High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors

被引:35
作者
Batsuli, Glaivy [1 ,2 ]
Deng, Wei [1 ]
Healey, John F. [1 ]
Parker, Ernest T. [1 ]
Baldwin, W. Hunter [1 ]
Cox, Courtney [1 ]
Nguyen, Brenda [1 ]
Kahle, Joerg [3 ]
Koenigs, Christoph [3 ]
Li, Renhao [1 ]
Lollar, Pete [1 ]
Meeks, Shannon L. [1 ,2 ]
机构
[1] Emory Univ, Aflac Canc & Blood Disorders Ctr, Atlanta, GA 30322 USA
[2] Childrens Healthcare Atlanta, Atlanta, GA USA
[3] Goethe Univ Hosp, Dept Paediat, Clin & Mol Haemostasis & Immunodeficiency, Frankfurt, Germany
基金
美国国家卫生研究院;
关键词
VON-WILLEBRAND-FACTOR; COAGULATION-FACTOR-VIII; C2; DOMAIN; DENDRITIC CELLS; COMPLEX; EPITOPES; BINDING; CHAIN; COST; RISK;
D O I
10.1182/blood-2016-02-701805
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Inhibitor formation in hemophilia A is the most feared treatment-related complication of factor VIII (fVIII) therapy. Most inhibitor patients with hemophilia A develop antibodies against the fVIII A2 and C2 domains. Recent evidence demonstrates that the C1 domain contributes to the inhibitor response. Inhibitory anti-C1 monoclonal antibodies (mAbs) have been identified that bind to putative phospholipid and von Willebrand factor (VWF) binding epitopes and block endocytosis of fVIII by antigen presenting cells. We now demonstrate by competitive enzyme-linked immunosorbent assay and hydrogen-deuterium exchange mass spectrometry that 7 of 9 anti-human C1 mAbs tested recognize an epitope distinct from the C1 phospholipid binding site. These mAbs, designated group A, display high binding affinities for fVIII, weakly inhibit fVIII procoagulant activity, poorly inhibit fVIII binding to phospholipid, and exhibit heterogeneity with respect to blocking fVIII binding to VWF. Another mAb, designated group B, inhibits fVIII procoagulant activity, fVIII binding to VWF and phospholipid, fVIIIa incorporation into the intrinsic Xase complex, thrombin generation in plasma, and fVIII uptake by dendritic cells. Group A and B epitopes are distinct from the epitope recognized by the canonical, human-derived inhibitory anti-C1 mAb, KM33, whose epitope overlaps both groups A and B. Antibodies recognizing group A and B epitopes are present in inhibitor plasmas from patients with hemophilia A. Additionally, group A and B mAbs increase fVIII clearance and are pathogenic in a hemophilia A mouse tail snip bleeding model. Group A anti-C1 mAbs represent the first identification of pathogenic, weakly inhibitory antibodies that increase fVIII clearance.
引用
收藏
页码:2055 / 2067
页数:13
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