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Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld
MD,FRCP,
IVIG;The myth and realityIVIG;The myth and reality
IVIG
CONPO Barcelona2013
Harnessing the innate immunity to
modulate autoimmunity and cancer
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Future Congresses
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Definitive way of preparation; produced by 25Definitive way of preparation; produced by 25
pharmaceutical companies (very expensive).pharmaceutical companies (very expensive).
Clinical applications: treatment of severe immuneClinical applications: treatment of severe immune
deficiency diseases and a variety of autoimmunedeficiency diseases and a variety of autoimmune
conditions.conditions.
Pooled IgG (immunologlobulin G) from 6,000Pooled IgG (immunologlobulin G) from 6,000--20,00020,000
blood donation.blood donation.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
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
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.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Paul Imbach
IVIG
Wiskott Aldrich
Lancet 1981;1-1228-30
IVIG in ITP
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Immune thrombocytopenia (ITP)
ITP is an
autoimmune
disease due to
autoantibody
to endogenous
platelets
Causes platelet
destruction by
macrophages
and bleeding
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Michel .D.Kazatchkine
NEJM
2001;345;747
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Successful IVIG treatment inSuccessful IVIG treatment in
autoimmune 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 atopic
dermatitis
 Crohn’s disease
 Chronic Inflamatory Demyelinating
Polyneuropathy
Yehuda Shoenfeld, MD,FRCP ( Hon.)
A study of 20 SLE patients withA study of 20 SLE patients with
intravenous immunoglobulinintravenous immunoglobulin
clinical and serologic responseclinical and serologic response
Yair 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 following
IVIg treatment was noted in 17 out of
20 patients (85%).
 Some clinical manifestations responded
more to treatment: arthritis, fever,
thrombocytopenia, and neuropsychiatric
lupus.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Successful treatment of early secondarySuccessful treatment of early secondary
myelofibrosismyelofibrosis
in SLE with IVIG.in SLE with IVIG.
Aharon A, Levy Y, Bar Dayan Y, Afek A, Zandman-Goddard, Skurnik
Y, Fabrrizzi F, Shoenfeld Y
Lupus 6: 408-411,1997.
IVIG
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Reduced proteinuria followingReduced proteinuria following
repeated courses of IVIGrepeated courses of IVIG
0
2
4
6
8
2m
on
bf1m
on
bf1stcycle
2nd
cycle3rd
cycle4th
cycle5th
cycle6cycle
12m
on
af
18m
on
af
30m
on
af
Urinaryprotein
extraction(g/24h)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
A Comparison Between Prednisone DosesA Comparison Between Prednisone Doses
used for the Treatment of SLE Patientsused for the Treatment of SLE Patients
Before and After IVIgBefore and After IVIg
0
10
20
30
40
50
60
BeforeIVIG After6cyclesofIVIG
P<0.05P<0.05
Yehuda Shoenfeld, MD,FRCP ( Hon.)
2. Anti2. Anti--idiotypicidiotypic AbsAbs
Anti-Id Ab
Pathogenic auto-
Ab
Anti-Id Abs modulates the immune system by suppressing
auto-Abs production
Yehuda Shoenfeld, MD,FRCP ( Hon.)
AIM :
To evaluate theTo evaluate the
efficacy of theefficacy of the
antianti--dsDNA antidsDNA anti--idiotypesidiotypes
enrichedenriched IVIGIVIG
B.Gilburde
M.Blank
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Affinity purification of antiAffinity purification of anti--dsDNAdsDNA
antianti--ID from IVIGID from IVIG
Anti-dsDNA-Sepharose
Loading dialyzed
IVIG
YY
YY
YY
YY
YY
YY
YYYY
YYYY
YY
YY
Elution with
HCl-glycine
16 hours at 4oC
YYYYYY
YYYYYY
YYYY
YY
antianti--dsDNA antidsDNA anti--IDID
YY
YY
YY
YY
YY
YY
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Treatment of NZB/W F1 mice
with IVIG-ID
Three weekly injections to the tail vein
of NZB/W F1 mice:
IVIG-ID : 2 mg/kg = 60 µg/mouse
IVIG: 400 mg/kg = 12 mg/mouse
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Proteinuria in NZB/W F1 miceProteinuria in NZB/W F1 mice
treated with SUPERIVIG and IVIGtreated with SUPERIVIG and IVIG
0
5
10
15
20
25
30
IVIG-ID IVIG CONTROL
G/L
*
Yehuda Shoenfeld, MD,FRCP ( Hon.)
