Skip to main content
SpringerLink
Log in

Therapeutic Potential of Toleragens in the Management of Antiphospholipid Syndrome

  • Novel Therapeutic Strategies
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

Autoantibodies to β2-glycoprotein I (β2GPI) are believed to be the primary cause of coagulation abnormalities in patients with antiphospholipid syndrome (APS). Clinical features include a range of life-threatening thrombotic events and microangiopathies affecting multiple organ systems. Current standard of care relies on long-term, high-intensity anticoagulation and is associated with a high risk for serious bleeding events. The relation between autoantibodies and the pathophysiology of APS is not clearly understood, but numerous in vitro studies have characterized the effects of antiphospholipid autoantibodies on various components of the coagulation cascade, including tissue factor and the protein C pathway. The fine specificity of autoantibodies to β2GPI is a subject of considerable debate; however, a body of evidence may offer resolution by integrating concepts of antibody affinity and assay sensitivity with carefully designed molecular studies. An investigational new therapy for APS is based on the approach that pathogenic antibodies may be reduced via depletion of circulating autoantibodies and induction of immune tolerance at the B-cell level. Preliminary results from a phase I/II clinical trial with LJP 1082, a B-cell toleragen, indicate the drug was well tolerated and may warrant further development for reduction of thrombotic events in patients with APS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Table II
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Wilson WA, Gharavi AE, Koike T, et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum 1999; 42: 1309–11

    Article  PubMed  CAS  Google Scholar 

  2. Galli M, Finazzi G, Barbui T. Thrombocytopenia in the antiphospholipid syndrome: pathophysiology, clinical relevance and treatment. Ann Med Interne (Paris) 1996; 147Suppl. 1: 24–7

    Google Scholar 

  3. Muir KW, Squire IB, Alwan W, et al. Anticardiolipin antibodies in an unselected stroke population. Lancet 1994; 344: 452–6

    Article  PubMed  CAS  Google Scholar 

  4. Italian Registry of Antiphospholipid Antibodies (IR-APA). Thrombosis and thrombocytopenia in antiphospholipid syndrome (idiopathic and secondary to SLE): first report from the Italian Registry. Haematologica 1993; 78: 313–8

    Google Scholar 

  5. Hamsten A, Norberg R, Bjorkholm M, et al. Antibodies to cardiolipin in young survivors of myocardial infarction: an association with recurrent cardiovascular events. Lancet 1986; I: 113–6

    Article  Google Scholar 

  6. Asherson RA, Khamashta MA, Ordi-Ros J, et al. The “primary” antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore) 1989; 68: 366–74

    CAS  Google Scholar 

  7. Alarcon-Segovia D, Deleze M, Oria CV, et al. Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus: a prospective analysis of 500 consecutive patients. Medicine (Baltimore) 1989; 68: 353–65

    CAS  Google Scholar 

  8. Asherson RA, Higenbottam TW, Dinh Xuan AT, et al. Pulmonary hypertension in a lupus clinic: experience with twenty-four patients. J Rheumatol 1990; 17: 1292–8

    PubMed  CAS  Google Scholar 

  9. Koike T, Tsutsumi A. Pulmonary hypertension and the antiphospholipid syndrome [letter]. Intern Med 1995; 34: 938

    Article  PubMed  CAS  Google Scholar 

  10. Kunieda T. Antiphospholipid syndrome and pulmonary hypertension. Intern Med 1996; 35: 842–3

    Article  PubMed  CAS  Google Scholar 

  11. Asherson RA, Cervera R, Piette JC, et al. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore) 2001; 80: 355–77

    Article  CAS  Google Scholar 

  12. Au A, O’Day J. Review of severe vaso-occlusive retinopathy in systemic lupus erythematosus and the antiphospholipid syndrome: associations, visual outcomes, complications and treatment. Clin Exp Ophthalmol 2004; 32: 87–100

    Article  Google Scholar 

  13. Cuadrado MJ, Lopez-Pedrera C. Antiphospholipid syndrome. Clin Exp Med 2003; 3: 129–39

    Article  PubMed  CAS  Google Scholar 

  14. Derksen RH, Khamashta MA, Branch DW. Management of the obstetric antiphospholipid syndrome. Arthritis Rheum 2004; 50: 1028–39

