Haematologica 2000;85:supplement to no. 10 - Supplements ...

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Haematologica 2000; 85(suppl. to n.10) p. 35-39 Epidemiology and Biomolecular Aspects of FVIII inhibitors Inhibition of CD40 ligand (CD154) in the treatment of factor VIII inhibitors BRUCE M. EWENSTEIN,* W. KEITH HOOTS,° JEANNE M. LUSHER, # DONNA DIMICHELE, @ GILBERT C. WHITE II,^ BURT ADELMAN, § KARI NADEAU § *Division of Hematology, Brigham & Women’s Hospital, Boston, MA; °Department of Pediatrics, University of Texas Health Sciences Center, Houston, TX; # Division of Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI; @ New York Hospital-Cornell Medical Center, New York, NY; ^Division of Hematology, University of North Carolina School of Medicine, Chapel Hill, NC; § Biogen, Cambridge, MA, USA Abstract The development of persistent, high titer inhibitors represents a serious complication of the treatment of patients with severe hemophilia A. Elimination of these inhibitory antibodies is usually attempted through repeated administration of high doses of factor VIII. Such regimens are costly, time-consuming and often fail when the inhibitor is of very high titer or of longstanding duration. A potential alternative approach to inhibit the production of antifactor VIII antibodies is blockade of the T-cell/Bcell collaboration that is required to generate humoral responses. One cognate receptor pair that is required for T-cell-dependent B-cell activation consists of CD40, which is expressed on B-lymphocytes and other antigen presenting cells, and CD40 ligand (CD40L, CD154), which is transiently expressed on activated T-cells. To determine whether blockade of the CD40-CD40L pathway can inhibit the production of anti-factor VIII antibodies, a clinical study has been designed in which patients with hemophilia A and a high titer inhibitor (> 10 BU) receive monthly exposures to factor VIII in the presence of a humanized mouse monoclonal antibody to human CD40L (hu5c8*). Subjects must be between the ages of 5 and 60 years old and be HIV seronegative. To date, three subjects have received at least three doses of hu5c8 at the initial protocol dose of 10 mg/kg. Preliminary results suggest that anti-CD40L inhibition may be effective in blocking anamnestic responses to factor VIII in some patients. It remains to be determined whether this effect will persist and whether patients may eventually become tolerant to factor VIII in the absence of hu5c8 co-administration. ©2000, Ferrata Storti Foundation Key words: hemophilia, factor VIII, inhibitors, CD40 ligand, immune tolerance, CD154 *Hu5c8 is being developed under the trademark name ANTOVA at Biogen, Inc., Cambridge, Massachusetts. Correspondence: Bruce M. Ewenstein, M.D, Ph.D., Division of Hematology, Brigham & Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA. Phone: international +001-617-7325844- Fax: international +001-617-7325706 - E-mail: bewenstein@partners.org Replacement of factor VIII with high purity or recombinant factor VIII concentrates represents the mainstay of the treatment of hemophilia. This treatment is associated with the development of inhibitory IgG antibodies in up to 40% of patients with severe hemophilia A (factor VIII 5-10 Bethesda units [BU]), rendering the further use of factor VIII replacement impractical. Bleeding episodes in patients who develop inhibitors must be treated with other agents that “bypass” the need for factor VIII in the generation of thrombin. 2 Because these agents are both expensive and generally less effective than factor VIII concentrates, the development of a high titer inhibitor is associated with an inevitable increase in morbidity and resource utilization. 3 It is thus highly desirable to characterize the immune response to factor VIII more fully and to devise therapeutic strategies capable of abrogating this response. Immune responses to factor VIII Mutations in the factor VIII gene that result in a major loss of coding sequence (multi-domain deletions, nonsense mutations) are associated with the highest incidence of inhibitor formation. 4 This is not surprising since these mutations are also associated with a lack of detectable factor VIII protein. Natural tolerance, which may be defined as the abrogation of the immune response to non-pathogenic or self-antigens, begins prenatally and must be maintained during adult life. Theory predicts that patients expressing mutations that result in the total absence of factor VIII would be more likely not to become tolerized to the protein and therefore be at greatest risk for the development of factor VIII inhibitors. However, not all patients who lack detectable factor VIII develop inhibitors. Other determinants, such as the HLA class II phenotype 1,5,6 and the type of factor VIII concentrate to which the patient is Haematologica vol. 85(supplement to n. 10):October 2000