IVIG-IDIVIG-ID IVIGIVIG NON-TREATEDNON-TREATED
Prevention of mesangial mouse IgG
deposits in NZB/W F1 mice
treated (early treatment) with:
Prevention of mesangial mouse IgGPrevention of mesangial mouse IgG
deposits in NZB/W F1 micedeposits in NZB/W F1 mice
treated (early treatment) with:treated (early treatment) with:
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Cumulative number of deaths withCumulative number of deaths with
concomitant proteinuria in NZB/W F1 miceconcomitant proteinuria in NZB/W F1 mice
Weeks of ageWeeks of age
25 30 35 40 45
0
2
4
6
8
10
12
IVIGIVIG--IDID
IVIGIVIG
ControlControl
NumberofdeathsNumberofdeaths
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Efficacy of IVIG affinityEfficacy of IVIG affinity--purified antipurified anti--
doubledouble--stranded DNA antistranded DNA anti--idiotypicidiotypic
antibodies in the treatment of anantibodies in the treatment of an
experimental murine model ofexperimental murine model of
systemic 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
Yehuda Shoenfeld, MD,FRCP ( Hon.)
YY
YY
YY
YY
YY
YY
YY
YY
AntiAnti-- dsDNAdsDNA
SLESLE
YY
YY
YY
YY
YY
YY
YY
YY
AntiAnti--2GPI2GPI
AntiphospholipdAntiphospholipd
syndromesyndrome
Myasthenia
Myasthenia
GravisGravis
YY
YY
YYYY
YY
YY
YY
YY
AntiAnti-- AChRAChR
Autoimmune Disease Specific IVIg:Autoimmune Disease Specific IVIg:
Low Dose, High EfficacyLow Dose, High Efficacy
Special types of IVIg for autoimmune diseases
Pemphigus
Pemphigusvulgaris
vulgaris
YY
YY
YY
YY
YYYY
YY
YY
Anti
Anti--desmoglein
desmoglein1/31/3
Yehuda Shoenfeld, MD,FRCP ( Hon.)
IVIG Treatment of Cancer
Y. Shoenfeld, Sheba Medical Center, Israel
Reactivity of the human IVIG with a panel of
human cell line
Human bladder carcinoma cell line T24, human glioma cell line U-138MG, human
head-and-neck cancer cell line PCI-13, human lymphoid cell line LG2 and human
melanoma 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 lines
0
1
2
T2 4 8 3 6 C o lo 3 8 M el-13 8 6 DAM -
M B -2 3 1
553 B 2 9 3 /KDR 13 79 PC I-13 LG2 50 1 U-13 8 M G
Cell lines
ODat450nm
IV IG
control
Yehuda Shoenfeld, MD,FRCP ( Hon.)
IVIg: Prevention of Melanoma
Metastases
Gamma-globulin inhibits tumor spread in mice
Yehuda Shoenfeld and Pnina Fishman
International immunology
11: 1247 - 1251, 1999
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Effect of IVIg (I.V.) on the Development of
Melanoma Metastases
6 IVIG - Presentation, Oct 95
0
25
50
75
100
125
No.offoci
(%ofcontrol)
Control 0 0,4 0,4,9
DAYS OF IVIG TREATMENT
P<0.001 P<0.001 P<0.001
Yehuda Shoenfeld, MD,FRCP ( Hon.)
IVIg Prolongs the Survival of Tumor
Bearing Mice
0
20
40
60
80
100
0 20 40 60 80 100
Days after amputation
%survival
Treated
Control
a - Sarcoma
0
20
40
60
80
100
0 20 40 60 80 100
Days after amputation
%survival
Treated
Control
b - Melanoma
Sarcoma Melanoma
Yehuda Shoenfeld, MD,FRCP ( Hon.)