    Article  PubMed  CAS  Google Scholar 

  15. Erkan D, Cervera R, Asherson RA. Catastrophic antiphospholipid syndrome: where do we stand? Arthritis Rheum 2003; 48: 3320–7

    Article  PubMed  Google Scholar 

  16. Fakhouri F, Noel LH, Zuber J, et al. The expanding spectrum of renal diseases associated with antiphospholipid syndrome. Am J Kidney Dis 2003; 41: 1205–11

    Article  PubMed  Google Scholar 

  17. Katzav A, Chapman J, Shoenfeld Y. CNS dysfunction in the antiphospholipid syndrome. Lupus 2003; 12: 903–7

    Article  PubMed  CAS  Google Scholar 

  18. Lockshin M, Tenedios F, Petri M, et al. Cardiac disease in the antiphospholipid syndrome: recommendations for treatment: committee consensus report. Lupus 2003; 12: 518–23

    Article  PubMed  CAS  Google Scholar 

  19. Meroni PL, Moia M, Derksen RH, et al. Venous thromboembolism in the antiphospholipid syndrome: management guidelines for secondary prophylaxis. Lupus 2003; 12: 504–7

    Article  PubMed  CAS  Google Scholar 

  20. Paran D, Fireman E, Elkayam O. Pulmonary disease in systemic lupus erythematosus and the antiphospholpid syndrome. Autoimmun Rev 2004; 3: 70–5

    Article  PubMed  Google Scholar 

  21. Sastre-Garriga J, Montalban X. APS and the brain. Lupus 2003; 12: 877–82

    Article  PubMed  CAS  Google Scholar 

  22. Tincani A, Branch W, Levy RA, et al. Treatment of pregnant patients with antiphospholipid syndrome. Lupus 2003; 12: 524–9

    Article  PubMed  CAS  Google Scholar 

  23. Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992; 117: 303–8

    PubMed  CAS  Google Scholar 

  24. Derksen RH, de Groot PG, Kater L, et al. Patients with antiphospholipid antibodies and venous thrombosis should receive long term anticoagulant treatment. Ann Rheum Dis 1993; 52: 689–92

    Article  PubMed  CAS  Google Scholar 

  25. Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med 2003; 349: 1133–8

    Article  PubMed  CAS  Google Scholar 

  26. Fihn SD, McDonell M, Martin D, et al. Risk factors for complications of chronic anticoagulation: a multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Ann Intern Med 1993; 118: 511–20

    PubMed  CAS  Google Scholar 

  27. Galli M, Comfurius P, Maassen C, et al. Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet 1990; 335: 1544–7

    Article  PubMed  CAS  Google Scholar 

  28. McNeil HP, Simpson RJ, Chesterman CN, et al. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci U S A 1990; 87: 4120–4

    Article  PubMed  CAS  Google Scholar 

  29. Matsuura E, Igarashi Y, Fujimoto M, et al. Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet 1990; 336: 177–8

    Article  PubMed  CAS  Google Scholar 

  30. Bevers EM, Galli M, Barbui T, et al. Lupus anticoagulant IgG’s (LA) are not directed to phospholipids only, but to a complex of lipid-bound human prothrombin. Thromb Haemost 1991; 66: 629–32

    PubMed  CAS  Google Scholar 

  31. Arvieux J, Darnige L, Caron C, et al. Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants. Thromb Haemost 1995; 74: 1120–5

    PubMed  CAS  Google Scholar 

  32. Oosting JD, Derksen RH, Bobbink IW, et al. Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C, or protein S: an explanation for their pathogenic mechanism? Blood 1993; 81: 2618–25

    PubMed  CAS  Google Scholar 

  33. Matsuda J, Saitoh N, Gohchi K, et al. Anti-annexin V antibody in systemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipin antibody. Am J Hematol 1994; 47: 56–8

