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Structure of coagulation factor VIII bound to a patient-derived anti-C1 domain antibody inhibitor

Journal Article · · Blood
 [1];  [1];  [1];  [2];  [2];  [3];  [4];  [5];  [1]
  1. Western Washington University, Bellingham, WA (United States)
  2. Oregon Health & Science University, Portland, OR (United States); Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
  3. Emory University, Atlanta, GA (United States)
  4. Emory University, Atlanta, GA (United States); Expression Therapeutics Inc., Tucker, GA (United States)
  5. National Institute for Biological Standards and Control, Potters Bar (United Kingdom)
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The development of pathogenic antibody inhibitors against coagulation factor VIII (FVIII) occurs in ~30% of congenital hemophilia A patients receiving FVIII replacement therapy as well as in all cases of acquired hemophilia A. KM33 is an anti-C1 domain antibody inhibitor previously isolated from a severe hemophilia A patient. In addition to potently blocking FVIII binding to von Willebrand factor and phospholipid surfaces, KM33 disrupts FVIII binding to lipoprotein receptor-related protein 1 (LRP1), which drives FVIII hepatic clearance and antigen presentation in dendritic cells. Here, we report on the structure of FVIII bound to NB33, a recombinant derivative of KM33, by single-particle cryo-electron microscopy. Furthermore, structural analysis reveals the NB33 epitope localizes to FVIII residues R2090-S2094 and I2158-R2159 which constitute membrane-binding loops in the C1 domain. Further analysis reveals multiple FVIII lysine and arginine residues, previously shown to mediate binding to LRP1, dock onto an acidic cleft at the NB33 variable domain interface, thus blocking a putative LRP1 binding site. Together, these results demonstrate a novel mechanism of FVIII inhibition by a patient-derived antibody inhibitor and provide structural evidence toward engineering FVIII with reduced LRP1-mediated clearance.
Research Organization:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC05-76RL01830
OSTI ID:
2000028
Report Number(s):
PNNL-SA--183525
Journal Information:
Blood, Journal Name: Blood Journal Issue: 2 Vol. 142; ISSN 0006-4971
Publisher:
American Society of HematologyCopyright Statement
Country of Publication:
United States
Language:
English

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Figure 1(p. 2)figure Figure 1
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