQ ID NO: 18, 19, 20, 21 or 22; and wherein the amino acid sequence of the VL region comprises SEQ ID. NO: 28, 29^ 30, 31, or an amino acid sequence that is at least 95%, 3 6%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO' 28, 29, 30 or 31, In addition to this embodiment# there is provided herein the use of the ng monoclonal antibody or antibody fragment thereof- in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The inflammation may be an inflammation related to the 138 xnflamasome. Phlimation may be in the lungs and / or in the CNS. Inflammation in the lungs and / or ECS may be the result of injury (for example, traumatic brain injury (TBI) d .spinal cord injury "CIB c disease, condition or affliction of the CNS or affecting the CNS As discussed herein, the disease, condition, or affliction of CDS or that affects ESC may be cerebrovascular accident, as well as autoimmune diseases and / or CSE diseases, including amyotrophic lateral sclerosis, ELAj dé ' Leu Géhrig, multiple sclerosis (MS), ECS immune dysfunction, muscle breakdown, muscle dystrophy (MD, disease of Alzheimer's (LA), Parkinson's disease (PD). The use of the monoclonal antibody or antibody fragment thereof in a method of treating Inflammation can reduce inflammation -in the CNS and / or lungs of the patient. The reduction can be compared to a control (eg, untreated pac-lens and / or patient before treatment). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the monoclonal antibody or antibody fragment derived therefrom to a patient having or suspected of having MS. In some cases, the 139 manclonal antibody or the antibody fragment thereof in this embodiment is present in each composition. The composition may be a pharmaceutical composition as provided herein. [001091 In one embodiment, provided herein is an an t 1 monedone 1 body or u' < antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a variable region of heavy-chain (VH) and a light-chain or kappa-chain (VL) variable region, where. the arainoacic sequence of the VH region comprises SEQ ID NO: 18t or an amino acid sequence that is at least 951, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ. ID was 10; and wherein the amino acid sequence of the Vi region comprises SEQ ID NO: 28 or an amino acid sequence which is 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of: seq ID NO; 28. In addition to this embodiment, provided herein is the use of the monoantibody or antibody fragment of gg itself in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The inflammation may be an inflammation related to the infLamasoma. The inflammation may be in the lungs and / or 140 in the CNS. Inflammation in the lungs and / or CNS may be the result of injury (for example, traumatic brain injury (ΤΒΪ) or spinal cord injury (SCI)) or disease, condition, or affliction of the CNS or affecting the g CNS, As provided herein, the disease, condition, or affliction of or affecting the CNS may be stroke, as well as autoimmune diseases and / or CNS diseases, including: amyotrophic lateral sclerosis (ALS) of Leu Gehrig, iq; multiple sclerosis (JMD, CNS immune dysfunction, muscle breakdown, muscular dystrophy (DM), Alzheimer's disease (LD), Earkinson's disease (BE). The use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation can reduce the 2.5 inflammation in the CNS and / or lungs of the patient. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to 2Q treat MS by administering the monoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of having MS. In some cases, the monoclonal antibody or antibody fragment thereof 141 in this way. of realization is present in a composition. The oompposition may be a pharmaceutical composition as provided herein.

[00110] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain variable region (VH ) and a light chain or kappa (VI) chain variable region, wherein the amino acid sequence of the VH region comprises SEQ IB NO: 18, or an amino acid sequence that is at least 951.9 6%, 9 7%, 98% or 99% identical to the amino acid sequence of 3EQ .0 NO: 18; and wherein, the amino acid sequence of the VL region comprises SEQ ID NO: 2 9 or a sequence of 15' amino acid that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 29. In addition to this embodiment, provided herein is the use of the monoclonal antibody or antibody fragment thereof in a method for treating 1.a. ínClawci^^ in a subject* The inflammation may be an innate immune inflammation. The inflammation may be an inflammasome-related inflammation. The inflammation may be in the lungs and / or: in the CNS. Inflammation in the lungs and / or CNS can 142 be the result. of an injury (from traumatic brain injury (TBi) or spinal cord injury (SCI)) or disease, condition or affliction of the CNS or affecting the CNS. As provided herein, the disease, condition, or affliction of the CNS or that affects the SEC may be stroke, as well as autoimmune diseases and / or CNS diseases, including Leu Gehrig's amyotrophic lateral sclerosis (ALS), tsclw&síi multiple -(EM) , <isfunpión . fnm -of the ?CNS, 2Q muscle breakdown, muscular dystrophy (DM), Alzheimer's disease (AD), Parkinson's disease (PD)* The use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation may reduce inflammation in the CNS and / or lungs of the patient. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In a redlization method, the monoclonal antibody c miamo-derived antibody fragment is used to treat Xa .EN by administering the mongclonal antibody o. the antibody fragment derived therefrom to a patient suffering from or suspected of suffering from EN, En. some .gray, e.l. monocolonal antibody c the antibody fragment thereof in this embodiment is present in a 143 composition. The composition can be a pharmaceutical composition as provided herein. μΜΗΐη In one embodiment, a monoclonal antibody or antibody fragment thereof that specifically binds ASC is provided herein, wherein the antibody or antibody fragment thereof comprises a variable heavy chain (VS) regdm regdm. and a light chain or kappa chain (VL) variable region, wherein the amino acid sequence of the VH region comprehends SEQ. ID NO; 18, or 10 an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ. ID NO: 18i and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 30 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the sequence of .aaincados of SEQ ID NO: 30. In addition to this embodiment, provided herein is the use of the lonal antibody or antibody fragment thereof in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The inflammation may be an inflammasome-related inflammation. The inflammation may be in the lungs and / or in the CNS. Inflammation in the lungs and / or SBC may be the result of injury (for example, brain injury 144 trauma (TBI) or spinal cord injury (SCI)) © disease, condition © CNS affliction © affecting the SNü. As provided herein, the disease, condition © affliction of the CNS. or affecting the CNS can be a cerebroWPulat accident, as well as autoimmune diseases and / or CNS diseases, including myotrotic lateral sclerosis. Lou Gehrig's {ALS), multiple sclerosis (MS), CNS immune dysfunction, muscle breakdown, muscular dystrophy (MD), da Alzheimer's (AD), Parkinson's disease CEP} . Use of the monodonal antibody or antibody fragment thereof in a method of treating inflammation can reduce inflammation in the CNS and / or lungs of the patient. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the monoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of suffering from MS. In some instances, the monoclonal antibody or "antibody" fragment thereof of this embodiment is present in a 145 composition.. The composition can be a: pharmaceutical composition as provided in the present document.

[00112] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASE, wherein the antibody or antibody fragment thereof comprises a heavy chain variable region. fW) and a light chain or kappa (Vi) chain variable region, wherein the amino acid sequence of the VH region comprises SEQ ID NO: 18, ol,g an amino acid sequence that is at least 351-, 9 %%, 9.7i, 98% or 9 9% identical to the amino acid sequence of SEQ ID NO i 18; and where the amino acid sequence of region VI comprises SEQ ID NO: 31 or an amino acid sequence that is at least 951,-90,. 97%, 98% or 93% identical to the amino acid sequence of SEQ ID No: 31. In addition to this embodiment, use of the monoclonal antibody or fragment of is provided herein. antibody thereto in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The:inflammation may be an inflammation related to the Inflammasome. The infiamaGion can be in the lungs and / or in the CNS. Inflammation in the lungs and / or CNS may be the result of injury (for example, brain injury 146 traumatic (TBI) OR injury d® the spinal cord. (SCI)) or disease, condition or affliction of the CNS or that afédté al. SEL. As provided herein, the CNS disease, condition, or affliction affecting the CNS may be stroke, as well as autoimmune diseases and / or CNS disease, including amyotrophic lateral sclephosis (ALS) of Leu Gehrig, multiple sclerosis (EN), immune dysfunction of the CNS, muscle breakdown, muscular dystrophy (MD.), disease of Alzheimer's (ΈΑ), Pariison's disease (PD). Use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation can reduce inflammation in the CNS and / or lungs of the patient. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the monoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of suffering from MS. In some cases, the single monoantibody or antibody fragment thereof is of this form Je x v ci. n cate present in A 147 composition. The composition can be a- composition. pharmaceutical as provided herein. [0M13] In one embodiment, Sé herein provides a monoclonal antibody or an antibody fragment thereof that binds v. ]; f κίΙ< a ASC, wherein the antibody or antibody fragment thereof comprises a. heavy-chain (VH) variable region and a light-chain or kappa-chain (VL) variable region, wherein the amino acid sequence of the VH region comprises SEQ ID NO: 19, © an amino acid sequence that is at least 95i, 96%, 971, XI © 99% identical to the amino acid sequence of SEQ ID NQ: 19; and wherein the amino acid sequence of the VL region comprises SEQ ID NQ: 2 8 or an amino acid sequence that is at least 95%, 9 6%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 28. In addition to this embodiment, there is provided herein the use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The inflammation may be an inflammasome-related inflammation. The inflammation can be in the aphids and / or in the SNd. Inflammation in the lungs and / or 8NC may be the result of injury (for example, brain injury 148 traumatic LTBX) or spinal cord injury (SCI)) or disease, condition or affliction of the CNS or affecting the SNCI As provided herein as a cure, the disease, condition or affliction of the CNS or affecting to the CNS can be a cerebrovascular accident, as well as self-immune diseases and / or CNS diseases, including Bou Gehrig's amyotrophic lateral sclerosis (ALS), multiple sclerosis (HD), CNS immune dysfunction, muscle breakdown, dystrophy muscle (DM), pg Al che i me r disease (EA), Par'kinscn disease (PD) . The use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation can reduce inflammation in the CNS and / or lungs of the patient. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the monoclonal antibody or antibody fragment derived therefrom to a patient who 2Q has or is suspected of having MS. In some cases, the "oclonal" antibody or antibody fragment thereof in this embodiment is present in a 149 composition, The composition may be a pharmaceutical composition as provided herein.

[00114] In one embodiment, an aP-body is provided herein; monoclonal antibody or antibody fragment thereof that specifically binds to ASC, wherein the ifun antibody or antibody fragment comprises a heavy chain variable region (VH) and a light chain or kappa chain variable region ( VL), in which the amino acid sequence of Iq W region comprises SEQ: Ib ΕΘ; 19yÓ an amino acid sequence that is at least 131, 96%, 97%, 98% or 99% identical to the amino acid sequence of the. SEQ ib NC: 19; and wherein the amino acid sequence of the VL region comprises SEQ 10 NO; 29 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence:® of SEQ ID NO: 29. In addition to this embodiment, provided herein is the use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The inflammation may be an inflammasome-related inflammation. The inflammation may be in the lungs and / or in the CNS. Inflammation in the lungs and / or the CNS may be the result of injury (for example, brain injury 150 traumatic (TBI) © spinal cord injury (SCXD or disease, condition © affliction of the CNS or affecting the CNS. As provided herein, the disease, condition, affliction of the CNS or what affects the CNS may be stroke, as well as autoimmune diseases and / or diseases of the CNS, including amyotrophic lateral sclerosis (ALS). Gehrig, multiple sclerosis (MIEM), CNS immune dysfunction, muscle breakdown, muscular dystrophy (W), brain disease, Alzheimer's (AD), Fark.inson's disease (PD). The use of. monoplonal antibody or antibody fragment thereof in a method of treating inflammation can reduce inflammation in the CNS and / or lungs of the patient. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient)♦ In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the antibody monoel©nal © the antibody fragment derived therefrom to a patient who 2q have or are suspected of having MS. In some cases, the monoclonal antibody or antibody fragment thereof of this embodiment is present in a 151 The Latvian fields can be a pharmaceutical GoMposidian as provided herein.

[00115] In one embodiment, a monclonal antibody or an antibody fragment thereof is provided herein: which specifically binds to ASO, where the . antibody or the antibody fragment of the. It comprises a heavy chain variable region (VH) and a light chain or kappa chain (VL) variable region, wherein the amino acid sequence of the region: VH comprises SEQ ID NOc 19, or 1G ana amino acid sequence what is at least 959, 96%, 97%, 8% or 996- identical to the amino acid sequence of SEQ ID NO: 19; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 30 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 30. In some cases, a monoclone1 antibody or an antibody fragment derived therefrom comprising a VH region amino acid sequence comprising SEQ ID NO: 19 and a VL region amino acid sequence comprising SEQ ID NO: 30 may be referred to as IC 100. In addition to this The embodiment, provided herein, is the use of the monoclonal antibody or antibody fragment thereof in a method of treating the 152 inflammation in a fasten. The inflammation may be an innate immune inflammation. The inflammation can be an inflammation related to the inflammation, La. inflammation may be in the lungs and / or in the CNS. Inflammation in the lungs and / or the CNS. may be the result of injury (eg, traumatic brain injury (TBI) c spinal cord injury íSCIj) or disease, condition: or CNS affliction or affecting the CNS. As provided in the. present document, the illness, condition or affliction of the CNS or affecting the CNS can be a cerebrovascular accident, as well as autoimmune diseases and / or CNS diseases, including chemical lateral sclerosis (ALS Lou Gebrig's, e salar ce multiple LW), immune dysfunction of the CNS, degradation muscular, 15 Muscular dystrophy (DN), Alzheimer's disease (AD, PafUáson's disease (ES). The use of the antibody Monoclonal or antibody fragment thereof in a method of treating inflammation may reduce inflammation in the patient's CNS and / or lungs. The reduction may be compared to a control (eg, untreated patient and / or patient before treatment). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat MS. 153 adm / introducing the mclonal antibody or the antibody fragment, derived therefrom to a. patient who has or is suspected of having In some cases7 the monocolonal antibody or the antibody fragment thereof; 5 embodiment is present in a composition. The composition can be a pharmaceutical composition as provided herein. |00116] In one embodiment, a monoclonal antibody or an antibody fragment thereof that binds is provided herein. specifically to ASO, wherein the antibody or antibody fragment thereof comprises a variable: heavy chain (VH) region and a p:kappa light chain variable chain (VL) region, wherein the amino acid sequence of the VH region SEQ ID NO: 19, or 15 comprises an amino acid sequence: which is- at least 9d%, 96%, 97%, 98% or 99% identical to the amino acid sequence of £EQ ID 19; and where .the sequence: of amino acids of the. VL region comprises 1st SEQ ID NO: 31 or an amino acid sequence that is at least 95%,. 961, 97%, 98%, or 99% identical to the yg amino acid sequence of SEQ ID NO: 31. In addition to this form of replication, the use of the monoclonal antibody or antibody fragment thereof in a method for treat inflammation in one subject, n&: 154 Inflammation may be an innate immune inflammation, The inflammation may be an inflammation related to. he inflamed me Inflammation may be in the lungs and / or BEL, Inflammation in the lungs and / or CNS may be the result of injury (eg, traumatic brain injury (TBI) or spinal cord injury (BCI)) or disease, condition or affliction of the CNS or affecting the CNS, As provided herein, the disease, condition or affliction of the CNS or affecting the CNS 2G can be stroke, as well as autoimmune diseases and / or CNI diseases, including Lou Gehrig's amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), immunological CNS dysfunction, muscle breakdown, muscular dystrophy (DM), disease of Alzheimer's (AD), Parkinson's disease (PD). Use of the nonoclonal antibody or antibody fragment thereof in a method of treating inflammation can reduce inflammation in the CNS and / or lungs of the patient. The reduction can be compared to a -control (eg, untreated patient and / or patient before treatment). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is. used to treat MS by administering the aonocloaal antibody OR the 155 niMé-derived antibody fragment to a patient suffering from © is suspected of suffering from Eli. In some cases, the monoclonal antibody or antibody fragment thereof of this embodiment is present in a composition. The composition can be a p a r m a c o u t i c a v .

[00117] In one embodiment, provided herein is a monodonic antibody or antibody fragment thereof that specifically binds to ASO, wherein the antibody or ID: the antibody fragment thereof comprises a variable heavy chain (VH) region and a variable light chain or tappa chain (VI) region, wherein the amino acid sequence Pe the VH region comprises SEQ ID: MO : 20, or a raeueñola gives amino acids which w ai Μοηόο 9 5'%, IW# 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 201 and wherein the amino acid sequence of region VI comprises SEQ ID NO: 2 8: or an amino acid sequence that is: at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NQ:: 28, In addition to this embodiment, there is provided herein the use of the primary antibody or antibody fragment thereof in a method of treating inflammation in a subject. Inflation may be innate immune inflammation. The 156 inflammation may be inflammation related to soma inflamma.. Inflammation may be in the lungs and / or in <1 CNS. Inflammation in the lungs and / or CNS may be the result of injury {for example, traumatic brain injury (ΤΒΓ) q: spinal cord injury (SCI)) to disease, condition, or affliction of the CNS or affecting the CNS. As provided herein, the disease, condition, or affliction of or affecting the CNS may be stroke, as well as autoimmune diseases and / or CNS diseases, including Lou Gahrig's amyotrophic lateral sclerosis (ALS). , multiple sclerosis {MS?, CNS immune dysfunction, muscle breakdown, muscular dystrophy (DM), Alzheimer's disease (AD), Parkinson's disease (PD). Use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation can reduce inflammation in the patient's CNS and / or lungs. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the monoclonal antibody or Antibody fragment derived therefrom to a patient who 157 has or is suspected of having MS. In some cases, the monoclonal antibody or antibody fragment thereof of this embodiment is present in a composition. The composition may be a pharmaceutical composition as provided herein. [00118| In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain (VH) variable region. and a light chain or kappa chain (VL) variable region, wherein the s-amino acid sequence of the VH region comprises SEQ ID NO: 2Q, or an amino acid sequence that is at least 95%, 96% , 97%, 98% or 9 9% identical to the amino acid sequence of SEQ ID NO: 20; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 29 or an amino acid sequence that is at least 95%, 761 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 29. In addition to this embodiment, the use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation in a subject is herein proposed. The inflammation may be an innate immune inflammation. The inflammation may be an inflammation related to the 158 inf Iw soma. Inflammation may be in the lungs and / or CNS, Inflammation in the lungs and / or CNS may be the result of: injury (for example, traumatic brain injury (TBI) or spinal cord injury ÍSCIH or 5 disease, condition or: affliction of the CNS or that affected the CNS, Copio is provided herein, the disease, condition or affliction of the CBS p that affects the CNS can be a cerebrovascular accident, as well as autoimmune diseases and / or CMD diseases, including 13 amyotrophic lateral sclerosis (ALS) of Lou Gehrig, Multiple Sclerosis (E®), CNS Immunological Dysfunction, Muscle Degradation, Muscular Dystrophy (OM), Aleheimer's Disease (AD), Parkinscm's Disease (BE). Use of the monoclonal antibody or antibody fragment thereof in a method of treating Inflammation can reduce inflammation in the CNS and / or lungs of the patient. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the monoelonal antibody or antibody fragment derived therefrom is used to treat MS by administering the antibody. monoclonal or the antibody fragment derived therefrom to a pecle-nte. who have or are suspected of having MS. In some cases, the 159 monoclonal antibody or the antibody fragment thereof of this embodiment is present in a composition. The composition can be a pharmaceutical composition as provided herein.