    Article  PubMed  CAS  Google Scholar 

  34. Cugno M, Dominguez M, Cabibbe M, et al. Antibodies to tissue-type plasminogen activator in plasma from patients with primary antiphospholipid syndrome. Br J Haematol 2000; 108: 871–5

    Article  PubMed  CAS  Google Scholar 

  35. Petri M. Classification and epidemiology of the antiphospholipid syndrome. In: Asherson RA, Cervera R, Piette JC, et al., editors. The antiphospholipid syndrome II. Amsterdam: Elsevier, 2002: 11–20

    Chapter  Google Scholar 

  36. Tanne D, Levine SR, Kittner SJ. Epidemiology of antiphospholipid antibodies and vascular disease. In: Levine SR, Brey RL, editors. Clinical approach to antiphospholipid antibodies. Boston (MA): Butterworth Heinemann, 2000: 1–18

    Google Scholar 

  37. Hess DC, Krauss J, Adams RJ, et al. Anticardiolipin antibodies: a study of frequency in TIA and stroke. Neurology 1991; 41(4): 525–8

    Article  PubMed  CAS  Google Scholar 

  38. The Antiphospholipid Antibodies in Stroke Study Group (APASS). Clinical, radiological, and pathological aspects of cerebrovascular disease associated with antiphospholipid antibodies. Stroke 1993; 24(12 Suppl.): I120–3

    Google Scholar 

  39. Eschwege V, Peynaud-Debayle E, Wolf M, et al. Prevalence of antiphospholipid-related antibodies in unselected patients with history of venous thrombosis. Blood Coagul Fibrinolysis 1998; 9(5): 429–34

    Article  PubMed  CAS  Google Scholar 

  40. Zielinska J, Ryglewicz D, Wierzchowska E, et al. Anticardiolipin antibodies are an independent risk factor for ischemic stroke. Neurol Res 1999; l21(7): 653–7

    Google Scholar 

  41. Tuhrim S, Rand JH, Wu XX, et al. Elevated anticardiolipin antibody titer is a stroke risk factor in a multiethnic population independent of isotype or degree of positivity. Stroke 1999; 30: 1561–5

    Article  PubMed  CAS  Google Scholar 

  42. Balasch J, Creus M, Fabregues F, et al. Antiphospholipid antibodies and human reproductive failure. Hum Reprod 1996; 11(10): 2310–5

    Article  PubMed  CAS  Google Scholar 

  43. Yetman DL, Kutteh WH. Antiphospholipid antibody panels and recurrent pregnancy loss: prevalence of anticardiolipin antibodies compared with other antiphospholipid antibodies. Fertil Steril 1996; 66(4): 540–6

    PubMed  CAS  Google Scholar 

  44. Branch DW, Silver R, Pierangeli S, et al. Antiphospholipid antibodies other than lupus anticoagulant and anticardiolipin antibodies in women with recurrent pregnancy loss, fertile controls, and antiphospholipid syndrome. Obstet Gynecol 1997; 89(4): 549–55

    Article  PubMed  CAS  Google Scholar 

  45. Kutteh WH. Antiphospholipid antibodies and reproduction. J Reprod Immunol 1997; 35(2): 151–71

    Article  PubMed  CAS  Google Scholar 

  46. Buchanan RR, Wardlaw JR, Riglar AG, et al. Antiphospholipid antibodies in the connective tissue diseases: their relation to the antiphospholipid syndrome and forme frust disease. J Rheumatol 1989; 16(6): 757–61

    PubMed  CAS  Google Scholar 

  47. Cervera R, Font J, Lopez-Soto A, et al. Isotype distribution of anticardiolipin antibodies in systemic lupus erythematosus: prospective analysis of a series of 100 patients. Ann Rheum Dis 1990; 49(2): 109–13

    Article  PubMed  CAS  Google Scholar 

  48. Worrall JG, Snaith ML, Batchelor JR, et al. SLE: a rheumatological view: analysis of the clinical features, serology and immunogenetics of 100 SLE patients during long-term follow-up. Q J Med 1990; 74: 319–30

    PubMed  CAS  Google Scholar 

  49. Galli M, Luciani D, Bertolini G, et al. Anti-β2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood 2003; 102: 2717–23