36 B.M. Ewenstein et al. exposed, 7-9 have also been shown to be determinants of inhibitor development. There is a growing body of evidence in support of the concept that the humoral response to factor VIII is T-cell-dependent, as with most protein antigens. Findings to date include the serendipitous discovery of an association of a factor VIII-derived peptide with purified human DR molecules 10 and the demonstration of T-lymphocyte proliferative responses to rFVIII in patients with hemophilia A and inhibitors. 11 More recently, results obtained in a murine model of hemophilia A demonstrated that blockade of the B7/CD28 co-stimulatory pathway can prevent or diminish the development of anti-factor VIII antibodies. 12 The results of these experiments are also consistent with the clinical observation that longstanding factor VIII inhibitors often disappear in HIV-infected patients concurrent with an overall decline of T- cell immune function. 13 The inhibitory antibodies to factor VIII are predominantly of the IgG4 and, to a lesser extent, IgG1 subclasses, 14,15 further suggesting the involvement of both Th1 and Th2 subsets of CD4 + T-cells. Induction of immune tolerance The elimination of inhibitory antibodies to factor VIII has often been successfully accomplished through a variety of treatment protocols collectively termed induction of immune tolerance (ITI), which typically involves the daily infusion of large doses of factor VIII for periods as long as 18-24 months. In some instances, immune modulating agents and procedures are also employed. The cellular mechanism(s) responsible for the success of ITI using these largely empiric approaches have not been elucidated, but may involve the induction of anergy or active suppression as has been reported in other tolerance regimes. 16 The majority of protocols used to date demonstrate similar efficacy (63-83%) but differ appreciably with respect to dose and the time required for success. 17 Reports from three large registries with pooled data from multiple centers and a variety of ITI regimens have identified high historical peak titers, longstanding inhibitors and inhibitor titers greater than 10 BU at the initiation of ITI therapy as significant negative predictors of eventual success. 17,18 Thus, current ITI protocols are particularly likely to fail in the subset of patients with very high titer inhibitors that remain elevated (≥ 10 BU) despite prolonged intervals without exposure to factor VIII. Role of CD40/CD40L in the humoral response The interaction of activated T-cells with B-cells is a required component in the humoral response to most protein antigens. This B-cell/Tcell interaction is mediated through several receptor-ligand binding signal events. Prominent among these are CD40, which is expressed on B- lymphocytes and other antigen presenting cells, and CD40 ligand (CD40L, CD154), which is transiently expressed on activated T-cells. CD40 is a 50 kD protein that belongs to the tumor necrosis factor (TNF)-α receptor family of cell surface receptors that have been shown to mediate both cell activation and programmed cell death. CD40L is a 32 kD type II membrane protein with significant sequence homology to TNF. 19 In addition to lymphoid cells, CD40 has also been identified on a variety of non-lymphoid cell types, including fibroblasts, endothelial cells and renal tubular epithelial cells, while CD40L has been identified on both macrophages and the cell surface of activated platelets. Interactions between CD40 and CD40L have been shown to be essential for the full development of humoral responses. 20-23 B-lymphocytes and other antigen presenting cells (APC) display antigen in the form of MHC-peptide complexes to T-lymphocytes which are thus stimulated to upregulate CD40L on their cell surface (Figure 1). Engagement of CD40L by CD40 then stimulates the B-cell in a variety of ways, including proliferation and differentiation, immunoglobulin class switch, and upregulation of CD80 (B7- 1) and CD86 (B7-2). Engagement of CD80 and CD86 by CD28 induced on the T-cell further amplifies the T-cell response. T-cells lacking CD40L are unable to activate antigen presenting cells resulting in the failure to produce IgG, as well as IgA and IgE, responses. 24,25 Importantly, in the absence of co-stimulation, antigen-specific CD4+ T-cells may be anergized or selectively deleted by apoptosis, resulting in a durable state of tolerance. 26 Study Design Methodology The study is being conducted as an open-label, multi-center, multiple-dose trial to evaluate the safety and efficacy of hu5c8 when given approximately two days prior to an infusion of factor VIII to stable hemophilia A subjects with hightiter factor VIII inhibitors. Fifteen to twenty hemodynamically stable subjects, aged 5-60 years old, with inhibitor titers of greater than 10 BU will be enrolled at five or more treatment centers. On day 1 of the 29-day treatment cycle, hu5c8 is administered at a dose of 10 mg/kg. Forty to sixty hours later, recombinant factor VIII (Recombinate [Hyland Immuno, Baxter Healthcare Corp], 100 U/kg) is infused. The Haematologica vol. 85(supplement to n. 10):October 2000
Page 1 and 2: Haematologica established in 1920 e
Page 3 and 4: Acknowledgments We wish to thank th
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Page 7 and 8: 4 J.M. Lusher (range 1-34) for pati
Page 9 and 10: 6 J.M. Lusher ALEDORT: I’d just l
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II Immune Tolerance and the Treatme
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