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WO2011072265A1 - AMINOACYL-ARNt SYNTHÉTASES DESTINÉES À MODULER UNE INFLAMMATION - Google Patents

AMINOACYL-ARNt SYNTHÉTASES DESTINÉES À MODULER UNE INFLAMMATION Download PDF

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Publication number
WO2011072265A1
WO2011072265A1 PCT/US2010/059963 US2010059963W WO2011072265A1 WO 2011072265 A1 WO2011072265 A1 WO 2011072265A1 US 2010059963 W US2010059963 W US 2010059963W WO 2011072265 A1 WO2011072265 A1 WO 2011072265A1
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Prior art keywords
polypeptide
amino acid
seq
composition
cell
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PCT/US2010/059963
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English (en)
Inventor
Jeffry Dean Watkins
Alain P. Vasserot
Leslie Ann Greene
Ryan Andrew Adams
Kyle P. Chiang
Wei Zhang
Kristi Helen Piehl
Fei Hong
Alina He
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aTyr Pharma Inc
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aTyr Pharma Inc
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Priority to ES10793402.8T priority Critical patent/ES2535951T3/es
Priority to EP10793402.8A priority patent/EP2509625B1/fr
Priority to CA2783731A priority patent/CA2783731C/fr
Priority to DK10793402.8T priority patent/DK2509625T3/en
Priority to HK13103208.7A priority patent/HK1176288B/en
Priority to US13/514,952 priority patent/US9127268B2/en
Priority to CN201610693924.3A priority patent/CN106474462A/zh
Priority to CN201080061989.7A priority patent/CN102821784B/zh
Priority to JP2012543321A priority patent/JP5819314B2/ja
Priority to AU2010327926A priority patent/AU2010327926B2/en
Application filed by aTyr Pharma Inc filed Critical aTyr Pharma Inc
Publication of WO2011072265A1 publication Critical patent/WO2011072265A1/fr
Anticipated expiration legal-status Critical
Priority to US13/762,151 priority patent/US9328340B2/en
Priority to US14/541,792 priority patent/US9540628B2/en
Priority to US15/365,079 priority patent/US9943577B2/en
Ceased legal-status Critical Current

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    • C12Y601/00—Ligases forming carbon-oxygen bonds (6.1)
    • C12Y601/01—Ligases forming aminoacyl-tRNA and related compounds (6.1.1)
    • C12Y601/01021—Histidine-tRNA ligase (6.1.1.21)
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    • C07K2319/00—Fusion polypeptide

Definitions

  • SEQ ID NO: 1 1 is the polynucleotide sequence that encodes the SP3 human YRS splice variant (SEQ ID NO: 10).
  • SEQ ID NO: 105 is the amino acid sequence of a full-length human aspartyl-tRNA synthetase (AspRS) polypeptide.
  • Figure 5 shows the in vivo and in vitro cytokine release in response to the Dl AspRS polypeptide (amino acids 1-154 of SEQ ID NO: 105).
  • Figure 5A shows circulating serum levels of TNF-a and IL-10 in mice injected intravenously with lOmg/kg Dl . TNF-a is increased at early time points but is rapidly cleared while the anti-inflammatory cytokine, IL-10, shows a prolonged time course.
  • Figure 5B shows in vivo serum levels for five cytokines from mice injected with Dl .
  • Figure 5C shows in vitro analysis of PBMCs stimulated with Dl, with an increase in TNF-a at 4 hours that is markedly higher than the full length DRS.
  • Figure 5D shows that secreted IL-10 levels are significantly increased at 24hrs after Dl treatment of PBMCs.
  • AARS polypeptides over other treatments include, for example, a different mechanism of action than traditional treatments, synergism with inflammatory-based signaling, higher potency, and the benefits associated with using a de -immunized molecule.
  • Other advantages will be apparent to a person skilled in the art.
  • derivative is meant a polypeptide that has been derived from the basic sequence by modification, for example by conjugation or complexing with other chemical moieties (e.g., pegylation) or by post-translational modification techniques as would be understood in the art.
  • derivative also includes within its scope alterations that have been made to a parent sequence including additions or deletions that provide for functionally equivalent molecules.
  • AARS aminoacyl-tR A synthetase
  • AARS polypeptides that may exist and occur from one genus or species to another.