    Article  PubMed  CAS  Google Scholar 

  50. Ginsburg KS, Liang MH, Newcomer L, et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med 1992; 117: 997–1002

    PubMed  CAS  Google Scholar 

  51. Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy: Duration of Anticoagulation Study Group. Am J Med 1998; 104: 332–8

    Article  PubMed  CAS  Google Scholar 

  52. Petri M, Rheinschmidt M, Whiting-O’Keefe Q, et al. The frequency of lupus anticoagulant in systemic lupus erythematosus: a study of sixty consecutive patients by activated partial thromboplastin time, Russell viper venom time, and anticardiolipin antibody level. Ann Intern Med 1987; 106: 524–31

    PubMed  CAS  Google Scholar 

  53. Derksen RH, Bouma BN, Kater L. The prevalence and clinical associations of the lupus anticoagulant in systemic lupus erythematosus. Scand J Rheumatol 1987; 16: 185–92

    Article  PubMed  CAS  Google Scholar 

  54. Wahl DG, Guillemin F, De Maistre E, et al. Meta-analysis of the risk of venous thrombosis in individuals with antiphospholipid antibodies without underlying autoimmune disease or previous thrombosis. Lupus 1998; 7: 15–22

    Article  PubMed  CAS  Google Scholar 

  55. Wahl DG, Guillemin F, De Maistre E, et al. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus: a meta-analysis. Lupus 1997; 6: 467–73

    Article  PubMed  CAS  Google Scholar 

  56. Vaarala O, Manttari M, Manninen V, et al. Anti-cardiolipin antibodies and risk of myocardial infarction in a prospective cohort of middle-aged men. Circulation 1995; 91: 23–7

    Article  PubMed  CAS  Google Scholar 

  57. Brey RL, Abbott RD, Curb JD, et al. Beta(2)-glycoprotein 1-dependent anticardiolipin antibodies and risk of ischemic stroke and myocardial infarction: the honolulu heart program. Stroke 2001; 32: 1701–6

    Article  PubMed  CAS  Google Scholar 

  58. Kornberg A, Blank M, Kaufman S, et al. Induction of tissue factor-like activity in monocytes by anti-cardiolipin antibodies. J Immunol 1994; 153: 1328–32

    PubMed  CAS  Google Scholar 

  59. Reverter JC, Tassies D, Font J, et al. Hypercoagulable state in patients with antiphospholipid syndrome is related to high induced tissue factor expression on monocytes and to low free protein S. Arterioscler Thromb Vasc Biol 1996; 16: 1319–26

    Article  PubMed  CAS  Google Scholar 

  60. Amengual O, Atsumi T, Khamashta MA, et al. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb Haemost 1998; 79: 276–81

    PubMed  CAS  Google Scholar 

  61. Cuadrado MJ, Lopez-Pedrera C, Khamashta MA, et al. Thrombosis in primary antiphospholipid syndrome: a pivotal role for monocyte tissue factor expression. Arthritis Rheum 1997; 40: 834–41

    Article  PubMed  CAS  Google Scholar 

  62. Dobado-Berrios PM, Lopez-Pedrera C, Velasco F, et al. Increased levels of tissue factor mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome. Thromb Haemost 1999; 82: 1578–82

    PubMed  CAS  Google Scholar 

  63. Salemink I, Blezer R, Willems GM, et al. Antibodies to beta2-glycoprotein I associated with antiphospholipid syndrome suppress the inhibitory activity of tissue factor pathway inhibitor. Thromb Haemost 2000; 84: 653–6

    PubMed  CAS  Google Scholar 

  64. Borrell M, Sala N, de Castellarnau C, et al. Immunoglobulin fractions isolated from patients with antiphospholipid antibodies prevent the inactivation of factor Va by activated protein C on human endothelial cells. Thromb Haemost 1992; 68: 268–72

    PubMed  CAS  Google Scholar 

  65. Cariou R, Tobelem G, Soria C, et al. Inhibition of protein C activation by endothelial cells in the presence of lupus anticoagulant. N Engl J Med 1986; 314: 1193–4

