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WO2021028469A1 - Compositions et méthodes de traitement du syndrome de libération de cytokines et de neurotoxicité - Google Patents

Compositions et méthodes de traitement du syndrome de libération de cytokines et de neurotoxicité Download PDF

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Publication number
WO2021028469A1
WO2021028469A1 PCT/EP2020/072617 EP2020072617W WO2021028469A1 WO 2021028469 A1 WO2021028469 A1 WO 2021028469A1 EP 2020072617 W EP2020072617 W EP 2020072617W WO 2021028469 A1 WO2021028469 A1 WO 2021028469A1
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rsl
subject
rsl7561
rsl6944
antigen
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Gordon Duff
Kenneth S. Kornman
Lynn Doucette-Stamm
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Sitokine Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/31—Chimeric antigen receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/30—Cellular immunotherapy characterised by the recombinant expression of specific molecules in the cells of the immune system
    • A61K40/32—T-cell receptors [TCR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/42—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the prevention and treatment of cytokine release syndrome (CRS) and neurotoxicity associated with immunotherapy.
  • CRS cytokine release syndrome
  • Immunotherapies such as chimeric antigen receptor T-cell therapies (CAR-T) and antibody-based therapies, are increasingly being used to treat a wide range of diseases, including cancers, infections, auto-immune disorders and genetic diseases.
  • immunotherapies can be associated with life-threatening side effects.
  • Cytokine release syndrome (CRS) and neurotoxicity are potentially life-threatening toxicities that can be caused by immunotherapies.
  • CRS Cytokine release syndrome
  • CRS is seen in 70-94% of patients treated with CAR-T therapy and is the most common side effect of CAR-T therapy.
  • immunotherapies such as CAR-T therapy cause aberrant activation of large numbers of white blood cells, such as B cells,
  • T cells T cells, natural killer (NK) cells, macrophages and dendritic, which release pro-inflammatory cytokines. Release of pro -inflammatory cytokines in turn leads to activation of the vascular endothelial system and loss of vascular integrity.
  • Neurotoxicity is a second side effect of immunotherapies. Neurotoxicity is almost always preceded by CRS and is also associated with markers of endothelial activation. There are currently very few treatments available for CRS and neurotoxicity, and what treatments exist are largely palliative. There thus exists a need in the art for additional methods to treat and prevent CRS and neurotoxicity. The disclosure provides compositions and methods for the treatment and prevention of CRS and neurotoxicity.
  • the disclosure provides methods of reducing a risk of developing cytokine release syndrome (CRS) or neurotoxicity induced by immunotherapy in a subject, comprising : (a) identifying a subject with a disease with a recommended course of treatment comprising an immunotherapy; (b) obtaining information regarding the subject’s single nucleotide polymorphism (SNP) alleles for: (i) each of the rsl7561 polymorphic locus, the rsl6944 polymorphic locus and the rs 1143634 polymorphic locus; (ii) each of the rs 16944 polymorphic locus, the rs 1143623 polymorphic locus and the rs4848306 polymorphic locus; or (iii) each of the rsl7561 polymorphic locus, the rsl6944 polymorphic locus the rsl 143634 polymorphic locus, the rsl 143623 polymorphic locus and the rsssl
  • the disclosure provides methods of reducing the severity of cytokine release syndrome (CRS) or neurotoxicity induced by immunotherapy in a subject, comprising: (a) identifying a subject with a disease with a recommended course of treatment comprising an immunotherapy; (b) obtaining information regarding the subject’s single nucleotide polymorphism (SNP) alleles for: (i) each of the rsl7561 polymorphic locus, the rsl6944 polymorphic locus and the rsl 143634 polymorphic locus; (ii) each of the rs 16944 polymorphic locus, the rsl 143623 polymorphic locus and the rs4848306 polymorphic locus; or (iii) each of the rsl7561 polymorphic locus, the rsl6944 polymorphic locus the rsl 143634 polymorphic locus, the rsl 143623 polymorphic locus and the rs484830306 poly
  • an IL-1 positive genotype pattern is selected from the group consisting of: (i) T/T or T/G at rsl7561, C/C, T/T, C/T or T/C at rs4848306, G/G at rsl 143623, C/C at rs 16944 and T/T or T/C at rsl 143634; (ii) G/G at rsl7561, C/C, T/T, C/T or T/C at rs4848306, G/G at rsl 143623, C/C at rsl6944 and C/C, T/T, C/T or T/C at rsl 143634; (iii) G/G, T/T, G/T or T/G at rsl7561, C/C, T/T, C/T or T/C at rs4848306, G/G at rsl 143623, C
  • the methods further comprise measuring at least one biomarker indicating that the subject is undergoing a broad release of cytokines.
  • the at least on biomarker is selected from the group consisting of interleukin- 1 (IL-1), interleukin -2 (IL-2), interferon gamma (IFNy), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNFa), monocyte chemoattractant protein- 1 (MCP-1), interleukin 6 signal transducer (gpl30), Fms-related tyrosine kinase 3 ligand (Flt3L), C-X3-C motif chemokine ligand 1 (CX3CL1) or colony stimulating factor 2 (CSF).
  • IL-1 interleukin- 1
  • IL-2 interleukin -2
  • IFNy interferon gamma
  • IL-5 interleukin 5
  • IL-6
  • the at least one biomarker comprises a two-cytokine max fold change of at least 75 fold each, a one cytokine max fold change of at least 250, a C-reactive protein level of greater than or equal to 200 mg/L, or a combination thereof.
  • the cytokine is selected from the group consisting of IL-1, IL-2, IL-2R, IFNy, IL- 5, IL-6, IL-10, TNFa, MCP-1, gpl30, Flt3L, CX3CL1 and CSF.
  • the inflammation inhibitor is administered before the immunotherapy. In some embodiments, the inflammation inhibitor is administered in temporal proximity to the immunotherapy. In some embodiments, the inflammation inhibitor is administered after the immunotherapy. In some embodiments, a dose of the inflammation inhibitor is administer within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 days of administering the immunotherapy. In some embodiments, a dose of the inflammation inhibitor is administered within 30 days of the immunotherapy. In some embodiments, the inflammation inhibitor is administered prior to the onset of the CRS or neurotoxicity. In some embodiments, the inflammation inhibitor is administered after the onset of the CRS or neurotoxicity.
  • the disease is cancer.
  • the cancer comprises a solid tumor or a liquid tumor.
  • the liquid tumor comprises leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, lymphoma, or multiple myeloma.
  • the leukemia comprises acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia or hairy cell leukemia.
  • the lymphoma comprises Hodgkin lymphoma or non- Hodgkin lymphoma.
  • the immunotherapy comprises an antibody therapy, an adoptive cell therapy, a cancer vaccine or an oncolytic virus.
  • the immunotherapy comprises an adoptive cell therapy.
  • the adoptive cell therapy is autologous or allogeneic.
  • the adoptive cell therapy comprises a chimeric antigen receptor T-cell (CAR-T) therapy, a modified T Cell Receptor T-cell (TCR-T) therapy, or non- genetically modified activated T-cells.
  • CAR-T chimeric antigen receptor T-cell
  • TCR-T modified T Cell Receptor T-cell
  • non- genetically modified activated T-cells non- genetically modified activated T-cells.
  • the CAR-T therapy comprises a CAR targeting an antigen selected from the group consisting of Mesothelin, prostate stem cell antigen (PSCA), carcinoembryonic antigen (CEA), erb-b2 receptor tyrosine kinase 2 (HER2), mucin 1 (MUC1), epidermal growth factor receptor variant III (EGFRvIII), glypican-3, CD19 molecule (CD19), epithelial cell adhesion molecule (EpCAM), Claudin 18.2, CD70 molecule (CD70), Lewis Y antigen, interleukin 3 receptor subunit alpha (CD 123), disialoganglioside GD2 (GD2), prostate specific membrane antigen (PSMA), epidermal growth factor receptor (EGFR), interleukin 13 receptor subunit alpha 2 (IL13Ra2), EPH receptor A2 (EphA2), prominin 1 (CD133), Transforming Growth Factor Alpha (TGFA), TIE portion of TGFA (TIE
  • CD5 molecule CD5
  • VGFR2 vascular endothelial growth factor receptor 2
  • CD4 molecule CD4
  • TNF receptor superfamily member 8 CD30
  • human gastric carcinoma- associated antigen MG7 from CEA MG7
  • AXL receptor tyrosine kinase AXL
  • B7-H3 antigen B7-H3
  • FRa a-folate receptor
  • cMET MET proto-oncogene
  • cMET MHC class I polypeptide -related sequence A
  • MHC class I polypeptide -related sequence B MIC-B
  • melanoma-associated antigen MAGE
  • MAGE-A3 MAGE-A3
  • MAGE-A4 MAGE-A3/12, MAGE-A3/A6, New York esophageal squamous cell carcinoma 1 (NY-ESO-1), Human Papillomavirus E6 (HPV16-
  • the TCR-T therapy comprises a TCR targeting an antigen selected from the group consisting of elected from the group consisting of Mesothelin, PSCA, CEA, HER2, MUC1, EGFRvIII, glypican-3, CD19, EpCAM, Claudin 18.2, CD70, Lewis Y antigen, CD123, GD2, PSMA, EGFR, IL13Ra2, EphA2, CD133, TGFA, TIE, CD33, BCMA, CD22, CD5, VGFR2, CD20, CD4, CD30, MG7, AXL, B7-H3, FRa, cMET, MIC-A, MIC-B, MAGE- A3, MAGE-A4, MAGE-A3/12, MAGE-A3/A6, NY-ESO-1, HPV16-E6, MART-1, gplOO, ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, ULBP6, ROR1, ROR2, TRAIL, PRAME,
  • the immunotherapy comprises an antibody therapy.
  • the antibody therapy comprises a monoclonal antibody or a bi-specific antibody.
  • the monoclonal antibody comprises rituximab, obinutuzumab, brentuximab, dacetuzumab or nivolumab.
  • the bi-specific antibody comprises a bi-specific T-cell engager antibody (BiTE).
  • the bi-specific T-cell engager antibody comprises a first antigen binding domain that recognizes a cancer associated antigen, and a second antigen binding domain that recognizes a T-cell antigen.
  • the cancer associated antigen selected from the group consisting of Mesothelin, PSCA, CEA, HER2, MUC1, EGFRvIII, glypican-3, CD19, EpCAM, Claudin 18.2, CD70, Lewis Y antigen, CD123, GD2, PSMA, EGFR, IL13Ra2, EphA2, CD133, TGFA, TIE, CD33, BCMA, CD22, CD5, VGFR2, CD20, CD4, CD30, MG7, AXL, B7-H3,
  • the T-cell antigen is selected from the group consisting of CD3g molecule (CD3 gamma), CD3d molecule (CD3 delta), CD3e molecule (CD3 epsilon), and CD247 (CD3 zeta).
  • the bi-specific T-cell engager antibody is selected from the group consisting of blinatumomab, solitomab, AMG 330,
  • the subject has an infection.
  • the infection comprises a viral infection, a fungal infection or a bacterial infection.
  • the viral infection comprises human immunodeficiency virus (HIV), Epstein-Barr vims (EBV) or cytomegalovirus (CMV).
  • the immunotherapy comprises an antibody therapy or an adoptive cell therapy.
  • the adoptive cell therapy is autologous or allogeneic.
  • the adoptive cell therapy comprises a chimeric antigen receptor T-cell (CAR-T) therapy, a T Cell Receptor modified T-cell (TCR-T) therapy, or non-genetically modified activated T-cells.
  • the disease is multiple sclerosis.
  • the immunotherapy comprises an antibody therapy.
  • the antibody therapy comprises alemtuzumab.
  • the inflammation inhibitor is an IL-1 inhibitor.
  • the IL-1 inhibitor comprises an inflammasome modulator.
  • the inflammasome modulator can cross the blood brain barrier.
  • the inflammasome modulator comprises Diacerein, Sarei-To, Binimetinib, Can-04, Rilonacept, XL- 130, Givinostat or Ammonium trichloro-tellurate.
  • the IL-1 inhibitor is an IL- la inhibitor or an IL-Ib inhibitor.
  • the IL-la inhibitor is selected from the group consisting of Bermekimab, ABT- 981, Isunakinra, AC-701, Sairei-To, Can-04, XL-130, a MABpl antibody and Givinostat.
  • the L-Ib inhibitor is selected from the group consisting of ABT-981, Anakinra, Anakinra Biosimilar, APX-002, binimetinib, CAN-04, Diacerein, DLX-2681, Givinostat, Isunakinra, Rilonacept, SER-140, XL-130, gevokizumab, Can-04, a DOM4-130-201 antibody, DOM4-130-202 antibody and canakinumab.
  • the inflammation inhibitor is an IL-6 inhibitor.
  • the IL-6 inhibitor is Tocilizumab, Siltuximab, Olokizumab, Elsilimomab, Sirukumab, Levilimab, ALX-0061, Gerilimzumab, FE301, FM101, sarilumab, clazakinumab or CPSI-2364.
  • the inflammation inhibitor prevents a sign or a symptom of the CRS or neurotoxicity. In some embodiments, the inflammation inhibitor reduces a sign or a symptom of the CRS or neurotoxicity.
  • the sign or symptom of CRS comprises fever, tachycardia, tachypnea, hypoxia, hypotension, coagulopathy, hypoalbuminemia, hypoproteinemia, respiratory failure, refractory shock, multi-organ failure, two cytokine max fold changes of at least 75, one cytokine max fold change of at least 250, a C-reactive protein level of greater than or equal to 20 mg/dL or a combination thereof.
  • the cytokine comprises interleukin- 1 (IL-1), interleukin-2 (IL-2), interferon gamma (IFNy), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNFa), monocyte chemoattractant protein-1 (MCP-1), interleukin 6 signal transducer (gpl30), Fms-related tyrosine kinase 3 ligand (Flt3L), C-X3-C motif chemokine ligand 1 (CX3CL1) or colony stimulating factor 2 (CSF).
  • IL-1 interleukin- 1
  • IL-2 interleukin-2
  • IFNy interferon gamma
  • IL-5 interleukin 5
  • IL-6 interleukin 6
  • IL-10 interleukin 10
  • TNFa tumor necrosis factor alpha
  • MCP-1 monocyte chemoattractant protein-1
  • the sign or symptom of neurotoxicity comprises encephalopathy, aphasia, delirium, tremor, seizure activity, status epilepticus, obtundation, increased intracranial pressure, cerebral edema, brain hernia, or a combination thereof.
  • the IL-1 inhibitor reduces a level of a pro-inflammatory cytokine in the subject.
  • the pro- inflammatory cytokine is IL-la, IL-Ib or IL-6.
  • the IL-1 inhibitor reduces a level of a cytokine selected from the group consisting of IL-1, IL-2, IL-5, IL-6, IL-10, TNFa, PTNGg, MCP-1, gpl30, Flt3L, CX3CL1 and CSF2, in the subject.
  • a cytokine selected from the group consisting of IL-1, IL-2, IL-5, IL-6, IL-10, TNFa, PTNGg, MCP-1, gpl30, Flt3L, CX3CL1 and CSF2, in the subject.
  • Cytokine release syndrome (CRS) and neurotoxicity are associated with, and caused by, elevated levels of pro-inflammatory cytokines.
  • cytokines include interleukin- 1 (IL-1) family cytokines, interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin- 10 (IL-10), tumor necrosis factor alpha (TNFa), interferon gamma (IFNy), monocyte chemoattractant protein -1 (MCP-1) and interleukin 6 signal transducer (gpl30).
  • IL-1 interleukin-2
  • IL-6 interleukin-6
  • IL-10 interleukin- 10
  • TNFa tumor necrosis factor alpha
  • IFNy interferon gamma
  • MCP-1 monocyte chemoattractant protein -1
  • gpl30 interleukin 6 signal transducer
  • IL-1 cytokine release syndrome
  • the present invention is based on the discovery that specific IL-1 genotype patterns stratify subjects into groups relating to their member’s likelihood of over-producing IL-1. It is thus possible to specifically target subjects who have high levels of inflammation and who are at risk of developing, or who have developed CRS or neurotoxicity, for treatment with inflammation inhibitors and other therapies.