[06119] In one embodiment, provided herein is a monoantibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain (VH) variable region. and one: light chain or kappa chain (VL) variable region, wherein the amino acid sequence of the VH region comprises SEQ ID NO: 20, o. an amino acid sequence that is: at least 95%, 96%, 97%. 98% or 99% identical to the amino acid sequence of SEQ ID 'NO: 20; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 30 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to. the amino acid sequence of SEQ: ID NO:30. In addition to this embodiment, provided herein is the use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The inflammation may be an inflammation related to inflammation. The inflammation may be in the lungs and / or. 160 in the CNSx Inflammation in the lungs and / or CNS can be the result of injury (for example, traumatic brain injury (TBI) or spinal cord injury (SCI)) or disease, condition, or affliction of the SéC or that affects the CNS. As provided herein, the disease, condition or affliction of the. S.NC or: that affects the CNS can be a. .cerebrovascular accident., .as well as autoimmune diseases and / or diseases of the CNS, including amiptrophic lateral sclerosis f.ALS) of Leu, Géhrig, X0 multiple sclerosis (MS), immunological dysfunction of. CNS, muscular degradation, -muscular dystrophy í.DM), Míbeimer's disease (AD), Parkinson's disease (PD). The use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation may reduce the X5 inflammation in the SPC and / or lungs of the patient. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the moneeLocal antibody or antibody fragment derived therefrom is used to 2Q: treat administered MS. the monoclonal antibody or the antibody fragment derived therefrom to a patient suffering from or suspected of suffering from MS. In some cases, the mondclonal antibody or antibody fragment thereof 161 of this embodiment is present in a composition. The composition may be a pharmaceutical composition as provided herein. (00120] In one embodiment, provided herein is a moclonal antibody or antibody fragment of >ismc that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain variable region (VHj and a light chain or kappa chain (VL) variable region, wherein the amino acid sequence of the VH region comprises S.EQ ID NO: 20, or an amino acid sequence that is at least 9Sbf96%, 97%. , 9§í or 99% identical to the amino acid sequence of SEQ ID eqí 20; and where the amino acid sequence of the VL region comprises SEQ ID NO: 31 or an amino acid sequence that is at least 9S2, 96% , 97%, 98 3' or 992 identical to the amino acid sequence of SEQ ID NO: 31. In addition to this embodiment, provided herein is the use of the mcnoclona1 antibody or antibody fragment thereof in a method of treating inflammation in a subject Inflammation may be innate immune inflammation* Clone inflammation may be inflammation; related with. the inflammasome. Inflammation may be in the -lungs and / or CNS> Inflammation in the lungs and / or CNS may 162 be the result of: an injury (for example, traumatic brain injury (TBI) or spinal cord injury (SCI)) or disease, condition, or CNS affliction. As provided in this document The disease, condition, afflicting the SBC or affecting the CNS may be a stroke, as well as autoimmune diseases and / or bMS diseases including Amyotrophic Lateral Sclerosis (ALS) from Lou Géhríg, Multiple Sclerosis (MS) , SBC immune dysfunction, jg muscle breakdown, muscular dystrophy (MD) , Alzheimer's (AD), Farkinson's disease (PD)> The use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation can reduce inflammation in the CNS and / or lungs of the patient. The jg reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the mcnoclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the mcnoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of having MS. In some cases, the monoclonal antibody or antibody fragment thereof in this embodiment is present in a 163 composition. The composition can be a pharmaceutical composition as provided. in this document. |00i21] In one embodiment, provided herein is a monotonal antibody or em.nnerpo fragment of the miMO that specifically binds to ASC, wherein the antibody or antibody fragment of the . itself comprises a heavy chain (VH) variable region and a light chain or kappa chain (VL) variable region, wherein the amino acid sequence of the VH region comprises SEQ LO NO: 21, or an amino acid sequence which is at least 95%, 9 85, 97%, 98% or 9 9% identical to the amino acid sequence of SE-Q ID NO: 21; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 28 or an amino acid sequence which is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 28, In addition to this form of implementation, the use of the mononational antibody is provided here. fragment of. antibody thereto in a method of treating inflammation in a subject. The inf Lamaeion. it may be an innate immune inflammation. ..The. inflammation may be an inflammasuma-related inflammation. Inflammation may be in the lungs and / c in the CNS, Inflammation in the lungs and / or SNS may be the result of injury (eg brain injury 164 traumatic injury (TBI) © spinal cord injury (SCI)') or disease, condition or affliction of the WC or affecting the CNS. As provided herein, the disease, condition, afflicting the SBC or affecting the CNS § may be a cerebrovascular accident, as well as autoimmune diseases and / or CNS diseases, including Lou Cehrig's amyotrophic lateral sclerosis (ALS). , multiple sclerosis (MS) , CNS immune dysfunction, muscle breakdown, muscular dystrophy (DM), disease of Alzheimer's (OE , ​​Parkinson's disease (PD) < The use of the menoclenal antibody or antibody fragment thereof- in a method of treating inflammation can reduce inflammation in the NGN and / or lungs of the patient., The reduction can be compared with a control (eg, gg untreated patient and / ρ patient before treatment) < In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the monoclonal antibody or the antibody fragment derived therefrom to a patient suffering from or suspected of suffering from MS In some instances, the monoclonal antibody or antibody fragment thereof of this embodiment is present in a 165 composition. The composition can be a pharmaceutical composition as provided herein. 100122] In one embodiment, herein a mclonal antibody is provided with an antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain (VH) variable region and a light chain or kappa chain variable region (Vi-, wherein the amino acid sequence of the VH region comprises SEQ XD NO: 21, or 10 an amino acid sequence that is at least 95%, 96%, 971, or 991 identical; to the amino acid sequence of SEQ ID NO: 2.1; and wherein, the amino acid sequence of the VD region comprises SEQ ID NO: 2 9 or an amino acid sequence that is at least 95%, 961, 97%, 98% or 99% identical, to the amine or acid sequence of SEQ: XD NO: 29. In addition to this embodiment, use of the primary antibody or antibody fragment is provided herein thereof in a method of treating inflammation in a subject The inflammation may be an innate immune inflammation. The. inflammation can be an inflammation related non-inflammation. The inflammation may be in the lungs and / or. in the SNG. Inflammation in the lungs and / or SNQ may be the result of injury (for example, brain injury 166 traumatic (TBI) or injury to the. spinal cord {SCI)) or disease, condition, c CNS affliction c affecting the CNS. As provided in this document, the disease, condition or affliction of the CNS or that affects the CNS § can be a cerebrovascular accident, as well as autoimmune diseases and / and Diseases of the CNS, including Lou Gehrig's ALS:, multiple sclerosis (MS ), ircmuno^ dpi CNS dysfunction, muscle breakdown, muscular dystrophy (DM), XO Alcbeimer's disease (AD), Parkinscn disease (PD). Use of the monoclonal antibody, or antibody fragment thereof, in a method of treating inflammation can reduce inflammation in the CNS and / or lungs of the patient. The reduction can be compared to a control {eg, patient his treated and / or patient, before treatment). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom: re: us-a pama.: treat MS by administering the monoclonal antibody or antibody fragment derived therefrom- a. a patient who 20: You have or are suspected of having MS. In some cases, the rmrmcíorei antibody or micro dpi antibody fragment of this embodiment. is present in a 167 composition. The composition may be a pharmaceutical composition as provided herein.

[00123] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain variable region (VH ) and a variable region of. light chain or kappa (Vi) chain, wherein the amino acid sequence of the VH region comprises SEQ ID NO: 21, or an amino acid sequence that is al. minus 95%, 9ói, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 21; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 30 or an amino acid sequence that is 95%, 96%, 97%, 99% or 99% identical to the amino acid sequence of the VL region. SEQ ID NO: 30. In addition to this embodiment, provided herein is the use of the mcnoclonal antibody or antibody fragment thereof in a method of treating inflammation in a subject. The inflwation can be a still? -' or s, inflammation may be an iriflamasome-related inflammation. The inflammation may be in the lungs and / or in the CNS. Inflammation in the lungs and / or CNS may be the result of injury (for example, brain injury 168 traumatic injury (TBI) or spinal cord injury (SCI) or disease, condition or affliction of the ENC or affecting the CNS. As provided herein, the. disease, condition or affliction of the CNS or affecting the CNS 5 can be a cerebrovascular accident, as well as autoimmune diseases and / or diseases of the CNS, including: Amyotrophic Lateral Scieraeis (ALS) of Lou dehríg, multiple sclerosis CEM), immune dysfunction of the CNS, muscle breakdown, muscular dystrophy (DM), disease of Alzheimer's (AD), Parkinson's disease (ΈΡ). The use of the wn«c.UnaX antibody or antibody fragment thereof in a method of treating inflammation, can reduce inflammation in the CNS and / or lungs of the patient. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the monoclonal antibody or antibody fragment derived therefrom to a patient who 2Q has or is suspected of having MS< In some cases, the monoclonal antibody or antibody fragment thereof of this embodiment is present in a. 169 composition. The composition can be a meat pharmaceutical composition is provided in the present document.

[00124] In one embodiment, a monoclonal antibody or an antibody fragment thereof is provided herein. 5, which specifically binds to ASQ, wherein the antibody or antibody fragment thereof comprises a heavy chain variable region (VH) and a light chain or kappa chain variable region (Vi], wherein the sequence The amino acid sequence of the VH region comprises SEQ ID NO: 21, or an amino acid sequence that is at least 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 21; and where the amino acid sequence of the VL region comprises SEQ ID NO: 31 or an amino acid sequence that is at least 95%, 96%, 97%, 98%: © 99% identical to the amino acid sequence of SEQ ID NO: 31. In addition to this embodiment, provided herein is the use of the monoclinal antibody or antibody fragment thereof in a method of treating inflammation in a subject Inflammation may be an innate immune disorder .. Inflammation may be inflammation related to inflammation The inflammation may be in the lungs and / or in the CNS. Inflammation in the lungs and / or the CNS may be the result of injury (for example, brain injury 170. traumatic (TBI) © spinal cord injury (SCI) ) .or e.nf erm.gda.d, condition and affliction .of the CNS or affecting the CNS, As provided herein,. the disease, condition, or affliction of the. CNS or CMS affecting may be stroke, as well as autoimmune diseases and / or CNS diseases, including Lou Gohng's amyotrophic lateral sclerosis (ALS), sclerosis. multiple (MS) , disjunction · Inwnológica of muscle degradation, .dystrophy, muscular (DM) , disease, of Xq Alzheimer- (AD), Parkinson's disease (PD). The Use of the monoantibody or antibody fragment thereof: in a method of treating inflammation can reduce inflammation in the CNS and / or lungs of the patient. the reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the monoelonal antibody or antibody fragment derived therefrom is s® asn for treating MS by administering the monoelonal antibody or antibody fragment. derived from. gisma to a patient who has or is suspected of having MS. In some cases, the roonoclona! p the antibody fragment thereof in this embodiment is present in a 171 composition. The composition may be a pharmaceutical composition as provided herein.

[00125] In one form, d®. In this embodiment, provided herein is a monoclonal antibody and an antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment of the mlsmc: comprises a heavy chain (VH) variable region and a heavy chain (VH) variable region. light chain or kappa chain (VL), in which the sequence of. amine acids of the VH region comprise SEQ ID NO' 22., q: a sequence' yields amino acids that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of ctQ ID NO: 22; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 28 or a sequence. α<amino acids which is at least 95%, 96%, 97%, 98% p 99% identical to 1a. amino acid sequence of SEQ ID NO: 2'8. In addition to this embodiment, provided herein is the use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The inflammation may be an inflammation, related to the inflammasome. The inflammation may be in the lungs and / or in the CNS. Inflammation in the lungs and / or CNS may be the result of injury (for example, brain injury 172 injury (TBI) or spinal cord injury (SCI)) or disease, condition or affliction of the CNS or affecting the OC. As provided herein, the disease, condition or affliction of or affecting the CNS may be cerebrovascular accident, as well as autoimmune diseases and / or CNS diseases, including Eou Gehrig's ALS. , multiple plephosis (ΕΓ-f), immunological CNS dysfunction, muscle breakdown, muscular dystrophy (bM), 10. Alzheimer's (AD), Earkinscn disease (EB). The use of monee.Ional antibody or antibody fragment thereof in a method of treating the. inflammation can reduce inflammation in the patient's CNS and / or lungs. The reduction can be compared to a control (eg, untreated patient and / or pre-treatment patient). In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the monoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of having £M. . In some cases, the monotlahal antibody or ο1 antiaudrya fragment of the .same of this form of real i hall is present in a 173 composition. The composition can fit any pharmaceutical field as ion-a is proposed herein.

[00126] In one embodiment, provided herein is a currency antibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a. heavy chain (VH) variable region and a light chain or kappa chain (VL) variable region, wherein the amino acid sequence of the VH region comprises SEQ ID NO: 22, or an amino acid sequence that is at least 95 %, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 22; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 2 9 or an amino acid sequence - which is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO; 29. In addition to this form of real!sate, the use of the mqnaclanal antibody is provided herein for an antibody fragment thereof in a method for treating inflammation in a subject. The inflammation may be an innate immune inflammation. The yg inflammation could be an inflammation related to iúflamasama. Inflammation may be in the lungs and / or CNS. Inflammation in the lungs and / or CNS may be the result of injury (for example, brain injury 174 tuberculosis (TB1) or spinal cord injury (SCI)) or disease, condition, or CNS affliction or affecting the CNS. As provided herein, the "disease, condition, or affliction of or affecting the CNS may be cerebrovascular accident, as well as autoimmune diseases" and / or impaired CNS diseases, including: amyotrophic lateral sclerosis (ALS); da Loe Gehrig, multiple sclerosis (MS), CNS immune dysfunction, muscle breakdown, muscular dystrophy (jDM, Alzheimer's disease (AD), Parkinson's disease (PD). The use of the monoclenal antibody or antibody fragment thereof in a method of treating: inflammation can reduce inflammation in the SMC and / or lungs of the patient.The reduction can be compared to a control (eg, untreated patient and / or patient before treatment}. In a method of treating In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat 1st MS by administering the monoclonal antibody or antibody fragment derived therefrom to a patient suffering from or suspected of having MS. In some instances, the wonoclunal antibody or antibody fragment thereof in this embodiment is present in a 175 composition. The composition may be a pharmaceutical composition as s® provided herein:.