  • Illustrative reference sequences include those set forth in any one of SEQ ID NOS: 1, 2, 3, 6, 8, 10, 12, 14, 16, 25, 28, 30, 32-108, and 109-115.
  • Biologically active fragments of an AARS polypeptide include peptides comprising amino acid sequences sufficiently similar to, or derived from, the amino acid sequences of a (putative) full-length AARS polypeptide sequence, such as SEQ ID NO: l, or portions thereof, or the polypeptides of SEQ ID NOS:2, 3, 6, 8, 10, 12, 14, 16, 25, 28, 30, 32-108, or 109-115.
  • a biologically active fragment of a truncated AARS polypeptide can be a polypeptide fragment which is, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300, 320, 340, 360, 380, 400, 450, 500, 550, 600, 650, 700, 750 or more contiguous or non-contiguous (e.g., splice variants are sometimes non-contiguous) amino acids, including all integers in between, of the amino acid sequences set forth in any one of SEQ ID NOS: 1, 2, 3, 6, 8, 10, 12, 14, 16, 25, 28, 30, 32-108, or 109-115, or the known amino acid sequences of the various human AARS polypeptides.
  • a “comparison window” refers to a conceptual segment of at least 6 contiguous positions, usually about 50 to about 100, more usually about 100 to about 150 in which a sequence is compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned.
  • the comparison window may comprise additions or deletions (i.e., gaps) of about 20% or less as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences.
  • erythrocyte refers to a red blood cell that consists mainly of hemoglobin, a complex metalloprotein containing heme groups whose iron atoms temporarily link to oxygen molecules (0 2 ) in the lungs. Erythrocytes are produced by a process called erythropoiesis, in which they develop from committed stem cells through reticulocytes to mature erythrocytes in about 7 days and live a total of about 100-120 days.
  • Polycythemias or erythrocytoses
  • erythrocytoses are diseases characterized by a surplus of erythrocytes, in which the increased viscosity of the blood can cause a number of symptoms.
  • Anemias are diseases characterized by low oxygen transport capacity of the blood, because of low red cell count or some abnormality of the red blood cells or the hemoglobin.
  • the vector can be an autonomously replicating vector, i.e., a vector that exists as an extra-chromosomal entity, the replication of which is independent of chromosomal replication, e.g., a linear or closed circular plasmid, an extra-chromosomal element, a mini-chromosome, or an artificial chromosome.
  • the vector can contain any means for assuring self-replication.
  • the vector can be one which, when introduced into the host cell, is integrated into the genome and replicated together with the chromosome(s) into which it has been integrated.
  • polypeptides of the present invention include a full-length aminoacyl-tR A synthetase polypeptide, in addition to any biologically active fragments, or variants or modifications thereof, of an aminoacyl-tRNA synthetase polypeptide, wherein the polypeptide is capable of modulating an inflammatory response, either in a subject, in vitro, or ex vivo.
  • Aminoacyl-tR A synthetases typically catalyze the aminoacylation of tR A with their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution.
  • aminoacyl-tRNA synthetases include tyrosyl-tRNA synthetases (YRS), tryptophanyl-tRNA synthetases (WRS), glutaminyl- tRNA synthetases (QRS), glycyl-tRNA synthetases (GlyRS), histidyl-tRNA synthetases (HisRS), seryl-tRNA synthetases (SRS), phenylalanyl-tRNA synthetases (PheRS), alanyl-tRNA synthetases (AlaRS), asparaginyl-tRNA synthetases (AsnRS), aspartyl- tRNA synthetases (AspRS), cysteinyl-tRNA synthetases (CysRS), glutamyl-tRNA synthetases (ERS), prolyl-tRNA synthetases (ProRS), arginyl-tRNA synthetases (
  • stearothermophilus tyrosyl-tRNA synthetases expressed in Escherichia coli indicate that human tyrosyl-tRNA synthetase aminoacylates human but not B. stearothermophilus tRNA Tyr , and vice versa. It is believed that the carboxyl- terminal domain of human tyrosyl-tRNA synthetase evolved from gene duplication of the carboxyl-terminal domain of methionyl-tRNA synthetase and may direct tRNA to the active site of the enzyme.
