Mechanisms in autoimmunity and cancer
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Mechanisms in autoimmunity and cancer

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Harnessing the innate immunity to modulate autoimmunity and cancer, IVIG; The Myth and Reality ...

Harnessing the innate immunity to modulate autoimmunity and cancer, IVIG; The Myth and Reality

Presented by Professor Yehuda Shoenfeld, MD, FRCP at CONPO Barcelona 2013

IVIG
*Definitive way of preparation; produced by 25 pharmaceutical companies (very expensive).
*Clinical applications: treatment of severe immune deficiency diseases and a variety of autoimmune conditions.
*Pooled IgG (immunologlobulin G) from 6,000--20,000 blood donation.

Intravenous Immunoglobulin-IVIg
*Pooled IgG (immunologlobulin G) from 6,000- 20,000 blood donation (representing the Innate Immune repertoire)
*Definitive way of preparation; produced by 25 pharmaceutical companies (very expensive)
*Clinical applications: Treatment of severe immune deficiency diseases and a variety of autoimmune conditions

CONCLUSIONS:
IVIg- the myth and reality
* IVIG is effective in autoimmune conditions –multiple mechanisms
* IVIg anti -cancer effects in; melanoma, carcinoma, sarcoma and lymphoma
* IVIG representing the innate immune system affect tumors by diverse mechanisms

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  • 1. Yehuda Shoenfeld, MD,FRCP ( Hon.)Yehuda ShoenfeldMD,FRCP,IVIG;The myth and realityIVIG;The myth and realityIVIGCONPO Barcelona2013Harnessing the innate immunity tomodulate autoimmunity and cancer
  • 2. Yehuda Shoenfeld, MD,FRCP ( Hon.)Future Congresses
  • 3. Yehuda Shoenfeld, MD,FRCP ( Hon.)Definitive way of preparation; produced by 25Definitive way of preparation; produced by 25pharmaceutical companies (very expensive).pharmaceutical companies (very expensive).Clinical applications: treatment of severe immuneClinical applications: treatment of severe immunedeficiency diseases and a variety of autoimmunedeficiency diseases and a variety of autoimmuneconditions.conditions.Pooled IgG (immunologlobulin G) from 6,000Pooled IgG (immunologlobulin G) from 6,000--20,00020,000blood donation.blood donation.
  • 4. Yehuda Shoenfeld, MD,FRCP ( Hon.)Intravenous Immunoglobulin-IVIgPooled IgG (immunologlobulin G) from 6,000-20,000 blood donation (representing the Innate Immunerepertoire)Definitive way of preparation; produced by 25pharmaceutical companies (very expensive)Clinical applications: Treatment of severeimmune deficiency diseases and a variety ofautoimmune conditions
  • 5. Yehuda Shoenfeld, MD,FRCP ( Hon.)IVIgIVIg THERAPYTHERAPYHigh-dose: 2-g/kg body weight IVIg.The preparation: Octapharma,MedImmune,Sclavo, BPL, tegeline , endobuline, gammagard ,ZLB,Omrix)A 5-days schedule.A monthly interval.Every patient received 1-6 treatment courses.