[00127] In a way of. In this embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASO, wherein the antibody or antibody fragment thereof comprises a heavy (VH) chain variable region and a light chain variable region. or cappa (VL) chain, in which the amino acid sequence of the VH region comprises SEQ ID NO: 22, or 10- an amino acid sequence that is at least 98%, 96%, 971, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 22; and where- the amino acid sequence of the VL region comprises SEQ ID NO: 30 or an amino acid sequence that is at least 95%, 96%, 97%, 98% © 99% identical to the amino acid sequence of SEQ ID NO:30. In addition to this embodiment, provided herein is the use of the monoclonal antibody or antibody fragment thereof in a method of treating inflammation in a subject. The inflammation may be an innate immune inflammation. The inflammation may be an inflammation related to inflammation. Inflammation may be in the lungs and / or CNS Inflammation in the lungs and / or CNS may be the result of injury (for example, brain injury 176 traumatic (TBX) or spinal cord injury (SCI) ) or disease, condition or affliction of the CNS or affecting the CNS1 As provided herein, the disease, condition or affliction of or affecting the CNS may be cerebrovascular accident, as well as autoimmune diseases and / c CHS diseases, including Lou Gehrig's amyotrophic lateral sclerosis (CELA), multiple sclerosis (MS), CNS immune dysfunction, muscle breakdown, muscular dystrophy (DM), Alzheimer's disease, AD, Parkinson's disease (PD). Use of the monoantibody or antibody fragment thereof in a method of treating inflammation can reduce inflammation. the CNS and / or lungs of the patient. The reduction can be compared to a control (for example, P5 patient not trafedfr ylc paciantp: before the. rfefemife . In one embodiment, the monoclonal antibody or antibody fragment derived therefrom is used to treat MS by administering the monoclonal antibody or antibody fragment derived therefrom to a patient who 2Q has or is suspected of having MS, In some cases, the monoclonal antibody or antibody fragment thereof of this embodiment is present in a 177 compositionii» The composition may be a pharmaceutical composition as provided herein. [001281 In one embodiment, it is provided herein. a mosoclonal antibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or fragment of. antibody thereof comprises a heavy chain (VH) variable region and a light chain or kappa chain variable region íVL}, wherein the amino acid sequence of the VH region comprises SEQ ID NO: 22, or 10' a sequence. of amino acids that is at least 915%, 96®, 97%, 989 or 991 identical to the amino acid sequence of SEQ ID NO: 22; and where the amino acid sequence of the VL region comprises SEQ ID NO; 31 or an amino acid sequence that. is at least 95%, 96%, 97%, 986' or 99% identical to the amino acid sequence of SEQ ID. NO: 31. In addition to this embodiment, provided herein is the use of the monclonal antibody or antibody fragment thereof in a method of treating inflammation. sn a subject. The inflammation may be an innate immune inflammation. The 1uflunation may be an inflammation related to inflammation. In one embodiment, the monoclonal antibodies or antibody fragments thereof proposed herein can only be used in one method. 178 to reduce inflammation in a mammal as described in US 8'685,400, the contents of which are incorporated herein by reference in their entirety. The I . >ation may be in the lungs and / or in the CNS. The inflammation in the . lungs and / or ENE may be the result of injury (eg, traumatic brain injury (jTBI or spinal cord injury (SGX)) or. disease, condition, or affliction of the CNS or affecting the CNS. As provided In the present document, the disease, condition that afflicts the CNS or that affects the CNS may be a stroke, as well as autoimmune diseases and / or diseases of the CNS, including Leu Gehrig's am.otrophic lateral sclerosis (ALS). , multiple sclerosis (MS), CBS immune dysfunction, muscle breakdown, χ§ muscular dystrophy (ND), Alcheimer's disease (AD), Parkinson's disease (PD) The use of the monoclonal antibody or antibody fragment of the m .iamc in a method of treating inflammation can reduce inflammation in the CNS and / or:lung©s:of the patient The reduction can be compared with a control (eg, untreated patient and / or patient before treatment) In one embodiment, the monoclonal antibody or the antibody fragment derived therefrom: is used para. treat MS 179 administering the mcnoclonaL antibody or the antibody fragment derived therefrom to a patient suffering from or suspected of suffering from MS. In some cases, ;Lw(.trmup ronoclocal or the antibody fragment thereof- of this embodiment is present in a composition. The composition may be a pharmaceutical composition as provided herein. |00129| In another embodiment, a composition for reducing inflammation in the CNS or lungs of a mammal includes an antibody or an active fragment thereof as provided herein that specifically binds to NLRP1 (eg, antibody of chicken or a domain thereof Any suitable anti-NLRPI antibody can be used, and several are commercially available Examples of anti-NLRPI antibodies NLR.P1 for use in the methods herein may be those. are found therein in document US8085400, the contents of which are incorporated herein by reference in their entirety. Examples: of commercially available anti-NLRP1 antibodies 2ó for use in the methods provided in the ρη.^ητί documented include, but are not. limitation, human polyclonal antibody NL.RP1 AF6788 from R&D Systems·,- anti-NLRP1 Rabbit polyclonal ASO2 from: ERD. Millipare, anti-NLRO ISO ΝΒΙΟΟ-δβΜδ rabbit polyclone1 from Novas Biologicals, mouse anti-NLRP1 SAB1407151 polydian1 from Mgma-Aldrích, mouse anti-NLRB1 a.P36B3 polyelonal from Abcam, mouse anti-NLRF1 0X1325922 polyelunal from:'Biorpyt; anti-NLRRl MBS7051225 mouse polydunal from Siybiosource, AF6788 sheep ppliclcnai from P&D systems, anti-NLRPl oaed00344 mouse monoolonal from Aviva ' iystems, anti-ÑLPFl 0.05447 8__P050 rabbit polyelonal from Aviva Systems, anti~ NLRP1 ΑΡΡΘ77 rabbit Original , anti~ NLRP1 ABXH768983 pollerona! of rabbit give Antibcdies choline, anti— NLRFl 303? rabbit pollclcnal from Froscí, rabbit polyolonal anti-NLRP1 12256-1-ΆΡ from Proteintéch, mouse monoclonal anti-Nl.RPl ALX-8Q4-8O3-C10O from Eneo, mouse monoclonal anti-NLRPl MA1-25S42 from Invitrogen, anti-NLRPL mouse GTX1S091 moneeletal from Genelex, rabbit anti-NLBB1 200-401CX5 palicdnal from Rockland, or rabbit polyclonal anti-NLRP1 4990 from Sell Signaling Technology. The human NLRP1 protein may have accession numbers AAH3I787, NP_O01028225, NP_ 055737, NP__!27497, NP .127499 or NP__1275O0, In a tsalization form the antibody binds to a pyrin domain, ÑACHI, LRR1-6, FIXND o. ORAC or a portion or fragment thereof of a mammalian NLRP1 protein. (by ojcopy, human NLRF1). In this form of 181 embodiment, a .antibody- as described; herein it specifically binds to an amino acid sequence that has at least 65% (eg, 65, 70, 75, 80, 85%) sequence identity with a 'specific' domain (eg, pinin, KACHT, LRR1-6, FILND or CARO) or human NLRP1 fragment thereof. In one embodiment, a chicken anti-KLRFi polyolonal that was custom dissected and produced by Ayes Laboratories is used to reduce lung inflammation. This antibody can be directed against the following amino acid sequence: in human NLRP1: CEYYTEIREREREKSEKGR (SEQ ID NO: 3). In one embodiment, an antibody that binds to an NLRR1 domain and a fragment thereof as described herein: inhibits NLRPI activity in cells, eg, lung, type II alveolar cells of a mammal. . 100130] In yet another embodiment, a composition for reducing inflammation in the CNS or lungs of a mammal includes an antibody or an active fragment thereof: as provided herein that binds to 2Q. specifically to AId2 or a domain thereof. Any suitable anti-Alto antibody can be used, and several are commonly available. Examples of anti~AIM2 antibodies. commercially available. for your use 182 in the methods provided in this document include, but are not limited to, a rabbit polyclonal anti-AlM2 with catalog number 20590~l~AP from Proteintech, anti-AIMS antibody from Abcam (abl19791), rabbit polyclonal anti-AIK2 (N-terminal region; ECM biosciences catalog number AP3851, rabbit polyclonal anti-ASC Elabsciences catalog number S-AB-30449, mouse Anti-AlMl moneclonal antibody called AIM2 (3C4G11) antibody with Santa Cruz Biotechnology catalog sc-293174, gg AIM2 Wd&l®ái antibody from retan é®, Qrígene catalog number TA324973, AXM2 Í10M2B3) monoclonal antibody from Thermofishex Scientific, rabbit polyclonal AIN2 antibody ASIN928372 or ΑΒΓΝ760766 from Antibodies-Online, antibody polyclonal Biematix coat anti~AIM2 with catalog number CAE02153, polyclonal anti-AlN2 antibody (OABF01S33) from Aviva Systems Bidogy, polyclonal rabbit anti-AIÜl antibody LS-Cíltll from bSBio-C354127, monoclonal rabbit anti~AÍK2 antibody from Ce11 Signaling Technology, catalog number 19 A5-16259. morational antibody 2p polyclonal rabbit anti-AIM.2 from Fab Gennix Internar Incorporated, with catalog number AIM2 201AP, polyclonal rabbit anti-AIG2 from MyBíosource with catalog numbers MBS65S320, polyclonal rabbit anti-AIM'2 from Signalvay with 183 catalog number 36253, rabbit polyclonal anti-ATM2 from Novas Biological with catalog number 43900002, rabbit polyclonal anti-AIM2 from GeneTex GTX5491Q, rabbit polyclonal anti-ArME 2 654O from Prosci, mouse monoclonal anti-ÁIM2 orb333 9D- 2 from Biprbyt, anti-ΑΠό abó3015 mouse polyclone 1 from Abcam), anti~AlM2 ab'76423- mouse polyclonal from Aboam, anti-AIM2 SAB1406827 mouse polyclonal from Sigma Aldrich or anti~AIM2 3510 from Biolegend. The human AIM2 protein may have the accession numbers NXJH4 862, NB004824, !q:XW1B5B337, W0 5 24.5 673, AAB81613, 3AF8473.1 Q.r ÁAH1Q940. In one embodiment, the antibody binds to a Pyric domain. or HIN-200 or a portion, © fragmented thereof from a mammalian AIM2 protein (eg, human ΑΪΜ2). In this embodiment, a camo antibody is described in P5 herein specifically binds to an amino acid sequence that has at least 65% (eg, 65, 70, 75, 80, 85%) sequence identity to a specific domain' (eg, pyrins < H1N -200) © fixation of, same .of human AIM2, In. a form of realization, a 2q Antibody that binds to an AIM2 domain or fragment thereof described herein inhibits ATM2 activity in lung cells, eg, peanut type II alveolar cells. 184 (001311 Anti-flammable orna antibodies (eg, AntiASC, anti-HLRP1 or anti-AIMS) as described herein include rodent polyclonal and monoclonal antibodies, human palliclonal and ammunitional antibodies, or any part of the same, having at least one antigen-binding region of an immunoglobulin variable region, the antibody of which specifically binds to a component of a mammalian inflammasome (eg, ínOaw^ A1M2) tdX: ©Wo, by example:,:ASP or In In some cases, the antibody is specific for ASC such that an antibody is specific for ASC if it occurs at the center of an epitope of the polypeptide and binds to at least part of the natural or recombinant protein. (00132( In certain embodiments, an antibody provided herein comprises a polypeptide that has a number of amino acid substitutions, deletions, or insertions. For example, an anti-ASC monoclonal antibody or a fragment of - ASC-binding antibody comprises a .polypeptide^ having one or more amino acid substitutions, deletions, or insertions as compared to a polypeptide having an amino acid sequence of one or more of the following SEO- ΤΟ Νθ: 6-8, 12 -14, 18-22 q 28-31 An antibody provided herein 185 document can have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid substitutions, deletions or insertions. For example, an anti-ASC monoclonal antibody or an ASC-binding antibody fragment may have 1, 2, 3, 4, 5, or, 7, S, 9, 10 or more amino acid substitutions, deletions or insertions. Substitutions, deletions, or insertions can be introduced by standard techniques, such as site-directed mutagenesis or PCR-mediated mutagenesis of a nucleic acid molecule encoding an anti-ASC antibody polypeptide or an antibody fragment that binds to ASO.

[00133] In certain embodiments, conservative s-amino acid substitutions are made at one or more positions in the amino acid sequences of antibodies or antibody fragments described herein. A conservative amino acid substitution is one in which the amino acid residue is replaced by an amino acid residue having a similar side chain. In certain embodiments, substitutions Amino acid conservative 2Qs are performed only on the FE sequences and not on the CDR sequences of an antibody or antibody fragment. Families of amino acid residues have been defined in the art that have 186 similar renal la chains, including badic side chains (eg, lysine, arglnine, histidine), acidic side chains (eg, aspartite acid, glutamic acid), uncharged polar side chains (eg, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (for example, alanine, valine, laucine, isoleusine, proline, phenylalanine, methionine, tryptophan), beta branching side chains ('for example lo., threonina, valina, 1Q isoleucine) and aromatic side chains: (eg tyrosine, phenylalanine, histidine tryptophans). Thus, for example, an amino acid residue in an atonoslonal anti-ASC antibody polypeptide © an ASC-binding antibody fragment: may be replaced with another amino acid residue from the same family of side-chains. In certain embodiments , a chain of amino acids can be replaced with a chain, structurally similar that differs in the order and / or óampóo islan of the members of the family of -chains 2Q sides. Those skilled in the art will be able to assess whether an anti-ASC mcndclonal antibody or antibody fragment binds to A5C that comprises a polypeptide that has one or more amino acid substitutions, deletions, or insertions. 187 in comparison with a polypeptide having an amino acid sequence of one or more of SEQ id NOí 6-8, 12-14, 18*22 c 28~31 bind to ASC protein using recognized routine methods in the art including, but not limited to, ELISA, Western blots, phage display, etc. [001341 Calculations of sequence homology or identity (terms are used interchangeably in this document) between sequences can be performed as follows, [0013S1 To determine the percentage, of .identity of two amino acid sequences, or of two nucleic acid sequences, the .sequences. are aligned for optimal comparison purposes (for example, gaps can be introduced into one © both of a- first and second amino acid or nucleic acid sequences for optimal alignment and non-homologous sequences can be discarded for comparison purposes}. In one way , of exemplary embodiment, the length of an aligned reference sequence for purposes of comparison is at least 30%, 4 0%, SQ%, 60%, 7 0%, 7 5%, 2Q 80?, 81%, 82%, 53%, 84%. W%:, 86%, 87%, 58%, 89%, 90?, 91%, 923, 93%, 94%, 95%, 93%, 97%, 98%, 99% to 100% of the length of the reference sequence. Subsequently, the .residues of aminoná.cidG'S or nucí ectidos in the 188 CQrrésponoieutss requests for amino acid or nucleotide positions» When a position in the first sequence is occupied by the same amino acid or nucleotide residue as the corresponding position in the second: sequence, then the molecules are identical at that position (as used here, amino acid or nucleic acid identity is equivalent to amino acid or nucleic acid homology). The percentage identity between the two sequences is a function of the number of identical LO positions shared by the sequences, taking into account the number of gaps and the length of each gap, which must be introduced for optimal alignment of the two sequences. [00,136] Sequence comparison and determination of 15 percent identity between two sequences can be accomplished using a mathematical algorithm. In one embodiment, the chemistry of identity between two amino acid sequences is determined using the Needleman et al. method. (.(1970) JL Mol. Biol. 4§ : 44'4-453) algorithm that has been 2Ό incorporated into the GAP program in the GCG software package (available at www.gcg.com), using a BLOSUM 62 matrix or a FAM250 matrix, and a space weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In another In one embodiment, the percent identity between two nuQ:Ie.ot:idox sequences is determined using the GAL program in the GCG software package (available at www.gcg»com), using a WSgapdna CMP matrix and a weight. of space of 4:Q, 5Q, 60, 70 or 88 and a length weight of 1, 2, 3, 4, 5 or ». One set of parameters (and the one that can be used if: the clinician is not sure which parameters should be applied to determine if a molecule falls within a sequence identity or "homology limitation of the invention") is an array of punctuation. BLUSUM 62 not a .12 gap penalty, an .extension penalty, a 4 gap penalty, and a frame change gap penalty. of 1,

[00137] The percentage gives. identity between two sequences of 15 amino acids. or nucleotides can be determined using the algorithm of «eyers et al. ((1989) CABIOS 4: 11-17) that has been incorporated into the ALIGA program (version 2.0), using a table of residual weights ΡΑΜΙ20 , a length penalty of: 'space Λ& ΙΑ::and an i zation penalty d® space of·. 20 4.