  • CAR Chimeric antigen receptor
  • CAR-T Chimeric antigen receptor T cell therapy
  • T cells from either a donor or the recipient are genetically engineered to express a specific chimeric antigen receptor designed to recognize a specific tumor associated antigen, with the expectation that the T cells will actively target and selectively kill cells expressing a specific cancer antigen.
  • CRS cytokine release syndrome
  • Immunotherapy toxicities for example CAR T-cell associated toxicities, primarily involve an exaggerated response from T-cell activation, which involves release of a broad range of cytokines led in part by IL-Ib and TNFa.
  • the specific pathophysiological mechanism is not known although the 2nd wave of cytokines, in particular IL-6 activated by IL-Ib, appears to result in aberrant activation of the vascular endothelial system (Hay 2017, Santomasso 2018,
  • CAR T-cells do not directly produce IL-6, and monocyte-derived IL-Ib is strongly implicated in driving IL-6 and the overall CRS and neurotoxicity due to CAR T-cells (Norelli 2018; Giavridis 2018).
  • IL-6 levels nor CRS are required for an effective antitumor response (Titov 2018) to CAR-T therapy. Therefore, treatments that reduce IL-Ib and/or IL-6 driven inflammation, will not reduce the effectiveness of CAR-T therapy while at the same time reducing the harmful effects of CRS and/or neurotoxicity.
  • tocilizumab The IL-6 receptor antagonist, tocilizumab, is the only currently approved agent for the treatment of CRS. Evidence to date suggests that treatment of CRS with tocilizumab does not affect CAR T-cell efficacy (Singh 2017). However, tocilizumab, an injectable antibody, is in and of itself associated with a number of adverse effects.
  • Neurotoxicity is a second complication that presents as an encephalopathy and may or may not include aphasia and is somewhat distinct from CRS (Guitierrez 2018; Santomasso 2018; Gust 2017; Titov 2018).
  • CRS Cerebral Reactive protein
  • Autopsies from patients who died from neurotoxicity showed disrupted endothelium with reactive microglia in a perivascular distribution (Gust 2017; Echeverry 2019).
  • CAR T-cells infiltrate the brain, but the presence of CAR T-cells in the brain has not correlated with severity of neurotoxicity (Gust 2017; Echeverry 2019).
  • the IL-6 inhibitor tocilizumab has been used to ameliorate neurotoxicity but has been less effective at reversing symptoms of neurotoxicity than symptoms of CRS (Neelapu 2017; Santomasso 2018). Tocilizumab does not readily penetrate the central nervous system and has been reported to increase serum IL-6 concentration by interfering with IL-6 clearance through uptake in peripheral tissues (Neelapu 2017; Echeverry 2019). [0024] Therefore, there is a need for additional therapies for CRS and/or neurotoxicity, and to more precisely target therapies for CRS and/or neurotoxicity to those subjects who will derive a therapeutic benefit, which are provided by the instant disclosure.
  • the present invention is based upon the discovery that inflammation, such as that caused by an overproduction of IL-1, is associated with an increased risk of developing CRS and neurotoxicity in response to immunotherapy, and that specific IL-1 genotype patterns stratify subjects into groups relating to their member’s likelihood of over-producing IL-1. It is thus possible to specifically target subjects who have high levels of inflammation and who are at risk of developing, or who have developed CRS or neurotoxicity for treatment with IL-1 inhibitors, IL-6 inhibitors, and other therapies.
  • Subjects can be stratified into one of two IL-1 genotype patterns, i.e., positive or negative, based upon their complex IL-1 genotype for three or five single nucleotide polymorphisms (SNPs) in the IL-1 locus.
  • SNPs single nucleotide polymorphisms
  • a subject having an uncommon complex IL-1 genotype not exemplified in Tables 1-3 is considered herein as having an IL-1 genotype pattern of “Negative”.
  • a subject may be stratified into an IL-1 genotype pattern by the SNP loci listed in Tables 1-3 and/or SNP loci in linkage disequilibrium (LD), e.g., 80% LD, with the SNP loci listed in Tables 1-3.
  • LD linkage disequilibrium
  • a subject of certain racial/ethnic groups may be stratified into an IL-1 genotype pattern based upon five SNP loci listed in Table 1.
  • Other racial/ethnic groups may require three SNP loci (as in Table 2 or Table 3) to be stratified into an IL-1 genotype pattern. Differences in the frequencies or even the absence of a specific SNP in certain racial/ethnic groups may require the inclusion of additional informative SNPs.
  • the three SNPs disclosed in Table 2 are able to stratify Caucasian populations but may fail to accurately stratify Asian populations.
  • the methods comprise obtaining information regarding the subject’s single nucleotide polymorphism (SNP) alleles for each of the rsl7561 polymorphic locus, the rsl6944 polymorphic locus and the rs 1143634 polymorphic locus. In some embodiments, the methods further comprise obtaining information regarding the subject’s SNPs at the rs 1143623 polymorphic locus and the rs4848306 polymorphic locus.
  • SNP single nucleotide polymorphism
  • the methods comprise obtaining information regarding the subject’s single nucleotide polymorphism (SNP) alleles for: (i) each of the rsl7561 polymorphic locus, the rsl6944 polymorphic locus and the rsl 143634 polymorphic locus; (ii) each of the rsl6944 polymorphic locus, the rsl 143623 polymorphic locus and the rs4848306 polymorphic locus; or (iii) each of the rsl7561 polymorphic locus, the rsl6944 polymorphic locus the rsl 143634 polymorphic locus, the rsl 143623 polymorphic locus and the rs4848306 polymorphic locus.
  • SNP single nucleotide polymorphism
  • a subject can be diagnosed as IL-1 positive if the subject has an IL-1 genotype pattern that is the same as any of: T/T or T/G at rsl7561, C/C at rsl6944 and T/T/ or T/C at rsl 143634; G/G at rsl7561, C/C at rsl6944 and C/C, T/T, C/T or T/C at rsl 143634; G/G, T/T, G/T or T/G at rsl7561, C/C at rsl6944 and C/C at rsl 143634; and T/T or T/G at rsl7561, C/T atrsl6944 and T/T or T/C at rsl 143634.
  • a subject can be diagnosed as IL-1 positive if the subject has an IL-1 genotype pattern that is the same as any of: C/C, T/T, C/T or T/C at rs4848306, G/G at rsl 143623, C/C at rs 16944; C/C or C/T at rs4848306, G/G at rsl 143623, C/T at rsl6944; C/C atrs4848306, C/G at rsl 143623, C/T at rsl 6944; or C/C at rs4848306, G/G at rsl 143623, T/T atrsl6944.
  • a subject can be diagnosed as IL-1 positive if the subject has an IL-1 genotype pattern that is the same as any of: (i) T/T or T/G at rsl7561, C/C, T/T, C/T or T/C at rs4848306, G/G at rsl 143623, C/C at rsl6944 and T/T or T/C at rsl 143634; (ii) G/G at rsl7561, C/C, T/T, C/T or T/C at rs4848306, G/G at rsl 143623, C/C at rs!6944 and C/C, T/T, C/T or T/C at rsl 143634; (iii) G/
  • the disclosure provides methods to unambiguously identify a subject as IL-1 positive or IL-1 negative using haplotype pairs determined from a survey of naturally occurring haplotypes.
  • the methods of the instant disclosure are able to determine whether a subject is IL-1 positive or IL-1 negative without recourse to statistical models that may not be applicable to all populations.
  • the 5 SNP-based haplotype pairs of the instant disclosure have been analyzed relative to actual tissue fluid levels of IL-Ib protein for more than 900 subjects carrying all of the 10 possible haplotype pairs. Additional populations have been analyzed for specific diseases.
  • haplotype pairs of the instant disclosure identify a subject’s specific IL- 1 haplotype pair and define that subject as one who will produce high or lower levels of IL-Ib when challenged.
  • the inventors have identified 3 haplotype pairs that are predictably high producers of IL-Ib and 3 pairs that are predictably lower producers of IL-Ib and 4 pairs that are somewhere in the middle.
  • the high IL-1 producing haplotype pairs chronically produce approximately 30% higher tissue levels than the 3 lower producers.
  • haplotype context is required for the different functional SNPs working together to regulate transcription of the IL1B gene in response to complex activation of transcription.
  • the haplotypes of the instant disclosure are unambiguously determined from the composite genotype of the subject.
  • Routine mathematical projections used in genotyping are based upon certain assumptions about the general population that may be influenced in the individual due to ancestry of the population from which they come. That means that for almost any place in North America, South America, and Europe, the admixture must be considered and therefore modifies the accuracy of the projection.
  • the ability to unambiguously define the two haplotypes carried by a specific subject provides greater precision in identifying which two haplotypes are carried by that subject. That capability exists because out of 8 possible haplotypes from 3 functional SNPs assayed, only 4 of the 8 are actually observed in nature across all major racial populations. However, these haplotypes are observed in different frequencies in different populations. For example, one haplotype, termed B4 (Rogus et al., 2008), accounts for 6% of Caucasian haplotypes in the IL1 promoter, while the B4 haplotype accounts for 46% of haplotypes carried by subjects of African ancestry.
  • B4 Rogus et al., 2008
  • the other two SNPs add further information about the biologic activity of the subject’s IL-1 transcription rates when cells are activated. That provides, in some racial populations, a substantially different assessment of the subject’s IL-1 biologic activity than one may derive from nonfunctional patterns that may be generated using standard mathematical formula.
  • non-functional SNPs, rsl7561 and rsl 143634 are also associated with inflammatory biomarkers.
  • carriage of both minor alleles at rsl7561 and rsl 143634 is found in only approximately 35% of the population.
  • the minor alleles are found in 84% of the pro-inflammatory haplotype pairs B1/B3, B3/B3, B2/B3, and B3/B4 identified in Rogus et al. (2008).
  • Adding genotype information from rs!7561 and rsl 143634 to genotyping at rs4848306, rsl 143623 and rs!6944, and classifying the 5 SNP haplotype pairs of the instant invention, as shown in Table 1 allows, for the first time, for the successful stratification of IL-1 haplotype pairs that are common in populations beyond those that are predominantly Caucasian, such as African-American populations.
  • the 5 SNP haplotype patterns of the instant disclosure account for differences in ancestry to a greater degree than previous studies.
  • the set of patterns that include 5 SNPs of the instant disclosure represent additional ancestry context that goes beyond the IL-Ib haplotype.
  • the 5 SNP test of the instant invention provides more refined information about how IL- 1 haplotype pairs translate into higher or lower IL-Ib production across all major racial populations.
  • a subject at risk of CRS and neurotoxicity for example a subject with a disease for which immunotherapy is recommended as a treatment, will provide or has provided a biological sample comprising a nucleic acid.
  • Single nucleotide polymorphism (SNP) alleles in the isolated nucleic acid for each of the, at least 3, or 5 polymorphic loci identified in Tables 1-3, or polymorphic loci in linkage disequilibrium to the polymorphic loci identified in Tables 1-3 will be detected by any method known in the art and a composite IL-1 genotype will be determined. From the determined composite IL-1 genotype, a positive or negative IL-1 genotype pattern will be determined based on the information disclosed in Tables 1-3.
  • the disclosure provides methods of reducing a risk of, preventing, or treating cytokine release syndrome (CRS) or neurotoxicity induced by immunotherapy, comprising (a) identifying a subject with a disease with a recommended course of treatment comprising an immunotherapy; (b) obtaining information regarding the subject’s single nucleotide polymorphism (SNP) alleles for (i) each of the rsl7561 polymorphic locus, the rsl6944 polymorphic locus and the rs 1143634 polymorphic locus; (ii) each of the rs 16944 polymorphic locus, the rs 1143623 polymorphic locus and the rs4848306 polymorphic locus; or (iii) each of the rsl7561 polymorphic locus, the rsl6944 polymorphic locus the rsl 143634 polymorphic locus, the rsl 143623 polymorphic locus and the rs48484848
  • the disclosure provides methods of reducing the risk of developing CRS and/or neurotoxicity induced by immunotherapy, preventing the development of CRS and/or neurotoxicity induced by immunotherapy, treating CRS and/or neurotoxicity that has been induced by immunotherapy, or reducing a sign or a symptom of CRS and/or neurotoxicity that has been induced by immunotherapy comprising administering inflammation inhibitors to subjects diagnosed as IL-1 positive using the compositions and methods described herein.
  • symptom is defined as an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the subject experiencing the symptom, but may not easily be noticed by others. Others are defined as non- health-care professionals.
  • signs are also defined as an indication that something is not right in the body. But signs are defined as things that can be seen by a doctor, nurse, or other health care professional.
  • CRS is a potentially life-threatening condition that occurs with many types of immunotherapies.
  • CRS is caused by a large, rapid release of cytokines into the blood by immune cells that are affected by the immunotherapy.
  • Symptoms of cytokine release syndrome include, but are not limited to, fever, nausea, headache, rash, rapid heartbeat (tachycardia), low blood pressure, trouble breathing, tachypnea (fast, shallow breathing), hypoxia (inadequate oxygen supply to one or more regions of the body, or the whole body), hypotension (low blood pressure), coagulopathy (impaired clotting), hypoalbuminemia (abnormally low blood albumin), hypoproteinemia (abnormally low blood protein), respiratory failure (low blood oxygen, high blood CO2), refractory shock (lethal cardiovascular failure) and multi-organ failure.
  • CRS can be mild (e.g., mild fever and rash), or severe and life threatening.
  • CRS typically develops within two days of immunotherapy, although onset of CRS can be significantly delayed, for example by 10-12 days or more.
  • any one or more of the symptoms of CRS can be reduced or prevented by the methods described herein.
  • the methods of the disclosure can reduce or prevent fever, nausea, headache, rash, tachycardia, low blood pressure, trouble breathing, tachypnea, hypoxia, hypotension, coagulopathy, hypoalbuminemia, hypoproteinemia, respiratory failure, refractory shock, multi-organ failure, or a combination thereof, associated with immunotherapy induced CRS in a subject.
  • Neurotoxicity is a potentially life-threatening condition that occurs with many types of immunotherapies. For example, 40% of patients undergoing CAR-T therapy will develop neurological complications.
  • the neurotoxicity is associated with CRS.
  • the neurotoxicity is not associated with CRS.
  • Neurotoxicity frequently manifests as encephalopathy. The encephalopathy can occur with expressive or receptive aphasia, i.e. loss of ability to produce and/or understand language.
  • Signs and symptoms of neurotoxicity include, but are not limited to encephalopathy, aphasia, delirium, tremor, seizure activity, status epilepticus, obtundation, increased intracranial pressure, cerebral edema, brain hernia or a combination thereof.
  • Methods of measuring signs and symptoms of neurotoxicity will be apparent to the person of ordinary skill in the art. Methods include screening to assess the degree of aphasia and obtundation, inserting a pressure sensitive probe through the skull to measure intracranial pressure, cranial computed tomography to visualize cerebral edema, and electroencephalograms to measure seizure activity.
  • Neurotoxicity frequently manifests about 5 days following immunotherapy. However, symptoms of neurotoxicity can manifest as early as 2 days after immunotherapy and be delayed up to 11 or more days following immunotherapy.
  • Cytokines are small proteins that are secreted by cells into the circulatory system, and act through receptors to modulate cellular behavior. Cytokines include pro-inflammatory cytokines secreted by cells of the immune system, for example IL-la, IL-Ib, TNFa and IL-6. When large numbers of white blood cells are activated and release pro- inflammatory cytokines, this cytokine release can lead to CRS and/or neurotoxicity.