    Article  PubMed  CAS  Google Scholar 

  66. Cariou R, Tobelem G, Bellucci S, et al. Effect of lupus anticoagulant on antithrombogenic properties of endothelial cells: inhibition of thrombomodulin-dependent protein C activation. Thromb Haemost 1988; 60: 54–8

    PubMed  CAS  Google Scholar 

  67. Malia RG, Kitchen S, Greaves M, et al. Inhibition of activated protein C and its cofactor protein S by antiphospholipid antibodies. Br J Haematol 1990; 76: 101–7

    Article  PubMed  CAS  Google Scholar 

  68. Marciniak E, Romond EH. Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant. Blood 1989; 74: 2426–32

    PubMed  CAS  Google Scholar 

  69. Matsuda J, Gotoh M, Gohchi K, et al. Resistance to activated protein C activity of an anti-beta 2-glycoprotein I antibody in the presence of beta 2-glycoprotein I. Br J Haematol 1995; 90: 204–6

    Article  PubMed  CAS  Google Scholar 

  70. Oosting JD, Preissner KT, Derksen RH, et al. Autoantibodies directed against the epidermal growth factor-like domains of thrombomodulin inhibit protein C activation invitro. Br J Haematol 1993; 85: 761–8

    Article  PubMed  CAS  Google Scholar 

  71. Pengo V, Biasiolo A, Brocco T, et al. Autoantibodies to phospholipid-binding plasma proteins in patients with thrombosis and phospholipid-reactive antibodies. Thromb Haemost 1996; 75: 721–4

    PubMed  CAS  Google Scholar 

  72. Ruiz-Arguelles GJ, Ruiz-Arguelles A, Deleze M, et al. Acquired protein C deficiency in a patient with primary antiphospholipid syndrome: relationship to reactivity of anticardiolipin antibody with thrombomodulin. J Rheumatol 1989; 16: 381–3

    PubMed  CAS  Google Scholar 

  73. Lutters BC, Derksen RH, Tekelenburg WL, et al. Dimers of beta 2-glycoprotein I increase platelet deposition to collagen via interaction with phospholipids and the apolipoprotein E receptor 2′. J Biol Chem 2003; 278: 33831–8

    Article  PubMed  CAS  Google Scholar 

  74. Shi T, Iverson GM, Qi JC, et al. β2glycoprotein I binds factor XI and inhibits its activation by thrombin and factor XIIa: loss of inhibition by clipped β2g-lycoprotein I. Proc Natl Acad Sci U S A 2004; 101: 3939–44

    Article  PubMed  CAS  Google Scholar 

  75. Rand JH, Wu XX, Andree HA, et al. Antiphospholipid antibodies accelerate plasma coagulation by inhibiting annexin-V binding to phospholipids: a “lupus procoagulant” phenomenon. Blood 1998; 92: 1652–60

    PubMed  CAS  Google Scholar 

  76. Hanly JG, Smith SA. Anti-beta2-glycoprotein I (GPI) autoantibodies, annexin V binding and the anti-phospholipid syndrome. Clin Exp Immunol 2000; 120: 537–43

    Article  PubMed  CAS  Google Scholar 

  77. Willems GM, Janssen MP, Comfurius P, et al. Competition of annexin V and anticardiolipin antibodies for binding to phosphatidylserine containing membranes. Biochemistry 2000; 39: 1982–9

    Article  PubMed  CAS  Google Scholar 

  78. Bancsi LF, van der Linden IK, Bertina RM. Beta 2-glycoprotein I deficiency and the risk of thrombosis. Thromb Haemost 1992; 67: 649–53

    PubMed  CAS  Google Scholar 

  79. Yasuda S, Tsutsumi A, Chiba H, et al. Beta(2)-glycoprotein I deficiency: prevalence, genetic background and effects on plasma lipoprotein metabolism and hemostasis. Atherosclerosis 2000; 152: 337–46

    Article  PubMed  CAS  Google Scholar 

  80. Hunt JE, Simpson RJ, Krilis SA. Identification of a region of beta 2-glycoprotein I critical for lipid binding and anti-cardiolipin antibody cofactor activity. Proc Natl Acad Sci U S A 1993; 90: 2141–5