[00138] E.n. In certain respects, an antibody is a monoclonal antibody. In other aspects, an antibody is an antibody, poli cation al. The term, antibody mono- tion to go is 1:90 refers to a combination of antibody molecules that contain only one species of an antigen-binding site capable of immunoreacting with a particular epitope of an antigen, Acr therefore, a composition. A monoclonal antibody typically displays a single binding affinity for a particular protein with which it limnoreacts. [001391 In some aspects, an antibody of the invention (An auLj-ñSC raonoclonal antibody or an ASC-binding antibody fragment; is humanized, chimeric or human. [001401 In some embodiments, an antibody of the invention is a humanized antibody. [001411 ^Humanized antibody, as the term is used in this document, refers to your antibody that has been designed to comprise one or more human atareo regions in the variable region together with. the non-human (for example, mouse, rat, or hamster) heavy and / or light chain complementatility cDRs (CDRs). In certain embodiments, a humanized antibody comprises sequences that are fully human except for regions ; CDR. In some cases, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Also, the 191 humanized antibody may comprise residues that are found neither in the human form of the antibody nor in the imported COR framework sequences©, but are included, to further refine and optimize the performance of the antibody. In general, the humanized antibody will comprise the entirety of at least one, and usually two, variable domains, in which all or substantially all of the CDR regions correspond to those of a Non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulixia consensus sequence. The FR rule can be modified in any manner known in the art and / or provided herein. Paedeu modifications confer desirable properties such as an increased half-life X5 and / or an Enhanced expression in the » host cells. In one embodiment, the FR region(s) may be modified or mulled as described in US2015O232 557, which is incorporated herein by reference. Other forms of humanized anl xc..üp.'s may have used or more CDRs (CDR El, CDR 12, CDR L3, CDR Hl, CDR H2 or CDR H3? that are altered from the original antibody, which are also called one or more CDRs derived from one or more CDRs of the original antibody.The humanized antibody© also 192 will optimally comprise at least a part of a region or constant domain of immunoglobulin i Fe), typically: that of a human immunoglobulin, [001421 Humanized antibodies are typically less and immunogenic for humans, compared to non-humanized antibodies, and therefore offer therapeutic benefits in certain situations, for example, the constant region of the antibody can be designed so that it is immunologically inert (for example, it does not trigger complement lysis). See, for example, BCT Publication No. RCT / GB99 / 01441; Patent Application of the UK No, 9809951.8, each of which is incorporated herein by reference in its entirety. Those skilled in the art: eostwto the ant.lcue:r:p.QS human! Nades and 15 will also know the appropriate techniques for their generation. See, for example, Huang, W, Y.K., et al., Methods 36:35, 2005; Queen et al., Proc, Nati. acad. Sci. USA, 86: Ι002910033, 1989; Jones et al', Nature, 321: 522-25, 1986; Riechmann et al., Natura, 332 : 3.23-27, 19SS; Verhoeyen et al 20>, Science, 239: 1534-36, 1988; Orlandi et al, Proa. nati. Acadu Sel. USA, 36: 3833-37, 1939; US Latent, No. 5,225,539; 5,530,101; 5,585,089; 5,693,761; 5,693,762; 6,L8G;,3?O·; and SéXíck et al,, WQ 90 / 0-7861., each smo of the 193 cuais is incorporated herein by reference in its entirety. Other antibody humanization methods that can also be used are described in Daugherty et al., Nuci. Acid Res:. 19: 2471-2475, 1991 and in US Pat. No. 5. 6.180.37 7; 6,054,297; 5,997,867; 5,866,692; 6,210,671; and 6,350,861; and in PCT Publication Nc, WO 01 / 27160, each üha\ of which is incorporated herein by reference in its entirety. For example, an anti-ASC antibody -p an anti-ASC antigen binding fragment of the invention xg may comprise an amino acid sequence from the region VH comprising HCDR1 of SEQ ID NO: 6, HC.DR2 of SEQ ID NO: and HCÜR3 of SEQ ID NO:- 8; and amino acid sequences of region VI comprising LCDR1 of SEQ ID NO; 12, LCDR2 of SEQ ID NO: 13 and LCDR3 of SEQ ID NO: 14; and one or more ^5 human framework sequences,

[00143] In some embodiments, an antibody of the invention is a chimeric antibody and specifically binds ASC. In some cases, the anti-ASC kinetic antibody reduces ASC activity. Chimeric 2Q antibody^, as the term is used herein, refers to an antibody that has been designed to comprise at least one human constant region. For example, one or all of the variable regions of the light chain(s) 194 and / or one or all of the variable regions of the is) heavy chain(s) of a mouse antibody (eg, a mouse monoclonal antibody) may each be linked to a human constant region, such. as, without limitation, a human XgGl expression region. Chimeric antibodies are typically less immunogenic for humans, relative to non-chimeric antibodies, and therefore offer therapeutic benefit in certain situations. Those skilled in the art will know. chimeric antibodies and will also know the appropriate techniques for their. generation. See, for example, Cabilly et al. US Patent F 4.81S. 567; Shoemaker et al., EEfeü patent. Ka4, 97 8,775; Beaverset, al., Batente, USA. bU. No. 4,975,369; and Boss et al., US Pat. No. 4,815,3.97, each of which is incorporated herein by reference in. its entirety. For example, an antibody or antigen-binding fragment: of the invention may comprise a VH region comprising SEQ ID >0:22; a VL region comprising SEQ' Ip NQ: 31 and one: human constant region, 100144] As used herein, the terms immunological binding and Immunological binding properties1 refer to non-ovalent interactions of the type that occur between an immunoglobulin molecule (eg, 195 an antibody) and an antigen©: for which the ínwnoglebullna is specific. The strength or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (Kd) of the interaction, where a smaller Kd represents: a higher affinity, The immunological binding properties of selected polypeptides can be quantifying using methods well known in the art, both of these methods involve measuring the rates of formation and dissociation of the antigen / antigen binding site complex, where those rates depend on the concentrations of the partners: of the complex, the affinity of the interaction and geometric parameters that equally influence the rate in both directions^ nor both the active rate constant (Kan) and «a© the inactive rate constant (Kcff) can be determined by calculating the concentrations and rates real association and dissociation. (Afe Nature 361: 186-87 (1993)), The Koff / Kan relationship allows for the. cancellation of all non-gg affinity related parameters and is equal to the dissociation constant Kd. (See generally Davies et al. (1990) Annual Rev Blochem 39: 439-473). An antibody of the present invention is said to specifically bind to an epitope 196 (eg, ASC Fragment with amino acid SEQ: IP NOí 5) when the equilibrium binding constant (Edj is < 10 μΜ, P' 10 nM, < 10 nM, and < 100 pM to about' 1 pM, measured ' by assays such as na di silgando binding assays: or similar assays known to those skilled in the art *

[00145] In certain aspects, an antibody of the invention is monovalent or bivalent and comprises single or double chain. Functionally, the binding affinity of an antibody can be in the range of 10~&M to 10uM. For example, the binding affinity of an antibody is from 10*M to 10'UM, from JCT7M to 1GUM, from 1(FSM to 10~i2M, from 10sM to 10‘i2Mr from 10sM to 1:0nM, from. 10“éM to 10~uM, from 107Ma ΙΟ’2M, from 10“8M to 10ríM, give 1Q9® to 1QUM?from 10ίαM to 10’uM, from 10“sM to 10'uM, give 1 0δM to 10^ M, give 10~7Ma ΙΟ10Mr from 10^ M to 10:° M, from 10' M to 10iSM, from 105Ma 10*9M, from 10“δM to 10'5* M, from 107M to ΙΟ'5M, from 10~® M to 10~® Μ, from 10sM to 1G~SM, from 10® M to 104M, from 107M to 10sM, from 10® M to 10?M, from 10*® M to 10*7M cr from ΙΟ5M to 1G“® M. 100146] Methods for determining the specificity and affinity of monoclonal antibodies by competitive inhibition can be found in Harlow, et al., Antibodies: A Laboratcry Manual, Cald Spring Harbor. 197 Laboratory Press, Caló Spring Harbor, ΝΉ / 1988, Colligan et al», eds., Current Prolócela in Tmmvnology, Greene Publishing Assoc. and Niley Interscience, N.Y., (1992, 1993), and Mui 1 ex, Meth. 'Ennymól.' 92:589-601, 1983, all 5 of which are incorporated by reference herein in their entirety. WH71 The antiUnilamamaoma antibodies (eg, AntiASC and antiL-ATM2) of the present invention can be routinely prepared according to methods such as, but not limited to, inoculation of an appropriate animal with the polypeptide or fragment. , antigenic, in vitro stimulation of populations of lymphocytes, synthetic methods, hybridomas and / or recombinant cells that express the nucleic acid encoding said anti-ASC or anti15 NT¿R1 < Immunization. from an animal using purified recombinant ASC or peptide fragments thereof, eg, Rat ASO Residucs 178-193 (SEQ ID NO: 1) (eg, BAC4 Accession Number 37 54), SEQ ID NO: 2 of human ASC c residues 21-43 (SEQ ID NO: 5) of human ASC (for example, accession number NP_037396»2), is an example of a method for preparing anti-ASC» antibodies. Similarly, immunization give an animal using purified recommended NLR21 or peptide fragments thereof, IB eg, MEE SQS «EE SEL EG-cys (GEQ Ib B: 4) from NALE1 from: rat or SEQ: ID NQ: 3 from human NALFI, is an example of an anti-NLRP1 antibody preparation method. [001481 Monoclonal antihis in pos that specifically bind to ASC or NLRP1 can be designated m.edi.apte. methods known to those skilled in the art. See, for example, Roblar and Müstein, Nature zd:ds-497, 1975; U.S. Ead No·. 4,376,110; Ausubel et al., eds. , Current 'Protoesls in Molecular Bidogy, Green Publishing Assoc. and wiley Inter Science, N.Y. , (1087, 1992); Haxlow and Lana AETIBQDIES: A Laboratcry Manual Quid Spring Harber Laborat ory Fress.., Csld Spring Harbor, 1.98 Br Eglligan et al., eds., Gurrent Prducols in Immunology, Graene Fublishing Assoc. and. Víil.e.y Inter·scienc.e, di. , (1992, 1993), the contents of which are incorporated, in their entirety, below as .erenda.. niche® ant bodies can be of any class of immunoglobulin, including TgG, IgM, IgE, IgA, GILD and any subsistence of those. same. A hlpridoma that produces: a monodonal antibody of the present invention can :Cu:l:dva.rs.e: i.ñ vi tro,. 18 d'tu or in yivo... In one embodiment, a hybridoma that produces a iodonal anti-ASC antibody of the present disclosure is the 199 Hybridome ICCNI.OH. In another embodiment, a hybridoma producing a monoclonal anti-ASC antibody of the present disclosure produces monoclonal antibodies comprising a heavy chain variable region (VHj) and a light chain variable region:(VI), wherein the amino acid sequence of the VH region comprises HCDR1 of SEQ ID NO: 6fHCDR1 of SEQ ID NO: 7 and HCDR3 of SEQ ID NO: 8, or a variant thereof having at least one amino acid substitution in HCDR1, HCDR2 and / or HCDR3 In another and g embodiment, a hybridoma producing an anti-ASC mcnoclonal antibody of the present disclosure produces monoclonal antibodies comprising a heavy chain variable region (VH) and a light chain variable region (VI). ), given the amino acid sequence of region VI i 5 comprises LCDR1 of SEQ ID NO: 12, LCDR2 of SEQ ID NO: 13 and LCDM3 of SEQ ID NO: 14, or a variant thereof having at least one substitution of. amino acid in LCDR1, LCDR2 and / or LCDR3. In yet another embodiment, a hybridoma producing an anti-ASO monoclonal antibody of the present disclosure produces oral monoclonal antibodies comprising a heavy chain variable region (VH) and a light chain variable region (Vi). , wherein -where the amino acid sequence of the VH region comprises HCDR1 of SEQ ID NO: 6, 200 HCDR2 of SIQ ID NO; 7 and HÜDR3 of SEQ ID NO; §, or a variant thereof that has at least one amino acid substitution in HDDR1, HCDF.2 and / or HCDR3 and in which the amino acid sequence of region VI comprises LCDR1 of 5 SEQ ID NO: 12, LCDR2 of SEQ ID NQ: 13 and DCDR3 of SEQ ID NO; 14, or a variant thereof having at least one amino acid substitution in LCDK1ZLCDR2 and / or LCDR3. Admission of compositions 1Q

[00149] The fields of the invention may be administered to mammals (eg, rodents, humans) in any suitable formulation. For example, anti-ASC antibodies can be formulated in pharmaceutically acceptable carriers or diluents such as physiological saline or buffered saline. Suitable carriers and diluents can be selected based on the mode and route of administration and standard pharmaceutical practice. A description of carriers and diluents can be found pharmaceutically 2nd acceptable copies, as well as pharmaceutical formulations, in Remington's Pharaceutical Sciences, a standard text in this field, and in DSP / NF. Other substances may be added to 201 the compositions to stabilize and / or preserve the compositions. (001501 The compositions of the invention can be administered to mammals by means of any conventional technique. Normally, said administration will be by inhalation or by parenteral route (for example: intravenously, subcutaneously, intratumorally, intramuscularly, intraperitoneally or intrathecally). The compositions may also be administered directly to a target site by, for example, surgical administration to an internal or external target site, or via catheter to a site accessible by a blood vessel.The compositions may be administered as a single bolus. , multiple injections, or by continuous infusion (eg, intravenously, by peritoneal dialysis, pump infusion.) For parenteral administration, the compositions may be formulated in a sterile, pyrogen-free form. Effective dose [OOISlj] The compositions described above can be administered to a mammal (eg, rat, human) in an effective amount, i.e., an amount capable of producing a desirable result in a treated mammal. 202 (for example, reduce inflammation in the CNS of a mammal · subjected to a traumatic injury of the SW or accident · aerettovascalar ©: that has an autoimmune, autoinflamatorla, metabolic, neurodegenerative or CNS 1 disease) Such a quantity therapeutically. effective can be determined as: described: below.. The therapeutically effective amount of a composition comprising an agent as provided herein (for example, a monoelonal antibody:p 2nd derivative thereof as provided herein how, for example, TC 10G) can generally be about 0.G01, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 2, 4 , , 8., 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 7 5, 8 0, 85, 90, 95, 100, 115, 150, 17 5 or 200 mg / kg of the patient's body weight. The therapeutically effective amount of a composition comprising an agent as provided herein (for example, a monoclonal antibody or an antibody fragment^-derived thereof as provided herein, how, for example, IC 2Q 100) can generally be from about 0.001 to about 20Q:mg / kg of the patient's body weight. The effective therapeutic^^^ amount of a field kidney that is provided herein comprises an agent such as 203 (for example, a monoclonal antibody or antibody fragment derived therefrom as provided herein). duo amento, or om οΎ eg IC 100) can generally be from about 0.001 mg / kg to about 0.01 mg / kg. 5 approximately 0.01 mg / kg to approximately me nt® 0.1 mg / kg. from about 0.1 mg / kg to about 1 mg / kg. approximately 1 mg / kg to approximately 10 mg / kg, approximately 10 mq / kg to approximately 7 5 mg / kg. approximately 2 5 pg / kg to approximately 5.0 mg / kg, approximately 10-50 mg / kg to approximately 75 mg / kg, approximately g and ες / ρ to approximately 100 mg / kg. approximately .100 mg / kg a. approximately 125 mg / kg, approximately 125 mg / kg a approximately π t e 150 mg / kg, approximately 150 mg / kg a approximately 17 5 mg / kg p: 15 approximately d unent 17 5-mg / kg to approximately 200 mg / kg of the subject's body weight. The composition comprising an agent as provided herein (for example, an antibody monoel una 1 or an antibody fragment-derived thereof c o unknow pr u pore i on a en e 1 I presented document such as, for example, IC 100) can be administered in single or multiple doses.

[00152] The toxicity and therapeutic efficacy of the compositions used in the iüve'ncl'ón methods are 204 can be exterminated by standard pharmaceutical procedures, using cultured cells or experimental animals to determine the LD50 (the lethal dose for 50% of the population). The dose relationship between the toxic and therapeutic effects is the therapeutic indicator and can be expressed as the LD50 / EDS0 ratio. In some cases, the compositions provided herein exhibit large therapeutic indices. Although those that exhibit toxic side effects may be used, care must be taken to design a Delivery System that minimizes the potential for such side effects. In some cases, the dose of the -compare oses given here- is within a range that includes an ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form used and the route of administration used.

[00153] As is well known in the medical and veterinary arts, the dosage for any subject depends on many factors, including the subject's size, body surface area, age, the particular composition to be administered, time, and route of administration. administration, general health and other medicines that are administered at the same time. 205

[00154] The present invention is further illustrated by the following specific examples. The examples are provided for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way. Example Go Role of EV-mediated inflammasome signaling in ALI after a. LCT and effects of its neutralization

[00155] Pulmonary dysfunction often presents as a complication of severe traumatic brain injury (1). Approximately 10-15 percent of subjects with TBI develop acute lung injury (ALI) (2), but the mechanisms mediating the pathology of TBI-induced ALI remain poorly defined. Previous literature has supported 1. to. idea that pulmonary dysfunction after TBI is due to the sympathetic response to increased 2Q intracranial pressure leading to cardiopulmonary dysfunction (Ό). However, more recent studies have shown that a systemic inflammatory response also plays a key role in TB1-induced lung injury. 206 (43).. Specifically, the HMGBI-RAGE-ligand receptor pathway serves as the central transduction mechanism for lung dissolution after TBI (8) . In addition, HMGBl induces the activation of the inflamaseme AIM2 (37). In addition, previous literature reveals that pathogens secrete EVs that carry DAMPs, such as HMGB1, and trigger inflammation (Buzas et al., 2014). Several studies have shown that the blood cell-Oephalite (BBB) ​​barrier is leaky after traumatic GERD as early as 3-β hours after injury, impairing the protective barrier between the GERD and the intravasedal compartment and leading to leakage. protein- and fluid (44) . Disruption of ΒΉΕ after injury results in the secretion of inflammatory mediators, such as DAMPs, which can increase 15 1st brain inflammation and damage distal organs (5). Several inflammatory mediators can act as clear markers of brain injury, however, their validity is not widely accepted (45). Furthermore, there is currently no treatment or biomarker 2Q clinically approved for TSI-induced Aid. Recently, EVs have become an area of ​​interest in biomarker research for several different types of disease, including injury 207 pulmonary (4 6) and TBI (47K It has previously been shown that in the EV isolated from the cerebrospinal fluid of a patient with CLI, there is an increase in inflammasome proteins in comparison with the cells after control ( 14) In this example, the contribution of EV-mediated inflammasome signaling to the etiology of TBI-induced ALI was examined. Materials, and methods ag Animals and traumatic brain injury

