Techniques to treat neurological disorders by attenuating the production of pro-inflammatory mediators

• US 20050095246A1
• Filed: 10/22/2004
• Published: 05/05/2005
• Est. Priority Date: 10/24/2003
• Status: Abandoned Application

• Current Assignee: Medtronic Incorporated (Medtronic Plc), Warsaw Orthopedic Incorporated (Medtronic Plc)
• Original Assignee: Medtronic Incorporated (Medtronic Plc)
• Inventors: Shafer, Lisa L.
• Application Number:
  US10/972,157
• Publication Number:
  US 20050095246A1
• Time in Patent Office: Days
• US Class Current: 424/145.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 38/02 Peptides of undefined number of amino acids; Derivatives thereof
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/206 IL-9
• CPC Class Codes: A61K 38/2066 IL-10
• CPC Class Codes: A61M 2205/04 implanted
• CPC Class Codes: A61M 2210/0693 Brain, cerebrum
• CPC Class Codes: A61M 25/00 Catheters; Hollow probes dilators A61M29/00; peritoneal catheters A61M1/285; tracheal tubes A61M16/04; for drainage A61M27/00; for uterus, vagina or rectum A61M31/00 ; for measuring or testing A61B; materials for catheters A61L29/00
• CPC Class Codes: A61M 39/0208 Subcutaneous access sites for injecting or removing fluids transcutaneous access sites A61M39/0247; implantable infusion devices A61M5/14276
• CPC Class Codes: A61M 5/14276 specially adapted for implantation
• CPC Class Codes: A61M 5/1723 using feedback of body parameters, e.g. blood-sugar, pressure measurement of body parameters A61B5/00
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: C07K 16/241 Tumor Necrosis Factors
• CPC Class Codes: G01N 2333/54 Interleukins [IL]
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 33/6863 Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease
• CPC Class Codes: G01N 33/743 Steroid hormones
• CPC Class Codes: G01N 33/948 : Sedatives, e.g. cannabinoids, barbiturates opiates G01N33/9486

Abstract

Methods and devices to attenuate tumor necrosis factor (TNF) and other pro-inflammatory mediators in the CNS to treat neurological, neurodegenerative, neuropsychiatric disorders, pain and brain injury are described. More particularly, TNF blocking agents that target intracellular signals and downstream effects associated with the production and secretion of TNF are described. Devices described include therapy delivery devices comprising a reservoir capable of housing a TNF blocking agent and a catheter operably coupled to the device and adapted to deliver the TNF blocking agent to a target site within a subject.

Claims

19. A method for treating a CNS disorder associated with a proinflammatory agent in a subject in need thereof, the method comprising:

administering an intracellular TNF modifying agent to the subject in an amount effective to treat the CNS disorder.

1. A medical device comprising:

a pump;

a reservoir operably coupled to the pump;

an intracellular TNF modifying agent housed in the reservoir and being deliverable to a target site in a patient in an amount effective to treat a CNS disorder; and

a catheter operably coupled to the pump and configured to deliver the intracellular TNF modifying agent to the target site.

2. The medical device of claim 1, wherein the pump is a programmable pump.

3. The medical device of claim 1, wherein the pump is a fixed-rate pump.

4. The medical device of claim 1, wherein the pump is an osmotic pump.

5. The medical device of claim 1, wherein the intracellular TNF modifying agent is selected from the group consisting of an agent that blocks the translocation or binding of death domain proteins to the TNF receptor complex, an agent that blocks the translocation or binding of death effector domain proteins to the TNF receptor complex, and agent that blocks the translocation or binding of TNF receptor-associated factors (TRAFs) to the TNF receptor complex, an agent that blocks the translocation or binding of caspase recruitment domain proteins to the TNF receptor complex, an anti-apoptosis agent, a kinase inhibitor, a tyrosine kinase inhibitor, an NFκ

b inhibitor, an Iκ

B inhibitor, an IKK inhibitor, a phosphodiesterase inhibitor, an agent that block the transcription or translation of TNFα

, and a TACE inhibitor.