  • the one or more cytokines comprises interleukin- 1 (IL-1), interleukin-2 (IL-2), interferon gamma (IFNy), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNFa), monocyte chemoattractant protein- 1 (MCP-1), interleukin 6 signal transducer (gpl30), Fms-related tyrosine kinase 3 ligand (Flt3L), C-X3-C motif chemokine ligand 1 (CX3CL1) or colony stimulating factor 2 (CSF).
  • the IL-1 cytokine is IL- la or IL-Ib.
  • the methods further comprise measuring at least one biomarker indicating that the subject is undergoing a broad release of cytokines.
  • the at least on biomarker is selected from the group consisting of interleukin- 1 (IL-1), interleukin-2 (IL-2), interferon gamma (IFNy), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNFa), monocyte chemoattractant protein- 1 (MCP-1), interleukin 6 signal transducer (gpl30), Fms-related tyrosine kinase 3 ligand (Flt3L), C-X3-C motif chemokine ligand 1 (CX3CL1) or colony stimulating factor 2 (CSF).
  • IL-1 interleukin- 1
  • IL-2 interleukin-2
  • IFNy interferon gamma
  • IL-5 interleukin 5
  • IL-6 interleukin 6
  • IL-10 interleukin 10
  • TNFa tumor necrosis factor alpha
  • MCP-1 mon
  • a sign, or biomarker, of CRS and/or neurotoxicity comprises an elevated level of at least one cytokine.
  • the at least one cytokine is elevated at least 50X, at least 100X, at least 150X, at least 200X, at least 250X or at least 350X compared to the level of the at least one cytokine in a subject who does not have CRS and/or neurotoxicity.
  • the sign of CRS comprises an elevated level of at least two cytokines.
  • the at least two cytokines are elevated at least 25X, at least 50X, at least 75X, at least 100X, at least 125X, at least 150X, at least 175X or at least 200X compared to the level of the at least two cytokines in a subject who does not have CRS and/or neurotoxicity.
  • the sign of CRS comprises an elevated level of at least one cytokine, at least two cytokines, at least three cytokines, at least 4 cytokines, at least 5 cytokines, at least 6 cytokines, at least 7 cytokines, at least 8 cytokines, at least 9 cytokines or at least 10 cytokines.
  • Levels of cytokines in the subject with CRS and/or neurotoxicity can be compared to levels of cytokines in a subject, e.g. before the administration of the immunotherapy associated with CRS and/or neurotoxicity.
  • levels of cytokines in the subject with CRS and/or neurotoxicity can be compared to levels of cytokines in a healthy subject without CRS and/or neurotoxicity, or reference levels of cytokines known in the art to be within the normal range for a healthy subject without CRS and/or neurotoxicity.
  • administering an inflammation inhibitor to a subject who is IL-1 positive and has CRS and/or neurotoxicity reduces a level of a cytokine in the subject.
  • the level of the pro-inflammatory cytokine is reduced at least about IX, 2X, 3X, 4X, 5X, 10X, 20X, 30X, 40X, 50X, 60X, 70X, 80X, 90X, 100X, 125X, 150X, 175X, 200X, 225X, 250X, 275X or 300X.
  • administering an inflammation inhibitor to the subject reduces a level of at least one cytokine, at least two cytokines, at least three cytokines, at least 4 cytokines, at least 5 cytokines, at least 6 cytokines, at least 7 cytokines, at least 8 cytokines, at least 9 cytokines or at least 10 cytokines.
  • the cytokine or cytokines are selected from the group consisting of interleukin- 1 (IL-1 a and IL-Ib), IL-2, IFNy, IL-5, IL-6, IL-10, TNFa, MCP-1, gpl30, Flt3L, CX3CL1 and CSF.
  • cytokines levels of cytokines can be measured, for example by enzyme-linked immunosorbent assay (ELISA), bead based systems (e.g. Luminex), the Cytokine Bead Array (Pharmingen) and array-based systems (e.g., EMD Biosciences’ ProteoPlex).
  • ELISA enzyme-linked immunosorbent assay
  • bead based systems e.g. Luminex
  • the Cytokine Bead Array e.g., EMD Biosciences’ ProteoPlex
  • CRP C reactive protein
  • CRP is a blood protein marker of inflammation. In subjects without inflammation, CRP is typically below about 3 mg/L.
  • a level of CRP in the blood is greater than or equal to 10 mg/L, 20 mg/L, 30 mg/L, 40 mg/L, 50 mg/L, 60 mg/L, 70 mg/L, 80 mg/L, 90 mg/L, 100 mg/L, 110 mg/L, 120 mg/L, 130 mg/L, 140 mg/L, 150 mg/L, 160 mg/L, 170 mg/L, 180 mg/L, 190 mg/L, 200 mg/L, 210 mg/L, 220 mg/L, 230 mg/L, 240 mg/dL, 250 mg/L, 260 mg/L, 270 mg/L, 280 mg/L, 290 mg/L, 300 mg/L, 350 mg/L, 400 mg/L,
  • Levels of CRP in the subject with CRS and/or neurotoxicity can be compared to levels of CRP in a subject, e.g. before the administration of the immunotherapy associated with CRS and/or neurotoxicity.
  • levels of CRP in the subject with CRS and/or neurotoxicity can be compared to levels of CRP in a healthy subject without CRS and/or neurotoxicity, or reference levels of CRP known in the art to be within the normal range for a healthy subject without CRS and/or neurotoxicity.
  • administering an inflammation inhibitor to a subject who is IL-1 positive and has CRS and/or neurotoxicity reduces a level of CRP.
  • the level of CRP is reduced at least about IX, 2X, 3X, 4X, 5X, 10X, 20X, 30X, 40X or 50X.
  • Methods of measuring concentrations of CRP will be known to the person of ordinary skill in the art and include ELISA, radial immunodiffusion (RID), electroimmunoassay (EIA), rapid immunodiffusion, visual agglutination, immunoturbidimetry (IT), and laser nephelometry (LN).
  • the present invention allows for optimal treatment for a subject based upon his/her IL-1 genotype pattern.
  • this treatment can include an inflammation inhibitor to lower levels of inflammation.
  • the inflammation inhibitor can be, for example, an IL-1 or IL-6 inhibitor.
  • IL-1 inhibitors such as IL-Ib inhibitors
  • IL-1 inhibitors in general suppress the IL-1 mediated innate immune response and increase the risk of fatal infection.
  • treatment with an IL-1 inhibitor is more likely to result in immunosuppression and infection.
  • subjects with higher IL-1 driven inflammation are more likely to benefit from anti-IL-1 treatment, and less likely to experience suppression of innate immunity with the associated risk of infection.
  • the disclosure features methods for predicting the risk of and preventing CRS and neurotoxicity in response to immunotherapy in a human subject comprising diagnosing a subject as IL-1 positive using the SNP genotypes described herein, and optionally administering an inflammation inhibitor, for example an IL-1 inhibitor or IL-6 inhibitor, if the subject is diagnosed as IL-1 positive to reduce inflammation and thereby reduce the risk of developing CRS and neurotoxicity.
  • an inflammation inhibitor for example an IL-1 inhibitor or IL-6 inhibitor
  • the disclosure also features methods for treating CRS and neurotoxicity in a subject in need thereof comprising diagnosing a subject as IL-1 positive using the SNP genotypes described herein and administering an inflammation inhibitor such as an IL- 1 or IL-6 inhibitor to the subject.
  • Subjects likely to derive more benefit from an inflammation inhibitor such as an IL- la, IL-Ib inhibitor or IL-6 inhibitor; subjects with a positive IL-1 genotype pattern who may respond favorably to lower levels of an inflammation inhibitor than subjects of a negative IL-1 genotype pattern; subjects who should be on an inflammation inhibitor earlier than others because their genotype pattern is more aggressive; and subjects with a IL-1 dominant CRS and/or neurotoxicity predictably responsive to inflammation inhibitors but not to other agents which have different modes of action.
  • an inflammation inhibitor such as an IL- la, IL-Ib inhibitor or IL-6 inhibitor
  • Modulators of IL-1 biological activity can comprise any type of compound, including a protein, peptide, peptidomimetic, lipid, small molecule, or nucleic acid.
  • a modulator may be a botanical, or an extract of a botanical.
  • a modulator may indirectly act upon an IL-1 gene in that the modulator activates or represses a gene or protein that, in turn or ultimately, acts upon the IL-1 gene.
  • the term “ultimately” is meant that the modulator acts upon a first gene or protein and the first gene or protein directly acts upon the IL-1 gene or the first gene or protein acts upon a second gene or protein which directly (or indirectly) acts upon the IL-1 gene.
  • Such indirect gene regulation is well known in the art.
  • a modulator that acts upstream to the IL-1 gene is useful in the present invention.
  • a modulator that acts upstream of the IL-1 gene is Aldeyra’s NS2 compound which traps excess free aldehydes, which are known to activate a number of intracellular inflammatory factors including NF-kB, a prominent protein in the inflammatory response.
  • Aldeyra NS2 compound which traps excess free aldehydes, which are known to activate a number of intracellular inflammatory factors including NF-kB, a prominent protein in the inflammatory response.
  • Ionis Pharmaceutical IONIS -APO(a)-L RX
  • Arrowhead s ARC-LPA , which reduces Lp(a) levels that would be expected to activate arterial wall macrophages to produce IL-Ib.
  • a modulator may act downstream of the IL-1 gene by directly or indirectly affecting a gene or protein that operates in parallel to IL-1 in an inflammatory cascade.
  • An agonist can be a protein or derivative thereof having at least one bioactivity of the wild-type protein, e.g., receptor binding activity.
  • An agonist can also be a compound that upregulates expression of a gene or which increases at least one bioactivity of a protein.
  • An agonist can also be a compound which increases the interaction of a polypeptide with another molecule, e.g., a receptor.
  • An inhibitor (sometimes referred to as an antagonist) can be a compound which inhibits or decreases the interaction between a protein and another molecule, e.g., blocking the binding to receptor, blocking signal transduction, and preventing post-translation processing (e.g., IL-1 converting enzyme (ICE) inhibitor).
  • ICE IL-1 converting enzyme
  • An inhibitor can also be a compound that downregulates expression of a gene or which reduces the amount of a protein present.
  • the inhibitor can be a dominant negative form of a polypeptide, e.g., a form of a polypeptide which is capable of interacting with a target.
  • Inhibitors include nucleic acids (e.g., single (antisense) or double stranded (triplex)
  • DNA or PNA and ribozymes DNA or PNA and ribozymes), protein (e.g., antibodies) and small molecules that act to suppress or inhibit IL-1 transcription and/or protein activity.
  • protein e.g., antibodies
  • small molecules that act to suppress or inhibit IL-1 transcription and/or protein activity.
  • An anti-inflammatory drug refers to any agent or therapeutic regimen (including a pharmaceutical, biologic, nutraceutical, and botanical) that prevents or postpones the development of or alleviates a symptom of the particular disease, disorder, or condition that involved an inflammatory process in the subject.
  • the drug can be a polypeptide, peptidomimetic, nucleic acid or other inorganic or organic molecule, a “small molecule,” vitamin, mineral, or other nutrient.
  • the drug modulates the production of the active IL-Ib or IL-1 a polypeptides, or at least one activity of an IL-1 polypeptide, e.g., interaction with a receptor, by mimicking or potentiating (agonizing) or inhibiting (antagonizing) the effects of a naturally-occurring polypeptide.
  • An anti-inflammatory drug also includes, but is not limited to, anti-cholesterol drugs (e.g., statins), diabetes mellitus drugs, drugs that treat acute syndromes of the heart and vascular system (e.g., a cardiovascular disease), and arthritis.
  • Non-limiting examples of anti-inflammatory agents that modulate or inhibit IL-1 biological activity useful in the present invention are listed in Table 4. These agents generally have a mode of action that includes modulation of IL-1 gene expression, modulation of inflammasomes, IL-1 receptor blocking agents, and agents that bind IL-Ib or IL-1 a to inhibit attachment to the active receptor. IL-1 blocking agents may also indirectly target IL-1 by blocking key activators of IL-1 gene expression.
  • IL-1 inhibitors of the disclosure can inhibit IL-Ib, IL-1 a, or both IL-Ib and IL-1 a.
  • Exemplary IL-Ib inhibitors include ABT-981, Anakinra, Anakinra Biosimilar, APX-
  • the IL-Ib inhibitor is Canakinumab or a derivative thereof.
  • Exemplary IL-1 a inhibitors include Bermekimab, ABT-981, Isunakinra, AC-701, Sairei-To, Can-04, XL- 130, a MABpl antibody and Givinostat.
  • the IL-1 a inhibitor is Bermekimab or a derivative thereof.
  • the IL-1 inhibitor comprises an inflammasome modulator.
  • the inflammasome modulator can cross the blood brain barrier.
  • the inflammasome modulator comprises Diacerein, Sarei-To, Binimetinib, Can- 04, Rilonacept, XL- 130, Givinostat or Ammonium trichloro-tellurate.
  • the inflammation inhibitor is an interleukin 6 (IL-6) inhibitor.
  • IL-6 is a multifunctional cytokine that mediates cytokine release syndrome.
  • IL-6 inhibitors include inhibitors that target IL-6 and the interleukin 6 receptor (IL6R), for example antibodies, biologies or small molecules that bind to IL-6 or IL6R.
  • Exemplary IL-6 inhibitors are shown in Table 5 below: [0082] Table 5.
  • the IL-6 inhibitor is selected from the group consisting of tocilizumab, olokizumab, sirukumab, sarilumab, clazakinumab, siltuximab, elsilimomab, levilimab, and gerilimzumab.
  • IL-6 inhibitor is Tocilizumab, Siltuximab, Olokizumab, Elsilimomab, Sirukumab, Levilimab, ALX-0061, Gerilimzumab, FE301, FM101, sarilumab, clazakinumab or CPSI-2364.
  • any of the agents listed in Table 4 and Table 5 may be used in the present invention.
  • the subject may be administered one or more agents of Table 4 or 5 at a higher dose or at a lower dose (e.g., the dose of a single treatment and/or a daily dose comprising one or more single treatments) depending on his/her IL-1 genotype.
  • one or more clinical indicators may also be measured, such as levels of C-reactive protein (CRP) or cytokines.
  • the cytokines comprise one or more cytokines selected from the group consisting of interleukin- 1 (IL-1), interleukin -2 (IL-2), interferon gamma (IFNy), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNFa), monocyte chemoattractant protein- 1 (MCP-1), interleukin 6 signal transducer (gpl30), Fms- related tyrosine kinase 3 ligand (Flt3L), C-X3-C motif chemokine ligand 1 (CX3CL1) or colony stimulating factor 2 (CSF).
  • the subject may be not given the particular agent depending on his/her IL-1 genotype pattern and optionally, status of one or more clinical indicators, and instead may be administered a different agent.
  • agents other than those listed in Table 4 may be used in the present invention.
  • an alternate agent having a mode of action (MOA) similar to or identical to a drug listed in Table 4 or 5 may be provided instead of or in addition to the agents listed in Table 4 or 5.
  • MOA mode of action
  • One skilled in the art is able to determine alternate agents that are useful in the present invention.
  • a subject may be administered one or more agents from Table 4 or 5 or one or more alternate agents having a MO A similar to or identical to an agent listed in Table 4 or 5 at the standard therapeutic dose.
  • An agent may be given at a dose lower than the standard therapeutic dose, e.g., 99%, 95%, 90%, 85%, 80%, 75%, 70%, 60%, 50%, 40%, 30%, 20%, 15%, 10%, or 5%, and any percentage in between lower than the standard therapeutic dose.
  • a agent may be given at a dose higher than the standard therapeutic dose, e.g., 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, 175%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1000%, 2000%, or more, and any percentage in between higher than the standard therapeutic dose. For example, if a standard therapeutic dose is 10 mg per day, a subject may be given 7 mg per day as a lower than standard therapeutic dose or 13 mg per day as a higher than standard therapeutic dose.
  • the inflammation inhibitor is formulated as an aerosol. Aerosols can be inhaled into the lungs, and are thus able to target inflammation inhibitors to inflamed lung tissues. In some embodiments, the aerosol is administered as a nasal spray.