[00156] All procedures with animals were: approved by the Institutional Committee for the Use and Care of Animals of the Millar School of Medicine of the University of Miami (Animal Welfare Guarantee A3224~Q1) and were carried out in accordance with the Guide of NIH for the Care and Use of Laboratory Animals. ORIVE guidelines were followed in conducting this study. All C57 / BL6 mice were 8 1.2 weeks old and 2 4 to 32 grams. Mice were prospectively randomized into experimental groups (sham, 4 h, 24) for TBI, experimental groups (no pretreatment, sham saline, untreated, enoxaparin, anti-ASC) for non-foster transfer, and u -!?i love. For groups of 208 TBI experiments, simulated animals were subjected. a •surgical procedure but were not injured. For adoptive transfer treatment studies, the sham saline group was submitted. surgical procedures and received saline solution with carrier treatment. Naïve animals did not undergo surgical procedures. A sample size of 5 to 6 was used for each group based on power analysis (using G q * power analysis, with effect size F ~ 0.85, a set at 8.05) and historical data. 4 9, 50. All mice were housed in the University of Miami Luis Pope Life Canter antigen-free (VAF) animal facility on 12-h light / dark cycles and provided food and water ad libitum. :. The facility performs brooding procedures twice a week and checks feeding conditions daily. Animals were observed postoperatively, where they were kept on a heating pad and body temperature was monitored with a rectal q probe where it was kept at 37°C in our operating room and then moved to the animal rooms. 209 |0O1$7] Before surgery, ic-s animals are anesthetized with katamine and xylazine Clntraperitoneal, ,i.p.). The anesthetized animals were then placed on a heating pad to ensure a body temperature of 37°C. TCL was performed using a Controlled Cortical Impact (CCI) model » Sé performed a 5 te craniotomy in the right cortex (-2.5 te posterior, 2.0 lateral Brégma rom). Lesion was induced using the ECCI6.3 device (Custom Design & Fabrication, Richmend, VA, USA) with a 3-mm seizer at a velocity of t m / s, a depth of 0.8 mm, and a duration of impact of 15© ms (15) . Following these procedures, the animals were returned to their cages and given food and water. Animals were sacrificed 4 hours and 24 hours after TBI as described. Sham animals were anesthetized and underwent the same surgical incision as the injured animals, but did not undergo head injury or contusion. tissue collection J0O158] All animals were anesthetized with ketamine and xylene, before perfusion. Subsequently, the animals know gomethiexone, tracheal perfusion. Le» lungs I know 210 were infused with paralpernaldue (PEA) to Ó using a tracheal catheter at 20 cm H2O and then fixed in 4% PEA overnight at 4SC. Fixed lung tissues were embedded in parafine and 5 pm (Id) sections processed. Right lung tissue was collected for protein isolation and molecular analyses. Animals were then decapitated and right cortical tissue was collected for protein isolation and molecular analyses. ÍÓ Pyroptosome isolation assay

[00159] Uses of mouse lung tissue were filtered through a μρ low-binding polyvinylidene difluoride (PVDF) membrane (Millipore). After filtration, the supernatant is centrifuged at 2700 xg for 8 min. The pellet was resuspended in 49 pl of 3 Π3~oolamidoprdpil)dimethylammonium]-propanesulfonic acid (CHAFS) buffer (2C mmcl / L HEPES-KOü, pH 7.5, 5 mmol / L MgC12, 2Q 0.5 mmol / L ESTA, 0.1 mmol / L phenylmatylsulf or ni-Lo fluoride, protease inhibitor cocktail, and 0.1% CHAfS). The pyroptosome was pelleted by centrifugation at 2 7u0 xg for 3 minutes. The pellet was then Π r©suspended and incubated- in 27.8 pl of 2HAPS buffer with 2.2 ul of austral diPdéCinímíd!^ (9) for 30 minutes at room temperature to crosslink the ASC dimers. Finally, an equal amount of 2x Laemmli buffer was added and proteins were analyzed by immunoblotting using commercially available antibodies to ASC and Gasdermin D (GSD). .Nuclear and cytoplasmic extraction [00160 J Nuclear and cytoplasmic fractions were extracted using NE-PSR nuclear and oitoplasmic extraction reagents (Thermo Se:entific) according to the manufacturer's instructions. Briefly, mouse lung tissue samples were cut into 20-100 mg pieces and centrifuged at 500 x g for 5 minutes. The tissue pieces were homogenized with the cytoplasmic extraction reagent and centrifuged at 16,000 x g for 5 minutes. Then the supernatant (cell extract) was removed and the pellet was centrifuged with rudc.ivo 2Q Nuclear Extraction (Thermo Scientific) at 16,000 x g for 10 min. This supernatant corresponded to the nuclear fraction, which was removed and stored at -80 2-:12 Immuno tran s farene i a

[00161] Lung and brain tissue samples were snap frozen in liquid nitrogen and stored a. ~§0eC, 2-mm sections of right lower lung and right cortical tissue were homogenized in Lampos©e extraction containing a pretense and phosphatase inhibitor cocktail (Sigma, St LouiSi MO, USA) and resolved in precast qels Tris-TGX Crilorian 4-20% (Bao-Rao, 1Q Hercules, CA, ÉÉ. ÜU.) As described in de Rivero Vaecari et al. 2015 (13) using antibodies against easpase-1 (Novas Biológica l.s), ASC (Santa Cruz), IL-1 or (Cell signaling), IL-18 (Abcam) AIM.2 (Santa Eruc) and HMGBI (Hillípore). The quantification of band density was performed using Imaqe Lab and all data normalized to β-aetin. JnWn oh i a t o qu i m i c a.

[00162] Tissue sections were deparaffinized^ on niwood and then rehydrated^ using ethanol and buffered saline sad,. Immunohistochemical procedures for double staining were then carried out as previously described (16). The imctions will be incubated, during, the 213 overnight at 4 °C with antibodies against Caspasé-1 and ASC íMillipore}rÁIM2 (Santa: Cruzh HMGBL (Millipore) and SPC (Killipore). Immunostained lung sections from 4-h and 24-h mock mice were examined under a confocal microscope Ceiss laser scanning (Seiss, Ihc.tThcrnwood, SY, USA. bb,}♦ Lung sections were analyzed by individuals who were blinded to the groups. Isolation .of. EV [08101 EVs were isolated from the sera of TEI-lesioned mice and lesioned mice using the total excosome isolation solution according to the manufacturer's instructions (invltrogen). Briefly, 100 µl of each sample was centrifuged at .2000 x g for 30 minutes. A cent in nation, was incubated: the supernatant with. 2 0 qi. of Total Exosome Isolation Reagent (TEI) for 30 minutes at 4. *0 followed by centrifugation at 16,000 x g for 10 minutes at room temperature. The supernatants were discarded and the pellet was resuspended in 100 pl of BES. The EVs were characterized by CD81 expression and by Nanesight follow-up analysis (ΕΙΆ. &). VE adoptive transfer 214

[00164] Inject themselves. Serum-derived EV of CólBl-S TBI and naive C57SL-6 catch sham mice via vein: jugular at a dose of 1.0 x 1010 particles per gram / body weight 4B. The count of 5 particles was measured by follow-up analysis of Nanosight and samples were diluted accordingly. Before surgery, the animals were anesthetized with ketamine and xylsno. A 1-2 cm incision was made between the mandible and the clavicle. The jugular vein was elevated and tied off, followed by catheter placement. Serum-derived EVs were blotted and lung and brain tissues were collected 24 hours post-injection for analysis (n=5). Treatment with enoxaparin and anti-APO

[00165] EV derived from serum from TBI mice were injected into naïve C57-BL6 mice via jugular vein injection. One hour later, enexaparin (3 mg / kg) (n=4) and Anti-ASC HC 100 were administered; 5 mg / kg) (n ~ 4} to recipient animals. 2.0 used the following groups:. 1) the naïve group received no treatment, 2) the sham saline group was used as a negative control and underwent a jugular vein injection of s or 1 ps or 1 u a i δ n s a 1. i n a, 215 3) the naive group received EV from TSI mice without any treatment and was used as a positive control, 4) the ENOX group received EV from TBI and enoxapsxin mice, and 5; the Anti~ASC group. recf^ EV of mice TBI and Anti-ASC. The order of treatment was randomized. Lung and brain tissues were collected 24 hours after injection for analysis. It should be noted that the anti~ASC antibody used in the treatment experiments was a humanized, monocolonal antibody against ASC y. ig recognizes murine, human and porcine ASE. Histology score and lung injury [00.166] Sections of lung tissue were stained by a standard hematoxylin and eosin method for histology, morphametry and scoring: from ALI. Lung sections were scored by a blinded pathologist using the American Thpracio Society Workshop Report Lung Lesion Scoring System (17). Twenty high powered random fields were chosen for scoring. Criteria for the pg ALI score were based on the number of neutrophils in the alveolar space, interstitial space, hyaline tangles, proteinaceous debris filling the airspaces, and thickening of the alveolar septum. Based on 216 these criteria, a score between 0 (no injury) and 1 (severe injury) was awarded. Statistical analysis (001671) Data were analyzed using a study t-test for two groups, and a one-way ANOVA followed by Tukey's multiple comparison tests (GraphPad. Prism version 7.0) for two © more groups. the DrAgostino-Pearsun test to verify normality. Í0 are expressed as median / - SEM. The p values ​​of significance used were *p < 0.05. Results Severe FBI increases the Inflammasama AIM2 proteins and the expression of. HMGBd in the mouse brain

[0010] Excessive levels of the proinflammation cytokines IL-Ιβ and IL~1B and inflammasome proteins are associated with secondary damage-after fluid percussion brain injury. (18). To determine whether severe GGI induced piminflammatory roquiras processing and alterations in inflammasome protein levels, the 217 Used cortical, however, there is limited research on inflammasome activation in severe TBI. In this example, after a . Severe CCI, the cortical cells were examined to determine the levels of caspase-1 (Fig 1.A, B) (p < Q,OÜ1), ASC (Fig 1A, C) (p ® 0.003), 11-18 (FIG 1 A, D) (p = 0.0042), Α1Μ2 (FIG 1A, F) (p - 0.0197) and IL-Ιβ (FIG 1 A, G) (p 0.0141) at 4 and 24 hours after injury. Caspase-1, ASC, Alió and IL~IÓ levels peaked 4 hours after 2Q the ICC and they decided after 24 hours. The time course for the maturation of the inflammatory eitogins differed slightly, but a1o a1zos η p αn t o maximally 2 4 h after LCl. Since others have demonstrated a role of the inflamed DAMP HMGB1 soma in the activation of the i.nf lamas Qm.a AIM2, the levels of these proteins were also determined in cortical cells. As shown in Figs. ΙΑ,1E, GCI induced a significant increase in HMGBl levels (Fig. ΙΑ,1E) (p<0.0121) at 4 and 24 hours post-injury. These data indicate that after severe CCX in mice, levels of the AIM2 inflammasome proteins were significantly elevated in the cortex after injury. 218 Severe TBI increases AIM2 soma inflator protein and HMGBl expression in the lungs of mice |W169] To determine whether COI induced soma inflator activation in the lungs, a lung immunoblot assay was performed to caspas a-1 (Fig. 1H, I) (p 0.00.26), ASC (Fig 1K, 0) (p. - 0.007), IL-18 (FIG 1H, K) (p - 0.0025) -, IL-Ιβ (FIG 1 H, A) (p 0.0012) and AIR? (FIG X Η, M.) (p « 0.001.) and NLRF3 (p = 0.0047) (Supplementary FIG 1). Increased levels of caspase-1, ASC, IL*18, and ΑΓΜ2 were significantly increased a. at 4 hours and 24 hours post-injury compared to sham control. Without. However, the time course of the increase in protein expression differed slightly from that observed in the brain where they peaked 24 hours after COI. While agreeing that the HMGB1-RAGE axis plays a role in the mechanism by which FBI induces lung dysfunction (8), lung lysates were analyzed for expression levels of the HAGB1 protein.a, FIG 1H, 1L ip = 0.1158: shows that the expression of HMGB1 increased at 4 and 24 hours after BCT, which indicates that the inflamma-sorna AIM2: and HMGB1· play a role in the inflammatory response in the lungs after FBI. 219 TBI induces pyroptosis in mouse lungs

[00170] As previously shown, activation of Inflamasorna AIM2 in curtical neurons leads to death of pyroptotic cells (19) ♦ To investigate whether TBI results in pyroptosis in mouse lung tissue, pircptQsome was isolated in lung tissue after TBI. Animals with TBI, sacrificed 4 hours later; of the lesion;, show. de· •odlgmeé of ASC in campaigns. or π with the mock animals fFIG O), ASC dimures and trimers were observed in TBI animals (50, 7 5 kOA respectively). These results were indicative of the formation of pyroptosomes, which can be characterized by supramoleocular assembly of ASC oligomers. Furthermore, gasdermin D (GSDMD), which is cleaved upon activation of caspase-1 and triggers pyroptosis and IL-10 release (20), was significantly increased in the lungs of TBI animals compared to TBI. simulation (FIG 4B and 4C) (p 0.00'01). These findings indicated that pyroptosis contributes to cell death in lung tissue after TBI. 220 Tbi increases immunoreactivity. of inflammasome proteins in type II alveolar epithelial cells |Θ0171| TBI can lead to capillary leak, resulting in increased vascular permeability and damage to specialized alveolar epithelial cells, called type II pneumocytes (5) . To examine the cellular effects of LCT on inflammasome expression in the lungs after injury, immunohistochemical analysis was performed on lung sections from simulated, 4-hour, and 2-4-hour injured animals. Type II alveolar epithelial cells are known to be the main type of lung cells injured in 1st ALT. (17). Lung sections were stained with sntlousrpos against AIM2, caspase-1 and ASC; (green) and co-stained with Pro-surfacing protein C (Pro-SPC, red), a marker of type 11 epithelial cells, and PAPI nuclear staining (blue). As shown in FIG 2Α~ 2C, active caspase-1 (FIG 2A), ASC (FIG 2B), as well as AIM2 (FIG 2C) are present in SBC-positive cells. 2; (arrow): The immunoreactivity of these inflammasome proteins was increased after TBI. These findings indicate that the inflammasome proteins: are expressed in type II alveolar epithelial cells and that TBI results in increased in. m: unórréa^ én. these cells. TBI increases nuclear and oitoplasmic HMGB1 expression 100172] Ρέα To determine the cellular distribution of HMGB1 in lung cells after TBI, nucis ares· and cytoplanmatic^^^ fractions of homogene® lung cells were isolated: (FIG, 3A, .30 (p - 0.0337). Immunotransference indicated that both fractions had significant increases® in HMGBl expression at 4 hours after TBI (FtG, 3B, 3D) (p » 0,(134:5:). An immunohistochemical analysis of HMGB1 to determine changes in immunoreactivity in lung sections after TBI Sections were co-stained for HMGB1 (green) and SPC (red) and DAFI nuclear staining (blue) HMGB1 immunoreactivity increased at 4 hours and 24 hours compared to sham, a weak immunoreactivity of HMGB1 in SBC-positive cells (arrow) (FIG 3E) was used, thus suggesting that HMGB1 changes in tissue Injured lung may be cytoplasmic. TBI induces the same values ​​in lung morphology and induces ALI.

[00173] ALI can be characterized by inflammatory processes, leading to alveolar edema e. interstitial, as well as inf 11 trusion of inflammatory cells into the alveolar space (23), Histopathological analysis of lung tissue (FIG 6A) indicates that severe TBI causes substantial changes in lung architecture and morphology 4 and 24 hours later. give the injury The simulated animals show normal alveolar morphology, while the lesioned animals show: acute changes in the LO alveolar edema, but decreased slightly 24 hours after injury (long arrows). In addition, there was evidence of neutrophil infiltration (arrowheads) and changes in the morphology of the alveolar capillary membranes. (*j at both time points. Animals 15-heiiucs show signs of interstitial edema, which was most pronounced at 4 hours post-injury, but was still evident at 24 hours post-injury (short arrows). Finally, the injured animals also showed evidence of thickening of the interstitial area and ?g of the alveolar septum (pound, #),

[00174] To confirm that severe injury induces ALI, histological sections were analyzed using the ALI scoring system defined by the American Thoracic Society. 223(17). This system is based on the evidence of hundreds of neutrophils infiltrating the alveolar and interstitial spaces, formation of hyaline membranes, protein debris that. .fill the air spaces and thickening of the alveolar septum 5. (17) . These characteristics were significantly elevated in lesioned animals and ALT scores were generally higher in TBI compared to sham animals (FIG, 5B) (p - 0.0017). Treatment with enQxaparin and anti-ASC antibodies significantly reduces inflammasome and ALT expression after adoptive transfer of EVs from TBI mice

[00175] In order to provide evidence that EV and its cargo that can be released into the circulation after TBI can induce inflammasomal activation in the lung, a classical adoptive transfer experiment was performed using EY derived from Serum for severe CCI reasons. EV preparations were validated using Western blotting for the EV marker CD81 (FIG, 6). Controls received EV isolated from pre-naive p-sham animals. As shown in FIG, 7A-7F, active caspase-1 (FiG, 7Ar7B), 224 ASC (TIG, 7A, 7CJ , IL-18 (FXG. 7A, 7D.) , AXM.2 (EI&. 7¼ 7E) and HMGB1(FIQ.A,Fj) were significantly elevated in the lungs of animals receiving EV from TBX-lesioned animals compared to the lungs of i animals receiving EV from uninjured or naive mice or naive mice. Iñflawtoriaáá cell infiltration (arrows) was evident in EV-treated aphids from TBX mice (Fig. 7Gj . Finally, the AL.I score was also significantly higher in animals receiving EV from lesioned mice (FIG 7Gj <, These studies provided evidence for a neural-inflammasome-respiratory axis in which EV released into the circulation after TBI activates the most orna in lung target cells contributing to the pathogenesis of the ÁjaXi

[00176] Next, blockade of exosome uptake was attempted by treatment with enenaparin or a monoclonal antibody -against AEG (IC 1.00) after aduptive transfer of EV from injured mice to previc naïve •0 mice. . Negative control animals received saline and positive control animals received no treatment. Coran is shown in FXG, EA-W, Caspa-sa-·-! (FXG. 8A, 8B) , AEG (FXG„ 8A, GC) , IL- 225 (FIG 8A, §E), AIM2 (FIG 8A, 8E) and HMGBI (FIG 8A>8F) were significantly reduced (p~<0.0001) compared to the untreated group (positive control) after treatment with enosaparin or a humanized monocolonal anti-ASG antibody (eg, IC 100 antibody). In addition, HiE-stained lung sections showed significantly less neutrophil infiltration into the alveolar and interstitial space, as well as no signs of septal thickening (FIG SA-D). the AEI scores for the animals. treated are plate fight and anti.i~.ASC antibody (IC 100) were significantly lower compared to the untreated group (FIG 9E) (p ~ < 0.0001). Par la tanta, the EV released into the circulation after a T8I a role in the activation of inflamma-orna in lung cells leading to ALI. Conclusions: [001771 TBI may be associated with higher rates of certain medical complications or events, especially pulmonary and central nervous system dysfunction.- In this example, severe TBI was shown to increase HMGBl and inflamma-some expression. (for example, AIMG-, caspase~l and ASC expression) in tissue C-oa : io^.l and lung-r and induces o-amblas in the 226 died praises lungs compatible with There (eg, interstitial space, alveolar septal enlargement, and alveolar edema and hemorrhage) and introduces the idea of ​​an inflammatory axis: nauta! respiratory. Importantly, TBI resulted in pyreptosis. in lung tissue (eg, presence of evidence of GSDMD) and increased expression of inflammasome proteins in type II alveolar epithelial cells. In addition, the adoptive transfer of. EV from raiouss TBI activated the inflammasome and induced ALIr indicating that brain injury induces the release of EV containing a cargo of inflammasome proteins which are then transported to the inflammasome, giving rise to ALI. In addition, it was shown that by inhibiting the uptake of EV (enoxaparin) and the activation of inflammasorne (treatment with anti-ASC antibody (IC 100)), there is a reduction in the expression of the inflamaseme protein and in the development of ALIr.