  • 6. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 7. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 8. Yehuda Shoenfeld, MD,FRCP ( Hon.)Paul ImbachIVIGWiskott AldrichLancet 1981;1-1228-30IVIG in ITP
  • 9. Yehuda Shoenfeld, MD,FRCP ( Hon.)Immune thrombocytopenia (ITP)ITP is anautoimmunedisease due toautoantibodyto endogenousplateletsCauses plateletdestruction bymacrophagesand bleeding
  • 10. Yehuda Shoenfeld, MD,FRCP ( Hon.)Michel .D.KazatchkineNEJM2001;345;747
  • 11. Yehuda Shoenfeld, MD,FRCP ( Hon.)Successful IVIG treatment inSuccessful IVIG treatment inautoimmune diseasesautoimmune diseases ITPITP Autoimmune hemolytic anemia Viral-associated red-cell aplasia Guillain-Barre syndrome Myastenia gravis Polymyositis Dermatomyositis Kawasaki disease ANCA-positive systemic vasculitis Antiphospholipid syndrome Recurrent spontaneous abortions Multiple sclerosis Felty’s syndrome Juvenile RA SLE GVHD Multiple sclerosis IDDM Steroid-dependent asthma Steroid dependent severe atopicdermatitis Crohn’s disease Chronic Inflamatory DemyelinatingPolyneuropathy
  • 12. Yehuda Shoenfeld, MD,FRCP ( Hon.)A study of 20 SLE patients withA study of 20 SLE patients withintravenous immunoglobulinintravenous immunoglobulinclinical and serologic responseclinical and serologic responseYair Levy, Yaniv Sherer, Alaa Ahmed, Pnina Langevitz, Jacob GeorYair Levy, Yaniv Sherer, Alaa Ahmed, Pnina Langevitz, Jacob George,ge,Fabizio Fabbrizzi, Jeff Terryberry, Martyna Meissner, Margalit LFabizio Fabbrizzi, Jeff Terryberry, Martyna Meissner, Margalit Lorber,orber,James B Peter,James B Peter, Yehuda Shoenfeld.Yehuda Shoenfeld.Lupus 8, 705Lupus 8, 705--712, 1999712, 1999 A beneficial clinical response followingIVIg treatment was noted in 17 out of20 patients (85%). Some clinical manifestations respondedmore to treatment: arthritis, fever,thrombocytopenia, and neuropsychiatriclupus.
  • 13. Yehuda Shoenfeld, MD,FRCP ( Hon.)Successful treatment of early secondarySuccessful treatment of early secondarymyelofibrosismyelofibrosisin SLE with IVIG.in SLE with IVIG.Aharon A, Levy Y, Bar Dayan Y, Afek A, Zandman-Goddard, SkurnikY, Fabrrizzi F, Shoenfeld YLupus 6: 408-411,1997.IVIG
  • 14. Yehuda Shoenfeld, MD,FRCP ( Hon.)Reduced proteinuria followingReduced proteinuria followingrepeated courses of IVIGrepeated courses of IVIG024682monbf1monbf1stcycle2ndcycle3rdcycle4thcycle5thcycle6cycle12monaf18monaf30monafUrinaryproteinextraction(g/24h)
  • 15. Yehuda Shoenfeld, MD,FRCP ( Hon.)A Comparison Between Prednisone DosesA Comparison Between Prednisone Dosesused for the Treatment of SLE Patientsused for the Treatment of SLE PatientsBefore and After IVIgBefore and After IVIg0102030405060BeforeIVIG After6cyclesofIVIGP<0.05P<0.05
  • 16. Yehuda Shoenfeld, MD,FRCP ( Hon.)2. Anti2. Anti--idiotypicidiotypic AbsAbsAnti-Id AbPathogenic auto-AbAnti-Id Abs modulates the immune system by suppressingauto-Abs production
  • 17. Yehuda Shoenfeld, MD,FRCP ( Hon.)AIM :To evaluate theTo evaluate theefficacy of theefficacy of theantianti--dsDNA antidsDNA anti--idiotypesidiotypesenrichedenriched IVIGIVIG