  • the IL-Ib inhibitor is Canakinumab or a derivative thereof.
  • Canakinumab is administered to the subject at a dose of 25 mg to 300 mg.
  • the subject weighs less than 40 kg and the Canakinumab is administered to the subject at a dose of 2 mg/kg or 4 mg/kg.
  • the Canakinumab can be administered to the subject at a dose of 150 mg or 300 mg.
  • Canakinumab is administered parenterally. Parenteral administration includes intravenous injection, intravenous infusion, intramuscularly, via intrapulmonary administration or subcutaneously.
  • the IL-la inhibitor is Bermekimab.
  • the Bermekimab is administered at between 3 mg/kg to 20 mg/kg. In some cases, the Bermekimab is administered at 7.5 mg/kg.
  • Parenteral administration includes intravenous injection, intravenous infusion, intramuscularly, via intrapulmonary administration or subcutaneously.
  • administering the inflammation inhibitor to a subject who is IL-1 positive reduces the risk of developing, or prevents the development of, CRS and/or neurotoxicity as a result of an immunotherapy.
  • diagnosing subjects as IL-1 positive and administering inflammation inhibitors prior to the development of immunotherapy-induced CRS and/or neurotoxicity can reduce the risk of developing immunotherapy-induced CRS and/or neurotoxicity.
  • the inflammation inhibitor is administered prior to the immunotherapy.
  • an inflammation inhibitor is administered 1, 2, 3, 4, 5, 6 or 7 days prior to immunotherapy.
  • the inflammation inhibitor is administered in temporal proximity to the immunotherapy.
  • a dose of an inflammation inhibitor is administered in within an hour of an immunotherapy.
  • temporary proximity refers to two or more events that occur close to each other in time. Events that occur within an hour, 3 hours, 6 hours, 12 hours, 18 hours or 24 hours can be said to occur in temporal proximity.
  • the inflammation inhibitor is administered after immunotherapy, but prior to the onset of CRS or neurotoxicity.
  • CRS frequently develops about 2-14 days after immunotherapy, while neurotoxicity frequently develops about 5 days after immunotherapy.
  • a dose of the inflammation inhibitor is administered 1, 2, 3, 4, 5,
  • administering an inflammation inhibitor to a subject who is IL-1 positive and has CRS and/or neurotoxicity reduces the severity of CRS and/or neurotoxicity. In some embodiments, administering an inflammation inhibitor to a subject who is IL-1 positive and has CRS and/or neurotoxicity reduces a sign or a symptom of CRS and/or neurotoxicity. In some cases, a dose of the inflammation inhibitor is administered 1, 2, 3, 4, 5, 6,
  • a dose of the inflammation inhibitor is administered within 30 days of administering the immunotherapy.
  • the disclosure provides methods of treating or preventing CRS and/or neurotoxicity associated with immunotherapy as a course of treatment for a disease or disorder. All immunotherapies that have CRS and/or neurotoxicity as a side effect, and all diseases or disorders comprising immunotherapy as a recommended course of treatment, are within the scope of the instant disclosure. [0096] Exemplary diseases treated by immunotherapies include, but are not limited to, cancers, infections and auto-immune diseases.
  • the disease treated by an immunotherapy comprises cancer.
  • Cancer or “tumor” is intended to include any neoplastic growth in a patient, including an initial tumor and any metastases.
  • the cancer can be of the liquid or solid tumor type.
  • Liquid tumors include tumors of hematological origin, including, e.g., myelomas (e.g., multiple myeloma), leukemias (e.g., Waldenstrom's syndrome, chronic lymphocytic leukemia, chromic myeloid leukemia, acute lymphocytic leukemia, acute myeloid leukemia, other leukemias), and lymphomas (e.g., B-cell lymphomas, non-Hodgkin’s lymphoma,
  • myelomas e.g., multiple myeloma
  • leukemias e.g., Waldenstrom's syndrome, chronic lymphocytic leukemia, chromic myeloid leukemia, acute lymphocytic leukemia, acute myeloid leukemia, other leukemias
  • lymphomas e.g., B-cell lymphomas, non-Hodgkin’s lymphoma
  • Solid tumors can originate in organs, and include cancers such as lung, breast, prostate, ovary, colon, kidney, and liver.
  • cancer cells including tumor cells, refer to cells that divide at an abnormal (increased) rate.
  • Cancer cells include, but are not limited to, carcinomas, such as squamous cell carcinoma, basal cell carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, adenocarcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, undifferentiated carcinoma, bronchogenic carcinoma, melanoma, renal cell carcinoma, hepatoma-liver cell carcinoma, bile duct carcinoma, cholangiocarcinoma, papillary carcinoma, transitional cell carcinoma, choriocarcinoma, semonoma, embryonal carcinoma, mammary carcinomas, gastrointestinal carcinoma, colonic carcinomas, bladder carcinoma, prostate carcinoma, and squamous cell carcinoma of the neck and head
  • the disease treated by an immunotherapy comprises an infection.
  • the infection comprises a viral infection, a fungal infection, or a bacterial infection.
  • the infection can be chronic (slow and persistent, but eventually capable of being cleared by the host), a latent infection or an acute infection.
  • Exemplary viral infections that can be treated by immunotherapies include human immunodeficiency vims (HIV), Epstein-Barr vims (EBV), cytomegalovims (CMV), respiratory syncytial vims (RSV), and Ebola.
  • Exemplary bacterial infections that can be treated by immunotherapies include bacillus anthracis and Clostridium difficile colitis.
  • Exemplary fungal infections that can be treated with immunotherapies include Candida infections.
  • the disease treated by an immunotherapy comprises an autoimmune or inflammatory disease.
  • autoimmune or inflammatory diseases include psoriasis, psoriatic arthritis, asthma, rheumatoid arthritis, axial spondyloarthritis, Crohn’s disease, ulcerative colitis, cardiovascular diseases inflammations of the airways, skin and gastrointestinal tract, organ transplant rejection, ankylosing spondylosis, plaque psoriasis, juvenile idiopathic arthritis, systemic lupus erythematosus and uveitis.
  • Further exemplary disease treated by immunotherapies include Cryopyrin-associated periodic syndrome, haemophilia, cardiovascular disease, hypercholesterolemia, retinopathies, macular degeneration, migraine and cluster headache, multiple sclerosis, paroxysmal nocturnal hemaglobinuria, atypical hemolytic uremic syndrome, transplant rejection, anti-coagulant effects, hemolytic disease of newborns, thrombotic thrombocytopenic purpura, thrombosis, X-linked hypophosphatemia, idiopathic pulmonary fibrosis and focal segmental flomemlosclerosis.
  • Immunotherapies are therapies aimed at disease prevention or treatment through the stimulation of the subject’s own immune system.
  • Exemplary immunotherapies include antibody-based therapies, adoptive cell therapies, oncolytic viruses and cancer vaccines.
  • the immunotherapy comprises an antibody therapy.
  • the antibody therapy comprises a monoclonal antibody or a bi-specific antibody.
  • an “antibody” refers to a protein consisting of one or more polypeptides substantially encoded by immunoglobulin genes, fragments of immunoglobulin genes or a functionally equivalent scaffold.
  • the recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as myriad immunoglobulin variable region genes.
  • Light chains are classified as either kappa or lambda.
  • Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
  • a typical immunoglobulin (antibody) structural unit is known to comprise a tetramer.
  • Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD).
  • the N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the terms variable light chain (VL) and variable heavy chain (VH) refer to these light and heavy chains respectively.
  • Antibodies exist as intact immunoglobulins or as a number of well characterized fragments produced by digestion with various peptidases.
  • pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)'2, a dimer of Fab which itself is a light chain joined to VH-CH1 by a disulfide bond.
  • the F(ab)'2 may be reduced under mild conditions to break the disulfide linkage in the hinge region thereby converting the (Fab')2 dimer into a Fab' monomer.
  • the Fab' monomer is essentially a Fab with part of the hinge region (see, Fundamental Immunology, W. E. Paul, ed., Raven Press, N.Y.
  • Antibodies also include single chain antibodies, for example single chain Fv (scFv) antibodies in which a variable heavy and a variable light chain are joined together (directly or through a peptide linker) to form a continuous polypeptide.
  • scFv single chain Fv
  • Antibodies also include single domain antibodies, such as VH and VHH antibodies derived from camelids.
  • Antibodies also include chimeric antibodies, humanized antibodies and antibody conjugates, for example antibodies conjugated to drugs, prodrugs or radioactive isotopes.
  • Antibodies also include polyspecific or bi-specific antibodies, i.e. antibodies capable of targeting and binding to more than one antigen.
  • an “antigen-binding site” or “binding portion” refers to the part of an immunoglobulin molecule that participates in antigen binding.
  • the antigen binding site is formed by amino acid residues of the N-terminal variable (“V”) regions of the heavy (“H”) and light (“L”) chains.
  • V N-terminal variable
  • L light
  • Three highly divergent stretches within the V regions of the heavy and light chains are referred to as “hypervariable regions” which are interposed between more conserved flanking stretches known as “framework regions” or “FRs”.
  • FR refers to amino acid sequences that are naturally found between and adjacent to hypervariable regions in immunoglobulins.
  • the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three- dimensional space to form an antigen binding “surface”. This surface mediates recognition and binding of the target antigen.
  • the three hypervariable regions of each of the heavy and light chains are referred to as “complementarity determining regions” or “CDRs” and are characterized, for example by Rabat et al. Sequences of proteins of immunological interest, 4th ed. U.S. Dept. Health and Human Services, Public Health Services, Bethesda, Md. (1987).
  • the terms “recognizing” and “targeting” an antigen refer to the non- covalent interactions of the type which occur between an immunoglobulin molecule and an antigen for which the immunoglobulin is specific.
  • the strength or affinity of immunological binding interactions can be expressed in terms of the dissociation constant (Kd) of the interaction, wherein a smaller Kd represents a greater affinity.
  • Immunological binding properties of selected polypeptides can be quantified using methods well known in the art. One such method entails measuring the rates of antigen-binding site/antigen complex formation and dissociation, wherein those rates depend on the concentrations of the complex partners, the affinity of the interaction, and on geometric parameters that equally influence the rate in both directions.
  • both the “on rate constant” (K on ) and the “off rate constant” (K 0ff ) can be determined by calculation of the concentrations and the actual rates of association and dissociation.
  • the ratio of K 0ff /K 0n enables cancellation of all parameters not related to affinity and is thus equal to the dissociation constant Kd. See, generally, Davies et al. Ann. Rev. Biochem., 59: 439-473 (1990).
  • a variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies specifically immunoreactive with a protein.
  • Exemplary, but non-limiting, disorders and antibodies associated with CRS and/or neurotoxicity include, but are not limited to alemtuzumab for multiple sclerosis, muromonab- CD3 (transplant rejection), rituximab (rheumatoid arthritis and cancer), obinutuzumab (Chronic lymphatic leukemia), brentuximab (Hodgkin lymphoma), dacetuzumab (lymphoma) and nivolumab (immune checkpoint inhibitor for cancer).
  • the antibody therapy comprises rituximab, obinutuzumab, brentuximab, dacetuzumab or nivolumab.
  • the antibody therapy comprises an antibody from table 4.
  • the antibody is a bi-specific antibody.
  • Bi-specific antibodies are antibodies that contain two different antigen-binding sites in a single molecule.
  • the bi-specific antibody comprises a bi-specific T-cell engager antibody.
  • Bi-specific T-cell engager antibodies are a class of bi-specific antibodies that direct T- cells to cancer cells.
  • An exemplary Bi-specific T-cell engager antibodies comprises two antigen binding domains, for example two different ScFvs, one of which targets a cancer antigen and the other of which targets an antigen on a T cell.
  • the bi-specific T-cell engager antibody mimics physiological processes observed during T cell targeting of cancer cells, and brings the T cells of the subject into proximity with the cancer cells, facilitating T cell cytotoxic activity and killing of cancer cells.
  • Bi-specific T-cell engager antibodies can recognize and bind to T cells through binding of proteins on the T cell surface, for example members of the T cell receptor (TCR) complex.
  • a bi-specific T-cell engager antibody comprises a first antigen binding domain that recognizes a cancer associated antigen, and a second antigen binding domain that recognizes a T-cell associated antigen.
  • the cancer associated antigen is selected from the group consisting of Mesothelin, prostate stem cell antigen (PSCA), carcinoembryonic antigen (CEA), erb-b2 receptor tyrosine kinase 2 (HER2), mucin 1 (MUC1), epidermal growth factor receptor variant III (EGFRvIII), glypican-3, CD19 molecule (CD19), epithelial cell adhesion molecule (EpCAM), Claudin 18.2, CD70 molecule (CD70), Lewis Y antigen, interleukin 3 receptor subunit alpha (CD123), disialoganglioside GD2 (GD2), prostate specific membrane antigen (PSMA), epidermal growth factor receptor (EGFR), interleukin 13 receptor subunit alpha 2 (IL13Ra2), EPH receptor A2 (EphA2), prominin 1 (CD133), Transforming Growth Factor Alpha (TGFA), TIE portion of TGFA (TIE), CD33 molecule (CD33), T
  • the T-cell associated antigen is selected from the group consisting of CD3g molecule (CD3 gamma), CD3d molecule (CD3 delta), CD3e molecule (CD3 epsilon), and CD247 (CD3 zeta).
  • Bi-specific T cell engager (BiTE) antibodies are selected from the group consisting of blinatumomab, solitomab, AMG 330, AMG420, AMG 562, AMG 427 and mozunetuzumab.
  • the immunotherapy comprises an adoptive cell therapy.
  • adoptive cell therapies are therapies in which immune cells, such as T cells or B cells, or progenitor cells thereof, are given to a subject to help the body fight a disease, such as cancer. Such cells may have originated with the subject (autologous adoptive cell therapy), or from another subject (allogeneic adoptive cell therapy).
  • an adoptive cell therapy comprises a chimeric antigen receptor T-cell (CAR-T) therapy, a modified T Cell Receptor T-cell (TCR-T) therapy, or non-genetically modified activated T-cells.
  • CAR-T chimeric antigen receptor T-cell
  • TCR-T modified T Cell Receptor T-cell
  • chimeric antigen receptor T-cell therapy or “CAR-T therapy” refers to treating a disease by administering T-cells expressing a chimeric antigen receptor (CAR), for example a CAR targeting a cancer associated antigen.
  • CAR chimeric antigen receptor
  • a “chimeric antigen receptor” refers to a synthetic receptor consisting of a targeting moiety that is associated with one or more signaling domains in a single fusion molecule.
  • the binding moiety of a CAR consists of an antigen-binding domain of a single-chain antibody (scFv), comprising the light and variable fragments of a monoclonal antibody joined by a flexible linker, although other antigen-binding domains can be used.
  • scFv single-chain antibody
  • binding moieties based on receptor or ligand domains have also been used successfully.
  • the signaling domains for first generation CARs are derived from the cytoplasmic region of the CD3zeta or the Fc receptor gamma chains.
  • First generation CARs have been shown to successfully redirect T-cell cytotoxicity, however, they failed to provide prolonged expansion and anti-tumor activity in vivo.
  • Signaling domains from co- stimulatory molecules including CD28, OX-40 (CD134), and 4-1BB (CD137) have been added alone (second generation) or in combination (third generation) to enhance survival and increase proliferation of CAR modified T cells.
  • CARs have successfully allowed T cells to be redirected against antigens expressed at the surface of tumor cells from various malignancies including lymphomas and solid tumors (Jena, Dotti et al. 2010).
  • modified T cell receptor T-cell therapy or “TCR-T therapy” refers to treating a disease by administering T-cells expressing a T cell receptor of interest, for example a T cell receptor engineered to target a cancer associated antigen.
  • T cell receptor refers to a receptor complex found on the surface of T cells. TCRs are responsible for recognizing antigens bound to major histocompatibility complex molecules.