[00178] In summary, this Example showed that AIK2 inflammasome signaling plays a central role in the pathomechanism of lung injury after TBI and demonstrates a TBI-induced ALI mechanism involving EV-mediated inflammasome signaling. These data provided evidence that signaling of the 227 inflames soma., by EV may play a central role in a rwuronal-respiraw axis 1 amarar tu. Therefore, target this axis with antibodies against proteins of the. Inflammation, or drugs that block EV uptake may provide a therapeutic approach in neurotrauma-induced API. in all areas of intensive care medicine. In light of these results, the described therapeutic strategies may be useful for the treatment of inflammatory lung diseases in general. incorporation by reference

[00179] The following references are incorporated. as re f c r & cx a u n s u c t a l a d a d o s les p r o po s x o o s >

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[00220] 41. Chx Wzát al. (2015) HMGB1 pro®ates the aetivaiisa of. NLAP3 and ©aspase~B· inElammas©^ pathway >F~ kappaB pathway 1© acate glaucoma. Jóuml of asitoinflaMha tión 12:137.

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[00225] 46. Silverman et al, (2009) The pannexin 1 nhannel acts the inf lámase in neurona and astrccyteá. The Journal of biological! ahemfstry 284 (27) i 18143-18151. [002261 47. Tenderness S, by Aivero Vaccari JP, Feane RW, Braml&tt Η®, δ Gíetrích Wb (2012) Effects of thet apaut ic hypothérmia on inflammasome álgnaling after traumatic brain injury» Journal of cerebral blood fio® and metabolism ; yfflpial Journal of the International Society of Cerebral Binad fia® and >eta^ 32 (10) rló^^

[00227] 48. Wiklander, 0. B, , Nárdín, J.Z., , 0' LougAlin, A. , Gystafsson, Y., Corso, G., Mugar, I.fVader, P», Lee, Y., Sork , H., Seow, Y., Heldring, 5L, Alvare r~Erviti, L., Smith, G, 1.,, Le Blanc, K. , Macahiarini, P. , Jungebluth., P. , Mood, 15 M 0. and Andaluussi, S. E. (2015) . Extravellular vesiule^ in vivo biodlsrribution is determined, by aell source, route of administration and. targeting. 0 Extrace 11 Watcles 4, 2 6316.

[00228] 49. de Rivero Vaccarl, J.P., Lotocki, G., Mardllp, A.E., Dietrích, W.D, and Reare, B.W.:(2008), A molecular platfcrm in nwon-s. regulates information after spinal cord injury .: J Neurasdi 25, 3M@M~M.1M» [0.0229] 50. Assis-MascimenM^ Pt , Umland, G, , Capero,. M.L. and Liubl, D.J. (2016). A fl.ow uytametric apprcach te 236 Analyzing matare and progeni cor endethelial cells following traumatic brain injury, J Eeurosci Methods 263, 57-67, Example 2: Role of EV-mediated inflamma signaling in ALX after. a L€T in human patients

[00230] Cone follow-up of the experiments in mice of the Example 1, the role of EV isolated from human TBI patients in inflammation signaling in human lung endothelial cells was examined., ¡00231] In a first experiment, serum-derived EVs were isolated from patients with TBI and de:control using Total Exosome Isolation Kit (Thermofisher), Human Lung Microvacular Endutelial Cells (HMVEC-Lonza) were cultured and plated in a 12-well plate. Once confluence was reached, EV isolated from TBI and control patients (1.94 x 108 particle^) were administered to the cells for a 4 hour incubation period. After incubation, cells were harvested with 200 ul of llsis buffer and 2Q used Cells used for Western blot analysis,

[00232] In a second experiment, serum-derived EVs were isolated from TBI patients and controls, using the kit 237 Total Exosome Isolation (Thermoíis^ . Human lung microvaecular endothelial cells were cultured and plated: in a 96-well plate. After g with fluency was reached, EV isolated from TBI were administered and patients control 11.94 x 108 cells for an incubation period of 2 hours and then an additional 1 hour with caspase-1 FAM FLICA (Immunptrr^^ Technologies with a 1; 30:volume to volume ratio yg After Incubation, medium was removed and cells were washed 3 times with apoptosis wash buffer (Iwunohistecchémistry Technologies).The •cells were then: co-stained with Hoecbst for nuclear staining and propyl iodide for cell death. They were imaged using an EVOS microscope and then the cells were read under a fluorescent plate reader at an excitation wavelength of 492 nm and an emission wavelength of 523 nm.In a second experiment, the following were isolated: EV derived from serum of TBI patients and controls using the total exosome isolation kit (Thatmofisher). Pulmonary human microvascular syndrome (HHVEI'-Lon^) cells were cultured and plated in a W-well plate... After 238 that centluence was reached, EV isolated from TBI and lo® control patients (1.94 x 108 particles / ml) were administered to. cells for a 3 hour incubation period and then: i additional hour with caspase-1 FAM FLICA {Immumohistochemistry Technologies) ooh an It 30 volume to volume ratio. After incubation, the medium was removed and the cells were washed 3 times with apoptosis wash buffer (Immuiwhist^ Technologies}.. The cells were then co-stained with Hoechst for nuclear yo staining and propidium iodide. for cell death.Images were taken using an EVOS microscope and then the cells were read under a fluorescent plate reader at an excitation wavelength of 492 nm and an emission wavelength of .520 nm. [Results

[00233] ] As shown in FIG 10A~10F, the administration of EV derived from serum of TBI patients increased inOamasome protein expression in lung endothelial cells. ha FIG ΙϋΆ-ΙΠΕ showed that caspase-1, ASC, ΑΧΜ2 and HMGB1 were elevated in PMVEC incubated with TBX-EV for 4 hours compared to FMVEG incubated with control-EV for 4 hours. The results of the 239 Immunos showed a significant apm.entd in the expression of IL-lbeta using the Ella simple plex assay (FIG I0F). |M234j Comp is shown in FIG 11A-11C, TSI-EV administration to lung endothelial cells increased, caspase immunoreactivity! and cell death. C oh.pl as i da

[00235] These studies provided further evidence for a neural-respiratory-tonOam^ axis where EVs released into the circulation after active TBI show the inflammasome in lung target cells which contribute to the pathogenesis of lung cancer. ALI. Example 3: Effect of the use of humanized anti-ASC antibody in an animal model of multiple sclerosis 100236] To determine the utility of a wiggle antibody.! ocal anti-humanized ASC in the treatment of MS, said antibody was administered to experimental allergic encephalomyclitis (EAE) .20 mice. EAE is an animal (i.e. rodent) model of EM as described in Róftbergar R, Eeisser M, Bauer J, Lassmann H (Dec 2015). ^Autoimmune enoephalitis in humus: bou closely dees it reflect multiple 240 Solerosis?, Anta Neuropathol Commun. 3 (1) : 80 and Laasman Hans (Feb 2010) . Aeute disseminated encephalomyelitis and multiple sclerosis. Brain. 133: 317-319 and L. Gomez Vincent et al. Relapses in a paueisymp^ form of multiple sclerosis in a patient tied with nlvolnmab, Neuro Onepl (2010) IB (suppl 4): 1^25. METHODS EAE induction and treatment with IC 100

[00237] Active EAE was induced in 2-month-old female C57BL / 6 mice with myelin oligodendrum glycoprotein 3 3-35 peptide (MQG3S-55, BiaSynthesis) as previously described (Brambilla et al., 2034). . Briefly, mice received an intraperitoneal (ip) injection of 1S pertussis toxin (dissolved ®n BES (3 50 ng / mouse; day 0), followed by subcutaneous administration of MOG3.5~55:(30Θ ng / mouse; day 1) emulsified© in Freund's Adjuvant^ Cpmplat©. and a second ip injection of pertussis toxin (350 ng / mouse; day 2). Í3& and 4B by ip injection every 4 days, beginning on day 8 after EAE induction.Clinical symptoms: of EAE were assessed daily in a 241 scale from 0 to 6 of. as follows: 0> unsigned Clinics; 1, loss of tone d® the ocla; 2, calla flaccid; 3, complete paralysis of hindlimbs; 4, complete paralysis of the forelimbs; 5, moxibund:; €, dead. A i s 1 a m e n t o c e 1 u 1 a r. 1 .i ujo para c i t o m e t r i a

[00238] After transcardial perfusion in PBS, spinal cords were collected and placed in cold Karts balanced salt solution without Mg2+ and Ga2® (KBSS w / o). Samples were manually dissociated into single cell suspensions® via through a 70 um strainer and washed in HSSS w / p. The spleen samples were centrifuged at 12 00 rpm for 10 min at 4 °Cf, the supernatants were removed and the red blood cells were used. (RBC) in 2 ml RSC cytometry buffer (eBiosciéncej according to manufacturer's instructions. A, spleen cells were resuspended in PBS. Cells isolated from spinal cord were resuspended in RBC cytometry buffer. flow (FCB, eBioscience) and incubated with Myelin Removal Beads II (Miltenyl).Myelin was depleted using the LS magnetic columns as described in the manufacturer's prató.Cólo: (Míltényi). Using 242 splpnocytes, spinal cord cells were resuspended in PBS and stained as described below. immunolabeling and flow cytometry analysis [00.230] For: the Iqa experiments that Caspase-1 was evaluated, the FAM FLICÁTM Cuspase 1 kit (BióRad) was used according to the manufacturer's instructions. Cells were incubated for 30 man at 4 °C in FLICA tbiaRad solution, washed with apoptosis wash buffer (BioRad) and resuspended in 1 ml of PBS. Samples were then incubated for 30 min at 4 °C with heating. yivo / auert® fidle {Tonbo Biosciencsa), were centrifuged at 1200 rpm for 10 min at 4 *C and the supernatants were removed. Cells were resuspended in 100 ul of FACS buffer, blocked with anti-CD16 / 32 (FcR block, eBioscience j at room temperature for 5 min, immunized for 30 min at 4 °C and fixed with 1% PEA. , Samples were analyzed with a flow cytometer CytoFLEX S equipped with CytExpert 2.1 software (Beckman Coulter). The number of spinal cord leukocytes was determined with 123count eBeads (eBioscience). The number of splenic leukocytes was determined by cytometry of 243 flow in combination with trpan blue exclusion counting using: an automated cell counter TC2:0Tb CSio-Rad) > One is provided. List of flow cytometry antibodies below Table 3. [002461 Table X Flow cytometry antibodies for use in the methods, provided herein. Antigen Col cr Dilution Pr o veedor Catalog NX CD4 5 FITG: IrlóOO eBioscie^ 11-0451-52 CDO PE 1:1500 eBioScience 1.2-0451-52 CM WCy7 1 :2 05 cBiosniance 25-0042-81 CD8 Perep^Cy 5.5 lAÍQO B.i ol egend 10034 822 0 PE 1:200 Bíolegsnd 103208 122 0 APC e Fluor 7 8:0 1:20 0 e?iose lenca 47-0452-80 GDI Ib APG eEl un r7*0 1 : 2 0 0 eB1o s ci en or e 47-010-82 DD O PE / Cy7 1:-2::00 Biol.egsnd 101215 WICTI ; A:»G Ϊ : 200 sBíoscience 17-5 32:1-81 LyS-G Percp” Cyó.S 1:200 B i o 1 c o o u d 12 '7 616 244

[0241] Staining with Luxpl fast blue and quantification of the vo 1 umen of white roataria of sm.i e 1 ini za da.

[00242] Segments of the spinal cord fixed with paraformaldehyde (PFA) were embedded in paraffin, sectioned 10 into 10 min cross sections to thicken with. a ñíiarotama Laica RM 2135 and stained with luxol fast bise CLFB). Ten serial sections at 50 gm intervals were used to estimate the volume of demyelinated white matter < Areas from 1 inired were outlined with a Slympus SX51 microscope and the volume of demyelinated white matter was quantified with Stéréainvestigator software (MicroBrightfield} , ID scrapings of the desmielini zeda spinal cord were performed in the same serial sections with Loarelucida 20 software (MBF Biosaience). Quantification of XC 100 in tissues 245

[00243] TC 100 was quantitated in brain, spinal cord, liver and spleen at 35 days after {dpi} induction of EAE using an assay developed by laflamaCORE, LLC using Meso Scale Technology. The assay was read using the Qu.iekPlex SQ 120 instrument (Meso Scale Diagnostics, Marylaud).

[00244] Similar experiments were carried out in a breed model of cervical spinal cord contusion injury to determine if anti-ASO penetrates all 10 spinal cord neurons.

[00245] To determine if cells take up IC 100, fluorescein-labeled IC 100 is added to tissue culture medium containing THP-1 cells (human monocytic cell line).. Results Treatment with anti-ASC XC 100 antibody improves functional outcome in experimental a^toimmune encephalomyelitis. (EAE)

[00246] To evaluate e.1 therapeutic potential of TC 100, EAE was induced with peptide MQG35:-.55 (Bramhilla et al,, 0010 in two-month-old female C57RL / 6 mice and I© 100 was administered or carrier only from day 8 post-induction 246 (dpi) disease. The administration was repeated every four days until sacrifice, which was set at 35 dpi. fe tested three doses, 10, 30 and 4 5 mg / kg.

[00247] IC 100 significantly improved functional recovery, when used at the 30 and 45 mg / kg doses, with a: strong, -reduction in clinical disease scores: over the duration of the experiment (FIG 12A). Treatment reduced the mean maximum clinical scores (Figure 12B) as well as the overall severity of 1:Q' EAE reported a reduction in the cumulative disease indicator (CDI) (Figure 12C). Mice treated with 30 and 4 5 mg / kg IC. 100 also showed a trend for a delayed onset of the disease (FIG 12D). No differences were observed in the day -5 mice reached their peak disease score (FIG 12E). Treatment with anti-ASC antibody IC 100 reduces peripheral immune cell infiltration into the spinal cord after EAE

[00248] The start, the Persian batch and the. Symptom severity, symptoms of EAE are directly correlated with immune cell infiltration of the spinal cord. To assess whether 1C IDO affected this process, the 247 populations of immune cells isolated from the spinal cord at 35 dpi were profiled using flow cytometry. The treatment: m 3 0 mg / kg of IC 10 0: significantly reduced the total number of CL-snoephalitogenic T cells as well as CDSe I cells (FIG 13Aj, the most crucial immune cell populations for driving EAE pathology All other immune cell populations showed a clear declining trend No difference in cell number was observed with any yg of TC:100 doses in the bath, suggesting that no treatment interfered with the ability of mice to mount an adequate immune response to challenge, to .EAE (FIG 13B). ;5 Treatment with anti-ASC antibody IC 100 reduces the number and activation status of micruglia after EAE

[00249] Microglia are involved in the immunoinflammatory response to NCD disease. As their activation state increases, proHf were and upregulate surface expression of MHCII. To assess whether IC 100 affected this response, we quantified the number of total microglia and MHCII+ activated microglia in the 248 spinal cord using flow cytometry, Both populations were significantly reduced by treatment with 30 mg / kg ce IC 10 0.1 o. indicating that at this dose, IC 100 is effective in suppressing microglia activation and microglia-mediated neuroinflammation (see FIG 14). ÍC 100 penetrates the brain and spinal cord

[00250] An important parameter in drug design for: to withdraw the NE is to determine if the drug penetrates the CNS at a therapeutic level. This is an important feature, particularly in the treatment of the progressive form of MS, as the blood-brain barrier appears relatively intact at this stage of the disease (Lassman et al, 2012). Therefore, we collected brain, spinal cord, liver, and spleen to determine da levels. IG 100 in these fabrics. As shown in FIG 15, IC 100 penetrated all of these tissues at all three doses, including the brain and spinal cord. Interestingly, Cl 100 levels in the spinal cord were higher with the 30 mg / kg dose, consistent with greater therapeutic effects at this dose. 249

[00251] THP-1 cells. (human monacit lea cell line.) absorb fluorescein-labelled IC 100 and are incorporated into the® ASC specks when added to tissue culture medium. In addition, inflammasome induction of these cells stimulates IC 100 uptake labeled on ASC spots along with pan-rhodamine-labeled dexfranp, Ig suggesting that IC 100 uptake is mediated by endocytosis (see FIG 16).

