recent advances in fc receptor- dependent therapies alan h. lazarus, phd canadian blood services st....
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Recent advances in Fc receptor-dependent therapies
Alan H. Lazarus, PhD
Canadian Blood ServicesSt. Michael’s HospitalUniversity of Toronto
CBS Transfusion Medicine Resident Scientific SessionNov 2, 2010
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Outline
•Mechanisms of platelet destruction in ITP
•Recent advances in:
• Fc receptor blockade• IVIg• anti-D• Inhibition of Fc receptor signaling
•Conclusions
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Immune thrombocytopenic purpura (ITP)
Platelet
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An Fc-independent mechanism of potential immune thrombocytopenia-ROS
Zang W et al, Blood 2008Li Z et al, J Biol Chem 2008Li Z et al, Blood 2009
GPIIbIIIa
ROSROSHCVHCV
Wright JF et al, Br J Haem 1996Wright JF et al, Br J Haem 1996VZVVZV
QuinineQuininePeterson, Blood 2008
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Fc-independent immune thrombocytopenia-GPIb
Platelet
Nieswandt et al Blood 2000Webster et al Blood 2006Go et al Haematologica 2007
GPIb
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Carbohydrates important for IgG function?
Fc
F(ab’)2
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Albert H et al. PNAS 2008;105:15005-15009
©2008 by National Academy of Sciences
IgG subclass-specific effects of EndoS-mediated hydrolysis of the IgG-associated sugar side chain.
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A potential alternative mechanism of platelet destruction?Cell Mediated Immunity
Olsson et al, Nature Medicine 2003Zhang et al, Eur J Haem 2006
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An alternative mechanism which may contribute to immune thrombocytopenia?
PLTPLTPLT
MK in Bone MarrowMK in Bone Marrow
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Decreased platelet production due to antibody and/or T cells inhibiting or destroying MK
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Mechanism Fc receptors Reference
classic anti-IIbIIIa yes Harrington Experiment 1951
anti-IIbIIIa (49-66) no Zhang, 2008 Li, 2008 Li, 2009
anti-GPIb no Nieswandt, 2000 Webster, 2006 Go, 2007
T cells no Olsson, 2003 Zhang, 2006Chow, 2010
Direct effect on MK ? Chang 2003McMillan 2004Houwerzijl 2004
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Outline
•Mechanisms of platelet destruction in ITP
•Recent advances in:
• Fc receptor blockade• IVIg• anti-D• Inhibition of Fc receptor signaling
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+other potential Fc receptors for IgG (FCRL’s)
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Fc receptor blockade
•Antibody specific for FcRIIIa worked in refractory ITP (Clarkson, 1986)
•Antibody specific for FcRI worked in ITP (Terjanian, 2000 abstract in Blood)
•Humanized antibody for FcRIIIa (GMA161& 3G8) worked but with side effects (Bussel, 2006 & Nakar, 2009 abstracts in Blood)
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Fc receptor blockade
• Clodronate is effective in a mouse model of passive ITP (Alves-Rosa 2000, 2002; Deng & Balthasar 2005, 2007; Li 2006)
Taken from, www.clodronateliposomes.org
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Outline
•Mechanisms of platelet destruction in ITP
•Recent advances in:
• Fc receptor blockade• IVIg• anti-D• Inhibition of Fc receptor signaling
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IVIg is IgG
Fc
F(ab’)2
Intravenous Immunoglobulin
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How does IVIg work?
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What does IVIg bind to?
• Other antibodies [Schussler, 1997]• Glycolipids [Vuist, 1997]• Superantigens [Takei, 1993]• HLA antigens [Glotz, 1993]• DNA & Phospholipid [Krause, Blank, Shoenfeld. 1998]• Fas/FasL [Viard, 1998, Prasad, 1998, Altznauer, 2003]• IgE Fc receptor & Tetanus toxoid [Horn, 1999]• Galactose disaccharides [Barreau, 2000]• Auto-antigens [reviewed in St-Amour, 2009]• Red Blood cells [Salama, 1984]• ……
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Theories of IVIg action
• Fc receptor blockade• Inhibitory FcγRIIB expression• Regulation of cytokine production• Anti-idiotypic antibodies• Inhibits complement activation• Clearance of pathogenic antibody-FcRn.• Apoptosis• IVIg possesses anti-inflammatory sugars• IVIg forms soluble immune complexes• Dendritic cells
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Hypothesis
Can antibodies which form an immune complex ameliorate ITP?
