H e m a t o lo g y E d u c a t io n - European Hematology Association

estored function. 43,44 A phase I trial has been completed
with this compound (NCT00956345, Novo Nordisk).
Polysialic acid
Polysialic acid (PSA) is an anionic moiety that adds
multiple negative charges to the protein thereby changing
its surface charge and binding capabilities. PSA is
thought to interfere with receptor-mediated clearance
processes of FVIII as a result of these changes. 45 The
compound is under preclinical evaluation.
Albumin fusion
Albumin has a long half-life which exceeds 20 hours. 46
As albumin is a product with a long safety record and
does not seem to be immunogenic, it would be an
option for extension of clotting factor half-life using
genetic fusion. Weimer et al. 47 reported the generation
of a recombinant FVIIa molecule with an extended halflife
based on genetic fusion to human albumin. The
recombinant FVII albumin fusion protein (rVII-FP) was
expressed in mammalian cells and upon activation, displayed
a FVII activity close to that of wild type FVIIa.
Pharmacokinetic studies in rats demonstrated that the
half-life of the activated recombinant FVII albumin
fusion protein (rVIIa-FP) was extended six- to sevenfold
compared with wild type rFVIIa. The in-vitro and
in-vivo efficacy was evaluated and was found to be
comparable with a commercially available rFVIIa
(NovoSeven, Novo Nordisk). The results of this study
demonstrated that it is feasible to develop a half-life
extended FVIIa molecule with haemostatic properties
very similar to the wild-type factor. Albumin has also
been fused to FIX and a phase I trial has started
(NCT01233440,CSL Behring) but no results are yet
available.
London, United Kingdom, June 9-12, 2011
Fc fusion
The neonatal Fc receptor (FcRn) is a MHC class I like
molecule that functions to protect IgG and albumin
from catabolism, mediates transport of IgG across
epithelial cells, and is involved in antigen presentation
by professional antigen presenting cells. Its function is
evident in early life in the transport of IgG from mother
to fetus and neonate for passive immunity, and later in
the development of adaptive immunity and other functions
throughout life. The unique ability of this receptor
to prolong the half-life of IgG and albumin has guided
engineering of novel therapeutics. 48 Peters et al. 49 have
summarized studies where Fc has been fused to FIX.
Taken together, these studies showed the enhanced
pharmacodynamic and pharmacokinetic properties of
the rFIXFc fusion protein and provided the basis for
evaluating rFIXFc in patients with hemophilia B.
A recombinant fusion protein (rFIXFc) containing a
single FIX molecule attached to the Fc region of
immunoglobulin G was administered intravenously and
found to have an extended half-life, compared with
recombinant FIX (rFIX) in normal mice, rats, monkeys,
and FIX-deficient mice and dogs. The half-life of rFIXFc
was approximately three- to four-fold longer than that
of rFIX in all species. In contrast, in mice in which the
neonatal Fc receptor (FcRn) was deleted, the half-life of
rFIXFc was similar to rFIX, confirming the increased circulatory
time was due to protection of the rFIXFc via
the Fc/FcRn interaction. Whole blood clotting time in
FIX-deficient mice was corrected through 144 hours for
rFIXFc, compared with 72 hours for rFIX; similar results
were observed in FIX-deficient dogs. The fusion of Fc
and FVIII has also been obtained with similar beneficial
results although full publications are still not present.
The phase I trial has been completed for FIX
Figure 2. Hypothetical plasma coagulation levels during treatment with long-acting clotting factor concentrates.
Extradoses of regular concentrate are given in anticipation of bleeds or in case of a bleeding event.
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 87 |