  • An exemplary TCR comprises TCR alpha and TCR beta subunits, each comprising a variable extracellular domain capable which together are capable of recognizing and binding to antigen-bound MHC, and invariant CD3 delta, epsilon, gamma, and zeta subunits.
  • CARs and TCRs of the disclosure can be engineered to target any number of antigens.
  • the antigen comprises a cancer associated antigen.
  • a cancer associated antigen or “tumor antigen” refers to an antigen produced by a cancer cell.
  • the antigen is selected from the group consisting of glioma- associated antigen, CEA, EGFRvIII, interleukin 11 receptor subunit alpha (IL-llRa), interleukin 13 receptor subunit alpha 1 (IL-13Ra), epidermal growth factor receptor (EGFR), fibroblast activation protein alpha (FAP), CD276 molecule (B7H3),
  • KIT proto-oncogene receptor tyrosine kinase (Kit), carbonic anhydrase 9 (CA-IX), chorionic somatomammotropin hormone 1 (CS-1), mucin-1 (MUC1), BCMA, bcr-abl, HER2, b-human chorionic gonadotropin, alphafetoprotein (AFP), AFK receptor tyrosine kinase (AFK), CD 19 molecule (CD19), interleukin 3 receptor subunit alpha (CD123), cyclin Bl, lectin-reactive AFP, Fos-related antigen 1, adrenoceptor beta 3 (ADRB3), thyroglobulin, EPH receptor A2 (EphA2), MOK protein kinase (RAGE-1), Scm like with four mbt domains 1 (RU1), doublecortin domain containing 2 (RU2), SSX family member 2 (SSX2), A -kinase anchor
  • the antigen is selected from the group consisting of Mesothelin, PSCA, CEA, HER2, MUC1, EGFRvIII, glypican-3, CD 19, EpCAM, Claudin 18.2, CD70, Lewis Y antigen, CD123, GD2, PSMA, EGFR, IL13Ra2, EphA2, CD133, TGFA, TIE, CD33, BCMA, CD22, CD5, VGFR2, CD20, CD4, CD30, MG7, AXL, B7-H3, FRa, cMET, MIC-A, MIC-B, MAGE- A3, MAGE-A4, MAGE-A3/12, MAGE-A3/A6, NY-ESO-1, HPV16-E6, MART-1, gplOO, ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, ULBP6, ROR1, ROR2, TRAIL, PRAME, DR5, DR4, HPV16-E7, WT1, AFP,
  • the CAR or TCR recognizes an antigen that is an epitope from the infectious agent.
  • the antigen comprise a fragment of a bacterial cell wall protein from a bacterial agent, or a viral coat protein from a viral agent.
  • the adoptive cell therapy comprises immune cells that have not been genetically modified.
  • an adoptive cell therapies can comprise expanding and activating a population of T cells before introducing the activated T cells back into the subject. Methods of activating T cells will be known to the person of ordinary skill in the art, and include in vitro stimulation via antigen or agonistic antibodies to TCR.
  • the immunotherapy comprises an oncolytic virus.
  • an “oncolytic virus” is a virus that preferentially infects and kills cancer cells.
  • Oncolytic viruses include natural and genetically modified viruses, such as herpes, adenovirus, vaccinia and vesicular stomatitis virus.
  • Oncolytic viruses can be targeted to tumors via transductional targeting (i.e. selective entry into tumor cells), and non-transductional targeting, for example through the use of tumor specific promoters.
  • the immunotherapy comprises a cancer vaccine.
  • a cancer vaccine refers to a vaccine that treats certain types of cancers. Cancer vaccines deliver cancer antigens to a subject, with the aim of stimulating the subject’s immune cells to target cancer cells expressing the antigen or antigens delivered by the vaccine.
  • the disease or disorder is cancer, multiple sclerosis, infection, such as bacterial, fungal or viral infection, and the methods comprises a standard of care for the disease or disorder.
  • the methods of treating, preventing or reducing the severity of CRS and/or neurotoxicity associated with an immunotherapy, and the immunotherapy for the viral infection can be combined with one or more viral inhibitors.
  • the methods of the disclosure can be combined with one or more retroviral inhibitors such as HIV protease inhibitors.
  • the methods of treating, preventing or reducing the severity of CRS and/or neurotoxicity associated with an immunotherapy, and the immunotherapy for the bacterial or fungal infection can be combined with an antibiotic or anti-fungal agent.
  • the methods of treating, preventing or reducing the severity of CRS and/or neurotoxicity associated with an immunotherapy, and the immunotherapy for cancer can be combined with one or more additional cancer therapies.
  • exemplary cancer therapies include, but are not limited to, surgery, radiation, chemotherapy, antitumor antibiotics, receptor tyrosine kinase inhibitors, mitotic inhibitors, cyclin dependent kinase inhibitors and immune checkpoint inhibitors.
  • a subject with cancer can be administered an immunotherapy, an inflammation inhibitor to treat the CRS and/or neurotoxicity associated with the immunotherapy, and an additional cancer therapy such as chemotherapy.
  • the additional cancer therapy can be administered at the same time as the immunotherapy and/or inflammation inhibitor, prior to administration of the immunotherapy and/or inflammation inhibitor, in temporal proximity to the immunotherapy and/or inflammation inhibitor, or after the immunotherapy and/or inflammation inhibitor.
  • Surgery is a preferred treatment for patients with early stage (e.g., non-metastatic) cancers.
  • Surgery for cancer can involve removal of part or all of the cancer.
  • surgery for breast cancer can involve removal of part or all of the breast.
  • Wedge resections remove only the tumor and a small portion of healthy tissue.
  • the appropriate surgical intervention will depend on the type, position, and stage of the cancer.
  • Surgery is frequently combined with other cancer therapies of the disclosure such as radiation, chemotherapy, antibody therapy and immune checkpoint inhibitors.
  • Radiation therapy can be used to treat cancers of the disclosure.
  • Radiation therapy can be delivered from an external source, such as external beam radiation therapy (EBRT).
  • EBRT external beam radiation therapy
  • radiation can be delivered via an implant placed close to or inside the tumors in the body (internal radiation).
  • An example of the latter sort of therapy is high dose rate (HDR) brachytherapy.
  • HDR high dose rate
  • Radiation is frequently combined with other cancer therapies of the disclosure such as chemotherapy, antibody therapy and immune checkpoint inhibitors. The appropriate radiation therapy will depend on the type, position, and stage of the cancer.
  • Chemotherapies interfere with the ability of cancer cells to grow and divide.
  • Chemotherapies of the disclosure include, but are not limited to, DNA damaging agents such as alkylating agents, antimetabolites, alkaloids, mitotic inhibitors, topoisomerase inhibitors, antitumor antibiotics, tyrosine kinase inhibitors, mTOR inhibitors, a B-Raf inhibitors, EGFR inhibitors, PARP inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, CDK inhibitors or a combination thereof.
  • DNA damaging agents such as alkylating agents, antimetabolites, alkaloids, mitotic inhibitors, topoisomerase inhibitors, antitumor antibiotics, tyrosine kinase inhibitors, mTOR inhibitors, a B-Raf inhibitors, EGFR inhibitors, PARP inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, CDK inhibitors or a combination thereof.
  • Antimetabolites include, for example, folic acid, pyrimidine and purine analogues, and can interfere with the enzymatic reactions in cancer cells.
  • Exemplary antimetabolites include but are not limited to methotrexate and gemcitabine.
  • Alkaloids attack cancer cells during various phases of the cell cycle.
  • Alkaloid chemotherapies include, but are not limited to, vinca alkaloids such as vincristine, vinblastine and vinorelbine, taxanes such as paclitaxel and docetaxel, podophyllotoxins such as etoposide and teniposide and camptothecan analogs such as irinotecan and topotecan.
  • Topoisomerase inhibitors interfere with the action of topoisomerase enzymes, which are critical for successful DNA replication.
  • exemplary topoisomerases include, but are not limited to, irinotecan, topotecan, etoposide, etoposide phosphate and teniposide.
  • Antitumor antibiotics slow or stop the growth of cancer cells.
  • exemplary antitumor antibiotics include doxorubicin, mitoxantrone or bleomycin.
  • Taxanes bind to microtubules and interfere with cancer cell division.
  • Exemplary taxanes include taxol, docetaxel or paclitaxel.
  • Platinum-based agents are important drugs or drug candidates for cancer chemotherapy.
  • exemplary platinum agents comprise cisplatin, oxaliplatin or carboplatin.
  • B-Raf kinase dysregulation has been implicated in a number of cancers, including colorectal cancer.
  • Exemplary B-Raf inhibitors include dabrafenib.
  • EGFR signaling plays an important role in cell proliferation, survival, gene expression and apoptosis.
  • EGFR signaling has been implicated in the progression of a number of cancers. For example, mutations in members of the EGFR pathway are frequently found in lung cancers, and mutations in the EGFR family member HER2 are associated with aggressive breast cancer.
  • EGFR inhibitors include erlotinib, gefetinib and osimertinib.
  • Some cancers are more dependent on poly-ADP ribose polymerase (PARP) than regular cells.
  • PARP poly-ADP ribose polymerase
  • BRCA1, BRCA2 or triple negative breast cancers can be susceptible to PARP inhibitors.
  • Exemplary PARP inhibitors include veliparib, olaparib and talazoparib.
  • PI3K The phosphoinositide 3-kinase (PI3K) pathway can frequently be upregulated in cancer cells such as breast, lung and colorectal cancer, and can be targeted in cancer therapies.
  • Exemplary PI3K inhibitors include pubarlisib.
  • Tyrosine kinase inhibitors inhibit the activity of tyrosine kinases, which can be important mediators of the cell proliferation, differentiation, migration and metabolism of cancer cells.
  • exemplary tyrosine kinase inhibitors include afatinib, apatinib, alectinib, brigantinib, ceritinib, CDX-301, crizotinib, trametinib, selumetinib, lapatinib, neratinib and sunitinib.
  • mTOR or target of rapamycin plays a key role in cell growth and proliferation, and the inhibition of mTOR can treat certain cancers, including lung, breast and colorectal cancers.
  • exemplary mTOR inhibitors include everolimus.
  • Mitotic inhibitors are drugs that inhibit mitosis, or cell division, frequently by disrupting microtubule structure.
  • exemplary mitotic inhibitors include, but are not limited to, ixabepilone, paclitaxel and eribulin.
  • Cyclin Dependent Kinase inhibitors inhibit cyclin dependent kinases, and can be used to inhibit cellular proliferation.
  • CDK inhibitors can be used to many cancers, including lung, colorectal and breast cancer.
  • CDK4/6 inhibitors such as abemaciclib, palbociclib and ribocliclib can be used to treat metastatic breast cancer.
  • Chemotherapies of the disclosure include, but are not limited to, paclitaxel, paclitaxel albumin- stabilized nanoparticle formulation, afatinib dimaleate, apatinib, alectinib, everolimus, pemetrexed disodium, brigantinib, cisplatin, carboplatin, ceritinib, crizotinib, CDX-301, dabrafenib, docetaxel, erlotinib hydrochloride, irinotecan, indoximod, gefetinib, gemcitabine hydrochloride, mechlorethamine hydrochloride, trametinib, methotrexate, vinorelbine tartrate, osimertinib, taxol, doxorubicin, doxorubicin hydrochloride, etoposide, etoposide phosphate, topotecan hydrochloride, vinblastine,
  • Immune checkpoints are regulators of the immune system. Immune checkpoints play a critical role in maintaining self-tolerance, preventing autoimmunity and protecting tissues from damage from the immune system. Immune checkpoints can function by downregulating the immune system. Negative immune checkpoints are frequently co-opted by tumors to inhibit the ability of the immune system to mount an effective immune response to the tumor. Blocking negative regulators of immune checkpoints thus allows for the activation of anti-cancer immunity. Because blocking negative regulators increases the immune response to cancer, administering an immune checkpoint inhibitor to a subject increases the risk of developing CRS and/or neurotoxicity.
  • Immune checkpoints comprise the programmed cell death 1 (PD-1) checkpoint, the CD274 molecule (PD-L1) checkpoint and the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) checkpoint.
  • the immune checkpoint inhibitor comprises a programmed cell death 1 (PD-1) inhibitor, a CD274 molecule (PD-L1) inhibitor or a cytotoxic T-lymphocyte associated protein 4 (CTLA-4) checkpoint inhibitor.
  • PD-1 inhibitors comprise nivolumab and pembrolizumab.
  • Exemplary but non-limiting PD-L1 inhibitors comprise atezolizumab, avelumab and durvalumab.
  • Exemplary but non-limiting CLTA-4 inhibitors comprise ipilimumab.
  • the immune checkpoint inhibitor comprises atezolizumab, avelumab, durvalumab, ipilimumab, tremelimumab, indiximod, nivolumab, pembrolizumab or a combination thereof.
  • Exemplary but non-limiting immune checkpoint inhibitors are disclosed in Table 9:
  • a cancer that is to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry.
  • a cancer that is to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division (e.g., in S phase of cell division).
  • a cancer that is to be treated can be typed as having a low S -phase fraction or a high S -phase fraction.
  • a “normal cell” is a cell that cannot be classified as part of a “cell proliferative disorder”.
  • a normal cell lacks unregulated or abnormal growth, or both, that can lead to the development of an unwanted condition or disease.
  • a normal cell possesses normally functioning cell cycle checkpoint control mechanisms.
  • monotherapy refers to the administration of a single active or therapeutic compound to a subject in need thereof.
  • monotherapy will involve administration of a therapeutically effective amount of an active compound.
  • cancer monotherapy with one of the compounds of the present invention, or a pharmaceutically acceptable salt, polymorph, solvate, analog or derivative thereof, to a subject in need of treatment of cancer.
  • Monotherapy may be contrasted with combination therapy, in which a combination of multiple active compounds is administered, preferably with each component of the combination present in a therapeutically effective amount.
  • monotherapy with a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof is more effective than combination therapy in inducing a desired biological effect.
  • the terms “prevent,” “preventing,” “prevention,” “prophylactic treatment” and the like refer to reducing the probability of developing a disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disorder or condition.
  • the terms “treat,” treating,” “treatment,” and the like refer to reducing or ameliorating a disorder and/or a symptom associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated. Treating may include a health care professional or diagnostic scientist making a recommendation to a subject for a desired course of action or treatment regimen, e.g., a prescription.
  • Treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, to alleviate one or more symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • the term “treat” can also include treatment of a cell in vitro or an animal model.
  • a compound of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof can also be used to prevent a disease, condition or disorder, or used to identify suitable candidates for such purposes.
  • preventing describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder. “Prevent” or “preventing” also describes reducing the probability, or risk, of developing a sign or a symptom of a disease of the disclosure.
  • the term “alleviate” is meant to describe a process by which the severity of a sign or symptom of a disorder is decreased.
  • a sign or symptom can be alleviated without being eliminated.
  • the administration of pharmaceutical compositions of the invention leads to the elimination of a sign or symptom, however, elimination is not required.
  • Effective dosages are expected to decrease the severity of a sign or symptom.
  • a sign or symptom of a disorder such as cancer, which can occur in multiple locations, is alleviated if the severity of the cancer is decreased within at least one of multiple locations.
  • severity is meant to describe the potential of cancer to transform from a precancerous, or benign, state into a malignant state.
  • severity is meant to describe a cancer stage, for example, according to the TNM system (accepted by the International Union against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)) or by other art-recognized methods.
  • TNM system accepted by the International Union against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)
  • UNM system International Union against Cancer
  • AJCC American Joint Committee on Cancer
  • Cancer stage refers to the extent or severity of the cancer, based on factors such as the location of the primary tumor, tumor size, number of tumors, and lymph node involvement (spread of cancer into lymph nodes).
  • Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered when determining tumor grade, including the structure and growth pattern of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Severity also describes a histologic grade, also called differentiation, which refers to how much the tumor cells resemble normal cells of the same tissue type (see, National Cancer Institute, www.cancer.gov).