6. The medical device of claim 5, wherein the intracellular TNF modifying agent is selected from the group consisting of a SangStat molecule, RDP58, Efalizumab (anti-LFA 1), Antegren (natalizumab), CDP 232, CTLA-41g, Rituximab I (anti-CD20 antibody), Xanelim (anti-CD11b antibody), a caspase inhibitor, pan-caspase inhibitor z-VAD, Pralnacasan (VX-740, Vertex), an inhibitor of the inflammation target caspase-1(ICE), VX-765, VX-799, CV1013 (Maxim Pharmaceuticals), IDN 6556(Idun Pharmaceuticals), IDN 6734 (Idun Pharmaceuticals), Activase, Retavase, TNKase, Metalyse, Tenecteplase, TNK-tPA, Pexelizumab, CAB2, RSR13 (Efaproxiral Sodium), VP025, Gleevec, Herceptin, Iressa, Imatinib (ST1571), Herbimycin A, Tyrphostin 47, Erbstatin, Genistein, Staurosporine, PD98059, SB203580, CNI-1493, VX-50/702 (Vertex/Kissei), SB203580, BIRB 796 (Boehringer Ingelheim), Glaxo P38 MAP Kinase inhibitor, RWJ67657 (J&

J), UO126, Gd, SCIO-469 (Scios), RO3201195 (Roche), Semipimod (Cyotkine PharmaSciences), BMS345541 (IKK-B inhibitor, Bristol), Millennium NFκ

B of IKK-B inhibitor, a pyrrolidine dithiocarbamatem (PDTC) derivative, SPC600839 (Celgene/Serono), an IKK-B inhibitor, a nuclear translocation inhibitors, deoxyspergualin (DSG), a PDE IV inhibitor, Roflumilast, Arofylline, Pentoxyfylline, Ariflo (cilomilast, GSK), CDC-801 (Celgene), CD-7085 (Celgene), Rolipram, Propenofylline, a TNF α

antisense molecule, Isis 104838, Isis 2302, an siRNA targeted to TNF α

mRNA, a matrix metalloproteinase inhibitor, BMS561392 (Bristol-Myers Squibb), PKF242-484 (Novartis), PKF241-466 (Novartis) and aminopyridazine (MW01-070C).

7. The medical device of claim 1, wherein the intracellular TNF modifying agent is selected from the group consisting of an agent that blocks the translocation or binding of death domain proteins to the TNF receptor complex, an agent that blocks the translocation or binding of death effector domain proteins to the TNF receptor complex, and agent that blocks the translocation or binding of TNF receptor-associated factors (TRAFs) to the TNF receptor complex, an agent that blocks the translocation or binding of caspase recruitment domain proteins to the TNF receptor complex, an anti-apoptosis agent, a kinase inhibitor, a tyrosine kinase inhibitor, an NFκ

b inhibitor, an Iκ

B inhibitor, an IKK inhibitor, a phosphodiesterase inhibitor, an agent that block the transcription or translation of TNFα

, and a TACE inhibitor.

8. The medical device of claim 7, wherein the intracellular TNF modifying agent is selected from the group consisting of a SangStat molecule, RDP58, Efalizumab (anti-LFA 1), Antegren (natalizumab), CDP 232, CTLA-41g, Rituximab I (anti-CD20 antibody), Xanelim (anti-CD11b antibody), a caspase inhibitor, pan-caspase inhibitor z-VAD, Pralnacasan (VX-740, Vertex), an inhibitor of the inflammation target caspase-1(ICE), VX-765, VX-799, CVI1013 (Maxim Pharmaceuticals), IDN 6556(Idun Pharmaceuticals), IDN 6734 (Idun Pharmaceuticals), Activase, Retavase, TNKase, Metalyse, Tenecteplase, TNK-tPA, Pexelizumab, CAB2, RSR13 (Efaproxiral Sodium), VP025, Gleevec, Herceptin, Iressa, Imatinib (ST1571), Herbimycin A, Tyrphostin 47, Erbstatin, Genistein, Staurosporine, PD98059, SB203580, CNI-1493, VX-50/702 (Vertex/Kissei), SB203580, BIRB 796 (Boehringer Ingelheim), Glaxo P38 MAP Kinase inhibitor, RWJ67657 (J&