  • 18. B.GilburdeM.Blank
  • 19. Yehuda Shoenfeld, MD,FRCP ( Hon.)Affinity purification of antiAffinity purification of anti--dsDNAdsDNAantianti--ID from IVIGID from IVIGAnti-dsDNA-SepharoseLoading dialyzedIVIGYYYYYYYYYYYYYYYYYYYYYYYYElution withHCl-glycine16 hours at 4oCYYYYYYYYYYYYYYYYYYantianti--dsDNA antidsDNA anti--IDIDYYYYYYYYYYYY
  • 20. Yehuda Shoenfeld, MD,FRCP ( Hon.)Treatment of NZB/W F1 micewith IVIG-IDThree weekly injections to the tail veinof NZB/W F1 mice:IVIG-ID : 2 mg/kg = 60 µg/mouseIVIG: 400 mg/kg = 12 mg/mouse
  • 21. Yehuda Shoenfeld, MD,FRCP ( Hon.)Proteinuria in NZB/W F1 miceProteinuria in NZB/W F1 micetreated with SUPERIVIG and IVIGtreated with SUPERIVIG and IVIG051015202530IVIG-ID IVIG CONTROLG/L*
  • 22. Yehuda Shoenfeld, MD,FRCP ( Hon.)IVIG-IDIVIG-ID IVIGIVIG NON-TREATEDNON-TREATEDPrevention of mesangial mouse IgGdeposits in NZB/W F1 micetreated (early treatment) with:Prevention of mesangial mouse IgGPrevention of mesangial mouse IgGdeposits in NZB/W F1 micedeposits in NZB/W F1 micetreated (early treatment) with:treated (early treatment) with:
  • 23. Yehuda Shoenfeld, MD,FRCP ( Hon.)Cumulative number of deaths withCumulative number of deaths withconcomitant proteinuria in NZB/W F1 miceconcomitant proteinuria in NZB/W F1 miceWeeks of ageWeeks of age25 30 35 40 45024681012IVIGIVIG--IDIDIVIGIVIGControlControlNumberofdeathsNumberofdeaths
  • 24. Yehuda Shoenfeld, MD,FRCP ( Hon.)Efficacy of IVIG affinityEfficacy of IVIG affinity--purified antipurified anti--doubledouble--stranded DNA antistranded DNA anti--idiotypicidiotypicantibodies in the treatment of anantibodies in the treatment of anexperimental murine model ofexperimental murine model ofsystemic lupus erythematosus.systemic lupus erythematosus.Shoenfeld Y,Shoenfeld Y, Rauova L, Gilburd BRauova L, Gilburd B, Kvapil F,, Kvapil F,Goldberg I, Kopolovic J, Rovensky J,Goldberg I, Kopolovic J, Rovensky J, Blank M.Blank M.Int Immunol. 2002 ;14:1303Int Immunol. 2002 ;14:1303--1111
  • 25. Yehuda Shoenfeld, MD,FRCP ( Hon.)YYYYYYYYYYYYYYYYAntiAnti-- dsDNAdsDNASLESLEYYYYYYYYYYYYYYYYAntiAnti--2GPI2GPIAntiphospholipdAntiphospholipdsyndromesyndromeMyastheniaMyastheniaGravisGravisYYYYYYYYYYYYYYYYAntiAnti-- AChRAChRAutoimmune Disease Specific IVIg:Autoimmune Disease Specific IVIg:Low Dose, High EfficacyLow Dose, High EfficacySpecial types of IVIg for autoimmune diseasesPemphigusPemphigusvulgarisvulgarisYYYYYYYYYYYYYYYYAntiAnti--desmogleindesmoglein1/31/3
  • 26. Yehuda Shoenfeld, MD,FRCP ( Hon.)IVIG Treatment of CancerY. Shoenfeld, Sheba Medical Center, Israel
  • 27. Reactivity of the human IVIG with a panel ofhuman cell lineHuman bladder carcinoma cell line T24, human glioma cell line U-138MG, humanhead-and-neck cancer cell line PCI-13, human lymphoid cell line LG2 and humanmelanoma cell lines 501, 553B, 836,1379, Colo38 and Mel-1386 at 4oC for 2 hours.Reactivity of the humanized antibody IVIG with a panel of cell lines012T2 4 8 3 6 C o lo 3 8 M el-13 8 6 DAM -M B -2 3 1553 B 2 9 3 /KDR 13 79 PC I-13 LG2 50 1 U-13 8 M GCell linesODat450nmIV IGcontrol