  • severity describes a nuclear grade, which refers to the size and shape of the nucleus in tumor cells and the percentage of tumor cells that are dividing (see, National Cancer Institute, www.cancer.gov).
  • severity describes the degree to which a tumor has secreted growth factors, degraded the extracellular matrix, become vascularized, lost adhesion to juxtaposed tissues, or metastasized.
  • severity describes the number of locations to which a primary tumor has metastasized.
  • severity includes the difficulty of treating tumors of varying types and locations. For example, inoperable tumors, those cancers which have greater access to multiple body systems (hematological and immunological tumors), and those which are the most resistant to traditional treatments are considered most severe.
  • symptom is defined as an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the subject experiencing the symptom but may not easily be noticed by others. Others are defined as non- health-care professionals.
  • signs are also defined as an indication that something is not right in the body. But signs are defined as things that can be seen by a doctor, nurse, or other health care professional.
  • Treating cancer can result in a reduction in size of a tumor.
  • a reduction in size of a tumor may also be referred to as "tumor regression".
  • tumor size is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater.
  • Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer can result in a reduction in tumor volume.
  • tumor volume is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor volume is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater.
  • Tumor volume may be measured by any reproducible means of measurement.
  • Treating cancer results in a decrease in number of tumors.
  • tumor number is reduced by 5% or greater relative to number prior to treatment; more preferably, tumor number is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%.
  • Number of tumors may be measured by any reproducible means of measurement.
  • the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification.
  • the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
  • Treating cancer can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site.
  • the number of metastatic lesions is reduced by 5% or greater relative to number prior to treatment; more preferably, the number of metastatic lesions is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75%.
  • the number of metastatic lesions may be measured by any reproducible means of measurement.
  • the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification.
  • the specified magnification is 2x, 3x, 4x, 5x, lOx, or 50x.
  • Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer can result in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present invention, or a pharmaceutically acceptable salt, polymorph, solvate, analog or derivative thereof.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the present invention, or a pharmaceutically acceptable salt, polymorph, solvate, analog or derivative thereof.
  • the mortality rate is decreased by more than 2%; more preferably, by more than 5%; more preferably, by more than 10%; and most preferably, by more than 25%.
  • a decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means.
  • a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.
  • Treating cancer can result in a decrease in tumor growth rate.
  • tumor growth rate is reduced by at least 5% relative to number prior to treatment; more preferably, tumor growth rate is reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%.
  • Tumor growth rate may be measured by any reproducible means of measurement. Tumor growth rate can be measured according to a change in tumor diameter per unit time.
  • Treating cancer can result in a decrease in tumor regrowth.
  • tumor regrowth is less than 5%; more preferably, tumor regrowth is less than 10%; more preferably, less than 20%; more preferably, less than 30%; more preferably, less than 40%; more preferably, less than 50%; even more preferably, less than 50%; and most preferably, less than 75%.
  • Tumor regrowth may be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. A decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.
  • Treating cancer can result in a reduction in the rate of cellular proliferation.
  • the rate of cellular proliferation is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%.
  • the rate of cellular proliferation may be measured by any reproducible means of measurement.
  • the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
  • Treating cancer can result in a reduction in the proportion of proliferating cells.
  • the proportion of proliferating cells is reduced by at least 5%; more preferably, by at least 10%; more preferably, by at least 20%; more preferably, by at least 30%; more preferably, by at least 40%; more preferably, by at least 50%; even more preferably, by at least 50%; and most preferably, by at least 75%.
  • the proportion of proliferating cells may be measured by any reproducible means of measurement.
  • the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample.
  • the proportion of proliferating cells can be equivalent to the mitotic index.
  • Treating cancer can result in a decrease in size of an area or zone of cellular proliferation.
  • size of an area or zone of cellular proliferation is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%.
  • Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement.
  • the size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
  • Treating cancer can result in a decrease in the number or proportion of cells having an abnormal appearance or morphology.
  • the number of cells having an abnormal morphology is reduced by at least 5% relative to its size prior to treatment; more preferably, reduced by at least 10%; more preferably, reduced by at least 20%; more preferably, reduced by at least 30%; more preferably, reduced by at least 40%; more preferably, reduced by at least 50%; even more preferably, reduced by at least 50%; and most preferably, reduced by at least 75%.
  • An abnormal cellular appearance or morphology may be measured by any reproducible means of measurement.
  • An abnormal cellular morphology can be measured by microscopy, e.g., using an inverted tissue culture microscope.
  • An abnormal cellular morphology can take the form of nuclear pleiomorphism.
  • Treating cancer can result in cell death, and preferably, cell death results in a decrease of at least 10% in number of cells in a population. More preferably, cell death means a decrease of at least 20%; more preferably, a decrease of at least 30%; more preferably, a decrease of at least 40%; more preferably, a decrease of at least 50%; most preferably, a decrease of at least 75%.
  • Number of cells in a population may be measured by any reproducible means. A number of cells in a population can be measured by fluorescence activated cell sorting (FACS), immunofluorescence microscopy and light microscopy. Methods of measuring cell death are as shown in Fi et al., Proc Natl Acad Sci U S A. 100(5): 2674-8, 2003. In an aspect, cell death occurs by apoptosis.
  • a cancer that is to be treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of TX, Tl, Tlmic, Tla, Tib, Tic, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N) have been assigned a stage of NX, NO, Nl, N2, N2a, N2b, N3,
  • AJCC American Joint Committee on Cancer
  • N3a, N3b, or N3c where distant metastasis (M) can be assigned a stage of MX, MO, or Ml.
  • a cancer that is to be treated can be staged according to an American Joint Committee on Cancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV.
  • AJCC American Joint Committee on Cancer
  • a cancer that is to be treated can be assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4.
  • a cancer that is to be treated can be staged according to an AJCC pathologic classification (pN) of pNX, pNO, PNO (I-), PNO (I+), PNO (mol-), PNO (mol+), PN1, PNl(mi), PNla, PNlb, PNlc, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.
  • pN AJCC pathologic classification
  • the disclosure provides formulations of the inflammation inhibitors disclosed herein.
  • the formulations may comprise an IL-1 inhibitor or an IL-6 inhibitor.
  • a drug is prepared depending in its route of drug administration. Examples of drug administration routes that are useful in the present invention are described on the U.S. Food and Drug Administration’s website at the World Wide Web
  • Preparations for oral administration generally contain inert excipients in addition to the active pharmaceutical ingredient.
  • Oral preparations may be enclosed in gelatin capsules or compressed into tablets.
  • Common excipients used in such preparations include pharmaceutically compatible fillers/diluents such as microcrystalline cellulose, hydroxypropyl methylcellulose, starch, lactose, sucrose, glucose, mannitol, sorbitol, dibasic calcium phosphate, or calcium carbonate; binding agents such as alginic acid, carboxymethylcellulose, microcrystalline cellulose, gelatin, gum tragacanth, or polyvinylpyrrolidone; disintegrating agents such as alginic acid, cellulose, starch, or polyvinylpyrrolidone; lubricants such as calcium stearate, magnesium stearate, talc, silica, or sodium stearyl fumarate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; flavoring agents such as
  • Oral preparations may also be administered as aqueous suspensions, elixirs, or syrups.
  • the active ingredient may be combined with various sweetening or flavoring agents, coloring agents, and, if so desired, emulsifying and/or suspending agents, as well as diluents such as water, ethanol, glycerin, and combinations thereof.
  • the preparation may be an aqueous or an oil-based solution.
  • Aqueous solutions may include a sterile diluent such as water, saline solution, a pharmaceutically acceptable polyol such as glycerol, propylene glycol, or other synthetic solvents; an antibacterial and/or antifungal agent such as benzyl alcohol, methyl paraben, chlorobutanol, phenol, thimerosal, and the like; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid (EDTA); a buffer such as acetate, citrate, or phosphate; and/or an agent for the adjustment of tonicity such as sodium chloride, dextrose, or a polyalcohol such as mannitol or sorbitol.
  • the pH of the aqueous solution may include a sterile diluent such as water, saline solution, a pharmaceutically acceptable poly
  • transdermal or transmucosal administration penetrants appropriate to the barrier to be permeated are generally included in the preparation.
  • Transmucosal administration may be accomplished through the use of nasal sprays, aerosol sprays, tablets, or suppositories, and transdermal administration may be via ointments, salves, gels, patches, or creams as generally known in the art.
  • Topical ocular formulations e.g., eye drops and eye ointments, are considered.
  • the amount of agent that is administered to the subject can and will vary depending upon the type of agent, the subject, and the particular mode of administration. Those skilled in the art will appreciate that dosages may also be determined with guidance from Goodman & Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition (2011), Appendix II, pp. 1891-1991, and the Physicians’ Desk Reference 70 th Edition, 2016.
  • Pharmacogenomics is the methodology which associates genetic variability with physiological and clinical responses to a drug.
  • Pharmacogenetics is a subset of pharmacogenomics and is defined as “the study of variations in DNA sequence as related to drug response” (ICH E15; see the World Wide Web www.fda.gov/downloads/RegulatoryInformation/Guidances/ucml29296.pdf).
  • Pharmacogenetics often focuses on genetic polymorphisms in genes related to drug metabolism, drug mechanism of action, underlying disease type, and drug associated side effects.
  • Pharmacogenetics is the cornerstone of Personalized Medicine which allows the development and the targeted use of drug therapies to obtain effective and safe treatment, as well as to adjust existing treatment regimens to further optimize the efficacy and safety profile for the individual patient.
  • Pharmacogenetics has become a core component of many drug development programs, being used to explain variability in drug response among subjects in clinical trials, to address unexpected emerging clinical issues, such as adverse events, to determine eligibility for a clinical trial (pre-screening) to optimize trial yield, to develop drug companion diagnostic tests to identify patients who are more likely or less likely to benefit from treatment or who may be at risk of adverse events, to provide information in drug labels to guide physician treatment decisions, to better understand the mechanism of action or metabolism of new and existing drugs, and to provide better understanding of disease mechanisms as associated with treatment response.
  • pharmacogenetics analyses are often performed using the candidate genes research technique, which is a hypothesis-driven approach, based on the detection of polymorphisms in candidate genes pre-selected using knowledge of the disease, the drug’s mode of action, toxicology, or metabolism of the drug.
  • IL-1 levels can be measured ex vivo and in response to treatment with a therapeutic compound.
  • lymphocytes will be obtained from a subject.
  • the lymphocytes will be treated with an IL-1 activator and then IL-1 levels (protein and/or mRNA) will be measured. If the lymphocytes produce increased IL-1 and to a critical level, then a diagnosis of the subject can be made and a prediction regarding an optimal treatment can be determined.
  • an “isolated nucleic acid molecule” generally is one that contains one or more of the SNPs disclosed herein or one that hybridizes to such molecule such as a nucleic acid with a complementary sequence, and is separated from most other nucleic acids present in the natural source of the nucleic acid molecule.
  • a non-naturally occurring nucleic acid molecule generally is one that contains one or more of the SNPs disclosed herein or one that hybridizes to such a molecule, such as a nucleic acid with a complementary sequence, but which does not correspond to a naturally occurring molecule, e.g., it can be a molecule prepared by recombinant nucleic acid technology, chemical synthesis, or other synthetic means such as polymerase chain reaction (PCR), and/or a nucleic acid which comprises one or more synthetic components such as a non-natural nucleotide or an added tag/motif.
  • PCR polymerase chain reaction
  • the isolated nucleic acid may be obtained from any bodily fluid (such as blood, serum, plasma, urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin, hair, cell (especially nucleated cells), biopsy, buccal swab, tissue, or tumor specimen.
  • the isolated nucleic acid may be amplified or synthesized from a nucleic acid obtained from any bodily fluid, skin, hair, cell, biopsy, buccal swab, tissue, or tumor specimen.
  • an isolated SNP-containing nucleic acid molecule includes one or more of SNPs and/or one or more SNPs in linkage disequilibrium with one or more SNPs.
  • the isolated SNP-containing nucleic acid molecule may include flanking nucleotide sequences on either side of the SNP position.
  • a flanking sequence can include nucleotide residues that are naturally associated with the SNP site and/or heterologous nucleotide sequences.
  • flanking sequence is up to about 10,000, 1,000, 500, 300, 100, 60, 50, 30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between) on either side of a SNP position, or as long as the full-length gene, entire protein-coding sequence (or any portion thereof such as an exon), entire enhancer/promoter region or portion thereof, or entire intron or portion thereof.
  • An isolated SNP-containing nucleic acid molecule can include, for example, a full- length gene or transcript, such as a gene isolated from genomic DNA (e.g., by cloning or PCR amplification), a cDNA molecule, or an mRNA transcript molecule.
  • An isolated nucleic acid molecule of the disclosed subject matter further encompasses a SNP-containing polynucleotide that is the product of any one of a variety of nucleic acid amplification methods, which are used to increase the copy numbers of a polynucleotide of interest in a nucleic acid sample.
  • amplification methods are well known in the art, and they include but are not limited to, polymerase chain reaction (PCR) (U.S. Pat. Nos. 4,683,195 and 4,683,202; PCR Technology: Principles and Applications for DNA Amplification, ed. H. A. Erlich, Freeman Press, NY, N.Y.
  • LCR ligase chain reaction
  • SDA strand displacement amplification
  • TMA transcription-mediated amplification
  • LMA linked linear amplification
  • isolated nucleic acid molecules that include, consist of, or consist essentially of one or more polynucleotide sequences that contain one or more SNPs disclosed herein, complements thereof, SNPs in linkage disequilibrium with the SNPs disclosed herein, and/or SNP-containing fragments thereof.
  • SNPs in linkage disequilibrium with the SNPs disclosed herein include those listed in Table 10 below.
  • Isolated nucleic acid molecules can be in the form of RNA, such as mRNA, or in the form DNA, including cDNA and genomic DNA, which may be obtained, for example, by molecular cloning or produced by chemical synthetic techniques or by a combination thereof. Sambrook and Russell, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Press, N.Y. (2000).
  • isolated nucleic acid molecules particularly SNP detection reagents such as probes and primers, can also be partially or completely in the form of one or more types of nucleic acid analogs, such as peptide nucleic acid (PNA).
  • PNA peptide nucleic acid
  • the nucleic acid can be double- stranded or single- stranded.
  • Single-stranded nucleic acid can be the coding strand (sense strand) or the complementary non-coding strand (anti-sense strand).
  • DNA, RNA, or PNA segments can be assembled, for example, from fragments of the human genome (in the case of DNA or RNA) or single nucleotides, short oligonucleotide linkers, or from a series of oligonucleotides, to provide a synthetic nucleic acid molecule.
  • Nucleic acid molecules can be readily synthesized using the sequences provided herein as a reference; oligonucleotide and PNA oligomer synthesis techniques are well known in the art.
  • the isolated SNP-containing nucleic acid molecule may comprise modified, synthetic, or non-naturally occurring nucleotides or structural elements or other altemative/modified nucleic acid chemistries known in the art.
  • nucleic acid analogs are useful, for example, as detection reagents (e.g., primers/probes) for detecting the SNPs identified herein.
  • detection reagents e.g., primers/probes
  • kits/systems such as beads, arrays, etc. that include these analogs are also encompassed herein.
  • each of the one or more of the SNPs disclosed herein can be used for the design of SNP detection reagents.
  • a “SNP detection reagent” is a reagent that specifically detects a specific target SNP position disclosed herein, and that is preferably specific for a particular nucleotide (allele) of the target SNP position (i.e., the detection reagent preferably can differentiate between different alternative nucleotides at a target SNP position, thereby allowing the identity of the nucleotide present at the target SNP position to be determined).
  • such detection reagent hybridizes to a target SNP-containing nucleic acid molecule by complementary base-pairing in a sequence specific manner and discriminates the target variant sequence from other nucleic acid sequences such as an art-known form in a test sample.