[00252] Likewise, IC 100 prevented the ., release of 11-10 of the 10 w-l cells (see FIG. 17). |'00'253] Anti-ASC antibodies (eg IC 100) also penetrated spinal cord neurons in a rat model of concessive cervical spinal cord lesion.

[00254] IC 100 can work both intracellularly and «xtrao e 1 u 1 armeute. Intrace 1 u 1 a r m e n e, it can act by binding to and inhibiting the ASC protein, thus preventing the assembly of the inf 1 a m a s o m a . You can also ni rse ASC and η dots or ASC, avoiding the spread of the flaming signaling platform, thus inhibiting it. extracellular activation of pro-ILÚ respcnsaW for perpetuating inflammation in chronic-inflammatory diseases. 250 incorporation by reference

[00255] The following references are incorporated by reference in their entirety for all purposes *

[00250] Brambilla R, Morton PD, Ashbaugh JJ, Karmally 8, Lambertsen K and Bethea JR (2'014} Astrocytes play a key role in the pathophysiology of EAE by orchestrating the inflammatory response of resident and peripheral immune cells in the S:NG and suppressing remyelination. GLIA, 62: 452-457.

[00257] Lansmarm, H., van Horneen, J. and Wñad, Ó. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Nsuról 8, 647-656, doi: 10.1038 / nrneurol.2012«163 (2012). Example 4; Kinetic analysis of candidate anti-ASC mcnoclonal antibodies |0025§[ Kinetic analysis of candidate anti-ASC monoclonal antibodies was performed using biolayer interforometry (BLI). In BLI, the association or dissociation with the kO surface cases, a change in the wavelength of the reflected light and measure the change in permian time determining the binding kinetics. [00259.1 The bli trial consisted of the following251

[00260] [002 60] Check, sensor (30 s) -> Load Ab / Supnt. (7 00 si Baseline (300 s) -> Ab Asneo. (nOOs) -> Disson. (600s) -> Repeat

[00261] Antibody supernatants were tested for binding: candidate mouse IgG to human ASO peptide (SW ID NO: 5) at 7 different concentrations (ie, 540 nM; ISO nM SO nM; 20 pM; 6.67 nM, 2.22 nM, 0.7 41 nM|.The tester antibodies were ICCN 1.OH (ie, IC 1GQ1 ; ICCN 2.OH; e TCCN 3. OH. AMC hlosensors were loaded. (Anti Mocas IgG Fe) with mouse IgG, from the undiluted supernatant. Crude antibody kinetics data for the 3 candidate antibodies are shown in FIG 21, while FIG 22 shows the overall KD values. Example 5: Absorption, distribution, metabolism and excretion studies Pharmacokinetic studies of IC .100

[00262] To be performed. absorption, distribution, metabolism and excretion (ADME) experiments to describe the disposition of IC 100 in CD-I male rats.

[00263] In a first experiment, 30 six-week-old male CD-I rats will be obtained from Charles River. The experiments will be carried out in the Balden BioBath (BBP). Mice will acclimatize for at least seven days after arrival at BB?. Mice will be housed in four animals per cage,

[00264] Animals will be randomized into treatment groups (nine mice per group) based on body weight and will be dosed with IC 100 intravenously (IV). Treatment groups will receive 5 mg / kg, 15 mg / kg, or 30 mg / kg of CI 100«. Plasma will be collected at various times after a single intravenous dose for pharmacokinetic monitoring (Wl. In the: Table An exemplary plasma collection schedule is shown below 4. Acute toxicity will be monitored by clinical observations Plasma will be sent to Antibody Solutions for analysis Experiment 15 will continue for ten weeks.

[00265] Body weight measurements will be taken on days D, 7, 14, 21, 2 3 and 35.

[00266] Retroorbital bleeding will be used to collect adequate volumes of blood; mice will be anesthetized with isoflurane prior to sample collection. Animals 1, 2 and 3 of each group were bled on days 1 and 10; animals 4, 5 and 6 will bleed on days 2 and 15; animals 7, 8 and 9 will be bled on days S and 20,

[00267] At the final time point, animals will be anesthetized with is©llurano and bled to death followed by bilateral neuaotcrax. Animals .1, and 3 will be sacrificed on day 25. Animals 4, 5, and 6 will be sacrificed on day 30. ΙδΒ animals 7, 8, and 9 will be sacrificed on day 35. Table 4. Sample collection list Example 6. 81 or di attribution of 100 using female B:6 albino mice s Fluorescence images 254 [002681 In a second experiment, IC 1ΌΌ and control mouse IgG will be stained with VivoTag 680XL fluorescent labeling agent according to established VivoTag protocols, and binding affinity determined. In summary, according to the VivoTag protocols, the tagging protocol: will involve:: [002601 1 - Prepare antibody solutions C>7 kua) at 1-10 mq / ml in PBS. The antibodies will be free of ammonium ions or primary amines to reduce competition for the reaction with the reactive dye. [002701 2. 0.25 mg of Vivolag 68LXL will be dissolved in 10 ul of dry DMSO» Once reconstituted, VivoTag 688X1 is stable for up to 7 days when stored at 2~8 *C and protected from light- [002711 3« I know they will add. 0.5 ml of protein (0.5-5 mg), 50 ul of sodium bicarbonate, 2 μΐ of VivoTag 680XL for each mg of proisin to an eppendorf tube. The mixture will be incubated in the dark for 2 hours at room temperature with shaking.

[00272] 4>. Separate the protein conjugate from the free dye. Turn the bottom closure of the tail and loosen the lid. The column will be placed in a 15 mL conical collection tube and condensed at 1,000 xg for 2 min. 2 ml of PbS will be added to the column and centrifuged at 1000 xg for 1 min. If washed, it will be repeated qos more times. 100273] 5. The column will be placed in a new 15 ml conical collection tube. All protein samples will be loaded (200-700 µL) onto the column and contri- fugaled at 1000xq for 2 min. It will be collected. the flow to ligvks of the protein sample. í80274] 6. The collected labeled antibody sample can be assayed to determine the degree of labeling (DOL). 10- Determine the absorbance of the purified conjugate at 280 nm and 668 nm. 100275] 7. Adjust the absorbance to 2 80 nm of the purified protein by subtracting the 280 nm absorbance of VivoTag. 580XL, which is 16% of the ábáóxbhncia at 668 nm. L |O0276] 8. The analysis of. Absorbency can be performed with a UV spectrophotometer or a Manodrap spectrophatometer. To use the latter, samples must be diluted to a range of 0.5-2 mg / mL prior to measurement. Since the path of the light is 1 w, the reading should be normalized with a factor of 20 20.

[80277] In a third experiment, the bid distribution of IC 100 will be determined. Fifteen female mice will be used for the study. 36 Albino tC57'BL6) from 8-12 weeks of 256 age. The animals will be randomly distributed into groups according to the body weight of the first day.

[00278] BL Albino female mice will receive no treatment (negative control}, a single dose of Vive!ag 680XL-labeled IC 100, or a single dose of Vive!ag 680XL-labeled mouse TgG VivoTag 680XL (negative control). · Treatments will be administered intravenously (volume ~ 200 pL) at a dose of 100 pg / animal. [002791 In vivo fluorescence images will be performed at 10 2 hr, 8 hr, 24 hr, 48 hr, 72 br and 46 hr post. In vivo whole body, dorsal and ventral images will be captured using fluorescence imaging. at various time intervals up to 96 hours after treatment.” Ex vivo images of the brain, eyes without optic nerves, heartbeat, left and right kidneys, large intestine. including terminal colon, liver, lungs, ovaries, pancreas, small intestine, spine, stomach, thyroid and urinary bladder of all animals will be performed. [002:80] Whole blood will be collected and the immune infiltrate 28 will be analyzed for CD4+ T cells (CD4+ COIIb- CD3+ CD8~), CMé T cells (C.D8+ CDllb~CD3t Cp4~), 8 cells (CD3“-CDl,llb-'CD<5B+), manGcytes (Cdá-Cpi Ib i CLllS + j and NA cells (CB-: CKBL Μ353'3". The expression Ab257 will be quantified VivoTag 680 XL paw, determine the level of dizzy antibody delivered. A LIVE / DEAD dye will be included in the flow cytometry panel to quantify the number of live cells. The full panel of antibodies will include antibodies directed against: CS1, CEM, OS, CBll^ CD115, CD45R, CD49H, CD335 and a LIVE / DEAD dye. Example 7; Effect of XC 100 administration on inflammasome signaling

[00281] Blood from human patients with nonalcoholic steatohepatitis (NASH), diabetic nephropathy, and lupus nephritis will be obtained from BioHealamation IVT for inriamasome protein biomarker analysis. Tissues from patients with NASH, diabetic nephropathy and lupus nephritis will be obtained from Soldar BioPat.h, and protein samples will be obtained from those tissues and analyzed by immunoblotting. and other biochemical techniques for the expression of pheflamasome signaling proteins, including caspase-1 and ASC. [00282[ In addition, a human cancer cell line will be used to examine ASC-dependent inflammasome activation in real time. This study consisted of 358 two objectives and during- a period of 6 to 9 weeks s. [8Ό283] [Q9283] Specific objective 1: Labeling of antibodies 100284] Se maz a n 2 mg do ic .x uü ocn;.. ge—at v aL— í?L 5: (VivbTag® 680 XL, PerkinElmer # -NEVlllSO) odorant of fudroseant labeling and labeling stegulometry will be determined according to the manufacturer's instructions. The Control mouse IgG (provided by Charles River Laboratozies (CRL)) will be marked and analyzed in a similar way.

[00285] Specific objective 2: Determination of the binding affinity

[00286] The human cancer cell line THP-1 will be grown in log phase and plated at 20,000 cells Ib per well in a volume of 100 µl of medium in a 6-well white threno-pale microculture plate (Corning® Costar® 9δ-Flat Bottom Plate for Wells, Cat. # 917} , then the labeled antibody will be added. in duplicate to wells (10 point dose response, 1:3 dilution, highest concentration 2uÜ sH. Bound οηΟΐαοοχρο will be detected, in all wells following the Charles River protocol. This will represent bound antibody (fluotescence intensity average) depending on the 259 antibody concentration and binding affinity (Rd} will be estimated by fitting the following equation to the data: Y =» 1CX * X / ( Kd+ K; Example 8: In vivo studies ds IC 100 in. a NASH rat model 100287] Male Wistar Han rats, fed a choline high-fat diet (COHED) that have liver fibrosis, will serve: as animal model of: RASE. 55 mice will be used for this study. 8-9 week old Wistar Han rats will be obtained from Envigo or Charles River. Rats can acclimate for 3~? days after arrival at Bolder Biopath. Rats will be housed in 2~3 animals per cage. The animals will be fed with oom.ar. standard. 100288] On day 0, animals will be randomly divided into five groups based on body weight. Group 1 will be fed with Teklad Global Diet ~ Rodent 2014, which is a standard diet. Groups 2, 3, 4 and 5 will be fed a CDHFD diet.

[00289] On day 38 of the study, animals will be bled for clinical chemistry and placed into treatment groups based on alanine aminotransferase concentrations. 260 (ALT) . On day 42 of the study, treatment will begin. The efficacy of IC 100 will be tested using doses to be determined based on the pharmacokinetic data obtained from Example 5. The DA group will receive carrier treatment 5 to serve as a negative control. The group receiving a standard granddaughter will also receive carrier treatment: Body weight, food consumption, and cage-side clinical observation will be measured weekly. On day 3 8 and day 63, whole-blood 10 will be obtained by tail vein collection. The necropsy will be performed on day 84. The animals will be sacrificed under isoflurane anesthesia, bled to exsanguination, and then bilateral pneumothorax. [O0290| The animals will be weighed on days ~1, or, 2, 4, 6, 7, 15 14, 21, 28, 35, 42, 45, 49, 52, 56, 59, 63, 6.6, 71), 73, 77 , 0 and 8 3 of the study:. [002911 A weekly update of food consumption (grams / day / rat) will be recorded on days 0, 7, 14, 21, 28, 35, 42, 49, 5, 6, 63, 70, 77 and 84 of the study. [002921 Cage side clinical observations will be made on days Θ-7, 14, H, 2 8, 3 5, 42, 45, 49, 52, 56, 59, 63, 66, 70, 73, 77, «0, 83. If the animals begin to 261 show clinical signs of toxicity or disease, animals will be observed and weighed daily.

[90293] At necropsy, weights of the liver, brown adipose tissue, and right inguinal adipose tissue will be measured. 5 4x7 mm biopsies will be obtained from the left lateral lobe of the liver, frozen in liquid nitogen and stored at ~gQ ’C< Cross sections will be obtained from. 3 mm from the medial lobe, left lateral lobe and right lateral lobe of the liver and fixed in 10% formalin for 3 6-4 3 hours before storing in 76% ethanol at room temperature for pathology. Three 100 mg pieces of adipose tissue will be snap frozen in liquid nitrogen and stored in an Eppendorf secure-closing tray at -80°C. Three pieces of tissue: brown adipose, from the same stinger will be snap frozen in liquid nitrogen and stored in secure-closing Eppendorf tubes at ~8Q *C. [Ó0294] Inguinal subcutaneous adipose tissue, an aquarium white adipose tissue (WAT) reservoir, will be collected with the following protocol. Triangular and inguinal SQ deposits will be revealed by scrapping the lower half of the mouse. The upper appendages and the thorax will be held with one hand and the skin will be pulled towards the feet with the other. 262 mana, The mouse will be oriented in one position, supine, taking care not to contaminate the exposed reservoir with hair. Surgical instruments will be cleaned and gloves will be changed. Subsequently, the triangles of subcutaneous fat will be dissected, taking care not to. contaminate the sample are muscle, neighboring fat, mammary glands or blood. A dissecting microscope will be used if the borders are not clearly defined. Fatty deposits will be removed and transferred to 5Q fixative: 1 to tissue volume 101 neutral buffered formal and fixed for 3-8 to 4-8 hours at room temperature. If RNA or protein is to be extracted, the tissue should be frozen by immersion in liquid nitrogen and stored at -8u *C to avoid degradation. An effort will be made not to contaminate between deposits of grease by changing gloves frequently. [002951 The histology processing will be performed, by Histotox Labs. The histology processing- of LLL, MLL and ELL will be performed on three cross sections of. liver by 2L animal. Samples will be stained with Syrian red and humatoxylin and eosin (H 263 Example 9: In vivo studies of the effect of IC 100 on diabetic nephropathy in a BTBR Ob / Ob mouse model

[00296] The BTBR mouse strain with the ob / ob leptin deficiency mutation serves as a mouse model for diabetic nephropathy. Mache BTBR Gb / ©b mice will be used to evaluate the effect of I:C 10Q in reversing the effects of diabetic nephropathy. Five wild-type male BTBR mice (1WT) will be used as a negative control and will receive no treatment. 50 LO ratcnes BTBR Ób / Qb will be used and divided into five groups. The groups will receive carrier, control or IC 100 at the doses determined based on Example 5. The experiment will take place for six weeks,

[00297] Histology will be performed on mouse kidneys cor l.5:HistotOX Labs. The pathologist will determine the appropriate parameters using current Beldar BioFATH methods.

[00298] Blood glucose measurements will be taken by tail docking and applying a drop of blood S gl) on a test strip compatible with a True Metrix glucometer. Blood glucose measurements will be taken twice a week until the study is complete. 264 [OOW] Proteinuria scoring will be performed by removing the mouse's mane by holding the mouse upside down and applying pressure to the abdomen. I know Albustix test strips will be used to determine the amount of 5 protein in the urine.

[00300] If dead animals are found, no samples will be taken. If animals need to be euthanized, regardless of reason, samples will be taken as they would be taken at necropsy after day 7 of the study. 1O Example 1. Ir vivo studies of the effect of IC 100 on lupine nephritis in a mouse model.

[00301] Week-old MRL / MpJ-Thfrsfúlpr / J female mice will be used to develop a model of lupus nephritis. Mice will be obtained from Bolder BioÉath. Mice will be randomly assigned to treatment groups based on body weight. Lbs animals will be observed daily for significant clinical signs, morbidity and mortality. The onset of lupus nephritis will occur at approximately 12-14 weeks of age. [003021 After the onset of lupus nephritis, mice will be divided into five groups and treated with doses 265 variables of IC 100, according to the results of Example: 5, carrier or control IgG.

[00303] Body weight scores, proteinnria lithoadenopathy and skin lesions will be collected, Necropsy will be performed at week 20 and tissues and whole blood will be collected for analysis. The experiment is expected to last 15 weeks. Example IT; Injection toxicity study. 10 intravenous bolus at an interval of 21 days and acute TC 100 in the albino rat 100304] has albino rats to be obtained from Charles Riyer. Dose levels will be established. of XC 100 for 28-day definitive multiple-dose toxicity and pharmacokinetic studies in rats. Rats will be divided into four groups containing three rats / sex / dose. Be will perform a rise and fall study. 100305] I know will be doing a .repeat dose study over three weeks. The rats will be divided into groups of all 20 males or all females containing five rats. Rats will be dosed weekly at a dose level of IC 10 0:. Parameters will be made in life auc 266 i n o 1 a n o r l a y in m a r t a y, clinical signs, body weight and clinical laboratory with toxicocyte Example 12: Study of determination of the maximum tolerated dose and dose range of 22. days of Id 10'0 in the Cynonoigas monkey

[00306] Dose levels and pharmacokinetics for IC 100 will be established in Cynomclus monkeys, Experiments will occur at Charles Rívér, Monkeys will be divided into four groups containing one mono / sex / dose. A study will be performed: of up and down for 28 days.