  • 28. Yehuda Shoenfeld, MD,FRCP ( Hon.)IVIg: Prevention of MelanomaMetastasesGamma-globulin inhibits tumor spread in miceYehuda Shoenfeld and Pnina FishmanInternational immunology11: 1247 - 1251, 1999
  • 29. Yehuda Shoenfeld, MD,FRCP ( Hon.)Effect of IVIg (I.V.) on the Development ofMelanoma Metastases6 IVIG - Presentation, Oct 950255075100125No.offoci(%ofcontrol)Control 0 0,4 0,4,9DAYS OF IVIG TREATMENTP<0.001 P<0.001 P<0.001
  • 30. Yehuda Shoenfeld, MD,FRCP ( Hon.)IVIg Prolongs the Survival of TumorBearing Mice0204060801000 20 40 60 80 100Days after amputation%survivalTreatedControla - Sarcoma0204060801000 20 40 60 80 100Days after amputation%survivalTreatedControlb - MelanomaSarcoma Melanoma
  • 31. Yehuda Shoenfeld, MD,FRCP ( Hon.)IVIg: Prevention of Tumor focithe Peritoneum
  • 32. Yehuda Shoenfeld, MD,FRCP ( Hon.)IVIg: Prevention of Lung SarcomaMetastases
  • 33. Yehuda Shoenfeld, MD,FRCP ( Hon.)Inhibitory effect of IVIg on in vitro CT26 cellInhibitory effect of IVIg on in vitro CT26 cellproliferationproliferation* p < 0.05** p < 0.01*** p < 0.001010203040506070801 5 15 40IVIg concentration (mg/ml)%ofinhibition24h48h72h***********Time course and dose responseTime course and dose response
  • 34. Yehuda Shoenfeld, MD,FRCP ( Hon.)•Matrigel resultsEffect of IVIg on CT26 cell invasivenessThe invasive capacity of CT26 cells was decreased by IVIgThe invasive capacity of CT26 cells was decreased by IVIg(time(time-- and doseand dose--dependent effect)dependent effect)39.70010203040506048h 72h%ofinhibitionofinvasionIVIg 20mg/mlIVIg 40mg/mlp < 0.001
  • 35. Yehuda Shoenfeld, MD,FRCP ( Hon.)Dose Dependent Effect of IVIg on the Proliferation ofHuman Colon Carcinoma, HCT-116 Cells020406025 10 5 2.5 1.25IVIg Concentration (mg/ml) .[H3]Thymidineincorporation(%ofinhibition)
  • 36. Yehuda Shoenfeld, MD,FRCP ( Hon.)Shrinkage of Melanoma Metastases Following High doseIntravenous Immunoglobulin TreatmentShoenfeld Y, Levy Y, Fishman P.IMAJ 3; 698-699, 2001Human Experience
  • 37. Yehuda Shoenfeld, MD,FRCP ( Hon.)Total remission of thymuscarcinoma after treatment withintravenous immunoglobulinMurieMurie--Fernandez M, et al. Clin Transl Oncol. 2006; 8: 697Fernandez M, et al. Clin Transl Oncol. 2006; 8: 697--9942 year-old woman with myasthenia gravisassociated with a malignant thymoma.A complete remission of the thymoma wasconfirmed by FDG-PET after four cycles ofimmunoglobulins.
  • 38. IVIg as a natural anticancer agentMechanisms
  • 39. Yehuda Shoenfeld, MD,FRCP ( Hon.)IVIG 25mg/mlIVIG 25mg/ml ControlControlIVIG Exerts Apoptotic Effecton Nb2-11c Lymphoma cells
  • 40. Yehuda Shoenfeld, MD,FRCP ( Hon.)IVIGIVIG Inhibits MMPInhibits MMP--9 mRNA9 mRNA expression inexpression inmouse Melanoma cellsmouse Melanoma cells00.511.5MMP-9mRNAIVIG (mg/ml)6633002.8 kbMMP-9G3PDH 1.4 kbIVIG concentrationShapiro S, Shoenfeld Y, Gilburd B, Sobel E, Lahat N. Intravenous gamma globulin inhibits theproduction of matrix metalloproteinase-9 in macrophages. Cancer. 2002, 95: 2032 – 2037.
  • 41. ANTI-VEGF ACTIVITY OF IVIgIVIGIVIGIVIg as an anti-angiogenic agent ?IVIg as an antiIVIg as an anti--angiogenic agent ?angiogenic agent ?