  • YRS polypeptide variants include full-length YRS polypeptides, or truncations or splice variants thereof, having one or more amino acid substitutions selected from an R93Q substitution, an I14L substitution, an N17G substitution, an L271 substitution, an A85S substitution, and a V156L substitution, in addition to combinations thereof.
  • the HisRS polypeptide of the invention comprises a sequence set forth in SEQ ID NOS:28, 30, or 32, or is a contiguous or noncontiguous (e.g., splice variants may be non-contiguous) fragment of a polypeptide set forth in SEQ ID NOS:28, 30, or 32.
  • the fragments may be of essentially any length, provided they retain at least one non-canonical biological activity of interest.
  • such a fragment may comprise at least about 5, 10, 15, 20, 25, 50, 75 or 80, or more, contiguous amino acid residues of SEQ ID NOS:28, 30, or 32.
  • the human QRS enzyme differs from both the bacterial and yeast enzymes, suggesting that a considerable part of human QRS has evolved to perform functions other than the charging of tRNA.
  • at least two distinct regions (part I and part II) within the eukaryotic QRS (EC 6.1.1.18) N-terminal region have no counterpart in Escherichia coli. Even though these regions are thought to bind RNA in a non-specific manner, enhancing interactions between the tRNA and enzyme, they are not essential for enzyme function (see, e.g., Wang et al, J. Biol. Chem. 274: 16508-12, 1999).
  • QRS has been crystallised in a variety of complexes, most importantly with its cognate tRNA gln .
  • the enzyme makes extensive contacts with the concave face of the tRNA, and makes specific interactions with the CUG anticodon at positions 34 to 36, and with the base pairs between the 5' end and the 3' end of the tRNA, just before the aminoacyl acceptor.
  • an AARS polypeptide differs from the reference sequences in SEQ ID NOS: 1, 2, 3, 6, 8, 10, 12, 14, 16, 25, 28, 30, 32-108, or 109-115 by at least one but by less than 15, 10 or 5 amino acid residues. In other embodiments, it differs from the reference sequences in SEQ ID NOS: 1, 2, 3, 6, 8, 10, 12, 14, 16, 25, 28, 30, 32-108, or 109-115 by at least one residue but less than 20%, 15%, 10% or 5% of the residues.
  • Biologically active truncated and/or variant AARS polypeptides may contain conservative amino acid substitutions at various locations along their sequence, as compared to a reference AARS amino acid sequence ⁇ e.g., SEQ ID NOS: 1, 2, 3, 6, 8, 10, 12, 14, 16, 25, 28, 30, 32-108, and 109-115).
  • a "conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, which can be generally sub-classified as follows:
  • Neutral/polar The residues are not charged at physiological pH, but the residue is not sufficiently repelled by aqueous solutions so that it would seek inner positions in the conformation of a peptide in which it is contained when the peptide is in aqueous medium.
  • Amino acids having a neutral/polar side chain include asparagine, glutamine, cysteine, histidine, serine and threonine.
  • the alteration does not substantially abolish one of these activities, for example, the activity is at least 20%, 40%, 60%, 70% or 80% 100%, 500%, 1000% or more of a reference AARS polypeptide.
  • An "essential" amino acid residue is a residue that, when altered from the reference AARS polypeptide, results in abolition of an activity of the parent molecule such that less than 20% of the reference activity is present.
  • such essential amino acid residues include those that are conserved in AARS polypeptides across different species, including those sequences that are conserved in the active binding site(s) or motif(s) of AARS polypeptides from various sources.
  • a variant polypeptide includes an amino acid sequence having at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% 95%, 96%, 97%, 98% or more sequence identity or similarity to a corresponding sequence of an AARS polypeptide as, for example, set forth in SEQ ID NOS: 1, 2, 3, 6, 8, 10, 12, 14, 16, 25, 28, 30, 32-108, or 109-115 and has the ability to reduce pulmonary inflammation in a subject, such as by reducing the migration or recruitment of neutrophils or eosinophils to the lung.
  • sequence similarity or sequence identity between sequences are performed as follows. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes).
  • the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence.
  • Examples of such cell types include, without limitation, immune cells such as monocytes, dendritic cells, macrophages (e.g., RAW 264.7 macrophages; see Example 5), neutrophils, eosinophils, basophils, and lymphocytes, such as B-cells and T-cells (e.g., CD4+ helper and CD8+ killer cells), including primary T-cells and T-cell lines such as Jurkat T-cells, as well as natural killer (NK) cells.