[00307] A three week repeat dose study will be performed. The monkeys will be divided into groups of all males or. all females containing two monkeys. The 15 monkeys will be administered one dose weekly with a dose level of IC 100. Live parameters including mortality, muic signs, body weight, and clinical laboratory toxicokinetics will be performed.

[00308] This experiment is expected to last 15 weeks. Example 13: IC 100 toxicity study in the rat followed by a 4 week recovery period 267

[00309] Toxicity and toxicokinetics will be established after intravenous administration of IC 100 followed by a recovery period in rats obtained from Charles River. 100310] Rats will be divided into 16-15 rats / sex / group with three dose levels plus control. Additional groups will include. a high dose :group: and a control group containing .:S rats / sex for a four week recovery.

[00311] Mortality, body weight, food consumption, clinical observations, cyanotic pathology (hematology and clinical chemistry), necropsy findings, organ histopathology, and toxicology will be measured. after recovery, the same parameters will be measured, excl 1 u y n d o 1 a. t o x i c o o i n e t i c a .

[00312] This experiment is expected to last six months. Example 14: Toxicity study of IC 100 in the monkey Cynowolgus followed by a 4 week recovery period

[00313] In Charles River, toxicity and toxicocinetlea will be established following intravenous administration of IC 100 followed by a recovery period in non-human primates. 268'

[00314] The monkeys will be divided into. 3 monkeys / sex / group with three dose levels plus control. Additional groups will include a high dose group and a control group containing 2 monkeys / sex for a four § week recovery. (0031.5] I know .will measure mortality, body weight / food .consumption, clinical observations, pathology, clinic (hematology and clinical chemistry), nec.rop.aia findings, 1st organ histopathology and toxicokinetics 10. After recovery, the same parameters will be measured, excluding toxiokinetics.

[00316] This experiment is expected to last six months. Example 15: In vitro cardiovascular study using a hERG assay

[00317] The twlcity potential: cardiovascular (QT prolongation) will be evaluated in an in. trial. vitro with CHO or HEK293 cells.

[00318] This experiment will establish the 1C50 for blocking Id 100 of the HERG channel).

[00319] I know Pepe-ta that. This experiment lasted two days. Example 16: In vitro blood hemilysis study 269

[00320] The potential of will be evaluated. the intravenous formulation, of IC 100 to cause hemolysis of human red blood cells in vitro, Concentrations of IC 100 {determined based on Example 5} will be mixed with red guSbul'O'S- éh an ib vatro system. The degree of hemolysis will be established. The experiment is expected to last two months. Example 17 - Examination of the in vivo efficacy of IC 1.0Q in the treatment of Parkinson's disease (PD)

[00321] The efficacy of IC i 00 in the treatment of EL will be evaluated by administering XC 100 in various animal (ie, rodent) models of PD. 5mg / kg, 15mg / .kg, 30mg / kg.

[00322] The 5-ΟΗΟΛ rat model of PD is one model. 15. Chemically induced unilateral (intraest $ lethal lesion of the median forebrain bundle) of PD where mice present deficits of oopertamaente that include, rotational asymmetry and motor defects. The 6-QHDA model shows a decrease in the content of ddpamine, hOPAC and HVA in the striatum and shows...

Claims

CLAIMS 1» A monochloroantibody or an antibody fragment thereof binding to a Spec-like apoptosis-associated protein containing a caspase-activating resistance domain (ASO), wherein the antibody or antibody fragment binds specifically to an ASO epitope, wherein the epitope comprises or consists of the amino acid sequence of SEQ ID NO: 5 or 5-10 or 10-15 or 20 amino acids of SEQ ID NO:

5.

2. A monocolonial antibody or antibody fragment thereof that binds specifically to ASC, wherein the antibody or antibody fragment comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the amino acid sequence of the VH region comprises HCDR1 of SEQ ID W: 6, H0DR2 of SEQ ID NQ: 7, and ÜCDB 3. of SEQ ID NO: 8, or a variant thereof having an amino acid substitution in HCDR1, HCDR2 and / or HCDRO.. 305 3, . A monoclonal antibody or an antibody fragment thereof that binds specifically to ASC, wherein the antibody or antibody fragment comprises a light chain variable region (VI) and a heavy chain variable region (W), wherein the amino acid sequence of the VE region comprises LCDR1 of SEQ ID NO: 12, 10022 of SEQ ID NO: 13 and LCDF3 of SEQ ID NO: 14, or a variant thereof having at least one amino acid substitution in LCDR1, LCDR2 and / or 10 1CDR3.

4. A monoclonal antibody or an antibody fragment thereof that binds specifically to ASC, wherein the antibody or antibody fragment comprises a heavy chain variable region (VH) and a light chain variable region (Vi), wherein the amino acid sequence of the Vi region comprises HCDR1 of SEQ ID NO: 7, HCDR2 of SEQ ID NO: 7 and SUDES of SEQ ID NO; 8, or a variant thereof having at least one amino acid substitution in HCDR1, HCDR2 and / or SODPI; and wherein the amino acid sequence of the VL region comprises LCDR1 of SEQ ID NO: 12, 1022' of SEQ ID NO: 13 and 306 LCDR3 of SEQ: ID NO: 1.4, or a variant thereof having at least one amino acid substitution in LCDR1, LCDR2 and / or SODPI; 5. The antibody man detonal © the antibody fragment thereof according to claim 2, wherein the amino acid sequence of the VH region comprises SEQ ID NO: 19, 19, 20, 21, 22, or an amino acid sequence that is at least 95%, 95%, 97%, 98% or 9.9% identical to the amino acid sequence of SEQ ID DO: 18, 19, 20, 21 or 22.

6. The menoclcnal antibody or antibody fragment thereof according to claim 3, wherein the amino acid sequence of the VL region comprises SEQ ID NO: 28, 2^1 3.0, 31, or an amino acid sequence that is α-1 less 95%, 9E%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID SQ: 28, 29, 30 O < .

7. The antibody is the antibody fragment of the same according to claim 4, wherein the amino acid sequence of the VH region comprises SEQ ID NCR 19, 19, 20, 21, 22, or an amino acid sequence that is at least 95%, 96% or 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO; 18, 19, 20, 21 or 22; and wherein the amino acid sequence of the VL region comprises SEQ: jq nq:; 28, 29, 30, 31, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99%. identical to the amino acid sequence of SEQ ID NO: 28, 2:9, 30 to 31. §. The antibody mcnw or antibody fragment of the same is in accordance with claim 4, wherein the amino acid sequence of region VH comprises SEQ ID KQ: 18, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 18; and 25 in the amino acid sequence of line VL comprises the.SEQ ID NO: 28 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:

287.

9. The manicionic antibody or antibody fragment thereof according to claim 4, wherein the amino acid sequence of the VH region comprises SEQ ID NO: 19, P an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID DO: 18; and wherein the amino acid sequence Ί&- OEQ ID W4 29· e qu® is at least 95%, 96%, 2 amino acid sequence of . 308 ... to the amino acid sequence of the VE region or an amino acid sequence that is 97%, 98% or 99% identical to that of SEQ ID NO:

29.

10. The monoclonal antibody or antibody fragment thereof according to claim 4, wherein the amino acid sequence of the VH region comprises SEQ ID NO: 1S, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 18; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 30 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:

30.

11. The monelone antibody or antibody fragment thereof according to claim 4, wherein the amino acid sequence of region VH comprises SEQ ID NO: 18, or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 18; and wherein the amino acid sequence of region VL comprises SEQ ID NO: 31 or an amino acid sequence that is at least 93%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO:

31.

12. The monoclonal antibody or antibody fragment thereof according to claim 4, wherein the amino acid sequence of region VH comprises SEQ ID W: 19, an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ IOS; 19; and wherein the amino acid sequence of region VL 15 comprises SEQ ID NO: 28 or an amino acid sequence that is at least 95%, 9β%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:

28.

13. The monoclonal antibody or the pg antibody fragment thereof according to claim 4, wherein the amino acid sequence of the VH region comprises SEQ ID NO: 19, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 19; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 29 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 29.

14. The monoclonal antibody or antibody fragment thereof according to claim 4, wherein the X0 amino acid sequence of the VH region comprises SEQ ID NO: 19, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 19; and wherein the amino acid sequence of the VL X5 region comprises SEQ ID NO: 30 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:

30.

15. The monoclonal antibody or antibody fragment thereof according to claim 4, wherein the amino acid sequence of region VH comprises SEQ ID NO: 19, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 19; and wherein the amino acid sequence of region VL comprises SEQ ID NO: 31, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:

31.

16. The monoclonal antibody or antibody fragment thereof according to claim 4.n 4, wherein the amino acid sequence of the VH region comprises SEQ ID NQ: 20, or an amino acid sequence that is at least 95%, 96%, 97%, 93% or 99% identical to the amino acid sequence of SEQ ID NO: 20; and wherein the amino acid sequence of the VL region comprises SEQ ID NQ: 28 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:

28.

17. The monoclonal antibody or antibody fragment 20 thereof according to claim 4, wherein the amino acid sequence of region V comprises SEQ ID NO: 20, or an amino acid sequence that is at least 95%, 96%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 29; and wherein the amino acid sequence of region VL comprises SEQ ID NO: 29 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:

29.

18. The monoclonal antibody or its antibody fragment according to claim 4, wherein the XO amino acid sequence of the Vfí region comprises SEQ ID NQ: 20, or an amino acid sequence that is at least 95%, 96%, 57%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 20; and wherein the amino acid sequence of the region.VL does comprise SEQ ID NO: 30 or an amino acid sequence that is at least 95%, 96%, 57¼ 98% or 99% identical to the amino acid sequence of 1.a SEQ XD NO:

30.

19. The antibody: mun colon al o: the fragment? of antibody pQ of the same according to claim 4, wherein the amino acid sequence of region VH: comprises SEQ ID NO: 20, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 20; and wherein the amino acid sequence of region VI comprises SEQ ID NO: 31 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:

31.

20. The monoclonal antibody or antibody fragment thereof according to claim 4, wherein the amino acid sequence of region VH comprises SEQ ID NO: 21, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 21; and wherein the amino acid sequence of region yi comprises SEQ ID NO: 2.8 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 28, 21. The monoclonal antibody or the fragment thereof. antibody of the same according to claim 4, wherein the amino acid sequence of the VH region comprises SEQ ID NO: 21, or an amino acid sequence that is at least 9:5%, 314 96%, 975, 98% α 981 identical to the amino acid sequence of SEQ ID NO: 21; and wherein the amino acid sequence of the VL region comprises SEQ ID NO: 29 or aamino acid sequence that is at least 96%, 98% or 99% identical. a: the amino acid sequence of SEQ ID NO:

29.

22. The monodenal antibody or antibody fragment thereof according to claim 4, wherein the amino acid sequence of region VH comprises SEQ ID NO: 21, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 21; and wherein the amino acid sequence of region VL5 comprises SEQ ID NO: 30 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:

30.

23. The monovalent antibody or the antibody fragment 20 thereof according to claim 4, wherein the amino acid sequence of region VH comprises SEQ ID NO: 21, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 21; and wherein the amino acid sequence of region VL comprises SEQ ID NO: 31 or an amino acid sequence that is at least 93%, 96%, 97%, or 99% identical to the amino acid sequence of SEQ ID NO:

31.

2.

4. The monovalent antibody or its antibody fragment according to claim 4, wherein the amino acid sequence of region VH comprises SEQ ID NO: 22, or a amino acid sequence that is at least 95%, 96%, 97%, 93% or 99% identical to: the amino acid sequence of SEQ ID NO: 22; and wherein the amino acid sequence of the VL Xg region comprises SEQ ID NO: 28 or a .amino acid sequence: which is at least 95%, 96%, 97%, 9.8% to 99% identical to the amino acid sequence of SEQ. ID NO:

28.

25. The antibody or the fragment thereof according to claim 4, wherein the amino acid sequence of the VH region comprises a sequence of amino acids that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 22; and wherein the amino acid sequence of the VL region comprises a sequence of amino acids that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:

29.

26. The monoclonal antibody or antibody fragment thereof according to claim 4, wherein the amino acid sequence of the VH region comprises SEQ ID NQ: 22, or an amino acid sequence that is at least 95%, 95%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 22; and wherein the amino acid sequence of the VL region comprises SEQ ID Ni: 30 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 3Q.

27. The monochloroisothiazolinone antibody or antibody fragment 2Q thereof according to claim 4, wherein the amino acid sequence of region VH comprises SEQ ID NO: 22, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NOc 22; and wherein the amino acid sequence of region VI comprises SEQ: JD NC; 31 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ XD NO:

31.

28. The monoclonal antibody or antibody fragment thereof according to any of claims 2-2, wherein ASC is a human ASC protein.

29. The monodlon.al antibody fragment of any of claims 2-27, wherein the antibody fragment is a Fab, an F(abf)2, a Fab*, an sqFv, a single domain antibody, a diabody, or a single chain camelid antibody.

30. The monoclonal antibody or antibody fragment thereof according to any one of the claims, wherein the monoclonal antibody or antibody fragment thereof is human, humanized, or chimeric. 318 31. An isolated nucleic acid molecule encoding the monodonal antibody or antibody fragment thereof conforms to any one of claims 1-1'L 32. An expression vehicle comprising the nucleic acid molecule according to claim 31.

33. The expression vector according to claim X0 32, wherein the nucleic acid molecule is operatively linked to regulatory sequences suitable for the expression of the nucleic acid segment in a host cell.

34. A recombinant host cell comprising the expression vector according to claim 32.

35. A method for producing an antibody or antibody fragment that binds specifically to ASC, method 2Q comprising: cultivating a recombinant host cell comprising the expression vector according to claim 32 under conditions in which the nucleic acid molecule 319 is expressed, thereby producing the monoclonal antibody or antibody fragment thereof that binds specifically to ASC. 5 36. A pharmaceutical composition comprising the monoclonal antibody or antibody fragment thereof according to any one of claims 2-27, and a pharmaceutically acceptable carrier, diluent or excipient, 10 37. A method for treating inflammation in a subject, the method comprising administering to the subject a therapeutically effective amount of the monoclonal antibody or antibody fragment thereof according to any one of claims 2-27, thereby treating inflammation in the subject.

38. The method according to claim 37, wherein the administration of the monoclonal antibody or the antibody fragment thereof reduces the levels of at least one inflammatory enzyme. 320 3®. The method according to claim 1B, wherein the inflammation is an inflammation related to the inflammasome. 5 40. The method according to claim 39, wherein the inflammation related to the inflammasome is associated with a lesion of the central nervous system (CNS), an autoimmune, autoinflammatory, metabolic or neurodegenerative disease.

41. The method according to claim 4Q, wherein the CNS injury is selected from the group consisting of traumatic brain injury (TBI), stroke, and spinal cord injury (SCI).

42. The method according to claim 40, wherein the autoimmune or neurodegenerative disease is amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, muscular dystrophy (MD), systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), or multiple sclerosis (MS). 321 43. The method according to the. :re.i.vi.ndícabibn 40, where the autoinflammatory disease is cryopyrin-associated psychotropic syndrome (CAPS).

44. The method according to claim 43, wherein CAPS is selected from familial autoinflammatory syndrome by cold (E-CASi, (Mueble syndrome ~W (WÍI 1 inflammatory corla xftn.lt isistemic disease of neonatal onset (NOMXD) . 10 45. The method according to claim 40, wherein the metabolic disease is metabolic syndrome, obesity, diabetes mellitus, diabetic nephritis or renal disease (DKD), insulin resistance, atherosclerosis, a lipid storage disorder, a glycogen storage disease, medium-chain acyl-CoA dehydrogenase-α deficiency, non-alcoholic fatty liver disease (e.g., non-alcoholic steatohepatitis [NASH]), and gout.

46. ​​The method according to claim 37, wherein administration of the monoclonal antibody or antibody fragment thereof results in inhibition of inflammatory activation in the subject. 322 47. The method according to claim 37, wherein administration of the mononellone antibody or the antibody fraction thereof results in a reduction in ASC activity compared to a control.

48. The method according to claim 47, wherein the control is an untreated subject. X0 49. The method in accordance with the reivinM '37, wherein the administration is intracerebroventricular, intraperitoneal, intravenous, or by inhalation.

50. A method for treating multiple sclerosis (MS) in a subject, the method comprising administering to the subject a therapeutically effective amount of the monoclonal antibody or antibody fragment thereof of any of claims 2-27, thereby treating MS in the subject.

51. The method according to claim 50, wherein the administration of the monoclonal antibody or the antibody thereof reduces the levels of at least inflammatory cytokines.

52. The method according to claim 50, wherein the administration of the monoclonal antibody or antibody fragment thereof results in the inhibition of the activation of the inflammatory enzyme in the subject.

53. The method according to claim 50, wherein the administration of the monoclonal antibody or antibody fragment thereof results in a 10 reduction in AEC activity compared to a control.

54. The method according to claim 53, wherein the control is an untreated subject. 15 55. The method according to claim 50, wherein the administration is intracerebral-ventricular, intraperitoneal, intravenous, or by inhalation.