  • 42. Yehuda Shoenfeld, MD,FRCP ( Hon.)Binding of IVIg to the recombinant VEGFAnti-VEGF activity in an IVIg preparation(ELISA)0.00.51.01.52.02.53.00.0 0.4 0.8 1.6 3.1 6.3 12.5 25.0 50.0IVIg concentration (mg/ml)Absorbance(450nm)Anti-VEGF activity in an IVIg preparation(ELISA)0.00.51.01.52.02.53.00.0 0.4 0.8 1.6 3.1 6.3 12.5 25.0 50.0IVIg concentration (mg/ml)Absorbance(450nm)Anti-VEGF activity in an IVIg preparation(ELISA)0.00.51.01.52.02.53.00.0 0.4 0.8 1.6 3.1 6.3 12.5 25.0 50.0IVIg concentration (mg/ml)Absorbance(450nm)2000 238 kDIVIg (µg/ml)VEGF samples were loaded onto 12%SDS-PAGE and blotted on tonitrocellulose membranes
  • 43. Yehuda Shoenfeld, MD,FRCP ( Hon.)Competition of MAV and IVIg forbinding to the VEGF in an immunoblot••g/ml)µ(10incubated with MAV-pre(2mg/ml) to the VEGFIVIgIVIgBinding ofLane 1:Lane 1:••(2mg/ml)incubated with IVIg-preg/ml) to the VEGFµ(10MAVMAVBinding ofLane 2:Lane 2:••(2mg/ml) to the VEGFIVIgIVIgofDirect bindingLane 3:Lane 3:••g/ml) to the VEGFµ(10MAVMAVofDirect bindingLane 4.Lane 4.1 2 3 4
  • 44. Yehuda Shoenfeld, MD,FRCP ( Hon.)Injection of bFGFVEGFIVIG as an anti VEGF-Arei Solomon @Y Shoenfled
  • 45. Yehuda Shoenfeld, MD,FRCP ( Hon.)IVG & bFGFVEGFIVIG
  • 46. Yehuda Shoenfeld, MD,FRCP ( Hon.)Anti-VEGF activity of IVIg in vivoIVIG inhibits VEGF- induced bloodperfusion in mouse hind-limb ischemia0.400.500.600.700.800.901.001.10T0 T7 T14 T21Days post surgeryPerfusionratiowithout VEGFwith VEGFwith VEGF + IVIgIVIG inhibits VEGF- induced bloodperfusion in mouse hind-limb ischemia0.400.500.600.700.800.901.001.10T0 T7 T14 T21Days post surgeryPerfusionratiowithout VEGFwith VEGFwith VEGF + IVIgBlood flow recorded by LaserBlood flow recorded by LaserDoppler Perfusion ImagingDoppler Perfusion Imaging
  • 47. Yehuda Shoenfeld, MD,FRCP ( Hon.)Control IVIg treatedA rich vascular bed and thegrowing tumor mass.Complete eradication of tumormass.Corneal insemination of CT26 colon carcinoma cellsEffect of IVIg on colon carcinomaEffect of IVIg on colon carcinomaprimary tumor growing potentialprimary tumor growing potentialAfter10 daysAfter10 daysDamianovich M, Solomon A S, Blank M, Shoenfeld Y. Ann N Y Acad Sci 2007; 1110:567–577
  • 48. Yehuda Shoenfeld, MD,FRCP ( Hon.)Mechanisms for IVIg as Anti-metastatic Agent Increased secretion of Il-12 Increased activity of NK Induction of apoptosis in tumor cells Direct binding - cytostatic (cytotoxic)?- c’ dependent? Anti-MMP-9,Cathepsin D Anti –VEGF Anti –Blyss ( BAFF)
  • 49. Yehuda Shoenfeld, MD,FRCP ( Hon.)ConclusionsGammaGamma--globulins from anglobulins from an IVIgIVIg preparationpreparationcontain a subcontain a sub--fraction offraction of antianti--VEGF AbsVEGF Abs with awith apossible antipossible anti--angiogenicangiogenic activityactivityVEGF specific activity of IVIg mayVEGF specific activity of IVIg may suggestsuggestby which IVIg may suppressby which IVIg may suppressa new action mechanisma new action mechanismautoimmune diseasesautoimmune diseasesand someand somecancerIVIgIVIg