  • immune cells such as monocytes, dendritic cells, macrophages (e.g., RAW 264.7 macrophages; see Example 5), neutrophils, eosinophils, basophils, and lymphocytes, such as B-cells and T-cells (e.g., CD4+ helper and CD8+ killer cells), including primary T-cells and T-cell lines such as Jurkat T-cells, as well as natural killer (NK) cells.
  • NK natural killer
  • linker sequences which may be usefully employed as linkers include those disclosed in Maratea et al, Gene 40:39 46 (1985); Murphy et al, Proc. Natl. Acad. Sci. USA SJ:8258 8262 (1986); U.S. Pat. No. 4,935,233 and U.S. Pat. No. 4,751,180.
  • the linker sequence may generally be from 1 to about 50 amino acids in length. Linker sequences are not required when the first and second polypeptides have non-essential N-terminal amino acid regions that can be used to separate the functional domains and prevent steric interference.
  • codons preferred by a particular prokaryotic or eukaryotic host can be selected to increase the rate of protein expression or to produce a recombinant RNA transcript having desirable properties, such as a half- life which is longer than that of a transcript generated from the naturally occurring sequence.
  • polynucleotide sequences of the present invention can be engineered using methods generally known in the art in order to alter polypeptide encoding sequences for a variety of reasons, including but not limited to, alterations which modify the cloning, processing, expression and/or activity of the gene product.
  • a nucleotide sequence encoding the polypeptide, or a functional equivalent may be inserted into appropriate expression vector, i.e., a vector which contains the necessary elements for the transcription and translation of the inserted coding sequence.
  • appropriate expression vector i.e., a vector which contains the necessary elements for the transcription and translation of the inserted coding sequence.
  • Methods which are well known to those skilled in the art may be used to construct expression vectors containing sequences encoding a polypeptide of interest and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. Such techniques are described in Sambrook et al., Molecular Cloning, A Laboratory Manual (1989), and Ausubel et al, Current Protocols in Molecular Biology (1989).
  • sequences encoding polypeptides may be driven by any of a number of promoters.
  • viral promoters such as the 35S and 19S promoters of CaMV may be used alone or in combination with the omega leader sequence from TMV (Takamatsu, EMBO J. (5:307-311 (1987)).
  • plant promoters such as the small subunit of RUBISCO or heat shock promoters may be used (Coruzzi et al., EMBO J. 3: 1671- 1680 (1984); Broglie et al, Science 224:838-843 (1984); and Winter et al, Results Probl. Cell Differ. 77:85-105 (1991)).
  • reporter molecules or labels include radionuclides, enzymes, fluorescent, chemiluminescent, or chromogenic agents as well as substrates, cofactors, inhibitors, magnetic particles, and the like.
  • both the "on rate constant” (k on ) and the “off rate constant” (k 0 f) can be determined by calculation of the concentrations and the actual rates of association and dissociation.
  • the ratio of k 0/j /k 0 nie enables cancellation of all parameters not related to affinity, and is thus equal to the dissociation constant Kj. See, generally, Davies et al. (1990) Annual Rev. Biochem. 59:439-473.
  • antigen binding specificity can be preserved in a humanized antibody only wherein the CDR structures, their interaction with each other, and their interaction with the rest of the V region domains are carefully maintained.
  • exterior (e.g., solvent-accessible) FR residues which are readily encountered by the immune system are selectively replaced with human residues to provide a hybrid molecule that comprises either a weakly immunogenic, or substantially non-immunogenic veneered surface.
  • a linker group can function as a spacer to distance an antibody from an agent in order to avoid interference with binding capabilities.
  • a linker group can also serve to increase the chemical reactivity of a substituent on an agent or an antibody, and thus increase the coupling efficiency. An increase in chemical reactivity may also facilitate the use of agents, or functional groups on agents, which otherwise would not be possible. It will be evident to those skilled in the art that a variety of bifunctional or polyfunctional reagents, both homo- and hetero-functional (such as those described in the catalog of the Pierce Chemical Co., Rockford, IL), may be employed as the linker group.
  • inflammation refers generally to the biological response of tissues to harmful stimuli, such as pathogens, damaged cells (e.g., wounds), and irritants.