IVIg: Prevention of Tumor foci
the Peritoneum
Yehuda Shoenfeld, MD,FRCP ( Hon.)
IVIg: Prevention of Lung Sarcoma
Metastases
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Inhibitory effect of IVIg on in vitro CT26 cellInhibitory effect of IVIg on in vitro CT26 cell
proliferationproliferation
* p < 0.05
** p < 0.01
*** p < 0.001
0
10
20
30
40
50
60
70
80
1 5 15 40
IVIg concentration (mg/ml)
%ofinhibition
24h
48h
72h
**
***
*
**
**
*
Time course and dose responseTime course and dose response
Yehuda Shoenfeld, MD,FRCP ( Hon.)
•Matrigel resultsEffect of IVIg on CT26 cell invasiveness
The 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)
39.70
0
10
20
30
40
50
60
48h 72h
%ofinhibitionofinvasion
IVIg 20mg/ml
IVIg 40mg/ml
p < 0.001
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Dose Dependent Effect of IVIg on the Proliferation of
Human Colon Carcinoma, HCT-116 Cells
0
20
40
60
25 10 5 2.5 1.25
IVIg Concentration (mg/ml) .
[H
3
]Thymidineincorporation
(%ofinhibition)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Shrinkage of Melanoma Metastases Following High dose
Intravenous Immunoglobulin Treatment
Shoenfeld Y, Levy Y, Fishman P.
IMAJ 3; 698-699, 2001
Human Experience
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Total remission of thymus
carcinoma after treatment with
intravenous immunoglobulin
MurieMurie--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 gravis
associated with a malignant thymoma.
A complete remission of the thymoma was
confirmed by FDG-PET after four cycles of
immunoglobulins.
IVIg as a natural anti
cancer agent
Mechanisms
Yehuda Shoenfeld, MD,FRCP ( Hon.)
IVIG 25mg/mlIVIG 25mg/ml ControlControl
IVIG Exerts Apoptotic Effect
on Nb2-11c Lymphoma cells
Yehuda Shoenfeld, MD,FRCP ( Hon.)
IVIGIVIG Inhibits MMPInhibits MMP--9 mRNA9 mRNA expression inexpression in
mouse Melanoma cellsmouse Melanoma cells
0
0.5
1
1.5
MMP-9mRNA
IVIG (mg/ml)663300
2.8 kbMMP-9
G3PDH 1.4 kb
IVIG concentration
Shapiro S, Shoenfeld Y, Gilburd B, Sobel E, Lahat N. Intravenous gamma globulin inhibits the
production of matrix metalloproteinase-9 in macrophages. Cancer. 2002, 95: 2032 – 2037.
ANTI-VEGF ACTIVITY OF IVIg
IVIGIVIG
IVIg as an anti-angiogenic agent ?IVIg as an antiIVIg as an anti--angiogenic agent ?angiogenic agent ?
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Binding of IVIg to the recombinant VEGF
Anti-VEGF activity in an IVIg preparation
(ELISA)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.0 0.4 0.8 1.6 3.1 6.3 12.5 25.0 50.0
IVIg concentration (mg/ml)
Absorbance(450nm)
Anti-VEGF activity in an IVIg preparation
(ELISA)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.0 0.4 0.8 1.6 3.1 6.3 12.5 25.0 50.0
IVIg concentration (mg/ml)
Absorbance(450nm)
Anti-VEGF activity in an IVIg preparation
(ELISA)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.0 0.4 0.8 1.6 3.1 6.3 12.5 25.0 50.0
IVIg concentration (mg/ml)
Absorbance(450nm)
2000 2
38 kD
IVIg (µg/ml)
VEGF samples were loaded onto 12%
SDS-PAGE and blotted on to
nitrocellulose membranes
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Competition of MAV and IVIg for
binding 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
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Injection of bFGF
VEGF
IVIG as an anti VEGF-
Arei Solomon @Y Shoenfled
Yehuda Shoenfeld, MD,FRCP ( Hon.)