  • 50. Yehuda Shoenfeld, MD,FRCP ( Hon.)Immunomodulation with subcutaneous Ig2010
  • 51. Yehuda Shoenfeld, MD,FRCP ( Hon.)BAFF, a New Target for IntravenousBAFF, a New Target for IntravenousImmunoglobulin in Autoimmunity andImmunoglobulin in Autoimmunity andCancerCancerLe Pottier L, Bendaoud B, Dueymes M, Daridon C, Youinou P, ShoenLe Pottier L, Bendaoud B, Dueymes M, Daridon C, Youinou P, Shoenfeld Y,feld Y,Pers JO.Pers JO. J Clin Immunol. 2007J Clin Immunol. 2007 The excess in serum level and/or tissue production of BAFF in: SLE (Zhang J, et al. Cutting edge: A role for B lymphocyte stimulator in systemiclupus erythematosus. J Immunol 2001; 166: 6–10) SSc (Matsushita T, et al. Elevated serum BAFF levels in patients with systemicsclerosis: Enhanced BAFF signaling in systemic sclerosis B lymphocytes. ArthritisRheum 2006; 54: 192–201) MS(Thangarajh M, et al. Expression of B-cell-activating factor of the TNF family(BAFF) and its receptors in multiple sclerosis. J Neuroimmunol 2004; 152:183–190) B-CLL (Novak AJ, et al. Aberrant expression of B lymphocyte stimulator by Bchronic lymphocytic leukemia cells: A mechanism for survival. Blood 2002; 100:2973–2979)
  • 52. Yehuda Shoenfeld, MD,FRCP ( Hon.)BAFF, a new target for intravenousimmunoglobulin in autoimmunity andcancer.Le Pottier L, Bendaoud B, Dueymes M, Daridon C, Youinou P,Le Pottier L, Bendaoud B, Dueymes M, Daridon C, Youinou P,Shoenfeld Y, Pers JO. J Clin Immunol. 2007 ;27 : 257Shoenfeld Y, Pers JO. J Clin Immunol. 2007 ;27 : 257--265265 Nonglycosylated recombinant BAFF,glycosylated affinity-purified BAFF, andrecombinant APRIL (but not TNFalpha), wererecognized by certain IgG in IVIg, and theirF(ab)(2) fragments. The presence of anti-BAFF and anti-APRIL Absin IVIg.
  • 53. IVIG as Anti BLISS ( BAFF)(Functional)J Clin Immunol 2007
  • 54. Negi V  et al.,  J Clin Immunol 2007Anti-Mechanisms of IVIG3/17/2012 54Confidential - not to be distributedwithout prior approval
  • 55. Yehuda Shoenfeld, MD,FRCP ( Hon.)ADVERSE EFFECTS AND VIRAL SAFETY OFINTRAVENOUS IMMUNOGLOBULIN THERAPYIN 56 PATIENTS WITH AUTOIMMUNEDISEASESYaniv Sherer, Yair Levy, Pnina Langevitz, FabrizioFabbrizzi, Yehuda ShoenfeldDepartment of Medicine ‘B’ and Center of Autoimmune Diseases, ShebaMedical Center, Tel-Hashomer, and Sackler Faculty of Medicine, Tel-AvivUniversity, IsraelPharmacology 2001; 62: 133-137
  • 56. Yehuda Shoenfeld, MD,FRCP ( Hon.)CONCLUSIONS:IVIg- the myth and reality IVIG is effective inautoimmune conditions –multiplemechanisms IVIg anti -cancer effects in;melanoma, carcinoma, sarcoma andlymphoma IVIG representing the innateimmune system affect tumors bydiverse mechanismsIVIGGallileoEinstein
  • 57. Five Jews change theway we see the world:Moses: ‘’the Law is everything.’’Jesus: ‘’Love is everything.’’Marx: ‘’Money is everything.’’Freud: ‘’Sex is everything.’’Einstein: ‘’Everything is relative.’’