  • the term "inflammatory response” refers to the specific mechanisms by which inflammation is achieved and regulated, including, merely by way of illustration, immune cell activation or migration, cytokine production, vasodilation, including kinin release, fibrinolysis, and coagulation, among others described herein and known in the art.
  • inflammation is a protective attempt by the body to both remove the injurious stimuli and initiate the healing process for the affected tissue or tissues. In the absence of inflammation, wounds and infections would never heal, creating a situation in which progressive destruction of the tissue would threaten survival.
  • excessive or chronic inflammation may associate with a variety of diseases, such as hay fever, atherosclerosis, and rheumatoid arthritis, among others described herein and known in the art.
  • Chronic inflammation a prolonged and delayed inflammatory response, is characterized by a progressive shift in the type of cells that are present at the site of inflammation, and often leads to simultaneous or near simultaneous destruction and healing of the tissue from the inflammatory process.
  • chronic inflammatory responses involve a variety of immune cells such as monocytes, macrophages, lymphocytes, plasma cells, and fibroblasts, though in contrast to acute inflammation, which is mediated mainly by granulocytes, chronic inflammation is mainly mediated by mononuclear cells such as monocytes and lymphocytes.
  • Chronic inflammation also involves a variety of inflammatory mediators, such as IFN- ⁇ and other cytokines, growth factors, reactive oxygen species, and hydrolytic enzymes. Chronic inflammation may last for many months or years, and may result in undesired tissue destruction and fibrosis.
  • AARS polypeptides increase the levels of any one or more of TNF-a, MIP-lb, IL-12(p40), KC, MIP-2, or IL-10. In certain embodiments, AARS polypeptides increase the secretion of at least one of TNF-a and IL-10 by peripheral blood mononuclear cells (PBMCs), including monocytes, lymphocytes, or both. In certain embodiments, AARS polypeptides increase the secretion of IL-2 by lymphocytes such as activated T-cells.
  • PBMCs peripheral blood mononuclear cells
  • TNF tumor necrosis factors
  • type 3 tumor necrosis factors
  • CD40 CD27 and CD30
  • chemokine receptors such as CXCR4 and CCR5, as well as receptors for IL-8, MIP-1 and RANTES.
  • certain embodiments may employ AARS polypeptides to reduce or manage (i.e., prevent further increases) inflammation or inflammatory responses associated with particular tissues or organs. Included are inflammatory responses and conditions associated with the skin, including inflammation, infections, and cancers associated with the dermal, epidermal, and subcutaneous layers of the skin.
  • Examples of skin-associated inflammatory conditions include, without limitation, dermatitis, such as psoriasis, irritant dermatitis, seborrheic dermatitis, atopic dermatitis (eczema), allergic contact dermatitis, thermal-induced dermatitis, drug-induced dermatitis, dyshidrotic dermatitis, urticaria, autoimmune dermatitis, skin cancer such as melanoma, and bullous dermatitis. Also included are bacterial, viral and parasitic infections, erythema multiforme, erythema nodosum, granuloma annulare, poison oak/poison ivy, and toxic epidermal necrolysis.
  • dermatitis such as psoriasis, irritant dermatitis, seborrheic dermatitis, atopic dermatitis (eczema), allergic contact dermatitis, thermal-induced dermatitis, drug-induced dermatitis
  • COPD may also have an autoimmune component.
  • an autoimmune component For instance, lung and peripheral blood T cells in patients with severe emphysema secrete Thl cytokines and chemokines when stimulated with elastin peptides in vitro, and these patients have increased anti-elastin antibody as compared to controls ⁇ see Goswami et al, The Journal of Immunology. 178: 130.41, 2007).
  • IgG autoantibodies with avidity for pulmonary epithelium, and the potential to mediate cytotoxicity are prevalent in patients with COPD ⁇ see Feghali-Bostwick et al., Am J Respir Crit Care Med. 177: 156-63, 2008).
  • autoreactive immune responses may be important in the etiology of this disease, including, for example, auto-reactive responses to self-antigens such as elastin, may play a role in COPD, the use of AARS polypeptides to desensitize immune cells to these antigens may reduce pulmonary inflammation.
  • antigens include, without limitation, smoke such as cigarette smoke, air pollution, fumes such as the fumes from welding, dust, including silica dust and workplace dust such as those found in coal mining and gold mining, chemicals such as cadmium and isocyanates. Also included are known allergens and infectious agents, such as bacterial and viral or antigens, including lipopolysaccharide (LPS), which may exacerbate COPD in sensitive individuals.