    Article  PubMed  CAS  Google Scholar 

  81. Horbach DA, van Oort E, Lisman T, et al. Beta2-glycoprotein I is proteolytically cleaved in vivo upon activation of fibrinolysis. Thromb Haemost 1999; 81: 87–95

    PubMed  CAS  Google Scholar 

  82. Bouma B, de Groot PG, van den Elsen JM, et al. Adhesion mechanism of human beta(2)-glycoprotein I to phospholipids based on its crystal structure. EMBO J 1999; 18: 5166–74

    Article  PubMed  CAS  Google Scholar 

  83. Schwarzenbacher R, Zeth K, Diederichs K, et al. Crystal structure of human beta2-glycoprotein I: implications for phospholipid binding and the antiphospholipid syndrome. EMBO J 1999; 18: 6228–39

    Article  PubMed  CAS  Google Scholar 

  84. Hammel M, Kriechbaum M, Gries A, et al. Solution structure of human and bovine beta(2)-glycoprotein I revealed by small-angle X-ray scattering. J Mol Biol 2002; 321: 85–97

    Article  PubMed  CAS  Google Scholar 

  85. Matsuura E, Igarashi Y, Fujimoto M, et al. Heterogeneity of anticardiolipin antibodies defined by the anticardiolipin cofactor. J Immunol 1992; 148: 3885–91

    PubMed  CAS  Google Scholar 

  86. Ichikawa K, Khamashta MA, Koike T, et al. Beta 2-glycoprotein I reactivity of monoclonal anticardiolipin antibodies from patients with the antiphospholipid syndrome. Arthritis Rheum 1994; 37: 1453–61

    Article  PubMed  CAS  Google Scholar 

  87. Koike T, Tsutsumi A, Ichikawa K, et al. Antigenic specificity of the “anticardiolipin” antibodies. Blood 1995; 85: 2277–80

    PubMed  CAS  Google Scholar 

  88. Matsuura E, Igarashi Y, Yasuda T, et al. Anticardiolipin antibodies recognize beta 2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J Exp Med 1994; 179: 457–62

    Article  PubMed  CAS  Google Scholar 

  89. Pengo V, Biasiolo A, Fior MG. Autoimmune antiphospholipid antibodies are directed against a cryptic epitope expressed when beta 2-glycoprotein I is bound to a suitable surface. Thromb Haemost 1995; 73: 29–34

    PubMed  CAS  Google Scholar 

  90. Roubey RA, Eisenberg RA, Harper MF, et al. “Anticardiolipin” autoantibodies recognize beta 2-glycoprotein I in the absence of phospholipid: importance of Ag density and bivalent binding. J Immunol 1995; 154: 954–60

    PubMed  CAS  Google Scholar 

  91. Sheng Y, Kandiah DA, Krilis SA. Anti-beta 2-glycoprotein I autoantibodies from patients with the “antiphospholipid” syndrome bind to beta 2-glycoprotein I with low affinity: dimerization of beta 2-glycoprotein I induces a significant increase in anti-beta 2-glycoprotein I antibody affinity. J Immunol 1998; 161: 2038–43

    PubMed  CAS  Google Scholar 

  92. Arvieux J, Regnault V, Hachulla E, et al. Heterogeneity and immunochemical properties of anti-beta2-glycoprotein I autoantibodies. Thromb Haemost 1998; 80: 393–8

    PubMed  CAS  Google Scholar 

  93. Chamley LW, Duncalf AM, Konarkowska B, et al. Conformationally altered beta 2-glycoprotein I is the antigen for anti-cardiolipin autoantibodies. Clin Exp Immunol 1999; 115: 571–6

    Article  PubMed  CAS  Google Scholar 

  94. Forastiero RR, Martinuzzo ME, Kordich LC, et al. Reactivity to beta 2 glycoprotein I clearly differentiates anticardiolipin antibodies from antiphospholipid syndrome and syphilis. Thromb Haemost 1996; 75: 717–20