J), UO126, Gd, SCIO-469 (Scios), RO3201195 (Roche), Semipimod (Cyotkine PharmaSciences), BMS345541 (IKK-B inhibitor, Bristol), Millennium NFκ

B of IKK-B inhibitor, a pyrrolidine dithiocarbamatem (PDTC) derivative, SPC600839 (Celgene/Serono), an IKK-B inhibitor, a nuclear translocation inhibitors, deoxyspergualin (DSG), a PDE IV inhibitor, Roflumilast, Arofylline, Pentoxyfylline, Ariflo (cilomilast, GSK), CDC-801 (Celgene), CD-7085 (Celgene), Rolipram, Propenofylline, a TNF α

antisense molecule, Isis 104838, Isis 2302, an siRNA targeted to TNF α

mRNA, a matrix metalloproteinase inhibitor, BMS561392 (Bristol-Myers Squibb), PKF242-484 (Novartis), PKF241-466 (Novartis) and aminopyridazine (MW01-070C).

9. The medical device of claim 1, further comprising an extracellular TNF modifying agent deliverable via the catheter to the target site.

10. The medical device of claim 9, wherein the extracellular TNF modifying agent is housed in the reservoir.

11. The medical device of claim 9, further comprising a second reservoir, the second reservoir being operably coupled to the pump and housing the extracellular TNF modifying agent.

12. The medical device of claim 9, flurther comprising a second pump and a second reservoir, the second pump being operably coupled to the second reservoir, the catheter being operably coupled to the second pump and configured to deliver the extracellular TNF modifying agent to the target site.

13. The medical device of claim 1, further comprising a second catheter, a second pump and a second reservoir, the second reservoir being operably coupled to the second pump and housing an extracellular TNF modifying agent, the second catheter being operably coupled to the second pump and configured to deliver the extracellular TNF modifying agent to a second target site, wherein the target site within the patient and wherein the second target site are the same or different.

14. The medical device of claim 1, further comprising a sensor capable of detecting an event associated with the disorder or treatment of the disorder.

15. The medical device of claim 14, wherein the sensor is operably coupled to the pump.

16. The medical device of claim 15, wherein a parameter of the pump is capable of being modified by data from the sensor.

17. The medical device of claim 14, further comprising a memory operably coupled to the sensor and capable of storing sensed data.

18. The medical device of claim 14, wherein the sensor is capable of detecting a dysfunctional immune or sickness response or whether an inflammatory response has been attenuated or enhanced.

20. The method of claim 19, wherein administering the intracellular TNF modifying agent comprises administering the agent directly to the subject'"'"'s central nervous system.

21. The method of claim 20, wherein administering the agent directly to the subject'"'"'s central nervous system comprises administering the agent intraparenchymally.

22. The method of claim 20, wherein administering the agent directly to the subject'"'"'s central nervous system comprises administering the agent intracerebroventricularly.

23. The method of claim 19, wherein administering the intracellular TNF modifying agent comprises peripherally administering the agent to the subject.

24. The method of claim 23, wherein peripherally administering the agent to the subject comprises perispinal, intranasal or parenteral administration

25. The method of claim 19, wherein the CNS disorder is a neurological disorder, a neurodegenerative disorder, a neuropsychiatric disorder, pain or brain injury.

26. The method of claim 19, wherein the CNS disorder is stroke.

27. The method of claim 26, wherein the administering an intracellular TNF modifying agent comprises administering the agent intrathecally.

28. The method of claim 26, wherein the administering an intracellular TNF modifying agent comprises administering the agent intracerebroventricularly.

29. The method of claim 26, wherein administering an intracellular TNF modifying agent comprises administering the agent to a cerebral artery of the subject.

30. The method of claim 29, wherein administering the agent to a cerebral artery comprises administering the agent to the middle cerebral artery.

31. The method of claim 30, wherein the agent administering the agent to the middle cerebral artery comprises administering the agent to the middle cerebral artery at or near infarct.

32. The method of claim 26, wherein the administering an intracellular TNF modifying agent comprises administering the agent intraparenchymally.