  • smoke such as cigarette smoke
  • air pollution fumes
  • fumes such as the fumes from welding
  • dust including silica dust and workplace dust such as those found in coal mining and gold mining
  • chemicals such as cadmium and isocyanates.
  • allergens and infectious agents such as bacterial and viral or antigens, including lipopolysaccharide (LPS), which may exacerbate COPD in sensitive individuals.
  • LPS lipopolysaccharide
  • examples of self-antigens include, without limitation, receptor ligands, chemoattractants, and signaling molecules.
  • the response to the antigen or self-antigen signals via a CXCR-2 receptor.
  • certain AARS polypeptides may bind their putative receptor on the surface of neutrophils, such as the CXCR2 receptor, which then results in the desensitization of the receptor (i.e., the receptor is internalized and no longer be present at the cell surface).
  • CXCR-2 receptor i.e., the receptor is internalized and no longer be present at the cell surface.
  • IL-8 is is produced as a result of cigarette smoke in COPD, for example, the densitization of certain neutrophils to CXCR-2 ligands such as IL-8 reduces their migration to the lung, and thereby reduces the inflammation associated with COPD, especially that caused by cigarette smoke.
  • Certain embodiments relate to reducing inflammatory responses and conditions associated the gastrointestinal system, including inflammation, infections, and cancer associated with the mouth, esophagus, stomach, small intestines, large intestines, and rectum.
  • Gastrointestinal inflammation refers to inflammation of a mucosal layer of the gastrointestinal tract, and encompasses acute and chronic inflammatory conditions. Acute inflammation is generally characterized by a short time of onset and infiltration or influx of neutrophils. Chronic inflammation is generally characterized by a relatively longer period of onset and infiltration or influx of mononuclear cells. Chronic inflammation can also typically characterized by periods of spontaneous remission and spontaneous occurrence.
  • AARS polypeptides may also be employed to treat or manage inflammation associated with hypersensitivity.
  • examples of such conditions include type I hypersensitivity, type II hypersensitivity, type III hypersensitivity, type IV hypersensitivity, immediate hypersensitivity, antibody mediated hypersensitivity, immune complex mediated hypersensitivity, T-lymphocyte mediated hypersensitivity, and delayed type hypersensitivity.
  • SIRS may be identified by the presence of two or more of the following: (i) a body temperature that is less than 36°C or greater than 38°C, (ii) a heart rate that is greater than 90 beats per minute, (iii) tachypnea (high respiratory rate), with greater than 20 breaths per minute; or, an arterial partial pressure of carbon dioxide less than 4.3 kPa (32 mmHg), and (iv) white blood cell count less than 4000 cells/mm 3 (4 x 10 9 cells/L) or greater than 12,000 cells/mm 3 (12 x 10 9 cells/L); or the presence of greater than 10% immature neutrophils (band forms).
  • Cytokine storms can occur in a number of infectious and non- infectious diseases including graft versus host disease (GVHD), acute respiratory distress syndrome (ARDS), sepsis, avian influenza, smallpox, and SIRS. Cytokine storm may also be induced by certain medications. Treatment includes OX40 IG, which reduces T-cell responses, ACE inhibitors, Angiotensin II receptor blockers, corticosteroids, gemfibrozil, free radical scavengers, and TNF-a blockers. Accordingly, AARS polypeptides may be employed to treat or manage cytokine storm, alone or in combination with other therapies.
  • T-cell and B-cell immunodeficiencies include T-/B+ deficiencies such as yc deficiency, JAK3 deficiency, interleukin 7 receptor chain a deficiency, CD45 deficiency, CD35/CD38 deficiency; and T-/B- deficiencies such as RAG 1/2 deficiency, DCLRE1C deficiency, adenosine deaminase (ADA) deficiency, reticular dysgenesis.
  • T-/B+ deficiencies such as yc deficiency, JAK3 deficiency, interleukin 7 receptor chain a deficiency, CD45 deficiency, CD35/CD38 deficiency
  • T-/B- deficiencies such as RAG 1/2 deficiency, DCLRE1C deficiency, adenosine deaminase (ADA) deficiency, reticular dysgenesis.
