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Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide

Ostergaard, Henrik; Bjelke, Jais R.; Hansen, Lene; Petersen, Lars Christian; Pedersen, Anette A.; Elm, Torben; Moller, Flemming; Hermit, Mette B.; Holm, Pernille K. and Krogh, Thomas N., et al. (2011) In Blood 118(8). p.2333-2341
Abstract
Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the Km for activation by FVIIa-tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood-based assays and showed efficacy... (More)
Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the Km for activation by FVIIa-tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood-based assays and showed efficacy comparable with rFIX in stopping acute bleeds in hemophilia B mice. In animal models N9-GP exhibited up to 2-fold increased in vivo recovery and a markedly prolonged half-life in mini-pig (76 hours) and hemophilia B dog (113 hours) compared with rFIX (16 hours). The extended circulation time of N9-GP was reflected in prolonged correction of coagulation parameters in hemophilia B dog and duration of effect in hemophilia B mice. Collectively, these results suggest that N9-GP has the potential to offer efficacious prophylactic and acute treatment of hemophilia B patients at a reduced dosing frequency. (Blood. 2011; 118(8): 2333-2341) (Less)
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published
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Blood
volume
118
issue
8
pages
2333 - 2341
publisher
American Society of Hematology
external identifiers
  • wos:000294258000036
  • scopus:80052167452
ISSN
1528-0020
DOI
10.1182/blood-2011-02-336172
language
English
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yes
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aa6697a2-667a-4ba7-815f-3b024a657743 (old id 2161507)
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2011-10-03 08:34:41
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2017-10-22 03:24:45
@article{aa6697a2-667a-4ba7-815f-3b024a657743,
  abstract     = {Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the Km for activation by FVIIa-tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood-based assays and showed efficacy comparable with rFIX in stopping acute bleeds in hemophilia B mice. In animal models N9-GP exhibited up to 2-fold increased in vivo recovery and a markedly prolonged half-life in mini-pig (76 hours) and hemophilia B dog (113 hours) compared with rFIX (16 hours). The extended circulation time of N9-GP was reflected in prolonged correction of coagulation parameters in hemophilia B dog and duration of effect in hemophilia B mice. Collectively, these results suggest that N9-GP has the potential to offer efficacious prophylactic and acute treatment of hemophilia B patients at a reduced dosing frequency. (Blood. 2011; 118(8): 2333-2341)},
  author       = {Ostergaard, Henrik and Bjelke, Jais R. and Hansen, Lene and Petersen, Lars Christian and Pedersen, Anette A. and Elm, Torben and Moller, Flemming and Hermit, Mette B. and Holm, Pernille K. and Krogh, Thomas N. and Petersen, Jorn M. and Ezban, Mirella and Sorensen, Brit B. and Andersen, Mette D. and Agerso, Henrik and Ahmadian, Haleh and Balling, Kristoffer W. and Christiansen, Marie Louise S. and Knobe, Karin and Nichols, Timothy C. and Bjorn, Soren E. and Tranholm, Mikael},
  issn         = {1528-0020},
  language     = {eng},
  number       = {8},
  pages        = {2333--2341},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide},
  url          = {http://dx.doi.org/10.1182/blood-2011-02-336172},
  volume       = {118},
  year         = {2011},
}