66
replaced by recombinant FIX, and this remained the mainstay in the treatment of
haemophilia B. Recombinant factor IX was fused with the Fc domain of human
immunoglobulin G1 to form a fusion protein rFIXFc, the first bioengineered clotting factor. The fusion protein was expressed in human embryonic kidney (HEK)
293H cells. It is commercially available as Alprolix
®
. rFIXFc has a prolonged halflife, improved safety and efficacy, etc. (Peters et al. 2010). But the major disadvantage of Factor IX infusion is the development of antibodies in some patients.
2.7.3 Recombinant Activated Factor VIIa
Despite the advantages of infusion therapy with clotting factors, the major challenge encountered is the development of alloantibodies against clotting factors
FVIII/FIX. The antibodies developed act as inhibitors of infusion therapy and
demand bypassing agents. Inhibitor development is more common in haemophilia
A (30%) compared to haemophilia B (1–6%). Infusion therapy by replacing F VIII/
IX is unsuccessful in patients with inhibitors, thereby increasing the bleeding risk
and mortality. Thus there is a reduction of quality of life in haemophilia patients
with inhibitors compared to patients without inhibitors (Coppola et al. 2010).
Treatments with bypassing agents are also practised in patients with inhibitors.
Recombinant activated factor VII (rFVIIa) is a bypassing agent to manage bleeding
disorders in patients with inhibitors. It is a serine protease that can bypass FVIII and
FIX in clotting (Hoffman and Dargaud 2012). Recombinant FVIIa was licenced for
on-demand treatment of bleeding complications in patients with inhibitors. In 2007
it was approved by the European Medicines Agency. AryoSeven™ and NovoSeven
®
are two commercially available forms of rFVIIa.
2.8
Other Therapeutic Enzymes
There are many therapeutic enzymes which do not fit the previously discussed categories. A few of them with divergent properties are described here.
2.8.1 Serrapeptase
Serrapeptase (SP) is an exciting therapeutic enzyme with a wide variety of clinical
applications. It is an enzyme produced by the bacteria Serratia E-15 isolated from
the intestines of the silkworm Bombyx mori. It is also known as serratiopeptidase or
serralysin. It is zinc metalloprotease and comprises 470 amino acids with a molecular weight of approximately 50 KDa. Serrapeptase was later identified from various
species of Serratia, Pseudomonas aeruginosa and Aspergillus oryzae. It has been
used in Japan since the 1960s for reducing inflammation. It is administered orally as
a microencapsulated formulation to protect from gastric acid and has high bioavailability (Moriya et al. 1994). Reduction of inflammation is achieved through thinning and decreasing the amount of fluids accumulated in tissues and also by helping
S.S. Kumar and S. Abdulhameed
replaced by recombinant FIX, and this remained the mainstay in the treatment of
haemophilia B. Recombinant factor IX was fused with the Fc domain of human
immunoglobulin G1 to form a fusion protein rFIXFc, the first bioengineered clotting factor. The fusion protein was expressed in human embryonic kidney (HEK)
293H cells. It is commercially available as Alprolix
®
. rFIXFc has a prolonged halflife, improved safety and efficacy, etc. (Peters et al. 2010). But the major disadvantage of Factor IX infusion is the development of antibodies in some patients.
2.7.3 Recombinant Activated Factor VIIa
Despite the advantages of infusion therapy with clotting factors, the major challenge encountered is the development of alloantibodies against clotting factors
FVIII/FIX. The antibodies developed act as inhibitors of infusion therapy and
demand bypassing agents. Inhibitor development is more common in haemophilia
A (30%) compared to haemophilia B (1–6%). Infusion therapy by replacing F VIII/
IX is unsuccessful in patients with inhibitors, thereby increasing the bleeding risk
and mortality. Thus there is a reduction of quality of life in haemophilia patients
with inhibitors compared to patients without inhibitors (Coppola et al. 2010).
Treatments with bypassing agents are also practised in patients with inhibitors.
Recombinant activated factor VII (rFVIIa) is a bypassing agent to manage bleeding
disorders in patients with inhibitors. It is a serine protease that can bypass FVIII and
FIX in clotting (Hoffman and Dargaud 2012). Recombinant FVIIa was licenced for
on-demand treatment of bleeding complications in patients with inhibitors. In 2007
it was approved by the European Medicines Agency. AryoSeven™ and NovoSeven
®
are two commercially available forms of rFVIIa.
2.8
Other Therapeutic Enzymes
There are many therapeutic enzymes which do not fit the previously discussed categories. A few of them with divergent properties are described here.
2.8.1 Serrapeptase
Serrapeptase (SP) is an exciting therapeutic enzyme with a wide variety of clinical
applications. It is an enzyme produced by the bacteria Serratia E-15 isolated from
the intestines of the silkworm Bombyx mori. It is also known as serratiopeptidase or
serralysin. It is zinc metalloprotease and comprises 470 amino acids with a molecular weight of approximately 50 KDa. Serrapeptase was later identified from various
species of Serratia, Pseudomonas aeruginosa and Aspergillus oryzae. It has been
used in Japan since the 1960s for reducing inflammation. It is administered orally as
a microencapsulated formulation to protect from gastric acid and has high bioavailability (Moriya et al. 1994). Reduction of inflammation is achieved through thinning and decreasing the amount of fluids accumulated in tissues and also by helping
S.S. Kumar and S. Abdulhameed