  • Additional examples include Omenn syndrome, DNA ligase type IV deficiency, CD40 ligand deficiency, CD40 deficiency, purine nucleoside phosphorylase (PNP) deficiency, MHC class II deficiency, CD3y deficiency, CD8 deficiency, ZAP-70 deficiency, TAP- 1/2 deficiency, and winged helix deficiency.
  • PNP purine nucleoside phosphorylase
  • Exemplary diagnostic tests include, without limitation, performing counts of the different types of mononuclear cells in the blood (e.g., lymphocytes and monocytes, including lymphocytes, different groups of B lymphocytes such as CD 19+, CD20+, and CD21+ lymphocytes, natural killer cells, and monocytes positive for CD 15+), measuring the presence of activation markers (e.g., HLA-DR, CD25, CD80), performing tests for T cell function such as skin tests for delayed-type hypersensitivity, cell responses to mitogens and allogeneic cells, cytokine production by cells, performing tests for B cell function such as by identifying antibodies to routine immunizations and commonly acquired infections and by quantifying IgG subclasses, and performing tests or phagocyte function, such as by measuring the reduction of nitro blue tetrazolium chloride, and performing assays of chemotaxis and bactericidal activity.
  • AARS polypeptides may therefore be used to stimulate or maintain
  • causes of secondary immunodeficiencies include malnutrition, aging, and medications (e.g., chemotherapy, disease-modifying antirheumatic drugs, immunosuppressive drugs after organ transplants, glucocorticoids).
  • Additional causes include various cancers, including cancers of the bone marrow and blood cells (e.g., leukemia, lymphoma, multiple myeloma), and certain chronic infections, such as acquired immunodeficiency syndrome (AIDS), caused by the human immunodeficiency virus (HIV).
  • AARS polypeptides may be used to stimulate or maintain acute inflammation or acute inflammatory responses in subjects with an immunodeficiency, as described herein and known in the art.
  • AARS polypeptides may also be used to stimulate or maintain chronic inflammation or chronic inflammatory responses in subjects with a secondary immunodeficiency, as described herein and known in the art.
  • AARS polypeptides e.g., QRS polypeptides
  • AARS polypeptides e.g., QRS polypeptides
  • QRS polypeptides or compositions thereof are provided for inhibiting TNF-a production or secretion in mammalian cells, such as PBMCs, either in vivo or in vitro.
  • QRS polypeptides inhibit the TNF-a or IL- 12-based secretion response of cells to immune-stimulating antigens, including autoimmune disorder-related antigens and foreign antigens such as lipopolysaccharide (LPS).
  • the AARS polypeptides e.g., QRS polypeptides
  • Still further autoimmune diseases, disorders or conditions include, but are not limited to chronic active hepatitis (which is often characterized, for example by smooth muscle antibodies); primary biliary cirrhosis (which is often characterized, for example, by anti-mitochondrial antibodies); other endocrine gland failure (which is characterized, for example, by specific tissue antibodies in some cases); vitiligo (which is often characterized, for example, by anti-melanocyte antibodies); vasculitis (which is often characterized, for example, by immunoglobulin and complement in vessel walls and/or low serum complement); post-myocardial infarction conditions (which are often characterized, for example, by anti-myocardial antibodies); cardiotomy syndrome (which is often characterized, for example, by anti-myocardial antibodies); urticaria (which is often characterized, for example, by IgG and IgM antibodies to IgE); atopic dermatitis (which is often characterized, for example, by IgG and IgM antibodies to Ig
  • compositions of the invention may be used in the treatment of neuronal/neurological diseases or disorders, illustrative examples of which include Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeldt- Jacob disease, Huntington's chorea, alternating hemiplegia, amyotrophic lateral sclerosis, ataxia, cerebral palsy, chronic fatigue syndrome, chronic pain syndromes, congenital neurological anomalies, cranial nerve diseases, delirium, dementia, demyelinating diseases, dysautonomia, epilepsy, headaches, Huntington's disease, hydrocephalus, meningitis, movement disorders, muscle diseases, nervous system neoplasms, neurocutaneous syndromes, neurodegenerative diseases, neurotoxicity syndromes, ocular motility disorders, peripheral nervous system disorders, pituitary disorders, porencephaly, Rett syndrome, sleep disorders, spinal cord disorders, stroke, Sydenham's chorea, tourette syndrome, nervous system trauma and injuries, etc.