IVG & bFGF
VEGF
IVIG
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Anti-VEGF activity of IVIg in vivo
IVIG inhibits VEGF- induced blood
perfusion in mouse hind-limb ischemia
0.40
0.50
0.60
0.70
0.80
0.90
1.00
1.10
T0 T7 T14 T21
Days post surgery
Perfusionratio
without VEGF
with VEGF
with VEGF + IVIg
IVIG inhibits VEGF- induced blood
perfusion in mouse hind-limb ischemia
0.40
0.50
0.60
0.70
0.80
0.90
1.00
1.10
T0 T7 T14 T21
Days post surgery
Perfusionratio
without VEGF
with VEGF
with VEGF + IVIg
Blood flow recorded by LaserBlood flow recorded by Laser
Doppler Perfusion ImagingDoppler Perfusion Imaging
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Control IVIg treated
A rich vascular bed and the
growing tumor mass.
Complete eradication of tumor
mass.
Corneal insemination of CT26 colon carcinoma cells
Effect of IVIg on colon carcinomaEffect of IVIg on colon carcinoma
primary tumor growing potentialprimary tumor growing potential
After10 daysAfter10 days
Damianovich M, Solomon A S, Blank M, Shoenfeld Y. Ann N Y Acad Sci 2007; 1110:567–577
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)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Conclusions
GammaGamma--globulins from anglobulins from an IVIgIVIg preparationpreparation
contain a subcontain a sub--fraction offraction of antianti--VEGF AbsVEGF Abs with awith a
possible antipossible anti--angiogenicangiogenic activityactivity
VEGF specific activity of IVIg mayVEGF specific activity of IVIg may suggestsuggest
by which IVIg may suppressby which IVIg may suppressa new action mechanisma new action mechanism
autoimmune diseasesautoimmune diseasesand someand somecancer
IVIgIVIg
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Immunomodulation with subcutaneous Ig
2010
Yehuda Shoenfeld, MD,FRCP ( Hon.)
BAFF, a New Target for IntravenousBAFF, a New Target for Intravenous
Immunoglobulin in Autoimmunity andImmunoglobulin in Autoimmunity and
CancerCancer
Le 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 systemic
lupus erythematosus. J Immunol 2001; 166: 6–10)
 SSc (Matsushita T, et al. Elevated serum BAFF levels in patients with systemic
sclerosis: Enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis
Rheum 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 B
chronic lymphocytic leukemia cells: A mechanism for survival. Blood 2002; 100:
2973–2979)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
BAFF, a new target for intravenous
immunoglobulin in autoimmunity and
cancer.
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, and
recombinant APRIL (but not TNFalpha), were
recognized by certain IgG in IVIg, and their
F(ab')(2) fragments.
 The presence of anti-BAFF and anti-APRIL Abs
in IVIg.
IVIG as Anti BLISS ( BAFF)
(Functional)
J Clin Immunol 2007
Negi V  et al.,  J Clin Immunol 2007
Anti-Mechanisms of IVIG
3/17/2012 54
Confidential - not to be distributed
without prior approval
Yehuda Shoenfeld, MD,FRCP ( Hon.)
ADVERSE EFFECTS AND VIRAL SAFETY OF
INTRAVENOUS IMMUNOGLOBULIN THERAPY
IN 56 PATIENTS WITH AUTOIMMUNE
DISEASES
Yaniv Sherer, Yair Levy, Pnina Langevitz, Fabrizio
Fabbrizzi, Yehuda Shoenfeld
Department of Medicine ‘B’ and Center of Autoimmune Diseases, Sheba
Medical Center, Tel-Hashomer, and Sackler Faculty of Medicine, Tel-Aviv
University, Israel
Pharmacology 2001; 62: 133-137
Yehuda Shoenfeld, MD,FRCP ( Hon.)
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
IVIG
Gallileo
Einstein
Five Jews change the
way 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.’’