33. The method of claim 32, wherein administering the agent intraparenchymally comprises administering the agent at or near an infarct.

34. The method of claim 32, wherein administering the agent intraparenchymally comprises administering the agent at or near a site associated with secondary ischemic events following the stroke.

35. The method of claim 34, wherein administering the agent at or near a site associated with secondary ischemic events comprises administering the agent to the pons, midbrain, or medulla.

36. The method of claim 26, wherein the stroke is middle cerebral artery stroke.

37. The method of claim 36, wherein administering an intracellular TNF modifying agent comprises administering the agent intraparenchymally to the hippocampus.

38. The method of claim 37, wherein administering the agent intraparenchymally to the hippocampus comprises administering the agent intraparenchymally to the CA1 region of the hippocampus.

39. The method of claim 36, wherein administering an intracellular TNF modifying agent comprises administering the agent intraparenchymally to the striatum.

40. The method of claim 26, wherein the stroke results in hemiperesis.

41. The method of claim 40, wherein administering an intracellular TNF modifying agent comprises administering the agent intraparenchymally to the posterior limb of the internal capsule.

42. The method of claim 19, wherein the CNS disorder is Alzheimer'"'"'s disease.

43. The method of claim 42, wherein the administering an intracellular TNF modifying agent comprises administering the agent intrathecally.

44. The method of claim 42, wherein the administering an intracellular TNF modifying agent comprises administering the agent intracerebroventricularly.

45. The method of claim 44, wherein the administering the agent intraparenchymally comprises administering the agent at or near an amyloid beta plaque.

46. The method of claim 44, wherein the administering the agent intraparenchymally comprises administering the agent to the basal forebrain cholinergic region.

47. The method of claim 44, wherein the administering the agent intraparenchymally comprises administering the agent to the temporal lobe region.

48. The method of claim 44, wherein the administering the agent intraparenchymally comprises administering the agent to the hippocampus.

49. The method of claim 44, wherein the administering the agent intraparenchymally comprises administering the agent to the entorhinal cortex

50. The method of claim 44, wherein the administering the agent intraparenchymally comprises administering the agent to the dentate gyrus.

51. The method of claim 19, wherein the CNS disorder is epilepsy.

52. The method of claim 51, wherein the administering an intracellular TNF modifying agent comprises administering the agent intrathecally.

53. The method of claim 51, wherein the administering an intracellular TNF modifying agent comprises administering the agent intracerebroventricularly.

54. The method of claim 51, wherein the administering an intracellular TNF modifying agent comprises administering the agent intraparenchymally.

55. The method of claim 54, wherein the administering the agent intraparenchymally comprises administering the agent at or near an epileptic focus.

56. The method of claim 54, wherein the administering the agent intraparenchymally comprises administering the agent to the hippocampus.

57. The method of claim 56, wherein administering the agent to the hippocampus comprises administering the agent to the CA1 region of the hippocampus.

58. The method of claim 19, wherein the CNS disorder is depression.

59. The method of claim 58, wherein the administering an intracellular TNF modifying agent comprises administering the agent intrathecally.

60. The method of claim 58, wherein the administering an intracellular TNF modifying agent comprises administering the agent intracerebroventricularly.

61. The method of claim 60, wherein the administering the agent intracerebroventricularly comprises administering the agent to the floor of the fourth ventricle, dorsal to the abducens nuclei.

62. The method of claim 58, wherein the administering an intracellular TNF modifying agent comprises administering the agent intraparenchymally.

63. The method of claim 62, wherein the administering the agent intraparenchymally comprises administering the agent to a brain region associated with the hypothalamic-pituitary-adrenal (HPA)-axis.

64. The method of claim 63, wherein administering the agent to a brain region associated with the HPA-axis comprises administering the agent to the hypothalamus.

65. The method of claim 63, wherein administering the agent to a brain region associated with the HPA-axis comprises administering the agent to the anterior pituitary gland.

66. The method of claim 62, wherein the administering the agent intraparenchymally comprises administering the agent to a brain region associated with serotonin production or output.

