Prolonged activity of factor IX as a monomeric Fc fusion protein

Peters, Robert; Low, Susan C.; Kamphaus, George D.; Dumont, Jennifer; Amari, John V.; Lü, Qi; Zarbis-Papastoitsis, Greg; Reidy, Thomas J.; Merricks, Elizabeth P.; Nichols, Timothy C.; Bitonti, Alan J.

doi:10.1182/blood-2009-08-239665

Cited by 185 publications

(212 citation statements)

References 30 publications

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“…A significant application of monomeric Fc is for the so-called monomeric Fc fusion technology where a monovalency of the active protein is presented, but currently, it is fused to dimeric wild-type Fc (23)(24)(25). This "monomeric" technology is an upgraded version of the traditional dimeric Fc fusion molecules, which contain two effector molecules.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown to be more robust due to better tissue penetration offered by the smaller size, and a reduced steric hindrance, which can make effector protein and/or Fc part more effective. For instance, it has been found that monomeric factor IX-Fc fusion protein not only has an extended half-life compared with the factor IX-Fc dimer but also greatly enhanced pharmacokinetics, with a 10-fold increase in C max and more than a 12-fold increase in area under the curve (25). These advantages are valuable because they provide cheaper therapeutics and enhance the delivery of therapeutic proteins by non-invasive routes.…”

Section: Discussionmentioning

confidence: 99%

“…A typical Fc fusion protein contains two effector molecules because the Fc fragment of the IgG consists of a tightly packed homodimer, and each molecule is attached to one chain of the Fc dimer. Recently, so-called "monomeric Fc fusion proteins" were generated by fusing a single active protein to dimeric wildtype Fc (23)(24)(25). Such smaller molecules have been shown to possess extended half-lives compared with the dimeric version and are promising for therapeutic applications.…”

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confidence: 99%

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Soluble Monomeric IgG1 Fc

Ying

Chen

Gong

et al. 2012

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Soluble Monomeric IgG1 Fc

Ying

Chen

Gong

et al. 2012

Journal of Biological Chemistry

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“…63 Improved circulating half-life with concurrent improved therapeutic efficacy was demonstrated when monomeric factor IX Fc-fusion protein corrected the whole blood clotting time in factor IX deficient mice for 144 h compared with only 72 h for recombinant Factor IX. 64 The new generation of IgG-based therapeutics also includes Fab heavy and light chain fragments in various combinations and variations. However, these Fab fragments have very short circulating half-life.…”

Section: Qlmentioning

confidence: 99%

Neonatal Fc receptor and IgG-based therapeutics

Kuo

Aveson²

2011

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“…The strategy might also serve as gene therapy approach for hemophilia A which could be easily adapted from the current FIX gene transfer approaches which have been developed for hemophilia B [61]. preclinical [62] and clinical trials [63]. Similarly the pharmacokinetic properties of FIX could be also improved by genetic fusion to albumin via cleavable peptides derived from the FIX activation sequence [64].…”

Section: Engineering Fix Variants To Bypass Fviiimentioning

confidence: 99%

Engineered Factor VII, Factor IX, and Factor X Variants for Hemophilia Gene Therapy

2012

J Genet Syndr Gene Ther

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FVII/FVIIaPatients with hemophilia A and B have deficient protein concentrations of FVIII and FIX, respectively and therefore are treated by protein substitution with plasma-derived or recombinant factor FVIII or FIX concentrates. In about 20-30% of the patients with hemophilia A and in 3-5% of those with hemophilia B this can lead to the development of neutralizing antibodies against the infused proteins which makes therapy inefficient [1,2]. Recombinant activated factor VII (rFVIIa) protein is currently an alternative therapy available for inhibitor patients to treat excessive bleeding. However, supraphysiological concentrations and repeated administration are required to induce hemostasis [3].Consequently, FVIIa analogs were created for future protein replacement therapy or gene delivery approaches based on crystalline structure analysis of free and TF-bound FVIIa or on sequence homology of other more potent proteases [4,5].Like the other vitamin K dependent coagulation factors, FVII is physiologically synthesized in the liver. FVII is secreted into the circulation as a 406-residue single-chain polypeptide which contains an N-terminal γ-carboxyglutamic acid (Gla) domain in which all ten Glu residues are post-translationally carboxylated followed by two regions homologous to epidermal growth factor domains and a serine protease domain [3,6,7]. Upon vascular injury, the cofactor tissue factor (TF) is exposed to FVII and triggers the extrinsic pathway of the coagulation cascade by activation of FIX, factor X and FVII auto-activation on the TF-bearing cells resulting in large-scale thrombin generation and a fibrin clot. FVII is activated to FVIIa by internal proteolysis due to a cleavage of a single Arg152-Ile153 peptide bond. The physiological plasma concentration of FVII is around 10 nM, however, only about 1% of FVII is circulating in its free and active form. FVIIa has a plasma halflife of approximately 2.5 hours [8]. FVII activation results in connected FVII light and heavy chains which form a one-to-one complex with TF in the presence of Ca 2+ ions. The complex formation is an essential process in which TF allosterically leads to a fully active FVIIa [9]. The cleavage alone leaves FVIIa in a zymogen-like conformation of quite low specific activity [3,10]. Several residues in the first EGF-like domain of FVII and in the protease domain, especially methionine at position 306, seem to be pivotal for the cofactor-mediated allosteric stimulation [11]. TF stabilizes the active conformation of FVIIa for accelerated activation of its substrates FIX and FX [12,13] by inducing a conformational change and establishing a stable salt bridge between the residues Ile153 and Asp343 [14] and stabilization of the interaction between the residues Leu305 and Phe374 which in turn stabilizes S 1 and S 3 substrate pocket and the activation pocket [15]. These findings contributed to the development of FVIIa variants with enhanced TFindependent (intrinsic) specific activity by mimicking the effect of TF binding [16]. Additional fin...

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Prolonged activity of factor IX as a monomeric Fc fusion protein

Cited by 185 publications

References 30 publications

Soluble Monomeric IgG1 Fc

Soluble Monomeric IgG1 Fc

Neonatal Fc receptor and IgG-based therapeutics

Engineered Factor VII, Factor IX, and Factor X Variants for Hemophilia Gene Therapy

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