Mechanisms in autoimmunity and cancer

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Mechanisms in autoimmunity and cancer

  • 1. Yehuda Shoenfeld, MD,FRCP ( Hon.) Yehuda Shoenfeld MD,FRCP, IVIG;The myth and realityIVIG;The myth and reality IVIG CONPO Barcelona2013 Harnessing the innate immunity to modulate 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 25 pharmaceutical companies (very expensive).pharmaceutical companies (very expensive). Clinical applications: treatment of severe immuneClinical applications: treatment of severe immune deficiency diseases and a variety of autoimmunedeficiency diseases and a variety of autoimmune conditions.conditions. Pooled IgG (immunologlobulin G) from 6,000Pooled IgG (immunologlobulin G) from 6,000--20,00020,000 blood donation.blood donation.
  • 4. Yehuda Shoenfeld, MD,FRCP ( Hon.) 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
  • 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.
  • 8. Yehuda Shoenfeld, MD,FRCP ( Hon.) Paul Imbach IVIG Wiskott Aldrich Lancet 1981;1-1228-30 IVIG in ITP
  • 9. Yehuda Shoenfeld, MD,FRCP ( Hon.) Immune thrombocytopenia (ITP) ITP is an autoimmune disease due to autoantibody to endogenous platelets Causes platelet destruction by macrophages and bleeding
  • 10. Yehuda Shoenfeld, MD,FRCP ( Hon.) Michel .D.Kazatchkine NEJM 2001;345;747
  • 11. Yehuda Shoenfeld, MD,FRCP ( Hon.) Successful IVIG treatment inSuccessful IVIG treatment in autoimmune 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 atopic dermatitis  Crohn’s disease  Chronic Inflamatory Demyelinating Polyneuropathy
  • 12. Yehuda Shoenfeld, MD,FRCP ( Hon.) A study of 20 SLE patients withA study of 20 SLE patients with intravenous immunoglobulinintravenous immunoglobulin clinical and serologic responseclinical and serologic response Yair 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 following IVIg treatment was noted in 17 out of 20 patients (85%).  Some clinical manifestations responded more to treatment: arthritis, fever, thrombocytopenia, and neuropsychiatric lupus.
  • 13. Yehuda Shoenfeld, MD,FRCP ( Hon.) Successful treatment of early secondarySuccessful treatment of early secondary myelofibrosismyelofibrosis in SLE with IVIG.in SLE with IVIG. Aharon A, Levy Y, Bar Dayan Y, Afek A, Zandman-Goddard, Skurnik Y, Fabrrizzi F, Shoenfeld Y Lupus 6: 408-411,1997. IVIG
  • 14. Yehuda Shoenfeld, MD,FRCP ( Hon.) Reduced proteinuria followingReduced proteinuria following repeated courses of IVIGrepeated courses of IVIG 0 2 4 6 8 2m on bf1m on bf1stcycle 2nd cycle3rd cycle4th cycle5th cycle6cycle 12m on af 18m on af 30m on af Urinaryprotein extraction(g/24h)
  • 15. Yehuda Shoenfeld, MD,FRCP ( Hon.) A Comparison Between Prednisone DosesA Comparison Between Prednisone Doses used for the Treatment of SLE Patientsused for the Treatment of SLE Patients Before and After IVIgBefore and After IVIg 0 10 20 30 40 50 60 BeforeIVIG After6cyclesofIVIG P<0.05P<0.05