67. The method of claim 66, wherein administering the agent to a brain region associated with serotonin production or output comprises administering the agent to the dorsal raphe nucleus.

68. The method of claim 66, wherein administering the agent to a brain region associated with serotonin production or output comprises administering the agent to the midline of the brainstem.

69. The method of claim 66, wherein administering the agent to a brain region associated with serotonin production or output comprises administering the agent to a brain region selected from the group consisting of the ventral surface of the pyramidal tract, the nucleus raphe obscurans, the raphe at the level of the hypoglossal nucleus, at the level of the facial nerve nucleus surrounding the pyramidal tract, the pontine raphe nucleus, above and between the longitudinal fasiculi at the central substantia grisea, the medial raphe nucleus, and the medial lemniscus nucleus.

70. The method of claim 19, further comprising administering an extracellular TNF modifying agent to the subject in an amount effective to enhance treatment of the CNS disorder.

71. The method of claim 70, wherein administering an extracellular TNF modifying agent to the subject comprises administering an agent selected from the group consisting of TNF fusion protein, an antibody directed to TNF, a monoclonal antibody directed to TNF, a TNF binding protein, a soluble TNF receptor, a soluble pegylated TNF receptor, an antibody fragment directed to TNF, a dominant-negative TNF variant, an integrin antagonists, alpha-4 beta-7 integrin antagonists, a cell adhesion inhibitor, interferon gamma antagonists, a CTLA4-Ig agonists/antagonists, a CD40 ligand antagonists, a anti-IL-6 antibody, an anti-HMGB-1 antibody, an anti-IL2R antibody, an anti-IL-8 antibody, and an anti-IL-10 antibody.

72. The method of claim 70, wherein administering an extracellular TNF modifying agent to the subject comprises administering an agent selected from the group consisting of etanercept, infliximab, D2E7, onercept, CDP 870, CDP 571, PEGs TNF-R1, DN-TNF, BMS-188667, tocilizumab (Chugai), daclizumab, basilicimab, ABX (anti IL-8 antibody), and HuMax IL-15 (anti-IL15 antibody).

73. The method of claim 72, wherein administering an extracellular TNF modifying agent to the subject comprises administering the agent via a controlled administration system.

74. The method of claim 73, wherein the administering the agent via a controlled administration system comprises administering the agent in a depot.

75. The method of claim 74, wherein the administering the agent via a controlled administration system comprises administering the agent via a catheter operably coupled to a pump.

76. The method of claim 19, wherein the CNS disorder is pain.

77. The method of claim 76, wherein the pain is chronic pain.

78. The method of claim 76, wherein administering an intracellular TNF modifying agent comprises administering the agent intrathecally.

79. The method of claim 76, wherein administering an intracellular TNF modifying agent comprises administering the agent perispinally.

80. The method of claim 79, wherein administering the agent perispinally comprises administering the agent into a verterbral disc.

88. The method of claim 81, wherein administering an extracellular TNF modifying agent to the subject comprises administering an agent selected from the group consisting of etanercept, infliximab, D2E7, onercept, CDP 870, CDP 571, PEGs TNF-R1, DN-TNF, BMS-188667, tocilizumab (Chugai), daclizumab, basilicimab, ABX (anti IL-8 antibody), and HuMax IL-15 (anti-IL15 antibody).

44-1. The method of claim 42, wherein the administering an intracellular TNF modifying agent comprises administering the agent intraparenchymally.

81. A pharmaceutical depot comprising:

a pharmaceutical delivery formulation;

an intracellular TNF modifying agent disposed in or on the pharmaceutical delivery formulation; and

an extracellular TNF modifying agent disposed in or on the pharmaceutical delivery formulation.

82. The depot of claim 81, wherein the pharmaceutical delivery formulation comprises a capsule, a microsphere, a particle, a gel, a coating, a matrix, a wafer, or a pill.