  • neuronal/neurological diseases or disorders
  • Illustrative cytokines that may measured for monitoring biological effects of the QRS compositions include, but are not limited to IL-l , IL- ⁇ , IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-15, IL-18, IL-23 TGF- ⁇ , TNF-a, IFN-a, IFN- ⁇ , IFN- ⁇ , RANTES, MIP-la, ⁇ - ⁇ , MCP-1, GM-CSF, G-CSF, etc.
  • compositions of the invention formulation of pharmaceutically-acceptable excipients and carrier solutions is well-known to those of skill in the art, as is the development of suitable dosing and treatment regimens for using the particular compositions described herein in a variety of treatment regimens, including e.g. , oral, parenteral, intravenous, intranasal, and intramuscular administration and formulation.
  • aqueous solution for parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • a sterile aqueous medium that can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage may be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion (see, e.g., Remington 's Pharmaceutical Sciences, 15th Edition, pp.
  • compositions disclosed herein may be formulated in a neutral or salt form.
  • Pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms such as injectable solutions, drug-release capsules, and the like.
  • topical formulations examples include creams, ointments, pastes, lotions, and gels.
  • ⁇ were added to 6.5mm transwell filter inserts (Costar, Cambridge, MA) and 600 ⁇ 1 migration buffer containing a control chemokine, the tyrosyl-tRNA synthetase polypeptides or buffer only were added to the plate lower chambers. Cells were allowed to migrate for 4 hours and the remaining cells in the upper chamber (transwell filter inserts) were removed with a cotton swap. The filter inserts were then transferred to a new 24-well plate containing 500 ⁇ 1 cell dissociation buffer (Invitrogen, Carlsbad, CA) and 12 ⁇ g/ml Calcein AM (Invitrogen, Carlsbad, CA). After 1 hour incubation at 37°C, cells were collected and resuspended in ⁇ PBS, transferred into a 384-well opaque Greiner plate, and counted by fluorescence in a plate reader.
  • 500 ⁇ 1 cell dissociation buffer Invitrogen, Carlsbad, CA
  • 12 ⁇ g/ml Calcein AM Invitrogen, Carlsbad
  • peripheral blood mononuclear cells representing a mixture of both monocytes and lymphocytes isolated from human donors were exposed to the Dl protein in vitro (as well as the full-length AspRS protein), and the media was tested for the secretion of either TNF-a or IL-10 in response to treatment. Similar to the effects observed in vivo, treatment with Dl resulted in secretion of both TNF-a (after 4 hours treatment) and IL-10 (after 24 hours treatment) from the mixed cell population (see Figures 5C and D).
  • PBMCs peripheral blood mononuclear cells
  • THP-1 cells (ATCC catalog No. TIB-202) were cultured in RPMI- 1640 medium (ATCC catalog No. 30-2001) supplemented with 10% heat-inactivated FBS (Invitrogen, Catalog No. 10082147) and 0.05 mM 2-mercaptoethanol. Cell density was kept at ⁇ 1 x 10 6 cells/ml. Migration was done in Corning Transwell Permeable Supports in 24-well plates (6.5mm Diameter; 8.0 ⁇ pore size; Fisher Scientific catalog No. 07-200-150).

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Abstract

L'invention concerne des compositions modulant une réponse inflammatoire et d'autres réponses cellulaires et comprenant des polypeptides à aminoacyl-tRNA synthétases qui comprennent des variants et/ou des fragments actifs. L'invention concerne également des procédés d'utilisation de telles compositions dans le traitement d'états pathologiques améliorés par la modulation de l'inflammation, notamment des états pathologiques ou des maladies inflammatoires.
PCT/US2010/059963 2009-12-11 2010-12-10 AMINOACYL-ARNt SYNTHÉTASES DESTINÉES À MODULER UNE INFLAMMATION Ceased WO2011072265A1 (fr)

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US14/541,792 US9540628B2 (en) 2009-12-11 2014-11-14 Aminoacyl tRNA synthetases for modulating inflammation
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US9328340B2 (en) 2016-05-03
CN106474462A (zh) 2017-03-08
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US9127268B2 (en) 2015-09-08
US9943577B2 (en) 2018-04-17
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US20150140072A1 (en) 2015-05-21
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