  • 16. Yehuda Shoenfeld, MD,FRCP ( Hon.) 2. Anti2. Anti--idiotypicidiotypic AbsAbs Anti-Id Ab Pathogenic auto- Ab Anti-Id Abs modulates the immune system by suppressing auto-Abs production
  • 17. Yehuda Shoenfeld, MD,FRCP ( Hon.) AIM : To evaluate theTo evaluate the efficacy of theefficacy of the antianti--dsDNA antidsDNA anti--idiotypesidiotypes enrichedenriched IVIGIVIG
  • 19. Yehuda Shoenfeld, MD,FRCP ( Hon.) Affinity purification of antiAffinity purification of anti--dsDNAdsDNA antianti--ID from IVIGID from IVIG Anti-dsDNA-Sepharose Loading dialyzed IVIG YY YY YY YY YY YY YYYY YYYY YY YY Elution with HCl-glycine 16 hours at 4oC YYYYYY YYYYYY YYYY YY antianti--dsDNA antidsDNA anti--IDID YY YY YY YY YY YY
  • 20. Yehuda Shoenfeld, MD,FRCP ( Hon.) Treatment of NZB/W F1 mice with IVIG-ID Three weekly injections to the tail vein of NZB/W F1 mice: IVIG-ID : 2 mg/kg = 60 µg/mouse IVIG: 400 mg/kg = 12 mg/mouse
  • 21. Yehuda Shoenfeld, MD,FRCP ( Hon.) Proteinuria in NZB/W F1 miceProteinuria in NZB/W F1 mice treated with SUPERIVIG and IVIGtreated with SUPERIVIG and IVIG 0 5 10 15 20 25 30 IVIG-ID IVIG CONTROL G/L *
  • 22. Yehuda Shoenfeld, MD,FRCP ( Hon.) IVIG-IDIVIG-ID IVIGIVIG NON-TREATEDNON-TREATED Prevention of mesangial mouse IgG deposits in NZB/W F1 mice treated (early treatment) with: Prevention of mesangial mouse IgGPrevention of mesangial mouse IgG deposits in NZB/W F1 micedeposits in NZB/W F1 mice treated (early treatment) with:treated (early treatment) with:
  • 23. Yehuda Shoenfeld, MD,FRCP ( Hon.) Cumulative number of deaths withCumulative number of deaths with concomitant proteinuria in NZB/W F1 miceconcomitant proteinuria in NZB/W F1 mice Weeks of ageWeeks of age 25 30 35 40 45 0 2 4 6 8 10 12 IVIGIVIG--IDID IVIGIVIG ControlControl NumberofdeathsNumberofdeaths
  • 24. Yehuda Shoenfeld, MD,FRCP ( Hon.) Efficacy of IVIG affinityEfficacy of IVIG affinity--purified antipurified anti-- doubledouble--stranded DNA antistranded DNA anti--idiotypicidiotypic antibodies in the treatment of anantibodies in the treatment of an experimental murine model ofexperimental murine model of systemic 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.) YY YY YY YY YY YY YY YY AntiAnti-- dsDNAdsDNA SLESLE YY YY YY YY YY YY YY YY AntiAnti--2GPI2GPI AntiphospholipdAntiphospholipd syndromesyndrome Myasthenia Myasthenia GravisGravis YY YY YYYY YY YY YY YY AntiAnti-- AChRAChR Autoimmune Disease Specific IVIg:Autoimmune Disease Specific IVIg: Low Dose, High EfficacyLow Dose, High Efficacy Special types of IVIg for autoimmune diseases Pemphigus Pemphigusvulgaris vulgaris YY YY YY YY YYYY YY YY Anti Anti--desmoglein desmoglein1/31/3
  • 26. Yehuda Shoenfeld, MD,FRCP ( Hon.) IVIG Treatment of Cancer Y. Shoenfeld, Sheba Medical Center, Israel
  • 27. Reactivity of the human IVIG with a panel of human cell line Human bladder carcinoma cell line T24, human glioma cell line U-138MG, human head-and-neck cancer cell line PCI-13, human lymphoid cell line LG2 and human melanoma 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 lines 0 1 2 T2 4 8 3 6 C o lo 3 8 M el-13 8 6 DAM - M B -2 3 1 553 B 2 9 3 /KDR 13 79 PC I-13 LG2 50 1 U-13 8 M G Cell lines ODat450nm IV IG control