Teeling et al, Blood 2001
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Experimental Design
Cell-associated:
(anti-D like effect)
OVA
Soluble:
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A murine model of Passive Immune Thrombocytopenia
Anti-PLT
24h
FSC
SS
CRavetch et al (NY)
Bleeker et al (Amsterdam)
Balthasar & Deng (Buffalo)
Lemieux & Bazin (Quebec City)
Webster et al (Toronto)
Ravetch et al (NY)
Bleeker et al (Amsterdam)
Balthasar & Deng (Buffalo)
Lemieux & Bazin (Quebec City)
Webster et al (Toronto)
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0 1 2 3 40
200
400
600
800
1000
***
***
***
***
anti-platelet antibody
Tre
atm
en
t
Pla
tele
t cou
nt x
109 /L
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Inhibitory FcγRIIB
Activating FcγR
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FcγRIIB-/- mice
0 1 2 3 40
200
400
600
800
1000
anti-platelet antibody
Tre
atm
en
t
0 1 2 3 40
200
400
600
800
1000
*** ***
anti-platelet antibody
Tre
atm
en
t
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If IVIg functions via the formation of an immune complex, could these complexes be reacted with cells which could then be
adoptively transferred to recipients?
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Mix Wash Load
Inject
Amelioration of ITP?
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Adoptive-transfer of IVIg effects with leukocytes
Siragam et al, Nature Medicine 2006
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Proposed model of IVIg action in murine ITP
Siragam et al, J Clin Invest 2005
Siragam et al, Nat Med 2006
Tha-In et al, Blood 2007
Ephrem et al, Blood 2008
Aubin et al, Blood 2010
ITP
Park-Min, Immunity 2007
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Outline
•Mechanisms of platelet destruction in ITP
•Recent advances in:
• Fc receptor blockade• IVIg• anti-D• Inhibition of Fc receptor signaling
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Nil IVIg 30-F1 TER119 M1/690
50
100
150
200
* *
Fc R
IIIA
Ex
pre
ss
ion
Anti-D-like antibodies reduce the ability to detectactivating Fcγ receptors on macrophages
Song et al, Blood 105:1546-8, 2005
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Does anti-D ameliorate ITP via the same mechanism as IVIg?
Cooper et al, Br J Haem 2004
IVIG
Anti-D
IL-10
IL-10 MCP-1 IL-6 TNFα
2 hr
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Of the 6 patients in the study who had failed to respond to IVIG andanti-D given as single agents, 5 of them responded when given in combination.
Blood 2007
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Outline
•Mechanisms of platelet destruction in ITP
•Recent advances in:
• Fc receptor blockade• IVIg• anti-D• Inhibition of Fc receptor signaling
•Conclusions
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A new therapeutic intervention based upon the mouse model of ITP?
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Platelet phagocytosis in ITP
syksyksyksyk
R406R406
Braselmann, et al. J Pharmacol Exp Ther, 2006Braselmann, et al. J Pharmacol Exp Ther, 2006
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Inhibition of syk ameliorates murine ITP
0
200
400
600
800
1000
Treatment Nil IVIg2 g/kg
Vehicle R78825 mg/kg
R78840 mg/kg
Unmanipulated
Pla
tele
t co
un
t x
109 /L
Podolanczuk, A. et al. Blood 2009;113:3154-3160
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Copyright ©2009 American Society of Hematology. Copyright restrictions may apply.
Podolanczuk, A. et al. Blood 2009;113:3154-3160
syk inhibition in 16 adult refractory ITP patients
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Conclusions
•Multiple potential mechanisms of thrombocytopenia in ITP.
•The mechanism of IVIg remains unclear but may work via an Fc receptor-dependent cellular pathway (DC)
•Anti-D appears to work via a mechanism distinct from IVIg
•Inhibition of Fc receptor signaling or function could be a potential therapy in ITP
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Andrew R CrowDr. Zhong-Wei ChaiSara SuppaXi ChenJoan LegardaPatrick Mott
Thank you!Thank you!Dr. John FreedmanDr. Bernadette GarveyDr. John SempleDr. Heyu NiDr. Valery LeytinDr. Margaret Rand
Derry Roopenian
Jim BusselAnna Podolanczuk