    PubMed  CAS  Google Scholar 

  95. Iverson GM, Victoria EJ, Marquis DM. Anti-beta2 glycoprotein I (beta2GPI) autoantibodies recognize an epitope on the first domain of beta2GPI. Proc Natl Acad Sci U S A 1998; 95: 15542–6

    Article  PubMed  CAS  Google Scholar 

  96. Tincani A, Spatola L, Prati E, et al. The anti-beta2-glycoprotein I activity in human anti-phospholipid syndrome sera is due to monoreactive low-affinity autoantibodies directed to epitopes located on native beta2-glycoprotein I and preserved during species’ evolution. J Immunol 1996; 157: 5732–8

    PubMed  CAS  Google Scholar 

  97. Iverson GM, Matsuura E, Victoria EJ, et al. The orientation of beta2GPI on the plate is important for the binding of anti-beta2GPI autoantibodies by ELISA. J Autoimmun 2002; 18: 289–97

    Article  PubMed  Google Scholar 

  98. Giles IP, Isenberg DA, Latchman DS, et al. How do antiphospholipid antibodies bind beta2-glycoprotein I? Arthritis Rheum 2003; 48: 2111–21

    Article  PubMed  CAS  Google Scholar 

  99. McNeeley PA, Dlott JS, Furie RA, et al. Beta2-glycoprotein I-dependent anticardiolipin antibodies preferentially bind the amino terminal domain of beta2-glycoprotein I. Thromb Haemost 2001; 86: 590–5

    PubMed  CAS  Google Scholar 

  100. Iverson GM, Reddel S, Victoria EJ, et al. Use of single point mutations in domain I of beta 2-glycoprotein I to determine fine antigenic specificity of antiphospholipid autoantibodies. J Immunol 2002; 169: 7097–103

    PubMed  CAS  Google Scholar 

  101. Jones DA, Branks MJ, Campbell MA, et al. Multivalent poly(ethylene glycol)-containing conjugates for invivoantibody suppression. Bioconjug Chem 2003; 14(6): 1067–76

    Article  PubMed  CAS  Google Scholar 

  102. Cockerill KA, Smith E, Jones DS, et al. Invivocharacterization of bioconjugate B cell toleragens with specificity for autoantibodies in antiphospholipid syndrome. Int Immunopharmacol 2003; 3: 1667–75

    Article  PubMed  CAS  Google Scholar 

  103. Abetimus: Abetimus sodium, LJP 394. BioDrugs 2003; 17 (3): 212-5

  104. Abetimus sodium. Drugs of the Future 2001; 26 (7): 633-8

    Google Scholar 

  105. Weisman MH, Bluestein HG, Berner CM, et al. Reduction in circulating dsDNA antibody titer after administration of LJP 394. J Rheumatol 1997; 24(2): 314–8

    PubMed  CAS  Google Scholar 

  106. Furie RA, Cash JM, Cronin ME, et al. Treatment of systemic lupus erythematosus with LJP 394. J Rheumatol 2001; 28(2): 257–65

    PubMed  CAS  Google Scholar 

  107. Wallace DJ. Clinical and pharmacological experience with LJP-394. Expert Opin Investig Drugs 2001; 10(1): 111–7

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are employees of La Jolla Pharmaceutical Company, which is involved in the development of Toleragens® as therapeutics.

Author information

Authors and Affiliations

  1. La Jolla Pharmaceutical Company, San Diego, California, USA

    Keith A. Cockerill, G. Michael Iverson, David S. Jones & Matthew D. Linnik

  2. 6455 Nancy Ridge Drive, San Diego, CA, 92121, USA

    Keith A. Cockerill

Authors
  1. Keith A. Cockerill
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Michael Iverson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David S. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthew D. Linnik
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Keith A. Cockerill.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cockerill, K.A., Iverson, G.M., Jones, D.S. et al. Therapeutic Potential of Toleragens in the Management of Antiphospholipid Syndrome. BioDrugs 18, 297–305 (2004). https://doi.org/10.2165/00063030-200418050-00002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00063030-200418050-00002

Keywords

Search

Navigation