  • 28. Yehuda Shoenfeld, MD,FRCP ( Hon.) IVIg: Prevention of Melanoma Metastases Gamma-globulin inhibits tumor spread in mice Yehuda Shoenfeld and Pnina Fishman International immunology 11: 1247 - 1251, 1999
  • 29. Yehuda Shoenfeld, MD,FRCP ( Hon.) Effect of IVIg (I.V.) on the Development of Melanoma Metastases 6 IVIG - Presentation, Oct 95 0 25 50 75 100 125 No.offoci (%ofcontrol) Control 0 0,4 0,4,9 DAYS OF IVIG TREATMENT P<0.001 P<0.001 P<0.001
  • 30. Yehuda Shoenfeld, MD,FRCP ( Hon.) IVIg Prolongs the Survival of Tumor Bearing Mice 0 20 40 60 80 100 0 20 40 60 80 100 Days after amputation %survival Treated Control a - Sarcoma 0 20 40 60 80 100 0 20 40 60 80 100 Days after amputation %survival Treated Control b - Melanoma Sarcoma Melanoma
  • 31. Yehuda Shoenfeld, MD,FRCP ( Hon.) IVIg: Prevention of Tumor foci the Peritoneum
  • 32. Yehuda Shoenfeld, MD,FRCP ( Hon.) IVIg: Prevention of Lung Sarcoma Metastases
  • 33. Yehuda Shoenfeld, MD,FRCP ( Hon.) Inhibitory effect of IVIg on in vitro CT26 cellInhibitory effect of IVIg on in vitro CT26 cell proliferationproliferation * p < 0.05 ** p < 0.01 *** p < 0.001 0 10 20 30 40 50 60 70 80 1 5 15 40 IVIg concentration (mg/ml) %ofinhibition 24h 48h 72h ** *** * ** ** * Time course and dose responseTime course and dose response
  • 34. Yehuda Shoenfeld, MD,FRCP ( Hon.) •Matrigel resultsEffect of IVIg on CT26 cell invasiveness The 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) 39.70 0 10 20 30 40 50 60 48h 72h %ofinhibitionofinvasion IVIg 20mg/ml IVIg 40mg/ml p < 0.001
  • 35. Yehuda Shoenfeld, MD,FRCP ( Hon.) Dose Dependent Effect of IVIg on the Proliferation of Human Colon Carcinoma, HCT-116 Cells 0 20 40 60 25 10 5 2.5 1.25 IVIg Concentration (mg/ml) . [H 3 ]Thymidineincorporation (%ofinhibition)
  • 36. Yehuda Shoenfeld, MD,FRCP ( Hon.) Shrinkage of Melanoma Metastases Following High dose Intravenous Immunoglobulin Treatment Shoenfeld Y, Levy Y, Fishman P. IMAJ 3; 698-699, 2001 Human Experience
  • 37. Yehuda Shoenfeld, MD,FRCP ( Hon.) Total remission of thymus carcinoma after treatment with intravenous immunoglobulin MurieMurie--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 gravis associated with a malignant thymoma. A complete remission of the thymoma was confirmed by FDG-PET after four cycles of immunoglobulins.
  • 38. IVIg as a natural anti cancer agent Mechanisms
  • 39. Yehuda Shoenfeld, MD,FRCP ( Hon.) IVIG 25mg/mlIVIG 25mg/ml ControlControl IVIG Exerts Apoptotic Effect on Nb2-11c Lymphoma cells
  • 40. Yehuda Shoenfeld, MD,FRCP ( Hon.) IVIGIVIG Inhibits MMPInhibits MMP--9 mRNA9 mRNA expression inexpression in mouse Melanoma cellsmouse Melanoma cells 0 0.5 1 1.5 MMP-9mRNA IVIG (mg/ml)663300 2.8 kbMMP-9 G3PDH 1.4 kb IVIG concentration Shapiro S, Shoenfeld Y, Gilburd B, Sobel E, Lahat N. Intravenous gamma globulin inhibits the production of matrix metalloproteinase-9 in macrophages. Cancer. 2002, 95: 2032 – 2037.
