Crucell is investigating Protein Factor V–Leiden/Cambridge expressed on our PER.C6^® cell line for use as a therapeutic agent against certain bleeding disorders.

In recent years, there has been a rapid growth in the field of recombinant protein therapeutics, driven by advances in production and purification technology, which have also made recombinant protein therapeutics increasingly cost effective and commercially viable. 

One of the early categories of proteins developed as therapeutic agents were the blood coagulation factors. Blood factors are proteins that are involved in maintaining haemostasis through the blood coagulation cascade. This cascade comprises a series of complex biochemical reactions that involve and are regulated by blood coagulation factors. The cascade involves pro-coagulant factors, such as Factor VIII and Factor IX, as well as anti-coagulant factors, such as Protein C and Antithrombin III. A deficiency in any of these blood factors may result in significant hemorrhagic (due to deficiency of a pro-coagulant factor) or thrombotic (due to deficiency of an anti-cogaulant factor) events.

The objective of Crucell’s factor V project is to develop a factor V molecule that can be used to compensate impaired clotting in hemophilia A patients, particularly those having inhibitors.

Hemophilia is the name of any of several hereditary genetic illnesses that impair the body's ability to control bleeding. Genetic deficiencies (or, very rarely, an autoimmune disorder) cause lowered plasma clotting factor activity so as to compromise blood-clotting.

The most common bleeding disorder is Hemophilia A, which is an X chromosome-linked genetic disease affecting 1 in 5,000-10,000 males worldwide. Hemophilia A is caused by a deficiency of the blood protein factor VIII, which acts as a co-factor in the clotting system. The clinical picture of hemophilia ranges from a mild to severe bleeding tendency. Males with mild hemophilia may not bleed until after serious injury, trauma, or surgery; people with moderate hemophilia may bleed after injuries and sometimes spontaneously, whereas persons with severe hemophilia A, who are 60% of all hemophilia A cases, may suffer from frequent spontaneous bleeding episodes, often affecting joints or muscles. The severity of the bleeding tendency in hemophilia A correlates well with circulating levels of factor VIII, which are 6% to 40% in mild, 1 to 6% in moderate and less than 1% of normal in severe hemophilia.

Hemophilia A is treated with the prophylactic or therapeutic administration of factor VIII purified from human plasma or obtained as recombinant protein. In particular severe hemophiliacs are at risk to develop neutralizing antibodies, so-called inhibitors, upon administration of factor VIII, which reduces or even completely abolishes the efficacy of the therapy. In severe hemophilia A, inhibitors may develop in up to 30% of the cases. Currently, patients with inhibitors will be subjected to a costly immune tolerance therapy to induce tolerance to exogenous factor VIII,

which fails in 20-40% of the cases. Bleeding episodes in patients with persistent inhibitors can be treated with recombinant factor VIIa or any other factor VIII-bypassing agent, but these agents are not suitable for prevention of these episodes. Therefore, there is a medical need for prophylactic treatment in patients with factor VIII-inhibitors, which may be fulfilled with factor V-Leiden/Cambridge.

Factor V-Leiden/Cambridge

Factor V-Leiden/Cambridge contains two mutations FV-R306T/R506Q (Leiden/Cambridge), leading to APC resistance, thereby extending the half-life of the activated molecule. It is a pro-coagulant by enhancing thrombin formation. In addition to hemophilia with inhibitors, other indications for factor V-Leiden/Cambridge may include hemophilia without inhibitors, Factor V and Factor V/VIII deficiency, and bleeding disorders not due to deficiency of a clotting factor such as hemorrhagic stroke.