83. The depot of claim 82, wherein the pharmaceutical delivery formulation comprises a biopolymer.

84. The depot of claim 83, wherein the pharmaceutical polymer comprises a polymer selected from the group consisting of poly(alpha-hydroxy acid), poly(lactide-co-glycolide) (PLGA), polylactide (PLA), polyglycolide (PG), polyethylene glycol (PEG) conjugates of a poly(alpha-hydroxy acid), polyorthoester, polyaspirin, polyphosphagene, collagen, starch, chitosan, gelatin, alginate, dextran, vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylate, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymer, and PLGA-PEO-PLGA.

85. The depot of claim 81, wherein the intracellular TNF modifying agent is selected from the group consisting of an agent that blocks the translocation or binding of death domain proteins to the TNF receptor complex, an agent that blocks the translocation or binding of death effector domain proteins to the TNF receptor complex, and agent that blocks the translocation or binding of TNF receptor-associated factors (TRAFs) to the TNF receptor complex, an agent that blocks the translocation or binding of caspase recruitment domain proteins to the TNF receptor complex, an anti-apoptosis agent, a kinase inhibitor, a tyrosine kinase inhibitor, an NFκ

b inhibitor, an Iκ

B inhibitor, an IKK inhibitor, a phosphodiesterase inhibitor, an agent that block the transcription or translation of TNFα

, and a TACE inhibitor.

86. The depot of claim 81, wherein the intracellular TNF modifying agent is selected from the group consisting of a SangStat molecule, RDP58, Efalizumab (anti-LFA 1), Antegren (natalizumab), CDP 232, CTLA-41g, Rituximab I (anti-CD20 antibody), Xanelim (anti-CD11b antibody), a caspase inhibitor, pan-caspase inhibitor z-VAD, Pralnacasan (VX-740, Vertex), an inhibitor of the inflammation target caspase-1(ICE), VX-765, VX-799, CV1013 (Maxim Pharmaceuticals), IDN 6556(Idun Pharmaceuticals), IDN 6734 (Idun Pharmaceuticals), Activase, Retavase, TNKase, Metalyse, Tenecteplase, TNK-tPA, Pexelizumab, CAB2, RSR13 (Efaproxiral Sodium), VP025, Gleevec, Herceptin, Iressa, Imatinib (ST1571), Herbimycin A, Tyrphostin47, Erbstatin, Genistein, Staurosporine, PD98059, SB203580, CNI-1493, VX-50/702 (Vertex/Kissei), SB203580, BIRB 796 (Boehringer Ingelheim), Glaxo P38 MAP Kinase inhibitor, RWJ67657 (J&

J), UO126, Gd, SCIO-469 (Scios), RO3201195 (Roche), Semipimod (Cyotkine PharmaSciences), BMS345541 (IKK-B inhibitor, Bristol), Millennium NFκ

B of IKK-B inhibitor, a pyrrolidine dithiocarbamatem (PDTC) derivative, SPC600839 (Celgene/Serono), an IKK-B inhibitor, a nuclear translocation inhibitors, deoxyspergualin (DSG), a PDE IV inhibitor, Roflumilast, Arofylline, Pentoxyfylline, Ariflo (cilomilast, GSK), CDC-801 (Celgene), CD-7085 (Celgene), Rolipram, Propenofylline, a TNF α

antisense molecule, Isis 104838, Isis 2302, an siRNA targeted to TNF α

mRNA, a matrix metalloproteinase inhibitor, BMS561392 (Bristol-Myers Squibb), PKF242-484 (Novartis), PKF241-466 (Novartis) and aminopyridazine (MW01-070C).

87. The method of claim 81, wherein administering an extracellular TNF modifying agent to the subject comprises administering an agent selected from the group consisting of TNF fusion protein, an antibody directed to TNF, a monoclonal antibody directed to TNF, a TNF binding protein, a soluble TNF receptor, a soluble pegylated TNF receptor, an antibody fragment directed to TNF, a dominant-negative TNF variant, an integrin antagonists, alpha-4 beta-7 integrin antagonists, a cell adhesion inhibitor, interferon gamma antagonists, a CTLA4-Ig agonists/antagonists, a CD40 ligand antagonists, a anti-IL-6 antibody, an anti-HIMGB-1 antibody, an anti-IL2R antibody, an anti-IL-8 antibody, and an anti-IL-10 antibody.