  • An example of a detection reagent is a non-naturally occurring nucleic acid probe that hybridizes to a target nucleic acid containing one of the SNPs disclosed herein.
  • such a probe can differentiate between nucleic acids having a particular nucleotide (allele) at the target SNP position from other nucleic acids that have a different nucleotide at the same target SNP position.
  • a detection reagent may hybridize to a specific region 5' and/or 3' to the SNP position.
  • a detection reagent is a non-naturally occurring nucleic acid primer that acts as an initiation point of nucleotide extension along a complementary strand of a target polynucleotide.
  • the SNP sequence information provided herein is also useful for designing primers, e.g., allele- specific primers, to amplify (e.g., using PCR) the SNP of the disclosed subject matter.
  • a SNP detection reagent may be an isolated or synthetic DNA or RNA polynucleotide probe or primer or PNA oligomer, or a combination of DNA, RNA and/or PNA that hybridizes to a segment of a target nucleic acid molecule containing one of the SNPs disclosed herein.
  • a detection reagent in the form of a non-naturally occurring polynucleotide may optionally contain modified base analogs, intercalators, or minor groove binders.
  • probes may be, for example, affixed to a solid support (e.g., an array and bead) or supplied in solution (e.g., probe/primer sets for enzymatic reactions such as PCR, RT-PCR, TaqMan® assays, and primer-extension reactions) to form a SNP detection kit.
  • a solid support e.g., an array and bead
  • probe/primer sets for enzymatic reactions e.g., PCR, RT-PCR, TaqMan® assays, and primer-extension reactions
  • oligonucleotides specific for alternative SNP alleles Such oligonucleotides that detect single nucleotide variations in target sequences may be referred to by such terms as “allele- specific oligonucleotides,” “allele- specific probes,” or “allele- specific primers.”
  • allele-specific probes for analyzing polymorphisms is described in, e.g., Mutation Detection: A Practical Approach, Cotton et al., eds., Oxford University Press (1998); Saiki et al., Nature 324:163-166 (1986); Dattagupta, EP235,726; and Saiki, WO 89/11548.
  • a probe or primer may be designed to hybridize to a segment of target DNA such that the SNP aligns with either the 5 '-most end or the 3 '-most end of the probe or primer.
  • an oligonucleotide ligation assay U.S. Pat. No. 4,988,617
  • the 3' most nucleotide of the probe aligns with the SNP position in the target sequence.
  • Allele- specific probes are often used in pairs (or, less commonly, in sets of 3 or 4), and such pairs may be identical except for a one nucleotide mismatch that represents the allelic variants at the SNP position.
  • one member of a probe pair perfectly matches a reference form of a target sequence that has a more common SNP allele (i.e., the allele that is more frequent in the target population) and the other member of the pair perfectly matches a form of the target sequence that has a less common SNP allele (i.e., the allele that is rarer in the target population).
  • multiple pairs of probes can be immobilized on the same support for simultaneous analysis of multiple different polymorphisms.
  • an allele-specific primer hybridizes to a region on a target nucleic acid molecule that overlaps a SNP position and only primes amplification of an allelic form to which the primer exhibits perfect complementarity.
  • the primer’s 3'-most nucleotide is aligned with and complementary to the SNP position of the target nucleic acid molecule.
  • This primer is used in conjunction with a second primer that hybridizes at a distal site. Amplification proceeds from the two primers, producing a detectable product that indicates which allelic form is present in the test sample.
  • a control is usually performed with a second pair of primers, one of which shows a single base mismatch at the polymorphic site and the other of which exhibits perfect complementarity to a distal site.
  • the single-base mismatch prevents amplification or substantially reduces amplification efficiency, so that either no detectable product is formed or it is formed in lower amounts or at a slower pace.
  • the method generally works most effectively when the mismatch is at the 3 '-most position of the oligonucleotide (i.e., the 3 '-most position of the oligonucleotide aligns with the target SNP position) because this position is most destabilizing to elongation from the primer (see, e.g., WO 93/22456).
  • This PCR-based assay can be utilized as part of the TaqMan® assay, described below.
  • a primer may contain a sequence substantially complementary to a segment of a target SNP-containing nucleic acid molecule except that the primer has a mismatched nucleotide in one of the three nucleotide positions at the 3 '-most end of the primer, such that the mismatched nucleotide does not base pair with a particular allele at the SNP site.
  • the mismatched nucleotide in the primer is the second from the last nucleotide at the 3 '-most position of the primer.
  • the mismatched nucleotide in the primer is the last nucleotide at the 3 '-most position of the primer.
  • a SNP detection reagent may be labeled with a fluorogenic reporter dye that emits a detectable signal.
  • a fluorogenic reporter dye that emits a detectable signal.
  • the preferred reporter dye is a fluorescent dye
  • any reporter dye that can be attached to a detection reagent such as an oligonucleotide probe or primer is suitable for use in the disclosed subject matter.
  • Such dyes include, but are not limited to, Acridine, AMCA, BODIPY, Cascade Blue, Cy2, Cy3, Cy5, Cy7, Dabcyl, Edans, Eosin, Erythrosin, Fluorescein, 6- Fam, Tet, Joe, Hex, Oregon Green, Rhodamine, Rhodol Green, Tamra, Rox, and Texas Red.
  • the detection reagent may be further labeled with a quencher dye such as TAMRA, especially when the reagent is used as a self-quenching probe such as a TaqMan® (U.S. Pat. Nos. 5,210,015 and 5,538,848) or Molecular Beacon probe (U.S. Pat. Nos. 5,118,801 and 5,312,728), or other stemless or linear beacon probe (Livak et al., PCR Method Appl 4:357-362 (1995); Tyagi et al., Nature Biotechnology 14:303-308 (1996); Nazarenko et al., Nuc’ Acids Res 25:2516-2521 (1997); U.S. Pat. Nos.
  • a quencher dye such as TAMRA
  • Detection reagents may also contain other labels, including but not limited to, biotin for streptavidin binding, hapten for antibody binding, and an oligonucleotide for binding to another complementary oligonucleotide.
  • Reagents may not contain (or be complementary to) a SNP nucleotide as describe herein but that are used to assay one or more SNPs disclosed herein.
  • primers that flank, but do not hybridize directly to a target SNP position are useful in primer extension reactions in which the primers hybridize to a region adjacent to the target SNP position (i.e., within one or more nucleotides from the target SNP site).
  • a primer is typically not able to extend past a target SNP site if a particular nucleotide (allele) is present at that target SNP site, and the primer extension product can be detected in order to determine which SNP allele is present at the target SNP site.
  • ddNTPs are typically used in the primer extension reaction to terminate primer extension once a ddNTP is incorporated into the extension product (a primer extension product which includes a ddNTP at the Y-most end of the primer extension product, and in which the ddNTP is a nucleotide of a SNP disclosed herein, is a composition that is specifically herein).
  • reagents that bind to a nucleic acid molecule in a region adjacent to a SNP site and that are used for assaying the SNP site, even though the bound sequences do not necessarily include the SNP site itself are also contemplated by the disclosed subject matter.
  • the SNP may be identified using single-base extension (SBE).
  • SBE determines the identity of a nucleotide base at a specific position along a nucleic acid.
  • an oligonucleotide primer hybridizes to a complementary region along the nucleic acid, to form a duplex, with the primer’s terminal 3' end directly adjacent to the nucleotide base to be identified.
  • the oligonucleotide primer is enzymatically extended by a single base in the presence of all four nucleotide terminators; the nucleotide terminator complementary to the base in the template being interrogated is incorporated and identified. The presence of all four terminators ensures that no further extension occurs beyond the single incorporated base.
  • Many approaches can be taken for determining the identity of a terminator, including fluorescence labeling, mass labeling for mass spectrometry, measuring enzyme activity using a protein moiety, and isotope labeling.
  • Reagents and techniques described herein may be directed to performance of “Next Generation Sequencing.” (See, e.g., Srivatsan etal., PLoS Genet 4: el00139 (2008);
  • such techniques may involve the fragmentation of a genomic nucleic acid sample followed by parallel sequencing of those fragments and the alignment of the sequenced fragments to reconstruct the original sequence.
  • the genomic nucleic acid of interest is sheared into fragments and “adapters” (short nucleic acids of known sequence) are ligated to the fragments.
  • Adaptor- modified fragments can be enriched via PCR.
  • An adaptor-modified fragment (and amplified copies thereof, if present) may be flowed across a flow cell where the fragments are allowed to hybridize to primers immobilized on the surface of the cell.
  • the fragments are then amplified by isothermal bridge amplification into a cluster consisting of thousands of molecules identical to the original.
  • Sequencing primers can then be hybridized to the ends of one strand of the clusters, reversibly blocked, and labeled nucleotides added.
  • the addition of each particular nucleotide can be identified by the label, then the label can be removed and the nucleotide un-blocked so that another blocked and labeled nucleotide can be added to identify the next position in the nucleic acid sequence.
  • SNP genotyping includes, for example, collecting a biological sample from a human subject (e.g., sample of tissues, cells, fluids, secretions, etc.), isolating nucleic acids (e.g., genomic DNA, mRNA or both) from the cells of the sample, contacting the nucleic acids with one or more primers which specifically hybridize to a region of the isolated nucleic acid containing a target SNP under conditions such that hybridization and amplification of the target nucleic acid region occurs, and determining the nucleotide present at the SNP position of interest, or, in some assays, detecting the presence or absence of an amplification product (assays can be designed so that hybridization and/or amplification will only occur if a particular SNP allele is present or absent).
  • the size of the amplification product is detected and compared to the length of a control sample; for example, deletions and insertions can be detected by a change in size of the amplified product
  • SNP genotyping is useful for numerous practical applications, as described herein. Examples of such applications include, but are not limited to, SNP-disease association analysis, disease predisposition screening, disease diagnosis, disease prognosis, disease progression monitoring, determining therapeutic strategies based on a subject’s genotype (“pharmacogenomics”), developing therapeutic agents based on SNP genotypes associated with a disease or likelihood of responding to a drug, stratifying patient populations for clinical trials of a therapeutic, preventive, or diagnostic agent, and human identification applications such as forensics.
  • Nucleic acid samples can be genotyped to determine which allele is present at any given SNP position of interest by methods well known in the art.
  • the neighboring sequence can be used to design SNP detection reagents such as oligonucleotide probes, which may optionally be implemented in a kit format.
  • Exemplary SNP genotyping methods are described in Chen et al., “Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput,” Pharmacogenomics J 3 (2):77-96 (2003); Kwok et al., “Detection of single nucleotide polymorphisms,” Curr Issues Mol Biol 5 (2):43-60 (April 2003); Shi, “Technologies for individual genotyping: detection of genetic polymorphisms in drug targets and disease genes,” Am J Pharmacogenomics 2 (3): 197-205 (2002); and Kwok, “Methods for genotyping single nucleotide polymorphisms,” Annu Rev Genom Hum Genet 2:235-58 (2001). Techniques for high-throughput SNP genotyping are described in Mamellos, “High-throughput SNP analysis for genetic association studies,” Curr Opin Drug Disc Devel 6 (3):317-21 (March 2003).
  • SNP genotyping methods include, but are not limited to, TaqMan ® assays, molecular beacon assays, nucleic acid arrays, allele- specific primer extension, allele- specific PCR, arrayed primer extension, homogeneous primer extension assays, primer extension with detection by mass spectrometry, pyrosequencing, multiplex primer extension sorted on genetic arrays, ligation with rolling circle amplification, homogeneous ligation, Oligonucleotide Ligation Assay (OLA: U.S. Pat. No.
  • multiplex ligation reaction sorted on genetic arrays restriction- fragment length polymorphism, single base extension-tag assays, denaturing gradient gel electrophoresis, and the Invader assay.
  • detection mechanisms such as, for example, luminescence or chemiluminescence detection, fluorescence detection, time-resolved fluorescence detection, fluorescence resonance energy transfer, fluorescence polarization, mass spectrometry, and electrical detection.
  • SNP genotyping is performed using the TaqMan® assay, which is also known as the 5' nuclease assay (U.S. Pat. Nos. 5,210,015 and 5,538,848).
  • the TaqMan® assay detects the accumulation of a specific amplified product during PCR.
  • the TaqMan® assay utilizes an oligonucleotide probe labeled with a fluorescent reporter dye and a quencher dye.
  • the reporter dye is excited by irradiation at an appropriate wavelength, it transfers energy to the quencher dye in the same probe via a process called fluorescence resonance energy transfer (FRET). When attached to the probe, the excited reporter dye does not emit a signal.
  • FRET fluorescence resonance energy transfer
  • the proximity of the quencher dye to the reporter dye in the intact probe maintains a reduced fluorescence for the reporter.
  • the reporter dye and quencher dye may be at the 5' most and the 3' most ends, respectively, or vice versa.
  • the reporter dye may be at the 5' or 3' most end while the quencher dye is attached to an internal nucleotide, or vice versa.
  • both the reporter and the quencher may be attached to internal nucleotides at a distance from each other such that fluorescence of the reporter is reduced.
  • DNA polymerase cleaves the probe, thereby separating the reporter dye and the quencher dye and resulting in increased fluorescence of the reporter. Accumulation of PCR product is detected directly by monitoring the increase in fluorescence of the reporter dye.
  • the DNA polymerase cleaves the probe between the reporter dye and the quencher dye only if the probe hybridizes to the target SNP-containing template which is amplified during PCR, and the probe is designed to hybridize to the target SNP site only if a particular SNP allele is present.
  • Preferred TaqMan® primer and probe sequences can readily be determined using the SNP and associated nucleic acid sequence information provided herein.
  • a number of computer programs such as Primer Express (Applied Biosystems, Foster City, Calif.), can be used to rapidly obtain optimal primer/probe sets. These probes and primers can be readily incorporated into a kit format.
  • the disclosed subject matter also includes modifications of the TaqMan® assay well known in the art such as the use of Molecular Beacon probes (U.S. Pat. Nos. 5,118,801 and 5,312,728) and other variant formats (U.S. Pat. Nos. 5,866,336 and 6,117,635).
  • Another method for genotyping the SNPs can be the use of two oligonucleotide probes in an OLA (see, e.g., U.S. Pat. No. 4,988,617).
  • one probe hybridizes to a segment of a target nucleic acid with its 3' most end aligned with the SNP site.
  • a second probe hybridizes to an adjacent segment of the target nucleic acid molecule directly 3' to the first probe.
  • the two juxtaposed probes hybridize to the target nucleic acid molecule and are ligated in the presence of a linking agent such as a ligase if there is perfect complementarity between the 3 ' most nucleotide of the first probe with the SNP site. If there is a mismatch, ligation would not occur.
  • the ligated probes are separated from the target nucleic acid molecule and detected as indicators of the presence of a SNP.
  • OLA OLA
  • LDR LDR
  • PCR nucleic acid amplification
  • Mass spectrometry takes advantage of the unique mass of each of the four nucleotides of DNA. SNPs can be unambiguously genotyped by mass spectrometry by measuring the differences in the mass of nucleic acids having alternative SNP alleles.
  • MALDI-TOF Microx Assisted Laser Desorption Ionization-Time of Flight mass spectrometry technology is preferred for extremely precise determinations of molecular mass, such as SNPs.
  • Numerous approaches to SNP analysis have been developed based on mass spectrometry.
  • Preferred mass spectrometry-based methods of SNP genotyping include primer extension assays, which can also be utilized in combination with other approaches, such as traditional gel -based formats and microarrays.
  • a mass spectrometry with primer extension assay involves designing and annealing a primer to a template PCR amplicon upstream (5') from a target SNP position.
  • a mix of dideoxynucleotide triphosphates (ddNTPs) and/or deoxynucleotide triphosphates (dNTPs) are added to a reaction mixture containing template (e.g., a SNP-containing nucleic acid molecule which has typically been amplified, such as by PCR), primer, and DNA polymerase.
