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Recent advances in Fc receptor- dependent therapies Alan H. Lazarus, PhD Canadian Blood Services St. Michael’s Hospital University of Toronto CBS Transfusion.

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Presentation on theme: "Recent advances in Fc receptor- dependent therapies Alan H. Lazarus, PhD Canadian Blood Services St. Michael’s Hospital University of Toronto CBS Transfusion."— Presentation transcript:

1 Recent advances in Fc receptor- dependent therapies Alan H. Lazarus, PhD Canadian Blood Services St. Michael’s Hospital University of Toronto CBS Transfusion Medicine Resident Scientific Session Nov 2, 2010

2 Outline Mechanisms of platelet destruction in ITP Recent advances in: Fc receptor blockade IVIg anti-D Inhibition of Fc receptor signaling Conclusions

3 Immune thrombocytopenic purpura (ITP) Platelet

4 An Fc-independent mechanism of potential immune thrombocytopenia-ROS Zang W et al, Blood 2008 Li Z et al, J Biol Chem 2008 Li Z et al, Blood 2009 GPIIbIIIa ROS HCV Wright JF et al, Br J Haem 1996 VZV Quinine Peterson, Blood 2008

5 Fc-independent immune thrombocytopenia-GPIb Platelet Nieswandt et al Blood 2000 Webster et al Blood 2006 Go et al Haematologica 2007 GPIb

6 Carbohydrates important for IgG function? Fc F(ab’) 2

7 Albert H et al. PNAS 2008;105: ©2008 by National Academy of Sciences IgG subclass-specific effects of EndoS-mediated hydrolysis of the IgG-associated sugar side chain.

8 A potential alternative mechanism of platelet destruction? Cell Mediated Immunity Olsson et al, Nature Medicine 2003 Zhang et al, Eur J Haem 2006

9 An alternative mechanism which may contribute to immune thrombocytopenia? PLT MK in Bone Marrow

10 Decreased platelet production due to antibody and/or T cells inhibiting or destroying MK

11 MechanismFc receptorsReference classic anti-IIbIIIayesHarrington Experiment 1951 anti-IIbIIIa (49-66)noZhang, 2008 Li, 2008 Li, 2009 anti-GPIbnoNieswandt, 2000 Webster, 2006 Go, 2007 T cellsnoOlsson, 2003 Zhang, 2006 Chow, 2010 Direct effect on MK?Chang 2003 McMillan 2004 Houwerzijl 2004

12 Outline Mechanisms of platelet destruction in ITP Recent advances in: Fc receptor blockade IVIg anti-D Inhibition of Fc receptor signaling

13 +other potential Fc receptors for IgG (FCRL’s)

14 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)

15 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,

16 Outline Mechanisms of platelet destruction in ITP Recent advances in: Fc receptor blockade IVIg anti-D Inhibition of Fc receptor signaling

17 IVIg is IgG Fc F(ab’) 2 Intravenous Immunoglobulin

18 How does IVIg work?

19 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] ……

20 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

21 Hypothesis Can antibodies which form an immune complex ameliorate ITP? Teeling et al, Blood 2001

22 Experimental Design Cell-associated: (anti-D like effect) OVA Soluble:

23 A murine model of Passive Immune Thrombocytopenia Anti-PLT 24h FSC SSC Ravetch et al (NY) Bleeker et al (Amsterdam) Balthasar & Deng (Buffalo) Lemieux & Bazin (Quebec City) Webster et al (Toronto)

24

25

26 Inhibitory FcγRIIB Activating FcγR

27 FcγRIIB -/- mice

28 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?

29 MixWash Load Inject Amelioration of ITP?

30 Adoptive-transfer of IVIg effects with leukocytes Siragam et al, Nature Medicine 2006

31 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

32 Outline Mechanisms of platelet destruction in ITP Recent advances in: Fc receptor blockade IVIg anti-D Inhibition of Fc receptor signaling

33 Anti-D-like antibodies reduce the ability to detect activating Fcγ receptors on macrophages Song et al, Blood 105:1546-8, 2005

34 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

35 Of the 6 patients in the study who had failed to respond to IVIG and anti-D given as single agents, 5 of them responded when given in combination. Blood 2007

36

37 Outline Mechanisms of platelet destruction in ITP Recent advances in: Fc receptor blockade IVIg anti-D Inhibition of Fc receptor signaling Conclusions

38 A new therapeutic intervention based upon the mouse model of ITP?

39 Platelet phagocytosis in ITP syksyk R406 Braselmann, et al. J Pharmacol Exp Ther, 2006

40 Inhibition of syk ameliorates murine ITP Podolanczuk, A. et al. Blood 2009;113:

41 Copyright ©2009 American Society of Hematology. Copyright restrictions may apply. Podolanczuk, A. et al. Blood 2009;113: syk inhibition in 16 adult refractory ITP patients

42 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

43 Andrew R Crow Dr. Zhong-Wei Chai Sara Suppa Xi Chen Joan Legarda Patrick Mott Andrew R Crow Dr. Zhong-Wei Chai Sara Suppa Xi Chen Joan Legarda Patrick Mott Thank you! Dr. John Freedman Dr. Bernadette Garvey Dr. John Semple Dr. Heyu Ni Dr. Valery Leytin Dr. Margaret Rand Derry Roopenian Jim Bussel Anna Podolanczuk Dr. John Freedman Dr. Bernadette Garvey Dr. John Semple Dr. Heyu Ni Dr. Valery Leytin Dr. Margaret Rand Derry Roopenian Jim Bussel Anna Podolanczuk


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