  • 41. ANTI-VEGF ACTIVITY OF IVIg IVIGIVIG IVIg 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 VEGF Anti-VEGF activity in an IVIg preparation (ELISA) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0 0.4 0.8 1.6 3.1 6.3 12.5 25.0 50.0 IVIg concentration (mg/ml) Absorbance(450nm) Anti-VEGF activity in an IVIg preparation (ELISA) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0 0.4 0.8 1.6 3.1 6.3 12.5 25.0 50.0 IVIg concentration (mg/ml) Absorbance(450nm) Anti-VEGF activity in an IVIg preparation (ELISA) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 0.0 0.4 0.8 1.6 3.1 6.3 12.5 25.0 50.0 IVIg concentration (mg/ml) Absorbance(450nm) 2000 2 38 kD IVIg (µg/ml) VEGF samples were loaded onto 12% SDS-PAGE and blotted on to nitrocellulose membranes
  • 43. Yehuda Shoenfeld, MD,FRCP ( Hon.) Competition of MAV and IVIg for binding 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 bFGF VEGF IVIG as an anti VEGF- Arei Solomon @Y Shoenfled
  • 45. Yehuda Shoenfeld, MD,FRCP ( Hon.) IVG & bFGF VEGF IVIG
  • 46. Yehuda Shoenfeld, MD,FRCP ( Hon.) Anti-VEGF activity of IVIg in vivo IVIG inhibits VEGF- induced blood perfusion in mouse hind-limb ischemia 0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 T0 T7 T14 T21 Days post surgery Perfusionratio without VEGF with VEGF with VEGF + IVIg IVIG inhibits VEGF- induced blood perfusion in mouse hind-limb ischemia 0.40 0.50 0.60 0.70 0.80 0.90 1.00 1.10 T0 T7 T14 T21 Days post surgery Perfusionratio without VEGF with VEGF with VEGF + IVIg Blood flow recorded by LaserBlood flow recorded by Laser Doppler Perfusion ImagingDoppler Perfusion Imaging
  • 47. Yehuda Shoenfeld, MD,FRCP ( Hon.) Control IVIg treated A rich vascular bed and the growing tumor mass. Complete eradication of tumor mass. Corneal insemination of CT26 colon carcinoma cells Effect of IVIg on colon carcinomaEffect of IVIg on colon carcinoma primary tumor growing potentialprimary tumor growing potential After10 daysAfter10 days Damianovich 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 preparationpreparation contain a subcontain a sub--fraction offraction of antianti--VEGF AbsVEGF Abs with awith a possible antipossible anti--angiogenicangiogenic activityactivity VEGF specific activity of IVIg mayVEGF specific activity of IVIg may suggestsuggest by which IVIg may suppressby which IVIg may suppressa new action mechanisma new action mechanism autoimmune diseasesautoimmune diseasesand someand somecancer IVIgIVIg
  • 50. Yehuda Shoenfeld, MD,FRCP ( Hon.) Immunomodulation with subcutaneous Ig 2010
  • 51. Yehuda Shoenfeld, MD,FRCP ( Hon.) BAFF, a New Target for IntravenousBAFF, a New Target for Intravenous Immunoglobulin in Autoimmunity andImmunoglobulin in Autoimmunity and CancerCancer Le 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 systemic lupus erythematosus. J Immunol 2001; 166: 6–10)  SSc (Matsushita T, et al. Elevated serum BAFF levels in patients with systemic sclerosis: Enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum 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 B chronic lymphocytic leukemia cells: A mechanism for survival. Blood 2002; 100: 2973–2979)
  • 52. Yehuda Shoenfeld, MD,FRCP ( Hon.) BAFF, a new target for intravenous immunoglobulin in autoimmunity and cancer. 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, and recombinant APRIL (but not TNFalpha), were recognized by certain IgG in IVIg, and their F(ab')(2) fragments.  The presence of anti-BAFF and anti-APRIL Abs in IVIg.
  • 53. IVIG as Anti BLISS ( BAFF) (Functional) J Clin Immunol 2007
  • 54. Negi V  et al.,  J Clin Immunol 2007 Anti-Mechanisms of IVIG 3/17/2012 54 Confidential - not to be distributed without prior approval
  • 55. Yehuda Shoenfeld, MD,FRCP ( Hon.) ADVERSE EFFECTS AND VIRAL SAFETY OF INTRAVENOUS IMMUNOGLOBULIN THERAPY IN 56 PATIENTS WITH AUTOIMMUNE DISEASES Yaniv Sherer, Yair Levy, Pnina Langevitz, Fabrizio Fabbrizzi, Yehuda Shoenfeld Department of Medicine ‘B’ and Center of Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, and Sackler Faculty of Medicine, Tel-Aviv University, Israel Pharmacology 2001; 62: 133-137
  • 56. Yehuda Shoenfeld, MD,FRCP ( Hon.) 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 IVIG Gallileo Einstein
  • 57. Five Jews change the way 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.’’