  • template e.g., a SNP-containing nucleic acid molecule which has typically been amplified, such as by PCR
  • primer e.g., a SNP-containing nucleic acid molecule which has typically been amplified, such as by PCR
  • DNA polymerase e.g., a SNP-containing nucleic acid molecule which has typically been amplified, such as by PCR
  • the primer can be either immediately adjacent (i.e., the nucleotide at the 3' end of the primer hybridizes to the nucleotide next to the target SNP site) or two or more nucleotides removed from the SNP position. If the primer is several nucleotides removed from the target SNP position, the only limitation is that the template sequence between the 3' end of the primer and the SNP position cannot contain a nucleotide of the same type as the one to be detected, or this will cause premature termination of the extension primer.
  • primers are designed to bind one nucleotide upstream from the SNP position (i.e., the nucleotide at the 3' end of the primer hybridizes to the nucleotide that is immediately adjacent to the target SNP site on the 5' side of the target SNP site). Extension by only one nucleotide is preferable, as it minimizes the overall mass of the extended primer, thereby increasing the resolution of mass differences between alternative SNP nucleotides.
  • mass-tagged ddNTPs can be employed in the primer extension reactions in place of unmodified ddNTPs. This increases the mass difference between primers extended with these ddNTPs, thereby providing increased sensitivity and accuracy, and is particularly useful for typing heterozygous base positions.
  • Primer extension assays may be used in conjunction with MALDI-TOF mass spectrometry for SNP genotyping, see, e.g., Wise el al., “A standard protocol for single nucleotide primer extension in the human genome using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry,” Rapid Comm. Mass Spect. 17 (11): 1195-202 (2003).
  • SNPs can also be scored by direct DNA sequencing.
  • a variety of automated sequencing procedures can be utilized (e.g., Biotechniques 19:448 (1995)), including sequencing by mass spectrometry. See, e.g., PCT International Publication No. WO 94/16101; Cohen et al., Adv Chromatogr 36:127-162 (1996); and Griffin et al, Appl Biochem Biotechnol 38:147-159 (1993).
  • the nucleic acid sequences of the disclosed subject matter enable one of ordinary skill in the art to readily design sequencing primers for such automated sequencing procedures.
  • Commercial instrumentation such as the Applied Biosystems 377, 3100, 3700, 3730, and 3730x1 DNA Analyzers (Foster City, Calif.), is commonly used in the art for automated sequencing.
  • SSCP single-strand conformational polymorphism
  • DGGE denaturing gradient gel electrophoresis
  • the different electrophoretic mobilities of single- stranded amplification products are related to base-sequence differences at SNP positions.
  • DGGE differentiates SNP alleles based on the different sequence- dependent stabilities and melting properties inherent in polymorphic DNA and the corresponding differences in electrophoretic migration patterns in a denaturing gradient gel.
  • Sequence-specific ribozymes can also be used to score SNPs based on the development or loss of a ribozyme cleavage site. Perfectly matched sequences can be distinguished from mismatched sequences by nuclease cleavage digestion assays or by differences in melting temperature. If the SNP affects a restriction enzyme cleavage site, the SNP can be identified by alterations in restriction enzyme digestion patterns, and the corresponding changes in nucleic acid fragment lengths determined by gel electrophoresis.
  • detection reagents can be developed and used to assay the SNP of the disclosed subject matter individually or in combination with other SNPs, and such detection reagents can be readily incorporated into one of the established kit or system formats which are well known in the art.
  • kits and “systems,” as used herein in the context of SNP detection reagents, are intended to refer to such things as combinations of multiple SNP detection reagents, or one or more SNP detection reagents in combination with one or more other types of elements or components (e.g., other types of biochemical reagents, containers, packages such as packaging intended for commercial sale, substrates to which SNP detection reagents are attached, electronic hardware components, and software recorded on a non-transitory processor-readable medium).
  • elements or components e.g., other types of biochemical reagents, containers, packages such as packaging intended for commercial sale, substrates to which SNP detection reagents are attached, electronic hardware components, and software recorded on a non-transitory processor-readable medium.
  • the disclosed subject matter further provides SNP detection kits and systems, including but not limited to, packaged probe and primer sets (e.g., TaqMan® probe/primer sets), arrays/microarrays of nucleic acid molecules, and beads that contain one or more probes, primers, or other detection reagents for detecting one or more SNPs of the disclosed subject matter.
  • packaged probe and primer sets e.g., TaqMan® probe/primer sets
  • arrays/microarrays of nucleic acid molecules e.g., arrays/microarrays of nucleic acid molecules, and beads that contain one or more probes, primers, or other detection reagents for detecting one or more SNPs of the disclosed subject matter.
  • kits/systems can optionally include various electronic hardware components; for example, arrays (“DNA chips”) and microfluidic systems (“lab-on-a-chip” systems) provided by various manufacturers typically include hardware components.
  • Other kits/systems e.g., probe/primer sets
  • a SNP detection kit typically contains one or more detection reagents and other components (e.g., a buffer, enzymes such as DNA polymerases or ligases, chain extension nucleotides such as deoxynucleotide triphosphates, and in the case of Sanger- type DNA sequencing reactions, chain terminating nucleotides, positive control sequences, negative control sequences, and the like) necessary to carry out an assay or reaction, such as amplification and/or detection of a SNP-containing nucleic acid molecule.
  • detection reagents e.g., a buffer, enzymes such as DNA polymerases or ligases, chain extension nucleotides such as deoxynucleotide triphosphates, and in the case of Sanger- type DNA sequencing reactions, chain terminating nucleotides, positive control sequences, negative control sequences, and the like
  • a kit may further contain instructions for using the kit to detect the SNP-containing nucleic acid molecule of interest.
  • the instructions may include information which allows a user to identify whether a subject having or suspected of having an CRS and/or neurotoxicity has genotype-specific differential expression of IL-1, i.e., is a “high” or “low” producer of IL-1, based upon the composite IL-1 genotype or IL-1 genotype patterns disclosed in Tables 1-3.
  • the instructions may include information which allows a user to decide on an appropriate IL-1 inhibitor or IL-6 inhibitor (e.g., as disclosed in Table 4 or 5 and/or an alternate inhibitor having a similar or identical mode of action as an agent disclosed in Table 4 or 5) and at an appropriate dose.
  • kits which contain the necessary reagents to carry out one or more assays to detect one or more SNPs disclosed herein.
  • SNP detection kits/systems are in the form of nucleic acid arrays, or compartmentalized kits, including microfluidic/lab-on-a-chip systems.
  • SNP detection kits/systems may contain, for example, one or more probes, or pairs of probes, that hybridize to a nucleic acid molecule at or near each target SNP position. Multiple pairs of allele- specific probes may be included in the kit/system to simultaneously assay large numbers of SNPs, at least one of which is the SNP of the disclosed subject matter. In some kits/systems, the allele- specific probes are immobilized to a substrate such as an array or bead.
  • arrays are used herein interchangeably to refer to an array of distinct polynucleotides affixed to a substrate, such as glass, plastic, paper, nylon or other type of membrane, filter, chip, or any other suitable solid support.
  • a substrate such as glass, plastic, paper, nylon or other type of membrane, filter, chip, or any other suitable solid support.
  • the polynucleotides can be synthesized directly on the substrate or synthesized separate from the substrate and then affixed to the substrate.
  • probes such as allele- specific probes
  • each probe or pair of probes can hybridize to a different SNP position.
  • polynucleotide probes they can be synthesized at designated areas (or synthesized separately and then affixed to designated areas) on a substrate using a light-directed chemical process.
  • Each DNA chip can contain, for example, thousands to millions of individual synthetic polynucleotide probes arranged in a grid-like pattern and miniaturized (e.g., to the size of a dime).
  • probes are attached to a solid support in an ordered, addressable array.
  • a SNP detection kit/system can include components that are used to prepare nucleic acids from a test sample for the subsequent amplification and/or detection of a SNP-containing nucleic acid molecule.
  • sample preparation components can be used to produce nucleic acid extracts (including DNA and/or RNA), proteins or membrane extracts from any bodily fluids (such as blood, serum, plasma, urine, saliva, phlegm, gastric juices, semen, tears, sweat, etc.), skin, hair, cells (especially nucleated cells), biopsies, buccal swabs or tissue or tumor specimens.
  • nucleic acids, proteins, and cell extracts are well known in the art and can be readily adapted to obtain a sample that is compatible with the system utilized.
  • Automated sample preparation systems for extracting nucleic acids from a test sample are commercially available, and examples are Qiagen’s BioRobot 9600, Applied Biosystems’ PRISM 6700 sample preparation system, and Roche Molecular Systems’ COBAS AmpliPrep System.
  • an exemplary microfluidic system may integrate, for example, nucleic acid amplification, primer extension, capillary electrophoresis, and a detection method such as laser induced fluorescence detection.
  • nucleic acid samples are amplified, preferably by PCR.
  • the amplification products are subjected to automated primer extension reactions using ddNTPs (specific fluorescence for each ddNTP) and the appropriate oligonucleotide primers to carry out primer extension reactions which hybridize just upstream of the targeted SNP.
  • the primers are separated from the unincorporated fluorescent ddNTPs by capillary electrophoresis.
  • the separation medium used in capillary electrophoresis can be, for example, polyacrylamide, polyethyleneglycol or dextran.
  • the incorporated ddNTPs in the single nucleotide primer extension products are identified by laser- induced fluorescence detection.
  • Such an exemplary microchip can be used to process, for example, at least 96 to 384 samples, or more, in parallel.
  • An exemplary kit allows a user to determine whether a subject has genotype-specific differential expression of IL-1, i.e., is a “high” or “low” producer of IL-1, based upon the composite IL-1 genotype or IL-1 genotype patterns disclosed in Tables 1-3.
  • the exemplary kit may include instructions having information which allows a user to decide on an appropriate agent or agents for IL-1 based treatment (e.g., as disclosed in Table 4 or 5 and/or an alternate agents(s) having a similar or identical mode of action as those disclosed in Table 4 or 5) and at an appropriate dose.
  • the results of a test provide an identification of a composite IL-1 genotype or IL-1 genotype pattern, as disclosed in Tables 1-3, which determine whether or not a subject should be administered IL-1 inhibiting agent (e.g., a response to an agent disclose in Table 4 or 5 and/or an alternate agent having a mode of action similar to or identical to an agent from Table 4 or 5) prior to immunotherapy or the onset of CRS and/or neurotoxicity, or for the treatment of immunotherapy induced CRS and/or neurotoxicity.
  • IL-1 inhibiting agent e.g., a response to an agent disclose in Table 4 or 5 and/or an alternate agent having a mode of action similar to or identical to an agent from Table 4 or 5
  • the results may be referred to herein as a “report”.
  • the report may include other information based on assaying the SNPs disclosed herein, alone or in combination with other SNPs, and/or a subject’s allele/genotype at the SNPs disclosed herein, alone or in combination with other SNPs, etc.), and/or any other information pertaining to a test.
  • a tangible report can optionally be generated as part of a testing process (which may be interchangeably referred to herein as “reporting”, or as “providing” a report, “producing” a report, or “generating” a report).
  • Examples of tangible reports may include, but are not limited to, reports in paper (such as computer-generated printouts of test results or hand written reports) or equivalent formats and reports stored on computer readable medium (such as a CD, USB flash drive or other removable storage device, computer hard drive, or computer network server, etc.). Reports, particularly those stored on computer readable medium, can be part of a database, which may optionally be accessible via the internet (such as a database of patient records or genetic information stored on a computer network server, which may be a “secure database” that has security features that limit access to the report, such as to allow only the patient and the patient’s medical practitioners to view the report while preventing other unauthorized subjects from viewing the report, for example). In addition to, or as an alternative to, generating a tangible report, reports can also be displayed on a computer screen (or the display of another electronic device or instrument).
  • the report may be “intangible” in that it is orally presented to another.
  • a tangible report may be hand written or may be prepared using a computer.
  • a report may be provided to the subject who can then implement the information and/or instructions contained therein.
  • a report may be provided to a health care professional who can then implement the information and/or instructions contained therein and/or instruct the subject (e.g., prescribe and make a recommendation).
  • a report can include, for example, a recommendation of whether or not a subject should be administered an inflammation inhibitor either prophylactically or as a treatment for CRS and/or neurotoxicity.
  • the report can recommend administering agent disclosed in Table 4 or 5 and/or an alternate agent having a mode of action similar to or identical to an agent from Table 4 or 5 based upon his/her composite IL-1 genotype or IL-1 genotype pattern, as disclosed in Tables 1-3, as disclosed herein; the allele/genotype that a subject carries at the SNP locations disclosed herein; the status of his/her clinical indicators such as cytokine or CRP level; and/or his/her composite IL-1 genotype or IL-1 genotype pattern.
  • the report can include information of medical/biological significance (e.g., drug responsiveness, suggested treatment, and prophylactic methods).
  • the report may just include allele/genotype information and/or a composite IL-1 genotype or IL-1 genotype pattern and status of one or more clinical indicators but without including disease risk or other medical/biological significance; thus, the subject viewing the report can use the allele/genotype information and/or composite IL-1 genotype or IL-1 genotype pattern and status of one or more clinical indicators to determine the associated disease risk or other medical/biological significance from a source outside of the report itself, such as from a medical practitioner, publication, website, etc., which may optionally be linked to the report such as by a hyperlink.
  • a report can further be “transmitted” or “communicated” (these terms may be used herein interchangeably), such as to the subject who was tested, a medical practitioner (e.g., a doctor, nurse, clinical laboratory practitioner, genetic counselor, etc.), a healthcare organization, a clinical laboratory, and/or any other party or requester intended to view or possess the report.
  • a medical practitioner e.g., a doctor, nurse, clinical laboratory practitioner, genetic counselor, etc.
  • the act of “transmitting” or “communicating” a report can be by any means known in the art, based on the format of the report.
  • “transmitting” or “communicating” a report can include delivering a report (“pushing”) and/or retrieving (“pulling”) a report.
  • reports can be transmitted/communicated by various means, including being physically transferred between parties (such as for reports in paper format) such as by being physically delivered from one party to another, or by being transmitted electronically or in signal form (e.g., via e-mail or over the internet, by facsimile, and/or by any wired or wireless communication methods known in the art) such as by being retrieved from a database stored on a computer network server.
  • parties such as for reports in paper format
  • signals form e.g., via e-mail or over the internet, by facsimile, and/or by any wired or wireless communication methods known in the art
  • SNPs single nucleotide polymorphisms
  • a locus is the site at which divergence occurs. SNPs can result in modified amino acid sequences, altering structure and function of coded protein, and influence the splicing process when present at exon-intron transitions and modify gene transcription when part of promoters. This modification can lead to altered levels of protein expression.
  • the term subject is meant to include any human subject.
  • drug As used herein, the terms “drug”, “medication”, “therapeutic”, “active agent”,
  • therapeutic compound refers to any chemical entity, pharmaceutical, drug, biological, botanical, and the like that can be used to treat or prevent a disease, illness, condition, or disorder of bodily function.
  • a drug may comprise both known and potentially therapeutic compounds.
  • a drug may be determined to be therapeutic by screening using the screening known to those having ordinary skill in the art.
  • a “known therapeutic compound”, “drug”, or “medication” refers to a therapeutic compound that has been shown (e.g., through animal trials or prior experience with administration to humans) to be effective in such treatment.
  • a “therapeutic regimen” relates to a treatment comprising a “drug”, “medication”, “therapeutic”, “active agent”, “therapeutic compound”, “composition”, or “compound” as disclosed herein and/or a treatment comprising behavioral modification by the subject and/or a treatment comprising a surgical means.

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Abstract

L'invention concerne des compositions et des méthodes pour réduire le risque de développer un syndrome de libération de cytokines ou une neurotoxicité, qui peut être associé à des immunothérapies, par détermination d'un motif de génotype IL-1 d'un sujet.
PCT/EP2020/072617 2019-08-12 2020-08-12 Compositions et méthodes de traitement du syndrome de libération de cytokines et de neurotoxicité WO2021028469A1 (fr)

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